Are vitamin and mineral deficiencies a major cancer risk?

Key Points

  • Acute deficiencies of vitamins and minerals are rare in developed countries, but suboptimal nutrient intake — less than the recommended daily allowance (RDA) — is a widespread problem. Research indicates that considerable metabolic damage can still occur when nutrient intake levels fall below the RDA — even though they might not cause acute disease.

  • Evidence indicates that deficiencies of iron and zinc, and the vitamins folate, B12, B6 and C, can cause DNA damage and lead to cancer.

  • New animal bioassays of nutritional deficiencies are needed, particularly for studying cancer.

  • Reduced folate intake has been associated with cancer. Folate, B6 and B12 deficiencies cause the incorporation of deoxyuracil into DNA, leading to DNA breakage, and could promote tumorigenesis.

  • The relationship of vitamin and mineral deficiencies and cancer is extremely complex. An integrated analysis of the findings from epidemiological, animal-model, metabolic and intervention studies, as well as from genetic polymorphism research, is required.

  • Approaches to eliminating micronutrient deficiencies include improving diet, fortifying foods and providing multivitamin and mineral supplements. Prevention strategies such as these could have a significant impact on cancer and public health, with minimal risk being involved.


Diet is estimated to contribute to about one-third of preventable cancers — about the same amount as smoking. Inadequate intake of essential vitamins and minerals might explain the epidemiological findings that people who eat only small amounts of fruits and vegetables have an increased risk of developing cancer. Recent experimental evidence indicates that vitamin and mineral deficiencies can lead to DNA damage. Optimizing vitamin and mineral intake by encouraging dietary change, multivitamin and mineral supplements, and fortifying foods might therefore prevent cancer and other chronic diseases.

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Figure 1: Incorporation of uracil in DNA.


  1. 1

    Doll, R. & Peto, R. The Causes of Cancer (University Press, Oxford, 1981). (Reference deleted in proof.)This classical paper discusses the risk of cancer and the link to lifestyle factors.

    Google Scholar 

  2. 2

    Hagen, T. M. et al. Feeding acetyl-L-carnitine and lipoic acid to old rats significantly improves metabolic function while decreasing oxidative stress. Proc. Natl Acad. Sci. USA 99, 1870–1875 (2002).

    CAS  PubMed  Google Scholar 

  3. 3

    Liu, J. et al. Memory loss in old rats is associated with brain mitochondrial decay and RNA/DNA oxidation: partial reversal by feeding acetyl-L-carnitine and/or R-alpha-lipoic acid. Proc. Natl Acad. Sci. USA 99, 2356–2361 (2002).

    CAS  PubMed  Google Scholar 

  4. 4

    Liu, J., Killilea, D. & Ames, B. N. Age-associated mitochondrial oxidative decay: improvement of carnitine acetyltransferase substrate-binding affinity and activity in brain by feeding old rats acetyl-L-carnitine and/or R-alpha-lipoic acid. Proc. Natl Acad. Sci. USA 99, 1876–1881 (2002).

    CAS  PubMed  Google Scholar 

  5. 5

    Ames, B. N., Elson-Schwab, I. & Silver, E. A. High-dose vitamin therapy stimulates variant enzymes with decreased coenzyme binding affinity (increased Km): relevance to genetic disease and polymorphisms. Am. J. Clin. Nutr. 75, 616–658 (2002).

    CAS  PubMed  Google Scholar 

  6. 6

    Ames, B. N. DNA damage from micronutrient deficiencies is likely to be a major cause of cancer. Mutat. Res. 475, 7–20 (2001).Discusses how various micronutrient deficiencies can lead to DNA damage and cancer.

    CAS  PubMed  Google Scholar 

  7. 7

    Blount, B. C. et al. Folate deficiency causes uracil misincorporation into human DNA and chromosome breakage: Implications for cancer and neuronal damage. Proc. Natl Acad. Sci. USA 94, 3290–3295 (1997).The results of this study provide evidence that folate status can be a key determinant of DNA strand breaks.

    CAS  PubMed  PubMed Central  Google Scholar 

  8. 8

    MacGregor, J. T. Dietary factors affecting spontaneous chromosomal damage in man. Prog. Clin. Biol. Res. 347, 139–153 (1990).

    CAS  PubMed  Google Scholar 

  9. 9

    Fraga, C. G. et al. Ascorbic acid protects against endogenous oxidative damage in human sperm. Proc. Natl Acad. Sci. USA 88, 11003–11006 (1991).

    CAS  PubMed  Google Scholar 

  10. 10

    Willett, W. C. Eat, Drink, and Be Healthy (Simon & Schuster Source, New York, 2001).

    Google Scholar 

  11. 11

    Willett, W. C. Diet and breast cancer. J. Intern. Med. 249, 395–411 (2001).

    CAS  PubMed  Google Scholar 

  12. 12

    Willett, W. C. Diet and cancer: one view at the start of the millennium. Cancer Epidemiol. Biomarkers Prev. 10, 3–8 (2001).Describes the process by which diet and cancer relationships have been investigated epidemiologically in the past few decades, using fat and breast cancer as an example. Dietary methodology issues, as well as other epidemiological issues, are discussed.

    CAS  PubMed  Google Scholar 

  13. 13

    Meyer, J. P. & Gillatt, D. A. Can diet affect prostate cancer? Br. J. Urol. 89, 250–254 (2002).

    CAS  Google Scholar 

  14. 14

    Kim, Y. I. in Present Knowledge in Nutrition (eds Bowman, B. A. & Russell, R. M.) 573–589 (ILSI International Life Sciences Institute, Washington DC, 2001).

    Google Scholar 

  15. 15

    Truswell, A. S. Meat consumption and cancer of the large bowel. Eur. J. Clin. Nutr. 56 (Suppl. 1), S19–S24 (2002).

    PubMed  Google Scholar 

  16. 16

    World Cancer Research Fund. American Institute for Cancer Research, Food Nutrition and the Prevention of Cancer: a global perspective (World Cancer Research Fund, Washington DC, 1997).This is the most comprehensive review so far on the many aspects of the relationship of diet to cancer.

  17. 17

    Mehta, R. G. & Mehta, R. R. Vitamin D and cancer. J. Nutr. Biochem. 13, 252–264 (2002).

    CAS  PubMed  Google Scholar 

  18. 18

    Plantz, E. A. et al. Plasma 1,25 dihydroxy- and 25-hydroxyvitamin D and adenomatous polyps of the distal colorectum. Cancer Epidemiol. Biomarkers Prev. 9, 1059–1065 (2000).

    Google Scholar 

  19. 19

    Block, G., Patterson, B. & Subar, A. Fruit, vegetables and cancer prevention: a review of the epidemiologic evidence. Nutr. Cancer 18, 1–29 (1992).This review found a statistically significant protective effect of fruit and vegetable consumption in 128 out of 156 studies in which results were expressed in terms of relative risk.

    CAS  PubMed  Google Scholar 

  20. 20

    Steinmetz, K. A. & Potter, J. D. Vegetables, fruit, and cancer. I. Epidemiology. Cancer Causes Control 2, 325–357 (1991).This was the first comprehensive scientific review that concluded that consumption of higher levels of vegetables and fruit is associated consistently, although not universally, with a reduced risk of cancer at most sites.

    CAS  PubMed  Google Scholar 

  21. 21

    Steinmetz, K. A. & Potter, J. D. Vegetables, fruit, and cancer prevention: a review. J. Am. Diet Assoc. 96, 1027–1039 (1996).

    CAS  PubMed  Google Scholar 

  22. 22

    Terry, P. et al. Fruit, vegetables, dietary fiber, and risk of colorectal cancer. J. Natl Cancer Inst. 93, 525–533 (2001).

    CAS  PubMed  Google Scholar 

  23. 23

    Smith-Warner, S. et al. Fruits, vegetables and adenomatous polyps. Am. J. Epidemiol. 155, 1104–1113 (2002).

    PubMed  Google Scholar 

  24. 24

    Smith-Warner, S. et al. Intake of fruits and vegetables and risk of breast cancer: a pooled analysis of cohort studies. JAMA 285, 769–776 (2001).

    CAS  PubMed  Google Scholar 

  25. 25

    Voorrips, L. E. et al. Vegetable and fruit consumption and risks of colon and rectal cancer in prospective cohort sutdy: The Netherlands Cohort Study on Diet and Cancer. Am. J. Epidemiol. 152, 1081–1092 (2000).

    CAS  PubMed  Google Scholar 

  26. 26

    Chatenoud, L. et al. Whole grain food intake and cancer risk. Int. J. Cancer 77, 24–28 (1998).

    CAS  PubMed  Google Scholar 

  27. 27

    Jacobs, D. R., Marquart, L., Slavin, J. & Kushi, L. H. Whole-grain intake and cancer: an expanded review and meta-analysis. Nutr. Cancer 30, 85–96 (1998).

    PubMed  Google Scholar 

  28. 28

    Patterson, R. E., Kristal, A. R. & Neuhouser, M. L. in Primary and Secondary Preventive Nutrition (eds Bendich, A. & Deckelbaum, R. J.) 21–43 (Humana Press, Totowa, New Jersey, 2001).

    Google Scholar 

  29. 29

    Steinmetz, K. A. & Potter, J. D. Vegetables, fruit, and cancer. II. Mechanisms. Cancer Causes Control 2, 427–442 (1991).

    CAS  PubMed  Google Scholar 

  30. 30

    Murillo, G. & Mehta, R. G. Cruciferous vegetables and cancer prevention. Nutr. Cancer 41, 17–28 (2001).

    CAS  PubMed  Google Scholar 

  31. 31

    Milner, J. A. Strategies for cancer prevention: the role of diet. Br. J. Nutr. 87, S265–S272 (2002).

    CAS  PubMed  Google Scholar 

  32. 32

    Ames, B. N. Cancer prevention and diet: help from single nucleotide polymorphisms. Proc. Natl Acad. Sci. USA 96, 12216–12218 (1999).

    CAS  PubMed  Google Scholar 

  33. 33

    Ames, B. N., Shigenaga, M. K. & Gold, L. S. DNA lesions, inducible DNA repair, and cell division: three key factors in mutagenesis and carcinogenesis. Environ. Health Perspect. 101 (Suppl. 5), 35–44 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. 34

    Ames, B. N. Carcinogenesis mechanisms: the debate continues. Science 252, 902 (1991).

    Google Scholar 

  35. 35

    Cairns, J. Mutation and cancer: the antecedents to our studies of adaptive mutation. Genetics 148, 1433–1440 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. 36

    Henderson, B. E. & Feigelson, H. S. Hormonal carcinogenesis. Carcinogenesis 21, 427–433 (2000).

    CAS  PubMed  Google Scholar 

  37. 37

    Tomlinson, I. & Bodmer, W. Selection, the mutation rate and cancer: ensuring that the tail does not wag the dog. Nature Med. 5, 11–12 (1999).

    CAS  Google Scholar 

  38. 38

    Wild, C. P., Andersson, C., O'Brien, N. M., Wilson, L. & Woods, J. A. A critical evaluation of the application of biomarkers in epidemiological studies on diet and health. Br. J. Nutr. 86 (Suppl 1), S37–S53 (2001).

    CAS  PubMed  Google Scholar 

  39. 39

    Ames, B. N. & Gold, L. S. Paracelsus to parascience: the environmental cancer distraction. Mutat. Res. 447, 3–13 (2000).

    CAS  PubMed  Google Scholar 

  40. 40

    Gold, L. S., Slone, T. H. & Ames, B. N. What do animal cancer tests tell us about human cancer risk? Overview of analyses of the carcinogenic potency database. Drug Metab. Rev. 30, 359–404 (1998).This paper describes the Carcinogenic Potency Database (CPDB), which analyses and standardizes the literature of chronic carcinogenicity tests in laboratory animals. It discusses the usefulness of CPDB in addressing questions about the use of animal bioassays in the evaluation of potential cancer risks to humans.

    CAS  PubMed  Google Scholar 

  41. 41

    Giovannucci, E. et al. Alcohol, methyl-deficient diets and risk of colon cancer in men. J. Natl Cancer Inst. 87, 265–273 (1995).

    CAS  PubMed  Google Scholar 

  42. 42

    Giovannucci, E. et al. Multivitamin use, folate, and colon cancer in women in the nurses' health study. Ann. Intern. Med. 129, 517–524 (1998).

    CAS  Google Scholar 

  43. 43

    Rohan, T. E., Jain, M., Howe, G. R. & Miller, A. B. Dietary folate consumption and breast cancer risk. J. Natl Cancer Inst. 92, 266–269 (2000).

    CAS  PubMed  Google Scholar 

  44. 44

    Zhang, S. et al. A prospective study of folate intake and the risk of breast cancer. JAMA 281, 632–637 (1999).

    Google Scholar 

  45. 45

    Stolzenberg-Solomon, R. et al. Dietary and other methyl-group availability factors and pancreatic cancer risk in a cohort of male smokers. Am. J. Epidemiol. 153, 680–687 (2001).

    CAS  PubMed  Google Scholar 

  46. 46

    Stolzenberg-Solomon, R. Z. et al. Pancreatic cancer risk and nutrition-related methyl-group availability indicators in male smokers. J. Natl Cancer Inst. 91, 535–541 (1999).

    CAS  PubMed  Google Scholar 

  47. 47

    Mayne, S. T. et al. Nutrient intake and risk of subtypes of esophageal and gastric cancer. Cancer Epidemiol. Biomarkers Prev. 10, 1055–1062 (2001).

    CAS  PubMed  Google Scholar 

  48. 48

    Crott, J. W., Mashiyama, S. T., Ames, B. N. & Fenech, M. F. Methylenetetrahydrofolate reductase C677T polymorphism does not alter folic acid deficiency-induced uracil incorporation into primary human lymphocyte DNA in vitro. Carcinogenesis 22, 1019–1025 (2001).

    CAS  PubMed  Google Scholar 

  49. 49

    Fenech, M. F., Aitken, C. & Rinaldi, J. R. Folate, vitamin B12, homocysteine status and DNA damage in young Australian adults. Carcinogenesis 19, 1163–1171 (1998).

    CAS  PubMed  Google Scholar 

  50. 50

    Fenech, M. Micronutrients and genomic stability: a new paradigm for recommended dietary allowances (RDAs). Food Chem. Toxicol. 40, 1113–1117 (2002).

    CAS  PubMed  Google Scholar 

  51. 51

    Hagmar, L. et al. Chromosomal aberrations in lymphocytes predict human cancer: a report from the European Study Group on Cytogenetic Biomarkers and Health (ESCH). Cancer Res. 58, 4117–4121 (1998).

    CAS  PubMed  Google Scholar 

  52. 52

    Chen, J. et al. A methylenetetrahydrofolate reductase polymorphism and the risk of colorectal cancer. Cancer Res. 56, 4862–4864 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. 53

    Le Marchand, L. et al. B-vitamin intake, metabolic genes, and colorectal cancer risk (United States). Cancer Causes Control 13, 239–248 (2002).

    PubMed  Google Scholar 

  54. 54

    Ma, J. et al. Methylenetetrahydrofolate reductase polymorphism, dietary interactions, and risk of colorectal cancer. Cancer Res. 57, 1098–1102 (1997).

    CAS  Google Scholar 

  55. 55

    Slattery, M. L., Potter, J. D., Samowitz, W., Schaffer, D. & Leppert, M. Methylenetetrahydrofolate reductase, diet, and risk of colon cancer. Cancer Epidemiol. Biomarkers Prev. 8, 513–518 (1999).

    CAS  PubMed  Google Scholar 

  56. 56

    Levine, A. J. et al. The methylenetetrahydrofolate reductase 677C→T polymorphism and distal colorectal adenoma risk. Cancer Epidemiol. Biomarkers Prev. 9, 657–663 (2000).

    CAS  PubMed  Google Scholar 

  57. 57

    Ulrich, C. M. et al. Colorectal adenomas and the C677T MTHFR polymorphism: evidence for gene-environment interaction? Cancer Epidemiol. Biomarkers Prev. 8, 659–668 (1999).

    CAS  Google Scholar 

  58. 58

    Skibola, C. F. et al. Polymorphisms in the methylenetetrahydrofolate reductase gene are associated with susceptibility to acute leukemia in adults. Proc. Natl Acad. Sci. USA 96, 12810–12815 (1999).Shows the power of single-nucleotide polymorphisms in epidemiological studies to clarify mechanisms and risk factors in the area of diet and disease prevention.

    CAS  Google Scholar 

  59. 59

    Wiemels, J. L. et al. Methylenetetrahydrofolate reductase (MTHFR) polymorphisms and risk of molecularly defined subtypes of childhood acute leukemia. Proc. Natl Acad. Sci. USA 98, 4004–4009 (2001).

    CAS  PubMed  Google Scholar 

  60. 60

    Goodman, M. T. et al. Association of methylenetetrahydrofolate reductase polymorphism C677T and dietary folate with the risk of cervical dysplasia. Cancer Epidemiol. Biomarkers Prev. 10, 1275–1280 (2001).

    CAS  PubMed  Google Scholar 

  61. 61

    Wallock, L. M. et al. Low seminal plasma folate concentrations are associated with low sperm density and count in male smokers and nonsmokers. Fertil. Steril. 75, 252–259 (2001).Folate deficiency in men causes uracil incorporation in sperm DNA and decreased sperm count and quality.

    CAS  PubMed  Google Scholar 

  62. 62

    Mayr, C. A., Woodall, A. A. & Ames, B. N. in Preventive Nutrition: The Comprehensive Guide for Health Professionals (eds Bendich, A. & Deckelbaum, R. J.) 373–386 (Humana Press, Inc., Totowa, New Jersey, 2001).

    Google Scholar 

  63. 63

    Fenech, M. F., Dreosti, I. E. & Rinaldi, J. R. Folate, vitamin B12, homocysteine status and chromosome damage rate in lymphocytes of older men. Carcinogenesis 18, 1329–1336 (1997).

    CAS  PubMed  Google Scholar 

  64. 64

    Fenech, M. Micronucleus frequency in human lymphocytes is related to plasma vitamin B12 and homocysteine. Mutat. Res. 428, 299–304 (1999).

    CAS  PubMed  Google Scholar 

  65. 65

    Stabler, S. P., Sampson, D. A., Wang, L. P. & Allen, R. H. Elevations of serum cystathionine and total homocysteine in pyridoxine-, folate-, and cobalamin-deficient rats. J. Nutr. Biochem. 8, 279–289 (1997).

    CAS  Google Scholar 

  66. 66

    Alberg, A. J. et al. The risk of cervical cancer in relation to serum concentrations of folate, vitamin B12, and homocysteine. Cancer Epidemiol. Biomarkers Prev. 9, 761–764 (2000).

    CAS  PubMed  Google Scholar 

  67. 67

    Wu, K. et al. A prospective study on folate, B12, and pyridoxal 5′-phosphate (B6) and breast cancer. Cancer Epidemiol. Biomarkers Prev. 8, 209–217 (1999).

    CAS  PubMed  Google Scholar 

  68. 68

    Key, T. J., Silcocks, P. B., Davey, G. K., Appleby, P. N. & Bishop, D. T. A case–control study of diet and prostate cancer. Br. J. Cancer 76, 678–687 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. 69

    Hartman, J. T. et al. Association of B-vitamins pyrodoxal 5′-phosphate (B(6)), B(12) and folate with lung cancer risk in older men. Am. J. Epidemiol. 153, 688–694 (2001).

    CAS  PubMed  Google Scholar 

  70. 70

    Weinstein, S. J. et al. Elevated serum homocysteine levels and increased risk of invasive cervical cancer in US women. Cancer Causes Control 12, 317–324 (2001).

    CAS  PubMed  Google Scholar 

  71. 71

    Jacob, R. A. in Nutrition in Health and Disease (eds Shils, M., Olson, J. A. & Shike, M.) 467–484 (Williams & Wilkins, Baltimore, 1999).

    Google Scholar 

  72. 72

    Ames, B. N., Shigenaga, M. K. & Hagen, T. M. Oxidants, antioxidants, and the degenerative diseases of aging. Proc. Natl Acad. Sci. USA 90, 7915–7922 (1993).

    CAS  PubMed  Google Scholar 

  73. 73

    Kono, S. & Hirohata, T. Nutrition and stomach cancer. Cancer Causes Control 7, 41–55 (1996).

    CAS  PubMed  Google Scholar 

  74. 74

    Zhang, Z. W., Abdullahi, M. & Farthing, M. J. Effect of physiological concentrations of vitamin C on gastric cancer cell and Helicobacter pylori. Gut 50, 165–169 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. 75

    Moller, P. & Loft, S. Oxidative DNA damage in human white blood cells in dietary antioxidant intervention studies. Am. J. Clin. Nutr. 76, 303–310 (2002).

    CAS  PubMed  Google Scholar 

  76. 76

    Levine, M. et al. Vitamin C pharmacokinetics in healthy volunteers: evidence for a recommended dietary allowance. Proc. Natl Acad. Sci. USA 93, 3704–3709 (1996).

    CAS  PubMed  Google Scholar 

  77. 77

    Duthie, S. J., Ma, A., Ross, M. A. & Collins, A. R. Antioxidant supplementation decreases oxidative DNA damage in human lymphocytes. Cancer Res. 56, 1291–1295 (1996).

    CAS  PubMed  Google Scholar 

  78. 78

    Harats, D. et al. Citrus fruit supplementation reduces lipoprotein oxidation in young men ingesting a diet high in saturated fat: presumptive evidence for an interaction between vitamins C and E in vivo. Am. J. Clin. Nutr. 67, 240–245 (1998).

    CAS  PubMed  Google Scholar 

  79. 79

    McCall, M. R. & Frei, B. Can antioxidant vitamins materially reduce oxidative damage in humans? Free Radic. Biol. Med. 26, 1034–1053 (1999).This review examines the scientific evidence that supplementation of humans with vitamin C, vitamin E or β-carotene lowers in vivo oxidative damage to lipids, proteins or DNA based on the measurement of oxidative biomarkers.

    CAS  PubMed  Google Scholar 

  80. 80

    Block, G. in Vitamin C: The State of the Art in Disease Prevention Sixty Years after the Nobel Prize (eds Paoletti, R., Sies, H., Bug, J., Grossi, E. & Poli, A.) 51–58 (Springer–Verlag, Milano, 1998).

    Google Scholar 

  81. 81

    Byers, T. & Guerrero, N. Epidemiologic evidence for vitamin C and vitamin E in cancer prevention. Am. J. Clin. Nutr. 62(6 Suppl), 1385S–1392S (1995).

    Google Scholar 

  82. 82

    Chan, S. W. Y. & Reade, P. C. The role of ascorbic acid in oral cancer and carcinogenesis. Oral Dis. 4, 120–129 (1998).

    CAS  PubMed  Google Scholar 

  83. 83

    Jacobs, E. J. et al. Vitamin C, vitamin E, and multivitamin supplement use and stomach cancer mortality in the Cancer Prevention Study II cohort. Cancer Epidemiol. Biomarkers Prev. 11, 35–41 (2002).

    CAS  PubMed  Google Scholar 

  84. 84

    Jacobs, E. J. et al. Vitamin C and Vitamin E supplement use and colorectal cancer mortality in a large American Cancer Society cohort. Cancer Epidemiol. Biomarkers Prev. 10, 17–23 (2001).

    CAS  PubMed  Google Scholar 

  85. 85

    Dietrich, M. et al. Antioxidant supplementation decreases lipid peroxidation biomarker F(2)-isoprostanes in plasma of smokers. Cancer Epidemiol. Biomarkers Prev. 11, 7–13 (2002).

    CAS  PubMed  Google Scholar 

  86. 86

    Collins, A. R., Olmedilla, B., Southon, S., Granado, F. & Duthie, S. J. Serum carotenoids and oxidative DNA damage in human lymphocytes. Carcinogenesis 19, 2159–2162 (1998).

    CAS  PubMed  Google Scholar 

  87. 87

    Panayiotidis, M. & Collins, A. R. Ex vivo assessment of lymphocyte antioxidant status using the Comet Assay. Free Rad. Res. 27, 533–537 (1997).This study reports results that the three main antioxidants have a demonstrable, short-term protective effect against oxidative DNA damage, which is widely regarded as an important element in the aetiology of cancer.

    CAS  Google Scholar 

  88. 88

    Beckman, K. B., Saljoughi, S., Mashiyama, S. & Ames, B. N. A simpler, more robust method for the analysis of 8-oxoguanine in DNA. Free Radic. Biol. Med. 29, 357–367 (2000).

    CAS  PubMed  Google Scholar 

  89. 89

    Helbock, H. J. et al. DNA oxidation matters: the HPLC-EC assay of 8-oxo-deoxyguanosine and 8-oxo-guanine. Proc. Natl Acad. Sci. USA 95, 288–293 (1998).

    CAS  PubMed  Google Scholar 

  90. 90

    Branda, R. F. & Blickensderfer, D. B. Folate deficiency increases genetic damage caused by alkylating agents and gamma-irradiation in Chinese hamster ovary cells. Cancer Res. 53, 5401–5408 (1993).

    CAS  PubMed  Google Scholar 

  91. 91

    Institute of Medicine, Food and Nutrition Board. Dietary Reference Intakes for Vitamin C, Vitamin E, Selenium and Carotenoids (National Academy Press, Washington DC, 2001).

  92. 92

    Fraga, C. G., Motchnik, P. A., Wyrobek, A. J., Rempel, D. M. & Ames, B. N. Smoking and low antioxidant levels increase oxidative damage to sperm DNA. Mutat. Res. 351, 199–203 (1996).

    PubMed  Google Scholar 

  93. 93

    Lykkesfeldt, J. et al. Ascorbate is depleted by smoking and repleted by moderate supplementation: a study in male smokers and nonsmokers with matched dietary antioxidant intakes. Am. J. Clin. Nutr. 71, 530–536 (2000).

    CAS  PubMed  Google Scholar 

  94. 94

    Sorahan, T. et al. Childhood cancer and parental use of tobacco: deaths from 1971 to 1976. Br. J. Cancer 76, 1525–1531 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  95. 95

    Sorahan, T., Lancashire, R. J., Prior, P., Peck, I. & Stewart, A. M. Childhood cancer and parental use of alcohol and tobacco. Ann. Epidemiol. 5, 354–359 (1995).

    CAS  PubMed  Google Scholar 

  96. 96

    Sorahan, T., Lancashire, R. J., Hulten, M. A., Peck, I. & Stewart, A. M. Childhood cancer and parental use of tobacco deaths from 1953 to 1955. Br. J. Cancer 75, 134–138 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  97. 97

    Ji, B.-T. et al. Paternal cigarette smoking and the risk of childhood cancer among offspring of nonsmoking mothers. J. Natl Cancer Inst. 89, 238–244 (1997).Lymphoma, acute lymphocytic leukaemia and brain cancer are each increased three- to fourfold in the offspring of men who smoke.

    CAS  PubMed  Google Scholar 

  98. 98

    Toyokuni, S. Iron-induced carcinogenesis: the role of redox regulation. Free Radic. Biol. Med. 20, 553–566 (1996).

    CAS  PubMed  Google Scholar 

  99. 99

    Yip, R. in Present Knowledge in Nutrition (eds Bowman, B. A. & Russell, R. M.) 311–328 (ILSI Press, Washington DC, 2001).

    Google Scholar 

  100. 100

    Nelson, R. L. Iron and colorectal cancer risk: human studies. Nutr. Rev. 59, 140–148 (2001).

    CAS  PubMed  Google Scholar 

  101. 101

    Zhang, D. et al. Vitamin E inhibits apoptosis, DNA modification, and cancer incidence induced by iron-mediated peroxidation in Wistar rat kidney. Cancer Res. 57, 2410–2414 (1997).

    CAS  PubMed  Google Scholar 

  102. 102

    Walter, P. W. et al. Iron deficiency and iron excess damage mitochondria and mitochondrial DNA in rats. Proc. Natl Acad. Sci. USA 99, 2264–2269 (2002).

    CAS  PubMed  Google Scholar 

  103. 103

    Atamna, H., Walter, P. W. & Ames, B. N. The role of heme and iron-sulfur clusters in mitochondrial biogenesis, maintenance, and decay with age. Arch. Biochem. Biophys. 397, 345–353 (2002).

    CAS  PubMed  Google Scholar 

  104. 104

    King, J. C., Shames, D. M. & Woodhouse, L. R. Zinc homeostasis in humans. J. Nutr. 130, 1360S–1366S (2000).Provides background information on zinc metabolism and describes how adjustments in zinc homeostasis occur in animals and humans.

    CAS  PubMed  Google Scholar 

  105. 105

    Wood, R. J. Assessment of marginal zinc status in humans. J. Nutr. 130, 1350S–1354S (2000).

    CAS  PubMed  Google Scholar 

  106. 106

    Walsh, C. T., Sandstead, H. H., Prasad, A. S., Newberne, P. M. & Fraker, P. J. Zinc: health effects and research priorities for the 1990s. Environ. Health Perspect. 102 (Suppl 2), 5–46 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  107. 107

    King, J. & Keen, C. L. in Nutrition in Health and Disease (eds Shils, M., Olson, J. A. & Shike, M.) 223–239 (Williams & Wilkins, Baltimore, 1999).

    Google Scholar 

  108. 108

    Sarkar, B. Metal replacement in DNA-binding zinc finger proteins and its relevance to mutagenicity and carcinogenicity through free radical generation. Nutrition 11, 646–649 (1995).

    CAS  PubMed  Google Scholar 

  109. 109

    Pavletich, N. P., Chambers, K. A. & Pabo, C. O. The DNA-binding domain of p53 contains the four conserved regions and the major mutation hot spots. Genes Dev. 7, 2556–2564 (1993).

    CAS  Google Scholar 

  110. 110

    Ho, E. & Ames, B. N. Zinc deficiency induces APE/Ref–1 expression and induces DNA damage in C6 glioma cells. Free Rad. Biol. Med. 31, 518 (2001).

    Google Scholar 

  111. 111

    Castro, C. E., Kaspin, L. C., Chen, S.-S. & Nolker, S. G. Zinc deficiency increases the frequency of single-strand DNA breaks in rat liver. Nutr. Res. 12, 721–736 (1992).

    CAS  Google Scholar 

  112. 112

    Olin, K. L. et al. Maternal dietary zinc influences DNA strand break and 8-hydroxy-2′-deoxyguanosine levels in infant rhesus monkey liver. Proc. Soc. Exp. Biol. Med. 203, 461–466 (1993).

    CAS  PubMed  Google Scholar 

  113. 113

    Oteiza, P. L., Olin, K. L., Fraga, C. E. & Keen, C. L. Oxidant defense systems in testes from zinc-deficient rats (44040). Proc. Soc. Exp. Biol. Med. 213, 85–91 (1996).

    CAS  PubMed  Google Scholar 

  114. 114

    O'Connor, T. R., Graves, R. J., de Murcia, G., Castaing, B. & Laval, J. Fpg protein of Escherichia coli is a zinc finger protein whose cysteine residues have a structural and/or functional role. J. Biol. Chem. 268, 9063–9070 (1993).

    CAS  PubMed  Google Scholar 

  115. 115

    Newberne, P. M., Broitman, S. & Schrager, T. F. Esophageal carcinogenesis in the rat: zinc deficiency, DNA methylation and alkyltransferase activity. Pathobiology 65, 253–263 (1997).

    CAS  PubMed  Google Scholar 

  116. 116

    Fong, L. Y. Y., Lau, K.-M., Huebner, K. & Magee, P. N. Induction of esophageal tumors in zinc-deficient rats by single low doses of N-nitrosomethylbenzylamine (NMBA): analysis of cell proliferation, and mutations in H-ras and p53 genes. Carcinogenesis 18, 1477–1484 (1997).

    CAS  PubMed  Google Scholar 

  117. 117

    Fong, L. Y. Y., Li, J., Farber, J. L. & Magee, P. N. Cell proliferation and esophageal carcinogenesis in the zinc-deficient rat. Carcinogenesis 17, 1841–1848 (1996).

    CAS  PubMed  Google Scholar 

  118. 118

    Fong, L. Y., Nguyen, V. T. & Farber, J. L. Esophageal cancer prevention in zinc-deficient rats: rapid induction of apoptosis by replenishing zinc. J. Natl Cancer Inst. 93, 1525–1533 (2001).

    CAS  PubMed  Google Scholar 

  119. 119

    Anderson, M. B., Lepak, K., Farinas, V. & Geroge, W. J. Protective action of zinc against cobalt-induced testicular damage in the mouse. Reprod. Toxicol. 7, 49–54 (1993).

    CAS  PubMed  Google Scholar 

  120. 120

    Xu, B., Chia, S. E. & Ong, C. H. Concentrations of cadmium, lead, selenium and zinc in human blood and seminal plasma. Biol. Trace Element Res. 40, 49–57 (1994).

    CAS  Google Scholar 

  121. 121

    Wong, W. Y. et al. Effects of folic acid and zinc sulfate on male factor subfertility: a double-blind, randomized, placebo-controlled study. Fertil. Steril. 77, 491–498 (2002).

    PubMed  Google Scholar 

  122. 122

    Block, G. in Antioxidant Food Supplements in Human Health (eds Packer, L., Hiramatsu, M. & Yoshikawa, T.) 45–54 (Academic Press, San Diego, 1999).

    Google Scholar 

  123. 123

    Scholl, T. O. et al. Use of multivitamin/mineral prenatal supplements: influence on the outcome of pregnancy. Am. J. Epidemiol. 146, 134–141 (1997).Examines the association of prenatal multivitamin and mineral supplements during the first two trimesters of pregnancy and birth outcomes. Risk for preterm delivery and low birth weight was reduced with supplement use.

    CAS  PubMed  Google Scholar 

  124. 124

    Willett, W. C. & Stampfer, M. J. What vitamins should I be taking, Doctor? N. Engl. J. Med. 345, 1819–1824 (2001).

    CAS  PubMed  Google Scholar 

  125. 125

    Albanes, D. et al. Alpha-tocopherol and beta-carotene supplements and lung cancer incidence in the alpha-tocopherol, beta-carotene cancer prevention study: effects of base-line characteristics and study compliance. J. Natl Cancer Inst. 88, 1560–1570 (1996).

    CAS  PubMed  Google Scholar 

  126. 126

    Omenn, G. S. et al. Risk factors for lung cancer and for intervention effects in CARET, the Beta-Carotene and Retinol Efficacy Trial. J. Natl Cancer Inst. 88, 1550–1559 (1996).

    CAS  PubMed  Google Scholar 

  127. 127

    Levine, A. J. et al. Serum 25-hydroxyvitamin D, dietary calcium intake, and distal colorectal adenoma risk. Nutr. Cancer 39, 35–41 (2001).

    CAS  PubMed  Google Scholar 

  128. 128

    Kallay, E. et al. Vitamin D receptor activity and prevention of colonic hyperproliferation and oxidative stress. Food Chem. Toxicol. 40, 1191–1196 (2002).

    CAS  PubMed  Google Scholar 

  129. 129

    Chan, J. M., Stampfer, M. J., Gann, P. H., Gaziano, J. M. & Giovannucci, E. L. Dairy products, calcium and prostate cancer risk in Physicians' Health Study. Am. J. Clin. Nutr. 74, 549–554 (2001).

    CAS  PubMed  Google Scholar 

  130. 130

    Giovannucci, E. L. et al. Calcium and fructose intake in relation to risk of prostate cancer. Cancer Res. 58, 442–447 (1998).

    CAS  PubMed  Google Scholar 

  131. 131

    Clark, L. C. et al. Decreased incidence of prostate cancer with selenium supplementation: results of a double-blind cancer prevention trial. Br. J. Urol. 81, 730–734 (1998).

    CAS  PubMed  Google Scholar 

  132. 132

    Nomura, A. M., Lee, J., Stemmermann, G. N. & Combs, G. F. J. Serum selenium and subsequent risk of prostate cancer. Cancer Epidemiol. Biomarkers Prev. 9, 883–887 (2000).

    CAS  PubMed  Google Scholar 

  133. 133

    Yoshizawa, K. et al. Study of prediagnostic selenium level in toenails and the risk of advanced prostate cancer. J. Natl Cancer Inst. 90, 1184–1185 (1998).

    Google Scholar 

  134. 134

    Klein, E. A. et al. SELECT: the next prostate cancer prevention trial. Selenum and Vitamin E Cancer Prevention Trial. J. Urol. 166, 1311–1315 (2001).

    CAS  PubMed  Google Scholar 

  135. 135

    Negri, E. et al. Selected micronutrients and oral and pharyngeal cancer. Int. J. Cancer 86, 122–127 (2000).

    CAS  PubMed  Google Scholar 

  136. 136

    Franceschi, S. et al. Role of macronutrients, vitamins and minerals in the aetiology of squamous-cell carcinoma of the oesophagus. Int. J. Cancer 86, 626–631 (2000).

    CAS  PubMed  Google Scholar 

  137. 137

    Greenwald, P., Clifford, C. K. & Milner, J. A. Diet and cancer prevention. Europ. J. Cancer 37, 948–965 (2001).This review covers the evidence for a diet and cancer relationship, including the topics of vegetables and fruits, dietary fibre, micronutrients, phytochemicals, dietary fat, anthropometry/physical activity and alcohol. It also discusses the emerging evidence of gene–nutrient interactions and future directions.

    CAS  Google Scholar 

  138. 138

    Gupta, K., Krishnaswamy, G., Karnad, A. & Peiris, A. N. Insulin: a novel factor in carcinogenesis. Am. J. Med. Sci. 323, 140–145 (2002).

    CAS  PubMed  Google Scholar 

  139. 139

    IARC International Agency for Research on Cancer, WHO. Weight Control and Physical Activity (IARC Press, Lyon, 2002).

  140. 140

    Key, T. J. Epidemiology of breast cancer. Lancet Oncol. 2, 133–140 (2001).

    CAS  PubMed  Google Scholar 

  141. 141

    McCann, J. Obesity, cancer links prompt new recommendations. J. Natl Cancer Inst. 93, 901–902 (2001).

    CAS  PubMed  Google Scholar 

  142. 142

    Barnes, S. Role of phytochemicals in prevention and treatment of prostate cancer. Epidemiol. Rev. 23, 102–105 (2001).

    CAS  PubMed  Google Scholar 

  143. 143

    Wakimoto, P. & Block, G. Dietary intake, dietary patterns, and changes with age: an epidemiolgical perspective. J. Gerontol. A. Biol. Sci. Med. Sci. 56, 65–80 (2001).

    PubMed  Google Scholar 

  144. 144

    Block, G. Analysis of: National Health and Nutrition Examination Survey III 1988–1994 Public-Use Data Files (National Center for Health Statistics, Hyattsville, Maryland).

  145. 145

    Ames, B. N. The metabolic tune up: metabolic harmony and disease prevention. J. Nutr. (in the press).

  146. 146

    Ulrich, C. M. et al. Lack of association between the C677T MTHFR polymorphism and colorectal hyperplasic polyps. Cancer Epidemiol. Biomarkers Prev. 9, 427–433 (2000).

    CAS  PubMed  Google Scholar 

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This work was supported by grants from the National Foundation for Cancer Research, the US Department of Energy, the Wheeler Fund for the Biological Sciences at the University of California Berkeley, the Ellison Medical Foundation and the National Institute of Environmental Health Sciences Center. We thank L. Gold and J. Nides for their many useful comments.

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Correspondence to Bruce N. Ames.

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haem oxygenase II




The International Bibliographic Information on Dietary Supplements (IBIDS):

Linus Pauling Institute Micronutrient Information Center

National Institute of Health Office of Dietary Supplements

Scientific evaluation of US dietary reference intakes



Dietary intake of a vitamin or mineral at a level that is less than 50% of the recommended daily allowance — as distinguished from acute deficiency. For example, acute vitamin C deficiency causes scurvy.


(RDA). The dietary-intake level that is sufficient to meet the daily nutrient requirements of nearly all healthy individuals in a defined group.


An epidemiological study design in which individuals are selected based on the presence (case) or absence (control) of disease. Well-designed case–control studies require that the two groups are derived from the same population.


An epidemiological study design in which individuals with known characteristics (such as occupational exposure, smoking and exercise) are enrolled and followed over time for specific outcomes. The rate of cancer (or other disease) in the exposed population is compared to that in the unexposed population.


A retrospective analysis of the results from different studies, making certain assumptions, to reach a conclusion that is based on the pooled data.


These occur because behaviour-related variables of interest tend to cluster. An exposure (for example, vegetable consumption) might be of interest in protecting against a particular cancer. However, if smokers eat fewer vegetables than non-smokers, we might falsely attribute a risk reduction to vegetables that is really owing to the fact that a higher proportion of vegetable-eaters are non-smokers. Confounding factors can be controlled for by separating the smokers and the non-smokers and asking whether the vegetable–cancer association is seen in both groups, or by more sophisticated, but conceptually similar, statistical techniques.


Often called a clinical trial or experimental study, an epidemiological analysis of a hypothesized cause–effect relationship that is performed by modifying a supposed causal factor, such as lack of vitamin C consumption, in a population.


Occurs in individuals that describe events (such as exposures, diseases and pregnancy outcome) of the past in a non-comparable manner. It is primarily a problem in case–control studies when that presence of the disease in one group might result in differential recall (for example, of alcohol consumption or dietary behaviour) between the cases and controls.


A technique that uses electrophoresis of immobilized single cells to measure DNA strand breaks.


The number of years of tobacco use, multiplied by the number of packs per day. For example, 1 pack year is 20 cigarettes per day for 1 year, 40 cigarettes per day equals 2 pack years.


A genetic disorder and the most common form of iron overload disease, which is characterized by iron deposition in the liver and other tissues as a result of a small increase in intestinal iron absorption over many years. It most often affects white northern Europeans: 1 in 8–12 is a carrier of the abnormal gene, and men are five times more likely to be diagnosed with haemochromotosis than women.

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Ames, B., Wakimoto, P. Are vitamin and mineral deficiencies a major cancer risk?. Nat Rev Cancer 2, 694–704 (2002).

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