Comparative cholinergic neurotoxicity of oral chlorpyrifos exposures in preweanling and adult rats

Chlorpyrifos (CPF) is a common organophosphorus (OP) pesticide. Previous st udies have demonstrated that neonatal rats are more sensitive than adults t o the acute toxicity of high dosages of CPF. The present study examined let hality and age-related differences in neurochemical indicators and function al signs of neurotoxicity following a broad range of acute and repeated ora l CPF exposures. There was about a 9-fold difference in sensitivity to the acute-dose lethality of chlorpyrifos among neonatal (7 days-of-age) and adu lt (90 days-of-age) rats (LD10: neonates = 15 mg/kg; adults = 136 mg/kg), w hile juvenile rats (21 days-of-age) exhibited intermediate sensitivity (LD1 0 = 47 mg/kg). Neonatal and adult rats (n = 5-7/treatment/age group/time po int) were given CPF (0, 0.15, 0.45, 0.75, 1.5, 4.5, 7.5, or 15 mg/kg/day) f or 14 days and sacrificed 4 h after either the first or 14th dose for neuro chemical measurements (cholinesterase activity in frontal cortex, plasma an d RBC, and muscarinic ([H-3]QNB) and nicotinic ([H-3]epibatidine) receptor binding in frontal cortex. No overt signs of functional toxicity (involunta ry movements, SLUD signs) were noted in either age group by 4 h after the f irst dose. With repeated CPF exposures, however, signs of cholinergic toxic ity were noted in both age groups at the higher dose levels [no observed ef fect levels (NOELs): neonate = 4.5 mg/kg/day; adult = 7.5 mg/kg/day]. Simil ar degrees of ChE inhibition were noted in neonatal brain and blood fractio ns following acute exposure, but substantial ChE inhibition was only noted in adult plasma and RBC 4 h after the first treatment. Following repeated C PF exposures, similar degrees of ChE inhibition were again noted in tissues from immature animals, but a wide range of sensitivity to inhibition was n oted in adult tissues. NOELs based on ChE inhibition for adults were about 1-greater than or equal to 10-fold higher than in neonates with acute expos ure but only 0.2-2 times higher with repeated dosing. Moreover, dose-relate d inhibition of brain ChE was similar between age groups, and similar reduc tions in both QNB and epibatidine binding were noted between the age groups after repeated dosing, even though by the end of the dosing period young a nimals (juveniles) were still about 3 times more sensitive than adults, bas ed on acute lethality. We conclude that while immature animals can be marke dly more sensitive to lethal effects of high doses of CPF, lesser or no age -related differences are apparent, based on non-lethal endpoints, in partic ular with repeated exposures.