Review articleThe additive to background assumption in cancer risk assessment: A reappraisal
Introduction
This paper assesses a critical, but overlooked area of cancer risk assessment (i.e., cancer dose-response assessment), the additive to background assumption, that essentially ensures low dose linearity in the estimates of carcinogen exposure risks. This assumption was proposed for application to cancer dose-response assessment by Crump et al. (1976). A decade later it was incorporated into governmental risk assessment policy and practices during 1986 (Anderson, 1983, Crump, 1984, U.S. Environmental Protection Agency (EPA), 1986) and has continued to the present (U.S. Environmental Protection Agency (EPA), 2005, European Food Safety Authority (EFSA) Scientific Committee et al., 2017). This assumption was proposed during the mid 1970s when it was not possible to assess its scientific validity with the oncogene revolution starting in the mid-1980s and the continued clarification of molecular mechanisms for spontaneous and induced tumors to the present. It is now possible to evaluate the scientific validity of the additive to background assumption. The present paper demonstrates that the additive to background assumption that spontaneous and induced tumors occur via identical mechanisms is not compatible with the vast body of modern molecular findings. Prior to assessing the additive to background hypothesis, a brief historical reconstruction of how linearity at low dose was adopted for cancer dose-response assessment by U.S. regulatory agencies during the 1970s is presented, providing the necessary scientific and regulatory contexts and introduction needed to assess the additive to background assumption.
Section snippets
The Thanksgiving Cranberry Scare of 1959
Within five years following the National Academy of Sciences (NAS) Biological Effects of Atomic Radiation (BEAR) I Genetics Panel report (NAS/NRC, 1956) recommending the use of linear dose response modeling in risk assessment, Nathan Mantel and Raymond Bryan (1961) would publish their landmark paper on cancer risk assessment. The modestly entitled paper, Safety Testing of Carcinogenic Agents, was based on the use of the tolerance distribution probit dose response model. The probit model was
Ensuring linearity at low dose
The origin of the additive to background cancer risk concept was first suggested by Platt (1955) in a letter-to-the-editor of the Lancet. He proposed that the principal effect of a carcinogenic agent is likely to alter the functioning of a cell in such a manner that its clonal expansive descendants proliferate at a greater rate than other nearby cells. He then suggested that if aging were seen as an extended process of numerous cell divisions then cancerous processes would be a function of such
Discussion
The decision to adopt additive to background by the U.S. EPA for cancer risk assessment was influenced by the U.S. NAS SDWC (NAS, 1977) based on the Crump et al. (1976) paper, as well as the OSHA (1980) Carcinogen Hearings and Hoel (1980). Schneiderman, a member of that SDWC, summarized its recommendations in a follow-up paper, indicating that known carcinogens have never induced cancers in people that have never been seen before (i.e., novel cancers) (Schneiderman and Brown, 1978). With this
Conclusions
The question proposed in this paper is that posed by Hoel (1997), that is:
“Whether or not the original simple idea of background additivity is consistent with today's biology and whether the concept, if true, has any value for quantitative risk estimation.”
- 1.
Multiple, complementary and converging lines of evidence indicate that the “original simple idea” of additive to background for the induction of tumors that became incorporated into regulatory agency (i.e., EPA) cancer risk assessment is not
Declaration of Interest
None.
Funding Sources
This work was supported by the US Air Force Office of Scientific Research (AFOSR FA9550-13-1-0047) and ExxonMobil Foundation (S18200000000256). The U.S. Government is authorized to reproduce and distribute for governmental purposes notwithstanding any copyright notation thereon. The views and conclusions contained herein are those of the author and should not be interpreted as necessarily representing policies or endorsement, either expressed or implied. Sponsors had no involvement in study
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