PNNL

Abstract

Infants and children may be sensitive to adverse effects of dietary pesticide exposure associated with ingestion of residues on food. Organophosphorus (OP) insecticides, like chlorpyrifos (CPF), have been implicated as developmental neurotoxins; however, aspects of dose-response relationships are poorly understood particularly with regards to critical window(s) of vulnerability and target tissue (i.e. brain) dosimetry. The current manuscript is focused on an initial in vivo/in vitro evaluation of brain chlorpyrifos dosimetry in the preweanling rat pup and for comparison in adult male rats. At post-natal day-10 (PND-10), both male and female pups were orally administered CPF at 1 or 5 mg/kg/day for 5 consecutive days and humanely sacrificed 4 hours after the last dose, adult male rats were likewise orally dosed at 5 mg CPF/kg/day (5 doses). Whole brains and brain regions (forebrain, midbrain and cerebellum) were analyzed for CPF and trichloropyridinol (TCP), its major metabolite. In addition, brain region acetylcholinesterase (AChE) activity was determined in PND-15 pups. In vitro metabolism studies were conducted with hepatic and brain microsomes and whole brain homogenates prepared from naïve adult male rats. A comparison of whole brain dosimetry (5 mg CPF/kg/day) suggests that the concentration of CPF and TCP in the brain of preweanling rats is comparable to adults following oral exposure. Although not statistically significant for both male and female PND-15 pups, regional brain CPF concentration tended to be forebrain > midbrain > cerebellum; whereas, the concentration of TCP was fairly comparable across gender and brain regions. In vitro brain metabolism studies support both the bioactivation of CPF to the neurotoxic metabolite CPF-oxon and detoxification of CPF to TCP. The importance of localized brain metabolism is highly relevant for lipophilic pesticides that potentially sequester in the brain where, localized brain disposition and metabolism may be critically important for understanding target tissue dosimetry.