Statistical issues and techniques appropriate for developmental neurotoxicity testing: a report from the ILSI Research Foundation/Risk Science Institute expert working group on neurodevelopmental endpoints.

The data from developmental neurotoxicity (DNT) guideline studies present a number of challenges for statistical design and analysis. The importance of specifying the planned statistical analyses a priori cannot be overestimated. A review of datasets submitted to the US Environmental Protection Agency revealed several inadequate approaches, including issues of Type I error control, power considerations, and ignoring gender, time, and litter allocation as factors in the analyses. Since DNT studies include numerous experimental procedures conducted on the dam and offspring at several ages, it is not unusual to have hundreds of significance tests if each was analyzed separately. Two general approaches to control experiment-wise Type I inflation are: 1) statistical/design considerations that reduce the number of p-values, including factorial designs, multivariate techniques, and repeated-measures analyses; and 2) adjustments to the alpha level, including newer approaches that are less conservative than, for example, Bonferroni corrections. The design of the DNT study includes testing of both sexes, and gender must be included in the statistical analysis for the determination of sex-related differences, and, indeed, including both sexes may increase power. The influence of litter must be taken into account in the allocation of test animals as well as the statistical analyses. This manuscript reviews many key considerations in the analysis of DNT studies with recommendations for statistical approaches and reporting of the data.

A tiered approach to systemic toxicity testing for agricultural chemical safety assessment.

A proposal has been developed by the Agricultural Chemical Safety Assessment (ACSA) Technical Committee of the ILSI Health and Environmental Sciences Institute (HESI) for an improved approach to assessing the safety of crop protection chemicals. The goal is to ensure that studies are scientifically appropriate and necessary without being redundant, and that tests emphasize toxicological endpoints and exposure durations that are relevant for risk assessment. The ACSA Systemic Toxicity Task Force proposes an approach to systemic toxicity testing as one part of the overall assessment of a compound's potential to cause adverse effects on health. The approach is designed to provide more relevant data for deriving reference doses for shorter time periods of human exposure, and includes fewer studies for deriving longer term reference doses-that is, neither a 12-month dog study nor a mouse carcinogenicity study is recommended. All available data, including toxicokinetics and metabolism data and life stages information, are taken into account. The proposed tiered testing approach has the potential to provide new risk assessment information for shorter human exposure durations while reducing the number of animals used and without compromising the sensitivity of the determination of longer term reference doses.