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TESTING STRATEGIES TO ESTIMATE NEUROTOXIC RISK FOR CUMULATIVE EXPOSURE TO PYRETHROID MIXTURES.
Citation:
WOLANSKY, M., M. J. DEVITO, R. TORNERO-VELEZ, M. F. HUGHES, H. A. OZKAYNAK, T. J. SHAFER, C. J. GORDON, J. HARRILL, AND K. M. CROFTON. TESTING STRATEGIES TO ESTIMATE NEUROTOXIC RISK FOR CUMULATIVE EXPOSURE TO PYRETHROID MIXTURES. Presented at Society for Risk Analysis, Baltimore, MD, December 03 - 06, 2006.
Description:
The Food Quality Protection Act requires EPA to consider the cumulative risk of pesticides with
a common mechanism-of-toxicity. Evidence supports a mechanistic commonality for pyrethroid
insecticides: these chemicals all act on neuronal sodium channels. The lack of a predictive
biomarker for pyrethroids implies that previous approaches (e.g., organophosphates) for
estimating cumulative risk are not viable. In order to estimate the cumulative risk of pyrethroids,
we are developing an exposure-dose-response model. Cumulative and aggregate exposures are
being estimated from environmental and food residue data using SHEDS models. Human and
animal PBPK models are being built using both in vitro and in vivo animal data to facilitate
extrapolation between species, and to allow estimation of rat brain concentrations at human
exposure levels. Effects data are being generated using both in vivo (autonomic, sensory, and
motor effects; rat), and in vitro (neuronal firing and ion flux) models to develop relative
potencies at various levels of neuronal organization. Mixtures are being tested to determine
whether additivity theory will predict cumulative effects based on administered dose or target
tissue dose. The overall goal is to use the above models to relate human exposures to target
tissue dose, extrapolate target tissue dose from humans to rats, and use the effects data to define
the degree of adverse outcome (if any) associated with human exposures. Progress to date
includes preliminary analyses of environmental data, construction of initial PBPK models using
in vivo kinetics and in vitro metabolism data, development of dose-response data for in vitro and
in vivo endpoints and calculation of relative potencies, and initial testing of additivity with a
mixture of 11 pyrethroids. This research will provide quantitative estimates of potential risks
posed to humans from aggregate and cumulative exposures to pyrethroids in food and the
environment. (This is an abstract of a proposed presentation and does not reflect EPA policy)