Risk Assessment for Benefits Analysis Case Study, Part 1: Toxicology, Mode of Action, and Dose-Response Modeling of Chemical T (CT). L. K. Teuschler, K. Baetcke, R. Hertzberg, R. Hill, A. Lowit, and P. White, US Environmental Protection Agency
Dose-response models were fitted to link hypothyroidism (changes in hormone levels outside a biologically normal range for thyroid hormone levels, T4 and TSH) and thyroid cancer (tumor incidence) with exposure to the pesticide, CT, using male rat data. The goal of the modeling was to explore methods for estimating the number of cases of each disease in the human population attributable to different lengths of CT exposure for use in economic valuation. Significant increases in TSH due to CT exposure stimulates cell division in the thyroid, increasing the number of follicular cells, resulting in hyperplasia, a reversible condition. Continuous CT exposure sustains cell proliferation and, over time, leads to thyroid cancer. Humans, like animals, develop thyroid effects when exposed to antithyroid compounds, although there may be differences in potency. It is uncertain whether thyroid disruption is a prerequisite for cancer in humans as it is in rodents. Thus, modeling was consistent with EPA policy to presume thyroid cancer in rodents is applicable to humans and to use direct mg/kg body weight as the metric for interspecies dose conversion. Dose-response modeling efforts took into account intra-individual variability, the sequencing of disease endpoints, a threshold for thyroid cancer, background incidence, and exposure duration adjustments. Male rat data sets included a 56 day study of T4 and TSH changes, a 90 day study of thyroid hyperplasia, and a 2 year cancer bioassay with measures of thyroid hyperplasia. Duration adjustments across studies were evaluated using liver and thyroid weight changes as common endpoints. Results presented will include the evaluation of several dose-response functions, graphical displays of disease endpoint sequencing, and a discussion of the uncertainties in the analysis.
Disclaimer: The views expressed in this presentation are those of the authors, and do not necessarily represent the views of the U.S. Environmental Protection Agency.
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