Abstract
Children’s health issues are a major concern within the regulatory community because it is suspected that immature individuals may be at greater risk for chemically induced toxicity. From a regulatory perspective, this has translated into the requirement for additional safety factors applied during environmental risk assessments or the conduct of tests specifically designed to evaluate effects following in utero, perinatal, or juvenile exposures. In some cases, all three exposures have occurred for the same chemical. Because the development of the immune system in mammals begins during gestation and continues after birth through adolescence, the immune system was identified in the mid- to late-1990s as an organ system that may exhibit a more unique susceptibility during ontological development that may not be seen if chemical immunotoxicity data are only acquired in adult animals. Participants at scientific workshops on the topic placed a high priority on the need to determine if known immunosuppressants or chemical allergens demonstrated similar effects in young animals. As with developmental and reproductive toxicology and neurotoxicology, the basic tenet here is that children differ significantly from adults in their biological and/or physiological responses to environmental exposures. These differences may be qualitative—a chemical may alter the developing immune system but not the adult immune system or may alter the developing immune system differently than it alters the adult; or these differences may be quantitative—a chemical may alter the developing immune system but at lower doses than in the adult, or with effects that are more persistent than in adults.
There are a number of drug and nondrug chemicals that are generally considered to be developmental immunotoxicants in animal models, and clearly the immune system of the developing child (the ultimate species of interest) is a continually evolving, malleable entity. However, comparative scientific data clearly demonstrating that the developing immune system does in fact show greater vulnerability to chemical perturbation than the adult immune system are still very limited. Part of the reason for this limited database may be related to our incomplete, but growing, understanding of the developing immune system, as well as the recent debate over appropriate methods for assessing developmental immunotoxicology.
The stated purpose of Holladay’s text, Developmental Immunotoxicology, is to provide an extensive (but not exhaustive) review of the available information concerning adverse postnatal consequences associated with perinatal exposure to immunotoxic compounds. In this endeavor, Dr. Holladay has succeeded. Of note, some of the information contained within this text (predominantly located in Chapters 8 to 12) formed the basis of the conclusion in the mid-to late-1990s that the developing immune system may be more sensitive to chemical perturbation. The book is divided into five parts comprising: (1) a two-chapter description of the developing immune system (rodents and adults); (2) five chapters describing animal models of developmental immunotoxicology; (3) five chapters describing chemical exposure during critical windows of immune system development and some postnatal consequences of that exposure with a focus on immunosuppression; (4) two chapters describing chemical exposure during critical windows of immune system development and the consequences of that exposure with a focus on allergy and autoimmunity; and (5) two chapters describing the impact of developmental neurotoxicity and neuro-endocrine-immune interactions on the developing immune system.
The text is appropriate for immunologists, immunotoxicologists, or those who are generally fluent in the interworkings of the immune system and the ways in which xenobiotics can impinge on the delicate balance that is the homeostatic condition. The introductory chapters (1 and 2) provide a nice general overview of the development of the immune system in the rodent and human, though clearly one must be familiar with immunology to fully appreciate or comprehend the important comparative aspects of these chapters. The overall quality of the book is good, though a few chapters could benefit from the addition of some tables summarizing the extensive studies described. The tables and figures throughout the text are easily understood with the occasional error in typesetting (e.g., Figure 7.1) and a couple missing pieces of figures (e.g., slashed/hatched/dotted lines in Figure 3.3). These do not detract, however, from the overall quality. Some of the tables and figures deserve special recognition as being of excellent value to the understanding of the topic being discussed (e.g., most tables and figures in Chapters 7 and 16). One suggestion for future editions of this book is to provide an appendix containing a glossary of terms (for the readers not as well-versed in immunology or immunotoxicology) and a listing of some comparative data on the developing immune systems of humans and other mammals (e.g., dog, pig, mouse, rat, monkey). Some of the data are contained in tables in the first several chapters, others in the text, and some data are either not currently known or was not presented here.
The strengths of this text can be found in the broad nature of the topics discussed, with an emphasis on the data supporting the hypothesis that the developing immune system can be specifically impacted by exposure to drug and nondrug chemicals. And although the majority of the research and regulatory focus in developmental immunotoxicology has been on xenobiotics that produce immunosuppression, Dr. Holladay has included a section in the book on allergy and autoimmunity. Both are “hot topics” in immunotoxicology and of significant interest to the scientific community.
Possibly one of the most valuable chapters to nonacademic readers (e.g., the industrial or regulatory toxicologist) is Chapter 3, “Risk Assessment Perspectives for Developmental Immunotoxicology.” Written from the Environmental Protection Agency (EPA) perspective, the chapter provides the reader with the most up to date thinking regarding the appropriate design of a developmental immunotoxicology study for regulatory submission. The proposed approach is consistent with the most current recommendations from scientific workshops and roundtable discussions. The authors are careful to note that the suggested study design is “proposed” and their proposal provides flexibility to do what makes scientific sense and/or what makes the best use of animal resources. Until such a time as an official “test guideline” is published (if one is published), this chapter provides reasonable guidance regarding the performance of a developmental immunotoxicology study. The authors also offer their perspective on how these data may be utilized in a regulatory context, information that is valuable to the industrial toxicologist.
The inclusion of a section (Chapters 15 and 16) on neuroimmunology seems out of place in relation to the remainder of the book, which focuses more on the traditional aspects of immunotoxicology: immunosuppression, autoimmunity, and hypersensitivity/allergy. The objective of these chapters was to provide information on the potential for immune alteration as it relates to the health status of the mother or early perinatal development. It is critical to understand that the results of developmental immunotoxicology assessments can be impacted by factors other than the chemicals being evaluated, as this impacts the interpretation of the data obtained. Unfortunately, although well-written and very informative on the subject topics, it seems these chapters miss the mark somewhat relative to the stated objective.
One thing that is not abundantly clear when reading the text is the significant impact of the exposure duration and timing relative to development to the overall interpretation of developmental immunotoxicology. This should not be seen as a criticism of the book, per say, but one of the discipline of developmental immunotoxicology in general. The impact of the data that have been accumulated over the last couple of decades may suffer somewhat from the highly variable nature of the study designs utilized and the end points selected. Some expose only on certain days of gestation—and not always the same ones. Others expose only until birth but evaluate the immune system later in life. Some utilize assays that may, or may not, be appropriate for testing during that particular critical window of development. To fully understand the potential developmental impacts of a chemical on the immune system, one needs to fully appreciate the differences in results that the same chemical can provide when different exposure scenarios are utilized. The chapter authors appear to make their designs clear, but if the reader isn’t fully cognizant of the potential impact, the value of the information provided is not fully appreciated. Also, to fully understand the relative sensitivity of the developing immune system, comparative studies are needed with similar study designs, a research gap that has been identified in recent years. A suggestion for the next edition would be a brief chapter, possibly in the first section, describing these important considerations would be beneficial.
Overall Recommendation: If you are really interested in the developing subdiscipline (pardon the pun) of developmental immunotoxicology—get it. The book as an appropriate introductory resource in that it appears to capture much of what is known currently about developmental immunotoxicology. Because of the extensive immunology terminology, it is clearly targeted at the immunologist, immunotoxicologist, or those well versed in the interworkings of the immune system. The editor has succeeded in providing an extensive review of the available information concerning adverse postnatal outcomes associated with perinatal exposure to some immunotoxic compounds. Of note, some of the information contained within this text formed the basis of the conclusion in the mid- to late-1990s that the developing immune system may be more sensitive to chemical perturbation, and the recommendation that additional scientific studies, including comparative studies between adults and the developing offspring and methodology development, were needed. The text clearly shows that although much is known, there is still much to learn about the developing immune system and the impact that drug and nondrug chemicals can have on it.
Readers are advised, however, to be keenly aware of differing exposure scenarios and experimental end points evaluated in the data provided as these have significant impact on the interpretation of the data. Readers should also be aware that there are currently no validated or widely accepted methods for evaluating the effects of a chemical on individual critical windows of the developing immune system, or for assessing a cell-mediated immunity in the developing animal. Finally, when considering human data, realize that much of the data have not been obtained under controlled situations (as is often the case with human data) or are self-reported and that both of these situations can introduce bias in the collected data.