Nitrates Epq 2

IEA
International Journal of Epidemiology, 2022, 1106–1119

https://doi.org/10.1093/ije/dyac046
Advance Access Publication Date: 18 March 2022
International Epidemiological Association
Original article
Diet and Food Additives
Nitrites and nitrates from food additives and

natural sources and cancer risk: results from the
NutriNet-Sante cohort
Downloaded from https://academic.oup.com/ije/article/51/4/1106/6550543 by guest on 11 August 2024

Eloi Chazelas ,1,2* Fabrice Pierre,2,3 Nathalie Druesne-Pecollo ,1,2
Younes Esseddik,1 Fabien Szabo de Edelenyi,1 Ce dric Agaesse,1
Alexandre De Sa,1 Rebecca Lutchia,1 Ste phane Gigandet,4
Bernard Srour ,1,2 Charlotte Debras ,1,2 Inge Huybrechts,2,5
Chantal Julia ,1,6 Emmanuelle Kesse-Guyot ,1,2 Benjamin Allès ,1
Pilar Galan ,1,2 Serge Hercberg,1,2,6 Melanie Deschasaux-Tanguy 1,2
and Mathilde Touvier 1,2
1
Sorbonne Paris Nord University, Inserm U1153, Inrae U1125, Cnam, Nutritional Epidemiology Research
Team (EREN), Epidemiology and Statistics Research Center—University of Paris (CRESS), Bobigny,
France, 2French Network for Nutrition and Cancer Research (NACRe Network), Jouy-en-Josas,
France, 3Toxalim (Research Centre in Food Toxicology), Universite de Toulouse, INRAE, ENVT, INP-
Purpan, UPS, Toulouse, France, 4Open Food Facts, Saint-Maur-des-Fosses, France, 5International
Agency for Research on Cancer, World Health Organization, Lyon, France and 6Public Health
Department, Avicenne Hospital, AP-HP, Bobigny, France
*Corresponding author. Sorbonne Paris Nord University, Inserm U1153, Inrae U1125, Cnam, Nutritional Epidemiology
Research Team (EREN), Epidemiology and Statistics Research Center—University of Paris (CRESS), SMBH Paris 13, 74
rue Marcel Cachin F-93017 Bobigny Cedex, France. E-mail: e.chazelas@eren.smbh.univ-paris13.fr
Received 10 September 2021; Editorial decision 14 February 2022; Accepted 16 March 2022
Abstract
Background: Nitrates and nitrites occur naturally in water and soil. They are also used as
food additives (preservatives) in processed meats. They could play a role in the carcino-
genicity of processed meat. The objective was to investigate the relationship between ni-
trate and nitrite intakes (natural food, water and food additive sources) and cancer risk in
a large prospective cohort with detailed dietary assessment.
Methods: Overall, 101 056 adults from the French NutriNet-Sante cohort (2009–ongoing,
median follow-up 6.7 years) were included. Nitrites/nitrates exposure was evaluated us-
ing repeated 24-h dietary records, linked to a comprehensive composition database and
accounting for commercial names/brands of industrial products. Associations with can-
cer risk were assessed using multi-adjusted Cox hazard models.
Results: In total, 3311 incident cancer cases were diagnosed. Compared with non-
consumers, high consumers of food additive nitrates had higher breast cancer risk
[hazard ratio (HR) ¼ 1.24 (95% CI 1.03–1.48), P ¼ 0.02], more specifically for potassium ni-
trate. High consumers of food additive nitrites had higher prostate cancer risk [HR ¼ 1.58
C The Author(s) 2022. Published by Oxford University Press on behalf of the International Epidemiological Association.
V 1106
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International Journal of Epidemiology, 2022, Vol. 51, No. 4 1107
(1.14–2.18), P ¼ 0.008], specifically for sodium nitrite. Although similar HRs were ob-
served for colorectal cancer for additive nitrites [HR ¼ 1.22 (0.85–1.75)] and nitrates
[HR ¼ 1.26 (0.90–1.76)], no association was detected, maybe due to limited statistical
power for this cancer location. No association was observed for natural sources.
Conclusion: Food additive nitrates and nitrites were positively associated with breast
and prostate cancer risks, respectively. Although these results need confirmation in other
large-scale prospective studies, they provide new insights in a context of lively debate
around the ban of these additives from the food industry.
Key words: Nitrites, nitrates, food additives, cancer risk, prospective cohort

Key Messages
• 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.

• Although 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 and nitrate additives in the food industry.
Introduction
Nitrates and nitrites occur naturally in water and soil, and Agency for Research on Cancer (IARC) to classify processed
are commonly ingested from drinking water and a variety meat consumption as ‘carcinogenic to humans’ (Group 1),7
of dietary sources.1 They are also frequently used as food consistently with the conclusions of the World Cancer
additives to increase shelf life and avoid bacterial growth Research Fund (WCRF).8 Beyond other mechanistic hypothe-
(preservative function), and to provide a red coloration to ses, notably involving heme iron, carcinogenic properties of
ham and other processed meats (cosmetic purposes).1 NOCs from nitrite additives used in processed meat are seri-
Their use as food additives is massive: e.g. >15 000 indus- ous candidates to explain these links. Indeed, ingested nitrate
trial references contain added nitrites or nitrates in the cur- or nitrite under conditions that result in endogenous nitrosa-
rent French food market.2 tion is classified as probably carcinogenic to humans (Group
In several countries, debates recently emerged regarding 2A) by the IARC.1
a potential banning of nitrites and nitrates as food addi- Two meta-analyses recently highlighted positive associ-
tives. In France, a parliamentary inquiry commission has ations between nitrates (but not nitrites) from overall diet
been opened at the National Assembly on the opportunity and colorectal9 and ovarian10 cancer risks. In a third meta-
of such a ban and is now awaiting the official expertise of analysis, high or moderate nitrite intake from overall diet
the French food safety authority [French Agency for Food, was associated with higher risk of gastric cancer.11
Environmental and Occupational Health & Safety Regarding other cancer sites, the number of studies is very
(ANSES)], which should be issued by the end of 2021. scarce, in particular for breast and prostate, which are the
Experimental studies are accumulating and seem to sup- most frequent cancers in several countries.12 To our
port a prohibiting strategy. They highlighted the fact that knowledge, only two studies were conducted for breast
nitrites form N-nitroso compounds (NOCs) in the digestive cancer: a positive association was found between nitrites
tract, considered as potential carcinogens in humans and from processed meat and post-menopausal breast cancer
proven carcinogens in a number of animal species.3–5 Of risk in the National Institutes of Health and American
note, some of the ingested nitrates are converted into Association of Retired Persons (NIH-AARP) Diet and
nitrites by the oral microbiota and will also lead to the for- Health Study13 and no association was observed with
mation of NOCs. nitrates from overall diet in the Iowa Women’s Health
However, epidemiological data in humans are still very Study.14 Only one study was published for prostate cancer,
limited.6 The current state of knowledge led the International highlighting positive associations with nitrite and nitrate
1108 International Journal of Epidemiology, 2022, Vol. 51, No. 4
intakes from processed meat.15 Besides, most of these stud- of three non-consecutive, web-based 24-h dietary records
ies did not distinguish natural vs food additive nitrites/ (validated against an interview by a trained dietitian23 and
nitrates, whereas differential effects have been suggested against blood and urinary biomarkers24,25) randomly
depending on the source.16 Indeed, antioxidants—natural assigned over a 2-week period (2 weekdays and 1 weekend
inhibitors of the formation of NOCs17—are naturally pre- day). Participants reported all foods and beverages con-
sent in the same sources of natural nitrites and nitrates sumed on any eating occasion. Portion sizes were estimated
(mainly fruits and vegetables) and may reduce the carcino- by participants using validated photographs or usual serv-
genic potential of nitrites and nitrates from natural sour- ing containers.26 To assess daily intakes of macronutrients,
ces. Also, no study provided details on specific nitrite/ micronutrients, alcohol and total calories, dietary con-
nitrate food additives. Thus, the aim of this study was to sumption data were linked to the NutriNet-Sante food
investigate the relationship between nitrate and nitrite composition database, which contains >3500 generic
intakes (coming from different sources: natural food sour- items.27 Besides, participants were asked whether each

ces, water and food additive sources) and the risk of cancer food product was home-made or industrial and the brand
(overall and by most frequent cancer sites) in a large pro- and commercial name were collected for each industrial
spective cohort with detailed and up-to-date dietary assess- product. Intakes from home-made composite dishes were
ments that includes details of commercial names/brands of estimated by referring to French recipes as defined by nu-
products to properly estimate individual additive exposure. trition professionals. Baseline habitual dietary intakes were
averaged from all 24-h dietary records provided during the
first 2 years of follow-up (at least two 24-h records manda-
Methods tory for inclusion in the study). Identification of dietary
under-reporting was performed based on the method pro-
Study population
posed by Black, by using the basal metabolic rate and
NutriNet-Sante is a French online cohort launched in Goldberg cut-offs. Under-reporters of energy intake were
2009, which aims to study the associations between nutri- excluded.28
tion and health as well as the determinants of eating behav-
iours and nutritional status. It has already been described
in detail.18 Since May 2009, participants aged 18 years Nitrite and nitrate intakes
with Internet access have been continuously recruited from Nitrite and nitrate intakes were estimated combining con-
the general population through large multimedia cam- tributions of food additives: potassium nitrite (e249), so-
paigns. Participants are followed using an online platform dium nitrite (e250), sodium nitrate (e251) and potassium
connected to their e-mail address and questionnaires are nitrate (e252). Because they can also naturally occur in
completed online on a dedicated website (https://etude- food products, we also estimated intakes from natural
nutrinet-sante.fr). All participants provided informed elec- presence in food and drinking water.
tronic consent. Supplementary File 1 (available as Supplementary data at
IJE online) describes the determination process of food addi-
tive exposure. In brief, for each food consumption declara-
Data collection
tion, the presence of each food additive (qualitative
At inclusion, participants were asked to complete a set of composition data) and, if relevant, its dose (quantitative com-
five questionnaires related to socio-demographic and life- position data) were searched. To determine the qualitative
style characteristics (e.g. date of birth, sex, educational presence/absence of food additives, three complementary
level, smoking status),19 anthropometry,20,21 physical ac- databases were used: OQALI,29 a national database hosted
tivity [validated 7-day International Physical Activity by the French food safety authority (ANSES) to characterize
Questionnaire (IPAQ)],22 health status (e.g. personal and the quality of the food supply; Open Food Facts, an open col-
family history of diseases, menopausal status, drug use in- laborative database of food products marketed worldwide;2
cluding hormonal treatment for menopause and oral con- and Mintel Global New Products Database (GNPD),30 an
traceptives) and dietary intakes. online database of innovative food products in the world.
When several composition data existed for a same product at
different dates (reformulations), the date of consumption in
Dietary assessment the cohort (year) was considered in the matching of composi-
At inclusion and every 6 months thereafter (to vary the sea- tion data (dynamic matching). The quantitative composition
son of completion and consider seasonal variation in die- of additives was derived from several sources. First, 2677
tary intakes), participants were invited to complete a series ad hoc laboratory assays were carried out for the main
additive–vector food pairs, among which 700 assays were on and nitrates from total exposure and from natural sources,
nitrites and nitrates (ad hoc assays committed by our labora- we defined sex-specific tertiles of intakes, based on the
tory or by the consumers’ association ‘UFC Que Choisir’). whole population. For nitrites and nitrates from food addi-
The second step in the absence of data for a given food was tives, as the number of non-consumers was substantial
the use of doses by generic food categories transmitted by the (>25%), three categories of intakes were defined: non-
European Food Safety Authority (EFSA). Last, generic doses consumers, low consumers and high consumers (the latter
from the Codex General Standard for Food Additives two being separated by sex-specific median among con-
(GSFA)31 were used. The decision tree in Supplementary File sumers). Potassium nitrite (e249) and sodium nitrate
1 (available as Supplementary data at IJE online) describes (e251) were consumed by <1% of the population. They
this process in details. were therefore taken into account in the total food additive
To estimate natural nitrite and nitrate intakes in foods, analyses but their individual associations were not studied.
EFSA’s concentration levels for natural sources and con- The main studied cancers were overall, breast and prostate

tamination from agricultural practices were used by food cancers (the most frequent sites in the cohort). Colorectal
category.32,33 To estimate intakes through water consump- cancer was studied in secondary analyses (limited number
tion, we used national results of the official sanitary con- of cases). Cox proportional hazards models with age as the
trol of tap water, by region.34 primary timescale were used to evaluate the association be-
tween the consumption of nitrites and nitrates and cancer
risk. We tested the proportional hazard assumption of the
Case ascertainment Cox model by using rescaled Schoenfeld-type residuals and
Health events were reported through an annual question- by performing the Grambsch–Therneau test.35 Log-
naire, a specific check-up questionnaire every 6 months or linearity of exposure variable hazard rates was validated
at any time through a specific interface on the study web- using restricted cubic spline functions.36 Participants con-
site. Each incident cancer reported was reviewed by a phy- tributed person-time until the date of diagnosis of cancer,
sician from the study team who contacted the participants the date of last completed questionnaire, the date of death
and asked them to provide relevant medical records. When or 12 January 2021, whichever occurred first.
additional information was needed, the patient’s physician, The main model was adjusted for age (timescale), sex,
hospital or both were also contacted. All medical data energy intake without alcohol (kcal/d, continuous), alco-
were reviewed by a committee of physicians. Besides, the hol, sugar, saturated fatty acids and fibre intakes (g/d, con-
NutriNet-Sante cohort is linked to the medico- tinuous), sodium and heme iron intakes (mg/d,
administrative databases of the national health insurance continuous), BMI (kg/m2, continuous), height (cm, contin-
system (SNIIRAM databases) and to the French national uous), physical activity (high, moderate, low, calculated
cause-specific mortality registry (CepiDC). Based on these according to IPAQ recommendations37), smoking status
databases, we were able to complete the information con- (never, former, current smokers), number of 24-h dietary
cerning health events and deaths, thus limiting any poten- records (continuous), family history of cancer (yes/no) and
tial bias due to participants with cancer who might not educational level (primary, secondary, undergraduate,
report their disease to the study investigators. Cancer cases post-graduate). All models were mutually adjusted for ni-
were classified using the ICD-10 (International trate/nitrite intakes other than the specific one studied: e.g.
Classification of Diseases, 10th Revision). In this study, we when sodium nitrite (e250) was studied, models were ad-
considered as cases all primary malignant cancers diag- justed for potassium nitrite (e249), natural nitrite and
nosed between the inclusion date and 12 January 2021, overall nitrate intakes. Stratifications by menopausal status
with the exception of basal cell carcinoma of the skin, were performed for breast cancer analyses. For these,
which was not considered as cancer. women contributed person-time to the ‘pre-menopausal
model’ until their age at menopause and to the ‘post-meno-
pausal model’ from their age at menopause. For breast can-
Statistical analysis cer analyses, additional adjustments were made for the age
The Multiple Imputation by Chained Equations method at menarche (categorical: <12 years old, 12 years old),
using fully conditional specifications (20 imputed data age at first child (categorical: no child, before 30 years,
sets) was performed to handle missing data for the follow- 30 years), number of biological children (continuous),
ing covariates: smoking status (0.2% of missing data), level menopausal status at baseline (menopausal/non-meno-
of education (6.2%), physical activity level (14.0%), height pausal), hormonal treatment for menopause at baseline
(0.8%) and body mass index (BMI) (0.8%). For nitrites and during follow-up (for main breast cancer model and
post-menopausal analyses, yes/no) and oral contraception additives, high consumers were more likely to be males,
use at baseline and during follow-up (for main breast can- younger individuals, less physically active, less educated and
cer model and pre-menopausal analyses, yes/no). with a higher BMI. In terms of nutritional intakes, they had
As it has been suggested that antioxidants may inhibit higher caloric, alcohol, sugar, sodium and heme iron intakes
the formation of NOCs,17 interactions with antioxidant and lower fibre intakes. The median intake of nitrite addi-
intakes (total intake of vitamin A, C, E, selenium and zinc) tives was slightly higher among men compared with women
as well as fruit and vegetable intakes were tested as second- (0.15 vs 0.11 mg/d, data not tabulated). Regarding nitrate
ary analyses. Interactions with heme iron intakes were additives, the median was null for both sexes, but the mean
tested, as it may enhance endogenous NOC formation.38 intake was higher among men compared with women (0.26
Interactions with alcohol intake were also tested. vs 0.16 mg/d, data not tabulated). The Pearson correlation
Interaction variables were defined as two categories sepa- coefficient between nitrate and nitrite additives (in mg/d)
rated by sex-specific median. Several models were also was 0.24. Correlation between food additives nitrites/

tested as sensitivity analyses: (i) restriction of the study nitrates intakes (in mg/d) and intakes of food containing
population to participants with at least five 24-h dietary processed meat (as such or in mixed dishes, in g/d) were re-
records during the first 2 years of follow-up, (ii) exclusion spectively 0.73 and 0.67.
of the first 2 years of follow-up for all participants to chal- Contributors to total nitrite intake ranked as follows:
lenge a potential reverse causality bias, (iii) additional ad- natural presence/contamination in foods [mean (SD): 5.3
justment for antioxidant and fruit and vegetable intakes (SD 3.2) mg/d, 95.3%], food additives [0.3 (SD 0.6) mg/d,
and (iv) additional adjustment for the proportion in weight 4.7%] and natural presence/contamination in water
of ultra-processed food intake in the diet (as defined by the [0.0004 (SD 0.005) mg/d, 0.01%]. Contributors to total
NOVA classification39,40). For breast cancer analyses, nitrate intake were: natural presence/contamination in
stratification according to alcohol intake (high and low foods [197.5 (SD 110.1) mg/d, 93.0%], natural presence/
consumers separated by median) were also tested. contamination in water [14.7 (SD 12.4) mg/d, 6.9%] and
All tests were two-sided. R version 3.6.3 (R food additives [0.2 (SD 0.4) mg/d, 0.1%]. Supplementary
Foundation, Vienna, Austria) was used for the analyses. File 2 (available as Supplementary data at IJE online) illus-
trates natural food sources of nitrites and nitrates. For
both, the main vector was vegetables and vegetable-based
Results preparations (41% and 60%, respectively), followed by
After exclusion of energy under-reporters and prevalent can- processed meat for nitrites (19%) and seasonings for
cer cases at baseline, 101 056 participants were included in nitrates (23%). Supplementary File 3 (available as
this study (flowchart in Figure 1). Among the 101 056 par- Supplementary data at IJE online) illustrates the food sour-
ticipants included (78.5% women), the mean age at baseline ces of nitrites and nitrates as food additives: for both, the
was 42.3 years (SD 14.5) and mean number of dietary main vector was processed meat consumed as such (60%
records was 5.5 (SD 3.0). Table 1 shows the baseline char- and 92%, respectively), followed by various types of dishes
acteristics of the study population according to quantiles of containing processed meat.
nitrite intakes from food additives (non-consumers, low and The percentage of consumers for each nitrite and nitrate
high consumers, separated by sex-specific median among additive were as follows: sodium nitrite (e250): 73.9%, po-
consumers). Compared with non-consumers of nitrite tassium nitrate (e252): 31.6%, potassium nitrite (e249):
0.9% and sodium nitrate (e251): 0.9%.
During follow-up (median follow-up time 6.7 years),
3311 first incident cancer cases were diagnosed, among
which there were 966 breast cancers (381 pre-menopausal,
585 post-menopausal), 400 prostate cancers and 268 colo-
rectal cancers.
The proportional hazard assumptions of the Cox mod-
els were met, as well as the log-linearity of exposure vari-
able hazard rates (Supplementary File 4, available as
Supplementary data at IJE online). Tables 2–5 show the
associations between nitrites and nitrates intakes (total,
Figure 1: Flowchart of NutriNet-Sante cohort participants included in natural sources, food additives) and overall, breast, pros-
the investigation of nitrite and nitrate intakes and cancer risk. tate and colorectal cancer risk, respectively.
cohort, France, 2009–2021 (N ¼ 101 056)

Table 1 Baseline characteristics of the study population, NutriNet-Sante
Characteristics All participants Categories of nitrite intakes from food additivesa
Non-consumers Low consumers High consumers Ptrend
Number of participants 101 056 (100.0) 26 337 (26.1) 37 360 (36.9) 37 359 (36.9) <0.001
Mean (SD) age (years) 42.26 (14.51) 41.77 (14.6) 44.00 (14.7) 40.88 (14.1) <0.001
Women 79 284 (78.5) 20 894 (79.3) 29 195 (78.1) 29 195 (78.1) <0.001
Mean (SD) height (cm)b 166.75 (8.1) 166.71 (8.1) 166.48 (8.1) 167.04 (8.1) <0.001
Mean (SD) BMI (kg/m2)b 23.69 (4.5) 23.33 (4.5) 23.56 (4.2) 24.08 (4.8) <0.001
Family history of cancer (%)c 17 083 (16.9) 4202 (16.0) 6876 (18.4) 6005 (16.1) <0.001
IPAQ physical activity level (%): <0.001
High 28 631 (28.3) 7849 (29.8) 10 874 (29.1) 9908 (26.5)
Moderate 37 337 (36.9) 9591 (36.4) 14067 (37.7) 13 679 (36.6)

Low 20 988 (20.8) 5145 (19.5) 7513 (20.1) 8330 (22.3)
Missing 14 100 (14.0) 3752 (14.2) 4906 (13.1) 5442 (14.6)
Education level (%): <0.001
Primary 2635 (2.6) 730 (2.8) 984 (2.6) 921 (2.5)
Secondary 32 226 (31.9) 8123 (30.8) 11 913 (31.9) 12 190 (32.6)
Undergraduate 27 397 (27.1) 7021 (26.7) 9923 (26.6) 10 453 (28.0)
Post-graduate 32 495 (32.2) 8889 (33.8) 12125 (32.5) 11 481 (30.7)
Missing 6303 (6.2) 1574 (6.0) 2415 (6.5) 2314 (6.2)
Smoking status: <0.001
Current 17 575 (17.4) 4820 (18.3) 5975 (16.0) 6780 (18.1)
Former 32 538 (32.2) 8424 (32.0) 12 300 (32.9) 11 814 (31.6)
Never 50 703 (50.2) 12968 (49.2) 19 030 (50.9) 18 705 (50.1)
Missing 240 (0.2) 125 (0.5) 55 (0.1) 60 (0.2)
Oral contraceptiond 22 281 (28.1) 5335 (25.5) 7698 (26.4) 9248 (31.7) <0.001
Use of hormonal treatment for menopaused 3388 (4.3) 823 (3.9) 1475 (5.1) 1090 (3.7) <0.001
Mean (SD) number of biological childrend 1.28 (1.24) 1.16 (1.25) 1.39 (1.24) 1.26 (1.23) <0.001
Mean (SD) energy intake without alcohol (kcal/d) 1900.60 (471.8) 1828.33 (489.9) 1885.07 (443.6) 1967.09 (477.2) <0.001
Mean (SD) alcohol intake (g/d) 7.81 (11.83) 6.95 (11.69) 7.94 (11.43) 8.29 (12.28) <0.001
Mean (SD) sugar intake (g/d) 92.29 (33.14) 91.08 (36.00) 92.66 (31.31) 92.76 (32.80) <0.001
Mean (SD) fibre intake (g/d) 19.46 (7.26) 20.87 (8.93) 19.36 (6.57) 18.56 (6.38) <0.001
Proportion of ultra-processed food in the diet (%) 35.12 (13.76) 33.08 (15.00) 33.92 (12.88) 37.74 (13.27) < 0.001
Mean (SD) sodium intake (mg/d) 2718.88 (891.7) 2451.35 (902.3) 2669.86 (807.2) 2956.49 (903.3) <0.001
Mean (SD) heme iron intake (mg/d) 1.21 (1.19) 1.05 (1.36) 1.21 (1.11) 1.32 (1.13) <0.001
Mean (SD) total nitrate intake (mg/d) 212.44 (112.2) 226.76 (131.2) 212.71 (105.1) 202.07 (103.3) <0.001
Mean (SD) total nitrite intake (mg/d) 5.61 (3.36) 4.98 (3.43) 5.40 (2.95) 6.27 (3.56) <0.001
Mean (SD) nitrate intake from natural sources (mg/d) 212.26 (112.3) 226.64 (131.2) 212.55 (105.1) 201.83 (103.3) <0.001
Mean (SD) nitrite intake from natural sources (mg/d) 5.35 (3.30) 4.98 (3.40) 5.30 (2.95) 5.66 (3.40) <0.001
Mean (SD) nitrate intake from additives (mg/d) 0.18 (0.40) 0.12 (0.40) 0.17 (0.38) 0.24 (0.50) <0.001
Mean (SD) potassium nitrate (e252) intake (mg/d) 0.18 (0.42) 0.12 (0.40) 0.16 (0.36) 0.24 (0.48) <0.001
Mean (SD) nitrite intake from additives (mg/d) 0.26 (0.64) 0.00 (0.00) 0.10 (0.05) 0.61 (0.95) <0.001
Mean (SD) sodium nitrite (e250) intake (mg/d) 0.23 (0.32) 0.00 (0.00) 0.10 (0.05) 0.52 (0.37) <0.001
Values are n (%) unless stated otherwise.

IPAQ, International Physical Activity Questionnaire; BMI, body mass index; 1 kcal ¼ 4.18 kJ ¼ 0.00418 MJ.
a
Categories of consumption were defined as: non-consumers, low consumers and high consumers, separated by the sex-specific median among consumers, i.e.
0.19 mg/d in women and 0.25 mg/d in men.
b
Height and BMI were missing for 789 participants.
c
Among first-degree relatives.
d
Among women.
No association was detected for total nitrite and ni- [HRhigh vs low consumers ¼ 1.24 (95% CI 1.03–1.48),
trate intakes, nor for intakes from natural sources. P ¼ 0.02], especially for potassium nitrate (e252)
Compared with non-consumers, high consumers of food [HRhigh vs low consumers ¼ 1.25 (95% CI 1.04–1.50),
additive nitrates had higher risk of breast cancer P ¼ 0.01]. These associations were more specifically
cohort, France,
Table 2 Associations between nitrite and nitrate exposures by sources and overall cancer risk, NutriNet-Sante
2009–2021 (N ¼ 101 056)
Exposure Sex-specific categories of intakesa Ptrend
1 2 3
Total nitrites N cases/N total 831/33 686 1262/33 685 1218/33 685
HR (95% CI) Ref. 1.04 (0.95–1.14) 1.01 (0.91–1.11) 0.9
Nitrites from natural sources N cases/N total 828/33 686 1243/33 685 1240/33 685
HR (95% CI) Ref. 1.00 (0.91–1.09) 0.97 (0.88–1.08) 0.5
Nitrites from food additives N cases/N total 639/26 337 1467/37 360 1205/37 359
HR (95% CI) Ref. 1.08 (0.98–1.19) 1.08 (0.98–1.20) 0.3
Sodium nitrite (e250) N cases/N total 639/26 397 1463/37 331 1209/37 328
HR (95% CI) Ref. 1.08 (0.98–1.19) 1.10 (0.99–1.21) 0.2

Total nitrates N cases/N total 740/33 686 1195/33 686 1376/33 684
HR (95% CI) Ref. 1.02 (0.93–1.12) 1.02 (0.92–1.13) 0.8
Nitrates from natural sources N cases/N total 741/33 686 1196/33 686 1374/33 684
HR (95% CI) Ref. 1.02 (0.93–1.12) 1.02 (0.92–1.13) 0.8
Nitrates from food additives N cases/N total 1974/69 083 760/15 987 577/15 986
HR (95% CI) Ref. 1.08 (0.99–1.18) 1.09 (0.99–1.20) 0.09
Potassium nitrate (e252) N cases/N total 1975/69 086 760/15 985 576/15 985
HR (95% CI) Ref. 1.08 (0.99–1.18) 1.09 (0.99–1.21) 0.07
HR, cause-specific hazard ratio.

Median follow-up time: 6.7 years. Person-years: 639 756.
Multivariable Cox proportional hazard models were adjusted for: age (timescale), sex, energy intake without alcohol (kcal/d, continuous), alcohol, sugar, satu-
rated fatty acids and fibre intakes (g/d, continuous), sodium and heme iron intakes (mg/d, continuous), body mass index (kg/m2, continuous), height (cm, continu-
ous), physical activity (high, moderate, low, calculated according to International Physical Activity Questionnaire recommendations), smoking status (never,
former, current smokers), number of 24-h dietary records (continuous), family history of cancer (yes/no) and educational level (primary, secondary, undergradu-
ate, post-graduate). All models were mutually adjusted for nitrate/nitrite intakes other than the specific one studied.
a
For total nitrite and nitrate intakes and from natural sources, sex-specific tertiles of consumption were defined. Cut-offs were: 4.03 and 5.55 mg/d in women
and 5.18 and 7.44 mg/d in men for total nitrites, 150.09 and 233.89 mg/d in women and 162.11 and 251.59 mg/d in men for total nitrates, 3.83 and 5.29 mg/d in
women and 4.92 and 7.07 mg/d in men for nitrites from natural sources, 149.91 and 233.75 mg/d in women and 161.94 and 251.32 mg/d in men for nitrates
from natural sources.
For nitrites and nitrates from food additives, three categories of consumption were defined: non-consumers, low consumers and high consumers (separated by
sex-specific median among consumers). Cut-offs were: 0.19 mg/d in women and 0.25 mg/d in men for nitrites from food additives, 0.36 mg/d in women and
0.46 mg/d in men for nitrates from food additives, 0.19 mg/d in women and 0.25 mg/d in men for sodium nitrite (e250) and 0.36 mg/d in women and 0.46 mg/d in
men for potassium nitrate (e252).
During overall follow-up, 142 competing deaths occurred. Cause-specific HRs for death in the high consumers of total nitrites, nitrites from natural sources,
nitrites from food additives, sodium nitrite (e250), total nitrates, nitrates from natural sources, nitrates from food additives and potassium nitrate (e252) were re-
spectively: 0.65 (0.41–1.02), P ¼ 0.09; 0.58 (0.37–0.93), P ¼ 0.03; 1.17 (0.74–1.85), P ¼ 0.5; 1.15 (0.73–1.82), P ¼ 0.6; 0.99 (0.60–1.63), P ¼ 0.6; 1.05 (0.63–
1.73), P ¼ 0.8; 0.93 (0.57–1.52), P ¼ 0.004; 0.94 (0.58- 1.53), P ¼ 0.8.
observed among pre-menopausal women [HRhigh vs low this study, maybe due to limited statistical power for this
consumers ¼ 1.40 (95% CI 1.10– 1.78), P ¼ 0.006 for food cancer location (Table 5).
additive nitrates and HRhigh vs low consumers ¼ 1.41 (95% No interaction was detected between nitrite/nitrate expo-
CI 1.11–1.80), P ¼ 0.005 for potassium nitrate e252; sures and heme iron, antioxidant, fruit and vegetable or
Supplementary File 5, available as Supplementary data alcohol intakes (all P > 0.1, data not tabulated). Sensitivity
at IJE online]. Compared with non-consumers, high con- analyses did not substantially modify the results
sumers of food additive nitrites and specifically sodium (Supplementary File 6, available as Supplementary data at
nitrite (e250) had higher risk of first incident prostate IJE online). For breast cancer analyses, stratification by alco-
cancer [HRhigh vs low consumers ¼ 1.58 (95% CI 1.14– hol consumption did not modify the results (Supplementary
2.18), P ¼ 0.008 and HRhigh vs low consumers ¼ 1.62 (95% File 7, available as Supplementary data at IJE online).
CI 1.17–2.25), P ¼ 0.004, respectively]. Although simi-
lar HRs were observed for colorectal cancer [HRhigh vs
low consumers ¼ 1.22 (95% CI 0.85–1.75) for food additive
Discussion
nitrite intakes and 1.26 (95% CI 0.90–1.76) for food ad- In this large prospective cohort study, food additive
ditive nitrate intakes], no association was detected in nitrates intakes, in particular potassium nitrate (e252),
cohort, France,
Table 3 Associations between nitrite and nitrate exposures by sources and breast cancer risk, NutriNet-Sante
2009–2021 (N ¼ 79 284 women)
1 2 3
HR (95% CI) Ref. 1.19 (1.00–1.41) 1.09 (0.90–1.32) 0.7
HR (95% CI) Ref. 1.09 (0.92–1.30) 1.04 (0.86–1.26) 0.9
HR (95% CI) Ref. 1.22 (1.01–1.47) 1.15 (0.94–1.39) 0.8
HR (95% CI) Ref. 1.22 (1.02–1.47) 1.16 (0.95–1.41) 0.6

HR (95% CI) Ref. 0.99 (0.83–1.18) 0.99 (0.81–1.20) 1
HR (95% CI) Ref. 0.98 (0.82–1.17) 1.00 (0.82–1.21) 1
HR (95% CI) Ref 1.20 (1.02–1.41) 1.24 (1.03–1.48) 0.02
HR (95% CI) Ref. 1.20 (1.02–1.41) 1.25 (1.04–1.50) 0.01

Multivariable Cox proportional hazard models were adjusted for: age (timescale), energy intake without alcohol (kcal/d, continuous), alcohol, sugar, saturated
fatty acids and fibre intakes (g/d, continuous), sodium and heme iron intakes (mg/d, continuous), body mass index (kg/m2, continuous), height (cm, continuous),
physical activity (high, moderate, low, calculated according to International Physical Activity Questionnaire recommendations), smoking status (never, former,
current smokers), number of 24-h dietary records (continuous), family history of cancer (yes/no) and educational level (primary, secondary, undergraduate, post-
graduate). All models were mutually adjusted for nitrate/nitrite intakes other than the specific one studied.
For breast cancer analyses, additional adjustments were made for the age at menarche (categorical: <12 years old, 12 years old), age at first child (categorical:
no child, before 30 years, 30 years), number of biological children (continuous), menopausal status at baseline (menopausal/non-menopausal), hormonal treat-
ment for menopause at baseline and during follow-up (yes/no) and oral contraception use at baseline and during follow-up (yes/no).
a
For nitrites and nitrates from overall exposure and from natural sources, sex-specific tertiles of consumption were defined.
Cut-offs were: 4.03 and 5.55 mg/d in women for overall nitrites, 150.09 and 233.89 mg/d in women for overall nitrates, 3.83 and 5.29 mg/d in women for
nitrites from natural sources and 149.91 and 233.75 mg/d in women for nitrates from natural sources.
sex-specific median among consumers). Cut-offs were: 0.19 mg/d in women for nitrites from food additives, 0.36 mg/d in women for nitrates from food additives,
0.19 mg/d in women for sodium nitrite (e250) and 0.36 mg/d in women for potassium nitrate (e252).
During women’s follow-up, 58 competing deaths occurred and 1296 competing cases of cancers other than breast were diagnosed. Cause-specific HRs for
death in the high consumers of total nitrites, nitrites from natural sources, nitrites from food additives, sodium nitrite (e250), total nitrates, nitrates from natural
sources, nitrates from food additives, potassium nitrate (e252) were respectively: 0.87 (0.43–1.74), P ¼ 0.8; 0.96 (0.46–1.99), P ¼ 0.9; 0.93 (0.47–1.85), P ¼ 0.9;
0.95 (0.48–1.89), P ¼ 0.9; 0.94 (0.44–2.00), P ¼ 0.8; 0.93 (0.44–1.99), P ¼ 0.8; 0.83 (0.36–1.90), P ¼ 0.6; 0.88 (0.38–2.01), P ¼ 0.7.
Cause-specific hazard ratios for all cancers except breast in the high consumers of total nitrites, nitrites from natural sources, nitrites from food additives, so-
dium nitrite (e250), total nitrates, nitrates from natural sources, nitrates from food additives and potassium nitrate (e252) were respectively: 1.06 (0.90–1.24),
P ¼ 0.5; 1.00 (0.85–1.18), P ¼ 1; 0.98 (0.84–1.15), P ¼ 0.8; 1.00 (0.85–1.18), P ¼ 1; 0.96 (0.81–1.14), P ¼ 0.6; 0.96 (0.81–1.13), P ¼ 0.6; 1.03 (0.88–1.21),
P ¼ 0.7; 1.05 (0.89–1.23), P ¼ 0.6.
were associated with increased breast cancer risk, specifi- post-menopausal breast cancer, but nitrate intakes were
cally pre-menopausal breast cancer, and nitrite additives not studied.13 In the American Iowa Women’s Health
intakes, especially sodium nitrite (e250), were positively Study, nitrates from overall diet and from water were
associated with prostate cancer risk. Although similar HRs not associated with breast cancer risk and nitrites were
were observed for colorectal cancer, no association was not studied.14,41 Comparisons with our results are not
detected in this study. No association was detected for straightforward since the above-mentioned studies did
nitrites or nitrates from natural sources. not differentiate natural vs additive sources.
Consistently with our results, nitrites from processed
Comparison with epidemiological literature meat were positively associated with prostate cancer risk
In the US NIH-AARP Diet and Health Study, nitrites in the NIH-AARP study and an association was also
from processed meat were positively associated with found with nitrates from processed meat.15
cohort, France,
Table 4 Associations between nitrite and nitrate exposures by sources and prostate cancer risk, NutriNet-Sante
2009–2021 (N ¼ 21 772 men)
1 2 3
Total nitrites N cases/N total 95/7258 169/7257 136/7257

HR (95% CI) Ref. 1.27 (0.97–1.65) 1.28 (0.95–1.73) 0.2
Nitrites from natural sources N cases/N total 94/7258 167/7257 139/7257
HR (95% CI) Ref. 1.19 (0.91–1.55) 1.25 (0.92–1.68) 0.2
Nitrites from food additives N cases/N total 56/5443 182/8165 162/8164
HR (95% CI) Ref. 1.30 (0.95–1.77) 1.58 (1.14–2.18) 0.008
Sodium nitrite (e250) N cases/N total 56/5456 181/8159 163/8157
HR (95% CI) Ref. 1.31 (0.96–1.79) 1.62 (1.17–2.25) 0.004

Total nitrates N cases/N total 74/7258 146/7258 180/7256
HR (95% CI) Ref. 1.16 (0.87–1.55) 1.18 (0.87–1.60) 0.4
Nitrates from natural sources N cases/N total 74/7258 146/7258 180/7256
HR (95% CI) Ref. 1.16 (0.87–1.55) 1.16 (0.86–1.58) 0.4
Nitrates from food additives N cases/N total 198/13 622 133/4075 69/4075
HR (95% CI) Ref. 1.38 (1.10–1.74) 0.99 (0.74–1.33) 0.9
Potassium nitrate (e252) N cases/N total 198/13 623 133/4074 69/4075
HR (95% CI) Ref. 1.39 (1.10–1.75) 1.03 (0.77–1.38) 0.9

Multivariable Cox proportional hazard models were adjusted for: age (timescale), energy intake without alcohol (kcal/d, continuous), alcohol, sugar, saturated
fatty acids and fibre intakes (g/d, continuous), sodium and heme iron intakes (mg/d, continuous), body mass index (kg/m2, continuous), height (cm, continuous),
physical activity (high, moderate, low, calculated according to International Physical Activity Questionnaire recommendations), smoking status (never, former,
current smokers), number of 24-h dietary records (continuous), family history of cancer (yes/no) and educational level (primary, secondary, undergraduate, post-
graduate). All models were mutually adjusted for nitrate/nitrite intakes other than the specific one studied.
a
Cut-offs were: 5.18 and 7.44 mg/d in men for overall nitrites, 162.11 and 251.59 mg/d in men for overall nitrates, 4.92 and 7.07 mg/d in men for nitrites from
natural sources and 161.94 and 251.32 mg/d in men for nitrates from natural sources.
sex-specific median among consumers). Cut-offs were: 0.25 mg/d in men for nitrites from food additives, 0.46 mg/d in men for nitrates from food additives,
0.25 mg/d in men for sodium nitrite (e250) and 0.46 mg/d in men for potassium nitrate (e252).
During men’s follow-up, 84 competing deaths occurred and 649 competing cases of cancers other than prostate. Cause-specific HRs for death in the high con-
sumers of total nitrites, nitrites from natural sources, nitrites from food additives, sodium nitrite (e250), total nitrates, nitrates from natural sources, nitrates from
food additives and potassium nitrate (e252) were respectively: 0.58 (0.32–1.06), P ¼ 0.1; 0.45 (0.24–0.85), P ¼ 0.02; 1.37 (0.73–2.54), P ¼ 0.4; 1.31 (0.70–2.43),
P ¼ 0.4; 1.04 (0.53–2.04), P ¼ 0.7; 1.15 (0.59–2.28), P ¼ 0.9; 1.01 (0.55–1.86), P ¼ 1; 1.00 (0.54–1.84), P ¼ 1. Cause-specific hazard ratios for all cancers except
prostate in the high consumers of total nitrites, nitrites from natural sources, nitrites from food additives, sodium nitrite (e250), total nitrates, nitrates from natu-
ral sources, nitrates from food additives and potassium nitrate (e252) were respectively: 0.86 (0.69–1.08), P ¼ 0.2; 0.88 (0.70–1.10), P ¼ 0.3; 0.96 (0.76–1.22),
P ¼ 0.7; 0.96 (0.76–1.22), P ¼ 0.7; 1.15 (0.91–1.45), P ¼ 0.3; 1.13 (0.90–1.43), P ¼ 0.4; 1.05 (0.85–1.30), P ¼ 0.6; 1.05 (0.85–1.30), P ¼ 0.6.
To our knowledge, regarding colorectal cancer and ni- The number of cases was too limited to investigate sepa-
trite or nitrate exposures, eight prospective studies were rately other specific cancer locations. In the literature, a re-
published, among which three found positive associations cent meta-analysis suggested a positive association
for water nitrate42 or meat nitrate and nitrite,43,44 whereas between total nitrate intake and ovarian cancer risk (three
five others did not observe any association for water ni- cohorts included).10 One meta-analysis suggested a posi-
trate and dietary nitrite and nitrate. A recent meta-analysis tive association between total nitrite intake and gastric
including 15 prospective cohorts and case–control studies cancer risk (19 studies included, not distinguishing cohorts
suggested positive associations between total nitrate intake from case–control studies).11 A few studies suggested asso-
and colorectal cancer risk.9 These studies did not differen- ciations for other cancer locations: higher dietary nitrate
tiate natural vs food additive sources, limiting the compa- intakes (but not nitrites) were positively associated with
rability with our results. In the present study, we did not thyroid cancer risk among men of the US NIH-AARP co-
detect associations with colorectal cancer risk, but statisti- hort.45 Higher nitrite intakes from water (but not from
cal power was limited for this location and would need fur- food) were positively associated with bladder cancer risk in
ther investigation with longer follow-up. the Iowa Women’s Health Study.46 In the same cohort,
cohort, France,
Table 5 Associations between nitrite and nitrate exposures by sources and colorectal cancer risk, NutriNet-Sante
2009–2021 (N ¼ 101 056)
1 2 3
HR (95% CI) Ref. 1.00 (0.72–1.38) 1.03 (0.72–1.47) 0.8
HR (95% CI) Ref. 1.01 (0.73–1.39) 0.96 (0.67–1.38) 0.8
HR (95% CI) Ref. 0.99 (0.70–1.40) 1.22 (0.85–1.75) 0.1
HR (95% CI) Ref. 0.99 (0.70–1.40) 1.22 (0.85–1.75) 0.1

HR (95% CI) Ref. 0.95 (0.68–1.34) 1.03 (0.71–1.47) 0.8
HR (95% CI) Ref. 0.96 (0.68–1.35) 1.04 (0.72–1.49) 0.7
HR (95% CI) Ref. 1.15 (0.84–1.56) 1.26 (0.90–1.76) 0.2
HR (95% CI) Ref. 1.15 (0.85–1.56) 1.30 (0.93–1.82) 0.1

Multivariable Cox proportional hazard models were adjusted for: age (timescale), sex, energy intake without alcohol (kcal/d, continuous), alcohol, sugar, satu-
rated fatty acids and fibre intakes (g/d, continuous), sodium and heme iron intakes (mg/d, continuous), body mass index (kg/m2, continuous), height (cm, continu-
ous), physical activity (high, moderate, low, calculated according to International Physical Activity Questionnaire recommendations), smoking status (never,
former, current smokers), number of 24-h dietary records (continuous), family history of cancer (yes/no) and educational level (primary, secondary, undergradu-
ate, post-graduate). All models were mutually adjusted for nitrate/nitrite intakes other than the specific one studied.
a
Cut-offs were: 4.03 and 5.55 mg/d in women and 5.18 and 7.44 mg/d in men for overall nitrites, 150.09 and 233.89 mg/d in women and 162.11 and
251.59 mg/d in men for overall nitrates, 3.83 and 5.29 mg/d in women and 4.92 and 7.07 mg/d in men for nitrites from natural sources and 149.91 and
233.75 mg/d in women and 161.94 and 251.32 mg/d in men for nitrates from natural sources.
sex-specific median among consumers). Cut-offs were: 0.19 mg/d in women and 0.25 mg/d in men for nitrites from food additives, 0.36 mg/d in women and
0.46 mg/d in men for nitrates from food additives, 0.19 mg/d in women and 0.25 mg/d in men for sodium nitrite (e250) and 0.36 mg/d in women and 0.46 mg/d in
men for potassium nitrate (e252).
During overall follow-up, 142 competing deaths occurred. Cause-specific hazard ratios for death in the high consumers of total nitrites, nitrites from natural
sources, nitrites from food additives, sodium nitrite (e250), total nitrates, nitrates from natural sources, nitrates from food additives and potassium nitrate (e252)
were respectively: 0.65 (0.41–1.02), P ¼ 0.09; 0.58 (0.37–0.93), P ¼ 0.03; 1.17 (0.74–1.85), P ¼ 0.5; 1.15 (0.73–1.82), P ¼ 0.6; 0.99 (0.60–1.63), P ¼ 0.6; 1.05
(0.63–1.73), P ¼ 0.8; 0.93 (0.57–1.52), P ¼ 0.8; 0.94 (0.58–1.53), P ¼ 0.8.
higher nitrate intakes from water and higher nitrite intakes also result from exogenous exposure from nitrites (and
from processed meat were positively associated with renal nitrates, partly converted by the oral microbiota into
cancer among older women.47 Higher total nitrite intakes nitrites). NOCs are a potential human carcinogen and
were associated with increased esophageal squamous cell proven carcinogen in certain animal species.3,4,51
carcinoma in the Netherlands Cohort Study48 and higher Nitrosamines, a specific type of NOC, must be activated
nitrite intakes from processed meat were positively associ- by specific cytochrome P450 enzymes to be carcinogenic,1
ated with pancreatic cancer.49 which have been detected in many tissues including those
of the breast.52 Heme iron is found at high levels in red
meat and also enhances endogenous NOC formation,38
Mechanisms but it is unlikely that it may have driven the observed
The associations observed in this study are consistent with results since our models were adjusted for heme iron
experimental data on NOCs. These compounds could re- intakes and since no interaction was detected with this
sult from endogenous synthesis. Indeed, a high-red-meat compound.
diet led to the endogenous synthesis of NOCs in the colon In this study, only nitrites and nitrates as food additives
during an experiment on healthy volunteers.50 They can were associated with cancer risk, yet their contribution to
total nitrite/nitrate intakes were relatively low in compari- 91.1% in the INCA2 study (median 12.5 vs 28.6 g/d). It
son with natural sources. Since most natural nitrites and can be hypothesized that the associations observed in the
nitrates come from vegetables that are naturally rich in present study for nitrite/nitrate additives and cancer risk
antioxidants, it can be hypothesized that these antioxi- may be even stronger in the general population, with
dants—natural inhibitors of the formation of NOCs17— higher levels of exposure and increased contrast between
may have reduced the carcinogenic potential of nitrites and compared groups.
nitrates from these sources. This warrants confirmation in Second, the number of cases was limited for some can-
future experimental and epidemiological studies. cer locations, thus reducing the statistical power, which
could have impaired our ability to detect associations, par-
ticularly for colorectal cancer, and also prevented us from
Strengths and limitations studying other cancer locations.
Strengths of this study include its large sample size, its pro- Also, several socio-demographic and lifestyle character-

spective design and the detailed assessment of nitrites and istics were associated with the consumption of nitrites and
nitrates exposure from different sources. Indeed, repeated nitrates as food additives. These parameters were largely
24-h records allowed us to collect precise information on a accounted for in our multivariable statistical models but
wide range of foods containing nitrites and nitrates, with the possibility of residual confounding cannot entirely be
information about their source: natural presence or con- ruled out due to the observational design of this study.
tamination vs addition as food additives. As doses of food Finally, industrial products may be reformulated across
additives may vary according to brands for the same type time by choice of manufacturers or regulation require-
of product, commercial names/brands were collected and ments, thereby complicating the exposure assessment.
accounted for, which represents an important asset com- However, bias linked to this aspect was limited since the
pared with most nutritional studies worldwide. Three com- composition and consumption data were matched consid-
plementary databases were used to determine their ering the year (dynamic matching), accounting for different
qualitative additive composition and thousands of assays compositions of a same product/brand depending on its
were performed and complemented with EFSA and GSFA year of consumption.
data to retrieve information on quantitative doses.
However, some limitations must be acknowledged. First,
caution is needed in the generalizability of the findings Conclusion
since participants of the NutriNet-Sante cohort were more In this large prospective cohort, food additive nitrate
often women, with health conscious behaviours and higher intakes were positively associated with breast cancer risk
socio-professional and educational levels than the general (specifically pre-menopausal) and food additive nitrite
French population.53 This may have led to a greater con- intakes were positively associated with prostate cancer
sumption of fruit and vegetables and a lower consumption risk. Although similar HRs were observed for colorectal
of processed meat, which could explain that compared cancer, no association was detected in this study, maybe
with EFSA’s exposure simulations, natural nitrite and ni- due to limited statistical power. These results support pre-
trate intakes were higher in the NutriNet-Sante cohort, vious mechanistic data demonstrating that these preserva-
whereas the opposite trend was observed for nitrite and ni- tives may lead to the formation of NOCs, potential
trate additives. Indeed, in EFSA’s simulations (data from carcinogens in humans.3 Although these results need con-
the INCA2 nationally representative survey for France, firmation in other large-scale prospective studies and ex-
2006–2007), the total nitrite intake was 0.04 mg/kg of perimental research, they provide new insights in a context
body weight (BW)32 and total nitrate intake was 1.6 mg/kg of lively debate around the ban of nitrite and nitrate addi-
BW33 vs 0.09 and 3.34 mg/kg BW in the NutriNet-Sante tives in the food industry. At the individual/patient level,
cohort, respectively (data not tabulated). Conversely, several public health authorities worldwide recommend to
intakes from food additives were higher in EFSA’s simula- limit the consumption of foods containing controversial
tion compared with that of NutriNet-Sante: 0.01–0.04 mg/ additives in the name of the precautionary principle.54,55
kg BW for nitrites and 0.05–0.10 mg/kg BW for nitrates
(for all countries, as data specific to countries were not pre-
sented in the report) vs a mean of 0.004 mg/kg BW for Ethics approval
nitrites and 0.003 mg/kg BW for nitrates in the NutriNet-
The study is conducted according to the Declaration of Helsinki
Sante cohort. Also, when comparing processed meat guidelines and was approved by the Institutional Review Board of
intakes with the INCA2 study, the consumption rate of the French Institute for Health and Medical Research (IRB Inserm
processed meat was 26% in the NutriNet-Sante cohort vs no. 0000388FWA00005831), the Commission Nationale de
l’Informatique et des Libertes (CNIL no. 908450/no. 909216/no. interpretation of data, the writing of the report and the decision to
1460707) and the Consultation Committee for the Protection of submit the article for publication.
Participants in Biomedical Research (C09-42 on 5 May 2010).
Electronic informed consent was obtained from each participant. Acknowledgements
We thank Thi Hong Van Duong, Regis Gatibelza, Jagatjit Mohinder
and Aladi Timera (computer scientists); Julien Allegre, Nathalie
Data availability Arnault, Laurent Bourhis and Nicolas Dechamp (data-manager/sta-
Data described in the manuscript, code book and analytic code will tisticians); Sandrine Kamdem (health event validator); and Maria
be made available upon request pending application and approval. Gomes (Nutrinaute support) for their technical contribution to the
Researchers from public institutions can submit a collaboration re- NutriNet-Sante study. We also thank all the volunteers of the
quest including information on the institution and a brief descrip- NutriNet-Sante cohort.
tion of the project to collaboration@etude-nutrinet-sante.fr. All
requests will be reviewed by the steering committee of the NutriNet-
Sante study. A financial contribution may be requested. If the collab- Conflict of interest

oration is accepted, a data access agreement will be necessary and
F.P. received funding from the IFIP (French Pork Institute) for an-
appropriate authorizations from the competent administrative au-
other project dealing with experimental research on animal models
thorities may be needed. In accordance with existing regulations, no
(with no relationship to this epidemiological research). All other
personal data will be accessible.
authors have none declared. Where authors are identified as person-
nel of the International Agency for Research on Cancer/World
Health Organization, the authors alone are responsible for the views
Supplementary data expressed in this article and they do not necessarily represent the
Supplementary data are available at IJE online. decisions, policy or views of the International Agency for Research
on Cancer/World Health Organization. Study registration:
NutriNet-Sante cohort: clinicaltrials.gov (NCT03335644).
Author contributions
The authors’ contributions were as follows. E.C., N.D.P., Y.E.,
References
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IEA

International Journal of Epidemiology, 2022, 1106–1119

Diet and Food Additives

Nitrites and nitrates from food additives and

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additive nitrites were positively associated with prostate cancer risk.

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 cohort, France, 2009–2021 (N ¼ 101 056)

Characteristics All participants Categories of nitrite intakes from food additivesa

Non-consumers Low consumers High consumers Ptrend

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Values are n (%) unless stated otherwise.

Exposure Sex-specific categories of intakesa Ptrend

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HR, cause-specific hazard ratio.

Exposure Sex-specific categories of intakesa Ptrend

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HR, cause-specific hazard ratio.

Exposure Sex-specific categories of intakesa Ptrend

Total nitrites N cases/N total 95/7258 169/7257 136/7257

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HR, cause-specific hazard ratio.

Exposure Sex-specific categories of intakesa Ptrend

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HR, cause-specific hazard ratio.

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cohort, France, 2009–2021 (N ¼ 101 056)