Comparative Cholinergic Neurotoxicity of Oral Chlorpyrifos Exposures in Preweanling and Adult Rats

Abstract

Chlorpyrifos (CPF) is a common organophosphorus (OP) pesticide. Previous studies have demonstrated that neonatal rats are more sensitive than adults to the acute toxicity of high dosages of CPF. The present study examined lethality and age-related differences in neurochemical indicators and functional signs of neurotoxicity following a broad range of acute and repeated oral 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 adult (90 days-of-age) rats (LD(10): neonates = 15 mg/kg; adults = 136 mg/kg), while juvenile rats (21 days-of-age) exhibited intermediate sensitivity (LD(10) = 47 mg/kg). Neonatal and adult rats (n = 5-7/treatment/age group/time point) were given CPF (0, 0.15, 0.45, 0. 75, 1.5, 4.5, 7.5, or 15 mg/kg/day) for 14 days and sacrificed 4 h after either the first or 14th dose for neurochemical measurements (cholinesterase activity in frontal cortex, plasma and RBC, and muscarinic ([(3)H]QNB) and nicotinic ([(3)H]epibatidine) receptor binding in frontal cortex. No overt signs of functional toxicity (involuntary movements, SLUD signs) were noted in either age group by 4 h after the first dose. With repeated CPF exposures, however, signs of cholinergic toxicity were noted in both age groups at the higher dose levels [no observed effect levels (NOELs): neonate = 4.5 mg/kg/day; adult = 7.5 mg/kg/day]. Similar degrees of ChE inhibition were noted in neonatal brain and blood fractions following acute exposure, but substantial ChE inhibition was only noted in adult plasma and RBC 4 h after the first treatment. Following repeated CPF exposures, similar degrees of ChE inhibition were again noted in tissues from immature animals, but a wide range of sensitivity to inhibition was noted in adult tissues. NOELs based on ChE inhibition for adults were about 1->/=10-fold higher than in neonates with acute exposure but only 0.2-2 times higher with repeated dosing. Moreover, dose-related inhibition of brain ChE was similar between age groups, and similar reductions 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 animals (juveniles) were still about 3 times more sensitive than adults, based on acute lethality. We conclude that while immature animals can be markedly more sensitive to lethal effects of high doses of CPF, lesser or no age-related differences are apparent, based on non-lethal endpoints, in particular with repeated exposures.

Age-Related Differences in Acetylcholinesterase Inhibition Produced by Organophosphorus and N-Methyl Carbamate Pesticides

“…In this study, the ratio of brain ChE ED50s for chlorpyrifos was 4.3, similar to the 5-fold difference in maximally tolerated dose (MTD) at PND17 . While others have reported somewhat greater MTDs and LD10s in younger rats (PND7, MTD ratio 6.2-fold, LD10 ratio 9.1-fold; Pope et al 1991;Zheng et al 2000), they found the ratio of brain ED50 values at PND7 to be less (2.2-fold; Pope and Liu 1997) than reported here for older rat pups. In our data, RBC ChE inhibition was not greater in the pups, in contrast to other reports of juvenile sensitivity of around 4-fold (Pope et al 1991;Zheng et al 2000).…”

Review of the Toxicology of Chlorpyrifos With an Emphasis on Human Exposure and Neurodevelopment

“…Cholinergic Toxicity of Chlorpyrifos Several investigators have shown that young animals are more susceptible than adults to the acute toxicity of chlorpyrifos (Pope et al, 1991b;Whitney et al, 1995;Moser et al, 1996;Zheng et al, 2000). For example, the LD 50 of chlorpyrifos in neonatal [postnatal day (PND) 7] rats was reported to be 10-fold lower than in adult animals (Zheng et al, 2000).…”

Comparative effects of oral chlorpyrifos exposure on cholinesterase activity and muscarinic receptor binding in neonatal and adult rat heart

“…The dosages selected were based on the LD 10 (i.e., either vehicle, 0.5 × LD 10 or 1 × LD 10 : neonates = 0, 7.5 or 15 mg/kg; adults = 0, 68 or 136 mg/kg [Zheng et al, 2000]). Functional signs of toxicity were evaluated and rats were euthanized at 4, 24 and 96 hours after treatment.…”