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Beneficial Effects of Ionizing Radiation I. Prevention of Cancer Sep 18 2007 Charles L Sanders, Visiting Professor Graphic Assistance by Sukwhun Sohn Department Nuclear and Quantum Engineering, KAIST [email protected] Radiobiology Laboratory Successive generations of rats exposed continuously at 20 mSv/day to 60Co g-rays had significantly longer lifespans, more robust reproduction and fewer tumors than unexposed controls.* *Brown, S.O., Krise, G.M. and Pace, H.B. (1963) Continuous low-dose radiation effects on successive litters of the albino rat. Radiat. Res. 19, 270-276. Sanders, C.L. 1963. Effects of continuous low intensity radiation on the cotton rat. M.S. Thesis, Biology Department, Texas A & M University, College Station, Texas This study was inadvertently replicated in humans due to the accidental introduction of 60Co in structural steel of apartments in Taiwan Residents in Taiwan occupied 1700 apartments for up to 20 years (19832003) built with structural steel contaminated by 60Co Cohort Number of People Mean Cumulative Dose in 1983-2003 (mSv) High 1,100 4000 Medium 900 420 Low 8,000 120 All 10,000 600 Residents in Taiwan occupied 1700 apartments for up to 20 years (19832003) built with structural steel contaminated by 60Co Cohort Number of People Mean Cumulative Dose in 1983-2003 (mSv) High 1,100 4000 Medium 900 420 Low 8,000 120 All 10,000 600 Birth Defects were 7% of expected (93% protected). Cancer mortality was 3% of expected (97% protected) Chen et al. (13 authors) 2007. Effects of cobalt-60 exposure on health of Taiwan residents suggest new approach needed in radiation protection. Dose-Response 5:63-75. Washington State Franklin County Benton County Columbia River Hanford nuclear site All cancer mortality was less than expected in residents of counties immediately surrounding the Hanford site* and in Hanford workers**. *Boice et al. 2006; **Wilkinson 2000 Epidemiological terms for expressing cancer risk or benefit: Relative Risk (RR) RR – risk after radiation exposure/risk without radiation exposure Standardized Mortality Ratio (SMR) SMR – observed/expected for age-specific mortality For this presentation, RR and SMR are considered equivalent LNT (Linear-No-Threshold) Hypothesis (promoted by ICRP and IAEA) RR (SMR) >1.0 = harm RR (SMR) <1.0 = benefit LNT (Linear-No-Threshold) Hypothesis (promoted by ICRP and IAEA) RR (SMR) >1.0 = harm RR (SMR) <1.0 = benefit This means that you prevent cancer by being exposed to ionizing radiation The LNT is NOT accepted by some radioprotection agencies: The validity of using the LNT hypothesis to estimate radiation risks is questionable (UNSCEAR, 1972). No human data provide support for the LNT hypothesis and some studies… contradict the LNT hypothesis (NCRP, 1995)…it is important to note that the rates of cancer in most populations exposed to low-level radiation … have appeared to be decreased (NCRP, 2001). The LNT hypothesis should not be used at doses <100 mSv for assessing carcinogenic risks (French Academy of Sciences and National Academy of Medicine, 2005). Typical doses from radiological exams in the United States. [The majority of Americans, including physicians, believe that these radiation exposures cause cancer] Source Dose, mSv Mammogram X-ray 0.8 Full-mouth Dental X-ray 0.2 CT Scan, Chest 8 CT Scan, Head 2 CT Scan, Whole Body 10 Radiopharmaceutical Exams 3-7 Intravenous Pyelogram 2.5 Upper/Lower GI 3-7 Gallbladder 4 Angioplasty 9 Barium Studies 2-7 99mTc Example of the misuse of the LNT hypothesis, 1600 Breast Cancer in TB Patients Receiving multiple Fluoroscopic Examinations (NEJM 1989; 321:1285) 1200 6 Breast Cancer Deaths per 10Person-Year which, unfortunately, is common in the published literature 800 400 0 0.00 0.25 0.50 0.75 1.00 1.25 1.50 1.75 Breast Exposure, Gy The author says: “The data was most consistent with a linear dose-response relationship…Our additive model of lifetime risk predicts that exposure to 1 cGy at the age of 40 increases the number of deaths from breast cancer by 42 per million women”. Relative Risk of All Cause Mortality in published epidemiological studies of populations receiving low LET radiation (Sanders, 2007) 10 Relative Risk All Data Harm 1 Benefit 0.1 1 10 100 Dose (mSv) 1000 10000 (Vrijheid et al. Radiat. Res. 167, 2007) Nuclear workers employed in 154 facilities in 15 countries were examined. Cohort Mean Dose, mSv SMR, All Cause Mortality SMR, All Cancer Mortality Australia 6.1 0.55 0.65 Belgium 26.6 0.69 0.62 Canada 19.5 0.62 0.76 Finland 7.9 0.86 0.54 France CEA-COGEMA 3.8 0.59 0.65 France EDF 15.8 0.49 0.62 Hungary 5.1 0.40 0.68 Japan 18.2 0.78 0.87 South Korea 15.5 0.52 1.03 Lithuania 40.7 0.40 0.67 Slovak Republic 18.8 0.53 0.69 Spain 25.5 0.45 0.57 Sweden 17.9 0.80 0.95 Switzerland 62.3 0.77 0.91 UK 20.7 0.78 0.81 US Hanford 23.7 0.74 0.80 US INL 10.0 0.70 0.72 US NPP 27.1 0.41 0.65 US ORNL 15.2 0.72 0.82 MEAN 20.0 0.62 0.74 Proponents of the LNT hypothesis attribute reductions in mortality in nuclear workers to the socalled Healthy Worker Effect (HWE). HWE has been attributed to pre-employment medical screening examinations, better working and socioeconomic conditions, and annual physicals* for nuclear facility personnel. *No reduction in all cancer mortality was found in men who received annual medical physicals compared to men who did not (Franks et al. 1996. Health Serv. Res. 31:347-363; Friedman et al. 1986. J. Chronic Dis. 39:453-463). What is Radiation Hormesis? Low dose of low LET radiations activates a system of transient protective processes that includes antioxidants, high efficiency DNA repair, immunosurveillance and apoptosis removing genomically unstable (transformed) cells. The result is a reduced incidence of many diseases from expected frequencies. Reactive Oxygen Species (ROS) result from breathing an oxygen atmosphere Type Spontaneous ROS 2 mSv per Year DNA oxidative adducts/cell/day* 106 1 x 10-3 DNA Damage per cell per year** 70 x 106 4 Double-stranded DNA breaks per cell per year*** 40 ~0.1 *Pollycove, M. Radiation Hormesis: The Biological Response to Low Doses of Ionizing Radiation. Health Effects of Low-Level Radiation, BNES, 2002. **Billen, D. Spontaneous DNA damage and its significance for the “negligible dose” controversy in radiation protection. Radiat. Res. 124:242-245, 1990. ***Stewart, R.D. On the complexity of the DNA damages created by endogenous processes. Radiat. Res. 152:101-105, 1999. High Dose Radiation/Chemical-Induced or ROS-Induced Genomic Instability Prevention of radical damage: Increasing Antioxidants Repair of damage: Increasing DNA repair Removal of damage: Apoptosis and Immunosurveillance Low Dose, Low DoseRate, Low LET Radiation DNA Damage Accumulation DNA Repair Neoplastic Transformation Apoptosis Adaptive Response Proliferation of Malignant Cells Cancer Immune Functions Hundreds of studies have documented hormesis response mechanisms. Dose-dependence for neoplastic transformation of human hybrid cells exposed to X- and g-rays (Redpath JL, Q Lu, X Lao et al. 2003. Int J Radiat Biol 79:235-240). 15 Gy at 1.2 mGy/h Lifespan in mice carrying a deletion in the apoptosis-regulating Fas gene that received chronic g radiation: (a) nonirradiated controls; (b) irradiated with 0.35 mGy/h for 5 weeks; © irradiated with 0.35 mGy/h for lifespan; (d) irradiated with 1.2 mGy/h for 5 weeks; (e) irradiated with 1.2 mGy/h for 521 days (* P<0.0001 from unirradiated controls) (Ina Y and K Sakai. 2005. Radiat Res 163:418-423). Hormesis in experimental animal studies Hormesis is ubiquitous, being found for toxic chemicals and ionizing radiation (Calabrese. 2006.Toxicol Sci 94:368; Calabrese et al. 2003. Annu Rev Pharmacol Toxicol 43:175) Decreased tumors Decreased tumors MC = Methylcholanthrene (high dose) Kazuo Sakai, CRIEPI 100 Crude Incidence Lung Tumors, % 169Yb 175 keV g 169 YbO3 - 239 PuO2 80 60 239Pu 5.14 meV a 239 PuO2 40 20 0 1E-3 0.01 0.1 1 10 100 Lung Dose, Gy Frequency of lung tumors in female Wistar rats following inhalation of 239PuO2 or 169YbO3-239PuO2 (Sanders et al. Radiat. Res. 1976; 68:349; Sanders et al. Intern. J. Radiat. Biol. 1993; 64:417). Lung cancer in Mayak plutonium workers Workers also accumulated a mean of 1 Gy external 60Co g-rays Relative Risk of Lung Cancer 3 2 Mean239Pu Body Burden, kBq RR, Lung 0.010 1.0 0.34 0.56 1.18 0.59 4.2 0.83 16.5 2.48 54.2 59.3 Cancer 1 800 mGy a Threshold 0 (Tokarskaya et al. 1997 Health Phys. 73:899-905) 0 2 4 239 Pu Body Burden, kBq 6 Possible Explanation Alpha particles from 239Pu, along with cigarette smoke, produce genomically damaged, transformed cells. Gamma rays from 60Co induce apoptosis of transformed cells. Presence of radiation dose thresholds Approximate Human Threshold Dose-Rate for Low LET, Near Continuous Radiation Exposure (KeirimMarkus, 2002. Atomic Energy 93:836; Parsons, 2003. Biogerontology 4:227) All Cancer 200 mGy y-1 Bone Tumors in Radium Dial Painters 10 Gy Threshold This study was terminated by DOE when it was found that the radium dial painters were living longer than the controls. Participants in the United States Transuranium and Uranium Registries (USTUR) significantly exceeded ‘life table’ longevity expectation by an average of 10.4 years. N. Fallahian, R Brey, C Watson and A James. 2007. Does exposure to plutonium affect workers’ longevity? Health Physics 93:S11. Liver cancer in Mayak plutonium workers Dose Range, Gy OR 95% CI 0-0.07 1.0 - 0.07-0.54 0.40 0.14-1.12 0.54-16.9 2.44 1.09-5.44 Threshold for liver tumors was 2.0 Gy a-dose; no increased liver tumors from 1.0 Gy external g-rays. (Tokarskaya et al. 2006. Health Phys. 91:296-310) Threshold for liver tumors from Thorotrast (232ThO2) was also 2 Gy. (Van Kaick et al. 1991. J Radiat Res 32:20-33) Relative Risk of liver cancer mortality in published epidemiological studies of populations receiving low LET radiation (Sanders, 2007) 10 Relative Risk All Data 1 0.1 1 10 100 Dose (mSv) 1000 10000 Cumulative WLM Odds Ratio* <50 1.00 50-<100 1.23 100-<200 0.91 200-<400 0.94 400-<800 0.99 800-<1,600 2.08 1,600-2,911 3.68 *adjusted for age, smoking, asbestos exposure (Health Phys. 2006: 90:208) German Uranium and Chinese Tin Miners Relative Risk Lung Cancer Lung Cancer in German Uranium Miners 100 1 WLM = 5 mSv 10 1 0.1 1 10 100 1000 10000 100000 Dose, mSv Uranium Mine Location Threshold, mSv Yunnan, China 1000 Colorado Plateau, US 3000 Newfoundland, Canada 2000 Malmberget, Sweden 250 Grants, New Mexico, US 1000 Eastern Germany 4000 Radiation hormesis in populations that are not nuclear workers (radiation accidents, high natural background, A-bomb survivors, diagnostic and clinically exposed medical patients and other groups) 1955 Free Enterprise Radon Health Mine, Montana; air in the mine reaches 1600 pCi/L; EPA action level is 4 pCi/L Low dose radiotherapy is an effective therapy for acute and chronic inflammatory diseases and painful degenerative disorders (O. Micke and M.H. Seegenschmiedt. 2002. Consensus guidelines for radiation therapy of benign diseases: a multicenter approach in Germany. Int J Radiat Oncol Biol Phys 52:496-513). No evidence of increased cancer has been shown in 100,000s of patients that are annually treated by radon in former uranium mines or spas (balneology). No study has shown an increased cancer rate in high radiation background areas of the world Location Background Dose, mSv/year Ramsar, Iran Up to 700 Kerala, India Up to 35 Araxa, Brazil Up to 25 World Average 2.4 Highest radon level, lowest lung cancer mortality Eight health districts of Ramsar, Iran Lowest radon level, highest lung cancer mortality (Mortazavi et al. 2005. Intern Cong Ser 1276:436) Source of radiation dose in Kerala, India Dose Contribution Fraction (%) External g 76 Inhalation a 24 Cumulative Dose, mSv RR, All Solid Cancers 0-99 1.0 100-199 0.83 200-299 0.98 300-399 0.90 >400 0.66 Cancer in Cities of India (Health Phys 1987; 52:653) SIR 100 5 (J Radiat Res 2000; 41: Suppl 43) 150 Rate Per 10 Population Cancer in Yangjiang, China; background dose-rate is ~6 mSv/y-1 Site of Cancer ERR per SV Liver -0.99 Stomach -0.27 Lung -0.68 SMR 50 0 300 400 500 600 700 800 900 -6 1000 -1 External Natural Background Radiation, (*10 Sv y ) (Taken from Scott. LRRI, 2006) Corrected for Smoking Ecological study of radon exposure and risk of lung cancer; data from 1600 counties in the U.S. (Cohen, 1995; Health Phys. 68:157-174) Cancer Sex Cancers per 100,000 PY Lung M -8.7 ± 0.4 Lung F -9.3 ± 0.5 Oral M -10.2 ± 0.7 Oral F -11.3 ± 0.9 Larynx M -8.5 ± 0.8 Larynx F -14.1 ± 1.3 Esophagus M -4.1 ± 0.7 Esophagus F -7.9 ± 1.1 The estimated percentage change in mortality per unit radon for anatomical sites of smoking related cancer mortality (Puskin JS. 2003. Health Phys 84:526-532). Unexposed Japanese A-bomb survivors live longer! Threshold at ~200 mSv, for solid cancer mortality and leukemia (Pierce et al. Rad Res 2000. 154:178; Mine et al. 1990. Int J Rad Biol 58:1035) Nagasaki A-bomb survivors Unexposed Japanese A-bomb survivors live longer! Nagasaki A-bomb survivors Threshold at ~200 mSv, for solid cancer mortality and leukemia (Pierce et al. Rad Res 2000. 154:178; Mine et al. 1990. Int J Rad Biol 58:1035) Leukemia 50% less than expected Mean Individual Cumulative SMR, All Cancer Mortality Dose, mSv 120 0.61* 496 0.72* SMR for cancer in 10,000s of Eastern Urals residents exposed to radiation from a nuclear waste tank explosion in 1957 (*significantly less at p <0.05) Population Number of People Mean Dose (mSv) Liquidators 240,000 100 Evacuees 116,000 33 Low Contaminated Areas 5,200,000 10 High Contaminated Areas 270,000 50 1986 Chernobyl Fallout Populations Population Number of People Mean Dose (mSv) Liquidators 240,000 100 Evacuees 116,000 33 Low Contaminated Areas 5,200,000 10 High Contaminated Areas 270,000 50 1986 Chernobyl Fallout Populations Initially, using the LNT hypothesis, 53,400 excess cancer deaths were predicted over first 50 years. UN Chernobyl Forum (2006) found no increased cancer mortality. Dr. Peter Fong predicted in 1996 that >1,000,000 cancer deaths might be prevented. He may be right! Cancer deaths have been 15-30% less than expected! 1.1 1.0 SMR 0.9 0.8 0.7 0.6 0.5 90 91 92 93 94 95 96 97 98 99 Calendar Year SMR for malignant neoplasms among Chernobyl liquidators (redrawn from Health Physics 2001:81:514-521). Congenital Malformations Low radiation High radiation There were an estimated 100,000 excess abortions that resulted from fear of teratogenic effects following the Chernobyl accident. In fact, women who received high radiation doses experienced less birth defects (WHO, 2006). Odds Ratio for cancer in children whose fathers had been exposed to ionizing radiation prior to conception. Sever. Final Report U50/CCU012545-01, Battelle, Seattle, WA. 1997 Odds Ratio Dose, mSv CNS All Cancers <1 1.00 1.00 1-50 0.43 0.54 50-100 0 0.95 >100 0 0 Were ‘defective’ spermatogonia removed by apoptosis? twins/singletons Study California (Inskip et al. 1991) Connecticut Norway (Inskip et al. 1991) (Windham et al. 1985) Sweden (Rodvall et al. 1992) Total No. Twins Cancer Obs Cancer Exp RR 145,708 100 111 0.90 30,925 31 46 0.67 14, 504 14 16 0.90 35,582 59 62 0.95 226,719 204 234 0.87 Twin cohorts have a lower risk of childhood cancer than singletons despite more frequent X-rays. Hormesis in populations with internal controls Compared to all other UK physicians British Radiologists Years Joined British Radiological Societies Tolerance or Exposure Limits, mSv year-1 SMR All Cancers Lung Cancer 1897-1920 > 1000 1.75 2.46 1921-1935 700 1.24 1.06 1936-1954 70-350 1.12 0.74 1955-1979 <50 0.71 0 100 80 SMR, % 60 40 1946-79 20 Unexposed workers received the same medical care 1980-97 Mean Cumulative Dose 43 mSv 11 mSv 0 1945 1950 1955 1960 1965 1970 1975 1980 1985 1990 1995 2000 Calendar Year All cause mortality of employees of the United Kingdom Atomic Energy Authority, 1946–97. Radiation workers compared to non-radiation workers (redrawn from Occupational and Environmental Medicine 2004;61:577-585). Unexposed workers received the same medical care SMR (exposed/unexposed) Cause of Death INEEL1 12 US DOE Labs2 Shipyard3 Diseases-Blood & Blood-forming Organs 0.60 0.58 - Diseases-Respiratory System 0.72 0.86 0.56 Diseases-Digestive System 0.65 0.90 0.71 Diseases-Genitourinary System 0.70 0.65 0.36 Disease-Brain & Nervous System 0.94 0.71 0.51 Leukemia 0.89 0.92 0.93 All Tumors 0.90 0.92 0.85 All Causes 0.82 0.88 0.75 1NIOSH,2005-mean dose 13 mSv; 2NIOSH, 2000- mean dose 5.8 mSv; 3Int J Low Radiat 2005; 1:463- mean dose 97 mSv Unexposed workers received the same medical care SMR for causes of death among U.S. shipyard workers. Cumulative doses in radiation workers ranged from 5-400 mSv (Matanoski 2001). Use of small hormetic doses to treat cancer Pulmonary Metastases Total body irradiation (TBI) of mice given 12 days after tumor cell transplantation. Lung colonies counted at 20 days after TBI. (Sakamoto et al. 1997; J Jpn Soc Ther Radiol Oncol 9:161). Two clinical trials of low dose radiation therapy in patients with non-Hodgkin’s lymphoma have been published. Patients received multi-agent chemotherapy alone or added total body irradiation (TBI) or half-body irradiation (HBI). Both were effective. Radiation treatment fields of patients with non-Hodgkin’s lymphoma (Pollycove, 2004). 100mSv 3X/wk X 5wks = 1500 mSv 150mSv 2X/wk X 5wks = 1500 mSv Use of TBI or HBI non-Hodgkin’s lymphoma (Choi et al. 1979. Cancer 43:16361642). Comparison of TBI and HBI with chemotherapy and high-dose localized radiotherapy in non-Hodgkin’s lymphoma (Sakamoto et al. 1997. J Jpn Soc Ther Radiol Oncol 16:161-175). Some tumors outside the HBI field regressed completely. N = 23 N = 94 Implications of Radiation Hormesis are extremely important Current radiation protection standards do not protect against cancer; cancer results from radiation deficiency. Implications of Radiation Hormesis are extremely important Current radiation protection standards do not protect against cancer; cancer results from radiation deficiency. Radiation phobia leads to needless fear, abortions, and avoidance of medical diagnostic procedures. Implications of Radiation Hormesis are extremely important Current radiation protection standards do not protect against cancer; cancer results from radiation deficiency. Radiation phobia leads to needless fear, abortions, and avoidance of medical diagnostic procedures. Applying hormetic doses of low LET radiation for cancer therapy can extend and save many lives. Implications of Radiation Hormesis are extremely important Current radiation protection standards do not protect against cancer; cancer results from radiation deficiency. Radiation phobia leads to needless fear, abortions, and avoidance of medical diagnostic procedures. Applying hormetic doses of low LET radiation for cancer therapy can extend and save many lives. Public recognition of hormesis could save tens of billions of dollars spent in needless radiation protection and clean-up. Implications of Radiation Hormesis are extremely important Current radiation protection standards do not protect against cancer; cancer results from radiation deficiency. Radiation phobia leads to needless fear, abortions, and avoidance of medical diagnostic procedures. Applying hormetic doses of low LET radiation for cancer therapy can extend and save many lives. Public recognition of hormesis could save tens of billions of dollars spent in needless radiation protection and clean-up. The public would accept nuclear power facilities, including radioactive waste disposal sites, if they understood the beneficial effects of low LET ionizing radiation. Bias against Radiation Hormesis by Regulatory Agencies 1. All radiation is considered harmful without proof. 2. Individuals receiving low doses are included in the unexposed group. 3. Low-dose data are ignored or excluded by expressing as only ERR. 4. Low-dose data are aggregated with higher dose bins to hide evidence of hormesis. 5. Nonlinearity is not acknowledged. 6. Ecological data showing hormesis is discounted, while ecological data showing excess cancer is included. 7. Protective mechanisms (DNA repair/apoptosis) are ignored. 8. Evidence of lifespan lengthening are ignored. 9. Hormesis is attributed to the ‘Healthy Worker Effect’. 10. Years of dose accumulation are removed by dose lagging, removing threshold-like dose responses. Observations about many radioepidemiological studies 1. Ecological studies are bad if the result is not what you want, but are good if the result is what you expect. 2. Using ERR/Dose estimates derived from the LNT hypothesis, while not publishing data for individual dose points, hides beneficial effects of radiation at low doses 3. Combining low dose groups with higher dose groups hides beneficial effects of radiation at low doses 4. Claiming an increased risk of cancer whenever possible, but hesitant to admit a risk estimate that is less than expected 5. Using the healthy worker effect mantra in spite of the evidence 6. Inadequate determination of confounding biases (eg., smoking) 7. Ignoring papers and data that show hormesis 8. Redo the study to disprove hormesis 9. Denying publication because the data shows hormesis Bias in Epidemiological Studies (Ioannidis.2005. Why Most Research Findings Are False. PLOS Medicine 2:8) 1. Finding is less likely to be true when the effect size is small 2. A research finding is less likely to be true when more teams are involved in a scientific field in chase of statistical significance. 3. Selective bias entails manipulation in the analysis and reporting of findings. 4. If the effect size is very small in a scientific field, this field is likely to be plagued by ubiquitous false positive claims. 5. Prestigious investigators may suppress via the peer review process the appearance and dissemination of findings that refute their findings. 6. A meta-analysis finding from inconclusive studies where pooling is used to “correct” the low power of single studies, is probably false. 7. Investigators working in a field are likely to resist accepting that the whole field in which they have spent their careers is a “null field”. Relative Risk (RR) – observed/expected If RR >1, then there is an increased risk from expected If RR <1, then there is a decreased risk from expected Standardized Mortality Ratio (SMR) – observed/expected age-specific mortality For low doses and dose-rates in the hormetic zone, the Relative Risk (RR) at dose D is: RR = 1, for D = 0 RR = 1-PROFACE for D >0 PROFAC = 1-RR (or 1-SMR) The Protection Factor (PROFAC) gives the proportion of cancer mortality cases for low LET radiations. 100 x PROFAC = % of spontaneously expected cancers avoided, or cancers that would have occurred in the absence of radiation hormesis Each increment of 0.1 PROFAC would be expected to save 10,000 lives out of a population of 100,000 Factors influencing disease-related mortality in the U.S. (Murray et al. 2006. PloS Med 3(9). Epidemiological studies examining the relationship between radiation exposure and lung cancer include: (1) case-control studies (indoor radon), where exposure is compared in individuals with and without lung cancer (2) ecological studies (environmental radon) that compare average exposure with average lung cancer risk (3) cohort studies (uranium miners) that follow cohorts of underground miners during their lifetime, relating cumulative exposure with lung cancer rate. Case-control studies show null effect, while ecologic studies tend to show benefits from low exposures to radon. Shapes of doseresponse curves derived from epidemiological data should be treated very cautiously (Crump, 2006). Ubiquitous false positive claims are more likely in epidemiological studies when the increased risk is <100%. The results are difficult to interpret due to chance, statistical bias and effects of confounding factors. Some journals, such as the New England Journal of Medicine, do not accept epidemiological studies for publication unless the RR values are <0.5 or >3.0 (Taubes, 1995). Meta-analysis findings, with pooling of low power single studies, often prove to be false. These problems are most often seen in biomedical research (Ioannidis et al., 2001, Ioannidis, 2005, Vandenbroucke, 2004). Low dose ionizing radiations: Enhance removal of reactive oxygen species Induce repair of DNA damage Protect from chromosomal damage Protect from spontaneous DNA mutations Protect from spontaneous neoplastic transformation Enhance apoptosis Protect from spontaneous tumors in animals and humans Suppress experimental tumors and metastasis in animals Extend tumor latency in animals Activate the immune response Enhance traditional cancer therapy for lymphoma Protect from many other diseases in humans Relative Risk of All Cancer Mortality in unabridged published epidemiological studies of populations receiving low LET radiation (Sanders, 2007) 10 All Cancer Relative Risk (All Data) 1 0.1 1 10 100 Dose (mSv) 1000 Relative Risk of leukemia mortality in 86 published epidemiological studies of populations receiving low LET radiation 10 Relative Risk Nuclear Workers 10 1 All Data 0.1 10 100 1000 100 1000 Dose (mSv) 1 10 Others 0.1 1 10 100 Dose (mSv) 1000 10000 Relative Risk Relative Risk 1 1 0.1 1 10 Dose (mSv) Relative Risk of breast cancer mortality in unabridged published epidemiological studies of populations receiving low LET radiation (Sanders, 2007) 10 Breast Cancer Relative Risk (All Data) 1 0.1 1 10 100 Dose (mSv) 1000 Relative Risk of lung cancer mortality in 52 published epidemiological studies of populations receiving low LET radiation All Data 1 0.1 1 1 10 100 1000 100 1000 Dose (mSv) 10 Others 0.1 1 10 100 Dose (mSv) 1000 10000 Relative Risk Relative Risk Nuclear Workers Relative Risk 10 10 1 0.1 1 10 Dose (mSv) LNT hypothesis was mainly derived from the leukemia deaths at high doses of acute radiation: 905 leukemias observed among 86,572 Hiroshima survivors (1%) : - with dose >1 Sv, leukemia mortality increased 5 times. - with dose >2 Sv, leukemia mortality increased 14 times; represents a cohort of 2,819 survivors (3.2% of total 86,572). A cohort of 32,915 (44.5% of total 86,572 survivors) who received a dose of 5-100 mSv, had a decrease in leukemia mortality.