Society For Risk Analysis Annual Meeting 2013

Session Schedule & Abstracts


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.0  This is a test, pls ignore. Doe JB*; State University xx   test

Abstract: this is a

.0  Mutagenic mode of action inconsistent with tumor response in >40,000 trout exposed to the potent mutagen dibenzo[a,l]pyrene, contrary to Somatic mutation cancer theory. Bogen KT*; Exponent, Health Sciences   kbogen@exponent.com

Abstract: ED001 study data on liver and stomach tumor incidence in >40,000 trout fed the potent mutagen dibenzo[a,l]pyrene (DBP) were used to test the prediction by multistage somatic-mutation cancer (MSMC) theory that such agents increase tumor risk in linear no-threshold (LNT) proportion to dose at low doses. These data, which exhibit apparent substantial low-dose nonlinearity, provide the best low-dose dose-response resolution of any tumor bioassay to date. To test whether mutations substantially contributed to observed tumor responses, tumor-specific data sets were fit for the first time using biologically-based risk models. Each of two models applied assumes both mutation and cell-proliferation pathways contribute to increased tumor risk: the biologically-based stochastic 2-stage (MVK) model based on MSMC theory, and a model implementing a new, dysregulated adaptive hyperplasia (DAH) theory of tumorigenesis [Bogen KT. Med Hypoth 2013; 80:83–93]. Excellent MVK and DAH fits to each data set were obtained, but, surprisingly, all fits predict that DBP increases tumor risk exclusively by enhancing cell proliferation with a nonlinear, approximately lognormal dose-response pattern. Because DBP is a potent mutagen, the MVK-model fits are not biologically plausible under the assumptions of the MVK model. In contrast, the DAH-model fits reflect an alternative assumption that tumors induced by cytotoxic chemical exposures are typically driven by elevations in the size of a posited tumor-relevant stem-cell population. The DAH model posits that population to consist only of cells recruited into an epigenetically maintained adaptive hyperplastic (e.g., tissue-repair) state, and that a rare tissue-specific mutation can block normal termination of that state. The results obtained are inconsistent with the somatic mutation theory of cancer, which for the last half century has underlain all regulatory applications of LNT cancer-risk extrapolation for environmental chemical carcinogens.



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