Introduction

It has been estimated that as many as 600 million people worldwide have the habit of chewing betel quid (BQ). [1] This behavior is most prevalent in South Asia, such as India, Pakistan, Bangladesh, and Indonesia.[1] BQ usually comprises areca nut (areca catechu) and betel leaf (Piper betel) or areca fruit, together with slaked lime, tobacco, or spices inserted.[2] In contrast to the practices of other South Asian countries, betel quid in Taiwan does not contain tobacco; rather, tobacco is consumed separately by smoking cigarettes, resulting in side effects. [2, 3] Chewers in Taiwan were estimated between 1.5 million and 2 million in a population of 8 million adult males. Chewers chewed 5–15 betel quids a day and in addition, more than 90% of chewers also smoked approximately 20 cigarettes. With 5–15 betel quids chewed and 20 cigarettes smoked a day, the chewers suffered from 25–35 times assaults to their oral assaults per day.

The surge in betel quid chewing in Taiwan is a serious problem. Much of the increase has been attributed to the forced opening of the tobacco market by foreign tobacco companies since 1987. [2–5] The forced opening of the cigarette market aided the growth of BQ vendors.[3, 5] Currently, 8 million male chewers in Taiwan affecting the lower socio-economic class, chewed betel quid and widened the existing health disparity. [6, 7]

The harm of chewing betel quid included increase mortality from all cause and from at least 6 types of cancer.[8] It could also come cardiovascular disease, type 2 diabetes mellitus, chronic kidney disease and metabolic syndrome. [9–15] The most frequently encountered pathology was oral cancer and its pre-malignant lesions such as lichenoid changes, leukoplakia, submucous fibrosis. The areca nut and inflorescence piper betle contained carcinogens such as safrole.[2, 16, 17] The addition of lime, a common practice, induces surface injuries in the oral mucosa due to its caustic properties. In addition to oral cancer, chewers are known to have increased cancer at many other sites such as esophagus, liver, pancreas, larynx and lung.[8]

There are four dimensions of physical activity commonly described: Transportation, household chores, physical labor at worksite and leisure-time physical activity (LTPA).[18] Among them, only LTPA is promotable and effort-related and has been most reported with improved health benefits, and extended life expectancy.[18] Its positive effects are extensive with multi-system involvement.[18, 19] The current recommendation for LTPA is at least 30 minutes of daily exercise for 5 days or more per week (150 minutes/week) with moderate intensity.[20, 21] However, our recent study has shown the ability of extending 3 years of life from a daily exercise, not requiring 30 minutes each time but starting from 15 minutes or more of dedicated exercise in moderate intensity.[18]

Preventing chewing and encouraging cessation are the mainstay of strategies for betel quid control. Nevertheless, just like smoking, to quit an addiction like chewing has been met with limited success.[22] The average quit rate was around 6%-12%.[23] Given many chewers who either struggled with cessation or had no interest in quitting, we attempted to assess whether engaging in regular exercise could reduce the chewing harms. A critical question we asked was “to what extent can the harms of chewing BQ be reversed or mitigated by physical activity?”.

A prospective cohort study was conducted to assess the health benefits of engaging in LTPA by chewers who exercised either at a low (15 minutes/day) or recommended volume (30 minutes/day or more). All-cause mortality and life expectancy were assessed as the final outcome, with inactive chewers serving as the comparison group.

Methods

Results

Of the 204,533 males in the cohort, 38,324 (18.7%) were chewers (Fig 1). In contrast, very few females were chewers (0.7%). As a result, for this study, we focused on male chewers. More than half of chewers were younger than 40 years old, with few chewers older than age 60 (Table 1). Chewers with smoking made up nearly 90% of the chewers. In contrast, only one third of the cohort smoked. Chewers were less educated and engaged in more physical job at work. Chewers had more drinking habits and were less physically active. They also exhibited higher BMI, higher cholesterol and more diabetes.

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Fig 1. Flow diagram of study subjects by chewing and by smoking status.

https://doi.org/10.1371/journal.pone.0152246.g001

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Table 1. Demographics and clinical characteristics by chewing status.

https://doi.org/10.1371/journal.pone.0152246.t001

Mortality risks of chewers were compared with non-chewers among the entire cohort and among smokers in Table 2. For all-cause mortality, BQ chewers had nearly doubled the risk among the entire cohort, with HR at 1.92; while one third excess increase among smokers, with HR at 1.35. Chewers also doubled the cancer risks, and when they smoked, the significant increase remained compared to non-chewing smokers. Chewers had 10-fold increase in oral cancer risk compared to nonsmoking and non-chewers after adjusted for age, drinking, physical labor at work, education, BMI, systolic blood pressure, fasting blood glucose, and total cholesterol. Additional increases were found in lung cancer, esophageal cancer, liver cancer and liver diseases. Increases were also found in cardiovascular diseases (CVD), respiratory diseases like COPD, digestive diseases, and diabetes. Smoking chewers compared to smoking non-chewers also had higher risks in most of the diseases mentioned above. Significant mortality risk for injuries were observed compared to non-smoking chewers (HR, 1.92; 95% CI, 1.48–2.49) and smoking chewers (HR, 1.54; 95% CI, 1.17–2.01).

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Table 2. Mortality risk of chewers in total cohort and among smokers in cohort.

https://doi.org/10.1371/journal.pone.0152246.t002

Table 3 compared the active chewers with the inactive chewers. We also showed active non-chewers with inactive non-chewers. For all-cause mortality, active chewers reduced by 19% (HR: 0.81) and all-cancer mortality by 22% (HR: 0.78). Other than lung cancer (HR:0.64) and diabetes (HR:0.56), reduction in other causes did not reach statistical significance due to small sample size.

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Table 3. Benefits or reduced mortality for chewers and for non- chewers from being active.

https://doi.org/10.1371/journal.pone.0152246.t003

Inactive chewers at age 30 had their lifespan shortened by 4.3 years, when compared to “inactive” non-chewers (Fig 2 and Table 4). Active chewers improved their life span by 2.5 years, from 42.8 years to 45.3 years, but still fell short of “inactive” non-chewers by 1.8 years and “active” non-chewers by 6.3 years.

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Fig 2. Differences in remaining years in life by chewing status and by physical activity status (males at age 30).

https://doi.org/10.1371/journal.pone.0152246.g002

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Table 4. Comparison of life expectancy among inactive chewers, active chewers, and general population.

https://doi.org/10.1371/journal.pone.0152246.t004

Discussion

In this large prospective cohort, we showed that BQ chewers had an increased risk of mortality from almost every disease across every system of the body. Chewers doubled the all-cause mortality and had a ten-fold increase in oral cancer risk. They also increased cardiovascular disease and diabetes mortality. The finding that the risk of mortality for chewers increases for CVD and diabetes is consistent with previous studies.[9, 11, 26, 27] One out of two chewers died from chewing-related diseases, with HR for all-cause at 1.92. With nearly 1.5 million people involved in this behavior, the disease burden on society in Taiwan from mortality and morbidity is devastating when considering the financial costs and productivity loss involved.[4]

In this study, we reported the health effect of regular exercise on BQ chewers based on mortality differentials. We found that those who self-reported exercise extended their life span by 2.5 years. This is to say, by engaging in at least 15 minutes of exercise every day, chewers could mitigate considerable amount of harms caused by chewing, 2.5 years out of 4.3 years for the inactive chewer, and to reduce mortality by one fifth (19%). This finding is encouraging news for the struggling chewers who had difficulty in quitting. It should be noted that BQ chewing per se had serious health consequences, including a 2-fold increase in mortality risk and shortened life by as many as 8.8 years (Fig 2). From a harm reduction perspective, it is understandable that daily exercise could only reverse part of the harm from someone chewing 5–15 times a day. These findings suggest that cessation of chewing must remain a top priority, while encouraging chewers to engage in regular physical activity as an important remedial process.

The majority of chewers were inactive, with 78% not meeting the recommended LTPA. Chewers thus have a large opportunity to engage in exercise to take advantage of its benefits.[28, 29]With regular exercise at 15 minute/day or more, life span of chewers could be extended due to the combined effect of improved physical and mental well-being. However, exercise benefits were limited when compared with the harm of chewing. Of course, quitting chewing or early screening and timely intervention for early BQ-related cancer could also extend their lives.

By increasing the BQ price, warning chewers of its harms, and banning its marketing promotion, a series of actions proposed by “MPOWER” from the World Health Organization’s (WHO’s) in global tobacco control,[30] the growing tide in BQ chewing could be curbed. However, due to limited global experience or success stories in betel quid control and domestic political pressure (i.e., to avoid offending the voters who consume the substance), the government has not been aggressive in its effort to curb BQ consumption. Promoting exercise can be an effective way to combat this serious health menace, a move far better than inaction so far for decades.

There are important limitations to this study. First, this is a prospective cohort study and not a clinical trial; thus, causal relationships should not be over-interpreted. Chewers tended to be less active than non-chewers, and encouraging chewers to exercise can only be beneficial and cause no harm. The reasons why chewers were more inactive are not clear but could be speculated. With smoking 15 cigarettes and chewing 15 times of BQ a day, chewers had less time or efforts to exercise. They were also less educated with fewer friends who could exercise with them. However, exercise is not a panacea, and cessation remains the first intervention to pursue. Second, in this study, only leisure-time physical activity was considered, which represented only one aspect of physical activity. However, in our analysis, we have controlled the physical labor at work. Furthermore, the mental and physiological benefits from LTPA have been reported to be larger than the other three domains.[31, 32] Third, we used chewing history data gathered from the initial examination and did not follow-up to monitor any possible changes in this behavior. However, as most of the individuals in the study were past the age of initiation for chewing, with less than 13% started after age 30, few non-chewers at the commencement of the study picked up chewing during the study period. [3] Active chewers could quit chewing similar to or quit even more than inactive chewers, as found in active smokers who quit more when compared to inactive smokers.[33] Nevertheless, the benefits of exercise were large and significant, regardless of its mechanism. Fourth, the level of exercise was self-reported and could not be verified. Because people tend to overstate their exercise habits,[34] our results could be an underestimate of its beneficial effects. Fifth, the follow-up of this cohort for vital status relied solely on matching with National Death File. This assumed that all deaths of the cohort were captured in the National Death File, and no errors of recordings of individual identifications were made. In reality, some errors must have occurred and some deaths were not reported to the National Death File, although it was estimated to be minimal.[35] As a result, we must have under-estimated the number of deaths in this cohort. However, the under-reporting of deaths probably occurred at a similar rate for the chewers as for the never chewers, and for the “active” as for the “inactive”, and the final hazard ratios or differences in life expectancy would have remained the same as we reported.

Acknowledgments

We thank MJ Health Management Institution for making their large dataset available to us. Raw data used for analysis in this research were received from MJ Health Resource Center. Authorization Code: MJHRFB2014001C. The MJ Health Resource Foundation is responsible for the data distribution. Any interpretation or conclusions drawn from the research analysis does not represent the views of MJ Health Resource Center.