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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 etiology 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=7.8y). Dietary intakes and consumption of sweeteners was obtained by repeated 24h-dietary records including brand names of industrial products. Associations between sweeteners and cancer incidence were assessed by Cox hazard models, notably adjusted for age, sex, education, physical activity, smoking, body mass index, height, weight-gain during follow-up, diabetes, family history of cancer, baseline intakes of energy, alcohol, sodium, saturated fatty acids, fibre, sugar, 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=3358 cases, Hazard Ratio=1.13, 95% confidence interval=1.03 to 1.25, P-trend=0.002). In particular, aspartame (HR=1.15 (1.03 to 1.28) P=0.002) and acesulfame-K (HR=1.13 (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 (1.01 to 1.48) P=0.036 for aspartame) and obesity-related cancers (n=2023 cases, HR=1.13 (1.00 to 1.28) P=0.036 for total artificial sweeteners and HR=1.15 (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.

Background Nitrites 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 findings Overall, 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 (HR tertile 3 vs.1 = 1.27 (95% CI 1.04 to 1.54), P trend = 0.009 and 1.26 (95% CI 1.03 to 1.54), P trend = 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), P trend < 0.001 and 1.54 (95% CI 1.26 to 1.90), P trend < 0.001, respectively). There was no evidence for an association between total, foods and water-originated, or additives-originated nitrates and T2D risk (all P trend = 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. Conclusions The 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 registration ClinicalTrials.gov NCT03335644 ( https://clinicaltrials.gov/ct2/show/NCT03335644 )

AbstractObjectiveTo assess the prospective associations between consumption of ultra-processed foods and risk of cardiovascular diseases.DesignPopulation based cohort study.SettingNutriNet-Santé cohort, France 2009-18.Participants105 159 participants aged at least 18 years. Dietary intakes were collected using repeated 24 hour dietary records (5.7 for each participant on average), designed to register participants’ usual consumption of 3300 food items. These foods were categorised using the NOVA classification according to degree of processing.Main outcome measuresAssociations between intake of ultra-processed food and overall risk of cardiovascular, coronary heart, and cerebrovascular diseases assessed by multivariable Cox proportional hazard models adjusted for known risk factors.ResultsDuring a median follow-up of 5.2 years, intake of ultra-processed food was associated with a higher risk of overall cardiovascular disease (1409 cases; hazard ratio for an absolute increment of 10 in the percentage of ultra-processed foods in the diet 1.12 (95% confidence interval 1.05 to 1.20); P<0.001, 518 208 person years, incidence rates in high consumers of ultra-processed foods (fourth quarter) 277 per 100 000 person years, and in low consumers (first quarter) 242 per 100 000 person years), coronary heart disease risk (665 cases; hazard ratio 1.13 (1.02 to 1.24); P=0.02, 520 319 person years, incidence rates 124 and 109 per 100 000 person years, in the high and low consumers, respectively), and cerebrovascular disease risk (829 cases; hazard ratio 1.11 (1.01 to 1.21); P=0.02, 520 023 person years, incidence rates 163 and 144 per 100 000 person years, in high and low consumers, respectively). These results remained statistically significant after adjustment for several markers of the nutritional quality of the diet (saturated fatty acids, sodium and sugar intakes, dietary fibre, or a healthy dietary pattern derived by principal component analysis) and after a large range of sensitivity analyses.ConclusionsIn this large observational prospective study, higher consumption of ultra-processed foods was associated with higher risks of cardiovascular, coronary heart, and cerebrovascular diseases. These results need to be confirmed in other populations and settings, and causality remains to be established. Various factors in processing, such as nutritional composition of the final product, additives, contact materials, and neoformed contaminants might play a role in these associations, and further studies are needed to understand better the relative contributions. Meanwhile, public health authorities in several countries have recently started to promote unprocessed or minimally processed foods and to recommend limiting the consumption of ultra-processed foods.Study registrationClinicalTrials.gov NCT03335644.

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.

AbstractObjectivesTo study the associations between artificial sweeteners from all dietary sources (beverages, but also table top sweeteners, dairy products, etc), overall and by molecule (aspartame, acesulfame potassium, and sucralose), and risk of cardiovascular diseases (overall, coronary heart disease, and cerebrovascular disease).DesignPopulation based prospective cohort study (2009-21).SettingFrance, primary prevention research.Participants103 388 participants of the web based NutriNet-Santé cohort (mean age 42.2±14.4, 79.8% female, 904 206 person years). Dietary intakes and consumption of artificial sweeteners were assessed by repeated 24 h dietary records, including brand names of industrial products.Main outcomes measuresAssociations between sweeteners (coded as a continuous variable, log10 transformed) and cardiovascular disease risk, assessed by multivariable adjusted Cox hazard models.ResultsTotal artificial sweetener intake was associated with increased risk of cardiovascular diseases (1502 events, hazard ratio 1.09, 95% confidence interval 1.01 to 1.18, P=0.03); absolute incidence rate in higher consumers (above the sex specific median) and non-consumers was 346 and 314 per 100 000 person years, respectively. Artificial sweeteners were more particularly associated with cerebrovascular disease risk (777 events, 1.18, 1.06 to 1.31, P=0.002; incidence rates 195 and 150 per 100 000 person years in higher and non-consumers, respectively). Aspartame intake was associated with increased risk of cerebrovascular events (1.17, 1.03 to 1.33, P=0.02; incidence rates 186 and 151 per 100 000 person years in higher and non-consumers, respectively), and acesulfame potassium and sucralose were associated with increased coronary heart disease risk (730 events; acesulfame potassium: 1.40, 1.06 to 1.84, P=0.02; incidence rates 167 and 164; sucralose: 1.31, 1.00 to 1.71, P=0.05; incidence rates 271 and 161).ConclusionsThe findings from this large scale prospective cohort study suggest a potential direct association between higher artificial sweetener consumption (especially aspartame, acesulfame potassium, and sucralose) and increased cardiovascular disease risk. Artificial sweeteners are present in thousands of food and beverage brands worldwide, however they remain a controversial topic and are currently being re-evaluated by the European Food Safety Authority, the World Health Organization, and other health agencies.Trial registrationClinicalTrials.gov NCT03335644

Background: Ultra-processed food (UPF) consumption has increased drastically worldwide and already represents 50%–60% of total daily energy intake in several high-income countries. In the meantime, the prevalence of overweight and obesity has risen continuously during the last century. The objective of this study was to investigate the associations between UPF consumption and the risk of overweight and obesity, as well as change in body mass index (BMI), in a large French cohort.Methods and findings: A total of 110,260 adult participants (≥18 years old, mean baseline age = 43.1 [SD 14.6] years; 78.2% women) from the French prospective population-based NutriNet-Santé cohort (2009–2019) were included. Dietary intakes were collected at baseline using repeated and validated 24-hour dietary records linked to a food composition database that included >3,500 different food items, each categorized according to their degree of processing by the NOVA classification. Associations between the proportion of UPF in the diet and BMI change during follow-up were assessed using linear mixed models. Associations with risk of overweight and obesity were assessed using Cox proportional hazard models. After adjusting for age, sex, educational level, marital status, physical activity, smoking status, alcohol intake, number of 24-hour dietary records, and energy intake, we observed a positive association between UPF intake and gain in BMI (β Time × UPF = 0.02 for an absolute increment of 10 in the percentage of UPF in the diet, P < 0.001). UPF intake was associated with a higher risk of overweight (n = 7,063 overweight participants; hazard ratio (HR) for an absolute increase of 10% of UPFs in the diet = 1.11, 95% CI: 1.08–1.14; P < 0.001) and obesity (n = 3,066 incident obese participants; HR10% = 1.09 (1.05–1.13); P < 0.001). These results remained statistically significant after adjustment for the nutritional quality of the diet and energy intake. Study limitations include possible selection bias, potential residual confounding due to the observational design, and a possible item misclassification according to the level of processing. Nonetheless, robustness was tested and verified using a large panel of sensitivity analyses.Conclusions: In this large observational prospective study, higher consumption of UPF was associated with gain in BMI and higher risks of overweight and obesity. Public health authorities in several countries recently started to recommend privileging unprocessed/minimally processed foods and limiting UPF consumption.

BACKGROUND:More than 330 food additives (e.g. artificial sweeteners, emulsifiers, dyes) are authorized in Europe, with a great variability of use across food products.OBJECTIVE:The objective of this study was to investigate the distribution and co-occurrence of food additives in a large-scale database of foods and beverages available on the French market.DESIGN:The open access crowdsourced Open Food Facts database (https://world.openfoodfacts.org/) was used to retrieve the composition of food and beverage products commonly marketed on the French market (n = 126,556), based on the ingredients list. Clustering of food additive variables was used in order to determine groups of additives frequently co-occurring in food products. The clusters were confirmed by network analysis, using the eLasso method.RESULTS:Fifty-three-point eight percent of food products contained at least 1 food additive and 11.3% at least 5. Food categories most likely to contain food additives (in more than 85% of food items) were artificially sweetened beverages, ice creams, industrial sandwiches, biscuits and cakes. The most frequently used food additives were citric acid, lecithins and modified starches (>10,000 products each). Some food additives with suspected health effects also pertained to the top 50: sodium nitrite, potassium nitrate, carrageenan, monosodium glutamate, sulfite ammonia caramel, acesulfame K, sucralose, (di/tri/poly) phosphates, mono- and diglycerides of fatty acids, potassium sorbate, cochineal, potassium metabisulphite, sodium alginate, and bixin (>800 food products each). We identified 6 clusters of food additives frequently co-occurring in food products.CONCLUSIONS:Food additives are widespread in industrial French products and some clusters of additives frequently co-occurring in food products were identified. These results pave the way to future etiological studies merging composition data to food consumption data to investigate their association with chronic disease risk, in particular potential 'cocktail effects'.

Background: Emulsifiers 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 findings This 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.Conclusions In 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 registration ClinicalTrials.gov NCT03335644 .

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.

We tested the association between early childcare attendance in the first three years of life and child development at age 3.5 years in the French context, where early childcare is subsidized. In the ELFE (Étude Longitudinale Français depuis l'Enfance) birth cohort study set in metropolitan France, children’s development was reported by parents at age 3.5 years (n = 11,033) via the Child Development Inventory (CDI) questionnaire. CDI scores were transformed into a development quotient (DQ), with a DQ < 90 corresponding to possible and a DQ < 85 corresponding to a probable developmental delay. Inverse probability weighted multivariable regression models were used to analyse whether early childcare in the first three years of life (centre-based, childminder, informal or parental care) was associated to development delay. Compared to children in exclusive parental care, those in centre-based childcare (CBC) or with a childminder prior to school entry were significantly less likely to experience possible (OR = 0.56, [95% CI = 0.51–0.61] for CBC and OR = 0.77, [95% CI = 0.72–0.83] for childminder attendance) and probable developmental delay (OR = 0.62, [0.58–0.67] for CBC and OR = 0.80 [0.76–0.83] for childminder). Informal childcare attendance was not significantly associated with children’s possible nor probable developmental delay ((OR = 0.97, [0.84–1.12]) and (OR = 0.97, [0.82–1.15]), respectively). Conclusions: Overall, our findings add to the existing scientific literature, showing that in the French context, where childcare can start as early as 3 months of age, early childcare attendance can contribute to child’s development.