In this large prospective cohort of AARP members, we found that higher intake of dietary nitrate was associated with an increased risk of thyroid cancer in men. The positive association among men was present for both the papillary and follicular subtypes. These findings were only modestly changed when we adjusted for micronutrients that were correlated with nitrate intake, demonstrating that the association with nitrate was unlikely due to other micronutrients in vegetables. The findings were also unchanged when we excluded persons for whom contaminated drinking water may have constituted a substantial portion of their nitrate intake. Nitrite intake was not clearly associated with risk of thyroid cancer overall for either men or women; however, we observed an increased risk of follicular thyroid cancer in the highest nitrite intake quartile among men and a significant trend. When we stratified our results by smoking status, we found evidence of a significant increase in thyroid cancer risk with elevated nitrite intake among female smokers.
Our finding of an increased risk of thyroid cancer with increasing nitrate intake in men
is consistent with the recent report from a cohort of older women in Iowa (21
) where a positive association between both dietary and drinking water nitrate ingestion and thyroid cancer risk was observed. A RR of 2.9 (95% CI: 1.0–8.1) with a significant trend (p-trend=0.046) was observed comparing those in the highest quartile of dietary nitrate intake to the lowest quartile (21
). They also found an increased risk of thyroid cancer with higher average nitrate levels in public water supplies and with longer consumption of water exceeding 5 mg/L nitrate-N (for >/=5 years at >5 mg/L, RR = 2.6; 95% CI: 1.1–6.2). Given that the positive findings among women from the Iowa study are consistent with our findings among men, it is not clear why we observed no association with dietary nitrate among women. In both studies, leafy green vegetables (lettuce and spinach) were the major contributors to nitrate intake.
The gender difference we observed may be partially explained by differential dietary reporting errors between men and women in our study population. Studies have found that healthful attitudes, beliefs, and dietary habits were more strongly correlated with vegetable intake among women than among men (34
) and that women over-reported foods perceived as healthy (35
). In other studies of this cohort (37
), the authors found that vegetable intake was not associated with risk of total cancer among women, but was associated with a significant decrease in risk in men. Misreporting of vegetable intake by women in our study could have led to exposure misclassification, resulting in an attenuated association.
We did find evidence of an increased risk of thyroid cancer among female smokers with high nitrite intake. Endogenous nitrosation is known to be associated with tobacco smoking (38
). We subsequently hypothesized that nitrate and nitrite intake may result in different thyroid cancer risk profiles in smokers compared to non-smokers. This is because thiocyanate, which is present in tobacco smoke, is a strong catalyst of nitrosation of amines (39
). Our finding of an increased risk of thyroid cancer with increasing nitrite intake in female smokers is interesting. It is not clear why this was observed in women and not men. Although this has not been previously reported, and it could be due to chance, it is biologically plausible, and it suggests that the potential interaction of tobacco intake and NOC precursors should be evaluated in the future.
Factors associated with the detection of thyroid cancers are important to consider in the assessment of thyroid cancer risk due to the recent changes in technology and the greater availability of diagnostic tests in recent decades (1
). It is notable that men and women in the highest nitrate intake quintile had more education, increased physical activity, increased fruit and vegetable intake, and lower caloric intake. These characteristics are indicative of a more health conscious lifestyle and may be correlated with increased utilization of medical services and increased detection of thyroid tumors. However, it is unlikely that detection bias would occur only among men as such a detection bias would likely be higher among women due to their increased healthcare utilization patterns (40
). In addition, we observed similar results among men and women younger than 65 and 65 and older, when access to health care via Medicare is available to all Americans, suggesting that increased detection is not a substantial source of bias in our study population.
Drinking water nitrate can constitute the majority of nitrate intake at levels near or above the MCL (41
). Information on the primary source of drinking water was not obtained in this study; however, our findings were not altered when we excluded individuals living in areas where nitrate contamination of ground water is highly probable. Although a limitation of our study is that we did not have surface water estimates to identify persons for exclusion, more than half of the US population obtains drinking water from groundwater sources (42
). Furthermore, surface waters in areas with contaminated groundwater are also likely to be affected. Lack of individual level drinking water information likely resulted in some misclassification of nitrate exposure from drinking water. Future investigation in this area, if possible, should utilize a study design that captures drinking water intake of nitrate in addition to dietary intake.
The possibility that nitrate intake from both the water and diet may be correlated with exposure to pesticides is an important point to consider. Insecticides, herbicides, and fungicides have been previously reported to have thyroid disrupting effects through a variety of mechanisms (43
). Animal studies have shown that exposure to various pesticides can change the levels of thyroid hormones as well as increase TSH levels (45
). It would be expected that those consume high levels of vegetables, and therefore high nitrate intake, would also potentially experience have exposure to pesticides. Additionally, nitrate contamination in ground water often occurs in agricultural areas with high nitrogen-based fertilizer use; these areas would also likely have increased levels of pesticides in the water as well. Future studies in this area would be strengthened through evaluation of the body burden of pesticides using biological samples in addition to the consideration of the role of nitrate intake.
Strengths of this study include the use of a detailed questionnaire to assess dietary intake of nitrate and nitrite and the wide range of intake. Among participants in our study, median intake of nitrate in the highest quintile was over 5 times that in the lowest quintile for nitrate and over 3 times that in the lowest quintile for nitrite. Other strengths include the prospective nature of the study, completeness of follow-up, the relatively large number of thyroid cancer cases, and the ability to adjust for a large number of potential confounding variables including micronutrients in vegetables. The analysis of thyroid cancer risk by histologic type is also a strength of this study. Dietary intake based on FFQs is affected by measurement error, which, if nondifferential, could reduce an association. In this study diet was assessed later in life; however, it is possible that exposure at younger ages may be more important for risk of thyroid cancer.
In sum, we found an increased risk of thyroid cancer with increasing dietary nitrate intake among men. Additionally, dietary nitrite was associated with elevated risk of follicular thyroid cancer among men apparently due to plant sources of nitrite. Given the previous positive finding for nitrate in women, it is unclear why we observed an association in men but not women. Future investigation into this hypothesis should include populations for whom both drinking water source and dietary consumption data are available, as well as data on factors that affect nitrosation. Our findings suggest that dietary nitrate may be a risk factor for thyroid cancer.