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 Access to the organism Absorption Transport in bloodstream Transport to cytoplasm Metabolism to toxic form [=activation] Binding to target and/or inactivation of target But what does that mean ??? Metabolism to nontoxic metabolite [= inactivation] Excretion 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.

Major chronic toxicities: nervous system developmental reproductive But any organ can be damaged Chemical action Functional effects (e.g.: enzyme inhibition) Cell death Replacement of cells By increased cell division Irreversible effects: (neuro, developmental, organ failure, diabetes ….) Reversible illness Enzyme regeneration or resynthesis Death Recovery

Neurotoxicity Functional effects Types Functional 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 Types Interference with function Cell death Functional Usually acute Cells are not replaced. Function may or may not be compensated.

Neurotoxicity: Cell Death Cell Type Neuron Axon OPs Cell body Metals Membrane tetrodotoxin DDT Schwann cells Multiple sclerosis Glial cells Hexachlorophene Vasculature 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 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 Lead Mercury Iron Magnesium Copper Manganese Arsenic Nickel Aluminum Silver Gold Beryllium Selenium Metal-EDTA complex

Lead Toxicity Ancient/modern uses Plumbing Route of administration Ingestion Children Inhalation Fumes Dusts Symptoms Acute Gastrointestinal “Painter’s colic” Chronic Neurological Largely irreversible 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

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 Kesterson Wildlife Refuge 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 Toxicology Skin lesions Peripheral neuropathy Anemia Cancer 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 Tin 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