Caffeinated Beverages - American Chemical Society

Chapter 9

Evaluation of Coffee and Caffeine for Mutagenic, Carcinogenic, and Anticarcinogenic Activity Richard H . Adamson th

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National Soft Drink Association, 1101 16 Street, NW, Washington, DC 20036

The available scientific literature demonstrates that coffee is mutagenic in vitro due largely to the presence of methylglyoxal and hydrogen peroxide, but coffee is not mutagenic in vivo and its in vitro effects are not relevant to humans. Although caffeine induces chromosomal aberrations in plants and in human leukocytes in vitro, it is neither mutagenic in several S. typhimurium tester strains nor in vivo. Both coffee and caffeine have undergone bioassays in rodents for carcinogenicity and are not carcinogenic. Indeed, there is some evidence of a protective effect against cancer in these studies. Also, caffeine in combination with a variety of known rodent carcinogens generally inhibits tumor induction. Furthermore, epidemiologic studies in humans on coffee and total methylxanthine intake and cancer generally suggest no effect or a negative association with various cancers, especially large bowel and female breast cancer.

Beverages made from coffee beans, tea leaves, kola nuts and coca beans have been enjoyed by humans for thousands of years. Because of the long history of use and the wide consumption of these caffeine containing beverages, the potential adverse or beneficial effects of these beverages and caffeine have been studied, especially during the last several decades. Numerous studies have been carried out in several laboratories to evaluate the mutagenic, carcinogenic, and anticarcinogenic activity of caffeine in a variety of in vitro tests, in animals and in epidemiologic studies. These studies will be summarized in this paper. Some reviews on this subject have been published (7-3).

Standard Caffeine Content A wide range of values exist for the caffeine content of food and beverages. However, based on current information, standard values of caffeine content of various foods has been published and are displayed in Table I (1,4). © 2000 American Chemical Society

Parliment et al.; Caffeinated Beverages ACS Symposium Series; American Chemical Society: Washington, DC, 2000.

71

72 Table I. Standard Values of Caffeine Content of Various Beverages Beverage

Volume (oz)

Caffeine Content On mg)

mg/oz

5 5 5

85 60 3

17 12 0.6

5 5 6 5 6

30 20 18 4 4

6 4 3 0.8 0.67


Coffee ground roasted instant decaffeinated Tea leaf or bag instant Colas Hot chocolate Chocolate milk Source: References 1,4.

In Vitro Evaluation of Coffee and Caffeine for Mutagenic Activity Both coffee and caffeine have been evaluated for mutagenic activity in a variety of in vitro systems (1,5,6). Table II summarizes some of the available data for the effects of coffee in the S. typhimurium TA98 and T A 100 test system. Both brewed and decaffeinated coffee are mutagenic without activation but this activity is abolished with activation. Both ground and instant coffee are mutagenic in the A R A mutant S. typhimurium but catalyse abolishes more than 95% of this activity (6). Furthermore, both methylglyoxal and hydrogen peroxide have mutagenic activity in the Ara mutant assay, but caffeine is not mutagenic in this assay. Thus, the evidence indicates that most of the in vitro mutagenic effects of coffee are due to the presence of hydrogen peroxide and dicarbonyls and that caffeine is not involved in the in vitro mutagenic effects of coffee. Recent studies have also suggested that hydroxyhydroquinione, a component o f instant coffee, may be involved in some of the in vitro genotoxic effects of coffee (7). In host mediated assays using S. typhimurium, in which coffee was administered to Swiss mice by gavage, the results were negative. Also, instant coffee given to Swiss mice showed no significant induction of micronuclei. Coffee had been shown to exert protective effects against genotoxic activities of numerous environmental chemicals in several test systems. Coffee demonstrated protective effects against somatic mutation and mitotic recombination induced by cyclophosphamide, mitomycin C and urethane in both the standard and the high bioactivation crosses of the wing spot test in Drosophila melanogaster (8). Another report demonstrated that the administration of coffee with combinations of various dietary constituents, could lead to varying degrees of increases in the in vivo anti-genotoxic effects, compared to when these agents were given separately using the mousebone marrow micronucleus test. Although some combinations did not show an enhancement of anti-genotoxic effects, none of the combinations showed an antagonistic effect (9).


73 Table II. In Vitro Genetic Effects of Coffee Test System

Type of Coffee

S. Typhimurium T A 100, reverse mutation

Brewed

S. Typhimurium T A 98, reverse mutation

Without Activation +

With Activation

-

Instant Decaffeinated Brewed

+/-

--

Instant Decaffeinated

+

-


Source: References 1, 5.

In plants, caffeine increases chromosomal aberrations and increases the rate of point mutations. Also, caffeine has been shown to be mutagenic in algae and in some, but not all, fungi. However, caffeine was consistently not mutagenic in six different S. typhimurium his" reversion tester strains and in S. typhimurium forward mutation studies. Caffeine did not induce D N A strand breaks in mammalian cells in vitro and was equivocal in inducing sister chromatid exchange in human leukocytes. Caffeine was able to induce chromosomal aberrations in human leukocytes in vitro, but numerous studies on the clastogenic effects of caffeine evaluating micronuclei, bone marrow metaphases or dominant lethal mutations were almost uniformly negative, and when positive, the doses were in the toxic range (/).

Bioassays of Coffee and Caffeine Carcinogenicity Both instant and brewed coffee have undergone bioassays in rodents. In a life time study on instant coffee in the diet of mice, including the gestation period, no increase incidence of tumors was found (10). In a bioassay of 25, 50, and 100% freshly brewed coffee as the drinking fluid as compared to tap water, an increase in tumors was seen only in the lowest dose group in males but not in other groups of either sex (7/). A bioassay at the maximum tolerated dose (6%) of instant coffee in the diet of rats for two years was conducted using both regular, decaffeinated, and decaffeinated plus added caffeine instant coffee. With all groups, the total number of neoplasms was either similar to or significantly lower than the total number in the control group (/). The decrease incidence was seen in the rats fed regular coffee, but was not apparent in the decaffeinated treated group, and in addition there was a tendency toward a decrease in the decaffeinated plus caffeine treated group. Caffeine also has undergone a bioassay in both mice and rats and these studies are summarized in Table III (13-15). Caffeine did not demonstrate any carcinogenic potential in these studies, but in one study in rats it exhibited a dose dependent


74 reduction in the number of tumors, but the weight loss in the animals at the highest dose may have contributed to tumor reduction (15).


Table III. Bioassay of Caffeine in Rodents Dose 5 mg/Kg diet

Species C57 B L mice

No. of Animals 40 M ; 4 0 F

Results No effect

0.1% or 0.2% drinking wter

Wister rats

50 M ; 5 0 F per group

No effect

0.2-2% drinking water

S. D. rats

50 M ; 5 0 F per group

Dose dependent reduction of tumors

Source: References 13-15.

Caffeine Administration to Rodents in Combination with Known Carcinogens Following administration of caffeine to mice or rats in combination with known carcinogens, it has been reported that tumor promotion, no effect on tumor development or inhibition in tumor development occured. However, the majority of studies have shown that caffeine decreased the incidence of tumors that developed. Thus, caffeine decreased the incidence of skin tumors in mice treated with cigarette smoke condensate, ultraviolet light or 4-nitroquinoline-l-oxide and also decreased the incidence of lung tumors in mice treated with urethane (/, 16-19). When administered to rats, caffeine exhibited a biphasic effect on pancreatic tumor incidence by 4 - H A Q O (4-hydroxyaminoquinoline 1-oxide) inhibiting tumor formation at higher doses and stimulating tumor formation at lower doses. When administered at a concentration of 0.1% in the drinking water, caffeine did not have an effect on urinary bladder cancer in rats treated with B N N (A -butyl-A^-(4-hydroxybutyl)nitrosamine. However, caffeine in the drinking water at various doses did inhibit liver tumor development by 2 - A A F (2-acetylaminofluorene), or mammary tumors induced by D M B A (7,12-dimethylbenz[a]anthracene) or DES (diethylstilbestrol). Also caffeine, at doses equivalent to that found in 2% black tea (e.g. 680 ppm), reduced, by 79%, the incidence of lung tumorgenesis induced by N N K (4-(methylnitrosamino)-l-(3-pyridyl)1-butanone) in Fischer 344 rats. These studies have been summarized in Table IV (/, 20-22). Although the mechanism(s) of action of caffeine in inhibiting physical and chemical carcinogens in rodents is unknown, several different mechanisms have been postulated. Among theses are effects on cytochrome(s) P450, inhibition of enzymes of purine metabolism , inhibition of c A M P phosphodiesterase, and effects on D N A metabolism, chromatin structure and function (/). r


75 Table IV. Combination of Caffeine and Carcinogens in Rats Dose of Caffeine

Pre or Post Carcinogen

30-120 mg/Kg 0.1% drinking water 0.2% drinking water 0.1-0.8% drinking water 0.1 -0.2% drinking water 680 ppm drinking water

Post Same or Post Same Pre Same Pre

Carcinogen

4-HAQO BNN 2-AAF DMBA DES NNK

a

Target Organ Pancreas Bladder Liver Breast Breast Lung

Maximal Inhibition of Tumors 80% No effect 72% 58% >99% 79% a

b

b

c

c


Source: Reference 1, 20-22; Biphasic; dumber tumors/rat; Total cancers.

Epidemiologic Studies Both coffee and total methylxanthine intake have been studied in a number of epidemiologic studies relative to cancer in humans and these have been reviewed (1,23,24). Epidemiologic studies have involved studies of cancer at all sites and at specific organ sites. Two studies demonstrated no association between coffee consumption and risk of cancer at all sites. The first study evaluated caffeine consumption (coffee, tea, and caffeine containing medications) in over 10,000 persons in the Hypertension Detection and Follow Up study, and no association was found between caffeine consumption and mortality from cancer or any other cause (25). In the second study, a prospective study in Norway, of 21,735 men and 21,238 women age 35-54 followed for 10 years, there was no association between caffeine consumption and overall risk of cancer. There also was no significant association between coffee intake and incidence of cancer of the bladder or pancreas (26). There were some negative associations found with some types of cancer. The organ site at which the literature data is most inconsistent is bladder cancer (23,24). When the association is positive, the relative risk is generally minimal and only a few studies demonstrate an important dose response relationship. Many studies have found no correlation between coffee consumption and bladder cancer (1,23,24). Also, because of bias and confounding factors, especially smoking, occupational factors and diet, the totality of the studies do not implicate coffee as an important risk for bladder cancer. In contrast, several studies of cancer at other organ sites, indicate that coffee or methylxanthine intake may lessen the risk of cancer. Thus as summarized in Table V , in four studies of breast cancer, three of which were case control studies and one an international aggregate study, intake of coffee (or total methylxanthines) was correlated with a negative (protective) association with development of breast cancer (27-30). Also, in three studies, coffee intake was negatively associated with risk of colon cancer (31-34). Thus, in humans, the studies of coffee or total methylxanthine intake in general are supportive of no effect on cancer causation and indeed some studies, especially in large bowel cancer and female breast, are supportive of a protective effect.



Table V. Epidemiologic Studies of Methylxanthine Intake and Breast Cancer Study Type International Aggreagete Data

Cancer Breast

Case control: 818 cases, 1700 controls

Breast


Breast


Breast

Results Negative when fat intake is factored Negative association > 4 cups coffee/day; odds ratio 0.6 Negative association > 3 cups coffee/day; odds ratio 0.6 No association with coffee, decaffeinated coffee or tea intake

Source: References 27-30.

References

1.

2. 3.

4. 5. 6. 7. 8. 9. 10.

11. 12. 13.

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77 14. Takayama, S.; Kuwabara, N. Gann, 1982, 73, 365-371. 15. Mohr, U.; Althoff, J.; Ketkar, M. B . ; Conradt, P. Fd. Chem. Toxicol, 1984, 22, 377-382. 16. Zajdela, F.; Latarjet, R. National Cancer Inst. Monograph 1978, No. 50, 133140. 17. Theiss, J. C.; Shimkin, M. B . Cancer Res. 1978, 38, 1757-1761. 18. Huang, M-T.; Xie, J-G.; Wang, Ζ. Y.; Ho. C.-T.; Lou, Y-R.; Wang, C - X . ; Hard, G. C.; Conney, A . H . Cancer Res. 1997, 57, 2623-2629. 19. Lou, Y-R.; L u , Y-P.; Xie, J-G.; Huang, M-T.; Conney, A . H . Nutrition Cancer, 1999, 33, 146-153. 20. Minton, J. P.; Abou-Issa, H . ; Foecking, M. K . ; Sriram, M. G . Cancer 1983, 51, 1249-1253. 21. Petrek, J. Α.; Sandberg, W. Α.; Cole, M. N.; Silberman, M. S.; Collins, D. C. Cancer 1985, 56, 1977-1981. 22. Chung, F - L . ; Wang, M.; Rivenson, Α.; Iatropoulos, M . J.; Reinhardt, J. C.; Pittman, B.; Ho, C.-T.; Amin, S. G. Cancer Res. 1998, 58, 4096-4101. 23. Viscoli, C. M.; Lachs, Μ. Α.; Horowitz, R. I. Lancet 1993, 341, 1432-1437. 24. Nehlig, Α.; Debry, G . In Metabolic Consequences of Changing Dietary Patterns; Simopules, A . P., Ed.; World Rev. Nutr. Diet, Basel, Switzerland, 1996, pp. 185221. 25. Martin, J. B . ; Annegers, J. F.; Curb, J. D.; Heyden, S.; Howson, C.; Lee, Ε. N.; Lee, M. Preventive Med. 1988, 17, 310-320. 26. Stensvold, I.; Jacobson, Β. K . Cancer Causes and Control 1994, 5, 401-408. 27. Lè, M. G . Am. J. Epid. 1985, 122, 721. 28. Lubin, F.; Ron, E; Wax, Y . ; Mordan, B . J. Natl. Cancer Inst. 1985, 74, 569-573. 29. Tavani, Α.; Pregnolato, Α.; L a Vecchia, C.; Favero, Α.; Franceschi, S. Eur. J. Cancer Prev. 1998, 7, 77-82. 30. Phelps, Η. M.; Phelps, C. E. Cancer 1988, Vol. 61, 1051-1054. 31. LaVecchia, C.; Ferraroni, M.; Negri, E.; Avanzo, B . ; Decarli, Α.; Levi, F.; Franceschi, S. Cancer Res. 1989, 49, 1049-1051. 32. Tuyns, A . J.; Kaaks, R.; Haelterman, M . Nut. Cancer, 1988, 11, 189-204. 32. Baron, J. Α.; Gerhardsson de Verdier, M.; Ekbom, A . Cancer Epi Biomarkers Prev. 1994, 3, 565-570. 33. Munoz, S. E . ; Navarro, Α.; Lantieri, M . J.; Fabro, M . E . ; Peyrano, M . G . ; Ferraroni, M.; Decarli, Α.; LaVecchia, C.; Eynard, A . R . Eur. J. Cancer Prev. 1998, 7, 207-213.


Caffeinated Beverages - American Chemical Society

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