Citation:

PRESTON, J. CANCER RISK ASSESSMENT FOR 1,3-BUTADIENE: DATA INTEGRATION OPPORTUNITIES. CHEMICO-BIOLOGICAL INTERACTIONS. Elsevier Science Ltd, New York, NY, 166(1-3):150-155, (2007).

Impact/Purpose:

To help provide estimates of human tumor frequencies at low, environmentally relevant exposures to 1,3-butadiene.

Description:

The U.S. Environmental Protection Agency recently released its new Guidelines for Carcinogen Risk Assessment together with Supplemental Guidance for Assessing Susceptibility from Early-Life Exposure to Carcinogens. In particular, these guidelines encourage the use of mechanistic data in support of dose-response characterization at doses below those at which an increase in tumor frequency over background levels might be detected. In this context of the utility of mechanistic data for human cancer risk assessment, the International Life Sciences Institute (ILSI) has developed a Human Relevance Framework (HRF) that can be used to assess the plausibility of a Mode of Action (MoA) described for animal models operating in humans. The MoA is described as a sequence of key events and processes that result in an adverse outcome. A key event is a measurable precursor step that is in itself a necessary element of the MoA or is a bioindicator for such an element. A number of cellular and molecular perturbations have been identified as key events whereby DNA-reactive chemicals can produce tumors. These include DNA adducts in target tissues, gene mutations and/or chromosomal alterations in target tissues and enhanced cell proliferation in target tissues. This type of data integration approach to quantitative cancer risk assessment can be applied to 1,3¿butadiene, for example, using biomarker data from exposed Czech workers [ 1 ]. For this study, an extensive range of biomarkers of exposure and response was assessed, including: polymorphisms in metabolizing enzymes; urinary concentrations of several metabolites of 1,3-butadiene; hemoglobin adducts; HPRT mutations in T-lymphocytes; chromosomal aberrations using FISH and conventional staining procedures; and sister chromatid exchanges. Exposure levels were monitored in a comprehensive fashion. For risk assessment purposes, these data need to be considered in the context of how they are relevant to the MoA for leukemia, the tumor type reported to be increased in synthetic rubber workers exposed to 1,3-butadiene. Also, for the HRF it is necessary to establish key events for a MoA in rodents for the induction of tumors by 1,3-butadiene. There is clearly a species difference in sensitivity to tumor induction, with mice being much more sensitive than rats. Key events need to explain this difference. This approach of using key events for MoA to establish human relevance can lead to the development of specific informative bioindicators of response that can be used as surrogates to predict the shape of the tumor dose response curve at low doses. Truly informative predictors of tumor responses should be able to provide estimates of human tumor frequencies at low, environmentally relevant exposures to 1,3-butadiene.

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