Practical application of kinetic data in risk assessment--an IPCS initiative

In this paper, guidance developed in a project of the International Programme on Chemical Safety (IPCS) initiative on Harmonization of Approaches to the Assessment of Risk from Exposure to Chemicals is considered in the context of its application in the assessment of the adequacy of physiological-toxicokinetic (PTK) modeling to inform quantitatively extrapolations for interspecies differences and human variability in dose-response assessment. This guidance was developed in the context of a framework, which permits the incorporation of quantitative chemical-specific data, relating to either toxicokinetics or toxicodynamics to replace part or all of the usual 100-fold default uncertainty factor for interspecies differences or human variability in the development of tolerable or reference doses or concentrations. However, since the guidance relates specifically to adequacy of kinetic or dynamic data to replace default for interspecies and human variability, it is also applicable to other approaches of dose-response analyses such as estimation of cancer potency or risk. The framework also supports probabilistic characterization, where data are sufficient. This guidance has been developed and refined through a series of planning and technical meetings and larger workshops, in which a broad range of participants from academia, government agencies, and the private sector have prepared and gained experience in application through case studies. The guidance for adequacy of kinetic data to replace default is presented in the context of several categories, including determination of the active chemical species, choice of the appropriate kinetic parameter and experimental data, the latter which includes reference to relevance of population, relevance of route, relevance of dose/concentration, and adequacy of number of subjects/samples. The principal objective of this guidance, which has been developed primarily as a resource for risk assessors, is to foster better understanding of the criteria for adequacy of chemical-specific data to quantitate interspecies differences and human variability in kinetics and dynamics, including PTK models. It is anticipated that the guidance will also encourage generation of appropriate data and models, and facilitate their incorporation in dose/concentration-response assessment for regulatory purposes. In this paper, the application of the guidance is considered primarily through reference to examples, with emphasis on those where PTK models have been informative.