Comparative organophosphate-induced effects observed in adult and neonatal sprague–dawley rats during the conduct of multigeneration toxicity studies

Abstract

Five organophosphates: tribufos, oxydemeton-methyl, fenamiphos, coumaphos, and trichlorfon were evaluated for their potential to produce reproductive and neonatal toxicity following continuous dietary exposure during multigenerational reproduction toxicity studies in the Sprague–Dawley rat. Dietary concentrations were selected to demonstrate parental effects in the high dose and provide for a no-adverse effect level at the low dose. There were no clinical signs observed in the adults or neonates during either generation. Significant effects on body weight and food consumption, when observed, were typically observed only with the highest dietary concentration and were greater in the second generation. Reproductive effects, including decreased fertility and mating indices, were only observed with test compounds and at dietary concentrations demonstrating effects on body weight and/or food consumption. Similarly, pup body weight was also affected by those test compounds that produced significant maternal effects during lactation. Significant inhibition of parental cholinesterase activities (plasma, erythrocyte, and brain) was similarly observed in both generations with all test compounds, with at least the highest concentrations. In general, females demonstrated greater enzyme inhibition than the males. For example, mean PChe inhibition considering both generations and all test compounds was 74% for the females, whereas inhibition was 51% in the males. Effects on cholinesterase activities in the neonates (Lactation Day 4) were, for most test compounds, below 10% at the highest dietary concentration. However, by Lactation Day 21, inhibition of enzyme activity (considering all test compounds at the highest concentration and all enzymes) was approximately 30%. The increase in inhibition is attributed to the consumption of the treated feed during the latter stages of lactation. Considering the relative maternal (termination) and neonatal (Lactation Day 4) cholinesterase effects at the highest dietary concentration, it was observed that the effects in the neonate were, for all organophosphates tested, significantly less than those observed in the dam.