Soft drinks, aspartame, and the risk of cancer and cardiovascular disease.

The consumption of sugar-sweetened soft drinks has been associated with excess weight and an increased risk of type 2 diabetes in systematic reviews and meta-analyses of the evidence (1, 2), and these conditions are by themselves related to an increased risk of mortality, cardiovascular disease, some cancers, and other chronic diseases. Evidence for an association between soft drink intake and risk of cardiovascular disease and cancer is, however, more limited (3–7). Sugar-sweetened soft drinks are the primary source of added sugars in the American diet and contribute 9.2% of total energy intake in the United States (8). Recently, the American Heart Association released recommendations to reduce the intake of added sugar to no more than 100– 150 kcal/d for most Americans (9). Replacing sugar-sweetened beverages with nonor low-caloric beverages could be used to reduce sugar intake, and artificially sweetened diet soft drinks have been marketed as a healthier alternative due to their lack of calories. However, it is unclear whether they should be recommended as a replacement for sugar-sweetened soft drinks because some studies have found increased risk of type 2 diabetes, cardiovascular disease, or the metabolic syndrome with higher intake of diet soft drinks (10–12), although it is possible that these findings may be due to reverse causation (4). Most manufacturers have used aspartame as an artificial sweetener in diet soft drinks. Although many short-term animal studies have suggested the safety of aspartame, a recent large study that assessed aspartame intake throughout the life span in rats suggested an increased risk of lymphomas, leukemias, and transitional cell carcinomas of the pelvis, ureter, and bladder in a dose-dependent manner within ranges that are considered to be safe for human consumption (doses as low as 20 mg/kg body weight) (13). However, epidemiologic studies in humans on the health effects of diet soft drinks or aspartame intake are sparse and have not suggested an association with cancer risk [see references in (14)], but they have some limitations that include either retrospective design with potential recall and selection biases or only one baseline dietary assessment and short follow-up in the only other prospective study published on the subject. In addition, because diet soft drinks are often consumed by persons with excess weight and type 2 diabetes with the aim of reducing caloric intake and facilitating weight loss and because these 2 conditions are associated with an increased risk of several cancers including lymphomas and leukemias, studies need to be conducted and interpreted carefully because of the potential for residual confounding. In this issue of the Journal, Schernhammer et al (14) investigate the association between artificially sweetened and sugarcontaining sodas and the risk of hematopoetic cancers in the Nurses’ Health Study and the Health Professionals Follow-Up Study. Both studies have important strengths, including the prospective design (which avoids recall bias and reduces the potential for selection bias that may affect retrospective studies), repeated dietary assessments (which reduces random measurement error due to changes in diet during follow-up), and . 20 y of followup, which results in a considerable number of cancer cases. Schernhammer et al found that among men greater intake of diet sodas ( 1 serving/d) was associated with an increased risk of non-Hodgkin lymphoma (NHL; RR: 1.31; 95% CI: 1.01, 1.72) and multiple myeloma (RR: 2.02; 95% CI: 1.20, 3.40) compared with no intake. Intake of regular sugar-sweetened sodas was associated with an increased risk of NHL (RR: 1.66; 95% CI: 1.10, 2.51) in men, but no association was found for multiple myeloma or leukemia. None of the analyses showed a significant association among women only. In addition, the authors observed an increased risk of leukemia with a high compared with a low intake of diet soft drinks in the combined cohorts (RR: 1.42; 95% CI: 1.00, 2.02), with similar risk estimates but limited power in the sex-specific analyses. Intake of aspartame was directly associated with risk of NHL and multiple myeloma and suggestively associated with leukemia in men, although not in women. With regard to the mechanism that may explain the findings for diet soft drinks, it is known that aspartame breaks down to methanol, aspartic acid, and phenylalanine if stored near or above room temperature. The authors suggested that higher enzymatic activity of alcohol dehydrogenase type 1 (ADH) in men, which induces higher conversion rates from methanol to carcinogenic formaldehyde, could explain the sex differences in the results for NHL and multiple myeloma. Because ethanol intake inhibits methanol metabolism, persons with a low ethanol intake might have more unbound ADH activity and higher formaldehyde conversion rates.