Corresponding Author: Björn L.D.M. Brücher

Department of Surgery, Carl-Thiem-Klinikum, 03048 Cottbus (Germany)
E-Mail b-bruecher@gmx.de

Physics Essentials Enable Deeper Understanding in Signaling and Crosstalk of the Carcinogenesis Paradigm “Epistemology of the Origin of Cancer”

Björn L.D.M. Brüchera,b,c     Martin Daumera,b,d     Ijaz S. Jamalla,b,e    

aTheodor-Billroth-Academy®, Munich, Germany – Sacramento, CA, USA, bINCORE, International Consortium of Research Excellence of the Theodor-Billroth-Academy®, Munich, Germany – Sacramento, CA, USA, cDepartment of Surgery, Carl-Thiem-Klinikum, Cottbus, Germany, dSylvia Lawry Centre for Multiple Sclerosis Research e.V. – The Human Motion Institute, Munich, Germany, eRisk-Based Decisions Inc., Sacramento, CA, USA

Key Words
Cancer • Carcinogenesis • Mutation • Physics • Radioactivity • Radiation
Abstract
Radioactivity and radiation-induced mutations are believed to be primary causal examples of cancer-initiating events (stimulus). The assumption that an increase in cancer risk develops from any amount of radiation gave rise to the linear no-threshold model. This also led to the assumption that cancer is caused by somatic mutations as described by the somatic mutation theory. Against this backdrop, in actuality only ~5%–10% of cancers result from somatic mutations or its various modifications, while ~80% of cancers are still termed as ‘sporadic’, meaning that their cause is unknown. Therefore, both the linear no-threshold model and the somatic mutation theory have resulted in an incongruity in thinking. Decades of molecular and clinical research since 2012 led to the development of the cancer paradigm, “Epistemology of the origin of cancer”, which explains why the majority of cancers originate as a result of a six-step sequence of events. An understanding of the essentials of physics helps to explain the interconnections between physics and the biology of cancer. This allows for a much-needed reconciliation of past errors and leads to a deeper understanding of carcinogenesis.

 

Introduction

Radioactivity in the form of ionizing radiation can induce mutations in DNA and is believed to be the primary causal example of a cancer-initiating event. The Linear No-Threshold (LNT) model was created based on the assumption that any amount of radiation had some detrimental genetic effects in the form of DNA damage that could then lead to cancer, i.e. a zero-threshold assumption or that there is no radiation dose that is without an incremental quantifiable increase in cancer risk. This was the basis for the belief that cancer is caused by mutations as described by the somatic mutation theory (SMT). In fact, only a small proportion of cancers (~5%–10%) have been shown to result from mutations over the past 100 years and the majority (80%) of cancers are therefore still referred to as ‘sporadic’, meaning that their cause remains unknown [1-14].
Decades of molecular and clinical research led us in 2012 to the development of the cancer paradigm “Epistemology of the origin of cancer”, with a complex six-step set of events published in open-access format [9]. This paradigm explains why the majority of cancers originate after this sequence of events, namely (1) a pathogenic stimulus (biological or chemical) followed by (2) chronic inflammation, from which develops (3) fibrosis with associated changes in the cellular microenvironment. From these changes, (4) a pre-cancerous niche develops, which triggers the deployment of (5) a chronic stress escape strategy. When this condition fails to resolve, (6) the transition of a normal cell to a cancer cell occurs. The initial concept was realized between 2014 and 2016 including the original cancer paradigm and five papers [9-11, 15, 16]. This was followed by critical analyses of available knowledge five years after the paradigm was first published [17-26].
To date, the assessment of the contributions of physics to the process of carcinogenesis has been missing. Physics is of much greater significance in cancer research than is generally perceived. The essentials of physics provide a deeper understanding of how and why the LNT is invalid and thus gives an impetus for further critical thinking and analyses to more completely understand carcinogenesis, which describes the complex, incompletely understood process by which changes in cells/tissues/organs lead to the disease that we refer to as cancer (see also Supplementary Material – for all supplementary material see www.cellphysiolbiochem.com).


Radioactivity

For their joint discoveries, Antoine Henri Becquerel (1852–1908) (spontaneous radioactivity from uranium salts), and Marie (1867-1934) and Pierre Curie (1859-1906) (identification of polonium), received the Nobel Prize in Physics in 1903. Marie Curie reported on radium between 1898 and 1907 [27-33], and Pierre Curie and his student Albert Laborde measured continuous emissions from radium in 1903 [32]. More detailed information about the discoveries of radiation and in Physics is provided in the Supplementary Material (see also Fig. 1-10 in Supplementary Material).

Background radiation
Background radiation consists of approximately 82% natural and approximately 18% man-made radiation, which is mainly due to medical X-rays (58%), nuclear medicine (21%), consumer products (16%), occupational sources (2%), atomic bomb fallout (2%), and nuclear fuel cycles (1%) [34]. Exposure to ionizing radiation is a consistent occurrence for all life on Earth. Approximately 90% of the annual radiation dose “for a person living in the US comes from natural sources such as cosmic radiation and radioactive rocks” ([35], reviewed in [36]). Cosmic radiation originates from the sun and distant galaxies [37].
According to the International Atomic Energy Agency (IAEA) of the United Nations Scientific Committee on the Effects of Atomic Radiation (UNSCEAR) report in 1993, natural background radiation comes from “cosmic radiation, external radiation from radionuclides in the earth’s crust and internal radiation from radionuclides inhaled or ingested and retained in the body” [38]. In summary, “exposures due to cosmic rays, terrestrial gamma rays and ingestion vary only slightly with time, so they can be regarded as the background exposure to natural sources.
Radiation exposure in people is influenced by multiple factors. Geographic location is one such factor, as cosmic radiation increases with elevation above mean sea level. Background radiation also depends on local geology, and here preexisting radon is of importance, as radon sources affect exposure. In 1993, the UNSCEAR sought to establish a representative approach describing radiation exposure as follows: the determination of “radiation exposures from various sources consists of presenting the collective dose to the world population received or committed (a) from the end of 1945 to the end of 1992 (47 years) for discrete events and (b) for a period of 50 years at the current rate of practice or exposure for all other sources, including natural sources.” This approach was deemed to be reasonable for a period of 50 years (25 years before and after the present), although it has been stated that it is “likely that this assumption overestimates the future doses from practices that are not rapidly expanding, because improved techniques and standards of protection will reduce the doses per unit of practice” but it was not clear, how doses are affected by practice.
The worldwide average annual effective radiation dose in adults from all natural sources was estimated to be 2.0 mSv [39] in 1982, with a later estimate of 2.4 mSv (range: 1−10), consisting of 0.9 mSv (37.5%) from external exposure (cosmic rays: 0.4 mSv [16.7%]; terrestrial gamma rays: 0.5 mSv [20.8%]) and 1.5 mSv (62.5%) from internal exposure (inhalation [primarily radon]: 1.2 mSv [50%]; ingestion: 0.3 mSv [12.5%]) [40, 41]. The dosage levels are listed in Table 1 [modified according to 34] (see also Supplementary Material, Section ‘measurement parameters’). One’s exposure depends on several variables. For example, cosmic ray dose rates depend on altitude, with exposure rates being five-fold higher at higher altitudes compared with average rates at sea level [38]. Terrestrial γ-ray doses depend on local geology and residential ventilation such that some communities may have an exposure rate that is 100-fold higher than average due to the presence of certain types of naturally occurring radioactive minerals.
While the global average human exposure to natural background radiation is 2.4 mSv/a (270 nSv/h avg) [40, 41], there are large geographic variations [42]. For example, the average natural background radiation in Finland is ~8 mSv/a (~900 nSv/h avg) versus 90 μSv/h (800 mSv/avg) on a monazite beach near Guarapari, Brazil [43]. A Finish nationwide register-based case-control study on the Chernobyl fallout revealed that “Overall, background gamma radiation showed a non-significant association with the OR of childhood leukemia (OR 1.01, 95% CI 0.97, 1.05 for a 10-nSv/h increase in average equivalent dose rate to red bone marrow)” [44]. No accumulation of dose with age was found.

Table 1. Units of dose (modified from [34])

High background radiation (HBR) exposure
Depending on the geographic location, different effects of high background radiation exposure have been observed. For example, people living in mountainous areas can be exposed to high levels of natural background radioactivity because they live in so-called HBRAs (high-background-radiation areas) containing high concentrations of thorium and uranium [42, 45] (see also Supplementary Material, Section ‘nuclear fission and atom splitting’). However, to date no increases in cancer rates have been observed in HBRAs, such as China [46] or in Poland, and an even lower cancer death rate has been observed in these countries [47]. Moreover, the prevalence of thyroiditis and hypothyroidism have not been shown to be correlated with natural radiation exposures in Karunagapally, India, which is a HBRA [48].
Interestingly, higher rates of unscheduled DNA synthesis have been reported for people living in HBRAs compared with the control areas of Enping and Taishan Counties, China, without an increased all-cancer mortality rate. More specifically, rates for leukemia, breast cancer, and lung cancer, which are thought to be influenced by radiation, are not higher in HBRAs: “respective average annual doses are about 330 and 110 mR/yr, in the HBRAs in Yangjiang County approximately 90% of the annual radiation dose.” The above-mentioned areas showed nominally lower cancer mortality rates, although the differences were not statistically significant [49]. This finding agrees with various investigations: seeds from a given plant species do not exhibit phenotypic changes when exposed to radiation at high altitudes with correspondingly higher levels of cosmic rays [50], and data revealed that HBRAs did not have increased leukemia rates [51].
Furthermore, background radiation has not been demonstrated as a significant predictor of leukemia mortality rates when data were examined without regard to age [52]. A negative lung cancer correlation was found in three Rocky Mountain states, which have a 3.2-fold-higher natural background radiation level than three Gulf Coast states, and a strong negative correlation between lung cancer and natural radon levels has also been observed [53].
The Life Span Study (LSS) revealed that at doses below 0.1 Gray, cancer incidence is negligible; however, the cancer incidence increases to 29.5% at 1 Gray and to 61% at 2 Gray (hinting at a linear dose-response). However, in strongly irradiated survivors, such levels were observed for less than 10% of the survivors of the A-bomb [54]. Thus, 2 Gray (2 J/kg) is the amount of radiation necessary to produce the same effect on living organisms as 1 Gray of high-penetration X-rays, which is equal to 2000 mSv (2 Sv). There is no evidence of radiation effects for doses below about 500 mSv (0.5 Sv) [55]. It has been shown that a low LET radiation dose of 0.1 cGy per year results in an average of approximately 10−7 mutations per cell per day [56] but this is not just a very low number but also a number that does not take DNA repair, an integral component of all living organisms, into account.
Further detailed information on background radiation is also given in the Supplementary Material, section ‘background radiation’.


Hiroshima and Nagasaki 1945

Between 1939 and 1945, the Manhattan Project at the Los Alamos Scientific Laboratory in New Mexico, United States, revealed that plutonium was more toxic to humans than radium, but less hazardous in practical terms (see also Supplement, Section ‘quantum age’). These findings led to the development of nuclear bombs, with their use to devastating effect in 1945 [57, 58]. Following the first nuclear explosion on 16 July 1945 (Trinity test), the first atomic bombs were detonated on 6 August 1945 at 08:15 AM on Hiroshima and on 9 August 1945 at 11:02 AM on Nagasaki. The bombs were different in that the Hiroshima bomb contained uranium whereas the Nagasaki bomb contained plutonium as discussed elsewhere in this paper (see also Supplementary Material, Section ‘electromagnetic radiation’). Although reports vary, the direct casualties were devastating. Approximately 170,000 citizens died immediately [Hiroshima: 90,000–120,000; Nagasaki: 60,000–80,000] [59] due to the extreme heat and pressure of the blasts, which resulted in an extensive firestorm emanating from the hypocenter (explosion site). Ionizing radiation was emitted, and nearly all people within 1.5 km of the hypocenter were killed [54, 59, 60].
Both bombs exploded before reaching the ground (Table 2) (according to [34, 55, 61-63]); thus, the fission products were dispersed into the atmosphere and spread over a large area.
The perception at the time was that radiation from atomic bombs resulted in health effects such as leukemia and other cancers as well as a high risk of genetic malformations. However, the results of long-term studies do not support this view, particularly regarding the assumed genetic effects. The first study with a defined objective (not a report of one or multiple cases) was published in 1953: “There is no indication from this study of any ‘unusual’ sensitivity of human genes to irradiation” ([64], reviewed in [54]).
However, this perception remained and many long-term studies of the survivors were conducted. In 1947, the United States founded the Atomic Bomb Casualty Commission, which was later restructured as the Japanese Radiation Effects Research Foundation, financed by the United States and Japan. Since 1955, such investigations have been performed in a systematic manner, and the LSS began, which has follow-up data covering approximately 60 years for cohorts of individuals recruited between 1951 and 1953. This study includes approximately 120,000 individuals (54,000 within 2.5 km of the hypocenter [relatively high radiation doses], 40,000 2.5–10 km outside the hypocenter matched with regard to city, age, and sex [low/negligible radiation doses], and 26,000 unexposed residents) and approximately 77,000 children born between 1946 and 1984 with at least one parent who was exposed ([65], reviewed in [54, 60]). It was assumed that the LSS cohort included approximately 50% of survivors who were alive five years after the bombings ([66], reviewed in [54]).
The 1986 report on atomic bomb radiation dosimetry in Hiroshima and Nagasaki (in regard to the dosimetry system DS86) raised concerns about the calculated and measured values of thermal neutron activation of cobalt-60 (60Co), particularly because it was assumed that the neutron dosages were underestimated in this study ([67, 68], reviewed in [69]). The new dosimetry system, DS02, suggested improving the dosimetry estimates at the Radiation Effects Research Foundation (RERF) by using tools such as the Geographical Information System (GIS) which resulted in 5% to 10% reductions of house and body shielding transmission factors for neutrons.
Table 2.

Atomic bombs detonated at Hiroshima and Nagasaki [34, 55, 61, 63]



Linear No-Threshold (LNT) Model

The LNT model assumes that any amount of radiation has a detrimental effect in terms of mental health, genetic effects, and cancer, i.e. a zero-threshold assumption or put differently, that there is no radiation dose that is without an incremental quantifiable increase in cancer risk. Some have attempted to use this model to establish regulatory dose limits (Nuclear Regulatory Commission, NRC) although the model has not been verified as predictive (Fig. 1a and 1b). Furthermore, the LNT model is used to assess non-stochastic (deterministic) effects, but in actuality no response is seen until a threshold dose is exceeded. Contradictory findings have been observed in one of the most important cases of manipulated data in science, which gave rise to the dogma of the LNT model in the first instance [60, 70-73] and the LNT subsequently led to another dogma, the Somatic Mutation Theory or SMT used to explain the critical element in carcinogenesis [11]. An exploration of the data illustrates how the LNT and the later, the SMT, achieved widespread acceptance in the absence of strong supporting data (see also Supplementary Material, Section ‘nuclear fission and atom splitting’).
Herman Joseph Muller (1890–1967) irradiated Drosophila melanogaster (fruit flies) and observed lethal mutations within the F2 generation (88 lethal mutations in 758 cultures versus 1 lethal mutation in 947 cultures in the control group). However, in the F4 generation, hardly any mutations were observed [74-77]. Muller received the Nobel Prize in Physiology or Medicine in 1946. At that time, the atomic bombs had recently been detonated, and fears regarding radiation were substantial leading to the LNT model. Edward Butts Lewis (1918–2004), Professor of Biology at the University of California, San Francisco, supported the linear, no-threshold hypothesis as a model for radiation protection standards and afterwards the committee endorsed the LNT during the hearings of the Joint Committee on Atomic Energy Hearings at the end of the 50s, [78].
Science published an anonymous article in 1956 with the following conclusion: “The basic fact is - and no competent persons doubt this - that radiations produce mutations and that mutations are in general harmful…..We ought to keep all of our expenditures of radiation as low as possible….From the point of view of genetics, they are all bad” [79]. This statement was reported on the front page of the New York Times in an article entitled “Scientists term radiation a peril to future man” with the subtitle “Even small dose can prove harmful to descendants of victim, report states” [80], reporting on the LNT model. In 1957, Edward Butts Lewis (1918–2004), published observations that radiation caused leukemia in Science, [81] and he received the Nobel Prize in Physiology and Medicine in 1955 for his contribution to evolutionary developmental biology. Criticized by scientists [73], Lewis’ leukemia paper reported on heritable effects based on the LNT model and cancer induction in terms of the SMT. The SMT has been previously subjected to an exhaustive review [11].
The situation became worse over time, with the NAS Radiation Committee still promoting the LNT model as recently as in 2006 [34]: “LNT has also been applied to chemical carcinogens: the smallest amount of a carcinogen is hazardous without a threshold for positive excess risk” [72] (see also Supplementary Material, Section ‘radiation in living organism’).
The LNT and the SMT are based on models, not data, and have had unbelievable consequences for cancer research and oncology for the past 70+ years in that (1) use of a false radiation exposure model (LNT) resulted in “the road to linearity” (in regard to [73], and (2) a complete scientific molecular branch (carcinogenesis) was directed on the wrong path with the SMT being touted as the basis for the majority of cancers [11].
When the International Congress of Radiology was held in 1925 in London, an International X-ray Unit Committee was founded. The Second Congress in Stockholm, Sweden, took place in 1928, named the International X-ray and Radium Protection Committee (IXRPC). This meeting was followed by meetings in Paris (1931), Zurich (1934), and Chicago (1937). In 1950, the organization was named the International Commission on Radiological Protection (ICRP) (reviewed in [82-84]). In that year, the ICRP indicated “the dose limit from tolerance dose to maximum permissible dose.” There are now multiple societies and committees that determine radiation protection policies, such as the United Nations Scientific Committee on the Effects of Atomic Radiation (UNSCEAR) and the Committee on the Biological Effects of Ionizing Radiation (BEIR) of the National Research Council (NRC) of the United States. UNSCEAR and BEIR suggest ICRP recommendations to regional committees/institutions, such as the World Health Organization (WHO) and the IAEA, and industries, which result in national regulations (Fig. 1, reviewed in [84] - not provided here).
In 1950, the ICRP was not in the position of making firm recommendations regarding the maximum permissible amounts of radioactive isotopes [85, 86]; however, the committee recommended 300–600 mrem per week for skin, blood, gonads, and eyes in 1954 [87] and as a genetic dose in 1958 [88]. In 1956, the National Academy of Sciences (NAS), which is the highest scientific authority in the U.S., with its ‘The Biological Effects of Atomic Radiation (BEAR) committee’ adopted and wrongly recommended the LNT on 12 June ([89], reviewed in [73, 90]). According to the LNT, even the smallest amount of radiation is hazardous to human health. However, the LNT model is not based on solid data, but is instead a product of mathematical assumptions resulting in considerable uncertainty. If the LSS data had not been underestimated, the cancer risk would not have been overestimated. Currently, it is clear that the actual human data published in the LSS does not support the LNT model.
Today, we know that an ideologically driven decision based on unverified assumptions resulted in the genesis of the LNT. In 1977, the ICRP stated [91] that the induction of malignant tumors was a major risk based on the LNT model in terms of the SMT for carcinogenesis. In 1990, the Committee declared that even small radiation doses may produce deleterious health effects, as DNA changes would result in mutations and consequently cancer (reviewed in [82]), completely ignoring the role of DNA repair enzyme systems. However, their report stated that “the extent to which these diseases would increase with a given increase in the mutation rate have for the most part not been demonstrated directly in any organism” [91], an important caveat that has been ignored to date.
Another mistake was when rodent (mouse) studies were directly extrapolated and applied (1:1) to humans. We know that mouse studies cannot be automatically extrapolated to humans, especially if such investigations have not been performed for ages comparable to those of humans in terms of signaling pathways (Table 3) (adapted from [92]). In addition to the need to identify signaling pathways, although mice are the most commonly used animal model in cancer research, data reproducibility from these studies enables <8% of mice data to be successfully extrapolated from animal models to clinical cancer trials [93]. Mouse models are also primarily used because of the inherent genetic mutability in mice.
Only germline mutations can pass on characteristics (positive or negative) to the progeny. However, somatic mutations are those genetic changes that occur in non-germline cells and, in addition to not being passed down to progeny, also do not adequately describe the majority of cancers as is widely perceived (see also Supplementary Material, Table 1). Furthermore, we know that gene functions change in response to their environment [11, 15]. Epigenetics is the study of this phenomenon, where environmental factors determine whether a gene is activated (with subsequent effects on proteins/RNA) or whether a gene remains unactivated during a defined time. In experiments, genes are fixed (by a rigid definition) in a certain direction to elucidate parts of their function or study interactions. Rather, in biology, genes over multiple generations are responsible in for an organism’s ability to adapting to changes in its environment. Recent developments in cancer biology support a strong role for the tumor microenvironment and stroma in determining tumor progression [9, 94, 95].
It has been stated that “some somatic effects are stochastic; of these, carcinogenesis is considered to be the chief somatic risk of irradiation at low doses and therefore the main problem in radiation protection” [91]. In 1998, studies on genetic susceptibility to cancer were part of the official IRCP mission [96], suggesting that the ICRP directly supported and promoted the SMT. These studies were primarily based on mice or cell lines in vitro, such as investigations of p53 mutation accumulation in organs of mice irradiated with low-dose X-rays [97, 98].
Today, experiments still produce inconclusive results with equivocal evidence [93]; thus, it is no accident that UNSCEAR stated in 2012: “the Scientific Committee does not recommend multiplying very low doses by large numbers of individuals to estimate numbers of radiation-induced health effects within a population exposed to incremental doses at levels equivalent to or lower than natural background levels” [99]. Also, it is believed that radiation may be influenced by the presence of reactive oxygen species (ROS) and other free radicals [100]. This viewpoint is quite interesting as the cell nucleus is almost anoxic and approximately 90% of oxidation in the cell occurs inside the mitochondria [101], thus the short-lived free radicals would not be proximate to where the DNA resides inside the nucleus of the cell.
Researchers have sought to establish radiation-induced histone modifications [102-105] as an alternative mechanism to yield double-stranded DNA breaks (dsDNA). In this respect, three observations may be relevant: (1) the anthracycline drug, doxorubicin, induces substantial epigenetic changes in cultured cardiomyocytes in vitro with histone-3 acetylation [106]; (2) Histone modifications are mediated independently of ROS [99]; and (3) ionizing radiation induces locus-specific changes to histone modification enrichment in zebrafish and Atlantic salmon in generation F1, but not in subsequent generations [107]. Thus, changes in histone modifications in the investigated targets were not retained in a multi-transgenerational effects, in contrast to histone modifications that persist in transgenerational memory over 14 generations in Caenorhabditis elegans [108]. For this species, it has been shown that “Exposure to high temperatures [in Caenorhabditis elegans] led to expression of endogenously repressed copies of genes—sometimes called “junk” DNA,” which “persisted for >10 generations of worms.” The relevance of such findings cannot be extrapolated to humans, based on available data.
Although studies in cell lines and mice can be valuable, the reality is shown by clinical observations, which are too often underestimated. Out of 10,929 solid-cancer deaths within the LSS, only 527 (4.8%) were radiation-related ([109], reviewed in Table 4311 in [110]).
A 10-year follow-up of 1,292 children exposed in utero to radiation from atomic bombs in Hiroshima and Nagasaki showed no increase in malignant cancers [111], which is consistent with other reports [112]. No significant differences in mutation rates at microsatellite loci were reported, with an estimated mean mutation rate of 0.39 x 10-2 in the exposed group [(7 + 4)/2,789)] compared to 0.35 x 10-2 in the control group [113, 114], and which contradicts other reports [115]. However, in utero exposure to radiation seems to be considerably lower than early childhood exposure [116]. As discussed below, data from the Chernobyl nuclear plant accident affirms this phenomenon.
Fig. 1. Radioactivity and cancer risk (effect) models. (A) Linear no-threshold model with the assumption that that any amount of radiation has some detrimental genetic effects in the form of DNA damage that could then lead to cancer, i.e. a zero-threshold assumption or that there is no radiation dose that is without an incremental quantifiable increase in cancer risk. (B) Non-linear model: this model applies to non-stochastic (deterministic) effects: no response is seen until a threshold dose is exceeded. In this model non-stochastic effects are postulated and in this model, a defined minimum dose must be exceeded before the effect (diseases) occurs.
Table 3. Age equivalents in mice and humans and representative age ranges (adapted from [92])


Chernobyl nuclear power plant accident

The 1986 Chernobyl nuclear power plant accident is the most serious radiation exposure accident since WWII [41]. However, there is no scientific evidence to indicate that this accident increased the overall cancer incidence over that of the general United States population with regard to thyroid cancer: “National trends in cancer incidence rates for the nation of Ukraine are comparable to those observed in its neighbor country, Belarus, and are mostly comparable to those of the United States.” Moreover, the “...calculated average annual percent change for thyroid cancer incidence rates in the nation of Ukraine from 1999 to 2016 was 4.2%, which was not particularly different from the 3% to 4% observed in the United States Surveillance Epidemiology and End Results (SEER) registry over a similar time interval” [117].
Most recently it was shown by whole-genome sequencing of 130 children, born between 1987-2002 to parents exposed to ionizing radiation from the 1986 Chernobyl disaster, that “…no elevation in total germline de novo mutations regardless of cumulative preconception gonadal paternal (mean = 365 mGy, range = 0-4,080 mGy) or maternal (mean = 19 mGy, range = 0-550 mGy) exposure to ionizing radiation” was observed [118].
The question, scientists need to pose is “Why are no trans-generational effects observed after ionizing radiation, especially as this is still being promoted as the so-called prime example for initiating carcinogenesis?


Evaluation of the LNT model

Overall, radiation health effects (excluding physical/heat from the blasts) were due to γ-rays and neutron radiation from the atomic bomb blasts, for which dosages could be re-constructed based on the distance from the hypocenter.
It has long been believed that there exists a linear dose–response relationship between health effects and radiation exposure (dose). This belief is based on findings in Escherichia coli and D. melanogaster [75, 119-123], although it is also known that “the time rate of mutation varies greatly among different types of normal cells, representing different stages in the germinal cycle” [121]. Thus, several factors influence the results. “The results from Drosophila and from Tradescantia demonstrate that in the low-dose range, neutrons are much more efficient in the production of two-break chromosome aberrations than X- and γ-rays” [124].


Linear energy transfer (LET)

A small fraction of the dose absorbed by the Japanese atomic bomb survivors was due not to γ-rays but to fast neutrons. Directly ionizing particles are charged particles such as high-energy electrons, protons, α-particles, or fast heavy ions [34]. Indirect ionization occurs by uncharged rays, such as X- or γ-rays, which include fast neutrons.
LET is defined as the average energy lost by a particle due to electronic interactions per unit length along its trajectory, expressed in kiloelectronvolts per micrometer (keV/mm). High-energy electromagnetic radiation, such as X- or γ-rays is rarely ionized because in tissue it releases fast electrons with a low LET. The major energy transfers result from the photoelectric process, Compton scattering, and pair production. In tissues, the photoelectric process dominates at low energies (< 0.1 MeV), and most of the photon’s energy is imparted to the ejected electron as kinetic energy. At intermediate photon energies (0.5–3.5 MeV), Compton scattering is the most probable event, and the energy of the incoming photon is converted into the kinetic energy of an electron and a second (“scattered”) photon (with less energy). Pair production can occur at energies greater than 1.02 MeV. In this case, the photon energy is converted into a positron and electron after the radiation interacts with the atomic nucleus, and in turn, other molecules can be ionized.
The overall fraction of dose absorbed by atomic bomb survivors due to neutrons was small, approximately 2% in Hiroshima and 0.7% in Nagasaki ([125], reviewed in [34]). Here, it is important to note that small neutron doses can have large effects. Neutron energies reach up to millions of electron volts, which is higher than the energy of protons. Thus, high local concentrations produce far more clusters of ionization than low-LET photons, and result in more DNA damage [34]. The resulting recoil protons produce the maximum cellular damage per unit energy imparted ([126], reviewed in [34]).
The relative biological effectiveness (RBE) is the ratio of biological effectiveness of one type of ionizing radiation to another. The RBE of neutrons is about 12 compared to a γ-ray dose of 1 Gy (reviewed in [34]) (see also Supplementary Material, Section ‘radiation in living organism’). Using rats, Boerse and Gerber showed that 4 mGy of fast neutrons produced as many mammary neoplasms as 0.4 Gy of X-rays, implying an RBE of 100 ([127], reviewed in [34]). The experiments by Wolf in 2000 showed that a neutron dose of 20 mGy in Sprague–Dawley rats was equivalent to an acute 1-Gy X-ray dose, meaning that the neutron RBE is 50 versus a value of 1 for X-rays [128]. Approximately 70-80% of low-energy radiation-DNA interactions do not result in dsDNA breakages, a necessity to make DNA repair systems ineffective as there is no template to repair the damaged DNA. The more typical low-energy radiation-DNA interaction that results in DNA damage is primarily single-stranded DNA breaks (ssDNA), with only 0.5%–1.4% observed as dsDNA [129, 130] and these ssDNA are easily repaired as there is an intact strand to use as a template by the repair mechanisms [131-133]. However, dsDNA are believed to contribute to radiation-induced cancers. This assumption is also based on investigations in cell lines in vitro (reviewed in [134, 135]). However, as discussed, the reality in humans is different as only some 4.8% of solid-cancer deaths were causally shown to be radiation-related [109].
The Nagasaki atomic bomb produced low-LET radiation, resulting in a large number of ssDNA and consequently showed an S-shaped dose–response for leukemia. This is because DNA repair enzymes can use the intact strand as a template to repair the ssDNA damage as discussed above. Similar findings have been reported for most non-carcinogenic chemicals and/or pharmaceuticals (reviewed in [135, 136]).
Thus, agents that primarily produce dsDNA breaks are more relevant because repair enzymes have no template for repairing the damaged DNA [137] as occurred with the high LET radiation from the atomic bomb dropped on Hiroshima unless one has defective DNA repair enzymes. Such a condition occurs in children with the rare autosomal recessive condition, Xeroderma pigmentosum [11, 26, 138, 139].
It has long been known that many variables influence radiation resistance, such as age [140-143], gender [144, 145], and environment [146-148]. It was shown in 1937 that neutrons are approximately 5- to 6-fold more effective in inducing mutations than X-rays, which was confirmed in 1964 [149-151]. These findings led to the expectation that a dose–response effect would be found for neutrons [150].


Linear energy transfer (LET) and its effects

The above discussion explains why the dose–response curves differ in high- and low-LET radiation exposures and for acute versus chronic exposure. High-LET curves are typical for fissile reactions while low-LET curves are typical for X-rays, γ-rays, and tritium β-rays, as shown in Fig. 2. In this figure, the dashed curves for chronic exposure differ in both cases (high- versus low-LET) compared with single acute exposures. This figure was modified from the original presented by Straume and Carsten (1993) [152], which was based on earlier publications [153-163]. Only agents capable of dsDNA breakage become clinically relevant unless one has defective DNA repair enzymes, e.g. as in children with Xeroderma pigmentosum.
Fig. 2. Linear energy transfer (LET) and its effects. Observed differences in acute versus chronic effects for high versus low LET [this figure was modified from 152-163].


Somatic mutation theory (SMT)

As a result of the mathematically constructed but data-deficient LNT, the SMT grew in popularity to become the prime explanation for how the majority of cancers begin. Researchers have consistently tried to force fit the SMT, which holds true for only a minority of cancers by applying various changes and modifications [164, 165], such as introducing the concepts of driver and passenger mutations [166] and the hypermutation theory [167]. The so-called ‘bad luck’ paper was the latest such attempt to generate a mathematical explanation for the occurrence of carcinogenesis and it was based on the theory that somatic mutations cause cancer with a constant risk for a given number of cell divisions [168]. Furthermore, the statement that 66% of cancers would be explained by the SMT [168] was proven to be incorrect [169]. As the SMT can only be applied for some 5 to 10% of cancers, it is obvious that this is an untenable model that cannot be applied to explain the majority of cancers. Here, it is helpful to read the primary literature beyond the original papers [170-172] and none of the above papers cited the original publications.
Findings were simply combined into one box, reflecting biased thinking, without acknowledging the known significant differences between animal or cell line experiments and humans. It is known that the expression levels and composition of DNA repair genes differ considerably between humans and mice ([173, 174] reviewed in [175]). The same group investigated germline and somatic mutation rates in humans and mice [175]. Detecting mutations is not as easy as one may think. Germline mutations can be observed in all somatic cells, while post-zygotic somatic mutations are measurable only if a large fraction of the cell population is sampled. Thus, measured somatic mutations do not provide a direct estimate of the actual somatic mutation rate. Somatic mutation frequencies in single cells are based on investigating reporter loci whereas surrogate genes “cannot be considered as representative for the genome overall” [175] as “the high error rate of current high-throughput sequencing platforms (0.1%–1%) effectively masks low-abundance mutations” [176].
To overcome this challenge, the identification of clonally amplified mutations in most cells might provide more reliable results; however, this approach requires that one finds the same mutation in multiple independent reads from the same gene locus. Thus, whole genome amplification (WGA) has been suggested as a more accurate approach. When a reference sequence is aligned, “mutations are detected as differences between the amplified single-cell genomic DNA and the reference sequence normalized to the non-amplified genomic DNA of the mother cell population” [177]. Gundry et al. suggested sequencing the genomes of multiple single cells from D. melanogaster (S2 cells) and mouse embryonic cells (mouse embryonic fibroblasts, MEF), after treatment with the mutagen N-ethyl-N-nitrosourea to estimate the agent’s mutagenicity. It has been stated that this approach could provide “a direct measure of exposure to mutagenic agents and for assessing genotypic heterogeneity within tissues or cell populations”, but not much in this regard has been published.
Somatic mutation frequency “cannot be determined by sequencing total genomic DNA due to the very low abundance of such mutations, which are unique to individual cells” [175]. The frequencies of germline and somatic mutations in humans and mice are different: after adjusting for the number of mitosis cycles, a median germline mutation rate of 1.2 x 10-8 mutations per base pair (bp) per mitosis was calculated for humans, with a value of 5.7 x 10-9 mutations per bp for mice. As these differ significantly, findings in mice cannot easily be transferred 1:1 to humans in this regard. Furthermore, the mass of mutations have very small effects [178]. To fully elucidate radiation effects, we must explore radiation effects in living organisms in greater detail.


Radiation effects

The effects of radiation include damaging changes in the bases and polynucleotide chains of DNA as single- and double-stranded breaks. This damage is influenced by many variables. Cells in the mitotic and G2 phases are the most sensitive, while cells in the S phase are the most radiation-resistant. The tissue of origin influences the results, as rapidly proliferating cells such as those from the skin mucosa or bone marrow reveal effects within a few weeks while slow or non-proliferating tissues such as nerves, muscles, and bones can reveal adverse effects months or years post-exposure [179-181]. Knowledge of embryogenesis and fetogenesis, as well as the process of differentiation of the three germ layers into various tissues, is required to understand the different effects of radiation (see Supplementary Material, Table 1, and for further details see also Supplementary Material, Section ‘radiation in living organism’).
Franklin Paine Mall (1862–1917) attempted to classify embryology in 1914 [182-184] and founded the “Carnegie Collection” in 1887 (officially announced in 1902) (see also Supplementary Material, sections ‘radiation in living organism’ and ‘development during embryology’). Approximate Carnegie stages are delineated based on the development of structures in mice and rats according to Nishimura [185] based on Streeter [186-189], Nishimura [190, 191], Olivier and Pineau [192], Iffy [193], Jirásek [194], and O’Rahilly and Müller [195]. These stages were also reviewed in Yamada [196] and in terms of various irradiation dates in regard to rats [197-199] and mice [200, 201] (Fig. 3).
Fig. 3. Radiation effects and cancer response during development according to Carnegie stages in humans, mice, and rats. Approximate Carnegie stages delineated through the development of structures, modified according to [185-195]; also reviewed in [196]. Results are presented for various irradiation dates in rats [197-199] and mice [200, 201].

LD50/30
According to the United States Nuclear Regulatory Commission (USNRC), a radiation dose of 4–5 Sv is expected to cause death in 50% of an exposed population within 30 days (lethal dose [LD] 50/30) [202]. By comparison, flight attendants are subjected to an annual dose of 1.5–1.7 mSv [203], and a chest X-ray, mammogram, and a single abdominal computed tomography scan corresponds to an exposure of 0.1 mSv (range: 0.05–0.24), 0.4 mSv (range: 0.1–0.6), and 8 mSv (range: 3.5–25) [204]. Although an increase in some cancers have been reported in flight crews compared to the general population, the results should be interpreted in light of self-reported health information and a cross-sectional study design. A more equivocal finding was reported in Swedish cabin crews [205].
The total-body lethal radiation dose that causes death in 50% of individuals (LD50) is about 3–4 Gy [206, 207].

Time of radiation exposure
Many variables influence radiation-induced cancer risk, such as direct dose-time exposure/ radiation fallout/ingestion, time of exposure (prenatal, postnatal, or early childhood, late life), and time of prenatal exposure (embryogenesis or fetogenesis) (see also Supplementary Material, section ‘radiation in living organism’). These factors may explain some of the contradictory findings regarding decreased cancer risk for the majority of Japanese atomic bomb survivors in comparison to ongoing excessive thyroid cancer risk associated with childhood exposure to radiation [116, 208]. Observations of varying cancer incidences during the pre-implantation period versus in utero irradiation during embryogenesis (blastogenesis versus organogenesis) versus fetogenesis were reviewed by Lena Einhorn in 1991 (reviewed in [209]). The Zeitgeist culture of most of discoveries as well as important content to take into account are enabled in the Supplementary Material, section ‘Time in context European Vision’.


Conclusion

Only some 5 to 10% of cancers are proven to be caused by mutations. The continuous use of radiation as the origins of mutation-induced cancer is not valid as discussed for the majority of cancers. These erroneous inferences are all redicated on the LNT and SMT models as detailed above. From a scientific point of view, we should ask “Why are no trans-generational effects observed after ionizing radiation, especially as this is still being promoted as the so-called prime example for carcinogenesis?” The cancer paradigm “Epistemology of the origin of cancer” with its sex-step process for carcinogenesis includes signaling, as well as anti- and pro-inflammatory regulatory mediators or mechanotransduction, precancerous niche and cell transition that together enable a deeper understanding of the mistakes and incongruity in events that lead up to the development of cancers. Since 2019, the literature supporting this paradigm is being published with some regularity [210-249]. By this, both the essential principles of physics and the cancer paradigm provide insights to the puzzle of carcinogenesis and serve as an impetus to further critical thinking and analyses. The outcome could be new concepts and cognition in science for mankind and especially for cancer patients.


Abbreviations

BEIR (Committee on the Biological Effects of Ionizing Radiation); BIPM (Bureau international des poids et mesures (International Bureau of Weights and Measures)); CIPM (Comité international des poids et mesures (International Committee for Weights and Measures)); dsDNA (double-stranded DNA breaks); GIS (Geographical Information System); Gy (Gray); HBR (High background radiation); HBRAs (high-background-radiation areas); IAEA (International Atomic Energy Agency); ICRP (International Commission on Radiological Protection); ICRU (International Commission on Radiation Units and Measurements); IXRPC (International X-ray and Radium Protection Committee); LD50 (lethal dose for 50% of an exposed population); LD50/30 (lethal dose of radiation which is expected to cause death in 50% of an exposed population within 30 days); LET (linear energy transfer); LNT (linear no-threshold model); LSS (Life Span Study); MEF (mouse embryonic fibroblasts); NRC (Nuclear Regulatory Commission); RBE (relative biological effectiveness); RERF (Radiation Effects Research Foundation); ROS (reactive oxygen species); SEER (United States Surveillance Epidemiology and End Results registry); SI (Système international [d’unités] (International System of Units)); SMT (somatic mutation theory); ssDNA (single-stranded DNA breaks); Sv (Sievert); UNSCEAR (United Nations Scientific Committee on the Effects of Atomic Radiation); USNRC (United States Nuclear Regulatory Commission); WGA (whole genome amplification); WHO (World Health Organization).

Acknowledgements

We are thankful to the countless scientists, clinicians, and individuals of various disciplines and professions from Germany, Greece, Israel, Italy, Japan, Portugal, Spain, Switzerland, UK, and the USA for the personal exchanges during the last few decades. We acknowledge the intense and bias-free discussions, critical thinking, exchanges, and reviews by Professor Detlef Bartsch, Berlin, Germany, Professor Dr Marjan Slak Rupnik, Vienna, Austria, Professor em. Michael Baum, London, UK, Associate Professor Dr Jochen Salber, Bochum, Germany, Dr Gudrun Schueler, Cottbus, Germany and Professor Reshef Tenne, Rehovot, Israel.

 

Author Contributions
BB produced the first draft. MD and IJ worked on the various sections. All authors edited and modified the manuscript.

Funding
The manuscript was supported by the Theodor-Billroth-Academy® (TBA®) and INCORE (International Consortium of Research Excellence) of the TBA®.

 

Disclosure Statement

The authors declare that no conflicts of interest exist.

References

1 Lynch HT, Smyrk TC, Watson P, Lanspa SJ, Lynch JF, Lynch PM, Cavalieri RJ, Boland CR: Genetics, natural history, tumor spectrum, and pathology of hereditary nonpolyposis colorectal cancer: an updated review. Gastroenterology 1993;104(5):1535-1549. https://doi.org/10.1016/0016-5085(93)90368-m.
https://doi.org/10.1016/0016-5085(93)90368-M
 
2 Tomlinson IP, Novelli MR, Bodmer WF: The mutation rate and cancer. Proc Natl Acad Sci USA 1996;93(25):14800-14803. https://doi.org/10.1073/pnas.93.25.14800.
https://doi.org/10.1073/pnas.93.25.14800
 
3 Pisani P, Parkin DM, Muñoz N, Ferlay J: Cancer and infection: estimates of the attributable fraction in 1990. Cancer Epidemiol Biomarkers Prev 1997;6(6):387-400.
 
4 Blattner WA: Human retroviruses: their role in cancer. Proc Assoc Am Physicians 1999;111(6):563-572. https://doi.org/10.1046/j.1525-1381.1999.99210.x.
https://doi.org/10.1046/j.1525-1381.1999.99210.x
 
5 Burth RW: Colon cancer screening. Gastroenterology 2000;119(3):837-853. https://doi.org/10.1053/gast.2000.16508.
https://doi.org/10.1053/gast.2000.16508
 
6 Parkin DM: The global health burden of infection-associated cancers in the year 2002. Int J Cancer 2006;118(12):3030-3044. https://doi.org/10.1002/ijc.21731.
https://doi.org/10.1002/ijc.21731
 
7 Rustgi AK: The genetics of hereditary colon cancer. Genes Dev 2007;21(20):2525-2538. https://doi.org/10.1101/gad.1593107.
https://doi.org/10.1101/gad.1593107
 
8 Markowitz SD, Bertagnolli MM: Molecular origins of cancer: Molecular basis of colorectal cancer. N Engl J Med 2009;361(25):2449-2460. https://doi.org/10.1056/NEJMra0804588.
https://doi.org/10.1056/NEJMra0804588
 
9 Brücher BLDM, Jamall IS: Epistemology of the Origin of Cancer: A New Paradigm. BMC Cancer 2014;14(331):1-15. https://doi.org/10.1186/1471-2407-14-331.
https://doi.org/10.1186/1471-2407-14-331
 
10 Brücher BLDM, Jamall IS: Cell-Cell communication in tumor microenvironment, carcinogenesis and anticancer treatment. Cell Physiol Biochem 2014;34(2):213-243. https://doi.org/10.1159/000362978.
https://doi.org/10.1159/000362978
 
11 Brücher BLDM, Jamall JS: Somatic Mutation Theory - Why it's Wrong for Most Cancers. Cell Physiol Biochem 2016;38(5):1663-1680. https://doi.org/10.1159/000443106.
https://doi.org/10.1159/000443106
 
12 Kanth P, Grimmett J, Champine M, Burt R, Samadder NJ: Hereditary Colorectal Polyposis and Cancer Syndromes: A Primer on Diagnosis and Management. Am J Gastroenterol 2017;112(10):1509-1525. https://doi.org/10.1038/ajg.2017.212.
https://doi.org/10.1038/ajg.2017.212
 
13 Jonsson P, Bandlamudi C, Cheng ML, Srinivasan P, Chavan SS, Friedman ND, Rosen EY, Richards AL, Bouvier N, Selcuklu SD, Bielski CM, Abida W, Mandelker D, Birsoy O, Zhang L, Zehir A, Donoghue MTA, Baselga J, Offit K, Scher HI, et al.: Tumour lineage shapes BRCA-mediated phenotypes. Nature 2019;571(7766):576-579. https://doi.org/10.1038/s41586-019-1382-1.
https://doi.org/10.1038/s41586-019-1382-1
 
14 de Martel C, Georges D, Bray F, Ferlay J, Clifford GM: Global burden of cancer attributable to infections in 2018: a worldwide incidence analysis. Lancet Glob Health 2020;8(2):e180-e190. https://doi.org/10.1016/S2214-109X(19)30488-7.
https://doi.org/10.1016/S2214-109X(19)30488-7
 
15 Brücher BLDM, Yan L, Schnabel P, Daumer M, Wallace TJ, Kube R, Zilberstein B, Steele S, Jamall IS: Genomics, microRNA, epigenetics, and proteomics for future diagnosis, treatment and monitoring response in upper GI cancers. Clin Trans Med 2016;5(1):1-16. https://doi.org/10.1186/s40169-016-0093-6.
https://doi.org/10.1186/s40169-016-0093-6
 
16 Brücher BLDM, Lyman G, van Hillegersberg R, Pollock RE, Lordick F, Yang HK, Ushijima T, Yeoh KG, Skricka T, Polkowski W, Wallner G, Verwaal V, Garofalo A, D'Ugo D, Roviello F, Steinau HU, Wallace TJ, Daumer M, Maihle N, Reid III TJ, et al.: Imagine a World Without Cancer. BMC Cancer 2014;14(186):1-8. https://doi.org/10.1186/1471-2407-14-186.
https://doi.org/10.1186/1471-2407-14-186
 
17 Brücher BLDM, Jamall IS: Prelude and Premise to the Special Issue: Disruption of homeostasis-induced signaling and crosstalk in the carcinogenesis paradigm "Epistemology of the origin of cancer". 4open 2019;2(6):1-8. https://doi.org/10.1051/fopen/2019005.
https://doi.org/10.1051/fopen/2019005
 
18 Brücher BLDM, Jamall IS: Undervalued ubiquitous proteins. 4open 2019;2(7):1-13. https://doi.org/10.1051/fopen/2019002.
https://doi.org/10.1051/fopen/2019002
 
19 Brücher BLDM, Jamall IS: Chronic inflammation evoked by pathogenic stimulus during carcinogenesis. 4open 2019;2(8):1-22. https://doi.org/10.1051/fopen/2018006.
https://doi.org/10.1051/fopen/2018006
 
20 Brücher BLDM, Jamall IS: Eicosanoids in carcinogenesis. 4open 2019;2(9):1-34. https://doi.org/10.1051/fopen/2018008.
https://doi.org/10.1051/fopen/2018008
 
21 Brücher BLDM, Jamall IS: Microbiome and morbid obesity increase pathogenic stimulus diversity. 4open 2019;2(10):1-16. https://doi.org/10.1051/fopen/2018007.
https://doi.org/10.1051/fopen/2018007
 
22 Brücher BLDM, Jamall IS: Precancerous niche (PCN), a product of fibrosis with remodeling by incessant chronic inflammation. 4open 2019;2(11):1-21. https://doi.org/10.1051/fopen/2018009.
https://doi.org/10.1051/fopen/2018009
 
23 Brücher BLDM, Jamall IS: Metformin alters signaling homeostasis. 4open 2019;2(12):1-17. https://doi.org/10.1051/fopen/2019006.
https://doi.org/10.1051/fopen/2019006
 
24 Brücher BLDM, Lang F, Jamall JS: NF-κB signaling and crosstalk in carcinogenesis. 4open 2019;2(13):1-35. https://doi.org/10.1051/fopen/2019010.
https://doi.org/10.1051/fopen/2019010
 
25 Brücher BLDM, Jamall IS: Transition from normal to cancerous cell by precancerous niche (PCN) induced chronic cell-matrix stress. 4open 2019;2(14):1-31. https://doi.org/10.1051/fopen/2018996.
https://doi.org/10.1051/fopen/2018996
 
26 Brücher BLDM, Jamall IS: Synopsis - Special Issue: Disruption of homeostasis-induced signaling and crosstalk in the carcinogenesis paradigm "Epistemology of the origin of cancer". 4open 2019;2(28):1-30. https://doi.org/10.1051/fopen/2019023.
https://doi.org/10.1051/fopen/2019023
 
27 Curie P, Curie M: Sur une substance nouvelle radio-active, contenue dans la pechblende. C R Acad Sci 1898;127:175-178. URL: https://www.academie-sciences.fr/pdf/dossiers/Curie/Curie_pdf/CR1898_p175_178.pdf [accessed Jan 04, 2007].
 
28 Curie M: Recherches sur les Substances Radioactives. Doctorate thesis 1904;1-155. University of Paris. URL: https://lccn.loc.gov/04010116 [accessed Jan 04, 2007].
 
29 Becquerel H, Curie P: Action physiologique des rayons du radium. Comptes Rendus des Séances de L'Académie des Sciences 1901;132:1289-1291 [séance on 3 June 1901]. URL: https://www.academie-sciences.fr/pdf/dossiers/Curie/Curie_pdf/CR1901_p1289_1291.pdf [accessed Jan 04, 2007].
 
30 Curie M: Sur le poids atomique du radium. C R Acad Sci 1902;135:161-163. URL: https://hal.archives-ouvertes.fr/jpa-00242258/document [accessed Jan 04, 2007].
 
31 Curie M: Sur le poids atomique du Radium. Faculté des Sciences de Paris, Radium (Paris) 1907;4(10):349-352. https://doi.org/10.1051/Radium:01907004010034900.
https://doi.org/10.1051/radium:01907004010034900
 
32 Curie P, Laborde A: Sur la chaleur dégagée spontanément par les sels de radium. C R Acad Sci 1903:673-675. Paris: Gauthier-Villars. URL: https://www.biodiversitylibrary.org/item/31410#page/681/mode/1up [accessed Jan 04, 2007].
 
33 Curie M: Action de la pesanteur sur le dépôt de la radioactivité induite. Radium (Paris) 1907;4(11):381-382. https://doi.org/10.1051/Radium:01907004011038100.
https://doi.org/10.1051/radium:01907004011038100
 
34 National Research Council (U.S.). Health risks from exposure to low levels of ionizing radiation: BEIR VII, Phase 2 2000. Washington, DC, The National Academies Press. https://doi.org/10.17226/11340.
https://doi.org/10.17226/11340
 
35 Early PJ, Sodee DB: Principles and practice of nuclear medicine. Mosby, 1995.
 
36 Dadachova E, Casadevall A: Ionizing radiation: how fungi cope, adapt, and exploit with the help of melanin. Curr Opin Microbiol 2008;11(6):525-531. https://doi.org/10.1016/j.mib.2008.09.013.
https://doi.org/10.1016/j.mib.2008.09.013
 
37 Simpson JA. The cosmic radiation, in Bleeker JAM, Geiss J, Huber MCE (eds): The Century of Space Science. Springer, Dordrecht, 2001. https://doi.org/10.1007/978-94-010-0320-9_4.
https://doi.org/10.1007/978-94-010-0320-9_4
 
38 United Nations Scientific Committee on the Effects of Atomic Radiation (UNSCEAR). Sources and effects of ionizing radiation. Radiation Report to the National Assembly, New York, United Nations, 1993. URL: https://www.unscear.org/unscear/uploads/documents/unscear-reports/UNSCEAR_1993_Report.pdf.
 
39 United Nations Scientific Committee on the Effects of Atomic Radiation (UNSCEAR). Sources and effects of ionizing radiation. Radiation Report to the National Assembly, New York, United Nations, 1982. URL: https://www.unscear.org/docs/publications/1982/UNSCEAR_1982_Report.pdf.
 
40 United Nations Scientific Committee on the Effects of Atomic Radiation (UNSCEAR). Sources and effects of ionizing radiation. Radiation Report to the National Assembly, New York, United Nations, 1988. URL: https://www.unscear.org/docs/publications/1988/UNSCEAR_1988_Report.pdf.
 
41 United Nations Scientific Committee on the Effects of Atomic Radiation (UNSCEAR). Sources and effects of ionizing radiation. Radiation Report to the National Assembly, New York, United Nations, 2000. URL: https://www.unscear.org/docs/publications/2000/UNSCEAR_2000_Report_Vol.I.pdf.
 
42 Hendry JH Simon SL, Wojcik A, Sohrabi M, Burkart W, Cardis E, Laurier D, Tirmarche M, Hayata I: Human exposure to high natural background radiation: what can it teach us about radiation risks? J Radiol Prot 2009;29:A29-42. https://doi.org/10.1088/0952-4746/29/2A/S03.
https://doi.org/10.1088/0952-4746/29/2A/S03
 
43 United Nations Scientific Committee on the Effects of Atomic Radiation (UNSCEAR). Annex B. Sources and Effects of Ionizing Radiation 2000, Vol 1. United Nations. URL: https://www.unscear.org/unscear/en/publications/2000_1.html.
 
44 Nikkilä A, Erme S, Arvela H, Holmgren O, Raitanen J, Lohi O, Auvinen A: Background radiation and childhood leukemia: A nationwide register-based case-control study. Int J Cancer 2016;139(9):1975-1982. https://doi.org/10.1002/ijc.30264.
https://doi.org/10.1002/ijc.30264
 
45 Jaworowski Z: Ionizing radiation in the 20th century and beyond. Symposium Entwicklungen im Strahleschutz, Munich, November 29, 2001. URL: www.cns-snc.ca/branches/Toronto/radiation [accessed Jul 03, 2004].
 
46 Tao Z, Zha Y, Akiba S, Sun Q, Zou J, Li J, Liu Y, Kato H, Sugahara T, Wei L: Cancer mortality in the high background radiation areas of Yangjiang, China during the period between 1979 and 1995. J Radiat Res 2000;41 Suppl:31-41. https://doi.org/10.1269/jrr.41.s31.
https://doi.org/10.1269/jrr.41.S31
 
47 Fornalski KW, Dobrzyński L: The cancer mortality in high natural radiation areas in Poland. Dose Response 2012;10(4):541-561. https://doi.org/10.2203/dose-response.11-035.Fornalski.
https://doi.org/10.2203/dose-response.11-035.Fornalski
 
48 Sreekumar A, Jayalekshmi PA, Nandakumar A, Nair RRK, Ahammed R, Sebastian P, Koriyama C, Akiba S, Nakamura S, Konishi J: Thyroid nodule prevalence among women in areas of high natural background radiation, Karunagappally, Kerala, India. Endocrine 2020;67(1):124-130. https://doi.org/10.1007/s12020-019-02071-z.
https://doi.org/10.1007/s12020-019-02071-z
 
49 Chen D, Wei L: Chromosome aberration, cancer mortality and hormetic phenomena among inhabitants in areas of high background radiation in China. J Radiat Res 1991;32 Suppl(2):46-53.
https://doi.org/10.1269/jrr.32.SUPPLEMENT2_46
 
50 Beal JM: Negative results following exposure of several kinds of seeds to cosmic rays and other radiations at high altitudes. Bot Gaz 1951;112(24):533-534. https://doi.org/10.1086/335688.
https://doi.org/10.1086/335688
 
51 Craig L, Seidman H: Leukemia and lymphoma mortality in relation to cosmic radiation. Blood 1961;17(3):319-27.
https://doi.org/10.1182/blood.V17.3.319.319
 
52 Hickey RJ, Bowers EJ, Spence DE, Zemel BS, Clelland AB, Clelland RC: Low level ionizing radiation and human mortality: multi-regional epidemiological studies. Health Phys 1981;40(5):625-641. https://doi.org/10.1097/00004032-198105000-00003.
https://doi.org/10.1097/00004032-198105000-00003
 
53 Jagger J: Natural background radiation and cancer death in Rocky Mountain states and Gulf Coast states. Health Phys 1998;75(4):428-443. https://doi.org/10.1097/00004032-199810000-00012.
https://doi.org/10.1097/00004032-199810000-00012
 
54 Douple EB, Mabuchi K, Cullings HM, Preston DL, Kodama K, Shimizu Y, Fujiwara S, Shore RE: Long-term radiation-related health effects in a unique human population: lessons learned from the atomic bomb survivors of Hiroshima and Nagasaki. Disaster Med Public Health Prep 2011;5(0 1):S122-133. https://doi.org/10.1001/dmp.2011.21.
https://doi.org/10.1001/dmp.2011.21
 
55 Preston DL, Shimizu Y, Pierce DA, Suyama A, Mabuchi K: Studies of Mortality of Atomic Bomb Survivors. Report 13: Solid Cancer and Noncancer Disease Mortality: 1950-1997. Radiat Res 2003;160(4):381-407. https://doi.org/10.1667/rr3049.
https://doi.org/10.1667/RR3049
 
56 Pollycove M, Feinendegen LE: Biologie moléculaire, épidémiologie et la fin de la relation linéaire sans seuil. Comptes Rendus de l'Académie des Sciences - Series III 1999;322(2-3):197-204. https://doi.org/10.1016/S0764-4469(99)80044-4.
https://doi.org/10.1016/S0764-4469(99)80044-4
 
57 Langham WH, Lawrence JN, McClelland J, Hempelmann LH: The Los Alamos Scientific Laboratory's experience with plutonium in man. Health Phys 1962;8:753-760. https://doi.org/10.1097/00004032-196212000-00033.
https://doi.org/10.1097/00004032-196212000-00033
 
58 Hempelmann LH, Langham WH, Richmond CR, Voelz GL: Manhattan Project plutonium workers: a twenty-seven year follow-up study of selected cases. Health Phys 1973;25(5):461-479. https://doi.org/10.1097/00004032-197311000-00001.
https://doi.org/10.1097/00004032-197311000-00001
 
59 Hiroshima and Nagasaki: The Physical, Medical, and Social Effects of the Atomic Bombings. New York, Basic Books, 1981. The Committee for the Compilation of Materials on Damage Caused by the Atomic Bombs in Hiroshima and Nagasaki. Hutchinson & Co (Publishers) Ltd 1981.
 
60 Jordan BR: The Hiroshima/Nagasaki Survivor Studies: Discrepancies Between Results and General Perception. Genetics 2016;203(4);1505-1512. https://doi.org/10.1534/genetics.116.191759.
https://doi.org/10.1534/genetics.116.191759
 
61 Malik J: The Yields of the Hiroshima and Nagasaki Nuclear Explosions, LA-8819, UC-34, September 1985. Los Alamos National Laboratory, Los Alamos, New Mexico, USA. URL: http://large.stanford.edu/courses/2018/ph241/cheng2/docs/malik.pdf.
https://doi.org/10.2172/1489669
 
62 Preston DL, Pierce DA, Shimizu Y, Cullings HM, Fujita S, Funamoto S, Kodama K: Effect of recent changes in atomic bomb survivor dosimetry on cancer mortality risk estimates. Radiat Res 2004;162(4):377-389. https://doi.org/10.1667/rr3232.
https://doi.org/10.1667/RR3232
 
63 Kerr GD, Young RW, Cullings HM, Christy RF: Chapter 1, Bomb Parameters 2005, in Young RW, Kerr GD (eds): Reassessment of the atomic bomb radiation dosimetry for Hiroshima and Nagasaki-Dosimetry System 2002 (DS02), Vol 1. Radiation Effects Research Foundation, Hiroshima, Japan, pp 42-61. URL: http://rerf.or.jp/shared/ds02 [accessed at Oct 26, 2001].
 
64 Neel JV, Schull WJ, McDonald DJ, Morton NE, Kodani M, Takeshima K, Anderson RC, Wood J, Brewer R, Wright S, Yamazaki J, Suzuki M, Kitamura S: The effect of exposure to the atomic bombs on pregnancy termination in Hiroshima and Nagasaki: preliminary report. Science 1953;118(3071):537-541. https://doi.org/10.1126/science.118.3071.537.
https://doi.org/10.1126/science.118.3071.537
 
65 Beebe G, Usagawa M. The Major ABCC Samples. Hiroshima, Japan: Atomic Bomb Casualty Commission Technical Report, 1968:17-62. See Technical Report Series, 1968. URL: https://www.rerf.or.jp/en/library/archives-en/scientific_pub/trtoc-en/tr1968-en/ [accessed at Oct 26, 2001].
 
66 Pierce DA, Shimizu Y, Preston DL, Vaeth M, Mabuchi K: Studies of the mortality of atomic bomb survivors. Report 12, Part I. Cancer: 1950-1990. Radiat Res 1996;146(1):1-27.
https://doi.org/10.2307/3579391
 
67 US-Japan joint reassessment of atomic bomb radiation dosimetry in Hiroshima and Nagasaki, in Roesch W (ed): Final report. DS86. Dosimetry System 1986. Vol. 2 (Appendix to Vol. 1). URL: https://inis.iaea.org/search/search.aspx?orig_q=RN:35070155 [accessed at Oct 26, 2001].
 
68 Reassessment of the Atomic Bomb Radiation Dosimetry for Hiroshima and Nagasaki- Dosimetry System 2002 (DS02). Hiroshima, Japan: Radiation Effects Research Foundation 2005. URL: https://www.rerf.or.jp/en/library/list-e/scids/ds02-en/ [accessed at Oct 26, 2001].
 
69 Cullings HM, Levenson Z, Funamoto S, Teranishi S: Changes in Atomic Bomb Survivors' Dosimetry with the New Dosimetry System DS02. Jpn J Health Phys 2006;41(6):261-271. https://doi.org/10.5453/jhps.41.261.
https://doi.org/10.5453/jhps.41.261
 
70 Calabrese EJ: On the origins of no-threshold (LNT) dogma by means of untruths, artful dodges and blind faith. Environ Res 2015;142;432-442. https://doi.org/10.1016/j.envres.2015.07.011.
https://doi.org/10.1016/j.envres.2015.07.011
 
71 Sutou S: A message to Fukushima: nothing to fear but fear itself. Genes Environ 2016;38:12. https://doi.org/10.1186/s41021-016-0039-7.
https://doi.org/10.1186/s41021-016-0039-7
 
72 Sutou S: Low-dose radiation from A-bombs elongated lifespan and reduced cancer mortality relative to un-irradiated individuals. Genes Environ 2018;40:26. https://doi.org/10.1186/s41021-018-0114-3.
https://doi.org/10.1186/s41021-018-0114-3
 
73 Calabrese EJ: The road to linearity: why linearity at low doses became the basis for carcinogen risk assessment. Arch Toxicol 2019;83(3):203-225. https://doi.org/10.1007/s00204-009-0412-4.
https://doi.org/10.1007/s00204-009-0412-4
 
74 Müller HJ: Artificial Transmutation of the Gene. Science 1927;66(1699):84-87. https://doi.org/10.1126/science.66.1699.84.
https://doi.org/10.1126/science.66.1699.84
 
75 Müller HJ: The Measurement of Gene Mutation Rate in Drosophila, Its High Variability, and Its Dependence upon Temperature. Genetics 1927;13(4):279-357.
https://doi.org/10.1093/genetics/13.4.279
 
76 Müller HJ: The Production of Mutations by X-rays. Proc Nat Acad Sci U S A 1928;14(9):714-726. https://doi.org/10.1073/pnas.14.9.714.
https://doi.org/10.1073/pnas.14.9.714
 
77 Müller HJ: Types of visible variations induced by X-rays in Drosophila. J Genetics 1928;22:299-344. https://doi.org/10.1007/BF02984195.
https://doi.org/10.1007/BF02984195
 
78 Institute of Medicine (US) Committee for Review and Evaluation of the Medical Use Program of the Nuclear Regulatory Commission; Gottfried KLD, Penn G, editors. Radiation In Medicine: A Need For Regulatory Reform. Washington (DC): National Academies Press (US); 1996; K, The Linear, No-Threshold Model. URL: https://www.ncbi.nlm.nih.gov/books/NBK232710/ [accessed Aug 06, 2021].
 
79 Genetic effects of atomic radiation. Science 1956;123(3209):1157-1164. https://doi.org/10.1126/science.123.3209.1157.
https://doi.org/10.1126/science.123.3209.1157
 
80 Leviero A: Scientists term radiation a peril to future man. June 13, 1956. Special to The New York Times. URL: https://www.nytimes.com/1956/06/13/archives/scientists-term-radiation-a-peril-to-future-of-man-even-small-dose.html [accessed Aug 06, 2021].
 
81 Lewis EB: Leukemia and ionizing radiation. Science 1957;125(3255):965-972. https://doi.org/10.1126/science.125.3255.965.
https://doi.org/10.1126/science.125.3255.965
 
82 Sugahara T: Radiation paradigm and its shift. J Radiat Res 1993;35(1):48-52. https://doi.org/10.1269/jrr.35.48.
https://doi.org/10.1269/jrr.35.48
 
83 Clarke RH, Valentin J: The History of ICRP and the Evolution of its Policies, ICRP Publication 2008;109. URL: https://www.icrp.org/docs/The%20History%20of%20ICRP%20and%20the%20Evolution%20of%20its%20Policies.pdf [accessed Aug 06, 2021].
 
84 Kang KW: History and Organizations for Radiological Protection, J Korean Med Sci 2016;31 Suppl 1(Suppl 1):S4-5. https://doi.org/10.3346/jkms.2016.31.S1.S4.
https://doi.org/10.3346/jkms.2016.31.S1.S4
 
85 INTERNATIONAL recommendations on radiological protection, revised by the International Commission on Radiological Protection (ICRP) at the sixth International Congress of Radiology. London, July, 1950. Am J Roentgenol Radium Ther 1951;65(4):603-609.
 
86 ICRP, 1951. International recommendations on radiological protection. Br J Radiol 1951;24(277):46-53. https://doi.org/10.1259/0007-1285-24-277-46.
https://doi.org/10.1259/0007-1285-24-277-46
 
87 ICRP 1955, Recommendations of the ICRP. Br J Radiol 1954;(Suppl. 6):100. URL: https://www.icrp.org/publication.asp?id=1954%20Recommendations [accessed Aug 06, 2021].
 
88 ICRP The recommendation of ICRP 1958. Pergamon Press, London 1959. https://doi.org/10.1016/S0074-2740288001.
 
89 National Academy of Sciences (NAS)/National Research Council (NRC): The Effects on Populations of Exposure to Low Levels of Ionizing Radiation. National Academy 1972, Washington DC. https://doi.org/10.17226/18994.
https://doi.org/10.17226/18994
 
90 Calabrese EJ: Muller's Nobel lecture on dose-response for ionizing radiation: ideology or science? Arch Toxicol 2011;85(12):1495-1498. https://doi.org/10.1007/s00204-011-0728-8.
https://doi.org/10.1007/s00204-011-0728-8
 
91 International Commission on Radiological Protection Recommendations of the ICRP: ICRP Publication 1977;26. Ann ICRP 1(3). URL: https://www.icrp.org/publication.asp?id=ICRP%20Publication%2026 [accessed Aug 06, 2021].
 
92 Flurkey K, Currer JM, Harrison DE: The Mouse in Aging Research, in Fox JG, et al. (eds.): The Mouse in Biomedical Research 2nd Edition, American College Laboratory Animal Medicine (Elsevier), Burlington, MA 2007:637-672.
https://doi.org/10.1016/B978-012369454-6/50074-1
 
93 Mak IW, Evaniew N, Ghert AM: Lost in translation: animal models and clinical trials in cancer treatment. Am J Transl Res 2014;6(2):114.
 
94 Bremnes RM, Dønnem T, Al-Saad S, Al-Shibli K, Andersen S, Sirera R, Camps C, Marinez I, Busund LT: The role of tumor stroma in cancer progression and prognosis: emphasis on carcinoma-associated fibroblasts and non-small cell lung cancer. J Thorac Oncol 2011;6(1):209-217. https://doi.org/10.1097/JTO.0b013e3181f8a1bd.
https://doi.org/10.1097/JTO.0b013e3181f8a1bd
 
95 Plava J, Cihova M, Burikova M, Matuskova M, Kucerova L, Miklikova S: Recent advances in understanding tumor stroma-mediated chemoresistance in breast cancer. Mol Cancer 2019;18(1):67. https://doi.org/10.1186/s12943-019-0960-z.
https://doi.org/10.1186/s12943-019-0960-z
 
96 ICRP, 1998. Genetic Susceptibility to Cancer, ICRP Publication 79, Ann. ICRP 1998;28(1-2).
https://doi.org/10.1016/S0146-6435(98)00007-3
 
97 Anderson MW, Reynolds SH, You M, Maronpot RM: Role of proto-oncogene activation in carcinogenesis. Environ Health Perspect 1992;98:13-24. https://doi.org/10.1289/ehp.929813.
https://doi.org/10.1289/ehp.929813
 
98 Wang X, Matsumoto H, Takahashi A, Nakano T, Okaichi K, Ihara M, Ohnishi T: p53 accumulation in the organs of low-dose X-ray-irradiated mice. Cancer Lett 1993;104(1):79-84. https://doi.org/10.1016/0304-3835(96)04235-8.
https://doi.org/10.1016/0304-3835(96)04235-8
 
99 Lowe DJ, Herzog M, Mosler T, Cohen H, Felton S, Beli P, Raj K, Galanty Y, Jackson SP: Chronic irradiation of human cells reduces histone levels and deregulates gene expression. Sci Rep 2020;10(1):2200. https://doi.org/10.1038/s41598-020-59163-4.
https://doi.org/10.1038/s41598-020-59163-4
 
100 United Nations Scientific Committee on the Effects of Atomic Radiation (UNSCEAR). Biological mechanisms of radiation action as at low doses, A white paper to guide the Scientific Committee's future program of work, United Nations, New York, 2012. URL: http://www.unscear.org/docs/publications/2012/UNSCEAR_WP_2012.pdf [accessed Aug 06, 2021].
 
101 Joenje H: Genetic toxicology of oxygen. Mutat Res 1989;219(4):193-208. https://doi.org/10.1016/0921-8734(89)90001-5.
https://doi.org/10.1016/0921-8734(89)90001-5
 
102 Tjeertes JV, Miller KM, Jackson SP: Screen for DNA-damage-responsive histone modifications identifies H3K9Ac and H3K56Ac in human cells. EMBO J 2009;28(13):1878-1889. https://doi.org/10.1038/emboj.2009.119.
https://doi.org/10.1038/emboj.2009.119
 
103 Miller KM, Tjeertes JV, Coates J, Legube G, Polo SE, Britton S, Jackson SP: Human HDAC1 and HDAC2 function in the DNA-damage response to promote DNA nonhomologous end-joining. Nat Struct Mol Biol 2010;17(9):1144-1151. https://doi.org/10.1038/nsmb.1899.
https://doi.org/10.1038/nsmb.1899
 
104 Miller KM, Jackson SP: Histone marks: repairing DNA breaks within the context of chromatin. Biochem Soc Trans 2012;40(2):370-376. https://doi.org/10.1042/BST20110747.
https://doi.org/10.1042/BST20110747
 
105 Raut VV, Sainis JK: 60Co-γ radiation induces differential acetylation and phosphorylation of histones H3 and H4 in wheat. Plant Biol (Stuttg) 2012;14(1):110-117. https://doi.org/10.1111/j.1438-8677.2011.00463.x.
https://doi.org/10.1111/j.1438-8677.2011.00463.x
 
106 Hanf A, Oelze M, Manea A, Li H, Münzel T, Daiber A: The anti-cancer drug doxorubicin induces substantial epigenetic changes in cultured cardiomyocytes. Chem Biol Interact 2019;313:108834. https://doi.org/10.1016/j.cbi.2019.108834.
https://doi.org/10.1016/j.cbi.2019.108834
 
107 Lindeman LC, Kamstra JH, Ballangby J, Hurem S, Martín LM, Brede DA, Teien HC, Oughton DH, Salbu B, Lyche JL, Aleström P: Gamma radiation induces locus specific changes to histone modification enrichment in zebrafish and Atlantic salmon. PLoS One 2019;14(2):e0212123. https://doi.org/10.1371/journal.pone.0212123.
https://doi.org/10.1371/journal.pone.0212123
 
108 Klosin A, Casas E, Hidalgo-Carcedo C, Vavouri T, Lehner B: Transgenerational transmission of environmental information in C. elegans. Science 2017;356(6335):320-323. https://doi.org/10.1126/science.aah6412.
https://doi.org/10.1126/science.aah6412
 
109 Ozasa K, Shimizu Y, Suyama A, Kasagi F, Soda M, Grant EJ, Sakata R, Sugiyama H, Kodama K: Studies of the mortality of atomic bomb survivors, Report 14, 1950-2003: an overview of cancer and noncancer diseases. Radiat Res 2012;177(3):229-243. https://doi.org/10.1667/rr2629.1.
https://doi.org/10.1667/RR2629.1
 
110 Gupta RC: Handbook of toxicology of chemical warfare agents, 3rd edition. Academic Press, 2020.
 
111 Jablon S, Kato H: Childhood cancer in relation to prenatal exposure to atomic bomb radiation. Lancet 1970;2(7681):1000-1003. https://doi.org/10.1016/s0140-6736(70)92813-8.
https://doi.org/10.1016/S0140-6736(70)92813-8
 
112 Yoshimoto Y: Cancer risk among children of atomic bomb survivors. A review of RERF epidemiologic studies. Radiation Effects Research Foundation. JAMA 1990;264(5):596-600.
https://doi.org/10.1001/jama.264.5.596
 
113 Kodaira M, Izumi S, Takahashi N, Nakamura N: No evidence of radiation effect on mutation rates at hypervariable minisatellite loci in the germ cells of atomic bomb survivors. Radiat Res 2004;162(4):350-356. https://doi.org/10.1667/rr3243.
https://doi.org/10.1667/RR3243
 
114 Kodaira M, Ryo H, Kamada N, Furukawa K, Takahashi N, Nakajima H, Nomura T, Nakamura N: No evidence of increased mutation rates at microsatellite loci in offspring of A-bomb survivors. Radiat Res 2010;173(2):205-213. https://doi.org/10.1667/RR1991.1.
https://doi.org/10.1667/RR1991.1
 
115 Kato H, Yoshimoto Y, Schull WJ: Risk of cancer among children exposed to atomic bomb radiation in utero: a review. IARC Sci Publ 1989;(96):365-374.
 
116 Preston DL, Cullings H, Suyama A, Funamoto S, Nishi N, Soda M, Mabuchi K, Kodama K, Kasagi F, Shore RE: Solid cancer incidence in atomic bomb survivors exposed in utero or as young children. J Natl Cancer Inst 2008;100(6):428-436. https://doi.org/10.1093/jnci/djn045.
https://doi.org/10.1093/jnci/djn045
 
117 Leung KM, Shabat G, Lu P, Fields AC, Lukashenko A, Davids JS, Melnitchouk N: Trends in solid tumor incidence in Ukraine 30 years after Chernobyl. J Glob Cancer 2019;5:1-10. https://doi.org/10.1200/JGO.19.00099.
https://doi.org/10.1200/JGO.19.00099
 
118 Yeager M, Machiela MJ, Kothiyal P, Dean M, Bodelon C, Suman S, Wang M, Mirabello L, Nelson CW, Zhou W, Palmer C, Ballew B, Colli LM, Freedman ND, Dagnall C, Hutchinson A, Vij V, Maruvka Y, Hatch M, Illienko I, et al.: Lack of transgenerational effects of ionizing radiation exposure from the Chernobyl accident. Science 2021;372(6543):725-729. https://doi.org/10.1126/science.abg2365.
https://doi.org/10.1126/science.abg2365
 
119 Stadler J: Mutations in barley induced by X-rays and radium, Science 1928;68:186-187. https://doi.org/10.1126/science.68.1756.186.
https://doi.org/10.1126/science.68.1756.186
 
120 Timofeeff-Ressovsky NW: Auslösung von Vitalitätsmutationen durch Röntgenstrahlung bei Drosophila melanogaster. Strahlentherapie 1934;51:658-663.
 
121 Spencer WP, Stern C: Experiments to Test the Validity of the Linear R-Dose/Mutation Frequency Relation in Drosophila at Low Dosage. Genetics 1948;33(1):43-74.
https://doi.org/10.1093/genetics/33.1.43
 
122 Demerec M: Frequency of deletions amont spontaneous and induced mutations in salmonella. Proc Natl Acad Sci U S A 1960;46(8):1075-1079. https://doi.org/10.1073/pnas.46.8.1075.
https://doi.org/10.1073/pnas.46.8.1075
 
123 Shiomi T, Inagaki E, Inagaki H, Nakao Y: Mutaiton rates oif low dose level in drosophila melogaster. J Radiat Res 1963;4:105-110. https://doi.org/10.1269/jrr.4.105.
https://doi.org/10.1269/jrr.4.105
 
124 Traut H: The linear dose-dependence of radiation induced translocation frequency in drosophila melanogaster at relatively low x-radiation doses. Int J Radiat Biol Relat Stud Phys Chem Med 1963;7:401-403. https://doi.org/10.1080/09553006314551341.
https://doi.org/10.1080/09553006314551341
 
125 Roesch WC: Radiation Effects Research Foundation, and National Academy of Sciences (U.S.). 1987. US-Japan joint reassessment of atomic bomb radiation dosimetry in Hiroshima and Nagasaki. Minami-ku, Hiroshima: Radiation Effects Research Foundation. URL: https://inis.iaea.org/search/search.aspx?orig_q=RN:35050238 [accessed Feb 24, 2018].
 
126 Kellerer AM, Rossi HH: Dependence of RBE on neutron dose. Brit J Radiol 1972;45(536):626. https://doi.org/10.1259/0007-1285-45-536-626-a.
https://doi.org/10.1259/0007-1285-45-536-626-a
 
127 Commission of the European Communities: EURATOM Programme. Radiation protection. Progress Report 1982; EUR 8486 DE/EN/FR. ISBN 92-825-3601-7.
 
128 Wolf C, Lafuma J, Masse R, Morin M, Kellerer AM: Neutron RBE for induction of tumors with high lethality in Sprague-Dawley rats. Radiat Res 2000;154(4):412-420. https://doi.org/10.1667/0033-7587(2000)154[0412:nrfiot]2.0.co;2.
https://doi.org/10.1667/0033-7587(2000)154[0412:NRFIOT]2.0.CO;2
 
129 Nikjoo H, O'Neill P, Goodhead DT, Terrissol M: Computational modeling of low-energy electron-induced DNA damage by early physical and chemical events. Int J Radiat Biol 1997;71(5):467-483. https://doi.org/10.1080/095530097143798.
https://doi.org/10.1080/095530097143798
 
130 Nikjoo H, Bolton CE, Watanabe R, Terrissol M, O'Neill P, Goodhead DT: Modelling of DNA damage induced by energetic electrons (100 eV to 100 keV). Radiat Prot Dosim 2000;99(1-4):77-80. https://doi.org/10.1093/oxfordjournals.rpd.a006843.
https://doi.org/10.1093/oxfordjournals.rpd.a006843
 
131 Kohn KW, Ross WE, Ewig RAG: A relationship between DNA single strand breaks and DNA-protein crosslinks in intercalator-treated mouse LI210 cells; in Hanawalt PC, Friedberg EC, Fox CF (eds): DNA Repair Mechanisms. Academic Press, New York, 1978, 473-485. URL: https://wellcomecollection.org/works/d9mpkupz/items?canvas=16 [accessed Mar 10, 2002].
https://doi.org/10.1016/B978-0-12-322650-1.50092-8
 
132 Fuller LF, Painter RB: A Chinese hamster ovary cell line hypersensitive to ionizing radiation and deficient in repair replication. Mutat Res 1998;193(2):109-116. https://doi.org/10.1016/0167-8817(88)90041-7.
https://doi.org/10.1016/0167-8817(88)90041-7
 
133 Zdzienicka MZ: Mammalian X ray sensitive mutants: a tool for the elucidation of the cellular response to ionizing radiation. Cancer Surv 1996;28:281-293.
 
134 Collins AR: Mutant rodent cell lines sensitive to ultraviolet light, ionizing radiation and cross-linking agents: a comprehensive survey of genetic and biochemical characteristics. Mutation Res 1993;293(2):99-118. https://doi.org/10.1016/0921-8777(93)90062-l.
https://doi.org/10.1016/0921-8777(93)90062-L
 
135 Zdzienicka MZ: Mammalian mutants defective in the response to ionizing radiation-induced DNA damage. Mutation Res 1995;336(3):203-213. https://doi.org/10.1016/0921-8777(95)00003-3.
https://doi.org/10.1016/0921-8777(95)00003-3
 
136 Conolly RB, Lutz WK: Nonmonotonic dose-response relationships: mechanistic basis, kinetic modeling, and implications for risk assessment. Toxicol Sci 2004;77(1):151-157. https://doi.org/10.1093/toxsci/kfh007.
https://doi.org/10.1093/toxsci/kfh007
 
137 LaFond RE: Cancer: The Outlaw Cell. American Chemical Society. Washington, DC, 1978.
 
138 Cleaver JE: DNA repair and replication in xeroderma pigmentosum and related disorders. Basic Life Sci 1986;39:425-438. https://doi.org/10.1007/978-1-4684-5182-5_38.
https://doi.org/10.1007/978-1-4684-5182-5_38
 
139 Milota M, Jones DL, Cleaver J, Jamall JS: Xeroderma pigmentosum family support group: Helping families and promoting clinical initiatives. DNA Repair (Amst) 2011;10(7):792-797. https://doi.org/10.1016/j.dnarep.2011.04.027.
https://doi.org/10.1016/j.dnarep.2011.04.027
 
140 Abrams HL: Influence of age, body weight, and sex on susceptibility of mice to the lethal effects of X-radiation. Proc Soc Exp Biol Med 1951;76(4):729-732. https://doi.org/10.3181/00379727-76-18610.
https://doi.org/10.3181/00379727-76-18610
 
141 Sacher GA: Dependence of acute radiosensitivity on age in adult female mouse. Science 1957;125(3256):1039-1040. https://doi.org/10.1126/science.125.3256.1039.
https://doi.org/10.1126/science.125.3256.1039
 
142 Lindop PJ, Rotblat J: Shortening of lifespan of mice as a function of age at irradiation. Gerontologia 1959;3:122-127. https://doi.org/10.1159/000210887.
https://doi.org/10.1159/000210887
 
143 Spalding JF, Trujillo TT: Radiosensitivity of mice as a function of age. Radiat Res 1962;16(2):125-129. https://doi.org/10.2307/3571191.
https://doi.org/10.2307/3571191
 
144 Hamilton KF, Sacher GA, Grahn D: A sex difference in mouse survival under daily gamma irradiation and its modification by gonadectomy. Radiat Res 1963;18(1):12-16. https://doi.org/10.2307/3571421.
https://doi.org/10.2307/3571421
 
145 Sacher GA, Grahn D: Survival of mice under duration-of-life exposure to gamma rays, I. The dosage-survival relation and the lethality function. J Nat Cancer Inst 1964;32(2):277-321.
 
146 Raventos A: A factor influencing the significance of radiation mortality experiments. Brit J Radiol 1955;28(332):410-414. https://doi.org/10.1259/0007-1285-28-332-410.
https://doi.org/10.1259/0007-1285-28-332-410
 
147 Hahn EW, Howland JW: Modification of irradiation response of female rats by population density. Radiat Res 1963;19(4):676-681. https://doi.org/10.2307/3571489.
https://doi.org/10.2307/3571489
 
148 Roderick TH: The response of twenty-seven inbred strains of mice to daily doses of whole-body X-irradiation. Radiat Res 1963;20(4):631-639. https://doi.org/10.2307/3571354.
https://doi.org/10.2307/3571354
 
149 Snell GD, Aebersold PC: The production of sterility in male mice by irradiating with neutrons. Proc Nat Acad Sci USA 1937;23(7):374-378. https://doi.org/10.1073/pnas.23.7.374.
https://doi.org/10.1073/pnas.23.7.374
 
150 Batchelor AL, Phillips RJS, Searle AG: High effectiveness of chronic neutron exposures for the induction of specific locus mutations in mice. Nature 1964;201:207-208. https://doi.org/10.1038/201207a0.
https://doi.org/10.1038/201207a0
 
151 Russell WL, Kelly EM: Neutron-induced mutation in mouse spermatogonia. Lack of effect of dose rate. Relative biological effectiveness of neutrons, Biology Division Semiannual Progress Report for period ending August 15, 1964. Oak Ridge National Laboratory operated by Union Carbide Corporation for the US Atomic Energy Commission 1964. ORNL-3700, pp 83-85. URL: https://www.osti.gov/servlets/purl/4679348 [accessed at Dec 18, 2003].
 
152 Straume T, Carsten AL: Tritium radiobiology and relative biological effectiveness. Health Phys 1993;65(6):657-672. https://doi.org/10.1097/00004032-199312000-00005.
https://doi.org/10.1097/00004032-199312000-00005
 
153 Thomson JF, Williamson F, Grahn D, Ainsworth EJ: Life shortening in mice exposed to fission neutrons and y rays, I. Single and short-term fractioned exposures. Radiat Res 1981;86(3):559-572. https://doi.org/10.2307/3575470.
https://doi.org/10.2307/3575470
 
154 Thomson JF, Williamson F, Grahn D, Ainsworth EJ: Life Shortening in Mice Exposed to Fission Neutrons and γ Rays: II. Duration-of-Life and Long-Term Fractionated Exposures. Radiat Res 1981;86(3):573-579. https://doi.org/10.2307/3575471.
https://doi.org/10.2307/3575471
 
155 Thomson JF, Williamson FS, Grahn D, Ainsworth EJ: Life shortening in mice exposed to fission neutrons and gamma rays I. Single and short-term fractionated exposures. Radiat Res 1981 86(3):559-572.
https://doi.org/10.2307/3575470
 
156 Thomson JF, Williamson F, Grahn D: Life shortening in mice exposed to fission neutrons and y rays, III. Neuron exposures of 5 and 10 rad. Rad Res 1983;93(1):205-209. https://doi.org/10.2307/3575955.
https://doi.org/10.2307/3575955
 
157 Hill CK, Han A, Buonaguro F, Elkind MM: Multifractionation of Co Gamma Rays Reduces Neoplastic Transformation -In Vitro. Carcinogenesis 1984;5(2):193-197. https://doi.org/10.1093/carcin/5.2.193.
https://doi.org/10.1093/carcin/5.2.193
 
158 Storer JB, Mitchell FJ: Limiting values for the RBE of fission neutrons at low doses for life shortening in mice. Radiat Res 1984;97(2):396-406. https://doi.org/10.2307/3576290.
https://doi.org/10.2307/3576290
 
159 Hill CK, Carnes BA, Han A, Elkind MM: Neoplastic Transformation is Enhanced by Multiple Low Doses of fission-spectrum neutrons. Radiat Res 1985;102(3):404-410.
https://doi.org/10.2307/3576716
 
160 Thomson JF, Williamson F, Grahn D: Life shortening in mice exposed to fission neutrons and y rays, IV. Further studies with fractionated neutron exposures. Radiat Res 1985;103(1):77-88. https://doi.org/10.2307/3576672.
https://doi.org/10.2307/3576672
 
161 Thomson JF, Williamson F, Grahn D: Life shortening in mice exposed to fission neutrons and y rays, V. Further studies with single low doses. Radiat Res 1985;104(4):420-428. https://doi.org/10.2307/3576601.
https://doi.org/10.2307/3576601
 
162 Thomson JF, Grahn D: Relative Biological Effectiveness (RBE) of fission neutrons and gamma rays at occupational exposure levels, Volume II. Studies on the effects of 60 Equal One-Weekly exposures to fission neutrons and gamma rays on survival on mice. Prepared for the Division of Regulatory Applications Office of Nuclear Regulatory Commission, Washington, D.C. 1987. 20555, Under Interagency Agreement DOE 40-550-75, NRC Fin No. A2225. URL: https://www.nrc.gov/docs/ML2023/ML20238C552.pdf [accessed Nov 02, 2020].
 
163 Straume T, Blattnig S, Zeitlin C: Radiation Hazards and the Colonization of Mars: Brain, Body, Pregnancy, In-Utero Development, Cardio, Cancer, Degeneration. J Cosmology 2010;12:3992-4033. URL: http://journalofcosmology.com/Mars124.html [accessed Jul 25, 2020].
 
164 Knudson AG: Mutation and cancer: statistical study of retinoblastoma. Proc Natl Acad Sci U S A 1971;68:820-823. https://doi.org/10.1073/pnas.68.4.820.
https://doi.org/10.1073/pnas.68.4.820
 
165 Fearon ER, Vogelstein B: A genetic model for colorectal tumorigenesis. Cell 1990;61:759-767. https://doi.org/10.1016/0092-8674(90)90186-i.
https://doi.org/10.1016/0092-8674(90)90186-I
 
166 Greenman C, Wooster R, Futreal PA, Stratton MR, Easton DF: Statistical analysis of pathogenicity of somatic mutations in cancer. Genetics 2006;173(4):2187-2198. https://doi.org/10.1534/genetics.105.044677.
https://doi.org/10.1534/genetics.105.044677
 
167 Roberts SA, Gordenin DA. Hypermutation in human cancer genomes: footprints and mechanisms. Nat Rev Cancer 2014;14:786-800. https://doi.org/10.1038/nrc3816.
https://doi.org/10.1038/nrc3816
 
168 Tomasetti C, Marchionni L, Nowak MA, Parmigiani G, Vogelstein B: Only three driver gene mutations are required for the development of lung and colorectal cancers. Proc Natl Acad Sci U S A 2015;112:118-123. https://doi.org/10.1073/pnas.1421839112.
https://doi.org/10.1073/pnas.1421839112
 
169 Lumley T: Cancer isn't just bad luck. StatsChat Jan 03, 2015. URL: https://www.statschat.org.nz/2015/01/03/cancer-isnt-just-bad-luck/ [accessed Jan 10, 2015].
 
170 Boveri T: Zur Frage der Entstehung maligner Tumoren. Verlag Gustav Fischer, Jena, 1914, 29-32.
 
171 Bauer KH: Mutationstheorie der Geschwulst-Entstehung, Julius Springer Verlag, Berlin, 1928.
https://doi.org/10.1007/978-3-662-36429-1
 
172 Nordling CO: A new theory on the cancer-inducing mechanism, Br J Cancer 1953;7:68-72. https://doi.org/10.1038/bjc.1953.8.
https://doi.org/10.1038/bjc.1953.8
 
173 MacRae SL, Zhang Q, Lemetre C, Seim I, Calder RB, Hoeijmakers J, Suh Y, Gladyshev VN, Seluanov A, Gorbunova V, Vijg J, Zhang ZD: Comparative analysis of genome maintenance genes in naked mole rat, mouse, and human. Aging Cell 2015;14(2):288-291. https://doi.org/10.1111/acel.12314.
https://doi.org/10.1111/acel.12314
 
174 MacRae SL, Croken MM, Calder RB, Aliper A, Milholland B, White RR, Zhavoronkov A, Gladyshev VN, Seluanov A, Gorbunova V, Zhang ZD, Vijg J: DNA repair in species with extreme lifespan differences. Aging (Albany NY) 2015;7(12):1171-1184. https://doi.org/10.18632/aging.100866.
https://doi.org/10.18632/aging.100866
 
175 Milholland B, Dong X, Zhang L, Hao X, Suh Y, Vijg J: Differences between germline and somatic mutation rates in humans and mice. Nat Commun 2017;8:15183. https://doi.org/10.1038/ncomms15183.
https://doi.org/10.1038/ncomms15183
 
176 Quail MA, Kozarewa I, Smith F, Scally A, Stephens PJ, Durbin R, Swerdlow H, Turner DJ: A large genome center's improvements to the Illumina sequencing system. Nat Methods 2008;5(12):1005-1010. https://doi.org/10.1038/nmeth.1270.
https://doi.org/10.1038/nmeth.1270
 
177 Gundry M, Li W, Maqbool SB, Vijg J: Direct, genome-wide assessment of DNA mutations in single cells. Nucleic Acids Res 2012;40(5):2032-2040. https://doi.org/10.1093/nar/gkr949.
https://doi.org/10.1093/nar/gkr949
 
178 Loewe L: Genetic mutation. Nature Education 2008;1(1):113. URL: https://www.nature.com/scitable/topicpage/genetic-mutation-1127 [accessed Mar 13, 2009].
 
179 Colwell HA, Russ S: Radium, x-rays, and the living cell. London, Bell&Sons LTD, 1915, 253.
 
180 Patten REP, Wigoder SB: The cytological changes observable in irradiated Bean Root Tips. J Cell Sci (Former: Quart J Microscop Sci) 1930;73:633-650. URL: https://jcs.biologists.org/content/joces/s2-73/292/633.full.pdf [accessed Jun 16, 2006].
https://doi.org/10.1242/jcs.s2-73.292.633
 
181 Mendelsohn FA, Divino CM, Reis ED, Kerstein MD: Wound care after radiation therapy. Adv Skin Wound Care 2002;15(15):216-224. https://doi.org/10.1097/00129334-200209000-00007.
https://doi.org/10.1097/00129334-200209000-00007
 
182 Mall FP: On measuring human embryos. Anat Rec 1907;1:129-140. https://doi.org/10.1002/ar.1090010602.
https://doi.org/10.1002/ar.1090010602
 
183 Mall FP: A plea for an institute of human embryology. J Amer Med Ass 1913;60(21):1599-1601. https://doi.org/10.1001/jama.1913.04340210009002.
https://doi.org/10.1001/jama.1913.04340210009002
 
184 Mall FP: On stages in the development of human embryos from 2 to 25 mm long. Anatomischer Anzeiger 1914;46:78-84.
 
185 Nishimura H: Introduction; in Nishimura H (ed.): Atlas of Human Prenatal Histology. Tokyo, Igaku-shoin, 1983. https://doi.org/10.1016/0378-3782(85)90158-6.
https://doi.org/10.1016/0378-3782(85)90158-6
 
186 Streeter GL: Developmental horizons in human embryos. Description of age group XI, 13 to 20 somites, and age group XII, 21 to 29 somites, Carnegie Institution of Washington publication 541. Contributions to Embryology, Carnegie Institution of Washington 1942;541(30):211-245.
 
187 Streeter GL: Developmental horizons in human embryos. Description of age group XIII, embryos about 4 or 5 millimeters long, and age group XIV, period of indentation of the lens vesicle. Carnegie Institution of Washington publication 557. Contributions to Embryology, Carnegie Institution of Washington 1945;31:27-63.
 
188 Streeter GL: Developmental horizons in human embryos. Description of age groups XV, XVI, XVII, and XVIII, being the third issue of a survey of the Carnegie Collection. Carnegie Institution of Washington publication 575. Contributions to Embryology, Carnegie Institution of Washington 1948;32:133-203.
 
189 Streeter GL: Developmental horizons in human embryos. Description of age groups XIX, XX, XXI, XXII, and XXIII, being the fifth issue of a survey of the Carnegie Collection (prepared for publication by CH Heuser and GW Corner). Carnegie Institution of Washington publication 592. Contributions to Embryology 1951;34:165-196.
 
190 Nishimura H, Takano K, Tanimura T, Yasuda M: Normal and abnormal development of human embryos: first report of the analysis of 1,213 intact embryos. Teratology 1968;1:281-290. https://doi.org/10.1002/tera.1420010306.
https://doi.org/10.1002/tera.1420010306
 
191 Nishimura H, Tanimura T, Semba R, Uwabe C: Normal development of early human embryos: observation of 90 specimens at Carnegie stages 7 to 13. Teratology 1974;10:1-5. https://doi.org/10.1002/tera.1420100102.
https://doi.org/10.1002/tera.1420100102
 
192 Olivier G, Pineau H: Horizons de Streeter et age embryonnaire. Bulletin de l'Association des anatomistes 1962;47:573-576. https://doi.org/10.5772/38232.
https://doi.org/10.5772/38232
 
193 Iffy L, Shepard TH, Jakobovits A, Lemire RJ, Kerner P: The rate of growth in young human embryos of Streeter's horizons, 13 to 23. Acta anatomica 1967;66:178-186.
https://doi.org/10.1159/000142921
 
194 Jirásek JE: Development of the genital system and male pseudohermaphroditism. Baltimore, Johns Hopkins Press, 1971.
 
195 O'Rahilly R, Müller F: Developmental stages in human embryos: including a revision of Streeter's "horizons" and a survey of the Carnegie Collection, Washington, DC. Carnegie Institution of Washington Publication 1987. URL: http://shelf2.library.cmu.edu/Tech/16704571.pdf [accessed Nov 04, 2017].
 
196 Yamada S, Takakuwa T: Introduction - Developmental Overview of the Human Embryo; in Yamada S, Takakuwa T (eds.): The Human Embryo. IntechOpen 2012. https://doi.org/10.5772/1209.
https://doi.org/10.5772/1209
 
197 Streltsova VN, Pavlenko-Mikhailov JN: Tumors in animals irradiated during embryogenesis. Vopr Onkol 1978;24(9):25-30.
 
198 Wegner G, Damminger K: Early and late inhuries to the offspring of Wistar rats after total body irradiation on the 9th day of pregnancy, abnormalities, observations on the 1st 2 generations. Strahlentherapie 1963;121:374-382.
 
199 Wegner G, Grad EH: Tumors as late sequlae of the prgeny of Wistar rats after total body irradiation on the 9th day of pregnancy. Strahlentherapie 1964;123:609-1613.
 
200 Sasaki S, Kasuga T, Sato F, Kawashima N: Late effects of fetal mice x-irradiated at middle or late intrauterine stage. GAN 1978;69(2):167-177.
 
201 Vesselinovitch SD, Simmons E, Michailovich N, Rao KVN, Lombard LS: The effect of age, fractionation, and dose on radiation carcinogenesis in various tissues of mice. Cancer Res 1971;31(12):2133-2142.
 
202 United States Nuclear Regulatory Commission (USNRC) (2019) Lethal dose (LD). URL: https://www.nrc.gov/reading-rm/basic-ref/glossary/lethal-dose-ld.html [accessed Mar 26, 2003].
 
203 Grajewski B, Waters M, Whelan E, Bloom T: Radiation dose estimation for epidemiologic studies of flight attendants. Am J In Med 2002;41(1):27-37. https://doi.org/10.1002/ajim.10018. ISSN 0271-3586.
https://doi.org/10.1002/ajim.10018
 
204 Mettler FA Jr, Huda W, Yoshizumi TT, Mahesh M: Effective Doses in Radiology and Diagnostic Nuclear Medicine: A Catalog. Radiology 2008;248(1):254-263. https://doi.org/10.1148/radiol.2481071451.
https://doi.org/10.1148/radiol.2481071451
 
205 Linnersjö A, Hammar N, Dammström BG, Johansson M, Eliasch H: Cancer incidence in airline cabin crew: experience from Sweden. Occup Environ Med 2003;60(11):810-814. https://doi.org/10.1136/oem.60.11.810.
https://doi.org/10.1136/oem.60.11.810
 
206 Hall E, Giaccia AJ: Radiobiology for the radiologist, 6th ed. Lippincott Wilkins & Williams, Philadelphia, USA, 2006.
 
207 Cox J, Ang KK: Radiation Oncology, 9th ed, Mosby, 2009.
 
208 Furukawa K, Preston D, Funamoto S, Yonehara S, Ito M, Tokuoka S, Sugiyama H, Soda M, Ozasa K, Mabuchi K: Long-term trend of thyroid cancer risk among Japanese atomic-bomb survivors: 60 years after exposure. Int J Cancer 2013;132(5):1222-1226. https://doi.org/10.1002/ijc.27749.
https://doi.org/10.1002/ijc.27749
 
209 Einhorn L: Can prenatal irradiation protect the embryo from tumor development? Acta Oncol 1991;30(3):291-299. https://doi.org/10.3109/02841869109092374.
https://doi.org/10.3109/02841869109092374
 
210 Inaida S, Matsuno S: Previous Infection Positively Correlates to the Tumor Incidence Rate of Patients with Cancer. Cancer Immunol Res 2020;8(5):580-586. https://doi.org/10.1158/2326-6066.CIR-19-0510.
https://doi.org/10.1158/2326-6066.CIR-19-0510
 
211 Nejman D, Livyatan I, Fuks G, Gavert N, Zwang Y, Geller LT, Rotter-Maskowitz A, Weiser R, Mallel G, Gigi E, Meltser A, Douglas GM, Kamer I, Gopalakrishnan V, Dadosh T, Levin-Zaidman S, Avnet S, Atlan T, Cooper ZA, Arora R, et al.: The human tumor microbiome is composed of tumor type-specific intracellular bacteria. Science 2020;368(6494):973-980. https://doi.org/10.1126/science.aay9189.
https://doi.org/10.1126/science.aay9189
 
212 Lawson JS, Glenn WK: Evidence for a causal role by human papillomaviruses in prostate cancer - a systematic review. Infect Agent Cancer 2020;15:41. https://doi.org/10.1186/s13027-020-00305-8.
https://doi.org/10.1186/s13027-020-00305-8
 
213 Lei J, Ploner A, Elfström KM, Wang J, Roth A, Fang F, Sundström K, Dillner J, Sparén P: HPV Vaccination and the Risk of Invasive Cervical Cancer. N Engl J Med 2020;383(14):1340-1348. https://doi.org/10.1056/NEJMoa1917338.
https://doi.org/10.1056/NEJMoa1917338
 
214 Moore A, Hikri E, Goshen-Lago T, Barkan T, Morgenstern S, Brook E, Maderer A, Roth W, Gordon N, Kashtan H, Brenner B, Moehler M, Aharon IB: Young-onset gastric cancer and Epstein-Barr Virus (EBV) - a major player in the pathogenesis? BMC Cancer 2020;20(1):34. https://doi.org/10.1186/s12885-020-6517-0.
https://doi.org/10.1186/s12885-020-6517-0
 
215 Charostad J, Nakhaie M, Dehghani A, Faghihloo E: The interplay between EBV and KSHV viral products and NF-κB pathway in oncogenesis. Infect Agent Cancer 2020;15:62. https://doi.org/10.1186/s13027-020-00317-4.
https://doi.org/10.1186/s13027-020-00317-4
 
216 Gong X, Zou L, Wang M, Zhang Y, Peng S, Zhong M, Zhou J, Li X, Ma X: Gramicidin inhibits cholangiocarcinoma cell growth by suppressing EGR4. Artif Cells Nanomed Biotechnol 2020;48(1):53-59. https://doi.org/10.1080/21691401.2019.1699808.
https://doi.org/10.1080/21691401.2019.1699808
 
217 Hodge JM, Coghill AE, Kim Y, Bender N, Smith-Warner SA, Gapstur S, Teras LR, Grimsrud TK, Waterboer T, Egan KM: Toxoplasma gondii infection and the risk of adult glioma in two prospective studies. Int J Cancer 2021; DOI: https://doi.org/10.1002/ijc.33443.
https://doi.org/10.1002/ijc.33443
 
218 Elayapillai S, Ramraj S, Benbrook DM, Bieniasz M, Wang L, Pathuri G, Isingizwe ZR, Kennedy AL, Zhao YD, Lightfoot S, Hunsucker LA, Gunderson CC: Potential and mechanism of mebendazole for treatment and maintenance of ovarian cancer. Gynecol Oncol 2021;160(1):302-311. https://doi.org/10.1016/j.ygyno.2020.10.010.
https://doi.org/10.1016/j.ygyno.2020.10.010
 
219 Williamson T, Mendes TB, Joe N, Cerutti JM, Riggins GJ: Mebendazole inhibits tumor growth and prevents lung metastasis in models of advanced thyroid cancer. Endocr Relat Cancer 2021;27(3):123-136. https://doi.org/10.1530/ERC-19-0341.
https://doi.org/10.1530/ERC-19-0341
 
220 Williamson T, de Abreu MC, Trembath DG, Brayton C, Kang B, Mendes TB, de Assumpção PP, Cerutti JM, Riggins GJ: Mebendazole disrupts stromal desmoplasia and tumorigenesis in two models of pancreatic cancer. Oncotarget 2021;12(14):1326-1338. https://doi.org/10.18632/oncotarget.28014.
https://doi.org/10.18632/oncotarget.28014
 
221 Semkova ME, Hsuan JJ: TGFβ-1 Induced Cross-Linking of the Extracellular Matrix of Primary Human Dermal Fibroblasts. Int J Mol Sci 2021;22(3):984. https://doi.org/10.3390/ijms22030984.
https://doi.org/10.3390/ijms22030984
 
222 Ye M, Zhou J, Gao Y, Pan S, Zhu X: The prognostic value of the lysyl oxidase family in ovarian cancer. J Clin Lab Anal 2020;34(12):e23538. https://doi.org/10.1002/jcla.23538.
https://doi.org/10.1002/jcla.23538
 
223 Cao C, Lin S, Zhi W, Lazare C, Meng Y, Wu P, Gao P, Wei J, Wu P: LOXL2 Expression Status Is Correlated With Molecular Characterizations of Cervical Carcinoma and Associated With Poor Cancer Survival via Epithelial-Mesenchymal Transition (EMT) Phenotype. Front Oncol 2020;10:284. https://doi.org/10.3389/fonc.2020.00284.
https://doi.org/10.3389/fonc.2020.00284
 
224 Zheng GL, Liu YL, Yan ZX, Xie XY, Xiang Z, Yin L, Wang QQ, Chong DC, Xue GL, Xu LL, Zhou K, Wang Q: Elevated LOXL2 expression by LINC01347/miR-328-5p axis contributes to 5-FU chemotherapy resistance of colorectal cancer. Am J Cancer Res 2021;11(4):1572-1585.
 
225 Smithen DA, Leung LMH, Challinor M, Lawrence R, Tang H, Niculescu-Duvaz D, Pearce SP, Mcleary R, Lopes F, Aljarah M, Brown M, Johnson L, Thomson G, Marais R, Springer C: 2-Aminomethylene-5-sulfonylthiazole Inhibitors of Lysyl Oxidase (LOX) and LOXL2 Show Significant Efficacy in Delaying Tumor Growth. J Med Chem 2020;63(5):2308-2324. https://doi.org/10.1021/acs.jmedchem.9b01112.
https://doi.org/10.1021/acs.jmedchem.9b01112
 
226 Tong M, Zheng Q, Liu M, Chen L, Lin YH, Tang SG, Zhu YM: 5-methoxytryptophan alleviates liver fibrosis by modulating FOXO3a/miR-21/ATG5 signaling pathway mediated autophagy. Cell Cycle 2021;20(7):676-688. https://doi.org/10.1080/15384101.2021.1897241.
https://doi.org/10.1080/15384101.2021.1897241
 
227 Jin L, Zhang J, Fu HQ, Zhang X, Pan YL: FOXO3a inhibits the EMT and metastasis of breast cancer by regulating TWIST-1 mediated miR-10b/CADM2 axis. Transl Oncol 2021;14(7):101096. https://doi.org/10.1016/j.tranon.2021.101096.
https://doi.org/10.1016/j.tranon.2021.101096
 
228 White RR, Maslov AY, Lee M, Wilner SE, Levy M, Vijg J: FOXO3a acts to suppress DNA double-strand break-induced mutations. Aging Cell 2020;19(9):e13184. https://doi.org/10.1111/acel.13184.
https://doi.org/10.1111/acel.13184
 
229 Hu L, Wang J, Wang Y, Wu L, Wu C, Mao B, Maruthi Prasad E, Wang Y, Chin YE: LOXL1 modulates the malignant progression of colorectal cancer by inhibiting the transcriptional activity of YAP. Cell Commun Signal 2020;18(1):148. https://doi.org/10.1186/s12964-020-00639-1.
https://doi.org/10.1186/s12964-020-00639-1
 
230 Zhao W, Yang A, Chen W, Wang P, Liu T, Cong M, Xu A, Yan X, Jia J, You H: Inhibition of lysyl oxidase-like 1 (LOXL1) expression arrests liver fibrosis progression in cirrhosis by reducing elastin crosslinking. Biochim Biophys Acta Mol Basis Dis 2018;1864(4 Pt A):1129-1137. https://doi.org/10.1016/j.bbadis.2018.01.019.
https://doi.org/10.1016/j.bbadis.2018.01.019
 
231 Su J, Morgani SM, David CJ, Wang Q, Er EE, Huang YH, Basnet H, Zou Y, Shu W, Soni RK, Hendrickson RC, Hadjantonakis AK, Massagué J: TGF-beta orchestrates fibrogenic and developmental EMTs via the RAS effector RREB1. Nature 2020;577(7791):566-571. https://doi.org/10.1038/s41586-019-1897-5. https://doi.org/10.1038/s41586-020-1956-y.
https://doi.org/10.1038/s41586-019-1897-5
 
232 Wang Q, Tao Y, Xie H, Liu C, Liu P: MicroRNA‑101 inhibits renal tubular epithelial‑to‑mesenchymal transition by targeting TGF‑β1 type I receptor. Int J Mol Med 2021;47(6):119. https://doi.org/10.3892/ijmm.2021.4952.
https://doi.org/10.3892/ijmm.2021.4952
 
233 Zhou DW, Fernández-Yagüe MA, Holland EN, García AF, Castro NS, O'Neill EB, Eyckmans J, Chen CS, Fu J, Schlaepfer DD, García AJ: Force-FAK signaling coupling at individual focal adhesions coordinates mechanosensing and microtissue repair. Nat Commun 2021;12(1):2359. https://doi.org/10.1038/s41467-021-22602-5.
https://doi.org/10.1038/s41467-021-22602-5
 
234 Dinca SC, Greiner D, Weidenfeld K, Bond L, Barkan D, Jorcyk CL: Novel mechanism for OSM-promoted extracellular matrix remodeling in breast cancer: LOXL2 upregulation and subsequent ECM alignment. Breast Cancer Res 2021;23(1):56. https://doi.org/10.1186/s13058-021-01430-x.
https://doi.org/10.1186/s13058-021-01430-x
 
235 Xue J, Bai J, Long Q, Wei Y, Pan J, Li X, Tang Q:. TCF-3-mediated transcription of lncRNA HNF1A-AS1 targeting oncostatin M expression inhibits epithelial-mesenchymal transition via TGFβ signaling in gastroenteropancreatic neuroendocrine neoplasms. Aging (Albany NY) 2021;13(10):14065-14077. https://doi.org/10.18632/aging.203024.
https://doi.org/10.18632/aging.203024
 
236 Colombero C, Cárdenas S, Venara M, Martin A, Pennisi P, Barontini M, Nowicki S: Cytochrome 450 metabolites of arachidonic acid (20-HETE, 11,12-EET and 14,15-EET) promote pheochromocytoma cell growth and tumor associated angiogenesis. Biochimie 2020;171-172:147-157. DOI: 10.1016/j.biochi.2020.02.014.
https://doi.org/10.1016/j.biochi.2020.02.014
 
237 Chen J, Tong W, Liao M, Chen D: Inhibition of arachidonate lipoxygenase12 targets lung cancer through inhibiting EMT and suppressing RhoA and NF-kappaB activity. Biochem Biophys Res Commun 2020;524(4):803-809. https://doi.org/10.1016/j.bbrc.2020.01.
https://doi.org/10.1016/j.bbrc.2020.01.166
 
238 Cheng J, Fan YQ, Liu BH, Zhou H, Wang JM, Chen QX: ACSL4 suppresses glioma cells proliferation via activating ferroptosis. Oncol Rep 2020;43(1):147-158. https://doi.org/10.3892/or.2019.7419.
https://doi.org/10.3892/or.2019.7419
 
239 Gao S, Hu J, Li Y: Targeting of the Alox12-12-HETE in Blast Crisis Chronic Myeloid Leukemia Inhibits Leukemia Stem/Progenitor Cell Function. Cancer Manag Res 2020;12:12509-12517. https://doi.org/10.2147/CMAR.S280554.
https://doi.org/10.2147/CMAR.S280554
 
240 Shan K, Feng N, Cui J, Wang S, Qu H, Fu G, Li J, Chen H, Wang X, Wang R, Qi Y, Gu Z, Chen YQ: Resolvin D1 and D2 inhibit tumour growth and inflammation via modulating macrophage polarization. J Cell Mol Med 2020;(14):8045-8056. https://doi.org/10.1111/jcmm.15436.
https://doi.org/10.1111/jcmm.15436
 
241 Chen A, Zhang Y, Sun D, Xu Y, Guo Y, Wang X: Investigation of the content differences of arachidonic acid metabolites in a mouse model of breast cancer by using LC-MS/MS. J Pharm Biomed Anal 2021;194:113763. https://doi.org/10.1016/j.jpba.2020.113763.
https://doi.org/10.1016/j.jpba.2020.113763
 
242 Mattoscio D, Isopi E, Lamolinara A, Patruno S, Medda A, De Cecco F, Chiocca S, Iezzi M, Romano M, Recchiuti A: Resolvin D1 reduces cancer growth stimulating a protective neutrophil-dependent recruitment of anti-tumor monocytes. J Exp Clin Cancer Res 2021;40(1):129. https://doi.org/10.1186/s13046-021-01937-3.
https://doi.org/10.1186/s13046-021-01937-3
 
243 Miyazaki Y, Nakamura T, Takenouchi S, Hayashi A, Omori K, Murata T: Urinary 8-iso PGF2alpha and 2,3-dinor-8-iso PGF2alpha can be indexes of colitis-associated colorectal cancer in mice. PLoS One 2021;16(1):e0245292. https://doi.org/10.1371/journal.pone.0245292.
https://doi.org/10.1371/journal.pone.0245292
 
244 Bilodeau JF, Gevariya N, Larose J, Robitaille K, Roy J, Oger C, Galano JM, Bergeron A, Durand T, Fradet Y, Julien P, Fradet V: Long chain omega-3 fatty acids and their oxidized metabolites are associated with reduced prostate tumor growth. Prostaglandins Leukot Essent Fatty Acids 2021;164:102215. https://doi.org/10.1016/j.plefa.2020.102215.
https://doi.org/10.1016/j.plefa.2020.102215
 
245 Lee HN, Choi YS, Kim SH, Zhong X, Kim W, Park JS, Saeidi S, Han BW, Kim N, Lee HS, Choi YJ, Baek JH, Na HK, Surh YJ: Resolvin D1 suppresses inflammation-associated tumorigenesis in the colon by inhibiting IL-6-induced mitotic spindle abnormality. FASEB J 2021;35(5):e21432. https://doi.org/10.1096/fj.202002392R.
https://doi.org/10.1096/fj.202002392R
 
246 Arwert EN, Milford EL, Rullan A, Derzsi S, Hooper S, Kato T, Mansfield D, Melcher A, Harrington KJ, Sahai E: STING and IRF3 in stromal fibroblasts enable sensing of genomic stress in cancer cells to undermine oncolytic viral therapy. Nat Cell Biol 2020;22(7):758-766. https://doi.org/10.1038/s41556-020-0527-7.
https://doi.org/10.1038/s41556-020-0527-7
 
247 Guo K, Chen J, Chen Z, Luo G, Yang S, Zhang M, Hong J, Zhang L, Chen C: Triptolide alleviates radiation-induced pulmonary fibrosis via inhibiting IKKβ stimulated LOX production. Biochem Biophys Res Commun 2020;527(1):283-288. https://doi.org/10.1016/j.bbrc.2020.04.023.
https://doi.org/10.1016/j.bbrc.2020.04.023
 
248 Gwon MG, An HJ, Kim JY, Kim WH, Gu H, Kim HJ, Leem J, Jung HJ, Park KK: Anti-fibrotic effects of synthetic TGF-β1 and Smad oligodeoxynucleotide on kidney fibrosis in vivo and in vitro through inhibition of both epithelial dedifferentiation and endothelial-mesenchymal transitions. FASEB J 2020;34(1):333-349. https://doi.org/10.1096/fj.201901307RR.
https://doi.org/10.1096/fj.201901307RR
 
249 Hauge A, Rofstad EK: Antifibrotic therapy to normalize the tumor microenvironment. J Transl Med 2020;18(1):207. https://doi.org/10.1186/s12967-020-02376-y.
https://doi.org/10.1186/s12967-020-02376-y