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Lecture No. 5

Toxicology

Chapter 5, p.225

A waste is hazardous if it is: reactive, corrosive, ignitable and/or toxic. Human toxicity is of

particular concern.

Toxicology deals with the adverse effects caused by exposure of living organisms to chemical

substance.

Toxicology is supported by information obtained from experiments on animals which is then

extrapolated to humans and carries uncertainty.

1. Pharmacokinetics

Pharmacokinetics refers to the rate at which various body mechanisms deal with toxicants; it is

the quantitative description of the time course for uptake, transformation, storage and

transport of compounds.

The exposure pathway is the series of steps starting with a release of waste and concluding

with interface with a human being. The exposure route is gaining entry into the body. There

are three exposure routes (Fig. 5-1, p.227) :

- Inhalation. Respiratory tract.

- Ingestion. Gastrointestinal tract.

- Dermal contact. Skin.

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Lecture No. 5, Toxicology, Page No. 2

A. Adsorption

Adsorption is the transport of a pollutant across any body barrier.

-These barriers consist basically of cellular membranes having a similar structure of a two-

molecule thick, inner layer of various fatty substances (lipids) blanketed between two layers of

proteins.- The uptake dose is the amount of toxic chemical that becomes available to the body.

- The target or effective dose is the amount of toxic chemical that reaches the target

organ.

Most toxic agents pass through cell membranes by simple diffusion.

- Lipid (fat) solubility is the most important property. Lipid solubility is a measure of the

affinity of a chemical substance for fat-like solvents as opposed to water water-like solvents.

Polar substances readily dissolve or ionize in water and are hydrophilic. Non-polar

substances do NOT readily dissolve in water and are hydrophobic or lipophilic.

Adsorption via ingestion may occur along the whole length of the gastrointestinal tract.

In the gaseous state, the inhaled compound is transferred into the liquid layer lining the airway

by diffusion. Particles with a diameter of 2 m ( p.xxxii, micrometer, meter x 10-6) and aboveare deposited in the upper respiratory tract, removed by the mucous present in the airways and

swallowed. Smaller particles penetrate to the alveoli of the lung.

Skin is an excellent barrier to many toxic compounds. The body has the potential to tolerate

100 to 1000 times the exposure amount by dermal contact versus ingestion or inhalation.

B. Distribution and Storage

Upon reaching the blood stream, the toxic agents can move throughout the body, they are

systemic ( system-wide) as opposed to local. Many substances may accumulate at sites other

than the target organ to be released over an extended period of time; a process called storageand include:

- Fat for non-polar (lipophilic) compounds such as organochloride pesticides, PCBs.

- Blood plasma for compounds bound by blood proteins such as mercuric ions.

- Bone for lead, radium and fluoride

- Kidneys for cadmium

Dieting, stress and other use of fat reserves can induce rapid release of the stored substance,

causing a toxic reaction.

C. Biotransformation and Elimination

Upon reaching an organ, three events other than storage can occur:

- Biotransformation. Enzyme rich organs metabolize the toxicant to other molecular

species. The new species may be worse than the original.

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- Elimination. Feces, urea, sweat.

- Formation of chemical receptor complex. A target organ is attacked.

The two most important organs for biotransformation and elimination are the liver and the

kidneys.

Example:

Given: I can metabolize 11 mL of ethanol per hour and my favorite cabernet sauvigon is 13% alcohol. Ihave 12 hours before I have to drive.

Find: How many 6 oz. glasses of wine can I have? Assume a zero-order reaction. That is, my body purges

the alcohol at the same rate regardless of how drunk I am.

Amount of alcohol in a glass of wine.

= 6 oz x 1l/33.815 oz (p. 1099) x .13 (% alcohol) x 1000ml/l

= 23.1 ml

Amount I can absorb in 12 hours

= 11 ml/hr x 12 hr

= 132 ml

Glasses of wine

132 ml over 12 hours / 23.1ml/glass= 5.71 say 6 glasses of wine.

2. Toxic Effects

Three phases leading to a toxic effect:

- Exposure

- Pharmacokinetic

- Manifestation. Clinically overt symptoms.

F5-6, p.239. Mechanisms are NOT well understood. The toxic chemical binds with of a

molecule of the target organ known as the receptor. The typical receptor is an enzyme butalso could be a cell membrane or DNA. If DNA, mutation or cancer can result.

- A pharmacologic toxic action might result in inhibition, decreased efficiency.

- Genotoxic results in a mutation.

- Pathologic results in destruction.

A. Structural Affinity

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An affinity exists if the structure of the toxicant is complementary with that of a cellular

receptor. A key and lock analogy is appropriate. When a toxicant binds to a receptor, the

receptors can no longer perform their normal function such as enzymatic functions. The more

exact the fit, the more toxic the response.

The manifestation of toxic effects can range from nothing to death. For example, cyanidedecreases oxygen exchange at the cellular level to the point of disrupting nervous system

function to the point of respiratory failure or organophosphorous pesticides act as acetyl-

cholinesterase inhibitors. Allergic reactions represent the most widespread manifestation of

toxicity in humans that are caused by chemical agents. The allergic reaction is a dysfunction of

the immune system and respiratory tract is usually the target.

B. Classification of Toxic Actions and Effects T5-2, p.244

End Point.

- Carcinogenic (tumor induction) or non-carcinogenic.

- Target organism.

- Immediate vs. delayed effects.

- Irreversible vs. reversible.

- Local vs. systemic

C. Dose-Response Relationships

Dose represents the major determinant of the extent of toxic action and a correlation between

dose and response is called a dose-receptor relationship. F5-11, p248.

Median Lethal Dose. LD50. The dose at which 50% of the organisms remain alive usually

expressed as mg per kg of body weight. The equivalent for inhaled substance is median lethal

concentration, LC50. The LD50 for ethanol (booze) is 13,000 mg/kg, 3800 for table salt and

2 for parathion.

Dose-effect relationship. Adverse health effects v. dose.

D. Toxicological Data

Based on human populations or laboratory animals.

In most cases, the scientific database is not adequate to describe the quantitative risks of all

health effects from exposure to toxic substances.

3. Non-Carcinogens

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Non-carcinogenic effects include toxicological responses other than the induction of tumors.

The assessment of the toxicity of non-carcinogenic chemical substances is based on the

concept of threshold below which no effects can be observed on the cellular, sub cellular or

molecular level.

No Observed Adverse Effect Level (NOAEL).

Acceptable Daily Level (ADI). The level of daily intake of a particular substance whichshould not produce an adverse health effect. The ADI contains safety factors and is much

smaller than the theoretical threshold.

The reference dose (RfD) is used by the EPA and is established as follows:

- Most sensitive species.

- Most appropriate of exposure.

- Select supporting studies.

- Identify NOAEL.

- Adjust NOAEL downward based on:

- A factor of 10 for sensitive humans such as children and pregnant women.

- A factor of 10 when extrapolating from animals to humans

- A factor of 10 when dealing with a chronic instead of a sub-chronic study.- A factor of 10 if there is no NOAEL and use the LOAEL (Lowest Adverse

Effect Level)

Toxicological Databases. Integrated Risk Information System (IRIS). The EPA's preferred

source for toxicity information for hazardous wastes typically encountered in site remediation

projects.

ATSDR. Toxicological profiles prepared by the US Agency for Toxic Substances and Disease

Registry as mandated by SARA (Superfund, 1986). Each profile may be 100 pages in length

and presents the following information:

- Assessment of all testing and inf.

- Does adequate inf. exist.

- Chronic health effects at various levels of exposure

- Pathogenic properties.

Risk Calculation.

- Identify exposure

- Derive reference dose

- Ratio exposure dose to RfD

- Combine individual hazards.

Example:Given: The local dry cleaner puts enough 2,4 dinitrotoluene in the water to get the concentration up to 5

mg/l. The average people drink 2l per day and weight 70kg.

Find: Is there a problem?

The dose is:

=5mg/l x 2l/day

70kg

= .143 mg/kg.day

The RfD from F5-18, p. 262:

= 2.0 x 10-3 mg/kg/day

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The hazard ratio (dose/RfD)

=.143 mg/kg.day

2.0 x 10-3 mg/kg/day

hazard ratio = 71.5, There is a problem, anything over 1 is unacceptable.

4. Carcinogens

Cancer is a disease marked by cellular abnormalities in which a normal cell becomes altered

and divides uncontrollably and is characterized by tumors which may be malignant or benign.

Malignant tumors spread (metastasize) and invade surrounding structures. The process may

take 10-40 years when induced by radiation or chemical agents. Three stages:

- Initiation.

- Promotion.

- Progression.

A. Initiation

Alteration of the structure and function of the DNA.

Oncogenes regulate pre-natal growth and are turned off upon growth. Mutation can fully

activate an oncogene. The cell affected by the oncogene is completely capable of autonomous

growth and replication because is makes it own hormone and has a receptor for it. This is the

stem cell for a cancer. A single cell can NOT cause cancer. At least TWO changes in the

SAME CELL are necessary. Those agents which cause mutation of genes are referred to as

genotoxic consisting of carcinogenic chemicals and ionizing radiation.

B. Promotion of Cancer

Increase in the number of initiated cells.

High fat diets promote breast cancer in women and colon cancer in both sexes.

C. Progression

Following cells which have undergone two or more genetic changes and which have been

promoted, there is an invasion of adjacent tissues and the metastasis or movement to distant

organs. Invasion and metastasis are collectively known as progression and require additionalmutations beyond that necessary to initiate carcinogenesis. Further exposure to genotoxic

agents seems necessary for the progression of initiated and promoted cells which is why the

cancer risk goes away when you stop smoking.

D. Carcinogenic Chemicals

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Exposure to carcinogenic chemicals can result in cancer via different mechanisms. Genotoxic

may initiate and promote while non-genotoxic (epigenetic) may promote or suppress the

immune system.

T5-6, p.271.

Classes. T5-8, p.273. Group A. Human Carcinogens. Testing. Involve animal experiments particularly lifetime studies in rodents.

E. Background and Lifestyle

25% of us will contact cancer in our lifetimes.

The inhalation of tobacco smoke is a major pathway for delivery of carcinogens and is

responsible for more lung, bladder, pancreatic and breast cancer than all other artificial source

of carcinogenic insult combined.

5. Ecotoxicology

Ecotoxicology is the study of toxicology as it effects the natural environment for the purpose

of evaluating the potential impact of toxic materials.

Empirical constants used to predict bioaccumulation in the octanol-water partition coefficient,

Kow, which approximates a chemical's behavior between the lipid and water phase, and the

bioconcentration factor, BCF, which describes the relationship between the chemical

concentration in an organism and the concentration in the exposure medium typically water.

T5-14, p.292.

Corg = (BCF)(Cw) eq.5-4 units p.292

Example:Given: Spraying with lindane will results in concentrations in the local fish ponds of .5ppb.

Find:

1.) What is the concentration of lindane in the fish.

2.) If Big Jake eats two pounds of catfish at all-you-can-eat night, how much lindane did he get?

1.) Concentration of Lindane

.5ppb = .0005 ppm or mg/l ( billion = 1000 million)

From T5-14, p.292, BCF for fish=log 2.51, therefore,

BCF = 102.51

BCF = 324 mg/kg / mg/l

Corg = (BCF)(Cw) units p.292 = 324mg/kg / mg/l x .0005 mg/lCorg = .162 mg/kg

2.) Big Jake

Intake = C x pounds = .162 mg/kg x 2lbs. x 1kg/2.2046lb (conversion p.1098)

Intake = .146 mg. Not much, but I'll take tartar sauce instead.

Biomagnification is the increased concentration of a chemical as it is transferred up through

trophic levels in the food chain. F5-28, p.294.

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Trace metals. Occurs when a receptor is exposed to an available form of a trace metal for

sufficient duration at a concentration which elicits an adverse response. Many trace metals are

essential micro nutrients and are toxic only when concentrations exceed nutritional

requirements. Copper, iron, zinc, manganese, cobalt and selenium are essential to metabolism;

lead, cadmium and mercury are not.

Hydrocarbons. Aromatics are worse than aliphatics because the latter are generally less

persistent because of greater volatility and solubility. PAHs (polycyclic aromatic

hydrocarbons) are pervasive(200,000 tons/year) and persistent in the aquatic environment.

PAH's are toxic from .2-10mg/l.

HOMEWORK

Read Chapter 5, Toxicology, pp. 225-316

Problems, p.306, 5-1, 5-3, 5-8, 5-9, 5-13, 5-15, 5-16, 5-21, 5-27, 5-30

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