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

DEVELOPMENTAL TOXICITY TESTING — METHODOLOGY 251j. Transitional FindingsThese may be upgraded to “malformation” or downgraded to “variation” status, depending onseverity and/or frequency of occurrence.• Nonlethal and generally not detrimental to postnatal survival• Generally irreversible• Frequently may involve reduction or absence of nonessential structures, e.g., innominate artery• Frequently may involve reduction in number or size (if extreme) of nonessential structures or mayinvolve their absence• Exhibit a dose-dependent increased incidencek. Variations• Nonlethal and not detrimental to postnatal survival• Generally reversible or transitory, such as wavy rib or the reduced ossification in a cephalocaudalsequence frequently seen associated with immaturity or delayed development as result of toxicity,e.g., reduced ossification in fore- and hindpaws, caudal vertebrae, pubis (but usually not ilium orischium), skull plates, sternebrae (especially 5, 6, 2, or 4, in that order), cervical centra (especially1) 126• May occur with a high frequency and/or not exhibit a dose-related increased incidence, e.g., reducedrenal papilla and/or distended ureter in CD ® rat fetuses at term, 127 dilated lateral cerebral ventricles(in rodents), extra ribs (on lumbar vertebra I) in rat and rabbit fetuses• Detectable change (if not extreme) in size of specific structures (subjective), e.g., renal papillaone-half to one-quarter normal width; spleen greater than 1.5 times normal; kidney less than onehalfnormal size, kidney two times normal size; liver lobe less than one-half or up to 2 timesnormal size.A profile of recent historical control data from the authors’ laboratory of developmental toxicitystudies on CD ® rats, CD-1 ® mice, and New Zealand White rabbits is presented in Table 7.6. Thesetest animal species exhibit characteristics that maximize their usefulness for such studies, such as:• High pregnancy rate with very low levels of spontaneous full litter resorptions• Large litters (total implants) with low preimplantation loss• Large live litters with low postimplantation loss• Approximately equal sex ratios in fetuses• Consistent fetal body weights• Low malformation rates• Reasonable variation rates (high enough to provide sensitivity to test agents that increase theincidence of variations and/or exacerbate the variations to malformations; low enough to allowdetection of treatment-related increases)The interpretation of fetal findings requires a “weight of the evidence” approach (examplesfollow). If the incidence of fetal malformations is increased at the middle dose but not at the highdose, but the in utero mortality is highest at the high dose, then it is likely that the most affectedconceptuses at the high dose died, especially with the prolonged dosing period specified in the newguidelines. In this case, the lack of a dose-response pattern is spurious, and an umbrella parameterlike affected implants (nonlive plus malformed) will indicate the real dose-response pattern.In the presence of reduced fetal body weights, it is typical to observe increased incidences ofreduced ossification, especially in the skeletal areas that ossify last in utero, such as sternebrae V andVI of the prenatal sternum, bipartite or dumbbell ossification sites in the thoracic centra, and anteriorand posterior phalangeal segments of the paws. 58 Reduced fetal body weights are commonly associatedwith dilated renal pelves (a delay in growth of the renal papilla; 98 and/or dilated (enlarged) lateralventricles of the cerebrum without compression of the cerebral walls (again a delay in growth). 57© 2006 by Taylor & Francis Group, LLC