In these large prospective cohort studies of men and women, our results did not support a strong role of zinc or iron, whether from food sources only or including supplements, in colorectal carcinogenesis. However, a modest inverse association of dietary zinc intake with risk of rectal cancer in women cannot be excluded. In addition, these associations were not significantly modified by alcohol consumption or several other colorectal cancer risk factors.
Several mechanisms have been proposed to support a role of zinc in colorectal carcinogenesis. In addition to the potential effect of zinc on insulin, animal models have suggested a role of zinc to protect against chemically induced colonic proneoplastic progression43
. Further, zinc has been shown in experimental studies to play an important role in antioxidant defense system, DNA synthesis, and immune function44
. Despite the experimental evidence, only two epidemiological studies to date have examined the association between zinc intake and colon cancer risk and both were in women. The Swedish study10
reported a weak non-significantly lower risk of colon cancer (highest vs lowest quintile, RR=0.90, 95%CI: 0.65, 1.25, P
trend=0.71). However, they had a relatively limited range in intake to examine this association (≥ 11.1 vs < 9.0 mg/day). In contrast, the study from Iowa11
had a wider range across quintiles of dietary zinc intake (≥ 17.6 vs ≤ 8.5 mg/day). Although associations with dietary zinc intake for colon cancer were not reported, they did observe a significantly lower risk of proximal colon cancer (highest vs lowest quintile, RR=0.38, 95%CI: 0.17, 0.74, P
trend=0.01) and a non-significantly lower risk of distal colon cancer (highest vs lowest quintile, RR=0.58, 95%CI: 0.26, 1.30, P
trend=0.15). We had a reasonable contrast in zinc intake (≥ 13.4 vs ≤ 8.7 mg/day) but we observed a non-significant lower risk for colon cancer (highest vs lowest quintile, RR=0.84; 95%CI: 0.64, 1.09) with no difference by colon cancer subsite. Although results were not reported in these earlier studies for rectal cancer, we observed a significant lower risk for rectal cancer (highest vs lowest quintile, RR=0.51, 95%CI: 0.29, 0.86) in women. Reasons for the inconsistent results observed in these few observational studies are unclear and the difference in ranges across quintiles of dietary zinc intake might partly explain the inconsistencies in the results. In addition, food sources of zinc differ between the US and Sweden. In the US diet, the major food sources of dietary zinc are meat, dairy foods, and fortified cereals while the primary sources in Sweden are mainly grains and red meat45
. Zinc from meat is more bioavailable than zinc from plant sources46
and plant sources of zinc such as whole grains and beans contain phytates, which can inhibit zinc absorption46
. However, further adjustment for phytate intake did not change the results in our study. Nonetheless, future studies in different populations with a wide range of zinc intake should help elucidate the of zinc intake on colorectal carcinogenesis.
Zinc supplement use was not associated with colorectal cancer risk in our study, which was consistent with the study from Iowa10
. The mean dietary zinc intake in our population was higher than the US recommended dietary allowance, which is 8 mg/day for women and 11mg/day for men, and relatively few participants had high zinc supplement intake (i.e., ≥25 mg/d) or intakes less than 8mg/d, which limited our ability to examine associations with very high or low intake. Taken together, no firm conclusion regarding zinc intake and colorectal cancer incidence can be drawn based on the current limited epidemiological evidence.
In contrast to zinc, heme iron has been hypothesized to be associated with an increased risk of colorectal cancer. To date, five cohort studies have examined this hypothesis10,11,14,18,25
. In the Iowa Women’s Health Study, heme iron intake was positively associated with risk of proximal (for ≥ 2.05 vs ≤ 0.76 mg/day, RR=2.18, 95%CI: 1.24, 3.86, P
trend=0.01) but not with risk of distal colon cancer (RR=0.90, 95%CI: 0.45, 1.81, P
. The association of proximal colon cancer with heme iron intake was particularly strong among women who consumed at least 10 grams of alcohol per day (RR=7.20, 95%CI: 1.33, 38.91, P
trend=0.03). Similarly, a study from Sweden reported a positive association with heme iron intake among women drinking at least 20 grams of alcohol per week (≥ 2.06 vs ≤ 0.67 mg/day, RR=2.29, 95%CI: 1.25, 4.21, P
. In contrast, in a study of women and men from the Netherlands, no association between heme iron intake and colon cancer risk was observed, but there was a suggestion of a positive association among women who drank at least 5 grams of alcohol per day (tertile 3 vs tertile 1, RR=1.50, 95%CI: 0.95, 2.36)18
. The NIH-AARP study of both men and women suggested a positive association between heme iron intake and colorectal cancer risk (highest vs lowest quintile, RR=1.13, 95%CI: 0.99–1.29, P
trend = 0.02) although whether the association was modified by alcohol consumption was not reported25
. A Canadian study of women showed null results for heme iron intake (>2.95 vs <1.58 mg/day; RR=0.99, 95%CI:0.70, 1.40) and the associations did not differ by the amount of alcohol consumed14
. A recent meta-analysis of these five studies suggested a modest positive association between heme iron intake and colon cancer risk (highest vs lowest quintile, RR=1.18, 95%CI: 1.06, 1.32)20
. Our findings of non-significant associations for heme iron intake are somewhat consistent with the early two studies14,18
but not the others10,11,25
. The narrower comparison across quintiles may partly explain the non-significant positive associations we observed. The stronger associations observed among alcohol drinkers in two of the previous studies10,11
may also be due to chance because of the relatively small number of cases in the highest quintile of heme iron and highest alcohol consumption categories (< 50 cases). Future studies in populations with a wide range of heme iron intakes should help confirm these findings or identify any potential threshold effect of heme iron. Notably, the significant positive associations between relatively high iron supplemental use (i.e., ≥ 25 mg/day vs none) and rectal cancer risk in women were unexpected. Given that this subgroup finding is based on a relatively small number of cases, the results might be due to chance. On the other hand, we cannot rule out the possibly that iron intake may influence the rectal cancer.
Limitations of our study need consideration. Our study had relatively narrow quintile intake ranges of zinc and heme iron, which limited our ability to evaluate associations with these micronutrients for high or low intake ranges (i.e., zinc deficiency). We lacked information on cooking methods, which might impact the amount of heme iron because heme iron can be partially converted to non-heme iron depending the type and extend of the cooking method47
. The suggestive inverse associations between dietary zinc intake and rectal cancer risk, particularly in women, might be due to chance because of the relatively small number of rectal cancer cases. We cannot exclude the possibility that residual confounding may explain the suggestive inverse associations observed with dietary zinc intakes although we adjusted for multiple lifestyle and dietary confounders. In addition, our study population consisted of mainly Caucasians and the results may not be generalizable to other ethnic groups with different dietary patterns. Our study has several strengths, including its large size, prospective design, long follow-up time, and the comprehensive updated measurements of zinc and iron intakes.
In summary, although a beneficial effect of zinc and a detrimental effect of heme iron on colorectal carcinogenesis have been suggested by some experimental evidence, our study did not support a strong role of zinc or heme iron intake in colorectal cancer risk. However, a potential modest inverse association with dietary zinc intake and rectal cancer risk in women requires further study.