Abstract
Immunotoxicology is a rapidly expanding area of toxicology and includes new disciplines of immunotoxicology, e.g., developmental immunotoxicology. Over the last 5 years or more, there has become a greater and specific emphasis on the assessment of immune function for drugs and chemicals in toxicological studies. Indeed, in the last 2 years, regulatory agencies, e.g., the Food and Drug Administration (FDA), have issued guidance that provides specific recommendations for testing of drugs in preclinical toxicity programs.
With such greater emphasis for immune function end points, the literature has expanded significantly. Several recognized leaders in the field of immunotoxicology have published references, including the book that is the basis for this review. Researchers from different disciplines have shown interest in this new field, and presented results of their work on immunotoxicological issues from extremely varied perspectives. As a bridging between the disciplines of immunology and toxicology, immunotoxicology is genuinely multidisciplinary, reflected in this introductory book on the subject.
The author, Professor Jacques Descotes, has authored several books on the topic of immunotoxicology. This current volume represents the first of a three-volume compendium, an ambitious undertaking of a comprehensive review of immunotoxicology. The three-volume set is intended to examine the preclinical, clinical, regulatory, and mechanistic aspects of the effects of drugs and chemical on immune function. This first volume is a general review of the topic of immunotoxicology, providing the physiological foundation of the immune system.
Since the second edition of this book was published in 1988, an increasing amount of data has resulted in the publication of many articles and reviews. This book covers the many general facets of current immunotoxicology—clinical, experimental, mechanistic, and regulatory aspects, including a chapter on the immune system giving toxicologists that do not practice often in the area of immunology the opportunity to become familiar with the knowledge necessary to conduct and interpret immunotoxicity studies.
The first several chapters of the book deal primarily with the immunological adverse effects and mechanisms of immunotoxicity of drugs and other chemicals. In these chapters Professor Descotes defines what constitutes an immunotoxic response and the possible biological mechanisms involved in the expression of the adverse effect. Like most of the writings in this book, the author uses many examples to demonstrate his point regarding immunostimulation or immunosuppression. However, it is noted that the author repeats these examples numerous times. Might it have been more useful to provide a greater diversity of examples? Possibly. The field of immunotoxicity continues to expand such that a plethora of examples of different compounds that produce immunotoxicity are not yet identified. Indeed, Professor Descotes makes this point in the last chapter on “Categories of Immunotoxicity.”
Regardless, Professor Descotes thoroughly describes the immune system physiology and the mechanisms involved in an immunotoxic effect in the first three chapters. Taking a toxicological point of view, the author is quite descriptive of the role of lymphoid cells and tissue in the development of an immune response, and mechanisms involved in expression of natural killer cells, T-helper cells, etc. As noted previously, for those that do not often practice in the area of immunotoxicology, this is a very worthwhile introduction.
From these introductory chapters, Professor Descotes then launches into the evaluation of immunotoxicity describing a number of preclinical assays, in vivo and in vitro, to evaluate potential immunotoxicity. There is nothing really new in these chapters, i.e., the methodologies described should be well known to the practicing toxicologist. The advantage, however, is that Professor Descotes describes the methods in terms of mechanisms of responsiveness, a useful approach. Unfortunately, there is a great deal of repetition of examples from one chapter to the next, a not unexpected outcome as noted above.
In the following chapters, the author describes the current state of the regulations related to immunotoxicity testing, and outlines a strategy for both preclinical and clinical evaluation of immunotoxicity. The author points out the nuisances of the regulatory guidance as it applies to immunotoxicology. Furthermore, he is critical in some of the writings of the lack of clarity for testing in some guidance (International Conference on Harmonization or ICH S6), but is supportive of the depth in others (Center for Devices and Radiological Health or CDRH Guidance). The most recent ICH Guidance on immunotoxicity testing, however, is not included, and I suspect that Professor Descotes would have welcomed such guidance in this chapter.
In the chapter on nonclinical strategies, the author takes exception of the lack of immunotoxicity testing prior to early clinical evaluation. He states that immunotoxicity evaluation should be a routine assessment in early preclinical testing. In early stage testing, however, hematology and pathological evaluation of lymphoid tissue is always included such that signals of immunotoxicity are assessed. Inclusion of these parameters in routine toxicology studies was encouraged by Professor Descotes in a previous chapter, and are, indeed, part of routine toxicology testing of agents. Clearly, if findings of potential immunotoxicity are observed added testing would be undertaken. In addition, if a new molecular entity is within a drug class of suspected immunotoxicants, the inclusion of immunotoxicity testing would be included in early sage development. Therefore, including various nonroutine immunotoxicity assays in early preclinical studies would not be generally warranted.
Professor Descotes provides two interesting chapters on clinical immunotoxicity and immunotherapy for human poisonings. In the former chapter, the author describes various testing modalities for detection of immunotoxicants, and many of the described tests are, as expected, similar to those described for preclinical evaluations. Furthermore, Professor Descotes discusses the evaluation of epidemiological studies as a means for detection of immunotoxic environmental chemicals. The chapter concentrates too much on evaluation of immunotoxicants in clinical trials, with minimal assessment of environmental toxicants. However, in the chapter on immunotherapy, Professor Descotes does provide additional description of the immunotoxicity of environmental toxicants as well as natural toxicants. In particular, he describes treatment of poisonings using antibody therapies that have been successful. This is the first publication that this reviewer has seen with such a thorough discussion of this concept in medical practice. Clearly, however, many of the immunotherapies for environmental chemicals have been less than successful, although the use of treatment regimens towards natural toxicants, e.g., snake bite, has been a standard of care for years. Overall, the information contained in these two chapters is worthwhile, but a more thorough description of the immunotoxicity of environmental chemicals with less reliance on clinical evaluation would have added greatly to these chapters.
The topics of immunoteratology and developmental immunotoxicology (DIT) have received significant attention in the scientific literature during the last few years, and Professor Descotes has taken the opportunity to summarize the findings of these new fields of toxicology. In this chapter the author defines these terms appropriately, and underscores the need for further research. As the author notes, there is an absence of data of chemicals and drugs that are developmental immunotoxicants, although the methods and animal models used for detection of agents that are potentially developmental immunotoxicants continues to grow. The author describes the results for several pharmaceuticals and environmental chemicals that maybe potential developmental toxicants, with the data for certain chemicals being more robust, e.g., dioxin. However, because a detailed description of this field needs further elucidation, a definitive conclusion remains somewhat elusive. Regardless, Professor Descotes provides sufficient insight into these fields of toxicology that will cause an ever greater recognition and consideration when evaluating new agents.
In the last few chapters of the book, the author proposes new methods for detection of immunotoxicants and proposes a scheme for categorization of immunotoxicants. In the chapter of emerging methods, Professor Descotes describes both in vitro and in vivo methods for detecting immunotoxicants using different cell systems and alternative animal models, e.g., transgenic animals. Furthermore, the author suggests in silico methods (immunogenomics?) as a method for considerations for the future. Professor Descotes clearly has opened a number of possible avenues when evaluating new agents for immunotoxicity in this chapter, and many of the considerations presented represent possible advances in the field. Over time, as he proposes, many of these methods will need to be validated and many of the methods represent the future in immunotoxicology.
In the last chapter, Professor Descotes recommends a means of categorizing immunotoxicants, and the scale is similar to that for carcinogens used by International Agency for Research of Cancer (IARC). To support his suggestion, the author uses six well known chemicals that have demonstrable immunotoxicity and he classifies these agents according to his scheme. There appears to be sufficient overlap in the conclusions of potential immunotoxicity with these agents such that classifying them in one category versus another appeared to be somewhat arbitrary. This reviewer is not currently convinced that categorization of an agent in terms of immunotoxicity is warranted, and the database on chemicals is not sufficiently developed that it would allow for such categorization. Regardless, Professor Descotes has taken the first step in terms of developing an acceptance criteria for classification of chemicals based on hazard and does suggest that, with time, the classification should be based on a quantitative scale, i.e., a risk-based approach.
In summary, Professor Descotes’ book on immunotoxicity provides a general and thorough overview of the topic, and the book would be worthwhile to those who do not routinely practice in the area of immunotoxicology. Although there are several shortcomings of the book, many of these shortcomings are due to the lack of immunotoxicity data for chemicals. He covers many important areas of immunotoxicity, including recent developments in DIT and the emergence of new methods and animal models for detecting immunotoxicants. The author expresses several opinions within the book that are, in the view of this reviewer, not well founded but represent the right of authorship. Finally, within each chapter, Professor Descotes includes numerous references that would prove valuable to anyone reviewing the topic of immunotoxicity. For one chapter, Professor Descotes provides over 700 references on the health consequences of immunotoxicity, and the least number of references being 15 for the chapter on classification. Clearly, the topic on immunotoxicology has been well represented by Professor Descotes.