INTRODUCTION TO CHRONIC TOXICITIES

Neurotoxins and Metals

Adaptation:Response to long-term exposures

• Long-term exposures result in changes in– Enzyme levels

• OPs destroy AChE– Hormone levels?

• higher turnover due to metabolism– Response of receptors

• Type II diabetes

• Each of these changes may affect other metabolic pathways

Toxicity - How does It Happen?

Events in toxicoses

1. Access to the organism2. Absorption 3. Transport in bloodstream4. Transport to cytoplasm5. Metabolism to toxic form [=activation]6. Binding to target and/or inactivation of target

But what does that mean ???7. Metabolism to nontoxic metabolite [= inactivation]8. Excretion 9. Repair of toxic effects

• Like what???

Toxicity - How does It Happen?

Binding to target causes– Interference with function

• Inhibiting an enzyme• Mimicking a messenger

– Successfully» Augments response

– Unsuccessfully» Prevents response

• Interference with function is usually (but not always) reversible.

– Cell death• Cells may or may not be replaced.• Function of those cells may or may not be compensated.

• The amount of injury needed to make damage irreversible depends on the organ and the function affected.

Reversible illness

Irreversible effects:(neuro, developmental, organ failure, diabetes ….)

Functional effects (e.g.: enzyme inhibition)

Death

Chemical action

Cell death

Enzyme regeneration or resynthesis

Replacement of cellsBy increased cell division

Recovery

Major chronic toxicities: nervous system developmental reproductive

But any organ can be damaged

Neurotoxicity

• Types– Interference with function– Cell death

• Functional– Usually acute

• Cell death– Cells are not replaced.– Function may or may not be

compensated.

• Functional effects– Peripheral Nervous system

• Inhibition of neural impulses– Example: curare

» Flaccid paralysis» Catatonia» ??

• Facilitation of neural impulses– Example: OPs

» Inhibition of AChE– Central Nervous System

• Fundamental functions– breathing– heart rate

• Behavioral effects– Confusion– Inappropriate emotions

Neurotoxicity: Cell Death• Cell Type

– Neuron• Axon

– OPs• Cell body

– Metals• Membrane

– tetrodotoxin– DDT

– Schwann cells• Multiple sclerosis

– Glial cells• Hexachlorophene

– Vasculature• Metals

• Cell type continued– Receptor

• Brain region– Hippocampus --MPTP– Cerebellum -- Hg– Prefrontal lobes

• Effects– Permanent

• Cell death• Developmental ??

– Sometimes reversible• Neurotransmitter levels• Receptor levels

Neurotoxicants • Metals and Organo-metals– Lead– Thallium– Mercury– Manganese– Triethyltin– Methylmercury– Tetraethyl lead– Gold thioglucose

• Life-style chemicals– Cocaine– Alcohol– Opioids– Nicotine– Marijuana?– Solvents

• Pharmaceuticals– Glutamate– Hexachlorophene– Isoniazid– Enterovioform

• Physical agents– Anoxia

• Pesticides– Most insecticides

• Organochlorines• Organophosphates• Pyrethroids• DEET

• Solvents and Industrial Intermediates– Acrylamide– Hexane– Methanol– Ethanol– Tri-ortho-cresyl phosphate– Methyl butyl ketone

• Miscellaneous– PCBs– Carbon monoxide– Carbon disulfide– Acetylpyridine

OPIDN: Organophosphorus ester-induced delayed neuropathy

• Dying back axonopathy• It is not due to inhibition of AChE

(acetylcholinesterase)• Only compounds that can inhibit AChE

cause it.– So it is presumably an esterase

• May result from single exposure – Or from multiple smaller exposures

• Irreversible• Rats and mice do not become

paralyzed• Adult hens become paralyzed

– Chicks do not.• Human children do become paralyzed• An estimated 100,000 people

worldwide have been affected

Leptophos (Phosvel™)

Assignment For Monday 9 February

• Read the leptophos case history on the website.

• Consider what lessons should have been learned from it.

• Have they been learned?

Metals And Their Toxicity

• Lead• Mercury• Iron• Magnesium• Copper• Manganese• Arsenic• Nickel• Aluminum• Silver• Gold• Beryllium• Selenium

• General mechanism:– Form ligands with organic molecules

• Oxygen• Sulfur• Nitrogen

– Loss of function of these ligand-molecules

• Specific target differs– Between metals– Between tissues

• Antidote: chelators– Are also toxic

• BAL• EDTA• Penicillamine

Metal-EDTA complex

Lead

• Ancient/modern uses– Plumbing– Roofing– Window mullions

• 20th century uses– Tetraethyl lead in gasoline– Paint pigments– Lead shot– Putty

• 21st century uses– Lead-acid storage batteries– Pigments and glazes– Bullets– Decorative glass

• Toxicity– Route of administration

• Ingestion– Children

• Inhalation– Fumes– Dusts

– Symptoms• Acute

– Gastrointestinal– “Painter’s colic”

• Chronic– Neurological– Largely irreversible

Mercury• Source– Mining

• Cinnabar ore• Environmental

– Burining coal• Uses

– Obsolete• Treatment for syphilis • Felting• Pesticides

– Fungicides– Seed treatments

– Continuing• Amalgams in gold mining• Thermometers• Catalyst in plastics

– vinyl chloride production• Artist’s paint pigments

Minamata:William Eugene Smith

Selenium

• Deficiency Diseases– Keshan cardiomyopathy– Kashin-Beck arthritis– Immunomodulation– Cancer?– Male fertility?

• Excess– Loss of hair, nails– Colic & diarrhea

• Kesterson Wildlife Refuge– Natural levels of selenium– Released by irrigation– Concentrated by evaporation

Kesterson: Geography

Arsenic

• Uses– Pesticides

• Rodenticides• Herbicides• Insecticides• Wood treatment• Veterinary medications• Electronics industries

• Sources of exposure– Coal burning– Burning treated wood– Smelting

• Copper– Water

• 10 ppb is EPA limit• Deep wells in India, Bangladesh

• Toxicology– Skin lesions– Peripheral neuropathy– Anemia– Cancer

• Lung• Skin• Other?

• Arsenic trioxide– No taste, no odor

Miscellaneous Metals

• Nickel– Potent allergen– Present in alloys

• Stainless steel• Jewelry

– Yellow/white gold– Silver

• Tin– Triphenyltin

• against barnacles

Triphenyltin

Precautionary Principle: All Metals are Toxic

• Organo-metals are easily absorbed– Through skin– Though the intestines– Through the lungs

• Most metals are neurotoxic– Some more than others

• Mercury • Lead

• Metal fumes are insidiously toxic– metal fume fever– Nickel carbonyl