Risk Factors and Cancer

Smoking. An estimate of 30% of all cancer deaths in the USA can be attributed to the use of tobacco and is still increasing reflecting smoking among young women since the 1950s. Tobacco smoke is a Group A carcinogen for which there is no known safe level of exposure. Smoking causes more than 90% of lung cancer and is a major cause of cancers of the larynx, mouth, esophagus, bladder, kidney and pancreas. About 25% of colon cancer, as well as precursors like polyps can be attributed to smoking. There may also be an association with cervical cancer. The cancer risk decreases after stopping smoking. Within 5 years of quitting the risk drops to half and after 10 – 15 years it drops to that of never-smokers. Nonsmokers are at increased risk of lung cancer and other diseases when exposed involuntarily to environmental tobacco smoke. Early onset of smoking, usually as a social event in adolescence, increases the risk of lung cancer, and continuing to smoke into adult years promotes the final stages of tumor formation and invasion into the surrounding lung. Reducing the epidemic of tobacco smoking is currently the most effective means for cancer prevention.

Diet and Obesity. An additional estimated 30% of all cancer deaths in the USA is attributable to diet and obesity in adults, but the details are complex and difficult to sort out. With breast cancer excess caloric intake in childhood and adolescence may increase risk, but these is no apparent association with the intake of fat in mid-life. A high vegetable consumption is protective, but two alcoholic drinks daily may increase risk by about 25%. For colorectal cancer high meat consumption doubles the risk, while consumption of vegetables and folic acid are protective. The role of fiber is uncertain, but high alcohol consumption is a risk factor. In the case of lung cancer green and yellow vegetables are protective for smokers, but no dietary factor can completely counter the adverse effects of smoking. Red meat is a possible risk factor for prostate cancer. Alcohol, especially with smoking, increases risk of esophageal cancer while fruits and vegetables seem to be protective. In Asia salted foods may give higher rates of stomach cancer while vegetables and fruit reduce its risk.

Adult obesity is an important cause of endometrial cancer and a cause also of postmenopausal breast cancer. It is also associated with cancers of the colon, rectum and kidney. Obesity is a well-established risk factor for stroke, cardiovascular disease and diabetes. Its relationship to cancer is poorly understood and complex. It acts in concert with other risks such as low activity level, menopausal status and predisposition to insulin resistance with subsequent higher circulating blood insulin levels. When an individual exceeds ideal body weight by 35 to 40% insulin sensitivity (effectiveness) drops 30 to 40%. Insulin and insulin-like growth factors (IGF) affect cell development and proliferation and act as growth factors for colonic mucosa, mammary tissue development and play a role in colon cancer development. Estradiol and IGF work together in the development of certain types of breast cancer. Women who are more than 35% above ideal body weight have a 55% higher chance of developing cancers of the gallbladder, breast, cervix, endometrium, uterus and ovary. Men who weigh more than 35% above ideal body weight have a 40% greater chance of developing colon and prostate cancer. In countries with high socioeconomic status the rate of breast cancer is 50 to 80 cases per 100,000 women and the rate of colon cancer is 25 to 35 per 100,000 people.

A diet that reduces cancer risk should be high in fruits and vegetables (cancers of the lung, stomach, esophagus and larynx), high in legumes and grains including bread, pasta and cereals (cancers of the stomach and pancreas), low in red meat (colorectal cancer), low in salt (stomach cancer), and low in saturated animal fat (prostate cancer). Added fats should be of plant origin and olive oil is particularly beneficial.

Exercise and sedentary lifestyle. Sedentary lifestyle may account for 5% of all cancer deaths. In both sexes physical activity reduces the risk of colon cancer while little or no exercise increases the risk two-fold. The evidence that physical activity prevents breast cancer is suggestive but not conclusive. Only high levels of physical activity may reduce prostate cancer.

Occupation. Occupational factors may account for 5% of all cancer deaths, mostly lung, bladder and bone marrow. Control through governmental regulations of occupational exposures to carcinogens in industrialized countries is an important and often underappreciated achievement for primary cancer prevention. The International Agency for Research on Cancer (IARC) in Lyons, France, has identified over 30 agents to be human carcinogens and another 10 as probable. Tobacco smoke is the most important carcinogen, but next to it the most important are workplace exposures. Some are relatively strong and can increase the rate of cancer by 10 to 100 times the rate in unexposed people, but most are weak with risk increases of five-fold or less. Body surfaces that have direct contact have the highest risk: externally the skin, nasal passages and lung, and internally the urinary bladder. Overall less than 5% of cancer in men and no more than 1% in women relates to occupational exposure. In men about 15% of lung cancer and about 10% each of skin and bladder cancers are occupationally caused.

Genetic Susceptibility. A family history of cancer accounts for perhaps 5% of total cancer deaths in the USA. For major types of cancer such as breast, colon, prostate and lung, the risk increase associated with a family history is 1.5 to 2 or 3 times. Susceptibility to cancer in certain individuals is due to genetic mutations running in families, resulting in about 2% of all fatal cancers. It is estimated that 5 to 10% of most types of cancer are due to defects in single genes that run in families. Cancer incidence also depends on genetic polymorphisms that affect the absorption, transport, metabolic activation, or detoxification of environmental carcinogens, and act as cancer-facilitating influences.

Infectious Agents. Viruses and other biologic agents account for about 5% of total cancer deaths in the USA. The tumors include lymphomas and cancers of the liver, nasopharynx, cervix and stomach as well as Helicobacter pylori (gastric cancer and even gastric lymphoma) and Schistosoma haematobium (urinary bladder cancer), and the multiple opportunistic malignancies associated with AIDS. These agents share the ability to establish latent and chronic infections with associated higher levels of viral or bacterial replication that increases the probability of causing secondary genetic damage to target tissues. The associated immune dysfunction assists the process. In some populations these infections are quite prevalent but malignancies are rare. Perhaps 5% of adult T-cell leukemias/lymphoma are due to human lymphotropic virus-type I (HTLV-I) characteristically in south Japan, central Africa and the South Pacific islands. Epstein-Barr Virus (EBV) accounts for 10-15% of non-Hodgkin’s lymphoma (Burkitts’ lymphoma: almost all in children in central Africa and 20% of cases occurring elsewhere), 35-50% of Hodgkin’s disease, and 40-70% of nasopharyngeal carcinoma (especially in southern Chinese). Hepatitis B virus (HBV) accounts for 40-60% of hepatocellular carcinoma and hepatitis C virus (HCV) for 20-30%. HBV is more common among Asian populations and sub-Saharan Africans. Some subtypes (16&18) of the human papilloma viruses (HPV) account for 90% of cervical cancer which is now recognized to be a sexually transmitted disease with special risk from early sexual exposure before the cervix is fully mature. These viruses cause benign warts and may be involved in cancers of the oral cavity and upper respiratory tract. Globally the developing countries bear the greatest impact from these cancers from very early infections with these agents. A vaccine is available only for HBV.

Perinatal Factors and Growth may account for about 5% of total cancer deaths in the USA. Resulting from excess energy intake in early life. There are positive associations between height and risk of breast and other cancers, and between larger birth weight and cancers of the breast and possibly prostate.

Reproductive Factors account for perhaps 3% of total cancer deaths in the USA. Reproductive factors are associated with substantial hormonal changes. Early age at menarche, late age at first birth, late age at menopause, and nulliparity each increase risk for breast cancer in the range of 1.2 to 2 times. Nulliparity is associated with endometrial and ovarian cancers with an increased risk of 1.3 to 1.5 times. Other associations are of minor significance. Multiple sexual partners and early age at first intercourse increase the risk of cervical cancer more likely through HPV infections, but high parity independently increases risk. Nulliparity and colon cancer risk is controversial. Menstrual cycle length and regularity may be associated with breast, endometrial and ovarian cancers while tubal ligation is associated with decreased risk of ovarian cancer. Men who have had vasectomy have a 30% to 100% increased risk of prostate cancer.

Alcohol accounts for about 3% of total cancer deaths in the USA. It interacts with tobacco smoking in the causation of cancers of the upper respiratory and gastrointestinal tracts. By itself it plays a role in liver cancer arising in cirrhosis and it may be involved in a proportion of colon and breast cancer.

Socioeconomic Status accounts for about 3% of total cancer deaths in the USA where the total cancer incidence attributable to poverty is 16.5% for Whites and 12.1% for Blacks. Cancers of the lung, cervix and stomach have an established association with low socioeconomic status, while cancers of the oral cavity, esophagus, larynx, liver and bladder have a probable association. In contrast cancer of the breast and melanoma are associated with higher socioeconomic status. It has been said that "poverty is a carcinogen" and that "fighting cancer also requires a war on poverty". Poverty is associated with increased exposure to tobacco smoke, alcoholism, poor nutrition, and certain infectious agents.

Environmental Pollution accounts for perhaps 2% of total cancer deaths in the USA. In the broadest sense most cancer is due to environmental causes but most relate to topics review elsewhere such as behavioral habits, viruses, occupational exposures or dietary factors. The focus here is on air pollution and hormonally active aromatic organochlorines. There is a small role for urban air pollution in causing lung cancer – perhaps 1% of lung cancer deaths yearly in the USA. There is a higher risk for urban smokers compared with rural smokers. Investigations of the carcinogenic potential of environmental pollution has focused on water fluoridation, chlorinated water byproducts, metabolites of organochlorine pesticides like DDT, and residential proximity to hazardous waste sites or contaminated wells. Risks associated with environmental exposures are several orders of magnitude less than that associated with smoking. Aromatic organochlorines like DDT and PCBs accumulate along the food chain in fatty tissues and can bind to estrogen receptors causing estrogenic or antiestrogenic effects in animals. At the present time evidence for an association of cancer, such as breast cancer, with hormonally active organochlorines remains inconclusive.

Ionizing and Ultraviolet (UVL) Radiation accounts for about 2% of total cancer deaths in the USA. Over 90% of each of melanoma, basal cell carcinoma and squamous cell carcinoma is due to sunlight. Most skin cancers are non-melanoma skin cancers and account for 40% of all new cancers in the USA yearly. While the major DNA-damaging spectrum is UV-B radiation excessive exposure to the UV-A rays used in sun lamps and sun beds can also cause DNA damage.

Ionizing radiation is a universal but a weak carcinogen because it kills cells so effectively. Of the average dose per capita per year from all sources of radiation 88% comes from natural sources and 12% from medical exposures. Perhaps 1 to 3% of all cancers can be attributed to radiation from natural sources, and about 10% of all lung cancer deaths might result from indoor radon. Less than 1% of all breast cancers might be attributed to medical uses of radiation, but the possible hazard from mammography for breast screening is very low. Radiation can cause most types of cancer, especially myelogenous leukemia and cancers of the breast, thyroid and lung. Some tumors like sarcoma and tumors of the bone and rectum require very large exposures. Some cancers have not been linked to radiation: chronic lymphocytic leukemia, non-Hodgkin’s lymphoma, Hodgkin’s disease, and cancers of the cervix, testis, prostate and pancreas. Despite the massive radiation contamination resulting from the nuclear reactor accidents at Chernobyl and Chelyabinsk thus far only increases in childhood thyroid cancer is well-documented, but it is early yet in the surveillance. It is not known whether there is a genetic predisposition to cancer development with radiation exposure, except in the cases of inherited retinoblastoma (bone tumors) and hereditary ataxia telangiectasis (lymphoid tumors) where this is the case. The risk of cancer following low radiation exposures is overestimated in general. Only 1% of Japanese atomic bomb survivors have died from cancers related to radiation.

Electric and magnetic fields have been studied in relation to leukemia, lymphoma and tumors of the brain, breast and lung. Studies showing a small increase in risk of childhood cancers are weak and inconsistent. At present a causal relationship between electric and magnetic fields and cancer is neither established nor can it be ruled out.

Prescription Drugs and Medical Procedures account for perhaps 1% of total cancer deaths in the USA. There are three groups of drugs that cause or prevent cancer. Cancer chemotherapy, especially the alkyating agents, increases the risk of leukemia in particular. Immunosuppresive agents increase the risk of some cancers, especially lymphoma. Hormones and hormone antagonists increase the risk for some cancers and decrease it for others. Replacement estrogens used to treat menopausal symptoms increase the risk of endometrial cancer and perhaps breast cancer. Oral contraceptives reduce by half the risk of ovarian and endometrial cancers, but may raise the risk rarely of liver cancer. Their effect in raising the risk of breast cancer is controversial. Tamoxifen used in the treatment of breast cancer may cause endometrial cancer. Anabolic steroids (liver cancer) and phenacetin analgesics (kidney and renal pelvis) also raise cancer risk. Radiotherapy also can cause cancer. Overall the risk of cancer form conventional medicines is very much smaller than the direct benefits of therapy.

Salt and Other Food Additives and Contaminants account for about 1% of total cancer deaths in the USA. Salt intake has been associated with risk of stomach cancer, but no other food additive or contaminant (except for aflatoxins) has been linked conclusively to cancer.

Source: Adapted and summarized from Harvard Report on Cancer Prevention. (1996) Volume 1: Causes of Human Cancer. Cancer Causes and Control Vol 7, Supplement 1, November

A Word about Risk Factors.

When studying epidemiological, experimental and other data, how does one decide when there is good evidence of causal relationships between environmental risk factors and cancer outcome? The answer is important for legislators and policy-makers who want to make recommendations from scientific evidence that are sound, significant and feasible. There are three measures to assess the strength of the association between exposure to the risk factor and disease. These, in turn, estimate the extent to which the risk factor may affect cancer incidence. The absolute risk depends on the strength of the causal association and the prevalence of the disease. In contrast, the population-attributable risk depends on both the strength of the causal relationship and the prevalence of the exposure. Dose-response data look at how much the risk decreases or increases with increasing exposure. Bradford Hill (1965; IARC (1990)) has set out criteria for causality which judge associations to be causal when exposures precede outcomes, and when the associations are consistent, unbiased, strong, graded, coherent, repeated, predictive and plausible. Most knowledge of cancer causation (and thus cancer prevention through modifying or avoiding environmental risk factors), is based primarily on epidemiological findings supported by biologic evidence of plausibility. Examples would include smoking, solar and ionizing radiation, asbestos, occupational exposure to carcinogens, pollution, viral infections and exogenous hormones.

Quantification of risk. The strength of an association between a risk factor and the occurrence of cancer is expressed in terms of relative risk. This is the ratio of risk (or incidence) of a particular cancer among people exposed to a risk factor to that among people not so exposed. Relative risks above 1.0 indicate and increased risk. Relative risks below 1.0 are inverse associations or protective effects. A relative risk of 0.5 for some risk factor implies a halving of risk; a relative risk of 2.0 for a risk factor implies a doubling of risk. Even a large relative risk may constitute a small absolute risk in the population if the associated cancer is rare. In contrast, even a small relative risk may constitute a large absolute risk in a population if the cancer is common. Moreover, even a small relative risk may amount to strong evidence if it is consistently found well-designed and large studies. Dose-response curves will quantify the results of case-control and cohort studies by plotting the relative risk (or odds ratio) of cancer at a particular site (the response or risk of disease) as a function of the degree of exposure (dose) to the environmental risk factor. To guide policy-makers one also wants to know the extent to which a specific cancer may be caused or prevented by modifying a risk factor on a population basis. The population-attributable risk is used to indicate the number or proportion of cancers preventable in a population if everyone at increased risk were to modify or avoid the risk factor to reduce its effect.

The strength of evidence for a causal link is judged by the following criteria for relative strengths of associations. A strong association has a statistically significant relative risk or odds ratio which is >2.0 or <0.5. In a moderate association the relative risk or odds ration is >2.0 or <0.5 but not statistically significant, or is 1.5-2.0 or 0.5-0.75 and statistically significant. In a weak association the relative risk or odds ratio is 1.5-2.0 or 0.5-0.75 but not statistically significant, or is <1.5 or >0.75 and statistically significant. Where the relative risk or odds ratio lies between 0.75 and 1.5 and is not statistically significant, no association is judged to exist.

Source: Adapted and summarized from World Cancer Research Fund in Association With American Institute for Cancer Research (1997) Food, Nutrition and the Prevention of Cancer: A Global Perspective.

Hill AB () The environment and disease: association or causation? Proc R Soc Med 58:295-300.

IARC (1990) Tomatis L et al. (eds) Cancer: Causes, Occurrence and Control. Lyon: International Agency for Research on Cancer.

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