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

284 DEVELOPMENTAL REPRODUCTIVE TOXICOLOGY: A PRACTICAL APPROACH, SECOND EDITIONstudies may be undertaken when the registrant believes that the toxicity observed in a generaltoxicity screening study is species specific and not relevant to humans. These studies are designedto address specific issues and/or class effects, and do not necessarily involve large numbers ofanimals or long exposure periods. They do not generally include many endpoints; however, thoseparameters that are evaluated are typically much more closely examined than would be the casein a general toxicity screen. For example, in a study designed to examine the toxic potential of theangiotensin converting enzyme inhibitor, ramipril, 16 rat pups per sex per group were administeredthe test article on one of two discrete days during development (PND 14 or 21). Clinical chemistrieswere assessed together with macroscopic and microscopic examination of several organs 3 or 14days later. 92 In addition, the pharmacokinetic profile of the parent and metabolite were evaluatedon the days of dose administration. Although only limited numbers of animals were used (8 persex per group per age at necropsy), statistically significant changes in renal structure and functionwere noted, and dramatic differences were observed in the exposure of the juvenile rats to boththe parent molecule and metabolite when ramipril was administered on PND 14 or 21.B. Model SelectionSelection of the animal model is based on the study objective, the available data for the test articlein the model, the availability of historical control data, and the experience of the researcher andtesting laboratory with the model chosen. Several key factors must be considered when selectingthe animal model to be used in a juvenile toxicity study. These factors include the species, age,sex, sample size, and relevance to human development. 511. SpeciesA majority of nonclinical juvenile studies utilize the rodent as the animal model of choice for anumber of reasons. For adapted adult toxicity studies, the animal model is dictated by basic guidelinerequirements for the standard study, which in most cases tends to be the rodent. Moreover, ratsand mice are well characterized with regard to growth and development, given the large numberof reproductive, developmental, and general toxicity studies that have been conducted with thesespecies. However, very little historical control data, such as the ontogenic profile of clinicalchemistry parameters (refer to Table 8.3 for one example in rats) or the microscopic changes thatoccur in many organ systems during development, are available for more traditional toxicityendpoints in developing animals.Despite the paucity of historical control data for traditional toxicity endpoints in the developingrodent, there is a greater breadth of literature regarding the developmental changes that occur inthe rodent than in other species selected for juvenile toxicity testing (e.g., dog, swine, and nonhumanprimate). Furthermore, if the intent is to administer the test article during the period of adolescentdevelopment, larger animal species will typically require much longer exposure periods than therodent, given the longer developmental spans of larger species. Dog, swine, or nonhuman primatestudy designs also require more test article, housing space, technical involvement, and socializationthan a comparable rodent study. However, large animal models afford some key advantages in anonclinical juvenile study. For example, the larger circulating blood volume in these speciesprovides the opportunity to evaluate changes in clinical chemistry parameters very early in developmentand repeatedly over time in the same animal; longitudinal assessments of standard clinicalchemistry panels are extremely difficult, if not impossible, to conduct in rodents, because of thesmall circulating blood volume.2. Sample SizeThe number of animals required for a nonclinical juvenile toxicity study entails a balance betweenachieving the statistical power required to detect potentially adverse outcomes and the logistical© 2006 by Taylor & Francis Group, LLC