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

404 DEVELOPMENTAL REPRODUCTIVE TOXICOLOGY: A PRACTICAL APPROACH, SECOND EDITIONor is a direct effect of the test agent presents its own challenges and is discussed in detail in Chapter4 of this text.C. Criticality of Accurate and Consistent Historical Control DataA comparison with the laboratory’s historical control data should be a first step toward determiningwhether a small increase or decrease (not statistically significant) in an endpoint constitutes atreatment-related effect. To illustrate this point, control mean values and ranges from over 1300litters for selected reproductive endpoints are shown in Table 9.39. These data originate from theCrl:CD ® (SD)IGS BR rat historical control database at the authors’ laboratory. Since inception ofcollecting these data for this animal model (1996), endpoints such as mean viable litter size, survivalbefore or on PND 4, total litter loss, and newborn pup weights have been found to be very consistentwhen coupled with good animal husbandry. Occurrences above or below means and ranges of theseendpoints may, therefore, indicate the threshold of a positive signal for a treatment-related effect.Live litter size and early pup viability (before PND 4) are sensitive endpoints. Neonatal deathsmay be small as a mean percentage, and a death rate exceeding approximately 5% per group shouldbe closely evaluated for a potential treatment-related effect. Likewise, a decrease in PND 1 pupweight below a mean of 6.5 g is most likely past the threshold of a positive signal. Finally, intoday’s modern facilities with good animal husbandry and highly skilled technicians, total litterloss for one or two dams in the same group probably constitutes a treatment-related effect, evenin the absence of statistical significance. These examples demonstrate the importance of creatinga historical control database and using it consistently when interpreting overall results from individualstudies.D. Case StudiesThe following discussion examines scenarios involving three different compounds that demonstratethe difficulties with rare event data interpretation and consequences that may occur if the signalsare missed in safety testing.1. DystociaTable 9.39Historical control data and values indicating a positive signalEndpoint Historical Control Positive Signal ThresholdViable litter size Mean = 14.1 ± 0.94 Decrease of ≥1Survival before/on PND 4 Mean = 95.9% ≤91%Range = 91.3%–99.3%Total litter loss Mean = 1.21% 1 is equivocal(N = 1905 litters) 2 is a stronger signalPND 1 pup weights Mean = 7.1 g ± 0.25 ≤6.5 g is a strong signalRange = 6.5–7.6 g(N = 1100 litters)Source: Data from WIL Research Laboratories, Inc. Crl:CD ® (SD)IGS BR rat reproductivehistorical control database (55 studies conducted during 1996–2002).The example shown in Table 9.40 refers to a two-generation reproductive toxicity and developmentalneurotoxicity study with a second mating phase for the F 1 generation. 136 The agent tested, octamethylcyclotetrasiloxane(D4), was used industrially as well as in over-the-counter products andwas administered via whole-body vapor inhalation. Five groups of 30 rats per sex received target© 2006 by Taylor & Francis Group, LLC