Pesticide Toxicology

Week 2:Organophosphate Insecticides

a. Acute toxicity

Categories of Effects• Muscarinic

– Mimic action of muscarine• Peripheral nervous system only

– Smooth muscle, heart, exocrine glands• Bronchoconstriction, salivation, lacrimation, perspiration• Nausea, vomiting, diarrhea, cramps• Urination, defecation• Bradycardia, miosis

• Nicotinic– Mimic action of nicotine

• Neuromuscular junction of voluntary muscles• Muscle weakness (including respiratory muscles)• Twitching, cramps, pallor• Elevated blood pressure, tachycardia

• CNS symptoms– Confusion, restlessness, irritability, slurred speech, – Insomnia, emotional instability– Coma

Time Course of Toxicity• Onset of symptoms– Minutes

• Sarin, parathion, TEPP– Hours

• EPN– Days

• Chlorpyrifos

• Abatement of symptoms– Slow onset tends to mean slow abatement– Acute symptoms rarely last more than a few days

• Regeneration of AChE takes ~ 1 month– Ample opportunity for re-intoxication

Chronic Effects of OPs: OPIDN• Organophosphate-induced delayed neuropathy

(neurotoxicity)• Caused by subset of AChE-inhibiting OPs but not

due to AChE inhibition• Delayed onset– Symptoms begin 7-30 days after exposure– Recovery continues up to 1 year– Permanent effects– Longest axons most vulnerable

• Mechanism– Inhibition of neurotoxic esterase– Axonal damage– Death of neuron

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™)

Leptophos: How Not to Identify a Neurotoxicant

Case history on website deals more with the regulatory process than with toxicology.

Chronic Effects of OPs: Reproductive Toxicity

• Avian– Subset of OPs– Inhibition of AChE– Inhibition of kynurenine formamidase

• Mammalian– No physical defects due to AChE inhibition– Human evidence for developmental CNS damage

• Chlorpyrifos (Dursban)– Delayed neuropathy also causes erectile dysfunction

Chronic Effects of OPs: Miscellaneous

• Intermediate syndrome– Subset of insecticidal OPs– Onset delayed for several days– Not OPIDN– Recovery?

• Long-term CNS effects– Epidemiological evidence– Documented by EEG after sarin exposure

• Gulf War syndrome?

Regulatory Aspects of OP Toxicity

• What is the measure of toxicity– Symptoms– AChE inhibition– ChE inhibition

Ecotoxicology• Chemical attributes

– Persistence– Potential for bioaccumulation

• Ecosystem effects– Secondary poisoning– Temporary changes in ecosystem– Permanent changes in ecosystem

• Ecosystem simplification• Stressed ecosystems

– Reproductive toxicology• Non-mammalian species

– Evolutionary consequences of efforts at extermination

Bioaccumulation and Persistence• OPs are– More water soluble than OCs– Less persistent• Days or months, not years

– Malathion (outdoors)

– Bioaccumulation is unlikely

Secondary poisoning

• May result from– Rapid lethality + residue

• Fenthion used as avicide– LD50

» 5 mg/kg in birds» 250 mg/kg in rats

– Weakened target• Cooper’s hawk in S America

– Hard to detect• Small dead organisms disappear fast

Temporary changes in ecosystem composition

• Insecticides kill insects– Disrupts food supply for• Insects• Fish• Mammals• Birds

• Agricultural applications occur during spring– primary breeding season

• Single applications should be repairable

Reproductive toxicity• Difficult to assay– Stage-specific– Species-specific

• Historical Examples– Organochlorines

• DDT thins birds’ eggshells• PCBs cause malformations• Dioxin-like chemicals cause GLEMEDS in trout

– OPs• Malformations in birds

– Sprayed on quail eggs– Site specific, not global

• Local effects repairable if no other stresses occur

Ecosystem Simplification

• Elimination of already stressed species• Destruction of habitat– Herbicides– Large-scale agriculture– Monocultures– Lack of hedgerows

Consequences of evolutionary pressures

• Resistance– Degradation of chemical– Insensitivity to chemical– Blocking entry of chemicalOther– Western corn rootworm

• Dieldrin• Migration rate?

– Crop rotation• Overwintering cycle• Egg laying behavior

– Malaria control and mosquito behavior