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

376 DEVELOPMENTAL REPRODUCTIVE TOXICOLOGY: A PRACTICAL APPROACH, SECOND EDITION4 Groups (of 25 Dams) × 350 Fetuses= 1400 FetusesFreehandSectionWhole-BodyMicrodissection1 /2 Skeletal 1 /2 Visceral 1 /2 Control andHigh GroupSkeletal andVisceral100% Skeletaland VisceralFigure 9.7Comparison of the number of fetuses available for visceral and skeletal examination using thefreehand section and whole-body microdissection techniques.MalformationsEarlyresorptions%AffectedLateresorptionsIncreasing doseFigure 9.8Idealized depiction of the relationship of dose and adverse developmental outcome.Wilson sectioning method requires the investigator to commit to either a visceral or skeletalexamination, but not both.Some of the rationale behind a priori subsetting of the fetuses may be defensible if theinvestigator is using a high dose of a compound that will affect at least 15% to 20% of the fetuses.However, this rationale presumes that each compound tested will evoke such a response and thatthis would be known prior to the study, which is not usually the case. Therefore, adverse effectson fetal morphology are much more likely to be overlooked if a large number of compounds aretested by the subsetting approach.Further compounding the visceral-skeletal subsetting problem is the ICH guideline–drivenoption of only evaluating control and high-dose group fetuses when no apparent effects are observedat the high-dose level. This approach assumes that any treatment-related findings that occur will© 2006 by Taylor & Francis Group, LLC