The Selection and Relevance of Developmental Toxicity Endpoints for Acute Exposure Limit Setting. M. T. M. Van Raaij, P. A. H. Janssen, P. C. M. Bos, and A. H. Piersma, National Institute of Public Health and Environment, The Netherlands
One of the most difficult issues in setting of acute exposure limits for human toxicity is the selection of relevant endpoints. Most guideline-based toxicity studies use repeated dosing and as a consequence the risk evaluator has to decide whether observed toxic effects in such studies are relevant also for a single exposure. Developmental effects are generally considered as highly relevant endpoints for acute exposure limit setting (e.g. ARfD, AEGLs). This obviously holds true for true teratogenic effects, for which single exposures within the sensitive time window will often suffice. However, it is questionable whether this also applies for general developmental effects such as reduced foetal weight or retarded skeletal ossification. We have evaluated available data for various developmental toxicants for which both developmental studies with a single day dosing during gestation as well as repeat dose studies were available (e.g. phtalates, methanol, thiobendazole). We systematically investigated the effect- and no-effect-levels for a range of developmental endpoints (e.g. resorptions, foetal weight, skeletal variants, retarded ossification). We compare the ratio of effect- and no-effect-levels between different exposure protocols. Findings will be presented on a number of non-specific endpoints such as retarded skeletal ossification and foetal body weight. The results will be discussed taking into account maternal toxicity and the exposure timing during gestation. We hope this analysis will be a first step towards assisting risk evaluators to select the most relevant endpoints for acute exposure limit setting.
Project funded by the Dutch Ministry of Public Health, Sports, and Well being.
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