Key topic summary Classification of Pesticides Organophosphorous Pesticides General structure, mechanism of action, clinical signs, treatment. Organophosphates vs. Carbomates Organochlorines Examples, mechanism of action, clinical signs, treatment Herbicides Examples, mechanism of action, clinical signs, treatment Fungicides and Fumigants Examples, toxic effects

PESTICIDES Alexander V. Lyubimov, M.D., Ph.D. Director Toxicology Research Laboratory Department of Pharmacology University of Illinois at Chicago

Pesticide is a substance or mixture of substances intended for preventing, destroying, repelling, or mitigating any pest (US EPA). Pest includes harmful, destructive, or troublesome animals, plants, or microorganisms.

APPLICATORS ONLY? Are there ANY other populations (besides occupationally exposed) who can be poisoned by PESTICIDES?

HOW WE CAN SURVIVE IT? NO-EFFECT-LEVEL (NOEL) in animals is used to determine: Residue Tolerance Limits maximum safe levels of pesticide in food

PESTICIDES CLASSIFICATION 1.Insecticides 1.1 Organophosphates (most are actually thiophosphates) 1.2 Carbamates 1.3 Organochlorines 1.4 Botanical compounds 2.Herbicides 2.1 Chlorophenoxy compounds 2.2 Bipyridyl compounds 2.3 Miscellaneous compounds 3. Rodenticides * Continued

4. Fungicides 4.1 HCB 4.2 Organomercurials 4.3 PCP 4.4 Phthalimides 4.5 Dithiocarbamates (EBDC) * Continued

5. Fumigants 5.1 Phosphine 5.2 Ethylene Dibromide / Dibromochloropropane (DBCP)

Dealkylation of the intermediate dialkylphosphorylated enzymes

OPIDP – Organophosphate- Induced Delayed Polyneuropathy Distal Sensorimotor axopathy (degeneration of distal axons) Symptoms Tingling of the hands and feet Progressive muscle weakness ataxia Mechanism Phosphorylation of NTE – neuropathy target esterase

Organophosphorus(OP) vs. Carbomates(CB) Esters OPCB Anti-AChE effectYes Pesticide + AChE complex Most stableStable AgingYesNo OPIDPYesNo Treatment with Oximes (pralidoxime & toxogonin) YesNo

Treatment of Poisoning Diazepam (0.3 mg/kg IV, max 10 mg) or Phenobarbital (15 mg/kg IV, max 1 g) to control the convulsions Anion-exchange resin, cholestyramine enhanced fecal excretion of chlorodecone (reduced reabsorption of compound excreted with bile)

Chlorophenoxy Herbicides Mechanism of action 2,4-D interferes with lipid metabolism enhancing lipid utilization in liver. Induces peroxisome hepatic proliferation Decreases cholesterol Induces myotonia by increasing basic p-NPPase (p-nitrophenylphosphatase) activity

BIPYRIDYL DERIVATIVE Paraquat LD 50 ≈ 22 – 262 mg/kg, moderately toxic Target Organ : Lung in all species Mechanism of action : Free Radical  superoxide anion, O 2 -  Lipid peroxidation Treatment : Gastric lavage mineral adsorbents hemoperfusion No hyperbaric oxygen!

FUNGICIDES Low acute toxicity LD 50 ~ 800 – 10,000 mg/kg. Cytotoxic Mutagenic (mechanism of action to fungus) Teratogenic Carcinogenic ~ 90% in animal models.

HCB Immunosuppression Hepatic and thyroid tumors (animals) Teratogen (transplacental and milk acquisition)

DITHIOCARBAMATES (EBDC) Low toxicity (Biotransformation  Ethylene Thyourea (ETU) in animals is well known to produce: Mutagenicity, Carcinogenicity Teratogenicity, Embryotoxicity

FUMIGANTS Phosphine (ALP  PH 3 ) Ethylene Dibromide / Dibromochloropropane (DBCP) produce: gastric carcinomas DBCP – sterility in humans