Grantee Research Project Results
2000 Progress Report: Age and Interactive Toxicity of Organophosphorus Insecticides
EPA Grant Number: R825811Title: Age and Interactive Toxicity of Organophosphorus Insecticides
Investigators: Pope, Carey
Current Investigators: Pope, Carey , Liu, Jing
Institution: Oklahoma State University
EPA Project Officer: Aja, Hayley
Project Period: January 1, 1998 through December 31, 2000
Project Period Covered by this Report: January 1, 2000 through December 31, 2001
Project Amount: $438,120
RFA: Issues in Human Health Risk Assessment (1997) RFA Text | Recipients Lists
Research Category: Human Health
Objective:
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 acetylcholinesterase inhibition and highlight mechanisms of interactive toxicity of anticholinesterases.
Progress Summary:
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. High affinity choline uptake, the rate limiting step in acetylcholine synthesis, is reduced in an age- and brain regional-dependent manner following CPF exposure, i.e., uptake was inhibited earliest in neonatal, later in juvenile and latest in adult brain. In vitro studies suggest that the active metabolites of parathion, methyl parathion, and chlorpyrifos (paraoxon, methyl paraoxon, and chlorpyrifos oxon) have qualitatively different direct effects on muscarinic autoreceptors in adult brain, with paraoxon and methyl paraoxon acting as agonists and chlorpyrifos oxon acting as an antagonist. These differential effects at the muscarinic autoreceptor may contribute to differential toxicity with these OP pesticides. Muscarinic autoreceptors also appear to develop in an age- and brain regional-dependent manner. In vivo, muscarinic autoreceptor function was reduced by chlorpyrifos in both juvenile and adult rats, but with a different timecourse (again, earlier in younger animals compared to 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 anticholinesterases. Toxicity from combined exposures to parathion and chlorpyrifos in adult rats is markedly influenced by the sequence of administration. In contrast to our hypothesis that chlorpyrifos has an additional action(s) that lessens cholinergic toxicity, animals pretreated with chlorpyrifos and then exposed to parathion exhibited more extensive cholinergic toxicity than animals pretreated with the same dosage of parathion and then challenged with chlorpyrifos. Studies are underway to evaluate the influence of sequence of administration of these two pesticides in other age groups, and to examine the interactive toxicity of methyl parathion and parathion, methyl parathion and chlorpyrifos, and finally all three pesticides.
Future Activities:
We will finish the evaluation of changes in high affinity choline uptake and muscarinic autoreceptor function following parathion and methyl parathion exposures. Pilot studies on interactive toxicity in adults with dosages based on LD1 showing differential effects of sequential OP exposures will be followed with similar studies in neonatal and juvenile rats and mechanistic studies to evaluate the basis for such differences.
Journal Articles on this Report : 3 Displayed | Download in RIS Format
| Other project views: | All 43 publications | 13 publications in selected types | All 10 journal articles |
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Liu J, Chakraborti T, Pope C. In vitro effects of organophosphorus anticholinesterases on muscarinic receptor-mediated inhibition of acetylcholine release in rat striatum. Toxicology and Applied Pharmacology 2002;178(2):102-108. |
R825811 (2000) R825811 (Final) |
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Won YK, Liu J, Olivier Jr. K, Zheng Q, Pope CN. Age-related effects of chlorpyrifos on acetylcholine release in rat brain. Neurotoxicology 2001;22(1):39-48. |
R825811 (2000) R825811 (Final) |
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Zheng Q, Olivier K, Won YK, Pope CN. Comparative cholinergic neurotoxicity of oral chlorpyrifos exposures in preweanling and adult rats. Toxicological Sciences 2000;55(1):124-132. |
R825811 (2000) R825811 (Final) |
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Supplemental Keywords:
neurotoxicity, developmental, risk assessment, FQPA, common mechanism, infants and children, health effects, susceptibility, sensitive populations, enzymes, infants, children, age.,Relevant Websites:
http://www.cvm.okstate.edu/research/facilities/toxicologylab/ Exit
Progress and Final Reports:
Original AbstractThe perspectives, information and conclusions conveyed in research project abstracts, progress reports, final reports, journal abstracts and journal publications convey the viewpoints of the principal investigator and may not represent the views and policies of ORD and EPA. Conclusions drawn by the principal investigators have not been reviewed by the Agency.