Associations between dietary intake of meat-borne carcinogens and pancreatic cancer were assessed in this large, multi-center, prospective cohort study of subjects randomized to screening in the PLCO trial. The analyses suggest that intake of meat-derived HCAs confers a higher risk of pancreatic cancer, but are less suggestive for BaP. Upward trends in risk of pancreas cancer were observed with increasing quintiles of dietary intake of DiMeIQx and MeIQx (P for linear trend: 0.01 and 0.03, respectively). There were increased hazards associated with higher quintiles of intake of each HCA measure and statistically significantly increased HRs were found for the MAI. Increasing BaP intake was associated with elevation in risk in some quintiles, but these were not statistically significant and there was not a dose response pattern. There were increased hazards among individuals reporting preferences for well-done meat intake versus meat cooked to lower degrees of doneness, particularly when both doneness preference and intake level were considered. Analyses of cooking method alone did not reveal consistent patterns of elevated risk for categories of high temperature cooked meats. It is not surprising that measures with less information about carcinogen exposure, such as meat cooking methods, doneness preferences or type, yield less consistent patterns of risk than summary measures. The most striking and consistent patterns of increased risk with increasing intake were found with the integrated measures of HCA carcinogen intake and the MAI. These data may help explain the inconsistent results from previous studies that analyzed limited information on meat preparation and intake.
Approximately 30 epidemiologic studies have examined meat intake in relation to pancreatic cancer and overall, and those data point to an increased risk with increasing intake of meat, but there are many inconsistencies (Anderson 2006
; WCRF 2009
). There have only been three studies that examined cooking methods and doneness preferences in detail and all report increases in the hazard associated with various measures of well-done meat intake and meat-derived carcinogens. These previous studies include a population-based case-control study in the upper Midwest (Anderson, et al., 2002
); a hospital-based case-control study in Texas (Li D et al., 2007
) and the NIH-AARP prospective study in retired men and women (Stolzenberg-Solomon et al., 2006).
The study based in the upper Midwest (Anderson, et al 2005
) found elevated odds ratios and 95% confidence intervals (CI) in comparisons of fifth to first quintiles of intake for PhIP 1.8 (1.0-3.1); DiMeIQx 2.0 (1.2-3.5), MeIQx 1.5 (0.9-2.7), BaP 2.2 (1.2-4.0) and the MAI 2.4 (1.3-4.3).
In the Texas study (Li D et al., 2007
), daily intake of MeIQx, DiMeIQx, BaP and the MAI were all statistically significant predictors of pancreatic cancer when comparisons were based on the upper 40% of intake versus lower 60%. Odds ratios (95%, CI) were 1.48 (1.12-1.95) for MeIQx; 1.39(1.05-1.83) for DiMeIQx; 1.12 (0.85-1.48) for PhIP; 1.51 (1.15-1.98) for BaP and 1.41 (1.07-1.85) for the MAI.
The AARP cohort study (Stolzenberg-Solomon et al., 2006) was the only other prospective study to have reported on meat-derived carcinogens and risk of pancreatic cancer. The strongest associations were for meat-derived MAI in men (OR = 2.11, 95% CI 1.39-3.91) for the fifth versus first quintile of intake. High versus low intake of high-temperature cooked meat also increased risk in men. The findings in women were generally null, which may have resulted from lower power due to a smaller number of cases as well as lower absolute intake of meat and meat-derived carcinogens.
In general, the results in the current study are similar to those reported in the previous studies cited. The differences among these studies may reflect, in part, differences in methods of dietary assessment of meat doneness preferences and intake. The studies in Minnesota and Texas administered questionnaires with colored photographs of meat cooked to varying degrees of doneness and in the former, three-dimensional food models were used to help subjects accurately estimate portion sizes.
The AARP study and this PLCO study relied on data from dietary surveys that assessed meat doneness preferences with written descriptions; subjects were instructed to report intake based in relation to specified serving sizes. This approach may result in less accurate assessment of doneness preferences and intake resulting in more misclassification and attenuated HRs.
The prospective nature of this analysis within the PLCO cohort is a strength. The dietary information collected at baseline, reduces the potential for both recall bias and recall error present in retrospective observational studies. Another strength of this study is the use of multiple levels of aggregation in exposure assessment, so designed to better approximate the total intake of the targeted carcinogens. Rather than relying on either meat doneness preferences or cooking methods alone, both dimensions, along with meat intake, were surveyed and incorporated. Furthermore, by using the CHARRED database of estimated mutagen content associated with these doneness preferences and cooking methods, net measures of carcinogens are obtained across the most commonly consumed meats. Finally, the MAI provides a measure of the total mutagenic potential across all of the meats; accounting for mutagens - both known and unknown. These aggregational features are likely responsible for the relative significance of increased MAI among the results.
This study does have limitations. Despite our findings implicating meat-derived carcinogens and pancreas cancer, it is difficult to implicate specific meat-derived carcinogens and cancer risk in any population study (Report on Carcinogens 2004
). The HCAs and polycyclic aromatic hydrocarbons in cooked meat are correlated with each other and with other potentially carcinogenic constituents. Both the relative and absolute amounts of these carcinogens vary in any meal or diet, and cannot be entirely captured by surveys. However, their cumulative effect as measured by the MAI, and their concentration in meats that are prepared as described merits understanding.
This was not a randomized study of these exposures and the possibility remains that these diet-related effects are confounded with some unmeasured, but more directly causal, characteristic. In addition, the PLCO includes subjects that may be healthier overall, than the general population. Since healthier subjects are more likely to accept screening, and possibly less likely to consume meat, the resulting estimates of relative hazard among higher quintiles of exposure would then be lower than in the population at large.
In sum, the results of this prospective study support the hypothesis that consuming meat cooked at high temperatures, and to a high degree of doneness, with the resulting production of mutagenic compounds, confers a higher risk of pancreatic cancer. This association, if causal, identifies means to reduce risk of pancreatic cancer by reducing meat consumption or, by adopting simple changes in meat preparation techniques that reduce or eliminate production of these compounds.