The application of dosimetry models to identify key processes and parameters for default dose-response assessment...

Mathematical dosimetry models should improve the accuracy of various extrapolations required in dose-response assessment because they include explicit descriptions of the major mechanistic determinants of the exposure-dose-response continuum. The availability of these anatomic and physiologic parameters for different mammalian species (including humans) and the physicochemical parameters for individual chemicals is an important consideration in the formulation of model structures and the application of simplifying assumptions to develop default models. A framework is presented that includes iterative development of model structures as more data become available. Development of the default dosimetry adjustments for interspecies extrapolation used in the inhalation reference concentration (RfC) methods of the U.S. Environmental Protection Agency (EPA) is discussed as an example of iterative model development, a process intended to ensure that model structures are commensurate with available data. The framework also aids evaluation of different model structures and can be applied to identify key parameters. Examples are provided to illustrate how insight on the key mechanistic determinants of exposure-dose-response can guide interpretation of data in the absence of comprehensive model structures, identify gaps in the database for a given chemical, or direct data gathering for chemicals that are yet to enter production.