Developmental toxicology: new directions workshop: refining testing strategies and study designs

Abstract

In April 2009, the International Life Sciences Institute (ILSI) Health and Environmental Sciences Institute's (HESI) Developmental and Reproductive Toxicology Technical Committee held a two-day workshop entitled "Developmental Toxicology-New Directions." The third session of the workshop focused on ways to refine animal studies to improve relevance and predictivity for human risk. The session included five presentations on: (1) considerations for refining developmental toxicology testing and data interpretation; (2) comparative embryology and considerations in study design and interpretation; (3) pharmacokinetic considerations in study design; (4) utility of genetically modified models for understanding mode-of-action; and (5) special considerations in reproductive testing for biologics. The presentations were followed by discussion by the presenters and attendees. Much of the discussion focused on aspects of refining current animal testing strategies, including use of toxicokinetic data, dose selection, tiered/triggered testing strategies, species selection, and use of alternative animal models. Another major area of discussion was use of non-animal-based testing paradigms, including how to define a "signal" or adverse effect, translating in vitro exposures to whole animal and human exposures, validation strategies, the need to bridge the existing gap between classical toxicology testing and risk assessment, and development of new technologies. Although there was general agreement among participants that the current testing strategy is effective, there was also consensus that traditional methods are resource-intensive and improved effectiveness of developmental toxicity testing to assess risks to human health is possible. This article provides a summary of the session's presentations and discussion and describes some key areas that warrant further consideration.

Fig. 1

Chronology of early events during gestation of mouse embryos. (Reproduced with permission from DeSesso, JM (2009). Comparative embryology and interspecies concordance. Presented at the HESI Developmental Toxicology—New Directions Workshop, Washington, DC, April 29.)

Fig. 2

The postnatal survival of pups is shown as the percent of the litter alive on PND1 to 10, 14, 17, and 22 for WT (A) and PPARa KO (B) strains. A significant decrease (p < 0.001) compared to control occurred only in the WT litters of dams exposed to 0.6 or 1 mg/kg on GD1 to 17. Data shown are the mean of litter means for 10, 9, 6, 7, and 10 WT and 7, 11, 9, 8, and 16 KO litters, in the order listed in the legends, respectively. (Reproduced with permission from Abbott BD, et al. 2007. Perfluorooctanoic acid-induced developmental toxicity in the mouse is dependent on expression of peroxisome proliferator-activated receptor-alpha. Toxicol Sci 98:571–581.)