Toxicological Sciences 54, 251-261 (2000)
Copyright © 2000 by the Society of Toxicology
Family Approach for Estimating Reference Concentrations/Doses for Series of Related Organic Chemicals
* K. S. Crump Group, ICF Kaiser, Research Triangle Park, North Carolina 27709;
Health and Environment Laboratories, Eastman Kodak Company, Rochester, New York 14652-6272;
Health, Safety, and Environmental Affairs Department, Union Carbide Corporation, Danbury, Connecticut 06817-0001; and
§ Toxicology, Health, Safety, and Environment, Shell Chemical Company, Houston, Texas 77002
The family approach for related compounds can be used to evaluate hazard and estimate reference concentrations/doses using internal dose metrics for a group (family) of metabolically related compounds. This approach is based upon a simple four-step framework for organizing and evaluating toxicity data: 1) exposure, 2) tissue dosimetry, 3) mode of action, and 4) response. Expansion of the traditional exposure-response analysis has been increasingly incorporated into regulatory guidance for chemical risk assessment. The family approach represents an advancement in the planning and use of toxicity testing that is intended to facilitate the maximal use of toxicity data. The result is a methodology that makes toxicity testing and the development of acceptable exposure limits as efficient and effective as possible. An example is provided using butyl acetate and its metabolites (butanol, butyraldehyde, and butyrate), widely used chemicals produced synthetically by the industrial oxo process. A template pharmacokinetic model has been developed that comprises submodels for each compound linked in series. This preliminary model is being used to coordinately plan toxicity studies, pharmacokinetic studies, and analyses to obtain reference concentrations/doses. Implementation of the family approach using pharmacokinetic modeling to obtain tissue dose metrics is described and its applications are evaluated.
Key Words: hazard identification; dose-response assessment; butyl acetate; tissue dosimetry; mixtures; risk assessment; pharmacokinetics; reference dose (RfD); reference concentration (RfC).
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