Grantee Research Project Results
Final Report: Age and Interactive Toxicity of Organophosphorus Insecticides
EPA Grant Number: R825811Title: Age and Interactive Toxicity of Organophosphorus Insecticides
Investigators: Pope, Carey , Liu, Jing
Institution: Oklahoma State University
EPA Project Officer: Aja, Hayley
Project Period: January 1, 1998 through December 31, 2000
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 (OPs) chlorpyrifos (CPF), parathion (PS) and methyl parathion (MPS). The contributions of presynaptic neurochemical processes, i.e., regulation of acetylcholine (ACh) synthesis and release, in the differential expression of anticholinesterase toxicity were examined. We hypothesized that limited activity or adaptability of presynaptic regulatory processes in young animals would be correlated with higher acute sensitivity to OPs. We further hypothesized that selective changes in ACh synthesis and/or release by some OPs through additional, direct presynaptic receptor interactions could modulate anticholinesterase toxicity and influence age-related differences in OP sensitivity. Such selective actions of some OP agents could also influence the toxicity resulting from combined OP exposures. Interactive effects of co-exposure to selected OPs in neonatal and adult rats were evaluated. The information from these studies suggests an important role for presynaptic modulation of cholinergic neurotransmission in the ultimate expression of toxicity following acetylcholinesterase inhibition and highlights mechanisms of interactive toxicity of anticholinesterases.
Summary/Accomplishments (Outputs/Outcomes):
Estimates of acute sensitivity to all three pesticides in the three age groups used 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 PS, MPS and CPF (i.e., paraoxon, methyl paraoxon and CPF oxon) have qualitatively different direct effects on muscarinic autoreceptors in adult brain, with paraoxon and methyl paraoxon acting as agonists and CPF oxon acting as an antagonist. These differential effects at the muscarinic autoreceptor may contribute to differential toxicity with these OP pesticides. Muscarinic autoreceptors develop postnatally in an age- and brain regional-dependent manner. In vivo, muscarinic autoreceptor function was reduced by CPF in both juvenile and adult rats, but with a different timecourse (again, earlier in younger animals compared to adults). Autoreceptor function was also impaired by MPS but in a relatively similar manner following LD10 exposures in juvenile and adult rats. 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. Toxicity from combined exposures to PS and CPF in adult rats was markedly influenced by the sequence of administration. In contrast to our hypothesis that CPF has an additional action(s) that lessens cholinergic toxicity, animals pretreated with CPF and then exposed to PS exhibited more extensive cholinergic toxicity than animals pretreated with PS and then challenged with CPF. Similar effects of sequential dosing were noted with interactive CPF and MPS exposures (i.e., adult rats pre-exposed to CPF exhibited markedly greater toxicity than rats given the same dosages but with the sequence of exposure reversed). In contrast, little evidence for sequence-dependent differences in toxicity was noted in neonatal rats exposed to interactive CPF and PS exposures. These studies illustrate the complexity of interactions occuring with combined exposures to organophosphorus toxicants having a common mechanism of toxicity.
Journal Articles on this Report : 10 Displayed | Download in RIS Format
| Other project views: | All 43 publications | 13 publications in selected types | All 10 journal articles |
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Howard MD, Pope CN. In vitro effects of chlorpyrifos, parathion, methyl parathion and their oxons on cardiac muscarinic receptor binding in neonatal and adult rats. Toxicology 2002;170(1-2):1-10. |
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Karanth S, Olivier Jr. K, Liu, J, Pope C. In vivo interaction between chlorpyrifos and parathion in adult rats: sequence of administration can markedly influence toxic outcome. Toxicology and Applied Pharmacology 2001;177(3):247-255. |
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Liu J, Pope CN. Comparative presynaptic neurochemical changes in rat striatum following exposure to chlorpyrifos or parathion. Journal of Toxicology and Environmental Health-Part A 1998;53(7):531-544. |
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Liu J, Olivier K, Pope CN. Comparative neurochemical effects of repeated methyl parathion or chlorpyrifos exposures in neonatal and adult rats. Toxicology and Applied Pharmacology 1999;158(2):186-196. |
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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. |
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Mileson BE, Chambers JE, Chen WL, Dettbarn W, Ehrich M, Eldefrawi AT, Gaylor DW, Hamernik K, Hodgson E, Karczmar AG, Padilla S, Pope CN, Richardson RJ, Saunders DR, Sheets LP, Sultatos LG, Wallace KB. Common mechanism of toxicity: a case study of organophosphorus pesticides. Toxicological Sciences 1998;41(1):8-20. |
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Olivier Jr. K, Liu J, Pope C. Inhibition of forskolin-stimulated cAMP formation in vitro by paraoxon and chlorpyrifos oxon in cortical slices from neonatal, juvenile, and adult rats. Journal of Biochemical and Molecular Toxicology 2001;15(5):263-269. |
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Pope CN. Organophosphorus pesticides: do they all have the same mechanism of toxicity? Journal of Toxicology and Environmental Health, Part B 1999;2(2):161-181. |
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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. |
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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. |
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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.