Combined Studies

While a developmental immunotoxicity study could be conducted as a standalone study, there are a number of reasons to consider a combined study design, which incorporates immunotoxicity endpoints into another study protocol. A combined study avoids the conduct of a separate developmental immunotoxicity study (thereby reducing the number of animals required for testing), provides an opportunity to more efficiently utilize offspring that are already in a study, and often maximizes exposure to the developing organism. For example, immunotoxicity assessments could be incorporated into a multigeneration reproductive toxicity study. This study includes test substance exposure to developing animals during in utero and postnatal life stages, coinciding with the ontogeny of the immune system. Publications by Chapin et al. (1997) and Smialowicz et al. (2001) have demonstrated success in conducting such combined studies. Protocol adjustments that must be addressed when attempting to incorporate immunotoxicity testing of offspring into a reproduction study are not extensive. A separate subgroup of either F1 or F2 offspring, other than those already designated as parental animals for the second generation or as subjects for other extensive postmortem or extended in-life evaluations, must be assigned to the developmental immunotoxicity study phase. In order to ensure an adequate population from which to select offspring, it may be necessary to retain five pups/sex/litter (rather than four pups/sex/litter) when standardizing litter size on day 4 of lactation. Developmental immunotoxicity testing requires termination of offspring at PND 42; therefore, pups that are designated for these procedures must be retained on study past the time of weaning. Care should be taken to ensure that exposure to the offspring is adequate throughout the pre- and postnatal dosing periods since lack of exposure during these critical periods of immune system development could limit the study. It is not sufficient to simply rely on an unsubstantiated assumption that test substance administration to the dam automatically results in transplacental exposure to the offspring during gestation and exposure in the milk during lactation (which is an approach that is often taken with multigeneration reproduction studies). The uses of pharmacokinetic data to more fully characterize the dose during each life stage and to refine the exposure methodology, if necessary, could define the difference between a developmental immunotoxicity study that is scientifically defensible and one that is not.

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