Null association between frequency of cured meat consumption and methylvaline and ethylvaline hemoglobin adduct levels: the N-nitroso brain cancer hypothesis.

Introduction Numerous animal experiments have shown definitively that methylnitrosoureas, and particularly ethylnitrosoureas, are potent neurocarcinogens (1). Furthermore, experimental studies have demonstrated that ingestion of nitrites and alkylureas results in the formation of alkylnitrosoureas in the stomach, which can be delivered transplacentally to the fetus leading to malignant brain tumor formation in offspring of exposed dams (2). In the human diet, cured meats such as hot dogs, bacon, packaged lunch meats, cured ham, and sausage are commonly treated with nitrites to inhibit botulism and to enhance the visual appeal of the meats (3). Accordingly, nonexperimental human studies have been conducted to evaluate the potential association between cured meat consumption by mothers during pregnancy and the subsequent elevated risk of brain tumors in their children (4). Although far from conclusive, the majority of these epidemiological studies have provided suggestive evidence in favor of the relation (5). The hypothesized alkylnitrosourea-brain cancer causal pathway can be summarized as follows: ingestion of nitrites facilitates the formation of alkylnitrosoureas in the acidic stomach environment. Alkylnitrosoureas, which are highly reactive and do not require metabolic activation, decompose into diazonium ions. Diazonium ions react to form promutagenic Oalkylguanine DNA adducts. O-alklyguanine adducts are efficiently repaired by the O-alkylguanine alkyltransferase DNA repair protein. This repair mechanism, however, is subject to a high degree of phenotypic variation, and those with the MER phenotype, in contrast to the MER phenotype, have poor capacity for repair (6). Accumulation and persistence of Oalkylguanine adducts can lead to tumor formation (7). In this pilot study, we sought to provide evidence consistent with this hypothesis, that the formation of methylnitrosurea and ethylnitrosurea is higher from foods treated with nitrites, i.e., cured meats, by evaluating differences in methylation and ethylation of NH2-terminal valine in Hb. 3 Hb adducts have been used effectively as biomarkers of exposure to carcinogens and other alkylating agents (8, 9). Advantages of hemoglobin adducts include the relatively long lifetime of the red cell ( 120 days), the ease of obtaining adequate quantities of material, and the lack of any known repair processes. We hypothesized that persons who consume cured meats would, in a dose-response fashion, have substantially higher mean blood levels of NH2terminal Hb-alkylvaline biomarkers for alkylnitrosourea formation, MV and EV, than persons who do not consume cured meats.