Risks from occupational and dietary exposure to mevinphos.

Mevinphos (trade name, Phosdrin), a category 1 organophosphorus insecticide, has been used mainly as a cleanup pesticide for vegetable crops. A risk assessment for occupational and dietary exposure to mevinphos was initiated because of the high acute toxicity of the compound. Repetitive dosing with mevinphos did not cause any discernible histopathological effects in mice or rats, nor was it oncogenic in either species. The principal toxic effects of mevinphos, both short- and long term, were due to inhibition of cholinesterase activity. Consequently, potential adverse effects from short-term exposures were the primary concern. A human no-observed-effect level (0.025 mg/kg) for cholinergic signs was used as the regulatory basis for calculating margins of safety (MOSs) for potential acute dietary and short-term occupational exposures. Estimates of exposure to mixer/loaders, pilots, and flaggers associated with aerial application of mevinphos were based on passive dosimetry. Because no acceptable exposure studies for work tasks associated with ground application of mevinphos were available, surrogate data based on ground application of oxydemeton-methyl were used. Exposure estimates for field workers and harvesters relied on measured dislodgeable foliar residues of mevinphos and transfer factors generated from studies of other active ingredients. MOSs for mean acute occupational exposure of mixer/loader/applicators associated with ground application and of harvesters working in fruit trees were less than the value conventionally recommended to protect people from the toxic effects of mevinphos. MOSs for the 95th percentile of short-term worker exposure for all mixer/loader work categories associated with mevinphos application were also inadequate. Calculated MOSs for potential acute dietary exposure to measured residue levels of mevinphos were adequate for the various population subgroups. However, 25 of the USEPA tolerances for mevinphos on agricultural commodities were not adequate to protect for the toxic effects of mevinphos from theoretical acute dietary exposure to one or more population subgroups if commodities are consumed with residues at the tolerance level. When the mean short-term occupational exposures were combined with potential acute dietary exposure, the MOSs for mixer/loaders engaged in aerial applications, as well as ground applications, were inadequate to protect people from the toxic effects of mevinphos. As mitigation of the estimated excessive occupational exposures did not appear possible, both California and the USEPA were preparing to cancel registration of the product. However, an agreement was worked out between the manufacturer and the two agencies that ended production for domestic use but allowed existing stocks in the channels of trade to continue to be used for a limited period.

Acetylcholinesterase and neuropathy target esterase in chickens treated with acephate.

Reports that near-lethal doses of the pesticide methamidophos (O,S-dimethyl phosphoramidothioate) caused a delayed neurotoxicity (OPIDN) in humans and that another phosphoramidate, isofenphos, caused OPIDN in the hen at high doses, prompted a study of the abilities of acephate (O,S-dimethyl acetylphosphoramidothioate) to inhibit brain acetylcholinesterase (AChE) and neuropathy target esterase (NTE) in vivo. Hens were treated orally with 5-700 mg/kg of acephate, or im with 50-200 micrograms/kg of diisopropyl-fluorophosphate (DFP, positive control) and sacrificed 24 hr later. Brain homogenates were assayed for AChE as an estimate of acute toxicity, for NTE to indicate acephate's potential to cause OPIDN, and for residues of acephate and its metabolite methamidophos. A range finding study confirmed the LD50 level for acephate was approximately 800 mg/kg. Regression analyses indicated an ID50 (a dose that inhibits 50% of activity) for acephate inhibition of AChE of 10 mg/kg and an extrapolated ID50 for inhibition of NTE of 1300 mg/kg, almost twice the LD50. In contrast, ID50 values for DFP were similar for AChE (146 micrograms/kg) and NTE (132 micrograms/kg). Brain methamidophos levels were 10 to 16 percent of the total acephate plus methamidophos brain concentration. The lower the dose of acephate, the higher was the relative percentage of methamidophos. The results show acephate is a more potent inhibitor of AChE than it is of NTE in hens and suggest it would be difficult to administer a single dose of acephate sufficient to cause OPIDN without killing the animal.

Atropine and DFP-induced delayed neurotoxicity.

Atropine is often given as an antidote for acute cholinergic effects in studies of a delayed neuropathy (OPIDN) caused by some organophosphorus esters. These experiments examined if atropine would also affect the onset and/or severity of signs of OPIDN. Chickens were given one to six 200 micrograms/kg doses of diisopropyl phosphorofluoridate (DFP) with or without 20 mg/kg atropine (IM). Locomotion, brain neurotoxic esterase (NTE) activity, and histology of the nervous system were examined. The results demonstrated that atropine treatments delayed onset of the signs of OPIDN and may have slightly increased brain NTE activity in vivo. Relatively high levels (Ki: approximately 3.0 mM) of atropine inhibited NTE activity in vitro.

Toxicity of repeated doses of organophosphorus esters in the chicken.

Hens were repeatedly exposed to paraoxon (PO, phosphonothioic acid, diethyl paranitrophenyl ester), the chemical warfare agent VX/phosphorofluoridic acid, methyl-S-(2-[bis(1-methylethyl)amino/ethyl)O-ethyl ester], or the neuropathic DFP [phosphorofluoridic acid, bis(1-methylethyl)ester] as evidence was sought for nerve or other tissue damage following long-term treatments at high dose levels. Thirty-day and 90-d trials were performed in which each bird was injected 3 or 5 times per week with atropine as protection, weighed, their eggs collected, and their blood enzymes (cholinesterases creatine kinase, and lactic dehydrogenase) and locomotion periodically examined. Muscle and brain enzymes were assayed at the end of the experiments. Doses of PO and VX were at or above LD50 levels. DFP doses were lowered with each run to estimate a no-observable-effect level for organophosphate-induced delayed-neuropathy (OPIDN). No abnormalities attributable to repeated exposures to either PO or VX were found, even though acute, short-term symptoms of toxicity appeared after each injection. No evidence for OPIDN was obtained with repeated exposures to PO and VX under conditions where OPIDN was caused by DFP. Histological signs of OPIDN appeared in the spinal cord without gross symptoms of ataxia following repeated treatments of 25 mg/kg of DFP. The results of one experiment suggested that exposure to protective injections of atropine delays the appearance of the locomotor symptoms of the DFP-induced neuropathy.