The dose-response relationship and the estimation of carcinogenic effects of low doses of ionizing radiation

Report on behalf of a joint working group, for Institut de France Académie des sciences, and Académie Nationale De Médecine

by Maurice TUBIANA et André AURENGO

French with English summary (pdf)

English (pdf)

Executive Summary

The assessment of carcinogenic risks associated with doses of ionizing radiation from 0.2 Sv to 5 Sv is based on numerous epidemiological data. However, the doses which are delivered during medical X-ray examinations are much lower (from 0.1 mSv to 20 mSv). Doses close to or slightly higher than, these can be received by workers or by populations in regions of high natural background irradiation.

Epidemiological studies have been carried out to determine the possible carcinogenic risk of doses lower than 100 mSv, and they have not been able to detect statistically significant risks even on large cohorts or populations. Therefore, these risks are at worse low since the highest limit of the confidence interval is relatively low. It is highly unlikely that putative carcinogenic risks could be estimated or even established for such doses through case-control studies or the follow-up of cohorts. Even for several hundred thousands of subjects, the power of such epidemiological studies would not be sufficient to demonstrate the existence of a very small excess in cancer incidence or mortality adding to the natural cancer incidence which, in non-irradiated populations, is already very high and fluctuates according to lifestyle. Only comparisons between geographical regions with high and low natural irradiation and with similar living conditions could provide valuable information for this range of doses and dose rates. The results from the ongoing studies in Kerala (India) and China need to be carefully analyzed.

Because of these epidemiological limitations, the only method for estimating the possible risks of low doses (< 100 mSv) is extrapolation from carcinogenic effects observed between 0.2 and 3 Sv. A linear no-threshold relationship (LNT) describes well the relation between the dose and the carcinogenic effect in this dose range where it could be tested. However, the use of this relationship to assess by extrapolation the risk of low and very low doses deserves great caution. Recent radiobiological data undermine the validity of estimations based on LNT in the range of doses lower than a few dozen mSv which leads to the questioning of the hypotheses on which LNT is implicitly based:

1. constancy of the probability of mutation (per unit dose) whatever the dose or dose rate,
2. independence of the carcinogenic process which after the initiation of a cell evolves similarly whatever the number of lesions present in neighboring cells and the tissue.

Indeed,

1. progress in radiobiology has shown that a cell is not passively affected by the accumulation of lesions induced by ionizing radiation. It reacts through at least three mechanisms: a) by fighting against reactive oxygen species (ROS) generated by ionizing radiation and by any oxidative stress, b) by eliminating injured cells (mutated or unstable), through two mechanisms: i) apoptosis which can be initiated by doses as low as a few mSv, thus eliminating cells the genome of which has been damaged or misrepaired, ii) death of cells during mitosis when lesions have not been repaired. (Recent works suggest that there is a threshold of damage under which low doses and dose rates do not activate intracellular signalling and repair systems, a situation leading to cell death.) c) by stimulating or activating DNA repair systems following slightly higher doses of about ten mSv. Furthermore, intercellular communication systems inform a cell about the presence of an insult in neighboring cells. Modern transcriptional analysis of cellular genes using microarray technology reveals that many genes are activated following doses much lower than those for which mutagenesis is observed. These methods have been a source of considerable progress by showing that depending on the dose and the dose rate not the same genes are transcribed.

   At doses of a few mSv (< 10 mSv), lesions are eliminated by disappearance of the cells; at slightly higher doses damaging a large number of cells (therefore capable of causing tissue lesions), repair systems are activated. They permit cell survival but may generate misrepairs and irreversible lesions. For low doses (< 100 mSv), the extent of mutagenic misrepairs is small but its relative importance, per unit dose, increases with the dose and dose rate. The duration of repair varies with the complexity of the damage and its amount. Several enzymatic systems are involved and a high local density of DNA damage may lower their efficacy. At low dose rates the probability of misrepair is smaller. The modulation of the cell defense mechanisms according to the dose, dose rate, the type and number of lesions, the physiological condition of the cell, and the number of affected cells explains the large variations in radiosensitivity (variations in cell mortality or the probability of mutations per unit dose) depending on the dose and the dose rate that have been observed. The variations in cell defense mechanisms are also demonstrated by several phenomena: initial cell hypersensitivity during irradiation, rapid variations in radiosensitivity after short and intense irradiation at a very high dose rate, adaptive responses which cause a decrease in radiosensitivity of the cells during hours or days following a first low pre-conditionning dose of radiation, etc.

2. Moreover, it was thought that radiocarcinogenesis was initiated by a lesion of the genome affecting at random a few specific targets (proto-oncogenes, suppressor genes, etc.). This relatively simple model, which provided a theoretical framework for the use of LNT, has been replaced by a more complex one including genetic and epigenetic lesions, and in which the relationship between the initiated cells and their microenvironment plays an essential role. This carcinogenic process is counteracted by effective defense mechanisms in the cell, tissue and the organism. With regard to tissue, the mechanisms which govern embryogenesis and direct tissue repair after injury appear to play also an important role in the control of cell proliferation. This is particularly important when a transformed cell is surrounded by normal cells. These mechanisms could explain the lower efficacy of heterogeneous irradiation, i.e. local irradiations through a grid, as well as the absence of a carcinogenic effect in humans or experimental animals contaminated by small quantities of a-emitter radionuclides. The latter data suggest the existence of a threshold. This interaction between cells could also help to explain the difference in the probability of carcinogenesis according to the tissues and the dose, since the death of a large number of cells disorganizes the tissue and favors the escape of initiated cells from tissue controls.
3. Immunosurveillance systems are able to eliminate clones of transformed cells, as is shown by tumor cell transplants. The effectiveness of immunosurveillance is also shown by the large increase in the incidence of several types of cancers among immunodepressed subjects (a link seems to exist between a defect in DNA repair (NHEJ) and immunodeficiency).

All these data suggest that the lower effectiveness of low doses, or the existence of a practical threshold which could be related to either the failure of a very low doses to sufficiently activate cellular signalling and thereafter DNA repair mechanisms or to an association between apoptosis error-free repair and immunosurveillance.. However on the basis of our present knowledge, it is not possible to define the threshold level (between 5 and 50 mSv?) or to provide the evidence for it. The stimulation of cell defense mechanisms, in particular to cope with reactive oxygen species. Indeed, a meta-analysis of experimental animal data shows that in 40% of these studies there is a decrease in the incidence of spontaneous cancers in animals after low doses. This observation has been overlooked so far because the phenomenon was difficult to explain.

These data show that it is not justified to use the linear no-threshold relationship to assess the carcinogenic risk of low doses observations made for doses from 0.2 to 5 Sv since for the same dose increment the biological effectiveness varies as a function of total dose and dose rate. The conclusion of this report is in fact in contradiction with those of other authors [43,118], which justify the use of LNT by the following arguments.

1. for doses lower than 10 mGy, there is no interaction between the different physical events initiated along the electron tracks through the DNA or the cell;
2. the nature of lesions caused and the probability of error prone or error free repair and the elimination of damaged cells by cell death is neither influenced by the dose nor the dose rate;
3. cancer is the direct and random consequence of a DNA lesion in a cell apt to divide and the probability of the initiated cell to give rise to cancer is not influenced by the damage in the neighbor cells and tissues;
4. the LNT model correctly fits the dose-effect relationship for the induction of solid tumors in the Hiroshima and Nagasaki cohort;
5. the carcinogenic effect of doses of the order of 10 mGy is proven for humans by results from in utero irradiation studies.

The first argument concerns the initial physico-chemical events which are proportional to dose; however, the nature and efficiency of cellular defense reactions that are activated vary with dose and dose rate. The second argument is contradicted by recent radiobiological studies considered in the present report. The third argument does not take into account recent findings on the complexity of the carcinogenic process and the particular role of intercellular relationships and the stroma.. Regarding the fourth argument, it can be noted that besides LNT, other types of dose-effect relationships are also compatible with data concerning solid tumors in atom bomb survivors, and can also satisfactorily fit epidemiological data that are incompatible with the LNT concept, notably the incidence of leukemia in these same A-bomb survivors. Furthermore, taking into account the latest available data, the dose-effect relationship for solid tumors in Hiroshima- Nagasaki survivors is not linear but curvilinear between 0 and 2 Sv. Moreover, even if the dose-effect relationship were demonstrated to be linear for solid tumors between, for example, between 50 mSv and 3 Sv, a generalization would not be possible because of experimental and clinical data show that the dose effect relationship considerably varies according to type of tumor and age of individuals at the time of irradiation. The global and empirical relationship observed for solid tumors corresponds to the sum of relationships which can be quite different according to the type of cancer, for example, some being linear or quadratic, with or without threshold.

Finally, with regard to in utero irradiation, whatever the value of the Oxford study, some inconsistencies between the available data sets call for great caution before concluding the existence of a causal relationship from data showing simply an association. Furthermore, it is highly questionable to extrapolate from the fetus to the child and adult, particularly, since the developmental state, cellular interactions and immunological control systems are very different.

In conclusion, this report raises doubts on the validity of using LNT for evaluating the carcinogenic risk of low doses (< 100 mSv) and even more for very low doses (< 10 mSv). The LNT concept can be a useful pragmatic tool for assessing rules in radioprotection for doses above 10 mSv; however since it is not based on biological concepts of our current knowledge, it should not be used without precaution for assessing by extrapolation the risks associated with low and even more so, with very low doses (< 10 mSv), especially for benefit-risk assessments imposed on radiologists by the European directive 97-43. The biological mechanisms are different for doses lower than a few dozen mSv and for higher doses. The eventual risks in the dose range of radiological examinations (0.1 to 5 mSv, up to 20mSv for some examinations) must be estimated taking into account radiobiological and experimental data. An empirical relationship which has been just validated for doses higher than 200 mSv may lead to an overestimation of risks (associated with doses one hundred fold lower), and this overestimation could discourage patients from undergoing useful examinations and introduce a bias in radioprotection measures against very low doses (< 10 mSv).

Decision makers confronted with problems of radioactive waste or risk of contamination, should re-examine the methodology used for the evaluation of risks associated with very low doses and with doses delivered at a very low dose rate. This report confirms the inappropriateness of the collective dose concept to evaluate population irradiation risks.

Bulletin of the Atomic Pseudo-Scientists?

Just when you thought they couldn't get any nuttier, the BotAS top their previous record by publishing this loony called Lutz Mez. The author of this drivel, on why nuclear power causes global warming claims

THIS COMMENTARY WAS MADE UNDER THE EXPERTS ON NUCLEAR POWER AND CLIMATE CHANGE

(his capitals). The same repeats the myth of climate change due to Kr-85 from nuclear power.

Krypton 85 is produced in nuclear power plants and released on a massive scale in the reprocessing of spent fuel

This hypothetical risk is something I looked at 3 months ago and found there could be as much as 23.27 kg per year of krypton-85 leaking into the atmosphere each year. Not quite a "massive scale". Maybe, at most, 371 kg in the whole of earth's atmosphere. Kr-85 has no effect on climate at all. My back of envelope calculations were overestimates because krypton is a heavy gas (relative to atmospheric gases), so stays closer to earth's surface.

So 0.37 tonnes of Krypton-85 in the atmosphere, with a half-life of 10.756 years. The theoretical risk to climate is not caused by radiative forcing but by its decay, when it makes two charged particles. This is actually no risk at all because there's so little of it. On average it takes 10.756 years to make these charged particles. On Earth, the lightning frequency is approximately 40–50 times a second or nearly 1.4 billion flashes per year and the average duration is 0.2 seconds made up from a number of much shorter flashes (strokes) of around 30 microseconds. An average bolt of negative lightning carries an electric current of 30,000 amperes (30 kA), and transfers 15 coulombs of electric charge and 500 megajoules of energy. There's not really any risk from a small amount of new charge which will soon be discharged by lightning. No climate scientist has written seriously about the risk for 30 years because the risk does not exist.

Yet anti-nukes continue to mine this paranoia with a number of anonymous websites inventing krypton-85 risk out of thin air. The fact their postings are anonymous is surefire evidence to me they know they're lying.

So if Lutz Mez knows we know he's faking it, why does he continue? He's just rallying his troops.

What's so good about thorium nuclear reator fuel?

• Availability. Thorium is more plentiful in the earth's crust than uranium (about 3, or 4 times more so). Thorium is 400 to 500 times more plentiful than uranium-235 (which is currently the only fuel we really make use of).
• It doesn't even need to be mined because it's available as waste from the tailings of many rare earth mines. The kind of rare earth mines needed to make wind turbines, and solar panels. There's so much of this waste, we make about 40 times more, per year, than we need to power the world with!
• It does not need to be enriched like uranium, saving considerably on cost and energy.
• The thorium fuel cycle can begin using a blended mixture of plutonium and thorium. Such plutonium can be made from nuclear bombs or reprocessed 'spent nuclear fuel'. Britain has 140 tonnes of such plutonium stored, waiting to be disposed of.
• Thorium is then bred to make uranium-233
• In the thermal neutron reactor range, U-233 has superior neutronics to any other fissile material:

  	Thermal cross-section (barn)			ratio of capture+fission neutrons to capture neutrons
  	Scatter	Capture	Fission
  U-233	12	45	531	12.8
  U-235	10	99	583	6.9
  Pu-239	8	269	748	3.8

  
  With U-233, only one in 12.8 neutrons are wasted. In comparison, 1 in 3.8 Pu-239 neutrons are wasted.
  When Pu-239 absorbs such a neutron, it makes transuranic waste which can't be fissioned, and has a half-life of hundreds to thousands of years. This is radiotoxic, and is a reason reprocessed spent nuclear fuel, called MOX, is so limited - the more it's reprocessed, the more transuranics, the more radiotoxic it becomes. Transuranic waste like this can only be disposed of with time, or a fast reactor. Thorium fuel can be reprocessed avoiding this pitfall. It will make only a small fraction of the transuranics made in Pu-239, and U-235 powered reactors.
• Even when U-233 absorbs a neutron (capture) to make U-234, such U-234 can absorb a second neutron to make U-235, at which point it gets another chance to fission.
• Because so little U-233 is wasted, thorium/U-233 has by far, the best waste profile of any fuel type. It makes the least possible quantity of transuranics.
• A LFTR is a molten salt reactor using thorium fuel. The fuel can be denatured to protect it against the possibility of diversion for weapons making, so making the LFTR proliferation resistant.
• Some of the spent fuel waste is actually valuable. For example it contains considerable amounts of rhodium, one of the rarest elements on earth, which has specialist applications in chemical catalysis.

Reference

1. Revisiting the thorium-uranium nuclear fuel cycle (pdf) [DOI: 10.1051/EPN:2007007], 2007, by Sylvain David, Elisabeth Huffer and Hervé Nifenecker
2. Rethinking the Thorium Fuel Cycle: An Industrial Point of View (pdf), 2007, by Dominique GRENECHE, William J. SZYMCZAK, John M. BUCHHEIT, M. DELPECH, A. VASILE, H GOLFIER
3. Thorium fuel cycle — Potential benefits and challenges (pdf), IAEA, 2005

NORM waste

Here is an example of the stupidity and paranoia over low-level radiation. They are complaining about NORM waste (which is "Naturally occurring radioactive material"). USA defines NORM waste at 5 picocuries/gram. I calculated a 70kg person is about 235135 picocuries (8,300 Bq), or 3.36 picocuries/gram. That makes living people 2/3 radioactive waste. Our ashes certainly must be NORM waste.

How the NRC stopped the U.S. nuclear power industry.

It was the U.S. Congress that created the NRC in 1975 at the behest of the coal industry. Official line was that the Atomic Energy Commission had a conflicting mission of promoting nuclear energy and ensuring safety. The mission of promoting nuclear was given to the DOE and dropped. The NRC was given the mission to “maximize safety”. Orders for nuclear plants were cancelled as electric companies correctly anticipated skyrocketing costs and delays from onerous NRC regulation. In the 40 years since the NRC opened its doors not a single nuclear power plant was built from conception to completion. It will take the proverbial act of congress to reign in the NRC, or better yet, abolish it and replace it with something similar to the Atomic Energy Commission under which about 70 or 80 nuclear reactors were built in 10 or 15 years. That act of congress isn’t going happen as long as the fossil fuel industries own congress.

-- Jerry Nolan (first comment here)

What is the real cost of nuclear power?

Anti nukes will always quote the most expensive projects. Recently a thorough analysis of worldwide nuclear plants show the cost varies a lot. Hinkley C is almost 3½ times the cost of Indian, Chinese and South Korean reactors.

Hinkley C EPR :

US $7018/kW

Indian, Chinese and South Korean reactor, closer to

US $2000/kW

"Historical construction costs of global nuclear power reactors", 2016, Lovering, Yip, Nordhaus