Food additives in childhood: a review on consumption and health consequences

Mariana Vieira dos Santos Kraemer Ana Carolina Fernandes Maria Cecília Cury Chaddad Paula Lazzarin Uggioni Vanessa Mello Rodrigues Greyce Luci Bernardo Rossana Pacheco da Costa Proença About the authors

ABSTRACT

OBJECTIVE

To discuss the context of scientific publications on the consumption of food additives by children and the possible health consequences in this age group.

METHODS

A literature review, with a search carried out between April 2020 and April 2021 in the Web of Science, Scopus, PubMed and Google Scholar databases, as well as in websites of Brazilian and foreign official bodies. Official documents and studies published since 2000 were selected. Keywords related to food additives, children, food consumption, and health were used for the search.

RESULTS

Food additives are substances intentionally added to foods for technological purposes. Processed foods are the main sources of additives in food and their consumption occurs since childhood. It is observed, however, that there are limitations inherent to the scientific method regarding the analysis of consumption and toxicity of food additives in humans, causing scarcity of data in the scientific literature. Additionally, existing data suggest that the additives have a higher toxic potential in children, considering that the body weight in this age group is lower than in adults. This context emphasizes the need to observe the precautionary principle, according to which risks of harm must be prevented.

CONCLUSIONS

This is a scenario in which the literature points to a risk to people’s health and, in particular, to children, about whom the duty of protection must be even greater, with absolute priority. Thus, the relevance of an expanded technical-scientific debate regarding the establishment of specific and stricter parameters for children is considered, regarding the consumption and toxicity of additives, as well as the different sources of exposure to these substances.

Child Nutrition; Eating; Industrialized Foods; Food Additives, toxicity; Review

INTRODUCTION

Studies indicate, in Brazil and other countries, an increase in the purchase of processed foods for consumption from the first months of life11. Vandevijvere S, Jaacks LM, Monteiro CA, Moubarac JC, Girling-Butcher M, Lee AC, et al. Global trends in ultraprocessed food and drink product sales and their association with adult body mass index trajectories. Obes Rev. 2019;20 Suppl 2:10-19. https://doi.org/10.1111/obr.12860
https://doi.org/10.1111/obr.12860...
,22. Karnopp EVN, Vaz JS, Schafer AA, Muniz LC, Souza RLV, Santos I, et al. Food consumption of children younger than 6 years according to the degree of food processing. J Pediatr. 2017;93(1):70-8. https://doi.org/10.1016/j.jped.2016.04.007
https://doi.org/10.1016/j.jped.2016.04.0...
, especially those classified as ultra-processedaaPart of the so-called NOVA classification of foods. Ultra-processed foods are usually made from multiple ingredients. These foods may contain ingredients extracted from other foods (casein, gluten, etc.) or derived from other foods (maltodextrin, invert sugar, hydrogenated oils, etc.). In addition, food additives such as dyes, sweeteners, stabilizers, flavor enhancers, among others, are used intensively.,33. Popkin BM. Global nutrition dynamics: the world is shifting rapidly toward a diet linked with noncommunicable diseases. Am J Clin Nutr. 2006;84(2):289-98. https://doi.org/10.1093/ajcn/84.1.289
https://doi.org/10.1093/ajcn/84.1.289...
. In Brazil, soft drinks, industrialized fruit-based drinks (in long-life or powdered packaging), snacks, sweets, chocolates, sausages, breads and cookies are among the most consumed foods by children77. Assis MAA, Calvo MCM, Kupek E, Vasconcelos FAG, Campos VC, Machado M, et al. Qualitative analysis of the diet of a probabilistic sample of schoolchildren from Florianópolis, Santa Catarina State, Brazil, using the Previous Day Food Questionnaire. Cad Saude Publica. 2010;26(7):1355-65. https://doi.org/10.1590/s0102-311x2010000700014
https://doi.org/10.1590/s0102-311x201000...
. These foods usually contain significant amounts of sugar, fat and sodium1717. Reedy J, Krebs-Smith SM. Dietary sources of energy, solid fats, and added sugars among children and adolescents in the United States. J Am Diet Assoc. 2010;110(10):1477-84. https://doi.org/10.1016/j.jada.2010.07.010
https://doi.org/10.1016/j.jada.2010.07.0...
, and many of them contain food additives2222. Lorenzoni ASG, Cladera-Olivera F. Food additives in products for children marketed in Brazil. Food Public Health. 2012;2(5):131-6. https://doi.org/10.5923/j.fph.20120205.03
https://doi.org/10.5923/j.fph.20120205.0...
, in addition to their packaging often featuring marketing strategies aimed at children2525. Rodrigues VM, Rayner M, Fernandes AC, Oliveira RC, Proença RPC, Fiates GMR. Comparison of the nutritional content of products, with and without nutrient claims, targeted at children in Brazil. Br J Nutr. 2016;115(11):2047-56. https://doi.org/10.1017/S0007114516001021
https://doi.org/10.1017/S000711451600102...
.

These additives are not normally consumed as food or used as a typical food ingredient and are intentionally added for technological purposes2626. Food and Agriculture Organization of the United Nations; World Health Organization. Codex Alimentarius: general standard for food additives. Rome (IT); FAO; 1995 [cited 2021 Apr 10]. Available from: http://www.fao.org/fao-who-codexalimentarius/sh-proxy/en/?lnk=1&url=https%253A%252F%252Fworkspace.fao.org%252Fsites%252Fcodex%252FStandards%252FCXS%2B192-1995%252FCXS_192e.pdf
http://www.fao.org/fao-who-codexalimenta...
,2727. Ministério da Saúde (BR), Secretaria de Vigilância Sanitária. Portaria Nº 540, de 27 de outubro de 1997. Aprova o Regulamento técnico Aditivos Alimentares - definições, classificação e emprego. Diário Oficial da União. 28 out 1997; Poder Executivo.. Criteria for the ingestion and use of additives in processed foods are established worldwide by the Codex Alimentarius, a program of the United Nations Food and Agriculture Organization (FAO) and the World Health Organization (WHO), which develops standards and guidelines related to foods and establishes criteria for the ingestion and use of additives in processed foods, through the assistance of an International Scientific Committee, formed by specialists from different countries, called the Joint FAO/WHO Expert Committee on Food Additives (JECFA)2323. Teixeira AZA. Sodium content and food additives in major brands of Brazilian children’s foods. Cienc Saude Colet. 2018;23(12):4065-75. https://doi.org/10.1590/1413-812320182312.21812016
https://doi.org/10.1590/1413-81232018231...
.

The expert committee of FAO/WHO (JECFA) analyzes and discusses data from scientific studies on toxicity and safety of additives and, based on these data, the Committee establishes two values for each food additive, designated by the acronyms NOAEL and ADI. NOAEL, acronym for No Observed Adverse Effect Level, is the limit amount in which each substance did not show toxic effects in existing studies in the scientific literature. From the NOAEL value, the acceptable daily intake (ADI) is stipulated, the estimated amount in which a substance can be consumed daily, throughout life, without presenting health risks. This value is calculated by dividing the NOAEL value by a safety/uncertainty coefficient, stipulated at 100, which has the purpose of covering potential uncertainties regarding scientific data2323. Teixeira AZA. Sodium content and food additives in major brands of Brazilian children’s foods. Cienc Saude Colet. 2018;23(12):4065-75. https://doi.org/10.1590/1413-812320182312.21812016
https://doi.org/10.1590/1413-81232018231...
. That is, it considers possible differences between animal and human models, as well as between sex and age groups, such as different toxicities for children and adults, for example2828. Tomaska LD, Brooke-Taylor S. Food Additives – general. In: Montarjemi Y, Moy G, Todd E, editors. Encyclopedia of Food Safety. Vol 2. Cambridge, Mass: Academic Press; 2014. p.449-54. https://doi.org/10.1016/B978-0-12-378612-8.00234-1
https://doi.org/10.1016/B978-0-12-378612...
. Thus, the ADI recommended by the Codex Alimentarius is, on average, 100 times lower than the amount found to be safe or of low toxicity in scientific studies.

However, there are limitations in assessing the safety of consumption of additives in humans. This is because most studies are performed in animal models or in vitro. Authors emphasize that substances react in different ways according to the cellular characteristics of each organism2929. Dybing E, Doe J, Groten J, Kleiner J, O’Brien J, Renwick AG, et al. Hazard characterization of chemicals in food and diet: dose response, mechanisms and extrapolation issues. Food Chem Toxicol. 2002;40(2-3):237-82. https://doi.org/10.1016/s0278-6915(01)00115-6
https://doi.org/10.1016/s0278-6915(01)00...
. Moreover, foods are considered complex mixtures of chemical substances, in which different elements, of different molecular weights and chemical configurations, interact with each other and with the organism that ingests them2929. Dybing E, Doe J, Groten J, Kleiner J, O’Brien J, Renwick AG, et al. Hazard characterization of chemicals in food and diet: dose response, mechanisms and extrapolation issues. Food Chem Toxicol. 2002;40(2-3):237-82. https://doi.org/10.1016/s0278-6915(01)00115-6
https://doi.org/10.1016/s0278-6915(01)00...
. The level of exposure and individual sensitivity are determining factors to assess whether substances such as additives have toxic potential3030. Renwick AG, Barlow SM, Hertz-Picciotto I, Boobis AR, Dybing E, Edler L, et al. Risk characterization of chemicals in food and diet. Food Chem Toxicol. 2003;41(9):1211-71. https://doi.org/10.1016/s0278-6915(03)00064-4
https://doi.org/10.1016/s0278-6915(03)00...
.

Since the ADI is established per kilogram of weight, the toxicity of additives may be greater in children. Considering their body weight, children drink more water, eat more food and breathe more air than adults. In the first six months of life, children drink seven times more water per kg of body weight and, aged between one and five years, they eat three to four times more food per kg of body weight than the average adult3131. World Health Organization. Children’s health and the environment: a global perspective: a resource manual for the health sector. Geneva (CH): WHO; 2005. 367p.. Furthermore, as they potentially have more years of future life than adults, children have more time to develop chronic diseases triggered by early exposure to environmental substances3131. World Health Organization. Children’s health and the environment: a global perspective: a resource manual for the health sector. Geneva (CH): WHO; 2005. 367p.,3232. Landrigan PJ, Trasande L, Thorpe LE, Gwynn C, Lioy PJ, D’Alton ME, et al. The National Children’s Study: a 21-year prospective study of 100,000 American children. Pediatrics. 2006;118(5):2173- 86. https://doi.org/10.1542/peds.2006-0360
https://doi.org/10.1542/peds.2006-0360...
, such as food additives.

It is observed, however, that there are few experimental studies in the scientific literature that evaluate the toxicity of food additives in humans, both in adults and in children, which leads to the need to observe the precautionary principle, according to which the risks of damage must be prevented. This principle, under Brazilian legislation, is based on article 196 of the Constitution, which imposes on the State the duty to guarantee public policies aimed at reducing the risk of disease, in addition to actions and services for the promotion, protection and recovery of health3333. Brasil, Constituição (1988). Constituição da República Federativa do Brasil de 1988. Brasília, DF: Senado Federal; 1988.. Also implicit in article 9 of the Consumer Protection Code is the duty to provide information about products that are potentially harmful or dangerous to the health or safety of consumers3434. Brasil. Lei Nº 8.078, de 11 de setembro de 1990. Dispõe sobre a proteção do consumidor e dá outras providências. Diário Oficial da União. 12 set 1990.,3535. Hartmann IAM. O princípio da precaução e sua aplicação no direito do consumidor: dever de informação. Direito Justiça. 2012 [cited 2021 Jul 9];38(2). Available from: https://revistaseletronicas.pucrs.br/ojs/index.php/fadir/article/view/12542
https://revistaseletronicas.pucrs.br/ojs...
, since access to information is a condition for the conscious exercise of choice by consumers3636. Chaddad MCC. Rotulagem de alimentos: o direito à informação, à proteção da saúde e à alimentação adequada da população com alergia alimentar. Curitiba, PR: Juruá; 2014.. The issue is particularly relevant given the duty of the State, the family and society to ensure children and adolescents, with absolute priority, the right to life, health, food, etc. as recommended by article 227 of the Brazilian Constitution3333. Brasil, Constituição (1988). Constituição da República Federativa do Brasil de 1988. Brasília, DF: Senado Federal; 1988..

In view of the above, no review studies were found that seek to discuss the methodological challenges involved in research with humans on the consumption of food additives and health effects in children. Thus, the objective of this article is to discuss the context of scientific publications on the consumption of food additives by children and the possible consequences of this consumption for health in this age group.

METHODS

A narrative review of the literature was carried out, which began with bibliographic searches in the Web of Science, Scopus, PubMed and Google Scholar databases, as well as websites of Brazilian and foreign official bodies, between April 2020 and April 2021. Figure 1 shows the search strategy and the sets of keywords.

Figure 1
Keyword sets and search strategy.

Studies published from the year 2000 onwards, as well as official documents on the consumption of food additives by children and their health consequences, were selected and analyzed. In addition, the documents of recommendations and regulations on the intake and use of additives in processed foods were used.

RESULTS AND DISCUSSION

Consumption of Food Additives in Childhood

Several methodologies can be used to estimate the consumption of food additives, combining methods of evaluation of food consumption and measurement of food additives content.

Considering food consumption, studies usually use data from population surveys or apply food consumption assessment methods, especially a 24-hour recall, food record and food frequency questionnaire. Based on these data, it is possible to estimate which foods were consumed by individuals and thereby analyze which additives were present in these foods3737. Jain A, Mathur P. Estimation of food additive intake: overview of the methodology. Food Rev Int. 2015;31(4):355-84. https://doi.org/10.1080/87559129.2015.1022830
https://doi.org/10.1080/87559129.2015.10...
.

As information on the number of additives is not available on food labels, some studies use laboratory analysis for quantification of additives added to foods, with the liquid chromatography technique3838. Choi SH, Suh HJ. Determination and estimation of daily nitrite intake from processed meats in Korea. J Consum Prot Food Saf. 2017;12(1):15-22. https://doi.org/10.1007/s00003-016-1075-8
https://doi.org/10.1007/s00003-016-1075-...
,3939. Long NH, Hao LTH, Trang VT, Son TC, Hung LQ. Assessing dietary risks caused by food additives: a case study of total diet in Vietnam. Health Risk Anal. 2019;2:74-82. https://doi.org/10.21668/health.risk/2019.2.08.eng
https://doi.org/10.21668/health.risk/201...
being the most accurate. Other studies infer this amount assuming that the maximum value allowed for each additive was added to the food, as stipulated by the Codex Alimentarius (maximum limit) or by the regulatory agencies of the countries. This inference has more limitations, since there is no precision in determining the values and it is not possible to know if the industry used the limit amount allowed, underestimating or overestimating the amount of additive present in the food.

A review study3737. Jain A, Mathur P. Estimation of food additive intake: overview of the methodology. Food Rev Int. 2015;31(4):355-84. https://doi.org/10.1080/87559129.2015.1022830
https://doi.org/10.1080/87559129.2015.10...
investigated the methodologies used to assess the consumption of additives in the world between 2000 and 2014. Data on the consumption of food additives in all age groups were also analyzed. The studies found focused on four classes of additives: antioxidants, sweeteners, color and preservatives. The quantification of additives in food was performed in two ways: laboratory analysis, usually by liquid chromatography, and content estimation using the maximum permitted limits, with the first methodology being the most frequent in the studies. Food consumption was obtained through population surveys by most studies, the rest used 24-hour recalls and food frequency questionnaires.

The review evaluated 13 studies carried out in nine countries, most of them located in Europe and Asia, which analyzed, primarily in the adult population, the consumption of the sweeteners saccharin, sucralose, aspartame, stevia, acesulfame and cyclamate. Only one study conducted in Canada focused on the consumption of sweeteners by children, which was not higher than the ADI. Six studies analyzed the consumption of sweeteners in different age groups, including children. Of these, a study carried out in India found saccharin consumption values above the ADI by children and adults3737. Jain A, Mathur P. Estimation of food additive intake: overview of the methodology. Food Rev Int. 2015;31(4):355-84. https://doi.org/10.1080/87559129.2015.1022830
https://doi.org/10.1080/87559129.2015.10...
. No studies found consumption of additives above the ADI of the antioxidants BHAbbAcronym for buthylated hydroxyanisole (buthylated hydroxyanisole), BHTccAcronym for butylated hydroxytoluene (butylated hydroxytoluene), and TBHQddAcronym for tertiary butylhydroquinone (tertiary butylhydroquinone).

In 18 studies, the consumption of colors, especially tartrazine, sunset yellow, erythrosine and carmoisine, was analyzed. Seven studies carried out in India, one study in Kuwait and one in Thailand found consumption values above the ADI for children. Finally, when analyzing preservatives such as benzoic acid, sorbic acid, sulfites, nitrites and nitrates, the 41 studies conducted in 26 countries found that, on average, the ADI is not exceeded. However, in the highest consumption cases (90th and 95th percentiles), the intake exceeded the ADI, especially by children. Among the conclusions, the authors point out the importance and the need for countries to have mechanisms for monitoring the content of additives used in processed foods3737. Jain A, Mathur P. Estimation of food additive intake: overview of the methodology. Food Rev Int. 2015;31(4):355-84. https://doi.org/10.1080/87559129.2015.1022830
https://doi.org/10.1080/87559129.2015.10...
.

It is observed in this review study that the consumption of additives by children can exceed the ADI values, especially for colors and preservatives3737. Jain A, Mathur P. Estimation of food additive intake: overview of the methodology. Food Rev Int. 2015;31(4):355-84. https://doi.org/10.1080/87559129.2015.1022830
https://doi.org/10.1080/87559129.2015.10...
. Remember that these values are stipulated by amount of additive per kilogram of weight. Therefore, it is noteworthy that these parameters can be more harmful to the health of children than adults, in view of the physical and biological factors already discussed. The document General Standard on Food Additives by FAO and WHO2626. Food and Agriculture Organization of the United Nations; World Health Organization. Codex Alimentarius: general standard for food additives. Rome (IT); FAO; 1995 [cited 2021 Apr 10]. Available from: http://www.fao.org/fao-who-codexalimentarius/sh-proxy/en/?lnk=1&url=https%253A%252F%252Fworkspace.fao.org%252Fsites%252Fcodex%252FStandards%252FCXS%2B192-1995%252FCXS_192e.pdf
http://www.fao.org/fao-who-codexalimenta...
, the main recommendation on the subject worldwide, does not provide the value per kilogram of weight to be considered as a basis for calculating the maximum limit. Thus, it is not clear if the amounts considered safe for the addition of additives in food consider the child’s weight and if they are really safe for children to consume.

Official data from the United States show that the use of artificial colors increased, on average, fivefold between 1950 and 2012, from 12 mg to 68 mg per capita per day4040. Trasande L, Shaffer RM, Sathyanarayana S. Food additives and child health. Pediatrics. 2018;142(2):e20181408. https://doi.org/10.1542/peds.2018-1408
https://doi.org/10.1542/peds.2018-1408...
. In Brazil, authors analyzed in the laboratory the amount of artificial colors present in four types of food: candy, chewing gum, chocolate confectionery and breakfast cereals and the results showed that the colors tartrazine and sunset yellow were the most used. Candies and chocolate confectionery presented amounts of coloring within the permitted range. However, 33% of the chewing gums had amounts of artificial coloring above those allowed by Brazilian Health Regulatory Agency (Anvisa), and one of the brands exceeded fivefold the maximum stipulated limit. On the other hand, all samples of breakfast cereals analyzed showed amounts above those allowed for artificial coloring4141. Prado MA, Godoy HT. Teores de corantes artificiais em alimentos determinados por cromatografia líquida de alta eficiência. Quim Nova. 2007;30(2):268-73. https://doi.org/10.1590/S0100-40422007000200005
https://doi.org/10.1590/S0100-4042200700...
. It is noteworthy that the analyzed foods are often consumed by the population since childhood. In addition, artificial colors, especially sunset yellow and tartrazine, are the target of toxicological studies that relate them to the development of allergy and hyperactivity symptoms in children4242. Schab DW, Trinh NHT. Do artificial food colors promote hyperactivity in children with hyperactive syndromes? A meta-analysis of double-blind placebo-controlled trials. J Dev Behav Pediatr. 2004;25(6):423-34. https://doi.org/10.1097/00004703-200412000-00007
https://doi.org/10.1097/00004703-2004120...
.

In addition, the risk from the cumulative consumption of additives, arising from different types of food ingested throughout the day, is questioned. Using the foods analyzed by the study4141. Prado MA, Godoy HT. Teores de corantes artificiais em alimentos determinados por cromatografia líquida de alta eficiência. Quim Nova. 2007;30(2):268-73. https://doi.org/10.1590/S0100-40422007000200005
https://doi.org/10.1590/S0100-4042200700...
as an example, it is possible to infer that the risk of toxicity by colors seems to be high when a child consumes a breakfast cereal and one or more chewing gums during the day. Considering the other foods consumed each day and the other food additives ingested, the risk of toxicity becomes greater.

In this sense, it is reinforced that children are more vulnerable to the consumption of food additives. As evidenced by the review study3737. Jain A, Mathur P. Estimation of food additive intake: overview of the methodology. Food Rev Int. 2015;31(4):355-84. https://doi.org/10.1080/87559129.2015.1022830
https://doi.org/10.1080/87559129.2015.10...
, the results on the consumption of food additives differ considerably, depending on the country, the substance analyzed and the methodology used. However, when analyzing the consumption of additives by children, the ADI values are often exceeded.

Box 1 presents the main results of studies found that evaluated the consumption of food additives by children.

Box 1
Studies that evaluated the consumption of food additives by children, in chronological order.

We found 22 studies, carried out in 21 countries, that analyzed the consumption of six functional classes of additives by children: colors, preservatives, sweeteners, antioxidants, emulsifiers and stabilizers. It is noteworthy that the colors, especially sunset yellow and tartrazine, were the most studied. In sixteen studies, at least one additive had consumption estimated to be above the safety limits, of the following functional classes: colors1414. Polônio MLT, Peres F. Consumo de corantes artificiais por pré-escolares de um município da baixada fluminense, RJ. Rev Pesq Cuid Fundam. 2012 [cited 2021 Apr 15];4(1):2748-57. Available from: http://www.seer.unirio.br/index.php/cuidadofundamental/article/view/1609/pdf_487
http://www.seer.unirio.br/index.php/cuid...
, preservatives3939. Long NH, Hao LTH, Trang VT, Son TC, Hung LQ. Assessing dietary risks caused by food additives: a case study of total diet in Vietnam. Health Risk Anal. 2019;2:74-82. https://doi.org/10.21668/health.risk/2019.2.08.eng
https://doi.org/10.21668/health.risk/201...
,4949. Larsson K, Darnerud PO, Ilback NG, Merino L. Estimated dietary intake of nitrite and nitrate in Swedish children. Food Addit Contam Part A Chem Anal Control Expo Risk Assess. 2011;28(5):659-66. https://doi.org/10.1080/19440049.2011.555842
https://doi.org/10.1080/19440049.2011.55...
,5454. Mancini FR, Paul D, Gauvreau J, Volatier JL, Vin K, Hulin M. Dietary exposure to benzoates (E210-E213), parabens (E214-E219), nitrites (E249-E250), nitrates (E251-E252), BHA (E320), BHT (E321) and aspartame (E951) in children less than 3 years old in France. Food Addit Contam Part A Chem Anal Control Expo Risk Assess. 2015;32(3):293-306. https://doi.org/10.1080/19440049.2015.1007535
https://doi.org/10.1080/19440049.2015.10...
,6161. Martyn D, Lau D, Darch M, Roberts A. Benzoates intakes from non-alcoholic beverages in Brazil, Canada, Mexico and the United States. Food Addit Contam Part A Chem Anal Control Expo Risk Assess. 2017;34(9):1485-99. https://doi.org/10.1080/19440049.2017.1338836
https://doi.org/10.1080/19440049.2017.13...
, antioxidants5151. Urtiaga C, Amiano P, Azpiri M, Alonso A, Dorronsoro M. Estimate of dietary exposure to sulphites in child and adult populations in the Basque Country. Food Addit Contam Part A Chem Anal Control Expo Risk Assess. 2013;30(12):2035-42. https://doi.org/10.1080/19440049.2013.840930
https://doi.org/10.1080/19440049.2013.84...
,5252. Vin K, Connolly A, McCaffrey T, McKevitt A, O’Mahony C, Prieto M, et al. Estimation of the dietary intake of 13 priority additives in France, Italy, the UK and Ireland as part of the FACET project. Food Addit Contam Part A Chem Anal Control Expo Risk Assess. 2013;30(12):2050-80. https://doi.org/10.1080/19440049.2013.851417
https://doi.org/10.1080/19440049.2013.85...
,5454. Mancini FR, Paul D, Gauvreau J, Volatier JL, Vin K, Hulin M. Dietary exposure to benzoates (E210-E213), parabens (E214-E219), nitrites (E249-E250), nitrates (E251-E252), BHA (E320), BHT (E321) and aspartame (E951) in children less than 3 years old in France. Food Addit Contam Part A Chem Anal Control Expo Risk Assess. 2015;32(3):293-306. https://doi.org/10.1080/19440049.2015.1007535
https://doi.org/10.1080/19440049.2015.10...
, emulsifiers6262. Bel S, Struyf T, Fierens T, Jacobs G, Vynks C, Bellemans M. Dietary exposure of the Belgian population to emulsifiers E481 (sodium stearoyl-2-lactylate) and E482 (calcium stearoyl-2-lactylate). Food Addit Contam Part A Chem Anal Control Expo Risk Assess. 2018;35(5):828-37. https://doi.org/10.1080/19440049.2018.1435911
https://doi.org/10.1080/19440049.2018.14...
and sweeteners6363. Garavaglia MB, García VR, Zapata ME, Rovirosa A, González V, Marcó FF, et al. Non-nutritive sweeteners: children and adolescent consumption and food sources. Arch Argent Pediatr. 2018;116(3):186-91. https://doi.org/10.5546/aap.2018.eng.186
https://doi.org/10.5546/aap.2018.eng.186...
.

In 13 studies, food consumption was analyzed through previously collected population surveys. Official government data, food frequency questionnaire, 24-hour recall and purchase information in supermarket chains were also used. In 10 studies the additives were quantified through laboratory analysis and the rest inferred the amounts by the maximum limit allowed (seven studies) and information provided by the industry (five studies).

Four studies were found in Brazil: one on preservatives (benzoates) and three on colors. Martyn et al.6161. Martyn D, Lau D, Darch M, Roberts A. Benzoates intakes from non-alcoholic beverages in Brazil, Canada, Mexico and the United States. Food Addit Contam Part A Chem Anal Control Expo Risk Assess. 2017;34(9):1485-99. https://doi.org/10.1080/19440049.2017.1338836
https://doi.org/10.1080/19440049.2017.13...
(2017) used consumption data from the 2008/2009 Family Budget Survey (POF) of the Brazilian Institute of Geography and Statistics (IBGE), with 34,003 individuals over 10 years of age, and did not identify values above the ADI for benzoates, quantified from contact with manufacturers. However, Schumann et al.4646. Schumann SPA, Polônio MLT, Gonçalves ECBA. Avaliação do consumo de corantes artificiais por lactentes, pré-escolares e escolares. Food Sci Technol. 2008;28(3):534-9. https://doi.org/10.1590/S0101-20612008000300005
https://doi.org/10.1590/S0101-2061200800...
(2008), Polônio and Peres1414. Polônio MLT, Peres F. Consumo de corantes artificiais por pré-escolares de um município da baixada fluminense, RJ. Rev Pesq Cuid Fundam. 2012 [cited 2021 Apr 15];4(1):2748-57. Available from: http://www.seer.unirio.br/index.php/cuidadofundamental/article/view/1609/pdf_487
http://www.seer.unirio.br/index.php/cuid...
(2012), as well as Feitosa et al.5858. Feitosa LCA, Rodrigues PS, Silva AS, Rios AO, Cladera-Olivera F. Estimate of the theoretical maximum daily intake of Sunset Yellow FCF by the Brazilian population. Food Addit Contam Part A Chem Anal Control Expo Risk Assess. 2017;34(5):687-94. https://doi.org/10.1080/19440049.2017.1290829
https://doi.org/10.1080/19440049.2017.12...
(2017), found consumption values above the ADI for the sunset yellow, burgundy red, and amaranth colors. These three studies estimated the amount of food additives using the maximum allowable limits. However, while Schumann et al.4646. Schumann SPA, Polônio MLT, Gonçalves ECBA. Avaliação do consumo de corantes artificiais por lactentes, pré-escolares e escolares. Food Sci Technol. 2008;28(3):534-9. https://doi.org/10.1590/S0101-20612008000300005
https://doi.org/10.1590/S0101-2061200800...
(2008) and Polônio and Peres1414. Polônio MLT, Peres F. Consumo de corantes artificiais por pré-escolares de um município da baixada fluminense, RJ. Rev Pesq Cuid Fundam. 2012 [cited 2021 Apr 15];4(1):2748-57. Available from: http://www.seer.unirio.br/index.php/cuidadofundamental/article/view/1609/pdf_487
http://www.seer.unirio.br/index.php/cuid...
(2012) administered a food frequency questionnaire to the participating children, Feitosa et al.5858. Feitosa LCA, Rodrigues PS, Silva AS, Rios AO, Cladera-Olivera F. Estimate of the theoretical maximum daily intake of Sunset Yellow FCF by the Brazilian population. Food Addit Contam Part A Chem Anal Control Expo Risk Assess. 2017;34(5):687-94. https://doi.org/10.1080/19440049.2017.1290829
https://doi.org/10.1080/19440049.2017.12...
(2017) used consumption data from the 2008/2009 POF/IBGE.

As in Brazil, the consumption of colors seems to exceed the ADI in Kuwait4545. Husain A, Sawaya W, Al-Omair A, Al-Zenki S, Al-Amiri H, Ahmed N, et al. Estimates of dietary exposure of children to artificial food colours in Kuwait. Food Addit Contam. 2007;23(3):245-51. https://doi.org/10.1080/02652030500429125
https://doi.org/10.1080/0265203050042912...
, Switzerland4747. Sardi M, Haldemann Y, Nordmann H, Bottex B, Safford B, Smith B, et al. Use of retailer fidelity card schemes in the assessment of food additive intake: Sunset Yellow a case study. Food Addit Contam Part A Chem Anal Control Expo Risk Assess. 2010;27(11):1507-15. https://doi.org/10.1080/19440049.2010.495728
https://doi.org/10.1080/19440049.2010.49...
, India4848. Dixit S, Purshottam SK, Khanna SK, Das M. Usage pattern of synthetic food colours in different states of India and exposure assessment through commodities preferentially consumed by children. Food Addit Contam Part A Chem Anal Control Expo Risk Assess. 2011;28(8):996-1005. https://doi.org/10.1080/19440049.2011.580011
https://doi.org/10.1080/19440049.2011.58...
, China5050. Lok KYW, Chung YW, Benzie IFF, Woo J. Synthetic colourings of some snack foods consumed by primary school children aged 8-9 years in Hong Kong. Food Addit Contam Part B Surveill. 2011;4(3):162-7. https://doi.org/10.1080/19393210.2011.585246
https://doi.org/10.1080/19393210.2011.58...
and Germany5353. Diouf F, Berg K, Ptok S, Lindtner O, Heinemeyer G, Heseker H. German database on the occurrence of food additives: application for intake estimation of five food colours for toddlers and children. Food Addit Contam Part A Chem Anal Control Expo Risk Assess. 2014;31(2):197-206. https://doi.org/10.1080/19440049.2013.865146
https://doi.org/10.1080/19440049.2013.86...
. In the analysis of preservatives consumption, the results indicate consumption both above and below the ADI. Unlike Brazil6161. Martyn D, Lau D, Darch M, Roberts A. Benzoates intakes from non-alcoholic beverages in Brazil, Canada, Mexico and the United States. Food Addit Contam Part A Chem Anal Control Expo Risk Assess. 2017;34(9):1485-99. https://doi.org/10.1080/19440049.2017.1338836
https://doi.org/10.1080/19440049.2017.13...
, in Vietnam3939. Long NH, Hao LTH, Trang VT, Son TC, Hung LQ. Assessing dietary risks caused by food additives: a case study of total diet in Vietnam. Health Risk Anal. 2019;2:74-82. https://doi.org/10.21668/health.risk/2019.2.08.eng
https://doi.org/10.21668/health.risk/201...
, Canada6161. Martyn D, Lau D, Darch M, Roberts A. Benzoates intakes from non-alcoholic beverages in Brazil, Canada, Mexico and the United States. Food Addit Contam Part A Chem Anal Control Expo Risk Assess. 2017;34(9):1485-99. https://doi.org/10.1080/19440049.2017.1338836
https://doi.org/10.1080/19440049.2017.13...
, Mexico6161. Martyn D, Lau D, Darch M, Roberts A. Benzoates intakes from non-alcoholic beverages in Brazil, Canada, Mexico and the United States. Food Addit Contam Part A Chem Anal Control Expo Risk Assess. 2017;34(9):1485-99. https://doi.org/10.1080/19440049.2017.1338836
https://doi.org/10.1080/19440049.2017.13...
and France5454. Mancini FR, Paul D, Gauvreau J, Volatier JL, Vin K, Hulin M. Dietary exposure to benzoates (E210-E213), parabens (E214-E219), nitrites (E249-E250), nitrates (E251-E252), BHA (E320), BHT (E321) and aspartame (E951) in children less than 3 years old in France. Food Addit Contam Part A Chem Anal Control Expo Risk Assess. 2015;32(3):293-306. https://doi.org/10.1080/19440049.2015.1007535
https://doi.org/10.1080/19440049.2015.10...
the consumption of preservatives exceeded the ADI. Regarding the other classes of additives studied, there is evidence of possible excessive consumption of antioxidants5151. Urtiaga C, Amiano P, Azpiri M, Alonso A, Dorronsoro M. Estimate of dietary exposure to sulphites in child and adult populations in the Basque Country. Food Addit Contam Part A Chem Anal Control Expo Risk Assess. 2013;30(12):2035-42. https://doi.org/10.1080/19440049.2013.840930
https://doi.org/10.1080/19440049.2013.84...
,5454. Mancini FR, Paul D, Gauvreau J, Volatier JL, Vin K, Hulin M. Dietary exposure to benzoates (E210-E213), parabens (E214-E219), nitrites (E249-E250), nitrates (E251-E252), BHA (E320), BHT (E321) and aspartame (E951) in children less than 3 years old in France. Food Addit Contam Part A Chem Anal Control Expo Risk Assess. 2015;32(3):293-306. https://doi.org/10.1080/19440049.2015.1007535
https://doi.org/10.1080/19440049.2015.10...
and emulsifiers6262. Bel S, Struyf T, Fierens T, Jacobs G, Vynks C, Bellemans M. Dietary exposure of the Belgian population to emulsifiers E481 (sodium stearoyl-2-lactylate) and E482 (calcium stearoyl-2-lactylate). Food Addit Contam Part A Chem Anal Control Expo Risk Assess. 2018;35(5):828-37. https://doi.org/10.1080/19440049.2018.1435911
https://doi.org/10.1080/19440049.2018.14...
by children.

Based on the data available in the scientific literature, summarized in Box 1, a possible high consumption of additives in childhood is highlighted, according to the ADI values stipulated by the Codex Alimentarius, especially for colors. Additionally, it is noteworthy that no article was found that analyzed the cumulative consumption by children of different additives over time. This gap in the scientific literature is relevant, given that, throughout each day, individuals consume multiple servings of different types of food that can potentially be sources of different additives.

Corroborating this statement, one of the objectives of the NutriNet-Santé cohort study, carried out in France with 106,000 adults, was to describe the exposure profiles to different additives by the population (one additive or mixtures of different types of additives). Five groups were found, composed of different foods. The first group comprises additives found in cookies and cakes (lecithins, mono- and diglycerides of fatty acids, carbonates, diphosphates, glycerol and sorbitol), consumed mostly by non-smokers with graduate degrees, with the highest energy and lipid consumption averages. The second group corresponds to additives found in broths, butter, breads and meal replacements (modified starches, monosodium glutamate, fatty acid esters and BHA), consumed by physically active, older non-smokers. Then the third group of additives found in dairy desserts, breakfast cereals and baked goods (carrageenan, lactic acid, calcium propionate and phosphates), consumed by people with the highest carbohydrate intakes. The fourth group concerns the additives found in sauces and processed meats (sodium nitrite, sodium erythorbate, phosphates and cochineal), often consumed by men with the lowest levels of education. Finally, the fifth group refers to additives found in sugary and artificially sweetened beverages (mixture of sweeteners – acesulfame K, aspartame, sucralose, steviol glycosides – colors, pectins, carotenes, sodium citrate, benzoates, phosphates, nitrates), consumed by younger individuals, with higher body mass indexes, lower levels of physical activity and more likely to be smokers6565. Chazelas E, Druesne-Pecollo N, Esseddik Y, Edelenyi FS, Agaesse C, Sa A, et al. Exposure to food additive mixtures in 106,000 French adults from the NutriNet-Santé cohort. Sci Rep. 2021;11:19680. https://doi.org/10.1038/s41598-021-98496-6
https://doi.org/10.1038/s41598-021-98496...
.

On the other hand, this study highlights a sixth group, related to the lower consumption of additives, found in whole foods, legumes, breakfast cereals without added sugar, vegetable juices, oilseeds, vegetable oils and cheeses. This food group was mostly consumed by women, with the lowest consumption of energy and ultra-processed food and the highest consumption of organic foods and alcoholic beverages. As conclusions, the authors highlight that the health impact and potential effects of the consumption of different types of additives should be explored in epidemiological and experimental studies. Following the precautionary principle, several public health authorities around the world have recently started to recommend the consumption of foods without or with as little additives as possible6565. Chazelas E, Druesne-Pecollo N, Esseddik Y, Edelenyi FS, Agaesse C, Sa A, et al. Exposure to food additive mixtures in 106,000 French adults from the NutriNet-Santé cohort. Sci Rep. 2021;11:19680. https://doi.org/10.1038/s41598-021-98496-6
https://doi.org/10.1038/s41598-021-98496...
.

It was observed that the studies presented in Box 1 analyze food consumption and quantify food additives using different methodologies. The main methods of assessing food consumption were a 24-hour recall, food purchase data and a food frequency questionnaire. The amount of additives in food was identified by laboratory analysis, data provided by the industry or inferred by means of an estimate by maximum limit. This scenario of little standardization in the method of data collection and analysis may indicate a methodological limitation in studies on the subject, insofar as the results of the studies cannot be compared with each other, weakening the existing scientific evidence on the consumption of additives.

It should be noted that there are additives that do not have maximum limit values determined due to the absence of an ADI established by JECFA and, therefore, their use is recommended by the Codex Alimentarius and/or authorized by the regulatory agencies of the countries on a quantum satis basis. This term means that the manufacturer is allowed to add the amount of additive that he deems necessary and sufficient to achieve the intended technological function, with no maximum value determined for addition at the time of manufacture (maximum limit). As an example, in Brazil, Anvisa authorizes in bakery products and cakes, among other additives, the use of the emulsifier soy lecithin and all flavorings in the quantum satis amount6666. Ministério da Saúde (BR), Agência Nacional de Vigilância Sanitária. Resolução - RDC Nº 45, de 3 de novembro de 2010. Dispõe sobre aditivos alimentares autorizados para uso segundo as Boas Práticas de Fabricação (BPF). Brasília, DF: Anvisa; 2010 [cited 2021 Sep 20]. Available from: https://bvsms.saude.gov.br/bvs/saudelegis/anvisa/2010/rdc0045_03_11_2010.html
https://bvsms.saude.gov.br/bvs/saudelegi...
. With this, it is inferred that it is only possible to analyze the effective consumption of these additives through laboratory analysis or contact with the industry, limiting the performance of studies on such substances.

However, although the quantum satis limit is authorized in Brazil and validated by the Codex Alimentarius, the subjectivity of the definition of this amount of additive to be added to foods is conjectured, as well as the potential risks, with the understanding that the manufacturers are authorized to add the amount of additive they deem necessary, without necessarily considering the safety of consumption of the substance. Furthermore, it should be noted that the consumer does not have any mechanism for accessing information, neither regarding the permitted amount of use nor the amount actually added to the food. This is because the current legislation indicates that food additives must be declared after the ingredients (and not in descending order of proportion, as is the case with ingredients).

In addition to the lack of consumer information on labels, this context can therefore lead to inaccuracies in the quantification of additive consumption. Consequently, it can bring limitations not only for the analysis of additive consumption, but also for the assessment of toxicity and health effects in humans.

Food Additives and Consequences for Children’s Health

The consumption of ultra-processed foods may be directly related to the development of obesity, diabetes, cancer and other chronic noncommunicable diseases6767. Canella DS, Levy RB, Martins APB, Claro RM, Moubarac JC, Baraldi LG, et al. Ultra-processed food products and obesity in Brazilian households (2008-2009). PLoS One. 2014;9(3):e92752. https://doi.org/10.1371/journal.pone.0092752
https://doi.org/10.1371/journal.pone.009...
,6868. Lane MM, Davis JA, Beattie S, Gómez-Donoso C, Loughman A, O’Neil A, et al. Ultraprocessed food and chronic noncommunicable diseases: a systematic review and meta-analysis of 43 observational studies. Obes Rev. 2021;22(3):e13146. https://doi.org/10.1111/obr.13146
https://doi.org/10.1111/obr.13146...
. However, it is still uncertain which variables present in ultra-processed foods most contribute to these results, citing the need to better analyze food additives, among other components6969. Fiolet T, Srour B, Sellem L, Kesse-Guyot E, Allès B, Méjean C, et al. Consumption of ultraprocessed foods and cancer risk: results from NutriNet-Santé prospective cohort. BMJ. 2018;360:k322. https://doi.org/10.1136/bmj.k322
https://doi.org/10.1136/bmj.k322...
.

Most studies to identify the toxicity of food additives are carried out with rodents in the laboratory7070. Swidsinski A, Ung V, Sydora BC, Loening-Baucke V, Doerffel Y, Verstraelen H, et al. Bacterial overgrowth and inflammation of small intestine after carboxymethylcellulose ingestion in genetically susceptible mice. Inflamm Bowel Dis. 2009;15(3):359-364. https://doi.org/10.1002/ibd.20763
https://doi.org/10.1002/ibd.20763...
, which must follow design and execution protocols so that their results are validated by the Codex Alimentarius and by regulatory agencies around the world when establishing the ADI. The main protocol used comes from the Organization for Economic Cooperation and Development (OECD) guidelines for chemical testing, which comprise around 150 internationally agreed methods to identify and characterize the potential hazards of chemicals8585. Organisation for Economic Cooperation and Development. OECD Guidelines for the testing of chemicals, Section 1: Physical-Chemical properties. Paris (FR): OECD; 2021 [cited 2021 Sep 20]. https://doi.org/10.1787/20745753
https://doi.org/10.1787/20745753...
. Although there are strict methodological protocols for experimental studies, it is questionable, in the light of scientific methodology and the precautionary principle, whether it is appropriate to extrapolate results found in cells or animal models to humans, in order to establish limits for human consumption for potentially toxic substances, such as additives.

In Technical Report No. 70 of 20168686. Ministério da Saúde (BR), Agência Nacional de Vigilância Sanitária. Esclarecimentos sobre a declaração de alegações de conteúdo para aditivos alimentares na rotulagem de alimentos e bebidas. Informe Técnico. 2016 jan 19 [cited 2021 Apr 20];(70):1-9. Available from: https://www.gov.br/agricultura/pt-br/assuntos/inspecao/produtos-vegetal/legislacao-1/biblioteca-de-normas-vinhos-e-bebidas/informe-tecnico-no-70-de-19-de-janeiro-de-2016.pdf/view
https://www.gov.br/agricultura/pt-br/ass...
, which aimed to clarify questions about the declaration and content claims for food additives in food labeling, Anvisa states that:

Although food additives are subjected to a safety and technological efficacy assessment prior to authorization of use, the globally accepted approach used in safety assessment has several limitations, such as: the difficulty in transposing toxicological data obtained in studies with animals to humans and the difficulty of predicting inter-individual variability. Furthermore, new studies have suggested that these substances may cause adverse reactions not identified in the safety assessment, including allergic reactions, food intolerances and hyperactivity (...)

However, it is these toxicological evaluation studies, carried out mainly in animal models, that support the Codex Alimentarius in the ADI and maximum limits recommendations in foods. This aspect is considered a methodological limitation in studies on health effects in humans, since, even properly performed, the effects (or lack of them) found in animals will not necessarily occur in humans or at the same intensity.

Dybing et al.2929. Dybing E, Doe J, Groten J, Kleiner J, O’Brien J, Renwick AG, et al. Hazard characterization of chemicals in food and diet: dose response, mechanisms and extrapolation issues. Food Chem Toxicol. 2002;40(2-3):237-82. https://doi.org/10.1016/s0278-6915(01)00115-6
https://doi.org/10.1016/s0278-6915(01)00...
(2002) emphasize that, although methodologically there are formulas to extrapolate the results to human beings, it is known that substances react in different ways according to the cellular characteristics of each organism. In addition, authors question the use of the NOAEL value as a reference to support ADI recommendations for additives. The sample size of the studies is considered a sensitive point, as they vary between them and because, often, there are small samples to consider that a substance does not have toxic effects8787. Leisenring W, Ryan L. Statistical properties of the NOAEL. Regul Toxicol Pharmacol. 1992;15(2 Pt 1):161-71. https://doi.org/10.1016/0273-2300(92)90047-d
https://doi.org/10.1016/0273-2300(92)900...
. Furthermore, they consider that the determination of the NOAEL value does not consider the progression of the toxic effect in relation to the duration and/or dose of the additive8888. Dorato MA, Engelhardt JA. The no-observable-adverse-effect level in drug safety evaluations: use, issues, and definition(s). Regul Toxicol Pharmacol. 2005;42(3):265-74. https://doi.org/10.1016/j.yrtph.2005.05.004
https://doi.org/10.1016/j.yrtph.2005.05....
.

As an example regarding the controversies and methodological challenges to attest to the toxicity of food additives, the recent discussion regarding the use of titanium dioxide in foods stands out. The use of this dye is attested by JECFA in the quantum satis limit since 1969, the year of the last toxicological evaluation carried out by the committee. In this analysis, the studies did not demonstrate toxic effects of titanium dioxide in animal models. However, in March 2021, the European Food Safety Authority (EFSA) published a new toxicity assessment and concluded that the additive should no longer be considered safe for human consumption, in any quantity8989. Younes M, Aquilina G, Castle L, Engel KH, Fowler P, Fernandez MJF, et al. Safety assessment of titanium dioxide (E171) as a food additive. EFSA J. 2021;19(5):e6585. https://doi.org/10.2903/j.efsa.2021.6585
https://doi.org/10.2903/j.efsa.2021.6585...
. This debate began with a position taken by the French regulatory agency (l’Agence Nationale de Securité Sanitaire de l’Alimentation – ANSES) which, after an analysis carried out by experts, published a decree suspending the marketing of foods containing titanium dioxide, as of January 1, 2021, for not considering this additive safe for human consumption9090. France. Arrêté du 17 avril 2019 portant suspension de la mise sur le marché des denrées contenant l’additif E 171 (dioxyde de titane - TiO2). Journal Officiel de la République Française. 26 avril 2019 [cited 2021 Oct 8]. Available from: https://www.legifrance.gouv.fr/jorf/id/JORFTEXT000038410047?r=LNz0mqURAZ
https://www.legifrance.gouv.fr/jorf/id/J...
. Thus, the use of titanium dioxide has been (re)discussed in several countries around the world, also being included in Anvisa’s Food Regulatory Agenda 2021/20239191. Ministério da Saúde (BR), Agência Nacional de Vigilância Sanitária. Webinar com a Gerência de Padrões e Regulação de Alimentos aborda a Agenda Regulatória de Alimentos 2021/2023. Brasília, DF: Anvisa; 2021 [cited 2021 Oct 08]. Available from: https://www.gov.br/anvisa/pt-br/assuntos/educacaoepesquisa/webinar/alimentos/arquivos/apresentacao-we-22-21-agenda-regulatoria-de-alimentos-2021-2023.pdf
https://www.gov.br/anvisa/pt-br/assuntos...
.

In this context, safety and toxicity assessments are generally performed with only one additive, underestimating the effects of associating two or more substances, which may interact when ingested9292. Paula Neto HA, Ausina P, Gomez LS, Leandro JGB, Zancan P, Sola-Penna M. Effects of food additives on immune cells as contributors to body weight gain and immune-mediated metabolic dysregulation. Front Immunol. 2017;8:1478. https://doi.org/10.3389/fimmu.2017.01478
https://doi.org/10.3389/fimmu.2017.01478...
. Thus, the cumulative and concomitant consumption of different types of additives is another latent aspect regarding toxicity. The interaction of different additives together, both with each other and with the human organism, is little studied. Therefore, the relevance of this issue in the establishment of the ADI of food additives is uncertain. In a study carried out with 50 Wistar rats, for example, the effect of the concomitant consumption of different types of additives (colors, preservatives and sweeteners) on blood markers and on liver, kidney and brain tissues was evaluated. The additives present in foods consumed by children and that were the subject of controversies regarding safety of consumption were chosen. As a result, the authors point out that, although the NOAEL value established for each additive separately appears to be safe, when different types of additives are consumed together, this safety can be compromised. Consumption of different types of preservatives and, concomitantly, of preservatives, colors and sweeteners demonstrated potential risks of damage to the DNA of brain, kidney and liver cells. In addition, as the number of administered additives increased, there was a reduction in the levels of hemoglobin, albumin and total serum protein, as well as an increase in urea, creatinine, bilirubin and liver enzyme activity. These changes can trigger various metabolic damages, as well as diseases resulting from DNA damage and imbalances in biochemical parameters8383. Raya SA, Aboul-Enein AM, El-Nikeety MMA, Mohamed RS, Abdelwahid WMA. In Vivo comet assay of food additives’ combinations and their effects on biochemical parameters in albino rats. Biointerface Res Appl Chem. 2021;11(2):9170-83. https://doi.org/10.33263/BRIAC112.91709183
https://doi.org/10.33263/BRIAC112.917091...
.

Figure 2 presents the results associating toxicity of food additives in animal models7070. Swidsinski A, Ung V, Sydora BC, Loening-Baucke V, Doerffel Y, Verstraelen H, et al. Bacterial overgrowth and inflammation of small intestine after carboxymethylcellulose ingestion in genetically susceptible mice. Inflamm Bowel Dis. 2009;15(3):359-364. https://doi.org/10.1002/ibd.20763
https://doi.org/10.1002/ibd.20763...
.

Figure 2
Diseases identified in animal models resulting from the consumption of food additives.

A systematic review study9393. Piper JD, Piper PW. Benzoate and sorbate salts: a systematic review of the potential hazards of these invaluable preservatives and the expanding spectrum of clinical uses for sodium benzoate. Compr Rev Food Sci Food Saf. 2017;16(5):868-80. https://doi.org/10.1111/1541-4337.12284
https://doi.org/10.1111/1541-4337.12284...
on the potential risks of benzoate and sorbate preservatives indicated that, in isolation, these substances do not seem to have toxic effects in mammals. However, in contact with other additives in the gastric environment, such as nitrites and ascorbic acid, they can form substances with carcinogenic potential. Furthermore, results in animal models indicate potential teratogenic effects and liver damage; deleterious effects on neuronal development and growth retardation, hematological abnormality and organ damage. The authors of the review also discuss that in studies carried out in vitro, there are results indicating increased oxidative stress, damage to genetic material, inhibition of leptin release in adipocytes and mitochondrial damage9393. Piper JD, Piper PW. Benzoate and sorbate salts: a systematic review of the potential hazards of these invaluable preservatives and the expanding spectrum of clinical uses for sodium benzoate. Compr Rev Food Sci Food Saf. 2017;16(5):868-80. https://doi.org/10.1111/1541-4337.12284
https://doi.org/10.1111/1541-4337.12284...
.

In humans, most of the review studies found that evaluated the possible health consequences of the consumption of additives are inconclusive. Possibly, inconclusive results occur due to the impossibility of comparison determined by the different methodologies used. In this sense, studies that evaluated the consumption of artificial sweeteners and metabolic effects9494. Brown RJ, Banate MA, Rother KI. Artificial sweeteners: a systematic review of metabolic effects in youth. Int J Pediatr Obes. 2010;5(4):305-12. https://doi.org/10.3109/17477160903497027
https://doi.org/10.3109/1747716090349702...
,9595. Reid AE Chauhan BF Rabbani R, Lys J, Copstein L, Mann A, et al. Early exposure to nonnutritive sweeteners and longterm metabolic health: a systematic review. Pediatrics. 2016;137(3):e20153603. https://doi.org/10.1542/peds.2015-3603
https://doi.org/10.1542/peds.2015-3603...
, as well as nitrites and nitrates and cancer9696. Blot WJ, Henderson BE, Boice JD Jr. Childhood cancer in relation to cured meat intake: review of the epidemiological evidence. Nutr Cancer. 1999;34(1):111-8. https://doi.org/10.1207/S15327914NC340115
https://doi.org/10.1207/S15327914NC34011...
,9797. Dietrich M, Block G, Pogoda JM, Buffler P, Hecht S, Preston-Martin S. A review: dietary and endogenously formed N-nitroso compounds and risk of childhood brain tumors. Cancer Causes Control. 2005;16(6):619-35. https://doi.org/10.1007/s10552-005-0168-y
https://doi.org/10.1007/s10552-005-0168-...
stand out. These studies point to the need for further investigations in humans to draw conclusive results.

A scoping review aimed at mapping possible health outcomes associated with frequent consumption of artificial sweeteners found 372 articles that investigated various health changes, such as: cancer, diabetes, changes in appetite, caries, weight gain, obesity, headache, depression, behavioral and cognitive effects, neurological effects, risk of preterm birth, cardiovascular effects and risk of chronic kidney disease. However, the authors consider the results to be inconclusive and point to the need for more research, especially longitudinal studies with rigorous and detailed methodological procedures, as well as well-executed systematic reviews, allowing quantitative summary and validity analysis of existing data9898. Lohner S, Toews I, Meerpohl JJ. Health outcomes of non-nutritive sweeteners: analysis of the research landscape. Nutr J. 2017;16:55. https://doi.org/10.1186/s12937-017-0278-x
https://doi.org/10.1186/s12937-017-0278-...
.

Other review studies point out that, although there is no conclusion that confirms the relationship between additives consumption and health outcomes, there is also no evidence to reject it9999. Shankar P, Ahuja S, Sriram K. Non-nutritive sweeteners: review and update. Nutrition. 2013;29(11-12):1293-9. https://doi.org/10.1016/j.nut.2013.03.024
https://doi.org/10.1016/j.nut.2013.03.02...
. It is known that the methodology of experimental and observational studies must be carefully analyzed to verify if there was methodological rigor that scientifically validates the results. However, data obtained from primary studies should be considered, especially by public health bodies and regulatory agencies. Additionally, in view of the lack of consensus in the scientific literature regarding damage to health, especially for potentially toxic substances, such as food additives, the precautionary principle should be considered, which provides, when there is no scientific proof of safety, the adoption of measures against potential risks whenever there is a danger of serious or irreversible damage102102. United Nations Conference on Environment and Development; 3-14 Jun 1992; Rio de Janeiro, Brazil. New York: UN; 1993 [cited 2021 Apr 20]. https://undocs.org/en/A/CONF.151/26/Rev.1(vol.I)3-4
https://undocs.org/en/A/CONF.151/26/Rev....
.

Although many studies do not find conclusive results, there are reviews in the scientific literature that, when evaluating primary experimental and/or observational studies, point to the relationship between consumption of additives by humans and potential damage to health. Given the scarcity of review studies with this objective, Box 2 summarizes the results found, both in children and adults.

Box 2
Review studies, with conclusive results, that analyzed the effects of additives consumption on the health of adults and children.

Nine studies were found, of which six analyzed the health effects in adults9292. Paula Neto HA, Ausina P, Gomez LS, Leandro JGB, Zancan P, Sola-Penna M. Effects of food additives on immune cells as contributors to body weight gain and immune-mediated metabolic dysregulation. Front Immunol. 2017;8:1478. https://doi.org/10.3389/fimmu.2017.01478
https://doi.org/10.3389/fimmu.2017.01478...
,103103. Vally H, Misso NLA, Madan V. Clinical effects of sulphite additives. Clin Exp Allergy. 2009;39(11):1643-51. https://doi.org/10.1111/j.1365-2222.2009.03362.x
https://doi.org/10.1111/j.1365-2222.2009...
and three in children4242. Schab DW, Trinh NHT. Do artificial food colors promote hyperactivity in children with hyperactive syndromes? A meta-analysis of double-blind placebo-controlled trials. J Dev Behav Pediatr. 2004;25(6):423-34. https://doi.org/10.1097/00004703-200412000-00007
https://doi.org/10.1097/00004703-2004120...
. The results seem to point to the potential for the development of attention deficit hyperactivity disorder (ADHD), alterations in the intestinal microbiota, metabolic dysregulation, weight gain, cardiometabolic effects, development of cancer in the gastrointestinal tract, respiratory problems, rhinitis, urticaria, and angioedema. In addition, studies have looked at the health effects of different types of additives, such as: sulfites, nitrites, nitrates, nitrosamines, sweeteners, carrageenan, citrate, and emulsifiers.

In children, the review studies identified analyzed the health effects caused by only one functional class of additives, the colors. Three studies were found, associating its consumption with short- and long-term effects on the development of allergic reactions, such as rhinitis, urticaria and angioedema, as well as behavioral disorders, such as ADHD. Schab and Trinh4242. Schab DW, Trinh NHT. Do artificial food colors promote hyperactivity in children with hyperactive syndromes? A meta-analysis of double-blind placebo-controlled trials. J Dev Behav Pediatr. 2004;25(6):423-34. https://doi.org/10.1097/00004703-200412000-00007
https://doi.org/10.1097/00004703-2004120...
(2004) point out that artificial colors promote hyperactivity in children, considering symptoms measured by behavioral assessment scales. Kanarek4444. Kanarek RB. Artificial food dyes and attention deficit hyperactivity disorder. Nutr Rev. 2011;69(7):385-91. https://doi.org/10.1111/j.1753-4887.2011.00385.x
https://doi.org/10.1111/j.1753-4887.2011...
(2011), when analyzing the same variables, highlights that, although the consumption of colors seems to be associated with the worsening of symptoms of hyperactivity and/or attention deficit, their complete withdrawal from food may not be enough for the treatment of ADHD symptoms, considering the multifactorial nature of the causes.

Polônio and Peres4343. Polônio MLT, Peres F. Consumo de aditivos alimentares e efeitos à saúde: desafios para a saúde pública brasileira. Cad Saude Publica. 2009;25(8):1653-66. https://doi.org/10.1590/s0102-311x2009000800002
https://doi.org/10.1590/s0102-311x200900...
(2009), emphasize that the number of studies was greater, and the results were more consistent regarding the clinical manifestations of non-specific hypersensitivity, such as rhinitis, urticaria and angioedema, related to the consumption of artificial colors. However, they also point out that, although with divergent results, studies have found a relationship between the consumption of additives and the development of cancers, especially when consumption was higher than the ADI.

Although no review study was found with conclusive results about the effects of sweeteners on children’s health, Shum and Georgia108108. Shum B, Georgia S. The effects of non-nutritive sweetener consumption in the pediatric populations: what we know, what we don’t, and what we need to learn. Front Endocrinol (Lausanne). 2021;12:625415. https://doi.org/10.3389/fendo.2021.625415
https://doi.org/10.3389/fendo.2021.62541...
(2021), in their review, emphasize that the consumption of this additive seems to be frequent in this age group and, sometimes, higher than the recommended limits. Thus, they point to the need for studies regarding the potential effects on children’s health, especially regarding the possible risk of developing type 2 diabetes and cardiometabolic diseases resulting from the consumption of sweeteners; they also point out the importance of investigating how intrauterine exposure to sweeteners can influence metabolic outcomes during life.

In this sense, a systematic review with meta-analysis analyzed the effects of maternal consumption of sweeteners on outcomes during birth, specifically birth weight, preterm delivery and gestational age. The authors emphasize that the evidence is of low quality; however, it suggests that the daily consumption of sweeteners during pregnancy is associated with an increased risk of preterm birth, decreasing gestational age and increasing birth weight109109. Cai C, Sivak A, Davenport MH. Effects of prenatal artificial sweeteners consumption on birth outcomes: a systematic review and meta-analysis. Public Health Nutr. 2021;24(15):5024-33. https://doi.org/10.1017/S1368980021000173
https://doi.org/10.1017/S136898002100017...
.

There are few experimental studies relating the effects of additives consumption to the health of children, but there are hypotheses under study. The most cited research and that has produced the most robust results to date was carried out in England and published in the Lancet journal in 2007, by McCann et al.110110. McCann D, Barrett A, Cooper A, Crumpler D, Dalen L, Grimshaw K, et al. Food additives and hyperactive behaviour in 3-year-old and 8/9-year-old children in the community: a randomised, double-blinded, placebo-controlled trial. Lancet. 2007;370(9598):1560-7. https://doi.org/10.1016/S0140-6736(07)61306-3
https://doi.org/10.1016/S0140-6736(07)61...
(2007). It is a randomized, placebo-controlled, double-blind clinical trial. The authors evaluated the effect of consuming two beverages containing different concentrations of food additives, compared to placebo, on behavioral outcomes of hyperactivity in children aged three to four years and eight to nine years. Both drinks contained artificial colors (sunset yellow, carmoisine, tartrazine and ponceau 4R), in higher concentration in the second drink, and sodium benzoate preservative in the same concentration in both drinks. As a result, consumption of both beverages, in both age groups, increased the mean level of hyperactivity in relation to placebo, correlating the consumption of artificial colors and sodium benzoate with the behavioral outcome in children110110. McCann D, Barrett A, Cooper A, Crumpler D, Dalen L, Grimshaw K, et al. Food additives and hyperactive behaviour in 3-year-old and 8/9-year-old children in the community: a randomised, double-blinded, placebo-controlled trial. Lancet. 2007;370(9598):1560-7. https://doi.org/10.1016/S0140-6736(07)61306-3
https://doi.org/10.1016/S0140-6736(07)61...
. It is noteworthy that there were criticisms of the study methodology, especially the dose of additives used111111. Connoly A, Hearty A, Nugent A, McKevitt A, Boylan E, Flynn A, et al. Pattern of intake of food additives associated with hyperactivity in Irish children and teenagers. Food Addit Contam Part A. 2010;27(4):447-56. https://doi.org/10.1080/19440040903470718
https://doi.org/10.1080/1944004090347071...
. However, McCann et al.110110. McCann D, Barrett A, Cooper A, Crumpler D, Dalen L, Grimshaw K, et al. Food additives and hyperactive behaviour in 3-year-old and 8/9-year-old children in the community: a randomised, double-blinded, placebo-controlled trial. Lancet. 2007;370(9598):1560-7. https://doi.org/10.1016/S0140-6736(07)61306-3
https://doi.org/10.1016/S0140-6736(07)61...
(2007) indicate in the method of the article that the doses used in drinks for children aged three to four years correspond to the consumption of two packages of 56g candies. The amounts of additives present in one of the eight- and nine-year-olds’ drinks correspond to four packets of candy. Initially, the question is, which child within the age groups surveyed would habitually consume this amount of candies?

Randomized clinical trials are known to provide high levels of scientific evidence if properly performed. In addition, this study design usually has space for publication in journals with a high impact factor, as in the aforementioned study110110. McCann D, Barrett A, Cooper A, Crumpler D, Dalen L, Grimshaw K, et al. Food additives and hyperactive behaviour in 3-year-old and 8/9-year-old children in the community: a randomised, double-blinded, placebo-controlled trial. Lancet. 2007;370(9598):1560-7. https://doi.org/10.1016/S0140-6736(07)61306-3
https://doi.org/10.1016/S0140-6736(07)61...
. However, the discussion about ethical aspects involved in the design and execution of this type of study is considered relevant, when the main outcome is the effect of the ingestion of substances potentially harmful to the body.

This situation is even more latent when the target of the studies is children. First, authorization from those responsible for the participation of children in any type of study is required. It is questioned whether all the risks involved in the administration of potentially toxic substances, such as additives, are fully explained to those responsible for authorizing the participation of a child in a study with this design, in which there are risks involved and, certainly, the child you will not have any health and well-being benefits from participating. In addition, consideration is given to the harmful and permanent effects that can be generated to participants in experimental studies that analyze the toxicity of ingested substances. It is considered that the responsibility of the researchers regarding the possible consequences for the study participants and the ethical aspects involved in experimental designs that assess toxicity may be limitations for the development of research in this area.

In a report by the American Academy of Pediatrics, Trasande et al.4040. Trasande L, Shaffer RM, Sathyanarayana S. Food additives and child health. Pediatrics. 2018;142(2):e20181408. https://doi.org/10.1542/peds.2018-1408
https://doi.org/10.1542/peds.2018-1408...
(2018) discuss the results of studies on the consequences of consuming nitrite and nitrate preservatives on children’s health. The authors argue that some evidence points to the action of these preservatives as endocrine disruptors, altering thyroid metabolism and the interaction with other substances in the body (amines and amides) forming carcinogenic compounds, mainly in the brain and gastrointestinal tract. This situation can be potentiated in the organism of infants and young children, due to the immaturity of the organism. There is even evidence that highlights the relationship between maternal consumption of nitrites and nitrates with the development of brain cancer in babies .

Occurrences of allergic reactions in children due to the consumption of additives have already been scientifically published in clinical reports, mainly associated with preservatives of the benzoate class112112. Petrus M, Bonaz S, Causse E, Rhabbour M, Moulie N, Netter JC, et al. Asthme et intolérance aux benzoates. Arch Pediatr. 1996;3(10):984-7. https://doi.org/10.1016/0929-693X(96)81719-2
https://doi.org/10.1016/0929-693X(96)817...
,113113. Jacob SE, Hill H, Lucero H, Nedorost A. Benzoate allergy in children: from foods to personal hygiene products. Pediatr Dermatol. 2016;33(2):213-5. https://doi.org/10.1111/pde.12759
https://doi.org/10.1111/pde.12759...
, as well as with colors114114. Inomata NA, Osuna HA, Fujita HA, Ogawa TA, Ikezawa Z. Multiple chemical sensitivities following intolerance to azo dye in sweets in a 5-year-old girl. Allergol Int. 2006;55(2):203-5. https://doi.org/10.2332/allergolint.55.203
https://doi.org/10.2332/allergolint.55.2...
. The consumption of colors, specifically, can activate the inflammatory cascade, resulting in the induction of intestinal permeability to large antigenic molecules. In addition to allergic reactions, intestinal permeability can lead to autoimmune diseases and neurobehavioral disorders115115. Vojdani A, Vojdani C. Immune reactivity to food coloring. Altern Ther Health Med. 2015;21 Suppl 1:52-62.. A clinical report on the subject points out that there are no data on the prevalence of allergy to food additives in children, which makes the diagnosis difficult. However, this relationship should be clinically investigated whenever the patient is allergic to multiple foods and medications116116. Skrie VC, Orellana JC. Reacción adversa por aditivos alimentarios en un paciente pediátrico. Rev Alerg Mex. 2018;65(2):187-91. https://doi.org/10.29262/ram.v65i2.288
https://doi.org/10.29262/ram.v65i2.288...
.

There are also observational studies (population and cohort) that found possible correlations between: consumption of artificial sweeteners and early menarche117117. Mueller NT, Jacobs DR Jr, MacLehose RF, Demerath EW, Kelly SP, Dreyfus JG, et al. Consumption of caffeinated and artificially sweetened soft drinks is associated with risk of early menarche. Am J Clin Nutr. 2015;102(3):648-54. https://doi.org/10.3945/ajcn.114.100958
https://doi.org/10.3945/ajcn.114.100958...
; consumption of artificial sweeteners by pregnant women and excessive weight gain in babies up to one year of age118118. Ali F. Consumption of artificial sweeteners in pregnancy increased overweight risk in infants. Arch Dis Child Educ Pract Ed. 2017;102(5):277. https://doi.org/10.1136/archdischild-2017-312618
https://doi.org/10.1136/archdischild-201...
; and risk of overweight in seven-year-old children119119. Zhu Y, Olsen SF, Mendola P, Halldorsson TI, Rawal S, Hinkle SN, et al. Maternal consumption of artificially sweetened beverages during pregnancy, and offspring growth through 7 years of age: a prospective cohort study. Int J Epidemiol. 2017;46(5):1499-508. https://doi.org/10.1093/ije/dyx095
https://doi.org/10.1093/ije/dyx095...
; as well as consumption of monosodium glutamate, aspartame and nitrites as triggers for headaches in children120120. Taheri S. Effect of exclusion of frequently consumed dietary triggers in a cohort of children with chronic primary headache. Nutr Health. 2017;23(1):47-50. https://doi.org/10.1177/0260106016688699
https://doi.org/10.1177/0260106016688699...
.

Due to the already discussed ethical issue of the unsuitability of carrying out experimental studies offering potentially toxic additives to human beings, longitudinal observational studies are the most important sources of evidence gathering on the subject. However, the impossibility of inferring a causal relationship in this study design is highlighted, as well as the difficulty of separating the health effects arising from the additives from the other components of the foods that contain them.

As previously stated, most of the review studies found on additives consumption and human health address the effects of the consumption of sweeteners and preservatives in adults, while in children only the effects of artificial colors were analyzed. The most related health outcomes in children were behavioral and immunological disorders, although in adults, studies point to other possible consequences, such as the development of cancers in the gastrointestinal tract, metabolic dysregulation, weight gain and cardiometabolic effect. However, considering that there are hundreds of additives allowed for use in the world, a minimal portion of these substances are studied and tested in humans, especially in children. In addition, no studies were found that evaluated the health impact due to the regular and cumulative intake of food additives in humans.

When it comes to children, the context of consumption recommendations and the assessment of additive toxicity is even more complex, as an important aspect, the initial stage of life, is not considered when establishing recommendations. The ADI, maximum consumption parameter for, ideally, no toxic effect, is established by milligrams of additive per kilogram of weight, but it is not clear which kilogram of weight value is used as a reference to establish this parameter. Thus, it is questioned whether the mg/kg weight ratio is applied by processed food manufacturers, considering an average child weight or, as a consequence, the greater toxicity of food additives in children. When dealing with additives without an established ADI, this situation becomes even more worrying. In these cases, their addition to foods must follow good manufacturing practices, that is, additives can be added in a quantum satis amount, which is the smallest amount possible to achieve the desired technological effect, without altering the identity and genuineness of the food, according to identity and quality standards determined by specific regulations2424. Braga LVM, Silva ARCS, Anastácio LR. Levantamento de aditivos alimentares em produtos alimentícios voltados para o público infantil. Segur Aliment Nutr. 2021;28:e021013. https://doi.org/10.20396/san.v28i00.8659994
https://doi.org/10.20396/san.v28i00.8659...
,6666. Ministério da Saúde (BR), Agência Nacional de Vigilância Sanitária. Resolução - RDC Nº 45, de 3 de novembro de 2010. Dispõe sobre aditivos alimentares autorizados para uso segundo as Boas Práticas de Fabricação (BPF). Brasília, DF: Anvisa; 2010 [cited 2021 Sep 20]. Available from: https://bvsms.saude.gov.br/bvs/saudelegis/anvisa/2010/rdc0045_03_11_2010.html
https://bvsms.saude.gov.br/bvs/saudelegi...
. In such cases, it is not possible to identify what amount of additive is added to the food and whether this amount can be toxic for children, and it is unknown what the effects are of the combination of these additives with each other and for which the legislation provides a maximum limit of use.

CONCLUSIONS

It is a scenario in which the literature points to a risk to the health of people and, in particular, children, whose duty of protection must be even greater, with absolute priority. However, the establishment of an additive consumption limit, or ADI, is carried out considering effects identified in toxicological studies carried out, mostly, in animal models. When applied to children, the context of consumption limits and the assessment of toxicity of additives are more complex, since an important aspect, the initial stage of life, is not considered when establishing safety limits. It is known that the toxicity of food additives is greater in children, because the amount ingested per kilogram of weight is greater. Furthermore, organs and systems are still being formed at this stage of life, exposing children to potentially greater health risks that can arise from additives consumption. In addition, the level of exposure throughout life may be higher in children today, since they started to consume processed foods and food additives in the first years of life3131. World Health Organization. Children’s health and the environment: a global perspective: a resource manual for the health sector. Geneva (CH): WHO; 2005. 367p.,3232. Landrigan PJ, Trasande L, Thorpe LE, Gwynn C, Lioy PJ, D’Alton ME, et al. The National Children’s Study: a 21-year prospective study of 100,000 American children. Pediatrics. 2006;118(5):2173- 86. https://doi.org/10.1542/peds.2006-0360
https://doi.org/10.1542/peds.2006-0360...
.

In this sense, the existing limitation in the scientific method for carrying out toxicity studies of potentially toxic substances in humans, especially in children, is considered evident. Additionally, it is noteworthy that there are methodological limitations for the evaluation of children’s additives consumption, firstly, because the methods for evaluating food consumption are diverse and not always comparable, in addition to the fact that the quantification of additives in food is performed in different ways, with laboratory analysis being considered the gold standard. However, many studies estimate the amount of additives in foods, through the maximum limit allowed for each substance, causing methodological differences that make it difficult to compare the results across studies, as well as to analyze methodological quality. Thus, it is understood that this context contributes to the fragility of the existing evidence, as well as to the scarcity of discussions on the subject.

Based on the precautionary principle, it is up to the State to promote measures aimed at protecting the health of the population (including risk, under the terms of article 196 of the Constitution and article 9 of Consumer Protection Code), which results in the duty to promote public debate on the subject and public policies that allow access to information on the amount of additive used in food, so that people can make informed and conscious choices.

It is observed that studies on additives consumption, as well as those that evaluated health consequences, focus their analyses on three functional classes: colors, sweeteners and preservatives. However, the representativeness of the additives studied in relation to the total number of additives allowed for use is questioned. In Brazil, there are 23 regulated functional classes and hundreds of Anvisa norms that establish which additives and in what quantity can be used in foodseeAnvisa is in the process of compiling the rules that regulate the use of additives in processed foods in Brazil.. This context makes it impossible to accurately analyze how many additives are allowed for use in the country, so that it becomes possible to verify the scenario of scientific discussions on the subject. Additionally, the analysis of the notification of additives on processed food labels is scarce in Brazil and in the world. Through these data, it would be possible to assess which additives are used most frequently in processed foods and, thus, relate data on frequency of use, consumption and health consequences.

Finally, additives, such as colors and sweeteners, are present not only in foods, but also in medicines and oral hygiene products, and can be ingested through different sources. Thus, the relevance of an expanded technical-scientific debate regarding the establishment of stricter parameters of consumption and toxicity of specific additives for children is appreciated, considering the different sources of exposure to these substances.

REFERENCES

  • 1
    Vandevijvere S, Jaacks LM, Monteiro CA, Moubarac JC, Girling-Butcher M, Lee AC, et al. Global trends in ultraprocessed food and drink product sales and their association with adult body mass index trajectories. Obes Rev. 2019;20 Suppl 2:10-19. https://doi.org/10.1111/obr.12860
    » https://doi.org/10.1111/obr.12860
  • 2
    Karnopp EVN, Vaz JS, Schafer AA, Muniz LC, Souza RLV, Santos I, et al. Food consumption of children younger than 6 years according to the degree of food processing. J Pediatr. 2017;93(1):70-8. https://doi.org/10.1016/j.jped.2016.04.007
    » https://doi.org/10.1016/j.jped.2016.04.007
  • 3
    Popkin BM. Global nutrition dynamics: the world is shifting rapidly toward a diet linked with noncommunicable diseases. Am J Clin Nutr. 2006;84(2):289-98. https://doi.org/10.1093/ajcn/84.1.289
    » https://doi.org/10.1093/ajcn/84.1.289
  • 4
    Monteiro CA, Cannon G, Levy RB, Mourabac JC, Louzada ML, Rauber F, et al. Ultra-processed foods: what they are and how to identify them. Public Health Nutr. 2019;22(5):936-41. https://doi.org/10.1017/S1368980018003762
    » https://doi.org/10.1017/S1368980018003762
  • 5
    Martins APB, Levy RB, Claro RM, Moubarach JC, Monteiro CA. Participação crescente de produtos ultraprocessados na dieta brasileira (1987-2009). Rev Saude Publica. 2013;47(4):656-65. https://doi.org/10.1590/S0034-8910.2013047004968
    » https://doi.org/10.1590/S0034-8910.2013047004968
  • 6
    Theurich MA, Zaragoza-Jordana M, Luque V, Gruszfeld D, Gradowska K, Xhonneux A, et al. Commercial complementary food use amongst European infants and children: results from the EU Childhood Obesity Project. Eur J Nutr. 2020;59(4):1679-92. https://doi.org/10.1007/s00394-019-02023-3
    » https://doi.org/10.1007/s00394-019-02023-3
  • 7
    Assis MAA, Calvo MCM, Kupek E, Vasconcelos FAG, Campos VC, Machado M, et al. Qualitative analysis of the diet of a probabilistic sample of schoolchildren from Florianópolis, Santa Catarina State, Brazil, using the Previous Day Food Questionnaire. Cad Saude Publica. 2010;26(7):1355-65. https://doi.org/10.1590/s0102-311x2010000700014
    » https://doi.org/10.1590/s0102-311x2010000700014
  • 8
    Conceição SIO, Santos CJN, Silva AAM, Silva JS, Oliveira TC. Consumo alimentar de escolares das redes pública e privada de ensino em São Luís, Maranhão. Rev Nutr. 2010;23(6):993-1004. https://doi.org/10.1590/S1415-52732010000600006
    » https://doi.org/10.1590/S1415-52732010000600006
  • 9
    Matuk TT, Stancari PCS, Bueno MB, Zaccarelli EM. Composição de lancheiras de alunos de escolas particulares de São Paulo. Rev Paul Pediatr. 2011;29(2):157-63. https://doi.org/10.1590/S0103-05822011000200005
    » https://doi.org/10.1590/S0103-05822011000200005
  • 10
    Instituto Brasileiro de Geografia e Estatística. Pesquisa de Orçamentos Familiares 2008-2009: análise do consumo alimentar pessoal no Brasil. Rio de Janeiro: IBGE; 2011. 351 p.
  • 11
    Costa FF, Assis MAA, Leal DB, Campos VC, Kupek E, Conde WL. Mudanças no consumo alimentar e atividade física de escolares de Florianópolis, SC, 2002-2007. Rev Saude Publica. 2012;46 Suppl 1:117-25. https://doi.org/10.1590/s0034-89102012005000058
    » https://doi.org/10.1590/s0034-89102012005000058
  • 12
    Hinnig PF, Bergamaschi DP. Itens alimentares no consumo alimentar de crianças de 7 a 10 anos. Rev Bras Epidemiol. 2012;15(2):324-34. https://doi.org/10.1590/S1415-790X2012000200010
    » https://doi.org/10.1590/S1415-790X2012000200010
  • 13
    Nobre LN, Lamounier JA, Franceschini SCC. Padrão alimentar de pré-escolares e fatores associados. J. Pediatr. 2012;88(2):129-36. https://doi.org/10.2223/JPED.2169
    » https://doi.org/10.2223/JPED.2169
  • 14
    Polônio MLT, Peres F. Consumo de corantes artificiais por pré-escolares de um município da baixada fluminense, RJ. Rev Pesq Cuid Fundam. 2012 [cited 2021 Apr 15];4(1):2748-57. Available from: http://www.seer.unirio.br/index.php/cuidadofundamental/article/view/1609/pdf_487
    » http://www.seer.unirio.br/index.php/cuidadofundamental/article/view/1609/pdf_487
  • 15
    Costa CS, Rauber F, Leffa PS, Sangalli CN, Campagnolo PDB, Vítolo MR. Ultra-processed food consumption and its effects on anthropometric and glucose profile: a longitudinal study during childhood. Nutr Metab Cardiovasc Dis. 2019;29(2):177-84. https://doi.org/10.1016/j.numecd.2018.11.003
    » https://doi.org/10.1016/j.numecd.2018.11.003
  • 16
    Ferreira CS, Silva DA, Gontijo CA, Rinaldi AEM. Consumption of minimally processed and ultra-processed foods among students from public and private schools. Rev Paul Pediatr. 2019;37(2):173-80. https://doi.org/10.1590/1984-0462/;2019;37;2;00010
    » https://doi.org/10.1590/1984-0462/;2019;37;2;00010
  • 17
    Reedy J, Krebs-Smith SM. Dietary sources of energy, solid fats, and added sugars among children and adolescents in the United States. J Am Diet Assoc. 2010;110(10):1477-84. https://doi.org/10.1016/j.jada.2010.07.010
    » https://doi.org/10.1016/j.jada.2010.07.010
  • 18
    Piernas C, Popkin BM. Increased portion sizes from energy-dense foods affect total energy intake at eating occasions in US children and adolescents: patterns and trends by age group and sociodemographic characteristics, 1977-2006. Am J Clin Nutr. 2011;94(5):1324-32. https://doi.org/10.3945/ajcn.110.008466
    » https://doi.org/10.3945/ajcn.110.008466
  • 19
    Louzada MLC, Martins APB, Canella DS, Baraldi LG, Levy RB, Claro RM, et al. Ultra-processed foods and the nutritional dietary profile in Brazil. Rev Saude Publica. 2015;49:38. https://doi.org/10.1590/S0034-8910.2015049006132
    » https://doi.org/10.1590/S0034-8910.2015049006132
  • 20
    Rodrigues VM, Rayner M, Fernandes AC, Oliveira RC, Proença RPC, Fiates GMR. Nutritional quality of packaged foods targeted at children in Brazil: which ones should be eligible to bear nutrient claims? Int J Obes. 2017;41(1):71-5. https://doi.org/10.1038/ijo.2016.167
    » https://doi.org/10.1038/ijo.2016.167
  • 21
    Louzada MLC, Ricardo CA, Steele EM, Levy RB, Cannon G, Monteiro CA. The share of ultra-processed foods determines the overall nutritional quality of diets in Brazil. Public Health Nutr. 2018;21(Spec Nº 1):94-102. https://doi.org/10.1017/S1368980017001434
    » https://doi.org/10.1017/S1368980017001434
  • 22
    Lorenzoni ASG, Cladera-Olivera F. Food additives in products for children marketed in Brazil. Food Public Health. 2012;2(5):131-6. https://doi.org/10.5923/j.fph.20120205.03
    » https://doi.org/10.5923/j.fph.20120205.03
  • 23
    Teixeira AZA. Sodium content and food additives in major brands of Brazilian children’s foods. Cienc Saude Colet. 2018;23(12):4065-75. https://doi.org/10.1590/1413-812320182312.21812016
    » https://doi.org/10.1590/1413-812320182312.21812016
  • 24
    Braga LVM, Silva ARCS, Anastácio LR. Levantamento de aditivos alimentares em produtos alimentícios voltados para o público infantil. Segur Aliment Nutr. 2021;28:e021013. https://doi.org/10.20396/san.v28i00.8659994
    » https://doi.org/10.20396/san.v28i00.8659994
  • 25
    Rodrigues VM, Rayner M, Fernandes AC, Oliveira RC, Proença RPC, Fiates GMR. Comparison of the nutritional content of products, with and without nutrient claims, targeted at children in Brazil. Br J Nutr. 2016;115(11):2047-56. https://doi.org/10.1017/S0007114516001021
    » https://doi.org/10.1017/S0007114516001021
  • 26
    Food and Agriculture Organization of the United Nations; World Health Organization. Codex Alimentarius: general standard for food additives. Rome (IT); FAO; 1995 [cited 2021 Apr 10]. Available from: http://www.fao.org/fao-who-codexalimentarius/sh-proxy/en/?lnk=1&url=https%253A%252F%252Fworkspace.fao.org%252Fsites%252Fcodex%252FStandards%252FCXS%2B192-1995%252FCXS_192e.pdf
    » http://www.fao.org/fao-who-codexalimentarius/sh-proxy/en/?lnk=1&url=https%253A%252F%252Fworkspace.fao.org%252Fsites%252Fcodex%252FStandards%252FCXS%2B192-1995%252FCXS_192e.pdf
  • 27
    Ministério da Saúde (BR), Secretaria de Vigilância Sanitária. Portaria Nº 540, de 27 de outubro de 1997. Aprova o Regulamento técnico Aditivos Alimentares - definições, classificação e emprego. Diário Oficial da União. 28 out 1997; Poder Executivo.
  • 28
    Tomaska LD, Brooke-Taylor S. Food Additives – general. In: Montarjemi Y, Moy G, Todd E, editors. Encyclopedia of Food Safety. Vol 2. Cambridge, Mass: Academic Press; 2014. p.449-54. https://doi.org/10.1016/B978-0-12-378612-8.00234-1
    » https://doi.org/10.1016/B978-0-12-378612-8.00234-1
  • 29
    Dybing E, Doe J, Groten J, Kleiner J, O’Brien J, Renwick AG, et al. Hazard characterization of chemicals in food and diet: dose response, mechanisms and extrapolation issues. Food Chem Toxicol. 2002;40(2-3):237-82. https://doi.org/10.1016/s0278-6915(01)00115-6
    » https://doi.org/10.1016/s0278-6915(01)00115-6
  • 30
    Renwick AG, Barlow SM, Hertz-Picciotto I, Boobis AR, Dybing E, Edler L, et al. Risk characterization of chemicals in food and diet. Food Chem Toxicol. 2003;41(9):1211-71. https://doi.org/10.1016/s0278-6915(03)00064-4
    » https://doi.org/10.1016/s0278-6915(03)00064-4
  • 31
    World Health Organization. Children’s health and the environment: a global perspective: a resource manual for the health sector. Geneva (CH): WHO; 2005. 367p.
  • 32
    Landrigan PJ, Trasande L, Thorpe LE, Gwynn C, Lioy PJ, D’Alton ME, et al. The National Children’s Study: a 21-year prospective study of 100,000 American children. Pediatrics. 2006;118(5):2173- 86. https://doi.org/10.1542/peds.2006-0360
    » https://doi.org/10.1542/peds.2006-0360
  • 33
    Brasil, Constituição (1988). Constituição da República Federativa do Brasil de 1988. Brasília, DF: Senado Federal; 1988.
  • 34
    Brasil. Lei Nº 8.078, de 11 de setembro de 1990. Dispõe sobre a proteção do consumidor e dá outras providências. Diário Oficial da União. 12 set 1990.
  • 35
    Hartmann IAM. O princípio da precaução e sua aplicação no direito do consumidor: dever de informação. Direito Justiça. 2012 [cited 2021 Jul 9];38(2). Available from: https://revistaseletronicas.pucrs.br/ojs/index.php/fadir/article/view/12542
    » https://revistaseletronicas.pucrs.br/ojs/index.php/fadir/article/view/12542
  • 36
    Chaddad MCC. Rotulagem de alimentos: o direito à informação, à proteção da saúde e à alimentação adequada da população com alergia alimentar. Curitiba, PR: Juruá; 2014.
  • 37
    Jain A, Mathur P. Estimation of food additive intake: overview of the methodology. Food Rev Int. 2015;31(4):355-84. https://doi.org/10.1080/87559129.2015.1022830
    » https://doi.org/10.1080/87559129.2015.1022830
  • 38
    Choi SH, Suh HJ. Determination and estimation of daily nitrite intake from processed meats in Korea. J Consum Prot Food Saf. 2017;12(1):15-22. https://doi.org/10.1007/s00003-016-1075-8
    » https://doi.org/10.1007/s00003-016-1075-8
  • 39
    Long NH, Hao LTH, Trang VT, Son TC, Hung LQ. Assessing dietary risks caused by food additives: a case study of total diet in Vietnam. Health Risk Anal. 2019;2:74-82. https://doi.org/10.21668/health.risk/2019.2.08.eng
    » https://doi.org/10.21668/health.risk/2019.2.08.eng
  • 40
    Trasande L, Shaffer RM, Sathyanarayana S. Food additives and child health. Pediatrics. 2018;142(2):e20181408. https://doi.org/10.1542/peds.2018-1408
    » https://doi.org/10.1542/peds.2018-1408
  • 41
    Prado MA, Godoy HT. Teores de corantes artificiais em alimentos determinados por cromatografia líquida de alta eficiência. Quim Nova. 2007;30(2):268-73. https://doi.org/10.1590/S0100-40422007000200005
    » https://doi.org/10.1590/S0100-40422007000200005
  • 42
    Schab DW, Trinh NHT. Do artificial food colors promote hyperactivity in children with hyperactive syndromes? A meta-analysis of double-blind placebo-controlled trials. J Dev Behav Pediatr. 2004;25(6):423-34. https://doi.org/10.1097/00004703-200412000-00007
    » https://doi.org/10.1097/00004703-200412000-00007
  • 43
    Polônio MLT, Peres F. Consumo de aditivos alimentares e efeitos à saúde: desafios para a saúde pública brasileira. Cad Saude Publica. 2009;25(8):1653-66. https://doi.org/10.1590/s0102-311x2009000800002
    » https://doi.org/10.1590/s0102-311x2009000800002
  • 44
    Kanarek RB. Artificial food dyes and attention deficit hyperactivity disorder. Nutr Rev. 2011;69(7):385-91. https://doi.org/10.1111/j.1753-4887.2011.00385.x
    » https://doi.org/10.1111/j.1753-4887.2011.00385.x
  • 45
    Husain A, Sawaya W, Al-Omair A, Al-Zenki S, Al-Amiri H, Ahmed N, et al. Estimates of dietary exposure of children to artificial food colours in Kuwait. Food Addit Contam. 2007;23(3):245-51. https://doi.org/10.1080/02652030500429125
    » https://doi.org/10.1080/02652030500429125
  • 46
    Schumann SPA, Polônio MLT, Gonçalves ECBA. Avaliação do consumo de corantes artificiais por lactentes, pré-escolares e escolares. Food Sci Technol. 2008;28(3):534-9. https://doi.org/10.1590/S0101-20612008000300005
    » https://doi.org/10.1590/S0101-20612008000300005
  • 47
    Sardi M, Haldemann Y, Nordmann H, Bottex B, Safford B, Smith B, et al. Use of retailer fidelity card schemes in the assessment of food additive intake: Sunset Yellow a case study. Food Addit Contam Part A Chem Anal Control Expo Risk Assess. 2010;27(11):1507-15. https://doi.org/10.1080/19440049.2010.495728
    » https://doi.org/10.1080/19440049.2010.495728
  • 48
    Dixit S, Purshottam SK, Khanna SK, Das M. Usage pattern of synthetic food colours in different states of India and exposure assessment through commodities preferentially consumed by children. Food Addit Contam Part A Chem Anal Control Expo Risk Assess. 2011;28(8):996-1005. https://doi.org/10.1080/19440049.2011.580011
    » https://doi.org/10.1080/19440049.2011.580011
  • 49
    Larsson K, Darnerud PO, Ilback NG, Merino L. Estimated dietary intake of nitrite and nitrate in Swedish children. Food Addit Contam Part A Chem Anal Control Expo Risk Assess. 2011;28(5):659-66. https://doi.org/10.1080/19440049.2011.555842
    » https://doi.org/10.1080/19440049.2011.555842
  • 50
    Lok KYW, Chung YW, Benzie IFF, Woo J. Synthetic colourings of some snack foods consumed by primary school children aged 8-9 years in Hong Kong. Food Addit Contam Part B Surveill. 2011;4(3):162-7. https://doi.org/10.1080/19393210.2011.585246
    » https://doi.org/10.1080/19393210.2011.585246
  • 51
    Urtiaga C, Amiano P, Azpiri M, Alonso A, Dorronsoro M. Estimate of dietary exposure to sulphites in child and adult populations in the Basque Country. Food Addit Contam Part A Chem Anal Control Expo Risk Assess. 2013;30(12):2035-42. https://doi.org/10.1080/19440049.2013.840930
    » https://doi.org/10.1080/19440049.2013.840930
  • 52
    Vin K, Connolly A, McCaffrey T, McKevitt A, O’Mahony C, Prieto M, et al. Estimation of the dietary intake of 13 priority additives in France, Italy, the UK and Ireland as part of the FACET project. Food Addit Contam Part A Chem Anal Control Expo Risk Assess. 2013;30(12):2050-80. https://doi.org/10.1080/19440049.2013.851417
    » https://doi.org/10.1080/19440049.2013.851417
  • 53
    Diouf F, Berg K, Ptok S, Lindtner O, Heinemeyer G, Heseker H. German database on the occurrence of food additives: application for intake estimation of five food colours for toddlers and children. Food Addit Contam Part A Chem Anal Control Expo Risk Assess. 2014;31(2):197-206. https://doi.org/10.1080/19440049.2013.865146
    » https://doi.org/10.1080/19440049.2013.865146
  • 54
    Mancini FR, Paul D, Gauvreau J, Volatier JL, Vin K, Hulin M. Dietary exposure to benzoates (E210-E213), parabens (E214-E219), nitrites (E249-E250), nitrates (E251-E252), BHA (E320), BHT (E321) and aspartame (E951) in children less than 3 years old in France. Food Addit Contam Part A Chem Anal Control Expo Risk Assess. 2015;32(3):293-306. https://doi.org/10.1080/19440049.2015.1007535
    » https://doi.org/10.1080/19440049.2015.1007535
  • 55
    Suomi J, Ranta J, Tuominen P, Putkonen T, Backman C, Ovaskainen ML. Quantitative risk assessment on the dietary exposure of Finnish children and adults to nitrite. Food Addit Contam Part A Chem Anal Control Expo Risk Assess. 2016;33(1):41-53. https://doi.org/10.1080/19440049.2015.1117145
    » https://doi.org/10.1080/19440049.2015.1117145
  • 56
    Reddy MV, Aruna G, Parameswari SA, Banu BH, Reddy PJ. Estimated daily intake and exposure of sodium benzoate and potassium sorbate through food products in school children of Tirupati, India. Int J Pharm Pharmaceutical Sci. 2015 [cited 2021 Apr 15];7(7):129-33. Available from: https://innovareacademics.in/journals/index.php/ijpps/article/view/6114
    » https://innovareacademics.in/journals/index.php/ijpps/article/view/6114
  • 57
    Martyn DM, Nugent AP, McNulty BA, O’Reilly E, Tlustos C, Walton J, et al. Dietary intake of four artificial sweeteners by Irish pre-school children. Food Addit Contam Part A Chem Anal Control Expo Risk Assess. 2016;33(4):592-602. https://doi.org/10.1080/19440049.2016.1152880
    » https://doi.org/10.1080/19440049.2016.1152880
  • 58
    Feitosa LCA, Rodrigues PS, Silva AS, Rios AO, Cladera-Olivera F. Estimate of the theoretical maximum daily intake of Sunset Yellow FCF by the Brazilian population. Food Addit Contam Part A Chem Anal Control Expo Risk Assess. 2017;34(5):687-94. https://doi.org/10.1080/19440049.2017.1290829
    » https://doi.org/10.1080/19440049.2017.1290829
  • 59
    Bastaki M, Farrell T, Bhusari S, Bi X, Scrafford C. Estimated daily intake and safety of FD&C food-colour additives in the US population. Food Addit Contam Part A Chem Anal Control Expo Risk Assess. 2017;34(6):891-904. https://doi.org/10.1080/19440049.2017.1308018
    » https://doi.org/10.1080/19440049.2017.1308018
  • 60
    Choi SH, Suh HJ. Determination and estimation of daily nitrite intake from processed meats in Korea. J Consum Prot Food Saf. 2017;12(1):15-22. https://doi.org/10.1007/s00003-016-1075-8
    » https://doi.org/10.1007/s00003-016-1075-8
  • 61
    Martyn D, Lau D, Darch M, Roberts A. Benzoates intakes from non-alcoholic beverages in Brazil, Canada, Mexico and the United States. Food Addit Contam Part A Chem Anal Control Expo Risk Assess. 2017;34(9):1485-99. https://doi.org/10.1080/19440049.2017.1338836
    » https://doi.org/10.1080/19440049.2017.1338836
  • 62
    Bel S, Struyf T, Fierens T, Jacobs G, Vynks C, Bellemans M. Dietary exposure of the Belgian population to emulsifiers E481 (sodium stearoyl-2-lactylate) and E482 (calcium stearoyl-2-lactylate). Food Addit Contam Part A Chem Anal Control Expo Risk Assess. 2018;35(5):828-37. https://doi.org/10.1080/19440049.2018.1435911
    » https://doi.org/10.1080/19440049.2018.1435911
  • 63
    Garavaglia MB, García VR, Zapata ME, Rovirosa A, González V, Marcó FF, et al. Non-nutritive sweeteners: children and adolescent consumption and food sources. Arch Argent Pediatr. 2018;116(3):186-91. https://doi.org/10.5546/aap.2018.eng.186
    » https://doi.org/10.5546/aap.2018.eng.186
  • 64
    Martínez X, Zapata Y, Pinto V, Cornejo C, Elbers M, Graaf M, et al. Intake of non-nutritive sweeteners in Chilean children after enforcement of a new food labeling law that regulates added sugar content in processed foods. Nutrients. 2020;12(6):1594. https://doi.org/10.3390/nu12061594
    » https://doi.org/10.3390/nu12061594
  • 65
    Chazelas E, Druesne-Pecollo N, Esseddik Y, Edelenyi FS, Agaesse C, Sa A, et al. Exposure to food additive mixtures in 106,000 French adults from the NutriNet-Santé cohort. Sci Rep. 2021;11:19680. https://doi.org/10.1038/s41598-021-98496-6
    » https://doi.org/10.1038/s41598-021-98496-6
  • 66
    Ministério da Saúde (BR), Agência Nacional de Vigilância Sanitária. Resolução - RDC Nº 45, de 3 de novembro de 2010. Dispõe sobre aditivos alimentares autorizados para uso segundo as Boas Práticas de Fabricação (BPF). Brasília, DF: Anvisa; 2010 [cited 2021 Sep 20]. Available from: https://bvsms.saude.gov.br/bvs/saudelegis/anvisa/2010/rdc0045_03_11_2010.html
    » https://bvsms.saude.gov.br/bvs/saudelegis/anvisa/2010/rdc0045_03_11_2010.html
  • 67
    Canella DS, Levy RB, Martins APB, Claro RM, Moubarac JC, Baraldi LG, et al. Ultra-processed food products and obesity in Brazilian households (2008-2009). PLoS One. 2014;9(3):e92752. https://doi.org/10.1371/journal.pone.0092752
    » https://doi.org/10.1371/journal.pone.0092752
  • 68
    Lane MM, Davis JA, Beattie S, Gómez-Donoso C, Loughman A, O’Neil A, et al. Ultraprocessed food and chronic noncommunicable diseases: a systematic review and meta-analysis of 43 observational studies. Obes Rev. 2021;22(3):e13146. https://doi.org/10.1111/obr.13146
    » https://doi.org/10.1111/obr.13146
  • 69
    Fiolet T, Srour B, Sellem L, Kesse-Guyot E, Allès B, Méjean C, et al. Consumption of ultraprocessed foods and cancer risk: results from NutriNet-Santé prospective cohort. BMJ. 2018;360:k322. https://doi.org/10.1136/bmj.k322
    » https://doi.org/10.1136/bmj.k322
  • 70
    Swidsinski A, Ung V, Sydora BC, Loening-Baucke V, Doerffel Y, Verstraelen H, et al. Bacterial overgrowth and inflammation of small intestine after carboxymethylcellulose ingestion in genetically susceptible mice. Inflamm Bowel Dis. 2009;15(3):359-364. https://doi.org/10.1002/ibd.20763
    » https://doi.org/10.1002/ibd.20763
  • 71
    Chassaing B, Koren O, Goodrich JK, Poole AC, Srinivasan S, Ley RE, et al. Dietary emulsifiers impact the mouse gut microbiota promoting colitis and metabolic syndrome. Nature. 2015;519(7541):92-6. https://doi.org/10.1038/nature14232
    » https://doi.org/10.1038/nature14232
  • 72
    Viennois E, Merlin D, Gewirtz AT, Chassaing B. Dietary emulsifier-induced low-grade inflammation promotes colon carcinogenesis. Cancer Res. 2017;77(1):27-40. https://doi.org/10.1158/0008-5472.CAN-16-1359
    » https://doi.org/10.1158/0008-5472.CAN-16-1359
  • 73
    Tobacman JK. Review of Harmful gastrointestinal effects of carrageenan in animal experiments. Environ Health Perspect. 2001;109(10):983-94. https://doi.org/10.1289/ehp.01109983
    » https://doi.org/10.1289/ehp.01109983
  • 74
    Bhattacharyya S, O-Sullivan I, Katyal S, Unterman T, Tobacman JK. Exposure to the common food additive carrageenan leads to glucose intolerance, insulin resistance and inhibition of insulin signalling in HepG2 cells and C57BL/6J mice. Diabetologia. 2012;55(1):194-203. https://doi.org/10.1007/s00125-011-2333-z
    » https://doi.org/10.1007/s00125-011-2333-z
  • 75
    Bhattacharyya S, Feferman L, Unterman T, Tobacman JK. Exposure to common food additive carrageenan alone leads to fasting hyperglycemia and in combination with high fat diet exacerbates glucose intolerance and hyperlipidemia without effect on weight. J Diabetes Res. 2015;2015:513429. https://doi.org/10.1155/2015/513429
    » https://doi.org/10.1155/2015/513429
  • 76
    Moutinho ILD, Bertges LC, Assis RVC. Prolonged use of food dye tartrazine (FD&C yellow nº5) and its effects on the gastric mucosa of Wistar rats. Braz J Biol. 2007;67(1):141-5. https://doi.org/10.1590/s1519-69842007000100019
    » https://doi.org/10.1590/s1519-69842007000100019
  • 77
    Mehedi N, Ainad-Tabet S, Mokrane N, Addou S, Zaoui C, Kheroua O, et al. Reproductive toxicology of tartrazine (FD and C Yellow No. 5) in Swiss albino mice. Am J Pharmacol Toxicol. 2009;4(4):130-5. https://doi.org/10.3844/ajptsp.2009.130.135
    » https://doi.org/10.3844/ajptsp.2009.130.135
  • 78
    Abou-Donia MB, El-Masry EM, Abdel-Rahman AA, McLendon RE, Schiffman SS. Splenda alters gut microflora and increases intestinal p-glycoprotein and cytochrome p-450 in male rats. J Toxicol Environ Health A. 2008;71(21):1415-29. https://doi.org/10.1080/15287390802328630
    » https://doi.org/10.1080/15287390802328630
  • 79
    Suez J, Korem T, Zeevi D, Zilberman-Schapira G, Thaiss CA, Maza O, et al. Artificial sweeteners induce glucose intolerance by altering the gut microbiota. Nature. 2014;514(7521):181-6. https://doi.org/10.1038/nature13793
    » https://doi.org/10.1038/nature13793
  • 80
    Simon BR, Parlee SD, Learman BS, Mori H, Scheller EL, Cawthorn WP, et al. Artificial sweeteners stimulate adipogenesis and suppress lipolysis independently of sweet taste receptors. J Biol Chem. 2013;288(45):32475-89. https://doi.org/10.1074/jbc.M113.514034
    » https://doi.org/10.1074/jbc.M113.514034
  • 81
    Swithers SE, Davidson TL. A role for sweet taste: calorie predictive relations in energy regulation by rats. Behav Neurosci. 2008;122(1):161-73. https://doi.org/10.1037/0735-7044.122.1.161
    » https://doi.org/10.1037/0735-7044.122.1.161
  • 82
    Albasher G, Maashi N, Alfarraj S, Almeer R, Albrahim T, Alotibi F, et al. Perinatal exposure to tartrazine triggers oxidative stress and neurobehavioral alterations in mice offspring. Antioxidants. 2020;9(1):53. https://doi.org/10.3390/antiox9010053
    » https://doi.org/10.3390/antiox9010053
  • 83
    Raya SA, Aboul-Enein AM, El-Nikeety MMA, Mohamed RS, Abdelwahid WMA. In Vivo comet assay of food additives’ combinations and their effects on biochemical parameters in albino rats. Biointerface Res Appl Chem. 2021;11(2):9170-83. https://doi.org/10.33263/BRIAC112.91709183
    » https://doi.org/10.33263/BRIAC112.91709183
  • 84
    Landrigan PJ, Straif K. Aspartame and cancer – new evidence for causation. Environ Health. 2021;20:42. https://doi.org/10.1186/s12940-021-00725-y
    » https://doi.org/10.1186/s12940-021-00725-y
  • 85
    Organisation for Economic Cooperation and Development. OECD Guidelines for the testing of chemicals, Section 1: Physical-Chemical properties. Paris (FR): OECD; 2021 [cited 2021 Sep 20]. https://doi.org/10.1787/20745753
    » https://doi.org/10.1787/20745753
  • 86
    Ministério da Saúde (BR), Agência Nacional de Vigilância Sanitária. Esclarecimentos sobre a declaração de alegações de conteúdo para aditivos alimentares na rotulagem de alimentos e bebidas. Informe Técnico. 2016 jan 19 [cited 2021 Apr 20];(70):1-9. Available from: https://www.gov.br/agricultura/pt-br/assuntos/inspecao/produtos-vegetal/legislacao-1/biblioteca-de-normas-vinhos-e-bebidas/informe-tecnico-no-70-de-19-de-janeiro-de-2016.pdf/view
    » https://www.gov.br/agricultura/pt-br/assuntos/inspecao/produtos-vegetal/legislacao-1/biblioteca-de-normas-vinhos-e-bebidas/informe-tecnico-no-70-de-19-de-janeiro-de-2016.pdf/view
  • 87
    Leisenring W, Ryan L. Statistical properties of the NOAEL. Regul Toxicol Pharmacol. 1992;15(2 Pt 1):161-71. https://doi.org/10.1016/0273-2300(92)90047-d
    » https://doi.org/10.1016/0273-2300(92)90047-d
  • 88
    Dorato MA, Engelhardt JA. The no-observable-adverse-effect level in drug safety evaluations: use, issues, and definition(s). Regul Toxicol Pharmacol. 2005;42(3):265-74. https://doi.org/10.1016/j.yrtph.2005.05.004
    » https://doi.org/10.1016/j.yrtph.2005.05.004
  • 89
    Younes M, Aquilina G, Castle L, Engel KH, Fowler P, Fernandez MJF, et al. Safety assessment of titanium dioxide (E171) as a food additive. EFSA J. 2021;19(5):e6585. https://doi.org/10.2903/j.efsa.2021.6585
    » https://doi.org/10.2903/j.efsa.2021.6585
  • 90
    France. Arrêté du 17 avril 2019 portant suspension de la mise sur le marché des denrées contenant l’additif E 171 (dioxyde de titane - TiO2). Journal Officiel de la République Française. 26 avril 2019 [cited 2021 Oct 8]. Available from: https://www.legifrance.gouv.fr/jorf/id/JORFTEXT000038410047?r=LNz0mqURAZ
    » https://www.legifrance.gouv.fr/jorf/id/JORFTEXT000038410047?r=LNz0mqURAZ
  • 91
    Ministério da Saúde (BR), Agência Nacional de Vigilância Sanitária. Webinar com a Gerência de Padrões e Regulação de Alimentos aborda a Agenda Regulatória de Alimentos 2021/2023. Brasília, DF: Anvisa; 2021 [cited 2021 Oct 08]. Available from: https://www.gov.br/anvisa/pt-br/assuntos/educacaoepesquisa/webinar/alimentos/arquivos/apresentacao-we-22-21-agenda-regulatoria-de-alimentos-2021-2023.pdf
    » https://www.gov.br/anvisa/pt-br/assuntos/educacaoepesquisa/webinar/alimentos/arquivos/apresentacao-we-22-21-agenda-regulatoria-de-alimentos-2021-2023.pdf
  • 92
    Paula Neto HA, Ausina P, Gomez LS, Leandro JGB, Zancan P, Sola-Penna M. Effects of food additives on immune cells as contributors to body weight gain and immune-mediated metabolic dysregulation. Front Immunol. 2017;8:1478. https://doi.org/10.3389/fimmu.2017.01478
    » https://doi.org/10.3389/fimmu.2017.01478
  • 93
    Piper JD, Piper PW. Benzoate and sorbate salts: a systematic review of the potential hazards of these invaluable preservatives and the expanding spectrum of clinical uses for sodium benzoate. Compr Rev Food Sci Food Saf. 2017;16(5):868-80. https://doi.org/10.1111/1541-4337.12284
    » https://doi.org/10.1111/1541-4337.12284
  • 94
    Brown RJ, Banate MA, Rother KI. Artificial sweeteners: a systematic review of metabolic effects in youth. Int J Pediatr Obes. 2010;5(4):305-12. https://doi.org/10.3109/17477160903497027
    » https://doi.org/10.3109/17477160903497027
  • 95
    Reid AE Chauhan BF Rabbani R, Lys J, Copstein L, Mann A, et al. Early exposure to nonnutritive sweeteners and longterm metabolic health: a systematic review. Pediatrics. 2016;137(3):e20153603. https://doi.org/10.1542/peds.2015-3603
    » https://doi.org/10.1542/peds.2015-3603
  • 96
    Blot WJ, Henderson BE, Boice JD Jr. Childhood cancer in relation to cured meat intake: review of the epidemiological evidence. Nutr Cancer. 1999;34(1):111-8. https://doi.org/10.1207/S15327914NC340115
    » https://doi.org/10.1207/S15327914NC340115
  • 97
    Dietrich M, Block G, Pogoda JM, Buffler P, Hecht S, Preston-Martin S. A review: dietary and endogenously formed N-nitroso compounds and risk of childhood brain tumors. Cancer Causes Control. 2005;16(6):619-35. https://doi.org/10.1007/s10552-005-0168-y
    » https://doi.org/10.1007/s10552-005-0168-y
  • 98
    Lohner S, Toews I, Meerpohl JJ. Health outcomes of non-nutritive sweeteners: analysis of the research landscape. Nutr J. 2017;16:55. https://doi.org/10.1186/s12937-017-0278-x
    » https://doi.org/10.1186/s12937-017-0278-x
  • 99
    Shankar P, Ahuja S, Sriram K. Non-nutritive sweeteners: review and update. Nutrition. 2013;29(11-12):1293-9. https://doi.org/10.1016/j.nut.2013.03.024
    » https://doi.org/10.1016/j.nut.2013.03.024
  • 100
    Fowler SPG. Low-calorie sweetener use and energy balance: results from experimental studies in animals, and large-scale prospective studies in humans. Physiol Behav. 2016;164(Pt B):517-23. https://doi.org/10.1016/j.physbeh.2016.04.047
    » https://doi.org/10.1016/j.physbeh.2016.04.047
  • 101
    Daher MI, Matta JM, Abdel Nour AM. Non-nutritive sweeteners and type 2 diabetes: should we ring the bell? Diabetes Res Clin Pract. 2019;155:107786. https://doi.org/10.1016/j.diabres.2019.107786
    » https://doi.org/10.1016/j.diabres.2019.107786
  • 102
    United Nations Conference on Environment and Development; 3-14 Jun 1992; Rio de Janeiro, Brazil. New York: UN; 1993 [cited 2021 Apr 20]. https://undocs.org/en/A/CONF.151/26/Rev.1(vol.I)3-4
    » https://undocs.org/en/A/CONF.151/26/Rev.1(vol.I)3-4
  • 103
    Vally H, Misso NLA, Madan V. Clinical effects of sulphite additives. Clin Exp Allergy. 2009;39(11):1643-51. https://doi.org/10.1111/j.1365-2222.2009.03362.x
    » https://doi.org/10.1111/j.1365-2222.2009.03362.x
  • 104
    Song P, Wu L, Guan W. Dietary nitrates, nitrites, and nitrosamines intake and the risk of gastric cancer: a meta-analysis. Nutrients. 2015;7(12):9872-95. https://doi.org/10.3390/nu7125505
    » https://doi.org/10.3390/nu7125505
  • 105
    Romo-Romo A, Aguilar-Salinas CA, Brito-Córdova GX, Gómez Díaz RA, Valentín DV, et al. Effects of the non-nutritive sweeteners on glucose metabolism and appetite regulating hormones: systematic review of observational prospective studies and clinical trials. PLoS One. 2016;11(8):e0161264. https://doi.org/10.1371/journal.pone.0161264
    » https://doi.org/10.1371/journal.pone.0161264
  • 106
    Azad MB, Abou-Setta AM, Chauhan BF, Rabbani R, Lys J, Copstein L, et al. Nonnutritive sweeteners and cardiometabolic health: a systematic review and meta-analysis of randomized controlled trials and prospective cohort studies. CMAJ. 2017;189(28):E929-39. https://doi.org/10.1503/cmaj.161390
    » https://doi.org/10.1503/cmaj.161390
  • 107
    Crowe W, Elliott CT, Green BDA. Review of the in vivo evidence investigating the role of nitrite exposure from processed meat consumption in the development of colorectal cancer. Nutrients. 2019;11(11):2673. https://doi.org/10.3390/nu11112673
    » https://doi.org/10.3390/nu11112673
  • 108
    Shum B, Georgia S. The effects of non-nutritive sweetener consumption in the pediatric populations: what we know, what we don’t, and what we need to learn. Front Endocrinol (Lausanne). 2021;12:625415. https://doi.org/10.3389/fendo.2021.625415
    » https://doi.org/10.3389/fendo.2021.625415
  • 109
    Cai C, Sivak A, Davenport MH. Effects of prenatal artificial sweeteners consumption on birth outcomes: a systematic review and meta-analysis. Public Health Nutr. 2021;24(15):5024-33. https://doi.org/10.1017/S1368980021000173
    » https://doi.org/10.1017/S1368980021000173
  • 110
    McCann D, Barrett A, Cooper A, Crumpler D, Dalen L, Grimshaw K, et al. Food additives and hyperactive behaviour in 3-year-old and 8/9-year-old children in the community: a randomised, double-blinded, placebo-controlled trial. Lancet. 2007;370(9598):1560-7. https://doi.org/10.1016/S0140-6736(07)61306-3
    » https://doi.org/10.1016/S0140-6736(07)61306-3
  • 111
    Connoly A, Hearty A, Nugent A, McKevitt A, Boylan E, Flynn A, et al. Pattern of intake of food additives associated with hyperactivity in Irish children and teenagers. Food Addit Contam Part A. 2010;27(4):447-56. https://doi.org/10.1080/19440040903470718
    » https://doi.org/10.1080/19440040903470718
  • 112
    Petrus M, Bonaz S, Causse E, Rhabbour M, Moulie N, Netter JC, et al. Asthme et intolérance aux benzoates. Arch Pediatr. 1996;3(10):984-7. https://doi.org/10.1016/0929-693X(96)81719-2
    » https://doi.org/10.1016/0929-693X(96)81719-2
  • 113
    Jacob SE, Hill H, Lucero H, Nedorost A. Benzoate allergy in children: from foods to personal hygiene products. Pediatr Dermatol. 2016;33(2):213-5. https://doi.org/10.1111/pde.12759
    » https://doi.org/10.1111/pde.12759
  • 114
    Inomata NA, Osuna HA, Fujita HA, Ogawa TA, Ikezawa Z. Multiple chemical sensitivities following intolerance to azo dye in sweets in a 5-year-old girl. Allergol Int. 2006;55(2):203-5. https://doi.org/10.2332/allergolint.55.203
    » https://doi.org/10.2332/allergolint.55.203
  • 115
    Vojdani A, Vojdani C. Immune reactivity to food coloring. Altern Ther Health Med. 2015;21 Suppl 1:52-62.
  • 116
    Skrie VC, Orellana JC. Reacción adversa por aditivos alimentarios en un paciente pediátrico. Rev Alerg Mex. 2018;65(2):187-91. https://doi.org/10.29262/ram.v65i2.288
    » https://doi.org/10.29262/ram.v65i2.288
  • 117
    Mueller NT, Jacobs DR Jr, MacLehose RF, Demerath EW, Kelly SP, Dreyfus JG, et al. Consumption of caffeinated and artificially sweetened soft drinks is associated with risk of early menarche. Am J Clin Nutr. 2015;102(3):648-54. https://doi.org/10.3945/ajcn.114.100958
    » https://doi.org/10.3945/ajcn.114.100958
  • 118
    Ali F. Consumption of artificial sweeteners in pregnancy increased overweight risk in infants. Arch Dis Child Educ Pract Ed. 2017;102(5):277. https://doi.org/10.1136/archdischild-2017-312618
    » https://doi.org/10.1136/archdischild-2017-312618
  • 119
    Zhu Y, Olsen SF, Mendola P, Halldorsson TI, Rawal S, Hinkle SN, et al. Maternal consumption of artificially sweetened beverages during pregnancy, and offspring growth through 7 years of age: a prospective cohort study. Int J Epidemiol. 2017;46(5):1499-508. https://doi.org/10.1093/ije/dyx095
    » https://doi.org/10.1093/ije/dyx095
  • 120
    Taheri S. Effect of exclusion of frequently consumed dietary triggers in a cohort of children with chronic primary headache. Nutr Health. 2017;23(1):47-50. https://doi.org/10.1177/0260106016688699
    » https://doi.org/10.1177/0260106016688699

  • a
    Part of the so-called NOVA classification of foods. Ultra-processed foods are usually made from multiple ingredients. These foods may contain ingredients extracted from other foods (casein, gluten, etc.) or derived from other foods (maltodextrin, invert sugar, hydrogenated oils, etc.). In addition, food additives such as dyes, sweeteners, stabilizers, flavor enhancers, among others, are used intensively.
  • b
    Acronym for buthylated hydroxyanisole
  • c
    Acronym for butylated hydroxytoluene
  • d
    Acronym for tertiary butylhydroquinone
  • e
    Anvisa is in the process of compiling the rules that regulate the use of additives in processed foods in Brazil.

  • Funding:Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (Capes - Process 88882.438764/2019-01).

Publication Dates

  • Publication in this collection
    06 May 2022
  • Date of issue
    2022

History

  • Received
    14 July 2021
  • Accepted
    13 Dec 2021
Faculdade de Saúde Pública da Universidade de São Paulo São Paulo - SP - Brazil
E-mail: revsp@org.usp.br