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The Developmental Neurotoxicity Guideline Study: Issues with Methodology, Evaluation and Regulation
Citation:
Tsuji, R. AND K. M. CROFTON. The Developmental Neurotoxicity Guideline Study: Issues with Methodology, Evaluation and Regulation. Congenital Anomalies. Wiley-Blackwell, Hoboken, NJ, 52(3):122-8, (2012).
Impact/Purpose:
This work tests the mode-of-action (MOA) hypothesis that perinatal triclosan (TCS) exposure decreases circulating thyroxine (T4) concentrations via activation of pregnane X and!or constitutive androstane receptors (PXR, CAR), resulting in up-regulation ofhepatic catabolism and elimination ofT4. T4 reductions of 300/0 for dams and GD20 and PND4 offspring with concomitant increases in PROD and UGT activity suggest TCS may reduce T4 developmentally via up-regulated hepatic catabolism. Serum and liver TCS concentrations demonstrated greater fetal than postnatal internal exposure, consistent with the lack of T4 changes in PND 14 and PND21 offspring. These data support the MOA hypothesis: nuclear receptor mediated upregulation ofhepatic catabolism by TCS, particularly in dams, contributes to maternal and early neonatal hypothyroxinemia. This paper reviews some ofthese issues and summarizes discussions from the symposium "Developmental neurotoxicity testing: Scientific approaches towards the next generation to protecting the developing nervous system of children" held at the 2011 annual meeting ofthe Japanese Teratology Society. The U.S. Environmental Protection Agency (EPA) and the Organization for Economic Co-operation and Development (OECD) have published testing guidelines for Developmental Neurotoxicity (DNT). Appr-oximately 110 guideline studies have been conducted to date. And, importantly, information from these studies has provided data critical for regulatory decisions for a number of chemicals (Raffaele et al. 2010; Makris et al. 2009). However, the DNT guidelines do not always satisfy all stakeholders because some uncertainties in their methodology, evaluation, and regulation. Methodological issues include incomplete harmonization between EPA and OECD guidelines, criticisms ofthe methodology for learning and memory testing, and unspecified positive control substances., potential artifacts in morphometric neuropathological measures, criteria for observation measures, uncertainty of postnatal offspring exposure especially in feeding studies, and extrapolation of data from rats to humans are major evaluation issues. The consensus during the discussions at the meeting were there these issues have been either resolved by regulatory agencies or can be resolved by interactions between the study director and the regulatory authorities prior to conducting the studies
Description:
Recently social concerns are increasing for the effects of environmental factors on children's health, especially on their nervous system. The U.S. Environmental Protection Agency (EPA) and the Organization for Economic Co-operation and Development (GECD) have published testing guidelines for Developmental Neurotoxicity (DNT). Approximately 110 guideline studies have been conducted to date. Importantly, information from these studies has provided data critical for regulatory decisions for a number of chemicals (Raffaele et al. 2010; Makris et al. 2009). However, the DNT guidelines do not always satisfy all stakeholders because of some uncertainties in their methodology, evaluation, and regulation. Methodological issues include incomplete harmonization between EPA and GECD guidelines, criticisms of the methodology for learning and memory testing, and unspecified positive control substances. Potential artifacts in morphometric neuropathological measures, criteria for observation measures, uncertainty of postnatal offspring exposure especially in feeding studies, and extrapolation of data from rats to humans are major evaluation issues. In addition, since there is some uncertainty in use of an additional safety factor for susceptibility of infants and children. Moreover, the DNT guidelines have extensive time and cost requirements, use large numbers of animals, and there are a limited set of laboratories that can conduct the study. This paper reviews some of these issues and summarizes discussions from the symposium "Developmental neurotoxicity testing: Scientific approaches towards the next generation to protecting the developing nervous systemofchildren" held at the 2011annual meeting of theJapanese Teratology Society.
