Toxicological screening for organophosphorus-induced delayed neurotoxicity: complications in toxicity testing

The acute biocidal effects of organophosphorus pesticides are a central feature of modern agricultural chemistry, and also define the concerns of regulatory toxicology. Less well known, but more complex and idiosyncratic, is the potential for some agents to produce a delayed and progressive polyneuropathy--Organophosphorus Induced Delayed Neurotox-icity (OPIDN). On three occasions during the past ten years, the National Institute for Occupational Safety and Health (NIOSH) had been asked to evaluate human delayed neurotoxicity from three commercially available pesticides. These were leptophos, fenthion, and isofenphos. In each case, human disease was either observed or suggested by specialized toxicity testing. The reasons that federally recommended screening measures failed to identify a potential for human neurotoxicity were not accidental, but stem from a systematic approach that focuses on a traditional definition of acute lethal toxicity. The oral single dose study on one species appears to be insufficient for recognizing the delayed neurotoxic hazard of many representatives of this chemical class. The recent addition of a recommended biochemical assay--neurotoxic esterase (NTE)--to federal guidelines potentially improves sensitivity, but it is purely adjunctive and does not amend underlying ambiguities in selecting the dose and route of administration. It is also quite probable that human neurotoxicity may be a potential hazard from exposure to more than the handful of organophosphorus pesticides that have been described in the literature.