The overall objective of this project is to provide information useful in predicting conditions in which non-target vertebrates may be unusually susceptible (or resistant) to the toxic action of pesticides, or of other chemicals including drugs, as a result of exposure to pesticides. The proposed research will focus on the anticholinesterase insecticides. It will examine the dynamic relationships among their sites of: 1) biotransformation, 2) primary action and 3) secondary action that are critical in determining their toxicity and that may be subject to modulation by other chemicals. It is expected that these toxicological studies will provide information useful in assessing the health hazards of pesticides, singly and in combinations, and will also further characterize the basic biological processes affected by these compounds. Specific hypothesis or questions to be addressed include: 1. What is the correlation between development of tolerance and changes in muscarinic receptor binding and function? 2. Is there any memory impairment following subchronic exposure to organophosphate insecticides? 3. Is there an altered sensitivity to anticholinergic and antidepressants in organophosphate-tolerant animals? 4. Can muscarinic receptors in circulating lymphocytes be used as peripheral markers of nerve tissue receptor response to exogenous chemicals? 5. What is the comparative metabolism of phosphorothionate insecticides in vivo and in vitro, in isolated hepatocytes and cell-free systems? 6. Does subchronic exposure to the carbamate propoxur alter hepatic metabolism of propoxur itself and/or of other insecticides?

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
2R01ES003424-03
Application #
3250682
Study Section
Toxicology Study Section (TOX)
Project Start
1983-12-01
Project End
1989-11-30
Budget Start
1985-12-01
Budget End
1986-11-30
Support Year
3
Fiscal Year
1986
Total Cost
Indirect Cost
Name
University of Washington
Department
Type
Schools of Public Health
DUNS #
135646524
City
Seattle
State
WA
Country
United States
Zip Code
98195
Costa, L G (1996) Biomarker research in neurotoxicology: the role of mechanistic studies to bridge the gap between the laboratory and epidemiological investigations. Environ Health Perspect 104 Suppl 1:55-67
Anderson, P N; Eaton, D L; Murphy, S D (1992) Comparative metabolism of methyl parathion in intact and subcellular fractions of isolated rat hepatocytes. Fundam Appl Toxicol 18:221-6
Balduini, W; Costa, L G; Murphy, S D (1990) Potassium ions potentiate the muscarinic receptor-stimulated phosphoinositide metabolism in cerebral cortex slices: a comparison of neonatal and adult rats. Neurochem Res 15:33-9
Costa, L G; McDonald, B E; Murphy, S D et al. (1990) Serum paraoxonase and its influence on paraoxon and chlorpyrifos-oxon toxicity in rats. Toxicol Appl Pharmacol 103:66-76
Costa, L G (1990) The phosphoinositide/protein kinase C system as a potential target for neurotoxicity. Pharmacol Res 22:393-408
Costa, L G; Kaylor, G; Murphy, S D (1990) In vitro and in vivo modulation of cholinergic muscarinic receptors in rat lymphocytes and brain by cholinergic agents. Int J Immunopharmacol 12:67-75
Balduini, W; Murphy, S D; Costa, L G (1990) Characterization of cholinergic muscarinic receptor-stimulated phosphoinositide metabolism in brain from immature rats. J Pharmacol Exp Ther 253:573-9
Costa, L G; Olibet, G; Wu, D S et al. (1989) Acute and chronic effects of the pesticide amitraz on alpha 2-adrenoceptors in mouse brain. Toxicol Lett 47:135-43
Stamper, C R; Balduini, W; Murphy, S D et al. (1988) Behavioral and biochemical effects of postnatal parathion exposure in the rat. Neurotoxicol Teratol 10:261-6
Schwartz, D A; LoGerfo, J P (1988) Congenital limb reduction defects in the agricultural setting. Am J Public Health 78:654-8

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