ToxSci Advance Access originally published online on April 11, 2006
Toxicological Sciences 2006 92(1):235-245; doi:10.1093/toxsci/kfj189
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Published by Oxford University Press 2006.
Neurotoxicological Interactions of a Five-Pesticide Mixture in Preweanling Rats
* Neurotoxicology Division and Experimental Toxicology Division, National Health and Environmental Effects Research Laboratory/Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina; and Department of Biostatistics, Virginia Commonwealth University, Richmond, Virginia
Received February 3, 2006; accepted April 6, 2006
The estimation of risk following exposure to mixtures is an important feature of pesticide risk assessment. Also of concern is the potential for increased sensitivity of the young to pesticide toxicity. We have conducted interaction studies using a mixture of five organophosphorus (OP) pesticides (chlorpyrifos, diazinon, dimethoate, acephate, and malathion) in both adult (published previously) and preweanling rats using a fixed-ratio ray design. In the present study, cholinesterase inhibition and behavioral changes (motor activity, gait, and tail-pinch response) were measured in 17-day-old Long-Evans male rats following acute exposure to the OPs. The ratio of pesticides in the mixture reflected the relative dietary exposure estimates projected by the U.S. Environmental Protection Agency Dietary Exposure Evaluation Model. Dose–response data were collected for each OP alone, which were used (alone or in conjunction with the mixture data) to build an additivity model to predict the effects of the pesticide mixture along a ray of increasing total doses, using the same fixed ratio of components. The mixture data (full ray) were similarly modeled and statistically compared to the additivity model along the ray. Since malathion has been shown to produce synergistic interactions with certain OPs, it was of interest to evaluate the influence of malathion in this study. A second pesticide mixture, without malathion (reduced ray), was tested using the same dose levels of the remaining four OPs. Analysis of the full ray revealed significant greater-than-additive responses for all endpoints. The magnitude of this shift ranged from two- to threefold for estimates of the ED20 and ED50. The deviation from additivity was also detected in the reduced ray for all but two endpoints (motor activity and tail-pinch response); however, for all endpoints, the reduced ray was significantly different from the full ray. Thus, greater-than-additive responses were detected in preweanling rats with this OP mixture, and this effect can only partially be attributed to the malathion in the mixture.
Key Words: mixtures; cumulative risk; neurotoxicity; age susceptibility; chlorpyrifos; acephate; malathion; dimethoate; diazinon.