Behavioral Evaluations in Reproductive Safety Assessments

Abstract

Since 1974, behavioral tests have been a required component of developmental toxicity studies submitted to certain regulatory agencies. Behavioral test batteries are now widely used in industry to satisfy the international regulatory guidelines for safety assessments, but the choice of the most appropriate study design(s) in which to include these tests varies. We present data for 12 pharmaceutical agents tested in two or more of 28 Segment I, II, and/or III studies. The lowest observable effect levels (LOELs) in these studies indicate that behavioral effects can occur in each study design (regardless of exposure period), and no one design is necessarily more likely to produce a behavioral effect than any other. However, in determining the most appropriate study design in which to include behavioral testing, other considerations (e.g., pharmacokinetics, dosage levels tested) are important factors. A study design suggested by a group of international scientists proposing to harmonize guidelines for pharmaceutical safety testing appears to offer the optimal study design for testing behavioral effects. This study design combines the exposure periods of the existing Segment II and III studies, with specialized behavioral safety designs conducted on an as needed, case-by-case basis to identify dose-response relationships, critical periods, the full manifestation of effects. This proposed study design and general approach are identified as the most appropriate method of evaluating behavioral effects in regulatory safety assessments.