In this NIH-AARP Diet and Health Study, we showed that heavy alcohol use (equivalent to ~40 g or 3 drinks daily), especially heavy liquor use, was associated with an increased risk of developing pancreatic cancer compared with light use. A significant positive association was observed for heavy liquor use among longtime former smokers. We observed a positive, albeit nonsignificant, association among never smokers.
Our findings of an increased risk of pancreatic cancer in heavy alcohol drinkers were in agreement with 5 case-control studies (18
) and 3 cohort studies (7
). Five studies have shown statistically significant relative risk ranging from 1.7 to 3.7 after adjustment for smoking (7
). A moderately increased risk of pancreatic cancer was also observed in alcohol abusers compared with the general population (46
). In our study, the positive association was mostly explained by heavy liquor use. Heavy liquor use has been associated with pancreatic cancer in 3 North American studies (10
). Volatile nitrosamines and polycyclic aromatic hydrocarbons are found in liquor and beer (48
). Because nitrosamines are known pancreatic carcinogens in hamsters (49
), the higher risk of pancreatic cancer could plausibly be explained by nitrosamines in liquor with heavy use (50
). Alternatively, the positive association may be due to residual confounding by factors such as smoking and lifestyle factors. For example, we found that heavy liquor drinkers not only were more likely to be current smokers but also tended to have less total folate intake. Our study did not suggest an increased risk related to beer use or a decreased risk related to wine use as previously reported (10
); however, we had few participants that were heavy beer or wine drinkers (≥3 drinks per day) and limited power to detect an association. Inconsistent findings on types of alcoholic beverage and pancreatic cancer risk may reflect different distributions of types of beverages consumed across different study populations. We may expect the association between alcohol use and pancreatic cancer to be confounded by other lifestyle behaviors if beverage preference differentially linked with such factors (51
). For example, a survey in 1995 revealed distinct drinking habits in the United States and Germany (53
To minimize the residual confounding by smoking, we attempted to examine the association among never smokers. We found that heavy total alcohol or liquor use showed a slightly increased risk of developing pancreatic cancer in never smokers. Although the association was not statistically significant, the magnitude of the association was similar to that of ever smokers, and there was no significant interaction across various smoking statuses. This observation was consistent with the results from 2 North American studies (17
) that suggested that heavy alcohol use was an independent etiologic component for pancreatic cancer. However, our study was limited by the fact that only 16 cases arose among 5,870 participants who were never-smoking heavy drinkers.
Notably, we found a significantly increased risk of pancreatic cancer associated with heavy total alcohol and liquor use among longtime former smokers. In our study, 38% of participants were former smokers who had quit smoking 10 or more years ago before baseline, and these participants, in particular men, did not have a significant, higher risk of developing pancreatic cancer compared with never smokers. Although we could not completely exclude residual confounding by cigarette smoking, the significant positive association between alcohol use and pancreatic cancer in longtime former smokers might suggest a potential etiologic role of alcohol use in pancreatic cancer development.
The mechanisms by which heavy alcohol use may increase human pancreatic cancer risk have not been well elucidated (54
). Animal studies have shown that the pancreas can metabolize ethanol by means of oxidative and nonoxidative pathways (55
). The metabolites of the oxidative pathway, acetaldehyde and reactive oxygen species, could injure pancreatic tissues and alter the pathways involved in the inflammatory response and carcinogenesis (56
). The metabolites of the nonoxidative pathway, fatty acid ethyl esters, could induce pancreatic injury in male rats (59
). Recently, Gukovsky et al. (60
) developed a rat model of alcohol-mediated postacute pancreatitis that produced the 3 key pathologic responses of human alcoholic chronic pancreatitis, including loss of parenchyma, sustained inflammation, and fibrosis. A prevailing opinion is that alcohol consumption sensitizes the pancreas to inflammatory, immune, and fibrosing responses induced by genetic and environmental predisposing factors (61
) and functions as a cofactor in the development of pancreatic disease. It is unknown whether heavy alcohol use would cause the aforementioned changes in the human pancreas and predispose the pancreas to inflammatory response and carcinogenesis. Because we did not collect information on pancreatitis or other pancreatic diseases, we could not test the hypothesis that pancreatitis is one of the mechanisms that explains the association between heavy alcohol use and pancreatic cancer.
The strengths of our prospective study include its considerable sample size and wide range of alcohol consumption. The NIH-AARP Diet and Health Study cohort of older individuals provided an appropriate population for the study of pancreatic cancer that may be generalizable to other older populations. Differential recall bias was precluded because information on exposure was collected before diagnosis of pancreatic cancer. Given the large number of cases, we had an adequate sample size to estimate the risk in heavy drinkers overall. We were able to examine the association in long-term former smokers who were no longer at a higher risk of developing pancreatic cancer due to cigarette smoking. However, we did not have an adequate number of cases among women and never smokers or among heavy beer or wine drinkers to observe a statistically significant association with pancreatic cancer risk. In addition, we may not have captured the etiologically relevant window of exposure using baseline exposure assessment. Along the same lines, we did not collect information on duration of alcohol use. It has been suggested that long periods of time may exert a measurable risk of pancreatic cancer (2
). Finally, because the majority of participants were non-Hispanic white, the study did not have enough power to examine the association among other ethnic groups.
In summary, we confirmed previous findings that moderate alcohol use was not a risk factor for pancreatic cancer. Our findings suggested that heavy alcohol use, especially heavy liquor use, may play a role in pancreatic cancer etiology, although we could not completely exclude residual confounding by smoking. We hope our study would stimulate more studies to address the residual confounding of smoking in the relation between alcohol use and risk of pancreatic cancer.