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NON-ADDITIVE INTERACTIONS OF AN ORGANOPHOSPHORUS PESTICIDE MIXTURE IN ADULT AND PREWEANLING RATS.
Citation:
MOSER, V. C. NON-ADDITIVE INTERACTIONS OF AN ORGANOPHOSPHORUS PESTICIDE MIXTURE IN ADULT AND PREWEANLING RATS. Presented at Dayton Conference on Toxicology, Cincinnati, OH, April 26 - 28, 2006.
Description:
Critical features of risk assessment include the evaluation of risk following exposure to pesticide mixtures as well as the potential for increased sensitivity of the young. The US EPA is required to regulate pesticides acting via a common mechanism of action as a group, e.g., cumulative risk assessment. The first common mechanism group identified was the organophosphosphorus (OP) pesticides which inhibit acetylcholinesterase. The current default assumption is dose-additivity for mixtures with a common mode of action. There are, however, literature reports on binary OP mixtures showing non-additivity in about half of the pairs tested, as well as synergy produced by malathion in combination with other certain OPs. This research tested for interaction(s) using a mixture of five OPs (chlorpyrifos, diazinon, dimethoate, acephate, and malathion) as well as four OPs (without malathion) in both adult and preweanling (17 days old) rats using a fixed-ratio ray design. The pesticide ratio was based on the relative dietary exposure estimates. Neurochemical (blood, brain cholinesterase activity) and behavioral (motor activity, gait score, tail-pinch response score) endpoints were assessed following acute oral exposure. To determine age-related differential responses, we conducted the study in both adult and preweanling (17 day old) rats. Single chemical dose-response data were used to construct a theoretical additivity model for each mixture. Mathematical curves fit to the empirical data were statistically compared to the predicted curves to determine deviations from dose-additivity. In both adult and preweanling rats, the analyses revealed significant greater-than-additive (synergistic) responses for blood and brain ChE inhibition, motor activity, gait alterations, and tail-pinch response (pups only). Most often, the deviations occurred at the low end of the curves, and effective doses (ED20, ED50) of the mixture were 2- to 3-times less that predicted under additivity. Comparing the full and reduced rays showed that malathion interacts with the other OPs for some endpoints; however, the deviation from additivity cannot fully be attributed to the malathion in the mixture. The results from these studies indicate that under certain experimental parameters, deviations from additivity are observed with these common mode-of-action pesticides. Correlating these findings with tissue levels of pesticide and kinetic models may allow mechanistic explanations for these deviations, and better predictions for their occurrence.
This is an abstract of a proposed presentation and does not necessarily reflect EPA policy