Time to Reject the Linear No-Threshold Theory (Carol Marcus)

OPINION PAPER/COMMENTARY

Time to Reject the Linear-No Threshold Hypothesis and Accept Thresholds and Hormesis: A Petition to the U.S. Nuclear Regulatory Commission Carol S. Marcus, PhD, MD

Abstract: On February 9, 2015, I submitted a petition to the U.S. Nuclear Regulatory Commission (NRC) to reject the linear-no threshold (LNT) hypothesis and ALARA as the bases for radiation safety regulation in the United States, using instead threshold and hormesis evidence. In this article, I will briefly review the history of LNT and its use by regulators, the lack of evidence supporting LNT, and the large body of evidence supporting thresholds and hormesis. Physician acceptance of cancer risk from low dose radiation based upon federal regulatory claims is unfortunate and needs to be reevaluated. This is dangerous to patients and impedes good medical care. A link to my petition is available: http://radiationeffects.org/wp-content/uploads/2015/03/HormesisPetition-to-NRC-02-09-15.pdf, and support by individual physicians once the public comment period begins would be extremely important.

Key Words: linear no-threshold hypothesis, radiation hormesis (Clin Nucl Med 2015;40: 617–619)

T

he linear-no threshold (LNT) hypothesis states that all radiation absorbed doses, no matter how small, have a finite probability of causing cancer. The lower the radiation absorbed dose, the lower the probability that a cancer may be caused, but the probability is never zero. The dose rate is irrelevant, and all absorbed doses are additive.

That this is not the case is evidenced by the practices of radiation oncology and of nuclear medicine therapy. The threshold concept is that no cancer will be produced until a certain radiation absorbed dose is reached. The hormesis concept is that low radiation doses are beneficial because the repair mechanisms that are stimulated by the low dose radiation reverses the initial damage and continues to protect the organism from more radiation or other noxious exposures that might otherwise lead to cancer. Eventually, there is a radiation dose high enough so that damage reversal is incomplete, and there we see the deleterious effect of radiation resulting in excess cancer production.

Prof. Edward J. Calabrese has traced the origin of LNT to shocking scientific misconduct by the nation’s leading geneticists beginning in 1956.1–3 Some members of the U.S. National Academy of Sciences Biological Effects of Atomic Radiation I (BEAR I) Genetics Panel were motivated by self-interest to exaggerate risks to promote their science and the probability of grants. Combined with the antinuclear agenda of many during the Cold War era, in which lies to produce fear of any dose of radiation were commonplace, the LNT concept caught on. Radiation regulators used the LNT as the basis of radiation safety regulation “to be conservative”, and eventually NRC added “ALARA”. LNT became a religion, not a scientifically based concept. On May 17, 2001, the U.S. Food and Drug Administration (FDA) Center for Received for publication March 12, 2015; revision accepted March 26, 2015.

From the David Geffen School of Medicine at the University of California at Los Angeles, Los Angeles, CA. Conflicts of interest and sources of funding: none declared.

Reprints: Carol S. Marcus, PhD, MD, David Geffen School of Medicine at the University of California at Los Angeles, 1877 Comstock Avenue, Los Angeles, CA 90025-5014. E-mail: csmarcus@ucla.edu.

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ISSN: 0363-9762/15/4007–0617

Devices and Radiological Health created a national uproar by stating that CT scans were causing many cases of cancer, and tried to stop self-referral of patients for CT scans to rule out early cancer and cardiac calcifications that can predict heart disease. FDA’s claims were based upon LNT. Surprisingly, physician groups such as the American College of Radiology and the Society of Nuclear Medicine did not contest any of it and meekly went along with the idea that low doses from CT and diagnostic radiopharmaceuticals could cause cancer. The race began to get radiation doses down. There was never any evidence that these groups were examining the data upon which FDA’s dire predictions were based. Also, in 2001, the NCRP published Report no. 136 entitled “Evaluation of the Linear-Nonthreshold Dose–response Model for Ionizing Radiation”4 in which they upheld the LNT. This NCRP study was funded by the NRC. In 2003, Zbigniew Jaworowski of the United Nations Scientific Committee on the Effects of Atomic Radiation (UNSCEAR) and a past Chair of that group, and Michael Waligorski, destroyed that Report’s credibility with an astonishing exposé of scientific misconduct.5 Biological organisms are exceedingly complex and have evolved in a world of stressors, particularly oxygen, and also low dose background radiation. More than 150 genes have thus far been found that are involved in the defense of organisms against noxious stimuli.6 There are several thousand papers relating to hormesis, and two textbooks in the field. This is a whole field of science that regulators pretend does not exist. Let us review some human studies whose data support radiation hormesis.

The most commonly used data are those of the Life Span Study of the Radiation Effects Research Foundation which studies the Japanese atomic bomb survivors. Recent data7 show a hormetic effect for all solid cancers in the 0.3–0.7 Gy (30–70 rad) dose range, and the study of leukemia rates in the 96,000 survivors8 showed hormesis at low doses with a threshold at about 500 mSv (50 rem).

Nuclear power plant workers comprise the largest study of radiation workers, 400,000 from 154 power plants in 15 countries,9,10 and the study showed a decrease in the risk of all cancers including leukemia. In trying to explain this, the National Academy of Sciences Biological Effects of Ionizing Radiation (BEIR) VII Committee hypothesized the “healthy worker effect”. The idea is that people who work with radiation are healthier than the general population, and get less cancer, anyway. A little thought will show the fallacy here.11 Most radiation workers begin work when they are young, when most people are healthy. Cancer is largely a disease of older people, with half the cases occurring in people over 65 years old.12 So, you have to be healthy to get old enough to get cancer. Sickly people often die young, of something other than cancer. People with hyperlipidemia die young of myocardial infarctions, people with cystic fibrosis often die early of infections, and people with juvenile onset diabetes often die early from infections, myocardial infarctions, or renal failure. The “healthy worker effect” is backwards. Hormesis is a perfectly good explanation.

Female tuberculosis patients in Canadian sanatoriums from 1930 to 1952 were followed with fluoroscopy. There were 31,710 patients who were studied for eventual breast cancer in the irradiated versus the unirradiated side.13,14 Patients who received a total radiation

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absorbed dose in the 5–30 cGy (5–30 rad) range had a breast cancer incidence up to one third less than expected. Only at doses above 50 cGy (50 rad) did the cancer incidence increase above baseline.

The radium dial watch painters are another well-studied group.

Of 900 painters studied, there were 54 bone sarcomas and 25 carcinomas of the mastoids and paranasal sinuses. None of these malignancies occurred at a bone dose of less than 10 Gy (1000 rad).15 Although these studies were not designed to demonstrate hormesis, they do show a threshold, and a very high one, for the induction of bone cancer.

After WWII, hyperthyroid patients in the United States began to be treated with NaI-131 instead of surgery. Due to questions about eventual cancer from the radiation, The Cooperative Thyrotoxicosis Therapy Follow-Up Study16 looked at leukemia rates in over 36,000 treated hyperthyroid patients. Leukemia is the most radiosensitive cancer and occurs earlier after radiation than other radiation-induced cancers. The whole-body radiation dose from the 131I was 130–140 mSv (13–14 rem). The patients who received 131I had a 22% lower leukemia rate than those treated with surgery, a result that suggests hormesis.

A Russian nuclear fuel reprocessing facility called “Mayak” exploded in 1957, sending a stream of radioactive waste affecting an area in the East Urals. Research was performed on the occupants of 22 villages evacuated from the radioactive waste zone.17 The irradiated people were divided into three groups, those who received 40 mSv (4 rem), 120 mSv (12 rem), and 500 mSv (50 rem). The cancer death rate in all three groups was lower than in the controls and reached statistical significance for the 500 mSv (50 rem) group (29% fewer cancer deaths) and the 120 mSv (12 rem) group (39% fewer cancer deaths).

In 1982, several orphan 60Co sources were recycled accidentally in the steel scrap industry in northern Taiwan. This resulted in the contamination of more than 20,000 tons of steel used in the construction of over 200 residential, industrial, and school buildings in Taiwan. This was discovered in 1992, and the exposed population was studied for cancer incidence.18 The population of 7271 people averaged about 50 mGy (5 rad) from 1983 to 2002. The standardized incidence ratios (SIR) and the 95% confidence intervals calculated for all cancers was 0.8 (0.7, 1.0), for all cancers except leukemia was 0.8 (0.6, 0.9), and for solid cancers was 0.7 (0.6, 0.9). (A SIR of 1.0 means the same as that of unirradiated controls.) The lowered cancer incidence rate was significant at the 95% confidence interval for all cancers except leukemia and for solid cancers. The lowered cancer incidence rate for all cancers was significant at the 90% confidence interval. This suggests radiation hormesis.

The issue of residential radon and lung cancer in the United States is fascinating. The seminal research of Bernard Cohen19–22 showed that increasing levels of residential radon were associated with decreasing levels of lung cancer. His data were corrected for 54 socioeconomic variables, including smoking, but the inverse correlation of radon levels with lung cancer did not change. Bobby Scott23 has shown that low level radon and its daughters cause activated natural protection against lung cancer, including smoking-related lung cancer, at levels up to the Environmental Protection Agency’s (EPA’s) action level of 4 pCi/L (about 150 Bq m−3). Somewhat above this level, the activated natural protective effect progressively goes to zero, and then we see an increase in lung cancer. Low levels of radon are hormetic. Klaus Becker has shown a similar phenomenon in data from Central Europe.24 In 1986, the Chernobyl reactor accident became a world-wide concern.25 The LNT was responsible for much of the hysteria, in which small radiation doses were multiplied by hundreds of millions of people to predict large numbers of cancer deaths. The affected population in the former Soviet Union was followed for increased cancer incidence.

According to UNSCEAR 2000b26 and the United Nations Chernobyl Forum in 2006, except for thyroid cancers in the highly contaminated areas, there was no increased incidence of leukemias or solid tumors and no evidence of increased mutations. The increase of thyroid cancers was found in children under 15 years of age in 1987, the year of the 618

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accident. However, their radiation doses were too low to have caused this, and there was no dose–response relationship. Besides, the timing was wrong—the mean latent period for radiation-induced thyroid cancer is about 28 years.27 The increase was highly likely due to a mass screening effect.25 Occult thyroid cancer is extremely common, with an autopsy prevalence in various countries of 4.5% to 36%.28,29 The finding of these “incidentalomas” is much more common with modern ultrasound techniques. A screening program in the United States uncovered a 2100% increase in thyroid nodules,30 and mandatory yearly screening in children in the contaminated areas around Chernobyl likely resulted in a similar phenomenon. According to Jaworowski,25 the natural incidence of occult thyroid cancers is about 1000 times higher than the highest incidence of reported thyroid cancers in the countries with the greatest fallout from the Chernobyl accident. The supposed finding of increased radiation-induced thyroid cancer is actually due to intense screening.31 The Chernobyl accident resulted in 28 deaths among rescue workers and employees who received 2.9–16 Gy (290–1600 rad). Three others died of different causes. The surviving workers show a 15–30% lower mortality from solid cancers than the general Russian population. The residents of the Bryansk district, with the highest contamination, had a 5% lower solid tumor incidence than the controls.25 Good reviews on molecular mechanisms of hormesis and related findings may be found in the articles by Tang and Loke32 and Brooks and Dauer.33 While the United States has so far refused to drop the LNT, that is not the case with France. It is interesting to compare a joint report of the French Academy of Sciences and of the French Academy of Medicine34 on low dose radiation carcinogenic effects, published in 2005, shortly before a comparable report of BEIR VII/Phase 2 of the National Academy of Sciences–National Research Council35 was published.

Covering the same questions, the two groups came to different conclusions.36 The French report finds that there are no convincing data showing increased cancer in adults, children, or infants receiving doses under about 100 mSv (10 rem). They therefore find that the LNT greatly overestimates the risk of these low doses, and its use is unjustified and should be discouraged for doses below 20 mSv (2 rem). In contrast, the BEIRVII report concludes that “The committee judges that the balance of evidence from epidemiologic, animal, and mechanistic studies tends to favor a simple proportionate relationship at low doses between radiation dose and cancer risk. Uncertainties on this judgment are recognized and noted.” The BEIR VII report does not consider the cancer threshold data of the radium dial watch painters or that of patients in whom Thorotrast was used as an early x-ray contrast agent (liver dose of 2 Gy [200 rad] required for hepatomas). The French report does.

The two groups differ in their interpretation of the results of the Hiroshima/Nagasaki Life Span Study. The French report finds no significant increase in cancer after doses below 100 mSv (10 rem), whereas the BEIR VII report lumps the low dose data with the higher dose data to find cancer increases. Animal studies have not shown increased cancer at doses below 100 mSv (10 rem); many show thresholds and about 40% show hormesis. The French report points out the high efficacy of DNA repair mechanisms and apoptosis (death of damaged cells), whereas the BEIR VII report minimizes this research because all the mechanisms have not yet been worked out. An important difference between the two reports concerns in utero radiation. Although the BEIR VII report concludes that fetal doses of 10–20 mSv (1–2 rem) caused increased levels of leukemias and solid cancers, the French report doubts a causal relationship because this represents a biased sample of fetuses in which only pregnant women with problems were subjected to x-ray studies. The randomly irradiated fetuses in the Hiroshima/Nagasaki Life Span Study showed no such cancer increase, nor have post partum twin studies where one was irradiated and the other was not. More detailed comparisons are in.36 It is interesting to note that the BEIR VII report was funded by the EPA, the NRC, and © 2015 Wolters Kluwer Health, Inc. All rights reserved.

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Clinical Nuclear Medicine • Volume 40, Number 7, July 2015

the NIST. As EPA and NRC programs are based upon the LNT, there is the appearance of a conflict of interest.

In conclusion, my petition to the NRC makes several recommendations: 1. Worker dose limits should remain at present levels, with allowance of up to 100 mSv (10 rem) effective dose per year if the doses are chronic.

2. ALARA should be removed entirely from the regulations, as it makes no sense to decrease radiation doses that are not only harmless but may be hormetic.

3. Public dose limits should be raised to worker dose limits, as these low doses may be hormetic.

4. End differential doses to pregnant women and children under 18 years of age.

Obviously, many regulations will have to change if NRC drops the LNT, including much of the medical program, but stopping reliance on the LNT is the first step.

When the public comment period opens, I urge you to submit a personal comment, perhaps explaining how ending the LNT as the basis for radiation safety regulation will impact your medical practice.

REFERENCES 1. Calabrese EJ. The genetics panel of the NAS BEAR I Committee (1956): epistolary evidence suggests self-interest may have prompted an exaggeration of radiation risks that led to the adoption of the LNT cancer risk assessment model. Arch Toxicol. Published online: 04 July 2014. DOI 10.1007/s00204-014-1306-7.

2. Calabrese EJ. An abuse of risk assessment: how regulatory agencies improperly adopted LNT for cancer risk assessment. Arch Toxicol. Published online: 18 January 2015. DOI 10.1007/s00204-015-1454-4.

3. Calabrese EJ. Cancer risk assessment foundation unraveling: new historical evidence reveals that the U.S. National Academy of Sciences (US NAS), Biological Effects of Atomic Radiation (BEAR) Committee Genetics Panel falsified the research record to promote acceptance of the LNT. Arch Toxicol. Published online: 20 January 2015. DOI 10.1007/s00204-015-1455-3.

4. NCRP Report No. 136: Evaluation of the Linear-Nonthreshold Dose–response Model for Ionizing Radiation. Bethesda: NCRP; 2001.

5. Jaworowski Z, Waligorski M. Problems of U.S. policy on radiation protection.

EIR Science and Technology. 2003:18–26.

6. Cutler JM. Remedy for radiation fear—discard the politicized science. Dose Response.

2014;12:170–184.

7. Ozasa K, Shimizu Y, Suyama A, et al. Studies of the mortality of atomic bomb survivors, report 14, 1950–2003: an overview of cancer and noncancer diseases.

Radiat Res. 2012;177:229–243.

8. Cuttler JM. Leukemia incidence of 96,000 Hiroshima atomic bomb survivors is compelling evidence that the LNT model is wrong. Arch Toxicol. 2014;88: 847–848.

9. Cardis E, Vrijheid M, Blettner M, et al. The 15-country collaborative study of cancer risk among radiation workers in the nuclear industry: estimates of radiationrelated cancer risks. Radiat Res. 2007;167:396–416.

10. Verifying Canadian nuclear energy worker radiation risk: a reanalysis of cancer mortality in Canadian nuclear energy workers (1957–1994): summary report.

Minister of Public Works and Government Services Canada, Canadian Nuclear Safety Commission; 2011: Catalogue number CC172-65/2011E-PDF. ISBN 978-1-100-17760-1.

11. Marcus CS, Stabin MG, Siegel JA. The “healthy worker” effect could be backwards! Health Physics News. 2011:14.

Reject LNT and Accept Thresholds/Hormesis

12. Wallis C. Never too old for chemo. Sci Am. 2014:34–36.

13. Cuttler JM, Pollycove M. Can cancer be treated with low doses of radiation? J Am Phys Surg. 2003;8:108–111.

14. Miller AB, Howe GR, Sherman GJ, et al. Mortality from breast cancer after irradiation during fluoroscopic examinations in patients being treated for tuberculosis.

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15. Rowland RE. Dose and damage in long term radium cases. In Cloutier RJ, Edwards CL, Snyder WS, eds. Medical Radionuclides: Radiation Dose and Effects. Proceedings of a symposium held at the Oak Ridge Associated Universities Dec. 8–11, 1969, CONF-691212. Springfield VA, Clearinghouse for Federal Scientific and Technical Information, National Bureau of Standards, U.S. Dept. of Commerce; 1970:369–386.

16. Tompkins E. Late effects of radioiodine therapy. ibid. 1970:431–440.

17. Kostyuchenko VA, Krestinina LY. Long-term irradiation effects in the population evacuated from the East-Urals radioactive trace area. Sci Total Environ. 1994;142: 119–125.

18. Hwang SL, Guo HR, Hsieh WA, et al. Cancer risks in a population with prolonged low dose-rate γ-radiation exposure in radiocontaminated buildings, 1983–2002.

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19. Cohen BL. Expected indoor 222Rn levels in counties with very high and very low lung cancer rates. Health Phys. 1989;57:897–907.

20. Cohen BL. Test of the linear-no threshold theory of radiation carcinogenesis for inhaled radon decay products. Health Phys. 1995;68:157–174.

21. Cohen BL. Lung cancer rate vs. mean radon level in U.S. counties of various characteristics. Health Phys. 1997;114–119.

22. Cohen BL. The linear no-threshold theory of radiation carcinogenesis should be rejected. J Am Phys Surg. 2008;13:70–76.

23. Scott B. Residential radon appears to prevent lung cancer. Dose–response. 2011; 9:444–464.

24. Becker K. Health effects of high radon environments in central Europe: another test for the LNT hypothesis? Nonlinearity in Biology, Toxicology, and Medicine.

2003;1:3–35.

25. Jaworowski Z. Observations on Chernobyl after 25 years of radiophobia. 21st Century Science and Technology 2010; summer: 30–45.

26. UNSCEAR 2000b. United Nations Publication Sales No. E.00.IX.4; ISBN 92-1142239-6.

27. Cohen BL. Lung cancer rate vs. mean radon level in U.S. counties of various characteristics. Health Phys. 1997;72:114–119.

28. Moosa M, Mazzaferri EL. Occult thyroid carcinoma. Cancer J. 1997;10:180–188.

29. Tan GH, Gharib H. Thyroid incidentalomas: management approaches to nonpalpable nodules discovered incidentally on thyroid imaging. Ann Intern Med. 1997;126:226–231.

30. Ron E, Lubin J, Schneider AB. Thyroid cancer incidence. Nature. 1992;360:113.

31. Jargin SV. Chernobyl-related cancer and precancerous lesions: incidence increase vs. late diagnostics. Dose Response. 2014;12:404–415.

32. Tang FR, Loke WK. Molecular mechanisms of low dose ionizing radiationinduced hormesis, adaptive responses, radioresistance, bystander effects, and genomic instability. Int J Radiat Biol. Published online, pp1–15, 2014. ISSN 0955-3002 print/ISSN 1362-3095 online. DOI: 10.3109/09553002.2014.937510.

33. Brooks AL, Dauer LT. Advances in radiation biology: effect on nuclear medicine.

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34. Joint report no2, Académie Nationale de Médecine, Institut de France—Académie des Sciences: dose-effect relationships and the estimation of the carcinogenic effects of low doses of ionizing radiation. Edition Nucleon (Paris 2005) ISBN 2-84332-018-6.

35. BEIR VII, Phase 2. National Academy of Sciences–National Research Council: health risks from exposure to low levels of ionizing radiation. National Academies Press, 2006, Washington, D.C. ISBN 0-309-53040-7 (pdf ).

36. Tubiana M, Aurengo A, Averbeck D, et al. Recent reports on the effect of low doses of ionizing radiation and its dose-effect relationship. Radiat Environ Biophys. 2006;44:245–251.

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