1. Pesticide Toxicology Week 2: Organophosphate Insecticides a. Acute toxicity

2. 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

3. 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

4. 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

5. 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™)

6. Leptophos: How Not to Identify a Neurotoxicant Case history on website deals more with the regulatory process than with toxicology.

7. 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

8. 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?

9. Regulatory Aspects of OP Toxicity What is the measure of toxicity – Symptoms – AChE inhibition – ChE inhibition

10. 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

11. Bioaccumulation and Persistence OPs are – More water soluble than OCs – Less persistent Days or months, not years – Malathion (outdoors) – Bioaccumulation is unlikely

12. Secondary poisoning May result from – Rapid lethality + residue Fenthion used as avicide – LD 50 » 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

13. 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

14. 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

15. Ecosystem Simplification Elimination of already stressed species Destruction of habitat – Herbicides – Large-scale agriculture – Monocultures – Lack of hedgerows

16. Consequences of evolutionary pressures Resistance – Degradation of chemical – Insensitivity to chemical – Blocking entry of chemical Other – Western corn rootworm Dieldrin Migration rate? – Crop rotation Overwintering cycle Egg laying behavior – Malaria control and mosquito behavior