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ILSI/HESI Maternal Toxicity Workshop Summary: Maternal Toxicity and its Impact on Study Design and Data Interpretation
Citation:
BREYER, W., N. CHERNOFF, B. R. Danielsson, K. David-Bruno, W. Harrouk, R. Hood, J. Kim, M. Rocca, G. Janer, U. W. Liminga, J. M. ROGERS, AND A. R. Scialli. ILSI/HESI Maternal Toxicity Workshop Summary: Maternal Toxicity and its Impact on Study Design and Data Interpretation. BIRTH DEFECTS RESEARCH PART B: DEVELOPMENTAL AND REPRODUCTIVE TOXICOLOGY. John Wiley & Sons, Ltd., Indianapolis, IN, 92(1):36-51, (2011).
Impact/Purpose:
This paper summarizes a symposium on the impact of maternal toxicity in developmental toxicity studies. It will be of interest to Agency scientists involved in risk assessment for developmental and reproductive toxicity
Description:
Workshops on maternal toxicity were held at the annual meetings of the Society of Toxicology, Teratology Society, and European Teratology Society in 2009. Prior to a general discussion of the issues involved with maternal toxicity and its impact on study design and data interpretation, speakers presented background information. The presentations included an overview of the topic, the relationships of maternal and fetal weight changes in developmental toxicity bioassays, exaggerated pharmacology vs. true toxicity (maternal vs. direct embryonic effects, biologics), a retrospective analysis of developmental toxicity studies in rat and rabbit, postnatal consequences of maternal toxicity, and regulatory perspectives/case studies from the United States (US) and the European Union (EU). The following recommendations are based on the outcome of the discussions at the workshops: 1. A comprehensive evaluation of all available data from general toxicity studies, range-finding Developmental and Reproductive Toxicology (DART) studies, class effects, structure-activity relationships, exposure studies, etc. is essential for appropriate dose selection for definitive DART studies. The intent is to avoid marked maternal toxicity leading to mortality or decreased body weight gains of greater than 20% for prolonged periods. a. For biotherapeutics, where the maternal effects may range from classic toxicity to no toxicity, it is advisable to evaluate alternative endpoints for dose selection and data interpretation (e.g., target tissue effects, pharmacology). b. Consider evaluating additional maternal parameters based on effects and/or target organs observed in short-term (e.g., 2-or 4-week) general toxicity studies. 2. Evaluate all available data to determine a cause-effect relationship for developmental toxicity. a. Consider conducting a pair-feeding/pair-watering study as a follow-up. b. Include an evaluation of the individual data demonstrating maternal toxicity in the mother with adverse embryo-fetal outcomes in the litter associated with the affected mother. c. Consider conducting single-dose studies at increasing doses as a complement to conventional embryo-fetal toxicity studies for certain classes of compounds (e.g., those affecting the hERG channel). 3. Sponsors should support statements that embryo-fetal effects are caused by maternal toxicity and/or exaggerated pharmacology, especially in the case of malformations. a. Provide mechanistic or other supporting data. b. Establish the relevance of the DART findings in animals for human exposures.
