Transfer of leptophos in hen eggs and tissues of embryonic rats.

To estimate the delayed neurotoxic effect of OPs on the next generation, we tried two examinations; one was on the distribution of leptophos in tissues and eggs of hens which are highly susceptible to the delayed neurotoxic effect of OPs but have no placenta, and the other was on the concentration of OPs in tissues of both pregnant and embryonic rats which are not susceptible to the delayed neurotoxic effect but have placenta, after leptophos was administered to the mother in both experiments. First, organophosphorus compound-induced delayed neurotoxicity (OPIDN) was checked in 4 hens and the concentration of leptophos was determined in the other 16 hens after 20 adult laying hens were given 30 mg/kg leptophos (iv), a neurotoxic organophosphate. Three out of 4 hens treated with leptophos showed OPIDN. The concentration of leptophos decreased sharply in the blood, liver, brain and spinal cord from 24 to 48 hr after leptophos administration, but clearance of leptophos was relatively slow in the ovary. Leptophos in laid egg yolk was detected every day for 10 days, and the highest concentration of leptophos in egg yolk was observed on the 6th day after administration to hens. Secondly, in order to investigate the transfer of leptophos to the embryo through the placenta, we divided the thirty-two pregnant rats into 2 groups. The first group received 10 mg/kg leptophos intraperitoneally on the 17th day of pregnancy and the second received 20 mg/kg leptophos on the same day. The time-course of leptophos concentration in the tissues of pregnant and embryonic rats was checked, and the correlation between findings in the pregnant rats and the embryos was determined. The time-course of leptophos concentration in the blood, liver, brain and placenta of the rats was similar to that in hens. Leptophos concentration in the liver and brain of the embryos was equal to approximately 60% of leptophos concentration in each tissue of the pregnant rats, and the concentration of leptophos in the liver and brain of embryonic rats correlated with that in the blood and placenta of pregnant rats (p < 0.01). In both groups treated with 10 and 20 mg/kg leptophos, the concentrations of leptophos in the liver and brain of embryos were lower than that of pregnant rats in the early period after dosing, but the concentrations in embryos were inversely higher than those in pregnant rats in the latter period (48 hr). Compared with the biological half-lives of leptophos in the liver and brain of pregnant rats, these parameters in embryonic rats were 1.58 and 1.87 times, respectively. These results indicate that some of the fat-soluble organophosphorus compounds readily pass through the blood-placenta barrier into the embryos and accumulate there. Therefore, the neurobehavioral development of F1 rats exposed to some organophosphorus compounds through the placenta of pregnant rats should be further examined.

Acetylcholinesterase activity and degenerative changes in various segments of the spinal cord of hens induced by ingestion of subchronic levels of leptophos.

Changes in acetylcholinesterase (AChE) levels in the brain and various segments of the spinal cord of birds fed subchronic repeated oral doses of 0-(4-bromo-2,5 dichlorophenyl) 0-methyl phenylphosphonothioate, (leptophos, 15 mg/kg/day) is reported. The effect of leptophos on the histological structure of the spinal cord has also been described. Three birds each of four groups tested were sacrificed 7, 14, 21 and 35 days after treatment. AChE levels in the cervical, thoracic and lumbar cord were depressed from 29%-33% after 7 days to 34%-56% after 14 days of leptophos administration. This was followed by a gradual recovery at 21 days post treatment with a further decrease (23%-48%) at 35 days post treatment. Similar decreases in brain AChE levels were also observed. Spinal cord lesions in the cervical and thoracic segments were restricted to the anterior and lateral columns, while lumbar cord lesions were restricted to the anterior column. It is concluded that routine histopathology correlated with AChE levels in the cervical, thoracic and lumbar sections of the spinal cord may be useful in monitoring the onset of clinical neuropathy in laboratory animals fed prolonged subacute doses of neurotoxicants.

Delayed neurotoxicity and toxicokinetics of leptophos in hens given repeatedly by low-dose intravenous injections.

The repeated intravenous injections (RIVInj) of 5 mg/kg/day leptophos [O-(4-bromo-2, 5-dichlorophenyl) O-methyl phenylphosphonothioate] for 3 consecutive days caused delayed ataxia in 4 out of 9 hens (44.4%). And one out of 9 hens (11.1%) given RIVInj of 3 mg/kg leptophos for 5 days was affected with ataxia. Twenty hens, however, which received a single intravenous injection (SIVInj) of 15 mg/kg leptophos did not exhibit any delayed neuropathic signs at all. Thus, delayed neurotoxicity was increased by the subdividing RIVInj of the critical dose which was shown in the SIVInj of leptophos. The leptophos concentration in plasma and liver decreased very rapidly after finish of either SIVInj or RIVInj. Although no significant differences were observed in the biological half life of leptophos in plasma by different dosages, the mean level of leptophos decreased significantly with frequency of injections. On the contrary, the evident accumulation of leptophos was observed in only sciatic nerve with RIVInj. Leg muscle maintained relatively high level of leptophos after the last injection. These results suggest that leptophos seems to transfer from blood to affinitive tissues such as sciatic nerve or leg muscles and to accumulate there easily in initial stage after repeated iv injections, and that this causes the enhancement of neuropathy with repeated administrations of divided critical dose of leptophos in both iv and oral administration.

Delayed neurotoxicity resulting from administration of leptophos to the comb of domestic fowl.

We investigated the occurrence of delayed neurotoxicity in domestic fowl following percutaneous application of leptophos. Five groups of 5 adult hens received daily percutaneous doses of 1.0 ml/hen of leptophos emulsion (leptophos; 340 mg/hen/day) for 2, 5, 10, 15 or 20 days. There was no abnormal gait in the 2-day group. Two out of 5 hens in the 5-day group showed mild ataxia from about 2 weeks after the final administration, but did not develop severe neuropathy. On the contrary, 4 out of 5 birds in the 10-day group and all hens in the 15- and 20-day groups were affected by various stages of neurotoxicity. Some of them died from neurotoxicity. Ten of young male chickens were given the same dermal dose for 5 or 10 days. Although no abnormal chicken was observed in the 5-day group, all chickens in the 10-day group showed severe paralysis and two of them died. We studied the incidence rates of delayed neurotoxicity resulting from respective applications of the emulsion and the acetone solution of leptophos. No significant difference was observed between them. These results suggest that the daily dermal application of the relatively high dose of leptophos, even if for the short term, can cause the same delayed neurotoxic effects as by the oral administration in hens or chickens.

Neurotoxicity by the dividing administration of critical dose of phosvel.

Phosvel, an organophosphorus insecticide, produces delayed neurotoxicity in hens. A change in the toxicity, and in the residue of insecticide in the fat, were observed when the critical dose which was demonstrated in the case of a single dose was subdivided.