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Combined retrospective analysis of 498 rat multi-generation reproductive toxicity studies: on the impact of parameters related to F1 mating and F2 offspring
Citation:
PIERSMA, A. H., E. RORIJE, M. E. BEEKHUIJZEN, R. L. COOPER, D. J. DIX, B. HEINRICH-HIRSCH, M. T. MARTIN, E. MENDEZ, A. MULLER, M. PAPARELLA, D. RAMSINGH, E. REAVES, P. RIDGWAY, E. SCHENK, L. STACHIW, B. ULBRICH, AND B. C. HAKKERT. Combined retrospective analysis of 498 rat multi-generation reproductive toxicity studies: on the impact of parameters related to F1 mating and F2 offspring. REPRODUCTIVE TOXICOLOGY. Elsevier Science Ltd, New York, NY, 31(4):392-401, (2011).
Impact/Purpose:
The present review combines and elaborates existing databases, provides a new comprehensive retrospective analysis, and confirms earlier conclusions about the limited contribution of the second generation offspring in the two-generation reproductive toxicity study to risk assessments and C&L. It supports the replacement of the two-generation reproduction toxicity study with the EOGRTS on the basis of existing experience with multi-generation studies. EOGRTS is further supported by arguments of reduced animal use, increased parameter numbers and statistical power, and enhanced economy.
Description:
The multi-generation reproductive toxicity study (OECD TG 416 and USEPA 870.3800) has been extensively used internationally to assess the adverse effects of substances on reproduction. Recently the necessity of producing a second generation to assess the potential for human health risks has been questioned. The present standardized retrospective analysis of the impact of the second generation on overall study outcome combines earlier analyses and includes 498 rat multi-generation studies representing 438 different tested substances. Detailed assessment of study reports revealed no critical differences in sensitivities between the generations on the basis of a consideration of all endpoints evaluated. This analysis indicates that the second generation mating and offspring will very rarely provide critical information. These findings are consistent with the conclusions of previous retrospective analyses conducted by RIVM, USEPA and PMRA and support adoption of the proposed OECD extended one-generation reproductive toxicity study protocol in regulatory risk assessment testing strategies.
