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CANCER RISK ASSESSMENT FOR 1,3 BUTADIENE: DATA INTEGRATION OPPORTUNITIES
Citation:
PRESTON, J. CANCER RISK ASSESSMENT FOR 1,3 BUTADIENE: DATA INTEGRATION OPPORTUNITIES. Presented at 2005 International Symposium on Evaluation of Butadiene & Chloroprene Health Risks, Charleston, SC, September 20 - 22, 2005.
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. These new cancer guidelines benefit from the significant strides in scientific knowledge of the underlying mechanisms of diseases in general, and cancer specifically. In particular, the cancer 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, starting with the interaction of an agent with a cell, proceeding through operational and anatomical changes, and resulting 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 biomarker 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. Observations for similar endpoints in nontarget tissues can be informative but are not considered to be key events. This type of data integration approach to quantitative cancer risk assessment can be applied to 1,3 butadiene, in particular using data on biomarkers in exposed Czech Workers (Albertini et al., Res Rep Health Eff Inst. 2003, 116:1-141). For this study, an extensive range of biomarkers of exposure were assessed including: polymorphisms in metabolizing enzymes; urinary concentrations of several metabolites of 1,3 butadiene; hemoglobin adducts; HPRT mutations in T-lymphocytes; chromosomal aberrations by FISH and conventional staining procedures; and sister chromatid exchanges. Exposure levels were monitored in a comprehensive fashion. These biomarker data need to be considered for risk assessment purposes in the context of how they inform 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. In addition, there are a number of species-specific sites of tumor formation with only neoplasia of the mammary gland being a common tumorigenic site in rats and mice. Again the key events and MOA need to be consistent with this species specificity. This approach of using MOA and key events to establish the human relevance can lead to the development of specific informative biomarkers 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, environmental exposures to butadiene. The picture is definitely not a complete one, but the current status will be discussed.