期刊
ENVIRONMENTAL RESEARCH
卷 166, 期 -, 页码 175-204出版社
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.envres.2018.05.015
关键词
Cancer risk assessment; Linear non-threshold dose-response; Oncogenes; Threshold dose-response; Carcinogen mechanism
资金
- US Air Force Office of Scientific Research [AFOSR FA9550-13-1-0047]
- ExxonMobil Foundation [S18200000000256]
The assumption that chemical and radiation induced cancers act in a manner that is additive to background was proposed in the mid-1970s. It was adopted by the U.S. Environmental Protection Agency (EPA) in 1986 and then subsequently by other regulatory agencies worldwide for cancer risk assessment. It ensured that cancer risks at low doses act in a linear fashion. The additive to background process assumes that the mechanism(s) resulting in induced (i.e., treatment related) and spontaneous (i.e., control group) cancers are identical. This assumption could not be properly evaluated due to inadequate mechanistic data when it was proposed in the 1970s. Using the findings of modern molecular toxicology, including oncogene activation/mutation, gene regulation, and molecular pathway analyses, the additive to background assumption was evaluated in the present paper. Based on published studies with 45 carcinogens over 13 diverse mammalian models and for a broad range of tumor types compelling evidence indicates that carcinogen-induced tumors are mediated in general via mechanisms that are not identical to those affecting the occurrence of the same type of spontaneous tumors in appropriate control groups. These findings, which challenge a fundamental assumption of the additive to background concept, have significant implications for cancer risk assessment policy, regulatory agency practices, as well as fundamental concepts of cancer biology.
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