Family Approach for Estimating Reference Concentrations/Doses for Series of Related Organic Chemicals

Abstract

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.

Physiologically Based Pharmacokinetic Modeling of Styrene and Styrene Oxide Respiratory-Tract Dosimetry in Rodents and Humans

“…Delivered dose to the lower airways and available dose for systemic extraction require accurate characterization of the extraction of inhaled vapors in the nasal cavity (Barton et al, 2000). Morris and coworkers measured extraction of ST in surgically isolated upper respiratory tract of anesthetized CD mice and SD rats at multiple flow rates and concentrations to examine the effect of flow rate and concentration on nasal extraction (Morris, 2000).…”

Physiologically based pharmacokinetic modeling of ethyl acetate and ethanol in rodents and humans

“…To account for fractional respiratory bioavailability of water soluble volatiles such as ethyl acetate and ethanol, the incoming air concentration was multiplied by a factor (FA) representing the fraction of chemical that would be available for absorption (Barton et al, 2000;Corley et al, 2000). Ethyl acetate is metabolized to ethanol in the blood, liver and other perfused tissues, reflecting significant extrahepatic metabolism (Deisinger and English, 2003).…”

“…The metabolic series approach (previously, the "family approach") is a methodology that leverages the metabolic relationships between related compounds or series members (Barton et al, 2000). This method can facilitate efficient toxicity testing and the development of acceptable exposure levels, and has been used to assess the butyl series (n-butyl acetate, n-butanol, nbutyraldehyde, and n-butyric acid) (Teeguarden et al, 2005).…”

“…This method can facilitate efficient toxicity testing and the development of acceptable exposure levels, and has been used to assess the butyl series (n-butyl acetate, n-butanol, nbutyraldehyde, and n-butyric acid) (Teeguarden et al, 2005). Dosimetry-based analyses can be used to develop toxicity information using pharmacokinetic data for each related compound and toxicity data for the parent compound, because this data necessarily includes exposure to the downstream metabolites (Barton et al, 2000).…”

“…Because of this utility, such models are being used increasingly to develop human exposure limits and provide context to interpretation of laboratory studies on chemical toxicity. The family approach is one such application (Barton et al, 2000;Teeguarden et al, 2005).…”