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0 20-05-12 Madl 662287 Aerosols - Tiny & Powerful Pierre MADL, MSc.PhD.EE. Lab practicals – Aerosols 3/4 BeiJing, May 29 th – June 1 st 2017 Aerosols in a nutshell: Nobody can escape it and it affects us all the time. Every day we inhale approx. 15 000 liter of air. Depending on the location we live in and the time of the year we are exposed to the effects of civilization in terms of sulfur- or nitric oxides, airborne particle matter and aromatic hydrocarbons. According to the WHO, about 7 million people die every year as a result to air-pollution related diseases. At first pollutants deposit in the deeper lung where they trigger bronchitis and even lung cancer. The smaller-sized pollution fraction even trespasses into the blood circulatory system drastically increasing the risk of heart attacks and strokes. Besides these known adverse effects, more hidden side-effects become evident that are attributable to air- pollution and include cancer pathologies outside the lungs, diabetes and epigenetic factors. This lab-course material provides background information to aerosol dynamics, effects on climate and health. In addition it provides basic information on selected tools to measure and quantify aerosol inventories and how these data can be implemented into a computer code for lung deposition modelling. The core issue with air pollution: nobody can escape as it affects everyone. With a breathing turnover of 8.6kL a day (sedentary lifestyle at 12 breaths/min, tidal volume 0.5L of an adult) and based upon the location we live in, we are exposed to the traces of civilization that include sulfur-, and nitrogen-oxides, ozone, particle matter as well as hydrocarbons. Image: NZZ (2013) Luftverschmutzung in China – Harbin versinkt im Smog, NZZ (22.Okt) http://www.concert-h2020.eu/ Pierre MADL Div. of Material Sciences Dep. Physics & Biophysics University of Salzburg Hellbrunnerstr. 34 A-5020 Salzburg [email protected] http://biophysics.sbg.ac.at/talk/trott-2012.pdf v2020.01

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Page 1: Aerosols - Tiny & Powerfulbiophysics.sbg.ac.at/talk/aerosol-ptIII.pdf · susceptible to air pollutants because elderly: gradual decline in physiological processes & tolerance levels

0

20-05-12 Madl 0

662287

Aerosols - Tiny & PowerfulPierre MADL, MSc.PhD.EE.

Lab practicals – Aerosols 3/4BeiJing, May 29th – June 1st 2017

Aerosols in a nutshell: Nobody can escape it and it affects us all the time. Every day we inhale approx. 15 000 liter of air. Depending on the location we live in and the time of the year we are exposed to the effects of civilization in terms of sulfur- or nitric oxides, airborne particle matter and aromatic hydrocarbons. According to the WHO, about 7 million people die every year as a result to air-pollution related diseases. At first pollutants deposit in the deeper lung where they trigger bronchitis and even lung cancer. The smaller-sized pollution fraction even trespasses into the blood circulatory system drastically increasing the risk of heart attacks and strokes. Besides these known adverse effects, more hidden side-effects become evident that are attributable to air-pollution and include cancer pathologies outside the lungs, diabetes and epigenetic factors. This lab-course material provides background information to aerosol dynamics, effects on climate and health. In addition it provides basic information on selected tools to measure and quantify aerosol inventories and how these data can be implemented into a computer code for lung deposition modelling. The core issue with air pollution: nobody can escape as it affects everyone. With a breathing turnover of 8.6kL a day (sedentary lifestyle at 12 breaths/min, tidal volume 0.5L of an adult) and based upon the location we live in, we are exposed to the traces of civilization that include sulfur-, and nitrogen-oxides, ozone, particle matter as well as hydrocarbons.

Image: NZZ (2013) Luftverschmutzung in China – Harbin versinkt im Smog, NZZ (22.Okt)http://www.concert-h2020.eu/

Pierre MADLDiv. of Material Sciences

Dep. Physics & BiophysicsUniversity of Salzburg

Hellbrunnerstr. 34A-5020 Salzburg

[email protected]://biophysics.sbg.ac.at/talk/trott-2012.pdf

v2020.01

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No Time to Loose (1/3)

un-/newborns, children & the elderly are particularly susceptible to air pollutants becauseelderly: gradual decline in physiological processes & tolerance levels over timekids - increased PM-dose per lung surface area due to: a) amount of time spent outdoors ↑, b) activity levels ↑, minute volume / unit body weight,c) developing lung more susceptible to air pollution;

Zhang et al, 2016

Aerosol Climate Tools ModelHealth

Trends:

i) aging society - demographic change

All regions will see an ageing population. However, the impacts will be more immediately felt in Europe, Asia and Latin America. Asia, for example, has nine people of working age to support each elderly person on average (although trends vary considerably by country). By 2050 that number will more than halve to four people. In Europe, the decline in the working age population will be particularly acute. For every four working age people per elderly person in 2015 there’ll be just two by 2050. Addressing that shortfall will require greater workforce participation by two groups: women and the elderly themselves.[1]Given rapid economic developments and urbanization over the last few decades, China has experienced frequent haze episodes, which have adverse effects on public health. Children and elderly individuals are more susceptible than the general population to air pollution. In this study, we introduce interventions to reduce the exposure of elderly individuals and children to air pollution during hazy weather. These interventions include avoiding outdoor activities, wearing a dust mask, reducing burning biomass fuels, reducing frying and smoking at home, using an air filtration unit and taking supplemental antioxidants. However, the actual benefits of these measures remain unproven and are unlikely to be adequate. Sustained clean air policies remain the most important and efficient solution to reduce air pollution-related health effects.[2]

Source: UN population Division, World Poplation Projects (2015)[1] https://www.pwc.co.uk/issues/megatrends/demographic-and-social-change.htmlhttps://www.ageinternational.org.uk/policy-and-research/ageing-international-development/ageing-factfile/[2] Zhang S, Li LL, Gao W, Wang YJ, Yao X (2014) Interventions to reduce individual exposure of elderly individuals and children to haze: a review. J Thorac Dis. Vol.8(1):E62-E68

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Trends:

i) aging societyi) disease pattern shifts

No Time to Loose (2/3)

WHO, 2017

within 15 yrs:• neurol. dis. • diabetes • respirat. dis. • tumors • cardiovasc.

Legend:EU Europe

(0.74·E9 people)

SEA: Asia incl. SE

(4.48·E9 people)

…. most likely to soar !!

Aerosol Climate Tools ModelHealth

The summary tabulations of the Global Health Estimates 2015 are downloadable as spreadsheets from the following pages. The estimates are available at global, regional and country levels, and include: causes of death;. disability-adjusted life year (DALYs), years of life lost (YLL) and years lost due to disability (YLD).Due to changes in data and some methods, the 2000-2015 estimates are not comparable to previously-released WHO estimates.CAUSE-SPECIFIC MORTALITYThe latest global, regional and country-level cause-specific mortality estimates for the year 2000, 2005, 2010 and 2015 are available for download below.Recommended citation: Global Health Estimates 2015: Deaths by Cause, Age, Sex, by Country and by Region, 2000-2015. Geneva, World Health Organization; 2016. A summary of data sources and methods is available below. Due to changes in data and some methods, the 2000-2015 estimates are not comparable to previously-released WHO estimates.

Image: Prevalent causes of death for the years 2000 and 2015 for both Asia and Europe. The dominance in the EU with only 1/6th of of the population of the Asian continent of cardiovascular diseases is strikin. However, asian countries with their rapid macro-economic changes it is very likely that Asia will soon dominate global cardiovascular incidents. Even the other markers (tumor cases, respiratory diseases, diabetes and neurological disorders) seem to be adversely affected by air pollutants.

Source: WHO (2017) Heath Statistics & Information System. Estimates for 200 - 2015.

http://www.who.int/healthinfo/global_burden_disease/estimates/en/index1.html

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Trends:

i) aging societyi) disease pattern shiftsi) prevalence of chronic

diseases

…. for which satisfying treatments do not yet exist ….

Jones et al., 2012Bach, 2002

No Time to Loose (3/3)

Aerosol Climate Tools ModelHealth

A t first glance, the inaugural 1812 issue of the New England Journal of Medicine and Surgery, and the Collateral Branches of Science seems reassuringly familiar: a review of angina pectoris, articles on infant diarrhea and burns. The apparent similarity to today’s Journal, however, obscures a fundamental discontinuity. Disease has changed since 1812. People have different diseases, doctors hold different ideas about those diseases, and diseases carry different meanings in society. To understand the material and conceptual transformations of disease over the past 200 years, one must explore the incontrovertibly social nature of disease …. Just as organisms evolve to keep up with changing environmental conditions (the “Red Queen Effect”), medicine struggles to keep up with the changing burden of disease. Since therapeutic innovation takes time, the burden shifts even as solutions appear. By the time antibiotics and vaccines began combating infectious diseases, mortality had shifted toward heart disease, cancer, and stroke. Great progress has been made to meet these challenges, but the burden of disease will surely shift again. We already face an increasing burden of neuropsychiatric disease for which satisfying treatments do not yet exist.[1]

Image: Top 10 Causes of Death: 1900 vs. 2010. Data are from the Centers for Disease Control and Prevention.[1] / Insert: Inverse Relation between the Incidence of Prototypical Infectious Diseases (Panel A) and the Incidence of Immune Disorders (Panel B) from 1950 to 2000.[2]

Source: [1] Jones DS, Podolsky SH, Greene JA (2012) The Burden of Disease and the Changing Task of Medicine. N. Engl J Med Vol.366: 2333-2338[2]

Bach JF (2002) The Effect of Infections on Susceptibility to Autoimmune and Allergic Diseases. N Engl J Med, Vol.347(12): 911-920

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Part III

Health Effects

Aerosol Climate Tools ModelHealth

Particles and the Human Respiratory System

The ideal gate for the penetration of air contaminants is the lung. Because of its small size, Fine Particle Matter (<PM2.5) can be deposited deep into the lungs, where it can cause health problems and is known to alter lung functions [1]. NOXand SO2 are also major sources of fine PM. Recent studies have shown an association between PM and premature mortality from respiratory and cardiovascular disease, and increased incidence of respiratory illness, particularly in children and the elderly. For adults with heart or lung conditions, exposure to fine PM can cause more illness and in some cases premature death. More than 90 % of the particulates found in diesel exhaust are fine particles.

Source: [1] Ellenhorn (1996), CD-Rom

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Airborne Toxins (1/8)

Aerosol Climate Tools ModelHealth

• Primary aerosols (wet- / dry depo)

• Bio-accumulated (secondary) aerosols

• Dermal

• Ingestion organismic effect

• InhalationVallera, 2014

Modes of entry:

The physicochemical properties of a substance deter- mine how readily it will move among the environmental compartments, i.e. to and from sediment, surface water, soil, groundwater, air, and in the food web to be taken up by biota, including humans. So, if a substance is likely to leave the water, it is not persistent in water. However, if the compound moves from water to the sediment, where it persists for long periods of time, it must be considered environmentally persistent. This is an example of the difference in “chemical persistence” and “environ- mental persistence”. Persistence is indeed an intrinsic chemical property of a compound. However, most environmental and biomedical scientists and engineers consider persistence to be both intrinsic and extrinsic (i.e. a function of the media, energy and mass balances, and equilibria). So, the environmental behavior of a compound must not only account for the molecular weight, functional groups, and ionic form of the compound, but also whether it is found in the air or water, and the condition of the media (e.g. pH, soil moisture, sorption potential, and microbial populations). The movement among phases and environmental compartments is known as partitioning. Many toxic compounds are semivolatile (i.e. at 20°C and 101 kPa atmospheric pressure, vapor pressures 10·E-6 to 100·E-3 kPa), under typical environmental conditions. These low vapor pressures and low aqueous solubilities translate into low fugacities, i.e. they lack a strong propensity to flee a compartment, e.g. to move from water to air. Thus, a multi-pathway perspective must be employed for air pollution, with a time aspect to each pathway. After release into the environment, the deposition of air pollutants onto soil, plants, and water is followed by the uptake of the chemicals by biota, and potential exposures by organisms via contact with the contaminated soils, waters, and foods. A multi-pathway analysis goes beyond the expected inhalation pathway to include other exposure pathways.

Image: General overview of multisource, multi-pathway exposure pathways.

Source: Vallero D (2014) Fundamentals of Air Pollution, 5th ed., Ch.19 (Persistance) Academic Press, USA

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Some Airborne Toxins (2a/8)

Aerosol Climate Tools ModelHealth

• Carbon Monoxide (CO)

Adverse effects of:

Acute Carbon Monoxide Poisoning

Severity Symptoms and Signs Mild (COHb < 30%)

Headache, nausea, vomiting, dizziness, exertional dyspnoea

Moderate (COHb 30 - 40%)

Chest pain, blurred vision, confusion, weakness, increasing dyspnoea, tachycardia, tachypnoea, ataxia, severe headache, syncope, flushing, cyanosis, perspiration, decreased vigilance, diminished manual dexterity, impaired sensorimotor task performance, prolonged reaction time, difficulty thinking, impaired judgement, loss of muscular control, tinnitus or roaring in the ears, drowsiness, hallucinations and cardiovascular toxicity

Severe (COHb > 40%)

Trismus, muscle spasms, convulsions, palpitations, disorientation, ventricular dysrhythmias, hypotension, myocardial ischaemia, skin blisters, pulmonary oedema, respiratory failure, involuntary evacuations, coma, collapse, and death

Pillav, 2013Reichl, 2002

Carbon Monoxide (CO) - Synonyms: Carbonic oxide, Carbon oxide, Exhaust gas, Flue gas. Physical Appearance: Pure carbon monoxide is an odourless, colourless, non-irritating gas, which is lighter than air. Sources include incomplete combustion of almost any form of fuel (wood, charcoal, gas, kerosene). automobile exhaust, fires. paint remover (especially methylene chloride), tobacco smoke, endogenous CO resulting from haeme degradation can never reach toxic levels on its own. Normal CO level in plasma is in the range of 1 to 5 % and may rise up to 7 to 8 % in smokers.[1]

Uptake is said to be ventilation-limited, implying that virtually all the CO inspired in a breath is absorbed and bound to the available hemoglobin. Thus, continuous exposure of human subjects to 30 ppm CO leads to an equilibrium value of 5 percent COHb. The Haldane equation is used to compute the COHb equilibrium under a given exposure situation. The equilibrium values generally are reached after 8 h or more of exposure. The time required to reach equilibrium can be shortened by physical activity. Analysis of data from air-monitoring programs in California indicates that 8 h average values can range from 10 to 40 ppm CO. Depending on the location in a community, CO concentrations can vary widely. Concentrations predicted inside the passenger compartments of motor vehicles in downtown traffic were almost 3 times those for central urban areas and 5 times those expected in residential areas. Occupants of vehicles traveling on expressways had CO exposures somewhere between those in central urban areas and those in downtown traffic. Concentrations above 87 ppm have been measured in underground garages, tunnels, and buildings over highways.[2]

Fatal Dose: This is usually expressed in terms of plasma concentration of the gas(carboxyhaemoglobin or COHb). COHb level exceeding 50 to 60 % is potentially lethal. A carbon monoxide concentration of 5000 ppm in air is lethal to humans after five minutes of exposure.[1]

Source:[1] Pillay V.V. (2013) Modern Medical Toxicology. 4th ed. Ch. 26 Toxic Gases. Jaypee Brothers Medical Publishers, New Delhi, IND.

[2] Costa DL (2001) Air Pollution, Ch. 28. In: Klaassen CD (ed) Casarett and Doull's Toxicology. Basic Science of Poisons. 6th ed. MacGrawHill, New York, USA;

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Some Airborne Toxins (2b/8)

Aerosol Climate Tools ModelHealth

• Carbon Monoxide (CO)& Carbon Dioxide (CO2)

Guyton & Hall, 1996;

In closed environments pCO2 can easily reach 800 ppm some urban locations (downtown ChangSha, CHN, Feb.2017) values up to 1800 ppm are common;in cars with improper ventilation it can easily reach >3000 ppm current average atmospheric values values are ~400 ppm

Adverse effects of:

Carbon Dioxide (CO2): Depending on the arterial oxygen saturation, four stages havebeen described:[1]

• Indifferent Stage: pO2-saturation at 90% of normal (night vision decreased).

• Compensatory Stage: pO2-saturation: 82 to 90% (respiratory rate: compensatory increase, compensatory pulse increase, further decreased night vision, somewhat reduced performance ability:partly reduced alertness, symptoms may begin in those with significant pre-existing cardiac, pulmonary, or haematologic diseases).

• Disturbance Stage: pO2 Saturation at 64 to 82% (compensatory mechanisms become inadequate, air hunger, fatigue, tunnel vision, dizziness, headache, belligerence, euphoria, reduced visual acuity, numbness and tingling of extremities, hyperventilation, poor judgement, memory loss, cyanosis, decreased ability for escape from toxic environment).

• Critical Stage: pO2 saturation at 60 to 70% or less (deterioration in judgement and co-ordination may occur in 3 to 5 minutes or less, total incapacitation and unconsciousness follow rapidly).

Image: Reichl F, Hammelehle R (2002) Taschenatlas der Toxikologie (2nd ed); Thieme Verlag; Stuttgart, FRG

Source: Pillay V.V. (2013) Modern Medical Toxicology. 4th ed. Ch. 26 Toxic Gases. Jaypee Brothers Medical Publishers, New Delhi, IND.

Guyton AC, Hall JE (1996) Textbook of Medical Physiology, 9th ed. Saunders Co. Philadelphia, USA

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Some Airborne Toxins (2c/8)

Aerosol Climate Tools ModelHealth

Pillav, 2013

• Carbon Monoxide (CO)& Carbon Dioxide (CO2)

Pillav, 2013

Tortora & Grabowski, 1996;

Guyton & Hall, 1996;

Adverse effects of:

Carbon Dioxide (CO2): Colourless, odourless, non-flammable, heavier than air. Typical sources include combustion processes, fire extinguisher. carbonation of soft drinks, shielding gas during welding processes, synthesis of urea, for dry ice, and organic synthesis.[1]

Gradients of respiratory gases as they pass from the gas-exchanging domain into the liquid-transport domain all the way to the target area and back;[2]

1Pa = 7.5006·E-3 Torr = 7.5006·E-3 mmHg

Image: [2] Tortora GJ, Grabowski SR (1996) Principles of Anatomy and Physiology, 8th ed. Addison Wesley Longmann Inc, Mento Park, USA

Source: [1] Pillay V.V. (2013) Modern Medical Toxicology. 4th ed. Ch. 26 Toxic Gases. Jaypee Brothers Medical Publishers, New Delhi, IND.http://www.mfn.unipmn.it/~pons/index_file/Page1171.htm http://en.wikipedia.org/wiki/Pressure

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Some Airborne Toxins (2d/8)

Aerosol Climate Tools ModelHealth

Pillav, 2013

• Carbon Monoxide (CO)& Carbon Dioxide (CO2)

Pillav, 2013

Guyton & Hall, 1996;

Adverse effects of:

1 atm = 760 mm Hg (current average atmospheric values):(78.1% N2 = 594 mmHg; 21.0% O2 = 160 mmHg; 0.04% CO2 = 400 ppm or 0.30 mmHg)

0.06-0.1 % CO2 (0.6-1·E3 ppm): complaints of stiffness0.1-0.25 % CO2 (1-2.5·E3 ppm): general drowsiness

0.5-1% CO2 (5-10·E3 ppm): allowance for 8 hrs3-4 % CO2 (30-40·E3 ppm): ↑breathing, ↑pulse, nausea5 % CO2 (50·E3 ppm): -“-, headache, visual impairments

some urban locations (downtown ChangSha, CHN, 2016) values up to 1800 ppm are common;in cars with improper ventilation it can easily reach >3000 ppm

Carbon Dioxide (CO2): Depending on the arterial oxygen saturation, four stages have been described:[1]

• Indifferent Stage: pO2-saturation at 90% of normal (night vision decreased).

• Compensatory Stage: pO2-saturation: 82 to 90% (respiratory rate: compensatory increase, compensatory pulse increase, further decreased night vision, somewhat reduced performance ability, partly reduced alertness, symptoms may begin in those with significant pre-existing cardiac, pulmonary, or haematologic diseases).

• Disturbance Stage: pO2 Saturation at 64 to 82% (compensatory mechanisms become inadequate, air hunger, fatigue, tunnel vision, dizziness, headache, belligerence, euphoria, reduced visual acuity, numbness and tingling of extremities, hyperventilation, poor judgement, memory loss, cyanosis, decreased ability for escape from toxic environment).

• Critical Stage: pO2 saturation at 60 to 70% or less (deterioration in judgement and co-ordination may occur in 3 to 5 minutes or less, total incapacitation and unconsciousness follow rapidly).

Source: Pillay V.V. (2013) Modern Medical Toxicology. 4th ed. Ch. 26 Toxic Gases. Jaypee Brothers Medical Publishers, New Delhi, IND.

Ellenhorn M (1996) Medical Toxicology – Diagnosis and Treatment of Human Poisoning. Lippincott Williams & Wilkins;

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Some Airborne Toxins (3a/8)

Aerosol Climate Tools ModelHealth

• Carbon Monoxide (CO)& Carbon Dioxide (CO2)

• Hydrocarbons (HC)

Common Inhalants of Abuse Inhalant Constituent Acrylic paint Toluene Aerosol propellant Fluorocarbons, nitrous oxide Anaesthetics, Enflurane, halothane, isoflurane, nitrous oxide Dyes Acetone, methylene chloride Fire extinguisher Bromo-chloro-di-fluoro-methane (BCF) Bottled gas, torches Propane, butane Glues/adhesives Toluene, benzene, xylene, acetone, naphtha, n-hexane, tri-

chloro-ethylene, ethylacetate, tetra-chloro-ethylene, tri-chloro-ethane, carbon tetrachloride, methylethyl ketone

Lighter fluid Butane Nail polish remover Acetone, amyl acetate, isopropanol Paint stripper Methylene chloride Paint varnish/lacquer Tri-chloro-ethylene, toluene, mineral spirits Petrol (gasoline) Hydrocarbons Polystyrene cements Acetone, toluene, tric-hloro-ethylene, n-hexane Refrigerants Fluoro-Chloro-Methanes Rubber cement Benzene, n-hexane, trichloroethylene Shoe polish Chlorinated hydrocarbons, toluene Solvent (laboratory) Carbon tetra-chloride, chloroform, diethylether, n-hexane,

methyl iso-butyl-ketone Spot remover Tri-chloro-ethane, tri-chloro-ethylene, carbon tetra-chloride Typewriter correction fluid Tri-chloro-ethane, tri-chloro-ethylene, per-chloro-ethylene

Pillav, 2013Reichl, 2002

Adverse effects of:

Hydro-Carbons (HCs) - Ethane is an odourless gas which is used as a refrigerant and as a component of natural gas. It is methane (swamp gas), however, which is the major component of natural gas. Both are odourless gases and produce simple asphyxiation at high concentrations. Conversion of domestic gas from coal gas (mostly CO) to natural gas (mostly methane, CH4) has significantly reduced mortality from domestic gas leaks, since methane is much less toxic as compared to CO. CH4 being odourless, a stenching agent (alkyl mercaptan) is deliberately added to domestic gas so that leaks can be immediately recognised. It is important to remember that a build-up of CH4 resulting in 4.8 to 13.5% concentration in air constitutes an explosive mixture which can be ignited by a flame or even a tiny spark. Most explosions in mines (as well as homes using natural gas as fuel) occur because of this reason. Butane, liquefied petroleum gas, propane, and propylene have a faint petroleum-like odour and may be stenched with mercaptans for transport and storage. Butane is used as a raw material for automobile fuels, in organic synthesis, and as a solvent, refrigerant, and aerosol. Propane is used as a raw material in organic synthesis, as a component of industrial and domestic fuels, as an extractant, a solvent, and a refrigerant, and in the manufacture of ethylene. Incomplete combustion of these agents can release carbon monoxide into the ambient air. Butane is often abused by adolescents in the form of inhalation (see “glue sniffing”). These volatile substances are widely available and frequently abused, especially by adolescents from poor socioeconomic background. Abusers often begin sniffing (lower concentrations), and progress subsequently to higher levels of exposure. The most commonly abused HCs include toluene from paints and glues; petrol; butane from cigarette lighter fluids; butyl and isobutyl nitrite; and halogenated HCs from typewriter correction fluids, propellants, and dry cleaning fluids. Inhalation of volatile substances produces intoxicating effects rapidly. They are well absorbed through the lungs and distributed quickly to the CNS. One or two huffs will begin to intoxicate the user within seconds, and the effects usually last for several hours. Chronic users can maintain a prolonged high with periodic inhalations every few hours.

Image: toxicity of gasoline - Reichl F, Hammelehle R (2002) Taschenatlas der Toxikologie (2nd ed); Thieme Verlag; Stuttgart, FRG

Source: Pillay V.V. (2013) Modern Medical Toxicology. 4th ed. Ch. 26 Toxic Gases. Jaypee Brothers Medical Publishers, New Delhi, IND.

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Some Airborne Toxins (3b/8)

Aerosol Climate Tools ModelHealth

• Carbon Monoxide (CO)& Carbon Dioxide (CO2)

• Hydrocarbons (HC)Formaldehyde (CH2O)

Pillav, 2013Reichl, 2002

Adverse effects of:

Formaldehyde (CH2O) - Synonym: Dormol, fannoform, formalin, formalith, formic aldehyde, formol, lysoform, methanal, methyl aldehyde, methylene oxide, morbicid, oxomethane, oxymethylene. It is a colourless gas with strong pungent smell. Formalin is an aqueous solution of formaldehyde containing 37 to 40% CH2O and 10 to 15% methanol. A 10% formalin solution contains only 3.7% CH2O. Formalin is a clear, colourless liquid with a pungent odour. Some CH2O aqueous solutions can be amber to dark brown or even reddish in colour. CH2O is also available as a solid polymer, para-formaldehyde, in a powder or flaked form containing from 90 to 93% CH2O, and as its cyclic trimer, trioxane.

Toxic Doses: about 30 to 50 ml of 100% formalin (liquid); more than 100 ppm (gas). Ingestion of as little as 30 ml of 37% (approximately 2 tablespoons) formaldehyde solution (formalin) has been reported to cause death in an adult. Exposure to air concentrations as low as 2 ppm can cause eye and upper respiratory irritation. Dermal exposure to formalin can result in irritation (acute), or allergic dermatitis (chronic) in susceptible individuals. Exposure to solutions of 2 to 10% may result in blisters, fissures, and urticaria.

Image: Reichl F, Hammelehle R (2002) Taschenatlas der Toxikologie (2nd ed); Thieme Verlag; Stuttgart, FRG

Source: Pillay V.V. (2013) Modern Medical Toxicology. 4th ed. Ch. 26 Toxic Gases. Jaypee Brothers Medical Publishers, New Delhi, IND.

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Some Airborne Toxins (3c/8)

Aerosol Climate Tools ModelHealth

• Carbon Monoxide (CO)& Carbon Dioxide (CO2)

• Hydrocarbons (HC)Formaldehyde (CH2O)polyc. arom. HCs (PAH)

Pillav, 2013

Adverse effects of:

Polycyclic Aromatic Hydrocarbons (PAHs): These compounds contain three or more fused benzene rings in varying arrangements that consist of carbon and hydrogen Sources PAHs are components of most fossil fuels and are ubiquitous in the natural environment: forest fires, sea food and agricultural products, charring, barbecuing, smoking of foods; foodstuffs such as coffee, roasted peanuts; refined vegetable oils, crude coconut oil, heavily smoked ham, emissions sources, cigarette smoke, coal tar pitch, coke production, engine exhaust, engine oil, fuel burning, and open burning of refuse, restaurants and smokehouses, roof tarring, sidewalk tarring, wood-burning fireplaces.[3]

PAHs are also common constituents of air indoors, arising from coal and wood combustion, wood combustion, and environmental tobacco smoke, ETS …. Only a relatively few PAHs (ca. 100) are stable enough to survive the combustion-pyrolysis process and enter our air environment as primary pollutants in complex combustion-generated mixtures in amounts sufficient to be of concern.[1]

Toxic effects: In addition to being carcinogenic and mutagenic, PAHs suppress the antibody response to a variety of T cell dependent and T cell independent antigens. In addition, mice exposed to benzo[a]pyrene (BaP) exhibit suppressed lympho-proliferative responses to mitogens but not alloantigens …. It was also demonstrated that macrophages were the primary cell capable of metabolizing PAHs, and that these cells were capable of generating 7,8-dihydroxy-9,10-epoxy-7,8,9,BaP, the reactive metabolite proposed to be the ultimate carcinogenic form of BaP.[2]

Chronic exposure in the form of inhalation or dermal contact can predispose to lung and skin cancer. Increased incidence of cancers of the skin, bladder, lung and gastrointestinal tract have been described in PAH-exposed workers.Apart from such carcinogenic potential, PAHs are also responsible for eye irritation and photosensitivity, skin-erythema, cough and bronchitis, and haematuria. Chronic effects include: photosensitivity and irritation. Respiratory irritation with cough and bronchitis. Mouth/Leukoplakia. Coal tar warts (precancerous lesions enhanced by UV light exposure), erythema, dermal burns, photosensitivity, acneiform lesions, irritation. Hepatic/Renal mild hepatotoxicity or mild nephrotoxicity, Genitourinary/Haematuria.[3]

Image: Structures, Common Names, Empirical Formulas, Molecular Weights, Melting Points, Boiling Points, and CAS Numbers for the 16 U.S. EPA "Priority PAH Pollutants'’[1]

Image: Reichl F, Hammelehle (2002) Taschenatlas der Toxikologie (2nd ed); Thieme Verlag; Stuttgart, FRGSource: [1] Finlayson-Pitts BJ, Pitts JN (2000) Chemistry of the Upper and Lower Atmosphere - Theory, Experiments, and Applications. Academic Press, San Diego, California, USA

[2] Costa DL (2001) Air Pollution, Ch. 28. In: Klaassen CD (ed) Casarett and Doull's Toxicology. Basic Science of Poisons. 6th ed. MacGrawHill, New York, USA;

[3] Pillay V.V. (2013) Modern Medical Toxicology. 4th ed. Ch. 27 Hydrocarbons. Jaypee Brothers Medical Publishers, New Delhi, IND.

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Some Airborne Toxins (4a/8)

Aerosol Climate Tools ModelHealth

• Carbon Monoxide (CO)& Carbon Dioxide (CO2)

• Hydrocarbons (HC)Formaldehyde (CH2O)polyc. arom. HCs (PAH)

• Ammonia (NH4+)

Pillav, 2013Wikipedia, 2017

The toxicity of ammonia solutions does not usually cause problems for humans and other mammals, as a specific mechanism exists to prevent its build-up in the bloodstream. Ammonia is converted to carbomyl-phosphate by the enzyme carbomyl-phosphate synthetase, and then enters the urea cycle to be either incorporated into amino acids or excreted in the urine.

Fish and amphibians lack this mechanism, as they can usually eliminate ammonia from their bodies by direct excretion. Ammonia even at dilute concentrations is highly toxic to aquatic animals, and for this reason it is classified as dangerous for the environment.

Adverse effects of:

Ammonia (NH4+) - Physical Appearance: extremely irritant gas with a penetrating odour.

It is highly water soluble (forming ammonium hydroxide which is an alkaline corrosive). Aqueous ammonia is a colourless liquid with a strong alkaline reaction (pH 11.6) and a penetrating pungent odour. When heated to decomposition, it emits toxic fumes of ammonia and oxides of nitrogen.

Uses ins agriculture (as fertiliser), mining, manufacture of plastics and explosives, refrigerant, cleaning and bleaching agent, treatment of syncope in the form of smelling salts, household ammonia is 5 to 10%. Strong ammonia solution is 28% (sold in pharmacies).

Toxic Doses:

• About 5 to 10 ml of liquid ammonia can be lethal.

• Inhalation of the gas at concentrations above 5000 ppm can be rapidly fatal. Fatalities may also occur from exposure to ammonia concentrations of 2500 to 4500 ppm if inhaled for 30 minutes.

• Mixing of ammonia with hypochlorite bleach results in the formation of chloramine, which causes a toxic pneumonitis (pulmonary oedema) following inhalation, and may produce residual pulmonary function abnormalities.

Image: Reichl F, Hammelehle (2002) Taschenatlas der Toxikologie (2nd ed); Thieme Verlag; Stuttgart, FRG

Source: Pillay V.V. (2013) Modern Medical Toxicology. 4th ed. Ch. 26 Toxic Gases. Jaypee Brothers Medical Publishers, New Delhi, IND.

https://en.wikipedia.org/wiki/Ammonia#Toxicity

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Some Airborne Toxins (4b/8)

Aerosol Climate Tools ModelHealth

• Carbon Monoxide (CO)& Carbon Dioxide (CO2)

• Hydrocarbons (HC)Formaldehyde (CH2O)polyc. arom. HCs (PAH)

• Ammonia (NH4+)

Nitric Oxides (NOX)

Costa, 2001Reichl, 2002

Adverse effects of:

Nitrogen Dioxide (NO2): General Toxicology Nitrogen dioxide, like O3, is a deep lung irritant that can produce pulmonary edema if it is inhaled at high concentrations. It is a much less potent irritant and oxidant than O3, but NO2 can pose clear toxicologic problems. Potential life-threatening exposure is a real-world problem for farmers, as sufficient amounts of NO2 can be liberated from silage. Typically, shortness of breath ensues rapidly with exposures nearing 75 to 100 ppm NO2, with delayed edema and symptoms of pulmonary damage, collectively characterized as silo-filler’s disease. NO2 is also an important indoor pollutant, especially in homes with unventilated gas stoves or kerosene heaters. Sidestream tobacco smoke can also be a source of indoor NO2.

Chronic Effects: Concern about the chronic effects of NO2 stem from observations that 30-ppm exposures for 30 days produce emphysema in hamsters. Whether this has a bearing on human exposures at 100-fold lower exposure concentrations is questionable. Mice exposed for a year to a base level of 0.2 ppm NO2 with a 1-h spike of 0.8 ppm twice a day 5 days per week yielded effects that differed between base-only and peak only exposure groups. Early studies (Ehrlich and Henry, 1968) showed that clearance of bacteria from the lungs is suppressed with 0.5 ppm NO2through 12 months of exposure. Interestingly, recent studies with a similar double diurnal peak design for NO2, with NO used as a negative control, showed more pronounced effects of NO on alveolar septal remodelling than did NO2. Apparently, NO as an intercellular signal can alter collagen metabolism; the potential for NO2 to act in this manner is not known. These and similar studies utilizing peak-plus-baseline versus base-only or peak-only exposures indicate that, for NO2or its reduction product NO, the exposure profile may be an important determinant of response.

Image: toxicity of NO2 - Reichl F, Hammelehle (2002) Taschenatlas der Toxikologie (2nd ed); Thieme Verlag; Stuttgart, FRGComparison between limit values from EUs type approval regulations (black clouds) to emissions in “real life” city traffic from the average Euro 6 diesel passenger car. NOx, PM and CO2 emission when using the Helsinki city cycle. Measured at +23 °C (red clouds) and -7 °C (blue clouds). The size of the red and blue clouds indicate the difference in emission from the emission in the type approval test (NEDC).[2]

Source: Costa DL (2001) Air Pollution, Ch. 28. In: Klaassen CD (ed) Casarett and Doull's Toxicology. Basic Science of Poisons. 6th ed. MacGrawHill, New York, USA;

[2] http://www.ademloos.be/nieuws/diesel-cars-have-high-emissions-real-traffic

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Some Airborne Toxins (4c/8)

Aerosol Climate Tools ModelHealth

• Carbon Monoxide (CO)& Carbon Dioxide (CO2)

• Hydrocarbons (HC)Formaldehyde (CH2O)polyc. arom. HCs (PAH)

• Ammonia (NH4+)

Nitric Oxides (NOX)

NOX-dynamics• Decrease in PM ….• Boost in NOX• transmutation

from gas to solid & vice versa

McRae & Russel, 1984; Stemmler et al. 2006

Adverse effects of:

Major PM-sources in EU-countries originate from industry, wood-burning stoves and traffic. Recent trends in the automotive industry, along with rising fuel prices, favored the slightly more efficient diesel-engine over the 4-stroke engine (diesel engine emit on average 10% less CO2 than petrol-engines). This shift resulted in a steady increase of diesel-powered passenger cars. Today, about 20% of registered vehicles in Austria are diesel powered trucks and busses, while from the remaining 80% more than half of the passenger cars run likewise on diesel, with the reminder being petrol-powered.[1] As a result of this steady increase of mobile diesel sources, both nano-particle concentrations as well as nitric-oxide emissions steadily grew (see formation process in Figure). At the same time and due to the gravimetric detection principle along with an ongoing shift from larger particle emissions towards smaller ones, PM-measurements registered a gradual decline in overall mass. However, without the use of particle filters, the rise in number concentration would have been even more dramatic than currently observed. [2]While some nano-particles are already considered a hazard to human health, some other solid products are the result of gaseous educts (reactants) and likewise affect biota, including lower organisms. Ammonium nitrate (NH4NO3), itself an inhalable macromolecular particle, originates from such a reaction (see Figure below). Based on the corresponding temperature fluctuations, this reversible formation involves several intermediates that are formed during day- / night reactions.

Image: Formation of Ammonium Nitrate via precursors such as Nitrogen Dioxide and Nitric Acid.[3]

Source: Madl P (2009) Anthropogenic Environmental Aerosols: Measurements and Biological Implications. PhD-Thesis University of SalzburgStemmler K., Ammann M., Donders C., Kleffmann J., George C. (2006). Photosensitized reduction of nitrogen dioxide on humic acid as a source of nitrous acid. Nature 440, 195-198. [1] Statistics Austria: Kraftfahrzeugbestand nach Bundesländern und Antriebsart. Information Services; Vienna (2007). Available online, (accessed Feb. 2009). http://www.statistik.at/web_de/statistiken/verkehr/strasse/kraftfahrzeuge_-_bestand/023623.html [2] Sommer H.J. (2007). Verkehr und Holzverbrennung sind die wichtigsten Feinstaub-Quellen. NZZ, Forschung und Technik, 8.2.:29. [3] modified after McRae G.J., Russell A.G. (1984). Dry deposition of nitrogen-containing species, in deposition both wet and dry; in Hicks B.B. (ed.) Acid precipitation series, Boston, MA - USA.

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Some Airborne Toxins (4d/8)

Aerosol Climate Tools ModelHealth

NASA NASA ––AURAAURA--SatSat--NONO22.mp4.mp4

NASA, 2015

• Carbon Monoxide (CO)& Carbon Dioxide (CO2)

• Hydrocarbons (HC)Formaldehyde (CH2O)polyc. arom. HCs (PAH)

• Ammonia (NH4+)

Nitric Oxides (NOX)

NOX-dynamics• Decrease in PM ….• Boost in NOX• transmutation

from gas to solid & vice versa

Adverse effects of:

Using new, high-resolution global satellite maps of air quality indicators, NASAscientists tracked air pollution trends over the last decade in various regions and 195 cities around the globe. According to recent NASA research findings, the United States, Europe and Japan have improved air quality thanks to emission control regulations, while China, India and the Middle East, with their fast-growing economies and expanding industry, have seen more air pollution.

Scientists examined observations made from 2005 to 2014 by the Ozone Monitoring Instrument aboard NASA's Aura satellite. One of the atmospheric gases the instrument detects is nitrogen dioxide (NO2), a yellow-brown gas that is a common emission from cars, power plants and industrial activity. NO2 can quickly transform into ground-level ozone, a major respiratory pollutant in urban smog. NO2 hotspots, used as an indicator of general air quality, occur over most major cities in developed and developing nations.

The following visualizations include two types of data. The absolute concentrations show the concentration of tropospheric NO2, with blue and green colors denoting lower concentrations and orange and red areas indicating higher concentrations. The second type of data is the trend data from 2005 to 2014, which shows the observed change in concentration over the ten-year period. Blue indicated an observed decrease in NO2, and orange indicates an observed increase. Please note that the range on the color bars (text is in white) changes from location to location in order to highlight features seen in the different geographic regions.

Image: This global map shows the concentration of NO2 in the atmosphere as detected by the Ozone Monitoring Instrument aboard the Aura satellite, averaged over 2005 & 2014

Source: NASA Images Show Human Fingerprint on Global Air Quality – Release Materials (2015)

http://svs.gsfc.nasa.gov/12094#

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Some Airborne Toxins (4e/8)

Aerosol Climate Tools ModelHealth

NASA, 2015

• Carbon Monoxide (CO)& Carbon Dioxide (CO2)

• Hydrocarbons (HC)Formaldehyde (CH2O)polyc. arom. HCs (PAH)

• Ammonia (NH4+)

Nitric Oxides (NOX)

NOX-dynamics• Decrease in PM ….• Boost in NOX• transmutation

from gas to solid & vice versa

Adverse effects of:

Using new, high-resolution global satellite maps of air quality indicators, NASAscientists tracked air pollution trends over the last decade in various regions and 195 cities around the globe. According to recent NASA research findings, the United States, Europe and Japan have improved air quality thanks to emission control regulations, while China, India and the Middle East, with their fast-growing economies and expanding industry, have seen more air pollution.

Scientists examined observations made from 2005 to 2014 by the Ozone Monitoring Instrument aboard NASA's Aura satellite. One of the atmospheric gases the instrument detects is nitrogen dioxide (NO2), a yellow-brown gas that is a common emission from cars, power plants and industrial activity. NO2 can quickly transform into ground-level ozone, a major respiratory pollutant in urban smog. NO2 hotspots, used as an indicator of general air quality, occur over most major cities in developed and developing nations.

The following visualizations include two types of data. The absolute concentrations show the concentration of tropospheric NO2, with blue and green colors denoting lower concentrations and orange and red areas indicating higher concentrations. The second type of data is the trend data from 2005 to 2014, which shows the observed change in concentration over the ten-year period. Blue indicated an observed decrease in NO2, and orange indicates an observed increase. Please note that the range on the color bars (text is in white) changes from location to location in order to highlight features seen in the different geographic regions.

Image: The trend map of Europe shows the change in nitrogen dioxide concentrations from 2005 to 2014

Source: NASA Images Show Human Fingerprint on Global Air Quality – Release Materials (2015)

http://svs.gsfc.nasa.gov/12094#

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Some Airborne Toxins (5/8)

Aerosol Climate Tools ModelHealth

• Carbon Monoxide (CO)& Carbon Dioxide (CO2)

• Hydrocarbons (HC)Formaldehyde (CH2O)polyc. arom. HCs (PAH)

• Ammonia (NH4+)

Nitric Oxides (NOX)• Ozone (O3)

Reichl, 2002Costa, 2001

Villányi et al., 2010

Adverse effects of:

Ozone (O3) Ozone is the primary oxidant of concern in photochemical smog because of its inherent bio-reactivity and concentration. Unlike SO2 and the reducing-type pollution profile discussed above, current mitigation strategies for O3 have been largely unsuccessful despite significant reductions in individual automobile emissions. These reductions have been offset by population growth, which brings with it additional vehicles.Acute Effects: Exercising human subjects exposed to 0.12 to 0.4 ppm O3 experience reversible concentration-related decrements in forced exhaled volumes [forced vital capacity (FVC) and forced expiratory volume in 1 s (FEV1)] after a 2 to 3 h of exposure. With the recent concern that prolonged periods of exposure (6 to 8 h) may lead to cumulative effects, similar protocols with lower exercise levels were extended up to 6.6 h. In these studies, exposures to 0.12, 0.10, and 0.08 ppm induced progressive lung function impairment during the course of the exposure. Other lung function indices, such as nonspecific airway reactivity to various pharmacologic agents, indicate hyper-reactivity after acute 2- to 6-h exposures to O3 of 0.08, 0.10, and 0.12 ppm (by 56, 86, and 121 percent, respectively, to methacholine). It is widely thought that hyperreactive airways may predispose responses to other pollutants such as sulfuric acid or aeroallergens, but such evidence is limited.Chronic Effects: Morphometric studies of the acinar region of rats exposed for 12 h per day for 6 weeks to 0.12 or 0.25 ppm ozone showed hyperplasia and hypertrophy of type I alveolar cells and major alterations in ciliated and Clara cells in small airways. Although most of the morphologic changes induced by O3 clearly regress over time when the animals are returned to clean air, there is evidence of interstitial remodeling below the epithelium in this centri-acinar region, which may have long-term implications. Examination of autopsied lung specimens from young smokers shows many analogous tissue lesions that come to be described as the smoldering precursors of emphysema.Image: Major reactions pathways of O3 with lipids in lung lining fluid and cell membranes. Chan Reaction: Overview of photochemistry in the polluted planetary boundary layerSource: Costa DL (2001) Air Pollution, Ch. 28. In: Klaassen CD (ed) Casarett and Doull's Toxicology. Basic Science of Poisons. 6th ed. MacGrawHill, New York, USA; Reichl F, Hammelehle R. (2002) Taschenatlas der Toxikologie (2nd ed); Thieme Verlag; Stuttgart, FRGVillányi V, Turk B, Batic F, Csintalan Z (2010) Ozone pollution and its bioindication. Villányi V (ed) Air Polluiton. Sciyo Publ. Croatia.

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Some Airborne Toxins (6a/8)

Aerosol Climate Tools ModelHealth

• Carbon Monoxide (CO)& Carbon Dioxide (CO2)

• Hydrocarbons (HC)Formaldehyde (CH2O)polyc. arom. HCs (PAH)

• Ammonia (NH4+)

Nitric Oxides (NOX)• Ozone (O3)• Sulfur Dioxide (SO2)

Costa, 2001Reichl, 2002

Adverse effects of:

Sulfur Dioxide (SO2) it is a water-soluble irritant gas. As such, it is absorbed predominantly in the upper airways and, as an irritant, can stimulate broncho-constriction and mucus secretion in a number of species, including humans. While most fosil fuel derivateives nowadays are sulfur-free the only large remaining fuel complex containig high levels of sulfur regard ship (heavy oil o bunker) fuel.

Early studies with relatively high exposure concentrations of SO2 showed airway cellular injury and subsequent proliferation of mucus-secreting goblet cells. This attribute of SO2 has led to its use (>250 ppm) in the production of laboratory animal models of bronchitis and airway injury. At much lower concentrations (<1 ppm), such as might be encountered in the polluted ambient air of industrialized areas, long-term residents experience a higher incidence of bronchitis.

Acute effects: The basic pulmonary response to inhaled SO2 is mild bronchoconstriction, which is reflected as a measurable increase in airflow resistance due to narrowing of the airways. Human subjects exposed to 1, 5, or 13 ppm SO2 for just 10 min exhibit a rapid broncho-constrictive response, with 1 to 3 ppm being a threshold for most if exercise is involved. Healthy individuals at rest seem to have a clear response at about 5 ppm, though there is considerable variation among individuals. Even 0.25 to 1 ppm for a few hours can induce bronchoconstriction in adult and adolescent subjects with clinically defined mild asthma. Findings such as these (responses <0.5 ppm) have raised concerns about potential adverse effects in this sensitive subpopulation when it is exposed to peaks of SO2 that are known to occur near point sources.

Chronic Effects: Prolonged exposed guinea pigs to 0.13, 1.01, or 5.72 ppm SO2 continuously for a year without adverse impact on lung mechanics. Similarly, monkeys exhibited no alteration in pulmonary function when exposed continuously for 78 weeks to 0.14, 0.64, and 1.28 ppm SO2 (Alarie et al., 1972). Levels of SO2 for protracted periods of time [dogs to 5 ppm for 225 days; rats to 350 ppm for 30 days] have been shown to alter airway mucus secretion, goblet cell topography, or lung function, but these results are of little relevance to typical SO2 levels in ambient air.

Reichl F, Hammelehle R. (2002) Taschenatlas der Toxikologie (2nd ed); Thieme Verlag; Stuttgart, FRG

Source: Costa DL (2001) Air Pollution, Ch. 28. In: Klaassen CD (ed) Casarett and Doull's Toxicology. Basic Science of Poisons. 6th ed. MacGrawHill, New York, USA;

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Some Airborne Toxins (6b/8)

Aerosol Climate Tools ModelHealth

• Carbon Monoxide (CO)& Carbon Dioxide (CO2)

• Hydrocarbons (HC)Formaldehyde (CH2O)polyc. arom. HCs (PAH)

• Ammonia (NH4+)

Nitric Oxides (NOX)• Ozone (O3)• Sulfur Dioxide (SO2)

and its acid (H2SO4)

Costa, 2001

Adverse effects of:

Sulfuric Acid (H2SO4) - Synonym: Oil of vitriol; Oleum; Battery acid. Physical Appearance: Sulfuric acid is a heavy, oily, colourless, odourless, non-fuming liquid. It is hygroscopic, i.e. it has great affinity forwater with which it reacts violently, giving off intense heat.Sulfuric acid can be formed in smog from the photochemical oxidation of sulfur dioxide to sulfur trioxide and subsequent reaction with water. It is a major component of acid rain.[1]The conversion of SO2 to sulfuric acid is favored in the environment. During oil combustion or the smelting of metal, sulfuric acid condenses downstream of the combustion processes with available metal ions and water vapor to form submicron sulfated fly ash. SO2 continues to oxidize to sulfate in dispersing smokestack plumes in the presence of free soluble or partially coordinated transition metals such as iron, manganese, and vanadium within the ash particles. When coal is burned, the acid may adsorb to the surface or solubilize in ultrafine (<0.1 µm) metal oxide particles during emission. These sulfates on the surface of coal ash may constitute as much as 9% of the emitted sulfur—the rest is emitted as SO2 gas. Photochemical environments in the lower troposphere can also promote acid sulfate formation via both metal-dependent and independent mechanisms, but studies have shown that most of the oxidation of SO2 occurs within diluted plumes drifting in the atmosphere. Stack emissions may undergo longrange transport to areas distant from the emission source, allowing considerable time for sunlight-driven chemical reactions to occur. Although the fine-particle sulfates may exist as fine sulfuric acid (the primary source of free H+), partially or fully neutralized forms (ammonium bisulfate and ammonium sulfate) predominate due to the abundance of natural atmospheric ammonia.[2]Chronic Effects As might be expected, sulfuric acid induces qualitatively similar effects along the airways as are found with SO2 at much higher concentrations. As a fine aerosol, sulfuric acid deposits deeper along the respiratory tract, and its high specific acidity imparts greater injury effect on various cells (e.g., phagocytes and epithelial cells). Thus, a primary concern with regard to chronic inhalation of acidic aerosols is its potential to cause bronchitis, since this has been a problem in occupational settings in which employees are exposed to sulfuric acid mists (e.g., battery plants). Early studies in the donkey that later were expanded in a rabbit model have provided fundamental data on this issue. The profound depression of clearance found in donkeys exposed repeatedly (100 µg/m3 1 h per day for 6 months) promoted the hypothesis that a similar response (i.e., chronic bronchitis) can occur in humans. This argument was strengthened by the similar bronchitogenic responses of the two species when chronically exposed to cigarette smoke.[2]Source:[1] Pillay V.V. (2013) Modern Medical Toxicology. 4th ed. Ch. 26 Toxic Gases. Jaypee Brothers Medical Publishers, New Delhi, IND.[2] Costa DL (2001) Air Pollution, Ch. 28. In: Klaassen CD (ed) Casarett and Doull's Toxicology. Basic Science of Poisons. 6th ed. MacGrawHill, New York, USA;

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Some Airborne Toxins (6c/8)

Aerosol Climate Tools ModelHealth

• Carbon Monoxide (CO)& Carbon Dioxide (CO2)

• Hydrocarbons (HC)Formaldehyde (CH2O)polyc. arom. HCs (PAH)

• Ammonia (NH4+)

Nitric Oxides (NOX)• Ozone (O3)• Sulfur Dioxide (SO2)

and its acid (H2SO4) Vallero, 2014

Adverse effects of:

At a temperature of 20 C, the raindrops have a pH of 5.6, the value often labeled as that of clean or natural rainwater. It represents the base- line for comparing the pH of rainwater which may be altered by SO2 or NOX oxidation products. The pH of rainwater can vary from 5.6 due to the presence of H2SO4 and HNO3 dissolved or formed in the droplets. These strong acids dissociate and release hydrogen ions, resulting in more acidic droplets. Basic compounds can also influence the pH. Ca2+, Mg2+, and ammonium (NH4 ions help to neutralize the rain droplet and shift the overall H+ toward the basic end of the scale. The overall pH of any given droplet is a combination of the effects of carbonic acid, sulfuric and nitric acids, and any neutralizers such as ammonia. The principal elements of acidic deposition are i) Dry deposition occurs when it is not raining. Gaseous SO2, NO2, and HNO3 and acid aerosols are deposited when they come into contact with and stick to the surfaces of water bodies, vegetation, soil, and other materials; ii) if the surfaces are moist or liquid, the gases can go directly into solution; the acids formed are identical to those that fall in the form of acid rain. SO2 and NO2 can undergo oxidation, forming acids in the liquid surfaces if oxidizers are present. During cloud formation, when rain droplets are created, fine particles or acid droplets can act as seed nuclei for water to condense. This is one process by which sulfuric acid is incorporated in the droplets. While the droplets are in the cloud, additional gaseous SO2

and NO2 impinge on them and are absorbed. These absorbed gases can be oxidized by dissolved H2O2 or other oxidizers, lowering the pH of the raindrop. As the raindrop falls beneath the cloud, additional acidic gases and aerosol particles may be incorporated in it, also affecting its pH.Image: Atmospheric processes involved in acidic deposition. The two principal deposition pathways are dry deposition (nonrain events) and wet deposition (rain events). The pH scale is a measure of hydrogen ion con- centration. The pH of common substances is shown with various values along the scale. The Adirondack Lakes are located in the state of New York and are considered to be receptors of acidic deposition.

Source: Vallero D (2014) Fundamentals of Air Pollution, 5th ed., Ch.14 (Air Pollutant Impacts on terrestrial Ecosystems) Academic Press, USA

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Some Airborne Toxins (6d/8)

Aerosol Climate Tools ModelHealth

Pillav, 2013Reichl, 2002

• Carbon Monoxide (CO)& Carbon Dioxide (CO2)

• Hydrocarbons (HC)Formaldehyde (CH2O)polyc. arom. HCs (PAH)

• Ammonia (NH4+)

Nitric Oxides (NOX)• Ozone (O3)• Sulfur Dioxide (SO2)

and its acid (H2SO4) Hydrogen Sulfide (H2S)

Adverse effects of:

Hydrogen Sulfide (H2S) - Synonyms: dihydrogen monosulfide, dihydrogen sulfide, hydrosulfide, sulfur hydride, hydrogen sulfuric acid, hydrosulfuric acid, sulfureted hydrogen. Physical appearance: Colourless gas, heavier than air, with a strong ‘rotten eggs’ odour. Because it rapidly paralyses olfactory nerve endings in high concentrations, odour is not a dependable means of detecting this gas. Natural gas containing H2S is termed “sour gas”. H2S is a liquid at high pressures and low temperatures, and is shipped as the liquefied material under its own vapour pressure.

It is a decay product of organic sulfur-containing products such as fish, manure, sewage, septic tank contents, etc. It is produced by bacterial action on sewage effluents containing sulfur compounds when oxygen has been consumed by excessive organic loading of surface water (“sewer gas”), incl. paper mills, leather industry, petroleum distillation and refining, and coke manufacture from coal. Natural sources incl. volcanoes, caves, sulfur springs, and subterranean emissions. Other sources concern burning of wool, hair, and hides can release hydrogen sulfide.

Toxic Doses:

• Exposure to concentrations < 250 ppm causes irritation of mucous membranes, conjunctivitis, photophobia, lacrimation, corneal opacity, rhinitis, bronchitis, cyanosis, and acute lung injury.

• concentrations of 250 to 500 ppm, signs and symptoms include headache, nausea, vomiting, diarrhoea, vertigo, amnesia, dizziness, apnoea, palpitations, tachycardia, hypotension, muscle cramps, weakness, disorientation, and coma.

• concentrations of 750 to 1000 ppm, victims may experience abrupt physical collapse or “knock down”. Higher concentrations may also result in respiratory paralysis, asphyxial seizures, and death. The mortality rate is in the range of 6 %.

Reichl F, Hammelehle R. (2002) Taschenatlas der Toxikologie (2nd ed); Thieme Verlag; Stuttgart, FRG

Source: Pillay V.V. (2013) Modern Medical Toxicology. 4th ed. Ch. 26 Toxic Gases. Jaypee Brothers Medical Publishers, New Delhi, IND.

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Some Airborne Toxins (7a/8)

Aerosol Climate Tools ModelHealth

Pillay, 2013

Composition of Smoke

Material Burnt Combustion Products Wood, cotton, paper Carbon monoxide, acrolein, acetaldehyde, formaldehyde,

methane Plastics Cyanide, aldehydes, ammonia, nitrogen oxides, phosgene,

chlorine Rubber Hydrogen sulfide, sulfur dioxide Wool Carbon monoxide, hydrogen chloride, phosgene, cyanide,

chlorine Silk Sulfur dioxide, hydrogen sulfide, cyanide, ammonia Nylon Ammonia, cyanide PVC (polyvinyl chloride) Carbon monoxide, phosgene, chlorine Polyurethane Cyanide, isocyanates Nitrocellulose Nitrogen oxides, acetic acid, formic acid Acrylic material Acrolein, hydrogen chloride Petroleum products Carbon monoxide, acrolein, acetic acid, formic acid

• Carbon Monoxide (CO)& Carbon Dioxide (CO2)

• Hydrocarbons (HC)Formaldehyde (CH2O)polyc. arom. HCs (PAH)

• Ammonia (NH4+)

Nitric Oxides (NOX)• Ozone (O3)• Sulfur Dioxide (SO2)

and its acid (H2SO4) Hydrogen Sulfide (H2S)

• Total Suspended Particles (TSP)

Adverse effects of:

Total suspended particles, Smoke, (TSP) dominant constituents of smoke; Smoke is defined as a solid aerosol resulting from the incomplete combustion (pyrolysis) of any organic matter, and should be differentiated from fumes, which refer to a suspension of fine solid particles in a gas resulting from condensation (e.g. metal oxides generated during smelting, welding, etc.). The exact composition of smoke depends on the material burnt

Source:[1] Pillay V.V. (2013) Modern Medical Toxicology. 4th ed. Ch. 26 Toxic Gases. Jaypee Brothers Medical Publishers, New Delhi, IND.

[2] Costa DL (2001) Air Pollution, Ch. 28. In: Klaassen CD (ed) Casarett and Doull's Toxicology. Basic Science of Poisons. 6th ed. MacGrawHill, New York, USA;

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Some Airborne Toxins (7b/8)

Aerosol Climate Tools ModelHealth

Baron & Willeke, 2001

• Carbon Monoxide (CO)& Carbon Dioxide (CO2)

• Hydrocarbons (HC)Formaldehyde (CH2O)polyc. arom. HCs (PAH)

• Ammonia (NH4+)

Nitric Oxides (NOX)• Ozone (O3)• Sulfur Dioxide (SO2)

and its acid (H2SO4) Hydrogen Sulfide (H2S)

• Total Suspended Particles (TSP)

• High solubility.: rapid assimilation - particularly in the alveolar region with local effects (irritation & inflammation); systemic responses over very short time periods.

• Low solubility.: gradual release low-soluble agents exert an extended response time; i.e.: adsorption of nitrogen oxides and sulfur dioxide onto particles can lead to health effects at levels normally considered safe.

• Very low-S.: health effects associated with their physical characteristics; i.e.: lung overload associated with limitations in clearance mechanisms – regard particle shape-factor (fibrous aerosols).

Exposure during production, wear & tear, as well as disposal:• cosmetics, sunscreens (TiO2), inhalation therapy, medications.• electronics, fuel cells; coatings (lotus-leaf effect on glass).• disposable filters.• Nanotechnology in general, etc.

Adverse effects of:

Biol. Reactivity: Although particle aerodynamic diameter dominates deposition within the respiratory tract, the subsequent effect on health is a combination of physical particle characteristics and biological response. On deposition, the body may react to the chemical substances contained within the particle, interact with the particle surface, or be influenced by physical parameters such as size and morphology.[1]Highly soluble particles and droplets will be rapidly assimilated by the body, particularly in the alveolar region. Local effects, such as irritation and inflammation, and systemic responses may become manifest over very short time periods. The gradual release of agents from low-solubility particles will have a much longer response time. Low-solubility particles may also act as vectors for the transport of high-solubility solids, liquids, and gases present as thin surface layers, thus leading to a response not indicated by the bulk aerosol particle properties alone. For example, adsorption of nitrogen oxides and sulfur dioxide onto particles can lead to health effects at levels normally considered safe. Very low-solubility particles are more likely to have health effects associated with their physical characteristics. Lung overload phenomena are associated with the physical limitations of the lungs' clearance mechanisms as opposed to chemical interactions with the deposited particles (Morrow, 1994). Particle shape is a factor for fibrous aerosols …. It also influences available surface area, which may be related to toxicity through surface interactions (Lison et aI., 1997) or increased solubility. Where open agglomerates of particles exist, including those resulting from combustion (such as diesel exhaust particulates), metal processing, welding, or fine powder production, the aerosol may have a very high specific surface area and be formed from particles able to penetrate to the alveolar region.In some fine powders, including ultrafine titanium dioxide, carbon blacks, and fumed silicas, specific surface areas in excess of 2·E5m2/kg [200m2/g] are achieved among particles with aerodynamic diameters less than 4m. In comparison, an aerosol of spherical particles 4m in diameter and with unit density would have a specific surface area of 1.5 x 103m2/kg [1.5m2/g]. There is evidence that for some low-solubility materials toxic response may be associated with surface area or even particle number (Oberdorster et al., 1994; Lison et al., 1997; Donaldson et al., 1998).They are being used in personal-care products such as cosmetics and sunscreens and can therefore enter the environment on a continual basis from washing off of consumer products (Daughton and Ternes 1999). They are being used in electronics, tires, fuel cells, and many other products, and it is unknown whether some of these materials may leak out or be worn off over the period of use. They are also being used in disposable materials such as filters and electronics and may therefore reach the environment through landfills and other methods of disposal [3] ....

Source: B.A.Baron & K.Willeke (2001). Aerosol Measurement Principles, Techniques and Applications, 2nd e.d; [1] p.781-782;Oberdörster G., Oberdörster E., Oberdörster J. (2005). Nanotoxicology: An Emerging Discipline Evolvingfrom Studies of Ultrafine Particles; Environmental Health Perspective Vol. 113, No.7: 823-839, [3] p.825;

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Some Airborne Toxins (7c/8)

Aerosol Climate Tools ModelHealth

• Carbon Monoxide (CO)& Carbon Dioxide (CO2)

• Hydrocarbons (HC)Formaldehyde (CH2O)polyc. arom. HCs (PAH)

• Ammonia (NH4+)

Nitric Oxides (NOX)• Ozone (O3)• Sulfur Dioxide (SO2)

and its acid (H2SO4) Hydrogen Sulfide (H2S)

• Total Suspended Particles (TSP) Particle Matter (PM)

Pillay, 2013Reichl, 2002

Adverse effects of:

Particulate Matter (PM) Particulate matter in the atmosphere is a melange of organic, inorganic, and biological materials whose compositional matrix can vary significantly depending on local point sources. The contribution to any regional PM matrix from long-range transport of emissions or transformation products can also be substantial, particularly for fine (<2.5 µm) particles. Epidemiologic database contends that PM elicits both short- and long-term health effects at current ambient levels.

From research directed initially toward potential occupational hazards, it is known that several metals and silicates that make up at least part of the inorganic phase of PM can be cytotoxic to lung cells, and that organic constituents theoretically can induce toxicity either directly or via metabolism to genotoxic agents. Also, studies focusing on very small, ultrafine (<0.1 µm) particles suggest that though these particles are low in mass, they are high in number and thus provide substantial particle surface to biological surface interaction.

Chronic Effects and Cancer Chronic exposure studies have been conducted with a number of particles ranging from titanium dioxide to diesel exhaust aerosol (DEA) and coal fly ash. Of these substances, diesel exhaust has been the most extensively studied. The diesel particle is of interest because it can constitute a significant portion of an urban particulate load in some cities (especially in Europe). The primary concern with diesel has been the suspicion that it can induce lung cancer and thus is classified as a Class A carcinogen. At high concentrations of DEA (3.5 and 7 mg/m3), normal mucociliary clearance in rats is gradually overwhelmed, resulting in a progressive buildup of particles in the lungs. By 12 months (and increasingly upon approaching 18 to 24 months), clearance essentially ceases and there is evidence of ongoing inflammation, oxidant generation, epithelial hyperplasia, and fibrogenic activity around agglomerates of particles and phagocytic cells in the distal areas of the lung. These patchy sites of injury are associated with the eventual development of adenosarcomas and squamous cell carcinomas in the rats involved in these studies.

Reichl F, Hammelehle R. (2002) Taschenatlas der Toxikologie (2nd ed); Thieme Verlag; Stuttgart, FRG

Source: Costa DL (2001) Air Pollution, Ch. 28. In: Klaassen CD (ed) Casarett and Doull's Toxicology. Basic Science of Poisons. 6th ed. MacGrawHill, New York, USA;

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Some Airborne Toxins (7d/8)

Aerosol Climate Tools ModelHealth

Salzburg City measurement campaign

Kwasny et al. 2009

• Carbon Monoxide (CO)& Carbon Dioxide (CO2)

• Hydrocarbons (HC)Formaldehyde (CH2O)polyc. arom. HCs (PAH)

• Ammonia (NH4+)

Nitric Oxides (NOX)• Ozone (O3)• Sulfur Dioxide (SO2)

and its acid (H2SO4) Hydrogen Sulfide (H2S)

• Total Suspended Particles (TSP) Particle Matter (PM)

Pillay, 2013

Daily Average Particle Load Rudolfsplatz - Summer

0

5,000

10,000

15,000

20,000

25,000

30,000

35,000

40,000

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Avera

ge P

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) [c

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]

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Daily Average Particle Load Rudolfsplatz - Winter

0

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Aver

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6.Jan.2008

7.Jan.2008

Adverse effects of:

This study has shown that there is a significant difference in the size distribution of particles depending on the season. As expected, sites closely located to areas with heavy traffic were highly impacted. The comparison between the slow city traffic to the high speed highway traffic revealed a shift of the particle towards the smaller particle sizes for the highway traffic. The measurement site 30 km outside of Salzburg (Haunsberg) more closely approached the background concentrations of anthropogenic produced aerosols. Although it did not closely follow the day/night and weekend patterns, the fluctuations and influence of traffic exhaust was still recognizable and was most likely associated with the long-range transport of aerosols.Although PM10 seemed to be correlated with trends in ultrafine particles, it did not provide enough evidence that ultrafine particle behavior can be considered simply as a fraction of PM10.

Image: Composite graph of five sampling days obtained during the summer & winter-measurements at “Rudolfsplatz” in downtown Salzburg city,

Source: Kwasny F., Madl P., Hofmann W. (2008). Nanopartikel in Salzburg Stadt und Umland – Sommer- und Wintererhebung. Messkampagne, Land Salzburg (Sbg): In Madl (ed), PhD-Thesis: 270-309;

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Some Airborne Toxins (7e/8)

Aerosol Climate Tools ModelHealth

0.1

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CO [ppm]

NO2 [ppb]

NO [ppb]

Wind Speed [m/s]

Partic les

[N/cm3]/1000

PM10 [ug/m3]x10

-------- FRI --------- --------- SA T ------ ------- SUN -------- ------- MON ------- -------- TUE ------ -------- WED -------- ------- THU ------- -------- FRI ---------

Rudolfsplatz EnvironmentalData20.7.- 27.7.2007

Adverse effects of:

On the other hand, traffic related exhaust pollutants like NO and NO2 indeed unveiled a close link to the measured ultrafine particle concentrations. Hence, such exhaust chemicals can be used as an indicator for ultrafine particles in close proximity to road traffic conditions. Considering the health effects of the smallest nano-particles observed in this study, the difference in seasonal particle-size composition should play a roll in exposure and health assessments, in particular, as the winter measurements revealed a significantly higher amount in the spectrum of particles which easily penetrate into deeper lung areas.

Image: Summary plot of the sampling site “Rudolfsplatz” for the summer months - here Nox-values correlate much better with PN-data thani during the colder time of the year.

Source: Kwasny F., Madl P., Hofmann W. (2008). Nanopartikel in Salzburg Stadt und Umland – Sommer- und Winter-Erhebung. Messkampagne, Land Salzburg (Sbg): In Madl (ed), PhD-Thesis: 270-309;

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Some Airborne Toxins (7f/8)

Aerosol Climate Tools ModelHealth

Lichen & NOX:

Determination of lichen population density in a remote valley and its correlation to aerosol exposure from a nearby motorway.

• Carbon Monoxide (CO)& Carbon Dioxide (CO2)

• Hydrocarbons (HC)Formaldehyde (CH2O)polyc. arom. HCs (PAH)

• Ammonia (NH4+)

Nitric Oxides (NOX)• Ozone (O3)• Sulfur Dioxide (SO2)

and its acid (H2SO4) Hydrogen Sulfide (H2S)

• Total Suspended Particles (TSP) Particle Matter (PM)

Madl et al, 2009

Adverse effects of:

The area of the Bluntau-Valley is predestined to be influenced by solar radiation and changing wind conditions due to meso-climatical processes and the topographical setting of the valley.

Measurement days in summer showed higher particle concentrations, which correlates with the peak vehicle frequencies during the summer-holiday season.

Measurement sites closer to the highway produced higher concentrations as a result of the constant mixing of exhaust particles and resuspension of larger aerosol-clusters and elevated vehicle density (Hofmann, 2005). Consequently, particles are easily relocated by wind and transported over the sound-protective barriers to finally settle in neighbouring land strips. As expected, sampling sites further away and deeper within the Bluntau-Valley yielded lower particle concentrations. However, long-distance relocation of exhaust particle-loads originating from the motorway does regularly occur, as lichen-populations on exposed sites such as the remotest site surveyed (FFK-location) do reveal a suppressed species diversity. This observation correlates with those made by other authors that associate these ecological changes to excess eutrophication and an elevated pollutant load (Masuch, 1993). In particular, higher aerosol concentration results in lower species diversity by damaging the thalli of the lichens (Nimis, 2002). Therefore, measurement sites in close proximity to the E55 display a distinctive absence of species otherwise found in more pristine areas of similar geo-botanic character (Masuch, 1993).

Additionally, lichen associations near the highway tend to change to more nitrophilous lichen associations because of a higher amount of nitrogen available due to vehicle exhaust and being in a rural setting, the prevailing agricultural activities near the motorway along with the associated wind-related relocation of fertilizer. The dramatic reduction of lichen diversity observed at all measurement sites – with none to just a few in close proximity to the motorway backs up the hypothesis that certain particle sizes are able to enter the lichen thallus through pores of the polysaccharide layer of the epicortex thereby negatively affecting the fungi and in turn the symbiotic association between the mycobiont and the photobiont (Masuch, 1993).

Source: Madl P., Heinzelmann E., Hofmann W., Tuerk R., (2010). Gefahrenstoffe Reinhaltung der Luft / Air Quality Control; VDI, Springer, Vol.4: 147-163

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Some Airborne Toxins (8a/8)

Aerosol Climate Tools ModelHealth

• Carbon Monoxide (CO)& Carbon Dioxide (CO2)

• Hydrocarbons (HC)Formaldehyde (CH2O)polyc. arom. HCs (PAH)

• Ammonia (NH4+)

Nitric Oxides (NOX)• Ozone (O3)• Sulfur Dioxide (SO2)

and its acid (H2SO4) Hydrogen Sulfide (H2S)

• Total Suspended Particles (TSP) Particle Matter (PM)

• SmogCosta, 2001

Sm

og-c

ap

(bes

t vis

ible

fro

m a

bove

,

poor

ly v

isib

le f

rom

the

grou

nd)

Adverse effects of:

Short-Term Exposures to Smog: When human subjects were exposed to actual photochemical air pollution (Los Angeles ambient air pumped into a laboratory exposure chamber), they experienced changes in lung function similar to those described in controlled clinical studies of O3 alone (i.e., reduction in spirometric lung volumes; see below), thus supporting the view that this is the pollutant of primary concern. Acute animal studies using synthetic atmospheres (usually irradiated auto exhaust) provided evidence indicating deep lung damage, primarily within the small airway and proximal alveolar epithelium. In some of these studies, early evidence of edema appeared in the interstitium, particularly in older animals. Additionally, mice similarly exposed were found to be more susceptible to bacterial challenge and lung pneumonias. With time, after the termination of an acute exposure, end-airway lesions recovered and the susceptibility to infection waned, although some pathology in the distal lung persisted for more than 24 h. While O3 appeared to be the prime toxicant in many of these studies, there was some evidence that other co-pollutants were involved .... Thus, the array of effects of a complex atmosphere may be more diverse than would be predicted if it were assumed that O3 alone was responsible.

Chronic Exposures to Smog: Recently, studies have been conducted in children living in Mexico City, which has oxidant and PM levels far in excess of any city in the United States. These studies have focused on the nasal epithelium as an exposure surrogate for pulmonary tissues, using biopsy and lavage methodologies to assess damage. Dramatic effects were found in exposed children, consisting of severe epithelial damage and metaplasia as well as permanent remodeling of the nasal epithelium. When children migrate into Mexico City from cleaner, nonurban regions were evaluated, even more severe damage was observed, suggesting that the remodeling in the permanent residents imparted some degree of incomplete adaptation. Since the children were of middle-class origin, these observations were not likely confounded by poor diet (Calderon-Garciduenas et al., 1992). These dramatic nasal effects have raised concerns for the more fragile, deep lung tissues, where substantial deposition of oxidant air pollutants is thought to occur …. “Sentinel” studies have been attempted whereby the animals live in the same highly polluted air to which people are exposed …. One such study, conducted in rats exposed for 6 months to the air of Sao Paulo, Brazil, found considerable airway damage, lung function alterations, and altered mucus rheology (Saldiva et al., 1992). The concentrations of O3and PM in Sao Paulo frequently exceed daily maximum values (in the summer months of February and March) of 0.3 ppm and 75 µg/m3 , respectively. This collage of effects is not unlike a composite of injury one might suspect from a mixed atmosphere of oxidants and acid PM on the basis of controlled animal studies in the laboratory. However, the essential conclusion from most sentinel studies is that “pollution is unhealthy”, since individual and mixed pollutant effects and interactions cannot be easily addressed.

Image: Reactions occurring during atmospheric radical activity: photochemical smog episode.[2]

Source: Costa DL (2001) Air Pollution, Ch. 28. In: Klaassen CD (ed) Casarett and Doull's Toxicology. Basic Science of Poisons. 6th ed. MacGrawHill, New York, USA;

[2] Avino P, Manigrasso M (2001) Ozone formation in relation with combustion processes in highly populated urban areas. AIMS Environ. Scie. Vol. 2(3): 764-781.

https://www.washoecounty.us/health/programs-and-services/air-quality/nozone.php

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Some Airborne Toxins (8b/8)

Aerosol Climate Tools ModelHealth

• Carbon Monoxide (CO)& Carbon Dioxide (CO2)

• Hydrocarbons (HC)Formaldehyde (CH2O)polyc. arom. HCs (PAH)

• Ammonia (NH4+)

Nitric Oxides (NOX)• Ozone (O3)• Sulfur Dioxide (SO2)

and its acid (H2SO4) Hydrogen Sulfide (H2S)

• Total Suspended Particles (TSP) Particle Matter (PM)

• SmogCosta, 2001

NO2 + h·UV O• + NO•

O• + O2 O3

O3 + NO • NO2

arte - dicke luft.mp4(14:50-18:50)

• predominantly in Metropolitan areas

• photo-chemically induced

Adverse effects of:

Photochemical Air Pollution (Smog Machine): The oxidant of most toxicologic importance in the so-called photochemical “soup” is O3. It is important to appreciate that atmospheric O3 is not summarily undesirable. About 10 km above the earth’s surface there is sufficient short-wave ultraviolet (UV) light to directly split molecular O2 to atomic O•, which can then recombine with O2 to form O3. This O3 accumulates to several hundred ppm within a thin strip of the stratosphere and absorbs incoming short-wavelength UV radiation. The O3 forms and decomposes and reforms to establish a “permanent” barrier to UV radiation, which lately has become a issue of concern, as this barrier is threatened by various anthropogenic emissions (Cl2 gas and certain fluorocarbons) that enhance O3 degradation. The consequence is excess infiltration of UV light to the earth’s surface and the potential for excess skin cancer risk and immune suppression. The issue is different in the troposphere, where accumulation of O3 serves no known purpose and poses a threat to the respiratory tract. Near the earth’s surface, NO2 from combustion processes efficiently absorbs longer-wavelength UV light, from which a free O atom is cleaved, initiating the following simplified series of the above reactions.This process is inherently cyclic, with NO2 regenerated by the reaction of the NO• and O3. In the absence of unsaturated hydrocarbons, this series of reactions would approach a steady state with no excess or build-up of O3. The hydrocarbons, especially olefins and substituted aromatics, are attacked by the free atomic O•, resulting in oxidized compounds and free radicals that react with NO• to produce more NO2. Thus, the balance of the reactions is upset, leading to buildup of O3. This reaction is particularly favored when the sun’s intensity is greatest at midday, utilizing the NO2 provided by morning traffic. Aldehydes are also major by-products of these reactions. Formaldehyde and acrolein account for about 50 % and 5 %, respectively, of the total aldehyde in urban atmospheres. Peroxy-acetyl-nitrate (CH3COONO2), often referred to as PAN, and its homologs also arise in urban air, most likely from the reaction of the peroxyacyl radicals with NO2.

Image: http://www.lieyunwang.com/archives/267867Source: Costa DL (2001) Air Pollution, Ch. 28. In: Klaassen CD (ed) Casarett and Doull's Toxicology. Basic Science of Poisons. 6th ed. MacGrawHill, New York, USA;

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Some Airborne Toxins (8c/8)

Aerosol Climate Tools ModelHealth

• Carbon Monoxide (CO)& Carbon Dioxide (CO2)

• Hydrocarbons (HC)Formaldehyde (CH2O)polyc. arom. HCs (PAH)

• Ammonia (NH4+)

Nitric Oxides (NOX)• Ozone (O3)• Sulfur Dioxide (SO2)

and its acid (H2SO4) Hydrogen Sulfide (H2S)

• Total Suspended Particles (TSP) Particle Matter (PM)

• SmogCosta, 2001

Vallero, 2014

NO2 + h·UV O• + NO•

O• + O2 O3

O3 + NO • NO2

Adverse effects of:

The effect of photochemical oxidants, mainly O3 and PAN, on the forests located in the San Bernardino Mountains northeast of Los Angeles, California, has been to change the forest composition and to alter the susceptibility of forest species to pests. This area has been subjected to increasing levels of oxidant since the 1950s. During the late 1960s and early 1970s, changes in the composition and esthetic quality of the forest were observed. During this period, the photochemical problem was expanding to a wider geographical region; and photochemical oxidant was transported to the San Bernardino Mountains with increasing frequency and at higher concentrations. The receptor forest system has been described as a mixed conifer system containing ponderosa pine, Jeffrey pine, white fir, and cedar, along with deciduous black oak. The damage to the ponderosa pine ranged from no visible injury to death. As the trees came under increased stress due to exposure to oxidant, they became more susceptible to pine beetle, which ultimately caused their death. The ponderosa pine appears to be more susceptible than the other members of this forest system, and continued exposure to photochemical oxidant may very well shift it from the dominant species to a minor one.

Image: Relationship between Los Angeles Basin’s urban sources of photochemical smog and the San Bernardino Mountains, where ozone damage has occurred to the ponderosa pines. The solid lines are the average daily 1-h maximum does of ozone (ppm), July-September 1975-1977.

Source: Vallero D (2014) Fundamentals of Air Pollution, 5th ed., Ch.14 (Air Pollutant Impacts on terrestrial Ecosystems) Academic Press, USA

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Particle Uptake & Expulsion (Clearance):

Oberdörster et al, 2004 & 2005; Geiser et al., 2005

Pathways i/o of Organism

Aerosol Climate Tools ModelHealth

Organismic dispersal of inhaled nano-particles. The red pathways indicate alternative routes of entry.[1]

Red blood cell (RBC, erythrocyte) loaded with a 25 nm gold particle. [2]

Source: [1] supplemented by: Oberdörster G., Sharp Z., Atudorei V., Elder A., Gelein R., Kreyling W. Co, C.(2004). Translocation of Inhaled Ultrafine Particles to the Brain, Inhalation Toxicology,16: 6: 437- 445.

Oberdörster G., Oberdörster E., OberdörsterJ. (2005). Nanotoxicology: An Emerging Discipline Evolving from Studies of Ultrafine Particles. Environmental Health Perspectives, Vol.113, No.7: 823-839.

[2] Geiser M., Rothen-Rutishauser B.,Kapp N., Schürch S., Kreyling W., Schulz H., Semmler M., Hof V., Heyder J., Gehr P. (2005).Ultrafine Particles Cross Cellular Membranes by Nonphagocytic Mechanisms in Lungs and in Cultured Cells. Environmental Health Perspectives Vol.113, No. 11: 1555-1560.

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Respiration (1a/5)

The HumanLung&Lung Compartments

Menache, 2004Postlethwait & Hospon, 1995

Aerosol Climate Tools ModelHealth

The Human Lung: 5 lobes2 left lobes - superior and inferior3 right lobes - superior, middle, and inferior

Lung compartments: Nasopharyngeal - anterior nares to larynxTracheobronchial - begins at larynx, trachea, bronchi, bronchioles, terminal

bronchiolesPulmonary - respiratory bronchioles, alveolar ducts, alveoli

Source: Menache, 2004Postlethwait & Hopkins, 1995;

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Respiration (1b/5)

The HumanLung&Lung Compartments

Kleinstreuer & Zhang, 2010

Aerosol Climate Tools ModelHealth

Airflows in the nasal cavities and oral airways are rather complex, possibly featuring a transition to turbulent jet-like flow, recirculating flow, Dean’s flow, vortical flows, large pressure drops, prevailing secondary flows, and merging streams in the case of exhalation. Such complex flows propagate subsequently into the tracheo-bronchial airways. The underlying assumptions for particle transport and deposition are that the aerosols are spherical, non-interacting, and mono-disperse and deposit upon contact with the airway surface. Such dilute particle suspensions are typically modeled with the Euler-Lagrange approach for micron particles and in the Euler-Euler framework for nano-particles. Micron particles deposit non-uniformly with very high concentrations at some local sites (e.g., carinal ridges of large bronchial airways). In contrast, nano-material almost coats the airway surfaces, which has implications of detrimental health effects in the case of inhaled toxic nano-particles. Geometric airway features, as well as histories of airflow fields and particle distributions, may significantly affect particle deposition.

Image: Schematics of the human respiratory system

Source: Kleinstreuer C, Zhang Z (2010) Airflow and Particle Transport in the Human Respiratory System. Annu. Rev. Fluid Mech. Vol.42: 301–334

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Respiration (2/5)

The HumanLung&Lung Compartments

Jing CHAI , 2015

Chai Jing's review- Under the Dome – animation.mp400:09:57-00:12:31

Aerosol Climate Tools ModelHealth

Under the Dome 穹顶之下 (QióngDǐng Zhī Xià) is a 2015 self-financed, Chinese documentary film by Chai Jing, a former China Central Television journalist, concerning air pollution in China. It was viewed over 150 million times on Tencent within three days of its release. Chai Jing started making the documentary when her as yet unborn daughter developed a tumour in the womb, which had to be removed very soon after her birth. Chai blames air pollution for the tumour. The film, which combines footage of a lecture with interviews and factory visits, has been compared with Al Gore's An Inconvenient Truth in both its style and likely impact. The film openly criticises state-owned energy companies, steel producers and coal factories, as well as showing the inability of the Ministry of Environmental Protection to act against the big polluters. Despite demonstrating the failure of China's regulations on pollution, the Chinese government at first did not censor the film. Instead, the People's Daily reposted the film alongside an interview with Chai, while Chen JiNing, the recently appointed minister for environmental protection, praised the film, comparing its significance with Silent Spring, the 1962 book by US environmentalist Rachel Carson. However, within a week, the Communist Party’s publicity department confidentially ordered the film to be removed. An employee of China Business News was suspended for leaking the order.

Source: http://en.wikipedia.org/wiki/Under_the_Dome_%28film%29https://www.youtube.com/watch?v=MhIZ50HKIp0

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Respiration (3/5)

Respiration&Circulatory System

• Lung ventilation ispassive, via rib-cagemuscle & diaphragm;

Respiratory volume VTidal @ rest: 0.5L RateBreathing: 15/minTotal Vi´nhaled: 7.5L/min

Guyton & Hall, 1996

Aerosol Climate Tools ModelHealth

Ventilation Pattern can Affect Deposition: Respiratory Rate (breaths/minute)

increase respiratory rateincrease air velocity in the conducting airwaysenhance impactiondecrease sedimentation and diffusion

Tidal Volume (VT) volume of air entering or leaving the lung in a single breathIncreased VT results in deeper lung penetration by particlesPerson with increase VT will likely have a decreased respiratory rate. Thus, particles stay in lung longer making deposition more likely.

Source: Gyoton & Hall, 1996

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Respiration (4/5)

Respiration&Circulatory System

Hecht, 1994Bunde & Havlin, 1994

Aerosol Climate Tools ModelHealth

Filling of the lung happens in burst (avalanches) based on a power law distribution

Air bolus flux in the adult human male body. As the proximal end (trachea) the flow dynamics of the bolus fluctuates based on the respiration rate. With the branching out of the respiratory system branches in approximately 25 generations towards the distal end (towards the approx. 500 million alveoli), these fluctuations become smoothed along with the flow (reach a minimum). There, the air speed becomes shorter, and the retention times longer, which means, the deeper the gas molecules penetrates the lungs, the longer the air (incl. aerosols stay in a given region facilitating deposition via diffusion).[1]

The dynamic mechanism responsible for filling the lung involves "avalanches" or "bursts" of air that occur in all sizes-instead of an exponential distribution, one finds a power law distribution. The underlying cause of this scale-free distribution of avalanches is the fact that every airway inthe lung has its own threshold below which it is not inflated. Shown here is a diagram of the development of avalanches in the airways during airway opening. At first, almost all airways whose threshold value is smaller than the external pressure (red) are closed. Then the airway opening pressure increases until a second threshold is exceeded, and as a result all airways further up the tree whose thresholds are smaller become inflated (green). The airway opening pressure is successively increased until third, fourth, and fifth thresholds are exceeded (yellow, brown, and blue). The last threshold to be exceeded results in filling the airways colored violet; we notice that this last avalanche opens up over 25% of the total lung volume, thereby significantly increasing the total surface area available for gas exchange.[2]

Image: Shown here is the normalized amount of air ex/inhaled per breath at two different levels of activity (resting and light exercise). The deeper the gas molecules penetrate the lung the slower they become as the overall surface area / volume increases non-linearily.[1]

Source: [1] Hecht E (1994) Physics Calculus. Cole Publ. Pacific Grove (CA), USA; [1] AKPF (2000), p.7.[2] Bunde A, Havlin S (1994) Fractals in Science, 2nd ed. Springer, Berlin (FRG)

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Respiration (5/5)

Respiration&Circulatory System

Bronchioles

Bunde & Havlin, 1994Madl & Yip, 2003

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Aerosol Climate Tools ModelHealth

Fractal structures appear also in the human body; well known examples include the lung and the vascular system. Lungs exemplify this feature (see image). The surface area of a human lung is as large as a tennis court. The mammalian lung is made up of self-similar branches with many length scales, which is the defining attribute of a fractal surface. The efficiency of the lung is enhanced by this fractal property, since with each breath oxygen and carbon dioxide have to be exchanged at the lung surface. The structure of the bronchial tree has been quantitatively analyzed using fractal concepts. In particular, fractal geometry could explain the power law decay of the average diameter of the bronchial tube with the generation number, in contrast to the classical model which predicts an exponential decay.[2]

Image: Generation number on the abscissa (equivalent to depth level within the lung) versus overall volume.[1] Insert: The bronchi and bronchioles of the lung form a tree that has multiple generations of branchings. The small-scale branching of the airways look like branching at larger scales.[2]

Source: [1] Madl P, Yip M (2003) The Human Respiratory System. Seminar Report, PLUS, (AT)[2] Bunde A, Havlin S (1994) Fractals in Science, 2nd ed. Springer, Berlin (FRG)

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Anatomy (1/4)

Lung Casts

3-dimensional reconstruction of a human lung (from CT-images), right.

Lung Casts of Rodents (below)

Menache, 2004 Wikipedia, 2006

Aerosol Climate Tools ModelHealth

Silicone Rubber Casts: Silastic is injected into the airways, allowed to cure 24 hrs, then tissue is digested in sodium hydroxide

As the heart requires some space, the left lung lobe is usually smaller than the right lobe. This results in a asymmetrical bifurcation angle between right and left main bronchus – the angle to the right lobe poses less restriction to the flow of air than the left angle, thereby favouring ventilation of the right lobe. Hence inhaled particles are predominantly deposited in the right pulmonar lobe.

Each segment bronchus is divided into two so-called Rami subsegmentales. Up to a diameter of 1 mm, the bronchial wall is further divided and only up to this point does the bronchial wall contain cartilage in order to ensure that the bronchial tubes remain open and that the entire lung is ventilated. As division progresses, cup cells and ciliated epithelium decrease and a ring-shaped muscle system forms under the mucous membrane. Contraction of the latter can lead to spastic bronchial asthma.

Source: Menache M (2004); Introduction to the Anatomy of the Repsiratory Tract in Mammalia. PLUS lectures (AT)http://de.wikipedia.org/wiki/Lunge

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Anatomy (2/4)

Human Respiratory Tract:

Pons, 2005; Möller et al. 2007

Aerosol Climate Tools ModelHealth

The human bronchial tree. The tracheobronchial region (includes larynx, trachea, bronchi, bronchioles and terminal bronchioles) and the pulmonary region (espiratory bronchioles, alveolar ducts, alveoli). Not shown is the naso-pharyngeal region (anterior nares to larynx). [1]Scanning electron micrograph of the adult human lung showing alveolar duct with alveoli where gas exchange takes place.[2]

Epithelial cells: Respiratory epithelium is a type of epithelium found lining the upper and lower respiratory tracts, where it serves to moistenand protect the airways. It also functions as a barrier to potential pathogens and foreign objects, preventing infection by action of the ciliary escalator. The cilia of the respiratory epithelium beat in a concerted effort to move secreted mucus containing trapped foreign particles towards the oropharynx for either expectoration or swallowing to the stomach where the acidic pH helps to neutralize foreign material and micro-organisms. This system is collectively known as the ciliary escalator and serves two functions: to keep the lower respiratory tract sterile, and to prevent mucus accumulation in the lungs from drowning the organism.

Goblet cells: Mucus-secreting cells in which the nucleus is also closer to the base of the cell. The majority of the cell's cytoplasm is occupied by mucinogen granules, except at the bottom. Rough endoplasmic reticulum, mitochondria, the nucleus, and other organelles are concentrated in the basal portion. The apical plasma membrane projects microvilli to increase surface area for secretion.

Clara cells: are non-mucous and non-ciliated secretory cells found in the primary bronchioles of the lungs. Clara cells are dome-shaped and have short microvilli. One of the main functions of Clara cells is to protect the bronchiolar epithelium. They do this by secreting a small variety of products, including Clara cell secretory protein (CCSP) and a component of the lung surfactant. They are also responsible for detoxifying harmful substances inhaled into the lungs. Clara cells also multiply and differentiate into ciliated cells to regenerate the bronchiolar epithelium. Clara cells play an important defensive role, and they also contribute to the degradation of the mucus produced by the upper airways. The heterogeneous nature of the dense granules within the Clara cell's cytoplasm suggests that they may not all have a secretory function. Some of them may contain lysosomal enzymes, which carry out a digestive role, either in defense. Clara cells engulf airborne toxins and break them down via their their cytochrome P-450 enzymes present in their smooth endoplasmic reticulum; or in the recycling of secretory products. Clara cells are mitotically active cells. They divide and differentiate to form both ciliated and non-ciliated epithelial cells.

Pneumocytes: The lungs contain about 300 million alveoli, representing a total surface area of 70-90 (?) m2, each wrapped in a fine mesh of capillaries. The alveoli have radii of about 0.1 mm and wall thickness of about 0.2 µm. The alveoli consist of an epithelial layer and extracellular matrix surrounded by capillaries. In some alveolar walls there are pores between alveoli. There are three major alveolar cell types in the alveolar wall (pneumocytes):

• Type I cells that form the structure of an alveolar wall. They are very large, thin cell stretched over a very large area. This cell cannot replicate and is susceptible to a large number of toxic insults. Type I pneumocytes are responsible for gas exchange occurring in the alveoli.

• The Type II granular pneumocyte is a roughly cuboidal cell that is usually found at the alveolar septal junctions. Type II cells cover about 5% of the surface area of the alveoli, whereas type I pneumocytes (because of their squamous shape) cover 95% of the total area. Even though they cover less surface area, type II cells greatly outnumber type I cells. Type II cells are responsible for the production and secretion of surfactant, which lowers the surface tension of water thereby to increase the capability to exchange gases. The Type II pneumocyte can replicate in the alveoli and will replicate to replace damaged Type I pneumocytes.

• Type III cells that destroy foreign material, such as bacteria.The alveoli have an innate tendency to collapse (atelectasis) because of their spherical shape, small size, and surface tension due to water

vapor. Phospholipids, which are called surfactants, and pores help to equalize pressures and prevent collapse.

Source: [1] Möller W., Felten K., Sommerer K., Scheuch G., Meyer G., Häussinger K., Kreyling W.G. (2007). Prolonged retention of ultrafine carbon particles from the human airways and lung periphery. EAC, Salzburg – AT. [2] Pons G. (2005). Il Polmone. Anatomia Microscopica. Allessandria – ITA. Available online: http://www.mfn.unipmn.it/~pons/index_file/Page1171.htm

Image http://en.wikipedia.org/wiki/Clara_cellhttp://en.wikipedia.org/wiki/Alveoli

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Anatomy (3/4)

Lung Casts

Menache, 200423

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Aerosol Climate Tools ModelHealth

Allgemeines: Die Generationen 1-15 sind der bronchialen Lungenregion zugeordnet, die darüber liebenden Generationen sind dem alveolaren Lungenbereich (Gas-Austauschzone) zugeordnet. Dabei unterscheidet man noch die Unterbereiche AD (Generation 16-21), AS (Generation 22-25) und die AL bzw. alveolare Generation.[1]

Circle means airway is a terminal bronchiole

Architecture of the Tracheo-bronchial and Pulmonary Lung Compartments: Tracheo-bronchial compartment (zones 1- 16) with NO gas exchange in this compartment. Pulmonary compartment (zones 17-23), gas exchange occurs in this compartment. Circle means airway is a terminal bronchiole;

Image: Zonation of the Respiratory branching tree according to Yeh & Schum.[1]

Source: [1] Yeh HC, Schum GM, Duggan T (1979) Anatomic Models of the Tracheobronchial and Pulmonary Regions of the Rat. Anatom. Rec. Vol.195(3): 483-492

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Nano-Particle Deposition within the Human Respiratory Tract:

• Clearance via theOlfactory System

• Portal of entry for both nanoparticles & Viruses(e.g. miningitis, herpes)

• exerting ROS-activity inmitochondria (power-house of the cell)

• shortcutting the BBB;takes <1hr!

Oberdörster et al, 2004 & 2005

Inhalation (1/5)

Aerosol Climate Tools ModelHealth

with the nose being a very effective filter and deposition site for the smallest (<5 nm) NSP, and tracheobronchial and alveolar regions being mainly targeted by about 5 and 20 nm particles, respectively [7] …. Early studies (1940) concerned a large series of studies with 30-nm polio virus intranasally instilled into chimpanzees and rhesus monkeys revealed that the olfactory nerve and olfactory bulbs are, indeed, portals of entry to the CNS for intranasally instilled nanosized polio virus particles, which could subsequently be recovered from the olfactory bulbs .... 50-nm gold particles even crossed synapses in the olfactory glomerulus to reach mitral cell dendrites within 1hr after intranasal instillation .... nanoparticles in the olfactory bulb were no longer freely distributed in the cytoplasm but were preferentially located in mitochondria (excerting ROS-activity) [4] .... Neuronal transport of NSPs along sensory skin nerves is well established for herpes virus. After passing through the skin - especially broken skin - the viruses are transported retro- gradely along dendrites of sensory neurons to the dorsal root ganglion, where they remain dormant until a stress situation triggers anterograde translocation along the dendrites back to the skin [5] .... It was estimated that ~20% of the deposited amount translocated to the olfactory bulb within 7 days after the exposure [6] .... Healthy stray mongrel dogs exposed daily to high levels of ambient air pollutants (PM10 , ozone, etc.) in Mexico City + a control city. Persistent pulmonary inflammation and deteriorating olfactory and respiratory barriers was associated with the neuropathology observed in the brains of these highly exposed dogs [2]:

•expression of nuclear neuronal NF-kB and iNOS in cortical endothelial cells occurred at ages 2 and 4 weeks;

•subsequent damage included alterations of the blood–brain barrier (BBB),

•degenerating cortical neurons, apoptotic glial white matter cells, deposition of apolipoprotein E (apoE)-positive lipid droplets in smooth muscle cells and pericytes,

•nonneuritic plaques, and neurofibrillary tangles.

Neurodegenerative disorders such as Alzheimer’s may begin early in life with air pollutants playing a crucial role.

Naso-pharyngeal region with the olfactory system.[1]

Source: [1] after Tortora G.J., Grabowski S.R. (1996). Principles of Anatomy and Physiology, 8th ed. Harper Collins, Menlo Park, CA – USA.

Oberdörster G., Sharp Z., Atudorei V., Elder A., Gelein R., Kreyling W., Cox C. (2004). Translocation of Inhaled Ultrafine Particles to the Brain. Inhalation Toxicology, Vol. 16, No. 6-7: 437-445.

[4] Oberdörster G., Oberdörster E., Oberdörster J. (2005). Nanotoxicology: An Emerging Discipline Evolving from Studies of Ultrafine Particles. Environmental Health Perspectives Vol. 113 (7): 823-839; [4] p.832; [5] p.835;

Supplemental Material available online (http://ehp.niehs.nih. gov/members/2005/7339/supplemental.pdf [6] p.18; [7] p.22;

[2] Calderón-Garcidueñas L., Azzarelli B., Acuna H., Garcia R., Gambling T.M., Osnaya N., Monroy S., Tizapantzi M.R., Villarreal A. Air Pollution and Brain Damage. Tox Path. 2002; 30:373-389.s

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Nano-Particle Deposition within the Human Respiratory Tract:

• Nasal cavity revealsinter-subject variability.

Inhalation (2/5)

cut-A

cut-A

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Nasal Nasal cavity.flvcavity.flv Gray, 1918

Aerosol Climate Tools ModelHealth

Structure and functions of our nose: The nasal cavity is divided into two nearly equal halves by the nasal septum. This division increases the surface area of the organ and improves the filtering efficiency. The lining of the nasal cavity (mucous membrane) secretes a sticky substance called mucus which traps dust particles and microorganism. Cilia sweep away trapped dust and microorganisms by their movements. Multiple hairs crisscross the nasal cavity and contribute to its filtering function. The bridge of the nose is formed by bones and cartilages. The two nasal bones meet in midline forming the body walls. The frontal processes of the maxillary bones also contribute to the bony framework. The sidewalls of the nasal cavity are irregular due to bony projections (turbinates-superior middle and inferior) and are part of the ethmoid bone - the inferior nasal concha is a separate bone. The space below the superior turbinate is called superior meatus, that below the middle turbinate is called the middle meatus and the one below the inferior is called the inferior meatus. The bones forming the nasal boundaries contain air filled spaces called sinuses (singular=sinus). The sinuses open into the nasal cavity on the side walls in between the turbinates. The roof of the nasal cavity is narrow. It is formed by the sphenoid bone , horizontal plate of the ethmoid bone which has perforations, frontal and nasal bones from behind forwards. The fibers of the olfactory nerve which carry the sense of smell traverse through the perforations in the ethmoid bone to reach the brain where the impulses are interpreted by the brain. This part of the brain is called the olfactory lobe. It is situated on the lower surface of the brain. The lining of the superior nasal concha and the upper part of the nasal septum contain specialized cells called olfactory cells which can detect smell. Stimulation of these cells generates electrical impulses which are carried by the olfactory nerve to the brain.[1]

Nasal dimentions and particle deposition vary significantly among individuals. Nasal airway dimensions measured by K.H. Cheng et al. (1996) using MRI technique in 10 adults male were used in the current study to determine nasal and total deposition.

Source: [1 Gray’s Anatomy of the Human Body (1918). 20th ed. Warren H. Lewis. Lea & Febiger, Philadelphia – USA.

Tomographic pictures of nasal cross-sectional geometry by Montgomery et al. (1979)

http://nikas-culinaria.com/2006/07/03/molecular-gastronomy-101-biology-basics-part-1/

CT-scans: http://emedicine.medscape.com/article/875126-overview

Video: http://www.youtube.com/watch?v=Wh_7eP4iOwM

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Nano-Particle Deposition within the Human Respiratory Tract:

• .

Inhalation (2/5)

Aerosol Climate Tools ModelHealth

Shwe & Fujimaki, 2011

• NPs cross the blood–brain barrier (BBB),• different NPs have a specific neurotoxic and

neurobehavioral effects.• induction of oxidative stress in cells and• DEP-NPs produce extracellular superoxide

through NADPH oxidase

• Correlates with increasing incidence of neurodegenerative diseases

Humans are exposed to nanoparticles (NPs; diameter < 100 nm) from ambient air and certain workplaces. There are two main types of NPs; combustion-derived NPs (e.g., particulate matters, diesel exhaust particles, welding fumes) and manufactured or engineered NPs (e.g., titanium dioxide, carbon black, carbon nanotubes, silver, zinc oxide, copper oxide). Recently, there have been increasing reports indicating that inhaled NPs can reach the brain and may be associated with neurodegeneration. It is necessary to evaluate the potential toxic effects of NPs on brain because most of the neurobehavioral disorders may be of environmental origin. This review highlights studies on both combustion-derived NP- and manufactured or engineered NP-induced neuroinflammation, oxidative stress, and gene expression, as well as the possible mechanism of these effects in animal models and in humans.

Image: Potential pathways of nanoparticles-induced neurotoxicity: Potential pathways of nanoparticle-induced neurotoxicity. NPs deposited in the nasal mouse may enter the brain via olfactory bulb. Another portal of entry of NPs to brain is from systemic circulation. In the brain, NPs may induce inflammation, apoptosis and oxidative stress by releasing various mediators from microglia and astrocyte. Depends on production of toxic (e.g., NO, excitatory neurotranmsitters) or anti-toxic mediators (e.g., anti-inflammatory cytokines, neurotrophins), it may lead to neurodegeneration or neuroregeneration

Source: Win-Shwe TT, Fujimaki H (2011) Nanoparticles and Neurotoxicity. Int. J. Mol. Sci. Vol.12: 6267-6280; doi:10.3390/ijms12096267

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DEP-Lung deposits of a deceased patient

Prunault, 2015Oberdörster et al., 2005

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Nano-Particle Deposition within the Human Respiratory Tract:

Deposition (1/4)

Aerosol Climate Tools ModelHealth

arte arte –– DickeDicke Luft.mp4 Luft.mp4 (28:20(28:20--31:15)31:15)

In each of the three regions of the respiratory tract, significant amounts of a certain size of nanoparticles (1-100nm) are deposited. For example, 90% of inhaled 1-nm particles are deposited in the nasopharyngeal compartment, only approximately 10% in the tracheo-bronchial region, and essentially none in the alveolar region. On the other hand, 5-nm particles show about equal deposition of approxi- mately 30% of the inhaled particles in all three regions; 20-nm particles have the highest depo- sition efficiency in the alveolar region (~50%), whereas in tracheobronchial and naso- pharyngeal regions this particle size deposits with approximately 15% efficiency [3] ....

Graphics: Predicted fractional deposition of inhaled particles in the nasopharyngeal, tracheobronchial, and alveolar region of the human respiratory tract during nose breathing. Based on data from the International Commission on Radiological Protection (1994).

Image: Autopsy performed on an individual that died of non-aerosol related causes – one can clearly distinguish the natural coloration from the blackened patches loaded with combustion aerosols (prof. Paulo Saldiva University hospital San Paolo, Brazil).[2,4,5]

Source: Oberdörster G., Oberdörster E., Oberdörster J. (2005). Nanotoxicology: An Emerging Discipline Evolving from Studies of Ultrafine Particles; Environmental Health Perspective Vol. 113, No.7: 823-839, [3] p.829;

[2] Prunault D (2015) Dicke Luft – Wenn Staedte ersticken. Arte.tv

(https://www.youtube.com/watch?v=jd36m4m9Mfk)

[4] Fajersztajn L, Veras M, Barrozo LV, Saldiva P (2013) Air pollution: a potentially modifiable risk factor for lung cancer. Nature, Vol.(13): 674-678.[5] Prunault D (2015) Dicke Luft – Wenn Staedte ersticken. Arte.tv

(https://www.youtube.com/watch?v=jd36m4m9Mfk)

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Major Classes of Respirable Particles

• Coarse particles > 2.5 m (measured gravimetrically, e.g. TEOMor aerodynamically, e.g. Impactor)

• Fine particles 0.1-2.5 m (measuredgravimetrically, e.g. TEOMor optically, e.g. OPC)

• Nano particles 0.001-0.1 m (measuredelectro-optically, e.g. SMPSor electrostatically, e.g. FCE)

Deposition (2a/4)

Aerosol Climate Tools ModelHealth

Particle Deposition Mechanisms: The lung can be seen as a selective filter, into which the particle are stripped off the gas stream in different ways[1]. In the upper air ways (nose, throat) the air-speed is high enough to cause particles to deposit by impaction. Airway branching pattern favors non-uniform (focal) areas of deposition, especially when impaction is an important deposition mechanism.

Naso-pharyngeal: impaction, sedimentation, electrostatic (particles > 1 m)Tracheo-bronchial: impaction, sedimentation, diffusion (particles < 1 m)Pulmonary sedimentation, diffusion (particles < 0.1 m)

Image: the image depicts the air flow through the human respiratory system (excluding the extrathoraic region). Due to the higher flux through the bronchi and bronchioli, a pulsating pattern dominates, in which impaction as the primary deposition mechanism prevails. In the deeper lung – acinar to alveaolar regime, the flux is rather low giving way to sedimentation and ultimately to diffusion.

Source: [1] AKPF (2000), p.9-10.

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Major Classes of Respirable Particles

• Coarse particles > 2.5 m (measured gravimetrically, e.g. TEOMor aerodynamically, e.g. Impactor)

• Fine particles 0.1-2.5 m (measuredgravimetrically, e.g. TEOMor optically, e.g. OPC)

• Nano particles 0.001-0.1 m (measuredelectro-optically, e.g. SMPSor electrostatically, e.g. FCE)

Deposition (2b/4)

Aerosol Climate Tools ModelHealth

Particle Deposition Mechanisms: The lung has, like any filter, a certain range in which neither impaction nor diffusion predominates and typically occurs at around 300 nm.[2] Impaction: The particle’s momentum in air stream prevents it from making turn at a bifurcation (occurs in the following compartments naso-pharyngeal and tracheo-bronchial).Sedimentation: When gravitational forces on a particle are greater than air resistance and buoyancy, the particle will fall out of the air stream. As air moves deeper into the lung, air flow rate decreases. Sedimentation is proportional to:•particle time in airway•particle size and density•respiratory rate, i.e. breaths/minute(occurs in naso-pharyngeal, tracheo-bronchial, and pulmonary compartment). Diffusion: Particles have random motion, resulting in random impacts. The diffusion coefficient is: •inversely related to particle size•independent of particle density(diffusion occurs in the tracheo-bronchial and pulmonary compartment).Electrostatic Precipitation: A minor mechanism, but may be more important for freshly generated particles because these particles tend to have greater surface charge. Particle surface charge induces an “image” charge on lung surface.

Particle characteristic that affect deposition: Size: will effect location of deposition; sequential removal of particles as go through the lung.Particle hygroscopicity: If a particle is hygroscopic, it can pick up water in the humidified air of the lung. This will increase particle density and alter deposition.Particle surface charge: This will affect electrostatic deposition.

Source: [1] AKPF (2000), p.9-10.Madl P (2012) Exposure to Nano-Sized Particles and the Emergence of Contemporary Diseases with a Focus on Epigenetics, Ch.14. In: Khare M (ed) Air Pollution - Monitoring, Modelling and Health. InTech Publ. Croatia.

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Deposition (3a/4)

Aerosol Climate Tools ModelHealth

Particle Deposition within the Human Respiratory Tract:

Particle deposition Pattern:

• Superposition of two differentprocesses (Diffusion vs. Sedimentation/Impaction)

• According to lung regimes

Source: Madl, 2003

Particle Deposition Mechanisms: The lung has, like any filter, a certain range in which neither impaction nor diffusion predominates and typically occurs at around 300 nm.[2]

Impaction: The particle’s momentum in air stream prevents it from making turn at a bifurcation (occurs in the following compartments naso-pharyngeal and tracheo-bronchial). Sedimentation: When gravitational forces on a particle are greater than air resistance and buoyancy, the particle will fall out of the air stream. As air moves deeper into the lung, air flow rate decreases. Sedimentation is proportional to:•particle time in airway / • particle size and density / • respiratory rate, i.e. breaths/minute (occurs in naso-pharyngeal, tracheo-bronchial, and pulmonarycompartment). Diffusion: Particles have random motion, resulting in random impacts. The diffuion coefficient is: • inversely related to particle size / • independent of particle density (diffusion occurs in the tracheo-bronchial and pulmonarycompartment). Electrostatic Precipitation: A minor mechanism, but may be more important for freshly generated particles because these particles tend to have greater surface charge. Particle surface charge induces an “image” charge on lung surface.

Particle characteristic that affect deposition: Size: will effect location of deposition; sequential removal of particles as go through the lung. Particle hygroscopicity: If a particle is hygroscopic, it can pick up water in the humidified air of the lung. This will increase particle density and alter deposition.Particle surface charge: This will affect electrostatic deposition.

Source: [1] AKPF (2000), p.9-10.

Madl P (2012) Exposure to Nano-Sized Particles and the Emergence of Contemporary Diseases with a Focus on Epigenetics, Ch.14. In: Khare M (ed) Air Pollution - Monitoring, Modelling and Health. InTech Publ. Croatia.

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Deposition (3b/4)

Particle Deposition within the Human Respiratory Tract:

Particle deposition Pattern:

• Superposition of two differentprocesses (Diffusion vs. Sedimentation/Impaction)

• According to lung

• Alterations due to aerosol aging

Madl, 2012

Aerosol Climate Tools ModelHealth

secondary, older ETS

primary ETS

Pulmonary deposition. The graph is a superposition of diffusion (decending right half of the curve) and impaction & sedimentation (ascending left half of the curve) processes. Subimposed is a schematic view of the pulmonary domains, with the naso-pharyngeal and tracheo-bronchial pathway at the top and the brochiole and alveolar regime at the bottom, alongside the flow velocities of the in-/exhaled air. [1]

Image: Deposition of hygroscopic particles.[2]

Source: [1] modified after Yip M. (2003) Exposure Assessment in a Busway Canyon. MSc-thesis, Queensland University of Technology, Brisbane & Paris Lodron University of Salzburg. http://aleph.sbg.ac.at/F/target=%27_blank%27

[2] Madl P (2012) Exposure to Nano-Sized Particles and the Emergence of Contemporary Diseases with a Focus on Epigenetics, Ch.14. In: Khare M (ed) Air Pollution - Monitoring, Modelling and Health. InTech Publ. Croatia.

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Deposition (3c/4)

Aerosol Climate Tools ModelHealth

unit density

Particle Deposition within the Human Respiratory Tract:

Particle deposition Pattern:

• Superposition of two differentprocesses (Diffusion vs. Sedimentation/Impaction)

• According to lung

• Alterations due to aerosol aging

• hygroscopicity experiment (exp) &model (IDEAL) of

Winkler-Heil et al., 2007

Image: Deposition of hygroscopic particles.

Source: Winkler-Heil R., Ferron G.A., Hofmann W., (2007). Modelling deposition of hygroscopic particles in the human respiratory tract., European Aerosol Conference 2007, Salzburg, Abstract T08A014.

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Deposition (4/4)

Particle Deposition within the Human Respiratory Tract:

Hofmann, 2009

Aerosol Climate Tools ModelHealth

Deposition in extrathoracic, tracheobronchial and alveolar (acinar) regions using the IDEAL-code.[1]

Source: [1] Hofmann W. (2009). Deposition and clearance of inhaled particles in the human lung. Basic Aerosol Science, Summerschool, University of Vienna –AUT.

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Deposition (4/4)

Particle Deposition within the Human Respiratory Tract:

Prunault, 2015

Dicke Luft (25:00-26:00).mp4

Aerosol Climate Tools ModelHealth

DUring normal respiration microscopically small particles penetrate deep into our lungs and ultimately through our body. The larger ones of cathegory PM10 are held back in the nasal cavity by interaction with cilia and by impaction with the mucus. The particles of the category PM2.5 are even more dangerous as they penetrate into the alveoli where the gas exchange with the blood takes place. In addition, they can change their chemical structure much more easily and thereby unfold their toxic potential. There is no doubt that the smallest fraction, ie, nanoparticles (particles <PM1, below 1 μm), penetrate are cpable to even penetrate the membranes of our blood vessels and by doing so rush into all our organs (including heart and brain) where they ultimately exert their toxic effects.

Source: Prunault D (2015) Dicke Luft – Wenn Staedte ersticken. Arte.tv

(https://www.youtube.com/watch?v=jd36m4m9Mfk)

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Nano-Particle Clearance within the Human Respiratory Tract:

Major Pathways:• Olfactoric clearance; Neuronal C.• GIT-clearance; partial resorption via

intestinal mucosa;• Muco-cilliary Escalator clearance;• Alveolar C.; Lymphatic C., Blood Circ. C.

Oberdörster et al., 2005

Clearance (1/5)

Aerosol Climate Tools ModelHealth

The retention half-time of solid particles in the alveolar region based on this clearance mechanism is about 70 days in rats and up to 700 days in humans. The efficacy of this clearance mechanism depends highly on the efficiency of alveolar macrophages to “sense” deposited particles, move to the site of their deposition, and then phagocytize them. This process of phagocytosis of deposited particles takes place within a few hours, so by 6-12hr after deposition essentially all of the particles are phagocytized by alveolar macrophages, to be cleared subsequently by the slow alveolar clearance mentioned above. However, it appears that there are significant particle- size-dependent differences in the cascade of events leading to effective alveolar macrophage-mediated clearance. [3]

Jani et al. (1990) found a particle- sizeミdependent uptake of polystyrene particles (ranging from 50 to 3,000nm) by the GI mucosa. This uptake (6.6% of the adminis- tered 50nm, 5.8% of the 100nm nanoparticles, 0.8% of 1μm particles, and 0% for 3μm particles) [4]

Source: Oberdörster G., Oberdörster E., Oberdörster J. (2005). Nanotoxicology: An Emerging Discipline Evolving from Studies of Ultrafine Particles; Environmental Health Perspective Vol. 113, No.7: 823-839, [3] p.830; [4] p.834;

Supplemental Material available online (http://ehp.niehs.nih. gov/members/2005/7339/supplemental.pdf)

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Particle Clearance within the Human Respiratory Tract:

Bronchial Muco-Ciliar Escalator (BMCE) • pulmonary defense via mucus secretion and

clearance;• amount of mucus: b/w 10 & 100 mL per day

(healthy individuals);• BMCE operates in the tracheo-bronchial

region, up to generation 12, fading out at generation 16;

Wkipedia, 2006

Ryser et al., 2007

Clearance (2a/5)

TurkeyTurkey--trachea.movtrachea.mov

Aerosol Climate Tools ModelHealth

Nostril hair filters out larger particles. Those over 5.0 m diameter are stopped and deposited mainly in the nose and the throat. Smaller particles are stopped by mucous membranes that line the respiratory system and provide a surface to which the particles adhere. Dust is separated to damp surfaces, the mucous layer is moved by fine cilia constantly in the direction of the throat and a warning system with sensitive chemical sensors ensures that various mechanisms, ranging from coughs to sneezing that the lung remains at all cost free of particulates. The sizes and shapes of air passages effectively block some of the other particle fraction between 0.5-5.0m in diameter[1] by depositing them in bronchioles. They usually do not reach beyond the air ducts or bronchi, and are soon removed by ciliary’s action[2].

Most particles deposited in the bronchioles are removed by the cilia within two hours. Indeed, the bronchi’s and bronchioles cilia wave back and forth and move mucous along in a current that carries trapped the smaller particle fraction out of the respiratory system to the throat, where they are swallowed or ejected as sputum.

Respiratory tract secretions consist of mucus, surfactant, and periciliary fluid. The airway surface fluid is present as a bilayer, with a superficial gel or mucous layer and a layer of periciliary fluid interposed between the mucous layer and the epithelium. A thin layer of surfactant separates the mucous and periciliary fluid layers. The mucous layer extends from the intermediate airway to the upper airway and is approximately 2-10 m thick in the trachea. Airway mucus is the secretory product of the goblet cells and the submucosal glands. Sputum consists of lower respiratory tract secretions, nasopharyngeal and oropharyngeal material (including saliva), microorganisms, deposited aerosols and cells. Mucus clearance such as cough is critically important for airway hygiene.

Image: Scanning electron microscope image of lung trachea epithelium. There are both ciliated and on-ciliated cells in this epithelium. Note the difference in size between the cilia and the microvilli (on non-ciliated cell surface)

Source: [1] Stoker (1972), p.72. [2] idem, p.73. http://en.wikipedia.org/wiki/Ciliahttp://de.wikipedia.org/wiki/FlimmerepithelRyser M., Burn A., Wessel Th., Frenz M.,RičkaJ. 2007. Functional imaging of mucociliary phenomena -High-speed digital reflection contrast microscopy. Journal European Biophysics Journal. Vol.37 (1): 35-54. http://www.springerlink.com/content/054g726137870258/249_2007_Article_153_ESM.html

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Particle Clearance within the Human Respiratory Tract:

Bronchial Muco-Ciliar Escalator (BMCE) • pulmonary defense via mucus secretion and

clearance;• amount of mucus: b/w 10 & 100 mL per day

(healthy individuals);• BMCE operates in the tracheo-bronchial

region, up to generation 12, fading out at generation 16;

Madl, 2012

Rubin 2002

Clearance (2b/5)

TurkeyTurkey--trachea.movtrachea.mov

Aerosol Climate Tools ModelHealth

Image: Lung (350 week long exposure to 1.5 mg/m3). Schematic and microscopic image of mucociliary escalator transporting macrophages containing diesel exhaust particles (DEPs) through bronchial tubings (top).[1]

Bottom: Ciliary clearance versus cough clearance. Airway epithelium, cilia, surfactant and mucus layer during normal operation of cilia *left). Hypersecretion and cough clearance in the presence of ciliary dysfunction.[2]

Source: [1] Madl P (2012) Exposure to Nano-Sized Particles and the Emergence of Contemporary Diseases with a Focus on Epigenetics, Ch.14. In: Khare M (ed) Air Pollution - Monitoring, Modelling and Health. InTech Publ. Croatia - adapted from Vostal JJ (1980). Health aspects of diesel exhaust particulate emissions. Bull N.Y. Acad.Med., Vol.56(9): 914-934.[2] Rubin BK (2002) Physiology of Airway Mucus Clearance. Respiratory Care, Vol.47(7): 761-768.[3] Ryser M., Burn A., Wessel Th., Frenz M.,RičkaJ. 2007. Functional imaging of mucociliary phenomena - High-speed digital reflection contrast microscopy. Journal European Biophysics Journal. Vol.37 (1): 35-54.

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Particle Deposition within the Human Respiratory Tract:

• Clearance via theBronchial Tissue

Clearance (3/5)

McWilliam et al, 2000

By-stander effect(indirect collateral damage of decaying isotopic (β) particle -particularly with multipotent stem-cells)

Aerosol Climate Tools ModelHealth

Schematic drawing of airway epithelial barrier with macrophages and dendritic cells, exposed to a nano-particle.[1]

Source: [1] McWilliam A.S., Holt P.G., Gehr P. (2000) Dendritic cells as sentinels of immune surveillance in the airways. In: Particle-Lung Interaction. Lung Biology in Health and Disease, 143: 473-489.

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Nano-Particle Clearance within the Human Respiratory Tract:

Lung Lavage

• Up to 80% of nano-particles remain trapped in the lung;

• cleared off via lymphatic or circulatory system and flushed throughout the organism;

• w/n 30 min after inhalation these particles are found in the interstitial region;

Oberdörster et al., 2005

Clearance (4a/5)

Aerosol Climate Tools ModelHealth

used sponges as a visual analogy: trapped small-sized particle after regular use (left) vs. exposure to coarse-sized particles (right);

Approximately 20% of nanosized 15-20-nm and 80-nm particles could be lavaged with the macrophages. In effect, approximately 80% of the UFPs were retained in the lavaged lung after exhaustive lavage, whereas approximately 20% of the larger particles >0.5μm remainedin the lavaged lung .... This indicates that NSPs either were in epithelial cells or had further translocated to the interstitium .... This was also shown in studies with ultra-fine PTFE fumes: shortly after a 15-min exposure, the fluorine-containing particles could be found in interstitial and submucosal sites of the conducting airways as well as in the intersti- tium of the lung periphery close to the pleura. Such interstitial translocation represents a shift in target site away from the alveolar space to the intersti- tium, potentially causing direct particle-induced effects there .... Within 30min postexposure, they found large amounts of these 30-nm gold particles in platelets of pulmonary capillaries; the researchers suggested that this is an elimination pathway for inhaled particles that is significant for transporting the smallest air pollutant particles - in particular, particles of tobacco smoke - to distant organs. They also hypothesized that this might predispose to platelet aggregation with formation of microthrombi atheromatous plaques ....

Image: In vivo retention of inhaled nanosized and larger particles in alveolar macrophages (A) and in exhaustively lavaged lungs (epithelial and interstitial retention; B) 24hr postexposure. The alveolar macrophage is the most important defense mechanism in the alveolar region for fine and coarse particles, yet inhaled singlet nanoparticles are not efficiently phagocytized by alveolar macrophages.

Source: Oberdörster G., Oberdörster E., Oberdörster J. (2005). Nanotoxicology: An Emerging Discipline Evolving from Studies of Ultrafine Particles; Environmental Health Perspective Vol. 113, No.7: p.830-831;

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Nano-Particle Clearance within the Human Respiratory Tract:

Lung Lavage

• Up to 80% of nano-particles remain trapped in the lung;

• cleared off via lymphatic or circulatory system and flushed throughout the organism;

• w/n 30 min after inhalation these particles are found in the interstitial region;

• nano-particle (DEP) blackened rat lung

Vostal, 1980

Clearance (4b/5)

Aerosol Climate Tools ModelHealth

add Sao Paolo lung

The gross appearance of the respiratory system in experimental animals after 35 weeks of exposure to the highest concentration of 1.5 mg/m3. The black appearance of the exposed lung indicates clearly that the exposure resulted in a high level contamination of the respiratory system by diesel particulates (diesel exhaust particles, DEP). In spite of the gross appearance, microscopic examination of animals exposed to high levels of particulate concentration does not show any free diesel particulates in the alveoli or deposited in the epithelium.

Image: Exposed lung (35 week long exposure to 1.5 mg/m3) on the left, control lung from a filtered air exposed animal on the right.

Source: Vostal JJ (1980). Health aspects of diesel exhaust particulate emissions. Bull N.Y. Acad.Med., Vol.56(9): 914-934..

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Oberdörster et al., 2005

Particle Deposition within the Human Respiratory Tract:

• Clearance via Alveoli

Donaldson et al, 1998; Geiser et al., 2005

Clearance (5/5)

Aerosol Climate Tools ModelHealth

Clearance in the deeper lungs:

Nano-particles (less than 0.5 m in diameter) enter the human body almost exclusively by the way of the respiratory system – they do in fact reach the alveolar regime and settle there. The removal of such particles from these areas is less rapid and less complete than in the upper respiratory region. Some of the particles retained in the alveoli are absorbed into the bloodstream. Nano-particles can exert a toxic effect in three different ways:[1]

Hydrophobic aerosols easily penetrate the alveolar regime [2]. As there are no nerve receptors within the alveoli, they do not signal the brain of inflammatory reactions; i.e. pain. One can easily inhale large quantities of aerosols without feeling really any effects. Once there, these aerosols are transferred to the blood system where they can easily spread and affect tissues and target organs away from the lung system.

Diesel engine exhaust for example, exhibit sizes that are 100s of times smaller than the natural types of dust. Such nano-aerosols discourages the fine defense mechanisms of the lung: these tiny particles penetrate past the protected regimes of the bronchioles to reach the alveolar section and stay there for months or even years[3].

The human body is not without defensive mechanism for this cilia-less area. Mobile devouring cells (macrophages) digest these particles are (phagocytes) and remove them in a timely manner so that these ultrafine particles do penetrate the gas exchange barrier[4]. The only factor regulating this final barrier is the concentration of nano-particle load. The risks that this particle fraction crosses over into the blood vessel system or the lymphatic systems and thus spreading throughout the entire organism is quite high. After spreading though the entire organism, acute irritating effects can be released, for example, an increase of the blood viscosity or influence of the heart rhythm. On the other hand if these particles do not cross over or are digested by macrophages, they settle themselves into the lung fabrics, where they constantly irritate the lung epithelium[5]. It is known that Diesel soot – among other ailments - induces coronary heart disease, heart attacks.

Different forms of caveolae and cellular tight junctions function as translocation mechanisms across cell layers. Depending on particle surface chemistry, NSPs have been shown to transcytose across alveolar type I epithelial cells and capillary endothelial cells (Table 4), but not via cellular tight junctions in the healthy state (A). However, in a compromised or disease state (e.g., endotoxin exposure; B) translocation across widened tight junction occurs as well (Heckel et al. 2004). This indicates that assessing potential effects of NSPs in the compromised state is an important component of nanotoxicology. Adapted from Cohen et al. (2004). [6]

PAM-mediated removal from the lungs away towards other excretory organs.[7] Inlet: PAM loaded with 80 nm particle. [8]

Source: [1] Stoker, (1972), p.73. / [2] AKPF (2000), p.11. / [3] AKPF (2000), p.7. / [4] AKPF (2000), p.7. / [5] AKPF (2000), p.8.

[7] Donaldson K. Li X.Y., MacNee W. (1998). Ultrafine (Nanometre) Particle Mediated Lung Injury. Journal of Aerosol Science, Vol. 29, No. 5-6: 553-556.

[8] Geiser M., Rothen-Rutishauser B.,Kapp N., Schürch S., Kreyling W., Schulz H., Semmler M., Hof V., Heyder J., Gehr P. (2005).Ultrafine Particles Cross Cellular Membranes by Nonphagocytic Mechanisms in Lungs and in Cultured Cells. Environmental Health Perspectives Vol.113, No. 11: 1555-1560. [6] Gumbleton M. 2001. Caveolae as potential macromolecule trafficking compartments within alveolar epithelium. Adv Drug Deliv Rev 49:281-300.

Oberdörster G., Oberdörster E., Oberdörster J. (2005). Nanotoxicology: An Emerging Discipline Evolving from Studies of Ultrafine Particles. Environmental Health Perspectives Vol. 113 (7): 823-839

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Transmembrane Pathways (1/6)

Endocytosis via lipid raft formations;

Raft serve as• tools in cell-to-cell bio-

communication;• can be used therapeutically;• But are also subject to

nanoparticle interference;

Mulcahy et al., 2014

Aerosol Climate Tools ModelHealth

Extracellular vesicles (EVs) are small vesicles released by donor cells that can be taken up by recipient cells. Despite their discovery decades ago, it has only recently become apparent that EVs play an important role in cell-to-cell communication. EVs can carry a range of nucleic acids and proteins which can have a significant impact on the phenotype of the recipient. For this phenotypic effect to occur, EVs need to fuse with target cell membranes, either directly with the plasma membrane or with the endosomal membrane after endocytic uptake. EVs are of therapeutic interest because they are deregulated in diseases such as cancer and they could be harnessed to deliver drugs to target cells. It is therefore important to understand the molecular mechanisms by which EVs are taken up into cells. This comprehensive review summarizes current knowledge of EV uptake mechanisms. Cells appear to take up EVs by a variety of endocytic pathways, including clathrin-dependent endocytosis, and clathrin-independent pathways such as caveolin-mediated uptake, macropinocytosis, phagocytosis, and lipid raft-mediated internalization. Indeed, it seems likely that a heterogeneous population of EVs may gain entry into a cell via more than one route. The uptake mechanism used by a given EV may depend on proteins and glycoproteins found on the surface of both the vesicle and the target cell. Further research is needed to understand the precise rules that underpin EV entry into cells.

Image: Pathways shown to participate in EV uptake by target cells. EVs transport signals between cells. EVs have been shown to be internalized by cells through phagocytosis, clathrin- and caveolin-mediated endocytosis. There is also evidence to support their interaction with lipid rafts resulting in EV uptake. Lipid rafts are involved in both clathrin- and caveolin-mediated endocytosis. EVs can be internalized by macropinocytosis where membrane protrusions or blebs extend from the cell, fold backwards around the EVs and enclose them into the lumen of a macropinosome; alternatively EVs are macropinocytosed after becoming caught in membrane ruffles. EVs may also deliver their protein, mRNA and miRNA cargo by fusion with the plasma membrane. Alternatively, intraluminal EVs may fuse with the endosomal limiting membrane following endocytosis to enable their EV contents to elicit a phenotypic response.

Source: Mulcahy LA, Pink RC, Carter DR. (2014) Routes and mechanisms of extracellular vesicle uptake. J Extracell Vesicles. Vol.3.v3.24641.

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Transmembrane Pathways (2/6)

Endocytosis via lipid raft formations;

Raft forms by docking of• Intracellular proteins • intracellular proteins

onto membrane, • enabling trans-membrane

proteins to slide through

El-Sayed & Harashima 2013

Aerosol Climate Tools ModelHealth

These rafts include: (i) proteins attached to glycosylphosphatidylinositol anchors (GPI-AP) that are inserted in the outer leaflet of the membrane, (ii) proteins attached to the inner leaflet of the membrane, (iii) transmembrane proteins that have a cytoplasmic domain in addition to an outer domain that is exposed on the cell surface.

Image: Schematic presentation of the cell membrane domains. The cell membrane contains clusters of lipids, lipid rafts, which exist within the non-raft region, a generally disordered lipid milieu. These lipid rafts are small (10–200nm), heterogeneous, highly dynamic domains. Sphingolipids with long, unsaturated hydrocarbon chains associate with cholesterol within such domains. In addition, these rafts include: (i) pro- teins attached to glycosylphosphatidylinositol anchors (GPI-AP) that are inserted in the outer leaflet of the membrane, (ii) proteins attached to the inner leaflet of the membrane, (iii) transmembrane proteins that have a cytoplasmic domain in addition to an outer domain that is exposed at the cell surface.

Source: El-Sayed A, Harashima H. (2013) Endocytosis of gene delivery vectors: from clathrin-dependent to lipid raft-mediated endocytosis. Mol Ther. Vol.21(6):1118-1130.

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Transmembrane Pathways (3/6)

Endocytosis via lipid raft formations;

• Caveolae “for little caves”, flask-shaped, & 60–80 nm in diameter;

• Flotillin, (no caevolin present) but otherwise similar to the above;

• GRAF1, sensitive to choles-terol depletion, 50–80 nm

• Arf6 sensitive to histocompa-tibility complexes (MHC-1)

• RhoA, specific to IL-2 receptors of T-cells

El-Sayed & Harashima 2013

Aerosol Climate Tools ModelHealth

The ideal nonviral vector delivers its nucleic acid cargo to a specific intracellular target. Vectors enter cells mainly through endocytosis and are distributed to various intracellular organelles. Recent advances in microscopy, lipidomics, and proteomics confirm that the cell membrane is composed of clusters of lipids, organized in the form of lipid raft domains, together with non-raft domains that comprise a generally disordered lipid milieu. The binding of a nonviral vector to either region can determine the pathway for its endocytic uptake and subsequent intracellular itinerary. Given this model of the cell membrane structure, endocytic pathways should be reclassified in relation to lipid rafts. In this review, we attempt to assess the currently recognized endocytic pathways in mammalian cells. The endocytic pathways are classified in relation to the membrane regions that make up the primary endocytic vesicles. This review covers the well-recognized clathrin-mediated endocytosis (CME), phagocytosis, and macropinocytosis in addition to the less addressed pathways that take place in lipid rafts. These include caveolae-mediated, flotillin-dependent, GTPase regulator associated with focal adhesion kinase-1 (GRAF1)-dependent, adenosine diphosphate-ribosylation factor 6 (Arf6)-dependent, and RhoA-dependent endocytic pathways. We summarize the regulators associated with each uptake pathway and methods for interfering with these regulators are discussed. The fate of endocytic vesicles resulting from each endocytic uptake pathway is highlighted.

Image: Schematic presentation of the endocytic pathways that take place in lipid raft domains of the cell membrane and some of their key regulators. Caveolae-mediated endocytosis takes place in lipid rafts that are enriched in caveolin and the resulting vesicles are stabilized by cavin. Scission of the vesicles from the cell membrane takes place via the action of dynamin. Similarly, flotillin-dependent endocytosis results in the uptake of the cargo into vesicles enriched in flotillins shortly after flotillins become phosphorylated by Fyn kinase. GRAF1-dependent endocytosis is mediated by the complementary role of Cdc42 with Arf1 in meditating actin polymerization. Actin and GRAF1 then drive the for- mation of the endocytic vesicles. Similarly, Arf6 mediates the formation of the Arf6-dependent endocytic vesicles in addition to Rac1 which plays a role in scission of these vesicles. RhoA-dependent endocytic vesicles are formed via the function of RhoA and actin and vesicles formed are pinched off through the action of dynamin.

Source: El-Sayed A, Harashima H. (2013) Endocytosis of gene delivery vectors: from clathrin-dependent to lipid raft-mediated endocytosis. Mol Ther. Vol.21(6):1118-1130.

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Transmembrane Pathways (4/6)

Endocytosis via lipid raft formations;

Macro-pinocytosis• Actin-mediated, thus• occur anywhere

(unspecific)along the membrane surface;

• External triggers induce and promote cytosolic actinpolymerization(!)

El-Sayed & Harashima 2013

Aerosol Climate Tools ModelHealth

Macropinocytosis starts with ruffling that can be non-specific and spreads over the entire cell membrane due to a global increase in actin polymerization.68 These planar membrane ruffles may return back to the cell surface without forming macropinosomes, or they may fold and fuse with the plasma membrane to form macropinosomes,

Image: Schematic presentation of the stages of ruffling during macropinocytosis. Macropinocytosis starts with an increase in actin polymerization which results in cell membrane ruffling. The planar membrane ruffles may fold and fuse with the plasma membrane to form macropinosomes. In the cytosol, the macropinosome loses the actin fila- ments on its surface. Actin polymerization is inhibited in the presence of cytochalasin D while ruffling is inhibited by amiloride. Amiloride inhibits Na+/H+ exchanger protein resulting in protons being accumulated in the forming ruffle. The accumulating protons inhibit Cdc42 and Rac1 via acidification resulting in the suppression of ruffling. The closure of macropinosome can be inhibited by wortmannin.

Source: El-Sayed A, Harashima H. (2013) Endocytosis of gene delivery vectors: from clathrin-dependent to lipid raft-mediated endocytosis. Mol Ther. Vol.21(6):1118-1130.

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Transmembrane Pathways (5a/6)

Clathrin scaffolding at the plasma membrane;

Lattice-like coat formation for:• phagocytosis of prokaryotes• intracellular trafficing (e.g.

b/w Golgi & endosomes)

12 pentagons shape 1 clathrid(70-100 nm, some even 200 nm in diameter) Kirchhausen et al, 2014

El-Sayed & Harashima 2013

Aerosol Climate Tools ModelHealth

Clathrin is a molecular scaffold for vesicular uptake of cargo at the plasma membrane, where its assembly into cage-like lattices underlies the clathrin-coated pits of classical endocytosis. This review describes the structures of clathrin, major cargo adaptors, and other proteins that participate in forming a clathrin-coated pit, loading its contents, pinching off the membrane as a lattice-enclosed vesicle, and recycling the components. It integrates as much of the structural information as possible at the time of writing into a sketch of the principal steps in coated-pit and coated-vesicle formation.

Image: Assembly and disassembly of a canonical, endocytic clathrin-coated pit. AP2 adaptor complexes, associated at the membrane with PtdIns(4,5)P2 (PIP2), recruit clathin triskelions to initiate lattice assembly. Stable growth and lattice closure require endocytic accessory proteins (Eps15, epsin, FCHo1/2, intersectin, CALM/AP180; some of which are also ancillary cargo adaptors). Dynamin, assisted by actin polymerization when the membrane is under tension, drives membrane scission and coated-vesicle release. Hsc70, recruited by the J-domain protein auxilin, mediates clathrin uncoating and release of a free vesicle, primed to fuse with a target membrane. Text beneath the diagram indicates the overall timescale and the stages at which various components appear to function. Short arcs, Clathrin triskelions; T shapes, AP2.

Insert: A D6 clathrin coat. (A) Map from electron microscopy of a coat with bound auxilin (clathrin-binding and J-domain fragment) and Hsc70, showing the outer contour of clathrin density (blue), auxilin (red), and Hsc70 (green). (From Xing et al. 2010; with permission from the authors.) (B) Full Ca representation of the heavy chains in a coat (blue), with ribbon representation of light chain s-helical region (yellow) and volume outline of auxilin clathrin-binding and J-domain fragment (red) (Fotin et al. 2004a,b).

Source: Kirchhausen T, Owen D, Harrison SC.(2014) Molecular structure, function, and dynamics of clathrin-mediated membrane traffic. Cold Spring Harb Perspect Biol. Vol.6(5): a016725.

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Clathrin scaffolding at the plasma membrane;

Lattice-like coat formation for:• phagocytosis of prokaryotes• intracellular trafficing (e.g.

b/w Golgi & endosomes)

• GTPase mediates membrane fission

Sundborger & Hinshaw, 2014

Aerosol Climate Tools ModelHealth

Dynamin is a large GTPase that mediates plasma membrane fission during clathrin-mediated endocytosis. Dynamin assembles into polymers on the necks of budding membranes in cells and has been shown to undergo GTP-dependent conformational changes that lead to membrane fission in vitro. Recent efforts have shed new light on the mechanisms of dynamin-mediated fission, yet exactly how dynamin performs this function in vivo is still not fully understood. Dynamin interacts with a number of proteins during the endocytic process. These interactions are mediated by the C-terminal proline-rich domain (PRD) of dynamin binding to SH3 domain-containing proteins. Three of these dynamin-binding partners (intersectin, amphiphysin and endophilin) have been shown to play important roles in the clathrin-mediated endocytosis process. They promote dynamin-mediated plasma membrane fission by regulating three important sequential steps in the process: recruitment of dynamin to sites of endocytosis; assembly of dynamin into a functional fission complex at the necks of clathrin-coated pits (CCPs); and regulation of dynamin-stimulated GTPase activity, a key requirement for fission.

Image: Dynamin‘s role in clathrin-mediated endocytosis migrates through the sequential steps of recruitment, assembly and fission. The SH3 domain-containing binding partners intersectin, amphiphysin and endophilin control these steps and thus promote dynamin-mediated fission. Intersectin acts as a scaffold for dynamin and other endocytic proteins, ensuring its recruitment to sites of endocytosis. Amphiphysin and endophilin are BIN/amphiphysin/Rvs (BAR) proteins and generate constriction of the clathrin-coated pit neck that promotes the dynamin assembly into a polymer. The assembled dynamin polymer undergoes GTP-dependent conformational changes that lead to super-constriction of the neck, the bundle signaling element (BSE) powerstroke, re-arrangement of the pleckstrin homology (PH) domain and polymer disassembly all leading to plasma membrane fission.

Source: Sundborger AC, Hinshaw JE (2014). Regulating dynamin dynamics during endocytosis. F1000Prime Rep. Vol.1;6:85.

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Clathrin scaffolding at the plasma membrane;

Scope of Clathin-Coated Vesicles

• Falling pH-inside vesicle ‘predigests’ load and enables diffferentiation b/w usefulland unusfull cargo (pH 4.5)

• means to recycle metabolites

El-Sayed & Harashima 2013

Aerosol Climate Tools ModelHealth

The Clathrin-coated pit is followed by the fusion of these uncoated vesicles with each other and with various vesicles from other endocytic pathways to form an early endosome. In the early endosome, the vacuolar adenosine triphosphatase starts pumping protons into the endosome, resulting in its acidification to a pH range 6.1–6.8. During acidification, the cargos inside the endosome are sorted and some of the cargos are recycled back to the cell exterior through recycling endosomes. Acidification of the early endosome is a prerequisite for the sorting of various cargos. The unrecycled cargos remain in the endosome while the endosome continues acidification to mature into a late endosome, with the pH reaching 4.8–6. This is followed by fusion between the late endosome and a lysosome to form an endolysosome where digestive degradation of the cargo takes place at pH ~4.5. Therapeutic cargos delivered through the CME should be equipped with a device that allows them to escape from the endosome before reaching the stage of lysosomal degradation.

Image: Intracellular fate of clathrin-mediated endocytosis (CME). In CME, clathrin is recruited from the cytosol into the inner leaflet of the cell membrane to form the clathrin-coated pit. The pit then is pinched off, to form a clathrin-coated vesicle that then begins to lose its clathrin coat in the cytosol. This is followed by the fusion of these uncoated vesicles with each other and with various vesicles from other endocytic pathways to form an early endosome. The early endosome becomes acidified to a pH in the range 6.1–6.8 and during acidification, the cargos inside the endosome are sorted and some of the cargos are recycled back to the cell exterior through recycling endosomes. The endosome then matures into a late endosome, with the pH reaching 4.8–6. This is followed by fusion between the late endosome and a lysosome to form an endolysosome where digestive degradation of the cargo takes place at a pH of ~4.5.

Source: El-Sayed A, Harashima H. (2013) Endocytosis of gene delivery vectors: from clathrin-dependent to lipid raft-mediated endocytosis. Mol Ther. Vol.21(6):1118-1130.

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Particle Solubility• High S.: rapid assimilation - particularly in alveolar region -localized effects (irritation & inflammation); systemic responses over very short time periods; e.g. adsorbed radionuclides, chemical solvents, etc.

•Low S.: gradual release - low-soluble agents exert extended irritation; i.e.: adsorption of chemical agents (NOX, SO2 etc.), radionuclides onto particles can lead to health effects at levels normally considered safe.

•Very low S.: health effects associated with physical characteristics that impair clearance; i.e. regard particle shape-factor (fibrousaerosols).

Baron & Willeke, 2001

Aerosol Climate Tools ModelHealth

Biol. Reactivity: Although particle aerodynamic diameter dominates deposition within the respiratory tract, the subsequent effect on health is a combination of physical particle characteristics and biological response. On deposition, the body may react to the chemical substances contained within the particle, interact with the particle surface, or be influenced by physical parameters such as size and morphology.[1]

Highly soluble particles and droplets will be rapidly assimilated by the body, particularly in the alveolar region. Local effects, such as irritation and inflammation, and systemic responses may become manifest over very short time periods. The gradual release of agents from low-solubility particles will have a much longer response time.

Low-solubility particles may also act as vectors for the transport of high-solubility solids, liquids, and gases present as thin surface layers, thus leading to a response not indicated by the bulk aerosol particle properties alone. For example, adsorption of nitrogen oxides and sulfur dioxide onto particles can lead to health effects at levels normally considered safe.

Very low-solubility particles are more likely to have health effects associated with their physical characteristics. Lung overload phenomena are associated with the physical limitations of the lungs' clearance mechanisms as opposed to chemical interactions with the deposited particles (Morrow, 1994). Particle shape is a factor for fibrous aerosols …. It also influences available surface area, which may be related to toxicity through surface interactions (Lison et aI., 1997) or increased solubility. Where open agglomerates of particles exist, including those resulting from combustion (such as diesel exhaust particulates), metal processing, welding, or fine powder production, the aerosol may have a very high specific surface area and be formed from particles able to penetrate to the alveolar region.

In some fine powders, including ultrafine titanium dioxide, carbon blacks, and fumed silicas, specific surface areas in excess of 2·E5m2/kg [200m2/g] are achieved among particles with aerodynamic diameters less than 4 mm. In comparison, an aerosol of spherical particles 4mm in diameter and with unit density would have a specific surface area of 1.5 x 103m2/kg [1.5m2/g]. There is evidence that for some low-solubility materials toxic response may be associated with surface area or even particle number (Oberdorster et al., 1994; Lison et al., 1997; Donaldson et al., 1998).

Source: B.A.Baron & K.Willeke (2001). Aerosol Measurement Principles, Techniques and Applications, 2nd e.d; [1] p.781-782;

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Coho: Oncorhynchus kisutch;

Pink: O.gorbuscha;

Rainbow: O.mykiss

Epi

gene

tic

fact

or

Aerosol Climate Tools ModelHealth

Diesel fuel is a complex mixture of normal, branched, and cyclic alkanes (60 to > 90% by volume; hydrocarbon chain length, usually between C9 and C30); aromatic compounds, especially alkylbenzenes (5-40% by volume); and small amounts of alkenes (0-10% by volume) obtained from the middle-distillate, gas-oil fraction during petroleum separation. Benzene, toluene, ethylbenzene, and xylenes and polycyclic aromatic hydrocarbons (PAHs), especially naphthalene and its methyl-substituted derivatives, may be present at levels of parts per million in diesel fuel. The sulfur content of diesel fuels depends on the source of crude oil and the refinery process. It is regulated by law in a number of countries and is usually between 0.05 and 0.5 weight percent. Additives are used to influence the flow, storage, and combustion of diesel fuel, to differentiate products, and to meet trademark specifications. At room temperature, diesel fuels are generally moderately volatile, slightly viscous, flammable, brown liquids with a kerosene-like odour. The boiling ranges are usually between 140 and 385°C (> 588°C for marine diesel fuel); at 20°C, the density is 0.87-1.0 g/cm3 and the water solubility is 0.2-5 mg/litre. The quality and composition of diesel fuel influence the emissions of pollutants from diesel engines considerably. Important variables are ignition behaviour (expressed in terms of cetane number), density, viscosity, and sulfur content. The specifications of commercial diesel fuel differ considerably in different countries.

Heating fuels and some kerosene jet fuels produced during the refining process may have a composition similar to that of diesel fuel, although with different additives. Biological data on these mixtures have therefore also been taken into account in the assessments of toxicity and ecotoxicity.

Owing to the complexity of the diesel fuel mixture, there is no specific analytical method, and the analytical techniques used in most environmental assessments are suitable only for measuring the total petroleum hydrocarbon mixture. The methods consist of preliminary solvent extraction, a clean-up procedure to remove naturally occurring hydrocarbons, and subsequent detection by gravimetry, infrared spectroscopy or gas chromatography. Neither the gravimetric nor the infrared technique provides useful qualitative or quantitative information on contaminants and can thus be used only for screening. Gas chromatography combined with detection techniques such as flame ionization and mass spectrometry is the standard procedure for analysing environmental samples. Many other methods are available for the analysis of individual hydrocarbons in diesel fuels.

Image: Acute toxicity of diesel fuel to Daphnia (Cladocera), chironomid larvae (insects), and the mollusc Viviparus bengalensis (Gastropoda)

Source: Rosner g. (1996) Environmental Health Criteria 171 - Diesel Fuel and Exhaust Emissions. United Nations Environment Programme (UNEP). International Labour Organisation, World Health Organization (WHO), Iinternational Programme on Chemical Safety. ISBN 92 4 157171 3; p.9; 37;

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In-Vitro studies:

ALI (air liquid interface)• mimics lung (sumberged mimics gut)

A: phagocytosis (actin-based)B: macro-pinocytosis (-”-)C: Clathrin-mediated (GTPase dynamin)D: Clathrin/Caveolae-independentE: Caveolae-mediated (caveolin/dynamin)F: Duffusion

Paur et al., 2011

Submerged exposure vs ALI-exposure

Aerosol Climate Tools ModelHealth

In this consensus document from a workshop on in-vitro cell systems for nanoparticle toxicity testing1 an overview is given of the main issues concerning exposure to airborne nanoparticles, lung physiology, biological mechanisms of (adverse) action, invitro cell exposure systems, realistic tissue doses, risk assessment and social aspects of nanotechnology. The workshop participants recognized the large potential of in-vitro cell exposure systems for reliable, high-throughput screening of nanoparticle toxicity. For the investigation of lung toxicity, a strong preference was expressed for air–liquid interface (ALI) cell exposure systems (rather than submerged cell exposure systems) as they more closely resemble in-vivo conditions in the lungs and they allow for unaltered and dosimetrically accurate delivery of aerosolized nanoparticles to the cells. An important aspect, which is frequently overlooked, is the comparison of typically used in-vitro dose levels with realistic in-vivo nanoparticle doses in the lung. If we consider average ambient urban exposure and occupational exposure at 5 mg/m3 (maximum level allowed by Occupational Safety and Health Administration (OSHA)) as the boundaries of human exposure, the corresponding upper-limit range of nanoparticle flux delivered to the lung tissue is 3·E–5-5·E–3 μg/h/cm2 of lung tissue and 2–300 particles/h/(epithelial) cell. This range can be easily matched and even exceeded by almost all currently available cell exposure systems.Image Culture: Comparison of the protocols for exposing cells to (nano-)particles under submerged (left: a suspenson of particles is added as a bulk liquid to the cell culture, which is covered by cell culture medium) and air/liquid interface (ALI) (right: Aerosol-laden air is brought into direct contact with the cell culture, which is supplied with medium through a perforated membrane from below. Thus, a fraction of the airborne particles id deposited onto the cells) culture conditions to study particle-cell interactions. While the air–liquid interface exposure mimics the interaction of particles with cells in the lungs, the submerged exposure is more realistic for ‘internal’ cells such as in the gastro-intestinal tract.

Image Cell: Cellular uptake mechanisms of NPs and related intracellular trafficking: (a) phagocytosis, an actin-based mechanism occurring primarily in professional phagocytes, leading to phagosomes (AI) and phago-lysosomes (L). (b) macro-pinocytosis, also an actin-based pathway, engulfing NPs with poor selectivity, leading to macropinosomes (BI) which might be exocytosed or fuse with lysosomes (L). (c) Clathrin-mediated endocytosis, associated with the formation of a clathrin lattice and depending on the GTPase dynamin, forming primary endosomes (CI) and late endosomes (CII) including multivesicular bodies (CIII). (d) Clathrin and caveolae independent endocytotic pathways. (e) Caveolae-mediated endocytosis, with typical flask-shaped invaginations made of caveolin dimers, also dynamin-dependent and forming caveosomes (EI), which fuse with the ER (EII) or translocate through the cell (EIII). (f) particle diffusion/transport through the apical plasma membrane, resulting in particles located freely in the cytosol.

Source: Paur HR, Cassee FR, Teeguarden J, Fissan H, Diabate S, Aufderheide M, Kreyling MG, Haenninen O, Kasper G, Riediker M, Rothen-Rutishauser B, Schmid O (2011) In-vitro cell exposure studies for the assessment of nanoparticle toxicity in the lung—A dialog between aerosol science and biology. Journal of Aerosol Science, Vol.42: 668–692

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ALICE (25:50-27:45).mp4

adversely affected cells

In-Vitro studies:

ALI (air liquid interface)

ALICE (ALI-cell exposure system)• humidified aerosol: 80-90% rH• Temp at 37.5 °C• particles deposit as droplets (“cloud

settling“)• approx. ~15 min for 1 mL particle

suspension• total exposure 6h Lenz et al., 2009;

Praunault, 2015

Aerosol Climate Tools ModelHealth

A novel air-liquid interface cell exposure system (ALICE) for nanoparticles in liquids is presented and validated. The ALICE generates a dense cloud of droplets with a vibrating membrane nebulizer and utilizes combined cloud settling and single particle sedimentation for fast (~10 min; entire exposure), repeatable (<12%), low-stress and efficient delivery of nanoparticles, or dissolved substances, to cells cultured at the air-liquid interface. Validation with various types of nanoparticles (Au, ZnO and carbon black nanoparticles) and solutes (such as NaCl) showed that the ALICE provided spatially uniform deposition (<1.6% variability) and had no adverse effect on the viability of a widely used alveolar human epithelial-like cell line (A549).

Image: Experimental setup of the air-liquid interface exposure system (ALICE). After 6h of exposre the cells reveal visible changes. In coparison to cells not exposed, the cells here attain e neon-green appearance. Combustion aerosols either attach or enter the cell to trigger chemical reactions (ranging from ROS to mutations w/n the cells DNA) that do not kill the cell but alter its phenotype. A rather harmless response would be an inflamation, whereas a sever reaction would be a pre-cancerous dynamics).

Source: Prunault D (2015) Dicke Luft – Wenn Staedte ersticken. Arte.tv (https://www.youtube.com/watch?v=jd36m4m9Mfk)Lenz AG, Karg E, Lentner B, Dittrich V, Brandenberger C, Rothen-Rutishauser B, Schulz H, Ferron GA, Schmid O (2009) A dose-controlled system for air-liquid interface cell exposure and application to zinc oxide nanoparticles. Particle and Fibre Toxicology Vol.6:32. 17p.

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A …. Cell viabilityB …. CytotoxicityC …. IL-8 protein

release

Stoehr et al., 2015

Aerosol Climate Tools ModelHealth

In-Vitro studies:

ALI (air liquid interface)

ALICE (ALI-cell exposure system)

-- “ -- (Submerged & ALI culture)• A549 Lung Epitelial Cells• 30L Tedlar-Bag • exposure to DEA for 3 hrs

Air pollution is associated with increased risk of cardiovascular and pulmonary diseases, but conventional air quality monitoring gives no information about biological consequences. Exposing human lung cells at the air−liquid interface (ALI) to ambient aerosol could help identify acute biological responses. This study investigated electrode-assisted deposition of diesel exhaust aerosol (DEA) on human lung epithelial cells (A549) in a prototype exposure chamber. A549 cells were exposed to DEA at the ALI and under submerged conditions in different electrostatic fields (EFs) and were assessed for cell viability, membrane integrity, and IL-8 secretion. Qualitative differences of the DEA and its deposition under different EFs were characterized using scanning mobility particle sizer (SMPS) measurements, transmission electron microscopy (TEM), and electron energy loss spectroscopy (EELS). Upon exposure to DEA only, cell viability decreased and membrane impairment increased for cells at the ALI; submerged cells were unaffected. These responses were enhanced upon application of an EF, as was DEA deposition. No adverse effects were observed for filtered DEA or air only, confirming particle-induced responses. The prototype exposure chamber proved suitable for testing DEA-induced biological responses of cells at the ALI using electrode-assisted deposition and may be useful for analysis of other air pollutants.

Image: Biological response of A549 cells after exposure to DEA for 3 h with and without EF-assisted deposition. (A) Cell viability; (B) cytotoxicity; (C) IL-8 protein release. Data are presented as mean ± SEM of at least two independent experiments, except when no SEM is indicated. +5 and −5 kV indicate voltage applied to the counter electrode, resulting in deposition of charged particles onto the cells (grounded electrode). TriX, 0.1% Triton X-100; Inc., incubator control (37 °C/5% CO2); RT, room temperature (25 °C/0.04% CO2).

Source: Stoehr LC, Madl P, Boyles MSP, Zauner R, Wimmer M, Wiegand H,Andosch A, Kasper G, Pesch M, Lutz-Meindl U, Himly M, Duschl A (2015). Enhanced Deposition by Electrostatic Field-Assistance Aggravating Diesel Exhaust Aerosol Toxicity for Human Lung Cells. Environ. Sci. Technol. Vol.49: 8721−8730.

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In-Vitro studies:

ALI (air liquid interface)

ALICE (ALI-cell exposure system)

Navetta (inverted transwell)• A549 Lung Epitelial Cells• exposure to DEA up to 24 hrs

Aerosol Climate Tools ModelHealth

A & B …. spatial quantitative distribution of CuO-NPsC & D …. SEM images of deposited material Frijns et al., 2017

A new prototype air-liquid interface (ALI) exposure system, a flatbed aerosol exposure chamber termed NAVETTA, was developed to investigate deposition of engineered nanoparticles (NPs) on cultured human lung A549 cells directly from the gas phase. This device mimics human lung cell exposure to NPs due to a low horizontal gas flow combined with cells exposed at the ALI. Electrostatic field assistance is applied to improve NP deposition efficiency. As proof-of-principle, cell viability and immune responses after short-term exposure to nano-copper oxide (CuO)-aerosol were determined. We found that, due to the laminar aerosol flow and a specific orientation of inverted transwells, much higher deposition rates were obtained compared to the normal ALI setup. Cellular responses were monitored with post-exposure incubation in submerged conditions, revealing CuO dissolution in a concentration-dependent manner. Cytotoxicity was the result of ionic and non-ionic Cu fractions. Using the optimized inverted ALI/post-incubation procedure, proinflammatory immune responses, in terms of IL-8 promoter and NFκB activity, were observed within short time, i.e. 1 hour exposure to ALI-deposited CuO-NPs and 2.5 hours post-incubation. NAVETTA is a novel option for mimicking human lung cell exposure to NPs, complementing existing ALI systems. Image: Schematic diagram of aerosolization setup in fume hood with details like atomizer, dryer, carbon/HEPA filter unit, corona charger, mass flow controller, novel exposure chamber operating with inverted transwell ALI setup for electrostatic field (EF)-assisted laminar flow deposition of humidified/temperature-controlled nanoaerosol using high voltage, quartz crystal microbalance (QCM), scanning mobility particle sizer (SMPS), condensation particle counter (CPC), stainless steel 12-well plate, cell culture medium.

Spatial distribution of material deposited within 1 hour exposure onto inverted transwell inserts as captured by photographic imaging (A) and quantified by ICP-MS in percent total Cu per well (B). The flow direction was from right to left. Deposited material was agglomerated as visualized by SEM images (20 kV) taken at 5,000x (C) and 25,000x (D) magnifications, respectively.

Source: Frijns E, Verstreelen S, Stoehr L, vanLaer J, Jacobs A, Peters J, Tirez K, Boyles M, Geppert M, Madl P, Nelissen I, Himly M, Duschl A (2017). A novel exposure system termed NAVETTA for in vitro laminar flow electro-deposition of nano-aerosol and evaluation of immune effects in human lung reporter cells. Environ. Sci. Technol. Vol. 51(9):5259-5269

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tobacco whole smoke

(1:54)

vapour phase (1:44)

In-Vitro studies:

ALI (air liquid interface)

ALICE (ALI-cell exposure system)

Navetta (inverted transwell)

ALI & ETS (Environmental Tobacco Smoke)Azzopardi et al., 2015

Aerosol Climate Tools ModelHealth

In vitro toxicological studies for tobacco product assessment have traditionally been undertaken using the particulate phase of tobacco smoke. However, this does not truly reflect exposure conditions that occur in smokers. Thus in vitro cell culture systems are required in which cells are exposed to tobacco whole smoke (WS) at the air–liquid interface (ALI). In this study bronchial epithelial cells were cultured on semi-permeable membranes, transitioned to the ALI and the robustness and sensitivity of the cells to tobacco WS and vapour phase (VP) assessed. Although no effect of air exposure was observed on cell viability, IL-6 and IL-8 release was increased. Exposure to WS resulted in a significant dose dependent decrease in cell viability and a significant non-dose dependent increase in inflammatory mediator secretion. The VP was found to contribute approximately 90% of the total cytotoxicity derived from WS. The cell culture system was also able to differentiate between two smoking regimens and was sensitive to passage number with increased inflammatory mediator secretion and lower cell viability observed in cell cultures of low passage number following WS exposure. This simple cell culture system may facilitate studies on the toxicological impact of future tobacco products and nicotine delivery devices.

Image: Cytotoxicity of NCI-H292 cells exposed to 3R4F WS (blue) and VP (green). Data points are mean ―SD from three replicates cell culture inserts in five independent experiments.

A Borgwaldt RM20S smoking machine with 8 syringes. (A) Tobacco smoke generator. (Bi and Bii) A syringe based dilution system with 4 syringes that can be combined to give a total of 8. (C) Air flow controller. (D) Cell culture medium maintained at 37 C feeding exposure chambers with fresh cell culture medium. (E) BAT exposure chamber housed at 37 C, attached to the smoke diluter and cell culture medium

Mass: Log10 transformation of deposited particulate mass and WS dilution (smoke:air, vol:vol) for ISO and HCI generated 3R4F WS.

Source: see next slide

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ISO: Standardized combustion vs HCI more “human like”(!)In-Vitro studies:

ALI (air liquid interface)

ALICE (ALI-cell exposure system)

Navetta (inverted transwell)

ALI & ETS (Environmental Tobacco Smoke)Azzopardi et al., 2015

Aerosol Climate Tools ModelHealth

3R4F cigarettes were conditioned for a minimum of 48 h prior to use (60 ±3% relative humidity, 22 ±1 °C) and smoked in a test atmosphere of 60 ± 5% relative humidity, 22 ±2 °C) in accordance with ISO 3402:1999. Cigarettes were either smoked according to ISO 3308:2000 (35 mL puff volume, drawn over 2 s, once every minute with ventilation holes unblocked) or to the HCI smoking regimen (55 mL puff volume, drawn over 2 s, twice a minute with ventilation holes blocked). For the first two stages of the study, six puffs were taken from each of five cigarettes using the ISO 3308:2000 smoking regimen to give a total exposure time of 30 min. For the third stage, in which cultures were exposed to WS generated from the two smoking regimens, cells were exposed to WS generated according to ISO 4387:2000 (whereby cigarettes were smoked to the length of the filter +8 mm).

Technical parameters of cigarette combustion (somewhat reflecting typical smoking patterns)

ISO: International Organization for Standardization

HCI: Health Canada Intense

Image - Toxicants: %-difference in toxicant yields between ISO & HCI standards. All toxicants derived from the HCI smoking regimen were significantly (p < 0.001) increased compared to the ISO smoking regimen

Source: Azzopardi D, Haswell LE, Foss-Smith G, Hewitt K, Asquith N, Corke S, Phillips G (2015) Evaluation of an air–liquid interface cell culture model for studies on the inflammatory and cytotoxic responses to tobacco smoke aerosols. Toxicology in Vitro Vol.29: 1720–1728

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Biological Effects (7/7)

In-Vitro studies:

ALI (air liquid interface)

ALICE (ALI-cell exposure system)

Navetta (inverted transwell)

ALI & ETSObservations (e.g. w/ DPM):

• Inflammation

• Immune system responses

• Oxidative stress

Ristovski et al., 2011

Aerosol Climate Tools ModelHealth

Level 1 (acute) ………………….

Level 2 (intermediate) ….

Level 3 (chronic) ……….

There are three primary physico-chemical properties of DPM to consider when investigating their respiratory health effects, namely the DPM surface area, as well as the presence of adsorbed transition metals and organics. The literature consulted in this review indicates that all of these three factors are implicated in the development of oxidative stress. An important consequence related to the development of oxidative stress is that redox-sensitive signalling pathways, such as the MAPK, NF-kB and activator protein 1 (AP-1) cascades are activated, which can result in an inflammatory response mediated through the immune system. In this mechanism, inflammation related to PM is viewed as a potential precursor to the development and acute exacerbation of airway and lung diseases, such as asthma and COPD. Redox-sensitive signalling pathways, along with the organic fraction of DPM, are also implicated in the formation of DNA adducts, such as 8-oxo-2‘-deoxy-guanosine, which are viewed in this mechanism as a precursor to the development of cancer. While the primary route by which DPM causes health effects is via inhalation through the human respiratory system, other particle exposure pathways are possible. Translocation is a route of exposure, whereby particles can migrate to a secondary organ (such as the brain, liver or spleen) after inhalation, thereby causing health effects in that secondary organ. In rodent particle exposure studies, a well established link appears to be the translocation of ultra-fine particles to the brain via the olfactory bulb …. Convincing evidence of translocation of ultra-fine particles to the brain in rats and also in monkeys;however, much further work is required to demonstrate similar effects in humans. If this route of exposure is viable in humans, inhalation toxicological studies would need to consider the health effects of DPM that has migrated to secondary organs.

Image: A potential mechanism outlining the pathways to respiratory health effects upon diesel particulate matter (DPM) inhalation. AP-1, activator protein 1; NF-kB, nuclear factor-kB.Source: Ristovski ZD, Miljevic B, Surawski NC, Morawska L, Fong KM, Go F, Yang IA (2011) Respiratory health effects of diesel particulate matter. Respirology Vol.17: 201–212

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Biological Effects (6c/6)

Source: Chang, 1994

In-Vitro studies:

ALI (air liquid interface)

ALICE (ALI-cell exposure system)

Navetta (Submerged & ALI culture)

ALI & ETS (Environmental Tobacco Smoke)• 226Ra decays to 222Rn via α-emission;• Relocation of inhaled & deposited radionuclides w/n organism

Aerosol Climate Tools ModelHealth

The link between cigarette smoke and cancer has long been established. There is, however, another cancer-causing mechanism in smokers. The culprit in this case is a radioactive environmental pollutant present in the tobacco leaves from which cigarettes are made. The soil in which tobacco is grown is heavily treated with phosphate fertilizers, which are rich in uranium and its decay products. Consider a particularly important step in the 238Udecay- series: 226Ra decays to 222Rn + alpha rays

The product formed, 222Radon, is an unreactive gas (radon is the only gaseous product in the 238Uranium decay series). 222Radon emanates from 226Radium and is present at high concentrations in soil gas and in the surface air layer under the vegetation canopy provided by the field of growing tobacco (see plantation). In this layer some of the daughters of 222Radon such as 218Polonium and 214Lead become firmly attached to the surface and interior of tobacco leaves. As the table shows, the next few decay reactions leading to the formation of 210Lead proceeds rapidly. Gradually, the concentration of radioactive 210Lead can build to quite a high level. During the combustion of acigarette, small insoluble smoke particles are inhaled and deposited in the respiratory tract of the smoker and are eventually transported and stored at sites in the liver, spleen, and bone marrow. Measurements have shown that there is a high 210Lead content in the se particles. (Note that the 210Lead content is not high enough to be hazardous chemically, but because it is radioactive it is hazardous indeed). Because of its long half-life (20.4 years), 210Lead and its radioactive daughters, 210Bismuth and 210Polonium, can continue to build up in the body throughout the period of smoking. Constant exposure of organs and bone marrow to alpha- and beta-particle radiation increases the probability of cancer development in the smoker. The overall damaging effect on a person is quite similar to that caused by radon gas exposure indoors of houses built in particular geographical areas.

Source: Chang R.1994 – Chemistry 5th ed. McGrawHill.

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Toxicology (1/5)

Inflammatory response!

Phagocytosis of nano-particles produces intracellular ROS(reactive oxygen species);

ROS interferes w/:• metabolic equilibrium• protein synthesis• DNA activity• lipid peroxidation• cell-cycle

The smaller, the more toxic!

Oberdörster et al, 2005

Aerosol Climate Tools ModelHealth

Fibroblast: Fusiform cell with cytoplasm that is usually indistinguishable from the surrounding matrix; tapering processes are present but are difficult to visualize in most sections; some very active cells have basophilic cytoplasm; has elliptical nucleus, sometimes slightly folded, with sparse chromatin that presents a "speckled" appearance (may be mistaken for plasma cell); has one to two nucleoli; makes fibers and ground substance;Collectively, the invitro results have identified oxidative-stressミrelated changes of gene expression and cell signaling pathways as underlying mechanisms of UFP effects, as well as a role of transition metals and certain organic compounds on combustion- generated nanoparticles. These can alter cell signaling pathways, including Ca2+-signaling and cytokine signaling (e.g., interleukin-8). Effects were on a mass basis greater for model nanoparticles than for fine or even coarser particles, whereas effects for ambient nanoparticles cellular responses were sometimes greater and sometimes less than those of fine and coarse particles [1] .... With respect to potential health effects of nanoparticles, two examples should serve to illustrate: a) nanoparticles have a higher inflammatory potential per given mass than do larger particles, provided they are chemically the same, and b) nanoparticles .... can elicit severe acute lung injury.For example, 20 nm TiO2 and 20 nm Al2O3 particles induce both a significantly greater inflammatory response when 500 μg are administered intratracheally to the lung of rats compared to the same mass dose of larger-sized TiO2 and Al2O3 particles, corresponding to the larger specific surface area of the ultrafine particles. However, when the persistence of the inflammatory response was evaluated it turned out that the nano-sized TiO2-exposed animals had reached control levels much earlier than the Al2O3-exposed rats [2] ....

Receptor proteins and IMPs are the cell’s interface to the outer environment – interfering with or even destroying a cell’s receptor proteins renders the cell "brain-dead" even though it is still viable (a RBC is an enucleated but still viable cell; it is unable to express genes but capable to interact with their environment via their membrane receptors). In other words, the membrane with its receptors and IMPs is the information-processing unit of the cell. Thus, to exhibit "intelligent" behavior, a cell needs a functioning membrane with both receptor (awareness) and effector (action) proteins. These protein complexes are the fundamental units of cellular intelligence as they interpret, sense environmental signals; e.g. in the form of nano-aerosol-interference with inter- as well as intracellular communication. Hence, the behavior of a cell can only be understood by considering the activities of all the epigenetic “switches” at any given time. And since a perceived signal results in a complete readjustment of the entire cellular metabolic activity and eventually into a new state of equilibrium, [3] it becomes clear why knowledge about the aerosol-inducing effects at the very basic level, i.e. at the membrane level, are so crucial in inducing beneficial or detrimental cellular and ultimately organismic responses.

Source: Oberdörster G., Oberdörster E., Oberdörster J. (2005). Nanotoxicology: An Emerging Discipline Evolving from Studies of Ultrafine Particles; Environmental Health Perspective Vol. 113, No.7: 823-839, [1] p.825;Oberdörster G., Oberdörster E., Oberdörster J. (2005). Nanotoxicology: An Emerging Discipline Evolving from Studies of Ultrafine Particles -Supplemental WEB Sections; Environmental Health Perspective Vol. 113, No.7: http://ehp.niehs.nih.gov/members/ 2005/7339/supplemental.pdf, [2] p.6;

[3] Falkner G. Falkner R. (2006). Information Processing by Cyanobacteria During Adaptation to Environmental Phosphate Fluctuations. Plant Signaling & Behavior 1:4: 212-220.

[4] Madl P. (2009). Anthropogenic Environmental Aerosols: Measurements and Biological Implications. Dissertation; niversity of Salzburg.p.41-42;

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Toxicology (2/5)

Inflammatory response!

Phagocytosis of nano-particles produces intracellular ROS(reactive oxygen species);

ROS interferes w/:• metabolic equilibrium• protein synthesis• DNA activity• lipid peroxidation• cell-cycle

The smaller, the more toxic!

Oberdörster et al, 2005

Aerosol Climate Tools ModelHealth

Hypothetical cellular interactions of nanoparticles (NP). The diagram shows the potential effects of NP with emphasis on potential oxidative stress induced effects and their consequences. (A) Particle-associated characteristics induce lipid peroxidation, intracellular oxidative stress and increased cytosolic calcium ion concentration; (B) NP may be actively endocytosed via different mechanisms, including caveolae, clathrin coated pits, or receptor mediated mechanisms. In phagocytic cells phagocytosis triggers activation of NADPH oxidase and generation of ROS; (C) Particles and their associated metals, as well as oxidative stress, can activate the EGF receptor; (D) Oxidative stress, receptor activation and increased calcium ions activate transcription of pro-inflammatory genes via transcription factors such as NF-kB; (E) NP may enter the cell by passive diffusion and remain non-membrane bound from where they may enter mitochondria; (F) and disrupt normal electron transport leading to oxidative stress. (G) Free particles may also enter the nucleus via the nuclear pore complex and interact with the genetic material. (H) Lipid peroxide-derived products such as 4-hydroxy nonenal form DNA adducts that may lead to genotoxicity and mutagenesis. (Note that particle and cell structures are not to scale).

Source: Oberdörster G., Stone V., Donaldson K. (2007). Toxicology of nanoparticles: A historical perspective. Nanotoxicology Vol.1/ 1: 2-25 (doi:10.1080/17435390701314761)

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Phagocytosis of nano-particles produces intracellular ROS(reactive oxygen species);

ROS interferes with:• metabolic equilibrium• protein synthesis• DNA activity• lipid peroxidation• cell-cycle

Source: Limbach et al, 2005

Toxicology (3/5)

Aerosol Climate Tools ModelHealth

Fibroblast: Fusiform cell with cytoplasm that is usually indistinguishable from the surrounding matrix; tapering processes are present but are difficult to visualize in most sections; some very active cells have basophilic cytoplasm; has elliptical nucleus, sometimes slightly folded, with sparse chromatin that presents a "speckled" appearance (may be mistaken for plasma cell); has one to two nucleoli; makes fibers and ground substance;

Source: Limbach LK, Li Y, Grass RN, Brunner TJ, Hintermann MA, Muller M, Gunther D, Stark WJ, Environ. Oxide Nanoparticle Uptake in Human Lung Fibroblasts: Effects of Particle Size, Agglomeration, and Diffusion at Low Concentrations; Sci. Technol. 2005Brunner T.J., Wick P., Manser P., Spohn P., Grass R.N., Limbach L.K., Bruinink A., Stark W.J., In Vitro Cytotoxicity of Oxide Nanoparticles: Comparison to Asbestos, Silica, and the Effect of Particle Solubility; Environ. Sci. Technol.,40 (14), 4374-81, 2006. fibroblast: http://medinfo.ufl.edu/year1/histo/glossary.html#mesothelial_cell

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Phagocytosis of nano-particles produces intracellular ROS (reactive oxygen species);

Source: Oberdörster et al, 2005

Toxicology (4/5)

Aerosol Climate Tools ModelHealth

ROS production has been found in particles as diverse as C60 fullerenes, single-walled nanotubes, quantum dots, and nanosized particles, especially under concomitant exposure to light, UV, or transition metals .... Because mitochondria are redox active organelles, there is a likelihood of altering ROS production and thereby overloading or interfering with antioxidant defenses .... The diagram shows some of the antioxidant defense systems that occur in animals, and possible areas where nanoparticles may create oxyradicals .... [1]suggested mechanisms include a) photo excitation of fullerenes and single-walled nanotubes, causing intersystem crossing to create free electrons; b) metabolism of NPs to create redox active intermediates, especially if metabolism is via cytochrome P450s; and c) inflammation responses in vivo

Image: Nanoparticles have been shown to release oxyradicals [pictured here is the mechanism of C60 as determined by Yamakoshi et al. (2003)], which can interact with the antioxidant defense system. Abbreviations: GPx, glutathione peroxidase; GSH, reduced glutathione; GSSG, oxidized glutathione; ISC, intersystem crossing; R, any organic molecule; SOD, superoxide dismutase. In addition to fullerenes, metals such as cadmium, iron, or nickel quantum dots, or iron from single-walled nanotube manufacturing, could also act in Fenton-type reactions. Phase II biotransformation, ascorbic acid, vitamin E, beta carotene, and other interactions are not shown.

Source: Oberdörster G., Oberdörster E., Oberdörster J. (2005). Nanotoxicology: An Emerging Discipline Evolving from Studies of Ultrafine Particles; Environmental Health Perspective Vol. 113, No.7: 823-839, [1] p.827-828;

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Phagocytosis of nanoparticles has:

• Longterm effects ….

• Acute effects ….

Source: Limbach et al, 2005

…. mutagenicity (paramutations of DNA)* teratogenicity (deformations of cells)

….necrosis (traumatic cell death) apoptosis (accelerating programmed cell death) autophagy (digestion of damaged proteins & organelles in the lysosome)

(*) predominantly epigenetic in principle

Aerosol Climate Tools ModelHealth

Exposure of human lung fibroblast cells to ceria nanoparticles of 20-50 nm in diameter results in the uptake of agglomerates.

(A) Vesicles inside a fibroblast cell with ceria agglomerates. The high atomic mass of ceria and resulting contrast make the particles visible as dark spots.

(B) A series of nanoparticle agglomerates close to the cell membrane.

(C) Nanoparticles both inside the cell (vesicle) and outside are exclusively found in the form of agglomerates, confirming the dominant role of agglomeration. All bar sizes are 1.5 microm.

Cell death can occur through 3 mechanisms: apoptosis, autophagy, and necrosis. Apoptosis, or programmed cell death, results in controlled cell shrinkage and nuclear fragmentation via the action of caspases, as well as an anti-inflammatory cytokine release. In contrast, necrosis signals via RIPK1 (RIP1), leading to cell swelling, lysis, and a pro-inflammatory cytokine release. Autophagy destroys the cell's damaged proteins and organelles via an intracellular catabolic process in the lysosome.

Source: Limbach LK, Li Y, Grass RN, Brunner TJ, Hintermann MA, Muller M, Gunther D, Stark WJ, Environ. Oxide Nanoparticle Uptake in Human Lung Fibroblasts: Effects of Particle Size, Agglomeration, and Diffusion at Low Concentrations; Sci. Technol. 2005

Authophagy: http://www.qiagen.com/products/genes and pathways/complete biology list/cell death/?utm_content=P...

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Toxicology (5/5)

Phagocytosis of nanoparticles has:

• Longterm effects ….

• Acute effects ….

Source: KANDUC et al, 2002

Aerosol Climate Tools ModelHealth

Cell death and the subsequent post-mortem changes, called necrosis, are integral parts of normal development and maturation cycle. Despite the importance of this process, the mechanisms underlying cell death are still poorly understood. In the recent literature, cell death is said to occur by two alternative, opposite modes: apoptosis, a programmed, managed form of cell death, and necrosis, an unordered and accidental form of cellular dying. The incorrect consequence is the overlapping of: a) the process whereby cells die, cell death; and b) the changes that the cells and tissues undergo after the cells die. Only the latter process can be referred to as necrosis and represents a <no return> process in cell life. In this review, we discuss the excellent basic research developed in this field during last decades and problems that remain to be resolved in defining both experimentally and mechanicistically the events that lead to and characterize cell death.

Image: Cell death can occur by either of two distinct mechanisms – necrosis or apoptosis. In addition, certain chemical compounds are said to be cytotoxic to the cell – i.e., to cause its death:

•Necrosis (“accidental” cell death) – pathological process which occurs when cells are exposed to severe physical or chemical attack

•Apoptosis (“programmed” cell death) – physiological process by which unwanted or unused cells are eliminated during development and other normal biological processes

In either event, macrophages and other intact cells try to dispose of the remains by phagocytosis

Necrosis: i) tissue damage; i) due to trauma or other environmental factor impairing the structural integrity; i) intracellular contents released; i) thus may elicit local damage or inflammatory response; Apoptosis: programmed cell death (akin to suicide); i) fragmentation of cell compartments; i) does not cause peripheral damage; i) regulated; i) failure to apoptose may result in tumor formation

Source: Wilde et al., 1999Kanduc D, Mittelman A, Serpico R, Sinigaglia E, Sinha AA, Natale C, Santacroce R, Di Corcia MG, Lucchese A, Dini L, Pani P, Santacroce S, Simone S, Bucci R, Farber E.; (2002); Cell death: Apoptosis versus necrosis (Review). Int J Oncol. Vol.21(1):165-70.

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Short-Term Effects:

London 1952; wikipedia, 2009

Costa, 2001

Health Effects (1a/8)

Aerosol Climate Tools ModelHealth

The Circumstances:

• Inversion Layer (trapping smog) due to coal-powered household stoves

• Duration: few days (5th - 9th Dec. 1952)

• TSP: 4.5 mg/m3

• SO2: 1.34 ppm (average)• Immediate death toll: 4000

mostly among the elderly & those with pre-existing cardiac and/or respiratory diseases

The famous “London smog” of 1952 is estimated to have resulted in 4000 excess deaths. Hospital admissions increased dramatically, mainly among the elderly and those with preexisting cardiac and/or respiratory disease …. made up the majority of deaths …. In December 1991, London experienced a winter smog alert that exhibited black smoke at 148 µg/m3 and SO2 at 72 ppb. The difference here was that the polluted atmosphere was far more the result of air contamination by automobile emissions than domestic burning of coal (Anderson, 1999), in keeping with the trends noted above. Mortality and hospital admissions were again affected, and again mostly among the elderly and cardiopulmonary-impaired (mortality: ↑14 % cardiovascular and ↑22 % respiratory; ↑43 % for respiratory admissions).[1]

Image: Nelson's Column during the Great Smog of 1952. Reduced visibility due to smog-related light scattering and absorption.[2]

Documented fatalities based on the observed SO2-concentration.[3]

Source: [1] Costa DL (2001) Air Pollution, Ch. 28. In: Klaassen CD (ed) Casarett and Doull's Toxicology. Basic Science of Poisons. 6th ed. MacGrawHill, New York, USA;

[2] Wikipedia (2009) The Great Smog of 1952. Available online: http://en.wikipedia.org/wiki/Great_Smog_of_1952.

[3] Reichl F, Hammelehle R (2002) Taschenatlas der Toxikologie (2nd ed); Thieme Verlag; Stuttgart, FRG

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Short-Term Effects:

London 1952; wikipedia, 2009

Hunt et al., 2003

Health Effects (1b/8)

Aerosol Climate Tools ModelHealth

Confirmed deaths of the London smog (5th - 9th Dec. 1952) with analysis of autopsy tissue, by demographics and cause of death (* autopsy note: condition worsened during smog).[1]

Nelson's Column during the Great Smog of 1952. Reduced visibility due to smog-related light scattering and absorption.[2]

Source: [1] Hunt, A., Abraham, J.L.,. Judson, B., Berry, C.L. (2003). Toxicologic and Epidemiologic Clues from the Characterization of the 1952 London Smog Fine Particulate Matter in Archival Autopsy Lung Tissues. Environmental Health Perspectives, Vol.111 (9):1209-1214.

[2] Wikipedia (2009) The Great Smog of 1952. Available online: http://en.wikipedia.org/wiki/Great_Smog_of_1952.

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Short-Term Effects:

London 1952; wikipedia, 2009

Hunt et al., 2003

Health Effects (1c/8)

Great Smog of London – pt I.

mp4

Aerosol Climate Tools ModelHealth

The Great Smog of London remembered 60 years on 5 December 2012: Sixty years ago thick smog descended on London, contributing to the deaths of an estimated 4,000 people. The four-day "pea-souper", while worse than usual, was a familiar experience for Londoners. Visibility was so poor buses and taxis ground to a halt, forcing commuters to hurry underground to use the Tube. The legacy of the Great Smog was the Clean Air Act of 1956 which introduced a number of measures to reduce pollution.

Source: http://www.bbc.com/news/uk-england-london-20615186

http://www.bbc.com/news/uk-england-london-20269309

https://youtu.be/65KZXt1q2jM

https://youtu.be/cEK7POV8KSk

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Health Effects (2a/8)

Aerosol Climate Tools ModelHealth

Long-Term Effects:

Kuhlbusch, 2009

Costa, 2001

Effects on Respiratory System:• impaired lung function• accelerated “aging-like” loss of lung function• deterioration of lung-health

Organismic-wide Effects:• Cardio-vascular complications• Diabetes (Type-2 …. see later)• increased cancer-rate• increased mortality rate

Long-Term Exposures Epidemiologic studies of the chronic effects of air pollution are difficult to conduct because of the nature of the goal: outcomes associated with long-term exposures. Despite these deficiencies, there have been several epidemiology studies of both types conducted with the aim of determining long-term air pollution health effects. In general, these studies have suggested a positive association between urban pollution and progressive pulmonary impairment. On the one hand, cross-sectional studies in the Los Angeles Air Basin have found evidence of accelerated “aging-like” loss of lung function in people living for extended periods in regions of high oxidant pollution as compared with areas where sea air circulates and lowers the overall pollutant concentrations. Similarly, chronic exposure to SO2 and PM in the Netherlands over a 12-year period was shown prospectively to gradually impair lung function. And even rural areas in western Pennsylvania, which are swept by reducing-type pollutants transported from mid-western industrial centers, have been shown to have a higher incidence of respiratory symptoms as determined from a questionnaire-based design. While the role of any specific pollutant in these studies is difficult to dissect, the message that air pollution contributes to deterioration of lung health seems clear.[1]

Image: [2]

Source: Costa DL (2001) Air Pollution, Ch. 28. In: Klaassen CD (ed) Casarett and Doull's Toxicology. Basic Science of Poisons. 6th ed. MacGrawHill, New York, USA;

[2] Kuhlbusch TAJ (2009) Aerosol Exposure and Health Effects. European Aerosol Conference Karlsruhe, FRG

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Health Effects (2b/8)

Aerosol Climate Tools ModelHealth

Long-Term Effects:

• 6 City Study (USA)US-cities monitored for>20 yrsw/ some 20·E3 people

• children and elderly most affected

• Increased mortality (up to 17% higher)

• observed mutagenicity & carcinogenicity

Costa, 2001

…. PIC: products of incomplete combustion

Relative contribution of individual airborne hazardous pollutants to lung cancer rates (w/o tobacco smoke cancers).

Among the most detailed prospective epidemiologic studies of the chronic health effects of current levels of air pollution has been the so-called Harvard Six Cities Study of the early 1970s. The cities (Watertown, MA; Harriman, TN; St. Louis, MO; Steubenville, OH; Portage, WI; & Topeka, KS) were chosen to represent a range of air quality (based on SO2 and PM) …. The initial design of these studies included the gathering of parental questionnaire data (including some 20,000 people) about the prevalence of respiratory problems in schoolchildren and has been continued over twenty years with tracking of similar data along with periodic assessments of pulmonary function. When compared across cities, [H+] (measured in four of the six cities) was correlated better than was sulfate with the prevalence of bronchitis in children age 10 to 12. However, the relationship with acute mortality was less convincing than that associated with the sulfate or PM (≤2.5 µm). Over a 15-year period, the average human life span was reduced by about 2 years due to PM exposure. Another cohort-based mortality study of the long-term effects from PM, especially that derived from combustion (PM2.5 and sulfate), was conducted using the data from 151 cities. This study confirmed the impact of PM on mortality, showing a 15 to 17 % increased risk over 7 years, about equivalent to the risk of smoking over that period. Hence, there is now growing concern for the potential chronic health impacts and heightened risk of premature death from lifelong air pollution exposure.

The above image gives estimates of the relative contributions of various chemicals to the lung cancer rate that is not associated with cigarette smoking …. VOCs and nitrogen-containing and halogenated organics compounds are derived from combustion sources ranging from tobacco to power plants to incinerators …. A significant body of data suggests that the majority of cancer risk from ambient air pollution lies within the particulate fraction. Among the many potent chemicals are the PAHs, along with a group of less-volatile organics sometimes referred to as “semivolatiles” (including nitro-aromatics). These persistent organics associate with the particulate matrix and thus could have a prolonged residence time at deposition sites within the respiratory tract. Genetic bioassays have revealed the potent mutagenicity, and presumably carcinogenicity, of various chemical fractions of ambient aerosols.

The cells lining the respiratory tract turn over relatively quickly, since they continuously interface with the ambient environment …. For example, there is experimental evidence that benzo(a)pyrene inhaled by rats whose respiratory tracts have been chronically irritated by SO2 inhalation may result in bronchogenic carcinoma. Likewise, epidermoid carcinomas were produced in mice that inhaled ozonized gasoline, containing many reactive organic products, if these mice had been previously infected with influenza virus and had presumably developed inflammation. Many believe that the so-called rural-urban gradient of lung cancer, apparent even when corrected for cigarette smoking, is a product of these complex interactions.

Image: Relative contribution of individual airborne hazardous pollutants to lung cancer rates after removal of tobacco smoke cancer. The total number of cancers from non-tobacco-smoke sources is estimated to be about 2000 per year.Source: Costa DL (2001) Air Pollution, Ch. 28. In: Klaassen CD (ed) Casarett and Doull's Toxicology. Basic Science of Poisons. 6th ed. MacGrawHill, New York, USA;

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Long-Term Effects:

• 6 City Study (USA)• Mexico City

Chow et al., EAC 2001

Calderón-Garcidueñas et al., 2004

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Health Effects (2c/8)

Aerosol Climate Tools ModelHealth

Air pollution is a complex mixture of gases (e.g., ozone), particulate matter, and organic compounds present in outdoor and indoor air. Dogs exposed to severe air pollution exhibit chronic inflammation and acceleration of Alzheimer’s-like pathology, suggesting that the brain is adversely affected by pollutants. We investigated whether residency in cities with high levels of air pollution is associated with human brain inflammation. Expression of cyclooxygenase-2 (COX2), an inflammatory mediator, and accumulation of the 42-amino acid form of β-amyloid (Aβ42), a cause of neuronal dysfunction, were measured in autopsy brain tissues of cognitively and neurologically intact lifelong residents of cities having low (n:9) or high (n:10) levels of air pollution. Genomic DNA apurinic/apyrimidinic sites, nuclear factor-κB activation and apolipoprotein E genotype were also evaluated. Residents of cities with severe air pollution had significantly higher COX2 expression in frontal cortex and hippocampus and greater neuronal and astrocytic accumulation of Aβ42 compared to residents in low air pollution cities. Increased COX2 expression and Aβ42 accumulation were also observed in the olfactory bulb. These findings suggest that exposure to severe air pollution is associated with brain inflammation andAβ42 accumulation, two causes of neuronal dysfunction that precedethe appearance of neuritic plaques and neurofibrillary tangles, hallmarks of Alzheimer’s disease.

The average age and years of schooling for low- and high exposure groups were 58.1 ±4.6 and 51.2 ± 4.9 years of age and 9.2 ± 0.86 and 9.7 ± 1.1 years of schooling, respectively. The primary causes of death included accidents resulting in immediate death, arrhythmias, myocardial infarction, and carcinomas including: gastric, lung, colon, breast, and cervical. Clinical data for control and exposed subjects is presented in the table.

Source: Calderón-Garcidueñas L., Reed W., Maronpot R., Henriquez-Roldán C., Delgado-Chavez R., Calderón-Garcidueñas A., Dragustinovis I., Franco-Lira M., Aragón-Flores M., Solt A.C., Altenburg M., Torres-Jardón R., Swenberg J.A. (2004). Brain Inflammation and Alzheimer's-Like Pathology in Individuals Exposed to Severe Air Pollution. Toxicol Pathol. 32; 650-658.

Chow J.C, Watson J.G., Edgerton S.A., Vega E.; Chemical composition of PM2.5 and PM10 in Mexico City during winter 1997. Mexico City image: http://www.ucar.edu/news/releases/2006/images/mexico.jpg

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• 6 City Study (USA)• Mexico City• China

Ebenstein et al., 2015

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Health Effects (2d/8)

Trends in Health, Income & Pollution in China, before (1991), during (2000) and after (2012) its explosive economic growth.

dramatic drop in child-infection

Aerosol Climate Tools ModelHealth

annual avg – no PM2.5 & PM1.0

heart disease, stroke, lung cancer

The data cover the period 1991–2012, when China experienced its unprecedented economic boom. The analysis is conducted using detailed mortality data taken from China’s Disease Surveillance Points System (DSPS), a mortality-monitoring system covering a nationally representative sample of Chinese cities and counties.

Table: Life expectancy increased by 6.4 years between 1991 and 2012, raising average longevity from 69.3 to 75.7 years …. The explanation for this …. is found in the breakdown of cause-specific death rates. Striking differences between cardio-respiratory diseases versus the rest of causes of death were found. Non-cardio-respiratory diseases (include most communicable diseases) …. dropped dramatically from 432 to 221 deaths per 100·E3 …. Cardio-respiratory diseases are more sobering: mortality from heart diseases, stroke, and lung cancer remained virtually unchanged during the period. These diseases are known to be sensitive to air pollution …. The results suggest that pollution-related diseases have continued to have high mortality rates in China.

Image: Trends in Health, Income, and Pollution in China, 1991–2012. Author calculations using the Chinese Disease Surveillance Points Survey (1991–2012). Income data is taken from China’s Statistical Yearbooks. Pollution measures are taken from China’s Environmental Yearbooks (1981–2012). Fine particulate matter is imputed in 1991 by assuming a fixed proportion of Total Suspended Particulates.

Source: Ebenstein A, Fan MY, Greenstone M, He GJ, Yin P, Zhou MG (2015). Growth, Pollution, and Life Expectancy: China from 1991-2012. American Economic Review: Papers & Proceedings 2015, 105(5): 226–231.

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Long-Term Effects:

• 6 City Study (USA)• Mexico City• China• Italy

ILVA di Tarantowikipedia 201

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Health Effects (2e/8)

Factsheet: TARANTO Cohort study

+24 % ricoveri per malattie respiratorie dei bambini residenti quartiere tamburi, +2 6% quartiere paolo vi

l’esposizione alle polveri industriali è responsabile di un +4 % di mortalità (in particolare +5 % mortalità per tumore polmonare, +10 % per infarto del miocardio

per effetto dell’SO2 (anidride solforosa) industriale: +9 % mortalità, in particolare +17 % mortalità per tumore polmonare, +29 % per infarto del miocardio

entrambi gli inquinanti sono responsabili di nuovi casi di tumore del polmone tra i residenti (+29 % PM10 +42 % l’SO2)

Alessandrini et al., 2016ILVA ILVA –– Taranto.mp4Taranto.mp4

Aerosol Climate Tools ModelHealth

Nella prima perizia, sulle emissioni, si legge che nel 2010 Ilva ha emesso in aria le seguenti sostanze convogliate (tabella A-1 della perizia):

4.159.300 kg di polveri; 339 kg idrocarburi policiclici aromatici (PAH);

11.056.900 kg diossido di azoto (NO2); 280 kg cromo III (cromo trivalente, Cr);

11.343.200 kg anidride solforosa (SO2); 53 g benzo(a)pirene (C20H12);

7.000 kg acido cloridrico(HCl); 16 g poli-cloro-di-benzo-diossine e poli-cloro-di-benzo-furani;

1.300 kg benzene (C6H6); PCDD: (e.g. C4H4O2) PCDF: (e.g. C4H4O)

Inoltre, da dichiarazione E-PRTR della stessa ILVA (tabella C-1 della perizia):8.606.106.000 kg biossido di carbonio (CO2);

172.123.800 kg monossido di carbonio (CO); 564 kg cromo (Cr);

8.190.000 kg ossidi di azoto (NOX); 425 kg nichel (Ni);

7.645.000 kg ossidi di zolfo (S); 157 kg arsenico (As);

718.600 kg organici volatili non metanici (VOC); 138 kg cadmio (Cd);

356.600 kg cloro e composti organici (Cl & OC); 21 kg mercurio (Hg);

23.737 kg zinco (Zn);

20.063 kg fluoro e composti organici (F & OC);

9.023 kg piombo (Pb);

1.758 kg rame (Cu);

Source: http://it.wikipedia.org/wiki/Ilva. RaiNews Tg2 (23rd Oct. 2012)

Comba P, Conti S, Iavarone I, Marsili G, Musmeci L, Piratsu R (2012) Ambiente e salute a Taranto: evidenze disponibili e indicazioni di sanita’ pubblica. Ministero della Salute, Roma (ITA); taranto -http://www.salute.gov.it/portale/documentazione/p6_2_2_1.jsp?lingua=italiano&id=1833

Alessandrini ER, Leogrande S, Morabito A, Ancona C, Assennato G, Giua R, Mataloni F, Mincuzzi A, Minerba S, Nocioni A, Serinelli M, Spagnolo S, Stafoggia M, Bisceglia L, Forastiere F (2016) Studio di coorte sugli effetti delle esposizioni ambientali ed occupazionali sulla morbosità e mortalità della popolazione residente a Taranto. Rapporto conclusivo. Gruppo di lavoro per la conduzione di studi di epidemiologia analitica, Aree di Taranto e Brindisi

http://www.intechopen.com/books/air-pollution-monitoring-modelling-and-health/airborne-particles-and-the-emergence-of-contemporary-diseasesILVA di Taranto image: http://it.wikipedia.org/wiki/File:ILVA_-_Unit%C3%A0_produttiva_di_Taranto_-_Italy_-_25_Dec._2007.jpghttps://www.youtube.com/watch?v=Dp32fbIW30M

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Long-Term Effects:

Health Effects (3a/8)

Aerosol Climate Tools ModelHealth

Atherosclerosis • HDL (High Density

Lipoprotein) known to protect against heart disease;

• Higher PM-values suppress “good Cholesterol” (HDL);

• Shifting the ratio in favor of LDL (low density L.); less is decomposed in the liver favoring atherosclerosis;

• Precursor to cardiovascular disease;

Bell et al., 2017

Traffic-related air pollution and cardiovascular disease air pollution - cardiovascular; heart disease: What is the mechanism on the correlation between air pollution and development of cardiovascular disease is uncertain. The connection may be explained by a reduction in the number of small cholesterol-depleted high-density lipoprotein (HDL) particles, resulting in higher average amount of cholesterol in the HDL particles. Researchers recently found that exposure to black carbon from air pollution induced by traffic is associated with the "good cholesterol", further increase the risk of cardiovascular disease. It is suggested that the number and functionality of HDL particles matter more than their cholesterol content. The change may happen as quickly as a short exposure to the polluted air. Men and women show different responses: with a higher impact in women.

Objective: The relationship between air pollution and cardiovascular disease may be explained by changes in high-density lipoprotein (HDL).

Approach & Results” We examined the cross-sectional relationship between air pollution and both HDL cholesterol and HDL particle number in the MESA Air study (Multi-Ethnic Study of Atherosclerosis Air Pollution). Study participants were 6654 white, black, Hispanic, and Chinese men and women aged 45 to 84 years. We estimated individual residential ambient fine particulate pollution exposure (PM2.5) and black carbon concentrations using a fine-scale likelihood-based spatiotemporal model and cohort-specific monitoring. Exposure periods were averaged to 12 months, 3 months, and 2 weeks prior to examination. HDL cholesterol and HDL particle number were measured in the year 2000 using the cholesterol oxidase method and nuclear magnetic resonance spectroscopy, respectively. We used multivariable linear regression to examine the relationship between air pollution exposure and HDL measures.

Conclusions: These data are consistent with the hypothesis that exposure to air pollution is adversely associated with measures of HDL.

Image: Multivariable adjusted relationship between three month averaged PM2.5 and HDL-P in the Multi-Ethnic Study of Atherosclerosis (MESA)

Source: Bell G, Mora S, Greenland P, Tsai M, Gill E, D J (2017). Association of Air Pollution Exposures With High-Density Lipoprotein Cholesterol and Particle Number. Arterioscler Thromb Vasc Biol,, Vol ATVBAHA.116.308193

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Long-Term Effects:

Health Effects (3b/8)

Effects on electrical activity of the heart

Fatal arrhythmia‘s

direct action of particlesautonomic control

conductance-signaling

Deathof host with pre-existing disease

Effects on blood supply to the heart

Ischemia

plaque destabilizationblood coagulationdeformabilityhaemostasis

Aerosol Climate Tools ModelHealth

Cardiovascular effects

Kreyling., 2003

Two adverse effects are known from excessive exposure to polluted air:

Cardiac arrhythmia (also dysrhythmia) is a term for any of a large and heterogeneous group of conditions in which there is abnormal electrical activity in the heart. The heart beat may be too fast or too slow, and may be regular or irregular. The term sinus arrhythmia refers to a normal phenomenon of mild acceleration and slowing of the heart rate that occurs with breathing in and out. It is usually quite pronounced in children, and steadily decreases with age. This can also be present during meditation breathing exercises that involve deep inhaling and breath holding patterns.

Ischemia: In medicine, ischemia (Greek ισχαιμία, isch- restriction, hema or haema blood) is a restriction in blood supply, generally due to factors in the blood vessels, with resultant damage or dysfunction of tissue. It may also be spelled ischaemia or ischæmia. Rather than hypoxia (a more general term denoting a shortage of oxygen, usually a result of lack of oxygen in the air being breathed), ischemia is an absolute or relative shortage of the blood supply to an organ, i.e. a shortage of oxygen, glucose and other blood-borne fuels. A relative shortage means the mismatch of blood supply (oxygen/fuel delivery) and blood request for adequate metabolism of tissue. Ischemia results in tissue damage because of a lack of oxygen and nutrients [1]. Ultimately, this can cause severe damage because of the potential for a build-up of metabolic wastes. Ischemia can also be described as an inadequate flow of blood to a part of the body, caused by constriction or blockage of the blood vessels supplying it. Ischemia of heart muscle produces angina pectoris.

Source: Kreyling W.G. (2003). Translocation of ultrafine solid combustion particles into the vascular and the central nervous system. 7th ETH Conference on Combustion Generated Particles. Zurich - CH

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Long-Term Effects:

Health Effects (3c/8)

Aerosol Climate Tools ModelHealth

Type-2 Diabetes (T2D)• Long-term NO2 & PM10 exposure

(pathway primarily via nose i/o brain)• Increased HOMA index (marker of

insulin resistance)

• with every PM10* increase of 10 μg/m3:odds of T2D elevated by 8%odds of T2D risk allele risen by 35%

GRS: total genetic risk score; GRS-BCF: beta-cell function; GRS-IR:insulin resistance; (*) PM10 …. so PM2.5 or even PM1.0 must be more severe!

Eze et al., 2014, 2016

Epidemiologic evidence shows a positive association between air pollution and type 2 diabetes (T2D) risk. The underlying mechanisms and susceptibilities are still subject to active research. Effects of inhaled pollutants that are supported by experimental and epidemiological evidence include the contribution to systemic inflammation, autonomic imbalance, weight gain, and to insulin resistance, thought to be in part the result of inhalants stimulating an innate immune response, influencing endoplasmic reticulum, glucose and lipid metabolism, and activating the central nervous system. Gene-environment interaction (GEI) can inform on biological pathways by which air pollution affects diabetes, an aspect of relevance to air quality regulation.[1]

Air pollution causes subclinical inflammation and appears to mediate components of the metabolic syndrome including impaired vascular endothelial function, and alterations in the central autonomic tone, visceral and brown adipose tissue, with mitochondrial and hepatic insulin receptor dysfunction. Apart from the experimental studies on mouse models which showed insulin resistance among rats, regardless of the type of diet given, human epidemiological studies have also demonstrated insulin resistance after air pollution exposure. A positive association between long-term exposure to NO2 and PM10, and homeostatic model assessment (HOMA) of insulin resistance among 10-year old children in Germany was found. Insulin resistance increased by 17% [95% CI] and 18.7% [95% CI] for every 2SD increase in NO2 and PM10respectively. Similarly, a positive associations between exposure to PM10, and NO2 [and other markers of air pollution], and insulin resistance [and other markers of inflammation and oxidative stress] among children in Iran was found.[2]

Image: Interactions between PM10 and count-GRS on prevalent diabetes in the SAPALDIA study. GRS: total genetic risk score; GRS-BCF: beta-cell function genetic risk score; GRSIR:insulin resistance genetic risk score; GRS-IR (no obesity variants): insulin resistance GRS excluding polymorphisms on FTO and M4CR with primary effect on obesity; GRS-IR (only obesity variants): insulin resistance genetic risk score including

only polymorphisms on FTO and M4CR with primary effect on obesity ….

Source: [1] Eze IC, Imbodena M, Kumar A, Eckardstein A, Stolz D, Gerbase MW, Kuenzli N, Pons M, Kronenberg F, Schindler C, Probst-Hensch N (2016) Air pollution and diabetes association: Modification by type 2 diabetes. Environment International, Vol.94: 263-271.

[2] Eze IC, Schaffner E, Fischer E, Schikowski T, Adam M, Imboden M, Tsai M, Carballo D, Eckardstein A, Kuenzli N, Schindler C, Probst-Hensch (2014) Long-term air pollution exposure and diabetes in a population-based Swiss cohort. Environment International 70 (2014) 95ミ105

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Long-Term Effects:

Health Effects (3d/8)

Aerosol Climate Tools ModelHealth

Rheumatoid Arthritis• Long-term exposure to i) tobacco smoke exposure i) silica dust / asbestos

ACPA: anti-citrullinated protein antibodies; RA: rheumatoid arthritis;

Ilar et al., 2017a Adjusted for age group, geographical area and study design.b Additionally adjusted for cigarette smoking (0, <10, 10-19, ≥20 pack-years and smoking other

tobacco than cigarettes), alcohol use (non-drinkers, low, moderate, high), BMI (<20, 20-25, >25) and education (primary education, secondary education, university degree).

Objective: Environmental factors are of importance for the etiology of rheumatoid arthritis (RA), but much remains unknown concerning the contributions from distinct occupational hazards. We explored the association between occupation and the risk of anti-citrullinated protein antibody (ACPA) + RA or ACPA-RA.

Methods: We analyzed 3,522 cases and 5,580 controls from the Swedish population-based EIRA case-control study. A questionnaire was used to obtain information on work history and lifestyle factors. Blood samples were taken for serologic analyses. Unconditional logistic regression was used to calculate the odds ratio (OR) of RA associated with the last occupation before study inclusion. Analyses were performed with adjustments for known environmental exposures and lifestyle factors, including pack years of cigarette smoking, alcohol use, body mass index (BMI) and education.

Results: Among men, bricklayers and concrete workers (OR: 2.9, 95% CI: 1.4-5.7), material handling operators (OR: 2.4, 95% CI: 1.3-4.4) and electrical and electronics workers (OR: 2.1, 95% CI: 1.1-3.8), had an increased risk of ACPA+ RA. For ACPA- RA, bricklayers and concrete workers (OR: 2.4, 95% CI: 1.0-5.7) and electrical and electronics workers (OR: 2.6, 95% CI: 1.3-5.0) had an increased risk. Among women, assistant nurses and attendants had a moderately increased risk of ACPA+ RA (OR: 1.3, 95% CI: 1.1-1.6). No occupations were significantly associated to ACPA- RA among women.

Conclusion: Mainly occupations related to potential noxious airborne agents were associated with an increased risk of ACPA+ or ACPA- RA, after adjustments for previously known confounders.

The disease development of rheumatoid arthritis (RA) occurs through a complex interaction between genes, environmental factors and immunity. For a substantial part of RA patients, the disease is characterized by the occurrence of autoantibodies in serum, which are used to predict the disease course and treatment response. Autoantibodies also play an important part in disease detection and elevated levels of anti-citrullinated protein antibodies (ACPA), rheumatoid factor (RF) (5) and anti-carbamylated protein antibodies (anti-CarP) have been found in RA patients before onset of the symptoms. There is increasing evidence suggesting that ACPA+ RA and ACPA- RA are two different subtypes of the disease with partly different etiologies.

Table: Odds ratios (ORs) of developing anti-citrullinated protein antibodies positive (ACPA+) or ACPA rheumatoid arthritis (RA) with 95 % confidence intervals (95 % CIs) among men according to their last occupation before index year (n=2596).a Adjusted for age group, geographical area and study design.b Additionally adjusted for cigarette smoking (0, <10, 10-19, ≥20 pack-years and smoking other tobacco than cigarettes), alcohol use (non-drinkers, low, moderate, high), BMI (<20, 20-25, >25) and education (primary education, secondary education, university degree).c Professional, technical and related work and administrative, managerial and clerical work.

Source: Ilar A, Alfredsson L, Wiebert P, Klareskog L, Bengtsson C (2017) Occupation and Risk of Developing Rheumatoid Arthritis: Results From a Population-Based Case-Control Study. Arthritis Care & Research, Vol. DOI: 10.1002/acr.23321

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Health Effects (4a/8)

Long-Term Effects:

17 cohort studies based in nine European countries found:

Both PM2.5 & PM10 contribute to lung cancer incidence in EU

Raaschou-Nielsen et al., 2013

Aerosol Climate Tools ModelHealth

Background: Ambient air pollution is suspected to cause lung cancer. We aimed to assess the association between long-term exposure to ambient air pollution and lung cancer incidence in European populations.

Methods: This prospective analysis of data obtained by the European Study of Cohorts for Air Pollution Effects used data from 17 cohort studies based in nine European countries. Baseline addresses were geocoded and we assessed air pollution by land-use regression models for particulate matter (PM) with diameter of less than 10 μm (PM10), less than 2.5 μm (PM2.5), and between 2.5 and 10 μm (PMcoarse), soot (PM2.5 absorbance), nitrogen oxides, and two traffic indicators. We used Cox regression models with adjustment for potential confounders for cohort-specific analyses and random effects models for meta-analyses.

Findings: The 312 944 cohort members contributed 4 013 131 person-years at risk. During follow-up (mean 12・8 years), 2095 incident lung cancer cases were diagnosed. The meta-analyses showed a statistically significant association between risk for lung cancer and PM10 (hazard ratio [HR] 1.22 [95% CI 1.03-1.45] per 10 μg/m3). For PM2.5 the HR was 1.18 (0.96-1.46) per 5 μg/m3. The same increments of PM10 and PM2.5 were associated with HRs for adenocarcinomas of the lung of 1.51 (1.10-2.08) and 1.55 (1.05-2.29), respectively. An increase in road traffic of 4000 vehicle-km per day within 100 m of the residence was associated with an HR for lung cancer of 1.09 (0.99-1.21). The results showed no association between lung cancer and nitrogen oxides concentration (HR 1.01 [0.95-1.07] per 20 μg/m3) or traffic intensity on the nearest street (HR 1.00 [0.97-1.04] per 5000 vehicles per day).

Interpretation: Particulate matter air pollution contributes to lung cancer incidence in Europe.

Source: Raaschou-Nielsen O1, Andersen ZJ, Beelen R, Samoli E, Stafoggia M, Weinmayr G, Hoffmann B, Fischer P, Nieuwenhuijsen MJ, Brunekreef B, Xun WW, Katsouyanni K, Dimakopoulou K, Sommar J, Forsberg B, Modig L, Oudin A, Oftedal B, Schwarze PE, Nafstad P, De Faire U, Pedersen NL, Ostenson CG, Fratiglioni L, Penell J, Korek M, Pershagen G, Eriksen KT, Sørensen M, Tjønneland A, Ellermann T, Eeftens M, Peeters PH, Meliefste K, Wang M, Bueno-de-Mesquita B, Key TJ, de Hoogh K, Concin H, Nagel G, Vilier A, Grioni S, Krogh V, Tsai MY, Ricceri F, Sacerdote C, Galassi C, Migliore E, Ranzi A, Cesaroni G, Badaloni C, Forastiere F, Tamayo I, Amiano P, Dorronsoro M, Trichopoulou A, Bamia C, Vineis P, Hoek G. (2013). Air pollution and lung cancer incidence in 17 European cohorts:prospective analyses from the European Study of Cohorts for Air Pollution Effects (ESCAPE). Lancet Oncol. Vol.14(9):813-822.

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Long-Term Effects:

17 cohort studies based in nine European countries found:

Both PM2.5 & PM10 contribute to lung cancer incidence in EU

Raaschou-Nielsen et al., 2013

Health Effects (4b/8)

Aerosol Climate Tools ModelHealth

Distribution of particulate matter air pollution at participant addresses in each cohort: PM10 concentration (A) and PM2・5 concentration (B) in each of the cohort studies. Pink boxes show median (central vertical line) and 25th and 75th percentiles (ends of box); lines extending from the left of each box show the concentration range from the 10th to the 25th percentile; lines extending from the right of each box show theconcentration range from the 75th to the 90th percentile. The black circles show each concentration below the 10th percentile and above the 90th percentile. PM10 = particulate matter with diameter <10 μm. PM2.5 = particulate matter with diameter <2.5 μm.

Risk for lung cancer according to concentration of particulate matter in each cohort study: HRs for lung cancer according to PM10 concentration (A) and PM2.5concentration (B) in each of the cohort studies, based on confounder model 3. Weights are from random effects analysis. Datapoints show HR; lines show 95% CI; boxes show the weight with which each cohort contributed to the overall HR; vertical dashed line shows overall HR. HR = hazard ratio.

Source: Raaschou-Nielsen O1, Andersen ZJ, Beelen R, Samoli E, Stafoggia M, Weinmayr G, Hoffmann B, Fischer P, Nieuwenhuijsen MJ, Brunekreef B, Xun WW, Katsouyanni K, Dimakopoulou K, Sommar J, Forsberg B, Modig L, Oudin A, Oftedal B, Schwarze PE, Nafstad P, De Faire U, Pedersen NL, Ostenson CG, Fratiglioni L, Penell J, Korek M, Pershagen G, Eriksen KT, Sørensen M, Tjønneland A, Ellermann T, Eeftens M, Peeters PH, Meliefste K, Wang M, Bueno-de-Mesquita B, Key TJ, de Hoogh K, Concin H, Nagel G, Vilier A, Grioni S, Krogh V, Tsai MY, Ricceri F, Sacerdote C, Galassi C, Migliore E, Ranzi A, Cesaroni G, Badaloni C, Forastiere F, Tamayo I, Amiano P, Dorronsoro M, Trichopoulou A, Bamia C, Vineis P, Hoek G. (2013). Air pollution and lung cancer incidence in 17 European cohorts: prospective analyses from the European Study of Cohorts for Air Pollution Effects (ESCAPE). Lancet Oncol. Vol.14(9):813-822.

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Long-Term Effects:

Traffic-related air pollution and mortality in participants of the Netherlands Cohort study

Risk of:i) cardiopulmonary, i) non-cardiopul. non-lung cancer, i) mortality

associated with long-term exposure to traffic related air pollution.

Hoek et al., 2002

Health Effects (4c/8)

Aerosol Climate Tools ModelHealth

Background: Long-term exposure to particulate matter air pollution has been associated with increased cardiopulmonary mortality in the USA. We aimed to assess the relation between traffic-related air pollution and mortality in participants of the Netherlands Cohort study on Diet and Cancer (NLCS), an ongoing study.

Methods: We investigated a random sample of 5000 people from the full cohort of the NLCS study (age 55–69 years) from 1986 to 1994. Long-term exposure to traffic-related air pollutants (black smoke and nitrogen dioxide) was estimated for the 1986 home address. Exposure was characterised with the measured regional and urban background concentration and an indicator variable for living near major roads. The association between exposure to air pollution and (cause specific) mortality was assessed with Cox’s proportional hazards models, with adjustment for potential confounders.

Findings: 489 (11%) of 4492 people with data died during the follow-up period. Cardiopulmonary mortality was associated with living near a major road (relative risk 1·95, 95% CI 1·09–3·52) and, less consistently, with the estimated ambient background concentration (1·34, 0·68–2·64). The relative risk for living near a major road was 1·41 (0·94–2·12) for total deaths. Non-cardiopulmonary, non-lung cancer deaths were unrelated to air pollution (1·03, 0·54–1·96 for living near a major road).

Interpretation: Long-term exposure to traffic-related air pollution may shorten life expectancy.

Figure: Distribution of long-term average black smoke and nitrogen dioxide exposures at the 1986 home address.

Table: Risk of cardiopulmonary, non-cardiopulmonary non-lung cancer, and all-cause mortality associated with long-term exposure to traffic related air pollution, NLCS subcohort 1986–94.Values are relative risk (95% CI). Values are calculated for concentration changes from the 5th to the 95th percentile. For black smoke, this was rounded to 10 g/m3, for NO2 30 g/m3. Adjusted for age, sex, education, Quetelet-index, occupation, active and passive cigarette smoking, and neighbourhood socioeconomic score. *Models 1 and 3 contain the background concentration and an indicator variable for living near a major road. Models 2 and 4 contain an estimate of the home address concentration, by adding to this background concentration a quantitative estimate of living near a major road. Major road is an indicator variable (0/1, 1 indicating living near a major road). †Adjusted for confounders. ‡For individuals living 10 years or longer at their 1986 address, adjusted for above confounders.

Source: Hoek G, Brunekreef B, Goldbohm S, Fischer P, van den Brandt PA. (2002) Association between mortality and indicators of traffic-related air pollution in the Netherlands: a cohort study. Lancet. Vol.360(9341):1203-1209.

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Long-Term Effects:

Neurodegenerative effects

Multiple Sclerosis [2], Bizzozero et al., 2005

Alzheimer’s D. [3], Sayre et al., 1997

Parkinson’s D. [4], Zhang et al., 1999

Amyotrophic Lateral Sclerosis [5], Shibata et al., 2001

Creutzfeldt-Jakob Disease [6] Jablonka & Lamb, 2002

Health Effects (5a/8)

Aerosol Climate Tools ModelHealth

Olfactoric deposition, absorption via the associated epithelium and translocation along the olfactory nerve contributes to significant inflammatory and neurodegenerative changes in the olfactory mucosa, the associated bulb, and cortical as well as in the sub-cortical brain structures .... Campbell etal. (2005) and Veronesi etal .... found significant increases of tumor necrosis factor-α or decreases in dopaminergic neurons, supporting the hypothesis of ambient PM causing neuro-degenerative disease .... A study by Calderon- Garciduenas etal. (2002) may also point to an interesting link between air pollution and CNS effects: these authors described significant inflammatory or neurodegenerative changes in the olfactory mucosa, olfactory bulb, and cortical and subcortical brain structures in dogs from a heavily polluted area in Mexico City, whereas these changes were not seen in dogs from a less-polluted rural control city. [1]Exposure to airborne nanoparticles at certain occupational settings should also be considered in the context of CNS effects. For example, arc welding generates large number concentrations of ultrafine and fine metal oxide particles ...., and a recent epidemiological study suggested an increased risk of welders to develop Parkinson’s Disease almost 20 years earlier than the general population .... Manganese in welding fumes is a known neurotoxicant ...., and its ultrafine particle size in welding fumes could potentially facilitate translocation to the CNS. Studies in rats show efficient translocation of inhaled nano-sized Mn-oxide to the olfactory bulb in rats [1a]Other studies go even that far as to link nanoparticle exposure to the development of Multiple Sclerosis [2], Alzheimer’s D. [3], Parkinson’s D. [4], and Amyotrophic Lateral Sclerosis [5].

Source:[1] Oberdörster G., Oberdörster E., Oberdörster J. (2005). Nanotoxicology: An Emerging Discipline Evolving from Studies of Ultrafine Particles; Environmental Health Perspective Vol. 113, No.7: 823-839, p.827-828; p.833;[1a] Supplemental Material available online (http://ehp.niehs.nih. gov/members/2005/7339/supplemental.pdf) p.20;[2] Bizzozero O.A., DeJesus G., Bixler H.A., Pastuszyn A. (2005). Evidence of nitrosative damage in the brain white matter of patients with multiple sclerosis. Neurochem Res., 30(1): 139-49,[3] Sayre L.M., Zelasko D.A., Richey P.L., Perry G., Salomon R.G., Smith M.A. (1997); 4-Hydroxynonenal-derived advanced lipid peroxidation end-products are increased in Alzheimers disease. J Neurochem 68: 20922097.[4] Zhang J., Perry G., Smith M.A., Robertson D., Olson S.J., Graham D.G., Montine T.J. (1999). Parkinsons Disease is Associated with Oxidative Damage to Cytoplasmic DNA and RNA in Substantia Nigra Neurons, American Journal of Pathology, Vol. 154, No. 5.[5] Shibata N., Nagai R., Uchida K., Horiuchi S., Yamada S., Hirano A., Kawaguchi M., Yamamoto T., Sasaki S. and Kobayashi M. (2001). Morphological evidence for lipid peroxidation and protein glycoxidation in spinal cords from sporadic amyotrophic lateral sclerosis patients. Brain Res. 917: 97104.[6] JABLONKA E, LAMB M.J. (2002). The Changing Concept of Epigenetics. Ann. N.Y. Acad. Sci. 981: 82–96.

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Neurodegenerative effects

NPs interfere with convective bulk flow ….

Health Effects (5b/8)

…. similar to blockages of macrophages induced in tatoos

Ultrasonic Subcutanoeus Injection

ABC ABC ––Tatoo.mp4Tatoo.mp4 Iliff et al., 2012

Aerosol Climate Tools ModelHealth

Because it lacks a lymphatic circulation, the brain must clear extracellular proteins (and xenobiotics like nano-particles) by an alternative mechanism. The cerebrospinal fluid (CSF) functions as a sink for brain extracellular solutes, but it is not clear how solutes from the brain interstitium move from the parenchyma to the CSF. We demonstrate that a substantial portion of subarachnoid CSF cycles through the brain interstitial space.Since an exposed individual is constantly embedded into the cocktail of atmospheric particle mix (exposed to ambient aerosol concentration), flushing has limited effects as with every breath freshly inhaled nano-particles are routed through the CSF-circulatory system, thus substituting an older nano-particle load with a newer one.

Source: Iliff JJ., Wang MH, Liao YH, Plogg BA, Peng WG, Gundersen GA, Benveniste H, Vates GE, Deane R, Goldman SA, Nagelhus EA, Nedergaard M. (2012). A Paravascular Pathway Facilitates CSF Flow Through the Brain Parenchyma and the Clearance of Interstitial Solutes, Including Amyloid β. Science Translational Medicine Vol. 4 (147): 111;

http://www.abc.net.au/catalyst/stories/4052689.htm

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Neurodegenerative effects

NPs interfere with convective bulk flow ….

Protein-coating occurs (as a natural defense mechanism), agglomeration;

Health Effects (5c/8)

Aerosol Climate Tools ModelHealth

Nano-Particle

Corona complex

coated NPs interact via:• Hydrogen bonds• Van der Waals interactions • Cell recognition is due to bound biomolecules • Serum proteins • Immunological relevant ligands

Monopoli et al., 2012

The search for understanding the interactions of nanosized materials with living organisms is leading to the rapid development of key applications, including improved drug delivery by targeting nanoparticles, and resolution of the potential threat of nanotechnological devices to organisms and the environment. Unless they are specifically designed to avoid it, nanoparticles in contact with biological fluids are rapidly covered by a selected group of biomolecules to form a corona that interacts with biological systems. Here we review the basic concept of the nanoparticle corona and its structure and composition, and highlight how the properties of the corona may be linked to its biological impacts. We conclude with a critical assessment of the key problems that need to be resolved in the near future.Insert: The nanoparticle–corona, rather than the bare nanoparticle, that interacts with biological machinery, here with a cell membrane receptor.Image: Relevant processes (arrows), in both directions (on/off), for a nanoparticle interacting with a receptor. Biomolecules in the environment adsorb strongly to the bare nanoparticle surface (k1), forming a tightly bound layer of biomolecules, the ‘hard’ corona, in immediate contact with the nanoparticle. Other biomolecules, the ‘soft’ corona, have a residual affinity to the nanoparticle–hard-corona complex (primarily to the hard corona itself), but this is much lower, so those molecules are in rapid exchange with the environment (k2). If sufficiently long-lived in the corona, a biomolecule may lead to recognition of the nanoparticle–corona complex as a whole by a cell-membrane receptor (k3). The same biomolecule alone can also be recognized by the receptor (k4). If present, the bare surface of the nanoparticle may also interact with cell surface receptors (k5) or other constituents of the cell membrane. Proteins adapted from Protein Data Bank.

Source: Monopoli, M.P., et al., Biomolecular coronas provide the biological identity of nanosized materials. Nat Nano, 2012. 7(12): p. 779-786.

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Neurodegenerative effects

NPs interfere with bulk flow ….

Health Effects (5e/8)

Aerosol Climate Tools ModelHealth

→ NPs affecting astrocytomes;→ NPs inducing neuronal degeneration;→ NPs adversely affecting cognitive & social functions;

• PM levels are associated with worsening of mental health;• chronic PM2.5 exposure increases risk of depressive symptoms;• severe depressive symptoms are associated with increased levels of NO2;• short-term exposition to elevated NO2, PM10 & O3 increased number of suicides;• increased risk of autism with higher exposure to PM2.5 during pregnancy and

NO2 levels in early life.

Mueller, 2019Buoli, et al., 2018

Ulanbator w/ peak values up to 3300 μg/m3 PM2.5

What does PM 2.5 do inside children's body and brains.mp4

In Ulaanbaatar about 60 % of the inhabitants live in Gers (typical mongolian tents). As they are often the poorest of the poor, they lack infrastructure, with neither water supply nor sewage system, and during the cold winter months they burn almost everything including coal …. Polluted air are responsible for miscarriages and premature births, with newborns having a lower weights than babies from areas with clean air. In addition, respiratory diseases such as bronchitis and asthma are prevalent with the lung function up to 40 % lower than that of their peers in rural Mongolia. Thus, pneumonia is the second leading cause of death for children under the age of five. Pneumococcal vaccination is the only short term remedy. Long term effects of air pollution however concern the damage to glia cells (astrocytes), which are important for mental work and social competence.[1]Air pollution impacts mental health:[2]• PM levels are associated with worsening of mental health (effect size 0.18–0.78 for each increase of 10 μg/m3 of the air pollutant concentration);• chronic PM2.5 exposure increases risk of depressive symptoms (effect size: 0.05–0.81 for each increase of 5–10 μg/m3 of air pollutant concentrations); •severe depressive symptoms are associated with increased levels of NO2 especially in summer (effect size: 0.05 for each increase of 12.8 ppb mean concentration of air pollutant and 1.77 for each increase of 20.01 ppb mean concentration of air pollutant) and PM10 especially in winter (effect size d: 0.09–1.11);• short-term exposition to elevated NO2 levels (effect size: 0.08 for each increase in the interquartile range of pollutant concentrations), PM10 (effect size: 0.06 for each increase in the interquartile range of pollutant concentrations) and O3 (effect size: 0.02 for one unit increase of air pollutants-0.49 for correlation between pollutant concentrations and number of suicides);• increased risk of autism would be associated with higher exposure to PM2.5 (effect size: 0.08–0.27 for each increase in the interquartile range of mean pollutant concentrations) during pregnancy and NO2 (effect size d: 0.19–0.60) in early life.

Image: Hypothesized link between air pollution and mental health.[2]

Source: [1] Mueller M (2019) Die Mongolen ringen nach Atem (Mongolians struggle for air). NZZ [2] Buoli M, Grassi S, Caldiroli A, Carnevali GS, Mucci F, Iodice S, Cantone L, Pergoli L, BollatiV (2018) Is there a link between air pollution and mental disorders? Environment International 118 (2018) 154–168

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Neurodegenerative effects

Metallic NPs enter via ….

Health Effects (5e/8)

Aerosol Climate Tools ModelHealth

→ olfactory system;→ modifying olfactory sensation

(Cd has an estrogenic effect, disrupting hypothalamic-pituitary-gonadal axis);

→ inducing ROS formation;→ inducing apoptosis;

Vallero, 2014

A number of other metals are suspected of being neurotoxic, especially cadmium (Cd) and the metalloid arsenic (As) .... Normally in adults, Cd seldom crosses the blood-brain barrier; actually, Cd enters via the nasal exposure route. As such, Cd can move along the primary olfactory neurons to their terminations in the olfactory bulbs. The olfactory route is a plausible means of Cd reaching the brain. In addition, Cd has been shown to damage olfactory sensation. Upon entry into neurons, Cd induces a decrease in the activity of glutathione peroxidase catalase and super oxide dismutase, producing an increase in free radicals. This free radicals increase lipid peroxidation, which disrupts both cellular and mitochondrial membranes. This increases apoptosis and induces genetic damage. The net effect is a combination of these impacts and the extent to which metallothionein is activated, which scavenges free radicals and chelates Cd. The degradation of membrane potentials stimulates the release of a cytochrome enzyme.

Image: Potential mechanisms of cadmium (Cd) neurotoxicity. (1) Cd-induced neuron cell apoptosis and formation of a reactive oxygen species (ROS) are mediated through Ca2+-mitochondria signaling and Ca2+-membrane channels. (2) Cd impaired neurogenesis. (3) Cd accumulation in the brain, which in turn alters gene expression and epigenetic effect. (4) Cd has estrogenic or anti-androgenic effect, which can disrupt hypothalamic-pituitary-gonadal (HPG) axis. These potential mechanisms have possible, simultaneous interactions. The solid black arrows represent the stimulation, the solid black line segments indicate the inhibition, and the dotted lines represent the negative feedback control of the HPG axis.

Source: Vallero D (2014) Fundamentals of Air Pollution, 5th ed., Ch.13 (Neurological effects of Air Pollutants) Academic Press, USA

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Long-Term Effects:

Epigenetic Effects: Reversible changes in DNA function, without changing the DNA sequence.

Willet, 2002

Health Effects (6a/8)

• in polygenic inherited diseases only 30% probability of phenotypic expression

• evidence assign epigenetics a far more significant role

Aerosol Climate Tools ModelHealth

In fact, only 5% of cancer and cardiovascular patients can attribute their disease to heredity.[2] While the media made a big hoopla over the discovery of the BRCAI and BRCA2 breast cancer genes, they failed to emphasize that ninety-five percent of breast cancers are not due to inherited genes. The malignancies in a significant number of cancer patients are derived from environmentally-induced epigenetic alterations and not defective genes …. Genetic and environmental factors, including diet and life-style, both contribute to cardiovascular disease, cancers, and other major causes of mortality, but various lines of evidence indicate that environmental factors are most important. Overly enthusiastic expectations regarding the benefits of genetic research for disease prevention have the potential to distort research priorities and spending for health. However, integration of new genetic information into epidemiologic studies can help clarify causal relations between both life-style and genetic factors and risks of disease. Thus, a balanced approach should provide the best data to make informed choices about the most effective means to prevent disease.[2]

Image: Percentage of colon cancer, stroke, coronary heart disease, and type 2 diabetes that is potentially preventable by life-style modifications.[2]For colon cancer, the low-risk definition includes body mass index <25 kg/m2, physical activity equivalent to >30 min per day of brisk walking, folic acid supplement of 100 mg per day or more, less than three alcoholic drinks per day, lifetime non-smoking, and fewer than three servings of red meat per week. For stroke (unpublished data) and coronary heart disease, the low-risk definition includes nonsmoking, a good diet (incorporating low intake of saturated and trans fat and glycemic load and adequate intake of polyunsaturated fat, N-3 fatty acids, cereal fiber, and folic acid), body mass index <25 kg/m2, physical activity equivalent to >30 min per day of brisk walking, and moderate alcohol consumption. For diabetes, the low-risk definition was similar to that for coronary heart disease except that the dietary score did not include folic acid or N-3 fatty acids.

Small Image: Multifactorial causes of disease. This sketch is intended to show a sample disease which is caused by polygenic factors yet at the same time subject to environmental modulation. The occurrence of the four gene variants responsible for this disease was determined in epidemiological studies for a given diseased population group. In addition, the figure shows that the genetic predisposition along with other environmental / lifestyle factors have a severe influence to trigger the disease process. Furthermore, it becomes obvious that variants of gene A appear to have a greater influence on the disease pattern than variants B to C of the same gene.[4]

Source: [4] http://www.embryology.ch/allemand/kchromaber/genom01.html[1] Lipton B. (2005) Biology of Belief. Elite Books, p.51 & 72[2] Willett W.C. (2002) Balancing Life-Style and Genomics Research for Disease Prevention. Science 296: 695 – 698

Source: http://www.embryology.ch/allemand/kchromaber/genom01.htmlLipton B. (2005) Biology of Belief. Elite Books, p.51 & 72Willett W.C. (2002) Balancing Life-Style and Genomics Research for Disease Prevention. Science 296: 695 – 698

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Long-Term Effects:

Epigenetic Effects: Reversible changes in DNA function, without changing the DNA sequence.

Madl, 2012

Health Effects (6b/8)

Aerosol Climate Tools ModelHealth

• DNA methylation (-CH3)

• histone modifications

• mRNA silencing

How environmental influences leave their traces on our epigenome.

Image: Top-L: Environmental influences, exposure to constituents in the water we drink, the food we eat, the air we breath along with stress and emotions, can epigenetically modify genes, without changing the nucleotide sequence. The numbers above outline hierarchical interdependences of eco-systemic relationship in which the organism is embedded in.Top-R: Potential mechanism linking environmental exposures to epigenetic effects. These effects include DNA methylation, histone codes and miRNA expression. The associated changes modify chromatin organization and condensation, gene expression and ultimately disease risk.

Bottom: Supercoiling of DNA via histone mediated proteins trigger a cascade of condensation steps that yield the highly packed mitotic chromosome. Highlighted are the various levels of epigenetic modulation. Methylation at base-level (5-Met-Cysteine) represses gene activity and boosts chromatin compaction, histone-tail modification (e.g. di-methylation, acetylation, etc.) alters DNA-wrapping thereby act de-/activating.

Source: Madl P (2012) Exposure to Nano-Sized Particles and the Emergence of Contemporary Diseases with a Focus on Epigenetics, Ch.14. In: Khare M (ed) Air Pollution - Monitoring, Modelling and Health. InTech Publ. Croatia.

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Long-Term Effects:

Epigenetic Effects: Reversible changes in DNA function, without changing the DNA sequence.

Clark & Molloy, 2017

Health Effects (6c/8)

Aerosol Climate Tools ModelHealth

• 2-fold pathway:

- conventionally via genetic pathway (artificially knocking down p53 and over expression of KRASV12 & c-MYC)

- epigenetically via CSC-exposure led to progressive and extensive changes in DNA methylation, implicating epigenetic mechanisms as key drivers of the pro-oncogenic changes.

How genetic and epigenetic events synergize to generate the oncogenic state is not well understood. In this issue of Cancer Cell, Vaz et al. provide compelling evidence that exposure to chronic cigarette smoke causes progressive epigenetic alterations that prime for key genetic events to drive the development of lung cancer.

Introduction of KRASV12 led to greatly increased clonogenicity in soft agar and the ability to form tumors in immune-compromised mice …. CSC exposure had led to progressive and extensive changes in DNA methylation, implicating epigenetic mechanisms as key drivers of the prooncogenic changes induced by CSC …. environmentally induced epigenetic change can substitute for genetically driven alteration in cancer and provide a fertile ground for oncogenic transformation, in this case by a single mutant KRAS gene

Image: An Alternate Epigenetic Route to Oncogenic Transformation. HBEC cells (left) immortalized with hTERT and mCdk4 are anchorage dependent and have epithelial cell morphology. The lower, genetic pathway shows sequential knockdown of p53 expression, followed by expression of mutant KRASV12 and c-MYC overexpression necessary for full transformation. The upper, epigenetic pathway shows progressive changes in response to CSC, leading to epithelial-mesenchymal transition, altered signaling pathways, and the capacity to form colonies in soft agar. Subsequent introduction of mutant KRASV12 provides full tumorigenic transformation. Cells from both pathways (right) show fibroblastic morphology and can form colonies in soft agar and tumors in immune-compromised mice.

Source: Clark SJ, Molloy PL (2017) Smoke-Induced Changes to the Epigenome Provide Fertile Ground for Oncogenic Mutation. Cancer Cell. Vol.32(3): 278-280. doi: 10.1016/j.ccell.2017.08.016.

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Long-Term Effects:

Epigenetic Effects: Reversible changes in DNA function, without changing the DNA sequence.

Vaz et al, 2017

Health Effects (6d/8)

Aerosol Climate Tools ModelHealth

• long-term exposure of untransformed human bronchial epithelial cells to cigarette smoke condensate induces epigenetic changes

• so how it comes that cancer risk in ex-smokers is lower?

• this is only true if one quits “in time”, thus the entrained cells maintain their antitumor “robustness” for a while

• continuous smoking mediates single-step transformation (oncogene KRAS); i.e. >15 mths

• 10-15 mths cell cultures equiv. to 20-30 yrs of smoking

We define how chronic cigarette smoke-induced time-dependent epigenetic alterations can sensitize human bronchial epithelial cells for transformation by a single oncogene. The smoke-induced chromatin changes include initial repressive polycomb marking of genes, later manifesting abnormal DNA methylation by 10 months. At this time, cells exhibit epithelial-to-mesenchymal changes, anchorage-independent growth, and upregulated RAS/MAPK signaling with silencing of hypermethylated genes, which normally inhibit these pathways and are associated with smoking-related non-small cell lung cancer. These cells, in the absence of any driver gene mutations, now transform by introducing a single KRAS mutation and form adenosquamous lung carcinomas in mice. Thus, epigenetic abnormalities may prime for changing oncogene senescence to addiction for a single key oncogene involved in lung cancer initiation.

Image: First, by 10–15 months the cells become anchorage independent and form clonesin soft agar (Figures 6A and 6B). At this time point, when these CSC-exposed cells are grown in medium containing5%fetal bovine serum they become more elongated …. However, despite these changes, neither the CSC-exposed cells nor the isolated soft agar clones could form tumors in vivo …. Only KRASV12 alters the 15-month CSC-treated cells, while neither affects the 6-month CSC-exposed cells or their respective controls …. Most important, with exogenous expression of KRASV12 but not TP53 downregulation, the CSC-treated cells are now transformed. Neither of the genetic manipulations transformed control cells. KRASV12-expressing 15-month CSC-exposed cells from both replicates induce tumors at different rates in mice, which begin appearing 3 weeks post injection and grow to an average size ranging from 500 to 900 mm3.

Source: Vaz M, Hwang SY, Kagiampakis I, Phallen J, Patil A, O'Hagan HM, Murphy L, Zahnow CA, Gabrielson E, Velculescu VE, Easwaran HP, Baylin SB (2017) Chronic Cigarette Smoke-Induced Epigenomic Changes Precede Sensitization of Bronchial Epithelial Cells to Single-Step Transformation by KRAS Mutations. Cancer Cell. Vol.32(3): 360-376.e6. doi: 10.1016/j.ccell.2017.08.006.

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Epigenetic Effects: Reversible changes in DNA function, without changing the DNA sequence.

Pearson, 2002

Health Effects (6e/8)

Bookmarking: transmitting cellular memory of the pattern of gene expression in a cell, throughout mitosis, to daughter cells of same generation (i.e.: liver cells divide into liver cells and not some other cell type).

• DNA methylation (-CH3)

• histone modifications

• mRNA silencing

Ghost in Your Ghost in Your Genes Genes ––

Lamarck.mp4Lamarck.mp4

Aerosol Climate Tools ModelHealth

Bookmarking is a biological phenomenon believed to function as an epigenetic mechanism for transmitting cellular memory of the pattern of gene expression in a cell, throughout mitosis, to its daughter cells. This is vital for maintaining the phenotype in a lineage of cells so that, for example, liver cells divide into liver cells and not some other cell type.

Source: Pearson H. (2002) What is a Gene? Nature 441: 399-401

https://www.youtube.com/watch?v=fMxgkSgZoJs

http://www.bbc.co.uk/sn/tvradio/programmes/horizon/ghostgenes.shtml

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Long-Term Effects:

Epigenetic Effects: Reversible changes in DNA function, without changing the DNA sequence.

WHO, 2012

Health Effects (6f/8)

Aerosol Climate Tools ModelHealth

Confirmed cancerogenic effects

• Lung cancer

• Bladder cancer (increased risk)

due to exposure to Diesel Exhaust Particles (vehicular, trains, ships* power generators)

In June, 2012, 24 experts from seven countries met at the International Agency for Research on Cancer (IARC; Lyon, France)to assess the carcinogenicity of diesel and gasoline engine exhausts, and some nitroarenes. These assessments will be published as Volume 105 of the IARC Monographs.

Source: WHO (2012) IARC: Diesel Engine Exhaust Carcerogenig. Press Release No. 213; …. Based on:

Benbrahim-Tallaa L, Baan RA, Grosse Y, Lauby-Secretan B, El Ghissassi F, Bouvard V, Guha N, Loomis D, Straif K; International Agency for Research on Cancer Monograph Working Group (2012) Carcinogenicity of diesel-engine and gasoline-engine exhausts and some nitroarenes. Lancet Oncol. Vol.13(7):663-664.

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Long-Term Effects:

Epigenetic Effects: Reversible changes in DNA function, without changing the DNA sequence.

Pearson, 2002

Health Effects (6g/8)

Paramutation: the characteristic of a gene is "remembered" and seen in later generations, even if that particular version of the gene is no longer present.

• DNA methylation (-CH3)

• histone modifications

• mRNA silencing Ghost in Your Genes Ghost in Your Genes ––Jirtle.mp4Jirtle.mp4

Aerosol Climate Tools ModelHealth

Paramutation is a phenomenon whereby the characteristic of a gene is "remembered" and seen in later generations, even if that particular version of the gene is no longer present. It is an interaction between two alleles of a single locus, resulting in a heritable change of one allele that is induced by the other allele …. What may be transmitted in such a case are RNAs such as piRNAs, siRNAs, miRNAs or other regulatory RNAs. These are packaged in egg or sperm and cause paramutation upon transmission to the next generation. This means that RNA is a molecule of inheritance, just like DNA.

Source: Pearson H. (2002) What is a Gene? Nature 441: 399-401

https://www.youtube.com/watch?v=fMxgkSgZoJs

http://www.bbc.co.uk/sn/tvradio/programmes/horizon/ghostgenes.shtml

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Epigenetic Effects: Reversible changes in DNA function, without changing the DNA sequence.

Madl, 2012

Health Effects (6h/8)

• DNA methylation (-CH3)

• histone modifications

• mRNA silencing

Aerosol Climate Tools ModelHealth

Paramutation on the other hand, regards the quasi innheritance of gene-characteristics (allelic interactions) that are "remembered" and seen in later generations (e.g. via the germ cell linage). Paramutation occurs when certain alleles impose an epigenetic imprint on susceptible (paramutable) alleles. The epigenetic imprint is inherited through meiosis and persists even after the two interacting alleles segregate in progeny. The observation of heritable but reversible changes in gene expression, is evidence for non-Mendelian genetics, is apparent also in the mammalian systems. Paramutation fulfils the criteria for a parental identity mark or "imprint" because it can be established in either the sperm or oocyte by de novo methyl-transferases that act only in one gamete. It can be stably propagated at each embryonic cell division by a maintenance methyl-transferase, and it can be erased in the germ line to reset the imprint in the next generation, either by passive

Image: Epigenotype model of developmental origins of disease. Environmental factors acting in early life (from conception to early infancy) have consequences which become manifest as an altered disease risk in later life. The mother conveys a forecast of the environment it will encounter after birth onto the genome of the unborn. This includes modifications to its metabolism, whole body physiology and growth trajectory appropriately to maximize its chances of postnatal survival. These adaptations become detrimental if the conditions after birth are not the same as the ones encountered during early life. Ac - Histone acetylation/active genes; CH3 - DNA methylation/silent genes.

Source: Madl P (2012) Exposure to Nano-Sized Particles and the Emergence of Contemporary Diseases with a Focus on Epigenetics, Ch.14. In: Khare M (ed) Air Pollution - Monitoring, Modelling and Health. InTech Publ. Croatia.

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Epigenetic Effects: Reversible changes in DNA function, without changing the DNA sequence.

Malley et al, 2017

Health Effects (6i/8)

• 2.7·E6 (18% of total preterm births globally)

• associated with anthropogenic PM2.5

Aerosol Climate Tools ModelHealth

• South & East Asia: highest anthropogenic PM2.5-associated preterm births, as well as the largest contributions to the global total.

Globally, in 2010, the number of PM2.5-associated preterm births was estimated as 2.7·E6

(18% of total preterm births globally) with a low concentration cut-off (LCC) set at 10 μg/m3, and 3.4·E6 (23%) with a LCC of 4.3 μg/ m3. South and East Asia, North Africa/Middle East and West sub-Saharan Africa had the largest contribution to the global total, and the largest percentage of preterm births associated with PM2.5. Sensitivity analyses showed that PM2.5-associated preterm birth estimates were 24% lower when provider-initiated preterm births were excluded, 38–51% lower when risk was confined to the PM2.5 exposure range in the studies used to derive the effect estimate, and 56% lower when mothers who live in households that cook with solid fuels (and whose personal PM2.5

exposure is likely dominated by indoor air pollution) were excluded …. The substantial percentage of preterm births estimated to be associated with anthropogenic PM2.5 (18% of total preterm births globally) indicates that reduction of maternal PM2.5 exposure through emission reduction strategies should be considered alongside mitigation of other risk factors associated with preterm births.

The median percentage of anthropogenic PM2.5-associated preterm births (of all preterm births) was 5.1% for West sub-Saharan Africa, and 6.2% for North Africa/Middle East, compared to 18.1–26.7% and 20.7–29.1% (range across different LCCs) respectively for total PM2.5-associated preterm births …. Countries in South and East Asia had the highest anthropogenic PM2.5-associated preterm births, as well as the largest contributions to the global total.

Image: Percentage of total preterm births which were associated with anthropogenic ambient PM2.5 only in 2010.Source: Malley CS, Kuylenstierna JCI, Vallack HW, Henze DK, Blencowe H, Ashmore MR (2017) Preterm birth associated with maternal fine particulate matter exposure: A global, regional and national assessment. Environment International, Vol.101: 173–182

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Long-Term Effects:

Epigenetic Effects: Reversible changes in DNA function, without changing the DNA sequence.

Zhao et al, 2011

Health Effects (6i/8)

• daily avg preterm borns: 21.5 babies/day

• avg. mass conc. in GuangZhou of NO2: 61.04; PM10: 82.51; SO2: 51.67 μg/m3;

• cumulative effect of NO2, PM10 and SO2reached its peak on day 3-4;

Aerosol Climate Tools ModelHealth

• daily concentrations of air pollutants (NO2, PM10, SO2) correlate with the preterm births.

Background: Over the last decade, a few studies have investigated the possible adverse effects of ambient air pollution on preterm birth. However, the correlation between them still remains unclear, due to insufficient evidences.

Methods: The correlation between air pollution and preterm birth in GuangZhou city was examined by using the Generalized Additive Model (GAM) extended Poisson regression model in which we controlled the meteorological factors, time trends, weather and day of the week. We also adjusted the co-linearity of air pollutants by using Principal Component Analysis. The meteorological data and air pollution data were obtained from the Meteorological Bureau, while the medical records of newborns were collected from the perinatal health database in GuangZhou, China in 2007.

Results: In 2007, the average daily concentrations of NO2, PM10 and SO2 in GuangZhou, were 61.04, 82.51 and 51.67 μg/m3 respectively, where each day an average of 21.47 preterm babies were delivered. Pearson correlation analysis suggested a negative correlation between the concentrations of NO2, PM10, SO2, and temperature as well as rH. The results of single air pollutant model suggested that the cumulative effects of NO2, PM10

and SO2 reached its peak on day 3, day 4 and day 3 respectively. An increase of 100 μg/m3

of air pollutants corresponded to relative risks (RRs) of 1.0542 (95%CI: 1.0080 ~1.1003), 1.0688 (95% CI: 1.0074 ~1.1301) and 1.1298 (95%CI: 1.0480 ~1.2116) respectively.

Conclusions: This study indicates that the daily concentrations of air pollutants such as NO2, PM10, SO2 have a positive correlation with the preterm births in Guangzhou, China.

Image: Average number of preterm births per day by study month in GuangZhou, China in 2007. Descriptive statistical results of premature births shows the variations in preterm births over the entire study period. The average of preterm birth was 21.47 every day in 2007, the quartile range was 8 (P0: 7; P25: 17; P50: 21; P75; 25; P100: 39).Source: Zhao QG, Liang ZJ, Tao SJ, Zhu J, Du YK (2011) Effects of air pollution on neonatal prematurity in GuangZhou of china: a time-series study. Environmental Health, Vol. 10:2

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Long-Term Effects:

Epigenetic Effects: Reversible changes in DNA function, without changing the DNA sequence.

Health Effects (6j/8)

Aerosol Climate Tools ModelHealth

Bookmarking during various stages of gestation (embryo & fetal period)

Ritz & Wilhelm, 2008

Blue bars: time slot when major morphological abnormalities can occur, light blue bars: slots for minor abnormalities and funcitonal defect,yellow bars: overall air pollution associated risks.

The time between conception and birth is perhaps one of the most vulnerable life stages, during which the environment may have tremendous immediate and lasting effects on health. The fetus undergoes rapid growth and organ development and the maternal environment helps direct these processes, for better or for worse. Evidence is accumulating that environmental exposures can cause infants to be born premature (before 37 weeks of gestation) or low weight (less than 2500 grams), or to be born with certain birth defects. These babies are far more likely to die in infancy, and those who survive have high risks of brain, respiratory, and digestive problems in early life. The impact of environmental exposures on fetal development may be far-reaching, as data suggest growth and developmental delays in utero influence the risk for heart disease and diabetes in adulthood.

Image: Life stages between conception and birth with associated air pollution risks from maternal and in utero exposures. Blue bars indicate time periods when major morphological abnormalities can occur, while light blue bars correspond to periods at risk for minor abnormalities and funcitonal defects.

Source: Ritz B, M (2008) Air pollution impacts on infants and children. UCLA Institute of the Environmental and Sustainability. University of CaliforWilhelm nia, Los Angeles (USA)

Avialable online: https://www.ioes.ucla.edu/publication/air-pollution-impacts-on-infants-and-children/

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Long-Term Effects:

Epigenetic Effects: Reversible changes in DNA function, without changing the DNA sequence.

Abraham et al., 2014Prunault, 2015

Chai, 2015

Health Effects (6l/8)

SEPAGE-study investigating the effects of air-pollution of unborn

…. still ongoing …. 1st results shall be available soon

Aerosol Climate Tools ModelHealth

Fetal airFetal air--pollution.mp4pollution.mp4

Exposure of pregnant women to certain phenols could disrupt the growth of boys during the fetal period and early years of life: A research consortium involving Inserm teams, the University Hospital Centres of Nancy and Poitiers, Center for Disease Controls (CDC, Atlanta, USA), and the University of Grenoble (Unit 823), has just published a epidemiological study showing that exposure during pregnancy to certain phenols, including parabens and triclosan, could disrupt the growth of young boys during fetal life and the first few years of life. Bisphenol A was not associated with a modification net of growth.[1] These results were published in [2].

Image: Adjusted associations between maternal urinary concentrations of phenols and weight (A) at birth and (B) at the age of 3 years (Eden cohort, 2003–2006, 520 male newborns). Effect estimates are given for an increase by 1 IQR of ln-transformed phenol standardized concentrations. Adjustment factors for the birth weight analysis: gestational age, maternal and paternal height, pre-pregnancy weight, maternal active and passive smoking during pregnancy, maternal education level, recruitment center, and parity. Adjustment factors for the analysis of weight at 3 years: maternal and paternal height, pre-pregnancy weight, maternal active and passive smoking during pregnancy, maternal education level, recruitment center, parity, and breastfeeding duration.[2]

Source: [1] Remy Slama (2017) Institute Albert Bonniot, INSERM Grenoble (FRA); http://www.inserm.fr/layout/set/print/espace-journalistes/l-exposition-des-femmes-enceintes-acertains-phenols-pourrait-perturber-la-croissance-des-garcons-durant-la-periode-faetale-et-lespremieres-annees-de-vie. [1]

[2] Philippat C, Botton J, Calafat AM, Ye XY, Marie-Alinecd C, Rémy S (2014) Prenatal Exposure to Phenols and Growth in Boys. Epidemiology • Vol.25(5): 625-635.

[3] Prunault D (2015) Dicke Luft – Wenn Staedte ersticken. Arte.tv (https://www.youtube.com/watch?v=jd36m4m9Mfk)[4] Chai J (2015) Under the Dome (https://www.youtube.com/watch?v=MhIZ50HKIp0)

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Long-Term Effects:

Epigenetic Effects: Reversible changes in DNA function, without changing the DNA sequence.

Abraham et al., 2018

Health Effects (6m/8)

First study on air pollutants to focus on the issue based on an analysis of large-scale epigenetic data (more than 400·E3

epigenetic locations

6 CpG (5'-C-phosphate-G-3') showed significantly different methylation levels

Aerosol Climate Tools ModelHealth

A study based on 668 mothers and their children in the EDEN cohort observed that the mothers most exposed to NO2 (produced by automobile, industrial and thermal combustion processes) during their pregnancies presented an epigenetic modification on the ADORA2B gene. Defects in the expression of this gene have in other studies been associated with preeclampsia, a commonly - occurring condition in pregnancy which can be serious if it is not managed. The results of this study thereby confirm part of the hypothesis according to which prenatal exposures to air pollutants, at levels commonly found in EU, could be harmful to the health of the pregnant woman and unborn child. It is the first study on air pollutants to focus on the issue based on an analysis of large-scale epigenetic data (concerning more than 400·E3 epigenetic locations).[1]

Six CpGs (5'-C-phosphate-G-3') showed significantly different methylation levels. Among these, two CpGs had also been identified in the concept-driven analysis: cg07563400 and cg17580614, both located in ADORA2B; these CpGs remained significantly associated with NO2 exposure during the 2nd trimester of pregnancy …. [2]

Image: Environmental exposure across time window (d1,2,3,=day 1, 2, 3 before delivery; w=week before delivery; m=month before delivery; t1,2,3 =trimester 1, 2, 3 and P=whole pregnancy). Manhattan plots of p-values showing the association between environmental exposure (NO2, PM10) and 425,878 CpGs methylation using the agnostic EWAS. Each dot corresponds to the p-value of a CpG site and the horizontal lines indicates the level of statistical significance (FDR p < 0.05).[2]

Source: [1] Leoeuler J (2018) INSERM: https://presse.inserm.fr/wp-content/uploads/2018/06/2018_06-21_CP_Pollutionplacenta_en-US.pdf

[2] Abraham E, Rousseaux S, Agier L, Giorgis-Allemand L, Tost J, Galineau J, Hulin A, Siroux V, Vaiman D, Charles MA, Heude B, Forhan A, Schwartz J, Chuffart F, Bourova-Flin E, Khochbin S, Slama R, Lepeule J, EDENMCCSG (2018) Pregnancy exposure to atmospheric pollution and meteorological conditions and placental DNA methylation. Environment International, Vol.118: 334-347.

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Long-Term Effects:

Epigenetic Effects: Reversible changes in DNA function, without changing the DNA sequence.

Health Effects (6n/8)

Aerosol Climate Tools ModelHealth

Bookmarking during postnatal and early childhood as well as teen windows (newborn-adolescent stage)

Ritz & Wilhelm, 2008

Blue bars: time slot when major morphological abnormalities can occur, light blue bars: slots for minor abnormalities and funcitonal defect,yellow bars: overall air pollution associated risks.

Early childhood is also a critical period for the continued development and maturation of several biological systems such as the brain, lung, and immune system and air toxics can impair lung function and neurodevelopment, or exacerbate existing conditions, such as asthma. Infants who were born premature or growth-retarded may be particularly vulnerable to additional environmental insults, for example, due to immaturity of the lungs at birth. Exactly what compounds in the ambient air most affect reproductive and children’s health, and how these exposures result in restricted fetal growth, early parturition, and development of respiratory diseases remains largely unknown. The study of air pollution’s impact on reproductive outcomes is still a developing area of science with many important questions unanswered, but more evidence is emerging that air pollution exposures in pregnancy and early childhood put children at higher risk of adverse health outcomes. Despite the long history of research linking smoking to poorer birth outcomes and the known similarities in components of cigarette smoke and air pollution, the bulk of all air pollution research targeting reproductive health has been conducted only in the past decade. Recently this research has begun to focus on one specific source of modern-day air pollution -- traffic exhaust.

Image: Potential developmental respiratory problems resulting from in utero exposure to air pollutants. Air pollution exposure has also been more recently linked to respiratory symptoms and illnesses in early life including cough, bronchitis, wheeze and ear infections.

Source: Ritz B, Wilhelm M (2008) Air pollution impacts on infants and children. UCLA Institute of the Environmental and Sustainability. University of California, Los Angeles (USA)

Avialable online: https://www.ioes.ucla.edu/publication/air-pollution-impacts-on-infants-and-children/

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Long-Term Effects:

Epigenetic Effects: Reversible changes in DNA function, without changing the DNA sequence.

Health Effects (6n/8)

Aerosol Climate Tools ModelHealth

.

…. for detailssee

Epigenetics.

for details on epigenetics please refer to the script available at:

http://biophysics.sbg.ac.at/talk/epigenetics-2009.pdf

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Immune System Conditioning (1/3)

Allergy

• PM2.5-DEPs are respirable;• grass pollen allergen Lol-p1

attach to DEP;• Immuno-gold labelling of

Lol-p1 monoclonal antibodies,

• Allergen-DEP interaction –concentration of allergens in polluted air thus triggering attacks of asthma!

DEP-fractal aggregate

Au-particle

Knox et al., 1997

2 nm

Aerosol Climate Tools ModelHealth

Background Grass pollen allergens are known to be present in the atmosphere in a range of particle sizes from whole pollen grains (approx. 20 to 55 μim in diameter) to smaller size fractions < 2.5 μm (fine particles, PM2.5). These latter particles are within the respirable range and include allergen-containing starch granules released from within the grains into the atmosphere when grass pollen ruptures in rainfall and are associated with epidemics of thunderstorm asthma during the grass pollen season.

Methods We used diesel exhaust particles (DEP) derived from the exhaust of a stationary diesel engine, natural highly purified Lol-p1, immuno-gold labelling with specific monoclonal antibodies and a high voltage TEM imaging technique.

Results DEP are visualized as small carbon spheres, each 30–60 nm in diameter, forming fractal aggregates about 1–2 μm in diameter. Here we test our hypothesis and show by in vitro experiments that the major grass pollen allergen, Lol-p1. binds to one defined class of fine particles, DEP.

Conclusion DEP are in the respirable size range, can bind to the major grass pollen allergen Lol p1 under in vitro conditions and represent a possible mechanism by which allergens can become concentrated in polluted air and thus trigger attacks of asthma.

Image: Interaction of DEP with natural rye-grass pollen allergens. Aggregates of DEP after exposure to Lol-p1 and immuno-gold labeling of the allergen molecules. Note that Au-particles, imaged as 10 nm discs decorating DEP, which locate binding of allergen to carbon particles.

Source: Knox RB, Suphioglu C, Taylor P, Desai R, Watson HC, Peng JL, Bursill LA (1997). Major grass pollen allergen Lol p 1 binds to diesel exhaust particles (DECP): implications for asthma and air pollution. Clinical and Experimental Allergy Vol.27: 246-251.

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Immune System Conditioning (2/3)

Allergy

• UFP exposure 24 hours before allergen challenge significantly increase:inflammatory cell infiltrate, IL-4, IL-5, & IL-13.

• Effect observable even 4 days before allergen challenge.

• Controls do not show this correlation.

Alessandrini et al, 2006

Aerosol Climate Tools ModelHealth

Method: The effects of ultrafine particle inhalation on allergic airway inflammation was analyzed in ovalbumin-sensitized mice and nonsensitized controls. Particle exposure (526 μg/m3, 24 hours) was performed 24, 96, or 168 hours before or 24 or 72 hours after ovalbumin aerosol challenge. Allergic inflammation was analyzed at different time points after allergen challenge by means of bronchoalveolar lavage cell count and cytokine/total protein assays, lung histology, and airway hyperresponsiveness.

Results: In sensitized mice, inhalation of ultrafine particles 24 hours before allergen challenge caused a significant increase of bronchoalveolar lavage inflammatory cell infiltrate, protein, IL-4, IL-5, and IL-13 compared with relevant controls. These adjuvant effects were dose- and time-dependent and were still present when particle exposure was performed 4 days before allergen challenge. The adjuvant effect of ultrafine particles was also documented by increased mucus production, peribronchiolar and perivascular inflammation, and enhanced airway hyperresponsiveness. In contrast, particle exposure in sensitized mice after allergen challenge caused only moderate effects, such as a delay of inflammatory infiltrate and a reduction of cytokines in bronchoalveolar lavage fluid.

Conclusion: Exposure to ultrafine carbon particles before allergen challenge exerts strong adjuvant effects on the manifestation of allergic airway inflammation. Allergen-sensitized individuals may therefore be more susceptible to detrimental health effects of ultrafine particles.

Source: Alessandirni F., Schulz H., Takenaka S., Lentner B., Karg E., Behrendt H., Jakob T. (2006): Effects if ultrafine carbon particle inhalation on allergic inflammation of the lung. J.Allergy Clin. Immunology; 117:824-830.

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Immune System Conditioning (3/3)

Allergy

• PAH significantly enhances basophil activation of birch pollen allergic individuals up to 95%.

• Single PAHs significantly boost IL-8 secretion from sensitized basophils.

• None of the basophil samples from healthy controls showed any PAH effect on mediator release.

Lubitz et al, 2009

• Diesel exhaust particles (DEPs) contribute to the increased prevalence and morbidity of asthma and allergic rhinitis. PAHs are major components of DEPs.

Aerosol Climate Tools ModelHealth

Basophil granulocytes, sometimes referred to as basophils, are the least common of the granulocytes, representing about 0.01% to 0.3% of circulating white blood cells.

Diesel exhaust particles (DEPs) act as adjuvants in the immune system and contribute to the increased prevalence and morbidity of asthma and allergic rhinitis. Polycyclic aromatic hydrocarbons (PAHs) are major components of DEPs, which may be involved in the induction and enhancement of proallergic processes.

Method: Heparinized blood samples from birch pollen allergic and control donors were stimulated with Bet v 1, the major allergen of birch pollen grains, alone or together with a mixture of 16 environmental prominent PAHs (EPA-PAH standard). Flow cytometric analysis was performed for quantitative determination of PAH-enhanced basophil activation. To assess direct PAH effects on basophils, enriched cultures from both donor groups were exposed to benzo[a]pyrene (B[a]P) or phenanthrene (Phe), two major DEP-PAHs, with and without allergen. Supernatants were assayed for IL-4 and IL-8 secretion and histamine release by means of ELISA.

Results: At environmental relevant exposure levels EPA-PAH standard synergized with antigen and significantly enhanced basophil activation of all birch pollen allergic individuals up to 95%. Single PAHs significantly drove IL-8 secretion from sensitized basophils of all patients tested, and there was no further enhancement by addition of rBet v 1. B[a]P and Phe also significantly induced IL-4 secretion, a key factor for Th2 development, from purified sensitized basophils in the absence of antigen suggesting an adjuvant role of DEP-PAHs in allergic sensitization. None of the basophil samples from healthy controls showed any PAH effect on mediator release.

Conclusion: DEP-PAHs exert proallergic effects on sensitized basophils in an allergen independent fashion, suggesting a potential role of these pollutants for the allergic breakthrough in atopic individuals, who have not developed an allergic disease yet.

Source: Lubitz S., Schober W., Pusch G., Effner R., Klopp N., Behrendt H., Buters J.T.M. (2009). Polycyclic Aromatic Hydrocarbons from Diesel Emissions Exert Proallergic Effects in Birch Pollen Allergic Individuals Through Enhanced Mediator Release from Basophils. EnvironmentalToxicology, Vol.25 (2): 188-197.

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BioAerosols (1/3)

• Pollen grains are too large to penetrate bronchi; Troyan effect: rupture of humified pollen release

• ~750 μm-sized starch granules & • 1000s of cytoplasmic nano-debris• penetrate broncholi & trigger Thunderstorm

asthma

Pollen & Asthma:

Suphioglu et al., 1992

ABC ABC –– ThunderstormThunderstorm--Asthma.mp4Asthma.mp4Rye grass pollen rupture.mp4Rye grass pollen rupture.mp4

5 μm

1 μm

Aerosol Climate Tools ModelHealth

It is widely known and accepted that grass pollen is a major outdoor cause of hay fever. Moreover, grass pollen is also responsible for triggering allergic asthma, gaining impetus as a result of the 1987/1989 Melbourne and 1994 London thunderstorm-associated asthma epidemics. However, grass pollen is too large to gain access into the lower airways to trigger the asthmatic response and micronic particles d5 ím are required to trigger the response. We have successfully shown that ryegrass pollen ruptures upon contact with water, releasing about 700 starch granules which not only contain the major allergen Lol p 5, but have been shown to trigger both in vitro and in vivo IgE-mediated responses. Furthermore, starch granules have been isolated from the Melbourne atmosphere with 50-fold increase following rainfall. Free grass pollen allergen molecules have been recently shown to interact with other particles including diesel exhaust carbon particles, providing a further transport mechanism for allergens to gain access into lower airways. In this review, implication and evidence for grass pollen as a trigger of thunderstorm-associated asthma is presented ….[2]

Image: When exposed to water, pollen grains rupture at the single germinal aperture releasing their cytoplasmic contents. Prominent among the contents released from each grain are about 700 starch granules. Scanning electron micrographs of rye grass pollen grains and starch granules. Whole rye grass pollen grains are ~35 μm in diameter; Pollen grains rupturing in rainwater (a); Isolated starch granules following pollen rupture (b); [1,2]

Rye-grass pollen rupture: Real time rupture of rye grass pollen upon exposure to water. The contents of the pollen are ejected through a ruptured pore on the surface of the pollen grain. Approximately 750 starch granules of micron size are emitted from each pollen grain, along with thousands of nano-particles of cytoplasmic debris, which can trigger a thunderstorm-associated asthma.[3]Source: http://www.abc.net.au/catalyst/stories/3191776.htm

[1] Suphioglu C, Singh MB, Taylor P, Bellomo R, Holmes P, Puv R, Knox RB. (1992) Mechanism of grass-pollen-induced asthma. Lancet, Vol. 339(8793): 569-572.

[2] Suphioglu, C. (1998). Thunderstorm asthma due to grass pollen. International Archives of Allergy and Immunology, Vol.116:253-260.

[3] https://www.deakin.edu.au/students/faculties/sebe/les-students/airwatch

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BioAerosols (2a/3)

Kawasaki Disease:

Source: Wikipedia 2014

• related to synoptic flow of air masses from China

Aerosol Climate Tools ModelHealth

The causal agent of Kawasaki disease (KD) remains unknown after more than 40 years of intensive research. The number of cases continues to rise in many parts of the world and KD is the most common cause of acquired heart disease in childhood in developed countries. Analyses of the three major KD epidemics in Japan, major non-epidemic interannual fluctuations of KD cases in Japan and San Diego, and the seasonal variation of KD in Japan, Hawaii, and San Diego, reveals a consistent pattern wherein KD cases are often linked to large-scale wind currents originating in central Asia and traversing the north Pacific. Results suggest that the environmental trigger for KD could be wind-borne. Efforts to isolate the causative agent of KD should focus on the microbiology of aerosols.

Image: Major epidemics of monthly KD incidence in Japan. The three main historical KD epidemics are highlighted in red in panel a (cases). Time averaged sea level pressure (hPa) and surface winds (m/s) prior to the March/May 1979, May 1982 and March 1986 epidemics are shown in panels b, c and d, respectively. Monthly atmospheric variables were averaged for the preceding summer (JJA 1978 in b1, JJA 1981 in c1, and JJA 1985 in d1), when winds from the south typically blow across Japan, and for the rising phase of the epidemics, from September to the last month before the peak (Sep 1978 to Mar 1979 in b2, Sep 1981 to Apr 1982 in c2, and Sep 1985 to Feb 1986 in d2) , when winds shifted and blew from the northwest. Colored dots depict the increase in KD incidence (per million inhabitants) by prefecture between the preceding September and the peak (Apr 1979 minus Sep 1978 in b2, May 1982 minus Sep 1981 in c2, and Mar 1986 minus Sep 1985 in d2).

Source: Rodó X, Ballester J, Cayan D, Melish ME, Nakamura Y, Uehara R, Burns JC. (2011) Association of Kawasaki disease with tropospheric wind patterns. Sci Rep. 2011;1:152. doi: 10.1038/srep00152.

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BioAerosols (2b/3)

Kawasaki Disease:

Rodó et al., 2014

• related to synoptic flow of air masses from China

• probably of fungal origin

Aerosol Climate Tools ModelHealth

Evidence indicates that the densely cultivated region of northeastern China acts as a source for the wind-borne agent of Kawasaki disease (KD). KD is an acute, coronary artery vasculitis of young children, and still a medical mystery after more than 40 y. We used residence times from simulations with the flexible particle dispersion model to pinpoint the source region for KD. Simulations were generated from locations spanning Japan from days with either high or low KD incidence. The postepidemic interval (1987-2010) and the extreme epidemics (1979, 1982, and 1986) pointed to the same source region. Results suggest a very short incubation period (<24 h) from exposure, thus making an infectious agent unlikely. Sampling campaigns over Japan during the KD season detected major differences in the microbiota of the tropospheric aerosols compared with ground aerosols, with the unexpected finding of the Candida species as the dominant fungus from aloft samples (54% of all fungal strains). These results, consistent with the Candida animal model for KD, provide support for the concept and feasibility of a windborne pathogen. A fungal toxin could be pursued as a possible etiologic agent of KD, consistent with an agricultural source, a short incubation time and synchronized outbreaks. Our study suggests that the causative agent of KD is a preformed toxin or environmental agent rather than an organism requiring replication. We propose a new paradigm whereby an idiosyncratic immune response, influenced by host genetics triggered by an environmental exposure carried on winds, results in the clinical syndrome known as acute KD.

Map: Upstream grid cell locations registering residence times over 30 s for the ensemble of FLEXPART 10-d backward simulations (light brown) for dates within the three epidemics (1979, 1982, and 1986) when KD cases were at or above the 95% threshold of cases (threshold calculated for the entire timespan, 1977–2010). The ensemble represents a total of 257 dates. A 0.5° grid scale was used (latitude, longitude). Brown dots denote crops according to the land cover type yearly climate modeling grid (CMG) datasets with 0.05° resolution from the NASA Land Processes Distributed Active Archive Center (LP DAAC, Sioux Falls, SD), ASTER L1B (32). Grid cells with dots have at least 50% or more subgrids as crops or 100% subgrids as mosaic (mosaic representing crops + natural vegetation).Image: Differences in the mycobiome distribution from tropospheric and surface-level aerosols. (top) Fungal 18S rRNA gene PCR demonstrates amplification products in flight and surface filters. DNA extracted from soil was used as a positive control for fungal amplification. (bottom) Pie charts demonstrating the percent abundance of fungal taxa identified from clone library sequencing (100 clones per filter) of 18S rRNA gene amplification products from flight and surface filters. Candida sp. sequences accounted for 54% of total flight filter sequences, whereas Aspergillus sp. sequences accounted for 100% of surface filter sequences.

Source: Rodó X, Curcoll R, Robinson M, Ballester J, Burns JC, Cayan DR, Lipkin WI, Williams BL, Couto-Rodriguez M, Nakamura Y, Uehara R, Tanimoto H, Morguí JA. (2014) Tropospheric winds from northeastern China carry the etiologic agent of Kawasaki disease from its source to Japan. Proc Natl Acad Sci U S A. 2014 May 19. pii: 201400380.

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BioAerosols (2c/3)

Kawasaki Disease:

Source: Wikipedia 2014

• Sign & Symptoms

Kawasaki Kawasaki disease.mp4disease.mp4

Aerosol Climate Tools ModelHealth

Kawasaki disease, also known as Kawasaki syndrome, lymph node syndrome, and mucocutaneous lymph node syndrome, is an autoimmune disease in which the medium-sized blood vessels throughout the body become inflamed. It is largely seen in children under five years of age. It affects many organ systems, mainly those including the blood vessels, skin, mucous membranes, and lymph nodes; however, its rarest but most serious effect is on the heart, where it can cause fatal coronary artery aneurysms in untreated children. Without treatment, mortality may approach 1%, usually within six weeks of onset. With treatment, the mortality rate is 0.17% in the U.S. Often, a pre-existing viral infection may play a role in its pathogenesis. The conjunctivae and oral mucosa, along with the skin, become red and inflamed. Edema is often seen in the hands and feet. One or more cervical lymph nodes are often enlarged. Also, a recurrent fever, often 37.8°C (100.00°F) or higher, is characteristic of the acute phase of the disease. In untreated children, the febrile period lasts about 10 days, but may range from five to 25 days. The disorder was first described in 1967 by Tomisaku Kawasaki in Japan. [2]

Source: https://en.wikipedia.org/wiki/Kawasaki_disease.

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BioAerosols (4/4)

Infectious aerosols must be airborne:

Croddy et al., 2005

• warfare & terrorism • epi- / pandemics• <10 μm in size• can be of fungal, bacterial or viral origin, • also Encephalopathies (BSE, CJD), parasites ....

Abiotic factors promoting decay• air currents, • inversion conditions, • ultraviolet light, and • relative humidity

Aerosol Climate Tools ModelHealth

Microbediameter

Number of bacteria required to cause infection with Francisellatularensis - respiratory virulence (RLD50)

[μm] Guinea pig Rhesus monkey Human volunteers

1.0 2.5 14 10–52

6.5 4.70·E3 178 14–162

11.5 230·E3 672 n.a.

18.0 125·E3 3447 n.a.

22.0 230·E3 > 8,500 n.a.

The immediate hazard - and the type more likely to cause mass casualties - is the exposure to infectious aerosols. Following their release, these aerosols quickly degrade in both potency and concentration, lessening the need for deliberate efforts at decontamination. Environmental factors including air currents, inversion conditions, ultraviolet light, and relative humidity all play a role in the decay rate of BW agent aerosols. Over time and distance, at some point the concentration of infectious particles drops below that which is dangerous to humans or animals. When particles have reached the ground surface, they are usually resistant to reaerosolization, and exposure to the elements quickly denatures pathogenic microbes and toxins.

Image: Gruinard Island - the site of World War II - era anthrax weapons testing—has since been returned to the original owners. British military ceased testing in August 1943 and declared the island off limits. Contrary to government expectations, samples taken in 1943, 1944, and 1946 indicated that the B.anthracis spores on the island remained viable, so in 1946 the United Kingdom bought the entire island of Gruinard, promising to return it to the original owners for £500 (about one pound Sterling per acre) when it was deemed safe.

Table: Bacteria required to Create Medical Conditions. To reach the lower lung and be most effective, anthrax spores need to be delivered in particles 1–10 μm. Particles of much larger size are more apt to stick in upper airways and the throat, where a higher dose is required to cause infection. As the spores measure approximately 1 μm, a powder of individual spores is best, but natural surface charges cause spores to clump and to stick to surfaces, making aerosolization difficult.

Source: Croddy EA, Wirtz JJ, Larsen JA (2005) Weapon of mass destruction – Chemical and Biological Weapons, Vol.I. ABC-CLIO, Inc. Santa Barbara, USA.

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• exposure relevant issued during(i) production & manufacturing(i) during wear & tear(i) after usage, disposal & degradation

• Unique physical and chemical properties;

• Interaction with biomolecules;

• Contamination can occur during the life cycle;

RSE, (2004)

Nano-Toxicology (1/6)

Aerosol Climate Tools ModelHealth

Nanoscience and nanotechnologies are widely seen as having huge potential to bring benefits to many areas of research and application …. In June 2003 the UK Government therefore commissioned the Royal Society and the Royal Academy of Engineering to carry out this independent study into current and future developments in nano-science and nanotechnologies and their impacts.

The remit of the study was to:

· define what is meant by nanoscience and nanotechnologies;

· summarise the current state of scientific knowledge about nanotechnologies;

· identify the specific applications of the new technologies, in particular where nanotechnologies are already in use;

· carry out a forward look to see how the technologies might be used in future, where possible estimating the likely timescales in which the most far-reaching applications of the technologies might become reality;

· identify what health and safety, environmental, ethical and societal implications or uncertainties may arise from the use of the technologies, both current and future; and

· identify areas where additional regulation needs to be considered.

Image: Some possible exposure routes for nanoparticles and nanotubes based on current and potential future applications. Very little is known about exposure routes for nanoparticles and nanotubes and this figure should be considered with this in mind.

Source: RSE, (2004) Nanoscience and nanotechnologies: opportunities and uncertainties. Nanoscience and nanotechnologies. Royal Society of Engineering, London

http://www.nanotec.org.uk/report/Nano%20report%202004%20fin.pdf

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• especially for siblings of smaller size

Auffan et al., 2009

Nano-Toxicology (2/6)

Source: Chang, 1994

Aerosol Climate Tools ModelHealth

The regulation of engineered nanoparticles requires a widely agreed definition of such particles. Nanoparticles are routinely defined as particles with sizes between about 1 and 100 nm that show properties that are not found in bulk samples of the same material. Here we argue that evidence for novel size-dependent properties alone, rather than particle size, should be the primary criterion in any definition of nanoparticles when making decisions about their regulation for environmental, health and safety reasons. We review the size-dependent properties of a variety of inorganic nanoparticles and find that particles larger than about 30 nm do not in general show properties that would require regulatory scrutiny beyond that required for their bulk counterparts.

Image: Below what size do nanoparticles show properties not seen in larger particles with the same chemical composition? a, The number of published papers (vertical axis) reporting non-bulk properties in nanoparticles below a certain size plotted against the size of the nanoparticles (horizontal axis). b, The percentage of atoms localized at the surface of a nanoparticle as a function of the nanoparticle diameter. We argue that non-bulk properties only emerge for diameters of less than 20–30 nm (red line).

Source: Auffan M, Rose J, Bottero JY, Lowry GV, Jolivet JP, Wiesner MR. (2009) Towards a definition of inorganic nanoparticles from an environmental, health and safety perspective. Nat Nanotechnol. Vol.(10):634-641.

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• especially for siblings of smaller size

• increased surface reactivity

Auffan et al., 2009

Nano-Toxicology (3/6)

Aerosol Climate Tools ModelHealth

The regulation of engineered nanoparticles requires a widely agreed definition of such particles. Nanoparticles are routinely defined as particles with sizes between about 1 and 100 nm that show properties that are not found in bulk samples of the same material. Here we argue that evidence for novel size-dependent properties alone, rather than particle size, should be the primary criterion in any definition of nanoparticles when making decisions about their regulation for environmental, health and safety reasons. We review the size-dependent properties of a variety of inorganic nanoparticles and find that particles larger than about 30 nm do not in general show properties that would require regulatory scrutiny beyond that required for their bulk counterparts.

Image: Size dependence of the mechanisms of arsenic adsorption at the surface of iron oxide particles. The graph shows how the adsorption capacity of As(iii) at the surface of Fe3O4 nanoparticles (red line) and the surface free energy after saturation of all the adsorption sites at the surface (blue line) vary with diameter (on a logarithmic scale). Both quantities start to change significantly for diameters below about 20 nm (grey area). The evolution of the crystalline structure of the hkl plane of maghemite particles and the mechanisms for the adsorption of arsenic at the surface are shown for 6-nm particles (top) and >100-nm particles (bottom: adapted from ref. 68). FeOh, octahedral iron; FeTd, tetrahedral iron.

Source: Auffan M1, Rose J, Bottero JY, Lowry GV, Jolivet JP, Wiesner MR. (2009) Towards a definition of inorganic nanoparticles from an environmental, health and safety perspective. Nat Nanotechnol. Vol.(10):634-641.

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The smaller the more toxic

• especially for siblings of smaller size

• increased surface reactivity

• various pathways to interact w/ cell

Auffan et al., 2009

Nano-Toxicology (4/6)

Aerosol Climate Tools ModelHealth

The regulation of engineered nanoparticles requires a widely agreed definition of such particles. Nanoparticles are routinely defined as particles with sizes between about 1 and 100 nm that show properties that are not found in bulk samples of the same material. Here we argue that evidence for novel size-dependent properties alone, rather than particle size, should be the primary criterion in any definition of nanoparticles when making decisions about their regulation for environmental, health and safety reasons. We review the size-dependent properties of a variety of inorganic nanoparticles and find that particles larger than about 30 nm do not in general show properties that would require regulatory scrutiny beyond that required for their bulk counterparts.

Image: a number of physicochemical mechanisms can occur at the surface of an inorganic nanoparticle. The potential relationship between the size dependence of the crystalline structure of nanoparticles (typically <30 nm), their interfacial properties (for example dissolution,

oxidation, adsorption/desorption, electron transfer, redox cycles, Fenton reactions and surface acido-basicity) and potential mechanisms of toxicity (for example, the generation of ROS, the release of toxic ions, the oxidation of proteins and the adsorption of pollutants). OH·, hydroxyl radical; O2·-, anion superoxide.

Source: Auffan M1, Rose J, Bottero JY, Lowry GV, Jolivet JP, Wiesner MR. (2009) Towards a definition of inorganic nanoparticles from an environmental, health and safety perspective. Nat Nanotechnol. Vol.(10):634-641.

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• activation of Toll like receptors (TLRs) via NPs as these are (i) receptors for the immune system(i) sense viral/bacterial danger signals(i) down stream signaling leads to pro-inflammatory responses(i) most prominent factors are NF-kB activation and IL-8 release

Abbas et al., 2011

Radauer I. (2014)

Nano-Toxicology (5/6)

TLR ligand Recognition Sources

Lipopolysaccharide(LPS)

TLR4Cell membrane

Gramneg bacteria

Flagellin TLR5 Bacterial mobility

apparatus

CpG DNA TLR9 Bacterial DNA

Resiquimod (R848) TLR8 Viral DNA

Aerosol Climate Tools ModelHealth

The search for understanding the interactions of nanosized materials with living organisms is leading to the rapid development of key applications, including improved drug delivery by targeting nanoparticles, and resolution of the potential threat of nanotechnological devices to organisms and the environment. Unless they are specifically designed to avoid it, nanoparticles in contact with biological fluids are rapidly covered by a selected group of biomolecules to form a corona that interacts with biological systems. Here we review the basic concept of the nanoparticle corona and its structure and composition, and highlight how the properties of the corona may be linked to its biological impacts. We conclude with a critical assessment of the key problems that need to be resolved in the near future.

Insert: The nanoparticle–corona, rather than the bare nanoparticle, that interacts with biological machinery, here with a cell membrane receptor.

Image: Relevant processes (arrows), in both directions (on/off), for a nanoparticleinteracting with a receptor. Biomolecules in the environment adsorb strongly to the bare nanoparticle surface (k1), forming a tightly bound layer of biomolecules, the ‘hard’ corona, in immediate contact with the nanoparticle. Other biomolecules, the ‘soft’ corona, have a residual affinity to the nanoparticle–hard-corona complex (primarily to the hard corona itself), but this is much lower, so those molecules are in rapid exchange with the environment (k2). If sufficiently long-lived in the corona, a biomolecule may lead to recognition of the nanoparticle–corona complex as a whole by a cell-membrane receptor (k3). The same biomolecule alone can also be recognized by the receptor (k4). If present, the bare surface of the nanoparticle may also interact with cell surface receptors (k5) or other constituents of the cell membrane. Proteins adapted from Protein Data Bank.

Source: Abbas, AK, Lichtman AHH, Pillai S (2011). Cellular and Molecular Immunology: with STUDENT CONSULT Online Access. 2011: Elsevier Health Sciences.

Radauer I. (2014) Interaction of nanomaterials with toll like receptor ligands: Characterization of thebiomolecule corona and influence on the cellular response. Seminar talk. AG-Duschl.

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protein corona induces (i) agglomeration & (i) NF-kB Radauer I. (2014)

Nano-Toxicology (6/6)

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Aerosol Climate Tools ModelHealth

NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) is a protein complex that controls transcription of DNA. NF-κB is found in almost all animal cell types and is involved in cellular responses to stimuli such as stress, cytokines, free radicals, ultraviolet irradiation, oxidized LDL, and bacterial or viral antigens. NF-κB plays a key role in regulating the immune response to infection (κ light chains are critical components of immunoglobulins). Incorrect regulation of NF-κB has been linked to cancer, inflammatory, and autoimmune diseases, septic shock, viral infection, and improper immune development. NF-κB has also been implicated in processes of synaptic plasticity and memory.

Image: particle coating via biomolecules *Corona formation)

Source: http://en.wikipedia.org/wiki/NF-%CE%BAB

Radauer I. (2014) Interaction of nanomaterials with toll like receptor ligands: Characterization of the biomolecule corona and influence on the cellular response. Seminar talk. AG-Duschl.

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21st century - the Aluminium Age:

• was biologically non-available to the biochemical evolution until 20th century

• Al enters geochemical cycling - is deliberately introduced into biopshere

• Al is not required for cellular metabolism• Al is toxic to life

Exley, 2013

Aluminium (1/10)

Aerosol Climate Tools ModelHealth

Human activities have circumvented the efficient geochemical cycling of aluminium within the lithosphere and therewith opened a door, which was previously only ajar, onto the biotic cycle to instigate and promote the accumulation of aluminium in biota and especially humans. Neither these relatively recent activities nor the entry of aluminium into the living cycle are showing any signs of abating and it is thus now imperative that we understand as fully as possible how humans are exposed to aluminium and the future consequences of a burgeoning exposure and body burden. The aluminium age is upon us and there is now an urgent need to understand how to live safely and effectively with aluminium.

Image: Aluminium's exposome. A schematic which explores relationships between exposure, immediate targets mediating exposure, sinks and sources of biologically available aluminium with putative mechanisms of action and finallyexcretion of aluminium.

Source: Exley C. (2013). Human exposure to aluminium. Environ. Sci. Processes Impacts, Vol.15:1807-1816.

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Average personal Al-exposure :

• Inhalation: 1.4 µg/day • Ingestion: 1-20 mg/day• Epidermal: 2 g/day

Franz-cell exposure system to test transmigration of Aluminium chlorohydrate (ACH) via dermal layer

Pineau et al., 2012

Aluminium (2a/10)

Aerosol Climate Tools ModelHealth

Aluminum salts such as aluminum chlorohydrate (ACH) are known for use as an active antiperspirant agent that blocks the secretion of sweat. A local case report of hyperaluminemia in a woman using an aluminum-containing antiperspirant for 4 years raises the problem of transdermal absorption of aluminum (Al). Only a very limited number of studies have shown that the skin is an effective barrier to transdermal uptake of Al. In accordance with our analytical procedure, the aim of this study with an in vitro Franz™ diffusion cell was to measure aluminumuptake from three cosmetic formulations of antiperspirant: the base for an "aerosol" (38.5% of ACH), a "roll-on" emulsion (14.5% ACH), and a "stick" (21.2%), by samples of intact and stripped human skin (5 donors). The Al assays were performed by Zeeman Electrothermal Atomic Absorption Spectrophotometry (ZEAAS). Following contacts lasting 6, 12 and 24h, the Al assays showed only insignificant transdermal absorption of Al (≤0.07% of the quantity of Al deposited) and particularly low cutaneous quantities that varied according to the formulations (1.8 μg/cm² for "aerosol base" and "stick" - 0.5 μg/cm² for the "roll-on"). On stripped skin, for which only the "stick" formulation was tested, the measured uptake was significantly higher (11.50 μg/cm² versus 1.81 μg/cm² for normal skin). These results offer reassurance as regards to the use of antiperspirants for topical application of ACH-containing cosmetic formulations on healthy skin over a limited time span (24h). On the other hand, high transdermal Al uptake on stripped skin should compel antiperspirant manufacturers to proceed with the utmost caution.

Image: Franz™ diffusion cell (static type) to test transmigration of Aluminium chlorohydrate-salt: AlnCl(3n-m)(OH)m across skin.

Source: Pineau A, Guillard O, Favreau F, Marrauld A, Fauconneau B. (2012) In vitro study of percutaneous absorption of aluminum from antiperspirants through human skin in the Franz™diffusion cell. J. o. Inorg. Biochem., Vol.110: 21-26.

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Average personal Al-exposure :

• Inhalation: 1.4 µg/day • Ingestion: 1-20 mg/day• Epidermal: 2 g/day

Exley, 2013

Aluminium (2b/10)

AkteAkte AluAlu --Brustpatient.mp4Brustpatient.mp4

Aerosol Climate Tools ModelHealth

While the evidence to-date is that only a very small proportion of aluminium in topically-applied antiperspirant enters the bloodstream to ultimately be excreted via the kidney this observation does not preclude the persistence of such aluminium within the structures of the skin and neither does it preclude the entry of this aluminium into the lymphatic system. The nature of the aluminium compounds which are present in topical applications, the amount of aluminium which is often applied and the regularity of many such applications must mean that skin is a significant sink for aluminium and a persistent source of biologically available aluminium both locally and systemically.

Image: The skin is a sink for topically applied aluminium and will act as a source of biologically reactive aluminium both to structures within the skin and to the systemic circulation.

Source: Exley C. (2013). Human exposure to aluminium. Environ. Sci. Processes Impacts, Vol.15:1807-1816.

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Aluminium (3/10)

Epigenetics of Al-exposure :• Heterochromatin:

genetically inactive• Al inhibits eukaryotic gene

transcription • Al acts as transcriptional

repressor (of A+T-rich templates)

• Found across speciesAT, Arabidopsis thaliana (cress);LU, Linum usitatissimum (flax); CE, Caenorhabditis elegans (nematode); MS, Mus musculus (mouse); HS, Homo sapiens (human); (L) liver;

(B) brain. Lukiw, 2010

Aerosol Climate Tools ModelHealth

Averaging 8.1% (w/w) of the earth's crust, aluminum is the most highly abundant metal in our biosphere, yet has long been thought to serve no essential biological function. In aqueous solutions, aluminum salts and hydroxides are exceptionally potent aggregators of biological molecules, often coalescing molecular species to the point that they precipitate out of solution. A biological function for aluminumis proposed in which this abundant, high charge density metal cation has a significant role in biomolecular compaction. Sometimes, molecules ectopically aggregated by aluminum are associated with pathological conditions. The data further suggests that a specific consequence of ‚aluminum biocompaction‘ may be particularly important in the condensation of A + T-rich chromatin domains, and in silencing the expression of specific kinds of genetic information.

Image: Aluminum content and genetic activity are inversely correlated. Correlation of interphase heterochromatin status and aluminum content of chromatin in select eukaryotic nuclei. Eukaryotic nuclei contain complex arrangements of heterochromatic and euchromatic domains: ‘inactive, constitutive‘ heterochromatin is associated with the absence of gene expression. Mean constitutive heterochromatin was assayed for A+T-rich heterochromatic regions, and heterochromatin was expressed as a percent of total nuclear area; aluminum content, expressed as μg/g total chromatin.

Source: Lukiw WJ (2010). Evidence supporting a biological role for aluminum in chromatin compaction and epigenetics. Journal of Inorganic Biochemistry Vol.104: 1010-1012.

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Al-compounds in nipple aspirate found to induce breast tumors, as Al is:

• is a metalloestrogen (enabling oestrogenic effects)

• transmigrates across cells• known to interfere with DNA

(micronucleus asssays)• dermal absorption (e.g. via

anti-transpirants);• accumulates in biological

fluid (nipple aspirate)

Darbre et al. 2011

Aluminium (4a/10)

AkteAkte AluAlu –– Dabre.mp4Dabre.mp4

Aerosol Climate Tools ModelHealth

The human breast is exposed to aluminium from many sources including diet and personal care products, but dermal application of aluminium-based antiperspirant salts provides a local long-term source of exposure. Recent measurements have shown that aluminium is present in both tissue and fat of the human breast but at levels which vary both between breasts and between tissue samples from the same breast. We have recently found increased levels of aluminium in noninvasively collected nipple aspirate fluids taken from breast cancer patients (mean 268 +/-28 μg/l) compared with control healthy subjects (mean 131 +/-10 μg/l) providing evidence of raised aluminium levels in the breast microenvironment when cancer is present. The measurement of higher levels of aluminium in type I human breast cyst fluids (median 150 μg/l) compared with human serum (median 6 μg/l) or human milk (median 25 μg/l) warrants further investigation into any possible role of aluminium in development of this benign breast disease. Emerging evidence for aluminium in several breast structures now requires biomarkers of aluminium action in order to ascertain whether the presence of aluminium has any biological impact. To this end, we report raised levels of proteins that modulate iron homeostasis (ferritin, transferrin) in parallel with raised aluminium in nipple aspirate fluids in vivo, and we report overexpression of mRNA for several S100 calcium binding proteins following long-term exposure of MCF-7 human breast cancer cells in vitro to aluminium chlorhydrate.

It is possible that if levels of iron binding proteins are found to correlate with raised aluminium in larger repeat studies, that measurement of ferritin and/or transferrin might provide useful biomarkers in human breast tissue for the existing link between aluminium and iron suggested as pathogenetically impor- tant for human neurodegenerative disorders.

Image: Mean levels of aluminium, ferritin and transferrin in nipple aspirate fluid samples obtained from women with (Cancer) or without breast cancer and as compared to levels in blood serum or breast milk.

Source: Darbre PD, Pugazhendhi D, Mannello F. (2011) Aluminium and human breast diseases. Journal of Inorganic Biochemistry Vol.105:1484-1488

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Al-compounds in nipple aspirate found to induce breast tumors, as Al is:

• is a metalloestrogen (enabling oestrogenic effects)

• transmigrates across cells• known to interfere with DNA

(micronucleus asssays)• dermal absorption (e.g. via

anti-transpirants);• accumulates in biological

fluid (nipple aspirate)

Egartner et al. 2013

Aluminium (4b/10)

approx. 10 μL

Akte Alu Akte Alu ––AlClOH.mp4AlClOH.mp4

Aerosol Climate Tools ModelHealth

Source: Ehgartner B, Roth C., Ripper T., Freingruber A., Hohl T. (2013) – die Akte Aluminium. ARTE, ORF, SRF

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Al-compounds in nipple aspirate found to induce GCBD:

• GCBD: Gross cystic breast disease -most common benign breast disorder, (7% of Western women)

• antiperspirant formulations are designed to block apocrine sweat ducts of the axilla

Fluid obtained from human sweat glands• apocrine type I• transudative type II

Manello et al. 2009

Aluminium (4c/10)

Aerosol Climate Tools ModelHealth

Gross cystic breast disease (GCBD) is the most common benign breast disorder, but the molecular basis of cyst formation remains to be identified. If the use of aluminium-based antiperspirant salts is involved in the etiology of gross breast cyst formation, it might be expected that aluminium would be at elevated levels in human breast cyst fluid (BCF). Aluminium was measured by ICP-MS in 48 samples of BCF, 30 samples of human blood serum and 45 samples of human breast milk at different stages of lactation (colostrum, intermediate, mature). The median level of aluminium in apocrine type I BCF (n = 27, 150 microg l(-1)) was significantly higher than in transudative type II BCF (n = 21, 32 microg l(-1); P < 0.0001). By comparison, aluminium measurements gave a median concentration of 6 microg l(-1) in human serum and 25 microg l(-1) in human breast milk, with no difference between colostrum, intermediate and mature milk. Levels of aluminium were significantly higher in both types of BCF than in human serum (P < 0.0001). However when compared with human breast milk, aluminium levels were only significantly higher in apocrine type I BCF (P < 0.0001) and not in transudative type II BCF (P = 0.152). It remains to be identified why such high levels of aluminium were found in the apocrine type I BCF and from where the aluminium originated. However, if aluminium-based antiperspirants are found to be the source and to play any causal role in development of breast cysts, then it might become possible to prevent this common breast disorder.

Image: Median levels of aluminium in human breast gross cyst fluids according to breast gross cyst subtypes (*P < 0.0001).

Source: Mannello F, Tonti GA, Darbre PD. (2009). Concentration of aluminium in breast cyst fluids collected from women affected by gross cystic breast disease. J Appl Toxicol. Vol.29(1):1-6.

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Al-induced Neurodegenerative Diseases:

Al & Blood-Brain-Barrier (BBB) • Dialysis Encephalopathy Syndrome

(DES)• Amyotrophic Lateral Sclerosis (ALS)• Parkinsonism Dementia (PD)• Alzheimer‘s Disease (AD)

Exley & House, 2011

Aluminium (5/10)

Aerosol Climate Tools ModelHealth

The brain must expend energy in its ‘unconscious‘ response to an exposure to biologically available aluminium. There are many examples where ‚biological effect‘ has resulted in aluminium-induced neurotoxicity and most potently in conditions that have resulted in an aluminium-associated encephalopathy. However, since aluminium is non-essential and not required by the brain, its biological availability will only rarely achieve such levels of acuity, and it is more pertinent to consider and investigate the brain‘s response to much lower though sustained levels of biologically reactive aluminium. This is the level of exposure that defines the putative role of aluminium in chronic neurodegenerative disease and, though thoroughly investigated in numerous animal models, the chronic toxicity of aluminium has yet to be addressed experimentally in humans. The simplest way reduce the Al-burden is by facilitating the urinary excretion of aluminium through the regular drinking of a silicic acid-rich mineral water over an extended time period. This will lower the body and brain burden of aluminium, and by doing so will test whether brain aluminium contributes significantly to chronic neurodegenerative diseases such as Alzheimer‘s and Parkinson‘s.

AD: The main clinical feature of AD is a slowly-developing, relentless dementia characterized by memory deficit, confusion, inability to focus attention, incontinence, and per- severative behaviors. Neuropathologicalhallmarks of AD include cerebral NFTs, amyloid plaques, and granulo- vacuolar degeneration. Many studies have shown that NFTs correlate better with disease severity than amyloid plaques.

DES: Al increase in neural cells stimulates Ca2+ uptake, leading to seizures and death

ALS is characterized by progressive motor weakness affecting the limbs and premature death.

PD dementia is a severe and progressive dementia accompanied by extrapyramidal disease.

ALS and parkinsonism dementia often occur together in the same individuals of these populations. Spinal neurons of ALS/PD-affected Guamanians contain NFTs rich in Al, silicon and Ca2+. Granulovacuolardegeneration (GVD) occurs in the ALS/PD cortex, substantia nigra, and other subcortical nuclear. There is evidence that Al induces both NFT formation and GVD, which are also prominent in AD.

Image: A schematic of the possible distribution of aluminium in plasma, the blood- brain barrier (BBB), the cerebrospinal fluid (CSF), the brain interstitial fluid (BIF), and the cellular and pathological compartments of the human brain.

Source: Exley C, House ER (2011). Aluminium in the human brain. Monatsh Chem Vol.142: 357-363

Walton JR (2012). Evidence that Ingested Aluminum Additives Contained in Processed Foods and Alum-Treated Drinking Water are a Major Risk Factor for Alzheimer’s Disease. Current Inorganic Chemistry, Vol. 2: 000-000

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Al-compounds & Alzheimer's Disease (AD): Walton, 2012

• dietary patterns are akin to a grand-scale experiment whereby some individuals are consuming large quantities of Al

• selective accumulation over lifetime selective w/n neurons of the brain

• Al shows affinity to specificneuronal transporter proteins

• small amounts needed to promote AD

Tomljenovic, 2011

Aluminium (6/10)

Aerosol Climate Tools ModelHealth

The brain is a highly compartmentalized organ exceptionally susceptible to accumulation of metabolic errors. Alzheimer痴disease (AD) is the most prevalent neurodegenerative disease of the elderly and is characterized by regional specificity of neural aberrations associated with higher cognitive functions. Aluminum (Al) is the most abundant neurotoxic metal on earth, widely bioavailable to humans and repeatedly shown to accumulate in AD-susceptible neuronal foci. In spite of this, the role of Al in AD has been heavily disputed based on the following claims: 1) bioavailable Al cannot enter the brain in sufficient amounts to cause damage, 2) excess Al is efficiently excreted from the body, and 3) Al accumulation in neurons is a consequence rather than a cause of neuronal loss. Research, however, reveals that: 1) very small amounts of Al are needed to produce neurotoxicity and this criterion is satisfied through dietary Al intake, 2) Al sequesters different transportmechanisms to actively traverse brain barriers, 3) incremental acquisition of small amounts of Al over a lifetime favors its selective accumulation in brain tissues, and 4) since 1911, experimental evidence has repeatedly demonstrated that chronic Al intoxication reproduces neuropathological hallmarks of AD. Misconceptions about Al bioavailability may have misled scientists regarding the significance of Al in the pathogenesis of AD. The hypothesis that Al significantly contributes to AD is built upon very solid experimental evidence and should not be dismissed. Immediate steps should be taken to lessen human exposure to Al, which may be the single most aggravating and avoidable factor related to AD.

Image: �Major routes of Al transport in and out of the brain: from the blood, Al enters the brain extracellular fluid (ECF) primarily through the blood brain barrier (BBB) via transferrin-mediated uptake. Some Al in the brain is rapidly effluxed as Al-citrate by the MCT-transporter. A significant portion of Al is retained in the cellular compartments (nucleus, ER, bound to ATP or membrane phospholipids).

Inlet: Staging of aged rat (upper row) and aged human (lower row) of hippocampal CA1neurons stained; Stage 0: the entire cell appears Al-negative and has normal morphology; Stage I: magentanucleolus, no other staining for Al. Stage II: magenta nucleolus in pink nucleoplasm with visible chromatin; the cytoplasm is blue. Stage III: magenta nucleolus in an elongated or irregularly shaped purple nucleus.The cytoplasm is blue. Many apical dendrites from this stage onwards have a serpentine appearance. Stage IV: the magenta staining appears in the elongated nucleus which now shows less structural detail; the shrunken cytoplasm is still blue. Stage V: purple to magenta staining appears throughout the nucleus and cytoplasm. Cell shape is distorted and the axon and dendrites are disrupted.

Source: Tomljenovic L. (2011). Aluminum and Alzheimer‘s Disease: After a Century of Controversy, Is there a Plausible Link? Journal of Alzheimer‘s Disease Vol.23: 567-598.

Walton JR (2012). Cognitive Deterioration and Associated Pathology Induced by Chronic Low-Level Aluminum Ingestion in a Translational Rat Model Provides an Explanation of Alzheimer‘s Disease, Tests for Susceptibility and Avenues for Treatment. Journal of Alzheimer‘s Disease Vol.194947: 1-17.

Walton JR (2006). Aluminum in hippocampal neurons from humans with Alzheimer“s disease. NeuroToxicologyVol.27:385-394

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Titanium Dioxide (TiO2):

• natural occurance: rutile, anatase, brookite & in 2 hyperbaric forms;

• used as a pigment (white 6 or CI 77891) in paper, sunscreens, tatoos & food colouring (E171, to whiten milk, toothpaste);

• TiO2-dust, when inhaled, has been classified as possibly carcinogenic to humans; mutagenic in mice;

TiO2 (1/2)

Aerosol Climate Tools ModelHealth

Health and safety (http://en.wikipedia.org/wiki/TiO2)Titanium dioxide is incompatible with strong oxidizers and strong acids.[27] Violent or incandescent reactions may occur with metals (e.g. aluminium, calcium, magnesium, potassium, sodium, zinc and lithium).[28]

Titanium dioxide dust, when inhaled, has recently been classified by the International Agency for Research on Cancer (IARC) as an IARC Group 2B carcinogen possibly carcinogenic to humans.[29]

Titanium dioxide accounts for 70% of the total production volume of pigments worldwide. It is widely used to provide whiteness and opacity to products such as paints, plastics, papers, inks, foods, and toothpastes. It is also used in cosmetic and skin care products, and it is present in almost every sunblock, where it helps protect the skin from ultraviolet light.

[27] Occupational Health Services, Inc. (31 May 1988). "Hazardline" (Electronic Bulletin). New York: Occupational Health Services, Inc..[28] Sax, N.I.; Richard J. Lewis, Sr. (2000). Dangerous Properties of Industrial Materials. III (10th ed.). New York: Van Nostrand Reinhold. p. 3279. ISBN 978-0471354079.[29] "Titanium dioxide". International Agency for Research on Cancer. 2006. http://monographs.iarc.fr/ENG/Meetings/93-titaniumdioxide.pdf.

Image: http://www.envirocoat.com.au/photocatalyst.htm & http://www.webelements.com/compounds/titanium/titanium_dioxide.htmlhttp://www.docstoc.com/docs/17777502/ARBEITS--UND-UMWELTMEDIZINISCHE-A

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Titanium Dioxide (TiO2):

• natural occurance: rutile, anatase, brookite & in 2 hyperbaric forms;

• used as a pigment (white 6 or CI 77891) in paper, sunscreens, tatoos & food colouring (E171, to whiten milk, toothpaste);

• TiO2-dust, when inhaled, has been classified as possibly carcinogenic to humans; mutagenic in mice;

• used in plastics for its UV resistant properties (photocatalyst);

• in sunscreens TiO2 has to be coated with silica or alumina (otherwise creates carcinogenic radicals in the photocatalytic reaction);

TiO2 (2/2)

ABC ABC –– NP & NP & sundamage.mp4sundamage.mp4

Aerosol Climate Tools ModelHealth

Health and safety (http://en.wikipedia.org/wiki/TiO2)The findings of the IARC are based on the discovery that high concentrations of pigment-grade (powdered) and ultrafine titanium dioxide dust caused respiratory tract cancer in rats exposed by inhalation and intratracheal instillation.[30] The series of biological events or steps that produce the rat lung cancers (e.g. particle deposition, impaired lung clearance, cell injury, fibrosis, mutations and ultimately cancer) have also been seen in people working in dusty environments. Therefore, the observations of cancer in animals were considered, by IARC, as relevant to people doing jobs with exposures to titanium dioxide dust. For example, titanium dioxide production workers may be exposed to high dust concentrations during packing, milling, site cleaning and maintenance, if there are insufficient dust control measures in place. However, it should be noted that the human studies conducted so far do not suggest an association between occupational exposure to titanium dioxide and an increased risk for cancer. The safety of the use of these nanoparticles, which can penetrate the body and reach internal organs, has been criticized.[31] Studies have also found that titanium dioxide nanoparticles cause genetic damage in mice, suggesting that humans may be at risk of cancer or genetic disorders resulting from exposure.[32]

[30] Kutal, C., Serpone, N. (1993). Photosensitive Metal Organic Systems: Mechanistic Principles and Applications. American Chemical Society, Washington D.C.[31] " Suncream may be linked to Alzheimer's disease, say experts ". 24th August 2009. http://www.dailymail.co.uk/health/article-1208720/Suncream-linked-Alzheimers-disease-say-experts.html. Retrieved 2009-08-25.[32] " Nanoparticles Used in Common Household Items Cause Genetic Damage in Mice ". 17th November 2009. http://www.sciencedaily.com/releases/2009/11/091116165739.htm. Retrieved 2009-11-17.Image: http://www.envirocoat.com.au/photocatalyst.htm & http://www.webelements.com/compounds/titanium/titanium_dioxide.htmlhttp://www.docstoc.com/docs/17777502/ARBEITS--UND-UMWELTMEDIZINISCHE-Ahttp://www.abc.net.au/catalyst/stories/3589233.htm

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Quartz (SiO2):

• natural occurance: feldspar, citrine, amethyst, chalcedony, agate, onyx, prasiolite, carnelian;

• used as insulating matieral (mineral fiber);• Inhalation of crystalline SiO2-dust includes

acute macrophagal toxicity, carcinogenicity, reproductive &developmental toxicity;

• Particle-related toxicities and histo-pathology correlate better with surface activity rather than particle size.

Reuzel, et al., 1991; Moy et al., 1999; Warheit et al., 2007

Quartz

SiO2–fibers in the lung.

• Silikosis: 0.05 mg/m³• Tumor: 0.001 – 0.05 mg/m³

Aerosol Climate Tools ModelHealth

Quartz is the second most abundant mineral in the Earth's continental crust, after feldspar. It is made up of a continuous framework of SiO4 silicon-oxygen tetrahedra, with each oxygen being shared between two tetrahedra, giving an overall formula SiO2.There are many different varieties of quartz, several of which are semi-precious gemstones. Especially in Europe and the Middle East, varieties of quartz have been since antiquity the most commonly used minerals in the making of jewelryand hardstone carvings.As a person's exposure to fibers increases, because of being exposed to higher concentrations of fibers and/or by being exposed for a longer time, then that person's risk of disease also increases. Disease is very unlikely to result from a single, high-level exposure, or from a short period of exposure to lower levels.[19]

Smoking combined with asbestos exposure may increase the health risk dramatically.

Source: http://www.pesticideinfo.org/Detail_Chemical.jsp?Rec_Id=PC35565Warheit D.B., Webb T.R. Colvin V.L., Reed K.L., Sayes C.m. (2007). Pulmonary Bioassay Studies with Nanoscale and Fine-Quartz Particles in Rats: Toxicity is Not Dependent upon Particle Size but on Surface Characteristics. Toxicological Sciences 2007 95(1):270-280;Reuzel PG, Bruijntjes JP, Feron VJ, Woutersen RA. (1991). Subchronic inhalation toxicity of amorphous silicas and quartz dust in rats. Food Chem Toxicol. 1991 May;29(5):341-54.Moy E.V., Hu H., Christiani D.C. (1999). A Retired Shipyard Worker with Rapidly ProgressivePulmonary Interstitial Fibrosis. Environmental Health Perspectives Volume 107, Number 4, April 1999

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C-nano-Tubes:

• mesothelial irritation in mice

• inflammation• formation of

lesions(granulomas)

GI: granulamatous inflammation

Poland et al., 2008

C-Nanotubes ABC ABC –– Carbon Carbon Nanotubes.mp4Nanotubes.mp4

Aerosol Climate Tools ModelHealth

Carbon nanotubes have distinctive characteristics, but their needle-like fibre shape has been compared to asbestos, raising concerns that widespread use of carbon nanotubes may lead to mesothelioma, cancer of the lining of the lungs caused by exposure to asbestos. Here we show that exposing the mesothelial lining of the body cavity of mice, as a surrogate for the mesotheliallining of the chest cavity, to long multiwalled carbon nanotubes results in asbestos-like, length-dependent, pathogenic behaviour. This includes inflammation and the formation of lesions known as granulomas. This is of considerable importance, because research and business communities continue to invest heavily in carbon nanotubes for a wide range of products under the assumption that they are no more hazardous than graphite. Our results suggest the need for further research and great caution before introducing such products into the market if long-term harm is to be avoided.

Image: Effect of the particle/fibre on diaphragms after 7 days. a, TEM images show the presence (þ) or absence (–) of long fibres in the samples used. Female C57Bl/6 mice were injected i.p. with 50 mg of sample, killed after 7 days, and the diaphragms excised and prepared for visualization. b,c, SEM images (b) and haematoxylin and eosin histology sections (n ¼ 3) (c) of the diaphragms show the presence of granulamatous inflammation (GI) in mice exposed to LFA, NTlong1 and NTlong2. A small granuloma response in one of the three mice treated with NTtang2 (see Supplementary Information, Tables S1 and S2, for raw data and statistical analysis) was observed. The muscular portion of the peritoneal diaphragm (PD) and the mesothelial layer (ML) are aligned to show granulomatous inflammation at the peritoneal aspect of the diaphragm surface.Scale bars in b: 200 mm. Scale bars in c: 50 mm.

Source: Poland CA, Duffin R, Kinloch I, Maynard A, Wallace WA, Seaton A, Stone V, Brown S, MacneeW, Donaldson K. (2008) Carbon nanotubes introduced into the abdominal cavity of mice showasbestos-like pathogenicity in a pilot study. Nat Nanotechnol. Vol.3(7):423-428.

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Lichen @ Highway (1/3)

Lichen-Population Diversity & Highway Vehicle Exhaust

Measurement sites

• Golling 35 (G35, 20 m from motorway

• Golling 77 (G77, 20 m f. motorway)

• Parking Area (PA, 300 m f. motorway)

• Kneippanlage (KA, 500 m f. motorway)

• Baerenhof (BH, 2500 m f. motorway) (amidst a densly forested area)

• F. Ferdinand Kurve (FFK, 4000 m f. motorway) – open & exposed

Source: Madl & Heinzlmann, 2006

Aerosol Climate Tools ModelHealth

Measurement sites closer to the highway produced higher concentrations as a result of the constant mixing of exhaust particles and resuspension of larger aerosol-clusters and elevated vehicle density (Hofmann, 2005). Consequently, particles are easily relocated by wind and transported over the sound-protective barriers to finally settle in neighbouring land strips. As expected, sampling sites further away and deeper within the Bluntau-Valley yielded lower particle concentrations. However, long-distance relocation of exhaust particle-loads originating from the motorway does regularly occur, as lichen-populations on exposed sites such as the remotest site surveyed (FFK-location) do reveal a suppressed species diversity. This observation correlates with those made by other authors that associate these ecological changes to excess eutrophication and an elevated pollutant load (Masuch, 1993).

In particular, higher aerosol concentration results in lower species diversity by damaging the thalli of the lichens (Nimis, 2002). Therefore, measurement sites in close proximity to the E55 display a distinctive absence of species otherwise found in more pristine areas of similar geo-botanic character (Masuch, 1993).

Additionally, lichen associations near the highway tend to change to more nitrophilouslichen associations because of a higher amount of nitrogen available due to vehicle exhaust and being in a rural setting, the prevailing agricultural activities near the motorway along with the associated wind-related relocation of fertilizer. The dramatic reduction of lichen diversity observed at all measurement sites – with none to just a few in close proximity to the motorway backs up the hypothesis that certain particle sizes are able to enter the lichen thallus through pores of the polysaccharide layer of the epicortex thereby negatively affecting the fungi and in turn the symbiotic association between the mycobiont and the photobiont (Masuch, 1993).

Source: see next slide

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Lichen-Population Diversity & Highway Vehicle Exhaust

Measurement sites

• Golling 35 (G35, 20 m from motorway

• Golling 77 (G77, 20 m f. motorway)

• Parking Area (PA, 300 m f. motorway)

• Kneippanlage (KA, 500 m f. motorway)

• Baerenhof (BH, 2500 m f. motorway) (amidst a densly forested area)

• F. Ferdinand Kurve (FFK, 4000 m f. motorway) – open & exposed

Source: Madl & Heinzlmann, 2006

Lichen @ Highway (2/3)

Aerosol Climate Tools ModelHealth

Measurement sites closer to the highway produced higher concentrations as a result of the constant mixing of exhaust particles and resuspension of larger aerosol-clusters and elevated vehicle density (Hofmann, 2005). Consequently, particles are easily relocated by wind and transported over the sound-protective barriers to finally settle in neighbouring land strips. As expected, sampling sites further away and deeper within the Bluntau-Valley yielded lower particle concentrations. However, long-distance relocation of exhaust particle-loads originating from the motorway does regularly occur, as lichen-populations on exposed sites such as the remotest site surveyed (FFK-location) do reveal a suppressed species diversity. This observation correlates with those made by other authors that associate these ecological changes to excess eutrophication and an elevated pollutant load (Masuch, 1993).

In particular, higher aerosol concentration results in lower species diversity by damaging the thalli of the lichens (Nimis, 2002). Therefore, measurement sites in close proximity to the E55 display a distinctive absence of species otherwise found in more pristine areas of similar geo-botanic character (Masuch, 1993).

Additionally, lichen associations near the highway tend to change to more nitrophilouslichen associations because of a higher amount of nitrogen available due to vehicle exhaust and being in a rural setting, the prevailing agricultural activities near the motorway along with the associated wind-related relocation of fertilizer. The dramatic reduction of lichen diversity observed at all measurement sites – with none to just a few in close proximity to the motorway backs up the hypothesis that certain particle sizes are able to enter the lichen thallus through pores of the polysaccharide layer of the epicortex thereby negatively affecting the fungi and in turn the symbiotic association between the mycobiont and the photobiont (Masuch, 1993).

Source: Madl P, Heinzelmann E., Hofmann W., Türk R. (2010): Motorway exhaustaerosols and their effects on epiphytic lichen populations, Gefahrstoffe Reinhaltung der Luft, 4:147-153

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Lichen Chamber Exposure Experiment

Measurement conditions

• Chamber 1m3

• Light Ssource: 400W @ 300µmol m-2s-1

• Temp-control: water-cooled @ 18°C• Air: Hepa-filtered via H2O-impinger

• Aerosol: Diesel (Tedlar-bag) via Venturi

Source: Langmann et al., 2011

Lichen @ Highway (3/3)

0 [%] 1

Aerosol inventory @ steel tank (23rd Nov. 2011)

0.0

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exposed lichenqP

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Aerosol Climate Tools ModelHealth

In a sealed stainless steel-chamber the pollution with Diesel exhaust was simulated for three weeks, which corresponds to the rhythmic rush hours cycles of a local highway. The closed chamber guarantees, that influences other than Diesel exhausts are excluded. Diesel Aerosols were fed into the chamber using a Tedlar-bag. Appropriate humidity levels were provided using an impigerpowered with Hepa-filtered air. As a light source a HQ-400W lamp was used. A water-cooled system kept the tank temperature at physiologically optimal levels. Nanoparticles were quantified with an SMPS-system and the photosynthetic activity of lichens was measured with both a chlorophyll-fluorescence -Imaging-PAM as well as Mini-PAM devices. Vitality of lichens was determined by CO2 gas exchange measurements.

The distinct quenching-rates qP and qN of fluorescence trends are evidence of the negative impact of Diesel pollutants (see Figs). Therefore, we conclude: Diesel exhaust does not interfere directly with the photosystem II but affects the proton-gradient at the membrane between photosystem II and ATP-Synthase. Hence, ATP- and NADPH-yields along with the associated carbohydrate-synthesis of the Calvin-cycle of the photobiont are impaired. In effect the photobiont dies. The mycobiont is starved as it is dependent on the carbohydrate-synthesis of the photobiont.

Source: Langmann U., Mald P., Hofmann W., Brunauer G., Türk R. (2012); Experimental Investigations of Sensitivity of Lichens to Diesel Exhaust under Lab Conditions – work in progress

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Toxic marine diesel fumes • largely still unfiltered

• catalytic converters are simply overloaded

• Combustion of 1t of ‘bunker fuel‘ yields:

i) 19 kg SO2, (vs. 20g from diesel in std cars …. x 20 !! )

i) 6 kg NOX, (vs. 40g -“- …. x 12 !!)

i) 0.17 kg PM (Fe-oxides, V2O5, NiXOY, etc)

i) hotspots: >1000 ships/km2 ocean generating 1.05∙E9 t CO2.

Ship exhaust (1a/5)

Top: World fleet by principal vessel types, 1980–2013 (Beginning-of-year figures, in millions of dwt)

UNCTAD, 2013

Density of Ships/km2

Schroeder, 2015, Halpern et al., 2008

Aerosol Climate Tools ModelHealth

The year 2012 saw the turn of the largest shipbuilding cycle in recorded history. Between 2001 and 2011, year after year, newbuilding deliveries reached new historical highs. Only in 2012, for the first time since 2001, was the fleet that entered into service during the year less than that delivered during the previous 12 months. In spite of this slowing down of new deliveries, the world tonnage continued to grow in 2012, albeit at a slower pace than in 2011. The world fleet has more than doubled since 2001, reaching 1.63 billion deadweight tons (dwt) in January 2013.

Table: Compiled by the UNCTAD secretariat, on the basis of data supplied by Clarkson Research Services and previous issues of the Review of Maritime Transport. All propelled seagoing merchant vessels of 100 GT and above, excluding inland waterway vessels, fishing vessels, military vessels, yachts, and offshore fixed and mobile platforms and barges (with the exception of floating production storage and offloading units (FPSOs) and drillships).

Image: auf den seewegen ziwchen den kontitenten herrscht dichter verkehr. An den hauptrouten sind weit ueber1000 schiffe/km2 ozean unterwegs. Das geschaeftige treiben auf see geht an der natur nicht sprulos vorueber. Laut internationaler see-schiffahrt-organisation (IMO) emittierte die zivile schiffahrt im jahr 2007 allein1.05∙E9 t CO2.[3]

Source: UN (2013) Review of Maritime transport. UNCTAD (United nations conference on trade development), Chapter 2. United Nations. Available online:

http://unctad.org/en/PublicationsL~ibrary/rmt2013_en.pdf

Schroeder T (2015) Alternative Schiffsantriebe – Ideen fuer eine klimafreundliche Seefahrt. NZZ vom 29. April 2015

[3] Halpern BS, Walbridge S, Selkoe KA, Kappel CV, Micheli F, D'Agrosa C, Bruno JF, Casey KS, Ebert C, Fox HE, Fujita R, Heinemann D, Lenihan HS, Madin EM, Perry MT, Selig ER, Spalding M, Steneck R, Watson R. (2008) A global map of human impact on marine ecosystems. Science, Vol.319(5865):948-952.

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Toxic marine diesel fumes • largely still unfiltered

• catalytic converters are simply overloaded

• Combustion of 1t of ‘bunker fuel‘ yields:

i) 19 kg SO2, (vs. 20g from diesel in cars)

i) 6 kg NOX, (vs. 40g -“-)

i) 0.17 kg PM (Fe-oxides, V2O5, NiXOY, etc)

i) hotspots: >1000 ships/km2 ocean generating 1.05∙E9 t CO2.

Shepherd, 2015

Ship exhaust (1b/5)

Aerosol Climate Tools ModelHealth

Cloud seedling along ship routes (NZZ, 2015)

Bunker fuel of ships (low grade fuel) is rich in sulfur - see section: health effects

Prior to any large scale experimentation or deployment it is recommended that geo-engineering methods be evaluated based on the following criteria:[1] ….

Impacts:

• State of understanding of intended effects on the climate system?

• Verifiability of intended effects;

• Potential for the method and its effects be stopped once deployed;

• Likely effects on the climate system of turning the method off;

• Foreseeable environmental impacts (nature, spatial scale and magnitude)

• Potential for mitigation of environmental impacts;

• Potential for human health impacts;

• Potential for predictable, but unintended consequences, & scope for management of these;

• Potential liability issues from adverse environmental, economic or social impacts

Image: Shiptracks: schematic of processes leading to ship tracks in marine stratocumulus clouds; effective droplet radius (re) measured during two transects through a ship track in cloud 60 and 70 km from the ship. The center of the ship track is at ∼16 km along the transect. Satellite image that reveals tracks of clouds along the shipping routes as a result of the exhaust fumes originating from the combustion of bunker fuels by ships.[2]

Source: [1] Shepherd J. (2015). Geoengineering the climate - science, governance and uncertainty. Royal Society; https://royalsociety.org/policy/publications/2009/geoengineering-climate/

[2] Seinfeld J, Pandis S (2016)Indirect Effects of Aerosols on Climate, In: Atmospheric Chemistry and Physics, Ch.24; 3rd ed, John Wiley & Sons, Hoboken (NJ), USA

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Toxic marine diesel fumes • largely still unfiltered

• catalytic converters are simply overloaded

• Combustion of 1t of ‘bunker fuel‘ yields:*

i) 19 kg SO2, (vs. 20g from diesel in cars)

i) 6 kg NOX, (vs. 40g -“-)

i) 0.17 kg PM (Fe-oxides, V2O5, NiXOY, etc)

i) hotspots: >1000 ships/km2 ocean generating 1.05∙E9 t CO2.

• exhaust migrates far over land

• boosts oceanic acidification

Zimmermann et al., 2013

Karanc., 2013

Ship exhaust (2a/5)

WAS estimated that the 60,000 large ships of the global shipping industry emitted more CO2 than

the 6th largest CO2-emitting country, Germany.

Lack, 2015

*) Low grade diesel

ZDF– bunker fuel.mov

Aerosol Climate Tools ModelHealth

[1] The potential effect on surface water pH of emissions of SOX and NOX from global ship routes is assessed. The results indicate that regional pH reductions of the same order of magnitude as the CO2-driven acidification can occur in heavily trafficked waters. These findings have important consequences for ocean chemistry, since the sulfuric and nitric acids formed are strong acids in contrast to the weak carbonic acid formed by dissolution of CO2. Our results also provide background for discussion of expanded controls to mitigate acidification due to these shipping emissions.

Image: Die Belastung der Hafenstädte mit wahrscheinlich gesundheitsbedenklichen Feinstäuben ausSchiffsdieselmotoren ist ein ernstes und bisher viel zu wenig untersuchtes Problem“, erklärt Prof. Dr. Ralf Zimmermann,

Source: Zimmermann, R.; Buters, J.; Öder, S.; Dietmar, G.; Kanashova, T.; Paur, H.; Dilger, M.; Mülhopt, S.; Harndorf, H.; Stengel, B.; Rabe, R.; Hirvonen, M.; Jokiniemi, J.; Hiller, K.; Sapccariu, S.; Berube, K.; Sippula, O.; Streibel, T.; Karg, E.; Schnelle-Kreis, J.; Lintelmann, J.; Sklorz, M.; Arteaga Salas, M.; Orasche, J.; Müller, L.; Reda, A.; Passig, J.; Radischat, C.; Gröger, T.; Weiss, C. (2013). Ship diesel emission aerosols: A comprehensive study on the chemical composition, the physical properties and the molecular biological and toxicological effects on human lung cells of aerosols from a ship diesel engine operated with heavy or light diesel fuel oil. American Geophysical Union, Fall Meeting 2013, abstract #A44E-03

http://www.uni-rostock.de/aktuelles/pressemeldungen/detailansicht-pressemeldung/news-artikel/einzigartiges-experiment-in-rostock/

Winebrake JJ1, Corbett JJ, Green EH, Lauer A, Eyring V. (2009) Mitigating the health impacts of pollution from oceangoing shipping: an assessment of low-sulfur fuel mandates. Environ Sci Technol. Vol.43(13):4776-4782.

Lack D (2015) Cruis ship pollution not welcome in Sydney. Environment. Australian Broadcasting Coorporation, Sydney (AUS)

http://www.abc.net.au/environment/articles/2015/03/16/4198298.htm

Karanc: http://www.marineinsight.com/marine/marine-news/headline/how-massive-main-engines-are-fitted-in-the-ships-engine-room/

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Toxic marine diesel fumes • largely still unfiltered

• catalytic converters are simply overloaded

• Combustion of 1t of ‘bunker fuel‘ yields:

i) 19 kg SO2, (vs. 20g from diesel in cars)

i) 6 kg NOX, (vs. 40g -“-)

i) 0.17 kg PM (Fe-oxides, V2O5, NiXOY, etc)

i) hotspots: >1000 ships/km2 ocean generating 1.05∙E9 t CO2.

• exhaust migrates far over land

• boosts oceanic acidification

• chronic exposure: premature mortality

Winebraker et al., 2009

Ship exhaust (2b/5)

Aerosol Climate Tools ModelHealth

Concerns about health effects due to emissions from ships have magnified international policy debate regarding low-sulfur fuel mandates for marine fuel. Policy discussions center on setting sulfur content levels and the geographic specification of low-sulfur fuel use. We quantify changes in premature mortality due to emissions from ships under several sulfur emissions control scenarios. We compare a 2012 No Control scenario (assuming 2.7% or 27 000 ppm S) with three emissions control scenarios. Two control scenarios represent cases where marine fuel is limited to 0.5% S (5000 ppm) and 0.1% S (1000 ppm) content, respectively, within 200 nautical miles of coastal areas. The third control scenario represents a global limit of 0.5% S. We apply the global climate model ECHAMSSy-MESSy1-MADE to geospatial emissions inventories to determine worldwide concentrations of particular matter (PM2.5) from ocean going vessels. Using those PM2.5 concentrations in cardiopulmonary and lung cancer concentration-risk functions and population models, we estimate annual premature mortality. Without control, our central estimate is approximately 87 000 premature deaths annually in 2012. Coastal area control scenarios reduce premature deaths by approximately 33 500 for the 0.5% case and approximately 43 500 for the 0.1% case. Where fuel sulfur content is reduced globally to 0.5% S, premature deaths are reduced by approximately 41 200. These results provide important support that global health benefits are associated with low-sulfurmarine fuels, and allow for relative comparison of the benefits of alternative control strategies.

Source: Annual premature mortality for the No Control scenario compared to a “no shipping” case using ICOADS data.

Winebrake JJ1, Corbett JJ, Green EH, Lauer A, Eyring V. (2009) Mitigating the health impacts of pollutionfrom oceangoing shipping: an assessment of low-sulfur fuel mandates. Environ Sci Technol.Vol.43(13):4776-4782.

Hassellöv IM, Turner DR, Lauer A, Corbett J (2013) Shipping contributes to ocean acidification. Geophysical Research Letters Vol.40(11): 2731–2736.

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Toxic marine diesel fumes • largely still unfiltered

• catalytic converters are simply overloaded

• Combustion of 1t of ‘bunker fuel‘ yields:

i) 19 kg SO2, (vs. 20g from diesel in cars)

i) 6 kg NOX, (vs. 40g -“-)

i) 0.17 kg PM (Fe-oxides, V2O5, NiXOY, etc)

i) hotspots: >1000 ships/km2 ocean generating 1.05∙E9 t CO2.

• exhaust migrates far over land

• chronic exposure: premature mortality

Ship exhaust (3/5)

Annual mortality

Corbett et al., 2007

Aerosol Climate Tools ModelHealth

Epidemiological studies consistently link ambient concentrations of particulate matter (PM) to negative health impacts, including asthma, heart attacks, hospital admissions, and premature mortality. We model ambient PM concentrations from oceangoing ships using two geospatial emissions inventories and two global aerosol models. We estimate global and regional mortalities by applying ambient PM increases due to ships to cardiopulmonary and lung cancer concentration-risk functions and population models. Our results indicate that shipping-related PM emissions are responsible for approximately 60,000 cardiopulmonary and lung cancer deaths annually, with most deaths occurring near coastlines in Europe, East Asia, and South Asia. Under current regulation and with the expected growth in shipping activity, we estimate that annual mortalities could increase by 40% by 2012.

Image: Case 2b annual cardio-pulmonary mortality attributable to ship PM2.5

emissions across Europe & Asia.

Source: Corbett JJ, Winebrake JJ, Green EH, Kasibhatla P, Eyring V, Lauer A. (2007) Mortality from ship emissions: a global assessment. Environ Sci Technol. Vol.41(24): 8512-8518.

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Toxic marine diesel fumes • largely still unfiltered

• catalytic converters are simply overloaded

• Combustion of 1t of ‘bunker fuel‘ yields:

i) 19 kg SO2, (vs. 20g from diesel in cars)

i) 6 kg NOX, (vs. 40g -“-)

i) 0.17 kg PM (Fe-oxides, V2O5, NiXOY, etc)

i) hotspots: >1000 ships/km2 ocean generating 1.05∙E9 t CO2.

• exhaust migrates far over land

• chronic exposure: premature mortality

Ship exhaust (4/5)

Withfeld & Conolly, 2015

Immediate effects of Bunker fuel

unusual headache, nausea,

mid-term effects: asthma among kids

Aerosol Climate Tools ModelHealth

Cruise liners berthed near homes on Sydney harbour are burning a carcinogenic fuel banned in US and European ports. Residents say they’re getting sick but the cruise companies have refused to burn cleaner fuel and the government says it won’t act to stop the dirty ships for at least another year

Image: The Sun Princess is a frequent visitor to the White Bay Terminal (Sydney, AUS)

Source: Withfeld A, Conolly A (2015) Cruising’s dirty secret. BackgroudBriefing, Australian Broadcasting Coorporation, Sydney (AUS)

http://www.abc.net.au/radionational/programs/backgroundbriefing/2015-03-15/6293472

http://mpegmedia.abc.net.au/rn/podcast/2015/03/bbg_20150315_0805.mp3

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Toxic marine diesel fumes • Marine Gas Oil (MGO, a distillate fuel oil)

• Heavy fuel oil (HFO = bunker fuel)

Ship exhaust (5a/5)

Winnes & Fridell, 2009

The substance on the left has lower viscosity than the substance on the right

Aerosol Climate Tools ModelHealth

This paper presents the results of field emission measurements that have been carried out on the 4500-kW fourstroke main engine on-board a product tanker. Two fuel qualities—heavy fuel oil (HFO) and marine gas oil (MGO)—have been tested on the same engine for comparable load settings. A fuel switch within the marine sector is approaching and the aim of this study is to draw initial conclusions on the subsequent effects on ship exhaust gas composition and emission factors with a focus on particles. Measurements on exhaust gas concentrations of carbon dioxide (CO2), carbon monoxide (CO), nitrogen oxides (NO2), sulfur dioxide (SO2), total hydrocarbons (HCs), and particulate matter (PM) were conducted. The gases, except SO2, did not show any major differences between the fuels. Specific PM emissions were generally higher for HFO than for MGO; however, for the smallest size-fraction measured containing particles 0.30–0.40 m in diameter, the opposite is observed. This finding emphasizes that to minimize negative health effects of particles from ships, further regulation may be needed to reduce small-sized particles; a fuel shift to low sulfur fuel alone does not seem to accomplish this reduction. The average of this and previously published data from on-board studies on particle emissions from ships results in emissions factors of 0.33 and 1.34 g/kWh for marine distillate oil (MDO) and HFO, respectively. Accounting for 1 standard deviation in each direction from the average values gives a range of 0.18–0.48 g/kWh for MDO and 0.56–2.12 g/kWh for HFO.

Image: Number size distributions for steady-state loads of 50–55%, 65–70%, and 90% for 4.5-MW tanker diesel engine operating on HFO (top). Number size distributions for steady-state loads of 55–60%, 70%, and 85–90% for 4.5-MW tanker diesel engine operating on MGO (bottom). Main chemical composition and physical properties of HFO and MGO fuel oils (bottom left).

Source: Winnes H, Fridell E (2009) Particle Emissions from Ships: Dependence on Fuel Type, Journal of the Air & Waste Management Association, 59(12): 1391-1398,

Bunker Oil - Marine Fuel Oil: http://www.viscopedia.com/viscosity-tables/substances/bunker-oil-marine-fuel-oil/

https://en.wikipedia.org/wiki/Viscosity

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Toxic marine diesel fumes • Marine Gas Oil (MGO, a distillate fuel oil)

• Heavy fuel oil (HFO = bunker fuel)

Ship exhaust (5b/5)

Van et al., 2016

Aerosol Climate Tools ModelHealth

The composition of exhaust from a marine diesel auxiliary engine running on Heavy Fuel Oil (HFO) was investigated on-board a large cargo vessel. Measurements of particle number and size distributions in the range 5-1000 nm and gaseous emissions of O2, CO, CO2, SO2 and NOX were made. The measurements were performed in October and November 2015 on two large cargo ships at berth and during travel. Measurements were also carried out on auxiliary engines of two ships when they were at berth. Data on engine power, engine revolution, fuel oil consumption, intercooled air temperature, scavenging air pressure, cooling fresh water and exhaust gas temperature were measured using instrumentation of the ship. Results showed that emission factors (g/kWh) are higher than that of previous studies for SO2. This may be due to the high sulphur content of fuel used. Particle number size distribution was observed to be the highest around 35 – 45 nm in diameter, and the particle number remarkably decreased during higher engine load conditions.

Image: Specific emissions against engine load (Left, a 95% CI for each mean value is shown as the mean ± X); Number size distributions of measured particles (5-1000 nm) for idle, 24%, 35%, 55%, 70%, 83%, and 95% load.

Source: Van C, Rainey T, Ristovski Z, Pourkhesalian AM, Garaniya V, Abbassi R, Yang LP, Brown R (2016) Particle emissions from ships at berth using heavy fuel oil. In IAMU AGA2016, 26-29 October 2016,

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Heavy pollution due to 2-stroke exhaust

• gaseous precursors that oxidize & coagulate to PM

• use only 10% of overall fuel

• emit 10-1000 times primary and secondary organic aerosols (compared to 4-strokers)

• high source of benzene (cangerogenic) and other aromatic compounds

Platt et al., 2014

2-Stroker’s (1/1)

0 [%] 1

aged organic aerosol light aromatics

primary organic aerosol benzene

Aerosol Climate Tools ModelHealth

Fossil fuel-powered vehicles emit significant particulate matter, for example, black carbon and primary organic aerosol, and produce secondary organic aerosol. Here we quantify secondary organic aerosol production from two-stroke scooters. Cars and trucks, particularly diesel vehicles, are thought to be the main vehicular pollution sources. This needs re-thinking, as we show that elevated particulate matter levels can be a consequence of 'asymmetric pollution' from two-stroke scooters, vehicles that constitute a small fraction of the fleet, but can dominate urban vehicular pollution through organic aerosol and aromatic emission factors up to thousands of times higher than from other vehicle classes. Further, we demonstrate that oxidation processes producing secondary organic aerosol from vehicle exhaust also form potentially toxic 'reactive oxygen species'.

Image: Emission factors from scooters and other vehicles .... plotted as box-and-whiskers (median line, red; 25th and 75th percentile, box; 10th and 90th percentile, whiskers) of (a) POA, (b) aged OA (POA þ SOA formation), (c) benzene and (d) light aromatics (benzene, toluene and C2–C4 alkylated benzenes). Points shown next to the box-and-whiskers are the individual data points, coloured depending on measurement region for ambient data. 2S scooters (this study, n 1⁄4 3) were run in idle or during driving cycles (ECE47). Data on the other vehicles shown are from the literature (Supplementary Table 3) for light-duty and heavy-duty vehicles (LDVs and HDVs). LDVs data are further divided between vehicles meeting Euro 5 and those not meeting Euro 5, labelled oEuro 5 in parenthesis. Ambient data are split according to a contribution of HDVs to the data of higher than or lower than 50%.

Source: Platt SM, Haddad IE, Pieber SM, Huang RJ, Zardini AA, Clairotte M, Suarez-Bertoa R, Barmet P, Pfaffenberger L, Wolf R, Slowik JG, Fuller SJ, Kalberer M, Chirico R, Dommen J, Astorga C, Zimmermann R, Marchand N, Hellebust S, Temime-Roussel B, Baltensperger U, Prévôt AS (2014). Two-stroke scooters are a dominant source of air pollution in many cities. Nat Commun. 2014 May 13;5:3749. doi: 10.1038/ncomms4749.

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Heavy pollution due to 2-stroke exhaust

• gaseous precursors that oxidize & coagulate to PM

• use only 10% of overall fuel

• emit 10-1000 times primary and secondary organic aerosols (compared to 4-strokers)

• high source of benzene (cangerogenic) and other aromatic compounds

Platt et al., 2014

2-Stroker’s (2/2)

0 [%] 1

various modes of engine operation

& organic aerosol conc.

Organic aerosol as a function of age

Aerosol Climate Tools ModelHealth

Image: Contribution of aromatic oxidation to two-stroke scooter secondary aerosol formation. (a) Apparent SOA mass yields, yapparent (equation (1), as a function of suspended OA concentration (COA). Error bars show the sensitivity of yapparent to the chamber wall-loss factor, ±one s.d. yapparent for a Euro 1 and two Euro 2 2S scooters are shown in red, blue and orange, respectively. Ph 1 and Ph 2 are the first and second phases of the ECE47 driving cycle, I and L refer to idling and simulated low power, respectively. A predicted yield, concentration-weighted, for the mixture of all aromatics (Supplementary Note 1), is given in green triangles. The shaded region denotes the range between maximum (low NOX) and minimum (high NOX) SOA yields for m-xylene, a major aromatic constituent of gasoline. (b) Elemental ratios of OA emissions for the Euro 1 (squares) and a Euro 2 (triangles) scooter as a function of photochemical age. Elemental ratios observed for xylene and ambient SOA are shown, orange and purple, respectively.

Source: Platt SM, Haddad IE, Pieber SM, Huang RJ, Zardini AA, Clairotte M, Suarez-Bertoa R, Barmet P, Pfaffenberger L, Wolf R, Slowik JG, Fuller SJ, Kalberer M, Chirico R, Dommen J, Astorga C, Zimmermann R, Marchand N, Hellebust S, Temime-Roussel B, Baltensperger U, Prévôt AS (2014). Two-stroke scooters are a dominant source of air pollution in many cities. Nat Commun. 2014 May 13;5:3749. doi: 10.1038/ncomms4749.

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Aqueous Aerosols (1/4)

Peculiar effects of vaporized H2O:

• different spectra when open-air saltwater inhalation spa (Gradierwerk) was on or off (presence of traffic exhaust)

Source: Kwasny et al., 2008

Aerosol Climate Tools ModelHealth

This paper examines the effects of salt aerosol production at a Gradierwerk (GW) facility in Bad Reichenhall, Germany. The sampling campaign concentrated on the particle number concentration below 500 nm suspended in air. Sampling sites directly at the GW and at certain distances were chosen to investigate the effects of the salt aerosols on inhalation therapy and on the ambient aerosol inventory. For comparison, measurements were also made while the GW was turned off. Factoring the aerosol data into a stochastic lung deposition model showed a higher total deposition as well as a slightly higher deposition in the alveolar region for the day the GW was turned off. This directly illustrates the therapeutic benefit of the brine inhalation by reducing lung deposition and increasing clearance. The data also reveal a filtering effect in the ultrafine particle range when the GW was in function, which seems to reduce the amount of aerosols originating from the nearby traffic. The primary objectives of this study were (i) to examine the particle size distribution originating from a GW inhalation spa, and (ii) its effect on ambient aerosol size distributions and the visitors of the GW. The GW is a covered open-air saltwater inhalation facility, where people with respiratory problems seek relief. The site of investigation is located in the city center of Bad Reichenhall. Almost 400,000 liters of alpine saltwater trickle down every day through a 13 meter high wall made up of around 100,000 bundles of hawthorn and blackthorn twigs. The salt water is running down on the windward side of the GW, allowing the wind to press the brine-aerosol through the twigs onto the leeward side of the wall, where people walk along for therapeutic inhalation.

Image: Differences in particle size distributions during on/off cycles at the lee sides of the GW, representing a 3-scan average with standard deviation.

Source: Kwasny F. Madl P, Hofmann W (2008) Effects of Salt-Aerosols from a Gradierwerk on Inhalation Therapy and Ambient Aerosols. Ber. Nat.med.Ver. Salzburg, Vol 15: 99-108;

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Aqueous Aerosols (2/4)

Peculiar effects of vaporized H2O:

• electrical surface double layer;• charge separation during aerodynamic breakup;

- positive charge carried by large fragments & - negative charge carried by smaller fragments

• net charge of aerosol: approx. -100mV!

Source: Zilch et al., 2008

…. S

o far

the a

ttem

pt to

descr

ibe t

he phen

omen

on in

a clas

sical

way …

.

Aerosol Climate Tools ModelHealth

The charge separation associated with splashing and bubbling of water has .... been attributed to the presence of an electrical double layer at the surface of water, where the outermost layers acquire an excess negative charge. There is strong and compelling support for this view from electro-phoretic mobility measurements for air bubbles in water, which show that they move as if they have an excess negative charge .... which is not yet fully resolved. It probably follows from oriented dipoles at the water-vapor interface (... laid out already 80 years ago). Spectroscopic measurements at the interfacial region of water have shown that 20-30% of molecules exhibit dangling hydrogens. This leaves 70-80% of interfacial water dipoles with their positive end directed toward the water interior …. This picture is also confirmed by surface potential measurements. The accepted value for the surface potential of water is -100mV …. Furthermore, studies of the charge separation in the aerodynamic breakup of water droplets have shown that the positive charge is carried by large fragments (e.g. H3O

+) and the negative charge is carried by much smaller fragments (e.g. OH-).

Image: The figure illustrates how such charge separation could occur. Excess OH- ions are attracted to the interfacial region by the positive end of the surface dipoles. As the bag forms and thins, the H3O

+ counter-ions are swept into the annulus. When the bag breaks it generates a large number of small negatively charged fragments, and when the annulus breaks it produces a small number of large positively charged fragments …. (OH- ions attracted to the positive end of the surface dipoles, the H3O

+ ions swept into annulus. Upon breakage it generates a large number of small negatively charged fragments, and a small number of large positively charged fragments).

Source: Zilch L.W., Maze J.T., Smith J.W., Ewing G.E., Jarrold M.F. (2008) Charge Separation in the Aerodynamic Breakup of Micrometer-Sized Water Droplets.J. Phys. Chem. A 2008, 112, 13352–13363

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Aqueous Aerosols (3a/4)

Peculiar effects of vaporized H2O:

• Inhalable fraction of;• i) neg. charged aerosols

i) Lenard-effect (spray electrification, 1892);

• the further away from the falls, the more dominant the peak shifts towards smaller ion sizes peaking @ approx. 100 nm….

Source: Kolarž et al., 2012

Aerosol Climate Tools ModelHealth

During a three-year field campaign of measuring waterfall generated ions, we monitored five different waterfalls in the Austrian Alps. Most measurements were performed at the Krimmlwaterfall (Salzburg, Austria), which is the biggest waterfall in Europe, and the Gartl waterfall (Mölltal, Austria). We characterized spatial, time and size distributions of waterfall-generated ions under the influence of surrounding topography. The smallest ions with boundary diameters of 0.9, 1.5 and 2 nm, were measured with a cylindrical air ion detector (CDI-06), while ion sizes from 5.5 to 350 nm were measured using a modified Grimm SMPS aerosol spectrometer. High negative ion concentration gradients are detected in the vicinity of the waterfalls, whereas the increase of positive ions was only moderate. Ions in the nano range were the most abundant at 2 nm, and at 120 nm in the sub-micrometer range.

Image: Composite plot of the size distribution of negatively charged particles as measured with distance from the waterfall in Krimml, (Austria). Indices denote sampling locations at the falls (with the satellite view revealing the positions in the field). Size distribution till 2.5nm were recorded with the CDI, particles from 5-350nm have been obtained using the SMPS instrument; in-between GCID and SMPS measurements the interpolated region. For SMPS-measurements it was assumed that each particle carries a single charge.

Source: Kolarž PM, Gaisberger M, Madl P, Hofmann W, Ritter M, Hartl A (2012) Characterization of ions at Alpine waterfalls. Atmospheric Chemistry and Physics, 12: 3687–3697.

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Aqueous Aerosols (3b/4)

Peculiar effects of vaporized H2O:

• Network of flickering H-bonds favouring formation of coherence domains (CDs)

• CDs form when vapor condensesonto liquid phase (droplet).

• Formation of a CD (coherence domain) seems to be a fundamental property of H2O.

Source: Madl et al., 2013

h

e

V

f

2

1

OHEnm

nmCD 2

63

153.0

75

Aerosol Climate Tools ModelHealth

It is the scope of this paper to propose an additional charging mechanism of water-fall generated aerosols. The observations leading to this approach arose from a field study at five waterfalls in the Austrian Alps. Thereby, size distributions of ion clusters, their mobility and their intermediate progenies near waterfalls have been measured with a tandem ion spectrometer consisting of three aspirated Gerdien Cylindrical Ion Detectors (CDI) in combination with a Scanning Mobility Particle Sizer (SMPS). It was observed that the concentration of negative 0.9-10 nm ions was 2-3 orders of magnitude higher than at the reference points up to several 100s of meters away from the waterfalls. Here we discuss the observed features in a quantum electro-dynamic scheme. We find good agreement between theory and observations obtained in the field, which supports the view that water in this size range is highly structured and coherent.

Gases are fully non coherent systems. Liquids are systems where electron clouds are coherent. Solids are systems where nuclei too are coherent. Liquid water is peculiar, since the coherent oscillation connects two electronic configurations that have extreme features:[3]

1) the ground configuration where all electrons are tightly bound (the ionization potential is 12.60eV, corresponding to soft X-rays / far UV-range and to an excitation temperature of 140·E3 [K] …. E = k·T .… k = 86.174·E-6[eV/K];

2) the excited configuration has an energy E=12.06eV, only 0.54eV below the ionization threshold. So for each molecule there is almost one free electron (echarge = -1.6022·E-19 [A·s] = 1eV)!

Image: Formation of coherence domains (CDs) of aerosolized water molecules. The free-floating dipoles start to feel mutually attracted and establish coherent resonance clusters that result in the formation of 75 nm large CDs in which molecules resonate unisono and in phase. CDs themselves become entrapped by the newly formed coherent polarizing field and reveal a characteristic wavelength of about 100nm. The formation of CDs is a fundamental property of liquid water and unlike the laser, no energy pumping is required to establish coherence.

Source: Madl P, Del Giudice E, Voeikov VL, Tedeschi A, Kolarž P, Gaisberger M and Hartl A (2013) Evidence of Coherent Dynamics in Water Droplets of Waterfalls. Water, Vol 5: 57-68.

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Aqueous Aerosols (3c/4)

Peculiar effects of vaporized H2O:

• Two-phase system: FCD(T) + FnCD(T) = 1

• CDs are reservoirs of free electrons (= reducing agent; bulk water is an oxidant).

• NCD : NnCD = 0.4 : 0.6 @ TRoom!• multi-mode laser-like behavior.

Source: Madl et al., 2013

22

Agradm

eF]/[84 9 mVE

t

AE

Amplitude w/n CD

Aerosol Climate Tools ModelHealth

Coherence arises out of the electromagnetic fluctuations of the quantum vacuum and from the exchange of radiation at the natural photo-absorption resonances of water molecules. Such coherence is confined to domains whose size is different for molecules and electromagnetic fields (EMF). The field is trapped in a region whose diameter corresponds to 2∙rCD f, the wavelength of the spectral line involved (rCD f = /2). The involved spectral line is in the far-UV, close to the ionisation potential of water (Fig. 5). CDs obtained in this way are the liquid droplets produced by the condensation of water vapour. Permanent coherence becomes established in water and gives rise to a long-range-order within domains 75nm in diameter (see previous slide).

As long as the "vapor" density remains below the smallest of the critical densities of 0.31g/cm3 (belonging to 12.06eV) the system of water molecules remains in the perturbative ground state. This is the state where quantum fluctuations are not tuned together and consequently molecules are uncorrelated; characteristic for vapor. As soon as such a critical density is reached, the oscillation starts to "run away". When this happens, the electromagnetic "zero-point" fluctuations with the corresponding frequency = 12.06eV begins to build up and the water molecules will oscillate between the ground state and the excited level at 12.06 eV (image). At this runaway-state, all the other excitation levels of the affected water molecules will be from now on totally ignored by the dynamic evolution of the physical system, which is made of water molecules plus the EMF (Preparata, 1995). It is important to note here that we speak of a two-phase system, in which not all the water molecules take part in the formation of CDs (previous slide). In other words, at room-temperature the coherent versus the non-coherent fraction in the vapor phase is split into a 0.4 to 0.6 ratio, in favor of the latter – since the temperature at the falls (e.g. Krimml) was only about 15°C, this balance is slightly biased towards coherence, i.e. 0.425 vs.0.575 (Buzzacchi et al., 2002).

Image: Formation of the multimode laser-like properties within a CD as a result of the pumping mechanism, synchronized excitation and relaxation patterns between the ground level and excitation at 12.06eV of the involved water molecules.

Source: Madl P, Del Giudice E, Voeikov VL, Tedeschi A, Kolarž P, Gaisberger M and Hartl A (2013) Evidence of Coherent Dynamics in Water Droplets of Waterfalls. Water, Vol 5: 57-68.

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Aqueous Aerosols (3d/4)

Peculiar effects of vaporized H2O:

• Imuno-stimulation on asthmatics (with referenceto various interleukins & interferon-γ)

• T1 @ start vs. T2 @ end (after 20 days)• beneficial effects lasted till day 80 after exposure

Source: Gaisberger et al., 2012

water aerosol group (WAG); site of the control group (CG)

Aerosol Climate Tools ModelHealth

Ionized water aerosols have been suggested to exert beneficial health effects on pediatric allergic asthma. Their effect was evaluated in a randomized controlled clinical trial as part of a summer asthma camp. Methods. Asthmatic allergic children (n = 54) spent 3 weeks in an alpine asthma camp; half of the group was exposed to water aerosol of an alpine waterfall for 1 hour per day, whereas the other half spent the same time at a “control site”. Immunological analysis, lung function testing, and fractional exhaled nitric oxide (FeNO) testing were performed during the stay, and sustaining effects were evaluated 2 months later. Symptom score testing was done over a period of 140 days. Results. The water aerosol group showed a significant improvement in all lung function parameters, whereas only the peak expiratory flow improved in the control group. All patients showed a significant improvement in symptom score and a significant decrease in FeNO after the camp. Only the water aerosol group exhibited a long-lasting effect on asthma symptoms, lung function, and inflammation in the follow-up examination. Induction of interleukin (IL)-10 and regulatory T (Treg) cells was measured in both groups, with a pronounced increase in the water aerosol group. IL-13 was significantly decreased in both groups, whereas IL-5 and eosinophil cationic protein were decreased only in the water aerosol group. Conclusions. Our findings confirm the induction of Treg cells and reduction in inflammation by climate therapy. They indicate a synergistic effect of water aerosols resulting in a long-lasting beneficial effect on asthma symptoms, lung function, and airway inflammation.

More importantly, water aerosol exposure combined with high-altitude therapy improved the sustainability of the positive effects. In the follow-up period (day 80), PEF was 15% above baseline in the water aerosol group and 2% above baseline in the control group (p ¼ .026, data not shown). A similar trend could be detected for all other lung function parameters, with increased mean values in the water aerosol group in comparison to the control group values, which had returned to baseline at this point. Additionally, the results of FeNO measurements at day 80 indicated a longasting positive effect of water aerosols, as FeNO was reduced by 33% in the water aerosol group compared to only 6% in the control group.

Insert: Left photograph: site of the water aerosol group (WAG); right photograph: site of the control group (CG).

Table: Statistical analysis was performed between day 1 and day 20 for the water aerosol group (WAG) and the control group (CG), as shown in columns WAG delta and CG delta. Intergroup comparison is demonstrated for the deltas of day 20 to day 1 (group difference). The baseline values of qRT-PCR were set to 1; therefore, only intergroup statistics were performed between the groups. SEM, standard error of mean; IL, interleukin; ECP, eosinophil cationic protein; Treg cells, regulatory T cells; ELISpot, enzyme-linked immunosorbent spot assay; CFU, colony-forming unit; qRT-PCR, quantitative real-time PCR; IFN-γ, interferon gamma. P-values: *p ≤0.05, **p ≤0.01.

Source: Gaisberger M, Šanović R, Dobias H, Kolarž P, Moder A, Thalhamer J, Selimović A, Huttegger I, Ritter M, Hartl A. (2012) Effects of Ionized Waterfall Aerosol on Pediatric Allergic Asthma. Journal of Asthma, 49(8): 830-838.

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Aqueous Aerosols (4/4)

Peculiar effects of vaporized H2O:

• In theory it should ameliorate the on-site situation;

• In reality it is hopeless due to the sheer extent of pollution;

• Its just a symptomatic treatment, to calm the public;

Source: china.org.cn (2014)

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Giant water cannon won't kill smog: A government department in Xi'an, Shaanxi Province, has invested nearly one million yuan ($160,000) in a removable mist cannon designed to fight the city's dirty air, yet experts say the giant sprayer does little to reduce the density of PM2.5, the major contributor to the city's smog, the Beijing News reported on Monday. The Parks and Woods Bureau of the city's XinCheng district bought the machine from an environmental equipment manufacturer in GuangZhou with government financing of 900,000 yuan. The 10-ton machine can spray water a distance of up to 600 meters and 70 meters high. The water goes up as a fine mist and sticks to dust to form larger particles, which fall to the surface under force of gravity. Experts say that as a small-scale effort to dampen dust in Xi'an, the machine can help a little. Pan XiaoChuan, an environmental expert at Peking University, said on Sunday that the machine's role in cleaning air pollution is temporary. Although the machine can reduce its surrounding pollutants within a short period of time after water is sprayed, its effects don't last long. The machine is effective in controlling dust from construction sites, but it is useless in combating fine particles like PM2.5, according to a professor of atmospheric governance from Beijing. "Fine particles like PM2.5 can form pollution layers which are over 200 meters above the ground," said the professor. The major pollution sources in Xi'an are coal combustion, vehicle emissions and industrial releases, not dust, he added.

Image: The photo taken on May 9, 2014 shows a removable mist cannon which can reduce dust in air working on a street in Xi'an, Shaanxi province.

Source: http://www.china.org.cn/environment/2014-05/13/content_32367666.htm

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.... Continue with part 4 (Equipment) ....

Aerosol Climate Tools ModelHealth