Durk Pearson & Sandy Shaw’s®
Life Extension NewsTM
Volume 16 No. 5 • May 2013

Linear Threshold Dose Response Model of
Radiation Damage May Be About to Exit Stage Left

The model that has long been used to predict tissue damage from low dose radiation is based upon extrapolation from high dose radiation exposure. As has been noted in recent scientific studies,1–5 however, this model poorly predicts the effects in the low dose radiation range, whereas the hormetic model (a biphasic response) provides excellent predictions.

According to Edward J. Calabrese,1 the biphasic dose response model was originally proposed by Schulz in the 1880s based on his extensive testing of the effects of numerous disinfectants on the metabolism of yeast. Unfortunately, however, Schulz went on to claim that his dose-response findings provided the explanatory principle of homeopathy, leading to marginalization of both Schulz and his theory (due to the conflict between orthodox medicine and homeopathic practitioners). It would be another 60 years before the biphasic response (hormetic) explanation for low dose effects of radiation was to become a respected notion. However, government agencies that regulate toxic substances (such as the EPA) still use the linear threshold dose response model. By so doing, these agencies are costing huge sums of money using data that do not provide accurate estimates of toxicity at low doses, hence, not delivering greater safety in exchange for these immense costs.

We are beginning to see more scientific papers published in support of the hormesis explanation of why extrapolation of high dose radiation damage to tissues is not a proper way to estimate the damage, if any, to tissues derived from low dose radiation.

Dr. Calabrese1 reports his research and that of his colleagues during the past approximately ten years which, using three data sets, has found that “the threshold and the linear models poorly predicted the effects in the low dose zone whereas the hormetic model made uniformly accurate predictions.” The three data sets included1 publications in the peer-reviewed pharmacological and toxicological literature on a broad range of biological models, endpoints and chemicals, (2) an NCI series of 57,000 dose response involving over 2200 anti-tumor agents that had been tested on 13 strains of years considered models of human tumor cells, and (3) about 2100 agents in E. coli.

Dr. Calabrese notes that the threshold model was never validated and that during this long period during which a poor model was being used in toxicology and government agency regulations, it failed multiple, large objective validation tests. As Calabrese notes, getting the “dose response wrong was not simply an historical curiosity involving a conflict between homeopathy and traditional medicine, but one that has shaped the risk assessment process, profoundly affecting clinical medicine, public health, risk communication messages, personal health choices, the proper allocation of vast public/private resources as well as governmental legislation/regulatory programs.”

A second paper2 published in the latest FASEB J. examined the effects of low dose radiation exposure in a mouse model using mice that are very sensitive to low dose radiation, changing coat color in response to it. As the authors note in their introduction, “the human health risks of LDIR [low dose ionizing radiation] are still estimated by extrapolation from the biological effects observed at high doses, according to the linear no theshold (LNT) risk assessment model.” Pointing out that high doses of ionizing radiation can result in epigenetic modifications to DNA in adult mice, they wanted to study whether epigenetic alterations also occur in vivo in response to low dose ionizing radiation.

They used a type of mouse (the Avy mouse) that, in response to early developmental exposure to methyl donors (genistein, bisphenol A, ethanol) and in vitro culturing develop phenotype changes by altering the epigenome. In this study, the researchers show that low dose ionizing radiation causes both dose- and sex-dependent epigenetically induced adaptive changes at the Avy locus that in part depend on a cellular oxidative stress response.2

As the authors explain, this mouse is very sensitive to environmental effects on the fetal epigenome. Hypomethylation causes inappropriate Agouti gene expression in all tissues, leading to a yellow coat color but also other effects such as developing obesity, diabetes and cancer. When the promoter of this gene is hypermethylated, however, the animals have a much lower incidence of disease as well as having a pseudoagouti (brown) color. The experimental results showed that low dose ionizing radiation altered DNA methylation such that the animals ended up with a brown color and the reduced levels of disease as an adaptive response. This, the authors say, was due to exposure during pregnancy to doses of radiation equivalent to those received for a chest or head CT scan. “Hypomethylation of DNA at high doses of radiation and hypermethylation at low doses are indicative of a hormetic biphasic radiation dose response effect.”2 (The authors note that hypermethyl­ation was beneficial in this particular disorder but is not always beneficial. For example, tumor suppressor genes can become hypermethylated and, as a result, silenced, so that cancer risk is increased.)

The study2 “brings into question the assumption that every dose of radiation is harmful.”


  1. Calabrese. Hormesis: Toxicological foundations and its role in aging research. Exper Gerontol. 48:99-102 (2013).
  2. Bernal et al. Adaptive radiation-induced epigenetic alterations mitigated by antioxidants. FASEB J. 27:665-71 (2013).
  3. Son et al. Hormetic dietary phytochemicals. Neuromolecular Med. 10(4):236-46 (2008).
  4. Hayes. Nutritional hormesis and aging. Dose Response. 8:10-5 (2010).
  5. Wu et al. Multiple mild heat-shocks decrease the Gompertz component of mortality in Caenorhabditis elegans. Exper Gerontol. 44:607-12 (2009).

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