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Current knowledge of environmental exposure in children during the sensitive developmental periods Please cite this article as: Perlroth NH, Branco CW. Current knowledge of environmental exposure in children during the sensitive developmental periods. J Pediatr (Rio J). 2017;93:17-27.

Abstract:

Objective:

This study aims to identify the scientific evidence on the risks and effects of exposure to environmental contaminants in children during sensitive developmental periods.

Data source:

The search was performed in the Bireme database, using the terms: children's health, environmental exposure, health vulnerability, toxicity pathways and developmental disabilities in the LILACS, MEDLINE and SciELO systems.

Data synthesis:

Children differ from adults in their unique physiological and behavioral characteristics and the potential exposure to risks caused by several threats in the environment. Exposure to toxic agents is analyzed through toxicokinetic processes in the several systems and organs during the sensitive phases of child development. The caused effects are reflected in the increased prevalence of congenital malformations, diarrhea, asthma, cancer, endocrine and neurological disorders, among others, with negative impacts throughout adult life.

Conclusion:

To identify the causes and understand the mechanisms involved in the genesis of these diseases is a challenge for science, as there is still a lack of knowledge on children's susceptibility to many environmental contaminants. Prevention policies and more research on child environmental health, improving the recording and surveillance of environmental risks to children's health, should be an ongoing priority in the public health field.

KEYWORDS
Children's health; Environmental exposure; Vulnerability; Pathways of toxicity penetration; Developmental disability

Resumo:

Objetivo:

O presente estudo busca identificar as evidências científicas sobre os riscos e efeitos da exposição de contaminantes ambientais no organismo infantil durante os períodos sensíveis de seu desenvolvimento.

Fonte de dados:

As pesquisas foram feitas pelo banco de dados da Bireme, com os termos children's health, environmental exposure, health vulnerability, toxicity pathways e developmental disabilities nos sistemas Lilacs, Medline e SciELO.

Síntese de dados:

A criança difere do adulto por suas características singulares de ordem fisiológica, comportamental e do potencial de exposição a riscos frente às ameaças do ambiente. A exposição a agentes tóxicos é analisada por meio dos processos toxicocinéticos nos sistemas e órgãos durante as janelas sensíveis do desenvolvimento infantil. Os efeitos causados transparecem no aumento da prevalência de malformações congênitas, diarreia, asma, cânceres, distúrbios endócrinos e neurológicos, entre outros, com impactos negativos ao longo da vida adulta.

Conclusão:

Identificar as causas e compreender os mecanismos envolvidos na gênese desses agravos é um desafio que se impõe à ciência, visto que ainda há uma lacuna de conhecimento sobre a suscetibilidade infantil para muitos contaminantes ambientais. Políticas de prevenção e mais pesquisas em saúde ambiental infantil, que impulsionem o registro e a vigilância epidemiológica dos riscos ambientais à saúde da criança, devem ser uma prioridade contínua no campo da saúde pública.

PALAVRAS-CHAVE
Saúde infantil; Exposição ambiental; Vulnerabilidade; Vias de penetração da toxicidade; Deficiências do desenvolvimento

Introduction

In 1946, the World Health Organization declared, in an open letter to its members, that all children have the right to a healthy development where they can live harmoniously in a diversified environment11 WHO. Constitution of the World Health Organization. Copy of the original print version. Am J Public Health Nations Health. 1946;36:1315-1323. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1625885/pdf/amjphnation00639-0074.pdf [cited 13.01.15].
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so that, in a near future, they can reach their full potential as world citizens.22 WHO. Children's Health and the Environment - a global perspective. A resource guide for the health sector. Geneva: World Health organization; 2005. Available from: http://apps.who.int/iris/bitstream/10665/43162/1/9241562927_eng.pdf [cited 12.07.15].
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From a broader view, it can be suggested that this concept of environment includes not only the natural world, but also the physical context in which the child interacts with its world: the external environment (air, water, earth, and living beings); the community (social environment, school, and neighborhood where the child lives); and the home environment.33 David B. Introduction. In: Making a difference: indicators to improve children's environmental health. Geneva: World Health Organization; 2003. p. 1-2.

The interest and the degree of knowledge about the different ways in which the environment can influence children's health in the places where they routinely stay in their daily life has increased considerably in the last two decades.22 WHO. Children's Health and the Environment - a global perspective. A resource guide for the health sector. Geneva: World Health organization; 2005. Available from: http://apps.who.int/iris/bitstream/10665/43162/1/9241562927_eng.pdf [cited 12.07.15].
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They include not only the child as a biological being with a genetic potential, but also the interaction of a multitude of influences (physical, chemical, and biological), as well as factors (psychosocial, cultural, and economic) that have a complex impact on the life of these children.44 Brent RL, Weitzman M. The current state of knowledge about the effects, risks, and science of children's environmental exposures. Pediatrics. 2004;113:S1158-S1166.

5 The National Academies Press - NAP. Children's health, the nation's wealth: assessing and improving child health. National Research Council and Institute of Medicine. Washington, DC: The National Academies Press; 2004. p. 45-90.

6 Landrigan PG, Garg A. Children are not little adults. In: Pronczuk-Garbino J, editor. Children's health and the environment. A global perspective. Geneva: World Health Organization; 2005. p. 3-16.
-77 Paris EB. La importancia de la salud ambiental y el alcance de las unidades de pediatría ambiental. Rev Med Chile. 2009;137:101-105.

Children comprise 26% of the world's population and are among the most vulnerable groups to be exposed to environmental risks. It is estimated that they account for over 30% (31-40%) of the global disease burden, especially in children under 5 years of age.88 Prüss-Üstün A, Corvalán C. Preventing disease through healthy environments: towards an estimate of the environmental burden of disease. Geneva: World Health Organization; 2006.,99 WHO. Principles for evaluating health risks in children associated with exposure to chemical. Environmental Health Criteria Nº 237. Geneva: World Health Organization; 2006. Available from: http://apps.who.int/iris/bitstream/10665/43604/1/924157237X_eng.pdf [cited 16.03.15].
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Considering this terrible picture, of a completely imbalanced state between the child and its environment, there is a population of 223 million young citizens who, over the past two decades, died before reaching the age of 5 years.1010 United Nations Children's Fund. Compromisso com a sobrevivência infantil: uma promessa. Relatório de progresso 2014. Resumo executivo. Brasil: UNICEF; 2014.

Unhealthy environments, unfavorable situations regarding access to clean water, waste disposal (sanitation), limited family income, parents' low educational level, and early cessation of breastfeeding may contribute to the children's illnesses and mortality.1111 Ercumen A, Gruber JS, Colford JM. Water distribution system deficiencies and gastrointestinal illness: a systematic review and meta-analysis. Environ Health Perspect. 2014;122:651-660.,1212 Rodriguez L, Cervantes E, Ortiz R. Malnutrition and gastrointestinal and respiratory infections in children: a public health problem. Int J Environ Res Public Health. 2011;8:1174-1205. Worldwide, 10% of all diseases recorded in children could be prevented if governments invested more in access to clean water, hygiene measures, and basic sanitation.1313 Prüss-Ustün A, Bartram J, Clasen T, Colford JM, Cumming O, Curtis V, et al. Burden of disease from inadequate water, sanitation and hygiene in low- and middle-income settings: a retrospective analysis of data from 145 countries. Trop Med Int Health. 2014;19:894-905.

The fact that more than one million children die each year as a result of acute respiratory diseases, 60% of these deaths being related to environmental pollutants, cannot be ignored.1010 United Nations Children's Fund. Compromisso com a sobrevivência infantil: uma promessa. Relatório de progresso 2014. Resumo executivo. Brasil: UNICEF; 2014. Degraded ecosystems, environmental smoke, air pollution, and climate changes are the likely factors that cause changes in the health status of this population.1414 Mello-da-Silva CA, Fruchtengarten L. Riscos químicos ambientais à saúde da criança. J Pediatr (Rio J). 2005;81:S205-S211.,1515 Quiroga D. La historia ambiental pediátrica. In: Manual de salud ambiental infantil. Chile: LOM Editores; 2009. p. 27---31. The pathways through which these agents can act and mutually operate are not always clear and are often indirect, but their consequences are considered a risk to the integrity of the airways, due to changes in the respiratory system balance and their influence on the interactions between the host, pathogen, and environment, increasing the likelihood of infection in that population.1616 du Prel JB, Puppe W, Grondahl B, Knuf M, Weigl JAI, Schaaff F, et al. Are meteorological parameters associated with acute respiratory tract infections? Clin Infect Dis. 2009;49:861-868.,1717 Martins AL, Trevisol FS. Internações hospitalares por pneumonia em crianças menores de cinco anos de idade em um hospital no Sul do Brasil. Revista da AMRIGS (Porto Alegre). 2013;57:304-308.

Depending on their age, gender, geographic region, and socioeconomic status, children have peculiar behavior. They are dependent on the developmental stages characterized by physical, psychosocial, and cognitive changes, the potential of risk exposure and parental perceptions regarding the acquisition of skills and capabilities in the presence of different physical threats in the home environment.1818 Promoting health and preventing illness.Hagan JF, Shaw JS, Duncan PM, editors. Bright futures: guidelines for health supervision of infants, children, and adolescents. 3rd ed. Pocket Guide. Elk Grove Village IL: American Academy of Pediatrics; 2008, xii.,1919 Waksman RD, Blank D, Gikas RM. Injúrias ou lesões não-intencionais "acidentes" na infância e na adolescência. São Paulo: MedicinaNet; 2010. Available from: http://www.medicinanet.com.br/conteudos/revisoes/1783/injurias_ou_lesoes_nao_intencionais_%E2%80%9Cacidentes%E2%80%9D_na_infancia_e_na_adolescencia.htm [cited 14.06.15].
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The most challenging is that, while low levels of exposure to many chemicals are inevitable, little is known about the risks of such exposures on the morbidity, mortality, and subtle changes in this population.44 Brent RL, Weitzman M. The current state of knowledge about the effects, risks, and science of children's environmental exposures. Pediatrics. 2004;113:S1158-S1166.,2020 California Childcare Health Program - CCHP. Environmental health. 1st ed. California Training Institute. University of California, San Francisco School of Nursing, Department of Family Health Care Nursing; 2006. It is noteworthy that these products exposed in the environment can act synergistically, which means that their combined effect may be more harmful to children.

Based on the premise that the pediatric population reacts in a very unique way to the environment, scientific advances have provided hypotheses and even strong arguments about how lifestyle and the social environment where the child lives can change their gene functioning. Drugs, pesticides, air pollutants, chemicals, heavy metals, hormones, and nutrition products, among others, are examples of elements that can result in gene expression alterations that will be inherited by the next generations.2121 Smith MT, McHale CM, Wiemels JL, Zhang LP, Wiencke JK, Zheng SC, et al. Molecular biomarkers for the study of childhood leukemia. Toxicol Appl Pharmacol. 2005;206:237-245.,2222 Edwards TM, Myers JP. Environmental exposures and gene regulation in disease etiology. Environ Health Perspect. 2007;115:1264-1270.

This susceptibility is always focused on agents or specific compounds in specific exposure scenarios, including intrauterine exposure,2323 Juberg DR. Introduction. In: Are children more vulnerable to environmental chemicals? Scientific and regulatory issues in perspective. New York: American Council on Science and Health; 2003. p. 11-6. which can interfere during critical and sensitive growth and developmental periods and have a negative impact throughout life, possibly causing structural and functional deficits, temporary or permanent impairment, and even death.2424 Hertzman C. The case for an early childhood developmental strategy. Isuma. 2000;1:11-18. These occur because children have no control over the environment in the prenatal and postnatal periods, including the quality of the air they breathe, the water they drink, the food they eat,2525 Wigle DT. Environmental threats to child health: overview. In: Child health and the environment. New York: Oxford University Press; 2003. p. 1-26. and their exposure to disease-transmitting vectors.2626 Fiocruz. Pesquisa da Fiocruz Paraná confirma transmissão intra-uterina do zika vírus. Brasil: Fiocruz Paraná; 2016. Available from: http://portal.fiocruz.br/pt-br/content/pesquisa-da-fiocruz-parana-confirma-transmissao-intra-uterina-do-zika-virus [cited 28.03.16].
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Regarding infection transmitted by vectors, there is a scientific acknowledgment that Brazil with its epicenter in the Northeast region, has been showing since October 2015 an excess number of cases of newborns with microcephaly and severe brain abnormalities,2727 PAHO, WHO. Epidemiological alert. Neurological syndrome, congenital malformations, and Zika virus infection. Implications of public health in the Americas. USA: Pan American Health Organization and World Health Organization; 2015. Available from: http://www.paho.org/hq/index.php?option=com_docman&task=doc_view&Itemid=270&gid=32405&lang=en [cited 03.01.16].
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,2828 Brasil. Ministério da Saúde. Secretaria de Vigilância em Saúde. Protocolo de vigilância e resposta à ocorrência de microcefalia - Emergência de Saúde Pública de Importância Nacional - ESPIN. Versão 1.3. Brasília: Ministério da Saúde; 2016. whose the proven causative agent is the Zika virus, transmitted by the Aedes aegypti mosquito, resulting from maternal exposure during the first months of pregnancy.2929 Costa F, Sarno M, Ricardo Khouri R, Freitas BP, Isadora Siqueira I, Ribeiro GS, et al. Emergence of congenital zika syndrome: viewpoint from the front lines. Ann Intern Med. 2016. Available from: http://annals.org/article.aspx?articleid=2498549 [cited 24.03.16].
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30 European Centre for Disease Prevention and Control. Zika virus epidemic in the Americas: potential association with microcephaly and Guillain-Barré syndrome (first update). Stockholm: ECDC; 2016, 21 January 2016. Available from: http://ecdc.europa.eu/en/publications/Publications/rapid-risk-assessment-zika-virus-first-update-jan-2016.pdf [cited 24.03.16].
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31 Rasmussen SA, Jamieson DJ, Margaret A, Honein MA, Petersen LR. Zika virus and birth defects - reviewing the evidence for causality. Special report. N Engl J Med. 2016;:1-7.
-3232 WHO. WHO Director-General summarizes the outcome of the Emergency Committee regarding clusters of microcephaly and Guillain-Barré syndrome. Geneva: World Health Organization; 2016. Available from: http://who.int/mediacentre/news/statements/2016/emergency-committee-zika-microcephaly/en/ [cited 28.03.16].
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Because it also transmits dengue fever and chikungunya, the elimination of this mosquito has been considered by the World Health Organization, since February of 2016, an international public health emergency.3232 WHO. WHO Director-General summarizes the outcome of the Emergency Committee regarding clusters of microcephaly and Guillain-Barré syndrome. Geneva: World Health Organization; 2016. Available from: http://who.int/mediacentre/news/statements/2016/emergency-committee-zika-microcephaly/en/ [cited 28.03.16].
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Still during pregnancy, maternal exposure to chemicals resulting from industrial, agricultural and mining activities may reflect the possible increased prevalence of prematurity,3333 Winchester P, Proctor C, Ying J. County-level pesticide use and risk of shortened gestation and preterm birth. Acta Paediatr. 2016;105:e107-e115. hematopoietic cancers,3434 Chen M, Chang CH, Tao L, Lu C. Residential exposure to pesticide during childhood and childhood cancers: a meta-analysis. Pediatrics. 2015;136:719-729.,3535 Curvo HR, Pignati WA, Pignatti MG. Morbimortalidade por câncer infanto juvenil associada ao uso agrícola de agrotóxicos no Estado de Mato Grosso, Brasil. Cad Saúde Coletiva. 2013;21:10-17. birth defects, asthma, endocrine, neurological, and behavioral disorders of their children.3636 Grandjean P, Landrigan PJ. Neurobehavioural effects of developmental toxicity. Lancet Neurol. 2014;13:330-338.

37 Eskenazi B, Bradman A, Castorina R. Exposures of children to organophosphate pesticides and their potential adverse health effects. Environ Health Perspect. 1999;107:S409-S419.

38 Turner MC, Wigle DT, Krewski D. Residential pesticides and childhood leukemia: a systematic review and meta-analysis. Environ Health Perspect. 2010;118:33-41.
-3939 Rice D, Barone S. Critical periods of vulnerability for the developing nervous system: evidence from humans and animal models. Environ Health Perspect. 2000;108:511-533. As for the biological effects of maternal exposure to physical agents, such as ionizing radiation (dose above 250 mGy), they can lead to intrauterine death, fetal malformations, fetal growth disorders, and carcinogenic effects.4040 D'Ippolito G, Medeiros RB. Exames radiológicos na gestação. Radiol Bras. 2005;38:447-450.

Given these facts, the objective of this article was to explore the scientific evidence regarding the impact of exposure to environmental contaminants in children during sensitive developmental periods, based on their special characteristics.

Children's particular characteristics

Due to the fact that they are going through a phase of growth and development, the pediatric population is a special demographic group concerning biology, physiological, metabolic, and behavioral processes, which are complex and multilayered.88 Prüss-Üstün A, Corvalán C. Preventing disease through healthy environments: towards an estimate of the environmental burden of disease. Geneva: World Health Organization; 2006.,4141 Selevan SG, Kimmel CA, Mendola P. Identifying critical windows of exposure for children's health. Environ Health Perspect. 2000;108:S451-S455. From the embryonic phase to late adolescence, children are often exposed to intrinsic risk factors (genetic, metabolic, and hereditary, very often correlated) and extrinsic or environmental factors (food, socioeconomic, geophysical, and urbanization conditions, as well as mother-child relationship), which may adversely affect the dynamic processes of growth and development.4242 Aquino LA. Acompanhamento do crescimento normal. Revista de Pediatria SOPERJ. 2011;12:15-20.,4343 Romani SA, Lira PI. Fatores determinantes do crescimento infantil. Rev Bras Saúde Mater Infant. 2004;4:15-23. What determines the nature and severity of the effects of these factors on children's health is the occurrence of adverse environmental exposures at different stages, called "critical exposure windows", "windows of vulnerability",4444 Agency for Toxic Substances & Disease Registry - ATSDR. Why are children often especially susceptible to the adverse effects of environmental toxicants? In: Principles of pediatric environmental health; 2012. Available from: http://www.atsdr.cdc.gov/csem/csem.asp?csem=27&po=3 [cited 13.03.15].
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or "developmental windows",4545 WHO. Children's Health and the Environment. Children are not little adults. Geneva: World Health Organization; 2008. Available from: http://www.who.int/ceh/capacity/Children_are_not_little_adults.pdf [cited 12.01.15].
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where the functions of cell maturation, differentiation, and growth are occurring at different rates.

Since conception, there is a close association between fetal growth and the environment, to the point that, at a certain period, growth is limited by the space of the uterine cavity.4141 Selevan SG, Kimmel CA, Mendola P. Identifying critical windows of exposure for children's health. Environ Health Perspect. 2000;108:S451-S455. After 9 months of intrauterine growth, the child's organs and systems become relatively mature, enough to safely adapt to life.4646 The National Academies Press - NAP. Special characteristics of children. In: Pesticides in the diets of infants and children. National Research Council (US) Committee on Pesticides in the Diets of Infants and Children. Washington, DC: The National Academies Press; 1993. p. 24-44. The physical growth and functional maturation of the body will continue, and may vary from system to system, from organ to organ and from tissue to tissue, because each child is different in their structure and function at any age.4545 WHO. Children's Health and the Environment. Children are not little adults. Geneva: World Health Organization; 2008. Available from: http://www.who.int/ceh/capacity/Children_are_not_little_adults.pdf [cited 12.01.15].
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,4747 Agency for Toxic Substances & Disease Registry - ATSDR. Why do a child's age and developmental stage affect physiological susceptibility to toxic substances? In: Principles of pediatric environmental health; 2012. Available from: http://www.atsdr.cdc.gov/csem/csem.asp?csem=27&po=7 [cited 12.03.15].
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As an example of this differentiated rate of child growth, studies suggest that in the second month of intrauterine life, the fetal head should correspond to half of the body, whereas at birth it is 25%, and in adulthood, it should correspond to 10% of the whole physical structure.4242 Aquino LA. Acompanhamento do crescimento normal. Revista de Pediatria SOPERJ. 2011;12:15-20.,4848 Brasil. Ministério da Saúde. Secretaria de Políticas de Saúde. Departamento de Atenção Básica. Saúde da Criança: acompanhamento do crescimento e desenvolvimento infantil. Série Cadernos de Atenção Básica nº 11. (Série A. Normas e Manuais Técnicos). Brasília: Ministério da Saúde; 2002. At 6 months of life, the brain must reach 50% of its adult weight, and at 3 years, it should have reached approximately 90% of this weight.3939 Rice D, Barone S. Critical periods of vulnerability for the developing nervous system: evidence from humans and animal models. Environ Health Perspect. 2000;108:511-533.,4545 WHO. Children's Health and the Environment. Children are not little adults. Geneva: World Health Organization; 2008. Available from: http://www.who.int/ceh/capacity/Children_are_not_little_adults.pdf [cited 12.01.15].
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Approximately 50% of the size of an adult is reached at 2 years of age.4242 Aquino LA. Acompanhamento do crescimento normal. Revista de Pediatria SOPERJ. 2011;12:15-20.,4848 Brasil. Ministério da Saúde. Secretaria de Políticas de Saúde. Departamento de Atenção Básica. Saúde da Criança: acompanhamento do crescimento e desenvolvimento infantil. Série Cadernos de Atenção Básica nº 11. (Série A. Normas e Manuais Técnicos). Brasília: Ministério da Saúde; 2002. In contrast, 50% of the weight of the liver, heart, and kidneys of an adult is not reached until the child is approximately 9 years old. The same points in growth of skeletal muscle and total body weight are not reached until near the 11th year of life.4646 The National Academies Press - NAP. Special characteristics of children. In: Pesticides in the diets of infants and children. National Research Council (US) Committee on Pesticides in the Diets of Infants and Children. Washington, DC: The National Academies Press; 1993. p. 24-44. These periods of child development are especially sensitive to exposure to certain biological, chemical agents, and physical factors found in the environment.4646 The National Academies Press - NAP. Special characteristics of children. In: Pesticides in the diets of infants and children. National Research Council (US) Committee on Pesticides in the Diets of Infants and Children. Washington, DC: The National Academies Press; 1993. p. 24-44.

In children younger than 5 years of age, the influence of environmental factors is much more important than genetic factors. The younger the child, the more dependent and vulnerable he/she is in relation to the environment that surrounds him/her. And if that environment is not adequate, there is the possibility of failure regarding some aspect of child development.4242 Aquino LA. Acompanhamento do crescimento normal. Revista de Pediatria SOPERJ. 2011;12:15-20.,4949 Zick GSN. Os fatores ambientais no desenvolvimento infantil. Revista de Educação do Instituto de Desenvolvimento Educacional do Alto Uruguai - IDEAU. 2010. Available from: http://www.ideau.com.br/getulio/restrito/upload/revistasartigos/176_1.pdf [cited 23.01.15].
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In this context, the embryonic development taking place inside the mother's uterus (environment) would not be protected from the embryotoxic effects of harmful environmental agents.5050 Wilson JC. Current status of teratology. In: Wilson JC, Fraser FC, editors. General principles and mechanisms derived from animal studies. Handbook of teratology. General principles and etiology. Nova York: Plenum Press; 1977. p. 47-74. As an example, the tragedy of the drug thalidomide, used during pregnancy in the 1950s, led to the special attention of researchers on the occurrence of teratogenic effects of the drug on the fetus' health, causing phocomelia with irreversible damages.55 The National Academies Press - NAP. Children's health, the nation's wealth: assessing and improving child health. National Research Council and Institute of Medicine. Washington, DC: The National Academies Press; 2004. p. 45-90. In 2010, Japanese scientists identified how thalidomide interferes with fetal development. The drug binds to a protein called cereblon (CRBN), inactivating it, resulting in limb malformation.5151 Ito T, Ando H, Suzuki T, Ogura T, Hotta K, Imamura Y, et al. Identification of a primary target of thalidomide teratogenicity. Science. 2010;327:1345-1350.

The precocity and the persistence of adverse conditions in children's systems or organs before their complete maturation can cause temporary or permanent damage to the normal physical maturation and, consequently, to their current and future health.5252 Westwood M, Kramer MS, Munz D, Lovett JM, Watters GV. Growth and development of full-term nonasphyxiated small-for-gestational-age newborns: follow-up through adolescence. Pediatrics. 1983;71:376-382.

Exposure pathways of environmental toxicants in target systems and organs during children's developmental stages

Contamination occurs through an exposure pathway, as shown in Fig. 1, between the agent in the physical environment (in utero, breast milk, oral, parenteral) and the developmental period when the child was exposed (fetal, neonatal, childhood, puberty).5353 Alves C, Flores LC, Cerqueira TS, Toralles MB. Exposição ambiental a interferentes endócrinos com atividade estrogênica e sua associação com distúrbios puberais em crianças. Cad Saúde Pública. 2007;23:1005-1014. It is extremely important to know the magnitude of the adverse substance, the duration and frequency of exposure and the child's individual susceptibility, and the introduction pathways of the pathological agents.5454 Agencia Nacional de Vigilância Sanitária - ANVISA. Modulo III. Fundamentos de toxicologia. Fase 1 - Exposição; 2006. Available from: http://ltc-ead.nutes.ufrj.br/toxicologia/mIII.fase1.htm [cited 13.06.15].
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,5555 Stolf A, Dreifuss A, Vieira FL. Farmacocinética. In: III Curso de Verão em Farmacologia. Paraná: UFPR Biológicas; 2011. p. 3-22.

Figure 1
Adapted from Ruppenthal.104104 Ruppenthal JE. Toxicologia. Colégio Técnico Industrial de Santa Maria. UFSM. Rede e-Tec Brasil; 2013.

Breastfeeding: the ideal form of infant nutrition, it has ensured the survival of the human species, providing nutritional, immunological, cognitive, psycho-affective, economic, and social advantages,5656 Chaves RG, Lamounier JA, César CC. Medicamentos e amamentação: atualização e revisão aplicadas à clínica materno-infantil. Rev Paul Pediatr. 2007;25:276-288.,5757 Landrigan PJ, Sonawane B, Mattison D, McCally M, Garg A. Chemical contaminants in breast milk and their impacts on children's health: an overview. Environ Health Perspect. 2002;110:A313-A315. significantly reducing the child's risk of developing several diseases. Influenced by factors of the nursing mother, infant, and/or toxicant, breastfeeding can introduce into the baby's circulation several toxic substances, such as dioxins, polychlorinated biphenyls (PCBs), mercury and chlorinated pesticides,5858 Solomon GM, Weiss PM. Chemical contaminants in breast milk: time trends and regional variability. Environ Health Perspect. 2002;110:A339-A347. nicotine,5959 Primo CC, Ruela PB, Brotto LD, Garcia TR, Lima EF. Efeitos da nicotina materna na criança em amamentação. Rev Paul Pediatr. 2013;31:392-397. lead,6060 Agency for Toxic Substances & Disease Registry - ATSDR. Principles of pediatric environmental health. How are newborns, infants, and toddlers exposed to and affected by toxicants? In: Principles of pediatric environmental health; 2012. Available from: http://www.atsdr.cdc.gov/csem/csem.asp?csem=27&po=9 [cited 14.03.15].
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and medications,6161 Brasil. Ministério da Saúde. Secretaria da Atenção à Saúde. Departamento de Ações Programáticas e Estratégicas. Amamentação e uso de medicamentos e outras substâncias. Ministério da Saúde, Secretaria da Atenção à Saúde, Departamento de Ações Programáticas e Estratégicas. 2nd ed. Brasília: Ministério da Saúde; 2014. among others. While in the maternal toxicokinetics the breast milk/plasma ratio for PCB is high, ranging from 4 to 10, for organic and inorganic mercury it is 0.9.6060 Agency for Toxic Substances & Disease Registry - ATSDR. Principles of pediatric environmental health. How are newborns, infants, and toddlers exposed to and affected by toxicants? In: Principles of pediatric environmental health; 2012. Available from: http://www.atsdr.cdc.gov/csem/csem.asp?csem=27&po=9 [cited 14.03.15].
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Nicotine may be present in breast milk at the same maternal plasma concentration, and its half-life is also similar, with 60-90 min of elimination in both.5959 Primo CC, Ruela PB, Brotto LD, Garcia TR, Lima EF. Efeitos da nicotina materna na criança em amamentação. Rev Paul Pediatr. 2013;31:392-397. The lead excreted in breast milk has a concentration between 10% to 30% of maternal blood lead values; as lead is not lipophilic, it is not concentrated in the milk.6060 Agency for Toxic Substances & Disease Registry - ATSDR. Principles of pediatric environmental health. How are newborns, infants, and toddlers exposed to and affected by toxicants? In: Principles of pediatric environmental health; 2012. Available from: http://www.atsdr.cdc.gov/csem/csem.asp?csem=27&po=9 [cited 14.03.15].
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The recommendation to discontinue breast-feeding due to the presence of chemicals in breast milk is not supported in the literature, as long as the finding of these substances does not offer toxicity to the infant.5353 Alves C, Flores LC, Cerqueira TS, Toralles MB. Exposição ambiental a interferentes endócrinos com atividade estrogênica e sua associação com distúrbios puberais em crianças. Cad Saúde Pública. 2007;23:1005-1014.

Respiratory system - at birth, a full-term baby has approximately 10 million alveoli, whereas at 8 years old, he/she will have 300 million alveoli.6262 Pinkerton KE, Joad JP. The mammalian respiratory system and critical windows of exposures for children's health. Environ Health Perspect. 2000;108:S457-S462. The impact of passive smoking since the intrauterine phase can result in reduced weight, length, and cephalic perimeter in the newborn,6363 Zhang L, González-Chica DA, Cesar JA, Mendoza-Sassi RA, Beskow B, Larentis N, et al. Tabagismo materno durante a gestação e medidas antropométricas do recém-nascido: um estudo de base populacional no extremo sul do Brasil. Cad Saúde Pública. 2011;27:1768-1776. in addition to the increase in airway resistance, with a mean reduction of 20% in forced expiratory flow.6464 Stocks J, Desateaux C. The effect of parental smoking on lung function and development during infancy. Respirology. 2003;8:266-285. The continuity of postnatal parental smoking can have adverse effects on the child's immune system against pathogens, as well as on lung growth and development, causing a four-fold increased risk of wheezing during the first year of life.6464 Stocks J, Desateaux C. The effect of parental smoking on lung function and development during infancy. Respirology. 2003;8:266-285.

65 US Department of Health and Human Services. The health consequences of involuntary exposure to tobacco smoke: a report of the surgeon general. Atlanta: Centers for Disease Control and Prevention; 2006. Available from: http://www.ncbi.nlm.nih.gov/books/NBK44324 [cited 15.11.15].
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-6666 Schvartsman C, Farhat SC, Schvartsman S, Saldiva PH. Parental smoking patterns and their association with wheezing in children. Clinics. 2013;68:934-939.

A child breathes more air than an adult at rest, even though the adult has a greater lung capacity, which corresponds to about 6.5 l, whereas in a child this capacity is about 2 l.6262 Pinkerton KE, Joad JP. The mammalian respiratory system and critical windows of exposures for children's health. Environ Health Perspect. 2000;108:S457-S462. Considering the body weight, the air volume passing through the airways of the child at rest is twice of that in adults, under similar conditions.66 Landrigan PG, Garg A. Children are not little adults. In: Pronczuk-Garbino J, editor. Children's health and the environment. A global perspective. Geneva: World Health Organization; 2005. p. 3-16. An infant has three times the ventilation per minute (volume of air passing through the lungs at every minute) than an adult, and a 6-year-old child has twice this volume.4545 WHO. Children's Health and the Environment. Children are not little adults. Geneva: World Health Organization; 2008. Available from: http://www.who.int/ceh/capacity/Children_are_not_little_adults.pdf [cited 12.01.15].
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As children breathe more air and tend to be more physically active than adults, inhaling toxic gases may compromise their pulmonary function6767 Castro HA, Cunha MF, Mendonça GA, Junger WL, Cunha-Cruz J, Leon AP. Effect of air pollution on lung function in schoolchildren in Rio de Janeiro, Brazil. Rev Saude Publica. 2009;43:26-34. or exacerbate pre-existing conditions, increasing the incidence of acute respiratory infections in this population, expressed as increased hospitalizations6868 Rosa AM, Ignotti E, Hacon Sde S, Castro HA. Analysis of hospitalizations for respiratory diseases in Tangará da Serra, Brazil. J Bras Pneumol. 2008;34:575-582. and school absenteeism.6969 Abdulbari B, Madeeha K, Nigel JS. Impact of asthma and air pollution on school attendance of primary school children: are they at increased risk of school absenteeism? J Asthma. 2007;44:249-252. These substances include: particulate matter in suspension (dust, smoke and aerosols)7070 Riguera D, André PA, Zanetta DM. Poluição da queima de cana e sintomas respiratórios em escolares de Monte Aprazível, SP. Rev Saúde Pública. 2011;45:878-886.; pollutants of public health concern, such as O3,7171 Jasinski R, Pereira LA, Braga AL. Poluição atmosférica e internações hospitalares por doenças respiratórias em crianças e adolescentes em Cubatão, São Paulo, Brasil, entre 1997 e 2004. Cad Saúde Pública. 2001;27:2242-2252. NO2,7272 Vieira SE, Stein RT, Ferraro AA, Pastro LD, Pedro SS, Lemos M, et al. Urban air pollutants are significant risk factors for asthma and pneumonia in children: the influence of location on the measurement of pollutants. Arch Broncopneumol. 2012;48:389-395. CO, and SO27373 Ostro B, Roth L, Malig B, Mart M. The effects of fine particle components on respiratory hospital admissions in children. Environ Health Perspect. 2009;117:475-480.; lead, mercury and volatile organic compounds1414 Mello-da-Silva CA, Fruchtengarten L. Riscos químicos ambientais à saúde da criança. J Pediatr (Rio J). 2005;81:S205-S211.; as well as biomass burning residue4545 WHO. Children's Health and the Environment. Children are not little adults. Geneva: World Health Organization; 2008. Available from: http://www.who.int/ceh/capacity/Children_are_not_little_adults.pdf [cited 12.01.15].
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and tobacco smoke.7474 Pereira ED, Torres L, Macêdo J, Medeiros MM. Efeitos do fumo ambiental no trato respiratório inferior de crianças com até 5 anos de idade-Ceará. Rev Saúde Pública. 2000;34:39-43.

75 Carvalho LM, Pereira ED. Morbidade respiratória em crianças fumantes passivas. J Pneumol. 2002;28:8-14.
-7676 Coelho SA, Rocha AS, Jong LC. Consequências do tabagismo passivo em crianças. Cienc Cuid Saúde. 2012;11:294-301.

Endocrine-reproductive system: since embryonic life, events related to the child's formation, growth and development, require hormonal interactions at specific moments.7777 Landrigan P, Garg A, Droller DB. Assessing the effects of endocrine disruptors in the National Children's Study. Environ Health Perspect. 2003;111:1678-1682.,7878 Pryor JL, Hughes C, Foster W, Hales BF, Robaire B. Critical windows of exposure for children's health: the reproductive system in animals and humans. Environ Health Perspect. 2000;108:S491-S503. These hormones play a critical role in coordinating multiple cell activities, through the regulation of biological functions such as the hypothalamic-pituitary axis, the thyroid and sexual organs, keeping in homeostasis the metabolism, electrolyte balance, sleep and mood.7777 Landrigan P, Garg A, Droller DB. Assessing the effects of endocrine disruptors in the National Children's Study. Environ Health Perspect. 2003;111:1678-1682.,7979 Guimarães RM, Asmus CI, Coeli CM, Meyer A. Endocrine-reproductive system's critical windows: usage of physiological cycles to measure human organochlorine exposure biohazard. Cad Saúde Colet. 2009;17:375-390. However, these activities can be negatively impacted when susceptible to agents of exogenous origin to the body. Among these agents are substances known as endocrine disruptors, also known as eco-hormones, substances with hormonal activity or xenohormones.7777 Landrigan P, Garg A, Droller DB. Assessing the effects of endocrine disruptors in the National Children's Study. Environ Health Perspect. 2003;111:1678-1682.,7878 Pryor JL, Hughes C, Foster W, Hales BF, Robaire B. Critical windows of exposure for children's health: the reproductive system in animals and humans. Environ Health Perspect. 2000;108:S491-S503.,8080 Koifman S, Paumgartten FJ. O impacto dos desreguladores endócrinos ambientais sobre a saúde pública. Cad Saúde Pública. 2002;18:354-355.

Endocrine disruptors can reach the environment mainly through industrial and urban waste, agricultural runoff, and waste release; children's exposure to these toxicants can occur through ingestion of food, dust, and water, inhalation of gases and particles in the air, and skin contact.8181 WHO. Effects of human exposure to hormone-disrupting chemicals examined in landmark UN report. Geneva: World Health Organization; 2013. Available from: http://www.who.int/mediacentre/news/releases/2013/hormone_disrupting_20130219/e/ [cited 26.01.15].
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Some are natural substances, such as estrogens and phytoestrogens, whereas synthetic varieties can be found in pesticides, alkylphenols, polychlorinated biphenyls (PCBs), bisphenol A, food additives, toiletries, and cosmetics.8282 Guimarães RM, Asmus CI. Por quê uma saúde ambiental infantil? Avaliação da vulnerabilidade de crianças a contaminantes ambientais. Pediatria (São Paulo). 2010;32:239-245.

During the prenatal period, endocrine disruptors can have consequences on fetal development with a greater risk of sensitizing the future reproductive capability.7777 Landrigan P, Garg A, Droller DB. Assessing the effects of endocrine disruptors in the National Children's Study. Environ Health Perspect. 2003;111:1678-1682.,7878 Pryor JL, Hughes C, Foster W, Hales BF, Robaire B. Critical windows of exposure for children's health: the reproductive system in animals and humans. Environ Health Perspect. 2000;108:S491-S503. These substances act by mimicking estrogen action or antagonizing androgen action; they may result in early puberty8383 Aksglaede L, Juul A, Andersson AM. The sensitivity of the child to sex steroids: possible impact of exogenous estrogens. Hum Reprod. 2006;12:341-349. and have adverse effects on sexual differentiation, gonadal development, fecundity, and fertility, as well as sexual behavior.7878 Pryor JL, Hughes C, Foster W, Hales BF, Robaire B. Critical windows of exposure for children's health: the reproductive system in animals and humans. Environ Health Perspect. 2000;108:S491-S503.,7979 Guimarães RM, Asmus CI, Coeli CM, Meyer A. Endocrine-reproductive system's critical windows: usage of physiological cycles to measure human organochlorine exposure biohazard. Cad Saúde Colet. 2009;17:375-390.,8484 Flores AV, Ribeiro JN, Neves AA, Queiroz EL. Organochlorine: a public health problem. Ambient Soc. 2004;7:111-124. According to Alves et al.,5353 Alves C, Flores LC, Cerqueira TS, Toralles MB. Exposição ambiental a interferentes endócrinos com atividade estrogênica e sua associação com distúrbios puberais em crianças. Cad Saúde Pública. 2007;23:1005-1014. the literature suggests that sexual prematurity can also be related to accidental exposure to cosmetics containing estrogen or placental extracts, such as shampoo, conditioners, and body creams, among others, resulting in breast size increase and transitional impotence, with regression of the condition after the use of these products was discontinued.

Nervous system - from embryogenesis onwards, the nervous system continues to shape its structure not only in the beginning, but throughout the entire period of child development until the end of adolescence, in response to genetically programmed events and environmental influences, in a series of complex processes that occur at specific periods in time and space.2525 Wigle DT. Environmental threats to child health: overview. In: Child health and the environment. New York: Oxford University Press; 2003. p. 1-26.,3939 Rice D, Barone S. Critical periods of vulnerability for the developing nervous system: evidence from humans and animal models. Environ Health Perspect. 2000;108:511-533.

At birth, the brain of a child reaches approximately 24% of its adult weight. The brain weight at birth is approximately between 300 and 330 g. At 1 year, the brain mass will be tripled, growing at a much slower pace until the 1500 g of the adult phase is reached.3939 Rice D, Barone S. Critical periods of vulnerability for the developing nervous system: evidence from humans and animal models. Environ Health Perspect. 2000;108:511-533.,8585 Needlman RD. Crescimento e desenvolvimento. In: Behrman RE, Kliegman RM, Jenson HB, editors. Nelson, Tratado de pediatria. 17th ed. Rio de Janeiro: Elsevier; 2005. p. 25---71. The population of nerve cells is completed around the age of 2 years, but total neuronal tissue myelination will not be completed until 18 years of age.3939 Rice D, Barone S. Critical periods of vulnerability for the developing nervous system: evidence from humans and animal models. Environ Health Perspect. 2000;108:511-533. Because the brain is the main organ of stress and adaptation, it is at the same time both vulnerable and adaptable. It interprets and regulates behavioral, neuroendocrine, autonomic, and immunological responses.8585 Needlman RD. Crescimento e desenvolvimento. In: Behrman RE, Kliegman RM, Jenson HB, editors. Nelson, Tratado de pediatria. 17th ed. Rio de Janeiro: Elsevier; 2005. p. 25---71.

Vulnerable periods during the nervous system development are sensitive to environmental injuries, because they depend on the regional and temporal onset of critical developmental processes, such as proliferation, migration, differentiation, synaptogenesis, myelination, and apoptosis.3939 Rice D, Barone S. Critical periods of vulnerability for the developing nervous system: evidence from humans and animal models. Environ Health Perspect. 2000;108:511-533. In this sense, a wide range of chemical categories (benzene, ethanol, nicotine, methylmercury, polychlorinated biphenyl (PCBs), arsenic, lead, manganese, dichlorodiphenyltrichloroethane, tetrachloroethylene, and organophosphate insecticides)3636 Grandjean P, Landrigan PJ. Neurobehavioural effects of developmental toxicity. Lancet Neurol. 2014;13:330-338. may interfere with one or more of these processes, leading to developmental neurotoxicity3939 Rice D, Barone S. Critical periods of vulnerability for the developing nervous system: evidence from humans and animal models. Environ Health Perspect. 2000;108:511-533. through ingestion of contaminated food and liquids, gas inhalation, or skin contact.8181 WHO. Effects of human exposure to hormone-disrupting chemicals examined in landmark UN report. Geneva: World Health Organization; 2013. Available from: http://www.who.int/mediacentre/news/releases/2013/hormone_disrupting_20130219/e/ [cited 26.01.15].
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The result of such interference in the normal ontogeny of developmental processes in the nervous system will be children who may present clinical disorders, such as cognitive impairment, attention deficit/hyperactivity disorder, mental retardation, autism, and cerebral palsy, among others, that will persist throughout their life.3636 Grandjean P, Landrigan PJ. Neurobehavioural effects of developmental toxicity. Lancet Neurol. 2014;13:330-338. The development and maturation of the nervous system, the dose and duration of exposure, as well as the child's nutritional status, all influence this toxicity.8686 Soldin OP, Hanak B, Soldin SJ. Blood lead concentration in children: new range. Clin Chim Acta. 2003;327:109-113.

In addition to the exposure to toxic chemicals, biological agents can also have a negative effect on the infant's brain development. As mentioned before, there is an association between prenatal infection by the Zika virus and cases of microcephaly and other disorders of the nervous system in fetuses and newborns, called "congenital Zika syndrome".2929 Costa F, Sarno M, Ricardo Khouri R, Freitas BP, Isadora Siqueira I, Ribeiro GS, et al. Emergence of congenital zika syndrome: viewpoint from the front lines. Ann Intern Med. 2016. Available from: http://annals.org/article.aspx?articleid=2498549 [cited 24.03.16].
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Fetal autopsies have shown several changes in the brain, such as hydrops,8787 Mlakar J, Korva M, Tul N, Popović M, Poljšak-Prijatelj M, Mraz J. Zika virus associated with microcephaly. N Engl J Med. 2016;374:951-958.,8888 Sarno M, Sacramento GA, Khouri R, Rosário MS, Costa F, Archanjo G, et al. Zika virus infection and stillbirths: a case of hydrops fetalis, hydranencephaly and fetal demise. PLoS Negl Trop Dis. 2016;10:e0004517. hydrocephalus and multifocal dystrophic calcifications in the cortex,8787 Mlakar J, Korva M, Tul N, Popović M, Poljšak-Prijatelj M, Mraz J. Zika virus associated with microcephaly. N Engl J Med. 2016;374:951-958. intracranial calcifications in the periventricular parenchyma and parts of the thalamus,8989 Kline MW, Schutze GE. What pediatricians and other clinicians should know about zika virus. JAMA Pediatr. 2016;170:309-310. cell degeneration, and necrosis.9090 Martines RB, Bhatnagar J, Keating MK, Silva-Flannery L, Muehlenbachs A, Gary J, et al. Notes from the field: evidence of Zika virus infection in brain and placental tissues from two congenitally infected newborns and two fetal losses: Brazil, 2015. MMWR Morb Mortal Wkly Rep. 2016;65:159-160. The detection of viral RNA and antigens in the analyzed brain tissues was also confirmed.8787 Mlakar J, Korva M, Tul N, Popović M, Poljšak-Prijatelj M, Mraz J. Zika virus associated with microcephaly. N Engl J Med. 2016;374:951-958.,9090 Martines RB, Bhatnagar J, Keating MK, Silva-Flannery L, Muehlenbachs A, Gary J, et al. Notes from the field: evidence of Zika virus infection in brain and placental tissues from two congenitally infected newborns and two fetal losses: Brazil, 2015. MMWR Morb Mortal Wkly Rep. 2016;65:159-160. Moreover, an ophthalmological study in infants with microcephaly caused by the virus demonstrated the risk of visual impairment in these children, due to the presence of bilateral macular and perimacular lesions and optic nerve abnormalities.9191 de Paula Freitas B, de Oliveira Dias JR, Prazeres J, Sacramento GA, Ko AI, Maia M, et al. Ocular findings in infants with microcephaly associated with presumed zika virus congenital infection in Salvador, Brazil. JAMA Ophthalmol. 2016. E1-6. Available from: http://archopht.jamanetwork.com/article.aspx?articleid=2491896 [cited 03.03.16].
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In certain cases, the child's vulnerability to neurotoxins may be related not only to the stages of neurodevelopment, but also to the immaturity or failure of other protective barriers, as the blood-brain barrier9292 Banks WA. Characteristics of compounds that cross the blood-brain barrier. BMC Neurol. 2009;9:S3.,9393 Rojas H, Ritter C, Pizzol FD. Mechanisms of dysfunction of the blood-brain barrier in critically ill patients: emphasis on the role of matrix metalloproteinases. Rev Bras Ter Intensiva. 2011;23:222-227. and the placental barrier.5454 Agencia Nacional de Vigilância Sanitária - ANVISA. Modulo III. Fundamentos de toxicologia. Fase 1 - Exposição; 2006. Available from: http://ltc-ead.nutes.ufrj.br/toxicologia/mIII.fase1.htm [cited 13.06.15].
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,5555 Stolf A, Dreifuss A, Vieira FL. Farmacocinética. In: III Curso de Verão em Farmacologia. Paraná: UFPR Biológicas; 2011. p. 3-22.,9494 Silva AL. Interferentes endócrinos no meio ambiente: um estudo de caso em amostras de água in natura e efluente da estação de tratamento de esgotos da Região Metropolitana de São Paulo [dissertation]. USP: Programa de Pós-Graduação de Saúde Pública; 2009.

Blood-brain barrier - its primary function is to maintain a safe and constant chemical environment for proper functioning of the brain and protect it from xenobiotics, bacteria, fungi, parasites, viruses, and autoimmune reactions.4646 The National Academies Press - NAP. Special characteristics of children. In: Pesticides in the diets of infants and children. National Research Council (US) Committee on Pesticides in the Diets of Infants and Children. Washington, DC: The National Academies Press; 1993. p. 24-44. This protection is due to its lower permeability, having exclusion mechanisms that prevent the diffusion of adverse polar substances with low molecular weight, such as drugs, food additives, pesticides, and metals, such as nickel, chromium, and mercury.5454 Agencia Nacional de Vigilância Sanitária - ANVISA. Modulo III. Fundamentos de toxicologia. Fase 1 - Exposição; 2006. Available from: http://ltc-ead.nutes.ufrj.br/toxicologia/mIII.fase1.htm [cited 13.06.15].
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,9393 Rojas H, Ritter C, Pizzol FD. Mechanisms of dysfunction of the blood-brain barrier in critically ill patients: emphasis on the role of matrix metalloproteinases. Rev Bras Ter Intensiva. 2011;23:222-227. This barrier is not fully developed at birth; this may be one of the reasons for the higher toxicity of chemicals in newborns.9393 Rojas H, Ritter C, Pizzol FD. Mechanisms of dysfunction of the blood-brain barrier in critically ill patients: emphasis on the role of matrix metalloproteinases. Rev Bras Ter Intensiva. 2011;23:222-227. An example is the vulnerability of the neonatal brain when exposed to bilirubin, which may result in encephalopathy (kernicterus) in the first weeks of life, with irreversible neurological damage. While bilirubin concentrations of 40 mg/dL are not tolerated in neonates, these do not appear to cause any adverse effects on adults.4646 The National Academies Press - NAP. Special characteristics of children. In: Pesticides in the diets of infants and children. National Research Council (US) Committee on Pesticides in the Diets of Infants and Children. Washington, DC: The National Academies Press; 1993. p. 24-44.

Placental barrier - in addition to protecting the fetus against the passage of harmful substances from the mother's body, it performs the exchange of vital nutrients for fetal development.4646 The National Academies Press - NAP. Special characteristics of children. In: Pesticides in the diets of infants and children. National Research Council (US) Committee on Pesticides in the Diets of Infants and Children. Washington, DC: The National Academies Press; 1993. p. 24-44. In fact, the placenta is not an effective protective barrier against the inflow of foreign substances into the circulation, at a time of extreme fetal vulnerability. Although there are some biotransformation mechanisms (or metabolization) that can prevent the placental passage of these substances through a deactivating mechanism, making the resulting product less toxic than its precursor,5454 Agencia Nacional de Vigilância Sanitária - ANVISA. Modulo III. Fundamentos de toxicologia. Fase 1 - Exposição; 2006. Available from: http://ltc-ead.nutes.ufrj.br/toxicologia/mIII.fase1.htm [cited 13.06.15].
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,5555 Stolf A, Dreifuss A, Vieira FL. Farmacocinética. In: III Curso de Verão em Farmacologia. Paraná: UFPR Biológicas; 2011. p. 3-22.,9494 Silva AL. Interferentes endócrinos no meio ambiente: um estudo de caso em amostras de água in natura e efluente da estação de tratamento de esgotos da Região Metropolitana de São Paulo [dissertation]. USP: Programa de Pós-Graduação de Saúde Pública; 2009. more than 200 chemical products, foreign to the organism, were detected in the umbilical cord blood.3636 Grandjean P, Landrigan PJ. Neurobehavioural effects of developmental toxicity. Lancet Neurol. 2014;13:330-338.

Recent studies have reported that the placenta is not immune to the Zika virus. A group of researchers from Fiocruz2626 Fiocruz. Pesquisa da Fiocruz Paraná confirma transmissão intra-uterina do zika vírus. Brasil: Fiocruz Paraná; 2016. Available from: http://portal.fiocruz.br/pt-br/content/pesquisa-da-fiocruz-parana-confirma-transmissao-intra-uterina-do-zika-virus [cited 28.03.16].
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identified traces of viral DNA in the placental tissue of a pregnant woman who had the pregnancy interrupted. The study disclosed the immunopositivity in Hofbauer cells, present in the placenta and which, in pregnant women, should act as a fetal protection factor. The researchers suspect that the virus may be using the migratory ability of these cells to reach the fetal vessels. Martines et al.9090 Martines RB, Bhatnagar J, Keating MK, Silva-Flannery L, Muehlenbachs A, Gary J, et al. Notes from the field: evidence of Zika virus infection in brain and placental tissues from two congenitally infected newborns and two fetal losses: Brazil, 2015. MMWR Morb Mortal Wkly Rep. 2016;65:159-160. also showed in their study the detection of Zika viral RNA in placental tissue of early miscarriages.

Prenatal exposure to substances such as nicotine, lead, anesthetic gases, carbon monoxide, antineoplastic agents, and solvents, among others, can have negative effects on fetal development5454 Agencia Nacional de Vigilância Sanitária - ANVISA. Modulo III. Fundamentos de toxicologia. Fase 1 - Exposição; 2006. Available from: http://ltc-ead.nutes.ufrj.br/toxicologia/mIII.fase1.htm [cited 13.06.15].
http://ltc-ead.nutes.ufrj.br/toxicologia...
,9494 Silva AL. Interferentes endócrinos no meio ambiente: um estudo de caso em amostras de água in natura e efluente da estação de tratamento de esgotos da Região Metropolitana de São Paulo [dissertation]. USP: Programa de Pós-Graduação de Saúde Pública; 2009. and cause damage that cannot be predicted until their effects are observed in adulthood.9595 Weiss B. Vulnerability of children and the developing brain to neurotoxic hazards. Environ Health Perspect. 2000;108:375-381. Methylmercury, when crossing the placenta, can easily reach high levels in the umbilical cord blood and produce a variety of congenital abnormalities, including microcephaly, mental retardation, and motor deficit.9696 Sreedharan R, Mehta DI. Gastrointestinal tract. Pediatrics. 2004;113:1044-1050. As for lead, in addition to crossing the brain and the placental barriers and being secreted in milk, it is quickly and easily distributed to all tissues. The toxicity of this substance when ingested by infants and young children may reach an absorption rate of 50%, with effects on the central and peripheral nervous system.9797 Capitani EM. Metabolismo e toxicidade do chumbo na criança e no adulto. Medicina (Ribeirão Preto). 2009;42:278-286.

As observed, the effects of environmental toxicants in the complex process of the nervous system development can lead to an abnormal neuropsychomotor development, with transient or persistent deficits, with possible and more insidious consequences in adulthood.3939 Rice D, Barone S. Critical periods of vulnerability for the developing nervous system: evidence from humans and animal models. Environ Health Perspect. 2000;108:511-533.,4646 The National Academies Press - NAP. Special characteristics of children. In: Pesticides in the diets of infants and children. National Research Council (US) Committee on Pesticides in the Diets of Infants and Children. Washington, DC: The National Academies Press; 1993. p. 24-44. The development, the maturation of the nervous system and detoxification mechanisms, the dose, exposure duration, and the nutritional status of the child influence the toxicity.8686 Soldin OP, Hanak B, Soldin SJ. Blood lead concentration in children: new range. Clin Chim Acta. 2003;327:109-113.

Metabolism and digestion: the gastrointestinal (GI) tract, as well as the skin and the respiratory system, is in constant interaction with the environment. Depending on the age of the child, the GI function as a protective barrier is as important as its digestion and absorption functions.9696 Sreedharan R, Mehta DI. Gastrointestinal tract. Pediatrics. 2004;113:1044-1050. Young children have a faster metabolic rate and digest their meals faster than adults. They ingest more food and water per body weight unit.9898 Chaudhuri N, Fruchtengarten L. Where the child lives and plays: a resource manual for the health sector. In: Pronczuk-Garbino J, editor. Children's health and the environment: a global perspective. Geneva: World Health Organization; 2005. p. 29-39 [chapter 3]. Available from: http://whqlibdoc.who.int/publications/2005/9241562927_eng.pdf [cited10.03.15].
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A newborn consumes a greater amount of water (equivalent to 10-15% of body weight) than an adult (2-4% of body weight).9999 Agency for Toxic Substances & Disease Registry - ATSDR. Principles of pediatric environmental health. What are special considerations regarding toxic exposures to young and school-age children, as well as adolescents?; 2012. Available from: http://www.atsdr.cdc.gov/csem/csem.asp?csem=27&po=10 [cited 15.03.15].
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Infants who are formula-fed may have a mean daily consumption of 140-180 mL/kg/day of water, which would be equivalent to consuming an average of 35 cans (360 mL) of non-alcoholic beverages for an average adult male.9999 Agency for Toxic Substances & Disease Registry - ATSDR. Principles of pediatric environmental health. What are special considerations regarding toxic exposures to young and school-age children, as well as adolescents?; 2012. Available from: http://www.atsdr.cdc.gov/csem/csem.asp?csem=27&po=10 [cited 15.03.15].
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Preschool children (1-5 years) ingest three to four times more food per kilogram of body weight than the average adult.9898 Chaudhuri N, Fruchtengarten L. Where the child lives and plays: a resource manual for the health sector. In: Pronczuk-Garbino J, editor. Children's health and the environment: a global perspective. Geneva: World Health Organization; 2005. p. 29-39 [chapter 3]. Available from: http://whqlibdoc.who.int/publications/2005/9241562927_eng.pdf [cited10.03.15].
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Children, due to their little varied diet, containing more fruits and vegetables, have a greater chance of exposure to contaminated foods and liquids.9696 Sreedharan R, Mehta DI. Gastrointestinal tract. Pediatrics. 2004;113:1044-1050. Orally ingested environmental toxins can be modified in the GI tract by gastric pH, digestive enzymes or bacteria living in the intestine. When they are absorbed by the skin or by inhalation (through sinus drainage into the pharynx and esophagus), they can be secreted into the intestinal lumen through the biliary system and lead to gastrointestinal toxicity.9696 Sreedharan R, Mehta DI. Gastrointestinal tract. Pediatrics. 2004;113:1044-1050. As the digestive system is not capable of easily eliminating all the toxins, children may still be exposed to these agents for a longer period of time.8282 Guimarães RM, Asmus CI. Por quê uma saúde ambiental infantil? Avaliação da vulnerabilidade de crianças a contaminantes ambientais. Pediatria (São Paulo). 2010;32:239-245.,100100 Miller MD, Marty MA, Arcus A, Brown J, Morry D, Sandy M. Differences between children and adults: implications for risks assessment at California EPA. Int J Toxicol. 2002;21:403-418. Common childhood disorders, such as intestinal constipation, can also significantly increase toxin absorption by delaying the intestinal transit time.9696 Sreedharan R, Mehta DI. Gastrointestinal tract. Pediatrics. 2004;113:1044-1050.

In this context, it is noteworthy that the rate of calcium transport in the body of newborns and infants is approximately five times that of adults.101101 The National Academies Press - NAP. Adverse health effects of exposure to lead. In: Measuring lead exposure in infants, children, and other sensitive populations. Washington, DC: The National Academy Press; 1993. p. 31-93. If the child's diet is deficient in iron or calcium and exposure to lead occurs, the small intestine, still developing, will absorb this harmful agent, which will compete with calcium for cell transportation at a high pace. Thus, the rate of lead absorption children may also be five times higher than that by adults.9696 Sreedharan R, Mehta DI. Gastrointestinal tract. Pediatrics. 2004;113:1044-1050.,101101 The National Academies Press - NAP. Adverse health effects of exposure to lead. In: Measuring lead exposure in infants, children, and other sensitive populations. Washington, DC: The National Academy Press; 1993. p. 31-93. These lead concentrations in children's blood, especially in early childhood, may also be correlated to the intake of dust containing the metal, due to the oral exploration occurring in this phase of development, from sources within the household and the contaminated soil.4444 Agency for Toxic Substances & Disease Registry - ATSDR. Why are children often especially susceptible to the adverse effects of environmental toxicants? In: Principles of pediatric environmental health; 2012. Available from: http://www.atsdr.cdc.gov/csem/csem.asp?csem=27&po=3 [cited 13.03.15].
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,102102 Paustenbach K, Finley B, Long T. The critical role of house dust in understanding the hazards posed by contaminated soils. Int J Toxicol. 1997;16:339-362.

Acute exposures to toxic substances absorbed in the GI tract are sometimes difficult to diagnose. Clinical pictures of nausea, vomiting, diarrhea, and GI bleeding may suggest an infectious etiology contamination through ingestion of non-potable water and contaminated food, due to the lack of hand hygiene during meal preparation.1313 Prüss-Ustün A, Bartram J, Clasen T, Colford JM, Cumming O, Curtis V, et al. Burden of disease from inadequate water, sanitation and hygiene in low- and middle-income settings: a retrospective analysis of data from 145 countries. Trop Med Int Health. 2014;19:894-905. However, if there are other signs involving other organs, such as drowsiness, exposure to environmental toxins must be suspected, particularly heavy metals such as nickel, cadmium, lead, and mercury.9696 Sreedharan R, Mehta DI. Gastrointestinal tract. Pediatrics. 2004;113:1044-1050. In cases of ethanol intoxication, the limited glycogen reserves in infants and preschool children may increase the risk of hypoglycemia.103103 Bucaretchi F, Baracat EC. Acute toxic exposure in children: an overview. J Pediatr (Rio J). 2005;81:S212-S222.

Excretory system: differences between children and adults, regarding the susceptibility to intoxications, can result from the combination of toxicokinetics, toxicodynamics, and exposure factors.104104 Ruppenthal JE. Toxicologia. Colégio Técnico Industrial de Santa Maria. UFSM. Rede e-Tec Brasil; 2013. Kinetic factors are especially important in the postnatal period, largely as a result of the immaturity of the excretory system, either due to its reduced enzymatic metabolism and/or renal excretion.105105 Ramos CL, Targa MB, Stein AT. Perfil das intoxicações na infância atendidas pelo Centro de Informação Toxicológica do Rio Grande do Sul (CIT/RS), Brasil. Cad Saúde Pública. 2005;21:1134-1141. During fetal life, the kidneys have little excretory function due to the placenta, which also has this function.106106 Altemani JM. Dimensões renais em recém-nascidos medidas pelo ultrassom: correlação com idade gestacional e peso [dissertation]. UNICAMP: Programa de Pós-Graduação em Ciências Médicas; 2001. The maturation and nephrogenic induction usually occur after the 36th week of pregnancy.107107 Hoy WE, Ingelfinger JR, Hallan S, Hughson MD, Mott SA, Bertram JF. The early development of the kidney and implications for future health. J Dev Orig Health Dis. 2010;1:216-233. In this sense, preterm infants appear to be particularly at risk for kidney disease for a long period of time after the birth, because an increased number of these infants survive, including many who were born well before nephrogenesis is complete. Data indicate that during the process of preterm newborn treatment in the neonatal ICUs, the smaller children often receive nephrotoxic drugs, having as consequence larger glomeruli, but in smaller numbers.108108 Ingelfinger JR, Kalantar-Zadeh K, Schaefer F. In time: averting the legacy of kidney disease - focus on childhood. Rev Paul Pediatr. 2016;34:5-10.

The glomerular filtration rate of a child is a third of the rate found in adults, which allows harmful chemicals to remain for longer periods in the child's body, among them lead and mercury.4141 Selevan SG, Kimmel CA, Mendola P. Identifying critical windows of exposure for children's health. Environ Health Perspect. 2000;108:S451-S455. According to Capitani,9797 Capitani EM. Metabolismo e toxicidade do chumbo na criança e no adulto. Medicina (Ribeirão Preto). 2009;42:278-286. children have a retention rate in the lead excretion process of around 30%, while in adults it is around 1-4%. These heavy metals can make the kidneys incapable to filter the waste, salts, and liquids in the blood, which may result in the loss hydro-electrolyte homeostasis, leading to acute renal failure.109109 Vogt BA, Avner ED. Insuficiência renal. In: Behrman RE, Kliegman RM, Jenson HB, editors. Nelson, Tratado de pediatria, vol. 2, 17th ed. Rio de Janeiro: Elsevier; 2005. p. 1875-8.

Dermal exposure: the skin is the organ derived from embryonic mesoderm and ectoderm and the most extensive organ of the human body.110110 Noronha L, Medeiros F, Sepulcri RP, Fillus Neto J, Luiz Fernando Bleggi-Torres LF. Manual de dermatologia. Curitiba: PUCPR; 2000. The development and growth of fetal skin is characterized by a series of sequential and strictly controlled steps, which depend on a variety of cell interactions that constitute the organ. Its presence is vital for the functions of mechanical protection, thermoregulation, immunosurveillance, and maintenance of a barrier that prevents the insensitive loss of body fluid.111111 Mancini AJ. Skin. Pediatrics. 2004;113:S1114-S1119.

While the permeability of the skin barrier is still under development in preterm infants, resulting in a higher percutaneous absorption of chemicals,99 WHO. Principles for evaluating health risks in children associated with exposure to chemical. Environmental Health Criteria Nº 237. Geneva: World Health Organization; 2006. Available from: http://apps.who.int/iris/bitstream/10665/43604/1/924157237X_eng.pdf [cited 16.03.15].
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a full-term newborn has a more mature skin, whose barrier properties are similar to those of older children and adults.112112 Selevan SG, Kimmel CA, Mendola P. Windows of susceptibility to environmental exposures in children. In: Pronczuk-Garbino J, editor. Children's health and the environment. A global perspective. Geneva: World Health Organization; 2005. p. 17-25. Infants have a surface area relative to volume three times that of adults, and in children this proportion is two-fold higher per unit of body weight when compared to adults.4545 WHO. Children's Health and the Environment. Children are not little adults. Geneva: World Health Organization; 2008. Available from: http://www.who.int/ceh/capacity/Children_are_not_little_adults.pdf [cited 12.01.15].
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,9999 Agency for Toxic Substances & Disease Registry - ATSDR. Principles of pediatric environmental health. What are special considerations regarding toxic exposures to young and school-age children, as well as adolescents?; 2012. Available from: http://www.atsdr.cdc.gov/csem/csem.asp?csem=27&po=10 [cited 15.03.15].
http://www.atsdr.cdc.gov/csem/csem.asp?c...
As they are highly active, they tend to have more skin cuts, abrasions, and rashes, thus increasing the potential for skin absorption of xenobiotics and toxicants, such as dust contaminated with heavy metals.4545 WHO. Children's Health and the Environment. Children are not little adults. Geneva: World Health Organization; 2008. Available from: http://www.who.int/ceh/capacity/Children_are_not_little_adults.pdf [cited 12.01.15].
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,111111 Mancini AJ. Skin. Pediatrics. 2004;113:S1114-S1119.,112112 Selevan SG, Kimmel CA, Mendola P. Windows of susceptibility to environmental exposures in children. In: Pronczuk-Garbino J, editor. Children's health and the environment. A global perspective. Geneva: World Health Organization; 2005. p. 17-25. Concentrated ammonia can produce, in contact with the child's skin, tissue necrosis and deep burns. These burns, depending on the size of the affected area, can secondarily cause acute renal failure.109109 Vogt BA, Avner ED. Insuficiência renal. In: Behrman RE, Kliegman RM, Jenson HB, editors. Nelson, Tratado de pediatria, vol. 2, 17th ed. Rio de Janeiro: Elsevier; 2005. p. 1875-8.

Behavioral development: child behavioral development can include changes in maturation depending on the child's relationship with the environment. This development can have four interrelated aspects, such as: motor skills (gross and fine); cognitive ability; emotional development; and social development. Any alteration in one of these areas can affect the development of the other three.4646 The National Academies Press - NAP. Special characteristics of children. In: Pesticides in the diets of infants and children. National Research Council (US) Committee on Pesticides in the Diets of Infants and Children. Washington, DC: The National Academies Press; 1993. p. 24-44.

Small children are powerless and helpless. With their peculiar behaviors and habits, they live in a playful world, without fearing their limits of exposure to any mechanical energy. With their extraordinary curiosity, they approach objects with sources of thermal and electrical energy, put inside their mouths or breathe in agents containing chemical energy,1919 Waksman RD, Blank D, Gikas RM. Injúrias ou lesões não-intencionais "acidentes" na infância e na adolescência. São Paulo: MedicinaNet; 2010. Available from: http://www.medicinanet.com.br/conteudos/revisoes/1783/injurias_ou_lesoes_nao_intencionais_%E2%80%9Cacidentes%E2%80%9D_na_infancia_e_na_adolescencia.htm [cited 14.06.15].
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which they find in their environment, left within their reach, effectively contributing to increase the number of case reports of injuries caused by chemical, physical, and biological agents, mostly unintentional, whose results are often destructive to the entire family.113113 Valenzuela PM, Matus MS, Araya GI, Paris E. Environmental pediatrics: an emerging issue. J Pediatr (Rio J). 2011;87:89-99.

In brief, the following points are noteworthy:

  1. A child is not a small adult. They differ regarding their physiology, metabolism, growth, development, and behavior. From the intrauterine stage until the end of adolescence, the physical growth and functional maturation of their bodies are at a differentiated and constant rhythm. Exposure to environmental threats at these sensitive stages of the child's life may negatively influence these dynamic processes, and may cause irreversible damage.

  2. Worldwide, children are exposed to environmental contaminants, acknowledged or not, which silently deteriorate their health, damaging their future achievements, with physical, emotional, and social consequences, in addition to the burden for the family, society, and the state as a whole.

  3. To identify the causes and understand the mechanisms involved in the genesis of environmental harm in a pediatric patient is very difficult and a challenge to science. Epidemiological data generally focus on assessing exposure to individual contaminants at relatively high doses. However, many situations in the real world, involve low-dose, long-term exposure to single or multiple agents. With the exception of some chemicals, there are relatively few data on the mechanisms involved in the genesis of these damages in the development of childhood diseases.

  4. The occurrence of these damages and their determinants in childhood has, as key factors, poverty and lack of access to information on inherent health practices. The impacts on children's health caused by the combination of classic risks (home environmental pollution and non-potable water) and modern risks (toxic chemicals, hazardous waste, air pollution and climate changes), vary greatly between and within developing countries.

  5. The child's rights to a safe environment to grow, develop, play, and learn are decisive arguments for the state to define effective strategies to promote healthy environments, which will protect children from events that are harmful to their health, that will monitor these trends over time and promote interventions where they are most needed. Articulated intra and inter-sectorial actions that promote the recording and surveillance of environmental risks to children's health should be a continued priority in public healthcare.

  6. The relationship between research and politics are rarely direct - from politics reporting to the research, or vice versa. Research and politics appear to work as parallel groups, sometimes interconnected by interests, occasionally feeding on each other. Relevant academic discussions in different fields of knowledge and an active state on the main issues that affect the lives of children are strategic actions for the survival of future generations. Studies on economic and social impacts and children's relationship with their physical environment in different fields of knowledge are essential for the survival of future generations.

  7. The children's environmental health needs to become an adult science in the academic world and in society.

  • Please cite this article as: Perlroth NH, Branco CW. Current knowledge of environmental exposure in children during the sensitive developmental periods. J Pediatr (Rio J). 2017;93:17-27.

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Publication Dates

  • Publication in this collection
    Jan/Feb 2017

History

  • Received
    10 July 2016
  • Accepted
    19 July 2016
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E-mail: jped@jped.com.br