Toxicokinetics and Risk Assessment PDF

Preface

Risk assessment is sometimes erroneously referred to as an art. The scientific basis for risk assessment is rather objective, though, at times, not clearly or well annunciated to the general public and to those in laboratory research organizations. The goals of this text are to develop and communicate a clear description of the noncancer risk assessment process and its reliance on uncertainty factors (those addressing extrapolations of toxicity from animals to humans and within the human species); to present a synopsis of the limited available guidance on replacing default values for uncertainty factors with data-derived values; to distill, communicate, and discuss considerations that must be given to the generalization of findings of toxicity from animals to humans; to demonstrate proper methods for the development and interpretation of toxicokinetic data; to address and reinforce statistical considerations; and to provide a historical perspective and recent examples of the use of toxicokinetic information to inform the selection of uncertainty factors in risk assessments developed by the U.S. Environmental Protection Agency.

This text is aimed at several audiences: (i) the cadre of risk assessors who are undecided about the potential application of quantitative toxicokinetic findings for uncertainty factors; (ii) organizations, including those tasked with developing bench top and/or whole-animal studies of chemical metabolism and tissue dosimetry for risk assessment purposes; and (iii) those who make decisions about which areas of risk science to advance. At present, the International Programme on Chemical Safety has finalized a document that guides consideration of the quantitative value of chemical-specific toxicokinetic data for use in defining values for uncertainty factors, and in 1994, the U.S. Environmental Protection Agency finalized its guidance on the application of chemical-specific and animal species–specific measures of biochemical and physiologic differences that can lead to ‘‘data-derived'' values for toxicokinetic variability between animals and humans. While the U.S. Environmental Protection Agency's Integrated Risk Information System contains examples of inhalation risk assessments where species differences in toxicokinetics have been used for uncertainty factor values, very few oral risk assessments have been conducted at such a level of detail. It is hoped that unambiguous communication of methods, demonstrations of feasibility, and completed examples will stimulate additional research and policy work in this arena, which could culminate in the development of advanced risk assessment methods addressing this topic.

Regardless of policy, the availability of data may limit success if researchers are not fully cognizant of the implications and potential use of their data in risk assessment. This text will clearly demonstrate the application of physiologically based pharmacokinetic modeling in human health risk assessment and will separately demonstrate methods for data generation, extrapolation, and inclusion of laboratory results for chemical metabolism and computer-based predictions of biochemical constants to address animalto- human and human interindividual variability; specific attention will be devoted to Monte Carlo sampling techniques and the statistical considerations given to data demonstrating or predicting population variability, including that variability based on genetic polymorphisms. By communicating these topics, those investigators tasked with developing laboratory studies to address human risk and safety concerns will see the inclusion of such data in the desired end product-the completed risk assessment.

This text comprises the various topics of history and bases for human health risk assessment and its uncertainty factors; presents the available guidance on the inclusion of toxicokinetic data in risk assessment; communicates techniques and considerations to develop laboratory and whole-animal data of sufficient quality upon which to base estimates of variability and uncertainty factor derivation; presents, in some detail, the field of physiologically based pharmacokinetic modeling and computer-based predictions of biochemical values for inclusion in toxicokinetic models; demonstrates the value of characterizing human variability in chemical metabolism in large banks of human tissue samples; presents statistical considerations for the development and interpretation of study results; demonstrates considerations given in the translation of external exposures to tissue concentrations for application in mixtures and cumulative risk assessment; and demonstrates success stories where toxicokinetic information has been used to replace default values for uncertainty factors with data-derived uncertainty factors. In that regard, this text is unique-it addresses concerns of multiple organizations and divergent staff levels, and it is self-contained. While several, but not each, of these individual topics have been addressed at the ‘‘text'' level, there is no other single reference available that addresses all these topics. The development of this text will prove to be a boon to the development of additional studies to address toxicokinetics in animals and humans and to guide their evaluation as a means to replace default uncertainty factors in risk assessment, representing an overall improvement in their scientific basis.

Readers should be able to readily recognize the impact that their own fields of study-whether biochemical analyses, physiological measurement, computer simulation, in vivo studies, or pharmacokinetic analysis-can have on improving quantitative estimates of risk. Those scientists conducting risk assessment activities involving dose extrapolations should have a heightened awareness of the value, as well as the complexity, of toxicokinetic information. Through consideration of the information contained in this book, researchers and risk assessors should find common ground upon which to plan, conduct, and interpret new studies to continue the refinement of the scientific basis for health risk assessment.

Author: Lipscomb, John C.