Effects of Chronic Dietary and Repeated Acute Exposure to Chlorpyrifos on Learning and Sustained Attention in Rats

Abstract

Cognitive and motor impairment often follow acute poisoning with an organophosphorous (OP) pesticide. However, the persistence of these effects and the conditions necessary for their appearance are not clear: two specific concerns are whether symptomatic poisoning is necessary for persistent effects, and whether inhibition of cholinesterase (ChE) activity is a protective metric of OP exposure. This study examined the effects of chronic dietary and repeated high-level acute exposure to the pesticide chlorpyrifos (diethyl 3,5,6-trichloro-2-pyridyl phosphorothionate, CPF) on learning and attention. Beginning at 3 months of age, male Long-Evans rats received dietary CPF at a daily dose of 0, 1, or 5 mg/kg for 1 year. Half of each dietary group also received an acute oral dose of CPF (initial dose at 60 mg/kg, 5 doses at 45 mg/kg) every 2 months. Beginning 2 weeks before the fourth acute dose, behavioral assessments were conducted on the eight rats in each of the six exposure groups (0-Oil, 0-CPF, 1-Oil, 1-CPF, 5-Oil, and 5-CPF). Using an auto-shaping procedure, the groups learned to press a lever for food in the following order: 5-Oil, 5-CPF, 1-Oil, and 0-Oil. The 0-CPF and 1-CPF groups did not learn the response in three 50-trial sessions. Chronic CPF did not affect acquisition of other behaviors required by a signal detection task (SDT) designed to assess sustained attention. The sixth acute CPF dose significantly disrupted the SDT in all dosed groups. Two months after the end of dosing, performance of the SDT was impaired in the 5-CPF group. These data suggest that learning the contingency between an action and reward may be accelerated by chronic exposure to CPF and inhibited by previous symptomatic exposure to CPF, and that persistent cognitive impairment may follow if CPF exposure inhibits brain ChE activity and is accompanied by acute doses sufficient to induce signs of toxicity.

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

“…This is consistent with a report of asymmetric peripheral neuropathy following localized dermal exposure to chlorpyrifos (Meggs, 2003) (Table 7). Samsam et al (2005) evaluated the effects of chronic exposure to chlorpyrifos on learning and attention in 3-monthold Long-Evans rats, as well as the consequence of intermittent acutely toxic doses. No effects on learning or memory were observed in rats that received chlorpyrifos in the diet at a daily dose of 0, 1, or 5 mg/kg for 1 year.…”

Long‐Term Neurotoxicological Effects of Anticholinesterases after either Acute or Chronic Exposure

“…Chlorpyrifos did not affect neurobehavior, learning, or sustained attention two months after one year of exposure that caused significant brain AChE inhibition (about 50%) but no clinical signs (Moser et al, 2005;Samsam et al, 2005). In another experiment (Terry et al, 2007), rats treated with chlorpyrifos for 30 days showed about 50% AChE inhibition two weeks after the end of the treatment.…”

“…The chronic dose caused AChE inhibition but no clinical signs, whereas the spikes caused mild cholinergic syndrome. Using the same treatment schedule, Samsam et al (2005) found that acute doses of chlorpyrifos, causing signs of cholinergic toxicity, impaired learning and sustained attention. Sanchez-Santed et al (2004) did not find alteration in a neurobehavioral test involving memory 5 to 12 months after two doses, 22 weeks apart, of either paraoxon or chlorpyrifos that caused typical, not severe, cholinergic syndrome (paraoxon) or significant AChE inhibition, but no overt clinical signs (chlorpyrifos).…”

“…For conditioned behavior, only parathion, methamidophos, chlorpyrifos, and the carbamates carbaryl and arprocarb were tested in the absence of AChE inhibition (Desi et al, 1974;Ivens et al, 1998;Samsam et al, 2005;Temerowski and van der Staay, 2005;Terry et al, 2007). Chlorpyrifos did not affect neurobehavior, learning, or sustained attention two months after one year of exposure that caused significant brain AChE inhibition (about 50%) but no clinical signs (Moser et al, 2005;Samsam et al, 2005).…”

Organophosphorus Pesticides

“…The EPA also noted that several studies in the peer reviewed literature suggested that chlorpyrifos likely affects nervous system development via mechanisms that are independent of cholinesterase inhibition (e.g., (219)(220)(221)(222)(223)(224)(225)). Neurodevelopmental effects were not observed in a study of 3 month old rats given 0, 1, or 5 mg/kg/day chlorpyrifos in the diet for 1 year, showing no effect on learning or attention (226). However, rats that received additional "high-dose" chlorpyrifos (initial dose of 60 mg/kg followed every 2 months with single doses of 45 mg/kg/day) did exhibit deficits in learning.…”