Very high incidence rates of esophageal cancer have been reported from the Golestan Province, northeast of Iran, 8 where esophageal squamous cell carcinoma (ESCC) constitutes more than 90% of esophageal cancers. 9 Two previous case–control studies from the Golestan Province reported an association between hot tea drinking and esophageal cancer. 10 , 11 Both of these studies were limited by their retrospective design and using only self‐perceived reporting of tea drinking temperature. In 2004, we initiated the Golestan Cohort Study, a large prospective study of over 50,000 in the same region. 8 , 12 To our knowledge, this is the only large‐scale prospective study in the world in which actual tea drinking temperature has been measured by trained staff at baseline. 13 Herein, we examine the association of prospectively measured tea drinking temperature, as well as subjective preference for hot tea drinking, time from pouring tea to drinking, and other tea drinking habits with ESCC risk using data from the Golestan Cohort Study.

Multiple observational studies have reported an association between hot beverages and esophageal cancer. 1 - 3 However, except for three prospective studies, 4 - 6 previous studies on this association have been of retrospective design, which may be prone to recall bias. 1 - 3 A major limitation of all previous prospective studies is that tea drinking temperature data have been based on self‐reported perception of tea drinking temperature, which may vary across individuals and populations and could not be objectively verified. Due to these limitations, the International Agency for Research on Cancer (IARC) has concluded that the existing evidence in humans for the carcinogenicity of drinking hot beverages is limited and has classified “drinking very hot beverages at above 65°C” as “probably carcinogenic” (Group 2A according to IARC's classification system of carcinogens), rather than “carcinogenic” to humans (Group 1). 1 , 7

We repeated the latter analysis among never and ever cigarette and/or alcohol users, as a large‐scale prospective study in China recently reported a positive association between hot tea drinking and esophageal cancer only among those with tobacco or excessive alcohol use. 6 Other additional analyses were conducted by sex, for those with histologically confirmed ESCC, and after excluding ESCC cases occurred in the first 2 years of follow‐up, to allow for possible changes in drinking habits due to early symptoms of the disease or preneoplastic lesions. Based on Schoenfeld residuals, 19 the proportional hazards assumption was not violated in any Cox proportional hazards regression models in this study; global test p values ranged from 0.17 to 0.99 for main analyses and from 0.10 to 0.83 for additional analyses. We used likelihood ratio tests comparing fully adjusted Cox models with and without interaction terms to examine interactions between tea temperature (<60°C, ≥60°C) and amount (1–699 mL/day, ≥700 mL/day) for ESCC risk among tea drinkers. All statistical analyses were performed using Stata statistical software version 13 (Stata Corporation, College Station, Texas, USA).

Cox proportional hazards regression models were used to estimate hazard ratios (HRs) and corresponding 95% confidence intervals (CIs) for the association between tea drinking habits and ESCC risk. As distributions of established risk factors or factors with previously reported associations with ESCC in Golestan were different by tea variables, we adjusted HRs for those factors, as shown in Table 1 . 14 , 18 We also provide HRs for tea temperature variables after being additionally adjusted for black tea and green tea consumption, and HRs for black and green tea consumption after being additionally adjusted for measured tea temperature and consumption of the other tea type. Further, we examined combined associations of measured tea temperature and total tea (black plus green) consumption with ESCC risk.

After excluding 7 participants with upper gastrointestinal cancer at the time of recruitment and 11 cases of esophageal adenocarcinoma identified during follow‐up, 50,027 participants were included in this analysis. Black tea consumption is very common in the area, and the average amount of black tea consumed in milliliters per day was categorized in 5 categories by quintiles (rounded to the nearest 100 mL/day) based on baseline data. As most participants did not drink green tea, those who did were categorized in two groups of nearly equal size based on baseline data (average consumption of 1–39 and ≥40 mL/day). The measured tea temperature was categorized as <60, 60–64, and ≥65°C, as the recorded tea temperature of 60°C indeed represented temperatures from 60°C to less than 65°C, and we combined 65°C and higher temperatures due to small numbers. Participants with one or more missing values in tea drinking variables (<3% of the cohort for any tea variable) were excluded from corresponding analyses. Those who did not drink tea were excluded from tea temperature analyses.

All study participants are annually followed up through active telephone surveys and home visits by our staff. Further, monthly provincial death registration data and local health workers’ reports are reviewed to identify additional cancer cases and deaths. Losses to follow‐up in the Golestan Cohort Study has been less than 1%. The end of follow‐up for our study was the date of first diagnosis of esophageal cancer for cancer cases, the date of death for deaths from any other causes, and the date of last follow‐up for other participants, through December 31, 2017. The median duration of follow‐up was 10.14 years (505,865 person‐years), during which 328 primary esophageal cancers cases identified based on history, imaging, and/or other medical reports. The histological report was available for 296 cases (90.2%), among whom squamous cell carcinoma was the predominant subtype (285 cases, 96.3%); the remaining 11 cases had esophageal adenocarcinoma. The latter 11 cases were excluded from this analysis, leaving 317 histologically confirmed ( N = 285) or likely ( N = 32) ESCC cases.

In addition, trained nutritionists collected information on the amount of black and green tea consumed using the study food frequency questionnaire, which included questions about the volume of the usual cups used for and frequency of tea drinking. 15 To increase the accuracy of the reported volume, photographs of five types of cups and mugs commonly used in Golestan were provided.

Tea and water are the only drinks commonly consumed in Golestan, of which only tea is generally consumed at a high temperature. 11 , 16 We asked those who drank tea about the interval (in minutes, ranged from 0 to ≥10 min) between tea being poured and drunk and whether they usually drank tea warm/lukewarm, hot, or very hot. Further, we measured the temperature of tea drunk by the participants using a method that had shown good reliability in the pilot phase of the cohort study. 17 We prepared two fresh cups of tea at the time of interview for each participant, one for the participant and the other for the interviewer to measure the temperature using a digital thermometer. When the tea temperature was 75°C, participants were asked to sip the tea. If it was their usual tea drinking temperature or they usually drank higher temperature tea, it was recorded. Otherwise, the procedure was repeated by allowing the tea to cool to 70°C, or if necessary, to lower temperatures (at 5°C intervals). The lowest temperature category was 60°C. The tea temperature for the participants who drank tea at colder temperatures was recorded as <60°C.

Trained staff collected information on a wide range of personal characteristics and potential risk factors of ESCC using a structured questionnaire in face to face interviews. A composite score for wealth was calculated by applying multiple correspondence analysis to appliance ownership data, including personal car, motorbike, black and white TV, color TV, refrigerator, freezer, vacuum cleaner, and washing machine. 14 Average fresh fruit and vegetable intake per day was calculated using data collected through a food frequency questionnaire specifically designed for this population. 15 Cigarette smoking was classified as never, former (those who quit more than 1 year before enrolment), or current smokers at baseline. Nass (a chewing tobacco product), opium, and alcohol use were classified as never and ever users.

The HRs were generally similar in additional subgroup analyses by sex or history of cigarette and alcohol use, for histologically confirmed ESCC cases, or after excluding ESCC cases occurred in the first 2 years of follow‐up, although 95% CIs became slightly wider due to smaller numbers of events (Supporting Information Table S3 ). A noticeable difference was an increased risk associated with drinking ≥1,300 mL/day tea at <60°C among ever cigarette or alcohol users, among whom HRs for drinking tea at ≥60°C were also slightly greater than in other subgroups. However, this group included only 70 ESCC cases (with 5 cases in the reference group) and a much smaller number of noncancer participants due to the relatively low prevalence of these habits in this population.

Compared to drinking 1–699 mL/day tea (black and green combined) at <60°C, HRs (95% CI) for drinking tea at the same low temperature was 0.95 (0.52–1.74) for 700–1,299 mL/day and 1.66 (0.95–2.89) for ≥1,300 mL/day (Table 3 ). However, only a relatively small number of ESCC cases drank tea at <60°C. Compared to the same reference group, drinking 1–699 mL/day tea at ≥60°C did not show an association with ESCC risk (HR 1.10, 95% CI 0.61–2.00), but drinking 700–1,299 mL/day (HR 1.95, 95% CI 1.17–3.25) and ≥1,300 mL/day (HR 1.87, 95% CI 1.13–3.11) tea at ≥60°C did. However, we did not find a statistically significant interaction between tea temperature and amount for ESCC risk ( p = 0.39).

All tea temperature variables considered in this analysis were associated with ESCC risk (Table 2 ). In fully adjusted models, the HR (95% CI) for drinking tea at ≥60°C, compared to <60°C, was 1.41 (1.10–1.81); the HRs for drinking tea at 60–64°C and ≥65°C were comparable. Drinking self‐perceived very hot tea was also associated with ESCC risk (HR 2.41, 95% CI 1.27–4.56), compared to cold or lukewarm tea. Consistent with this finding, shorter duration from pouring to drinking was associated with higher risk (HR 1.10, 95% CI 1.01–1.21 per 2‐min shorter intervals vs . ≥10 min), although only self‐reported durations of less than 5 min appeared to be associated with the increased risk. Higher consumptions of black tea, green tea, and black and green tea combined were also associated with ESCC risk (Table 2 ).

Discussion

In this study, the measured tea temperature, reported preference for very hot tea drinking, and reported shorter time from pouring tea to drinking were each associated with ESCC risk. In analysis of the combined effects of measured temperature and amount, drinking 700 mL/day tea or more at ≥60°C was associated with about 90% higher risk of ESCC. Since in this study cigarette smoking prevalence was relatively low (particularly in women) and alcohol consumption was negligible,20 there would be minimal residual confounding from smoking and alcohol, which could be a problem in other studies.

Only two prospective cohort studies have previously examined the association between hot tea drinking and esophageal cancer. In a study in Japan, consumption of hot tea (vs. nonhot) was associated with a 1.5‐fold increased risk of esophageal cancer death.5 The other prospective study showed an adverse association only among tobacco and excessive alcohol users in China; compared to nonheavy drinkers (defined as drinking <15 g/day of alcohol) and nonsmokers who drank tea less than daily, the relative risk (RR) for drinking hot/burning hot tea in a daily basis was 1.6 for nonheavy alcohol drinking smokers, 2.3 for nonsmoking heavy drinkers, and 5.0 for heavy drinking smokers,6 although there is the possibility that the latter higher RRs (with drinking ≥15 g/day alcohol) resulted partly from a residual confounding effect of alcohol. However, the lack of an association among nontobacco or alcohol users in that study is likely related to relatively small sample size of that group; for example, the total number of nonsmoker cancer cases who daily drank tea was 75, compared to 360 cases among smokers.6 A third prospective study examined the association between unspecified hot liquid consumption and esophageal cancer but showed no association (RR, 0.96).4 However, that study asked only two very general questions (“How often do you drink hot liquids in the” “summer” and “winter?”) and the analysis compared only two categories (≥1 vs. 0 time per year).4

Multiple case–control studies have also shown an association between hot beverages, including tea, maté, and coffee, and esophageal cancer risk.3 When results are available by histological subtype, positive associations have been reported for ESCC.3 However, evidence on esophageal adenocarcinoma is limited to a handful of small‐scale case–control studies in Western populations, where beverages are usually consumed at more moderate amounts and temperatures.3 Earlier studies of hot beverages and esophageal cancer generally do not provide data on actual tea drinking temperature, but some more recent case–control studies have examined the association by measuring tea temperature in cases after the development of cancer and in controls.21, 22 However, this measurement does not consider any changes in temperature preferences or in dietary habits in cancer cases that could happen due to the disease. Previous case–control studies from Golestan reported a stronger association between drinking very hot tea and ESCC risk based on self‐perceived data 10, 11 than the current study. This could be in part related to some recall bias, as well as a decrease in temperature preferences or the amount of hot tea consumed in the region over time because of changes in dietary habits and availability of safe water.16 Further, drinking tea temperature preference among some participants in this study could have decreased over the 10‐year follow‐up period, perhaps after publication of our previous report in 2009;11 we did not update tea temperature data during the follow‐up. However, even with a relatively moderate magnitude of association, hot tea drinking is likely to be an important contributor to the high incidence of ESCC in Golestan due to its high prevalence and high quantities in both sexes.

Several mechanisms might explain how drinking hot beverages could lead to ESCC. Thermal injury may increase ESCC risk by inducing inflammatory processes, which might directly affect DNA bases and/or increase the formation of carcinogenic N‐nitroso compounds.23, 24 Another likely mechanism is an impairment in the barrier function of the esophageal mucosa because of thermal injury, perhaps after reaching a threshold temperature,25 which might increase exposure to intraluminal carcinogens, including N‐nitroso compounds and polycyclic aromatic hydrocarbons (PAHs). A few animal studies have examined the association between administration of hot water with or without N‐nitroso compounds and esophageal neoplasia. In those studies, hot water by itself did not show positive results, but it increased the incidence of esophageal preneoplastic or neoplastic lesions induced by N‐nitroso compounds.26-29 In two studies that examined this effect at two different temperatures, administration of water at 65–70°C, but not at 55–60°C, was associated with the increase.28, 29

The status of exposure to N‐nitroso compounds in Golestan is unknown, but a very high exposure to PAHs has been reported in this population.30, 31 Current evidence suggests an association between PAHs and ESCC, although a causal association is yet to be established.32 PAHs are products of incomplete combustion of organic matter, and exposure to PAHs is common in smokers.33 In Golestan, however, even nonsmokers are also highly exposed to PAHs, most probably through diet.18, 34 A study comparing samples of nontumoral esophageal epithelium from ESCC cases and controls in Golestan showed substantially higher levels of a PAH biomarker in cases.35 However, another study has suggested that drinking very hot beverages per se may be causally associated with esophageal cancer risk, with minimal contribution from exposure to PAHs.36 Further experimental studies are needed to identify mechanisms of the association between hot beverage drinking and ESCC.

Both black and green tea contain compounds with antioxidant activities (such as flavonoids), which might have the potential to reduce cancer risk.2, 37 However, tea also contains several other compounds with unknown effects, and some potentially carcinogenic compounds may be introduced to tea when being processed (such as possible contamination of black tea with PAHs).38 The number of prospective epidemiological studies on the association between amount of tea consumed and esophageal cancer risk is limited, and except for one showing an inverse association,39 4 studies have shown no association.40-43 In analysis of the combined effects of measured temperature and amount in this study, the amount of tea consumed appeared to be a factor only with drinking high‐temperature tea. Our observation of statistically nonsignificant HRs above unity for drinking ≥1,300 mL/day tea at <60°C may be due to some residual confounding from high tea temperature, as heavy tea drinkers in this study were more likely to drink tea at a higher temperature. However, we cannot entirely rule out an independent association between the amount of tea consumed and ESCC, because the number of individuals who drank tea at moderate temperatures was relatively modest in this study. Further, due to the lack of data, we were not able to incorporate in this analysis participants’ preference for stronger or lighter tea or chemical composition of tea consumed. More research on the nature of these associations, including consideration of the heterogeneity of the chemical constituents of tea,36 is needed.

The strengths of our study include its large size, prospective design, administration of structured questionnaires and physical measurement of tea temperature using a validated method by well‐trained interviewers, low proportions of participants with missing data or lost to follow‐up, accurate case ascertainment and confirmation, and adjustments for numerous potential confounders. In this study, the reference group included only those who drank tea, mostly in high amounts, which may provide stronger evidence on the association between tea drinking temperature and ESCC risk than when the reference group includes nontea drinkers or those who drank tea infrequently,6, 21 as the latter groups might have many other differences with regular, ‘heavy’ tea drinkers in terms of lifestyle factors, some of which might confound the association. It should be noted that we were not able to examine associations for drinking tea at lower amounts (<700 mL/day) or temperatures (e.g., 55‐59°C) or for esophageal adenocarcinomas due to inadequate statistical power or study design, indicating the need for further research in other populations. Other limitations include the observational nature of the study leading to potential residual confounding (e.g., hot tea drinking as marker of other lifestyle factors), and the potential misclassification of exposure despite the effort to objectively quantify tea temperature. However, we adjusted our results for multiple known risk factors, and any substantial differential misclassification is unlikely.