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 biology.
