Dietary exposure to persistent organic pollutants and risk of breast cancer in women and mortality in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort

Le cancer du sein est le principal cancer chez la femme touchant 2,3 millions de femmes en 2020 dans le monde. De précédentes études sur l’exposition professionnelle ou accidentelles suggèrent que les dioxines, polychlorobiphényles (PCBs) et hydrocarbures aromatiques polycycliques (HAPs) classés comme Polluants Organiques Persistants POPs pourraient favoriser la survenue du cancer du sein. Cette thèse a débuté par une revue systématique et une méta analyse montrant une absence d’association entre l’exposition totale aux PCBs et la mortalité toutes-causes dans la population générale. Ensuite nous avons créé une base de données de l’exposition alimentaire aux dioxines, PCBs et HAPs dans la cohorte EPIC (European Prospective Investigation into Cancer and Nutrition). L’exposition alimentaire aux dioxines, PCBs et HAPs n’était pas associé au risque de cancer du sein dans EPIC mais une relation non linéaire en forme de U entre l’exposition alimentaire aux dioxines et aux PCBs alimentaires et la mortalité toutes-causes et la mortalité par cancers a été observée. Les travaux de cette thèse mettent en lumière la complexité d’évaluer l’impact de ces polluants qui peuvent avoir des effets de perturbateurs endocriniens et à faible dose. Il est difficile de séparer leur effet propre potentiellement délétère de l’effet de l’alimentation.. Enfin, il est possible que des effets différents soient identifiés à des doses plus élevées que ceux d’EPIC.Breast cancer is the leading type of cancer in women in terms of incidence, affecting 2.3 million women worldwide in 2020. Previous studies on occupational or accidental exposure suggested that dioxins, polychlorinated biphenyls (PCBs) and polycyclic aromatic hydrocarbons (PAHs) classified as Persistent Organic Pollutants (POPs) may increase breast cancer risk. This thesis started with a systematic review and a meta-analysis showing an absence of association between total PCB exposure and all-cause mortality in the general population. Then we created a database of dietary exposure to dioxins, PCBs and PAHs in the EPIC (European Prospective Investigation into Cancer and Nutrition) cohort. Dietary exposure to dioxins, PCBs and PAHs was not associated with breast cancer risk in EPIC, although a non-linear U-shaped relationship between dietary exposure to dioxins and PCBs and all-cause mortality and cancer mortality was observed. The work in this thesis highlights the complexity of assessing the impact of these pollutants, which can have endocrine disrupting effects at low doses. It is difficult to disentangle their own potentially deleterious effect from the effect of diet. Finally, it is possible that different effects are identified at higher doses of POPs than those in EPIC cohort

Identification of chemical mixtures to which women are exposed through the diet: Results from the French E3N cohort

International audienceDue to the large number of chemical food contaminants, consumers are exposed simultaneously to a wide range of chemicals which can interact and have a negative impact on health. Nevertheless, due to the multitude of possible chemical combinations it is unrealistic to test all combined toxicological effects. It is therefore essential to identify the most relevant mixtures to which the population is exposed through the diet and investigate their impact on heath. The present study aims to identify and describe the main chemical mixtures to which women enrolled in the E3N study, a large French prospective cohort, are chronically exposed through the diet. 74 522 women who had answered a validated semi-quantitative food frequency questionnaire in 1993, were included in the present study. Dietary exposure to chemical contaminates was estimated based on the food contamination measured in 186 core food in France collected between 2007 and 2009 by the French agency for food, environment and occupational health, and safety (ANSES) in the framework of the second French total diet study (2TDS). The sparse non-negative matrix under-approximation (SNMU) was used to identify mixtures of chemical substances. A k-means clustering classification of the whole study population was then performed to define clusters with similar co-exposure profiles. Overall, 8 mixtures which explained 83% of the total variance, were retained. The first mixture, entitled "Minerals, inorganic contaminants, and furans", explained the highest proportion of the total variance (38%), and was correlated in particular with the consumption of "Offal" (rho = 0.22), "Vegetables except roots" (rho = 0.20), and "Eggs" (rho = 0.19). The other seven mixtures explained between 17% and 1% of the variance. Finally, 5 clusters were identified based on the adherence to the 8 mixtures. This study, being the largest ever conducted to identify dietary exposure to chemical mixtures, represents a concrete attempt to prioritize mixtures for which it is essential to investigate combined health effects based on exposure

Association between polycyclic aromatic hydrocarbons (PAH) dietary exposure and mortality risk in the E3N cohort

International audienceMost studies have explored the adverse health effects of polycyclic aromatic hydrocarbons (PAH) occupational exposure. However, the general population is also exposed to PAH, mainly through the diet. The goal of the present study is thus to investigate the association between PAH dietary exposure and mortality risk in middle-aged women of the E3N (Étude Épidémiologique auprès de femmes de la mutuelle générale de l'Éducation Nationale) French prospective cohort.The study included 72,513 women, whom completed a validated semi-quantitative food frequency questionnaire on 208 food items in 1993. Food contamination levels were assessed using data provided by the Anses (French Agency for Food, Environmental and Occupational Health & Safety) in the framework of the French second total diet study. PAH dietary exposure was studied as the sum of four PAH (PAH4), namely benzo[a]pyrene (BaP), chrysene (CHR), benzo[a]anthracene (BaA) and benzo[b]fluoranthene (BbF). Cox proportional hazard models were used to estimate hazard ratios (HR) and their 95 % confidence intervals (CI) for the risk of all-cause mortality as well as all-cancer, specific cancer (separately from breast, lung/tracheal, and colorectal cancer), cardiovascular disease (CVD), and specific CVD (including only stroke and coronary heart disease) mortality.During follow-up (1993–2011), 4620 validated deaths were reported, of which 2726 due to cancer and 584 to CVD. The median PAH4 dietary intake was 66.1 ng/day. There was no significant association between PAH4 dietary intake and the risk of all-cause, all-cancer, breast cancer, colorectal cancer, all-CVD and stroke and coronary heart disease mortality. On the contrary, we observed a positive and statistically significant association between PAH4 dietary intake and lung/tracheal cancer mortality risk, with a stronger association among current smokers than among former smokers and never smokers.In this study, we observed an association between PAH dietary exposure and lung/tracheal cancer mortality risk, especially among current smokers

Comparing COVID-19 vaccines for their characteristics, efficacy and effectiveness against SARS-CoV-2 and variants of concern

Vaccines are critical cost-effective tools to control the COVID-19 pandemic. However, the emergence of more transmissible SARS-CoV-2 variants may threaten the potential herd immunity sought from mass vaccination campaigns. The objective of this study was to provide an up-to-date comparative analysis of the characteristics, adverse events, efficacy, effectiveness and impact of the variants of concern (Alpha, Beta, Gamma and Delta) for fourteen currently authorized COVID-19 vaccines (BNT16b2, mRNA-1273, AZD1222, Ad26.COV2.S, Sputnik V, NVX-CoV2373, Ad5-nCoV, CoronaVac, BBIBP-CorV, COVAXIN, Wuhan Sinopharm vaccine, QazCovid-In, Abdala and ZF200) and two vaccines (CVnCoV and NVX-CoV2373) currently in rolling review in several national drug agencies. Overall, all COVID-19 vaccines had a high efficacy against the traditional strain and the variants of SARS-CoV-2, and were well tolerated. BNT162b2, mRNA-1273 and Sputnik V had the highest efficacy (>90%) after two doses at preventing symptomatic cases in phase III trials. Efficacy was ranging from 10.4% for AZD1222 in South Africa to 50% for NVX-CoV2373 in South Africa and 50 % for CoronaVac in Brazil, where the 501YV.2 and P1 variants were dominant. Seroneutralization studies showed a negligible reduction in neutralization activity against Alpha for most of vaccines, whereas the impact was modest for Delta. Beta and Gamma exhibited a greater reduction in neutralizing activity for mRNA vaccines, Sputnik V and CoronaVac. Regarding observational real-life data, most studies concerned the Pfizer and Moderna vaccines. Full immunization with mRNA vaccines effectively prevents SARS-CoV-2 infection against Alpha and Beta. All vaccines appeared to be safe and effective tools to prevent symptomatic and severe COVID-19, hospitalization and death against all variants of concern, but the quality of evidence greatly varied depending on the vaccines considered. There are remaining questions regarding specific populations excluded from trials, the duration of immunity and heterologous vaccination. Serious adverse event and particularly anaphylaxis (2.5-4.7 cases per million doses among adults) and myocarditis (3.5 cases per million) for mRNA vaccines ; thrombosis with thrombocytopenia syndrome for Janssen vaccine (3 cases per million) and AstraZeneca vaccine (2 cases per million) and Guillain-Barre syndrome (7.8 cases per million) for Janssen vaccine are very rare. COVID-19 vaccine benefits outweigh risks, despite rare serious adverse effect

COVID-19 vaccine boosters: What do we know so far?

International audienceNo abstract availabl

Background exposure to polychlorinated biphenyls and all-cause, cancer-specific, and cardiovascular-specific mortality: A systematic review and meta-analysis

International audienceBackground: Polychlorinated biphenyls (PCBs) are a large family of man-made organic, ubiquitous, and persistent contaminants with endocrine-disrupting properties. PCBs have been associated with numerous adverse health effects and were classified as carcinogenic to humans, but their long-term impact on mortality risk in the general population is unknown.Objective: To conduct a systematic review and meta-analysis in order to assess whether background exposure levels of PCBs increase all-cause and cancer- and cardiovascular-specific mortality risk in the general population. Methods: We searched the Pubmed, Web of Science, Cochrane Library, and Embase databases for eligible studies up to 1st of January, 2021. We included cohort and nested-case control studies comparing the lowest vs. the highest background exposure level of PCBs in the general population and reporting data for all-cause mortality and/or cancer-/cardiovascular-specific mortality. Studies reporting occupational and accidental exposures were excluded. Random-effects meta-analysis was used to estimate summary relative risks (SRRs) and 95% confidence intervals (CIs). Heterogeneity across studies was assessed by I2 statistics, and publication bias both graphically and using Egger's and Begg's tests. Quality of included studies was assessed using the National Toxicology Program/Office of Health Assessment and Translation (NTP/OHAT). Confidence in the body of evidence and related level of evidence were assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) based on the NTP/OHAT framework. The protocol was registered in PROSPERO (CRD42020178079).Results: The initial search led to 2,132 articles. Eight prospective cohort studies met our inclusion criteria, leading to 72,852 participants including 17,805 deaths. Overall exposure to PCBs was not statistically significantly associated with all-cause mortality (SRR = 1.13, 95% CI = 0.90–1.41, n = 7 studies, low certainty); however, dietary exposure to PCBs was associated with an increased risk of cardiovascular-specific mortality (SRR = 1.38, 95% CI = 1.14–1.66, n = 3 studies, moderate certainty), while no association was found with cancer-specific mortality (SRR = 1.07, 95% CI = 0.72–1.59, n = 5 studies, low certainty).Conclusion: Our meta-analysis suggests that background exposure to PCBs is associated with an increased risk of cardiovascular-specific mortality in the general population with a “moderate” level of evidence. These findings should be interpreted with caution given the small number of studies on mortality in the general population

Challenges of studying the dietary exposure to chemical mixtures: Example of the association with mortality risk in the E3N French prospective cohort

International audienceFood is contaminated by many chemicals which interact with each other, resulting in additive, synergistic or antagonistic effects. It is thus necessary to study the health effects of dietary exposure to chemical mixtures rather than single contaminants. We aimed to investigate the association between dietary exposure to chemical mixtures and mortality risk in the E3N French prospective cohort. We included 72,585 women from the E3N cohort who completed a food frequency questionnaire in 1993. From 197 chemicals, and using sparse non-negative matrix under-approximation (SNMU), we identified six main chemical mixtures to which these women were chronically exposed through the diet. We estimated the associations between dietary exposure to these mixtures and all-cause or cause-specific mortality using Cox proportional hazard models. During the follow-up (1993-2014), 6441 deaths occurred. We observed no association between dietary exposure to three mixtures and all-cause mortality, and a non-monotonic inverse association for the three other mixtures. These results could be explained by the fact that, despite the different dietary adjustment strategies tested, we did not fully succeed in excluding the residual confounding from the overall effect of the diet. We also questioned the number of chemicals to include in mixtures' studies, as a balance needs to be reached between including a large number of chemicals and the interpretability of the results. Integrating a priori knowledge, such as toxicological data, could lead to the identification of more parsimonious mixtures, thus to more interpretable results. Moreover, as the SNMU is a non-supervised method, which identifies the mixtures only on the basis of the correlations between the exposure variables, and not in relation to the outcome, it would be interesting to test supervised methods. Finally, further studies are needed to identify the most adequate approach to investigate the health effects of dietary exposure to chemical mixtures in observational studies

Dietary exposure to polychlorinated biphenyls (PCB) and risk of Non-Hodgkin's lymphoma: Evidence from the French E3N prospective cohort

International audienceIntroduction: Polychlorinated biphenyls (PCB) are persistent and bioaccumulative lipophilic substances, mostly used in the past by industry. Known to be cancerogenic, PCB are suspected to increase Non-Hodgkin's Lymphoma (NHL) risk in the general population mainly due to evidence from cases-controls studies. Since their interdiction in 1987, diet represents the main route of exposure for the general population, nevertheless no study has assessed the relationship between PCB dietary exposure and NHL risk. The aim of this study was to analyze the association between dietary exposures to dioxin like PCB (DL PCB) and non-dioxin like PCB (NDL PCB) and NHL risk in the E3N prospective cohort of French women. Materials and methods: Among 67,879 women included in this study, 457 cases of NHL were confirmed during 21 years of follow-up. Dietary exposure to PCB was estimated combining food consumption data collected in E3N and food contamination data provided by French Agency for Food, Environmental and Occupational Health & Safety (ANSES) in the second French total diet study. Cox regression models, adjusted for potential confounders, were used to estimate hazard ratio (HR) and 95% confidence intervals (CI). Results: Average age at diagnosis was 67 years. The median dietary exposure to DL PCB and NDL PCB was, 18.5 pg TEQ/d and 138,843.2 pg/d, respectively. While no association was found between dietary exposure to DL PCB or NDL PCB and overall NHL risk, analyses by NHL histological subgroups showed a positive association between dietary exposures to DL PCB and Diffuse Large B Cell Lymphoma (OR3vs1 1.90, 95%CI [1.03–3.51], ptrend 0.02). Nevertheless these findings were no longer statistically significant when the models were adjusted for fish and dairy products consumption. In addition, an inverse association was found between dietary exposure to NDL PCB and the risk of follicular lymphoma (OR3vs1 0.46, 95%CI [0.24–0.87], ptrend 0.01). Conclusion: This is the first study to evaluate the association between dietary exposure to DL and NDL PCB and the risk of NHL in a prospective cohort study. Overall, the findings suggest a lack of association between dietary exposure to DL or NDL PCB and NHL risk. Additional studies are needed to reproduce these findings

Positive association between dietary exposure to polybrominated diphenyl ethers and breast cancer risk in the French E3N cohort: The role of vegetable oil consumption

Exposure to endocrine-disrupting chemicals, like Polybrominated diphenyl ethers (PBDEs), is suspected of playing a role in the occurrence of breast cancer. Moreover, there is growing evidence that food chemical contaminants, especially lipophilic ones such as PBDEs, could interact with different components of the diet. The objective of the present study was to assess the association between dietary intake of PBDEs and breast cancer risk in the French E3N cohort study, and to investigate the potential modification of this association by vegetable oil consumption.The study included 67 879 women. Intakes of eight PBDEs were estimated using food consumption data from a validated semi-quantitative food frequency questionnaire, and food contamination levels measured by the French Agency for Food, Environmental and Occupational Health and Safety (ANSES). Cox proportional hazards models were used to estimate Hazard Ratios (HR) and 95% Confidence Intervals (CI) for the association between total PBDEs dietary intake and breast cancer risk. Interaction measures for vegetable oil consumption were estimated on both additive and multiplicative scales.The women were followed for a maximum of 21.4 years, and 5 686 developed an incident breast cancer. A positive linear trend was highlighted between dietary intake of PBDEs in quintile groups and breast cancer risk, borderline with statistical significance (p-trend = 0.06, HRQ5VSQ1 and 95% CI: 1.09 [0.99;1.20]). Interaction measures for vegetable oil consumption were significant in both additive and multiplicative scales. Higher effect sizes of the association were highlighted in high consumers of vegetable oil, i.e. >= 4.6 g/day (HRQ5vsQ1 and 95% CI: 1.23 [1.08; 1.40]), and almost no effect were found in low consumers (HRQ5vsQ1 and 95% CI: 0.97 [0.86; 1.10]).Highlighting such interactions between nutrients and chemicals is crucial to develop efficient dietary recommendations to limit the negative health effects associated with exposure to food chemical contaminants