Abstract
This book is the second volume in the first edition of the Molecular and Integrative Toxicology collection. The editor of the overall series is Rodney R. Dietert who also coedited the first volume with Robert W. Luebke entitled Immunotoxicity, Immune Dysfunction, and Chronic Disease.
The stated goal of the text is “to provide a concise reference addressing ocular anatomy and physiology across species, approaches for assessing ocular toxicity and regulatory expectations regarding ocular toxicity.” For the most part, the editors and chapter authors have successfully achieved this goal. The text is targeted toward “toxicologists and other scientists involved in conducting toxicology studies for regulatory purposes and/or reviewing data from such studies.”
The text is well organized, with the first chapter providing a brief but well-referenced primer on the comparative anatomy of the eye and ocular adnexa (extraocular tissues) of common laboratory species. Further chapters guide the reader through basic techniques of in-life ocular examination, including the common use of direct and indirect ophthalmoscopic instruments, photographic, tonometric, and electrophysiological devices as well as stationery and portable slit-lamp biomicroscopes. There are 2 chapters that discuss toxicologic pathology of the eye, with 1 covering histologic preparation and alterations of the anterior segment and the other describing alterations of the lens and posterior segment. The final 2 chapters are devoted to regulatory aspects dealing with nonclinical ocular testing.
The chapter on basic theory and techniques for assessing ocular toxicity potential provides general but practical guidance that can be useful in developing protocols and making the critical decisions necessary when determining the instruments to be used and the parameters to be examined during the in-life baseline, interim (if appropriate, depending upon the duration of the study), and terminal assessments. The color slit-lamp photographs presented in this chapter, illustrating the effects of using both diffuse and narrow-beam lighting, provide the reader with a clear demonstration of the usefulness of this equipment for biomicroscopic visualization of corneal and lenticular lesions. Color images of the ocular fundus of various species including rat, rabbit, dog, and primate show excellent examples of the appearance of the retinal vasculature, optic disk, and macula, including several types of normal variations and lesions that can be distinguished during in-life examinations in nonclinical studies. Photographic documentation of ocular changes serves as an aid in the assessment of progressive or regressive changes over time and a valuable component of toxicology study records. The authors acknowledge, however, that the primary factors such as the constraints of examination time and the need to minimize stress in subject animals generally limit ocular photography to special studies and/or individual examples of the types of lesions observed.
The chapters on emerging imaging and electrophysiological technologies for assessing ocular toxicity provide fascinating descriptions of a broad range of diagnostic instruments that were primarily developed within the past few decades and have been increasingly enhanced and adopted for use by veterinary clinicians. These chapters provide emphasis on the value of computerization for imaging and analysis. The advantages and limitations of each of the modern devices are clearly explained and well-illustrated through photographic examples and figures.
The discussions of toxicologic pathology of the eye deal with histologic preparation, alterations of the ocular adnexa, and histopathology of the anterior segment (chapter 5) as well as histopathology of the lens and posterior segment (chapter 6). Both of these sections of the book are particularly well referenced, with over 300 citations in the fifth chapter and nearly 200 in the sixth chapter. The discussions of changes that may be spontaneous or iatrogenic, rather than induced by drug or chemical treatment, are briefly highlighted in both the chapters. It potentially would have been even more instructive for readers, however, if a thorough and definitive discussion of species and strain-specific and commonly found incidental and age-related ocular lesions were presented in a separate chapter dedicated to this subtopic. As virtually all toxicologists are aware, it is critically important to differentiate structural and functional changes in laboratory animals that are directly related to treatment with a test article as opposed to those that are induced by environmental, dietary, genetic/congenital or age-related factors.
The book breaks down regulatory considerations for nonclinical ocular testing into 2 separate chapters, that is, 1 for ophthalmic drugs and the other for testing Food and Drug Administration (FDA) nondrug and Environmental Protection Agency (EPA)-regulated chemical and pesticide products.
The section devoted to nonclinical regulatory considerations for the development of ophthalmic drugs and related delivery systems leads the reader through a variety of factors that determine appropriate toxicity testing programs and evaluative methods. The various regulatory processes are described, and the corresponding technical guidelines are referenced for more detailed instruction.
The chapter on ocular regulatory considerations for nondrug products provides a useful summary table of corresponding guidelines for primary eye irritation testing criteria recommended by Federal agencies. The text of this chapter briefly discusses regulatory guidances (by the FDA) for cosmetic products under the Food, Drug, and Cosmetic Act; consumer products (by the Consumer Product Safety Commission) under the Federal Hazardous Substances Act; pesticides (by the EPA) under the Federal Insecticide, Fungicide and Rodenticide Act (FIFRA); and industrial chemicals (also by the EPA) under the Toxic Substances Control Act (TSCA). This chapter is limited to assessment of ocular irritation testing for premarket hazard classification. Much emphasis is placed on the continued reliance by the Federal agencies on adaptations of the Draize rabbit eye irritation test, which was developed and published nearly 70 years ago. While acknowledging ongoing attempts to replace the Draize test through the development and validation of alternative, in vitro systems, the author states that the Draize test “is the only acceptable ocular toxicity test for regulatory purposes and is the standard that all regulatory agencies use for evaluation of ocular toxicity hazard.” From a seemingly more progressive perspective, this chapter goes on to state “In fact, many cosmetic companies use in vitro testing to substantiate the ocular safety of cosmetic products. This is different than substances (eg, pesticides) that require premarket registration in which they must submit mandated test data for review by the EPA agency and, therefore, Draize eye testing is necessary.” This is certainly true for most premarket registrations. It should have been noted, however, that there is a subset of end-use products regulated by EPA as pesticides that have successfully gained premarket registration without resorting to the use of Draize testing; that is, over the past decade, insect repellent formulations have been approved by EPA under FIFRA through the reliance on in vitro eye irritation studies. Within this chapter, the sections on ocular testing of EPA-regulated pesticides and industrial chemicals under FIFRA and TSCA, respectively, handle these topics only in a very superficial manner. Coverage is given solely to primary eye irritation assessment and corresponding hazard classification and labeling schemes based on acute topical exposure to the eye. There is no mention of observations appropriate for gauging ocular effects resulting from systemic toxicity. The EPA (Office of Chemical Safety and Pollution Prevention) and Organization for Economic Cooperation and Development guidelines for repeated-dose subchronic and chronic general toxicity studies of active pesticide ingredients and industrial chemicals call for ocular assessment using an ophthalmoscope or “equivalent” instrument during the in-life phase for evaluation of systemic changes. The EPA guidelines also specifically require histological examination of the retina and optic nerve. The lack of discussion of these considerations for regulatory ocular testing requirements is disappointing.
The utility of any reference book depends to a significant degree on the thoroughness of its Index for direct and easy access to information on more narrowly defined topics within the broader range of the overall text. The index to this volume clearly meets this task. Likewise, all of the eight individual chapters in this book are replete with citations.
The text is very well illustrated, with 45 black-and-white and 75 color plates as well as 36 tables. Some readers, like this reviewer, may find the small font size a bit challenging.
Notwithstanding the few noted shortfalls, this book provides an excellent survey of nonclinical laboratory practices in ocular toxicology. I consider it to be a valuable reference for all nonclinical research toxicologists, pharmacologists, veterinarians and laboratory animal care technicians with an interest in ophthalmology.