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

DEVELOPMENTAL AND REPRODUCTIVE TOXICITY STUDY FINDINGS 367Table 9.20Maternal gestation body weight gain ranges, by species/strainMouse Rat RabbitEndpoint Crl:CD ® -1(ICR)BR Crl:CD ® (SD)IGS BR Hra:(NZW)SPFMean total body weight gain during gestation a (g) 24–29 122–171 434–820Mean net body weight gain during gestation a,b (g) 4–8 41–76 71–427Mean percentage of total body weight gain attributedto the products of conception75–82 55–67 47–93Note: The day of observation of evidence of mating (rodents) or artificial insemination (rabbits) was designatedgestational day 0. Approximate ages at GD 0 were 80-100 days, 12-15 weeks, and 5-7 months for mice, rats,and rabbits, respectively. Laparohysterectomies were conducted on GD 18 for mice, GD 20 for rats, and GD 29for rabbits.aGestational days 0–18 for mice, GD 0–20 for rats, and GD 0–29 for rabbits.bLean body mass of dam/doe.Source: Data tabulated from studies conducted at WIL Research Laboratories, Inc., including 10 mouse studies(1991 to 2001), 25 rat studies (1999 to 2003), and 25 rabbit studies (1998 to 2003).and clinical pathology evaluations. The onset, relationship to dose, and timing of clinical findingsof toxicity may be important factors to note, depending upon the effects observed in the developingembryos or fetuses. For example, an adverse effect on the gestating female that manifests clinicallyduring a critical developmental window could be implicated in the subsequent morphologic alterationof the offspring.In the absence of anatomic and clinical pathology evaluations and organ weight measurements,maternal body weight data (usually accompanied by food and/or water consumption data) providethe clearest measure of maternal toxicity in these studies. Thorough evaluation of maternal growthshould include assessment of body weight and body weight gain at minimum intervals of 3 to 4days throughout the treatment period, gravid uterine weight (weight of the uterus and contents),net body weight (the terminal body weight exclusive of the weight of the uterus and contents), andnet body weight change (the overall body weight change during gestation exclusive of the weightof the uterus and contents). Body weight deficits of 5% or greater that are sustained over a periodof several days are generally considered to be a signal of an adverse effect on maternal growth.Table 9.20 presents reference data from the authors’ laboratory for mean total and net body weightgain during gestation for the most commonly used species, as well as the mean percentages of totalweight gain during gestation that are due to the products of conception.Maternal food consumption should be evaluated and presented for the corresponding intervalsof body weight gain. Food consumption measurements in these studies are critical for monitoringof maternal homeostasis. Many studies have revealed an association between dietary restriction inmice, rats, and rabbits and adverse outcomes on the progeny during both gestation and lactation.Studies of dietary restriction have demonstrated that reductions in food consumption of as little as10% of the normal dietary intake (approximately 7 to 8, 20 to 25, and 150 to 200 g/d for mice,rats, and rabbits, respectively) may be associated with increased prenatal death, dysmorphogenesis,and/or growth retardation. 69–75 Therefore, reduced maternal food intake of 10% or greater in adevelopmental toxicity study may be an indication not only of maternal toxicity but also ofsecondary insult to the developing progeny. However, the extent to which dietary restriction mimicsmaternal inanition, failed weight gain, or weight loss due to compound-related toxicity is not known.Regulatory developmental toxicity studies are generally not designed to separate maternal anorexiceffects from other potential insults to the developing progeny.Despite the general correlation in various species between restricted maternal food consumptionor fasting and adverse developmental outcome, exceptions to this rule do exist. In a recent studyconducted at the authors’ laboratory, a proprietary compound that produced excessive maternaltoxicity when tested in Crl:CD ® (SD)IGS BR rats (extreme decrements in maternal food consumptionand body weight gain) at the high-dose level had no resultant (or concomitant) effect on thedeveloping progeny. At the high-dose level, mean food consumption over the treatment period (GD© 2006 by Taylor & Francis Group, LLC