No abstract

Chlorpyrifos [0,0-diethyl 0-(3,5,6-trichloro-pyridyl) phosphorothioate] caused delayed polyneuropathy in man. Contrary to previous studies, we report here that it also causes delayed polyneuropathy in the hen, the animal model for this toxicity. The minimal neuropathic dose was 60-90 mg/kg p.o., corresponding to 4-6 times the estimated LD50. Consequently, pralidoxime (2-PAM) in conjunction with atropine was necessary to reverse acetylcholinesterase (AChE) inhibition and cholinergic toxicity in hens given high enough doses of chlorpyrifos to cause neuropathy. Chlorpyrifos was slowly absorbed after single oral doses and the threshold of inhibition (greater than 70%) of neuropathy target esterase (NTE), the putative target for delayed neuropathy, was reached within 5-6 days. High AChE inhibition (greater than 90%), however, was measured within hours after dosing because of the higher potency of chlorpyrifos to inhibit this enzyme. In vitro studies showed that chlorpyrifos-oxon, the active metabolite of chlorpyrifos, was 10-20 times more active against AChE than against NTE, confirming the clinical observation. No differences were seen between human and hen enzymes in this respect. Hen and human brain homogenates contain A-esterases which hydrolysed chlorpyrifos to about the same extent in both species. In conclusion, chlorpyrifos causes delayed polyneuropathy in the hen, as was reported in man. The reasons for previous negative data in the hen are probably due to the relatively lower doses which were used. Judging from in vitro studies with hen and human enzymes, there are no differences in the two species as far as their relative sensitivity to delayed polyneuropathy. It is likely that delayed polyneuropathy would develop in both species only after severe cholinergic toxicity requiring aggressive antidotal treatment.

Measurement of neuropathy target esterase activity (NTE) in blood lymphocytes has been suggested as a possible biomonitor for organophosphate-induced delayed polyneuropathy. Human lymphocyte NTE was characterized in vitro according to the sensitivity to several organophosphate inhibitors, which was found similar to that of the nervous system enzyme. Methods for collection, storage, and processing of blood and the NTE assay are described (averaged coefficient of variation of the method is 8%). The mean (+/- SD) value of lymphocyte NTE activity in a caucasian population (108 healthy subjects) was 11.5 +/- 2.5 nMoles/min X mg of protein. No sex or age differences were detected. The averaged intraindividual coefficient of variation was 10.1%. These results suggest the feasibility of the test in clinical conditions, a sufficient reproducibility of the test, and a large interindividual variation. Appropriate baseline values are advisable when using the test to evaluate the effects of an occupational exposure to organophosphorus esters which may cause delayed polyneuropathy.

No abstract

Assay of free and acid labile carbon disulphide (free and total CS2 respectively) in human blood was performed by gas chromatography/ spectrometry. The method used a large dynamic head space volume and a "cryogenic trap". Blood CS2 concentration was measured in 42 subjects not occupationally exposed to CS2 (group A) and in 11 alcoholic subjects (group B) treated with disulfiram. Free CS2 concentration showed a mean value of 261 ng/l in the 42 subjects in group A and 9482 ng/l in eight subjects ofgroup B. Total CS2 concentration was 897 ng/l and 40 084 ng/l in groups A and B respectively. Differences between the groups were highly significant for concentrations of both free and total CS2. Total CS2 concentration was about four times as high as free CS2 concentration in both groups. A significant correlation was found between free and total CS2 concentration both in group A and in group B. In the alcoholic subjects (group B), blood concentrations ofboth free and total CS2 were related to time of sampling after treatment with disulfiram.