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MULTIPLE SOLVENT EXPOSURE IN HUMANS: CROSS-SPECIES EXTRAPOLATIONS
Citation:
Benignus, V A., P J. Bushnell, AND W K. Boyes. MULTIPLE SOLVENT EXPOSURE IN HUMANS: CROSS-SPECIES EXTRAPOLATIONS. Presented at Air Toxics Planning Meeting, Research Triangle Park, NC, June 11-12, 2002.
Description:
Multiple Solvent Exposures in Humans:
Cross-Species Extrapolations
(Future Research Plan)
Vernon A. Benignus1, Philip J. Bushnell2 and William K. Boyes2
A few solvents can be safely studied in acute experiments in human subjects. Data exist in rats for the acute behavioral effects of many solvents. A quantitative method has been developed by which data which exist in both humans and rats may be used to quantitatively estimate cross-species dose-equivalence equations (DEEs). A DEE will be developed for each available solvent. The parameters of the DEEs from available solvents will form a multivariate distribution of sample parameters. If the DEE parameters may be assumed to be samples from the same population of solvent DEEs, then true extrapolation from rats to humans becomes possible. For a new solvent, which cannot be studied in humans, rat data would be adjusted by a DEE, the parameters of which are drawn form the above sample distribution means.
Once the DEEs for various solvents are known, it will become possible to add doses for multiple simultaneous exposure to solvents. Assuming sufficient data, the blood doses for each solvent in a mix would first be converted to toluene equivalent by potency weighting and then added. Effects would be estimated from the toluene dose-effect curve.
DEEs can be estimated via meta analyses of the peer-reviewed literature. They can also be estimated from raw data provided by experiments. The former method has limitations due to differences between experiments in endpoints and methods. The latter procedure is time-consuming and expensive. Here the problem will be approached by a combination of methods. The DEE for toluene has been determined from a previously-published meta analysis. Experimental data from human exposures will be used to verify these results. Other solvents will be analyzed in the same way. Depending on the comparison between raw data and meta analyses, DEEs for other solvents will be determined. Predictions about new solvents and combinations will be used to test the methods.
The status of this project is (a) the method for estimation of the DEE and subsequent extrapolations has been published (b) a meta analysis for acute toluene effects in humans and rats has been published and (c) an experiment with acute toluene exposure in humans is underway. Meta analyses for other solvents and estimation of their DEEs will begin soon.
1US EPA, ORD, NHEERL, HSD
2US EPA, ORD, NHEERL, NTD