Fukushima AIDS, part 1 was a general overview of the immune system, and dealt with how Fukushima is affecting and will affect it in the coming years. Fukushima AIDS, part 2: Chronic radiation sickness described radiation illness in its different stages. This post will deal with protracted exposure to radiation, that is, radiation that lasts a long time, rather than in one shot, and how this affects the immune system and increases the risk of cancer.
PROTRACTED EXPOSURE TO RADIATION
Washington’s blog (1) has a good entry on the effects of low-level radiation and protracted exposure. Fukushima has been emitting radionuclides into the air and sea for almost 3 years now. This is a fundamentally different situation from the atomic bombings of Hiroshima and Nagasaki. It is also different from Chernobyl, which burned for 11 days.
Japan Times reports:
Protracted exposure to low-level radiation is associated with a significant increase in the risk of leukemia, according to a long-term study published Thursday in a U.S. research journal.
The study released in the monthly Environmental Health Perspectives was based on a 20-year survey of around 110,000 workers who engaged in cleanup work related to the Chernobyl nuclear plant disaster in 1986.
Scientists from the University of California, San Francisco, the U.S. National Cancer Institute and the National Research Center for Radiation Medicine in Ukraine were among those who participated in the research…
Dr. Beyea challenges a concept adopted by American safety regulators about small doses of radiation. The prevailing theory is that the relationship between dose and effect is linear – that is, that if a big dose is bad for you, half that dose is half that bad, and a quarter of that dose is one-quarter as bad, and a millionth of that dose is one-millionth as bad, with no level being harmless.
The idea is known as the “linear no-threshold hypothesis,” and while most scientists say there is no way to measure its validity at the lower end, applying it constitutes a conservative approach to public safety.
Some radiation professionals disagree, arguing that there is no reason to protect against supposed effects that cannot be measured. But Dr. Beyea contends that small doses could actually be disproportionately worse.
Radiation experts have formed a consensus that if a given dose of radiation delivered over a short period poses a given hazard, that hazard will be smaller if the dose is spread out. To use an imprecise analogy, if swallowing an entire bottle of aspirin at one sitting could kill you, consuming it over a few days might merely make you sick.
In radiation studies, this is called a dose rate effectiveness factor. Generally, a spread-out dose is judged to be half as harmful as a dose given all at once.
The so-called “radiation protection” organizations subscribe to this myth, that spreading out the dose over time is less harmful.
According to BEIR VII, cancer risk after LDRMD (low dose rate, moderate dose) exposure is expected to be by a factor of 1.5, according to the ICRP by a factor of 2, smaller than among atomic bomb survivors. However, the best estimates of the cancer risk in 11 of the 12 LDRMD studies are larger than both expectations (tables 3 and 4)…
The ICRP and BEIR VII base their DDREFs mainly on radiobiological results including animal data, which, in their majority, suggest a characteristically low risk for low-dose-rate exposures. It remains an open question as to why this characteristic is apparently not reflected in the human epidemiological data. (2)
But Dr. Beyea retorts: Dr. Beyea, however, proposes that doses spread out over time might be more dangerous than doses given all at once. [Background] He suggests two reasons: first, some effects may result from genetic damage that manifests itself only after several generations of cells have been exposed, and, second, a “bystander effect,” in which a cell absorbs radiation and seems unhurt but communicates damage to a neighboring cell, which can lead to cancer.
One problem in the radiation field is that little of the data on hand addresses the problem of protracted exposure. Most of the health data used to estimate the health effects of radiation exposure comes from survivors of the Hiroshima and Nagasaki bombings of 1945. That was mostly a one-time exposure… (1)
For example, in a study of 400,000 nuclear workers, Cardis et al. (2005) reported excess cancer from protracted exposure at a rate per Gray higher than that found in studies of one-time exposures in atomic bomb (A-bomb) survivors. In a study of 175,000 radiation workers receiving protracted exposures in the United Kingdom, Muirhead et al. (2009) observed excess cancer at the same rate as found in A-bomb survivors. Krestinina et al. (2007) found excess cancer in 17,000 members of the civilian population who received protracted exposure from emissions from the Soviet weapons complex—also at a higher rate than found in the A-bomb cohort. In addition, Chernobyl thyroid exposures meet the protracted test because > 90% of the dose came from iodine-131, which has an 8-day half-life (Gavrilin et al. 2004). (3)
This dependence on duration of time in radiation exposure is called the Petkau Effect:
… the chronic irradiation dose protracted in time can produce a stronger effect than the same dose delivered upon short-term exposure at a high rate.
The Canadian scientist A. Petkau first detected this effect in 1972 on cell membranes… Thus, for the radiobiological effect to be evident upon long-term exposure to low-intensity radiation, a dose five thousand times lower than upon irradiation at a high dose rate was sufficient. The phenomenon of the inverse dose rate dependence of radiation effect upon irradiation of cells with low doses and of cell hypersensitivity upon irradiation with superlow doses, estimated by some criteria, was later called the Petkau effect. (4)
TIME INTERVAL BETWEEN RADIATION EXPOSURE AND CANCER DEVELOPMENT
Brash and Cairns delve into internal mutagens, and ask why there is a time delay from the exposure to the carcinogen and the appearance of cancer. Cesium, strontium, and plutonium in our bodies are mutagens, mutators of DNA, like any other carcinogen.
Why does there have to be a long interval between a cell’s exposure to a mutagen and the expression of the resulting mutations, and why do only a minority of the cell’s descendants express these mutations?
It would have been tempting to postulate that the various methods for producing cancer in the cells of animals are not good models of human carcinogenesis, were it not for the fact that humans and animals show the same strange relationship between dose of carcinogen and time of appearance of their cancers. For example, although the incidence of lung cancer in smokers appears to be directly proportional to the number of cigarettes smoked per day (Zaridze and Peto, 1986), it is proportional to roughly the sixth power of the duration of smoking. Similarly, when rats are continuously exposed to dietary carcinogens, their incidence of cancer rises as the first or second power of the dose rate but as a much higher power of time (Druckrey, 1967; Peto et al, 1997). If the carcinogen had simply to mutate a set of N genes to create cancer, the frequency of cancer should rise as the Nth power of the dose, and time would not be a major factor. These numerous experiments suggest, therefore, that mutagenic carcinogens cause just one or two events and that these (similar to the initial event in in vitro carcinogenesis) are then followed by steps that accumulate solely with the passage of time, driven perhaps by cell division. (5)
The higher the power of time, the more important is the duration of exposure to the carcinogen. Protracted exposure to carcinogens is widely known, and illustrated by cigarette smoking and carcinogens in food. There is no controversy here. Why is there a controversy when the carcinogen is internal particles of cesium and plutonium?
Low-dose ionizing radiation enhances cell proliferation and division:
This study shows the human cellular responses and the mechanism of low-dose ionizing radiation in CCD 18 Lu cells, which are derived from normal human lung fibroblasts… These results suggest that 0.05 Gy of ionizing radiation enhances cell proliferation through the activation of ERK1/2 and p38 in normal human lung fibroblasts. (6)
Cell proliferation, which is part of the cancer process, itself may induce cancer:
Does cell proliferation modify the carcinogenesis process? The obvious answer is that there would not be a carcinogenesis process without cell proliferation and that cell proliferation is an essential component of the process. Two other questions would then need to be answered: Is cell proliferation carcinogenic per se? Should investigations on cell proliferation be included in routine tests on chemicals?…
The IARC Working Group of June 1991 recognized that cell proliferation is an important mechanistic aspect for both genotoxic and nongenotoxic carcinogens. Cell proliferation may act at each stage of the carcinogenesis process, altering the size of the pool of cells at risk for a next event. Cell proliferation was considered to be a potentially important factor, especially as a part of the process of converting DNA adducts to mutation, as a potential enhancing factor of the mutation frequency by increasing the number of DNA errors during replication, and for determining dose-response relationships for some carcinogens. (7)
So when cells proliferate by cell division, it is an important factor in the development of cancer. Radiation promotes this division. The time period between exposure and cancer is influenced by the rate of proliferation. Radiation also enhances the number of DNA errors in the daughter cell, that is, the cell which was created when the original cell divided into two… both directly and by the enhanced rate of replication itself.
THE MATHEMATICS OF CANCER
Cairns (8) developed a mathematical model of DNA damage to stem cells:
It seems that the combination, in the stem cell, of immortal strands and the choice of death rather than error-prone repair makes epithelial stem cell systems resistant to short exposures to DNA-damaging agents, because the stem cell accumulates few if any errors, and any errors made by the daughters are destined to be discarded. This paper discusses these issues and shows that they lead to a model that explains the strange kinetics of mutagenesis and carcinogenesis in adult mammalian tissues…
(i) If left undisturbed, stem cells accumulate few mutations, first because they are defective in DNA repair and tend to die if they suffer DNA damage, and second because they conserve immortal strands and therefore do not accumulate replication errors.
(ii) Most of the mutant clones in epithelia arose because a stem cell died and was replaced by a mutant daughter. To produce a permanently mutant clone, two events therefore are necessary: the existing stem cell has to be killed, and the mutation must have occurred in the lineage of the daughter that takes its place.
The original stem cell has to die first for this process to take place. DNA damage from ionizing radiation or other carcinogens does this. They are defective in DNA repair mechanisms.
(iii) The immediate descendants of a stem cell are growing exponentially, and thus, unlike the stem cell, they cannot avoid accumulating spontaneous errors of replication. This rather than mutagenesis driven by DNA damage is postulated to be their main route for acquiring changes in sequence.
We have already seen that ionizing radiation increases both cell proliferation and replication errors.
(iv) During continuous exposure to a DNA-damaging agent, no daughter cell can complete the steps needed to convert it into an immutable stem cell. Thus the probability that any given epithelial clone is mutant will be proportional to (a) the probability that at some point its stem cell was killed, and this will be proportional to the dose rate of the DNA-damaging agent and the duration of exposure, and (b) the probability that the replacing daughter has acquired a replication error, and this will be proportional simply to the time or the number of daughter cell divisions that have occurred since the stem cell was killed.
Part (a), the probability of the stem cell being killed, is proportion to the dose of radiation only. We shall see below that the immune system has a hand in this also. Part (b), is proportional to time.
… the incidence of cancer in experimental animals continuously exposed to carcinogens commonly increases as the first power of dose and a higher power of time. This is true for a wide variety of carcinogens and for many different tissues… The best studied example of human carcinogenesis is smoking-induced lung cancer, and here too the frequency of cancer is roughly proportional to the first or possibly second power of dose rate D (cigarettes per day) and to the sixth power of the duration of smoking… Fig. 2 shows the observed cumulative incidence of lung cancer in smokers in relation to duration of smoking (age 21) on the assumption that smokers
start smoking when they are 17 and that on average 4 years elapse between the creation of a cell with the requisite changes and the emergence of a detectable cancer.
The main curve on the graph would be a straight line if cancer rates were proportional to dose only. But the duration is to the sixth power. As time goes on, cancer rates skyrocket with continued smoking, which cannot be explained merely by the number of cigarettes smoked.
Cancer models that only take into account radiation doses do not work. They grossly underestimate cancer rates. Both dose and duration of radiation exposure must be taken into account.
As Fukushima goes on emitting radioactive poison into the air and ocean, the duration of protracted exposure becomes more and more important relative to dose rate, and cancer rates will skyrocket. This will happen at a much higher rate than at Hiroshima or Chernobyl.
CANCER IMMUNOSURVEILLANCE AND IMMUNOEDITING
The immune system plays a role both in protecting the body from cancer, and in promoting cancer in it.
Cellular transformation and tumor development result from an accumulation of mutational and epigenetic changes that alter normal cell growth and survival pathways. For the last 100 years, there has been a vigorous debate as to whether the unmanipulated immune system can detect and eliminate such altered host derived cells despite the fact that cancer cells frequently express either abnormal proteins or abnormal levels of normal cellular proteins that function as tumor antigens. In this review, we discuss the current state of this argument and point out some of the recent key experiments demonstrating that immunity not only protects the host from cancer development (i.e., provides a cancer immunosurveillance function) but also can promote tumor growth, sometimes by generating more aggressive tumors. The terminology “cancer immunoediting” has been used to describe this dual host protective and tumor promoting action of immunity, and herein we summarize the ever-increasing experimental and clinical data that support the validity of this concept. (9)
Elimination is the hallmark of the original concept in cancer immune surveillance for the successful eradication of developing tumour cells, working in concert with the
intrinsic tumour suppressor mechanisms of the non-immunogenic surveillance process. The process of elimination includes innate and adaptive immune responses to tumour cells…
The TA-speciﬁc T lymphocytes are recruited to the primary tumour site, and directly attack and kill tumour cells with the production of cytotoxic IFN-γ (interferon-gamma). (10)
The immune system attacks tumor cells with the cytokine IFN-γ. This is a Th1-associated cytokine (see Part 1). It is associated with autoimmunity rather than allergy. IFN-γ is given to people who have a genetic defect in producing this important immune system cytokine. It has side effects:
fever and chills
general feeling of discomfort or illness
nausea or vomiting
loss of appetite
Black, tarry stools
blood in urine or stools
cough or hoarseness
loss of balance control
lower back or side pain
painful or difficult urination
pinpoint red spots on skin
stiffness of arms or legs
trembling and shaking of hands and fingers
trouble in speaking or swallowing
trouble in thinking or concentrating
trouble in walking
unusual bleeding or bruising (11)
These side effects pretty much make up “Fuku flu”. The body is eliminating tumors from itself.
The next step in cancer immunoediting proceeds to the equilibrium phase in which a continuous sculpting of tumour cells produces cells resistant to immune effector cells. This process leads to the immune selection of tumour cells with reduced immunogenicity. These cells are more capable of surviving in an immunocompetent host, which explains the apparent paradox of tumour formation in immunologically intact individuals… Since the equilibrium phase involves the continuous elimination of tumour cells and the production of resistant tumour variants by immune selection pressure, it is likely that equilibrium is the longest of the three processes in cancer immunoediting and may occur over a period of many years. In this process, lymphocytes and IFN-γ play a critical role in exerting immune selection pressure on tumour cells. During this period of Darwinian selection, many tumour variants from the original are killed but new variants emerge carrying different mutations that increase resistance to immune attack. (10)
So here in the equilibrium phase, tumor cells are continuously being destroyed. Also, stem cells are being destroyed, and we know from above that this is necessary for mutated daughter cells to proliferate. If the stem cells are killed, but not all the mutant daughter cells, the exponential rise in tumor cells will occur.
Also natural selection provides that tumors now arise that are resistant to the immune system’s cytokine attacks, and they start sticking around.
In the final escape phase, the tumors express anti-inflammatory factors which are resistant to immune surveillance. A variety of tumour-derived soluble factors contribute to the emergence of complex local and regional immunosuppressive networks, including vascular endothelial growth factor (VEGF), IL-10, TGF-β, prostaglandin E2… (10)
Now the individual “has cancer”. There is nothing to stop its progression.
Many drugs and treatments for cancer have been proposed or are being developed based on the immunosurveillance model. Personally, I think it is a matter of finding the right balance of Th1, Th2, Th17, and Treg. Autoimmune-dominant people (like myself) have their bodies constantly being cleared of tumors, but the Darwinian selection of anti-inflammatory expressing tumors is speeded up also. Allergy-dominant individuals may wish to boost Th1 through probiotics or herbs.
But if Fukushima keeps going on for years and years, it’s going to finish everyone. People will die from cancer, autoimmune-related diseases, or from genetic defects passed on to future generations. Do not think, that there is X amount of radiation at Fuku, and that is not enough. That does not take into account protracted exposure. At some point it becomes an ELE.
(1) What Is The ACTUAL Risk for Pacific Coast Residents from Fukushima Radiation?
(2) Is cancer risk of radiation workers larger than expected?
(3) DNA Damage after Continuous Irradiation: Findings in Mice Compared with Human Epidemiologic Data
(4) Radiation Biophysics (Ionizing Radiations)
(5) The mysterious steps in carcinogenesis
(6) Low-dose of Ionizing Radiation Enhances Cell Proliferation Via Transient ERK1/2 and p38 Activation in Normal Human Lung Fibroblasts
(7) Cell Proliferation and Carcinogenesis: A Brief History and Current View Based on an IARC Workshop Report
(8) Somatic stem cells and the kinetics of mutagenesis and carcinogenesis
(9) Cancer immunosurveillance and immunoediting: the roles of immunity in suppressing tumor development and shaping tumor immunogenicity.
(10) Cancer immunoediting from immune surveillance to immune escape
(11) Interferon gamma-1b Side Effects