Family approach for estimating reference concentrations/doses for series of related organic chemicals

The family approach for related compounds can be used to evaluate hazard an d 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 da ta: 1) exposure, 2) tissue dosimetry, 3) mode of action, and 4) response, E xpansion of the traditional exposure-response analysis has been increasingl y incorporated into regulatory guidance for chemical risk assessment. The f amily approach represents an advancement in the planning and use of toxicit y 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 e xample is provided using butyl acetate and its metabolites (butanol, butyra ldehyde, and butyrate), widely used chemicals produced synthetically by the industrial oxo process. A template pharmacokinetic model has been develope d that comprises submodels for each compound linked in series. This prelimi nary model is being used to coordinately plan toxicity studies, pharmacokin etic studies, and analyses to obtain reference concentrations/ doses. Imple mentation of the family approach using pharmacokinetic modeling to obtain t issue dose metrics is described and its applications are evaluated.