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

TESTING FOR REPRODUCTIVE TOXICITY 459B. ObservationsThere are three basic types of observations — a viability check, a clinical observation, and anextended or detailed clinical observation — which are performed as described above for males.C. Female Body WeightBody weights are recorded daily, twice weekly, or weekly, depending upon the guideline requirementsand reproductive phase (premating, gestation, or lactation). During cohabitation and gestation,body weights are recorded daily or at protocol-specified intervals (e.g., GD 0, 6, 9, 12, 15,18, and 20). Maternal and pup body weights in the lactation or postnatal period are usually recordedweekly (PND 0, 7, 14, 21). Food consumption during gestation is usually recorded at the sameintervals as body weights. Body weights and food consumption should be recorded at approximatelythe same time of day during the course of the study. Monitoring female body weight during treatmentprovides an index of the general health status of the animal that may be relevant in the interpretationof reproductive effects. Female body weight fluctuates normally because estrogen and progesteroneinfluence food intake, energy expenditure, 117 water retention, and fat deposition rates. 118,119 Reductionin food intake and body weight in the female rat is one of the most sensitive noninvasiveindicators of an estrogenic compound. In addition to endocrine-related factors, body weight lossor reduction in body weight gain can be caused by other factors, including systemic toxicity, stress(such as restraint), treatment-induced anorexia, or decreased feed or water consumption due toaltered palatability caused by the test substance.Unless a direct causal link between the observed female reproductive effect and decreased bodyweight or body weight gain can be established, female reproductive system alterations should beconsidered an adverse effect and not secondary to the occurrence of systemic toxicity. Therefore,in the presence of mild to moderate body weight changes, alteration in a female reproductivemeasure should be considered an adverse female reproductive effect. In the presence of severebody weight change, it can be stated that an adverse effect on a female reproductive endpointoccurred, but the effect may have resulted from a more generalized toxic effect.D. Female Necropsy1. Gestation Day 13 Uterine Examination (Segment I Studies)The dams are routinely necropsied around GD 13 (early in the second half of gestation). The damis euthanized, and the uterine contents are examined (as described below). Uterine position andviability (live or dead) of each implant is recorded, as are the corpora lutea counts from each ovary.The dam is subjected to a complete necropsy, and the reproductive organs and other tissues specifiedin the protocol are weighed and saved for possible histopathological evaluation. Certain guidelinesrequire termination on GD 20 or 21 (term Cesarean section).2. Gestation Day 20 or 21 Term Cesarean Section (Segment II Studies)The dam is euthanized, the uterus is removed and weighed (recorded as gravid uterine weight),and the uterine contents are exposed. The number and uterine position of each resorption (early orlate) and/or fetus (viable or dead) are recorded. The number of corpora lutea from each ovary iscounted and recorded. The individual term fetuses are removed from their membranes, and theumbilical cord is clamped and cut. Each placenta is examined and weighed, if required, or discarded.The empty uterus is weighed and the value recorded. Tag, box position, or other suitable means ofidentification individually identifies each fetus. The fetus is examined externally for any abnormalities,sexed, and weighed. Abnormalities are classified as either malformations or variations. A© 2006 by Taylor & Francis Group, LLC