Abstract
The previous (ie, second) edition of this book was published in 2001. While regulatory changes related to toxicology may appear at times to advance at a glacial pace, this new edition is a welcome update after an 18-year gap. The authors who contributed chapters are all well-recognized and highly qualified experts in the specific areas of regulatory toxicology that they each address.
This book is well organized. In addition to the standard Table of Contents that lists the chapter titles and corresponding authors, a useful guidance feature that is introduced in this edition is the inclusion of a separate table of contents at the beginning of each chapter that directs the reader to the pages on which subtopics are covered.
In the opinion of this reviewer, this would be an ideal textbook for any graduate course presented to students that may be interested in pursuing a career in the field of toxicology, provided that they have first been exposed to general or advanced courses in toxicological sciences. This would also serve as a useful reference for any practicing professional engaged in product safety and regulatory affairs, particularly for disciplines covering multiple types of products for which commercial introduction and distribution may be controlled by any of a variety of US domestic or international regulatory authorities.
As the editor (Shayne Gad) suggests, most primary texts on the science of toxicology provide limited instruction in the realm of regulatory toxicology; consequently, many practicing toxicologists may begin their careers with relatively little preparation or appreciation for the breadth of regulations that will impact the responsibilities to which they (and/or their management or downstream customers or clients) must ultimately adhere. The objective of this book is best expressed in the editor’s own words, for example: “As this book seeks to make clear, virtually all commercial products have to meet regulatory toxicology requirements in their approval for market entry, manufacturing, distribution, and disposal. It is the object of this book to address this regulatory gap.”
The text of the Introduction (chapter 1, by Shayne Gad) is nearly identical to that of the previous edition. Notable upgrades include an expanded table of Key Safety Assessment Reference Texts, with many additional and more modern editions listed.
Chapter 2 (by Shayne Gad) deals with the regulatory aspects covering the safety of pharmaceutical products. As noted in the introductory section of this chapter, major changes that have occurred in the pharmaceutical regulatory arena since the 2001 edition include a substantially increased degree of international harmonization of nonclinical safety testing guidelines and a more pronounced emergence of generic drugs including the advent of regulatory acceptance of biosimilars. The body of this chapter begins with an interesting list of major historical events in the development of federal drug law in the United States, ranging from passage of the Virus Act in 1902 to the Food and Drug Administration (FDA) Modernization Act and the subsequent Amendments of 2002, 2007, and 2012. Organization charts are presented for the Center for Drug Evaluation and Research (CDER) and the Center for Biologics Evaluation and Research (CBER). As of this writing, the organizational structures of these 2 centers remain the same. Predictably, some of the individual office directors identified in the charts have since been replaced and several former vacancies have now been filled.
Much of the text in the second chapter is unchanged from the previous edition. A new and interesting upgrade is seen in the inclusion of a table entitled, “Comparison of FDA’s Expedited Programs for Serious Conditions (CDER and CBER, 2014).” In addition, a table listing the Guidelines established by the International Conference on Harmonization has been updated in this new edition through the inclusion of references to Guidelines issued since 1999.
Chapter 3 (by Elizabeth Roberts) captures several relatively recent changes that have impacted regulatory review of animal drug product applications, such as the establishment of the Animal Drug User Fee Act and subsequent revisions and reauthorization, and revised guidance for addressing human safety based on residues of new drugs in edible tissues of food-producing animals.
In chapter 4, Shayne Gad addresses aspects of regulatory strategy in safety evaluation of medical devices and biomaterials. Among the medical updates discussed in this chapter is the substantial improvement in the FDA review and decision-making timeline for 510(k) Premarket Notifications that has occurred in recent years as attributable to the enactment of the Medical Device User Fee Amendments. In a broader context through a discussion of the Conformité Européen marking of devices, the author provides an interesting update via a comparison and contrast with the more robust requirements of the US FDA. A useful table of ISO 10993 guidelines and dates of corresponding revisions has also been updated in the current edition.
Chapter 5 (by Chada S. Reddy and A. Wallace Hayes) covers regulatory aspects of food additives and nutrition supplements. This chapter has been substantially reorganized and updated from the preceding edition. It leads the reader through the regulatory distinctions between direct and indirect food additives, contaminants, and dietary supplements. An easy-to-follow “Food ingredient decision tree” diagram that was developed by FDA (adapted from: http://www.fda.gov/Food/IngredientsPackagingLabeling/FoodAdditivesIngredients/ucm228269.htm) is presented in this chapter, guiding the reader to determine the appropriate path forward depending on the intended use. Another helpful decision tree is included that diagrammatically shows the variety of potential regulatory paths for obtaining marketing approvals for new dietary ingredients (NDIs) and conditions where NDI notification may or may not be required.
Chapter 6, by Bennett Varsho and George DeGeorge, addresses regulations that affect cosmetic and personal care products. This provides an instructive list of examples of the types of consumer products that are regulated as cosmetics, over-the-counter drugs or both. It explains the regulatory distinctions used in categorizing these products and the level of oversight that may typically be applied by the US FDA, the Federal Trade Commission, the Consumer Product Safety Commission (CPSC), and/or established expert panels depending upon the types of products, intended uses, and their constituent ingredients.
The sections on OTC drugs and nutraceuticals in chapter 7 by Charles Spainhour summarize the regulatory evaluative and classification processes in the United States, Europe, and Japan. The narratives have changed only minimally in comparison to the previous edition by the same author; however, it is notable that the references provided have been substantially updated and expanded.
Chapter 8, “Consumer Products: Nonpersonal Care Products Regulatory Review and Labeling” by Robert Kapp and Denese Deeds, describes the origins of key legislation and formation of governmental agencies and committees aimed at protecting consumers from exposure to hazardous products. The primary focus in this chapter is aptly given to the US CPSC and its policies, regulatory scope, and limitations. The authors provide an incisive description of the current CPSC guidance on toxicity testing and hazard labeling of consumer products. On the other hand, there are other significant categories of nonpersonal care consumer products that are highly regulated in the United States but not mentioned in this chapter, such as household surface disinfectants and sanitizers, which require premarket approval and registration by the Environmental Protection Agency (EPA).
Chapter 9, “Agricultural Chemicals: Regulation, Risk Assessment and Risk Management” by Elliot Gordon describes the regulations and associated risk assessment and management processes regarding agricultural chemicals. This chapter provides a fresh and updated account of the regulatory toxicology framework related to safety evaluation and registration of agrochemical pesticides. The discussion centers primarily around the scope of key regulations and the general principles of determining the relevant testing requirements and policies of the US EPA, with some references to the Canadian Pest Management Regulatory Agency, the California Department of Pesticide Regulation, and other regulatory authorities. The author notes that the target audiences for this chapter are “(1) the newly minted toxicologist whose first position is in the agrochemical field, and (2) the toxicologist who has had limited experience with agrochemical registrations but is now moving into this field.”
As was the case in the preceding (2001) edition, the regulation of industrial chemicals in this third edition is covered in 2 chapters. The major topics addressed include discussion of the Toxic Substances Control Act and other similar international chemical control laws including the Registration, Evaluation, Authorization and Restriction of Chemicals law in Europe (chapter 10, by Sol Bobst and Richard Kraska), and an overview of United States and international regulatory requirements regarding hazard communication, workplace exposure limits, product labeling, and transportation (chapter 11, by Edward Sargent).
Chapter 12, by Alicia Taylor and M. Yusuf Khan, provides an overview of federal air and water regulations, including a summary of the legislative and regulatory histories and updates on the key US laws related to exposure to toxic substances in air and water. The principal focus of this chapter is on the US Clean Air Act, Clean Water Act, and the Safe Drinking Water Act including subsequent amendments and modifications to the scope of the original legislative actions. A table listing the primary and secondary standards for each of the 6 pollutants covered under the National Ambient Air Quality Standards has been updated in accordance with the limits established by EPA regulation in 2016. In addition, the list of chemicals included in the national primary drinking water standards and the corresponding maximum contaminant levels, as well as the maximum contaminant level goals, have been expanded in the new edition from primary organics, inorganics and radionuclides to now include the regulated limits for individual disinfection byproducts and microorganisms. This chapter also contains a brief mention of international regulations and policy statements for enhancement of air and water quality that have been developed since 2015, including the Paris Agreement and the UN list of Sustainable Development Goals.
The coverage of California’s Proposition 65 (the Safe Drinking Water and Toxic Enforcement Act of 1986) by Clint Skinner (Chapter 13) provides a concise summary of the basic law and major amendments since it was originally enacted in November 1986. The description of the modifications to the law is particularly timely in relation to the publication date of this edition since it includes discussion of significant changes and clarifications that were incorporated into the formal amendments that became effective on August 30, 2018.
A notable upgrade from the previous edition is the addition of a full chapter devoted to Safety Data Sheets (chapter 14, by Dexter Sullivan, Jr.). This chapter provides a review of the history of development and implementation of the internationally standardized format for SDS hazard communication under the Globally Harmonized System of Classification and Labeling of Chemicals (GHS). Each of the required 16 sections comprising the formal GHS standards for SDSs is described in useful detail, including the universal hazard and precautionary statement codes and pictograms, and recommendations on the specific types of information that should be included.
The topic of Genetically Modified Organisms, which was virtually overlooked in the previous edition, has since emerged and is now appropriately represented as a discrete chapter in the new edition. Chapter 15, by John A. Budny, is entitled “Genetically Modified Organisms – Evolution or Revolution of Genetics: Assessing the Health Risks of Foods and Crops.” This chapter begins with a discussion of terminology for genetically modified or genetically engineered organisms and relates the more recent history of the development and refinement of genome editing techniques up to the currently predominant CRISPR/Cas9 system. International controversy and discordant regulatory approaches are discussed and the primary focus on safety regulations for genetically engineered foods is devoted to the controlling agencies and evaluative policies and processes that have developed in the United States and European Union.
The final chapter of this book (chapter 16, by Robin C. Guy) is entitled “Oversight Regulations.” This chapter addresses Good Laboratory Practice regulations; FDA’s 21 CFR Part 11 requirements for the use and retention of electronic records; the Animal Rule and the responsibilities of researchers under the Animal Welfare Act; Occupational Safety and Health Administration regulations applicable to laboratory worker protection; and guidance on laboratory waste disposal.
A key consideration in selection of a book for use as a reference text is the level of detail provided in the overall Index section. This book is somewhat disappointing in this regard. For example, significant coverage is appropriately devoted to the Prescription Drug User Fee Act, particularly as a focal topic over several pages in chapter 2; however, this term is not found either by its full title or the abbreviated form in the Index at the back of the book. Another shortcoming of this book is that it does not include a chapter or even a substantive discussion of the regulatory processes that relate to entire classes of industrial or residential antimicrobial products, for example, those nonagricultural pesticide products that are regulated by the US EPA under the Federal Insecticide, Fungicide and Rodenticide Act, and in Europe under the EU Biocidal Products Regulation.
In the opinion of this reviewer, the overall benefits that readers are likely to derive from the authoritative guidance on safety regulations over the diverse range of products covered in this book significantly outweigh the few limitations cited above.