Society,Nuclear Energy and Radiological Protection - Beyond LNT

Abstract

In a recent paper, Allison (Health Phys. 2024) proposed that a daily limit of 2 mGy will adequately protect the general public and radiation workers against any health-threatening effects of ionizing radiation. The 2 mGy/day limit, established at the 1934 Congress of Radiology for radiologists exposed to diagnostic X-rays, is over 500 times that currently recommended by ICRP for the general public. This illustrates the severe over-restrictiveness and irrationality of the present LNT-based system of radiological protection that is recommended by ICRP and NCRP and is legally implemented worldwide. To stimulate further discussion on developing a more rational “post-LNT” system, we indicate and briefly discuss some relevant publications, which also present arguments which could be helpful in managing radiation risk and in reducing public fear of nuclear radiation. Society should then become more willing to accept and appreciate the unique opportunities offered by nuclear technology, especially in health care and energy production.

We read with great interest the comprehensive review by Dr Wade Allison ¹ on the socioeconomic impact of the present ICRP-designed system of radiological protection, which is implemented legally world-wide. We also noted Dr Allison’s allusion to road traffic regulations when discussing the legal aspects of radiation risk management. By considering the published data on bone cancer (osteogenic sarcoma) occurrence in radium dial painters, the mortality of people involved in the 1987 Goiania accident after their irradiation by high doses of ¹³⁷Cs gamma-rays, and the experiment where dogs were chronically irradiated at different dose rates throughout their lives, Allison concludes that a daily limit of 2 mGy for any kind of radiation (as established at the 1934 Congress of Radiology for radiologists exposed to diagnostic X-rays), will adequately protect the general public and most radiation workers against any health-threatening effects of ionizing radiation. As proposed by Dr Allison, this evidence-based dose limit is over seven hundred times higher than the present limit of 1 mSv/y (or 1 mGy/y, for X- or γ-rays) currently recommended for the general public by the ICRP and NCRP.

Here, we offer additional comments on this interesting work to stimulate further discussion on delivering a scientific basis for an evidence-based, “post-LNT” system of radiological protection.

Introduction of the limit proposed by Allison would rectify the present gross overestimation of the alleged health hazard from nuclear radiation, which introduces not only excessive costs of applying radiation technology (e.g., in medicine) but also inhibits broader reliance on nuclear power. The sensationalistic and hyperbolically negative public portrayal of any radiation accident has resulted in “radiophobia” – social distrust and fear of anything nuclear. Such are the long-term consequences of deciding, some 80 years ago, to base the system of radiological protection on the linear no-threshold (LNT) hypothesis of radiation action on living organisms, and humans in particular. Notably, as recommended by ICRP, over the years these limits have grown systematically more stringent—yet with no evidence-based justification.

Since the LNT-based dose-response dependence implies that even the tiniest absorbed dose augments the probability of developing a fatal radiogenic cancer, this probability must rise linearly with accumulated dose, from zero at zero exposure (this assumption not being experimentally verifiable). Under the LNT model, the possibility of any radiation-induced molecular or cellular damage repair is ignored; the model assumes no capacity for reversal of DNA damage or removal of severely damaged cells. There is abundant evidence to the contrary – living organisms can and do efficiently repair DNA damage, provided it is not catastrophically overwhelming. Much is now known about such DNA repair in the context of the normal oxidative stress imposed by living in an oxygen-rich environment. The actual use of such oxygen by aerobic cells forces a delicate balance between the systemic manifestations of reactive oxygen species (ROS) and a biological system’s ability to detoxify the reactive intermediates or to repair the resulting damage. For billions of years now, aerobic organisms have had to cope with oxidative stress due to oxygen-dependent respiration, which generates far more of the universal biochemical energy “currency” (ATP) than anaerobic fermentation can. But, as a consequence of moving to this far more efficient mechanism of energy production, eukaryotic (and some prokaryotic) cells have had to develop efficient means of coping with by-products of such aerobic respiration - endogenously-generated free radicals and ROS which are potent DNA damaging factors. Thus, the tremendous advantage in energy (ATP) production conferred by aerobic respiration – which powers the complex processes of cellular division, metabolism, communication and repair, acting at all structural levels of the living organism (atoms, molecules, cells, tissues, or whole body) – is offset by copious production of endogenous ROS. Cells have, over millions of years of evolution, learned to effectively take advantage of the availability of oxygen to meet their energy needs while simultaneously being able to deal with the chemical consequences of aerobic respiration. Having learned to cope with such endogenously generated free radicals and ROS has at the same time equipped cells with the capacity to handle low levels of exogenously-generated reactive chemical species, such as those produced via ionizing radiation: X-rays, gamma-rays, or energetic ions. The biochemistry is and has been the same for billions of years.

In their seminal article, ² Dr Myron Pollycove and the late Professor Ludwig F. Feinendegen quantitatively evaluated the relative contributions of the generally indistinguishable endogenous and exogenous (e.g. from radiation) ROS to cancer development in humans. They conclude: “…the various forms of non-radiation DNA damage in tissues far outweigh corresponding DNA damage from low-level radiation exposure at the level of, and well above, background radiation.” By referring to published experimental data and applying reasonable assumptions where necessary, Pollycove and Feinendegen ² estimated the rate of cellular DNA damage events arising mainly from normal oxygen metabolism by way of ROS at some 10⁶ per cell per day. The successive probability of a single nucleotide (of the 6 x 10⁹ base pairs in a diploid human cell ³ ) being damaged by endogenous ROS would then, on average, be 1.5 x 10^-4 per cell, per day. In the case of exogenous whole-body irradiation by background gamma-rays at a dose rate of 1 mGy per year, each cell weighing approximately 1 ng, will on average, receive one hit (i.e., one single track event) per year. Each hit will then possibly cause some two DNA alterations, hence, on average, about 5 x 10^-3 such single nucleotide alterations in a cell per day would occur. At such a low level, any bystander effects or the likelihood of a minute fraction of cells being hit by natural high-LET radiation (such as alpha-rays), as well as the possibility of generating lasting functional changes, would be negligible. The ratio of the above-quoted endogenous-to-exogenous DNA alterations is then some 10⁶/(5 x 10^-3) = 2 x 10⁸. This huge ratio indicates that the existing complex molecular repair system that addresses DNA damage and assures cellular integrity must have evolved in response to organisms living in an oxygen-rich environment and actively breathing oxygen, rather than being due to elevated natural background radiation dose rates in the distant geological past. This implies an inherent ability of aerobically respiring cells to tolerate low doses of ionizing radiation, demonstrating the potential ability of the repair system to recognize and correct DNA damage from doses and dose rates of external radiation higher, by many orders of magnitude, than those from natural sources observed in the environment. While external radiation dose will then mathematically cumulate linearly, the dynamic response of an exposed biological system is neither cumulative nor will it rise linearly with linearly increasing dose of external exposure. At low levels of radiation exposure, the system as a whole may adapt to the resulting oxygen stress through its internal mechanisms of homeostasis. In their article, Pollycove and Feinendegen ² also discuss homeostasis and adaptive response of cells, which result in a partly beneficial, non-linear, bi-phasic (or hormetic) dose response after low externally applied doses of ionizing radiation. To put the above comments in context, it may be useful to remind readers of the “oxygen enhancement effect,” in which oxygen acts as a potent radiosensitizer, making X-rays, electrons, and other low-LET radiation 2 to 3 times more effective at damaging DNA than under anoxic (anaerobic) conditions.^4,5 This occurs in part because oxygen fixes (makes permanent) the radiation-induced free radical damage to DNA. Furthermore, aerobic respiration with its use of molecular oxygen, generates free radicals (in the absence of additional radiation) that cells have learned to cope with. In fact, molecular oxygen itself is a potentially reactive, free bi-radical that, upon reduction to water, generates various intermediates that are chemically identical to the radiolysis products of ionizing radiation in aqueous media. ⁶

Indeed, using Bayesian techniques, a hormetic dependence of excess relative risk (EER) of solid cancer versus radiation dose over the range 0-10 mSv of absorbed colon dose could be fitted by Dr Shizuyo Soutou and colleagues ⁷ to the Hiroshima & Nagasaki Life Span Study data presented in the BEIR VII report. While such fit does not unequivocally prove hormesis, it is clear that over the 0-0.2 Gy dose region, negative values of excess relative risk - i.e., beneficial and non-linear effects - are observed. We note that, mathematically, for any non-linear dose-response function, neither linear averaging nor summation over sets of individual data points is possible. Similarly, calculations of the equivalent dose, in Sieverts (Sv) from the absorbed dose (in Gy) using the ICRP-recommended linear radiation factors (w_R) and tissue coefficients (w_T) are not possible either. Thus, mathematically, the LNT assumption on which the present system of radiological protection is based, falls apart like a house of cards. Should it then be replaced by a more realistic dose-effect dependence, such as a power-law or a threshold model? Mathematically, in neither case would linear radiation factors (w_R) and tissue coefficients (w_T) be applicable. Moreover, dose-effect dependences may vary – also in non-linear fashion - with applied dose rates.

In standard procedures of megavolt photon cancer radiotherapy, up to 39 daily 2 Gy dose fractions are regularly delivered to a tumour target volume at dose rates of about 1 Gy/minute or more - higher than a natural background dose rate of 1 mGy/year by a factor of some 5 x 10⁹, and, per absorbed dose, by some 5 x 10^{5 –} – for just a single 2 Gy daily dose fraction. The analysis by Pollycove and Feinendegen ² suggests that damage by exogenous ROS would then approach that from endogenous ROS, saturating the DNA repair system under ordinary circumstances. Of course, exposure to such radiation-induced exogenous ROS will stimulate natural repair mechanisms and raise damage repair enzyme levels above baseline activity. This will help normal tissues recover from the daily radiation therapy fractions, even when repeated 30 or more times. In contrast, thanks to their emphasis on cellular proliferation and growth rather than repair, limited or no repair of the extensive, exogenously-induced DNA damage is expected in cancer cells. Consistent with Poisson statistics, the curative intent of cancer radiotherapy requires that all tumour cells be inactivated, some by multiple overkill. Leaving only one cell alive, on average, will theoretically lead to a 37% (1/e) chance of cancer control (i.e. a 63% chance of recurrence).

Somewhere between the above-discussed ranges of low-dose and low dose-rate external exposures and the respective ranges applied in cancer radiotherapy, there lies a boundary between these two very different mechanisms of radiation action. Establishing the range of such dose- or dose-rate dependent boundaries could provide us with a “biological border” – scientific evidence supporting the choice of limits of dose and dose-ranges to be applied in a post-LNT system of radiological protection, also supporting past and new advances in low-dose radiotherapy. ⁸ Due to mechanistic differences in the cellular DNA repair processes, LNT-based downward extrapolation from the high dose-rate and high absorbed dose region to that of low dose-rates and low doses is not rational. In this context, we draw attention to the review by Sacks, Meyerson and Siegel ⁹ who illustrate the largely conjectural character of statistical LNT-based and recently published epidemiological analyses of data sets for several cohorts.

As all molecular repair processes of radiation-induced DNA damage are typically completed within a few hours after exposure, Dr Allison proposes a one-day (24 hour) reporting period – for low doses and low dose-rate exposures not exceeding 2 mGy/day. For more exotic radiation environments, such as space—where naked nuclei and high-LET radiation prevail, and where high doses or dose-rates may exceed Allison’s limit, further research should guide the design of a suitable system of radiological protection. “Bursts” of high doses and dose-rates, perhaps briefly saturating the DNA repair system, may then occur – due not only to the high-LET values involved, but also to the short time it takes an energetic ion to travel through a cell. Such “bursts” may need to be recorded and reported. How would such “bursts” affect repair of radiation-induced DNA damage requires further study – as indeed does a review of the estimates of Pollycove and Feinendegen developed over twenty years ago.

Do we need detailed knowledge of the dose-response curve in humans before we develop a post-LNT system of radiation protection? No. By analogy with traffic safety regulations, no detailed models of vehicular motion, of vehicle control as driven over different road surfaces, nor of human apprehension and response to sudden unexpected events, were needed before effective rules and regulations were implemented. Speed limits and other traffic regulations were developed independently in different countries by their national authorities as based on evidence and experience. These were gradually modified as car and road construction technology advanced – in order for the individual risk from driving a car at a given speed not to be excessive, compared with individual risks due to other human activities – but never to be completely eliminated. In good weather conditions and in a good car, safe driving at speeds exceeding the posted speed limit is certainly possible – but would still be legally penalised, if recorded by the police. Note that it is speed (like dose-rate or dose per episode) and not distance travelled (like cumulative absorbed dose) that is limited. Note also the similarity between road traffic regulations implemented in different countries – achieved due to their common goal of managing social risks of driving a car—against social risks from other occupations. Is radiation hazard so unique that world-wide coordination is required? It is the duty of the national regulator to guard and maintain the safety of citizens of any country.

As offered by Dr Allison, to adequately protect the general population from ionizing radiation on Earth, no restrictions below the 2 mGy/day limit would need to be observed for any radiation quality. In social management of radiation risk over the low-dose/dose rate region, the present legally enforced limits and measures, including the scientifically unverifiable ALARA and precautionary principles, the Sievert, and collective or committed dose – all relying on the LNT paradigm – would no longer be required.

A final point to consider is public education in radiation risk management, a very important element of radiological protection. To this end, for radiological protection purposes, multiples of national averages of local values of natural background dose or dose rates should replace those presently reported in Gy or Gy/h only – thus making the general public aware of the ubiquity, diverse composition and range of dose rates of natural background radiation - in some regions such as Ramsar, Iran, natural dose rates nearly 100 times higher than the worldwide average have been recorded. ¹⁰ Indeed, the importance of submitting clear and comprehensible information, as well as training of radiation safety inspectors in implementing the post-LNT, evidence-based, system of radiological protection cannot be overestimated. Only by elimination of radiophobia will the society begin to accept and appreciate the unique opportunities which nuclear technology offers, especially in health care and energy production.

To quote Marie Skłodowska-Curie: “Nothing in life is to be feared, it is only to be understood.” Indeed, both the general public and experts in many professions should understand radiation better, so that they may fear it less. We hope that our discussion on a post-LNT system of radiological protection will continue – as it certainly deserves further consideration. ¹¹