A quantitative comparison of points of departure between 28-day and 90-day repeated dose studies with a proposed extrapolation factor


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Abstract

The influence of exposure duration on chemical toxicity has important implications for risk assessment. Although a default 10-fold extrapolation factor is commonly applied when the toxicological dataset includes a subchronic (90-day) study but lacks studies of chronic duration, little consensus has been reached on an appropriate extrapolation factor to apply when the dataset includes a 28-day study but lacks studies of longer durations. The goal of the present assessment was to identify a 28-day to 90-day extrapolation factor by analyzing distributions of ratios of No-Observed-Adverse-Effect Levels (NOAELs) and Benchmark Doses (BMDs) derived from 28-day and 90-day studies. The results of this analysis suggest that a default 10-fold extrapolation factor in chemical risk assessment applications is sufficient to account for the uncertainty associated with evaluating human health risk based on results from a 28-day study in the absence of results from a 90-day study. This analysis adds significantly to the growing body of literature interpreting the influence of exposure duration on chemical toxicity that will likewise facilitate discussions on the future state of testing requirements in the international regulatory community.HighlightsThe effect of duration on toxicity was analyzed with a high-quality dataset.The NOAEL28day/90day ratio was ≤1 in nearly 50% of all evaluated study pairs.A 28-day to a 90-day extrapolation factor of 10 is adequately health-protective.Adjusting for variable dose spacing and study quality did not affect the results.

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