Key topic summary• Classification of Pesticides• Organophosphorous PesticidesGeneral structure, mechanism of action, clinical signs, treatment.

Organophosphates vs. Carbomates

• OrganochlorinesExamples, mechanism of action, clinical signs, treatment

• HerbicidesExamples, mechanism of action, clinical signs, treatment

• Fungicides and FumigantsExamples, toxic effects

PESTICIDES

Alexander V. Lyubimov, M.D., Ph.D.

DirectorToxicology Research Laboratory

Department of PharmacologyUniversity 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 CLASSIFICATION1.Insecticides

1.1 Organophosphates (most are actually thiophosphates)1.2 Carbamates1.3 Organochlorines1.4 Botanical compounds

2.Herbicides2.1 Chlorophenoxy compounds2.2 Bipyridyl compounds2.3 Miscellaneous compounds

3. Rodenticides* Continued

* Continued

4. Fungicides

4.1 HCB

4.2 Organomercurials

4.3 PCP

4.4 Phthalimides

4.5 Dithiocarbamates (EBDC)

* Continued

* 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

OP CB

Anti-AChE effect Yes Yes

Pesticide + AChE complex

Most stable Stable

Aging Yes No

OPIDP Yes No

Treatment with Oximes

(pralidoxime & toxogonin)

Yes No

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 HerbicidesMechanism 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 DERIVATIVEParaquat

LD50 ≈ 22 – 262 mg/kg, moderately toxic

Target Organ : Lung in all species

Mechanism of action :

Free Radical superoxide anion, O2-

Lipid peroxidation

Treatment :

Gastric lavage

mineral adsorbents

hemoperfusion

No hyperbaric oxygen!

FUNGICIDES

Low acute toxicity

LD50 ~ 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 PH3)

Ethylene Dibromide / Dibromochloropropane (DBCP)

produce:

gastric carcinomas

DBCP – sterility in humans