Janneke G. F. Hogervorst

The carcinogenicity of dietary acrylamide intake: A comparative discussion of epidemiological and experimental animal research

Since 2002, it is known that the probable human carcinogen acrylamide is present in commonly consumed carbohydrate-rich foods, such as French fries and potato chips. In this review, the authors discuss the body of evidence on acrylamide carcinogenicity from both epidemiological and rodent studies, including variability, strengths and weaknesses, how both types of evidence relate, and possible reasons for discrepancies. In both rats and humans, increased incidences of various cancer types were observed. In rats, increased incidences of mammary gland, thyroid tumors and scrotal mesothelioma were observed in both studies that were performed. In humans, increased risks of ovarian and endometrial cancers, renal cell cancer, estrogen (and progesterone) receptor–positive breast cancer, and oral cavity cancer (the latter in non-smoking women) were observed. Some cancer types were found in both rats and humans, e.g., endometrial cancer (observed in one of the two rat studies), but there are also some inconsistencies. Interestingly, in humans, some indications for inverse associations were observed for lung and bladder cancers in women, and prostate and oro- and hypopharynx cancers in men. These latter observations indicate that genotoxicity may not be the only mechanism by which acrylamide causes cancer. The estimated risks based on the epidemiological studies for the sites for which a positive association was observed were considerably higher than those based on extrapolations from the rat studies. The observed pattern of increased risks in the rat and epidemiological studies and the decreased risks in the epidemiological studies suggests that acrylamide might influence hormonal systems, for which rodents may not be good models.

Dietary Acrylamide Intake Is Not Associated with Gastrointestinal Cancer Risk

Acrylamide is a probable human carcinogen that was detected in several heat-treated foods, such as French fries and crisps, in 2002. Prospective studies are needed on acrylamide and human cancer risk. We prospectively investigated the association between acrylamide and gastrointestinal cancer risk. In 1986, 120,852 men and women (aged 55-69 y) were included in the Netherlands Cohort Study on diet and cancer. At baseline, a random subcohort of 5000 participants was selected for a case-cohort approach. Acrylamide intake was assessed with a FFQ at baseline and was based on acrylamide analyses in relevant Dutch foods. After 13.3 y of follow-up, 2190, 563, 349, and 216 cases of colorectal, gastric, pancreatic, and esophageal cancer, respectively, were available for analysis. The daily acrylamide intake of the subcohort was (mean +/- SD) 21.7 +/- 12.1 microg. A 10-microg/d increment of acrylamide intake was associated with multivariable-adjusted Cox proportional hazard rate ratios (HR) (95% CI) of 1.00 (0.96-1.06), 1.02 (0.94-1.10), 1.06 (0.96-1.17), and 0.96 (0.85-1.09) for colorectal, gastric, pancreatic, and esophageal cancer, respectively. For former or never-smokers, the corresponding HR were: 1.03 (0.94-1.12), 1.09 (0.98-1.22), 1.07 (0.93-1.24), and 0.92 (0.76-1.11). There were some significantly increased risks within subgroups stratified by obesity, nonoccupational physical activity, and age, factors that were a priori selected based on their capacity to modify cytochrome P4502E1 activity. Overall, acrylamide intake was not associated with colorectal, gastric, pancreatic, and esophageal cancer risk, but some subgroups deserve further attention.

Lung Cancer Risk in Relation to Dietary Acrylamide Intake

BACKGROUND Acrylamide is a probable human carcinogen that is present in several heat-treated foods. In epidemiological studies, positive associations between dietary acrylamide intake and the risks of endometrial, ovarian, estrogen receptor-positive breast, and renal cell cancers have been observed. The association between dietary acrylamide intake and lung cancer risk is not known. METHODS We conducted a case-cohort study among 58 279 men and 62 573 women (aged 55-69 years) in the Netherlands Cohort Study on Diet and Cancer. Intakes of acrylamide-containing foods and risk factors for cancer were assessed with a self-administered questionnaire at baseline in 1986 and combined with acrylamide levels in relevant Dutch foods to assess total dietary acrylamide intake. The number of person-years at risk was estimated by using a random sample of participants from the total cohort that was chosen at baseline (n = 5000). Incident lung cancer cases in the total cohort were detected by computerized record linkages to the Netherlands Cancer Registry and the Netherlands Pathology Registry. Hazard ratios and 95% confidence intervals (CIs) for the risk of lung cancer associated with acrylamide intakes were estimated using Cox proportional hazards models that controlled for smoking (status, quantity, and duration) and other lung cancer risk factors. All statistical tests were two-sided. RESULTS After 13.3 years of follow-up (September 17, 1986 up to January 1, 2000) there were 2649 cases of primary, histologically verified lung cancer (International Classification of Diseases for Oncology-3 code: C34) when cases with prevalent cancer at baseline (other than skin cancer) were excluded. The multivariable-adjusted hazard ratio of lung cancer for a 10-microg/d increment of acrylamide intake was 1.03 (95% CI = 0.96 to 1.11) for men and 0.82 (95% CI = 0.69 to 0.96) for women. The hazard ratio of lung cancer for the highest (median intake [microg/d]: men = 37.6 and women = 36.8) vs the lowest (median intake [microg/d]: men = 10.8 and women = 9.5) quintile of acrylamide intake was 1.03 (95% CI = 0.77 to 1.39, P(trend) = .85) for men and 0.45 (95% CI = 0.27 to 0.76, P(trend) = .01) for women. The inverse association in women was strongest for adenocarcinoma (hazard ratio for highest vs lowest tertile of intake = 0.40, 95% CI = 0.21 to 0.78; P(trend) = .01). CONCLUSIONS Acrylamide intake was not associated with lung cancer risk in men but was inversely associated in women, most strongly for adenocarcinoma. This finding suggests that acrylamide is involved in human carcinogenesis through pathways other than genotoxicity.

Dietary Acrylamide Intake and the Risk of Head-Neck and Thyroid Cancers: Results From the Netherlands Cohort Study

Acrylamide exposure has been related to an increased incidence of oral and thyroid tumors in animal studies. In 1986, 120,852 persons (aged 55-69 years) were included in the Netherlands Cohort Study. Dietary acrylamide intake was assessed with a food frequency questionnaire and was based on chemical analysis of all relevant Dutch foods. Hazard ratios were adjusted for smoking and other confounders. After 16.3 years of follow-up, there were 101, 83, 180, and 66 cases of oral cavity, oro-hypopharynx, larynx, and thyroid cancer, respectively. Average daily dietary acrylamide intake was 21.8 microg (standard deviation, 12.1). Dietary acrylamide intake was not associated with increased risk of oral cavity (hazard ratio (HR) per 10-microg intake/day = 0.90, 95% confidence interval (CI): 0.73, 1.10), oro-hypopharynx (HR = 0.74, 95% CI: 0.53, 1.03), larynx (HR = 1.05, 95% CI: 0.91, 1.21), or thyroid (HR = 1.03, 95% CI: 0.82, 1.27) cancer. For nonsmokers, hazard ratios were not increased either. Dietary acrylamide was statistically significantly associated with increased risk of oral cavity cancer in female nonsmokers, but case numbers were small. Dietary acrylamide intake was not positively associated with risk of head-neck and thyroid cancer, except with oral cavity cancer risk for female nonsmokers. A negative association for males was indicated.

Relationship between Radical Generation by Urban Ambient Particulate Matter and Pulmonary Function of School Children

The mechanisms by which particulate matter (PM) produces adverse effects on the respiratory system, such as pulmonary dysfunction in children, are largely unknown. However, oxidative stress is thought to play an important role. Various chemical compounds in ambient particulate matter, including transition metals and aromatic organic compounds, may contribute to adverse effects through intrinsic generation of reactive oxygen species (ROS). It was hypothesized that ROS generation by PM, as determined through electron spin resonance (ESR) spectroscopy, may be negatively associated with pulmonary function in school children. PM2.5, PM10, and total suspended particulates (TSP) were sampled at the playgrounds of six elementary schools in the city of Maastricht, the Netherlands. All children (8–13 yr) from the six schools were asked to undergo spirometry. Multivariate linear regression models were constructed to evaluate associations between oxygen radical formation by PM and lung function. The radical-generating capacity per microgram PM correlated negatively to forced expiratory volume in 1 s (FEV1) and forced expiratory flow at 50% (FEF50%) of forced vital capacity (FVC). The data indicate that chemical features that contribute to intrinsic generation of ROS may be relevant for PM risk assessment.

Validation of a database on acrylamide for use in epidemiological studies

Background/Objectives:Acrylamide, a probable human carcinogen, was detected in various heat-treated foods such as French fries and potato crisps. Recently, positive associations have been found between dietary acrylamide intakes, as estimated with a food frequency questionnaire using an acrylamide database, and cancer risk in some epidemiological studies. As acrylamide levels vary considerably within the same type of foods, a validation study was performed to investigate whether use of an acrylamide food database containing calculated mean acrylamide content, based on extensive sampling and chemical analysis of Dutch foods (several samples per food), can classify subjects with respect to true acrylamide intake.Subjects/Methods:We used the data from a 24-h duplicate diet study. The acrylamide content of 39 Dutch 24-h duplicate diets collected in 2004 was estimated using the mean acrylamide levels of foods available from the database and the menu list, on which the participants of the duplicate diet study had listed the amounts of individual foods and drinks in household units. Next, the acrylamide content of the total duplicate diets was analytically measured and correlated to the estimated acrylamide contents.Results:The Spearmans correlation coefficient between chemically determined acrylamide content and the calculated acrylamide content of the duplicate diets was 0.82 (P<0.001).Conclusions:This study indicates that it is possible to classify subjects with respect to acrylamide intake if mean instead of actual content of each food is applied. The database can therefore be applied in epidemiological studies on acrylamide intake and cancer risk, such as the Netherlands Cohort Study on Diet and Cancer.

Radicals in the church

To the Editors: Public health is seriously threatened by exposure to ambient and indoor particulate matter (PM). Epidemiological studies have demonstrated that long-term exposure is associated with lung cancer and other pulmonary diseases 1. In vitro studies have demonstrated the involvement of polycyclic aromatic hydrocarbons (PAH), inflammation and oxidative stress in these adverse health effects 2–4. As free radicals are also known to play a crucial role in these processes, we developed an electron spin resonance (ESR)-based methodology to quantify the radical-generating capacity of PM. We applied this methodology in order to evaluate the effect of burning candles and incense, known sources of indoor air PM …

The influence of single nucleotide polymorphisms on the association between dietary acrylamide intake and endometrial cancer risk

It is unclear whether the association between dietary acrylamide intake and endometrial cancer risk as observed in some epidemiological studies reflects a causal relationship. We aimed at clarifying the causality by analyzing acrylamide-gene interactions for endometrial cancer risk. The prospective Netherlands Cohort Study on diet and cancer includes 62,573 women, aged 55–69 years. At baseline, a random subcohort of 2589 women was selected for a case cohort analysis approach. Acrylamide intake of subcohort members and endometrial cancer cases (n = 315) was assessed with a food frequency questionnaire. Single nucleotide polymorphisms (SNPs) in genes in acrylamide metabolism, sex steroid systems, oxidative stress and DNA repair were assessed through a MassARRAY iPLEX Platform. Interaction between acrylamide and SNPs was assessed with Cox proportional hazards analysis, based on 11.3 years of follow-up. Among the results for 57 SNPs and 2 gene deletions, there were no statistically significant interactions after adjustment for multiple testing. However, there were nominally statistically significant interactions for SNPs in acrylamide-metabolizing enzymes: CYP2E1 (rs915906 and rs2480258) and the deletions of GSTM1 and GSTT1. Although in need of confirmation, the interactions between acrylamide intake and CYP2E1 SNPs contribute to the evidence for a causal relationship between acrylamide and endometrial cancer risk.

Prenatal arachidonic acid exposure and selected immune-related variables in childhood.

Arachidonic acid (AA) is considered essential in fetal development and some of its metabolites are thought to be important mediators of the immune responses. Therefore, we studied whether prenatal exposure to AA is associated with some immune-related clinical conditions and plasma markers in childhood. In 280 children aged 7 years, atopy, lung function and plasma inflammation markers were measured and their relationships with early AA exposure were studied by linear and logistic regression analyses. AA exposure was deduced from AA concentrations in plasma phospholipids of the mothers collected at several time points during pregnancy and at delivery, and in umbilical cord plasma and arterial and venous wall phospholipids. In unadjusted regression analyses, significant positive associations were observed between maternal AA concentrations at 16 and 32 weeks of pregnancy (proxies for fetal AA exposure) and peak expiratory flow decline after maximal physical exercise and plasma fibrinogen concentrations of their children, respectively. However, after correction for relevant covariables, only trends remained. A significant negative relationship was observed between AA concentrations in cord plasma (reflecting prenatal AA exposure) and the average daily amplitude of peak expiratory flow at rest, which lost significance after appropriate adjustment. Because of these few, weak and inconsistent relationships, a major impact of early-life exposure to AA on atopy, lung function and selected plasma inflammation markers of children at 7 years of age seems unlikely.

A prospective cohort study on dietary acrylamide intake and the risk for cutaneous malignant melanoma

Epidemiological studies have shown inconsistent associations between dietary acrylamide exposure and the risk for various malignancies. This is the first epidemiological study on the association between acrylamide intake and the risk for cutaneous malignant melanoma (CMM). A case–cohort analysis was carried out within the prospective Netherlands Cohort Study on diet and cancer. Acrylamide intake was estimated from a food frequency questionnaire combined with acrylamide data for Dutch foods. After 17.3 years of follow-up, 501 microscopically confirmed cases of CMM were identified. There was an increased risk for CMM when dietary acrylamide was modeled as a continuous variable [hazard ratio: 1.13 (95% confidence interval: 1.01–1.26)] per 10 &mgr;g increment among men but there was no clear linear trend over the quintiles (Ptrend=0.12). No associations were observed for women. Our study provides some indications that dietary acrylamide may increase the risk for CMM in men.