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

370 DEVELOPMENTAL REPRODUCTIVE TOXICOLOGY: A PRACTICAL APPROACH, SECOND EDITIONAn additional factor that must be considered for rat developmental toxicity studies is the numberof females per treatment group with an increased number of resorptions. Table 9.23 presents themodal distribution of the total numbers of females with resorptions in the authors’ Crl:CD ® (SD)IGSBR rat historical control database. These data indicate that an increase in the number of femalesthat have three or more resorptions is a signal of developmental toxicity.c. Prenatal GrowthThe most sensitive and reliable indicator of an alteration to intrauterine growth is a reduction infetal body weight. Fetal body weight collection in developmental toxicity studies occurs on theday of laparohysterectomy, generally GD 18, 20, and 29 for mice, rats, and rabbits, respectively.These time points represent the day prior to the expected day of delivery for each species.The consistency of fetal body weights, particularly for the rat model, has enabled investigatorsto censor those data that resulted from erroneous determination of evidence of mating. Incorrectassessment of the timing of mating in the Crl:CD ® (SD)IGS BR rat, even if only displaced by 24hours, may result in mean litter weights greater than 5.0 g (compared with the normal weight of3.6 g on GD 20). When evaluated against the considerable historical control database compiled inthe authors’ laboratory, the conclusion is that the fetuses are actually 21 or 22 days old, as opposedto the intended age of 20 days. In these presumably rare cases, the heavier litters should not beincluded in the group mean.A mature historical control database provides the best means of gauging the reasonableness ofa group mean fetal body weight (presented on a litter basis). It has been the authors’ observationsthat in mature historical control databases, the range of variation for control rat fetal body weightsis only 0.3 to 0.6 g, depending upon the sex and strain evaluated (see Table 9.24). In rabbits thisvariation is greater, but it is still small enough to enable consistent interpretation of study results.Furthermore, male fetal body weights are typically greater than female fetal body weights for themost commonly used species.d. Fetal Sex RatioTable 9.23Resorptions(No.)Modal distribution ofresorption rates inCrl:CD ® (SD)IGS BR ratsFemales(No.)0 7881 4472 1613 354 95 26 27 38 09 110 111 1Total 1450Source: Data tabulated from 61 Crl:CD ®(SD)IGS BR rat studies (1998–2003) conductedat WIL Research Laboratories, Inc.The sex ratio per litter, evaluated in conjunction with mean fetal body weights for males andfemales, may reveal whether or not the test agent preferentially affects survival of a particular© 2006 by Taylor & Francis Group, LLC