Developmental neurotoxicity guideline study: issues with methodology, evaluation and regulation.

Recently social concerns have been increasing about the effects of environmental factors on children's health, especially on their nervous systems. The U.S. Environmental Protection Agency (EPA) and the Organisation for Economic Co-operation and Development (OECD) 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. 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 OECD 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, there is some uncertainty in the 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 is 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 system of children' held at the 2011 annual meeting of the Japanese Teratology Society.