Experimental studies suggested potential adverse effects of preservative food additives, but epidemiological data are lacking. We aim to investigate associations between exposure to these compounds and type 2 diabetes incidence in the NutriNet-Santé prospective cohort (n = 108,723; 79.2

BACKGROUND AND AIMS:Experimental studies suggest that some preservative food additives may exert adverse cardiovascular effects, yet human data are lacking. The associations between exposure to these compounds and incidence of hypertension and cardiovascular diseases (CVD) were investigated in the NutriNet-Santé cohort (France, 2009-2024). METHODS:Dietary intakes were assessed using repeated 24-h dietary records (up to 96), including commercial brands. Exposure to food additives was evaluated through multiple composition databases and ad hoc laboratory assays in food matrices. Associations between cumulative time-dependent exposures to preservative food additives during follow-up and outcomes were characterized using multi-adjusted Cox models. RESULTS:Overall, 112 395 participants were included (78.7% women, mean age 42.8 ± 14.7 years) with a median follow-up of 7.9 years. The sum of total preservatives encompassed 58 substances consumed by at least one participant. Total non-antioxidant preservatives were positively associated with higher incidences of hypertension [n = 5544; hazard ratio (HR) higher vs. lower consumers: 1.29, 95% confidence interval (CI) 1.20-1.39] and CVD (n = 2450; HR 1.16, 95% CI 1.04-1.29), while total antioxidant preservatives were associated with higher incidence of hypertension (HR 1.22, 95% CI 1.13-1.31). Out of the 17 individual preservative food additives consumed by at least 10% of the study population, eight were associated with higher incidence of hypertension and one with higher incidence of CVD, after multiple test correction. CONCLUSIONS:Multiple associations between exposure to preservative food additives widely used in industrial foods and higher incidence of hypertension or CVD were observed in this large prospective cohort. Experimental research is needed to gain insight into underlying mechanisms. If confirmed, these new data call for the re-evaluation of regulations governing the use of these additives to improve consumer protection. TRIAL REGISTRATION:ClinicalTrials.gov NCT03335644.

Objective To investigate potential association between exposure to food colouring additives and type 2 diabetes incidence. Research Design and Methods 108,723 participants (79.2% female, mean age= 42.5 y, SD= 14.6) from the French NutriNet-Santé cohort were followed (2009-2023). Dietary data were assessed using repeated 24h-dietary records, including industrial food brands. Cumulative time-dependent exposure to food additives was evaluated through multiple composition databases and ad-hoc laboratory assays in food matrices. Associations between exposures to food colouring additives (sex-specific tertiles if proportion of exposed participants >2/3, or non-exposed/lower/higher exposed based on sex-specific median otherwise) and type 2 diabetes incidence were assessed using multivariable Cox proportional hazards models. Results 1,131 incident type 2 diabetes cases were diagnosed (median follow-up=8.05 y). After False Discovery Rate correction, intakes of following colours were associated with higher type 2 diabetes incidence: total food colouring additives (hazard ratio [HR]higher versus non/lower consumers (95% CI)= 1.38 [1.17-1.63], p=0.0002), total caramel (1.43 [1.21-1.67], p=0.0002), plain caramel (1.46 [1.26-1.70], p=0.0002), sulphite ammonia caramel (1.30 [1.07-1.59], p= 0.007), total carotene (1.27 [1.08-1.48], p=0.007), carotenoids (1.39 [1.19-1.62], p=0.0002), beta-carotene (1.44 [1.23-1.68], p=0.0002), paprika, capsanthin, and capsorubin (1.26 [1.08-1.46], p=0.004), lutein (1.20 [1.02-1.40], p=0.0002), curcumin (1.49 [1.29-1.73], p=0.0002), cochineal, carminic acid, and carmines (1.27 [1.10-1.48], p=0.003), and anthocyanins (1.40 [1.17-1.68], p=0.0002). Conclusion Several positive associations were observed between exposure to natural synthetic food colouring additives and type 2 diabetes incidence. Further studies are needed to gain insights into underlying mechanisms, and if confirmed, call for re-evaluation of food colouring additives to protect consumer health.

Our study aimed to assess potential associations between food colouring additives and cancer incidence in the French NutriNet-Santé cohort. A total of 105,260 adults (78.3

OBJECTIVE:To investigate the association between intake of food additive preservatives and cancer incidence in a large prospective cohort. DESIGN:Prospective cohort. SETTING:French NutriNet-Santé cohort, 2009-23. PARTICIPANTS:105 260 participants (≥15 years) without prevalent cancer who completed at least two 24 hour dietary records at baseline. MAIN OUTCOME MEASURES:Cumulative time dependent intake of preservatives, including those in industrial food brands, assessed using repeated 24 hour dietary records and evaluated through multiple composition databases and ad hoc laboratory assays in food products for the most frequently consumed additive-food pairs. Associations between intake of three categories of preservatives (defined as sex specific thirds if preservative was consumed by at least a third of participants, otherwise defined as non-consumers and lower or higher consumers separated by the sex specific median) and cancer incidence were characterised using multivariable proportional hazards Cox models adjusted for potential confounders. RESULTS:Mean age of participants was 42.0 years (standard deviation (SD 14.5) years), and 78.7% were women. 4226 participants received a diagnosis of incident cancer (mean follow-up 7.57 (SD 4.56) years), comprising 1208 breast, 508 prostate, 352 colorectal, and 2158 other cancers). Higher intakes of several preservatives were associated with higher cancer incidence: total non-antioxidants with overall cancer (hazard ratio for higher v non-consumers or lower consumers 1.16 (95% confidence interval (CI) 1.07 to 1.26); absolute risk of cancer at age 60 years, respectively, 13.3%, 12.1%) and breast cancer (1.22 (1.05 to 1.41); 5.7%, 4.8%); total sorbates, specifically potassium sorbate, with overall cancer (1.14 (1.04 to 1.24); 13.4%, 11.8%) and breast cancer (1.26 (1.07 to 1.49); 5.7%, 4.6%); total sulfites with overall cancer (1.12 (1.02 to 1.24); 13.4%, 11.9%); potassium metabisulfite with overall cancer (1.11 (1.03 to 1.20); 13.5%, 12.0%) and breast cancer (1.20 (1.04 to 1.38); 5.7%, 4.9%); sodium nitrite with prostate cancer (1.32 (1.02 to 1.70); 4.2%, 3.4%); potassium nitrate with overall cancer (1.13 (1.05 to 1.23); 14.0%, 12.0%) and breast cancer (1.22 (1.05 to 1.41); 5.9%, 4.8%); total acetates with overall cancer (1.15 (1.06 to 1.25); 14.3%, 12.2%) and breast cancer (1.25 (1.07 to 1.45); 6.1%, 4.9%); acetic acid with overall cancer (1.12 (1.01 to 1.25); 14.4%, 12.4%); and sodium erythorbate with overall cancer (1.12 (1.04 to 1.22); 13.5%, 11.9%) and breast cancer (1.21 (1.04 to 1.41); 5.7%, 4.8%). 11 of the 17 individually studied preservatives were not associated with cancer incidence. CONCLUSION:Multiple positive associations between intake of preservatives widely used in industrial foods and higher cancer incidence (overall, breast, and prostate) were observed in this large prospective cohort. Epidemiology based on health effect biomarkers and experimental research are needed to gain insight into outcome pathways. If confirmed, these new data call for the re-evaluation of regulations governing the food industry's use of these additives, to improve consumer protection. In the meantime, the findings support recommendations for consumers to favour freshly made, minimally processed foods. TRIAL REGISTRATION:ClinicalTrials.gov NCT03335644.

BACKGROUND:The potential cardiac toxicity of glutamate is debated and has been suggested by some epidemiological and experimental studies. To our knowledge, none have investigated the links between both naturally occurring and food additive glutamate and cardiovascular disease (CVD) risk. OBJECTIVES:Our objective was to assess the associations between intakes of total, food additive, and naturally occurring glutamate and risk of CVD, including cerebrovascular (CVA) and ischemic heart diseases (IHDs), in a large population-based study. METHODS:Participants {n = 108,932, NutriNet-Santé prospective cohort, 2009-2023, France, mean age = 42.4 y [standard deviation (SD) = 14.5], 79.3% females} completed repeated 24-h dietary records [mean = 21 (SD = 18), ≤84], including brands of industrial food consumed. Exposure to food additive glutamate was evaluated through multiple composition databases and ad hoc laboratory assays in food matrices. Associations between time-dependent continuous exposures to total, naturally occurring, and food additive glutamate and risk of CVD, CVA, and IHD were investigated using multivariable Cox models. RESULTS:During follow-up (median = 7.92 y), 2397 CVD, 1113 CVA, and 1284 IHD cases were diagnosed. Higher intakes of food additive glutamate [hazard ratio (HR) per 200 mg/d: 1.05; 95% confidence interval: 1.01, 1.09; P = 0.02], naturally occurring glutamic acid (HR3000 mg/d: 1.13; 95% CI: 1.03, 1.25; P = 0.009), and total glutamate (HR3000 mg/d = 1.15; 95% CI: 1.05, 1.26) P = 0.004) were associated with higher risks of IHD. For CVD, corresponding HRs were 1.03 (1.00, 1.06; P = 0.07), 1.09 (1.01, 1.18; P = 0.02), and 1.10 (1.02, 1.18; P = 0.01). No association was detected for CVA (all P ≥ 0.5). Residual confounding cannot be entirely ruled out, and causality cannot be established based on this single observational study. CONCLUSIONS:This large prospective study showed positive linear associations between higher glutamate intakes and increased risks of CVD. In particular, food additive glutamate, naturally occurring glutamic acid, and total glutamate intakes were all associated with higher IHD risk. This adds to previous experimental data showing a role of glutamate in regulating heart functioning at physiological doses, while also suggesting heart rate dysfunction at higher exposures. This trial was registered at clinicaltrials.gov as NCT03335644.

This study aimed to identify exposures to food additives and their mixtures in a nationally representative sample of French adults and children. Using repeated 24-hour dietary recalls and food records (including commercial brand information) from the cross-sectional Esteban survey (France, 2016), additive intake was estimated by merging with multiple food composition databases, and laboratory assays in food matrices. Non-negative matrix factorisation was used to identify additive mixtures. Their associations with sociodemographic, lifestyle, and dietary factors were assessed using survey-weighted regressions. A total of 2,177 adults (18–74 years old) and 1,279 children (6–17 years old) were included. Mean daily additive intake was 4.42 g/day in adults and 5.08 g/day in children. Sixty additives were consumed by at least 5

BACKGROUND:Mixtures of food additives are daily consumed worldwide by billions of people. So far, safety assessments have been performed substance by substance due to lack of data on the effect of multiexposure to combinations of additives. Our objective was to identify most common food additive mixtures, and investigate their associations with type 2 diabetes incidence in a large prospective cohort. METHODS AND FINDINGS:Participants (n = 108,643, mean follow-up =  7.7 years (standard deviation (SD) =  4.6), age =  42.5 years (SD =  14.6), 79.2% women) were adults from the French NutriNet-Santé cohort (2009-2023). Dietary intakes were assessed using repeated 24h-dietary records, including industrial food brands. Exposure to food additives was evaluated through multiple food composition databases and laboratory assays. Mixtures were identified through nonnegative matrix factorization (NMF), and associations with type 2 diabetes incidence were assessed using Cox models adjusted for potential socio-demographic, anthropometric, lifestyle and dietary confounders. A total of 1,131 participants were diagnosed with type 2 diabetes. Two out of the five identified food additive mixtures were associated with higher type 2 diabetes incidence: the first mixture included modified starches, pectin, guar gum, carrageenan, polyphosphates, potassium sorbates, curcumin, and xanthan gum (hazard ratio (HR)per an increment of 1SD of the NMF mixture score = 1.08 [1.02, 1.15], p = 0.006), and the other mixture included citric acid, sodium citrates, phosphoric acid, sulphite ammonia caramel, acesulfame-K, aspartame, sucralose, arabic gum, malic acid, carnauba wax, paprika extract, anthocyanins, guar gum, and pectin (HR = 1.13 [1.08,1.18], p < 0.001). No association was detected for the three remaining mixtures: HR =  0.98 [0.91, 1.06], p = 0.67; HR =  1.02 [0.94, 1.10], p = 0.68; and HR =  0.99 [0.92, 1.07], p = 0.78. Several synergistic and antagonist interactions between food additives were detected in exploratory analyses. Residual confounding as well as exposure or outcome misclassifications cannot be entirely ruled out and causality cannot be established based on this single observational study. CONCLUSIONS:This study revealed positive associations between exposure to two widely consumed food additive mixtures and higher type 2 diabetes incidence. Further experimental research is needed to depict underlying mechanisms, including potential synergistic/antagonist effects. These findings suggest that a combination of food additives may be of interest to consider in safety assessments, and they support public health recommendations to limit nonessential additives. TRIAL REGISTRATION:The NutriNet-Santé cohort is registered at clinicaltrials.gov (NCT03335644). https://clinicaltrials.gov/study/NCT03335644.

Background Experimental studies have suggested potential detrimental effects of emulsifiers on gut microbiota, inflammation, and metabolic perturbations. We aimed to investigate the associations between exposures to food additive emulsifiers and the risk of type 2 diabetes in a large prospective cohort of French adults. Methods We analysed data from 104 139 adults enrolled in the French NutriNet-Sant & eacute; prospective cohort study from May 1, 2009, to April 26, 2023; 82 456 (79 center dot 2%) were female and the mean age was 42 center dot 7 years (SD 14 center dot 5). Dietary intakes were assessed with three 24 h dietary records collected over three non-consecutive days, every 6 months. Exposure to additive emulsifiers was evaluated through multiple food composition databases and ad-hoc laboratory assays. Associations between cumulative time-dependent exposures to food additive emulsifiers and the risk of type 2 diabetes were characterised with multivariable proportional hazards Cox models adjusted for known risk factors. The NutriNet-Sant & eacute; study is registered at ClinicalTrials.gov (NCT03335644). Findings Of 104 139 participants, 1056 were diagnosed with type 2 diabetes during follow-up (mean follow-up duration 6 center dot 8 years [SD 3 center dot 7]). Intakes of the following emulsifiers were associated with an increased risk of type 2 diabetes: total carrageenans (hazard ratio [HR] 1 center dot 03 [95% CI 1 center dot 01-1 center dot 05] per increment of 100 mg per day, p<0 center dot 0001), carrageenans gum (E407; HR 1 center dot 03 [1 center dot 01-1 center dot 05] per increment of 100 mg per day, p<0 center dot 0001), tripotassium phosphate (E340; HR 1 center dot 15 [1 center dot 02-1 center dot 31] per increment of 500 mg per day, p=0 center dot 023), acetyl tartaric acid esters of monoglycerides and diglycerides of fatty acids (E472e; HR 1 center dot 04 [1 center dot 00-1 center dot 08] per increment of 100 mg per day, p=0 center dot 042), sodium citrate (E331; HR 1 center dot 04 [1 center dot 01-1 center dot 07] per increment of 500 mg per day, p=0 center dot 0080), guar gum (E412; HR 1 center dot 11 [1 center dot 06-1 center dot 17] per increment of 500 mg per day, p<0 center dot 0001), gum arabic (E414; HR 1 center dot 03 [1 center dot 01-1 center dot 05] per increment of 1000 mg per day, p=0 center dot 013), and xanthan gum (E415, HR 1 center dot 08 [1 center dot 02-1 center dot 14] per increment of 500 mg per day, p=0 center dot 013). Interpretation We found direct associations between the risk of type 2 diabetes and exposures to various food additive emulsifiers widely used in industrial foods, in a large prospective cohort of French adults. Further research is needed to prompt re-evaluation of regulations governing the use of additive emulsifiers in the food industry for better consumer protection. Copyright (c) 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC-BY-NC 4.0 license.

BackgroundEmulsifiers are widely used food additives in industrially processed foods to improve texture and enhance shelf-life. Experimental research suggests deleterious effects of emulsifiers on the intestinal microbiota and the metabolome, leading to chronic inflammation and increasing susceptibility to carcinogenesis. However, human epidemiological evidence investigating their association with cancer is nonexistent. This study aimed to assess associations between food additive emulsifiers and cancer risk in a large population-based prospective cohort.Methods and findingsThis study included 92,000 adults of the French NutriNet-Santé cohort without prevalent cancer at enrolment (44.5 y [SD: 14.5], 78.8% female, 2009 to 2021). They were followed for an average of 6.7 years [SD: 2.2]. Food additive emulsifier intakes were estimated for participants who provided at least 3 repeated 24-h dietary records linked to comprehensive, brand-specific food composition databases on food additives. Multivariable Cox regressions were conducted to estimate associations between emulsifiers and cancer incidence. Overall, 2,604 incident cancer cases were diagnosed during follow-up (including 750 breast, 322 prostate, and 207 colorectal cancers). Higher intakes of mono- and diglycerides of fatty acids (FAs) (E471) were associated with higher risks of overall cancer (HR high vs. low category = 1.15; 95% CI [1.04, 1.27], p-trend = 0.01), breast cancer (HR = 1.24; 95% CI [1.03, 1.51], p-trend = 0.04), and prostate cancer (HR = 1.46; 95% CI [1.09, 1.97], p-trend = 0.02). In addition, associations with breast cancer risk were observed for higher intakes of total carrageenans (E407 and E407a) (HR = 1.32; 95% CI [1.09, 1.60], p-trend = 0.009) and carrageenan (E407) (HR = 1.28; 95% CI [1.06, 1.56], p-trend = 0.01). No association was detected between any of the emulsifiers and colorectal cancer risk. Several associations with other emulsifiers were observed but were not robust throughout sensitivity analyses. Main limitations include possible exposure measurement errors in emulsifiers intake and potential residual confounding linked to the observational design.ConclusionsIn this large prospective cohort, we observed associations between higher intakes of carrageenans and mono- and diglycerides of fatty acids with overall, breast and prostate cancer risk. These results need replication in other populations. They provide new epidemiological evidence on the role of emulsifiers in cancer risk.Trial registrationClinicalTrials.gov NCT03335644.

Abstract Objective To assess the associations between exposure to food additive emulsifiers and risk of cardiovascular disease (CVD). Design Prospective cohort study. Setting French NutriNet-Santé study, 2009-21. Participants 95 442 adults (>18 years) without prevalent CVD who completed at least three 24 hour dietary records during the first two years of follow-up. Main outcome measures Associations between intake of food additive emulsifiers (continuous (mg/day)) and risk of CVD, coronary heart disease, and cerebrovascular disease characterised using multivariable proportional hazard Cox models to compute hazard ratios for each additional standard deviation (SD) of emulsifier intake, along with 95% confidence intervals. Results Mean age was 43.1 (SD 14.5) years, and 79.0% (n=75 390) of participants were women. During follow-up (median 7.4 years), 1995 incident CVD, 1044 coronary heart disease, and 974 cerebrovascular disease events were diagnosed. Higher intake of celluloses (E460-E468) was found to be positively associated with higher risks of CVD (hazard ratio for an increase of 1 standard deviation 1.05, 95% confidence interval 1.02 to 1.09, P=0.003) and coronary heart disease (1.07, 1.02 to 1.12, P=0.004). Specifically, higher cellulose E460 intake was linked to higher risks of CVD (1.05, 1.01 to 1.09, P=0.007) and coronary heart disease (1.07, 1.02 to 1.12, P=0.005), and higher intake of carboxymethylcellulose (E466) was associated with higher risks of CVD (1.03, 1.01 to 1.05, P=0.004) and coronary heart disease (1.04, 1.02 to 1.06, P=0.001). Additionally, higher intakes of monoglycerides and diglycerides of fatty acids (E471 and E472) were associated with higher risks of all outcomes. Among these emulsifiers, lactic ester of monoglycerides and diglycerides of fatty acids (E472b) was associated with higher risks of CVD (1.06, 1.02 to 1.10, P=0.002) and cerebrovascular disease (1.11, 1.06 to 1.16, P<0.001), and citric acid ester of monoglycerides and diglycerides of fatty acids (E472c) was associated with higher risks of CVD (1.04, 1.02 to 1.07, P=0.004) and coronary heart disease (1.06, 1.03 to 1.09, P<0.001). High intake of trisodium phosphate (E339) was associated with an increased risk of coronary heart disease (1.06, 1.00 to 1.12, P=0.03). Sensitivity analyses showed consistent associations. Conclusion This study found positive associations between risk of CVD and intake of five individual and two groups of food additive emulsifiers widely used in industrial foods. Trial registration ClinicalTrials.gov NCT03335644.

BackgroundNitrites and nitrates occur naturally in water and soil and are commonly ingested from drinking water and dietary sources. They are also used as food additives, mainly in processed meats, to increase shelf life and to avoid bacterial growth. Experimental studies suggested both benefits and harmful effects of nitrites and nitrates exposure on type 2 diabetes (T2D) onset, but epidemiological and clinical data are lacking. We aimed to study these associations in a large population-based prospective cohort study, distinguishing foods and water-originated nitrites/nitrates from those from food additives.Methods and findingsOverall, 104,168 adults from the French NutriNet-Santé cohort study (2009 to 2021, 79.1% female, mean age [SD] = 42.7 [14.5]) were included. Associations between self-reported exposure to nitrites and nitrates (evaluated using repeated 24-h dietary records, linked to a comprehensive food composition database and accounting for commercial names/brands details of industrial products) and risk of T2D were assessed using cause-specific multivariable Cox proportional hazard models adjusted for known risk factors (sociodemographic, anthropometric, lifestyle, medical history, and nutritional factors). During a median follow-up duration of 7.3 years (interquartile range: [3.2; 10.1] years), 969 incident T2D cases were ascertained. Total nitrites and foods and water-originated nitrites were both positively associated with a higher T2D risk (HRtertile 3 vs.1 = 1.27 (95% CI 1.04 to 1.54), Ptrend = 0.009 and 1.26 (95% CI 1.03 to 1.54), Ptrend = 0.02, respectively). Participants with higher exposure to additives-originated nitrites (i.e., above the sex-specific median) and specifically those having higher exposure to sodium nitrite (e250) had a higher T2D risk compared with those who were not exposed to additives-originated nitrites (HR higher consumers vs. non-consumers = 1.53 (95% CI 1.24 to 1.88), Ptrend < 0.001 and 1.54 (95% CI 1.26 to 1.90), Ptrend < 0.001, respectively). There was no evidence for an association between total, foods and water-originated, or additives-originated nitrates and T2D risk (all Ptrend = 0.7). No causal link can be established from this observational study. Main limitations include possible exposure measurement errors and the lack of validation versus specific nitrites/nitrates biomarkers; potential selection bias linked to the healthier behaviors of the cohort's participants compared to the general population; potential residual confounding linked to the observational design, as well as a self-reported, yet cross-checked, case ascertainment.ConclusionsThe findings of this large prospective cohort did not support any potential benefits for dietary nitrites and nitrates. They suggested that a higher exposure to both foods and water-originated and additives-originated nitrites was associated with higher T2D risk in the NutriNet-Santé cohort. This study provides a new piece of evidence in the context of current debates about updating regulations to limit the use of nitrites as food additives. The results need to be replicated in other populations.Trial registrationClinicalTrials.gov NCT03335644 (https://clinicaltrials.gov/ct2/show/NCT03335644).

Objectives To study the relationships between artificial sweeteners accounting for all dietary sources (total and by type of artificial sweetener) and risk of type-2-diabetes (T2D), in a large-scale prospective cohort. Research Design and Methods 105,588 participants from the web-based NutriNet-Santé study (France, 2009-2022, mean age=42.5±14.6y, 79.2% women) were included in the analyses. Repeated 24-hours dietary records including brands and commercial names of industrial products, merged with qualitative and quantitative food additive composition data enabled to assess artificial sweetener intakes accurately from all dietary sources. Associations between artificial sweeteners (total, aspartame, acesulfame-K, and sucralose) and T2D were investigated using Cox proportional hazard models adjusted for potential confounders, including weight variation during follow-up. Results During a median follow-up of 9.1y (946,650 person-years, 972 incident T2D), compared to non-consumers, higher-consumers of artificial sweeteners (i.e., above the sex-specific medians of 16.4 mg/d in men and 18.5 mg/d in women) had higher risks of developing T2D: HR=1.69 (1.45-1.97), P-trend<0.001. Positive associations were also observed for individual artificial sweeteners: aspartame (HR=1.63 (1.38-1.93), P-trend<0.001), acesulfame-K (HR=1.70 (1.42-2.04), P-trend<0.001), and sucralose (HR=1.34 (1.07-1.69), P-trend=0.013). Conclusions Potential for reverse causality cannot be eliminated, however many sensitivity analyses were computed to limit this and other potential biases. These findings of positive associations between artificial sweetener intakes and increased T2D risk strengthen the evidence that these additives may not be safe sugar alternatives. This study provides important insights in the context of on-going re-evaluation of artificial sweeteners by health authorities worldwide.

Background The food industry uses artificial sweeteners in a wide range of foods and beverages as alternatives to added sugars, for which deleterious effects on several chronic diseases are now well established. The safety of these food additives is debated, with conflicting findings regarding their role in the aetiology of various diseases. In particular, their carcinogenicity has been suggested by several experimental studies, but robust epidemiological evidence is lacking. Thus, our objective was to investigate the associations between artificial sweetener intakes (total from all dietary sources, and most frequently consumed ones: aspartame [E951], acesulfame-K [E950], and sucralose [E955]) and cancer risk (overall and by site). Methods and findings Overall, 102,865 adults from the French population-based cohort NutriNet-Santé (2009–2021) were included (median follow-up time = 7.8 years). Dietary intakes and consumption of sweeteners were obtained by repeated 24-hour dietary records including brand names of industrial products. Associations between sweeteners and cancer incidence were assessed by Cox proportional hazards models, adjusted for age, sex, education, physical activity, smoking, body mass index, height, weight gain during follow-up, diabetes, family history of cancer, number of 24-hour dietary records, and baseline intakes of energy, alcohol, sodium, saturated fatty acids, fibre, sugar, fruit and vegetables, whole-grain foods, and dairy products. Compared to non-consumers, higher consumers of total artificial sweeteners (i.e., above the median exposure in consumers) had higher risk of overall cancer ( n = 3,358 cases, hazard ratio [HR] = 1.13 [95% CI 1.03 to 1.25], P -trend = 0.002). In particular, aspartame (HR = 1.15 [95% CI 1.03 to 1.28], P = 0.002) and acesulfame-K (HR = 1.13 [95% CI 1.01 to 1.26], P = 0.007) were associated with increased cancer risk. Higher risks were also observed for breast cancer ( n = 979 cases, HR = 1.22 [95% CI 1.01 to 1.48], P = 0.036, for aspartame) and obesity-related cancers ( n = 2,023 cases, HR = 1.13 [95% CI 1.00 to 1.28], P = 0.036, for total artificial sweeteners, and HR = 1.15 [95% CI 1.01 to 1.32], P = 0.026, for aspartame). Limitations of this study include potential selection bias, residual confounding, and reverse causality, though sensitivity analyses were performed to address these concerns. Conclusions In this large cohort study, artificial sweeteners (especially aspartame and acesulfame-K), which are used in many food and beverage brands worldwide, were associated with increased cancer risk. These findings provide important and novel insights for the ongoing re-evaluation of food additive sweeteners by the European Food Safety Authority and other health agencies globally. Trial registration ClinicalTrials.gov NCT03335644 .

Background Nitrates and nitrites occur naturally in water and soil and are commonly ingested from drinking water and dietary sources. They are also used as food additives in processed meats to increase shelf life and to avoid bacterial growth. These compounds could have a role in the carcinogenicity of processed meat. Objective To investigate the relationship between nitrate and nitrite intakes (distinguishing between natural food, water and food additive sources) and the risk of cancer in a large prospective cohort with detailed and up to date dietary assessment. Design Population based prospective cohort study. Setting Overall, 101,056 adults from the French NutriNet-Santé cohort study (2009-ongoing) were included. Consumption of nitrites and nitrates was evaluated using repeated 24h dietary records, linked to a comprehensive food composition database and accounting for details of commercial names/brands of industrial products. Main outcome measures Associations between nitrite and nitrate exposures and the risk of cancer (overall and by main cancer sites) were assessed by Cox hazard models adjusted for known risk factors. Results During follow-up, 3311 first incident cancer cases were diagnosed (among which 966 breast and 400 prostate cancers). Compared with non-consumers, higher consumers of nitrates from food additives had higher risk of breast cancer (HR=1.24 (1.03-1.48), P=0.02); this was more specifically observed for potassium nitrate (e252, HR=1.25 (1.04-1.50), P=0.01). Higher consumers of nitrites from food additives had higher risk of prostate cancer (HR=1.58 (1.14-2.18), P=0.008), specifically for sodium nitrite (e250, HR=1.62 (1.17-2.25), P=0.004). No significant association was observed for nitrates and nitrites from natural sources. Conclusions In this large prospective cohort, food additive nitrates were positively associated with breast cancer risk and food additive nitrites were positively associated with prostate cancer risk. While these results need confirmation in other large-scale prospective studies, they provide new insights in a context of lively debate around the ban of nitrite additives in the food industry. Study registration The NutriNet-Santé cohort is registered at clinicaltrials.gov (NCT03335644). Citation Format: Eloi Chazelas, Fabrice Pierre, Nathalie Druesne-Pecollo, Younes Esseddik, Fabien Szabo de Edelenyi, Cédric Agaesse, Alexandre De Sa, Rebecca Lutchia, Stéphane Gigandet, Bernard Srour, Charlotte Debras, Inge Huybrechts, Chantal Julia, Emmanuelle Kesse-Guyot, Benjamin Allès, Laurent Zelek, Pilar Galan, Serge Hercberg, Mélanie Deschasaux-Tanguy, Mathilde Touvier. Breast and prostate cancer risk associated with nitrites and nitrates from food additives: Results from the NutriNet-Santé cohort [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-09-01.

Background: Added sugars’ deleterious effects have been established for several chronic diseases, leading food industries to use artificial sweeteners as alternatives in a wide range of foods and beverages. Their safety is debated and findings remain contrasted regarding their role in the etiology of various diseases. In particular, their carcinogenicity has been suggested by several experimental studies but robust epidemiological evidence is lacking. Objective: The objective was to investigate the associations between sweetener intakes (total from all dietary sources, and most frequently consumed ones: aspartame e951, acesulfame-K e950 and sucralose e955) and cancer risk (overall and by sites: breast, prostate and obesity-related cancers). Design: Population based prospective cohort study. Setting and Participants: Overall, 102,046 adults from the French NutriNet-Santé prospective cohort (2009-2021) were included. Consumption of sweeteners was obtained by repeated 24h-dietary records including brands and commercial names of industrial products. Associations between sweeteners and cancer incidence were assessed by multi-adjusted Cox hazard models. Main outcome measures: Association between sweetener intakes and cancer risk were assessed by Cox proportional hazard models adjusted for known risk factors (sociodemographic, anthropometric, lifestyle, medical history, and nutritional factors). Results: Compared to non-consumers, higher consumers of total sweeteners (i.e. above the median exposure in consumers) had higher risk of overall cancer (n=2,527 cases, hazard ratio=1.12, 95% confidence interval=1.00-1.25, P-trend=0.005). In particular, aspartame (HR=1.20 [1.05-1.38] P=0.001) and acesulfame-K (HR=1.18 [1.04-1.34] P=0.003) were associated with increased cancer risk. Similarly, higher risks were observed for breast (n=723 cases, HR=1.25 [1.02-1.53] P=0.01 for total sweeteners, HR=1.33 [1.05-1.69] P=0.007 for aspartame and HR=1.39 [1.11-1.74] P=0.003, for acesulfame-K) and obesity-related cancers. (n=1,509 cases, HR=1.16 [1.00-1.33] P=0.02 for total sweeteners, HR=1.22 [1.02-1.45] P=0.01 for aspartame and HR=1.23 [1.04-1.45] P=0.01, for acesulfame-K). Conclusion: In this large prospective cohort, artificial sweeteners (especially aspartame and acesulfame-K), which are found in >10,000 foods and beverage references worldwide, were associated with increased cancer risk. These findings provide important and novel insights for the ongoing re-evaluation of food additive sweeteners by the European Food Safety Authority and other health agencies globally. Citation Format: Charlotte Debras, Eloi Chazelas, Bernard Srour, Nathalie Druesne-Pecollo, Younes Essedik, Fabien Szabo de Edelenyi, Cédric Agaësse, Alexandre De Sa, Rebecca Lutchia, Stéphane Gigandet, Inge Huybrechts, Chantal Julia, Emmanuelle Kesse-Guyot, Laurent Zelek, Benjamin Allès, Valentina A. Andreeva, Pilar Galan, Serge Hercberg, Mélanie Deschasaux-Tanguy, Mathilde Touvier. Risk of breast and other cancers associated with the consumption of artificial sweeteners: Results from the prospective NutriNet-Santé cohort [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-09-02.

Food additives (e.g. artificial sweeteners, emulsifiers, dyes, etc.) are ingested by billions of individuals daily. Some concerning results, mainly derived from animal and/or cell-based experimental studies, have recently emerged suggesting potential detrimental effects of several widely consumed additives. Profiles of additive exposure as well as the potential long-term impact of multiple exposure on human health are poorly documented. This work aimed to estimate the usual intake of food additives among participants of the French NutriNet-Santé cohort and to identify and describe profiles of exposure (single substances and mixtures). Overall, 106,489 adults from the French NutriNet-Santé cohort study (2009-ongoing) were included. Consumption of 90 main food additives was evaluated using repeated 24 h dietary records including information on brands of commercial products. Qualitative information (as presence/absence) of each additive in food products was determined using 3 large-scale composition databases (OQALI, Open Food Facts, GNPD), accounting for the date of consumption of the product. Quantitative ingested doses were estimated using a combination of laboratory assays on food matrixes (n = 2677) and data from EFSA and JECFA. Exposure was estimated in mg per kg of body weight per day. Profiles of exposure to food additive mixtures were extracted using Non-negative Matrix Factorization (NMF) followed by k-means clustering as well as Graphical Lasso. Sociodemographic and dietary comparison of clusters of participants was performed by Chi-square tests or linear regressions. Data were weighted according to the national census. Forty-eight additives were consumed by more than 10% of the participants, with modified starches and citric acid consumed by more than 90%. The top 50 also included several food additives for which potential adverse health effects have been suggested by recent experimental studies: lecithins (86.6% consumers), mono- and diglycerides of fatty acids (78.1%), carrageenan (77.5%), sodium nitrite (73.9%), di-, tri- and polyphosphates (70.1%), potassium sorbate (65.8%), potassium metabisulphite (44.8%), acesulfame K (34.0%), cochineal (33.9%), potassium nitrate (31.6%), sulfite ammonia caramel (28.8%), bixin (19.5%), monosodium glutamate (15.1%) and sucralose (13.5%). We identified and described five clusters of participants more specifically exposed to five distinct additive mixtures and one additional cluster gathering participants with overall low additive exposure. Food additives, including several for which health concerns are currently debated, were widely consumed in this population-based study. Furthermore, main mixtures of additives were identified. Their health impact and potential cocktail effects should be explored in future epidemiological and experimental studies.