Causes of cancer

From Wikipedia, the free encyclopedia

Cancer requires multiple mutations to progress.

 

Cancer is a disease caused by genetic changes leading to uncontrolled cell growth and tumor formation. The basic cause of sporadic (non-familial) cancers is DNA damage and genomic instability. A minority of cancers are due to inherited genetic mutations. Most cancers are related to environmental, lifestyle, or behavioral exposures. Cancer is generally not contagious in humans, though it can be caused by oncoviruses and cancer bacteria. The term "environmental", as used by cancer researchers, refers to everything outside the body that interacts with humans. The environment is not limited to the biophysical environment (e.g. exposure to factors such as air pollution or sunlight), but also includes lifestyle and behavioral factors. Over one third of cancer deaths worldwide (and about 75-80% in the United States) are potentially avoidable by reducing exposure to known factors. Common environmental factors that contribute to cancer death include exposure to different chemical and physical agents (tobacco use accounts for 25–30% of cancer deaths), environmental pollutants, diet and obesity (30–35%), infections (15–20%), and radiation (both ionizing and non-ionizing, up to 10%). These factors act, at least partly, by altering the function of genes within cells. Typically many such genetic changes are required before cancer develops. Aging has been repeatedly and consistently regarded as an important aspect to consider when evaluating the risk factors for the development of particular cancers. Many molecular and cellular changes involved in the development of cancer accumulate during the aging process and eventually manifest as cancer.

Genetics

Multiple colon polyps within the colon of an individual with familial adenomatous polyposis

 

Although there are over 50 identifiable hereditary forms of cancer, less than 0.3% of the population are carriers of a cancer-related genetic mutation and these make up less than 3–10% of all cancer cases. The vast majority of cancers are non-hereditary ("sporadic cancers"). Hereditary cancers are primarily caused by an inherited genetic defect. A cancer syndrome or family cancer syndrome is a genetic disorder in which inherited genetic mutations in one or more genes predisposes the affected individuals to the development of cancers and may also cause the early onset of these cancers. Although cancer syndromes exhibit an increased risk of cancer, the risk varies. For some of these diseases, cancer is not the primary feature and is a rare consequence. 

Many of these syndromes are caused by mutations in tumor suppressor genes that regulate cell growth. Other common mutations alter the function of DNA repair genes, oncogenes and genes involved in the production of blood vessels. Certain inherited mutations in the genes BRCA1 and BRCA2 with a more than 75% risk of breast cancer and ovarian cancer. Some of the inherited genetic disorders that can cause colorectal cancer include familial adenomatous polyposis and hereditary non-polyposis colon cancer; however, these represent less than 5% of colon cancer cases. In many cases, genetic testing can be used to identify mutated genes or chromosomes that are passed through generations.

Cancer syndromes

• Ataxia telangiectasia
• Bloom syndrome
• BRCA1 & BRCA2
• Fanconi anemia
• Familial adenomatous polyposis
• Hereditary breast and ovarian cancer
• Hereditary non-polyposis colon cancer
• Li-Fraumeni syndrome
• Nevoid basal cell carcinoma syndrome
• Von Hippel-Lindau disease
• Werner syndrome
• Xeroderma pigmentosum

Physical and chemical agents

Particular substances, known as carcinogens, have been linked to specific types of cancer. Common examples of non-radioactive carcinogens are inhaled asbestos, certain dioxins, and tobacco smoke. Although the public generally associates carcinogenicity with synthetic chemicals, it is equally likely to arise in both natural and synthetic substances. It is estimated that approximately 20,000 cancer deaths and 40,000 new cases of cancer each year in the U.S. are attributable to occupation. Every year, at least 200,000 people die worldwide from cancer related to their workplace. Millions of workers run the risk of developing cancers such as lung cancer and mesothelioma from inhaling asbestos fibers and tobacco smoke, or leukemia from exposure to benzene at their workplaces. Cancer related to one's occupation is believed to represent between 2–20% of all cases. Most cancer deaths caused by occupational risk factors occur in the developed world. Job stress does not appear to be a significant factor at least in lung, colorectal, breast and prostate cancers.

Smoking

The incidence of lung cancer is highly correlated with smoking.

 

Tobacco smoking is associated with many forms of cancer, and causes 80% of lung cancer. Decades of research has demonstrated the link between tobacco use and cancer in the lung, larynx, head, neck, stomach, bladder, kidney, esophagus and pancreas. There is some evidence suggesting a small increased risk of developing myeloid leukemia, squamous cell sinonasal cancer, liver cancer, colorectal cancer, cancers of the gallbladder, the adrenal gland, the small intestine, and various childhood cancers. Tobacco smoke contains over fifty known carcinogens, including nitrosamines and polycyclic aromatic hydrocarbons. Tobacco is responsible for about one in three of all cancer deaths in the developed world, and about one in five worldwide. Lung cancer death rates in the United States have mirrored smoking patterns, with increases in smoking followed by dramatic increases in lung cancer death rates and, more recently, decreases in smoking rates since the 1950s followed by decreases in lung cancer death rates in men since 1990. However, the numbers of smokers worldwide is still rising, leading to what some organizations have described as the tobacco epidemic.

Electronic cigarettes or e-cigarettes are handheld electronic devices that simulate the feeling of tobacco smoking. Daily long-term use of high voltage (5.0 V) electronic cigarettes may generate formaldehyde-forming chemicals at a greater level than smoking, which was determined to be a lifetime cancer risk of approximately 5 to 15 times greater than smoking. However, the overall safety and long-term health effects of electronic cigarettes is still uncertain.

Materials

Asbestos body in a cytological slide

 

Some substances cause cancer primarily through their physical, rather than chemical, effects on cells. A prominent example of this is prolonged exposure to asbestos, naturally occurring mineral fibers which are a major cause of mesothelioma, which is a cancer of the serous membrane, usually the serous membrane surrounding the lungs. Other substances in this category, including both naturally occurring and synthetic asbestos-like fibers such as wollastonite, attapulgite, glass wool, and rock wool, are believed to have similar effects. Non-fibrous particulate materials that cause cancer include powdered metallic cobalt and nickel, and crystalline silica (quartz, cristobalite, and tridymite). Usually, physical carcinogens must get inside the body (such as through inhaling tiny pieces) and require years of exposure to develop cancer. Common occupational carcinogens include:

• arsenic
• asbestos
• benzene
• beryllium
• cadmium
• chromium
• ethylene oxide
• nickel
• Plutonium

Lifestyle

Many different lifestyle factors contribute to increasing cancer risk. Together, diet and obesity are related to approximately 30–35% of cancer deaths. Dietary recommendations for cancer prevention typically include an emphasis on vegetables, fruit, whole grains, and fish, and avoidance of processed meat, red meat, animal fats, and refined carbohydrates. The evidence to support these dietary changes is not definitive.

Alcohol

Chronic damage due to alcohol consumption can lead to liver cirrhosis (pictured above) and the development of hepatocellular carcinoma, a form of liver cancer.

 

Alcohol is an example of a chemical carcinogen. The World Health Organization has classified alcohol as a Group 1 carcinogen. In Western Europe 10% of cancers in males and 3% of cancers in females are attributed to alcohol. Worldwide, 3.6% of all cancer cases and 3.5% of cancer deaths are attributable to alcohol. In particular, alcohol use has been shown to increase the risk of developing cancers of the mouth, esophagus, pharynx, larynx, stomach, liver, ovaries, and colon. The main mechanism of cancer development involves increased exposure to acetaldehyde, a carcinogen and breakdown product of ethanol. Other mechanisms have been proposed, including alcohol-related nutritional deficiencies, changes in DNA methylation, and induction of oxidative stress in tissues.

Diet

Some specific foods have been linked to specific cancers. Studies have shown that individuals that eat red or processed meat have a higher risk of developing breast cancer, prostate cancer, and pancreatic cancer. This may be partially explained by the presence of carcinogens in food cooked at high temperatures. Several risk factors for the development of colorectal cancer include high intake of fat, alcohol, red and processed meats, obesity, and lack of physical exercise. A high-salt diet is linked to gastric cancer. Aflatoxin B1, a frequent food contaminate, is associated with liver cancer. Betel nut chewing has been shown to cause oral cancers.

The relationship between diet and the development of particular cancers may partly explain differences in cancer incidence in different countries. For example, gastric cancer is more common in Japan due to the frequency of high-salt diets and colon cancer is more common in the United States due to the increased intake of processed and red meats. Immigrant communities tend to develop the cancer risk profile of their new country, often within one to two generations, suggesting a substantial link between diet and cancer.

Obesity

Cancers related to obesity

Men	Women
Colorectal cancer	Colorectal cancer
Esophageal adenocarcinoma	Endometrial cancer
Kidney cancer	Esophageal adenocarcinoma
Pancreatic cancer	Gallbladder cancer
Thyroid cancer	Kidney cancer
	Pancreatic cancer
	Post-menopausal breast cancer

In the United States, excess body weight is associated with the development of many types of cancer and is a factor in 14–20% of all cancer deaths. Every year, nearly 85,000 new cancer diagnoses in the United States are related to obesity. Individuals who underwent bariatric surgery for weight loss have reduced cancer incidence and mortality.

There is an associated between obesity and colon cancer, post-menopausal breast cancer, endometrial cancer, kidney cancer, and esophageal cancer. Obesity has also been linked with the development of liver cancer. The current understanding regarding the mechanism of cancer development in obesity relates to abnormal levels of metabolic proteins (including insulin-like growth factors) and sex hormones (estrogens, androgens and progestogens). Adipose tissue also creates an inflammatory environment which may contribute to the development of cancers.

Physical inactivity is believed to contribute to cancer risk not only through its effect on body weight but also through negative effects on immune system and endocrine system. More than half of the effect from diet is due to overnutrition rather than from eating too little healthy foods.

Hormones

Macroscopic appearance of invasive ductal carcinoma of the breast. The tumor is the pale, crab-shaped mass at the center, surrounded by normal, yellow fatty tissue.

 

Some hormones play a role in the development of cancer by promoting cell proliferation. Insulin-like growth factors and their binding proteins play a key role in cancer cell growth, differentiation and apoptosis, suggesting possible involvement in carcinogenesis.

Hormones are important agents in sex-related cancers such as cancer of the breast, endometrium, prostate, ovary, and testis, and also of thyroid cancer and bone cancer. For example, the daughters of women who have breast cancer have significantly higher levels of estrogen and progesterone than the daughters of women without breast cancer. These higher hormone levels may explain why these women have higher risk of breast cancer, even in the absence of a breast-cancer gene. Similarly, men of African ancestry have significantly higher levels of testosterone than men of European ancestry, and have a correspondingly much higher level of prostate cancer. Men of Asian ancestry, with the lowest levels of testosterone-activating androstanediol glucuronide, have the lowest levels of prostate cancer.

Other factors are also relevant: obese people have higher levels of some hormones associated with cancer and a higher rate of those cancers. Women who take hormone replacement therapy have a higher risk of developing cancers associated with those hormones. On the other hand, people who exercise far more than average have lower levels of these hormones, and lower risk of cancer. Osteosarcoma may be promoted by growth hormones.

Some treatments and prevention approaches leverage this cause by artificially reducing hormone levels, and thus discouraging hormone-sensitive cancers. Because steroid hormones are powerful drivers of gene expression in certain cancer cells, changing the levels or activity of certain hormones can cause certain cancers to cease growing or even undergo cell death. Perhaps the most familiar example of hormonal therapy in oncology is the use of the selective estrogen-receptor modulator tamoxifen for the treatment of breast cancer. Another class of hormonal agents, aromatase inhibitors, now have an expanding role in the treatment of breast cancer.

Infection and inflammation

Worldwide, approximately 18% of cancer cases are related to infectious diseases. This proportion varies in different regions of the world from a high of 25% in Africa to less than 10% in the developed world. Viruses are the usual infectious agents that cause cancer but bacteria and parasites also contribute. Infectious organisms that increase the risk of cancer are frequently a source of DNA damage or genomic instability.

Viruses

HPV is the most common virus that infects the reproductive tract. Infection can lead to the development of cervical cancer in women.

 

Viral infection is a major risk factor for cervical and liver cancer. A virus that can cause cancer is called an oncovirus. These include human papillomavirus (cervical carcinoma), Epstein–Barr virus (B-cell lymphoproliferative disease and nasopharyngeal carcinoma), Kaposi's sarcoma herpesvirus (Kaposi's sarcoma and primary effusion lymphomas), hepatitis B and hepatitis C viruses (hepatocellular carcinoma), and Human T-cell leukemia virus-1 (T-cell leukemias). 

In Western developed countries, human papillomavirus (HPV), hepatitis B virus (HBV) and hepatitis C virus (HCV) are the most common oncoviruses. In the United States, HPV causes most cervical cancers, as well as some cancers of the vagina, vulva, penis, anus, rectum, throat, tongue and tonsils. Among high-risk HPV viruses, the HPV E6 and E7 oncoproteins inactivate tumor suppressor genes when infecting cells. In addition, the oncoproteins independently induce genomic instability in normal human cells, leading to an increased risk of cancer development. Individuals with chronic hepatitis B virus infection are more than 200 times more likely to develop liver cancer than uninfected individuals. Liver cirrhosis, whether from chronic viral hepatitis infection or alcohol abuse, is independently associated with the development of liver cancer, but the combination of cirrhosis and viral hepatitis presents the highest risk of liver cancer development.

Bacteria and parasites

Histopathology of Schistosoma haematobium eggs within the lining of the bladder.

 

Certain bacterial infections also increase the risk of cancer, as seen in Helicobacter pylori-induced gastric carcinoma. The mechanism by which H. pylori causes cancer may involve chronic inflammation or the direct action of some of the bacteria's virulence factors. Parasitic infections strongly associated with cancer include Schistosoma haematobium (squamous cell carcinoma of the bladder) and the liver flukes, Opisthorchis viverrini and Clonorchis sinensis (cholangiocarcinoma). Inflammation triggered by the worm's eggs appears to be the cancer-causing mechanism. Certain parasitic infections can also increase the presence of carcinogenic compounds in the body, leading to the development of cancers. Tuberculosis infection, caused by the mycobacterium M. tuberculosis, has also been linked with the development of lung cancer.

Inflammation

There is evidence that inflammation itself plays an important role in the development and progression of cancer. Chronic inflammation can lead to DNA damage over time and the accumulation of random genetic alterations in cancer cells. Inflammation can contribute to proliferation, survival, angiogensis and migration of cancer cells by influencing tumor microenvironment. Individuals with inflammatory bowel disease are at increased risk of developing colorectal cancers.

Radiation

Up to 10% of invasive cancers are related to radiation exposure, including both non-ionizing radiation and ionizing radiation. Unlike chemical or physical triggers for cancer, ionizing radiation hits molecules within cells randomly. If it happens to strike a chromosome, it can break the chromosome, result in an abnormal number of chromosomes, inactivate one or more genes in the part of the chromosome that it hit, delete parts of the DNA sequence, cause chromosome translocations, or cause other types of chromosome abnormalities. Major damage normally results in the cell dying, but smaller damage may leave a stable, partly functional cell that may be capable of proliferating and developing into cancer, especially if tumor suppressor genes were damaged by the radiation. Three independent stages appear to be involved in the creation of cancer with ionizing radiation: morphological changes to the cell, acquiring cellular immortality (losing normal, life-limiting cell regulatory processes), and adaptations that favor formation of a tumor. Even if the radiation particle does not strike the DNA directly, it triggers responses from cells that indirectly increase the likelihood of mutations.

Non-ionizing radiation

Squamous cell carcinoma on the sun-exposed skin of the nose.

 

Not all types of electromagnetic radiation are carcinogenic. Low-energy waves on the electromagnetic spectrum including radio waves, microwaves, infrared radiation and visible light are thought not to be because they have insufficient energy to break chemical bonds. Non-ionizing radio frequency radiation from mobile phones, electric power transmission, and other similar sources have been described as a possible carcinogen by the World Health Organization's International Agency for Research on Cancer. However, studies have not found a consistent link between cell phone radiation and cancer risk.

Higher-energy radiation, including ultraviolet radiation (present in sunlight), x-rays, and gamma radiation, generally is carcinogenic, if received in sufficient doses. Prolonged exposure to ultraviolet radiation from the sun can lead to melanoma and other skin malignancies. The vast majority of non-invasive cancers are non-melanoma skin cancers caused by non-ionizing ultraviolet radiation. Clear evidence establishes ultraviolet radiation, especially the non-ionizing medium wave UVB, as the cause of most non-melanoma skin cancers, which are the most common forms of cancer in the world.

Ionizing radiation

Cross section of a meningioma displacing the underlying brain.

 

Sources of ionizing radiation include medical imaging, and radon gas. Ionizing radiation is not a particularly strong mutagen. Medical use of ionizing radiation is a growing source of radiation-induced cancers. Ionizing radiation may be used to treat other cancers, but this may, in some cases, induce a second form of cancer. Radiation can cause cancer in most parts of the body, in all animals, and at any age, although radiation-induced solid tumors usually take 10–15 years, and can take up to 40 years, to become clinically manifest, and radiation-induced leukemias typically require 2–10 years to appear. Radiation-induced meningiomas are an uncommon complication of cranial irradiation. Some people, such as those with nevoid basal cell carcinoma syndrome or retinoblastoma, are more susceptible than average to developing cancer from radiation exposure. Children and adolescents are twice as likely to develop radiation-induced leukemia as adults; radiation exposure before birth has ten times the effect.

Ionizing radiation is also used in some kinds of medical imaging. In industrialized countries, medical imaging contributes almost as much radiation dose to the public as natural background radiation. Nuclear medicine techniques involve the injection of radioactive pharmaceuticals directly into the bloodstream. Radiotherapy deliberately deliver high doses of radiation to tumors and surrounding tissues as a form of disease treatment. It is estimated that 0.4% of cancers in 2007 in the United States are due to CTs performed in the past and that this may increase to as high as 1.5–2% with rates of CT usage during this same time period.

Residential exposure to radon gas has similar cancer risks as passive smoking. Low-dose exposures, such as living near a nuclear power plant, are generally believed to have no or very little effect on cancer development. Radiation is a more potent source of cancer when it is combined with other cancer-causing agents, such as radon gas exposure plus smoking tobacco.

Rare causes

Organ transplantation

Malignant melanoma metastases in a heart.

 

The development of donor-derived tumors from organ transplants is exceedingly rare. The main cause of organ transplant associated tumors seems to be malignant melanoma, that was undetected at the time of organ harvest. There have also been reports of Kaposi's sarcoma occurring after transplantation due to tumorous outgrowth of virus-infected donor cells.

Trauma

Physical trauma resulting in cancer is relatively rare. Claims that breaking bones resulted in bone cancer, for example, have never been proven. Similarly, physical trauma is not accepted as a cause for cervical cancer, breast cancer, or brain cancer. One accepted source is frequent, long-term application of hot objects to the body. It is possible that repeated burns on the same part of the body, such as those produced by kanger and kairo heaters (charcoal hand warmers), may produce skin cancer, especially if carcinogenic chemicals are also present. Frequently drinking scalding hot tea may produce esophageal cancer. Generally, it is believed that the cancer arises, or a pre-existing cancer is encouraged, during the process of repairing the trauma, rather than the cancer being caused directly by the trauma. However, repeated injuries to the same tissues might promote excessive cell proliferation, which could then increase the odds of a cancerous mutation.

Maternal-fetal transmission

In the United States, approximately 3,500 pregnant women have a malignancy annually, and transplacental transmission of acute leukemia, lymphoma, melanoma and carcinoma from mother to fetus has been observed. Excepting the rare transmissions that occur with pregnancies and only a marginal few organ donors, cancer is generally not a transmissible disease. The main reason for this is tissue graft rejection caused by MHCincompatibility. In humans and other vertebrates, the immune system uses MHC antigens to differentiate between "self" and "non-self" cells because these antigens are different from person to person. When non-self antigens are encountered, the immune system reacts against the appropriate cell. Such reactions may protect against tumor cell engraftment by eliminating implanted cells.

Radiation-induced cancer

From Wikipedia, the free encyclopedia

Up to 10% of invasive cancers are related to radiation exposure, including both ionizing radiation and non-ionizing radiation. Additionally, the vast majority of non-invasive cancers are non-melanoma skin cancers caused by non-ionizing ultraviolet radiation. Ultraviolet's position on the electromagnetic spectrum is on the boundary between ionizing and non-ionizing radiation. Non-ionizing radio frequency radiation from mobile phones, electric power transmission, and other similar sources have been described as a possible carcinogen by the World Health Organization's International Agency for Research on Cancer, but the link remains unproven.

Exposure to ionizing radiation is known to increase the future incidence of cancer, particularly leukemia. The mechanism by which this occurs is well understood, but quantitative models predicting the level of risk remain controversial. The most widely accepted model posits that the incidence of cancers due to ionizing radiation increases linearly with effective radiation dose at a rate of 5.5% per sievert. If the linear model is correct, then natural background radiation is the most hazardous source of radiation to general public health, followed by medical imaging as a close second.

Causes

According to the prevalent model, any radiation exposure can increase the risk of cancer. Typical contributors to such risk include natural background radiation, medical procedures, occupational exposures, nuclear accidents, and many others. Some major contributors are discussed below.

Radon

Radon is responsible for the worldwide majority of the mean public exposure to ionizing radiation. It is often the single largest contributor to an individual's background radiation dose, and is the most variable from location to location. Radon gas from natural sources can accumulate in buildings, especially in confined areas such as attics, and basements. It can also be found in some spring waters and hot springs.

Epidemiological evidence shows a clear link between lung cancer and high concentrations of radon, with 21,000 radon-induced U.S. lung cancer deaths per year—second only to cigarette smoking—according to the United States Environmental Protection Agency. Thus in geographic areas where radon is present in heightened concentrations, radon is considered a significant indoor air contaminant. 

Residential exposure to radon gas has similar cancer risks as passive smoking. Radiation is a more potent source of cancer when it is combined with other cancer-causing agents, such as radon gas exposure plus smoking tobacco.

Medical

In industrialized countries, Medical imaging contributes almost as much radiation dose to the public as natural background radiation. Collective dose to Americans from medical imaging grew by a factor of six from 1990 to 2006, mostly due to growing use of 3D scans that impart much more dose per procedure than traditional radiographs. CT scans alone, which account for half the medical imaging dose to the public, are estimated to be responsible for 0.4% of current cancers in the United States, and this may increase to as high as 1.5-2% with 2007 rates of CT usage; however, this estimate is disputed. Other nuclear medicine techniques involve the injection of radioactive pharmaceuticals directly into the bloodstream, and radiotherapy treatments deliberately deliver lethal doses (on a cellular level) to tumors and surrounding tissues.

It has been estimated that CT scans performed in the US in 2007 alone will result in 29,000 new cancer cases in future years. This estimate is criticized by the American College of Radiology (ACR), which maintains that the life expectancy of CT scanned patients is not that of the general population and that the model of calculating cancer is based on total-body radiation exposure and thus faulty.

Occupational

In accordance with ICRP recommendations, most regulators permit nuclear energy workers to receive up to 20 times more radiation dose than is permitted for the general public. Higher doses are usually permitted when responding to an emergency. The majority of workers are routinely kept well within regulatory limits, while a few essential technicians will routinely approach their maximum each year. Accidental overexposures beyond regulatory limits happen globally several times a year. Astronauts on long missions are at higher risk of cancer, see cancer and spaceflight. 

Some occupations are exposed to radiation without being classed as nuclear energy workers. Airline crews receive occupational exposures from cosmic radiation because of reduced atmospheric shielding at altitude. Mine workers receive occupational exposures to radon, especially in uranium mines. Anyone working in a granite building, such as the US Capitol, is likely to receive a dose from natural uranium in the granite.

Accidental

Chernobyl radiation map from 1996

 

Nuclear accidents can have dramatic consequences to their surroundings, but their global impact on cancer is less than that of natural and medical exposures.

The most severe nuclear accident is probably the Chernobyl disaster. In addition to conventional fatalities and acute radiation syndrome fatalities, nine children died of thyroid cancer, and it is estimated that there may be up to 4,000 excess cancer deaths among the approximately 600,000 most highly exposed people. Of the 100 million curies (4 exabecquerels) of radioactive material, the short lived radioactive isotopes such as ¹³¹I Chernobyl released were initially the most dangerous. Due to their short half-lives of 5 and 8 days they have now decayed, leaving the more long-lived ¹³⁷Cs (with a half-life of 30.07 years) and ⁹⁰Sr (with a half-life of 28.78 years) as main dangers.

In March 2011, an earthquake and tsunami caused damage that led to explosions and partial meltdowns at the Fukushima I Nuclear Power Plant in Japan. Significant release of radioactive material took place following hydrogen explosions at three reactors, as technicians tried to pump in seawater to keep the uranium fuel rods cool, and bled radioactive gas from the reactors in order to make room for the seawater. Concerns about the large-scale release of radioactivity resulted in 20 km exclusion zone being set up around the power plant and people within the 20–30 km zone being advised to stay indoors. On March 24, 2011, Japanese officials announced that "radioactive iodine-131 exceeding safety limits for infants had been detected at 18 water-purification plants in Tokyo and five other prefectures".

Other serious radiation accidents include the Kyshtym disaster (estimated 49 to 55 cancer deaths), and the Windscale fire (an estimated 33 cancer deaths).

Mechanism

Cancer is a stochastic effect of radiation, meaning that the probability of occurrence increases with effective radiation dose, but the severity of the cancer is independent of dose. The speed at which cancer advances, the prognosis, the degree of pain, and every other feature of the disease are not functions of the radiation dose to which the person is exposed. This contrasts with the deterministic effects of acute radiation syndrome which increase in severity with dose above a threshold. Cancer starts with a single cell whose operation is disrupted. Normal cell operation is controlled by the chemical structure of DNA molecules, also called chromosomes. 

When radiation deposits enough energy in organic tissue to cause ionization, this tends to break molecular bonds, and thus alter the molecular structure of the irradiated molecules. Less energetic radiation, such as visible light, only causes excitation, not ionization, which is usually dissipated as heat with relatively little chemical damage. Ultraviolet light is usually categorized as non-ionizing, but it is actually in an intermediate range that produces some ionization and chemical damage. Hence the carcinogenic mechanism of ultraviolet radiation is similar to that of ionizing radiation. 

Unlike chemical or physical triggers for cancer, penetrating radiation hits molecules within cells randomly. Molecules broken by radiation can become highly reactive free radicals that cause further chemical damage. Some of this direct and indirect damage will eventually impact chromosomes and epigenetic factors that control the expression of genes. Cellular mechanisms will repair some of this damage, but some repairs will be incorrect and some chromosome abnormalities will turn out to be irreversible. 

DNA double-strand breaks (DSBs) are generally accepted to be the most biologically significant lesion by which ionizing radiation causes cancer. In vitro experiments show that ionizing radiation cause DSBs at a rate of 35 DSBs per cell per Gray, and removes a portion of the epigenetic markers of the DNA, which regulate the gene expression. Most of the induced DSBs are repaired within 24h after exposure, however, 25% of the repaired strands are repaired incorrectly and about 20% of fibroblast cells that were exposed to 200 mGy died within 4 days after exposure. A portion of the population possess a flawed DNA repair mechanism, and thus suffer a greater insult due to exposure to radiation.

Major damage normally results in the cell dying or being unable to reproduce. This effect is responsible for acute radiation syndrome, but these heavily damaged cells cannot become cancerous. Lighter damage may leave a stable, partly functional cell that may be capable of proliferating and eventually developing into cancer, especially if tumor suppressor genes are damaged. The latest research suggests that mutagenic events do not occur immediately after irradiation. Instead, surviving cells appear to have acquired a genomic instability which causes an increased rate of mutations in future generations. The cell will then progress through multiple stages of neoplastic transformation that may culminate into a tumor after years of incubation. The neoplastic transformation can be divided into three major independent stages: morphological changes to the cell, acquisition of cellular immortality (losing normal, life-limiting cell regulatory processes), and adaptations that favor formation of a tumor.

In some cases, a small radiation dose reduces the impact of a subsequent, larger radiation dose. This has been termed an 'adaptive response' and is related to hypothetical mechanisms of hormesis.

A latent period of decades may elapse between radiation exposure and the detection of cancer. Those cancers that may develop as a result of radiation exposure are indistinguishable from those that occur naturally or as a result of exposure to other carcinogens. Furthermore, National Cancer Institute literature indicates that chemical and physical hazards and lifestyle factors, such as smoking, alcohol consumption, and diet, significantly contribute to many of these same diseases. Evidence from uranium miners suggests that smoking may have a multiplicative, rather than additive, interaction with radiation. Evaluations of radiation's contribution to cancer incidence can only be done through large epidemiological studies with thorough data about all other confounding risk factors.

Skin cancer

Prolonged exposure to ultraviolet radiation from the sun can lead to melanoma and other skin malignancies. Clear evidence establishes ultraviolet radiation, especially the non-ionizing medium wave UVB, as the cause of most non-melanoma skin cancers, which are the most common forms of cancer in the world.

Skin cancer may occur following ionizing radiation exposure following a latent period averaging 20 to 40 years. A Chronic radiation keratosis is a precancerous keratotic skin lesion that may arise on the skin many years after exposure to ionizing radiation. Various malignancies may develop, most frequency basal-cell carcinoma followed by squamous-cell carcinoma. Elevated risk is confined to the site of radiation exposure. Several studies have also suggested the possibility of a causal relationship between melanoma and ionizing radiation exposure. The degree of carcinogenic risk arising from low levels of exposure is more contentious, but the available evidence points to an increased risk that is approximately proportional to the dose received. Radiologists and radiographers are among the earliest occupational groups exposed to radiation. It was the observation of the earliest radiologists that led to the recognition of radiation-induced skin cancer—the first solid cancer linked to radiation—in 1902. While the incidence of skin cancer secondary to medical ionizing radiation was higher in the past, there is also some evidence that risks of certain cancers, notably skin cancer, may be increased among more recent medical radiation workers, and this may be related to specific or changing radiologic practices. Available evidence indicates that the excess risk of skin cancer lasts for 45 years or more following irradiation.

Epidemiology

Cancer is a stochastic effect of radiation, meaning that it only has a probability of occurrence, as opposed to deterministic effects which always happen over a certain dose threshold. The consensus of the nuclear industry, nuclear regulators, and governments, is that the incidence of cancers due to ionizing radiation can be modeled as increasing linearly with effective radiation dose at a rate of 5.5% per sievert. Individual studies, alternate models, and earlier versions of the industry consensus have produced other risk estimates scattered around this consensus model. There is general agreement that the risk is much higher for infants and fetuses than adults, higher for the middle-aged than for seniors, and higher for women than for men, though there is no quantitative consensus about this. This model is widely accepted for external radiation, but its application to internal contamination is disputed. For example, the model fails to account for the low rates of cancer in early workers at Los Alamos National Laboratory who were exposed to plutonium dust, and the high rates of thyroid cancer in children following the Chernobyl accident, both of which were internal exposure events. The European Committee on Radiation Risk calls the ICRP model "fatally flawed" when it comes to internal exposure.

Radiation can cause cancer in most parts of the body, in all animals, and at any age, although radiation-induced solid tumors usually take 10–15 years, and can take up to 40 years, to become clinically manifest, and radiation-induced leukemias typically require 2–9 years to appear. Some people, such as those with nevoid basal cell carcinoma syndrome or retinoblastoma, are more susceptible than average to developing cancer from radiation exposure. Children and adolescents are twice as likely to develop radiation-induced leukemia as adults; radiation exposure before birth has ten times the effect.

Radiation exposure can cause cancer in any living tissue, but high-dose whole-body external exposure is most closely associated with leukemia, reflecting the high radiosensitivity of bone marrow. Internal exposures tend to cause cancer in the organs where the radioactive material concentrates, so that radon predominantly causes lung cancer, iodine-131 for thyroid cancer is most likely to cause leukemia.

Data sources

Increased Risk of Solid Cancer with Dose for A-bomb survivors

 

The associations between ionizing radiation exposure and the development of cancer are based primarily on the "LSS cohort" of Japanese atomic bomb survivors, the largest human population ever exposed to high levels of ionizing radiation. However this cohort was also exposed to high heat, both from the initial nuclear flash of infrared light and following the blast due their exposure to the firestorm and general fires that developed in both cities respectively, so the survivors also underwent Hyperthermia therapy to various degrees. Hyperthermia, or heat exposure following irradiation is well known in the field of radiation therapy to markedly increase the severity of free-radical insults to cells following irradiation. Presently however no attempts have been made to cater for this confounding factor, it is not included or corrected for in the dose-response curves for this group.

Additional data has been collected from recipients of selected medical procedures and the 1986 Chernobyl disaster. There is a clear link (see the UNSCEAR 2000 Report, Volume 2: Effects) between the Chernobyl accident and the unusually large number, approximately 1,800, of thyroid cancers reported in contaminated areas, mostly in children.

For low levels of radiation, the biological effects are so small they may not be detected in epidemiological studies. Although radiation may cause cancer at high doses and high dose rates, public health data regarding lower levels of exposure, below about 10 mSv (1,000 mrem), are harder to interpret. To assess the health impacts of lower radiation doses, researchers rely on models of the process by which radiation causes cancer; several models that predict differing levels of risk have emerged. 

Studies of occupational workers exposed to chronic low levels of radiation, above normal background, have provided mixed evidence regarding cancer and transgenerational effects. Cancer results, although uncertain, are consistent with estimates of risk based on atomic bomb survivors and suggest that these workers do face a small increase in the probability of developing leukemia and other cancers. One of the most recent and extensive studies of workers was published by Cardis, et al. in 2005 . There is evidence that low level, brief radiation exposures are not harmful.

Modelling

Alternative assumptions for the extrapolation of the cancer risk vs. radiation dose to low-dose levels, given a known risk at a high dose: supra-linearity (A), linear (B), linear-quadratic (C) and hormesis (D).

 

The linear dose-response model suggests that any increase in dose, no matter how small, results in an incremental increase in risk. The linear no-threshold model (LNT) hypothesis is accepted by the International Commission on Radiological Protection (ICRP) and regulators around the world. According to this model, about 1% of the global population develop cancer as a result of natural background radiation at some point in their lifetime. For comparison, 13% of deaths in 2008 are attributed to cancer, so background radiation could plausibly be a small contributor.

Many parties have criticized the ICRP's adoption of the linear no-threshold model for exaggerating the effects of low radiation doses. The most frequently cited alternatives are the “linear quadratic” model and the “hormesis” model. The linear quadratic model is widely viewed in radiotherapy as the best model of cellular survival, and it is the best fit to leukemia data from the LSS cohort.

Linear no-threshold	F(D)=α⋅D
Linear quadratic	F(D)=α⋅D+β⋅D2
Hormesis	F(D)=α⋅[D−β]

In all three cases, the values of alpha and beta must be determined by regression from human exposure data. Laboratory experiments on animals and tissue samples is of limited value. Most of the high quality human data available is from high dose individuals, above 0.1 Sv, so any use of the models at low doses is an extrapolation that might be under-conservative or over-conservative. There is not enough human data available to settle decisively which of these model might be most accurate at low doses. The consensus has been to assume linear no-threshold because it the simplest and most conservative of the three. 

Radiation hormesis is the conjecture that a low level of ionizing radiation (i.e., near the level of Earth's natural background radiation) helps "immunize" cells against DNA damage from other causes (such as free radicals or larger doses of ionizing radiation), and decreases the risk of cancer. The theory proposes that such low levels activate the body's DNA repair mechanisms, causing higher levels of cellular DNA-repair proteins to be present in the body, improving the body's ability to repair DNA damage. This assertion is very difficult to prove in humans (using, for example, statistical cancer studies) because the effects of very low ionizing radiation levels are too small to be statistically measured amid the "noise" of normal cancer rates.

The idea of radiation hormesis is considered unproven by regulatory bodies. If the hormesis model turns out to be accurate, it is conceivable that current regulations based on the LNT model will prevent or limit the hormetic effect, and thus have a negative impact on health.

Other non-linear effects have been observed, particularly for internal doses. For example, iodine-131 is notable in that high doses of the isotope are sometimes less dangerous than low doses, since they tend to kill thyroid tissues that would otherwise become cancerous as a result of the radiation. Most studies of very-high-dose I-131 for treatment of Graves disease have failed to find any increase in thyroid cancer, even though there is linear increase in thyroid cancer risk with I-131 absorption at moderate doses.

Public safety

Low-dose exposures, such as living near a nuclear power plant or a coal-fired power plant, which has higher emissions than nuclear plants, are generally believed to have no or very little effect on cancer development, barring accidents. Greater concerns include radon in buildings and overuse of medical imaging. 

The International Commission on Radiological Protection (ICRP) recommends limiting artificial irradiation of the public to an average of 1 mSv (0.001 Sv) of effective dose per year, not including medical and occupational exposures. For comparison, radiation levels inside the US capitol building are 0.85 mSv/yr, close to the regulatory limit, because of the uranium content of the granite structure. According to the ICRP model, someone who spent 20 years inside the capitol building would have an extra one in a thousand chance of getting cancer, over and above any other existing risk. (20 yr X 0.85 mSv/yr X 0.001 Sv/mSv X 5.5%/Sv = ~0.1%) That "existing risk" is much higher; an average American would have a one in ten chance of getting cancer during this same 20-year period, even without any exposure to artificial radiation. 

Internal contamination due to ingestion, inhalation, injection, or absorption is a particular concern because the radioactive material may stay in the body for an extended period of time, "committing" the subject to accumulating dose long after the initial exposure has ceased, albeit at low dose rates. Over a hundred people, including Eben Byers and the radium girls, have received committed doses in excess of 10 Gy and went on to die of cancer or natural causes, whereas the same amount of acute external dose would invariably cause an earlier death by acute radiation syndrome.

Internal exposure of the public is controlled by regulatory limits on the radioactive content of food and water. These limits are typically expressed in becquerel/kilogram, with different limits set for each contaminant.

History

Although radiation was discovered in late 19th century, the dangers of radioactivity and of radiation were not immediately recognized. Acute effects of radiation were first observed in the use of X-rays when Wilhelm Röntgen intentionally subjected his fingers to X-rays in 1895. He published his observations concerning the burns that developed, though he attributed them to ozone rather than to X-rays. His injuries healed later. 

The genetic effects of radiation, including the effects on cancer risk, were recognized much later. In 1927 Hermann Joseph Muller published research showing genetic effects, and in 1946 was awarded the Nobel prize for his findings. Radiation was soon linked to bone cancer in the radium dial painters, but this was not confirmed until large-scale animal studies after World War II. The risk was then quantified through long-term studies of atomic bomb survivors. 

Before the biological effects of radiation were known, many physicians and corporations had begun marketing radioactive substances as patent medicine and radioactive quackery. Examples were radium enema treatments, and radium-containing waters to be drunk as tonics. Marie Curie spoke out against this sort of treatment, warning that the effects of radiation on the human body were not well understood. Curie later died of aplastic anemia, not cancer. Eben Byers, a famous American socialite, died of multiple cancers in 1932 after consuming large quantities of radium over several years; his death drew public attention to dangers of radiation. By the 1930s, after a number of cases of bone necrosis and death in enthusiasts, radium-containing medical products had nearly vanished from the market. 

In the United States, the experience of the so-called Radium Girls, where thousands of radium-dial painters contracted oral cancers, popularized the warnings of occupational health associated with radiation hazards. Robley D. Evans, at MIT, developed the first standard for permissible body burden of radium, a key step in the establishment of nuclear medicine as a field of study. With the development of nuclear reactors and nuclear weapons in the 1940s, heightened scientific attention was given to the study of all manner of radiation effects.