1998 Progress Report: Age and Interactive Toxicity of Organophosphorus Insecticides
EPA Grant Number:
Age and Interactive Toxicity of Organophosphorus Insecticides
Northeast Louisiana University
Oklahoma State University - Main Campus
EPA Project Officer:
January 1, 1998 through
December 31, 2000
Project Period Covered by this Report:
January 1, 1998 through December 31, 1999
Issues in Human Health Risk Assessment (1997)
Human Health Risk Assessment
This research program compares age-related sensitivity to the organophosphorus insecticides chlorpyrifos, parathion and methyl parathion. The contributions of presynaptic neurochemical processes, i.e., regulation of ACh synthesis and release, in the differential expression of anticholinesterase toxicity are examined. We hypothesize that limited activity or adaptability of presynaptic regulatory processes in young animals will be correlated with higher acute sensitivity to OPs. We further hypothesize that selective changes in ACh synthesis and/or release by some OPs through additional, direct presynaptic receptor interactions can modulate anticholinesterase toxicity and influence age-related differences in OP sensitivity. Such selective actions of some OP agents may also influence the toxicity resulting from combined OP exposures. Interactive effects of co-exposure to the three OPs in neonatal, juvenile and adult rats will be evaluated. The information gained from these studies may define the role of presynaptic modulation in the ultimate expression of toxicity following acety1cholinesterase inhibition and highlight mechanisms of interactive toxicity of anticholinesterases.
Estimates of acute sensitivity to all three pesticides in the three age groups have been obtained, using LD10 as the indicator. Adults were less sensitive than neonates and juveniles to all three agents: neonatal rats were 7-9 times more sensitive whereas juveniles were 2-5 times more sensitive to lethality from all three pesticides. In contrast to studies using subcutaneous administration, preliminary studies indicate that high affinity choline uptake is not particularly sensitive to disruption by oral chlorpyrifos exposure in either age group. In vitro studies suggest that the active metabolites of parathion and chlorpyrifos (paraoxon and chlorpyrifos oxon) have qualitatively different direct effects on muscarinic autoreceptors in adult brain, with paraoxon acting as an agonist and chlorpyrifos oxon acting as an antagonist. These differential effects at the muscarinic autoreceptor may contribute to differential toxicity with these OP pesticides. In vivo, muscarinic autoreceptor function was reduced by chlorpyrifos in both juvenile and adult rats, but with a different timecourse (i.e., within 24 hours after exposure in juveniles but not until 96 hours after exposure in adults). The inherent activity and adaptability of muscarinic autoreceptor function in different age groups may contribute to age-related differences in acute sensitivity to OP anticholinsterases.
Because we have been unable to demonstrate the reported link between cAMP and choline uptake using our method, we will continue to evaluate other methods for demonstrating regulation of choline uptake by cAMP. The studies on in vitro direct actions of chlorpyrifos oxon and paraoxon on muscarinic autoreceptor function in adult tissues will be extended to include methyl paraoxon and juvenile tissues. In vitro characterization of autoreceptor function in the different age groups by dose-response analysis of muscarinic agonist action is underway. Preliminary in vivo studies evaluating the modulation of muscarinic autoreceptor function by chlorpyrifos will be strengthened and extended to include the other OP insecticides. Pilot studies on interactive toxicity suggest that such studies will have to focus on AChE inhibition as the interactive endpoint. Detailed dose-response analysis of acetylcholinesterase inhibition with individual anticholinesterases in the different age groups will therefore have to be performed before in vivo interactive studies can be initiated.
No journal articles submitted with this report: View all 43 publications for this project
neurotoxicity, developmental, risk assessment, FQPA, common mechanism, infants and children
Progress and Final Reports: