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Tea drinking habits and oesophageal cancer in a high risk area in northern Iran: population based case-control study
  Published 26 March 2009, doi:10.1136/bmj.b929
Cite this as: BMJ 2009;338:b929
"Drinking hot tea, a habit common in Golestan province, was strongly associated with a higher risk of oesophageal cancer"
Farhad Islami, research fellow1,2,3, Akram Pourshams, associate professor1, Dariush Nasrollahzadeh, PhD student1,4, Farin Kamangar, research fellow5, Saman Fahimi, PhD student1,6, Ramin Shakeri, research fellow1, Behnoush Abedi-Ardekani, pathologist1, Shahin Merat, associate professor1, Homayoon Vahedi, associate professor1, Shahryar Semnani, associate professor and director7, Christian C Abnet, investigator5, Paul Brennan, group head2, Henrik Moller, professor and director3, Farrokh Saidi, professor1, Sanford M Dawsey, senior investigator5, Reza Malekzadeh, professor and director1, Paolo Boffetta, group head and cluster coordinator2
1 Digestive Disease Research Center, Shariati Hospital, Tehran University of Medical Sciences, 14117 Tehran, Iran, 2 International Agency for Research on Cancer, Lyon, France, 3 King?s College London, Thames Cancer Registry, London, 4 Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden, 5 Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA, 6 Department of Public Health and Primary Care, Institute of Public Health, University of Cambridge, Cambridge, 7 Golestan Research Center of Gastroenterology and Hepatology, Gorgan University of Medical Sciences, Gorgan, Iran
What is already known on this topic
Heavy alcohol and tobacco use are major risk factors for oesophageal squamous cell carcinoma, a disease more common in men than women
In some areas with a high incidence of oesophageal cancer, alcohol and tobacco use are not prominent risk factors, and women are as likely to develop oesophageal cancer as men
Common risk factors among both sexes may have a role in the carcinogenesis of oesophageal cancer; drinking hot beverages is a suggested risk factor
What this study adds
The risk of oesophageal cancer was noticeably increased in adults in Golestan Province, northern Iran, who drank tea hot
Drinking hot beverages is common and may account for a substantial number of cases of oesophageal squamous cell carcinoma, especially in areas with a high incidence
Objective- To investigate the association between tea drinking habits in Golestan province, northern Iran, and risk of oesophageal squamous cell carcinoma.
Design- Population based case-control study. In addition, patterns of tea drinking and temperature at which tea was drunk were measured among healthy participants in a cohort study.
Setting- Golestan province, northern Iran, an area with a high incidence of oesophageal squamous cell carcinoma.
Participants- 300 histologically proved cases of oesophageal squamous cell carcinoma and 571 matched neighbourhood controls in the case-control study and 48 582 participants in the cohort study.
Main outcome measure- Odds ratio of oesophageal squamous cell carcinoma associated with drinking hot tea.
Results- Nearly all (98%) of the cohort participants drank black tea regularly, with a mean volume consumed of over one litre a day. 39.0% of participants drank their tea at temperatures less than 60°C, 38.9% at 60-64°C, and 22.0% at 65°C or higher. A moderate agreement was found between reported tea drinking temperature and actual temperature measurements (weighted {kappa} 0.49). The results of the case-control study showed that compared with drinking lukewarm or warm tea, drinking hot tea (odds ratio 2.07, 95% confidence interval 1.28 to 3.35) or very hot tea (8.16, 3.93 to 16.9) was associated with an increased risk of oesophageal cancer. Likewise, compared with drinking tea four or more minutes after being poured, drinking tea 2-3 minutes after pouring (2.49, 1.62 to 3.83) or less than two minutes after pouring (5.41, 2.63 to 11.1) was associated with a significantly increased risk. A strong agreement was found between responses to the questions on temperature at which tea was drunk and interval from tea being poured to being drunk (weighted {kappa} 0.68).
Conclusion- Drinking hot tea, a habit common in Golestan province, was strongly associated with a higher risk of oesophageal cancer.
Case-control study

A total of 300 cases and 571 controls were recruited into the study. All cases had at least one matched control. The personal characteristics of the cases and controls were similar (table 1Go).
Only one participant did not drink tea. Tea temperature was significantly associated with risk of oesophageal squamous cell carcinoma (table 2Go). Compared with drinking warm or lukewarm tea, drinking hot tea (odds ratio 2.07, 95% confidence interval 1.28 to 3.35) or very hot tea (8.16, 3.93 to 16.91) was associated with an increased risk of oesophageal cancer (P for trend <0.001). The risk associated with drinking hot tea did not vary by education level or several other personal variables (see web extra table). The interval between tea being poured and drunk was inversely associated with risk of oesophageal cancer (table 2). Compared with an interval of four or more minutes, intervals of 2-3 minutes (odds ratio 2.49, 95% confidence interval 1.62 to 3.83) and less than two minutes (5.41, 2.63 to 11.14) were associated with an increased risk of oesophageal cancer (P for trend <0.001). The weighted {kappa} statistic and Spearman?s rank correlation coefficient for agreement between these two variables were 0..68 and 0.69, respectively (table 3Go). A similar agreement was observed within the case and control groups and among men and women separately (data not shown). Information on amount of tea drunk was available for only 267 cases and 385 controls. No clear pattern of association was found between the amount of black tea consumed and risk of cancer in crude or multivariate analyses, but the trend test was statistically significant (P value for trend 0.03). There was no statistically significant association between frequency of green tea consumption and risk of cancer.
Cohort study
Data on tea drinking variables were available for 48 582 cohort participants. Almost all (96.8%) of the participants drank black tea every day (47 043 participants), with a mean amount of 1179 ml (SD 761) a day. Only 2802 participants (5.8% of all participants) drank green tea every day; most of them were of Turkmen ethnicity. The mean amount of green tea consumption was 48 ml (SD 228) a day (table 4Go). Overall, 18 947 (39.0%) participants drank their tea at temperatures less than 60°C, 18 889 (38.9%) at 60-64°C, and 10 688 (22.0%) at 65°C or higher (table 5Go).
The weighted {kappa} statistic and Spearman?s rank correlation coefficient for agreement between reported tea drinking temperature and actual temperature measurements were 0.49 and 0.46, respectively (table 6Go). The corresponding values for agreement between actual measurements and the interval between tea being poured and drunk were 0.39 and 0.32, respectively.
Our study found that almost everyone in Golestan Province drinks tea. They drink large amounts of black tea every day, but drinking green tea is not common. We found a strong increase in the risk of oesophageal squamous cell carcinoma associated with drinking hot or very hot tea but not with the amount of tea consumed, which is consistent with the previous literature.3
Compared with rats that received only carcinogenic N-nitroso compounds or hot water, the mean number of benign and malignant oesophageal tumours significantly increased in rats that received both N-nitroso compounds and hot water.20 21 In one of these studies,21 in which hot water was administered by installation in the upper section of the oesophagus, more tumours were observed as the temperature increased, especially at 65°C and above. At a temperature of 70°C the number and size of oesophageal papillomas increased rapidly.21 A few studies have investigated the effect of hot beverages on intraoesophageal temperature in humans.22 23 One study showed that after drinking beverages with temperatures up to 65°C, distal oesophageal temperature increased to as high as 53°C.23 The volume swallowed in each sip was more important than the temperature of the beverage in determining intraoesophageal temperature.23 In our study we asked the participants if they sipped or gulped their tea, but we did not analyse these data because few participants gulped their tea. In addition, we did not find a good way to validate the answers to this question. The volume swallowed in each sip may differ from person to person, and a given volume may be divided in two or more quick swallows.
Possible mechanistic pathways
The mechanism by which thermal injury can cause oesophageal cancer is not clear but both direct and indirect effects have been suggested. Some authors have proposed that inflammatory processes associated with chronic irritation of the oesophageal mucosa by local hyperthermia might stimulate the endogenous formation of reactive nitrogen species, such as nitric oxide, and subsequently, N-nitroso compounds.24 Consistent with this idea, higher rates of transitions of somatic G to A in CpG dinucleotides of the TP53 gene have been reported in samples of oesophageal tumour from areas in which drinking hot beverages is considered an important risk factor for oesophageal cancer,25 26 27 28 and an association between these mutations and nitric oxide synthase activity has been reported in colorectal cancers in humans.29 Thermal injury can also impair the barrier function of the oesophageal epithelium, which may increase the risk of damage from exposure to intraluminal carcinogens20 21 30 such as polycyclic aromatic hydrocarbons or the compounds present in opium dross. The population of Golestan is highly exposed to polycyclic aromatic hydrocarbons, most probably through diet.31 32 Threshold temperatures have been suggested for the effect of hot beverages on the epithelial barrier of the oesophagus in rabbits (intraluminal temperature of 49°C for epithelium permeability and of 60°C for active ion transport). Once the threshold temperature is reached, the barrier function could be impaired rapidly and with short exposure times.30 Whatever the mechanism by which thermal injury increases the risk of oesophageal cancer, this risk can be augmented by other risk factors, such as low intake of fresh fruits and vegetables, which can impair DNA repair.33
Both green and black teas have shown cancer prevention activity in animal models, which may be attributable to flavonoids and other beneficial compounds34 35 36; however, such activity has not been convincingly shown in humans.37 38 After adjustment for tea temperature and other factors we did not find a clear pattern of association between the amount of tea consumed and the risk of oesophageal cancer. Although the P value for trend for this association was statistically significant, the risk decreased from the first to the third fifths and then increased, so there was no consistent pattern. In contrast with tea, which is possibly carcinogenic only if it is drunk at high temperatures,3 drinking mate, a herbal infusion consumed in certain areas of South America, may increase the risk of oesophageal cancer even at low temperatures.12 39 This increased risk may be due to carcinogens that are produced during the processing of the herbal leaves, such as polycyclic aromatic hydrocarbons, or to other compounds present in the unprocessed leaves.40 41
Comparison with other studies
The results of the cohort study showed that most inhabitants of Golestan drink their tea at temperatures higher than 60°C and in quantities greater than one litre a day. These patterns make the Golestan population particularly vulnerable to the possible carcinogenic effects of drinking hot tea. Several previous studies have assessed temperature preferences for beverages, and those from the United Kingdom have reported an average temperature preference of 56-60°C among healthy populations.16 22 42 43 44 45 One study reported a significantly higher tea drinking temperature among seven participants with oesophageal disorders (mean 62°C, range 53-73°C) than among 50 controls (mean 56°C, range 47.5-65°C, P<0.001).43 Another study reported a mean temperature of 69.5°C (SD 6..5°C) for drinking mate among 1388 inhabitants in southern Brazil, a moderate to high incidence area for oesophageal squamous cell carcinoma..44
The association between drinking hot beverages and risk of oesophageal cancer suggests that thermal injury could be a cause of other cancers of the upper aerodigestive epithelial; however, this hypothesis has been investigated in only a few epidemiological studies. For hot tea drinking, the evidence is too limited to draw any conclusions.46 47 48 All of the six studies that investigated mate drinking and cancer of the mouth, pharynx, and larynx showed an association with hot mate intake, which was statistically significant in four studies.48 Potential carcinogenic effects of hot beverages on other parts of the upper aerodigestive tract warrant further investigations.
Strengths and limitations of the study
To our knowledge the Golestan Cohort Study is the largest epidemiological study in which tea drinking temperature has been measured. The measurement method was validated in the pilot phase of this study19 and all measurements were done by trained staff. The strengths of our case-control study include histological verification of all cases of oesophageal squamous cell carcinoma, administration of a structured questionnaire by well trained interviewers, and adjustment for potential confounders. Furthermore, with no or minimal confounding from alcohol or tobacco use in Golestan, other risk factors for oesophageal cancer can be better studied there. As in all case-control studies, however, data on the amount and temperature of consumed tea can be subject to information bias. We found good agreement between questions on the temperature that tea was drunk and the interval between tea being poured and drunk, but responses to both questions could have been biased. The validation study in the cohort was carried out among healthy people, so the observed acceptable validity may not be applicable to case participants. Studies in the Caspian littoral in the 1970s suggested that drinking hot beverages may be a possible risk factor for oesophageal squamous cell carcinoma, so the hypothesis might be familiar to the interviewers and people of the study area; however, we are not aware of any public educational programme in this regard. We tried to minimise the risk of information bias by not discussing the study hypotheses with the interviewers. The questionnaires were fairly extensive, studying multiple hypotheses, which reduced the possibility of interviewers? focusing on a certain hypothesis. Also, we did not observe any evidence of inflated results for other known risk factors for oesophageal cancer, such as tobacco smoking or alcohol consumption, which further suggests that severe information bias is not highly likely.6 Case participants with no formal education might be less likely to be aware of the study hypotheses, so they might be less prone to recall bias. In our sensitivity analyses we found no substantial difference in the risk associated with hot tea drinking between participants with and without formal education, or between urban and rural areas. Another problem with a case-control design is selection bias. Since ascertainment of cases and controls in our study was high, selection bias may only explain our findings if the small proportion of non-participating cases were overwhelmingly drinkers of "cold tea" or, conversely, the non-participating controls were overwhelmingly drinkers of "hot tea." None of the scenarios are likely. In our study the amount of missing data on the variable for amount of tea drinking varied between cases and controls, which was due to a logistical issue rather than bias. The questions on amount of tea drunk came from a nutritional questionnaire that was administered by a nutritionist. On some days no nutritionist was available to accompany the control selection team and therefore this variable has some missing data. Since we used conditional logistic regression models, in which each case is compared with their matched controls, the missing values are not expected to differentially distort our findings even if there are some differences in the personal characteristics of participants with or without missing values. Despite the presence of the missing data, we report the results of amount of tea consumed in relation to the risk of oesophageal squamous cell carcinoma because even after excluding the participants with missing values, our study is still one of the largest that have reported on this association. Overall, we believe that the strong association between drinking hot tea and risk of oesophageal cancer found in this study is unlikely to be completely due to bias, considering its agreement with the previous literature and our efforts to collect accurate and valid data. Nonetheless, we acknowledge that the nature and strength of the association needs to be established in prospective studies.
Conclusions and policy implications
Our results showed a noticeable increase in risk of oesophageal squamous cell carcinoma associated with drinking tea hot. A large proportion of Golestan inhabitants drink hot tea, so this habit may account for a substantial proportion of the cases of oesophageal cancer in this population. Informing the population about the hazards of drinking hot tea may be helpful in reducing the incidence of oesophageal cancer in Golestan and in other high risk populations where similar habits are prevalent.
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