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Impact of Chemical Proportions on the Acute Neurotoxicity of a Mixture of Seven Carbamates in Preweanling and Adult Rats
Moser, V. C., S. Padilla, J. Simmons, L. Haber, AND R. Hertzberg. Impact of Chemical Proportions on the Acute Neurotoxicity of a Mixture of Seven Carbamates in Preweanling and Adult Rats. TOXICOLOGICAL SCIENCES. Society of Toxicology, RESTON, VA, 129(1):126-34, (2012).
Environmental exposures generally involve multiple chemicals and pathways. These real world exposures vary temporally and spatially in terms of specific chemicals and their relative proportions. There is no doubt that humans are exposed to a multitude of pesticides, given their widespread agricultural, industrial, and residential uses. There is, however, concern that the cumulative toxicity of these chemicals could be greater than that predicted by individual assessments. Research concerning mixture toxicity for risk assessment is a key ongoing environmental health issue.
Statistical design and environmental relevance are important aspects of studies of chemical mixtures, such as pesticides. We used a dose-additivity model to test experimentally the default assumptions of dose-additivity for two mixtures of seven N-methylcarbamates (carbaryl, carbofuran, formetanate, methomyl, methiocarb, oxamyl, propoxur). The best fitting models were selected for the single-chemical dose-response data and used to develop a combined prediction model, which was then compared to the experimental mixture data. We evaluated behavioral (motor activity) and cholinesterase (ChE)-inhibitory (brain, RBC) outcomes at the time of peak acute effects in adult and preweanling (17 days old) Long-Evans male rats. The mixtures varied only in their mixing ratios. In the relative potency (RPF) mixture, proportions of each carbamate were set at equitoxic component doses. A California environmental (CE) mixture was based on the 2005 sales of each carbamate in California. In adult rats, the RPF mixture showed dose-additivity for RBC ChE and motor activity, and brain ChE inhibition showed a modest greater-than-additive (synergistic) response, but only at a middle dose. In rat pups, the RPF mixture was either dose-additive (brain ChE inhibition, motor activity) or slightly less-than-additive (RBC ChE inhibition). On the other hand, at both ages, the CE mixture showed greater-than-additive responses on all three endpoints, with significant deviations from predicted at most to all doses tested. Thus, we observed different interactive properties for different mixing ratios of these chemicals. These approaches for studying pesticide mixtures can improve evaluations of potential toxicity under varying experimental conditions that may mimic human exposurure.