Abstracts

Introduction

Human development theories help to study multiple perspectives, further the scientific vision about reality, and facilitate communication from the scientific community to decision makers for the application of science to public and social programs. Valuable scientific contributions have been made, helping to shape educational systems and public policies. Some studies focused on specific patterns of neurodevelopment (maturationist theory, Freud’s psychoanalytic theory, and Erik Erikson’s psychosocial development theory), whereas other studies showed a more extended perspective (Piaget’s theory of cognitive development, Vygotsky’s sociocultural perspective, behaviorism, and biopsychosocial theories) ¹1. Wong DW, Hall KR, Hernandez LW. Counseling individuals through the lifespan. Thousand Oaks: SAGE Publications; 2015.. Bronfenbrenner ²2. Bronfenbrenner U. The ecology of human development: experiments by nature and design. Cambridge: Harvard University Press; 1979. suggested the “ecological model of human development”, a framework with a global approach of social contexts represented as four concentric levels (micro-, meso-, exo-, and macrosystems) in which development occurs. The microsystem is the immediate setting that occurs in everyday life interactions between a growing human being and the components (symbols and people) of that context, such as family and daycare. The interconnection between microsystems is the mesosystem. The exosystem includes settings in which growing human beings are not directly involved (e.g., parents’ occupation) but influence their reality. The macrosystem includes laws, culture, rules, and social norms of a given society. Later, Bronfenbrenner reconceptualized this framework as the “bioecological model of human development”, and included biological and genetic features, showing how the combination of the four settings, by proximal processes, define cognitive, behavioral, learning, and other neurological functions throughout human life ³3. Bronfenbrenner U, Ceci JS. Nature-nurture reconceptualized in developmental perspective: a bioecological model. Psychol Rev 1994; 101:568-86.^,44. Bronfenbrenner U, Evans GW. Developmental science in the 21st century: emerging questions, theoretical models, research designs and empirical findings. Soc Dev 2000; 9:115-25.^,55. Bronfenbrenner U, Morris PA. The bioecological model of human development. In: Damon W, Lerner RM, editors. Handbook of child psychology. Hoboken: John Wiley & Sons, Ltd.; 2007. p. 739-828.. This perspective is “inclusive” and may be applied to other areas involved in human development studies, going this study’s domain.

Recently, scientists have recognized the importance of a holistic approach in environmental sciences. However, they have criticized it for presenting a parallel and separate research with partial perspective from biological and social sciences areas instead of an interdisciplinary perspective. Environmental exposures are socially mediated and do not occur randomly; impoverished communities and non-white populations are frequently the most concerning ⁶6. Weiss B, Bellinger DC. Social ecology of children's vulnerability to environmental pollutants. Environ Health Perspect 2006; 114:1479-85.^,77. Senier L, Brown P, Shostak S, Hanna B. The socio-exposome: advancing exposure science and environmental justice in a post-genomic era. Environ Sociol 2017; 3:107-21.^,88. Gee GC, Payne-Sturges DC. Environmental health disparities: a framework integrating psychosocial and environmental concepts. Environ Health Perspect 2004; 112:1645-53.. According to Senier et al. ⁷7. Senier L, Brown P, Shostak S, Hanna B. The socio-exposome: advancing exposure science and environmental justice in a post-genomic era. Environ Sociol 2017; 3:107-21. (p. 5), there is a need to “...follow a path of theoretically-driven science that seeks to link environmental exposures and genetic variants to disease outcomes along precise and multilayered pathways that account not only for biological processes of disease formation, but also consider the social, political, and economic forces that create vulnerabilities to exposure”.

Some authors have suggested frameworks considering this complexity, such as the exposome concept ⁹9. Wild CP. Complementing the genome with an "exposome": the outstanding challenge of environmental exposure measurement in molecular epidemiology. Cancer Epidemiol Biomarkers Prev 2005; 14:1847-50.^,1010. Wild CP. The exposome: from concept to utility. Int J Epidemiol 2012; 41:24-32., total environmental ¹¹11. Tulve NS, Ruiz JDC, Lichtveld K, Darney SP, Quackenboss JJ. Development of a conceptual framework depicting a child's total (built, natural, social) environment in order to optimize health and well-being. J Environ Health Sci 2016; 2:1-8., integrated socio-environmental model of health and well-being ¹²12. Olvera Alvarez HA, Appleton AA, Fuller CH, Belcourt A, Kubzansky LD. An integrated socio-environmental model of health and well-being: a conceptual framework exploring the joint contribution of environmental and social exposures to health and disease over the life span. Curr Environ Health Rep 2018; 5:233-43., among others ⁸8. Gee GC, Payne-Sturges DC. Environmental health disparities: a framework integrating psychosocial and environmental concepts. Environ Health Perspect 2004; 112:1645-53.^,1313. Morello-Frosch R, Shenassa ED. The environmental "riskscape" and social inequality: implications for explaining maternal and child health disparities. Environ Health Perspect 2006; 114:1150-3.^,1414. Clougherty JE, Kubzansky LD. A framework for examining social stress and susceptibility to air pollution in respiratory health. Environ Health Perspect 2009; 117:1351-8.^,1515. Siroux V, Agier L, Slama R. The exposome concept: a challenge and a potential driver for environmental health research. Eur Respir Rev 2016; 25:124-9.. Nonetheless, research in this growing and emerging field faces some challenges with the implementation of such a perspective. Senier et al. ⁷7. Senier L, Brown P, Shostak S, Hanna B. The socio-exposome: advancing exposure science and environmental justice in a post-genomic era. Environ Sociol 2017; 3:107-21. illustrated the fallacy of environmental scientists giving more importance to the biological features even when using the previously mentioned models. They suggested the “socio-exposome” multidimensional framework, which considers the individual, local, and global levels (including sociopolitical conditions) based on the exposome concept ⁹9. Wild CP. Complementing the genome with an "exposome": the outstanding challenge of environmental exposure measurement in molecular epidemiology. Cancer Epidemiol Biomarkers Prev 2005; 14:1847-50.^,1010. Wild CP. The exposome: from concept to utility. Int J Epidemiol 2012; 41:24-32. and insights from social sciences, public health, and environmental justice activism. Therefore, as an emerging field, there is a need for more commitments to social justice and the use of environmental science expertise in addition to other disciplines to tackle inequalities that maintain the status quo.

To the best of our knowledge, considering the neurodevelopmental toxicity studies in environmental science, very few frameworks ¹¹11. Tulve NS, Ruiz JDC, Lichtveld K, Darney SP, Quackenboss JJ. Development of a conceptual framework depicting a child's total (built, natural, social) environment in order to optimize health and well-being. J Environ Health Sci 2016; 2:1-8.^,1313. Morello-Frosch R, Shenassa ED. The environmental "riskscape" and social inequality: implications for explaining maternal and child health disparities. Environ Health Perspect 2006; 114:1150-3. encompassing social and biological patterns exist. Ferguson et al. ¹⁶16. Ferguson KT, Cassells RC, MacAllister JW, Evans GW. The physical environment and child development: an international review. Int J Psychol 2013; 48:437-68. reported the situation of limited work on the impact of physical environment on neurodevelopment in the global south and the limits of the methods used in western countries. They suggested the importance of holistic approaches and recommended the use of the Bronfenbrenner bioecological model, extending the ecological concept to the physical environment. For more than a decade, our research group have actively reported on the case of urban and rural communities’ exposure to toxic metals due to industrial and artisanal activities in Bahia, a Northeastern state of Brazil and Latin America ¹⁷17. Menezes-Filho JA, Paes CR, Pontes AM, Moreira JC, Sarcinelli PN, Mergler D. High levels of hair manganese in children living in the vicinity of a ferro-manganese alloy production plant. Neurotoxicology 2009; 30:1207-13.^,1818. Menezes-Filho JA, de Carvalho-Vivas CF, Viana GF, Ferreira JR, Nunes LS, Mergler D, et al. Elevated manganese exposure and school-aged children's behavior: a gender-stratified analysis. Neurotoxicology 2014; 45:293-300.^,1919. Bah HAF, Bandeira MJ, Gomes-Junior EA, Anjos ALS, Rodrigues YJM, Dos Santos NR, et al. Environmental exposure to lead and haematological parameters in Afro-Brazilian children living near artisanal glazed pottery workshops. J Environ Sci Health A Tox Hazard Subst Environ Eng 2020; 55:964-74.^,2020. Mora AM, Córdoba L, Cano JC, Hernandez-Bonilla D, Pardo L, Schnaas L, et al. Prenatal mancozeb exposure, excess manganese, and neurodevelopment at 1 year of age in the Infants' Environmental Health (ISA) Study. Environ Health Perspect 2018; 126:057007.. Based on the literature and our experience as environmental epidemiologists and toxicologists, we suggested a radical shift in the method used to study this topic from the Bronfenbrenner bioecological model perspective due to its capacity to consider the multilevel of human reality, including people’s biology. The colleagues (neuropsychologists and pediatric physical therapists) of our research group provided their expertise along with discussions to establish this framework.

We presented a framework on environmental neurodevelopmental toxicity considering the period from gestation to the second year of life, focusing on early exposure to toxic metals. The first section briefly reviews the metals toxicity and other concepts included in our model. Then, the Bronfenbrenner bioecological model is introduced and these concepts are integrated to show how contaminants and social structure could affect the neurodevelopment of children.

Important concepts

Early exposure to toxic metals and child neurodevelopment

Toxic metals are components of diverse chemical forms and their use is the main source of exposure. The threats to human health may be derived from their structures and intrinsic physicochemical, biological, and environmental properties ²¹21. Engwa GA, Ferdinand PU, Nwalo FN, Unachukwu MN. Mechanism and health effects of heavy metal toxicity in humans. In: Karcioglu O, Arslan B, editors. Poisoning in the modern world: new tricks for an old dog? London: IntechOpen; 2019. p. 1-23.^,2222. Tchounwou PB, Yedjou CG, Patlolla AK, Sutton DJ. Heavy metal toxicity and the environment. Exp Suppl 2012; 101:133-64.. Metals such as lead (Pb), arsenic (As), mercury (Hg), and cadmium (Cd) present no physiological role but are found in humans due to environmental exposure and diet. Women are continuously exposed to these agents ²¹21. Engwa GA, Ferdinand PU, Nwalo FN, Unachukwu MN. Mechanism and health effects of heavy metal toxicity in humans. In: Karcioglu O, Arslan B, editors. Poisoning in the modern world: new tricks for an old dog? London: IntechOpen; 2019. p. 1-23.^,2222. Tchounwou PB, Yedjou CG, Patlolla AK, Sutton DJ. Heavy metal toxicity and the environment. Exp Suppl 2012; 101:133-64.^,2323. Amadi CN, Zelinjo NI, Orish EO. Heavy metals in miscarriages and stillbirths in developing nations. Middle East Fertil Soc J 2017; 22:91-100. and their biological levels can increase during pregnancy. These contaminants are harmful to the reproductive system and have been associated with several subsequent deleterious effects, including miscarriages and long-term damage to newborns ²³23. Amadi CN, Zelinjo NI, Orish EO. Heavy metals in miscarriages and stillbirths in developing nations. Middle East Fertil Soc J 2017; 22:91-100.. Given fetal nutrient demands for growth, many metals may easily cross the placenta and accumulate in fetal tissues, including in the central nervous system (CNS) ²⁴24. Gundacker C, Neesen J, Straka E, Ellinger I, Dolznig H, Hengstschläger M. Genetics of the human placenta: implications for toxicokinetics. Arch Toxicol 2016; 90:2563-81..

However, the mechanisms underlying the neurotoxicity of these contaminants remain unclear. Experimental and observational studies have provided valuable information about some plausible pathways ²¹21. Engwa GA, Ferdinand PU, Nwalo FN, Unachukwu MN. Mechanism and health effects of heavy metal toxicity in humans. In: Karcioglu O, Arslan B, editors. Poisoning in the modern world: new tricks for an old dog? London: IntechOpen; 2019. p. 1-23.. Pb can interfere with synaptic transmissions and cell adhesion molecules, blocking cell migration during CNS development ²³23. Amadi CN, Zelinjo NI, Orish EO. Heavy metals in miscarriages and stillbirths in developing nations. Middle East Fertil Soc J 2017; 22:91-100.. Oxidative stress and cytotoxicity are some of the mechanisms of As neurotoxicity ²⁵25. Thakur M, Rachamalla M, Niyogi S, Datusalia AK, Flora SJS. Molecular mechanism of arsenic-induced neurotoxicity including neuronal dysfunctions. Int J Mol Sci 2021; 22:10077.. The high affinity of Hg for the thiols group may contribute to apoptosis and modulate the cytoskeleton and neuronal receptors ²⁶26. Ajsuvakova OP, Tinkov AA, Aschner M, Rocha JBT, Michalke B, Skalnaya MG, et al. Sulfhydryl groups as targets of mercury toxicity. Coord Chem Rev 2020; 417:213343.. Exposure to Cd may inhibit the transport of nutrients from mother to fetus, thus causing a drop in anthropometric parameters, explaining neurological abnormalities and developmental delay ²⁷27. Geng HX, Wang L. Cadmium: toxic effects on placental and embryonic development. Environ Toxicol Pharmacol 2019; 67:102-7.. Another toxicity mechanism is the ability of metals to interact with genetic material, leading to dysfunction in the exposed individuals and their descendants ²¹21. Engwa GA, Ferdinand PU, Nwalo FN, Unachukwu MN. Mechanism and health effects of heavy metal toxicity in humans. In: Karcioglu O, Arslan B, editors. Poisoning in the modern world: new tricks for an old dog? London: IntechOpen; 2019. p. 1-23.^,2424. Gundacker C, Neesen J, Straka E, Ellinger I, Dolznig H, Hengstschläger M. Genetics of the human placenta: implications for toxicokinetics. Arch Toxicol 2016; 90:2563-81.^,2828. Gump BB, Stewart P, Reihman J, Lonky E, Darvill T, Parsons PJ, et al. Low-level prenatal and postnatal blood lead exposure and adrenocortical responses to acute stress in children. Environ Health Perspect 2008; 116:249-55.. As an example, evidence have shown that As exposure can cause chromosomal aberrations and cellular DNA damage ²⁵25. Thakur M, Rachamalla M, Niyogi S, Datusalia AK, Flora SJS. Molecular mechanism of arsenic-induced neurotoxicity including neuronal dysfunctions. Int J Mol Sci 2021; 22:10077..

Individual toxic metals have been associated with neurological damage in children after perinatal and childhood exposures. Due to concomitant exposure to multiple pollutants in everyday situations, epidemiological studies have recently focused on the possible interactions between these neurotoxic agents ²⁹29. Freire C, Amaya E, Gil F, Fernández MF, Murcia M, Llop S, et al. Prenatal co-exposure to neurotoxic metals and neurodevelopment in preschool children: the Environment and Childhood (INMA) Project. Sci Total Environ 2018; 621:340-51.^,3030. Henn BC, Coull BA, Wright RO. Chemical mixtures and children's health. Curr Opin Pediatr 2014; 26:223-9.. For instance, Pb toxicity was shown to be higher among children with high manganese (Mn) coexposure ³¹31. Henn BC, Schnaas L, Ettinger AS, Schwartz J, Lamadrid-Figueroa H, Hernández-Avila M, et al. Associations of early childhood manganese and lead coexposure with neurodevelopment. Environ Health Perspect 2012; 120:126-31.^,3232. Menezes-Filho JA, Carvalho CF, Rodrigues JLG, Araujo CFS, Dos Santos NR, Lima CS, et al. Environmental co-exposure to lead and manganese and intellectual deficit in school-aged children. Int J Environ Res Public Health 2018; 15:2418.. In addition to the neurotoxic effect of each toxic metal due to prenatal exposure, Freire et al. ²⁹29. Freire C, Amaya E, Gil F, Fernández MF, Murcia M, Llop S, et al. Prenatal co-exposure to neurotoxic metals and neurodevelopment in preschool children: the Environment and Childhood (INMA) Project. Sci Total Environ 2018; 621:340-51. reported a synergistic interactive effect between As and Pb on cognitive performance, whereas the interaction between Mn and Hg was antagonistic.

Furthermore, exposure to metals may be associated with low socioeconomic status or psychosocial stress to disrupt child development ³³33. Rauh VA, Whyatt RM, Garfinkel R, Andrews H, Hoepner L, Reyes A, et al. Developmental effects of exposure to environmental tobacco smoke and material hardship among inner-city children. Neurotoxicol Teratol 2004; 26:373-85.^,3434. Lucchini RG, Guazzetti S, Renzetti S, Conversano M, Cagna G, Fedrighi C, et al. Neurocognitive impact of metal exposure and social stressors among schoolchildren in Taranto, Italy. Environ Health 2019; 18:67.^,3535. Sobolewski M, Conrad K, Marvin E, Allen JL, Cory-Slechta DA. Endocrine active metals, prenatal stress and enhanced neurobehavioral disruption. Horm Behav 2018; 101:36-49.^,3636. Vreugdenhil HJ, Slijper FM, Mulder PG, Weisglas-Kuperus N. Effects of perinatal exposure to PCBs and dioxins on play behavior in Dutch children at school age. Environ Health Perspect 2002; 110:A593-8.. The possibility of this association makes it necessary to innovate approaches and study their neurotoxicity.

Social and structural determinants of children’s health and development

The social determinants of health (SDH) are: “the social, economic, cultural, ethnic or racial, psychological, and behavioral factors that influence the occurrence of health problems and their risk factors in the population” ³⁷37. Buss PM, Pellegrini Filho A. A saúde e seus determinantes sociais. Physis (Rio J.) 2007; 17:77-93. (p. 78).

Despite the SDH being beneficial since its incorporation into practices, according to Crear-Perry et al. ³⁸38. Crear-Perry J, Correa-de-Araujo R, Lewis Johnson T, McLemore MR, Neilson E, Wallace M. Social and structural determinants of health inequities in maternal health. J Womens Health (Larchmt) 2021; 30:230-5. and Krieger ³⁹39. Krieger N. Ladders, pyramids and champagne: the iconography of health inequities. J Epidemiol Community Health 2008; 62:1098-104., to tackle the roots of health inequity, it would be necessary to contextualize them as structural determinants of society that generate social stratification, reflecting the distribution of wealth, power, and privilege. The use of SDH as a simple factor perpetuates the fallacies about health and well-being, particularly at the individual level ³⁸38. Crear-Perry J, Correa-de-Araujo R, Lewis Johnson T, McLemore MR, Neilson E, Wallace M. Social and structural determinants of health inequities in maternal health. J Womens Health (Larchmt) 2021; 30:230-5..

To illustrate, despite the current social context being favorable for gender equality, in everyday life practice, a child’s well-being and development is mainly associated with women’s health since it is still thought to be a female role ⁴⁰40. Dunkel-Schetter C. Psychological science on pregnancy: stress processes, biopsychosocial models, and emerging research issues. Annu Rev Psychol 2011; 62:531-58.. Therefore, it is crucial to consider the place of women and how they see themselves in society, the oppressions they may suffer according to their skin color, class, other SDHs, and the socio-historical context ⁴¹41. Crenshaw K. Mapping the margins: intersectionality, identity politics, and violence against women of color. Stanford Law Rev 1991; 43:1241-99.. For instance, considering the higher risk of maternal mortality, adverse birth outcomes, and gynecological violence among black women in the United States and Brazil, studies have shown that they simultaneously suffer racism, classism, and gender oppression as the root causes of this situation ³⁸38. Crear-Perry J, Correa-de-Araujo R, Lewis Johnson T, McLemore MR, Neilson E, Wallace M. Social and structural determinants of health inequities in maternal health. J Womens Health (Larchmt) 2021; 30:230-5.^,4242. Greely JT, Dongarwar D, Crear L, Adeyeye M, Reyna-Carrillo A, Salihu HM. Violence against pregnant women and adverse maternal/fetal outcomes in the United States: racial/ethnic disparities. Women Health 2022; 62:513-21.^,4343. Curi PL, Ribeiro MTDA, Marra CB. A violência obstétrica praticada contra mulheres negras no SUS. Arq Bras Psicol (Rio J. 2003) 2020; 72(spe):156-69.^,4444. Diniz SG, Salgado HO, Andrezzo HFA, Carvalho PGC, Carvalho PCA, Aguiar CA, et al. Abuse and disrespect in childbirth care as a public health issue in Brazil: origins, definitions, impacts on maternal health, and proposals for its prevention. J Hum Growth Dev 2015; 25:377.. A similar perspective that goes beyond the simple use of SDH as factors is also perceived in the concept of “embodiment” suggested by Krieger ⁴⁵45. Krieger N. Proximal, distal, and the politics of causation: what's level got to do with it? Am J Public Health 2008; 98:221-30. (p. 225): “a concept that refers to how we literally incorporate, biologically, the material and social world in which we live, from in utero to death; a corollary is that no aspect of our biology can be understood absent knowledge of history and individual and societal ways of living”.

These mechanisms involve larger social and historical structures and processes, which create a differentiated distribution of disease processes among groups ⁴⁶46. Diez Roux AV. Conceptual approaches to the study of health disparities. Annu Rev Public Health 2012; 33:41-58.. Over time, life circumstances due to social and structural determinants may be embodied by chronic psychosocial stress, causing a wear and tear called “allostatic load”. Biologically, both real threats and the individual’s subjective interpretations of threats can trigger the release of catecholamines, glucocorticoids, and cortisol via the hypothalamic-pituitary-adrenal (HPA) axis ⁴⁷47. Juster RP, McEwen BS, Lupien SJ. Allostatic load biomarkers of chronic stress and impact on health and cognition. Neurosci Biobehav Rev 2010; 35:2-16.^,4848. McEwen BS. Allostasis and allostatic load: implications for neuropsychopharmacology. Neuropsychopharmacology 2000; 22:108-24.. These are considered stress hormones that may cross the placenta and impair the fetal CNS development. For example, fetal exposure to maternal cortisol is supposedly regulated by the placenta, which offers partial protection in case of high exposure. Therefore, the allostatic load is thought to be harmful during pregnancy and contributes to the observed disparities in fetal and child health ¹⁴14. Clougherty JE, Kubzansky LD. A framework for examining social stress and susceptibility to air pollution in respiratory health. Environ Health Perspect 2009; 117:1351-8.^,4040. Dunkel-Schetter C. Psychological science on pregnancy: stress processes, biopsychosocial models, and emerging research issues. Annu Rev Psychol 2011; 62:531-58.^,4949. González-Ochoa R, Sánchez-Rodríguez EN, Chavarría A, Gutiérrez-Ospina G, Romo-González T. Evaluating stress during pregnancy: do we have the right conceptions and the correct tools to assess it? J Pregnancy 2018; 2018:4857065.. The quality of mother-infant interactions also has long-term implications for children’s social, emotional, and psychological development ²2. Bronfenbrenner U. The ecology of human development: experiments by nature and design. Cambridge: Harvard University Press; 1979.^,4040. Dunkel-Schetter C. Psychological science on pregnancy: stress processes, biopsychosocial models, and emerging research issues. Annu Rev Psychol 2011; 62:531-58..

Bronfenbrenner bioecological model

The Bronfenbrenner bioecological model considers that human development occurs according to one’s immediate setting, biological characteristics, and the structural construct of society. It is a combination of contexts from the distal to the proximal level ²2. Bronfenbrenner U. The ecology of human development: experiments by nature and design. Cambridge: Harvard University Press; 1979.^,33. Bronfenbrenner U, Ceci JS. Nature-nurture reconceptualized in developmental perspective: a bioecological model. Psychol Rev 1994; 101:568-86.. Here, we will briefly present two properties of our framework ³3. Bronfenbrenner U, Ceci JS. Nature-nurture reconceptualized in developmental perspective: a bioecological model. Psychol Rev 1994; 101:568-86.^,44. Bronfenbrenner U, Evans GW. Developmental science in the 21st century: emerging questions, theoretical models, research designs and empirical findings. Soc Dev 2000; 9:115-25.^,55. Bronfenbrenner U, Morris PA. The bioecological model of human development. In: Damon W, Lerner RM, editors. Handbook of child psychology. Hoboken: John Wiley & Sons, Ltd.; 2007. p. 739-828..

According to the first property, throughout the life span, human development occurs across processes of reciprocal interactions of growing human being s with people, objects, and symbols in their external environment. This interaction must occur regularly for a sufficient period. Such enduring forms of interaction with the immediate social environment are “proximal processes” that actualize the genetic potential, allowing its expression into phenotypes (e.g., the subject’s psychological and neurological characteristics) ³3. Bronfenbrenner U, Ceci JS. Nature-nurture reconceptualized in developmental perspective: a bioecological model. Psychol Rev 1994; 101:568-86.. The model integrates possible non-additive and synergistic effects of the gene-environment relationship; genetic material does not determine neural characteristics but interacts with experiences in the immediate environment. A proximal process is then defined as the transfer of energy between children and the components of their immediate environment. The transfer may occur in one direction or both, separately or simultaneously ⁴4. Bronfenbrenner U, Evans GW. Developmental science in the 21st century: emerging questions, theoretical models, research designs and empirical findings. Soc Dev 2000; 9:115-25.. Children’s participation in this process may influence people’s involvement in their growth since, for instance, adults tend to interact more with friendly and smiling children ⁵⁰50. Plomin R, DeFries JC, Loehlin JC. Genotype-environment interaction and correlation in the analysis of human behavior. Psychol Bull 1977; 84:309-22..

Changes in proximal processes and their quality may contribute to two main types of developmental outcomes: competence and dysfunction. Competence refers to the demonstrated or additional acquisition of skills. For example, children may develop an awareness of their environment and interact with it, control their behavior, and establish and maintain stable relationships. Dysfunction refers to recurrent difficulties in maintaining, controlling, and/or integrating appropriate behaviors and improvements in different developmental domains ³3. Bronfenbrenner U, Ceci JS. Nature-nurture reconceptualized in developmental perspective: a bioecological model. Psychol Rev 1994; 101:568-86.^,44. Bronfenbrenner U, Evans GW. Developmental science in the 21st century: emerging questions, theoretical models, research designs and empirical findings. Soc Dev 2000; 9:115-25..

According to the second property, the form, power, content, and direction of proximal processes that affect the development vary systematically as a joint function of children’s characteristics and the ecological environment in which these processes occur. It is necessary to consider beyond the proximal processes, the children, the different settings, and the stages they pass over time ³3. Bronfenbrenner U, Ceci JS. Nature-nurture reconceptualized in developmental perspective: a bioecological model. Psychol Rev 1994; 101:568-86.^,55. Bronfenbrenner U, Morris PA. The bioecological model of human development. In: Damon W, Lerner RM, editors. Handbook of child psychology. Hoboken: John Wiley & Sons, Ltd.; 2007. p. 739-828.^,5151. Bronfenbrenner U. Ecology of the family as a context for human development: research perspectives. Dev Psychol 1986; 22:723-42.. The Bronfenbrenner bioecological model conceptualizes the ecological environment as a set of nested systems, ranging from the micro- to macrosystem, changing over time ²2. Bronfenbrenner U. The ecology of human development: experiments by nature and design. Cambridge: Harvard University Press; 1979.. The microsystem is composed of a complex set of relationships in the immediate environment of growing human beings (e.g., family and school). The mesosystem represents the relationships between two or more microsystems, in which children actively participate (e.g., the connection between home and school). The exosystem refers to one or more contexts that do not involve growing human beings as active participants but affect their experience in the immediate setting; for example, the parents’ workplace and their friendship networks. The macrosystem refers to the consistencies, in the form and content of lower-order systems that exist or could exist. It describes a system of meanings and customs, including values, attitudes, goals, laws, moral beliefs, and various physical artifacts ¹1. Wong DW, Hall KR, Hernandez LW. Counseling individuals through the lifespan. Thousand Oaks: SAGE Publications; 2015.^,22. Bronfenbrenner U. The ecology of human development: experiments by nature and design. Cambridge: Harvard University Press; 1979.. Figure 1 presents the four components of our model based on the Bronfenbrenner bioecological model.

The chronosystem (not discussed here) includes the socio-historical conditions at the community or society levels. It also includes conditions at the individual level, in which it represents a transition period (e.g., birth of siblings, parents’ divorce). Although not described here, each of these levels carry factors that define the exposure of mothers, fetuses, and children to toxic metals and other contaminants.

Bioecological model of child neurodevelopmental toxicity due to heavy metals

Figure 2 shows some factors that may define exposure to toxic metals and how they could influence the neurodevelopment of children via four components.

The macrosystem

This level affects people’s lives in other contexts (Figure 2, arrow A); how to educate, feed, and care for a child depends on the culture, geographical situation, among others. It also defines how society perceives pregnancy and the type of support a pregnant woman can receive from her partner, family, and friends (Figure 2, arrow B). Figure 2 (arrow C) represents a set of mechanisms that might (or might not) generate an equitable distribution of resources in the macrosystem according to structural determinant parameters between social classes ⁴⁶46. Diez Roux AV. Conceptual approaches to the study of health disparities. Annu Rev Public Health 2012; 33:41-58.. For example, depending on national policies, some countries ensure that the poorest families have access to safe housing, a healthcare system, or a good quality education even if they cannot afford it themselves. However, other countries disregard distributing resources beyond what the individuals can do on their own ³⁹39. Krieger N. Ladders, pyramids and champagne: the iconography of health inequities. J Epidemiol Community Health 2008; 62:1098-104..

Moreover, the macrosystem setting includes the possibility of limiting the exposure of populations to potentially toxic metals (Figure 2, arrow D). In this context, legislation-based public institutions may prohibit or monitor the use and management of chemical products and waste ⁵²52. Dignam T, Kaufmann RB, LeStourgeon L, Brown MJ. Control of lead sources in the United States, 1970-2017: public health progress and current challenges to eliminating lead exposure. J Public Health Manag Pract 2019; 25 Suppl 1:S13-22.. In Brazil, for instance, the Federal Supreme Court invalidated a labor reform rule that allowed pregnant and breastfeeding women to work in unhealthy activities ⁵³53. Moraes A. Ação Direta de Inconstitucionalidade 5.938. http://www.stf.jus.br/arquivo/cms/noticiaNoticiaStf/anexo/ADI5938EmentaeVOTO.pdf (accessed on 18/Oct/2022).
http://www.stf.jus.br/arquivo/cms/notici... . We highlight the role of universities and research institutions that, together with civil society, can pressure public authorities to take adequate measures to protect the population.

The exosystem

Three parameters may influence a family in the exosystem: employment, social support networks, and the community ⁵¹51. Bronfenbrenner U. Ecology of the family as a context for human development: research perspectives. Dev Psychol 1986; 22:723-42..

Work guarantees socioeconomic status, which provides necessary components for children’s development: adequate nutrition, access to healthcare services, and cognitive stimulation. Stress associated with unemployment can impair a couple’s relationship and their physical and mental health, which, in turn, can affect fetuses and children ⁵¹51. Bronfenbrenner U. Ecology of the family as a context for human development: research perspectives. Dev Psychol 1986; 22:723-42.^,5454. Heinrich CJ. Parents' employment and children's wellbeing. Future Child 2014; 24:121-46.. Work is an essential social determinant of mental health ⁵⁵55. Araújo TM, Palma TF, Araújo NC. Vigilância em saúde mental e trabalho no Brasil: características, dificuldades e desafios. Ciênc Saúde Colet 2017; 22:3235-46. and can cause unfavorable situations for children development ⁵¹51. Bronfenbrenner U. Ecology of the family as a context for human development: research perspectives. Dev Psychol 1986; 22:723-42.^,5454. Heinrich CJ. Parents' employment and children's wellbeing. Future Child 2014; 24:121-46.. Low-income workers are often exposed to various occupational stressors related to work organizations, such as moral harassments and other forms of violence ⁵⁵55. Araújo TM, Palma TF, Araújo NC. Vigilância em saúde mental e trabalho no Brasil: características, dificuldades e desafios. Ciênc Saúde Colet 2017; 22:3235-46.. This context might impact the quality of parenting skills at home and, thus, introduce stress into children’s lives ⁵⁴54. Heinrich CJ. Parents' employment and children's wellbeing. Future Child 2014; 24:121-46.. When considering the physical environment, occupation is the primary exposure factor for toxic metals, exposing pregnant women in unsafe working places. Additionally, secondary exposure may occur when a family member returns home with contaminated clothing or work materials ²³23. Amadi CN, Zelinjo NI, Orish EO. Heavy metals in miscarriages and stillbirths in developing nations. Middle East Fertil Soc J 2017; 22:91-100..

Pregnancy and motherhood are challenging and stressful for women due to changes in their appearance, physiology, emotional well-being, and relationships ⁴⁰40. Dunkel-Schetter C. Psychological science on pregnancy: stress processes, biopsychosocial models, and emerging research issues. Annu Rev Psychol 2011; 62:531-58.^,5656. Cremonese L, Wilhelm LA, Prates LA, Paula CC, Sehnem GD, Ressel LB. Social support from the perspective of postpartum adolescents. Esc Anna Nery Rev Enferm 2017; 21:e20170088.. It usually involves a context of a continuous relationship between two partners, their family, and friends, generating a network of “social support”. Depending on the cultural context, people may express it in several ways (Figure 2, arrow B): physical, emotional, verbal, and financial or assistance to the mother’s self-esteem. This support is important to relieve the physical and emotional stress experienced by mothers. Mothers who had access to social support during pregnancy have reported lower stress, anxiety, and depression, a better marital adjustment, and a more positive attitude towards pregnancy ⁴⁰40. Dunkel-Schetter C. Psychological science on pregnancy: stress processes, biopsychosocial models, and emerging research issues. Annu Rev Psychol 2011; 62:531-58.^,5757. Izadirad H, Niknami S, Zareban I, Hidarnia A. Effects of social support and self-efficacy on maternal prenatal cares among the first-time pregnant women, Iranshahr, Iran. J Family Reprod Health 2017; 11:67-73.. Furthermore, this kind of support favors the adoption of a better lifestyle and facilitates the mother’s return to work ⁵⁴54. Heinrich CJ. Parents' employment and children's wellbeing. Future Child 2014; 24:121-46.^,5656. Cremonese L, Wilhelm LA, Prates LA, Paula CC, Sehnem GD, Ressel LB. Social support from the perspective of postpartum adolescents. Esc Anna Nery Rev Enferm 2017; 21:e20170088..

Nevertheless, according to the culture and community level, there are situations in which social support is denied, inadequate, or even harmful, inhibiting children’s growth. For example, one study found that the influence of social support on well-being changed from positive to negative based on three types of factors: low socioeconomic status, occurrence of a tragedy (such as loss of a relative), and doubts about the mother’s ability to take care of herself ⁵⁶56. Cremonese L, Wilhelm LA, Prates LA, Paula CC, Sehnem GD, Ressel LB. Social support from the perspective of postpartum adolescents. Esc Anna Nery Rev Enferm 2017; 21:e20170088.. Indeed, pregnant women in adolescent couples depend significantly on the quality of social support (advice and instrumental, informational, and emotional support), which, when inadequate, causes stress that may harm fetuses and/or hinder parents’ relationship with the newborns ⁵⁶56. Cremonese L, Wilhelm LA, Prates LA, Paula CC, Sehnem GD, Ressel LB. Social support from the perspective of postpartum adolescents. Esc Anna Nery Rev Enferm 2017; 21:e20170088.^,5858. Hodgkinson S, Beers L, Southammakosane C, Lewin A. Addressing the mental health needs of pregnant and parenting adolescents. Pediatrics 2014; 133:114-22..

The mesosystem

From pregnancy to childhood, fetuses and children depend on their caregivers. However, the hospital service and the growing human being s’ genetic or epigenetic potential are other settings that affect them ⁵¹51. Bronfenbrenner U. Ecology of the family as a context for human development: research perspectives. Dev Psychol 1986; 22:723-42..

Hospital care plays an important role in child development from pregnancy to childhood ⁵¹51. Bronfenbrenner U. Ecology of the family as a context for human development: research perspectives. Dev Psychol 1986; 22:723-42.^,5656. Cremonese L, Wilhelm LA, Prates LA, Paula CC, Sehnem GD, Ressel LB. Social support from the perspective of postpartum adolescents. Esc Anna Nery Rev Enferm 2017; 21:e20170088.^,5858. Hodgkinson S, Beers L, Southammakosane C, Lewin A. Addressing the mental health needs of pregnant and parenting adolescents. Pediatrics 2014; 133:114-22.. Healthcare professionals can detect exposures to toxic metals and support the family by limiting their impact on health (Figure 2, arrow E). They also provide the informational support necessary for mental health and help adopt healthy habits ⁵⁸58. Hodgkinson S, Beers L, Southammakosane C, Lewin A. Addressing the mental health needs of pregnant and parenting adolescents. Pediatrics 2014; 133:114-22.. The positive impact of hospital care on maternal and child health is greater in an unfavorable social context ⁵⁶56. Cremonese L, Wilhelm LA, Prates LA, Paula CC, Sehnem GD, Ressel LB. Social support from the perspective of postpartum adolescents. Esc Anna Nery Rev Enferm 2017; 21:e20170088.^,5858. Hodgkinson S, Beers L, Southammakosane C, Lewin A. Addressing the mental health needs of pregnant and parenting adolescents. Pediatrics 2014; 133:114-22..

Another important aspect is that mesosystem results from the relationship between the genotype and child microsystem (Figure 2, arrow F). The Bronfenbrenner bioecological model hypothesizes that proximal processes are the engine that allows the update and improvement of the genetic potential that each human being is born with ³3. Bronfenbrenner U, Ceci JS. Nature-nurture reconceptualized in developmental perspective: a bioecological model. Psychol Rev 1994; 101:568-86.^,5151. Bronfenbrenner U. Ecology of the family as a context for human development: research perspectives. Dev Psychol 1986; 22:723-42.. Parents transmit genes to their children and provide them with an immediate environment to develop defined characteristics ⁵⁰50. Plomin R, DeFries JC, Loehlin JC. Genotype-environment interaction and correlation in the analysis of human behavior. Psychol Bull 1977; 84:309-22.. However, inadequate proximal processes or exposure to toxic metals may compromise their occurrence by direct effects on DNA or indirect effects via epigenetic processes ²¹21. Engwa GA, Ferdinand PU, Nwalo FN, Unachukwu MN. Mechanism and health effects of heavy metal toxicity in humans. In: Karcioglu O, Arslan B, editors. Poisoning in the modern world: new tricks for an old dog? London: IntechOpen; 2019. p. 1-23.^,2323. Amadi CN, Zelinjo NI, Orish EO. Heavy metals in miscarriages and stillbirths in developing nations. Middle East Fertil Soc J 2017; 22:91-100.^,2424. Gundacker C, Neesen J, Straka E, Ellinger I, Dolznig H, Hengstschläger M. Genetics of the human placenta: implications for toxicokinetics. Arch Toxicol 2016; 90:2563-81..

The family microsystem

Inappropriate social processes and exposure to toxic metals can lead to the appearance of vulnerabilities ³⁵35. Sobolewski M, Conrad K, Marvin E, Allen JL, Cory-Slechta DA. Endocrine active metals, prenatal stress and enhanced neurobehavioral disruption. Horm Behav 2018; 101:36-49.^,3636. Vreugdenhil HJ, Slijper FM, Mulder PG, Weisglas-Kuperus N. Effects of perinatal exposure to PCBs and dioxins on play behavior in Dutch children at school age. Environ Health Perspect 2002; 110:A593-8.^,5959. McEwen BS, Tucker P. Critical biological pathways for chronic psychosocial stress and research opportunities to advance the consideration of stress in chemical risk assessment. Am J Public Health 2011; 101 Suppl 1:S131-9.. The changes in the brain induced by stimuli from the microsystem are often referred to as “brain plasticity”. Sensitivity to stimuli, positive or negative, is high during sensitive and rapid growth periods, such as pregnancy and childhood, in which plasticity is greater ⁶⁰60. Johnson SB, Riis JL, Noble KG. State of the art review: poverty and the developing brain. Pediatrics 2016; 137:e20153075.. Figure 3 shows the main context of fetuses and children.

During pregnancy

During gestation, the microsystem is an intrauterine environment that transmits all the mother’s genetic potential to the fetus. To achieve this correctly, optimum conditions at all ecological levels are required (Figure 3, part i).

However, in real life, a mixture of positive and negative conditions is frequently observed and, depending on the balance between them, a competence or dysfunction might arise ⁵⁹59. McEwen BS, Tucker P. Critical biological pathways for chronic psychosocial stress and research opportunities to advance the consideration of stress in chemical risk assessment. Am J Public Health 2011; 101 Suppl 1:S131-9.. For example, the mother’s chronic stress due to socioeconomic status may lead to elevated cortisol production, which, after crossing the placenta, may harm the CNS of fetuses, making them more vulnerable since their early stages ⁶¹61. Cory-Slechta DA, Virgolini MB, Thiruchelvam M, Weston DD, Bauter MR. Maternal stress modulates the effects of developmental lead exposure. Environ Health Perspect 2004; 112:717-30.^,6262. Cory-Slechta DA. Interactions of lead exposure and stress: implications for cognitive dysfunction. Int Rev Res Ment Retard 2005; 30:87-139.. The release of toxic metals from mothers’ organs put fetuses at risk due to their neurotoxicity. A vicious cycle may be established in which stress and toxic metals impair neuronal processes ⁶⁰60. Johnson SB, Riis JL, Noble KG. State of the art review: poverty and the developing brain. Pediatrics 2016; 137:e20153075.^,6363. Tamayo y Ortiz M, Téllez-Rojo MM, Trejo-Valdivia B, Schnaas L, Osorio-Valencia E, Coull B, et al. Maternal stress modifies the effect of exposure to lead during pregnancy and 24-months old children's neurodevelopment. Environ Int 2017; 98:191-7.^,6464. Cory-Slechta DA. Studying toxicants as single chemicals: does this strategy adequately identify neurotoxic risk? Neurotoxicology 2005; 26:491-510.. Coexposure to psychosocial stress and metals has been associated with a type of toxicity, the mechanism of which might be characterized by interactions. Exposure to stress may decrease the CNS sensitivity threshold to metal toxicity and/or vice versa, affecting neurological functions such as cognition, behavior, and motor function ³⁵35. Sobolewski M, Conrad K, Marvin E, Allen JL, Cory-Slechta DA. Endocrine active metals, prenatal stress and enhanced neurobehavioral disruption. Horm Behav 2018; 101:36-49.^,6565. Bölte S, Girdler S, Marschik PB. The contribution of environmental exposure to the etiology of autism spectrum disorder. Cell Mol Life Sci 2019; 76:1275-97.^,6666. Cory-Slechta DA, Virgolini MB, Rossi-George A, Thiruchelvam M, Lisek R, Weston D. Lifetime consequences of combined maternal lead and stress. Basic Clin Pharmacol Toxicol 2008; 102:218-27..

Postpartum period and childhood

After delivery, children are in direct contact with the physical and social world. However, they still depend on their parents and other adults whose role is to provide the necessary conditions for their growth ²2. Bronfenbrenner U. The ecology of human development: experiments by nature and design. Cambridge: Harvard University Press; 1979.^,33. Bronfenbrenner U, Ceci JS. Nature-nurture reconceptualized in developmental perspective: a bioecological model. Psychol Rev 1994; 101:568-86.^,44. Bronfenbrenner U, Evans GW. Developmental science in the 21st century: emerging questions, theoretical models, research designs and empirical findings. Soc Dev 2000; 9:115-25.. Figure 3 (part ii) shows the possible types of the microsystems that children may be exposed to. Although real-life circumstances present many possibilities, for reasons of clarity, we limit ourselves to adequate and inadequate contexts, as suggested by Bronfenbrenner & Ceci ³3. Bronfenbrenner U, Ceci JS. Nature-nurture reconceptualized in developmental perspective: a bioecological model. Psychol Rev 1994; 101:568-86.. Children acquire their psychological and cognitive content by a dynamic fusion of the processes of correlations and interactions between the genotype (inherited) and their microsystem ⁶⁷67. Shanahan MJ, Hofer SM. Social context in gene-environment interactions: retrospect and prospect. J Gerontol B Psychol Sci Soc Sci 2005; 60 Spec No 1:65-76. (represented by the dotted central vertical arrow). The Bronfenbrenner bioecological model considers that proximal processes exert a relatively more powerful effect on development than the environments in which they operate ³3. Bronfenbrenner U, Ceci JS. Nature-nurture reconceptualized in developmental perspective: a bioecological model. Psychol Rev 1994; 101:568-86.. Consequently, differences in developmental outcomes between “inadequate versus adequate” environments are consistently smaller than those associated with “low versus high” levels of proximal processes, that is, the quality and strength of interactions between children and their family present a greater impact on neurodevelopment than the type of environment in which they are inserted.

Furthermore, when we extend to the physical environment, several studies showed that children from lower social classes were more sensitive (i.e., loss of IQ points, lower memory capacity) to environmental contaminants (Pb, cigarette smoke, polychlorinated biphenyls, etc.). Simultaneously, those in better conditions were less affected or not affected ³³33. Rauh VA, Whyatt RM, Garfinkel R, Andrews H, Hoepner L, Reyes A, et al. Developmental effects of exposure to environmental tobacco smoke and material hardship among inner-city children. Neurotoxicol Teratol 2004; 26:373-85.^,3434. Lucchini RG, Guazzetti S, Renzetti S, Conversano M, Cagna G, Fedrighi C, et al. Neurocognitive impact of metal exposure and social stressors among schoolchildren in Taranto, Italy. Environ Health 2019; 18:67.^,3636. Vreugdenhil HJ, Slijper FM, Mulder PG, Weisglas-Kuperus N. Effects of perinatal exposure to PCBs and dioxins on play behavior in Dutch children at school age. Environ Health Perspect 2002; 110:A593-8.^,6262. Cory-Slechta DA. Interactions of lead exposure and stress: implications for cognitive dysfunction. Int Rev Res Ment Retard 2005; 30:87-139.. Interpreting this from a bioecological perspective means that the microsystem can provide good conditions and proximal processes that may protect children from the neurotoxic effects of these pollutants. A study ⁶⁸68. Surkan PJ, Schnaas L, Wright RJ, Téllez-Rojo MM, Lamadrid-Figueroa H, Hu H, et al. Maternal self-esteem, exposure to lead, and child neurodevelopment. Neurotoxicology 2008; 29:278-85. showed that the social environment (expressed by mothers’ self-esteem) lowered the neurotoxicity of Pb in children. Lucchini et al. ³⁴34. Lucchini RG, Guazzetti S, Renzetti S, Conversano M, Cagna G, Fedrighi C, et al. Neurocognitive impact of metal exposure and social stressors among schoolchildren in Taranto, Italy. Environ Health 2019; 18:67. reported better cognitive performance in children with better social conditions than in others, regardless of exposure to Pb. These results were the same regardless of geographic position ³³33. Rauh VA, Whyatt RM, Garfinkel R, Andrews H, Hoepner L, Reyes A, et al. Developmental effects of exposure to environmental tobacco smoke and material hardship among inner-city children. Neurotoxicol Teratol 2004; 26:373-85.^,3434. Lucchini RG, Guazzetti S, Renzetti S, Conversano M, Cagna G, Fedrighi C, et al. Neurocognitive impact of metal exposure and social stressors among schoolchildren in Taranto, Italy. Environ Health 2019; 18:67.^,3636. Vreugdenhil HJ, Slijper FM, Mulder PG, Weisglas-Kuperus N. Effects of perinatal exposure to PCBs and dioxins on play behavior in Dutch children at school age. Environ Health Perspect 2002; 110:A593-8.. This may confirm the properties of the Bronfenbrenner bioecological model in proximal processes and demonstrate the higher vulnerability of disadvantaged families when exposed to pollutants such as toxic metals.

Activation of the HPA stress-response network has also been suggested as a possible pathway for the neurotoxic effect of Pb ⁶⁴64. Cory-Slechta DA. Studying toxicants as single chemicals: does this strategy adequately identify neurotoxic risk? Neurotoxicology 2005; 26:491-510.^,6767. Shanahan MJ, Hofer SM. Social context in gene-environment interactions: retrospect and prospect. J Gerontol B Psychol Sci Soc Sci 2005; 60 Spec No 1:65-76.. For example, Gump et al. ²⁸28. Gump BB, Stewart P, Reihman J, Lonky E, Darvill T, Parsons PJ, et al. Low-level prenatal and postnatal blood lead exposure and adrenocortical responses to acute stress in children. Environ Health Perspect 2008; 116:249-55. showed that early exposure to low levels of Pb could alter children’s adrenocortical responses to acute stress, proving the biological plausibility that Pb can also activate the HPA axis. However, we highlight that, among the toxic metals discussed in this study, Pb has been the most investigated regarding its interaction with stress or social context ⁶²62. Cory-Slechta DA. Interactions of lead exposure and stress: implications for cognitive dysfunction. Int Rev Res Ment Retard 2005; 30:87-139.. Considering other contaminants that have been studied ³⁵35. Sobolewski M, Conrad K, Marvin E, Allen JL, Cory-Slechta DA. Endocrine active metals, prenatal stress and enhanced neurobehavioral disruption. Horm Behav 2018; 101:36-49.^,5959. McEwen BS, Tucker P. Critical biological pathways for chronic psychosocial stress and research opportunities to advance the consideration of stress in chemical risk assessment. Am J Public Health 2011; 101 Suppl 1:S131-9.^,6262. Cory-Slechta DA. Interactions of lead exposure and stress: implications for cognitive dysfunction. Int Rev Res Ment Retard 2005; 30:87-139., their coexistence with inappropriate environment causes greater vulnerability in populations.

Application, strengths, and limitations

Investigating neurodevelopmental toxicity of pollutants involves great responsibility on scientists since their results may influence public policies. Due to the greater vulnerability of growing human being s and developing fetuses, with possible lifetime consequences, it is essential to conduct research adequately. Our framework was based on multiple environmental system perspectives of Bronfenbrenner bioecological model to contribute to current issues discussed in neurotoxicology and environmental sciences ⁶6. Weiss B, Bellinger DC. Social ecology of children's vulnerability to environmental pollutants. Environ Health Perspect 2006; 114:1479-85.^,77. Senier L, Brown P, Shostak S, Hanna B. The socio-exposome: advancing exposure science and environmental justice in a post-genomic era. Environ Sociol 2017; 3:107-21.^,1111. Tulve NS, Ruiz JDC, Lichtveld K, Darney SP, Quackenboss JJ. Development of a conceptual framework depicting a child's total (built, natural, social) environment in order to optimize health and well-being. J Environ Health Sci 2016; 2:1-8.^,6969. Bellinger DC. Interpreting epidemiologic studies of developmental neurotoxicity: conceptual and analytic issues. Neurotoxicol Teratol 2009; 31:267-74.. The radical shift in using social science and humanized approaches makes it unique and different. Considering the need for an environmental science interpreted through the lens of equity, we adapted valuable concepts such as intersectionality (for example, considering the effect of SDH such as gender, race, and social class simultaneously), allostatic stress, and embodiment. Bronfenbrenner bioecological model allows further exploration on pollutants’ impacts on health outcomes and children neurodevelopment, considering individuals, families, and community-level realities over time. The model also offers the opportunity to investigate how determinants at the macrosystem level (like a social policy or legislation) may influence this combined effect (enhancing or mitigating methylparathion - MPT toxicity). Findings obtained with this theoretical model may be more readily accepted and appreciated by the community, civil society, and stakeholders to establish new policies for change.

However, applying this model involves some issues not furthered in this study due to the length restrictions. First, the model includes ecological contexts besides biological (and toxicological) concepts, and it may be expensive to conduct studies that include all aspects of this model. According to Tudge et al. ⁷⁰70. Tudge JR, Mokrova I, Hatfield BE, Karnik RB. Uses and misuses of Bronfenbrenner's bioecological theory of human development. J Fam Theory Rev 2009; 1:198-210.^,7171. Tudge JR, Payir A, Merçon-Vargas E, Cao H, Liang Y, Li J, et al. Still misused after all these years? A reevaluation of the uses of Bronfenbrenner's bioecological theory of human development. J Fam Theory Rev 2016; 8:427-45., many scholars misuse Bronfenbrenner bioecological model when applying it in their study. Based on analyses of Bronfenbrenner’s scientific production ²2. Bronfenbrenner U. The ecology of human development: experiments by nature and design. Cambridge: Harvard University Press; 1979.^,33. Bronfenbrenner U, Ceci JS. Nature-nurture reconceptualized in developmental perspective: a bioecological model. Psychol Rev 1994; 101:568-86.^,44. Bronfenbrenner U, Evans GW. Developmental science in the 21st century: emerging questions, theoretical models, research designs and empirical findings. Soc Dev 2000; 9:115-25.^,55. Bronfenbrenner U, Morris PA. The bioecological model of human development. In: Damon W, Lerner RM, editors. Handbook of child psychology. Hoboken: John Wiley & Sons, Ltd.; 2007. p. 739-828.^,7070. Tudge JR, Mokrova I, Hatfield BE, Karnik RB. Uses and misuses of Bronfenbrenner's bioecological theory of human development. J Fam Theory Rev 2009; 1:198-210.^,7171. Tudge JR, Payir A, Merçon-Vargas E, Cao H, Liang Y, Li J, et al. Still misused after all these years? A reevaluation of the uses of Bronfenbrenner's bioecological theory of human development. J Fam Theory Rev 2016; 8:427-45., it appears clear that one can partly use the model. The most important is to clearly define potentially toxic metals (PTMs) exposure, the participants’ characteristics, and the considered and discarded contexts for the investigation. Tudge et al. ⁷¹71. Tudge JR, Payir A, Merçon-Vargas E, Cao H, Liang Y, Li J, et al. Still misused after all these years? A reevaluation of the uses of Bronfenbrenner's bioecological theory of human development. J Fam Theory Rev 2016; 8:427-45. (p. 429) suggested that: “...appropriate use of Bronfenbrenner’s bioecological theory requires a focus on proximal processes, a means to show that these proximal processes are simultaneously and synergistically influenced both by person characteristics (a minimum of two levels, for example, high and low levels of motivation) and by the context (a minimum of two relevant contexts), and the study should be longitudinal”.

Therefore, how PTMs exposure, jointly with proximal processes, affects neurodevelopment must be at the center of investigations. For example, a study may consider investigating the effect of exposure to Pb (or MPTs mixtures) on children’s cognition at two moments (after six months and two years), by comparing girls vs. boys (or low birth weight vs. normal birth weight) in two socioeconomic contexts; by the proximal processes being assessed by mother-child interaction quality using the Home Observation for Measurement of the Environment (HOME) questionnaire; or using other tools that evaluate the degree of interaction and stimulation from family members.

A second issue to consider is the assessment of MPTs (or pollutants) exposure and other biological parameters (genetic, immunologic, microbiome), which may be considered in the interplay between MPTs neurotoxicity and ecological aspects. For example, questionnaires, spatial distribution, biomarkers (blood, nails, saliva, hair), environmental sample (water, dust, air, soil), sensors, and “omics” technologies are some tools that may be helpful. However, as alerted by Siroux et al. ¹⁵15. Siroux V, Agier L, Slama R. The exposome concept: a challenge and a potential driver for environmental health research. Eur Respir Rev 2016; 25:124-9., a caution should be considered to avoid misclassification.

A third important issue is analyzing and interpreting large-scale and diverse data. Indeed, applying this multilevel framework involves statistical challenges. Separate regression analyses, multilevel modeling, nonparametric smoothing methods (such as locally weighted polynomial regression), and structural equation modeling are examples of statistical methods applied in literature ⁸8. Gee GC, Payne-Sturges DC. Environmental health disparities: a framework integrating psychosocial and environmental concepts. Environ Health Perspect 2004; 112:1645-53.^,6969. Bellinger DC. Interpreting epidemiologic studies of developmental neurotoxicity: conceptual and analytic issues. Neurotoxicol Teratol 2009; 31:267-74.^,7171. Tudge JR, Payir A, Merçon-Vargas E, Cao H, Liang Y, Li J, et al. Still misused after all these years? A reevaluation of the uses of Bronfenbrenner's bioecological theory of human development. J Fam Theory Rev 2016; 8:427-45. to estimate the joint effect of exposures and or ecological variables on human health. The choice of the adapted statistical tools should be well explained by the investigator to contribute critically and help to improve this theoretical model.

Conclusion

Biological sciences, such as toxicology, have allowed important advances in society, helping to understand and improve life. Although scientists practice with the intent of neutrality, in recent decades, the importance of including “what is experienced and resentful” by participants in research has been demonstrated to better approach reality. Concepts such as the “embodiment” of the social context, the allostatic load, and SDHs express this more accurately. Regarding human development, the Bronfenbrenner bioecological model has integrated several areas. Our theoretical model has attempted to assess the impact of contaminants, such as toxic metals on the neurodevelopment of children, suggesting explorations of new paths. Despite the presence of an extended period between the research results and the concrete political decisions for social justice, there is an urgent need for more humanized research that puts vulnerable populations at the heart of the scientific investigation.

Acknowledgments

The authors would like to thank the Brazilian National Research Council (CNPq) and the Bahia State Research Support Foundation (FAPESB) for funding through the grant (Universal Edital 421550/2018-0; PPSUS EFP_00019898) and students’ scholarships. We would like to express our gratitude to Dr. Federico Costa and Dr. Djanilson Barbosa dos Santos for their valuable contributions in revising the manuscript and providing suggestions to enhance its quality.

References

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