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The Causes and Prevention of Cancer: Gaining Perspective Bruce N. AmesI and Lois S. Gold1,2 1Division of Biochemistry and Molecular Biology, University of California, Berkeley, California; 2Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, California Epidem[51bgical studies have identifie~l several factors that are likely to have a major effect on reducing rates of cancer: reduction of smoking, increased consumption of fruits and vegetables, and control of infections. Other factors include avoidance of intense sun exposure, increased physical activity, and reduced consumption of alcohol and possibly red meat. Risks of many types of cancer can already be reduced, and the potential for further reductions is great. In the United States, cancer death rates for, all cancers combined are decreasing, if lung cancer (90% of which is due to smoking), is excluded from the analysis. VVe review the research on causes of cancer and show why much cancer is preventable. The idea that traces of'synthetic chemicals,, such as DDT, are major contributors to human can~er is not supported by the evidence, yet public concern and resource allocation for reduction of chemical pollution are very high, in part because standard, dsk assessment uses linear extrapolation from limited data in high~, ose animal cancer tests. T~se tests are done at the maximum tolerated dose (MTD) and are typical;y misinter- preted to mean that low doses of synthetic chemicals and industrial pollutants are relevant to human cancer. About half the chemicals tested, whether synthetic or natural, are carcinogenic to rodents at such high doses. Almost a!l chemicals in the human diet are natural. For example, 99.99%. Of the pesticides we eat are naturally present in plants to ward off insects and other predators. Half of the natural pesticides that have been tested at the MTD are rodent carcinogens. Cooking food produces large numbers of natural dietary chemicals. Roasted coffee, for example, contains more than 1000 chemicals: of 27 tested, 19 are rodent carcinogens. increasing evidence supports the idea that the high frequency of positive results in rodent bioassays is due to testing at the MTD, which frequently can cause chronic cell killing and consequent cell replacement---a risk: factor for cancer that can be limited to high doses. Because default ri~E assessments use linear extrapolation, which ignores effects of the high dose itself, low-dose dsks are often exaggerated. -- Environ Health Perspect t 05(Suppl 4):865-873 (1997) Key words: causes of cancer, environmental carcinogens, diet and cancer Cancer Trends According m the National Cancer Institutes 1993 Su.rvdllance, Epidemiology', and End Resu[rs Program (l), cancer caused 23% of the person-years of premature loss oflife death rates in the United States axe decreas- ing, after adjustment for age and exclusion of lung cancer. The age-adjusted mortality rate for all cancers combined (cxdudlng lung and bronchus) has declined 14% from 1950 to 1990. Smoking, in addition to musing 90% • of lung cancer, contributes to cancers of the mouth, esophagus, pancreas, bladder, and possibly colon; if these were taken into account, the decline would be greater. Peto and colleagues (2) have come to the same conclusion: "The common belief that there is an epidemic of death from cancer in developed cour~tries is a myth, except for the effects of tobacco. In many countries cancer deaths from tobacco are going up, and in some they" are at ]rat com- ing down• But, if we take away the cancer deaths that are attributed to smoking then the cancer death rates that remain are, if anything, declining." The number of people newly diagnosed with cancer (incidence rate) has been increasing for some types of cancer. In their comprehensive study on the causes of cancer, Doll and Peto (3) point out that incidence/ares should not be taken in iso- lation because reported incidence rates for a disease might rdlect increases in registra- dbn of cases and improvements in diagno- sis. For exaanple, the rapid increase in age-adjusted prostate cancer incidence without any major increases in mortality"/s mostly due to increased screening and inci- dental decectinn during ptostatectomy for benign prostatic hypertrophy (4). Devesa er al. (5) discuss incidence and mortality- trends by she in detail and about 530,000 death~ in the United States in I993. Four major cancers--lung, Major Contributors colon-rectum, breast, and prostate-- "to Risk of Cancer accounted for 55% of these deaths. Cancer Two critical factors in the formation of This paper is ba~d on a presentation at the symposium on Mechanisms a~d Prevention of Envircnmentally Caused Ca~cars held 21-25 October 1995 in Santa Fo. New Mexico. Manuscript reck'red 1996; accepted 15 November 1996. This work was supported by the National Institute of Environrnental Health Sciences Center Grant ESOi 896; by the National Cancer Institute C~tstanding Investigator Grant CA39910 to B.N. Ames and by ~.e Director, Office of Energy Research, Office of Health and Environmental Research of the U.S. Department of Energy under Contract DE-AC03-765F00098 to L.S. Gold. We are indebted to Waiter W~llstt for his help. , This s~de has been adapted in part from the following paper=: Ames BN. Gold LS. The causes and preven- tion of can~en the role of environment. In: The True State of the PIa~et (Bailey R. act). Hew York:Free Press, 1995;141-17.5. Ames BN, Gold LS, 'eVerett WC. The causes and prevention of cancer. Proc Nati Acad So{ USA 92:5258.5265 (1995). Ames BN, Gold LS..-he causes and prevention of cancer:, gaining para;:~ctives on man- agement of risk. In: Risks, Cos=, and Lives $~ved: Getting Better Results from Regulation (Hahn RW, ed). Oxford, England:Oxford Unik'ersity Press, Address correspondence to Dr. B.N. Ames, University of California. Division of Biochemistn/and MolecJlar Biology, 401 Barker Hall, Berkeley, CA 9472Q-3202. Telephorta: (510} 642-5165. Fax~ (510} 643-7935. E-mail: bnames~udink4.berkeley.edu Abbreviations used: DMN, dimathyl nitrosamine; HERP, human exposure to naminogenio potency in rodents; MMS. methyl methane sulfonate; MTD, max,'mum tolerated dose; U.S. EPA, U.S. Environmental Protection Agency; U.S. OSHA. U.S. Occupational Safety and Health Administration. muraxions are lesions in DNA (produced when DNA is damaged) and cell division (whicA converts DNA lesions to mutz- ' dons). Agents that increase either lesions or cell division in stem cells can increase ~nuta- tions, and a~ a consequence increase cancer incidence (below) (4,~f---8). Hormones stim- ulating cell division increase cancer inci- dence (e.g., estrogen in breast cancer and testosterone in prostate cancer); hormones may be a risk factor ia about 20% of human cancer (4,6). Oxidative Damage and the Degenerative Diseases of Aglng Aging and its degenerative d~ea~es appear ro be d~e in good pa~ to the acc~,doa Environment:el Health Perspectives - Vol 10S, Supp!emen~ 4 • June 1997 865 This article is for individual use only and may not be further reproduced or stored electronically without written permission from the copyright holder. Unauthorized reproduction may result in financial and other penalties. (c) US DEPT HEJ~LTH HUMAN SERVICES PUBLIC HEALTH SERVICE USA

AMES AND GOLD of oxidative damage co DNA and other macromolecules (9). By-products of nor- real metabolism--supernxide, hydrogen peroxide, and hydroxyl radical--are the same oxidative muragens produced by radi- ation (10). Oxidative lesions in DNA accumulate with age, so that by the time a rat is old (2 years) ic has about 1 million DNA lesions per cell, which is about twice the number in a young rat (9), Mutations also accumulate with age. DNA is oxidized in normal metabolism because antioxidant defenses, though numerous, are not per- fect. Endogenously produced oxidants can damage proteins as well as DNA (11). In two human diseases associated with prema- ture aging, Wcrner's syndrome and pro- geria, oxidized proteins accumulate at a much higher rate than normal (11). Chronic inflammation from chronic infection results in reJease of oxidative mutagens from phagocytic cells and is a major contributor to cancer (below). Amioxidant defenses against oxidative damage include vitamins C and E and carotenoids. To the extent that the major external risk factors for cancer--smoking, unbalanced diet, and chronic inflamma- tion-are diminished, cancer will appear at a later age, and the proportion of cancer that is caused by normal metabolic processes wi~ increase. Diet Doll and Peto (3) and others (6) esdmate that diet accounts for about one-third of cancer risk, and current research is slowly clarifying speckrc factors. Cancer Prevention by Calorie or Protein Restriction. In rodents, a calorie- restricted diet compared to ad libirura feeding markedly decreases tumor inci- dence and increases life span (12-14). Protein restriction appears to have a simi- lar effect on rodents, although research is less extensive (15). An understanding of mechanisms for the marked effect of dietary restriction on aging and cancer is becoming clearer and may be due largely to reduced oxidative damage and reduced rates of cA division. Although epidemio- logical evidence on restriction in humans is sparse, the possible importance of growth restriction in human cancer is sup- potted by cpidcmiologicai studies that indicate higher rates of breast cancer among taller persons (1~,17). For exam- pie, Japanese women are now taller, men- struate earlier, and have increased breast cancer rates. Also, many of the variations in breast cancer rates among countries and trends over time within c~untries are compatibIe with changes in growth rates and attained adult height (18). Cancer Prwa~ztlon by Dietary Fruits and Vegetables. Adequate consumption of fruits and vegetables is associated with a lowered risk of degenerative diseases such as cancer, cardiovascular disease, cataracts, and brain and immune dysfunction (9). Nearly 200 studies in the cpidemiological literature have been reviewed, and they show a consistent association between inad- equate consumption of fruits and vegeta- bles and cancer (19-21). The quarter of the population with the lowest dietary intake of fruits and vegetables has roughly twice the cancer risk for most types of cancer (lung, l~rynx, oral cavity, esophagus, stomach, colon and rectum, bladder, pan- creas, cervix, and ovary) compared with the quarter with the highest intake. For hor- monally related cancers, the protective effect of consumifig fruits and vegetables is weaker and les~. comistenu for breast cancer the protective effect appears to be about 30% ( 16,19,22). Laboratory studies suggest that antioxidants such as vitamins C and E and carotenoids account for a good part of the beneficial effect of fruits and vegetables (9); however, epidemiologisrs have diffi- culty disentangling the effects of dietary intakes of the antioxidants from other important vitamins and ingredients in fruits and vegetables (23,24). A wide array of compounds in fruits and vegetables in ad~tion to antioxidants may contribute significantly to the reduc- tion of cancer. Folic acid may be particu- larly important. Low follc acid intake causes chromosome breaks in rodents (25) and in humans (2~,27) and increases tumor inci- dence in some rodent models (28). Folio acid is essential for the synthesis of DNA. Low folare intake has been associated with several neoplasms including adenomas and cancers of the colon (2.9-31). Maternal deficiency of folase is associated with neural tube birth defects (32). Deficient intake of folic acid is common in U.S. diets. About 15% of the U.$. population (33) has a folatc levd at which chromosome breaks axe seen (26). A study of adolescents (34) and dderly (35) from urban, low-income, pre- dominandy African-American households, found that about half had such levels. Dietary fiber, obraiued only from foods of plant origin, may contribute to lower risk of colon cancer (36). Plant foods also coa- tala a wide variety of weak estrogens that may act as antiestrogens by cotupeting with estrogenic hormones (20,24,37). Other Aspects of Diet. Although epidemiological studies most dearly support the benefits of fruits and vegetables in the prevention of cancer, strong international corrdations suggest that animal (but not vegetable) fat and red meat may increase the incidence of cancers of the breast, colon, and prostate (38). However, large prospective studies have consistendy shown either a weak assodation or a lack of associ- ation between fat intake and breast cancer (16). Consumption of animal fat and red meat have been correlated with risk of colon cancer internationally, but the rela- tion with ~t intake has not been supported in most case-control and cohort studies (39,40); the association with meat cort- sumption appears more consistent (40-43). Consumption of animal fat and red meat has been associated with risk of prostate cancer (42,44). Mechanisms for these ~so- clarions are not clear, but may include the effects of dietary fats on endogenous hor- mone levels (4), the local effects of bile acids on the colonic mucosa, the effects of carcinogens produced by cooking meat, and excessive iron intake from red meat. Excess iron absorption, particularly heine iron from meat, is a plausible, though unproven, contributor to the production of oxygen radicals (9). Some of the large geo- graphical differences in colon cancer rates tha~ have been attributed to dietary factors are probably due to differences in physical activity, which is inversely related to colon cancer risk in many studies (45-47). Alcoholic beverages cause inflammation and cirrhosis of the liver, leading to liver cancer (48). Alcohol is an important cause of oral and esophageal cancer and is also synergistic with smoking (48) and possibly con~ibutes to colorectal cancer (31,49). Cooking food is plausible as a contrib- utor to cancer (50). Cooking forms a wide variety of chemicals. Four groups of chemicals that cause tumors in rodents have amacted attention because of mutagenichy, potency, or concentration: nitrosamines, heterocyclic amines, polycyclic hydrocar- bons, and furfural and similar furans. Epidemiological studies on cooking are dif- ficult and so far are inadequate to ev~uate a carcinogenic effect in humans (51). Tobacco Smoking contributes to about one-third of oancer, about one-quarter of heart disease, and about 400,000 premature deaths per year in the United States (52). Tobacco is a known cause of cancer of the lung, blad- der, mouth, pharynx, pancreas, stomach, 866 Environmental Health Perspectives • Vol 105. Supplement 4 • June 1997 This article is for individual use only and may not be further reproduced or stored elec~'onically without written permission from the copyright holder. Unauthorized reproduction may result in financial and other penalties. (c) US DEPT HEALTH HUMAN SERVICES PUBLIC HEALTH SERVICE USA

C.~U$~=$ ~D PREVEN'rlON OF CANCER: GNNING PERSPECTIVE larynx, esophagus (2), and possibly colon (53-55). Tobacco causes even more deaths by diseases other than cancer. The evidence for environmental tobacco smoke as a cause of cancer is much weaker. Studies have estimated that environmental tobacco smoke causes up to 3000 additional cases of cancer a year (5~57), although this estimate ~ been disputed (58). The carcinogenic mechanisms of tobacco smoking are not well understood. Smoke contaius a w/de variety of mutagens and rodent carcinogens, and smoking is a severe oxidative stress and causes flammation in the lung. The oxidants in dgatette smo~main~y nitrogen oxides-- deplete the body's antioxidants. Thus, smokers must ingest two to three times more ascorbate than nonsmokers to acbAeve the same levd of ascorbate in blood, but they rarely do (59-ffl). Men with inade- quate diets or who smoke mzy damage both their somatic DNA and the DNA of their sperm. When the level of dietary ascorbare is insufficient to keep seminal fluid ascorbate at an adequate level, the oxidative lesions in sperm DNA are increased 2.5 times (if2). Inadequate con- centmtion of ascotbate k~ plasma is more common among single males, the poor, and smokers (63). Paternal smoking may phu- sibly increase the risk of birth defects and chadhood c~ces h offspring (~#). C~ncer fi'om Int~'ama~on C~*_~ed by Chronic In~eaion W~re cells and other phagocyti~ ceils of the/minute system combat bacteria, para- sites, and virus-infected cells by destroying t~em with potent mutagenic oxidizing agents. The oxidants protect humans from immediate death from infection; but they also cause oxidative damage to DNA, mutation, and chronic cell killing with compensatory cell dMsion (~5,~) and thus contribute to the carcinogenic process. Antioxidants appear to Lahibit some of the pathology of chtonic inflammation (9). We estimate that chronic infections contribute to about one-third of the world's cancer. Hepatitis B and C viruses are a major cause of chsonic infI~ramation leading to Iiver cancer--one of the most common cancers in Asia and Africa (67-69). Hepatitis B and C viruses infect about 5.00 million people worldwide. Nearly half the world's l~ver cancer occurs ia China (70). Vaccinating babies at birth is potentially" an ~:ective method to reduce liver cancer and is routinely done for hepatitis B in Taiwan. The mutageaic mold toxin, aflatoxin, which is found in moldy peanut and corn products, interacts with chronic hepatitis infection in liver cancer development (71-7.3). Another major chronic infection is ~chistosomiasis, which is widespread • ia Egypt and Asia. In Egypt, the eggs of Schistosoma haematobium, deposited in the bladder, cause inflammation and bladder cancer (74). In Asia, the eggs of Schistosomajaponieum, deposited in the colonic mucosa, cause inflammation, and there is limited cpidcmiological evidence for an association with colon cancer (74). Opisthorchis viverrin~ a liver fluke, infects millions of people in Thailand and Malaysia. The flukes lodge in biJe ducts and increase the risk of choIaagiocarci- noma (74). Chlonorchis sinensis infects millions of people in China and increases the risk for biliary tract cancer (74). Hellcobacter pylori bacteria, which infect the stomach~ of more than one-third of the world's population, ate a ma~or cause of stomach cancer, ulcers, and gastritis (74). In the United States the infection is often asymptomaric, which suggests that inthm- marion may be at least partially suppressed, possibly by adequate leveIs of dietary andoxidants (75). Human papilloma virus, a major risk factor for cervical cancer, does nor appear to work through, an inflanamatory mecha- nism (76). It is spread by sexual contact, an e.ffecdve method of transmitting viruses. Chronic inflammation resulting from noninfectious sources can also le~d to can- cer. For example, asbestos exposure leading to chronic inflammation may be in good part the reason that asbestos is a significant risk factor for king cancer (77,78). Hormones Henderson et aL have reviewed the extensive iiterature on hormones and cancer, which indicates that endogenous reproductive hop moues play a large role in cancer, possibly contributing to as much as one-third of a.ll caficer, including breast, prostate, ovat% and endometrium (4). Hormones are likely to act by causing cell division (79). Loss Important Contributors to Risk of Cancer We have discussed dsewhem some of the less important contributors to cancer, indudlng hereditary" factor*, sun expo- sure, and medical intesventions (6). Here we discuss occupation and pollution because the scientific basis for concern needs clarification. Occupation The International Agency for Research on Cancer of the Wodd Health Organization evaluates potential cancer risks to humaoJ from a range of chemical exposures (80). Half of the 60 chemicals and chemical mix- tures the agency has evaluated as having sufficient evidence of carcinogenicity in humans represent occupational exposures, which tend to be concentrated among small groups of people who have been chtonically ~xposed at ~ levels. These include work- place exposures such as rubber indmtry or coke production, as well as exposure to spe- cfflc atomadc amines, petrochemicals, and metals. How much cancer can be attributed ro occupational exposure has been a contro- versial issue, but a few percent seems a rea- sonable estimate. Doll and Peto (3) have discussed difficulties in making such. esti- mates, incIuding the lack of accurate data on the history of exposure and current exposures, as well as confounding factors such as socioeconomic status and smoking. Lung cancer was by fa~ the largest contribu- tor to Dol~ and Peto's estimate of the pro- portion of ca~c~ts due to occupation. The preeminence of smoking as a cause of lung cancer confounds the interpretation of rates in terms of particular workplace exposures ~o substances such as asbestos; asbestos appears to multiply rather than just add to the effect of smoking. La contrast, asbestos alone is a lmown risk factor for mesothe- lioma. Doll and Pero (3) estimated that asbestos caused a high propordo~ of occu- pational cancers, but recent estimates for asbesros-rdated cancer am lower (81, 82). Exposures to substances in the work- place can be high in comparison wi~ other chemical exposures La food, air, or warer. Past occupatiogal exposures have often been high and comparativdy I~tde quanti- tative extrapolation may be required for risk assessment from high-dose rodent tests to high-dose occupational exposures. Because occupational cancer is concen- teated among small groups exposed at high levels, tl~re is an opportunity to control or eliminate risks once they are identified. The U.S. Occupational Safety and Health Administration (U.S. OSHA), however, unlike other federal agencies such as the U.S. Enviroamenta~ Protection Agency (U.S. EPA), regulates few chemicals as potenfal human cazcinogens. For 75 rodent carcinogens regulated by U.S. OSHA with permissible exposure I/mils, we recently ranked potenthl cazcinogenic hazards on an index t~t compares the permitted dose rate for workers with the carcinogenic dose Environmental Health Pe~pealves • Vc,' 105, Supptemen(: 4 • .June 1997 e, 867 This article is for individual use only and may not be further reproduced or stored electronically without wdtten permission from the copyright holder. Unauthorized reproduction may result in financial and other penalties. ~c) US DEPT HEALTH HUMAN SERVICES PUSLIC HEALTH SERVICE USA

AMES ~D GOLD for rodents (83). We found that for 9 chemicals the permitted exposures were within a factor of I0 of the rodent carcino- genic dose and for 17 they were between I0 and I00 times lower. These values are high in comparison with hypor.hedcaJ risks regu- lated by other federal agencies. An addi- tional 120 rodent carcinogens to which workers are exposed had no U.S. OSHA permissible exposure limit, which suggests the need for further regulatory attention and research on mechanism of carcinogenesis. Pollution Much of the public fears synthetic pollutants as major causes of cancer, but this fear is based un a misconception. Even assuming that the U.S. EPA's worst-case risk esti- mates for synthetic pollutants are true risks, the proportion of cancer that the U.S. EPA could prevent by regulation would be tiny (84). Epidemiological studies of pollutants, moreover, are diffl- cult to conduct because of inadequacies ka assessing low-level exposures and failure to account for confounding factors like smok- ing, diet, and geographic mobility of the population. Since the focus of this section is on cancer causation, we shall not discuss other issues in eavkonmental protection. Air Pollution Indoor air is generally of greater concern than outside air because people spend 90% of their time indoors and because the con- cemrarions of pollutants indoors tend to be higher than outdoors. Radon is likely to be the most important carcinogenic air pollu- tant. It occurs naturally as a radioactive gas thar is generated as a decay product of the radium present in trace quantities in the earth's crust. Radon primarily enters houses in air that is drawn from the under- lying soil. On the basis of epldemiological studies of high exposures of underground miners, researchers have estimated that radon causes as many as 15,000 lung can- cers per year in the United States, mostly among smokers because of the synergistic effect with smoking (85-87). Epidemio- logical studies of radon exposures in homes (88,89) have failed to demonstrate con- vincingly an excessive risk. About 50,000 to 100,000 of the homes in the United States (0.1%) are estimated to have annual average radon levels approximately 20 times the national average, and irthabitaaats receive annual radiation doses that exceed the current occupational standard for underground miners. Efforts to identify houses with high levels of radon indicate that they occur most frequently in concen- trated geographic areas (90). In areas with high levels of radon, individuals can per- form a measurement in their homes for about $20, and if high levels are found, they cart be reduced substantially--using available contractors--for perhaps $1500 (86). With respect to outdoor air pollu- tion, a recent large study has reported an association with lung cancer when sulfates are used as an index, but not wheu fine paxtides are used; the study did nor control for diet (91). Water Pollution Water pollution as a risk factor for cancer appears small. Among potential hazards that have been of concern, the most impor- tam are radon (exposure is sma]l compared to air) and arsenate. Natural arsenate is a known human carcinogen at high doses (92,93), and further research is needed to determine mechanisms of carcinogene- sis and the dose response in humans. Chlorination of water, an important public health intervention, produces large numbers of chlorine-containing chemicals as by- products, some of which are rodent carciae- gens. Evidence that chlorination of water increases cancer has been judged inadequate (94). A recent case-control interciew study did not confirm earlier associations with bladder and colon cancer but did find an association ~vith rectal cancer (95). Animal Cancer Tests and the Rachel Carson Fallacy Neither toxicology nor epidemiology supports the idea that synthetic industrial chemicals are causing an epidemic of human cancer. Although some epidemio- logical studies find an association b.etween cancer and low levels of industrial poilu- touts, the associations are usually weak, the results are usually conflicting, and the studies do not correct for diet, which is a potentially large confounding factor. Moreover, the levels of synthetic pollutants are low and rarely seem plausible as a c~usal factor when compared to the back- ground of natural chemicals that are rodent carcinogens (7). Rachel Carson's fundamental miscon- ception was, "For the first time in the his- tory of the world, every human being is now subjected to contact with daalgerous chemica/s, from the moment of conception untiI dearh" (96"). She was wrong: The vast bulk of the chemicals to which hmnans are exposed are natural, and for every chemical some amount is dangerous. Carson thus lacked perspective about the wide variety of naturally occurring chemicals to which all people axe exposed and did not address the fact that, outside the workplace, exposures to synthetic pollutants are extremely low relative to the uatural background. Animal cancer tests are conducted on synthetic chemicals at the maximum toler- ated dose (MTD) of the chemical, and reg- ulatory agencies use the results to predict human risk at low levels of expusure: Since the vast proportion of human exposures are to naturally occurring chemicals, while the vast proportion of chemicals tested for car. cinogenicity are synthetic, there is an imbalance in data and peroeprion about chemicals and cancer. The great bulk of chendcals ingested by humans is natural by both weight and number. We estimate that 99.99% of the pesticides in the diet are naturally present in plants to ward off hrsects and other predators (97). Half die natural pesticides tested--35 of 64~are rodent carcinogens (7,98,99). Reducing exposure to the 0.01% of pesticides that are synthetic, either individual chemicals or mixtures, will not appreciably reduce cancer rates. On the contrary, fruits and vegetables are important for reducing cancer; making them more expensive by reducing use of synthetic pesticides is likely to increase cancer. People with low incomes eat fewer fruits and vegetables (100) and spend a higher percentage of their income on food. Humans also ingest large numbers of natural chemicals from cooking food. Of the more than 1000 chemicals identified La roasted coffee, over half of those tested~l 9 of 27~are rodent carcinogens (99). There are more natural rodent carcinogens by weight in a single cup of coffee than poten- daily carcinogenic synthetic pesticide residues in the average U.S. diet in a year, and there are still about 1000 Imown chem- icals in roasted coffee that have not beet, tested. That does not necessarily mean that coffee is dangerous, but that high-dose ani- mal cancer tests and worst-case risk assess- ments build in enormous safety factors and should nor be considered true risks at the low dose of most human exposures. Because of their unusual lipophilicity and long environmental persistence, there has been particular concern for a small group of polychlodnated synthetic chemi- cals such as DDT and polychlorinated biphenyls. There is no convincing epidemi- ologlcal evidence (101), nor is there much toxicological plausibility (7), that the levds normally found in the environment are 868 Environmen~/Health Perspectives • Vo1105, Supplement q • June 1997 ,: This a~cle is for individual use only and may not be further reproduced or stored electronically without written permission from the copyright holder. Unauthorized reproduction may result in financial and other penalties. (c) US DEPT HEALTH HUMAN SERVICES PUBLIC HEALTH SERVICE USA

C.~US~$ AND P/'fI~/I~N'r/ON OF C..~NCER; G~NING PERSPECT/VE likely to contribute significantly to cancer. TCDD, which is produced naturally by burning when chloride ion is present, for example in forest and other fires, and as an industrial by-product, is an unusually potent rodent carcinogen but seems unlikdy to be a significant human carcinogen at the levels to which the genera2 population is exposed. The reason humans can eat the tremendous variety of rodent carcinogens in our diet is that, like other animals, we are extremely well protected by many gen- eral defense enzymes, most of which are inducible---that is, whenever a defense enzyme is in use, the body produces more of it (102). Defense enzymes axe effective against both natural and synthetic chemi- cals, including potentially muragen/~ reac- tive chemicals. One does not expect, nor does one find, a general difference between synthetic and natural chemicals in their ability to caose cancer ha high=dose rodent tern ( 7,,99,103). We have ranked possible carcinogenic hazards from known rodent carcinogens by using an index that relates hurn~ exposure to carcinogenic potency in rodents (HERP) (7,99,10ff-,105). Our ranking does not esti- mare risks because current sdence does not have the ability" to do so. Instead, we put possible haza~ of synthetic chemicals into perspective against the badqground of nat- urally occurring rodent carcinogens in typb cal portions and average exposures of common foods (.99). The residues of syn- thetic pesticides or environmentaI pollu- tants rank low in comparison with the background of naturally occurring rodent carcinogens, despite the fact that such a compasisun gives a minimal view of hypo- thetical background hazards because so few chemicals in the narural world have been tested for carcinogenicity in rodents. Our results indicate that many ordinary" foods would not pass the regulatory" dtiteria used for synthetic chemicals. Our analysis does nor necessarily indicate that coffee con- sumption, for example, is a significant risk factor for human cancer even though chem- icals ha coffee have HER~ values that rank much higher in possible hazard than the HERP that converts to the default one-in- a-million worst-case risk estimate used by the U.S. EPA (Z). Adequate risk assessment from animal cancer tests requixes more information about rrmay aspects of toxiccl- ogy, such as effects on ceil division, hadue- tioa of defense and repair systems, and species differences. The U.S. EPA has recently given attention to these factors in its newly proposed cancer risk assessment • gulddines (106). More than half the chemicals, whether synthetic or natural, that have been tested ar the MTD under standard tesdng proce- dur'es are classified as carcinogenic. The high positivity rate is consistent for syn- thetic chemicals, natural chemicals, natural pestiddes, and chemicals in roasted coffee, and has not changed through the years of testing (9.9,107,108). Half the drugs ha the Physician's Desk Reference that report ani- mal cancer test results are carcinogenic (109). The 1969 Innes series of tests of 119 synthetic chem/cals, mainly all of the commonly used pestleldes of the time, is frequently cited as evidence that the pro- portion of carcinogens in the world of chemicals is low, as only 9% were judged positive. Gold er al. (99,107) pointed out that these rests were quite det2cient in power compared to modern tests, and they have now reanalyzed Irmes by asking whether any of the Irmes-negarlve chemi- cals have been retested using current proto- cok. They found that 34 had been retested and 16 were judged carcinogenic, again about half (99). What is the explanation for the high posltivity rate in high-dose animal cancer tests? When the testing protocol was devd- oped in the 1960s, it was expected that chemical carcinogens would be rare and that they would be muragens. Bias ha pick- hag more suspicious chemicals does not appear to be the sole explanation for the high positivity rate for numerous reasons (107,108,110). There is, however, an expla- nation that is supported by an increasing azray of papers: that the MTD ofa chera2cal can cause chronic cell killing and cell replacement in the target tissue, a risk fac- tor for cancer that can be limited to the high dose. This explanation is supported by a wide variety of evidence. For example, endogenous oxidative damage to DNA is euormousnover 1 million oxidative lesions per tar cell (9). Thus, from first principles, the cell division rate must be a factor in converting such lesions ro muta- tions, thereby hacreasing cancer. Therefore, raising the levd of either DNA lesinns or cell division ha the cel~ that can give rise to tumors will increase cancer. Just as DNA repair protects against lesions, p55 guards the cell cycle and protects against cell division if the lesion level gets too high; however, neither defense is perfect. Cell division is also a major factor in loss of ker- erozygosity through nondisjuncriou and other medaanisrns (103,I10,111). In another line of evidence, many studies on rodent carcinogenicity show correlation between cell division ar the MTD and cancer. Cunningham and col- leagues have analyzed 15 chemicals at the MTD, 8 muragens and 7 nonmutagens, including several pairs of mutagenic iso- mers, one ofwhlch is a carcinogen and one of which is not (122-120). They have found a perfect corrdatioa between cancer causation and ¢dl division in the target tis- sue: when tested at the bioassay dose, the nine chemicals that cause cancer caused call division in the target tissue and the six chemicals that do not cause cancer did nor cause such cell d/vision. A similar result has been found in an analysis of Mirsalis et al. (121), e.g., both dimethyl nitrosamine (DMN) and methyl methane sulfonare (/vb.MS) methylate liver DNA and cause unscheduled DNA synthesis; however, DMN causes both cell division and liver tumors, whereas MMS does neither. The induction of cell division at high dose would explain why a high proportion of the known rodent carcinogens (42%) are not mutagenlc, which is otherwise not sat- isfactorily explained. There is a large body ofllrerature on rodent studies reviewed by Cohen and Lawson (122), Cohen (123), and Ames et al. (9) showing r_har chronic cell division can induce cancer. Work on chloroform induction of mouse liver tttmors by Larson et aL (124) also indi- cates the important rote of increased division at bioassay doses. A large epidemi- ological literature reviewed by Prestbn- Martin et al. (79,125) shows that increased cell division by hormones and other agents can increase human cancer. Thus it seems l/keiy that a high propor- tlon of the chemicals in the world may be carcinogens if tested in standard rodent bioassays at the MTD; but d~ will be warily due to high-dose effects for noamu- tagens, and a synergistic effect of cell dlvishan at high doses with DNA damage for muragens. Ad libitum feeding in the standard bioassay, which also cart iuerease ceil division, may also contribute to the high positivity rate, as shown by a recent National Toxicology Program study (126). If tumor induction in bioassays is due to effects unique to high doses, much more information on mechanism is required to understand the causes of human cancer. The default risk assessment vh:tuai.ly safe dose is simply a facror of 740,000 times bdow the MTD, as shown by Gaylor and Gotd (127). If tests are conducted primar- ily on synthetic chemicals and regulation is Environmental Heal~ Perspe~ves • Vol 10.5, Supplement 4. June 1997 869 This article is for individual use only and may not be further reproduced or stored electronically without written permission from the copyright holder. Unauthorized reproduction may result in financial and other penalties. (c) US DEPT HEALTH HUMAN SERVICES PUBLIC HEALTH SERVICE USA

AMES AND GOLD directed toward tiny traces of synthetic chemicals, as is now the case, resources will be diverted from more important issues. Thus, the positivity rat~ and the frequency of positive results that are unique to high doses are key questions in getting aa overview of the world of chemicals, both. natural and synthetic. Linear extrapolation from the MTD in rodents to low-levd exposure in humans for synthetic chemicals, whi~e ignoring the enormous background of natural chemicals, has led to exaggerated estimates of cancer risk and to an imbalance in the perception of hazaM and the ~ocadon of resources. If the costs wcrc minor, the issue of putting hypothetical risks into perspective would not be so important, but the costs are great (128,1,2.0) and escalate as cleanliness approaches perfection. Most attempts to deal with pollutants do not adequately deal with trade-offs; instead, policy makers assume thas upper-bound risk assessment to one in a million protects the public. Reports by the Office of Management and Budget (130) and the Harvard Center for Risk Analysis (131) compared costs of risk reduction among government agencies and concluded that the money spent to save a hypothetical life under U.S. EPA regula- tions is often orders of magnitude higher than that spent on regulations of other government agencies. The uncertainties in extrapolations to low-dose assessments arc great, and the true risk could be zero. Thus, the discrepancy between costs of U.S. EPA reguladous and other agencies' may be even greater, e.g., permitted worker exposure limits regulated by U.S. OSHA can be dose to the carcinogenic dose rate in rodent bio- assays and little extrapolation is required. Many scholars have pointed out that expen- sive regulations intended to save lives may actually lead to increased deaths (132), in part because they divert resources from important health risks and in part because higher incomes are associated with lower mortality (133,134). Worst-case assump- tions in risk assessment represent a policy" decision, not a scientific one, and they con- fuse attempts to allocate money effectively for cancer prevention (135,136). Discussion Epidemiological evidence in humans is sufficient to identify several broad categories of cancer causation for which the evidence is strong and plausible. Because many of those risks are avoidable, it is possible to reduce rates of many types of cancer. One approach to estimating the population impact of adopting major lifestyle factors associated with low cancer risk is to com- pare cancer incidence and mortality rates of the general population to those of Seventh-Day Adventistsmwho generally do not smoke, drink heavily, or eat much meat but do eat a diet rich in fruits and vegetables (137,138). Seventh-Day Adventists experience substantially lower mortality rates of lung, bladder, and colon cancers. Total cancer mortality is about half that of the general U.S. population. While this comparison has limitationsm better use of medical services may con- tribute to reduced mortality, and imperfect compliance with recommendations may underestimate the impact of lifestyle--the results strongly suggest that a large portion of cancer deaths can be avoided by using knowledge at hand. Incidence rates rather than mortality rates provide a similar pic- ture, although the differences are some- what less. For breast cancer, the healthy behavior of Seventh-Day Adventists was not sufficient to have a major effect on risk. Decreases in physical activity, and increases in smoking, obesity, and recre- ational sun exposure have contributed Lmportandy to increases in some cancers in the modern industrial world, whereas improvements in hygiene have reduced other cancers related to infection. There is no good reason to believe that synthetic chemicals underlie tb.e changes in inci- dence of some cancers. 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