A reappraisal of the additive- to- background assumption in cancer risk assessment

A series of 15+ papers published by Ed Calabrese over more than 10 years have detailed the history behind the 1956 recommendations of the U.S. National Academy of Sciences (NAS) Biological Effects of Atomic Radiation (BEAR) I Committee (Genetics Panel) to switch from a threshold –– to a linear non-threshold (LNT) dose–response model. Adoption of the LNT Model has been the most significant risk-assessment policy change ever made, and it was rapidly adopted by highly influential national and international advisory committees. This policy also has determined the setting of “exposure standards” for ionizing radiation and chemical carcinogens in the Western world.

The LNT model, whether for ionizing radiation or chemicals, assumes that even a “single hit” of irradiation, or a “single molecule” of a chemical is dangerous. This same genetic-risk prediction would apply to chemotherapeutic agents and other drugs. The threshold model, on the other hand, says that a certain amount of irradiation, or chemical, can be conveniently “absorbed” (i.e.”tolerated”) by the living cell, by the organism. This brings to mind “oxidative stress”, nitric oxide, and carbon monoxide –– all of which can be toxic at sufficiently high doses –– actually act as second-messenger “signals” –– important in many genetic-network pathways and critical-life processes including cell division/migration and physiological functions, as well as embryogenesis. Moreover, in pharmacology it is well known that a drug administered to a patient can lead to therapeutic failure, efficacy, or toxicity (i.e. dosage too low to see any effect, dosage “just right” that benefits the patient, or dosage too high, respectively).

In any carcinogen dose-response study, the “control” group of animals virtually always shows “spontaneous” tumors, which are regarded as “the “background”; these are routinely “subtracted” from the number of tumors seen in the experimental group. However, an important, but often overlooked, area of cancer-risk assessment (i.e. cancer dose-response assessment) is the additive-to-background” assumption. This hypothesis essentially assumes the LNT Model (i.e. any agent causes cancer at any dose and by the same mechanism). This assumption was proposed in the mid-1970s, and was incorporated into governmental risk assessment policy/practices a decade later. It was not possible in the 1970s to assess its validity scientifically, because the explosion in molecular biology studies and discoveries of oncogenes had just begun. Today, it is now possible to evaluate the scientific validity. The attached publication shows that the additive-to-background assumption (i.e. spontaneous vs induced tumors occur via the same mechanisms) is not compatible with the extensive publications now available in cancer research.

Authors [attached] evaluated the additive-to-background assumption by using findings of modern molecular toxicology –– including oncogene activation/mutation, gene regulation, and molecular pathway analyses. Based on published studies with 45 carcinogens over 13 diverse mammalian models and over a broad range of tumor types, compelling evidence indicates that carcinogen-induced tumors are mediated in general via mechanisms that are not the same as those which cause spontaneous tumors in appropriate control groups. This interesting conclusion therefore challenges a fundamental hypothesis of the additive-to-background concept. Such findings should lead to new considerations by those involved in cancer-risk-assessment policy, regulatory agency practices, as well as in fundamental concepts of cancer biology.

Environ Res 2o18; 166: 175–204

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