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The Causes and Prevention of Cancer B ruce N. A mes Professor of Biochemistry & Molecular Biology Director of the National Institute of Environmental Health Science&Center University of California at Berkeley, Berkeley, California 94720 Tel. 510 642-5165, Fax 510 643-7935 1. Aging is in good part due to the oxidants produced as by-products of normal metabolism. These oxidants, such as superoxide and hydrogen peroxide, are the same mutagens that are produced by radiation, and cause damage to DNA, proteins, and lipids. The DNA in each cell of a normal rat receives on average about 100,000 oxidative lesions per day. DNA repair enzymes constantly remove this damage, but they do not keep up: a young rat has about I million oxidative lesions in the DNA of each cell, which increases to about two million in an old rat. A human cell receives about ten times less damage than a rat cell, in agreement with the higher cancer rate and shorter life span of a rat. 2. The degenerative diseases of aging such as cancer, cardiovascular disease, cataracts, and brain dysfunction, are increasingly found to have, in good part, an oxidative origin. It is argued that dietary antioxidants, such as Vitamins C and E and carotenoids, play a major role in minimizing this damage and that most of the world's population is receiving inadequate amounts of them, at a great cost to health. The main source of dietary antioxidants is fruits and vegetables. Humans should eat 5 portions of fruits and vegetables per day, yet only 9% of the U:S, population eats that much. Epidemiological studies show that the incidence of most types of cancer is double among people who eat few fruits and vegetables as compared to those who eat about 5 portions per day. Considerable evidence indicates that oxidative damage is important in cardiovascular disease, cataracts, and brain and immune system dysfunction, and that adequate dietary antioxidants can minimize their incidence. 3. Men with low Vitamin C intake have low vitamin C in their seminal fluid and much more oxidative damage to the DNA in their sperm. Male smokers are particularly at risk as they have depleted1 antioxidant pools (cigarette smoke is extremely high in oxidants). A smoker must eat 2 to 3 times as much Vitamin C as a non-smoker to maintain an equal plasma level, yet smokers tend to eat worse diets than non-smokers. Indeed, male smokers have aconsiderably higher risk of having children with birth defects and childhood cancer. 4. The three main causes of cancer are smoking, dietary imbalances (excess fat and calories; inadequate intake of fruits, vegetables, fiber, and calcium), and chronic infections leading to chronic inflammation (hepatitis B and C viruses, Helicobacter pylori infection, schistosomiasis, etc.). Chronic inflammation is a major cause of cancer in the world because it releases powerful oxidants which both stimulate cell division and are mutagens. Past occupational exposures might cause about 2% of current human cancer, a major part being asbestos exposure in smokers, and industrial or synthetic chemical pollution causes less than 0.1%, immy view. The age-adjusted cancer death rate in the U.S. for all cancers combined (excluding those attributable to smoking) has been remaining steady since 1950, while life expectancy increases every year. We are the healthiest we have ever been in human history. 5. Two factors are eritical in the formation of mutations: lesions in DNA, formed! when DNA i& damaged, and cell division, which converts DNA lesions to mutations. Agents increasing either lesions or cell division increase mutation&and as a consequence increase cancer incidence. Hormones stimulating cell division increase cancer incidence (e.g. levels of estrogen in breast cancer and testosterone in prostate cancer); hormones may be a ri* factor in about 20% of human cancer.

6. Animal cancer tests; which arc done at the maximum tolerated dose (MTD), are being misinterpreted to mean that low doses of the chemicals tested and'found positive are thereby relevant to human cancer. Animali cancer tests are mainiy done on synthetic chemicals and industrial pollutanis, yet half of all natural chemicals that have been tested at the MTD are rodent carcinogens. It is argued that the explanation~for the high frequency of positive results in animal cancer tests is that high dose animal cancer tests are mainly measuring increases in cell division due to cell killing and compensatory cell division; this is a high dose effect that does not occur at low doses. In any case, 99:9% or more of the chemicals we eat are natural. For example 99:99% of the pesticides we eat are natural chemicals that are present in plants to ward off insects and other predators. More than half of those natural pesticides tested in high dose animal tests are rodent carcinogens. There are about 10.000 or so different natural pesticides in our diet, and they are usually present at enormously higher levels than synthetic pesticides: Cooking food also generates thousands of chemicals. Theree are over !000 chemicals reported in a cup of coffee. Only 26 have been tested in animal cancer tests and more than half are rodent carcinogens; there are still a thousand chemicals!left to test. The amount of potentiallycarcinogenic pesticide residues consumed in a year is less than the known amount of rodent carcinogens in a cup of coffee. The reason we can eat the tremendous varietv of natural chemical rodent carcinogens in our food~ is t~.at animals are extremely well defended against all chemicals by many general defense systems. These enzymes, e.g: DNA repair and glutathione transferaseswhich defend against reactiv.e :ompounds such as mutagens, are all inducible (more of them are made when they are in use). T'r.°y are equally effective against natural and synthetic reactive chemicals. Thus, animals are extremc:i-weR defended against low doses of chemicals: One does not expect, nor does one find, a genera]I ;:ifference between~synthetic an&natural chemicals in their carcinogeniciry, and though les& welli stuLed„ the same would be expected for mutagenicity, teratogenicity, and acute toxicity. The effort! to eliminate synthetic pesticides because of unsubstantiated fears about residues in food will make fr.:its and vegetables more expensive, decrease consumption„and thus increase cancer rates. The Ieve!s of synthetic pesticide residues are trivial'in~companson to natural chemicals, and thus their potentiii: for cancer causation is extremely low. Ames, S.N: and Gold, L.S. (1990) Chemical Carcinogenesis: Too many rodent carcinogens. Proc. Natl. A,-zd: Sci. USA 87, 7772-7776, Ames, E.M, Profet, M.,,and Gold, L.S. (1990) Dietary Pesticides (99:99CO All'Natural). Proc. Natl. Ai ad. Sci. USA 87, 7777-7781. Ames, E.N'., Profet, M., and Gold, L.S: (1990) Nature's Chemicals and Synthetic Chemicals: Comparative Toxicology. Proc. Natl: Acad. Sci. USA 87, 7782-7786. Fraga; C.G., Motchnik, P.A., Shigenaga, M.K.,, Helbock, H! J., Jacob, R.A., and Ames, B.N. (1991) Ascorbic Acid Protects Against Endogenous Oxidative DNA Damage in Human Sperm. Proc. Natl: Acad. Sci. USA 88, 1 1003-1 1006. Gold, LS., Slone, T.H., Stern, B.R., Manley, N.B., and Ames, B.N. (1992) Rodent Carcino_ens: Setting Priorities. Science 258, 261-265. B1ock, C., Patterson, B., and Subar, A. (1992) Fruit, Vegetables, and Cancer Prevention: A Revic« A the Epidemiologicali Evidence. Nuir. Cancer 18, 1-29. N Ames„S.N., Motchnik, P., Fraga, C.G.,, Shigenaga, M.K., and Hagen, T.M. (1993) AntioxidantQ Prevent:on of Birth Defects and Cancer. (International Conference on Male-Mediated',DevelopmenW Toxicit~. September 16-1i9„ 1992 inPittsburgh,,PA) Plenum Press, in press. (~ . W Ames, 3.N., Shigenaga, M.K., and~ Hagen, T.M. (1993), Qxidants, Antioxidants, and the ~ Degene-ative Diseases of Aging. Proc. Nat. Acad. Sci. inipress. CA CA 06