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

DEVELOPMENTAL AND REPRODUCTIVE TOXICITY STUDY FINDINGS 385and cost of the study are typically greatly increased, reproductive toxicity studies using suchalternative species are only rarely performed.2. Timing and Duration of TreatmentThe EPA, OECD, and FDA food additives requirements for reproductive toxicity studies aredesigned to assess the effects of long-term exposure, while the treatment periods for drug studiesare much shorter and less comprehensive. The rationale behind the long-term exposure regimensemployed by the EPA and OECD is to mimic the ambient, low-level, long-term exposures toindustrial chemicals in the workplace and to low-level residues of pesticides in the diet. Similarly,exposure to food additives may occur over a lifetime. In contrast, treatment during defined stages(phases) of reproduction in the ICH guidelines generally better reflects human exposure to medicinalproducts and allows more specific identification of stages at risk. In the EPA, OECD, and FDAmultigeneration studies, both generations of parental animals are exposed prior to mating andthroughout the mating, gestation, and lactation periods in the rat. The ICH studies are divided intothree segments: (1) fertility assessment, (2) embryo-fetal development assessment, and (3) pre- andpostnatal development assessment. Within each of the ICH segments (phases), the direct exposureperiod is also more limited than is required in the EPA and OECD study designs. For example, a10-week premating period is recommended for the EPA, OECD, and FDA multigeneration studies,while the premating period in the ICH fertility study is generally only 4 and 2 weeks for the malesand females, respectively. In a collaborative study of 16 compounds, the shorter premating maleexposure period for ICH studies was found to be appropriate for detection of drug effects on malefertility. 98 In that collaborative study, the 4-week premating period was found to be as effective asa 9-week premating period for identification of male reproductive toxicants, albeit in a limited setof agents. In addition, exposure ends at the time of implantation in the ICH fertility study butcontinues throughout the entire gestation and lactation periods in the EPA, OECD, and FDAmultigeneration study. Unlike the EPA, OECD, and food additive multigeneration studies, exposureof offspring following weaning cannot be assumed in the ICH pre- and postnatal study.Because of the short premating treatment regimen in the ICH fertility study, compound administrationdoes not begin until the rats are 8 to 9 weeks of age, which is after puberty has occurred.This is in contrast to the EPA, OECD, and food additive design in which direct F 1 exposure beginsat weaning (prior to sexual maturation) and F 0 exposure begins typically at 5 to 9 weeks of age,during the process of sexual maturation in the females and prior to maturation in the males.Another difference among the guidelines is that only the OECD requires adult thyroid weightevaluation. This is a surprising omission from the food additive and EPA guidelines because of therole of the thyroid in development and sexual maturation, recent welling concerns for endocrinemodulation, and questions and concerns regarding the thyroid toxicity of ammonium perchlorate.99,100B. Interpretation of Reproductive Toxicity Study EndpointsIn this section, the endpoints listed in Table 9.34 (male-female or coupled) for evaluating reproductivetoxicity are discussed. These endpoints are listed first in approximate chronological orderof collection and then ranked by approximate sensitivity of the endpoints (those endpoints that arebolded may be assessed in and/or appropriate for evaluation in humans). In this ranking, endpointsconsidered most sensitive are those that are most often affected in general or those most oftenaffected by lower doses of xenobiotics. In the following sections, discussion of Crl:CD ® SD(IGS)BR rat historical control data for reproductive toxicity endpoints is based on the database compiledin the authors’ laboratory. Unless specifically noted otherwise, these data originate from 55 studies(92 separate matings) conducted during 1996 to 2002.© 2006 by Taylor & Francis Group, LLC