Assessing Risks from Simultaneous Time-Varying Longitudinal Exposure Profiles to Several Organophosphorus Pesticides. L. R. Rhomberg, Gradient Corporation
The 1996 Food Quality Protection Act requires EPA to assess the joint effects of simultaneous exposure to pesticides acting by the same mechanism of action. The organophosphorus pesticides acting through inhibition of cholinesterase constitute such a group. Increasingly, exposure assessment is able to chart (or simulate) the daily fluctuations in exposure for an individual to a series of such agents, posing a complex dosimetry question in which cholinesterase inhibition levels are continually changing as a function of differing daily increments in exposure and of the lingering inhibition stemming from exposures on previous days. Neither single-day nor ongoing steady-state exposure experiments serve as a good model for the effects to be expected from such ongoing but non-steady-state internal doses. I propose a simple, readily accomplished, default dosimetry approach that assumes linear kinetics and is driven by compound-specific half-lives of cholinesterase-activity recovery. This default approximates the results of full pharmacokinetic models, and clarifies how temporally fluctuating cholinesterase-inhibition values are to be interpreted toxicologically. Relative potencies among agents determined in steady-state experiments can be shown to be relevant to non-steady-state exposures if applied in the context of this approach.
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