Proc. Natl. Acad. Sci. USAVol. 92, pp. 5258-5265, June 1995

Review

The causes and prevention of cancerBruce N. Ames*, Lois Swirsky Gold*t, and Walter C. Willettt*Division of Biochemistry and Molecular Biology, University of Califomia, Berkeiey, CA 94720; tLife Sciences Division, Lawrence Berkeley Laboratory, Berkeley,CA 94720; and +Departments of Epidemiology and Nutrition, Harvard School of Public Health and the Channing Laboratory, Department of Medicine, HarvardMedical School and the Brigham and Women's Hospital, Cambridge, MA 02138

Contributed by Bruce N. Ames, March 1, 1995

ABSTRACT Epidemiological evi-dence indicates that avoidance of smok-ing, increased consumption of fruits andvegetables, and control of infections willhave a major effect on reducing rates ofcancer. Other factors include avoidance ofintense sun exposure, increases in physi-cal activity, and reduction of alcohol con-sumption and possibly red meat. A sub-stantial reduction in breast cancer islikely to require modification of sex hor-mone levels, and development of practicalmethods for doing so is a high researchpriority. Resolution of the potential pro-tective roles of specific antioxidants andother constituents of fruits and vegetablesdeserves major attention. Mechanisticstudies of carcinogenesis indicate an im-portant role of endogenous oxidativedamage to DNA that is balanced by elab-orate defense and repair processes. Alsokey is the rate of cell division, which isinfluenced by hormones, growth, cytotox-icity, and inflammation, as this deter-mines the probability of converting DNAlesions to mutations. These mechanismsmay underlie many epidemiologic obser-vations.

We discuss the causes of cancer with anemphasis on mechanisms. As causes andmechanisms become clear, prevention be-comes possible. Henderson et at (1) re-viewed the causes of cancer in 1991, fol-lowing by a decade the comprehensivereview of Doll and Peto (2).

Trends

Cancer was estimated to cause 23% of theperson-years of premature loss of life andabout 530,000 deaths in the United Statesin 1993 (3). Four major cancers (lung,colon-rectum, breast and prostate) ac-count for 55% of the deaths. According tothe 1993 SEER update from the NationalCancer Institute, the age-adjusted mortal-ity rate for all cancers combined (exclud-ing lung and bronchus) has declined from

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1950 to 1990 for all individual age groupsexcept 85 and above (3). The declineranged from 71% in the 0- to 4-year-oldgroup to 8% in the 74- to 85-year-oldgroup. "If lung cancer were eliminated,then the overall cancer death rate wouldhave declined over 14% between 1950 and1990." Smoking, in addition to causingabout 90% of lung cancer, contributes toother cancers, such as mouth, esophagus,stomach, kidney, pancreas, bladder, leu-kemia, and possibly colon; if these weretaken into account the decline would begreater.

If lung cancer is included, overall cancermortality has decreased for each agegroup under 45 and has increased for agegroups over 55. The decreases in cancerdeaths during this period have been pri-marily from stomach, cervical, uterine,and rectal cancer. The increases have beenprimarily from lung cancer, due to smok-ing (which causes 30% of all U.S. cancerdeaths), and non-Hodgkin lymphoma(NHL). Reasons for the increase in NHLare not clear, but smoking may possiblycontribute (4, 5), and human immunode-ficiency virus is a small, but increasingcause.To interpret changes in mortality rates,

one must consider both changes in inci-dence rates (the number of people newlydiagnosed with the cancer) and effects oftreatment. Incidence rates have been in-creasing for some types of cancer in partdue to early detection. Doll and Peto (2)pointed out that incidence rates shouldnot be taken in isolation, because they mayreflect increases in registration of casesand improvements in diagnosis. The re-ported rise in cancer rates among menborn in the 1940s compared with the 1890s(6) may be due to such artifacts. Forexample, the rapid increase in age-adjusted prostate cancer incidences with-out major increases in mortality is almostcertainly due largely to increased screen-ing and incidental detection during pros-tatectomy for benign prostatic hypertro-phy.

Mechanisms of Carcinogenesis

Mutations. Mutations in several criticalgenes can lead to tumors (7). Mutations in

the tumor-suppressor gene p53 are foundin about half of human tumors. The p53protein guards a cell cycle checkpoint, andinactivation of p53 allows uncontrolledcell division.DNA Lesions. DNA lesions (damaged

bases or chromosome breaks) have a cer-tain probability of giving rise to mutationswhen the cell divides. Endogenous DNAdamage is high (8). An exogenous muta-gen produces an increment in lesions overthe background rate of endogenous le-sions. The mutagenic effectiveness of aparticular lesion depends on its rate ofexcision by DNA repair enzymes and onthe probability that it gives rise to a mu-tation when the cell divides.

Cell Division. This is a critical factor inmutagenesis, because when the cell di-vides a DNA lesion can give rise to a pointmutation, deletion, or translocation (9-11). Thus, an important factor in the mu-tagenic effect of an agent is the incrementit causes over the background cell divisionrate in those cells that matter. Those cellsthat appear to matter most for cancer arethe stem cells, which are not discarded,whereas their daughter cells are. Increas-ing the cell division rate of stem cellsincreases mutation and therefore cancer.As expected, there is little cancer in non-dividing cells. Increased cell division, andtherefore an increased risk for cancer, canbe caused by such diverse agents as in-creased levels of particular hormones(12), excess calories, chronic inflamma-tion, or chemicals at doses causing celldivision (13-16). If both the rate of DNAlesions and cell division are increased,then there will be a multiplicative increasein mutagenesis, for example, by high dosesof a mutagen which also increases celldivision through cell killing and conse-quent cell replacement. Chronic dosing athigh levels of chemicals that do not dam-age DNA can also cause cell killing andconsequent cell division and thus increasecancer. Studies of cell division in stemcells, and the signaling systems responsiblefor stem-cell proliferation, are active andimportant areas of research.

Cell Cycle Checkpoints. These check-points prevent division of cells with toomany DNA lesions, thus inhibiting theformation of mutations. This defense, like

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DNA repair, is not perfect. The sensing oflesions in transcribed genes is done by thetranscription apparatus that makesmRNA (17, 18). The presence of lesionsappears to induce DNA repair and also tohalt cell division at a cell cycle checkpoint.The mechanism may be that the p53 pro-tein, which controls the G1-to-S check-point, is associated with the replicationand repair protein RPA (19, 20). WhenDNA damage occurs, RPA appears tobind to single-strand DNA and release p53(19, 20), which in turn causes a block ofcell division at the checkpoint, thus pre-venting conversion of lesions to mutations(M. Botchan, personal communication).In addition, p53 is involved in triggeringcell death (apoptosis) (21), so that ahigher level ofDNA lesions may lead to anapoptotic signal (22).

Defense Systems. Defense systems suchas the glutathione transferases protectDNA against mutagens. These defensesare almost all inducible and, thus, buffercells from increments in reactive electro-philic chemicals that can cause DNA le-sions (23). DNA repair enzymes, almostall of which are inducible, buffer the cellagainst increments in DNA lesions. There-fore, the effect of a particular chemicalinsult is dependent on the level of eachdefense, which in turn is dependent on thepast history of exposure. Defenses can bepartially disabled by lack of particularmicronutrients in the diet (e.g., antioxi-dants) (8).

Major Risk Factors

Endogenous Damage. To the extent thatthe major exogenous risk factors for can-cer-smoking, chronic inflammation, andunbalanced diet-are diminished, cancerwill appear at a later age, and the propor-tion of cancer that is caused by endoge-nous processes will increase.

Oxidant by-products of normal metab-olism cause extensive damage to DNA,protein, and lipid. We argue that thisdamage (the same as that produced byradiation) is a major contributor to agingand to degenerative diseases of aging suchas cancer, heart disease, cataracts, andbrain dysfunction (8). Antioxidant de-fenses against this damage include ascor-bate, tocopherols, and carotenoids. De-generation of somatic cells during agingappears, in good part, to contribute todegenerative diseases.DNA is oxidized because antioxidant

defenses are not perfect. The number ofoxidative hits to DNA per cell per day isestimated to be about 100,000 in the ratand roughly 10 times fewer in the human(8). DNA repair enzymes efficiently re-move most, but not all, of the lesionsformed. Oxidative lesions in DNA accu-mulate with age, so that by the time a ratis old (2 years) it has about a million DNAlesions per cell, which is about twice that

in a young rat (8). Mutations also accu-mulate with age (24).The proximity of mitochondrial DNA

(mtDNA) to oxidants generated duringoxidative phosphorylation results in 10times the oxidative damage of nuclearDNA (25). The cell defends itself againstthis high rate of damage by a constantturnover of mitochondria, thus presum-ably removing altered mitochondria thatare producing more oxidants. Neverthe-less, oxidative lesions accumulate with agein mtDNA at a higher rate than in nuclearDNA (8). Oxidative damage could ac-count for the mutations in mtDNA thataccumulate with age (26, 27). Mitochon-dria produce more oxidants with age andmay be a weak link in aging (27).

Oxidants damage proteins as well asDNA (28). The protective proteolytic en-zymes that hydrolyze oxidized proteins arenot sufficient to prevent an age-associatedaccumulation of oxidized proteins. In twohuman diseases associated with prema-ture aging, Werner syndrome and proge-ria, oxidized proteins accumulate at amuch higher rate than normal (28). Flu-orescent age pigments, which are thoughtto be due in part to crosslinks betweenprotein and lipid peroxidation products,also accumulate with age (29).

Further understanding of the role andmechanism of endogenous damage couldlead to new prevention strategies for can-cer and other degenerative diseases.

Diet. Diet is thought to account forabout one-third of cancer in the UnitedStates (2), but the specific factors are onlyslowly being clarified. A brief overview ofthe field is presented, emphasizing mech-anism.

Calorie or protein restriction and cancerprevention. In rodents a calorie-restricteddiet compared to ad libitum feeding mark-edly decreases tumor incidence and in-creases lifespan but decreases reproduc-tion (30, 31). Protein restriction, thoughless well studied, appears to have similareffects (32). Darwinian fitness in animalsappears to be increased by hormonalchanges which delay reproductive func-tion during periods of low food availabilitybecause the saved resources are investedin maintenance of the body until foodresources are available for successful re-production (33, 34). Lower mitotic ratesare observed in a variety of tissues incalorie-restricted compared with ad libi-tum fed rodents (35, 36) and are likely tocontribute to the decrease in tumor inci-dence (37). Though epidemiological evi-dence on restriction in humans is sparse,the possible importance of growth restric-tion in human cancer is supported byepidemiologic studies indicating higherrates of breast and other cancers amongtaller persons (38)-e.g., Japanese womenare now taller, menstruate earlier, andhave increased breast cancer rates. Also,many of the variations in breast cancer

rates among countries, and trends overtime within countries, are compatible withchanges in growth rates and attained adultheight (39).

Dietary fruits and vegetables and cancerprevention. Consumption of adequatefruits and vegetables is associated with alowered risk of degenerative diseases suchas cancer, cardiovascular disease, cata-racts, and brain and immune dysfunction(8). Nearly 200 studies in the epidemio-logical literature have been reviewed andrelate, with great consistency, the lack ofadequate consumption of fruits and veg-etables to cancer incidence (40-42). Thequarter of the population with the lowestdietary intake of fruits and vegetablescompared to the quarter with the highestintake has roughly twice the cancer ratefor most types of cancer (lung, larynx, oralcavity, esophagus, stomach, colon and rec-tum, bladder, pancreas, cervix, and ova-ry). The protective effect for hormonallyrelated cancers is weaker and less consis-tent: for breast cancer the protection ap-pears to be about 30% (38, 40, 43). Only9% of Americans met the intake recom-mended by the National Cancer Instituteand the National Research Council (38,44, 45): two servings of fruits plus three ofvegetables per day.

Antioxidants in fruits and vegetablesmay account for a good part of theirbeneficial effect as suggested by mecha-nistic studies. However, the effects of di-etary intakes of the antioxidants ascor-bate, tocopherol, and carotenoids are dif-ficult to disentangle by epidemiologicalstudies from other important vitamins andingredients in fruits and vegetables (40,41, 44, 46). Also, it is unlikely that allcompounds sharing antioxidant proper-ties would have similar effects against alltypes of cancer, since each antioxidant hasa unique function and distribution withinthe body. Further, even though a specificantioxidant may play a critical role inlimiting cancer incidence, the levels al-ready present in a particular populationmay be sufficient, so that greater con-sumption would not be of benefit.Only a few randomized trials in humans

have evaluated antioxidants as possibleprotective agents. In a trial conducted inrural China, a combination of antioxidantsupplements appeared to reduce the inci-dence of gastric cancer (47), a diseasewhich has been repeatedly associated withlow intake of fruits and vegetables. How-ever, supplements of X3-carotene did notreduce recurrences of skin cancer, andvitamins C and E and 13-carotene did notreduce recurrences of colon polyps (48,49). In a recent large study of 30-year,heavy smokers in Finland (50), ,B-carotenesupplements appeared to sightly increasethe risk of lung cancer, coronary heartdisease, and total mortality, in contrast tothe findings of protection by intakes offruits and vegetables in many observa-

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tional studies. A modest dose ofvitamin Ewas unrelated to risk of lung cancer in thisstudy, perhaps because vitamin C, whichwas not given, is necessary to regeneratevitamin E. The duration of the Finnishstudy (six years) may have been insuffi-cient to observe a protective influencethat might operate in the early stages ofcarcinogenesis. Present epidemiologicalevidence regarding the role of greaterantioxidant consumption in human cancerprevention is thus inconsistent. Neverthe-less, biochemical data indicating massiveoxidative damage to DNA, proteins, andlipids, as well as indirect evidence, such asheightened oxidative damage to humansperm DNA with insufficient dietaryascorbate (51), indicate the need for fur-ther investigation of the wide variety ofpotentially effective antioxidants, bothnatural and synthetic.

Folic acid and other compounds infruits and vegetables may contribute tothe reduction of cancer. Low folic acidintake causes chromosome breaks in ro-dents (52) and humans (53, 54) and in-creases tumor incidence in some rodentmodels (55). Folic acid is required for thesynthesis of DNA nucleotides, and folatedeficiency causes breaks in DNA throughmisincorporation of uracil (53). Low fo-late intake has been associated with sev-eral neoplasms, including adenomas andcancers of the colon (56-58). Deficientintake of folic acid appears to be commonin U.S. diets as evidenced by elevatedblood homocysteine levels (59, 60) and bythe clear relationship with neural-tubebirth defects (61). About 15% of the U.S.population (62), and about half of low-income Black children (63) or Black eld-erly (64), are at a level (<4 ng/ml ofserum) where chromosome breaks havebeen seen (53). Dietary fiber, obtainedonly from foods of plant origin, may lowerthe risk of colon cancer (65). Vitamin A,which is derived from some carotenoids aswell as from animal sources in the diet,regulates cell differentiation and reducestumor incidence in many animal modelsand possibly humans (66). Fruits and veg-etables may also reduce cancer risk be-cause they contain antioxidants such asflavonoids, inducers of detoxifying en-zymes such as indoles, and weak estrogensthat act as antiestrogens (see Hormones)(41, 46, 67).

Other aspects of diet. Strong interna-tional correlations have suggested thatanimal (but not vegetable) fat and redmeat may increase the incidence of can-cers of the breast, colon, and prostate (68,69). However, large prospective studies offat intake and breast cancer have consis-tently shown a weak or no association (38).In contrast, animal fat and red meat havebeen associated with colon cancer risk innumerous case-control and cohort studies,but the association with meat consump-tion appears more consistent (70, 71).

Consumption of animal fat and red meathas been associated with prostate cancerin multiple studies (72, 73). Hypothesizedmechanisms for these associations includeeffects of dietary fats on endogenous hor-mone levels (1), proliferative effects ofbile acids on the colonic mucosa, effects ofrodent carcinogens produced in the cook-ing of meat, and excessive iron intake.Excess iron absorption (absorption ofheme iron from meat is unregulated) is aplausible, though unproven, contributorto production of oxygen radials (8). Someexperimental evidence suggests that in-creased calcium antagonizes high-fat-induced proliferation, thus reducing therisk of colon cancer (74, 75); however,case-control and cohort studies haveyielded divergent results (76). Physicalactivity is inversely related to colon cancerrisk in many studies and some of the largegeographical differences in colon cancerrates that have been attributed to dietaryfactors are probably due to differences inphysical activity (77, 78, 153). Furtherresearch on the mechanism of the bene-ficial effects of exercise is warranted.

Chinese-style salted fish, particularlywhen consumed in childhood, is associ-ated with nasopharyngeal cancer (81).Cooking of food is plausible as a con-

tributor to cancer. A wide variety of chem-icals are formed during cooking. Fourgroups of chemicals that cause tumors inrodents have attracted attention becauseof mutagenicity, potency, and concentra-tion (79-81). (i) Nitrosamines are formedfrom nitrogen oxides present in gas flamesor from other burning. Surprisingly littlework has been done on the levels of ni-trosamines in fish or meat cooked in gasovens or barbecued, considering their mu-tagenic and carcinogenic potency. (ii)Heterocyclic amines are formed fromheating amino acids or proteins. (iii) Poly-cyclic hydrocarbons are formed fromcharring meat. (iv) Furfural and similarfurans are formed from heating sugars.Heating fat generates mutagenic ep-oxides, hydroperoxides, and unsaturatedaldehydes and may also be of importance.Epidemiological studies on cooking aredifficult and so far are inadequate toresolve a carcinogenic effect in humans(81).

Alcoholic beverages cause inflamma-tion and cirrhosis of the liver and livercancer (82). Alcohol is an important causeof oral and esophageal cancer (and is alsosynergistic with smoking) (82) and possi-bly contributes to colorectal cancer (83).Breast cancer is also associated with alco-hol consumption (see below).

Tobacco. Tobacco is the most impor-tant global cause of cancer and is prevent-able. Smoking contributes to about one-third of cancer, and one-quarter of heartdisease, and about 400,000 prematuredeaths per year in the U.S. (84). Tobaccois a known cause of cancer of the lung,

bladder, mouth, pharynx, pancreas, kid-ney, stomach, larynx, esophagus (85), andpossibly colon (86-88). It causes evenmore deaths by diseases other than cancer.Tobacco is causing about three milliondeaths per year worldwide in the 1990sand will, if present rates of smoking con-tinue, cause about 10 million deaths peryear a few decades from now (84). Theevidence for environmental tobaccosmoke as a cause of cancer is muchweaker: it has been estimated to cause upto 3000 additional cases of cancer in theUnited States (89, 90), though this esti-mate has been strongly disputed (91).The carcinogenic mechanisms of to-

bacco smoking are not well understood.Smoking is a severe oxidative stress, andsmoke contains a wide variety of muta-gens and rodent carcinogens. The oxi-dants in cigarette smoke (mainly nitrogenoxides) deplete the body's antioxidants.Thus, smokers must ingest 2-3 times moreascorbate than nonsmokers to achieve thesame level of ascorbate in blood, but theyrarely do (92-94).Chronic Infection, Inflammation, and

Cancer. Leukocytes and other phagocyticcells combat bacteria, parasites, and virus-infected cells by destroying them withnitrogen oxide and superoxide, which re-act to form peroxynitrite, a powerful mu-tagenic oxidizing and nitrating agent; hy-pochlorite, a mutagenic chlorinating andoxidizing agent; and hydrogen peroxide, amutagenic oxidizing agent. These oxi-dants protect humans from immediatedeath from infection but also cause oxi-dative damage to DNA, mutation, andchronic cell killing with compensatory celldivision (95, 96), thereby contributing tothe carcinogenic process. Antioxidants ap-pear to inhibit some of the pathology ofchronic inflammation (8).

Chronic infections contribute to aboutone-third of the world's cancer. HepatitisB and C viruses are a major cause ofchronic inflammation leading to liver can-cer, which is one of the most commoncancers in Asia and Africa (97-99). Hep-atitis B and C viruses infect about 500million people worldwide. Vaccinating ba-bies at birth is potentially an effectivemethod to reduce liver cancer and is rou-tinely done for hepatitis B in Taiwan.The mutagenic mold toxin aflatoxin,

which is found in moldy peanut and cornproducts, appears to interact with chronichepatitis infection in liver cancer develop-ment (100). In the United States, livercancer is rare. Although hepatitis B and Cviruses infect <1% of the U.S. population,hepatitis viruses can account for half ofliver cancer cases among non-Asians (101)and even more among Asians (102).

Schistosomiasis infection is widespreadin Asia and Egypt. In Asia, the eggs ofSchistosoma japonicum, deposited in thecolonic mucosa, cause inflammation andcolon cancer (103). In Egypt, the eggs of

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Schistosoma haematobium, deposited inthe bladder, cause inflammation and blad-der cancer (103). Opisthorchis viverrini, aliver fluke, infects millions of people inThailand and Malaysia. The flukes lodgein bile ducts and increase the risk ofcholangiocarcinoma (103). Chlonorchis si-nensis infections in millions of Chineseincrease the risk of biliary tract cancer(104). Helicobacter pylori bacteria infectthe stomachs of more than one-third ofthe world's population and cause stomachcancer, ulcers, and gastritis (103). Inwealthy countries the infection is oftenasymptomatic, which suggests that inflam-mation may be at least partially sup-pressed, possibly by adequate levels ofdietary antioxidants (105).Human papilloma virus, a major risk

factor for cervical cancer, does not appearto work through an inflammatory mech-anism (106). It is spread by sexual contact,an effective way of transmitting viruses.

Asbestos exposure leading to chronicinflammation may be in good part thereason it is a significant risk factor forcancer of the lung (107, 108) (see below).

Nonsteroidal antiinflammatory drugs,particularly aspirin, may be useful in pre-vention of colon cancer (154).Hormones. Henderson et at (1) have

reviewed the extensive literature indicat-ing a role of sex hormones in cancercausation, likely through causing cell di-vision, and possibly contributing to asmuch as one-third of all cancer cases.Endometrial cancer appears most exquis-itely sensitive to cumulative estrogen ex-posure, with risks elevated 10- to 20-foldby long-term use of exogenous estrogens(109). Estrogens increase the division ofendometrial cells, but progestogens re-duce division; thus the addition of proges-togens to estrogen therapy after meno-pause may reduce the risk of endometrialcancer (1).

Ovarian cancer seems to be related tofactors that increase the division of sur-face epithelial cells; e.g., pregnancies sub-stantially reduce the number of ovulationsand therefore cell division and risk (1).Oral contraceptives, which also block ovu-lation, decrease risk, by as much as 50%with five years of use (110).

Factors that increase cumulative expo-sure to estrogens, such as early age at men-arche, late menopause, and prolonged es-trogen therapy after menopause, increasethe risk of breast cancer (1, 111). Breastcancer cells proliferate in the presence ofestrogens, and progestogens also appear toenhance cell division (1). Moreover, theaddition of progestogens to estrogen ther-apy does not reduce, and may possibly fur-ther increase, the risk ofbreast cancer (112).Pregnancy has a complex relation withbreast cancer, as risk is initially increased fora period of one to two decades (probablydue to hormonal stimulation), but lifetimeincidence is ultimately reduced (113, 114),

possibly due to a permanent differentiationof stem cells resulting in less proliferation(115). Lactation modestly reduces breastcancer incidence (116). The evidence thathormones influence the incidence of breastcancer suggests ways of reducing incidence.One proposal is to develop a hormonalcontraceptive that mimics the effect of anearly menopause; this might reduce breastcancer risk by half (117). Exercise may lowerbreast cancer risk in youngwomen, probablythrough influencing hormone levels (118).Alcohol consumption, which has been con-sistently associated with breast cancer risk inlarge prospective studies, as well as in mostcase-control studies (119), appears to in-crease endogenous estrogen levels (120);thus, reduced consumption of alcohol maydecrease breast cancer risk. Foods, such assoybeans, that contain weakly estrogenicsubstances that compete with more potentendogenous estrogen might also reduce therisk of breast cancer (41, 46, 67).

Less Important Risk Factors

Occupation. Half of the 60 chemicalsand chemical mixtures the InternationalAgency for Research on Cancer has eval-uated as having sufficient evidence ofcarcinogenicity in humans are occupa-tional exposures, which tend to be con-centrated among small groups of peoplewho have been chronically exposed at highlevels (121). These include workplace ex-posures such as "rubber industry" or"coke production" as well as exposure tospecific aromatic amines, petrochemicals,metals, etc. The issue of how much cancercan be attributed to occupational expo-sure has been controversial, but a fewpercent seems a reasonable estimate. Dolland Peto (2) have discussed difficulties inmaking such estimates, including the lackof accurate data on history of exposureand current exposures, as well as con-founding factors such as socioeconomicstatus and smoking. Lung cancer was byfar the largest contributor to Doll andPeto's estimate of the proportion of can-cers due to occupation. The preeminenceof smoking as a cause of lung cancerconfounds the interpretation of rates interms of particular workplace exposures-e.g., asbestos. Asbestos appears to multi-ply rather than just add to the effect ofsmoking. In contrast, asbestos alone is aknown risk factor for mesothelioma. As-bestos was estimated to cause a high pro-portion of occupational cancers (2); how-ever, recent estimates for asbestos-relatedcancer are lower (122, 123).

Exposures in the workplace can be highcompared with other chemical exposuresto humans-e.g., in air or water. We haveargued (10, 11) that increased cell divisionrates are important in causing mutationand cancer and, therefore, the extrapola-tion from the results of high-dose animalcancer tests to low-dose human exposures

cannot be done without considering themechanism of carcinogenesis for thechemical. However, some past occupa-tional exposures have been high, and com-paratively little quantitative extrapolationmay be required from high-dose rodenttests to high-dose occupational exposures.Since occupational cancer is concentratedamong small groups exposed at high lev-els, there is an opportunity to control oreliminate risks once identified. However,in contrast to other federal agencies suchas the Environmental Protection Agency(EPA), few chemicals are regulated by theU.S. Occupational Safety and Health Ad-ministration (OSHA) as potential humancarcinogens. For 75 rodent carcinogensregulated by OSHA with permissible ex-posure limits (PELs), Gold et at (124)recently ranked potential carcinogenichazards on an index (PERP) that com-pares the permitted dose-rate to workerswith the carcinogenic dose to rodents. Itwas found that for 9 chemicals the per-mitted exposures were within a factor of10 of the rodent carcinogenic dose and for17 they were 10-100 times lower than therodent dose. These values are high incomparison to hypothetical risks regu-lated by other federal agencies.Sun Exposure. Exposure to the sun is

the major cause of skin cancer, with mel-anoma being of the utmost importance.Exposure during the early decades of life,particularly when sufficient to causeburns, appears to be the dominant factor(125). Prevention of skin cancer is feasibleif fair-skinned people become aware ofthis information and take protective mea-sures.Medical Interventions. Some cancer

chemotherapeutic drugs, particularly al-kylating agents, cause second malignan-cies, most commonly leukemias, lympho-mas, and sarcomas (126, 127). Some for-merly used drugs, such as phenacetin anddiethylstilbesterol, were associated withincreased cancer risk (128). Potent immu-nosuppressive agents such as cyclosporinalso increase the risk of a variety of can-cers (129), and estrogen replacement ther-apy increases risk of endometrial andbreast cancer. Diagnostic x-rays have con-tributed to malignancies (130). Althoughthese side effects should weigh in thera-peutic decisions, the overall contributionof medications and diagnostic proceduresto cancer incidence is small.

Pollution. Synthetic pollutants are fearedby much of the public as major causes ofcancer, but this is a misconception. Even ifthe worst-case risk estimates for syntheticpollutants that have been made by the EPAwere assumed to be true risks, the propor-tion of cancer that EPA could prevent byregulation would be tiny (131). Epidemio-logical studies, moreover, are difficult toconduct because of inadequacies in expo-sure assessment and failure to account for

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confounding factors such as smoking, diet,and geographic mobility of the population.Air Pollution. Indoor air is generally of

greater concern than outside air because90% of people's time is spent indoors, andconcentrations of pollutants tend to behigher than outdoors. The most importantcarcinogenic air pollutant is likely to beradon, which occurs naturally as a radio-active gas that is generated as a decayproduct of radium present in trace quan-tities in the earth's crust. Radon entershouses primarily in air that is drawn fromthe underlying soil. Based on epidemio-logical studies of high exposures to under-ground miners, radon has been estimatedto cause as many as 15,000 lung cancersper year in the United States, mostlyamong smokers, due to the synergisticeffect with smoking (132-134). Epidemi-ological studies of radon exposures inhomes have failed to convincingly demon-strate an excess risk (135, 136). About50,000-100,000 of the homes in theUnited States (0.1%) are estimated tohave annual average radon levels -20times the national average, and inhabit-ants receive annual radiation doses thatexceed the current occupational standardof underground miners. Efforts to identifyhigh-radon houses indicate that they occurmost frequently in concentrated geo-graphic areas (137). In high-radon areas,homes can be tested and high levels can bereduced inexpensively with available tech-nology (133).A recent large study has reported an

association between lung cancer and out-door air pollution when sulfates are usedas an index, but not when fine particles areused; diet was not controlled for (155).

Water pollution. Water pollution as arisk factor for cancer appears small.Among potential hazards, the most impor-tant are radon (exposure is small com-pared with air) and natural arsenate,which is a known human carcinogen (138,139). Research is needed on mechanismand dose-response of arsenate in humans.

Chlorination of water, an importantpublic health intervention, produces largenumbers of chlorinated by-products, someof which are rodent carcinogens. The ev-idence has been judged inadequate for anassociation between human cancer andchlorinated water (140). An earlier asso-ciation with bladder cancer and coloncancer has not been confirmed in a recentcase-control, interview study, but an asso-ciation with rectal cancer was observed(K. Cantor, personal communication).

Hereditary Factors

Inherited factors clearly contribute to can-cer, particularly childhood cancer and can-cer in early adulthood. Overall cancerrates increase exponentially with age ex-cept for a blip on the curve for childhoodcancer, which is thought to be mainly due

to inheriting a mutant cancer gene (141,142). Heredity is likely to affect suscepti-bility to all cancers, but to what extent isnot clear, though it is obvious that skincolor plays a large role in sun-associatedcancers such as melanoma. With the rapidprogress of molecular biology, hereditaryfactors will become understood. Factorsother than heredity play the dominantcausative role for most major cancers, asindicated by the large differences in can-cer rates among countries, the observationthat migrants adopt cancer rates close tothose of their host populations, and thelarge temporal changes in the rates ofmany cancers. While there is little evi-dence that hereditary factors affect lungcancer (143), the attributable risk forbreast cancer appears to be in the range of10% (144). Identification of those at highgenetic risk can be particularly importantif modifiable factors can be identified thatinteract with genetic susceptibility and ifsensitive methods of screening exist, suchas colonoscopy.

Distractions

The idea that there is an epidemic ofhuman cancer caused by synthetic indus-trial chemicals is not supported by eithertoxicology or epidemiology. Though someepidemiologic studies have found an as-sociation between cancer and low levels ofindustrial pollutants, the studies did notcorrect for diet, which is a potentially largeconfounding factor; moreover, the levelsof pollutants are low and rarely seemplausible as a causal factor when com-pared with the background of naturalchemicals that are rodent carcinogens(79).Animal Cancer Tests and the Rachel

Carson Fallacy. Carson's fundamentalmisconception was "For the first time inthe history of the world, every humanbeing is now subjected to contact withdangerous chemicals, from the moment ofconception until death" (145). This iswrong: the vast bulk of chemicals humansare exposed to are natural, and for everychemical some amount is toxic.Animal cancer tests are usually done on

synthetic chemicals at the maximum tol-erated dose (MTD) of the chemical. Theseresults are being misinterpreted to meanthat low doses of synthetic chemicals andindustrial pollutants are relevant to hu-man cancer. About half of the chemicalstested, whether synthetic or natural, arecarcinogenic to rats or mice at these highdoses (11, 146, 147). A plausible explana-tion for the high proportion of positiveresults is that testing at the MTD fre-quently can cause chronic cell killing andconsequent cell replacement, which is arisk factor for cancer that can be limited tohigh doses (10, 11, 15, 16).The great bulk of chemicals ingested by

humans is natural, by both weight and

number. For example, 99.99% of the pes-ticides in the diet are naturally present inplants to ward off insects and other pred-ators (148). Half of the natural pesticidestested (29 of 57) are rodent carcinogens(79). Reducing exposure to the 0.01% thatare synthetic, either to individual chemi-cals or to mixtures, will not appreciablyreduce cancer rates. On the contrary,fruits and vegetables are important forreducing cancer; making them more ex-pensive by reducing the use of syntheticpesticides is likely to increase cancer. Peo-ple with low incomes eat fewer fruits andvegetables (149) and spend a higher per-centage of their income on food.Humans also ingest large numbers of

natural chemicals from cooked food. Forexample, more than a thousand chemicalshave been identified in roasted coffee;more than half of those tested (19 of 26)are rodent carcinogens (79). There aremore natural carcinogens by weight in asingle cup of coffee than potentially car-cinogenic synthetic pesticide residues inthe average.U.S. diet in a year, and thereare still a thousand known chemicals inroasted coffee that have not been tested.This does not necessarily mean that coffeeis dangerous but does indicate that animalcancer tests and worst-case risk assess-ments build in enormous safety factorsand should not be considered to reflecttrue risks.Because of their unusual lipophilicity

and long environmental persistence, therehas been particular concern for a smallgroup of valuable polychlorinated syn-thetic chemicals such as 1,1-bis(4-chloro-phenyl)-2,2,2-trichloroethane ("dichloro-diphenyltrichloroethane", DDT) andpolychlorinated biphenyls (PCBs). Thereis no convincing epidemiological evidence(150), nor is there much toxicologicalplausibility, that the levels usually found inthe environment are likely to be a signif-icant contributor to cancer. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD),which is produced naturally by burningwhen chloride ion is present and is anindustrial by-product, is an unusually po-tent rodent carcinogen but seems unlikelyto be a significant human carcinogen atthe levels to which the general populationis exposed.The reason humans can eat the tremen-

dous variety of natural "rodent carcino-gens" in our food is that, like other ani-mals, humans are well protected by gen-eral defense enzymes, most of which areinducible (i.e., when a defense enzyme isin use, more of it is made) (23). Defenseenzymes are effective against both naturaland synthetic chemicals, such as poten-tially reactive mutagens. One does notexpect, nor does one find, a general dif-ference between synthetic and naturalchemicals in ability to cause cancer inhigh-dose rodent tests (11, 79).

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We have ranked possible carcinogenichazards from known rodent carcinogens,using an index that relates human expo-sure to carcinogenic potency in rodents(HERP) (79). Our ranking does not esti-mate risks, which current science does nothave the ability to do. Rather, possiblehazards of synthetic chemicals are put intoperspective against the background of nat-urally occurring rodent carcinogens in typ-ical portions of common foods. The resi-dues of synthetic pesticides or environ-mental pollutants rank low in comparisonto the background, despite the fact thatsuch a comparison gives a minimal view ofhypothetical background hazards becauseso few chemicals in the natural world havebeen tested for carcinogenicity in rodents.Linear extrapolation from the MTD inrodents to low-level exposure in humansfor synthetic chemicals, while ignoring theenormous natural background, has led toexaggerated cancer-risk estimates and animbalance in the perception of hazard andallocation of resources.The tremendous variety of chemicals

that occur naturally in food, some in highconcentrations relative to their toxicity,may play some role in causing humancancer, and research is needed to identifypotentially important human carcinogens.

Discussion

Since many of the known causes of cancerare avoidable, it is possible to reduce theincidence rates of many types of cancer. Intheir 1981 review of avoidable risks ofcancer in the United States, Doll and Peto(2) attributed 30% of cancer deaths totobacco and roughly 35% to dietary fac-tors, although the plausible contributionof diet ranged from 10% to 70%. Otherfactors were judged to contribute far less.Since that time the contribution of smok-ing appears to have increased somewhat(35% seems more likely), even though theprevalence of smoking in U.S. adults hasdecreased, because the relative risk due tosmoking has greatly increased for almostall cancers as well as cardiovascular dis-ease (84). This is probably because of thedeclining risk of cancer death in nonsmok-ers and because the lifetime impact ofsmoking since adolescence is being expe-rienced only now. Available data on dietand cancer have increased manyfold since1981 and generally support the earlierestimate; a slightly narrower estimatedrange of 20-40% seems more plausible(151). In general, new data have moststrongly emphasized the inadequate con-sumption of protective factors rather thanexcessive intake of harmful factors. Theestimate for diet is revised slightly down-ward largely because the large interna-tional contrasts in colon cancer rates areprobably due to differences in physicalactivity as well as diet. The Doll and Peto(2) estimate for the dietary contribution to

breast cancer of50% is still plausible, eventhough this may not be avoidable in apractical sense if rapid growth rates arethe most important underlying nutritionalfactor. The estimate for alcoholic bever-ages can be increased slightly from 3% to5%, as many new studies support associ-ations with breast and colon cancer. Datasubsequent to 1981 have not provided abasis to alter the earlier estimates forother causes appreciably.One approach to estimating the popu-

lation impact of adopting major lifestylefactors associated with low cancer risk is tocompare the general population with Sev-enth-Day Adventists, who generally do notsmoke, drink heavily, or eat much meatbut do eat a diet rich in fruits and vege-tables (152). Substantially lower mortalityrates of lung, bladder, and colon cancersare experienced in this group; overall can-cer mortality is about half that of thegeneral U.S. population. While this com-parison has limitations-better use ofmedical services may contribute to re-duced mortality, and imperfect compli-ance with recommendations may under-estimate the impact of lifestyle-the re-sults strongly suggest that a large portionof cancer deaths can be avoided by usingknowledge at hand. Incidence rates ratherthan mortality rates provide a similar pic-ture, although the differences are some-what less. For breast cancer the healthybehavior of Seventh-Day Adventists wasnot sufficient to have a major impact onrisk.

Decreases in physical activity and in-creases in smoking, obesity, and recre-ational sun exposure have contributed im-portantly to increases in some cancers inthe modern industrial world, whereas im-provements in hygiene have reduced othercancers related to infection. There is nogood reason to believe that syntheticchemicals underlie the major changes inincidence of some cancers. In the indus-trial countries life expectancy is steadilyincreasing and will increase even faster assmoking declines. Further research on theways in which diet influences cancer risk isimportant because it is likely to have thegreatest impact on future prevention strat-egies.

For criticisms, we thank L. Bernstein, B.Blount, W. R. Bruce, R. Doll, H. Helbock, B.Mossman, T. Slone, and M. Yu. This work wassupported by National Institute of Environ-mental Health Sciences Center Grant ES01896and National Cancer Institute Outstanding In-vestigator Grant CA39910 to B.N.A. and by theDirector, Office of Energy Research, Office ofHealth and Environmental Research of theU.S. Department of Energy under ContractDE-AC03-76SF00098 to L.S.G.

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