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Die Hauptursachen für Krebs (einschließlich gefährlicher Umstände)

1. What are the main causes of cancer?

    Main causes of cancer, including hazardous circumstances are:

    2. Tobacco products
    3. Infectious agents
    4. Alcohol consumption
    5. Sunlight and ultraviolet radiation
    6. Ionizing radiation and radiofrequency electromagnetic fields including mobile phones
    7. Diet and nutrition
    8. Physical activity, sedentary behaviour and obesity
    9. Dietary carcinogens
    10. Contamination of air, water, soil, and food
    11. Occupational exposure
    12. Pharmaceutical drugs

    2. Tobacco products

      Tobacco products are projected to cause 1 billion deaths this century, many from cancer. Tobacco use is estimated to cause 22% of cancers worldwide and contributes to multiple other diseases. They are now mostly consumed worldwide in low- and middle-income countries in the form of smoked products. Laboratory studies can currently measure the carcinogen yield of novel electronic nicotine delivery systems and biomarkers of exposure among users but they cannot yet determine the potential long-term effects of these products on cancer risk.

      3. Infectious agents and chronic infections

        Infectious agents and chronic infections are the cause of about 13% of cancers worldwide, or 2.2 million cases per year, particularly in low- and middle-income countries such as in sub-Saharan Africa, which have limited ability to manage the disease, especially for cervical cancers caused by human papilloma viruses (HPV). Eleven infectious agents, or groups of related agents, including one bacterium, seven viruses, and three macro-parasites, are established human carcinogens (group 1).

        • The bacterium Helicobacter pylori was estimated to be responsible for about 800 000 new cancer cases in 2018, including 89% of non-cardia gastric cancers, 74% of gastric non-Hodgkin lymphoma and 29% of cardia gastric cancers in East Asia. Treatment by a combination of anti-microbial drugs is potentially preventive;
        • Thirteen sexually transmitted mucosal human papillomavirus subtypes are established human carcinogens. They are responsible for the 570 000 cervical cancer cases and of a variable proportion of cases of other anogenital and oropharyngeal cancers (totalling 120 000 cases). Vaccination against human papillomaviruses occurs in more than 80 countries;
        • Chronic infection with hepatitis B virus and hepatitis C virus resulted in about 360 000 cases and 140 000 cases, respectively, of hepatocellular carcinoma in 2018, amounting to about 76% of all cases of hepatocellular carcinoma. Preventive vaccines against hepatitis B virus have been available since 1982, and direct-acting antiviral agents have the potential to cure more than 95% of people with hepatitis C virus infection.

        Some infections with macroparasites (Schistosoma haematobium, Opisthorchis viverrini, and Clonorchis sinensis , are significant causes of cancer in endemic populations. Epstein–Barr virus, HIV, and macroparasites, also cause substantial morbidity and mortality but from non-malignant diseases.

        If existing strategies for prevention were more widely applied and new infection control strategies developed, the global cancer burden could be greatly reduced.

        4. Alcohol consumption

          Alcohol consumption is associated to a proportion of cancer deaths which varies by age group and which in 2016 ranged from about 14% of cancer deaths among people aged 30–34 years to 2.7% of cancer deaths among people aged 80–84 years, representing globally 3.0 million deaths from all causes worldwide, representing 5.3% of all deaths and 4.2% of all cancer deaths.

          Alcoholic beverages contain numerous carcinogenic compounds, but the majority of the risk relationship between alcohol consumption and the development of cancer is due to ethanol through various pathophysiological carcinogenic mechanisms. In particular, people with an enzymatic variant that is prevalent in eastern Asian populations have a higher risk of cancers of the upper aero-digestive tract and of colorectal cancer.

          Alcohol consumption causes cancers of the oral cavity, oropharynx, hypopharynx, oesophagus ( squamous cell carcinoma ), colon, rectum, liver and intrahepatic bile duct, larynx, and female breast (both premenopausal and postmenopausal). The risk relationships depend mainly on the level of lifetime exposure to alcohol. On the other hand, there is probable evidence that alcohol consumption is associated with a decreased risk of kidney cancer among people with light and moderate alcohol consumption that may be due to improved insulin sensitivity, improved blood lipid profiles and higher adiponectin levels. More research is also needed to further establish and quantify any indirect effect of alcohol on an increased risk of cancers caused by infectious diseases.

          Meanwhile, despite the evidence of the causal relationship between alcohol consumption and the development of cancer, it appears that the majority of the general population is unaware of this causal link. Warning labels could thus be more used to raise awareness of the link between alcohol and cancer.

          5. Ultraviolet radiation

            Ultraviolet radiation, besides its beneficial biological effects including enabling vitamin D synthesis, generate reactive oxygen species which, directly and indirectly, induce increased DNA lesions and mutations, trigger inflammation and immunosuppression, which mediate skin tumour growth.

            Furthermore, the process of photo-carcinogenesis is a complicated, multistep pathway which, via also via lipid peroxidation caused by ultraviolet radiation and reactive oxygen species, leads to the failure of immuno-surveillance and enables the cancer cells to grow and progress. In this context, people who are taking immuno-suppressants or some other kinds of medication, including voriconazole and hydrochlorothiazide, should be careful to protect particularly themselves from exposure to sunlight.

            The main source of human exposure to UV radiation is solar radiation. In addition, many people have been exposed through the use of tanning devices (sunlamps and sunbeds), which are artificial sources of UV radiation; this warrants concern for human health.

            The IARC Monographs classified UV-emitting tanning devices (sunlamps and sunbeds) as “ Carcinogenic to humans ” (Group 1). Although commercial use of tanning devices is prohibited in some states of the USA, in almost all states and territories of Australia and in some other countries, many people continue to use them. Until recently, studies on carcinogenesis induced by UV radiation have focused on UVB-induced DNA mutations. However, the role of UVA in photo-carcinogenesis now receiving much more attention.

            The incidence of skin cancers, both melanoma and non-melanoma, is increasing worldwide, and especially in older people, not only in White populations but also in Asian populations. The most effective way to reduce skin cancer incidence is to avoid unnecessary sun exposure, to use protective measures when in the sun, and to avoid tanning devices.

            There is also an experimental basis for the epidemiological evidence that childhood sunburn is a major risk factor for the development of melanoma. In Asian people, the UV signature mutations are significantly more frequent in skin cancers at sun-exposed body sites than in those at non-sun-exposed sites, suggesting that UV radiation is also closely involved in the development of non-melanoma skin cancer in Asian people.

            6. Ionizing radiations

              Ionizing radiations : X rays and gamma rays and energetic subatomic particles (neutrons, β-particles and α-particles).

              • Natural radiation exposure (80% to the average total dose) comes from four main sources: cosmic radiation, terrestrial radiation, ingestion of radionuclides that are present in the soil and ground, and inhalation of radon (which represents about half of the average exposure to natural radiation sources);
              • Artificial radiations exposures (the remaining 20%) include medical diagnostic procedures such as radiography, nuclear medicine, computed tomography, treatment by radiotherapy for cancer but also fallout from weapons testing, nuclear power plant accidents (such as those at Chernobyl and Fukushima), and routine releases from nuclear installations.

              Exposure of people to low levels from the environment (natural and artificial sources), occupations, or medical diagnostic procedures is demonstrated to increase the risk of leukaemia and other cancers with radiation dose.

              The latency between exposure to ionizing radiation and occurrence of an excess risk of cancer varies from several years to several decades. In addition, host factors such as age at exposure, attained age and sex, modify the dose–risk relationship. Ionizing radiation is one of the most intensely studied carcinogens.

              The mechanisms by which radiation may produce carcinogenic changes include mutations, alterations in the structure of genes or chromosomes and changes in gene expression. The latency between exposure to ionizing radiation and occurrence of an excess risk of cancer varies from several years to several decades. In addition, host factors such as age at exposure, attained age, and sex, modify the dose–risk relationship. There is a statistically significant dose–response relationship between leukaemia and the cumulative dose to the red bone marrow due to background radiation exposure, but there is no clear evidence of a relationship for other childhood cancers.

              Recent results from atomic bomb survivors confirmed the existence of a dose– risk relationship for a large variety of cancer types, such as leukaemia and cancer of the bladder, breast, colon, liver, lung, skin, stomach, and thyroid. Cohort studies showed a statistically significant dose–response relationship between the dose to the red bone marrow due to computed tomography examinations and the risk of leukaemia, and between the dose to the brain and the risk of brain tumours.

              For ionizing radiation among nuclear workers, analyses demonstrated a significant association between the dose to the red bone marrow and the risk of leukaemia (excluding chronic lymphoblastic leukaemia), and between the dose to the colon and the risk of solid cancer.

              After the Chernobyl nuclear plant in Ukraine, results confirmed the excess risk of thyroid cancer associated with exposure to iodine131 among people exposed during childhood, and demonstrated the persistence of this excess risk among people who are now adults.

              By contrast, no observable radiation-induced excess risk of cancer is expected after the Fukushima accident given the preventive measures taken, such as evacuation and food restrictions, which resulted in much lower thyroid doses to the resident populations than after the Chernobyl accident. Indeed, the estimated doses are low and are limited to a small population.

              Mobile phone use , according to most epidemiological studies, is not associated to tumours occurring in the head, which is the body part with the highest exposure to radiofrequency electromagnetic fields, notwithstanding simple calculations show that some of excess risks for brain tumours would have been noticed by now with the large proportion of the population having used a mobile phone for a few hundred hours. In studies reporting positive associations, it is difficult to exclude various forms of bias and, despite considerable research efforts, no mechanism relevant for carcinogenesis of radiofrequency electromagnetic fields has been consistently identified to date.

              Several clusters of childhood cancer reported in the vicinity of individual transmitters could not be confirmed in large population-based studies on childhood cancer in relation with emissions from broadcast transmitters and mobile phone base stations (Radio Frequency-Electro-Magnetic Fields or (RF-EMF).

              However, what the situation will be for the Long-Term Evolution network (4G)1 or for 5G is not yet known. Given the research uncertainties, precautionary measures can be taken; the simplest and the most effective one is to hold the mobile phone away from the body during transmission, resulting in a substantial reduction in exposure.

              1 https://en.wikipedia.org/wiki/LTE_(telecommunication) 

              7. Diet and nutrition influence

                Diet and nutrition influence on cancer risk have multiple aspects, some adverse and some beneficial. Overweight and obesity which are major risk factors for many cancer types are probably the most important account for much of the impact of diet.

                Although it is unknown which aspects may be related to cancer risk, possible factors include excess sugar and energy, low dietary fibre and micronutrients, added preservatives and other ingredients, carcinogens formed during processing, and/or lifestyle correlates of highly processed foods, such as sedentary behaviours. These factors were estimated to account for approximately 5% of cancer deaths in the USA and 9% in the UK.

                Therefore, an overall healthy dietary pattern that emphasizes avoidance of alcohol and sugar-sweetened beverages and replacement of refined carbohydrates with whole-grain alternatives to refined grains is particularly important. This together with limiting consumption of salt, red meat and especially processed meat, can decrease the risk of colorectal cancer.

                The Alternate Healthy Eating Index2, a measure of diet quality, represents an overall healthy dietary pattern. The high scores in some Mediterranean countries are consistent with the well-documented health benefits of the traditional diets of these regions.

                While generous consumption of fruits and vegetables has less impact on cancer risk than was thought earlier, even if some benefits exist, plant sources of protein and fat will reduce risk of cancer as well as of cardio-metabolic diseases, diabetes, and overall mortality. Although the results are spare, recent findings support benefit from adopting a similar dietary pattern as for prevention after cancer diagnosis for at least some cancer types. Potential, but as yet unproven, effects of the microbiome are currently a topic of great interest.

                Coffee consumption may lower the risk of liver cancer and endometrial cancer and possibly other cancer types, as recent research suggests and contrary to studies reported in the 1970s.

                Besides, although randomized trials would be desirable to confirm a protective effect of taking vitamin D for prevention particularly of colorectal cancer, the potential role of vitamin D in lowering this risk is of great interest.

                2 World Cancer Report, page 98 and https://doi.org/10.1093/jn/nxz010 

                8. Physical activity, sedentary behaviour and obesity

                  Physical activity, sedentary behaviour and obesity represent from 20 to 40% for all cancers. Strong epidemiological evidence from more than 450 epidemiological studies shows that being physically active reduces the risk of many types of cancer: bladder, breast, colon, endometrium, kidney, oesophagus, and stomach, and also cancer in association with obesity: postmenopausal, colo-rectum, endometrium, kidney, liver, oesophagus, and pancreas.

                  Moderate evidence exists for an association with cancers of the gall bladder, mouth, pharynx, larynx, ovary, prostate (advanced), and stomach, and emerging evidence further suggests that sedentary behaviour is associated with other increased risk of cancers of the breast, colon, endometrium, and lung.

                  Several common biological mechanisms are likely to be involved in the association between physical activity, sedentary behaviour, obesity and cancer risk. These include an effect on endogenous sex and metabolic hormones, insulin resistance, and chronic inflammation. Smoking and use of hormone replacement therapy are also being recognized as important effect modifiers of the association between obesity and cancer.

                  In general, individual behaviour change should lower personal risk of multiple non-communicable diseases, including cancer.

                  9. Dietary carcinogens

                    Dietary carcinogens include natural and single specific agents, such as aflatoxin, as well as complex mixtures, such as consumption of processed meat also recently classified by IARC as “ Carcinogenic to humans ” (Group 1).

                    For nearly 50 years, naturally occurring, cooking-derived and complex constituents of the diet have indeed been determined by many studies to be risk and causal factors for a wide variety of cancer types occurring at different organ sites in humans including cancers of the breast, colo-rectum, liver, pancreas, and prostate. However, the relative roles of individual agents or classes of chemical carcinogens in these products remain unresolved.

                    As highlighted previously, in many populations, the potential toxicological carcinogenic hazard from dietary carcinogens could be increased by the acceleration of the obesity pandemic and the rising incidence of type 2 diabetes, further illustrating the complexity of multiple chronic diseases contributing to the development of cancers.

                    Knowledge gleaned from mechanistic studies and epidemiological studies of dietary exposures are essential for the development of risk models from dietary exposures and has been successfully used in cancer prevention, particularly with respect to aflatoxin and liver cancer development.

                    The most challenging problems for future risk assessment analysis and for the informed deployment of prevention strategies remain the difficulty involved in exposure assessment, particularly across the lifespan, and whether exposure to dietary carcinogen factors of 20–40 years earlier continue to be risk factors for the cancers that will be diagnosed 20–40 years later.

                    10. Air, water, soil, and food contamination by environmental carcinogens

                      Air, water, soil, and food contamination by environmental carcinogens are widespread, and include a large number of agents emitted by different sources, mainly from fuel combustion for transportation, power generation, industrial activity, combustion of biomass and domestic heating and cooking are accounting for a substantial number of excess cancer cases:

                      • Air pollution , both outdoor and indoor, in particular including diesel engine exhaust, industrial processes and airborne particulate matter with particles of aerodynamic diameter less than 2.5 µm (PM 2.5) which is the eighth highest cause of death among the 84 risk factors in the Global Burden of Disease Study 2017. In 2017, 92% of the world’s population lived in areas that exceeded the WHO air quality guideline of 10 µg/m3 for outdoor PM 2.5. In the same time, results from a large cohort study of women in the USA indicated that surrounding greenness (vegetation) at the place of residence is associated with reduced cancer mortality;
                      • Indoor emissions from the household combustion of coal have been classified as “ Carcinogenic to humans ” (Group 1), and indoor emissions from the household combustion of biomass fuel3 are currently classified as “Probably carcinogenic to humans” (Group 2a); Other important contributors to indoor air pollution, from non-combustion sources, are radon and construction and building materials (glues, formaldehyde, lead in paint or pipes, and asbestos4) or second-hand tobacco smoke;
                      • Drinking-water, or water used for agricultural or recreational activities , polluted by naturally occurring carcinogenic contaminants (e.g. arsenic that causes lung cancer, bladder cancer, and skin cancer) or by anthropogenic pollutants (e.g. chlorinated agents, perfluorinated alkylated substances used as surfactants, and metals including cadmium, nickel and lead). Leaks from contaminated soils polluting water can also result in contamination of the food chain. While there is inadequate evidence in humans for the carcinogenicity of nitrate in drinking-water, ingested nitrate or nitrite under conditions that result in endogenous nitrosation is probably carcinogenic to humans;
                      • Persistent organic pollutants and heavy metals occurs mainly from foods of animal origin, because of bioaccumulation and biomagnification5;
                      • Endocrine disrupting chemicals that are present in the environment and are involved in cancer causation include dioxins, furans, polychlorinated biphenyls, various solvents, heavy metals, pesticides, cosmetics, plastics, and numerous chemicals in consumer products. The main cancer sites for which an etiological role of environmental endocrine disrupters has been suggested are the thyroid, together with the breast, testis, and prostate.

                      The impact of regulation can be seen as resulting in the relocation of certain industrial processes to low-income countries, exposing the local population to carcinogenic products or waste. International cooperation is needed to redress this phenomenon.

                      In assessing environmental exposures to complex chemical mixtures which are possibly related to cancer and other health effects, the so-called exposome approach which promotes systemic inter-disciplinarity in research, aims to assess and prevent health risks due to environmental exposures by integrating information on the external environment (contaminants, lifestyle factors, diet, socioeconomic status, etc.) and the internal environment (biological factors such as genetic and metabolic factors).

                      3 in India, 60% of the population; 32% in China, 79% in Bangladesh and 96% in the Democratic Republic of Congo.
                      4 To be noted that the available evidence on risk for inhabitants of asbestos-roofed houses is inadequate to assess risk of cancer.
                      5 which is the increasing concentration of a substance, such as a toxic chemical, in the tissues of organisms at successively higher levels in a food chain

                      11. Occupational circumstances and workplace exposure to several well-recognized carcinogens

                        Occupational circumstances and workplace exposure to several well-recognized carcinogens may be the cause of a substantial number of cancers as a large fraction of known human carcinogens are found in the workplace. Some of the carcinogens listed occur naturally, e.g. wood dust, solar radiation. Recognized carcinogens include chemical, physical, and biological agents of various families of agents. Some of the most frequent cancer types for which excess risk has been observed from one or more occupational carcinogens are lung cancer, bladder cancer, and skin cancer.

                        In general, it has been estimated that the fraction of cancer attributable to occupational exposures is between 2% and 8% in high-income countries. The estimates vary considerably among different types of cancer. The WHO Global Burden of Disease Study 2017 estimated that in 2017, about 334 000 cancer deaths were due to occupational exposures, and the major contributors were asbestos, crystalline silica, and diesel engine exhaust while that 5–7% of global deaths are attributable to work-related illnesses and occupational injuries.

                        To date, 38 occupational agents and 12 occupational exposure circumstances have been classified as carcinogenic to humans , and 41 occupational agents and 6 occupational exposure circumstances have been classified as probably carcinogenic to humans. The use of many of them such as asbestos, polycyclic aromatic hydrocarbons, heavy metals, diesel engine exhaust, certain metals involved in smelting and related work dust and crystalline silica is still widespread.

                        Among the challenges in discovering occupational carcinogens is that there is typically a long time period between exposure to carcinogens and onset of cancer, and therefore information is required about workers’ exposures many years before the onset of cancer.

                        Many successful regulations and programmes have been put in place during recent decades to eliminate or reduce exposure to carcinogens in the workplace. This particularly in high-income countries through the use of less hazardous materials, engineering controls, optimal procedures and training, and the use of personal protective equipment, together with the monitoring of exposure levels.

                        While little information is available on occupational cancer risk in low income countries, it can be reasonably expected to become a large problem in the future. Some particularly dirty and dangerous industrial work, like removing asbestos from ships that have been decommissioned, is now being performed in low-income countries. Furthermore, the rapid growth of industry in low- and middle-income countries is often unregulated and has inadequate occupational hygiene.

                        12. A range of pharmaceutical, in particular hormonal, drugs

                          A range of pharmaceutical, in particular hormonal, drugs has been recognized over decades as causing particular cancers among the people using them. However, given the long surveillance period required for any cancer risks or benefits to emerge, evaluating any possible cancer effects of pharmaceutical drugs is problematic, even if a drug is used by many people.

                          • Combined oral contraceptives , in particular combined estrogen–progestogen products use for 5 years or more, and their very long-term cancer effects can now be investigated, because the women who were the first users of these products in the 1960s are now entering later life. The IARC Monographs programme concluded indeed that there was sufficient evidence for combined hormonal contraceptives to be classified as carcinogenic to humans (Group 1), whereas progestogen-only contraceptives were classified as possibly carcinogenic to humans (Group 2B). Current or recent users of combined oral contraceptives have an increased risk of breast cancer, cervical cancer, and (in regions at low risk of hepatitis B virus infection) liver cancer.
                            By contrast, users of these combined oral contraceptives have a reduced risk of ovarian cancer; this protective effect increases with duration of use and persists for many years after stopping use. The risk of colorectal cancer may be reduced, although no consistent relationship has been found with duration or recency of use.
                          • Menopausal hormone therapy and a relationship with the risk of cancer of the ovary and colo-rectum has also been examined. The IARC Monographs programme concluded that estrogen-only menopausal hormone therapy is associated with cancer of the endometrium, ovary, and breast, and that combined estrogen–progestogen hormone therapy is associated with cancer of the breast and endometrium. By contrast, it is unlikely to increase the risk of colorectal cancer or alter the risk of ovarian cancer.
                            Evidence is also starting to emerge about the cancer risks associated with contemporary hormonal contraceptives, including new routes of delivery, new progestogens, and progestogen-only contraceptives.
                          • Fertility drugs do not appear to show a meaningful increase in the risk of breast cancer, invasive ovarian cancer, or endometrial cancer concluded the Practice Committee of the American Society for Reproductive Medicine on basis of the evidence available to date although there may be an increased risk of borderline ovarian tumours, any absolute risk is small. Meanwhile, studies examining these risks of cancer have many methodological challenges, particularly because sub-fertile women have an inherently increased cancer risk independent of any fertility treatments.
                          • Cytotoxic drugs , used in particular in chemotherapy either alone or in combination, may cause second cancers, and their use must consider these and other adverse effects;
                          • Diethylstilbestrol and phenacetin , have been among drugs withdrawn from widespread use as a result of cancer causation.

                          13. Are there cancer risks specifically associated to pesticides exposure?

                            Few studies are currently available that can evaluate associations between exposure to specific pesticides and risk of cancer. Despite widespread potential exposure, cancer risks associated with long-term exposure to specific pesticides are generally not well characterized.

                            Only one group of pesticides (inorganic arsenic compounds, which are not currently used), one pesticide contaminant (the dioxin 2,3,7,8-tetrachlorodibenzo-paradioxin), and two insecticides with limited current usage namely lindane and pentachlorophenol (PCP), PCP which is also used as a biocide, both not approved anymore in the EU and classified by the IARC Monographs as “ Carcinogenic to humans ” (Group 1).

                            Other pesticides including the fungicide captafol, DDT, malathion, diazinon and dieldrin, ethylene dibromide and the herbicide glyphosate are classified by IARC as “Probably carcinogenic to humans” (Group 2A).

                            Some issues include the seasonal nature of many exposures, which may be either indoor or outdoor, and the large number and types of agents as well as variability in exposure intensity, duration, and frequency, depending on the application and the purpose. In addition, most pesticides in use today have short half-lives, which are measured in days or even hours and work practices – including the amount and types of pesticides used – and application methods vary around the world.

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