Chlorpyrifos: Assessment of Potential for Delayed Neurotoxicity by Repeated Dosing in Adult Hens with Monitoring of Brain Acetylcholinesterase, Brain and Lymphocyte Neurotoxic Esterase, and Plasma Butyrylcholinesterase Activities

Abstract

Previous work has shown that acute exposures to chlorpyrifos (CPS; diethyl 3,5,6-trichloro-2-pyridyl phosphorothionate) cannot produce > 70% inhibition of brain neurotoxic esterase (NTE) and cause organophosphorus compound-induced delayed neurotoxicity (OPIDN) unless the dose is well in excess of the LD50, necessitating aggressive therapy for cholinergic toxicity. The present study was carried out to determine if repeated doses of CPS at the maximum tolerated daily dose without prophylaxis against cholinergic toxicity could cause cumulative inhibition of NTE and OPIDN. Adult hens were dosed daily for 20 days with CPS (10 mg/kg/day po in 2 ml/kg corn oil) or corn oil (vehicle control) (2 ml/kg/day po) and observed for an additional 4 weeks. Brain acetylcholinesterase (AChE), brain and lymphocyte NTE, and plasma butyrylcholinesterase (BuChE) activities were assayed on Days 0 (control only), 4, 10, 15, 20, and 48. During Days 4-20, brain AChE and plasma BuChE activities from CPS-treated hens were inhibited 58-70% and 49-80% of contemporaneous controls, respectively. At 4 weeks after the end of dosing, brain AChE activity in treated birds had recovered to 86% of control and plasma BuChE activity was 134% of control. Brain and lymphocyte NTE activities of treated animals throughout the study were 82-99% and 85-128% of control, respectively. Neither brain nor lymphocyte NTE activities in treated hens exhibited cumulative inhibition. The 18% inhibition of brain NTE seen on days 10 and 20 was significant, but substantially below the putative threshold for OPIDN.(ABSTRACT TRUNCATED AT 250 WORDS)

Poisoning by organophosphorus insecticides and sensory neuropathy

“…Therefore, to allow time for the development of clinical signs, a critical biochemical/pathophysiological effect in the nervous system of these patients should have been reached after about two weeks of exposure. The pharmacokinetics of chlorpyrifos is long,21 36 37 as indicated by the lengthy cholinergic symptomatology of our patients (about one and three weeks) associated with long lasting blood concentrations of chlorpyrifos and enzyme inhibition (case 9 and table1). Therefore it might be assumed that the chemical was present in the nervous system of our patients for at least two and four weeks, respectively.…”

Inhibition and recovery of maternal and fetal cholinesterase enzymes following a single oral dose of chlorpyrifos in rats

“…Children are more susceptible to the acute effects of chlorpyrifos and organophosphorous insecticides than adults (Benke and Murphy 1975; Van der Hoven and Gerritsen 1997; Davis and Ahmad 1998;Gibson et al 1998;Moser et al 1998;Tang et al 1999;Zheng et al 2000). Chlorpyrifos readily crossed the placenta into fetal tissues and inhibited fetal cholinesterase enzymes (Lassiter et al 1999;Abu-Qare et al 2001) and caused organophosphorus-induced delayed neurotoxicity (OPIDN) in hens (Richardson et al 1993;AbouDonia and Wilmarth 1995). Recently, after a risk assessment review (U.S. EPA 2000;Green 2000), the U.S. EPA decided to ban all home use of chlorpyrifos in the United States (Franz 2000).…”

Developmental cholinotoxicants: nicotine and chlorpyrifos.

“…tion. Susceptibility is directly related to the concentra-Norepinephrine content and turnover are suppressed in the forebrain during both the initial postnatal period, and tion of nicotinic cholinergic receptors in each region, more persistently with the onset of puberty (33 (74). Nevertheless, recent concern has arisen over domestic application, which can lead to infant exposures well above acceptable levels (75,76).…”