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

DEVELOPMENTAL AND REPRODUCTIVE TOXICITY STUDY FINDINGS 411Table 9.46How maldevelopment differs from tumorigenesisNot more frequent with timeMyriad possible underlying mechanismsAmniotic banding, oligohydramnios-skull dysgenesisInterference with signaling pathways (e.g., TGF-β)MutationMaternal influences possibleMultiple endpoints interrelatedWeight alterations causing cleft palate and neural tube defectsOccurs early in life and hence greater economic and social impactTable 9.47Selected differences in developmental toxicity vs. oncogenicity endpoint ascertainmentSmaller group sizes (25 litters vs. minimum 50/sex/group)Macroscopic examination (histopathology very rare)Physical limitations based on sizeLess standardized nomenclatureNo certification of personnel, controls over training, etc.This has potentially more of an affect because of the earlier inclusion of women in clinical trialsInvolves coapt organisms (dam and fetuses)Always potential for maternal influence, but fetal effects may affect the dam as wellDynamic morphology and functionACE fetopathy exampleAnimals evaluated in the midst of changing morphologyNo two points in development are the sameExposure hourly and daily key to outcomeAn important aspect of human studiesIn these instances, the use of historical control data may be the more appropriate comparison fordetermining relationship to treatment. However, some data sets will always appear uninterpretable.In these cases, additional studies with increased dosage levels, perhaps with an unbalanced design,can be useful to confirm or refute the initial findings.3. Does increasing dose increase severity and/or incidence?Despite the concerns raised above, the presence of a dose-response relationship can provide reasonsfor enhanced concern. Slightly increased responses (relative to the control group) at the lowestexposure level and greater responses with increasing exposure provide confidence that the effectsobserved at the lowest exposure level are likely to have been related to treatment, even in theabsence of statistical significance. The proper spacing of dose levels is critical to discernment ofdose-response relationships. Because of animal-to-animal variability, differences between doselevels of less than twofold may result in overlapping of responses with increasing exposure.Conversely, dose levels too widely spread (generally greater than fivefold) will hinder characterizationof the dose-response relationship. A likely outcome of this scenario is identification of ano-effect dose and one response level; however, it is likely that no information regarding the slopeof the dose-response curve will be obtained. In either case, improper spacing of dose levels canmake identification of the threshold response level problematic.It is interesting to contrast the dose-response relationships of developmental toxicity andcarcinogenicity. The cancer endpoint (nonepigenetic) is considered to exhibit linear dose-responsebehavior, whereas most regulators consider reproductive or developmental toxicity to be a thresholdphenomenon. Both developmental defects and cancer are generally irreversible endpoints, andcertain reproductive lesions may also be irreversible. The basis for distinction between carcinogenicityand developmental toxicity is not totally rational, nor is it entirely consistent with ourunderstanding of the possible mechanisms of carcinogenicity or with the dose-response outcomesof the two. Many differences exist between these two toxicologic endpoints (see Table 9.46 andTable 9.47) that contribute variably to this distinction (linear versus threshold). Nevertheless, it is© 2006 by Taylor & Francis Group, LLC