Low Dose  Radiation, Hormesis and Adaptive Response

Myron Pollycove, M.D., Visiting Medical Fellow USNRC
 

Washington, DC Professor Emeritus, Laboratory Medicine and
Radiology University of California, San Francisco, CA

Presented NCRP Scientific Committee 1-6 Meeting February 17, 1998
 

Abstract

   The prime concern of radiation protection policy since 1959 has been protecting DNA from damage. The 1995 NCRP Report 121 on collective dose states that since no human data provides direct support for the linear nonthreshold hypothesis (LNT), and some studies provide quantitative data that, with statistical significance, contradict LNT, ultimately, confidence in LNT is based on the biophysical concept that the passage of a single charged particle could cause damage to DNA that would result in cancer. Current understanding of the basic molecular biologic mechanisms involved and recent data will be examined after presenting several statistically significant epidemiologic studies that contradict the LNT hypothesis. Over eons of time a complex biosystem evolved to control the DNA alterations (oxidative adducts) produced by about 10E10 free radicals/cell/d derived from 2-3% of all metabolized oxygen. Antioxidant prevention, enzymatic repair of DNA damage, and removal of mis- or unrepaired DNA alterations by apoptosis, differentiation, necrosis, and the immune system, sequentially reduce DNA damage from about 10E6 DNA alterations/cell/d to about 1 mutation/cell/d. These mutations accumulate in stem cells during a lifetime with progressive DNA damage-control impairment associated with aging and malignant growth. A comparatively negligible number of mutations, an average of about 10E7 mutations/cell/d, is produced by low LET radiation background of 0.1 cGy/y. The remarkable efficiency of this biosystem is increased by the adaptive responses to low-dose ionizing radiation. Each of the sequential functions that prevent, repair, and remove DNA damage are adaptively stimulated by low-dose ionizing radiation in contrast to their impairment by high-dose radiation. The biologic effect of radiation is not determined by the number of mutations it creates, but by its effect on the biosystem that controls the relentless enormous burden of oxidative DNA damage. At low doses, radiation stimulates this biosystem with consequent significant decrease of metabolic mutations. This reduction of gene mutations in response to low-dose radiation provides a biological explanation of the statistically significant observations of mortality and cancer mortality risk decrements, and contradicts the biophysical concept of the basic mechanisms upon which, ultimately, the NCRP's confidence in the LNT hypothesis is based.
 

Background

     The best scientific evidence of human radiation effects initially came from epidemiologic studies of atomic bomb survivors in Hiroshima and Nagasaki. While no evidence of genetic effects has been found, these studies showed a roughly linear relationship between the induction of cancer and extremely high dose-rate single high doses of atomic bomb radiation. This was consistent with the knowledge that ionizing radiation can damage DNA in linear proportion to high-dose exposures and so produce gene mutations known to be associated with cancer. In the absence of comparable low dose effects it was prudent to propose tentatively the no threshold hypothesis that extrapolates linearly from effects observed at very high doses to the same effects at very low doses. It was accepted in 1959 by the International Commission on Radiological Protection (ICRP)1 and afterwards adopted by national radiation protection organizations to guide regulations for the protection of occupationally exposed workers and the public.2 This hypothesis that all radiation is harmful in linear proportion to the dose, is the principle used for collective dose calculations of the number of deaths produced by any radiation, natural or generated, no matter how small. The National Council of Radiation Protection and Measurements Report 121, quot;Principles and Application of Collective Dose in Radiation Protection," summarizes the basis for adherence to linearity of radiation health effects:3 "Taken as a whole, the body of evidence from both laboratory animals and human studies allows a presumption of a linear no threshold response at low doses and low-dose rates, for both mutations and carcinogenesis. Therefore, from the point of view of the scientific bases of collective doses for radiation protection purposes, it is prudent to assume the effect per unit dose in the low-dose region following single acute exposures or low-dose fractions in a linear response. There are exceptions to this general rule of no threshold, including the induction of bone tumors in both laboratory animals and in some human studies due to incorporated radionuclides, where there is clearly evidence for an apparent threshold. However, few experimental studies, and essentially no human data, can be said to prove or even to provide direct support for the concept of collective dose with its implicit uncertainties of nonthreshold linearity and dose-rate independence with respect to risk. The best that can be said is that most [sic] studies do not provide quantative data that, with statistical significance, contradict the concept of collective dose. Ultimately, confidence in the linear no threshold dose-response relationship at low doses is based on our understanding of the basic mechanisms involved. Genetic effects may result from a gene mutation, or a chromosome aberration. The activation of a dominant acting oncogene is frequently associated with leukemias and lymphomas, while the loss of suppressor genes appears to be more frequently associated with solid tumors. It is conceptually possible, but with a vanishing small probability, that any of these effects could result from the passage of a single charged particle, causing damage to DNA that could be expressed as a mutation or small deletion. It is a result of this type of reasoning that a linear nonthreshold dose-response relationship cannot be excluded. It is this presumption [sic], based on biophysical concepts, which provides a basis for the use of collective dose in radiation protection activities." NCRP Report 121 summarizes that while some studies "provide quantitative data that, with statistical significance, contradict the concept of collective dose," "ultimately, confidence in the linear no threshold dose-response relationship at low doses [LNT hypothesis] is based on our understanding of the basic mechanisms involved." Current understanding of the basic biologic mechanisms involved and recent data will be examined after presenting some of the statistically significant epidemiologic data that contradict the LNT hypothesis. The biologic data also contradict "the presumption, based on biophysical concepts, which provides a basis for the use of collective dose in radiation protection activities."
 

Epidemiologic Studies

    What are some of the statistically significant epidemiologic studies that demonstrate risk decrements (hormesis) as predicted by the adaptive responses to low-dose radiation of the DNA damage-control biosystem? 4 For several decades increased longevity and decreased cancer mortality have been reported in populations exposed to high background radiation. Established radiation protection authorities consider such observations to be spurious or inconclusive because of unreliable public health data or undetermined confounding factors such as pollution of air, water and food, smoking, income, education, medical care, population density, and other socioeconomic variables. Recently, however, several epidemiologic statistically significant controlled studies have demonstrated that exposure to low or intermediate levels of radiation are associated with positive health effects. Dr. Zbigniew Jaworowski, past chairman of UNSCEAR, in his current review of hormesis cites recent data showing hormetic effects in humans from the former Soviet Union.5 After radiation exposure from a thermal explosion in 1957, 7852 persons living in 22 villages in the Eastern Urals were divided into three exposure groups averaging 49.6 cGy, 12.0 cGy, and 4.0 cGy and followed for 30 years. Tumor-related mortality was 28%, 39%, and 27% lower in the 49.6 cGy, 12.00 cGy, and 4.0 cGy groups, respectively, than in the nonirradiated control population in the same region. In the 49.6 cGy and 12.0 cGy groups the difference from the controls was statistically significant (Figure 1). Epidemiologic studies showing beneficial effects of low doses of radiation in atomic bomb survivors (Figure 2) and other populations were reviewed by Sohei Kondo, Professor of Radiation Biology, Atomic Energy Research Institute, Kinki University, Osaka, Japan.6 Included are the apparently beneficial effects of low doses of external gamma rays on the life span of radium-dial painters and the significantly lower mortality from cancers at all sites of residents of Misasa, an urban area with radon spas, than residents of the suburbs of Misasa (Figure 3). [INLINE] These beneficial effects are consistent with the findings of B. L. Cohen, Professor of Physics, University of Pittsburgh, that relate the incidence of lung cancer to radon exposure in nearly 90% of the population of the United States.7 The 1601 counties selected for adequate permanence of residence provide extremely high-power statistical analysis. After applying the BEIR IV 8 correction for variations in smoking frequency, the study shows a very strong tendency for lung cancer mortality to decrease with increasing mean radon level in homes, in sharp contrast to the BEIR IV theoretical increased mortality derived by linear no threshold extrapolation of effects in uranium miners exposed to very high radon concentrations. The discrepancy between theoretical and measured slopes is 20 standard deviations (Figure 4). Rigorous statistical analysis of 54 socioeconomic, seven physical, and multiple geographic variables as possible confounding factors, both single and in combination, demonstrates no significant decrease in the discrepancy. The multiple independent requirements that a possible unknown confounding factor must meet, make its existence highly improbable. A reasonable explanation is that stimulated biological mechanisms more than compensate for the radiation "insult" and are protective against cancer in a low-dose, low-dose-rate range. The thirteen-year U.S. Nuclear Shipyard Workers study of the health effects of low-dose radiation was performed by the Johns Hopkins Department of Epidemiology, School of Public Health and Hygiene, reported to the Department of Energy in 1991 9 and reported in UNSCEAR 1994.4 Professor Arthur C. Upton, who concurrently chaired the NAS BEIR V Committee on "Health Effects of Exposure to Low Levels of Ionizing Radiation," 10 chaired the Technical Advisory Panel that advised on the research and reviewed results. The results of this study contradict the conclusions of the BEIR V report 10 that small amounts of radiation have risk - the LNT hypothesis. From the database of almost 700,000 shipyard workers, including about 108,000 nuclear workers, three closely matched study groups were selected, consisting of 28,542 nuclear workers with working lifetime doses 5 mSv (many received doses well in excess of 50 mSv), 10,462 nuclear workers with doses <5 mSv and 33,352 non-nuclear workers. Deaths in each of the groups were classified as due to: all causes, leukemia, lymphatic and hematopoietic cancers, mesothelioma, and lung cancer. The results demonstrated a statistically significant decrease in the standardized mortality ratio for the two groups of nuclear workers for 'death from all causes' compared with the non-nuclear workers. For the 5 mSv group of nuclear workers, the highly significant risk decrement to 0.76, 16 standard deviations below 1.00, of the standard mortality ratio for death from all causes is inconsistent with the LNT hypothesis and does not appear to be explainable by the healthy worker effect (Figure 5) 4. The non-nuclear workers and the nuclear workers were similarly selected for employment, were afforded the same health care thereafter, and performed the identical type of work, except for exposure to 60 Co gamma radiation, with a similar median age of entry into employment of about 34 years. This provides evidence with extremely high statistical power that low levels of ionizing radiation are associated with risk decrements. Nevertheless, Professor Arthur C. Upton and others consider the three-country low-dose radiation and cancer study of Cardis, et al11,12, to be the best occupational study of nuclear workers (Figure 6). This study concluded, "There was no evidence of an association between radiation dose and mortality from all causes or from all cancers. Mortality from leukemia, excluding chronic, lymphocytic leukemia (CLL) ...was significantly associated with cumulative external radiation dose (one-sided P value = 0.046: 119 deaths)." The statistical methods used state, "As there was no reason to suspect that exposure to radiation would be associated with a decrease in risk of any specific type of cancer, one-sided tests are presented throughout." The authors' analysis of the 119 deaths from all leukemias except CLL excluded 86 deaths in dose categories 1.3.4, and 6 in which there were fewer deaths than expected. Trend analysis of the remaining 33 deaths in dose categories 2, 5, and 7 for estimated P=0.046 was obtained "using computer simulations based on 5000 samples, rather than the normal approximation."11 The Canadian Breast Cancer Fluoroscopy Study13 reports the observations of the mortality from breast cancer in a cohort of 31,710 women who had been examined by multiple fluoroscopy between 1930 and 1952. The observed rates of mortality are related to breast radiation doses and presented only in tabular form. The authors compare linear and linear-quadratic dose-response models fit to the data and conclude, "that the most appropriate form of dose-response relations is a simple linear one, with different slopes for Nova Scotia and the other provinces." On the basis of this linear model that includes only non-significant data and excludes the data with the highest confidence limits (Figure 7), the authors predict the lifetime excess risk of death from breast cancer after a single exposure at age 30 to 1 cGy(1r) to be approximately 60 per million women or 900 per million women exposed to 15 cGy. The observed data, however, demonstrate with high statistical confidence, a reduction of the relative risk of breast cancer to 0.66 (P=0.05) at 15 cGy and 0.85 (P=0.32) at 25 cGy. The second author, in his 1996 revision of this study, removed this highly significant contradiction of the LNT hypothesis by lumping all low-dose data into a single 1-49 cGy category.14 The study actually predicts that a dose of 15 cGy would be associated with 7,000 fewer deaths in these million women. Lauriston S. Taylor, past president of the NCRP, considered application of LNT theory for calculations of collective dose as, "deeply immoral uses of our scientific heritage"15. METABOLIC AND RADIATION DNA DAMAGE CONTROL During the past decade rapid advances in our knowledge of molecular biology and cell function enable us to understand why low-dose radiation is associated with positive health effects in contrast to the carcinogenic effect of high-dose radiation. Our understanding is based upon current, cellular molecular biology observations. Estimates are based on published data and recent personal communications: * Two to three percent of all metabolized oxygen is converted to free radicals (reactive oxygen species),16 10E10/cell/d, that produce about 10E6 DNA oxidative adducts/cell/d.7, 8 These include about 0.5 double strand breaks/cell/d.17 In addition, a relatively small number of metabolic DNA alterations are produced by DNA replication and thermal instability.19 By comparison, 1 cGy low LET radiation produces 20 DNA oxidative adducts/cell that include an average of 0.4 double strand breaks/cell.18,19 * Over eons of time, as multicellular animals developed and metabolized oxygen, a complex DNA damage-control biosystem evolved (Fig. 8).17 The damage corresponding to 10E10 free radicals/cell/d is largely prevented by antioxidants that scavenge approximately 99% of these free radicals. The resultant 10E6 DNA oxidative adducts/cell/d are reduced by enzymatic repair to about 10E2 mis/unrepaired DNA alterations/cell/d. Apoptosis, differentiation, necrosis, and the immune system remove approximately 99% of these mis/unrepaired DNA alterations so that an average of 1 mutation/cell/d (possibly up to 2-3) accumulates during the lifetime of a stem cell to decrease DNA damage-control capability with associated aging and malignant growth (Figure 8).17 Cancer increases as the third to fifth power of age. This remarkably efficient biosystem prevents precocious aging and malignancy unless impaired by genetic defects, or damaged by high doses of radiation or other toxic agents. 9, 16-19, 22-33 * How does background radiation add to the metabolic accumulation of mutations? A much larger fraction of double strand breaks occurs in DNA oxidative adducts produced by radiation than in those produced by metabolism (2x10E-2 vs 5x10E -7).17,21 The mis/unrepaired fraction of these double strand breaks is also much larger than that of other metabolic DNA oxidative adducts (10E-1 vs 10E-4). Nevertheless, the number of metabolic DNA oxidative adducts (10E6/cell/d) is so much greater than the number of oxidative adducts from low LET background of 0.1 cGy/y (5x10 -3/cell/d), that an average of only 10E -7 radiation mutation/cell/d is added to 1 metabolic mutation/cell/d (Figure 8).17 

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Acknowledgement:

This Article is reproduced with permission of Dr. M. Pollycove.

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