Coffee drinking and bladder cancer

Fd Chem. Toxic'. Vol. 22, no. 6, pp. 481 495, 1984 Printed in Great Britain

0278-6915/84 $3.00 +0.00 Pergamon Press ktd

Information Section COFFEE D R I N K I N G AND BLADDER CANCER Epidemiologists have a great professional regard for coffee. Not only are people apparently content to be questioned about this particular indulgence, but society's neutral acceptance of coffee addiction allows the enquiring scientists more confidence than usual in the accuracy of the results of their interrogations. Although the attempts made over the last decade or so to demonstrate the carcinogenicity of coffee drinking have never produced any unequivocal conclusions, the suspicions of carcinogenic action fairly frequently aroused have encouraged the search to continue. The 1971 report of Cole (Lancet 197l, I, 1335) that coffee drinking was associated with an increased risk of developing cancer of the lower urinary tract was the first of a now impressive number of case-control studies that have attempted to link coffee drinking with bladder cancer. The study of Cole (loc. cit.) and that of Fraumeni et al. (ibid 1971, II, 1204), published at around the same time, each involved comparison of the coffee-drinking habits of approximately 500 cancer patients with those of an equal number of controls. Their findings could be said to set the pattern for subsequent reports. Statistically significant increases in the risk of developing bladder cancer (or cancer of the lower urinary tract) were associated with coffee exposure in some subgroups in females but not in males of the Cole study and in black women but not in white women or black or white men in the study of Fraumeni et a/.--but even for the apparently susceptible drinkers, no convincing dose-response relationships were evident. Cole estimated, for example, that for women whose regular coffee consumption (in cups/day) was over 4, 2 3 or 1, the risks were 2.19, 3.76 and 1.60, respectively, compared with a risk of 1.00 for those taking less than 1 cup/day. Later, Simon et al. (J. natn. Cancer Inst. 1975, 54, 587) compared 135 women with cancer of the lower urinary tract (95°; bladder cancers) and 390 patients from the same hospital but with no urinary-tract problems. This led to a similarly unsatisfactory outcome--a glimmer of a coffee-cancer association but no indication of an increase in risk with an increase in consumption. Taking those drinking less than 1 cup of coffee/day as having a cancer risk of 1.0, Simon et al. estimated that the consumption of more than l cup/day was associated with a risk of 2.1 (1.1-4.3, 95~, confidence intervals). Balancing the gender score somewhat, the studies of Howe et al. (ibid 1980, 64, 701) and of Mettlin & Graham (Am. J. Epidemiol. 1979, 110, 255) showed hints of coffee's carcinogenicity more clearly in males than females. Each study involved the participation of about 600 patients with bladder cancer and groups of age-matched controls. Howe et al., checking on the number of cancers seen in those who had ever drunk coffee and in those who had never drunk it, calculated

that for coffee-drinking males the relative risks of developing cancer were 1.4 (0.9 2.0, 95'~Joconfidence intervals) for all types of coffee, 1.5 (1.0 2.2) for regular coffee and 1.5 (1.1-2.0) for instant coffee. Using a multivariate method of analysis (which incorporated a factor to take account of the effect of smoking), the risk factors that were increased by a statistically significant amount were, in males, those associated with up to 2 cups of all types of coffee/day (but not with 3-4 cups or more than 5 cups/day) and with 1 2 and more than 5 cups/day of regular coffee. In females, there was a fourfold increase in risk for drinkers of 3 cups or more of instant coffee/day, but the risks were no higher in those drinking 5 cups or more than in those taking 3-4 cups. Mettlin & Graham found that males who had in the past regularly drunk more than 3 cups of coffee/day exhibited a cancer risk of 2.11 (relative to a risk of 1.00 for those drinking less than I cup/day), a statistically significant change. However~ the corresponding risk (1.64) for larger intakes and the 1.16 and 1.38 risk factors associated with intakes of 2 cups or 1 cup/day, respectively, were not statistically significant. Whilst neither Mettlin & Graham (Ioc. tit.) nor Howe et al. (loc.cit.) could uncover any evidence of a dose response, some investigators have generated data that point more convincingly to an increasing cancer risk with an increase in exposure. Three separate studies, in fact, have produced some indication of a dose response in males. In the 360 male patients with bladder cancer interviewed by Bross & Tidings (Prey. Med. 1973, 2, 445), the 574 male bladder-cancer patients seen by Wynder & Goldsmith (Cancer, N . Y . 1977, 40, 1246) and the 224 Japanese males (but not the 389 British or 423 US males) with cancer of the lower urinary tract who participated in the study of Morrison et al. (J. natn. Cancer hTst. 1982, 68, 91), the relative risks were shown to increase with increasing average daily coffee consumption. No similar trends were seen in the female groups in any of these three studies and, even in the susceptible males, those drinking the greatest amount of coffee experienced at most only a doubling of the risks of a coffee-free existence. Two additions to the coffee-bladder cancer literature have been published recently. Coincidentally, Connecticut cancer patients feature in both reports. In the smaller of the studies, an attempt was made to interview all the 516 Connecticut inhabitants who were first found to be suffering from bladder cancer in the year starting 15 January 1978 (Marrett et al. Am. J. Epidemiol. 1983, 117, 113). In the larger study, Connecticut was just one of ten areas of the USA in which newly diagnosed cases of bladder cancer were identified. As a consequence, a group led by Hartge set themselves the more ambitious task of trying to

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interview 4086 people whose bladder cancer was first diagnosed in a 4-month period from December 1977 (Hartge et al. J. n a m . C a n c e r Inst. 1983, 70, 1021). Both groups of investigators used information obtained during home interviews based on structured questionnaires to compare various aspects of the lifestyle of the cancer patients and of other individuals drawn from the same geographical area as the cancer patients and matched with them by age and gender. Success in converting eligibility for interview into actual interviews was roughly the same in both of the studies. Hartge el al. eventually gleaned inl\wmation from a cancer group of almost 3000 and a control group of 5800, 73 and 82'I 0 of those first identified. The corresponding percentages in the Marrett et al. study were 800, for the cancer patients and 851~i for controls, giving final group sizes of 412 and 881 respectively. The interviews generated data on the use of tobacco, artificial sweeteners and hair dyes, on occupation and on the consumption of coffee in a typical week in the winter I year prior to interview (at a time, it was thought, when the cancer victim would have had no knowledge of the disease). A litEtime intake of more than 100 cups of coffee was the chosen dividing line between a cotlEe drinker and non-drinker in both of the studies. The coffee intakes of around 100 of the participants in the Hartge el al. study were below this point. Comparing coffee drinkers with non-drinkers, the relative risk of developing bladder cancer adjusted for gender, age. race and area of residence was 1.8, which was reduced to 1.4 (1.1 1.8, 95'!,, confidence intervals) if the effect of smoking was included in the analysis. Both of these values were statistically significant. Although the risk figure of 1.6 for males was higher than the 1.2 for females, this gender difference was not statistically significant. Relative risk bore no relationship to duration of coffee drinking or to whether a person was an ex-drinker or a recent drinker. Using the information on recent drinking habits, and taking those drinking up to 7 cups/week as the risk baseline (equal to 1), no increase in risk with increase in consumption was seen in women, whilst in males a statistically significant value was obtained only in the top exposure group (63.1 155 cups/week), in which the relative risk was 1.5 (1.1 1.9. 95" 0 confidence limits.). By eliminating the cups of ground or instant decaflEinated coffee from the exposure figures, checks were made on whether the consumption of caffeine-containing coffee or tea was associated with any consistent changes in the likelihood of developing bladder cancer, but again no convincing trends were apparent. Various other manipulations of the data for example, identifying subgroups of coffee exposure such as non-drinkers and very heavy drinkers, or checking the effect of "ever drinking" versus "never drinking' within the various categories of tobacco history--similarly failed to uncover any convincing links between coffee drinking and the chances of developing bladder cancer. In their smaller study, Marrett el al. (lot. cir.) found that the relative bladder-cancer risk in coffee drinkers compared with abstainers was 1.5 in females (0.5 5.4, 95'.'o confidence intervals) and 4.0 ( 1.2 20.8) in males, the latter value achieving statistical

significance (P < 0.05). However, these figures were not adjusted for the effects of smoking. When data on coffee consumption were stratified for age, sex and smoking history, the risks for those drinking more than 7 cups/week compared with those drinking less were increased in all age-sex-smoking subgroups, with the exception of women smokers over 65 years old who had a lower risk. The reduced risk seen in these women smokers was nevertheless the only result in this series in which the 95"o confidence intervals did not include 1.00. Using methods of analysis based on logistic regression and incorporating terms for coffee intake, cigarette exposure and age, some significant associations of coffee consumption and disease state were identified in males. No similar links were seen in females. Lifetime coffee consumption and total weekly consumption in males were significantly associated with disease status. Since the number of years of coffee consumption was not a significant factor, the intensity of exposure seemed to be more important than the duration in increasing risk. There was a significantly increased risk associated with drinking 21 34 cups of coffee/week, but the risk associated with drinking 35 cups or more, although also elevated, just failed to achieve statistical significance. In both instances the calculated coefficients were said to be equal to an odds ratio (the ratio of observed to expected incidence) of around 2.0. A check on the effects of various types of colree uncovered significant positive results involving only the consumption of regular (call'einated) coffee, the increase in risk being seen whether the model used was logarithmic (log of cups/week) or dichotomous (risk of drinking more than 7 cups'week versus risk of drinking less than 7 cups:'week). A regression analysis of the data from non-smokers of either sex or from female smokers showed no indications of a coffee effect. In male smokers, however, there was some evidence that coffee consumption, expressed either in terms of cups of regular coffee week or lifetime consumption, was a significant risk factor for bladder cancer. The sensitivity of many epidemiologicat investigations is reduced because at sizeable proportion of most of the populations under scrutiny willingl> indulges in the far more hazardous practice of smoking cigarettes. Studies of coffee drinkers are particularly hard hit because of the well-established association between coffee and cigarettes, heavy coffee drinkers having a tendency also to be heavy cigarette smokers. Indeed the most consistent linding of the many case control studies of coffee and cancer (at any site) involves not coffee but cigarette smoking, an increased risk of disease being inwtriablv seen in the cigarette smokers (irrespective of their addiction to coffee) with the causal link being strengthened by the clear dose response relationships. Both Hartge e t a / . and Marrett et al. attempted to minimize the confounding effects of smoking, with the information gathering and data manipulation of Hartge et al. appearing to be slightly more vigorous m this important area. Neve,theless, an~ slight misclassification of smoking history is likely to reduce markedly the chances of picking up what, even on a most pessimistic view, must be a fairly weak association of bladder carcinogenicity with co0"ee. In spite

Information section Fd Chem. Toxic. Vol. 22, no. 6 of this difficulty, both of these studies have managed to achieve an approximately similar bottom line, adding two more citations to the already crowded column marked 'equivocal positive result'. The allimportant link between exposure and degree of risk remains elusive. Case-control studies must be interpreted with caution. Memory in normal circumstances is known to be imperfect. A patient who has recently been made aware of the presence of a potentially life-threatening disease is unlikely to be in the same emotional state as an apparently healthy individual. Therefore, even when cases and controls are being asked about an uncontentious detail of their lifestyle, there is a danger of marked differences in the accuracy of recall. With a widely criticized habit, such as cigarette smoking, there is scope for a more conscious distortion of the truth on the part of the interviewee. The validity of the findings from any of the coffee studies would be almost as seriously undermined by systematic errors in the cigarette history as by inaccuracies in the record of coffee exposure. With complications such as these, the difficulty of generating a neat conclusion from a series of case-control studies is hardly surprising. Taken as a whole, particularly now that the whole includes this large study of Hartge et al. (loc. tit.), the data suggest that coffee drinkers are marginally more likely to develop bladder cancer than are abstainers. However, because the search for evidence of a dose response relationship is seldom successful, the causal link--that coffee drinking is responsible for the increased number of bladder cancers--must still be considered unsupported by the epidemiology. The ambiguity of the epidemiology is mirrored experimentally. Coffee itself, although fairly poorly tested in animal carcinogenicity studies, is at present unconvicted as a carcinogen (Wfirzner et al. Fd Cosmet. Toxicol. 1977, 15, 289), a status shared by caffeine (Johansson, Int. J. Cancer 1981, 27, 521).

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Coffee, nevertheless, has been shown to be a direct mutagen in Ames tests (Aeschbacher et al. Fd Cosmet. Toxieol. 1980, 18, 605) and caffeine is mutagenic in a broad spectrum of in vitro systems but not apparently in the living mammal (Tarka, C R C Crit. Rev. Toxicol 1982, 9, 275). Where does the seeker-after-truth go from here? Hartge et al. (loc. cit.) felt that future epidemiology should concentrate on populations either with a low prevalence of coffee drinking, such as the Mormons, or with a very high consumption of coffee, as is the case in Scandinavia. Retrospective case-control studies of even an atypical community seem, however, unlikely to unravel the mystery. Prospective cohort studies, in which the health (and death) of groups with defined coffee exposures are monitored over a number of years, have surely earned by now a higher priority. Exposures, whether to coffee, tobacco or other risk factors, can be ascertained more accurately than is possible in any retrospective study. There is even scope for independent verification of the information offered by the direct participants. All of those involved, moreover, are questioned at a time of similar healthy optimism. On the other side of the balance sheet, with new cases of bladder cancer occurring in a typical, ageing, male population at an annual rate of about 100/100,000 (Waterhouse et al. (Eds), 1 A R C Scient. Publ. no. 42, p. 207, IARC, Lyon, 1982), a cohort study would realistically need to involve something of the order of 10,000 people and to continue for close on a decade if the epidemiologists are to have sufficient data (that is cancer cases) to manipulate. The many published case-control studies eliminate the possibility that coffee is anything other than, at worst, a weak bladder carcinogen. The leisurely (but more effective) cohort approach would seem to hold the best prospects of differentiating further between the remaining two credible verdicts. J. Hopkins--BIBRA

P A P A I N - - A L L E R G E N I C TENDENCIES Papain, a proteolytic enzyme obtained from unripe papaya fruit, has many industrial applications and, in particular, is used as an agent for tenderizing meat and clarifying beer. It is also a common ingredient in cosmetic, food and drug products. There have been several publications describing allergic reactions (expressed mainly as respiratory illness) which have been attributed to papain exposure (Cited in F.C.T. 1981, 19, 791; Baur et al. Clin Allergy 1982, 12, 9). However, despite the potentially considerable exposure of the general public to this enzyme, reports of papain allergy outside the workplace are rare. A recent paper by Mansfield & Bowers (J. Allergy clin. Immun. 1983, 71, 371) helps to fill this particular gap and is especially interesting since ingestion, rather than inhalation, was the chief route of exposure involved. The patient described by Mansfield & Bowers (Ioc. cit.), a 31-yr-old man, had a history of allergic reactions, including childhood asthma, but suffered a particularly severe response following the ingestion of

a beefsteak that had been liberally treated with a meat tenderizer containing an unspecified amount of papain. Within 20-30min of his meal, the patient experienced generalized itching, swelling of hands, feet, lips and eyelids, tightness of chest and throat, and wheezing. Initial laboratory data indicated a serum IgE level of 6000 IU/ml, but no IgG antibody was detected. The food and drink taken during the meal, other than the tenderized steak, had been previously tolerated without any recognized problems. Severe symptoms had occurred on two previous occasions, thought to be following the ingestion of large amounts of German draft beer, but had not occurred when different brands of meat tenderizer (at least one of which was known not to contain papain) had been used. In an attempt to determine whether papain was the causative agent, direct skin testing was carried out on the patient with the offending brand of tenderizer (0.1 g/ml) and with pure papain (0.1, 1.0 or