Abstract
This book focuses on the interactive relationship between toxicology and regulations of product safety and environmental health. Many regulatory professionals think that regulatory initiatives and policies drive the development of new toxicology data and toxicological methods. The reverse, however, is also true. That is to say that toxicology research drives the regulatory process. The development of new methods in toxicology enables and often demands new regulations. Discoveries of material adverse effects often require regulations to address the hazard determination, safety evaluation and risk assessment of the material. The book reviewed here provides several examples of the interaction between toxicology and regulatory process working in both directions.
There are two major sections in the book. Section 1 deals with the influence of the regulatory process on toxicology. This section consists of chapters covering the High Production Volume Challenge Program, homeland security and bioterrorism, the Food Quality Protection and the Safe Drinking Water Acts of 1996, chemical risk screening under the Toxic Substances Control Act and the Pollution Prevention Act, pharmaceutical safety data requirements, and the National Toxicology Program. Section 2 addresses the influence of biotechnology and toxicological research on the regulatory process. Section 2 includes chapters on toxicogenomics, physiologically based pharmacokinetics, safety assessment of pesticidal proteins in transgenic crops, alternative methods in toxicology, and genetic toxicology.
Section 1 begins with a chapter on the High Production Volume (HPV) Challenge Program, which has been responsible for the generation of new toxicity data on a larger number and wider variety of chemical materials than any other governmental program. It is ironic that the HPV Challenge Program is not a regulation with the force of law, but a voluntary cooperative effort between industry and government that runs in parallel with certain aspects of the Toxic Substances Control Act (TSCA). In large part, the HPV Challenge Program is due to the failure of TSCA Sections 4 and 5 to require toxicity data on existing and new industrial chemicals. It would be interesting to many readers and perhaps instructive to those drafting regulations and legislation, if the chapter included a discussion of factors causing this failure of TSCA.
In dealing with the difficulty of requiring new data to control chemicals under TSCA, EPA was driven to develop new methods to estimate necessary data by employing quantitative structure-activity relationships (QSAR) and computational toxicology. The evolution and description of systems used by EPA to meet this need in evaluating new chemical entities subject to Premanufacture Notifications (PMNs) is the topic of the chapter on chemical risk screening. This chapter describes the capabilities of the Windows-based Estimation Programs Interface (EPI) Suite. The EPI Suite provides estimates of physical-chemical and environmental fate properties with chemical structure as the only input. The output of EPI Suite in conjunction with ecological structure-activity relationships (ECOSAR), provide aquatic toxicity estimates. The application of expert systems to predict chemical carcinogenicity is also described. Furthermore there is an important discussion of the conservative assumptions, margins of exposure, and assessment factors used by EPA in the regulatory application of these estimates. The chapter concludes with a discussion and examples of the ways in which QSAR screening has affected regulatory policy under The Pollution Prevention Act of 1990.
The chapter titled “The Food Quality Protection Act [FQPA] and the Safe Drinking Water Act [SDWA]” says little about the latter legislation, other than to mention that many provisions of the FQPA were incorporated in or complimented by amendments to the SDWA. Nevertheless, this chapter provides perhaps the best and most significant example of how regulation has affected toxicology and risk assessment. The chapter begins by reviewing events and some scientific concerns with the regulation of pesticide residues in food, including the Delaney Clause, safety to children, and endocrine active chemicals in the environment. These issues were the driving forces for passage of the FQPA. The revolutionary changes brought about by the FQPA to standards and procedures for setting pesticide tolerances under the Food Drug and Cosmetic Act are discussed, including the determination of aggregate and cumulative risk, and the requirement to consider safety to children and sensitive subpopulations. Approximately half of this chapter is devoted to the endocrine disrupter screening program that EPA developed under the FQPA and the SDWA. The design, validation, and implementation of a tiered approach to screening and testing chemicals for endocrine effects are discussed at length.
A chapter on the National Toxicology Program (NTP) provides a comprehensive description of the traditional and current research initiatives at the NTP. The early focus of the NTP was mostly limited to the cancer bioassay program, which was inherited from the National Cancer Institute. Today, however, NTP is active in many areas of toxicology research involving many different types of potentially toxic materials. The manner in which NTP results are used by various federal and state regulatory agencies and international organizations is also discussed. This chapter is a good overview of the important supportive role NTP now fulfills in the regulation of toxic hazards.
The title “The Influence of Regulation on Toxicology” disguises a chapter on drug regulation. This chapter is an overview of the evolution and current state of toxicology data requirements to assure the safety of pharmaceutical products. It includes a summary of very basic pharmacologic and toxicologic principles, which would be more appropriate for an introductory textbook on these topics.
Finally, Section 1 covering the influence of regulatory process on toxicology, includes a chapter on homeland security and bioterrorism of all types. It is difficult to think of homeland security and bioterrorism as an area of regulatory toxicology and, as such, it does not add to the intended focus of this book. Nevertheless, the chapter provides an excellent background and overview of recent events impacting the field, as well as a good summary of agents that may be used as bioterrorism threats.
Section 2, which covers the influence of biotechnology and toxicological research on the regulatory process, begins with a chapter on the evolving science of toxicogenomics. The technologies employed are briefly described and some case examples of their application are presented. Early and limited activities at the EPA and FDA to prepare for eventual submission and use of toxicogenomics data by these regulatory agencies, is discussed.
The evolution of genetic toxicity testing from a societal and scientific concern to a standard component of all regulatory safety testing requirements is aptly described in the chapter titled “Genetic Toxicology and Regulatory Policy.” In fact, this chapter fully satisfies the stated intent of this book in a most interesting and engaging manner. All of the highs and lows in the quest for the rational use of genetic toxicity testing over the past 35 to 40 years are discussed. The retrospective review of factors and events that diverted focus to either somatic cell or germ cell effects at different times is enlightening. The key regulatory responses including EPA’s GENE-TOX program and Mutagenicity Risk Assessment Guidelines, the ICPEMC (International Commission for Protection Against Environmental Mutagens and Carcinogens), the NTP bioassay program and the ICH (International Conference on Harmonization) Genotoxicity Working Group, are clearly explained and their impact is discussed. The chapter also discusses genetic toxicity test batteries and problems encountered in their development for regulatory applications. These include (1) the need for standardized evaluation procedures when faced with heterogeneous results from multiple tests; (2) the need to extrapolate in vitro results to in vivo models; and (3) the need for validated methods. These same issues will be relevant to those developing and using alternative or in vitro tests now proliferating in other areas of toxicology.
The chapter on alternative methods in toxicology is mostly a scientific justification for alternatives and an overview of the societal factors leading to and fostering their development. The chapter concludes, however, with a discussion of a framework for development, validation and implementation of alternatives in regulatory toxicology. Problems with this process and regulatory initiatives intended to address the problems are discussed. The framework could be viewed as a general model for the steps that should be taken before any new toxicological method or research result might be utilized in regulatory processes.
The chapter on safety of pesticidal proteins in food is much like the chapter on drug regulation, except that the absorption, metabolism, and potential hazards of these biological materials are quite different than the hazards of most chemical pharmaceutical agents. This chapter provides a good overview of these factors and the regulatory approach to their evaluation in safety assessment of exogenous proteins in food.
The longest chapter in the book is devoted to physiologically based pharmacokinetic (PBPK) models. The first half of the chapter covers basic pharmacokinetics and explains the development of PBPK models with all the customary differential equations and kinetic model parameters. The rest of the chapter describes PBPK models designed to enlighten drug bioavailablity and kinetic mechanisms leading to pharmacodynamic effects. A few specific examples of models involving oral bioavailability and inhalation absorption are presented. As stated in the chapter, use of PBPK models by regulatory agencies in the review process has been limited, even though PBPK models have existed for over 20 years. It would have been interesting had the chapter considered the factors leading to this reality, and how the situation might change in the future.
In the preface, the Editor makes the following statement about the objective of the book: “This book will provide a greater depth of understanding about the relationship between [toxicology and regulatory agency approaches to hazard determination, exposure and risk assessment], and possibly will foster an atmosphere in which the mutually beneficial aspects of the relationship can be further enhanced.” Actually, few of the chapters directly address the interactive relationship between toxicology and regulations, which is the intended main focus of the book. It is up to the reader to glean these insights from the topics and examples discussed in the book. Furthermore, the only chapter written by an author working in the regulated community is that dealing with the influence of toxicogenomics research on regulation. Most of the chapter authors are well qualified and higher level employees of federal regulatory agencies including the EPA, FDA, and USDA, or other organizations of the federal government including NIEHS and DOD. The reader, however, would benefit and the Editor’s stated objective for the book might be better achieved, if the book offered a broader and different perspective on the relevant issues that could be provided by authors working in regulated industries as well as governmental organizations.
In summary, the premise of this book . . . that developments in toxicology affect regulations and vice versa . . . offers a unique perspective from which to consider the many issues in regulatory toxicology. It is somewhat disappointing that this perspective is not fully developed and explored in all chapters of the book. Nevertheless, the book will provide interesting and informative reading for general toxicologists and would be useful in a graduate course on regulatory toxicology.