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

DEVELOPMENTAL AND REPRODUCTIVE TOXICITY STUDY FINDINGS 377Table 9.27Advantages of fresh dissection of fetusesProsectors are more easily trained.Good visualization with less chance of missing a cleft, breach, or absence of structures (e.g., valve in heart),because of thickness and perpendicularity of cross-section of the sample.Direct visualization of structures, as one would learn in anatomy, instead of having to rotate images mentally inthree dimensions.Coloration (organs, vessels, tissues).Direct ascertainment of vessel patency by tactile manipulation of vessels to determine patency and if blood is moving.Evaluation of vascular tissue perfusion by coloration.All fetuses can be examined for both soft tissue and skeletal changes.Avoids the difficulty of sectioning every fetus in exactly the same way as is needed to ensure comparability ofviews among fetuses.Decreased probability of creating artifacts due to fixative tissue shrinkagebe discernible in the high-dose group (refer to Section VII for a further discussion of the dangersinherent in this assumption). The statistical power of these studies is already low relative toextrapolation to the human population, and when the dosage group has already been subsetted priorto evaluation, the probability of detecting treatment-related effects declines dramatically. Therefore,the authors conclude that morphologic evaluation of all fetuses by use of the fresh dissection methodis the most powerful approach for developmental toxicity studies, yielding the most conclusiveresults for hazard identification.c. Relative Severity of Findings (Malformations vs. Variations)A critical first step in fetal morphologic evaluation is determining the relative severity of thealteration. This determination is complicated by the potential continuum of responses betweennormal and extremely deviant fetal morphology. Fetal dysmorphogenic findings have been reportedas developmental deviations, structural changes, malformations, anomalies, congenital defects,anatomic alterations, terata, structural alterations, deformations, abnormalities, anatomic variants,or developmental variations, with little consistency across laboratories in definition of the terms.The current authors have chosen to report, and accordingly define, these external, visceral, andskeletal findings as either developmental variations or malformations. Variations are defined asalterations in anatomic structure that are considered to have no significant biological effect onanimal health or body conformity and/or occur at high incidence, representing slight deviationsfrom normal. Malformations are defined as those structural anomalies that alter general bodyconformity, disrupt or interfere with normal body function, or may be incompatible with life.d. Presentation of FindingsFetal morphologic findings should be summarized by: (1) presenting the incidence of a given findingboth as the number of fetuses and the number of litters available for examination in the group and(2) considering the litter as the basic unit for comparison and calculating the number of affectedfetuses in a litter on a proportional basis as follows:whereSummation per group (%) =Σ viable fetuses affected per litter (%)Number of litters per groupViable fetuses affected per litter (%) =Number of viable fetuses affected per litterNumber of viable fetuses per litter× 100© 2006 by Taylor & Francis Group, LLC