Changing Attitude Toward Radiation Carcinogenesis and Prospects for Novel Low-Dose Radiation Treatments

Abstract

All procedures involving ionizing radiation, whether diagnostic or therapeutic, are subject to strict regulation, and public concerns have been raised about even the low levels of radiation exposures involved in diagnostic imaging. During the last 2 decades, there are signs of more balanced attitude to ionizing radiation hazards, as opposed to the historical “radiophobia.” The linear no-threshold hypothesis, based on the assumption that every radiation dose increment constitutes increased cancer risk for humans, is increasingly debated. In particular, the recent memorandum of the International Commission on Radiological Protection admits that the linear no-threshold hypothesis predictions at low doses (that International Commission on Radiological Protection itself has used and continues to use) are “speculative, unproven, undetectable, and ‘phantom’.” Moreover, numerous experimental, ecological, and epidemiological studies suggest that low doses of ionizing radiation may actually be beneficial to human health. Although these advances in scientific understanding have not yet yielded significant changes in radiation regulation and policy, we are hopeful such changes may happen in the relatively near future. This article reviews the present status of the low-dose radiation hazard debate and outlines potential opportunities in the field of low-dose radiation therapy.

Controversy Over the Linear No-Threshold Hypothesis

Ionizing radiation in high doses is undoubtedly carcinogenic. However, its carcinogenicity is relatively weak in comparison to the natural cancer rate. For example, the total number of excess cancer deaths among the atomic bomb survivors until 2003 (inclusively) was about 600, while above 10 000 of them died of cancer due to natural reasons unrelated to the bombing. ¹

The linear no-threshold (LNT) hypothesis (LNTH) of radiation-induced cancers implies that every dose of ionizing radiation, no matter how small, constitutes increased (linear with the dose) cancer risk. This hypothesis, which became well established for use in radiation safety during the Cold War era, is the basis for current radiation safety regulations. The LNTH is also widely accepted by the general public. However, the scientific validity of this hypothesis has been questioned and debated for many decades without resolution. Actually, due to the fact that ionizing radiation is a rather weak carcinogen, LNTH cannot be either proven or rejected based on human statistics. The disagreement on this issue in the scientific community has always been acknowledged by the relevant professional bodies, including the US Congress Office of Technology Assessment. ² The US National Council on Radiation Protection and Measurements formulated in 1995:

… essentially no human data can be said to prove or even to provide direct support for the concept of collective dose (LNTH—Y.S. and J.S.W.) with its implicit uncertainties of nonthreshold, linearity and dose-rate independence with respect to risk. The best that can be said is that most studies do not provide quantitative data that, with statistical significance, contradict the concept of collective dose

Two recent examples given subsequently demonstrate how mistreatments of experimental data continue to lend support to the LNTH.

Atomic Bomb Survivors

The results of the atomic bomb survivors’ follow-up are often claimed to support the LNTH. ¹ However, this claim is baseless. Given limited statistical power of the follow-up study, the cancer mortality of the survivors is equally or better described by an S-shaped dependence on radiation exposure, ^3,4 with a threshold of about 0.3 Sv and saturation level at about 1.5 Sv (Figure 1, left). Moreover, Monte Carlo simulation of possible outcomes demonstrates that given the weak statistical power, the follow-up cannot provide support for LNTH. The data that were generated according to S-shaped (a priori) distribution (with variance Var = 1) could be well described (a posteriori) by a straight line (average Var ≈ 1.5), as shown at Figure 1, right. For example, if we use fit variance Var > 2.0 as a cut value to exclude LNTH, we have to reject the correct S-shaped description in about 0.5% of cases (7 of 1000 in this simulation), and still we have to accept LNTH in nearly 90% of cases (877 of 1000 in this simulation).

Figure 1.

The cancer mortality of the survivors can be described by an S-shaped dependence on radiation exposure with a threshold of about 0.3 Sv and saturation level at about 1.5 Sv, and such description is not worse than the linear one (left). Moreover, Monte Carlo simulation of possible outcomes demonstrates that given the weak statistical power, the follow-up cannot provide support for linear no-threshold hypothesis (LNTH; right). Source: Adapted from Socol. ³

Computed Tomography Scans and Childhood Cancer

Computed tomography (CT) scanning is a highly valuable diagnostic technique, and new applications continue to be identified. However, the increasing use of CT scans is being challenged by emerging concerns regarding carcinogenesis from the ionizing radiation. Pearce et al ⁵ made a significant contribution to the above-mentioned concerns by claiming, probably for the first time, evidence for direct association of the radiation from CT scans with cancer. Their interpretation of the data has been criticized because of the uncertainty of the CT doses, the lack of information on clinical data of the examined patients, and the possibility of reverse causation (ie, cancers may have been caused by the medical conditions prompting the CT scans rather than by the CT dose). ^6,7 In addition to the above-mentioned criticism, it has been noticed that data points on cancer relative risk versus CT dose in their publication fit LNTH straight lines suspiciously well, taking into account relatively large statistical errors (Figure 2). ³ Rigorous statistical analysis ⁸ demonstrates quantitatively that the data are statistically inconsistent with the LNTH being “too good to be true”: the probability of both fits to be that good or better simultaneously is 2% only (P = .02, below the generally assumed statistical significance threshold of P = .05). The credibility of the data is therefore compromised, and most probably, some kind of data manipulation was performed, possibly unknowingly, by Pearce et al.

Figure 2.

The data points on cancer relative risk versus computed tomography (CT) dose reported by Pearce et al ⁵ fit linear no-threshold hypothesis (LNTH) straight lines suspiciously well, taking into account relatively large statistical errors. By applying rigorous statistical analysis, ⁸ one can see that the probability of both fits to be that good or better simultaneously is 2% only. The credibility of the data is therefore compromised. Most probably, some kind of data manipulation was performed, possibly unknowingly, by Pearce et al. Source: Adapted from Socol. ³

Beneficial Health Effects of Low Doses

Furthermore, there is phenomenon called “hormesis,” which is a consequence of adaptive response: Although large amounts of some factor are detrimental, small doses are beneficial. Classical examples of hormesis are physical exercise (as opposed to extreme forced labor) and immunization (as opposed to infection). Low doses of biologically active ultraviolet radiation are also hormetic—limited sun exposure (as opposed to sunburns and skin cancer caused by overexposure) allows biosynthesis of the critically important hormone/nutrient, vitamin D. Numerous experimental and epidemiological studies show that low doses of ionizing radiation are hormetic. For example, in most of the nuclear industry worker studies, the rate of cancer mortality (as well as overall mortality) among the radiation workers is substantially lower than that in the reference population—see, for example, the US shipyard worker study. ⁹ Radon treatment is definitely not considered to be an “alternative therapy” by the mainstream medicine in Europe, especially for treating arthritis and other inflammatory diseases. Superiority of radon therapy when compared to a control intervention in rheumatic outpatients has been recently reported. ¹⁰ Actually, the healing properties of radon spas have been utilized for many centuries—as described by Herodotus and Hippocrates for springs with high concentration of radon in their water, as we know now. The above-mentioned facts and many others ^11,12 comprise emerging scientific support for the radiation hormesis hypothesis.

Low-dose total body irradiation (TBI) for cancer treatment (as opposed to high-dose localized tumor irradiation) has been studied decades ago in the United States ¹³ and, more recently, mainly in Japan. ¹⁴ It remains possible that the biological mechanism of action of this type of radiation therapy is immunologically mediated. In a study by Sakamoto et al, ¹⁵ TBI or half body irradiation was given by 15 times of 10 cGy or 10 times of 15 cGy (total 1.5 Gy) for 5 weeks (single-exposure threshold for blood count change is about 25 cGy; for acute radiation syndrome, 100 cGy). In this study, 84% of patients with leukemia non-Hodgkin lymphoma who underwent low-dose TBI supplementary treatment survived 9 years. In the control group, the 9-year survival rate was only 50%.

Recent Trends

Although the use of LNTH is still commonplace, there are at least 3 positive signs with reference to its eventual overthrow. These are (1) offensive on LNTH and defensive stance of LNTH supporters, (2) softening of the advisory bodies’ position on LNTH, and (3) pronuclear changes in Japan.

Offensive on LNTH

In 2013, a new international professional action group was formed: Scientists for Accurate Radiation Information (SARI). After its first year of existence, the group includes above 80 members—health professionals, physicists, educators, and writers. The SARI has created an easy-to-use Web site (http://RadiationEffects.org) stocked with useful reference documents. The group wrote open letters to officials and official bodies (including the Prime Minister of Japan), professional societies, and radiation health effects advisory groups. The SARI members have published journal articles and provided coordinated comments.

Two recent publications should be specially mentioned since they show a new trend. Namely, these are disputes where the LNTH supporters take defensive positions instead of just ignoring the anti-LNTH evidence, which was a standard practice in the past. In one case, ^16,17 Ralph Cicerone, the US National Academy of Sciences’ President, defends his position against Edward Calabrese, the chairman of the International Dose-Response Society. In the second case, ¹⁸ Mark Little, co-author of the above-discussed article claiming association of cancer with CT scans, defends his position against Mohan Doss, one of the active SARI members.

Softening of the Advisory Bodies’ Position on LNTH

The recent memorandum of the International Commission on Radiological Protection (ICRP) Task Group ¹⁹ contains the following statement:

While prudent for radiological protection, the LNT model is not universally accepted as biological truth …

Speculative, unproven, undetectable and ‘phantom’ numbers are obtained by multiplying the nominal risk coefficients by an estimate of the collective dose received by a huge number of individuals theoretically incurring very tiny doses that are hypothesised from radioactive substances released into the environment (highlighted by Y.S. and J.S.W.).

So the Task Group of the ICRP, one of the main bodies promoting the LNT model, admits that LNT predictions at low doses are “speculative, unproven, undetectable, and ‘phantom’,” raising the reasonable wonder how such a model can be “prudent for radiological protection.” The position of ICRP toward LNTH (ie, that LNTH should not be used for a posteriori estimation of cancer cases and deaths) is not new but has never been formulated earlier in such unambiguous expressions.

Another example is the position of the International Atomic Energy Agency (IAEA). In its recent document, ²⁰ IAEA stated that in case of nuclear power plant accident, radiation level below 2.5 mrem/hour (about 100 times natural background) is “safe for everyone.” This statement, although made with several comments, should be viewed as big progress in respect to the usual position “there is no safe level of radiation.” And, just an additional example, United Nations Scientific Committee on the Effects of Atomic Radiation in its 2013 report to the UN Assembly ²¹ predicted “no discernible health effects” of the Fukushima nuclear accident.

Japan: Pronuclear Changes

After the Fukushima accident in March 2011, about 160 000 residents of the Fukushima prefecture have been evacuated, and all the nuclear power plants in Japan were stopped due to the radiation concerns. During 2013 to 2014, however, the attitude to the radiation hazards began to change. One can mention at least 3 important developments. Already in mid-2012, the government began partial resettlement of the Fukushima prefecture. ²² Furthermore, in June 2015, the Cabinet decided a plan to lift evacuation orders so that residents will likely be given the option of returning to areas where doses are as high as 50 mSv/year, by the end of March 2017. ²³ In February 2014, Yōichi Masuzoe, known for his pronuclear views, was elected governor of Tokyo. In April, the Japanese cabinet approved the new energy strategy, effectively scrapping the after-Fukushima plans for nuclear power phase out. ²⁴

Applications

As discussed earlier, use of low-dose radiation in the treatment (and prophylaxis) of cancer is extremely interesting. ¹¹ It seems that low-dose TBI may substitute for chemotherapy for some types of cancer, especially for nonlocalized hematological malignancies such as leukemia or lymphoma. However, such research is presently in a very preliminary stage.

On the other hand, the anti-inflammatory action of low-dose ionizing radiation is well known. As mentioned above, the antiarthritic action of radon springs has been utilized for centuries. Moreover, during the first half of the 20th century, ionizing radiation was very successfully utilized for the treatment of many inflammatory and infectious conditions. For example, from 1940 through late 1960s, an estimated 500 000 to 2 million individuals, mostly children, were treated with nasopharyngeal radium irradiation (NRI) in the United States alone to treat hearing loss, chronic otitis, and other conditions. ²⁵ Neither carcinogenesis nor other adverse long-term effects of NRI were reported. ²⁶ Two simultaneous trends slowed and ultimately stopped all noncancer use of irradiation: development of effective antibiotics and emerging concerns regarding carcinogenesis from low-dose radiation. Presently, there are serious concerns about development of antibiotic-resistant disease bacteria. ^27,28 With declining efficiency of antibiotic treatment, low-dose irradiation may reemerge as a vital and viable alternative.

Conclusion

During the last 2 decades, the attitude to ionizing radiation hazards has been becoming more balanced, as opposed to the historical “radiophobia.” The LNTH, based on the assumption that every radiation dose increment constitutes increased cancer risk for humans, is more and more debated. Particularly, the recent memorandum of the ICRP admits that the LNTH predictions at low doses are “speculative, unproven, undetectable and ‘phantom’.” Moreover, numerous experimental, ecological, and epidemiological studies show that low doses of ionizing radiation may be beneficial to human health.

Therefore, use of low-dose irradiation for low-dose radiation in the treatment (and perhaps even prophylaxis) of cancer, first studied 4 decades ago, is extremely interesting. It seems that low-dose irradiation may substitute for chemotherapy for some types of cancer, especially for hematological malignancies.

Another important field of medical applications is related to anti-inflammatory action of low-dose ionizing radiation: antiarthritic action of radon springs has been utilized for centuries. Moreover, during the first half of the 20th century, low-dose ionizing radiation was very successfully utilized for the treatment of many inflammatory and infectious conditions, including treatment of inner ear infections in children. With the emergence of numerous antibiotic-resistant bacterial strains, low-dose irradiation may return as a vital and viable alternative.