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

348 DEVELOPMENTAL REPRODUCTIVE TOXICOLOGY: A PRACTICAL APPROACH, SECOND EDITIONduring the late fetal period appeared initially in the 1978 guideline, was later deemphasized in the1982 FIFRA and 1984 Toxic Substances Control Act (TSCA) guidelines, and was reintroducedunder the OPPTS 870.3800 guidelines in 1998.In addition to the guidelines for conduct of developmental and reproductive toxicity studies,the EPA has provided guidance documents to aid in interpretation and risk assessment of the dataderived from these studies. 39,40 These risk assessment guidelines represent the best effort thus farat codifying and documenting a thorough approach to risk assessment for the discipline.B. SpeciesIdeally, the principal factor in selecting the test species for developmental and reproductive toxicitystudies would be that they respond to toxicity in the same manner as humans. That is not possible,so historically, animal models were not selected for any reasons other than size, availability,economics, fecundity, and (probably) not appearing too anthropomorphic. The rat, mouse, andrabbit have fortunately proven to be acceptable surrogates, and the advent of higher-quality PKand TK studies has improved the utility of these models. On a scientific basis, and assuming theaforementioned, several key attributes of these models include the following: (1) basic physiologyand anatomy that are known or well-studied, (2) similar PK and TK profiles with humans, (3)comparable PD, and (4) in the absence of such information, apparently sufficient similarities inanatomical structure and reproductive physiology to permit comparison with humans. The prevailingassumption is that mammalian systems are most appropriate. The ideal test system would be easilymaintained in a laboratory environment, possess significant fecundity, display stable reproductiveindices, be polytocous, have a relatively low historical incidence of spontaneous structural malformations,and have other characteristics suitable for evaluating significant numbers of chemicalentities cost effectively. The rat is often preferred because the endocrinology and reproductivephysiology of this species have been thoroughly studied. In addition, general pharmacology modelshave been fully validated in the rat. Typically, animal models should be nulliparous becauseconfirmation of pregnancy in previously gravid females is frequently problematic (because ofimplantation scars). However, in the case of the rabbit and dog, use of proven breeders can lend stabilityto the reproductive indices. For most product development efforts, the rat or mouse is selected initially,but another relevant and presumably susceptible species is typically required. Alternatives include therabbit, guinea pig, hamster, dog, and nonhuman primate. Perceived advantages and disadvantages ofeach model are listed in Table 9.11 (enhanced from the ICH testing guidelines).In assessment of developmental toxicity data, the investigator must be cognizant of a keydifference in reproductive physiology among rodents (particularly rats), rabbits, and humans.Prolactin mediates maintenance of early pregnancy in the rat, unlike the rabbit and human. In thecase of the rabbit, progesterone secreted from the corpus luteum sustains maintenance of pregnancy.The fundamental control in the human and rabbit changes with advancing pregnancy to control viathe fetal-placental unit. This feature of endocrinology may predispose the rabbit to a higher riskof postimplantation loss and abortion when only a few implantations and limited hormonal signalingexist to maintain luteal function. This concept is illustrated by the data presented in Table 9.12. Of60 control rabbits evaluated at laparohysterectomy that had a single implantation site, 26 (43.3%)had completely resorbed litters while 6 additional rabbits (10.0%) terminated pregnancy prematurelyvia abortion. The remaining 28 animals had normal reproductive outcomes. Animals with twoimplants also were at high risk for abnormal reproductive outcomes. There was less associationbetween number of implantation sites and abnormal reproductive outcome in cases where theintrauterine contents consisted of three to five implants. Rabbits with greater than five implantsusually have no difficulty maintaining pregnancy to term. Therefore, when interpreting the significanceof abortion rates and total litter loss in compound-treated rabbits, the data must be evaluatedin light of the number of embryos that were implanted in the uterus following fertilization.© 2006 by Taylor & Francis Group, LLC