|Year : 2017 | Volume
| Issue : 1 | Page : 20-34
Mechanism of carcinogenesis after exposure of actinide radionuclides: Emerging concepts and missing links
Rakhee Yadav1, Manjoor Ali2, Amit Kumar1, Badri N Pandey1
1 Homi Bhabha National Institute, Mumbai, Maharashtra, India
2 Radiation Biology and Health Sciences Division, Mumbai, Maharashtra, India
|Date of Web Publication||1-Feb-2017|
Homi Bhabha National Institute, Mumbai, Maharashtra
Badri N Pandey
Homi Bhabha National Institute, Mumbai, Maharashtra
Source of Support: None, Conflict of Interest: None
Radiation carcinogenesis may be associated with external and/or internal sources of radiation exposure during accidental, occupational, or diagnostic/therapeutic conditions. Most of the radiation carcinogenic events are established after acute doses of low linear energy transfer external radiation. Moreover, the carcinogenic effects of internalized radioisotopes are also reported at their acute/chronic doses. In this regard, actinide radionuclides (like 238U, 239Pu, 232Th, and 241Am) are of great importance as fuel material or waste generated during nuclear power production. These radionuclides may result in incidence of cancer when internalized at high doses while accidental or occupation exposure. Even though the basic carcinogenic mechanism after external or internal radiation exposure remains the same, the magnitude of systemic or target specific radiation effects may vary in these radiation exposure conditions. The majority of the studies investigating biological, carcinogenic, and other health effects of actinide radionuclides are limited only up to quantification of these effects without much mechanistic insights. Moreover, the radiobiological processes, such as bystander effect, genomic instability, and adaptive response, governing the cellular radiosensitivity of targeted/nontargeted cells also need to be studied in the context of carcinogenesis after actinide radionuclides internalization. The review aims to highlight the emerging radiobiological concepts and missing links about actinide radionuclides-induced carcinogenesis. In addition, an overview has been presented about biological and health effects of major actinide radionuclides.
Keywords: Actinide radionuclides, chemical toxicity of actinide radionuclides, nontargeted radiation effects, radiation carcinogenesis, radiation-induced bystander effect
|How to cite this article:|
Yadav R, Ali M, Kumar A, Pandey BN. Mechanism of carcinogenesis after exposure of actinide radionuclides: Emerging concepts and missing links. J Radiat Cancer Res 2017;8:20-34
|How to cite this URL:|
Yadav R, Ali M, Kumar A, Pandey BN. Mechanism of carcinogenesis after exposure of actinide radionuclides: Emerging concepts and missing links. J Radiat Cancer Res [serial online] 2017 [cited 2019 Jan 18];8:20-34. Available from: http://www.journalrcr.org/text.asp?2017/8/1/20/199304
| Introduction|| |
Cancer incidence is one of the major health concerns after internal and external radiation exposure. The first case of radiation-attributed cancer incidence was reported in an ulcerated region of skin in 1902, and subsequent leukemia incidence in five radiation workers in 1911., Marie Curie and her daughter Irene were thought to have died from radiation-induced leukemia. Health effects of radiation and associated cancer risk received attention after Hiroshima and Nagasaki bombing in 1945 and nuclear accidents such as Chernobyl in 1986 and more recent Fukushima accident in 2011., Various types of cancer associated with different radiation exposure conditions (atom bomb, medical, and occupational) have been elucidated and reviewed., Carcinogenic effect of radiation was studied using various in vitro and in vivo experimental models in addition to the epidemiological studies in human populations exposed to a range of radiation doses. Even though incidence of cancer after external radiation exposure is well investigated, the mechanistic aspects of carcinogenesis especially after internal exposure with radionuclides have not been investigated in depth. While external radiation exerts its effects mainly during the exposure period only, the internalized radionuclides provide a continuous source of radiation near biological tissues till their radioactive decay/retention in the body. The chemical properties of the internalized radionuclides not only govern their retention in the target organ(s), but they may also add/synergize the radiological toxicity. Hence, the organ specificity and acute/long-term health effects of radionuclides (238 U and 232 Th) would be different even if they have similarities in their radiological properties. In addition, the internal contamination of radionuclides results in localized dose and consequent cancer incidence mainly in their target organs. However, the external radiation (especially low linear energy transfer [LET] radiation) causes carcinogenic effect rather at systemic level more to the radiosensitive organs. A comparative view highlighting the major events in external radiation and actinide-induced carcinogenesis is shown in [Figure 1].
|Figure 1: A comparative view of carcinogenesis by external radiation exposure and internalized alpha-emitting radionuclides|
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Internalization of radionuclides may occur while handling them in small to moderate quantities (3 H,131 I,32 P, etc.) during research, health care, and industrial applications., However, the bulk quantity of radioactivity is handled during nuclear energy production with increased risk of exposure to occupational workers and public. Actinide radionuclides (238 U,239 Pu,232 Th, and 241 Am),,,, are of great importance as fuel material or waste generated during nuclear power production [Table 1]. Due to limited reserve and depleting nonrenewable sources of energy (coal and petroleum), nuclear power could be a viable future source of clean energy for the developing countries like India. Most of the in vitro and in vivo studies investigating biological, carcinogenic, and other health effects ,,,,,,,,,,,,,,,,,,,,,,,, of actinides are limited only up to quantification of the effects [Table 2] without much mechanistic insights. The present work is an attempt to review the various biological and health effects of major actinide radionuclides (uranium, thorium, plutonium, and americium) with an emphasis on their carcinogenic effects. Mechanism of carcinogenesis after external exposure of X-ray/gamma radiation described in the review will provide clues about poorly understood process of actinide-induced carcinogenesis.
|Table 1: Major actinide radionuclides: radiological properties and their health effects,|
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|Table 2: In vitro, ex vivo, in vivo animals and human studies of actinide radionuclides relevant for radiation carcinogenesis|
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| Routes of Exposure of Actinide Radionuclides|| |
Actinide radionuclides can enter the body through inhalation, ingestion, and absorption (skin or wound). These radionuclides exert its toxicity depending on particle size, chemical form, sites of accumulation, and period of retention in the body.
Inhalation of radioisotopes in the dust or in the gaseous form is the most common routes of contamination, especially in the mining and milling/grinding workers. Localization and retention of the inhaled radionuclides in the lungs primarily depends on their chemical form and size. According to the International Commission on Radiological Protection guidelines, internalized radionuclides are categorized as D (days), W (weeks), and Y (years) class compounds having average lung clearance time of 0.5, 50, and 500 days, respectively. Actinide nitrate and other water soluble forms have rapid pulmonary clearance. However, the oxides of plutonium, americium, and curium have longer (50–1000 days) pulmonary clearance time. Particles in the range of 1–5 µm are deposited in the deep lung bronchial/bronchiolar airways while ultrafine (<0.1 µm) and coarse (>5 µm) particles generally deposited in the extrathoracic region., Almost all the particles trapped in the extrathoracic region get cleared by sneezing, coughing, or swallowing of the deposited material. Mucociliary action is another primary mechanism to remove insoluble particles from the tracheobronchial region. In this region, particles loaded with mucus are transported toward larynx where they are either swallowed or removed as sputum. The remaining particles, which get engulfed by macrophages, are transported upward to the tracheal region or circulatory/lymphatic system. The ultrafine particles (<0.1 µm) and relatively insoluble particles may be translocated from tracheobronchial or alveolar regions to other body tissues after passing through lung epithelial layer. It may be noted here that even if only a small fraction of particles are cleared through macrophages and translocation, they majorly contribute to delivery of inhaled radioisotopes to the target organs.
Radionuclides may also get internalized through ingestion of contaminated food material or water. Even the mucus loaded with radionuclides cleared from pulmonary region (through coughing and swallowing) may also contribute to ingestion contamination. Ingested radionuclides pass through four regions of the alimentary tract: stomach, small intestine, upper large intestine, and lower large intestine. The transfer rate coefficients in different regions are reciprocal to the mean residence time (stomach: 1 h; small intestine: 4 h; upper large intestine: 13 h, and lower large intestine: 24 h). The major absorption of ingested radionuclides to blood takes place in the small intestine. Since the alimentary tract is the site of absorption and excretion, variable dose will be received to different regions of the alimentary tract depending on the radionuclide and their chemical species. High level of absorption in small intestine can lead to lower doses to the large intestine. Moreover, the proliferating epithelial cells may contribute significantly to radiation damage to intestinal region. The extent of absorption of individual radionuclides depends on the chemical properties of the radionuclides. While occupational exposure includes mainly the inorganic forms of the radionuclides, the radionuclides ingested during environmental exposures are the organic constituents of food and inorganic forms of food and water. Radionuclides ingested through food contain complexing agents such as citrates, phytates, and other organic acids, which may result in greater absorption than the inorganic forms of the radionuclides. Ingested radionuclides may change its chemical form during traversal though different compartments of the digestion system with acidic to alkaline pH conditions. This may in turn significantly affect the magnitude of radionuclides absorption to the bloodstream and localization to the target organs. Radioisotopes such as tritium in water follow body water and hence have almost free passage from the alimentary tract to the blood  and subsequently excretion too. On the other hand, cesium ions with similarity to the potassium ions are also rapidly absorbed. Ions such as calcium (II) and iron (III) get absorbed by active transport mechanisms; however, actinide radioisotopes are poorly (<0.1% of ingested amounts) absorbed. Furthermore, the absorption of many elements is substantially greater in newborn mammals than the adults. The transfer fraction of Uranium in adult and newborn is 0.02 and 0.04, respectively, which is much lower for other actinides (cerium, thorium, neptunium, plutonium, americium; 0.0005 and 0.005 for adults and newborns, respectively).
Absorption through wounds and/or intact skin is additional routes of radionuclide contamination. While handling radionuclides, possibilities exist for accidental prick or puncture of skin by contaminated sharp objects, which will cause direct contact of radionuclides with blood and delivery of activity to the individual/occupational worker. Depending on the solubility, material may either retained at the wound site or translocated to the other organs through blood or lymphatic tissue. For most of the radionuclides, the distribution of soluble components internalized through wound/skin will be similar to the radionuclides that enter the blood through lungs or alimentary tract. However, the interaction of actinide with blood components determines the magnitude of retention and localization of radionuclide to the various organs. In this direction, our in vitro studies showed binding of actinides and lanthanides with human serum albumin (HAS) and hemoglobin depending on their charge-to-ionic-radii ratio.,
| Carcinogenic and Other Health Effects of Actinides|| |
The major source of thorium in the environment is mining, milling, and processing of material for nuclear applications. In addition, some of the areas are reported to have elevated levels of thorium in the soil posing higher risk of chronic exposure to inhabitants. Due to high melting temperature,232 Th is also used in lantern mantle and welding industry. Its isotopes are mostly alpha emitters  and deposited mainly in liver and bones. Biological half-life of thorium is very long with the possibility of causing liver and bone cancer. Internalized thorium exists only in the + IV oxidation state. Due to long half-life (1.4 × 1010 years), the major toxicity by natural thorium (232 Th) is reported through metal toxicity rather than radiological toxicity. The annual limit of intake (ALI) – amount of radionuclide that gives dose equivalent to 20 mSv – for 232 Th is 170 mg. In compliance with the Atomic Energy Regulatory Board (AERB) and the International Atomic Energy Agency, the Department of Atomic Energy, India, has set the values for thorium concentration in the working environment (25 mg/m 3 of air for 232 ThO2 and 0.05–0.75 mg/m 3 of air for 232 Th-nitrate) as a temporary emergency exposure limit.,,
During thorium mining and waste disposal, nuclear workers and public may be at the risk of exposure to 232 Th and its decay products [Table 1]. There is a potential risk of thorium exposure to workers by inhalation of thorium dioxide (232 ThO2). Two epidemiological studies in China and USA with more than 6000 exposed workers showed higher thorium burden, especially in the lung. However, the results of the study are not conclusive about elevated risk for lung cancer due to the inhaled radioactive substances. A 20-year follow-up study was carried out at Baiyun Obo Rare-earth Iron Mine in China. Its ore contains 0.04% of ThO2 and 10% of SiO2. The incidence of pneumoconiosis (lungs inflammation) was increased among thorium dust-exposed miners. Moreover, the lung cancer mortality of the dust-exposed miners was significantly (P < 0.005) higher than that of the nonexposed group, attributed to thorium-containing dusts and its thoron progeny.
Thorotrast patients are another source of information about health effects of thorium. Thorotrast was used extensively in medical practice between the 1930s and the 1950s as a radiographic contrast agent. Thorotrast was retained mostly (97%) in the reticuloendothelial system (59% in liver, 29% in spleen, and 9% in bone) after intravenous injection. Cohort studies of almost 10,000 thorotrast-administered patients and 10,000 controls in Denmark, Germany, Japan, Portugal, and Sweden have demonstrated significantly increased risks (36–129 times) for primary liver cancer, which are significantly correlated with the volume of thorotrast injected. Limited literature on the mechanism of thorotrast-induced human liver carcinogenesis (hepatocellular carcinoma, cholangiocellular carcinoma, and angiosarcoma) revealed the induction of point mutations in exons 5-8 of p53 (TP53) gene. Interestingly, the frequency of large deletion (e.g., loss of heterozygosity) was only 27% in liver tumors. However, mutations (e.g., transition, transversion, and single base-deletion) were more frequent (47%). Since α-particles can cause massive damage or loss of large DNA fragment due to double-strand breaks in DNA, It could be relevant to understand the mechanism responsible for such inverse effect. It could be interpreted that since 10% of total radiations of thorotrast comprises β- and γ-radiations, which can traverse longer than the α- particle, can irradiate whole liver organ more uniformly than the α-particles. Therefore, the probability of smaller DNA lesions is more than the larger deletion. The observed effects may involve either direct action of radiation or indirect mechanisms such as production of reactive oxygen species in the surrounding medium. In another report, in addition to mutation in p53 gene, the higher frequency of mini-satellite instability was reported in tumor tissue obtained after thorotrast-administered patients. This was attributed to the inactivation of mismatch repair gene (Human MutL Homolog 1) due to methylation of the promoter sequence. However, mutations in major oncogenic pathways (myc, jun, and ras) in thorium and other alpha-emitters-induced liver carcinogenesis still need to be investigated.
Chronic exposure of thorium nitrate (10 mg/kg, 30 days, i.p.) in mice models was found to cause oxidative stress-mediated liver dysfunctions and histopathological changes (lymphocytic infiltration, parenchymal injury). Decreased activities/level of antioxidant enzymes (superoxide dismutase and catalase) in liver tissue of these mice suggest redox injury after thorium administration. In addition to major target organs (liver, spleen, and bone), thorium was also found to accumulate in brain (3% of total injected) and alter the neurobehavioral changes in mice. These effects were ascribed to the chemical/heavy metal nature of thorium [Table 2].
In vitro studies on the effects of thorium nitrate on osmotic imbalance in human red blood cells showed hemolysis at higher concentration (<40 µM) and aggregation at lower concentration (<40 µM). Such differential effects of thorium were attributed to their interaction with cell membrane-bound negatively charged sialic acid. In another study of our group, human liver cells (HepG2) treated with lower concentrations of thorium (0.1–10 µM) showed insulin growth factor-1 receptor-mediated proliferation. These in vitro studies suggest that the cellular effect of thorium largely depends on its interaction with of protein and biomolecules. Compared to cell-bound protein/associated glycosyl residues, the interaction/binding of thorium with blood and lymph proteins could be different. The interaction of thorium with hemoglobin (Hb) decreased efficiency of transportation/delivery of oxygen to the tissues, which could be responsible for severe physiological dysfunction including morality in Chironomus larvae. Binding of thorium with HSA was found to alter its native conformation/folding. Further studies needed to characterize the coordination of thorium in protein and subsequent physiological consequences.
Uranium is a naturally occurring weakly radioactive element, commonly found in very small amounts in soil (2–5 µg/g), water (0.03 pCi/L), and air (4–10 ng/m 3) [Table 1]. It contributes to low levels of natural background radiation in the environment. Besides the naturally occurring amount, uranium exists in the environment because of emissions from the nuclear industry, discharge from mill tailings, combustion of coal and other fossil fuels, and use of uranium-containing phosphate fertilizers., Occupational workers can be exposed to uranium by inhaling dust or ingesting contaminated water/food. However, the general population is exposed to uranium primarily through food and water. The daily ingestion of uranium through foodstuff and water in the United States was found to be in the range of 1.0–4.0 µg/day  and 2.5 µg/L. Compared to 232 Th (170 mg), ALI of 238 U is significantly lower (100 mg). Uranium can enter the body when it is inhaled or swallowed, or under rare circumstances, it may enter through cuts in the skin. Uranium does not get absorbed through the skin, and alpha particles released by uranium cannot penetrate the skin, so uranium that is outside the body is much less harmful than it would be if it inhaled or swallowed. When uranium is internalized, it can lead to cancer or kidney damage. Among people who drank water from wells, uranium-attributed damage to proximal tubules of kidney nephrons and alterations of the renal absorption function were observed. Another study from drilled wells water users in Finland showed 61 bladder cancer and 51 kidney cancer cases between 1981 and 1995, which was correlated with the concentrations of radon, radium, and uranium in the drinking water. The maximum permissible limit for U in water is 15 µg/L by the WHO, 30 µg/L by the United Nations Scientific Committee on the Effects of Atomic Radiation/Environmental Protection Agency (EPA), and 60 µg/L by the AERB, India.
In vitro studies on HSA treated with Uranium decreased the α-helical structure and increased the random coil conformation suggesting the protein interaction of uranium  that could denature the protein and therefore deleterious at the molecular level [Table 2]. Studies on the interaction of 238 U with hemoglobin suggest altered oxygen binding/transport activity of heme moiety. Interestingly, unlike 232 Th, Uranium was not found to cause hemolytic effects on isolated erythrocytes or in whole-blood condition. These effects of 238 U were ascribed to its ability to complex with multiple biological ligands. The chemical toxicity has been demonstrated on the kidney and brain  and may possibly extend to other organs. Therefore, even if models exit to predict radiation-associated health effects after uranium exposure, additional research would be required to establish its radiological plus chemical health effects. This further justifies the need to directly quantify these effects in uranium-exposed populations.
Plutonium-239 is used as nuclear fuel and for nuclear weapons. The plutonium in the bomb undergoes fission in an arrangement that assures enormous energy generation and destructive potential [Table 1]. Nuclear weapons production and testing facilities may also release small amounts of plutonium. In addition, some releases have occurred in accidents with nuclear weapons and from the Chernobyl nuclear reactor accident. People living near nuclear weapons production or testing sites may have increased risk of exposure to plutonium. Plants growing in the contaminated soil can absorb small amounts of plutonium, which may be subsequently transferred to human through food chain.
The gastrointestinal absorption of plutonium is very low (<0.001%) and hence most of the plutonium swallowed with food or water passes from the body through the feces. When inhaled, plutonium can remain in the lungs depending on its particle size and how well the particular chemical form dissolves. The chemical forms that dissolve less easily may lodge in the lungs or move out with phlegm, and either be swallowed or spit out. However, the lungs may absorb chemical forms that dissolve more easily and pass them into the bloodstream. Once in the bloodstream, plutonium moves throughout the body and into the bones, liver, or other body organs. Plutonium that reaches body organs generally stays in the body for decades and continues to expose the surrounding tissue to radiation. Internal exposure to plutonium is an extremely serious health hazard, exposing organs and tissues to radiation, and increasing the risk of cancer.239 Pu distribution among organs and tissues depends on its physicochemical form and the route of administration.,, Once in the systemic compartment,239 Pu will deposit mainly in liver and skeleton.239 Pu intake by inhalation is one of the major potential consequences following an accident in the nuclear industry or after improvised nuclear device explosion [Table 2]. Macrophages are essential players in retention and clearance of inhaled compounds. However, the extent to which these phagocytic cells are involved in these processes highly depends on the solubility properties of the 239 Pu deposited in the lungs.
Most americium is produced by uranium or plutonium bombarded with neutrons in nuclear reactors. It is widely used in commercial ionization chamber-based smoke detectors, as well as in neutron sources and industrial gauges. Its common isotopes are 241 Am and 243 Am with half-life 432 years and 7370 years, respectively [Table 1].241 Am can be released to the environment from nuclear reactors, nuclear explosions, and nuclear accidents. Americium is a byproduct of plutonium production. After americium ingested through breathing, depending on the soluble (e.g., nitrate and chloride) or insoluble (e.g., oxide) forms, it gets dissolved easily in the lung fluid or stays in lungs for hours or days. Other forms (metallic) might stay in the lungs for months or years. Some americium that enters lungs may reach into the blood. Most of the americium entering blood leaves body through urine and feces.
Americium entering the body may get deposited on the surfaces of the bones where it remains for a long time. As americium undergoes radioactive decay in the bone, alpha particles energy gets deposited locally to bone tissue resulting in bone cancer. However, the gamma rays emitted can travel much farther away from the target bone tissue to the other tissue/organs. The specified occupational ALI for 241 Am is 6 × 10-3 µCi for inhalation and 8×/10 µCi for ingestion. The EPA has established a public drinking water limit of 15 pCi/L, which is the sum of radioactive materials that give off alpha radiation.
Harold R. McCluskey, a Hanford nuclear chemical operator exposed accidentally to Am at americium recovery facility in 1976. On postaccident, the total amount of 241 Am excreted in his urine and feces was 41 MBq (1.1 mCi). He died after 11 years due to complications of chronic coronary artery disease. A recent study showed that the femur bone was a site with the highest percentage of americium deposited in the leg (48.8%) [Table 2]. The percentage of Am in the leg relative to total skeletal activity was 20% with an average coefficient of variation of 13.63%. A study has compared the effectiveness of 241 Am with 239 Pu and 233 U to induce osteosarcoma and leukemia in CBA/H mice. For osteosarcoma, the relative order was found to be as 239 Pu > 241 Am > 233 U, which was consistent to the dose delivered to the endosteal surface. For leukemia, this order showed association with their relative accumulation in bone marrow. In another work, beagle dogs injected with 241 Am (11 kBq/Kg) showed induction of osteosarcoma in 92% of animals, which was found to be decreased by administration of DTPA. However, in-depth research is needed to identify the oncogenic pathway(s) involved in the bone carcinogenesis induced by these alpha-emitting and bone-seeking actinides.
| Mechanism of Radiation and Actinides-Induced Carcinogenesis|| |
Basic concept of radiation carcinogenesis
Radiation exposure (above certain dose) is known to increase the probability of cancer incidence both in experimental animals and humans, which however depends on many factors. Compared to chemical and viral carcinogenesis, radiation carcinogenesis differs as its causative agent radiation has ability to penetrate cells/tissues and deposit its energy randomly/nonspecifically to the tissue/organs. Hence, radiation carcinogenesis is a stochastic process, whose probability but not the severity depends on the dose. On the other hand, most of the chemical carcinogens are tissue specific and have to cross many tissue barriers. Many a times, to become potentially carcinogenic, individual chemical carcinogen requires a promoting agent. For example, for skin carcinogenesis, low dose of carcinogen (7,12-dimethylbenz[a] anthracene or benzo[a] pyrene) requires repeated applications of the irritant (like croton oil, with active component of 12-O-tetradecanoylphorbol-13-acetate). However, radiation may play role both in initiation and promotion processes of carcinogenesis, but it has been more evaluated as an initiating agent.
Radiation carcinogenesis may occur during various complex conditions: acute or prolonged, external or internal, localized or whole-body exposure, or mixed conditions of any/some of them. In case of acute dose of radiation, primary damage occurs only at the time of irradiation. However, in case of chronic radiation exposure conditions (low-dose radiation and internal contamination with long-lived radioisotopes), the damage is continuous and may combine damage and inducible repair processes. Indeed, under such radiation exposure conditions, possibly the sequential mutations (similar to reported in colon carcinoma and initiator-promoter-based skin carcinogenesis models) may exist, which has been not well investigated. It may be pertinent to mention here that contamination with actinide radionuclides will cause both chemical and radiological toxicities. However, the magnitude of chemical toxicity will be independent on the nature of radiation (i.e., alpha, beta, and gamma either alone or in combination) emitted by the radioisotope but will be governed by its residential time and the chemical properties of the actinide. Chemical interaction of these actinides is now being greatly realized as it may affect structure and function of key biomolecules such as Hb. Substantial chemical toxicity may be exerted by long-lived but poor clearance rate actinide radionuclides such as 232 Th. For short-lived and high specific activity radioisotopes, radiological toxicity would be dominating over the chemical toxicity. Hence, chemical toxicity of actinides also needs to be accounted, especially in case of radionuclides with long biological half-lives, which may add/synergize substantially the radiological toxicity and subsequent carcinogenesis processes.
Biological effects of radiation are known to be manifested mainly through DNA damage to cells either through direct deposition of energy to DNA or the free radicals/reactive oxygen species produced during the ionization process. Radiation can cause a broad spectrum of DNA lesions including damage to nucleotide bases, cross linking, and DNA SSB and double-strand breaks (DSBs). For instance, in each mammalian cell, one Gy of low LET γ-radiation induces around 850 pyrimidine lesions, 450 purine lesions, 1000 single-strand breaks (SSBs), and 20-40 DSBs., The SSB was found to be higher (5.98 × /108/Gy/Da) after gamma (LET: 0.3 keV/µM) than after alpha radiation (LET: 97 keV/µM; 8.66 × /1010/Gy/Da), which was quantified in plasmid DNA (pEC) postirradiation incubated with endonuclease-III. DSB was found to be 1.45 × /109/Gy/Da and 1.07 × /1010/Gy/Da for gamma and alpha radiation, respectively. In a recent study, ratios of non-DSB/DSB lesions calculated for different radiations in various mammalian cell lines were found to be ranged from 5 to 10 for X-rays and 3–5 for high-LET radiation. Out of radiation-induced DNA lesions, DSBs are considered to be the most critical cytotoxic event. The misrepaired DSBs are the principle lesions for induction of chromosomal aberrations and gene mutations. In this regard, while comparing the mutagenic ability of various ionizing radiations (namely, X-rays, neutrons,40 Ar ions,28 Si ions, and 125 IUrd),125 IUrd was found to be much higher cytotoxic and mutagenic than other radiation types. It may be important to mention here that a lethal dose of radiation will eliminate the damaged cells and hence reduce the possibility of cancer incidence. However, misrepaired DNA damages may subsequently initiate the neoplastic changes and pose greater risk for cancer incidence. Typically, the cancer cells contain multiple stable chromosomal aberrations (such as deletions, reciprocal translocations, and aneuploidy). Deletion of a piece of chromosome may result in inactivation of tumor suppressor genes (e.g., retinoblastoma [RB], p53) involving various mechanisms such as mutation, phosphorylation, or degradation of associated proteins. In some cases, specific chromosomal abnormalities have been associated with specific tumor types, for example, 8:14 translocation in Burkitt's lymphoma and 13q14 deletion in RB. A radiation-damaged cell bearing with chromosomal aberrations follows a series of molecular events during course of neoplastic transformation. It may be noteworthy to state that some of the cell transformation steps are reversible. Even though the magnitude of DNA damage governs the fate of individual cells, other determinants associated with nontargeted radiation effects (such as abscopal effect, clastogenic factors, communication from bystander/distant organs) would also contribute to the mechanism of radiation carcinogenesis, which will be discussed in later sections of the review.
Factors affecting radiation carcinogenesis
Radiation-induced cancer incidence is governed by many physical, biological, and physiological factors, which may either enhance (i.e., promoting agents) or suppress (i.e., cancer preventive agents) the magnitude of carcinogenesis. Initiator-promoter model of carcinogenesis has been well studied for chemical agents. In an early study, ability of X-ray as an initiating agent was also demonstrated in the process of carcinogenesis when combined with croton oil as a promoting agent. In such model, cancer incidence followed linear curve, which was otherwise linear-quadratic in case of radiation only. Such studies have been well documented and reviewed. Radiation quality (LET and energy) and dose/dose rate are important physical factors for external radiation exposure conditions. However, radiological/biological half-lives and chemical properties are additional physical factors for internalized radionuclides. For high LET radiation, cancer incidence generally rises more steeply as a function of dose but less dependent on the dose rate. At high dose, expression of carcinogenic effects tends to be suppressed by sterilization of potentially transformed cells or other forms of radiation injury. An acute and high dose of radiation is known to induce cancer and other adverse health effects. However, cancer incidence after low and low dose of radiation is a matter of debate.,, One school of radiation biologists advocates that low/low-dose radiation can prevent many ailments including diabetes and cancer. In a study, amelioration of type II diabetes was observed in db/db mice after continuous low-dose rate γ-irradiation (940 μGy/h for 24 days). Another study showed lower incidence of lung cancer in Wistar rats when animals were exposed to 239 PuO labeled with 169 Ytterbium (a low-dose [1–2 mGy] gamma-emitting radionuclide) than animals exposed only to 239 PuO. Another school of thought supports cancer risk after low dose/dose rate radiation exposure (medical/occupational exposure with X-rays, nuclear industry workers); however, contradictory results make the final picture hazy. In a study, cancer mortality in Canadian nuclear workers (1956–1994) showed significant heterogeneity of the dose response for solid cancer. In 3088 early (1956–1964) workers, it showed a significant increase in risk (excess relative risk [ERR]/Sievert [Sv] = 7.87, 95% confidence interval [CI]: 1.88–19.5), but no evidence of radiation risk was observed for 42,228 workers employed by three nuclear power plant companies and post-1964 Atomic Energy of Canada Limited (ERR/Sv = −1.20, 95% CI: <−1.47–2.39). All workers had mortality lower than the general population. Such low-dose radiation hormetic effect against cancer incidence has been suggested to involve possible mechanisms such as elimination of preneoplastic/aberrant cells by apoptosis, induction of the DNA-repair pathways, and activation of immune functions.
Hormones are known to affect process of carcinogenesis in experimental animals  and estrogen, and other sex hormones act like tumor promoting agents. In our study, increased incidence of radiation-induced thymic lymphoma (TL) was observed in female mice (3 Gy; whole-body irradiation [WBI]) suggesting gender disparity and possible role of sex hormones in the mechanism of radiation-induced carcinogenesis. Gender disparity in cancer incidence, progression, and therapeutic outcome has been observed in some of the cancer types, in addition to radiation-induced cancer incidence. In a study, female mice (adenomatous polyposis coli mutant Apc1638N/−) displayed lower susceptibility to radiation-induced intestinal tumorigenesis after whole-body γ-irradiation (1 and 5 Gy) compared to males. A pooled analysis of seven studies (from atomic bomb survivors in Japan and individuals exposed to Chernobyl accident) showed that women had a nearly two-fold increase in thyroid cancer risk, but no individual study showed a statistical difference between men and women. Thyroid is one of the sensitive organs for radiation-induced carcinogenesis, when exposed at young age. Increased level of thyroid stimulatory hormone contributes significantly to thyroid carcinogenesis. Age at the time of radiation exposure is another biological factor which contributes significantly to radiation-induced cancer incidence. Our studies showed increased TL incidence when animals were exposed at young age, which decreased significantly with increase in the age of animals at the time of irradiation. It was interesting to observe that effect of age on the decrease of radiation-induced TL incidence was more prominent in males than the females.
Cigarette smoke can act as a promoting agent in radiation-induced carcinogenesis and play as one of the major compounding factors in mine and milling workers involved in fuel fabrication and processing of actinides in nuclear industry. This line of thought gets further support by higher and early incidence of lung cancer in smokers than non-smokers uranium miners. X-ray-irradiated rats undergone anemic stress after repeated bleeding showed enhanced leukemia, which was attributed to the increased proliferation of bone marrow cells during replenishment of the blood shortage. Health status especially infection/microbial contamination will result in higher susceptibility of radiation-induced cancer incidence, which was supported by lower leukemia in germ-free mice. Other health-related issues such as obesity and diabetes have been known to be associated with risk of several types of cancers; however, not many studies were performed on risk associated with radiation-induced cancer in these health conditions. In a recent study, higher incidence of mammary cancer was observed in obesity-prone rat model. Caloric restriction has been shown to prevent radiation-induced leukemia in C3H/He mice after whole-body X-ray irradiation, which was suggested to be associated with decrease in spleen hematopoietic stem cells, the possible target for radiation-induced leukemia. Dietary components and antioxidants, being radioprotective in nature, are expected to ameliorate the radiation damage and thus consequent radiation carcinogenesis. Retinoids or Vitamin A analogs, are well studied class of chemopreventive agents in in vitro and in vivo models after radiation exposure. Chemopreventive ability of a mixture of antioxidant dietary supplements has been reported against occurrence of lymphoma and other neoplastic lesions after proton and iron ion irradiation. In our study, feeding of animals with antioxidants resulted in a significant inhibition of TL incidence, which was more prominent after curcumin (55%) feeding than ascorbic acid/eugenol feeding (20%). Protease inhibitors have been known as preventive agents against radiation carcinogenesis. The soybean-derived protease inhibitor, Bowman-Birk inhibitor has been developed as a cancer preventive agent tested in animals as well as during human trials., Based on these studies, it may be stated that soy-rich dietary habit might have substantially influenced the cancer incidence and mortality observed in atomic bomb survivors of Japanese population.
Genetic susceptibility is known to act as an important predisposing factor in radiation-induced cancer incidence. Sensitivity of the BALB/C mouse strain to radiation-induced mammary cancer has been related to a mutation in the gene coding for the DNA repair protein DNA-PKcs. Interestingly, transgenic mice heterozygous for either the p53 or ataxia-telangiectasia mutated  tumor-suppressor genes showed an increased sensitivity to radiation-induced cancer. Such genetic susceptibility has also been reported in a few human cancer types. RB patients with hereditary and heterozygous RB gene are at increased risk for the development of radiation-induced bone sarcomas  after radiotherapy. Breast cancer gene (BRCA) 1/2 mutant patients might be more sensitive for the deleterious effects of ionizing radiation due to an impaired DSB repair capacity. Such genetic predisposition might place these breast cancer patients at a higher risk of cancer during diagnosis or second cancer during therapy. A recent critical review suggests that sporadic breast cancer patients (>45 years) can be safely treated with radiotherapy. Moreover, the literature also suggest that mammography screening is not advised in BRCA1/2 mutation carriers <30 years. Caution for adjuvant radiotherapy was suggested in case of young BRCA1/2 mutation carriers. It may be pertinent to mention here that the factors governing the radiation carcinogenesis after external radiation (X-ray/gamma ray) have been well studied; the role of such factors (age, gender, mutation status, confounding factors, microbial infection, etc.) in case of contamination with internalized actinide radionuclides has not been investigated.
| Radiobiological Concepts in Actinide Carcinogenesis|| |
Mechanism of radiation carcinogenesis has been investigated in many experimental models. In case of WBI, relative contribution of different tissue/organs will determine the net magnitude of cancer incidence. The role of radiobiological concepts (such as bystander/distant [abscopal] effect, genomic instability, adaptive response, etc.) has received meager attention in the mechanism of radiation carcinogenesis, especially after exposure with actinide radionuclides. In later sections, few of the aspects have been reviewed and discussed in case of carcinogenesis after external radiation, which may provide essential clues about internalized radionuclides too. Radiation-induced bystander/abscopal effect and genomic instability are two major nontargeted radiation effects. Radiation-induced bystander effect is exhibition of radiation effects in cells, which did not receive radiation, but are adjacent or in close proximity to the irradiated cells. Effect exerted at distant organs/locations away from the irradiated organ is called “abscopal effect.” Although these nontargeted effects of radiation have been well studied for determining the cellular radiosensitivity under various in vitro and in vivo conditions, relationship between nontargeted effects and the risk of developing radiation-induced cancer is still uncertain. In a few studies, role of bystander or abscopal effects in the process of radiation carcinogenesis has been suggested mainly based on the indirect evidence (chromosomal aberrations, DNA damage, cytokine secretion, etc.) after low LET external radiation. In this direction, a few early studies performed in the beginning of the 20th century showed morphological changes in lymphoid cells when cultured in serum from radiation-exposed animals., Later on, the presence of soluble clastogenic factors was reported in the circulating blood of the radiotherapy patients. These clastogenic factors were also observed in the plasma of radiation-exposed workers from Chernobyl accident. Experiments conducted using partial-organ irradiation, which manifested radiation effects in shielded organ parts, provide evidence supporting the nontargeted radiation effects and its contribution in the process of carcinogenesis in distant/bystander regions. In a study, Mancuso et al. used young mice genetically susceptible to cerebellar tumors, which provided a model for medulloblastoma occurring during childhood. In this experiment, cranial area was shielded while WBI (3 Gy; X-ray). It was interesting to observe the tumor development in the shielded brain suggesting the transmittance of carcinogenic signal to distant organs away from the irradiated areas. In this connection, contribution of thymus (target organ) and bone marrow (nontarget organ) has been elucidated in the mechanism of radiation-induced TL after WBI. Being radiosensitive organ/tissue, thymus and bone marrow cells easily get damaged. To replenish the damaged T-cells, bone marrow cells are transported to thymus and survival/proliferation of the mutated cells will result in TL incidence. Suppression of radiation-induced TL incidence was observed in case of shielding and transplantation of bone marrow despite the thymus receiving the radiation dose. Our unpublished results showed that the antioxidants protecting only bone marrow (not thymus) are still able to inhibit the radiation-induced TL incidence. Compared to in vivo models, the evidence supporting the role of nontargeted radiation effects in the process of carcinogenesis at human level is rather sparse and inconclusive. In this direction, a few evidence showed connection between radiotherapy and second cancer. Incidence of second cancer, in the bladder and rectum in survivors of prostate cancer patients, 10 years after radiotherapy was suggested to be due to proximity of target organs to irradiation area.,
Radiation-induced genomic instability refers the increased acquisition of alterations or mutations in the genome being transmitted to the progeny cells, which may significantly play a role in cellular neoplastic transformation. In our study, the role of genomic instability in radiation-induced TL incidence was studied. About 85%–90% irradiated animals (WBI; 3 Gy) showed incidence of TL after 120 days. The magnitude of DNA damage was correlated with individual sensitivity for TL incidence after irradiation. DNA damage monitored in the peripheral blood cells of individual mice by comet assay at different intervals (5 min and 7 days of postirradiation) showed good correlation with the TL weight in the respective mice at the 120th day. Our results showed that in ex vivo irradiated (0.5 Gy) peripheral blood, the magnitude of DNA damage was higher in samples obtained from WBI mice than sham-irradiated controls suggesting role of genomic instability in TL incidence in irradiated mice. The multicellular responses and extracellular signaling after radiation exposure alter the irradiated tissue microenvironment governing the process of cellular transformation.,, Most of the information obtained in this direction was for mammary  or lung carcinogenesis  after radiation exposure. In this direction, strong evidence has been generated using radiation chimeric tissue by transplanting unirradiated preneoplastic mammary cells to an irradiated mammary gland. Surgical removal of the parenchyma results in a gland-free mammary fat pad, which is suitable for receiving donor tissue at the time of clearing or later. An occasional mouse nontumorigenic mammary epithelial cell line, COMMA-D, if injected into the cleared mammary pads gives intact gland. It was observed that the irradiated stroma dramatically promoted the ability of the cells to progress as tumors. Furthermore, the mean size of tumors from irradiated animals was nearly five times larger than the tumors (few in number) that arose in sham-irradiated hosts. These results suggest that tumor features, as well as frequency, were affected by irradiated stroma of mammary gland. Greenberger et al. have also shown that irradiated bone marrow stroma actively contributes to leukemogenesis in murine model.
Not many studies exist in literature studying the mechanistic insight about the process of carcinogenesis upon internalization of actinide radionuclides. A few in vitro and in vivo studies have been reported in which cells were labeled with radioisotopes such as 3 H,131 I,125 I,123 I, and 224 Ra  followed by chromosomal aberrations and neoplastic transformation. In another study, Chinese hamsters were injected intravenously with 239 Pu citrate or 239 PuO2 particle with different sizes (0.17, 0.30, 0.44, and 0.84 μm; 6 × /105–6 × /103 µCi/g). Such particles were chosen to vary the dose and dose rate to local and surrounding cells. The particles were mainly localized to liver (90%) with minor faction to spleen (3%) and the remainder are either the bone or bone marrow. The 239 Pu-citrate resulted in a linear increase in the chromosome aberration frequency with slope 4.8 × /103 aberrations/cell/rad.239 PuO2 particles resulted in higher chromosome aberration frequency, which was dependent on average dose and plateaued at higher average doses. It was interesting to observe that the number of cells at risk by particulate deposition of 239 PuO2 was much lower than the uniform distribution of the same activity by 239 Pu citrate. It has been argued by the authors that in case of uniform distribution of radioisotopes, higher fractions of cells may be receiving sublethal damage dose, which may at risk of developing cancer.
Nontargeted radiation effects and adaptive response could be important governing factor in case of actinide radionuclides-induced carcinogenesis due to the following reasons: (i) most of these radionuclides are short-range (micrometer to millimeter) alpha emitters and their effect is contained within the area of contamination. Such conditions provide an ideal platform for crosstalk between irradiated and bystander cells. (ii) Most of the actinide radionuclides internalized to cells also emit low energy gamma radiation in addition to high energy alpha radiation. While the range of alpha is up to few cell layers, the other tissue regions receiving low dose of gamma radiation can exert bystander cross talk or adaptive response for the irradiated cell population. (iii) The tissue regions constantly receiving low dose of gamma radiation will induce low-level bur repairable DNA damage. Genomic instability in these cells during course of their proliferation may increase the risk of cancer in these regions. On the other hand, it is matter of great interest for radiation biologists whether the tissue regions receiving low dose of gamma induce mechanism (s)/signals to rescue/protect the alpha-irradiated cells. Hence, a complex but exciting radiobiology could be envisaged for actinide radionuclides internalized in the target organ. These understanding suggest that in case of actinide radionuclides, the cells directly receiving the massive lethal dose of particulate radiation will be eliminated and at relatively at poor cancer risk. On the other hand, the cells which receive sublethal damage signals through any of the nontargeted mechanisms will be at higher risk of developing cancer. It is hoped that in coming years, researchers shall play greater attention exploring and integrating these radiobiologically exciting concepts in the context of actinide radionuclides-induced carcinogenesis.
Risk of carcinogenesis associated with actinide radionuclides will gain more importance with their increasing applications in nuclear, healthcare, and other applications. Emerging radiobiological concepts need to be explored in radiation carcinogenesis, and many of the lessons learned in this direction need to be extrapolated and integrated to actinide radionuclides-induced carcinogenesis. A few emerging lines of research directions are as follows:
Molecular mechanism of binding/interaction of actinides with proteins, DNA, and macromolecules especially under physiological conditions.
Spatial distribution of actinides (e.g., thorium, uranium, plutonium, and americium) at subcellular level and in different regions of target organ(s) has not been studied in detail, which will establish better correlation with the biological response of these actinides. Conditions may exist where target organ for the actinides may result in delivery of dose to the nontarget regions/organs. Studies need to be conducted to establish whether nontargeted effects of radiation (i.e., bystander and abscopal) reduce or enhance the actinide radionuclides-associated cancer risk.
Studying the role of biological and physiological factors (such as genetic background, age, gender, hormones, and health conditions) in the carcinogenesis after internalized radionuclides will be helpful assessing the actual risk of these radionuclides in different categories of occupational workers and public.
Development of therapeutic/decorporation approaches and medical intervention to mitigate the actinide-induced chronic and acute health effects arising from occupational and accidental exposure with actinides.
We would like to acknowledge Homi Bhabha National Institute Ph.D. Fellowship from Department of Atomic Energy, Government of India.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2]