What mechanisms underlie the health effects of radiation at low doses

1. What mechanisms underlie the health effects of radiation at low doses Keith Baverstock Department of Environmental andBiological Sciences University of Eastern Finland

2. ? INDIRECT DIRECT Respiratory and digestive conditions, weak immune response and “fatigue”, especially among children

3. Two processes by which radiation exposure may initiate DIRECT health effects: 1) Mutation of genomic DNA – leading to genetic effects (well established by mega mouse studies at Harwell in UK and Oak Ridge in USA between ~1960 and 1990) 2) Induced genomic instability – modification of cell phenotype due to stress on cellular processes, probably DNA repair processes (uncovered in 1992 at Harwell in UK but probably discovered in 1976 in Sweden and ignored) At diagnosis malignant tissue exhibits both these phenomena. Historically the former has been known for much longer than the latter and therefore by default is generally regarded as having priority as the initiating process for cancer. It is a widely held assumption that cancer is a genetic disease, but in fact it is not! Evidence from a Nordic study of twins found no evidence to suggest that common cancers had a genetic origin.

5. The lifetime risk of cancer is about 30% or 1 chance in 3. If mutations were the cause of cancer their occurrence in germ cells, which do not exhibit cancer, would carry over into the next generation affecting all somatic cells and thus predisposing that generation to cancer. Identical twins who share the same DNA sequence would then likely both suffer the disease. In the Nordic study only a few percent of twin pairs exhibited the same cancer and that could have been due to chance. It therefore seems most probable that cancer results from the environmental induction of genomic instability

6. Specific cases of illness can rarely be attributed to a cause: As with cancer associated with tobacco use it is, in general, not possible to say that a specific case of illness is due to either direct or indirect exposure to radiation. Due to the dominance of the genetic theory of cancer it is generally accepted that certain specific cancers are the result of the direct effect of radiation and the international scientific community (belonging to the international organisations, radiological protection institutes, national governments and the nuclear industry) accepts that this is an unavoidable hazard of exposure to radiation. Diseases that do not fall in this category are deemed to be indirect in their origin and, therefore, in the view of many such scientists, the responsibility of the victim, who “chooses” to be so affected. The psychosocial effect was at one time called “radiophobia” by proponents of the nuclear industry.

7. We are still left with this category of effect: is it direct or indirect?

8. On the basis that the direct effects are mediated by genomic instability and not mutation, we need to reassess the situation: What is genomic instability? Genomic instability is what is termed by the radiobiological community a “non-targeted effect”, i.e., not directly contingent on specific damage to the DNA sequence – i.e., mutation of specific bases. Between the early 2000s and 2010 the European Commission devoted considerable resources (10s of millions of €) to answering this question, most notably with the FP6 “Non-Targeted Effects of Ionising Radiation” (NOTE) integrated project. In answer to the question “What are the mechanisms of non-targeted effects and what factors modify their response” NOTE summarises what they learned empirically about signalling pathways within and between cells. So their answer was, in very generic terms, “signalling”.

9. “ Radiobiology is a sub-discipline of biology and biology is (or should be) underpinned by physics and this raises the question of whether the new paradigm is confined to radiobiology or has wider impact: one imagines it must be the latter. That point aside, experience shows that when the new paradigm emerges only a few will recognise it as such and many will respond with disbelief and even hostility, maybe until their dying day, …………. I therefore detect a fatal paradox here in terms of how the success of NOTE will be judged. If history is anything to go by, if NOTE is successful in finding a new paradigm most of the cognoscenti will regard it as a failure, unable to recognise the value of the new paradigm, while if NOTE fails to find a new paradigm those same people will regard it as a success, confirming in effect their faith in the existing paradigm: It appears then that NOTE’s success lies in its failure, or vice-versa!” Well in my view NOTE did not find a new paradigm, so it failed and was, therefore, a success!

10. However, at the 2008 NOTE workshop I presented a new paradigm that I maintained satisfied NOTE’s criteria: Instead of regarding the cell as a miniature machine I assumed that the cell was a complex dynamic system, governed by the appropriate physics, which differs from the default physics, namely that based on Newton’s mechanics. I call that the dynamic cell model in contrast to the machine cell model, upon which genetics is predicated. An important distinction between the two models is how the phenotype is conceptualised. Phenotypes are stable, but how that stability is achieved is important. You may be familiar with how a ball can be supported in a jet of air. This is a quasi-stable state that prevails within a range of conditions. Outside that range stability is lost. This is how I perceive the stability of the phenotype.

11. Imagine a system with many air jets and just one ball: If an external force pushes the ball out of the air jet, if there is only one jet the ball will fall to the ground. However, if there are many air jets the ball may transit from one jet to another. What I propose is that cellular phenotypes are quasi-stable states in a system (the cell) with many alternative or variant phenotypes available, all different in some or all respects. These stable states are termed attractors. What I call the home attractor is the cellular phenotype of a stably replicating organism and is reproduced at every cell division. Genomic instability arises from the adoption of a variant attractor/phenotype as the result of externally generated stress (for example damage to DNA). This is an irreversible process that leads to further attractor transitions. Such unstable cells may ultimately acquire the phenotypic characteristics of diseases, cancer, for example. Genes in this model are an irrelevance!

12. But if this is true why has genetics been so successful and why are so many people engaed in molecular genetic research – are they all misguided? Yes I think so One famous geneticist, Richard Lewontin, saw the light in 1974. He wrote about phenotypic traits to the effect: „what is measuable is not interesting and what it interesting is not measurable“. He was referring to the fact that all experimental genetics since Mendel‘s time had been conducted with traits that were very clear, like flower colour. Complex traits like common diseases had been ignored. Of course experimental genetics is the basis for our theoretical understanding of the subject so if that base is flawed so is the theory. On this basis I think we can understand why some disease traits are rare and incidently often can be linked to specific genes. They involve a single protein acting on its own to produce the trait. If it has a specific abnormality that prevents it functioning we get the trait.

13. These are the sweet pea flowers that Mendel allegedly studied, specifically the purple and white flowers. We now understand that the difference is due to one transcription factor that if modified at one base in the DNA sequence is unable to initiate the production of the chemical that gies the purple coulour. Most other traits are contingent on several proteins acting together so no such simple associations apply. Furthermore, proteins are refractory to mutations that might lead to changes that cause them to be dysfunctional – at least 90% of the molecule can be changed without affecting its functionality. From this we can conclude that: Molecular genetics is based on the generalisation of a special unrepresentative empirical foundation. Mutation is a possible, but inefficient way of modifying phenotypic traits.

14. We therefore need to look at the likely consequences of genomic instability being the primary cause of the health effects of ionising radiation more closely. If I convince you of nothing else today I will have succeeded

15. What then are the likely consequences of genomic instability in a chronic low dose environment? The somatic and germ cells of individuals are at risk of being rendered genomically unstable: does that matter? Let us consider these cells in four categories: adult/somatic; adult/germ; child/somatic and child/germ and the important distinction between child and adult is that the former are growing, that is, their somatic cells are proliferating rather than just being replaced, as in the adult. What we know empirically as the result of in vitro and in vivo research on genomic instability is the following:

16. Adult/somatic: potential induction of cancer and non-cancer (circulatory disease, cataract of the eye, possibly digestive disease etc.). The most important point being that outcomes are not limited to what are currently regarded as genetic diseases. Adult/germ: for males only, the induction of genomic instability in sperm results in offspring (male and female) with genomically unstable germ and somatic cells. These offspring are prone to diverse diseases, (including those applicable to adult/somatic above), for example, the early onset of normally late onset diseases. Male offspring will propagate the genomic instability to future generations. Child/somatic: as the child’s organs develop from the zygote they are liable to be rendered unstable (have a variant phenotype). Where that occurs early in the growth phase it can lead to tissues partly composed of normal cells and partly unstable (and therefore not fully functional) cells and, thus, possibly functionally impaired tissues leading to diverse and complex health conditions. Child/germ: essentially the same consequences as for adult/germ cells.

17. I want now to concentrate on the child/somatic cells’ response to chronic low dose exposure: To illustrate the consequences of this exposure I refer to an experiment carried out on a specific strain of mouse (pink-eyed unstable) that spontaneously undergo a loss of a DNA segment (reverts), the frequency of which is increased in the offspring of irradiated male mice. These mice are normally white coated but if they have lost the segment of the DNA (reverted) in their melanocytes they have black coats. The offspring of the irradiated male parents are generally white with black spots, arising from a clone of reverted melanocytes. The skins of the mice are therefore a ”mosaic” of reverted and un-reverted cells. Mice that are born with all black coats result from reversion in the sperm before fusion to form the zygote. What I am suggesting is that children who have grown up in a low dose rate environment may develop mosaic tissues with normal and abnormal, non- or partially- functional, cells.

18. Heart muscle cells when grown in culture beat spontaneously: This means that the “pump” function of the heart is derived from the phenotypic properties of individual cells acting collectively. It also means that if a such a cell undergoes a transition to a GI phenotype, that function could be lost, but the cell might still be able to divide so producing other cells without the pump function. In the growing heart this would lead to a mosaic effect where some cells were deficient, but others proficient: the heart would then still beat, but its efficiency would be reduced. The epithelial cells lining the insides of blood vessels due to their SHAPE, form an impenetrable barrier. When that barrier is broken atherosclerosis may follow. This is the build-up of fats in the arterial walls leading to a stiffening of arteries. Transition of epithelial cells to a GI phenotype in the growing blood vessels could result in the early onset of atherosclerosis.

19. Transgenerational inheritance of genomic instability was observed after the Chernobyl accident: The children of fathers living in the contaminated regions exhibited an increased level of mini-satellite mutations than the children of fathers living in clean areas. Mini-satellites are short segments of DNA that occur in multiple copies. The mutation takes the form of the number of repeat copies. This phenomenon, which has been observed in other exposed human populations as well as in mice and transmission is always down the male germline. These mini-satellite sequences are so small that a direct genetic effect can be confidently excluded (the radiation doses required to “hit” these sequences would be enormous), whereas these effects must be caused by doses in the range of a few tens of mSv. Genomic instability has been observed after Chernobyl.

20. A UN putative initiative to address the low dose problem in the contaminated territories in 2001: In 2001 United Nations held a meeting at the WHO headquarters in Geneva to develop a program of future work on Chernobyl. The meeting was chaired by Under-Secretary General Oshima with secretariat provided by UNDP. I proposed that WHO should set up a Chernobyl Research Board that would allow local scientists and physicians to bring their concerns to an international expert panel. this position agreed before the meeting with WHO/Geneva staff, specifically Richard Helmer and Michael Repacholi and accordingly a presentation for the meeting was prepared. The IAEA also made a proposal, but following discussion the WHO proposal was accepted by the meeting. The chairperson, apparently recognising there might be conflict between WHO and IAEA nominated a Swiss NGO to oversee the process.

21. A UN putative initiative to address the low dose problem in the contaminated territories: Several weeks later, when I’d heard nothing from the Swiss NGO, I rang them and was told that the project would be called the “Chernobyl Forum” and would be under the direction and financing of the IAEA, with the WHO tasked with preparing a report on the health effects, to be led by WHO/Geneva. I was informed that WHO/EURO would not be involved. I wrote to the UNDP staff member who had performed the role of secretariat at the meeting and he told me that no minutes of the meeting had been prepared. A UN Under-Secretary General and some 50 delegates from around the world had attended, but no record of the decisions reached was prepared! The “Chernobyl Forum” did not address the issue of the concerns of the low dose problem.

22. Our knowledge of the effects at low doses In the last decade our knbowledge of the effects of radiation at low doses has considerably strengthened. Some 10 human epidemiological studies conducted since 2006 all indicate linearity down to the lowest doses, none indicate a threshold – the so called LNT hypothesis is confirmed. There is no dose below which no effects are expected. These results are for various cancers – remember cancer is not a genetic disease so we have to assume it is underpinned by genomic instability – therefore other endpoints underpinned by genomic instability are alo subject to LNT. There are a few million inhabitants in Ukraine and Belarus living in enhanced radiation levels and the local doctors are reporting illness in children that is being ignored. In Japan where the official policy is to assume a threshold at 100mSv inhabitatnts of evacuated areas are expected to return whrn the external dose rate falls to 20mSv per year.

23. In 2007 the US National Academy of Sciences published a ‘landmark‘ review entitled Health Risks of Exposure to Low Levels of Ionizing Radiation (BEIR VII) “A comprehensive review of available biological and biophysical data supports a “linear-no-threshold” (LNT) risk model—that the risk of cancer proceeds in a linear fashion at lower doses without a threshold and that the smallest dose has the potential to cause a small increase in risk to humans.”

24. Courtesy of Ian Goddard

25. Relative risk of mortality from all cancer excluding leukaemia

26. What does this mean in practical terms? In the UK the lifetime risk of dying of cancer is about 25%. According to the BMJ study the relative risk is about 1.5/Gy or Sv (about a 50% increase in risk per Gy). Professor Wade Allison says 100mSv/month is a „safe dose rate“. 100mSv/month is 1.2 Sv/year, so after 1 year of exposure the lifetime risk of cancer is 40% and that risk will increase proportionately until it reaches 100% after 5 years of such exposure. For 100mSv the relative risk is 1.05, or a 5% increase bringing the lifetime risk to 26.5 but this is an average for adults: the BEIR VII Report indicates for the youngest children this risk can be between 4 and 7 times greater, giving lifetime risks of 30 to 34%. I estimate that a child born into an annual dose rate of 20mSv/year would, at the end of 5 years, have a lifetime risk of cancer of between 28 and 32%.

27. Let me return to the low dose problem as local doctors see it in the Chernobyl exposed children and summarise the situation: The International scientific community would like to assure these doctors that IF they are seeing anything by way of adverse health effects in children they are due to the psychosocial effect, BECAUSE those conditions are not explicable in terms of GENETICS. But the EVIDENCE shows (and has since 2000) that what the International scientific community BELIEVES is genetic, namely CANCER, is NOT and is likely due to GENOMIC INSTABILIY. The evidence shows that GENOMIC INSTABILITY induced by low dose exposure could be responsible for impaired tissue function in growing children. Transgenerational genomic instability has been observed in populations living in the Chernobyl contaminated regions.

28. Are MELODI, the IAEA, the WHO, UNSCEAR and IRSN all incapable of understanding the rather clear scientific evidence, or are they in the business of knowingly producing ignorance by closing the scientific mind? Thank you for your attention