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DOSE-TIME-RESPONSE MODELING FOR EVALUATING CUMULATIVE RISK OF N -METHYL CARBAMATE PESTICIDES
Impact/Purpose:
The approach to this problem is to adapt the dose-response model already used for modeling AChE activity after organophosphate exposure to include a model for recovery; to use a hierarchical model to account for the variability among studies, so that all the datasets for a chemical can be used to estimate dose-response parameters; to develop a model that accounts for AChE inhibition subsequent to multiple non-simultaneous exposures, using the parameter estimates derived from dose-response modeling. Progress to Date: A dose-time-response model has been developed that can be used both for modeling individual chemical dose-time-response data and for predicting AChE inhibition; preliminary parameter estimates have been generated. Impact: The dose-response results of this work will be used in the dose-response assessment portion of the Agency’s N-methyl carbamate cumulative risk assessment. Predictions of AChE inhibition under realistic exposure scenarios may be used in the hazard characterization portion of that risk assessment. Methods developed in this analysis could be used in the future for cumulative risk assessments for agents with ephemeral acute effects. Partnerships/Collaborations: This work is being done in collaboration with scientists in the Health Effects Division of OPPTS and from the Neurotoxicology Division of the National Health and Environmental Effects Research Laboratory.
Description:
EPA's Office of Prevention, Pesticides, and Toxic Substances (OPPTS) is required by the Food Quality Protection Act to completely reevaluate pesticide registrations by the end of August, 2006. This evaluation must include the evaluation of cumulative and aggregate risk of compounds that act through a common mechanism. One such group of pesticides is the N-methyl carbamates, whose common mechanism is the reversible inhibition of acetylcholine esterase (AChE) in nervous tissue. The inhibition of AChE is generally rapidly reversible, with half-lives in rodents at low doses of 1 – 3 hours or so. Accounting for episodic exposures of the carbamates, for example through the diet, then requires a more complex risk assessment model for combining the effects of multiple exposures (for example, an exposure of chemical A at breakfast, followed by an exposure of chemical B at lunch), than it would for exposures of compounds with longer-lived common effects. It also requires the estimation of parameters for models that describe both the dose-response and the recovery of AChE activity from multiple studies of the same dose response relationship.