Abstract
Haschek and Rousseaux’s Handbook of Toxicologic Pathology, since its first publication over 30 years ago, is standing the test of time as the renowned, comprehensive and definitive guide to this broad discipline both for students and practitioners alike. When the 3rd edition was published in 2013, it had already evolved into a huge 3-volume set, which at that time received a favorable expert review within the pages of this journal. 1 This first volume of the 4th edition preserves the previous format and again has 2 editors, 2 associate editors and an illustrations editor. The list of contributing authors has been expanded to over 90. These individual experts, who have been selected from academia, industry, contract research organizations and government across north America and Europe, bring collectively to the table a unique and valuable wealth and depth of relevant experience and insight. The preface indicates that the 4th edition is to be expanded to 4 volumes (Volume 2 covering “Safety Assessment” and “Environmental Toxicologic Pathology”, and Volumes 3 and 4 covering “Target Organ Toxicity). I assume that these remaining volumes to complete the new set can be expected to arrive in print shortly.
The Handbook was already a colossal work, and its growth evidently continues: The new Volume 1 alone now has over a thousand pages. The main reason for its size is the breadth of its scope, which extends far beyond the narrower discipline of veterinary anatomic pathology to include clinical pathology, drug metabolism and pharmacokinetics, animal science and more. One might question the need for such breadth, particularly when already there are other good texts that cover most of these topics individually. The editors, themselves, address this point in the introductory chapter, and propound their view that a toxicologic pathologist, particularly when aspiring to a more managerial role, should possess a much broader understanding of the related sciences as a basis for integrative skills (note that is my precis, not theirs). I happen to support this view – to me it’s consistent with the integrative concept of “pathobiology”, a term which, sadly, seems to have fallen out of vogue lately. Whatever the justification, however, there is little doubt that the Handbook manages effectively to meet this challenge of achieving both breadth and scope to bring things all “under one roof”.
The format of the new Volume 1, which conforms largely to the previous, starts with an introductory chapter followed by 4 main parts. The Introduction provides an overview of the discipline of toxicologic pathology and addresses challenges, training and the different roles within the discipline. Part 1: “Principles of Toxicologic Pathology” (Chapters 2-8) covers ADME and PK, pharmacodynamics, toxicokinetics, reproductive, developmental and juvenile toxicology, and carcinogenesis. Part 2: “Methods in Toxicologic Pathology” (Chapters 9-16) deals with anatomic and clinical pathology, special techniques, digital pathology, in vivo imaging, biomarkers, toxicogenomics, experimental design and stats. Part 3: Animal and Alternative Models in Toxicologic Research” (Chapters 17-24) covers the animal test species and transgenic models in impressive detail and addresses the relevance and utility of animal models and in vitro alternatives. Part 4: “Practice of Toxicologic Pathology” (Chapters 25-29) addresses anatomic pathology nomenclature, pathology peer review, GLPs and quality control, reporting of pathology data and the currently relevant issues in animal science.
Regarding the quality and readability of the new volume (I reviewed the e-book version), I found the format orderly and logical, the contents clearly and concisely worded and the print clearly legible throughout. The liberal use of cross references to other chapters (in blue text) on overlapping topics is also helpful. I particularly like the illustrations: Their quantity seems just right, and they clearly convey the intended messages. What I found a drawback, however, is the absence of electronic links from the Contents section to the text and from the cross references to overlapping topics and to the references. Maybe I have become spoilt by the links now routinely provided within toxicity study reports. Nonetheless, this lack of links makes it very laborious to navigate the book, especially given its size (the Contents section alone consists of 13 double-column pages!). I suggest that the publishers could achieve a valuable quick-win improvement by installing the links.
Importantly, what is new here that would justify buying the 4th edition of Volume 1 and discarding the old? This is, of course, the leading question in assessing any new edition. Firstly, have the existing chapters been thoroughly revised and updated with the new scientific literature published during the nine intervening years? Having scoped all chapters, my answer is a clear “yes”: the literature citations include recent reviews and primary papers the content of which has been well integrated throughout the book. Secondly, what new chapters and topics have been added? I paid particular attention to areas where there has been explosive growth in the past decade: methodologies, toxicogenomics, new biomarkers, the biome and digital pathology, to name just a few. Again, I was satisfied with the abundance of new material, carefully reviewed and assessed, in all these areas. New chapters also caught my attention: I particularly recommend the one on ADME of biopharms, which I found highly instructive, finely illustrated and very relevant to my own consultancy (which, in tune with the industry at large, reflects the ever-growing preponderance of biopharmaceutical agents). Another new chapter ably deals with reproductive and developmental and reproductive toxicology (DART) and also covers juvenile animal studies (particularly important now with the recent evolution of regulatory guidances and notably ICH S11. 2
Could I find any imperfections? I decided to trouble-shoot by probing the topic of reactive metabolites (a field with which I happen to be quite closely current through recent consultancy work). The topic was nicely and succinctly reviewed. However, I did notice that a recent review expressing an important school of thought and a couple of papers on new assessment methods had not been included. Perhaps it was not fair play to delve into a “cherry-picked” topic in such fashion and, indeed, I don’t believe it realistic to expect perfection for any book of this size. I was also somewhat disappointed that two recent and important milestone regulatory releases had not been mentioned. One relates to carcinogenesis (Chapter 8, Section 3.8), which discusses the future outlook for rodent carcinogenicity studies. In this context, the draft amendment to ICH S1A, which lays provision for a possible waiver for a 2-year rat study based on a weight-of-evidence assessment, was issued back in May of 2021. Therefore, I was disappointed that it had not been included. Maybe, however, I am underestimating the lead time necessary to prepare and publish such a large book. The other example relates to whole-slide imaging in digital pathology (Chapter 12, Section 2). In that context, an important new FDA draft guidance has recently been issued. In this latter example, the issue was too recent to be included, 3 and so it is not a criticism, but rather illustrates the impossibility for any textbook to keep completely current. On a more positive note, the next decade, and indeed probably only the next 5 years, will likely provide enough important new material for a 5th edition of this classic, to which I look forward!
In conclusion, I find this new edition thoroughly and expertly revised and updated. The editorial staff deserves high praise for managing effectively to organize and orchestrate such a magnum opus, which involved so many contributors. I can confidently recommend its purchase to students as a staple one-stop-shop instructional guide and as a helpful reference source for practitioners of toxicologic pathology.