A Practical Approach, Second Edition=Ronald D. Ho.pdf

342 DEVELOPMENTAL REPRODUCTIVE TOXICOLOGY: A PRACTICAL APPROACH, SECOND EDITIONand methanol attenuate or ablate the amplitude and alter the timing of the LH surge in the rat,thereby delaying or preventing ovulation. 23 Alteration of the LH surge in rats appears to be acommon site of vulnerability for a wide array of agents and chemistries. Most often the results ofsuch disruptions were initially observed as changes in fertility as well as changes in indices suchas fertility, ovulation, implantation efficiency, and litter size in two-generation reproductive performancetoxicity studies. Administration of a single dose of LH-disrupting agents on the day ofproestrus can produce multiple adverse reproductive outcomes. By interfering with the hypothalamicregulation of the preovulatory surge of LH, these agents accelerate the normal loss of ovariancycling in rats by inducing early onset of the normal age-associated impairment of central nervoussystem (CNS)–pituitary control of ovulation. The hormonal milieu present in the aging female ratis one of persistent estrogen secretion (from persistently developing follicles) and no secretion ofprogesterone. This milieu is the precise endocrine environment known to facilitate the developmentof mammary gland tumors in rats reported in a number of studies. 24–26 However, it is unlikely thatthis response bears relevance to humans because menopause in women results from depletion ofprimordial ovarian follicles and the subsequent decline in estrogen levels. Although inhibition ofovulation in the rat by these agents is relevant to human reproduction, effects on human fertilityare generally considered threshold-driven responses. Therefore, the benefits of drugs inducing thesechanges can outweigh the risks if a sufficiently large margin of safety can be demonstrated. Mostregulatory attention, however, focuses on the basis of carcinogenesis because it is viewed as obeyinga linear dose-response, even when the mode of action is on a reproductive process.From the previous discussion, the need for a well-conceived and conducted concordance studybecomes evident. Likewise, the complexities of such an endeavor are also obvious.III. STUDY DESIGN CONSIDERATIONSDevelopmental toxicity studies are designed to assess effects on prenatal morphogenesis, growth,and survival. These studies are generally required for all regulated agents (e.g., drugs, biologics,pesticides, industrial chemicals, food additives, veterinary drugs, and vaccines). While the studydesigns are similar for the various compounds that are tested, customized guideline requirementsare available to address unique properties and characteristics of each of the above categories. Forexample, the basic developmental toxicity study design for drugs suggests initiation of exposureeither at implantation or immediately following mating. However, administration of vaccines takesplace prior to mating to ensure that an immune response will occur during gestation. A pivotalconsideration in the evaluation of biologics is the frequent lack of demonstrable maternal internaldose. In these cases, a key pharmacologic biomarker may serve as a proxy measure of exposure.The key features to all developmental toxicity designs are: (1) that maternal exposure is sustainedthroughout major organogenesis and (2) that the dam is necropsied 1 to 2 days prior to expectedparturition so that all products of conception can be evaluated.In contrast to developmental toxicity studies, reproductive toxicity studies are designed to assessfertility and reproductive outcome. Since the advent of the 1966 FDA guidelines, 27 the testing ofmedicinal products has used a segmented approach to reflect human exposure. Because mostpharmaceuticals are administered for discrete courses of therapy, possess short half-lives, andminimally (if at all) bioaccumulate, the segmented approach using administration to a singlegeneration is appropriate. Alternatively, reproductive toxicity testing of industrial chemicals, pesticides,and food additives is intended to assess effects of low-level exposure (intentional and/orunintentional) over a significant portion of the life span that may result in bioaccumulation. Thetest animals are dosed via routes of administration that mimic human exposure. Later sections ofthis chapter provide more in-depth discussion of specific aspects of the guideline developmentaland reproductive toxicity study designs relating to data interpretation. Figure 9.4 presents a schematiccomparison of the various developmental and reproductive toxicity study designs.© 2006 by Taylor & Francis Group, LLC