Abstract

Central Nervous System (CNS) tumors represent more than half of all childhood malignant neoplasms. The aim of this study was to determine the relationship between environmental exposure to pesticides and the development of CNS tumors in children. We conducted a systematic review of the literature in the PubMed/MEDILINE, Embase, Web of Science, Scopus, and CINAHL databases. The inclusion criteria were cohort and case-control studies investigating the association between exposure to pesticides and CNS tumors (all histological types included in group III of the WHO Classification of Childhood Cancer) in children aged 0-14 years. The meta-analysis was performed using a random effects model and the Mantel-Haenszel method. Strength of association was measured using odds ratios (OR). The review was registered in the International Prospective Register of Systematic Reviews (PROSPERO) under identification number CRD42021209354. The search identified 1,158 studies, 14 of which were included in the review. There was evidence of an association between the development of astrocytomas and exposure to all classes of pesticides (OR 1.50; 95%CI 1.15-1.96; p=0.03). The synthesis of the evidence pointed to a relationship between exposure to pesticides and some histological types of CNS tumors in childhood.

Key words:
Central Nervous System neoplasms; Risk factors; Environmental exposure; Child

Introduction

Childhood cancer has become a major cause of morbidity and mortality among children in both developed and developing countries in recent years. In the United States, the incidence rate of malignant and non-malignant brain and central nervous system (CNS) tumors among children and adolescents (0-19 years) between 2013 and 2017 was 6.14 per 100,000 population¹1 Ostrom QT, Gittleman H, Liao P, Rouse C, Chen Y, Dowling J, Wolinsky Y, Kruchko C, Barnholtz-Sloan J. CBTRUS statistical report: primary brain and central nervous system tumors diagnosed in the United States in 2007-2011. Neuro Oncol 2014; 16(4):iv1-iv63..

In Brazil, cancer is one of the leading causes of death in children and adolescents aged 1-19 years. The most common types of cancer are leukemia, lymphomas, and CNS tumors²2 Brasil. Ministério da Saúde (MS). Instituto Nacional do Câncer (INCA). Câncer infantojuvenil [Internet]. 2019 [acessado 2020 ago 29]. Disponível em: https://www.inca.gov.br/tipos-de-cancer/cancer-infantojuvenil.
https://www.inca.gov.br/tipos-de-cancer/... . The latter is the most common cancer among children, accounting for 20% of all neoplasms, with incidence peaking between ages 1-4 years³3 Brasil. Ministério da Saúde (MS). Instituto Nacional do Câncer (INCA). Tumores do Sistema Nervoso Central (em crianças) - versão para Profissionais de Saúde [Internet]. 2018 [acessado 2020 dez 30]. Disponível em: https://www.inca.gov.br/tipos-decancer/cancer-infantojuvenil/tumores-do-sistema-nervoso-central/profissional-de-saude.
https://www.inca.gov.br/tipos-decancer/c... .

CNS tumors and leukemia combined account for more than half of all malignant tumors in children. Moreover, the former has the greatest variation of histological subtypes and metastatic capacity and highest infant mortality rate⁴4 Jacques G, Cormac O. Central nervous system tumors. Handb Clin Neurol 2013; 112:931-958.. Subtypes include ependymomas, astrocytomas, primitive neuroectodermal tumors (PNET), gliomas, and specified and unspecified intracranial and intraspinal neoplasms⁵5 Louis DN, Perry A, Reifenberger G, Deimling AV, Figarella-Branger D, Cavenee WK, Ohgaki H, Wiestler OD, Kleihues P, Ellison DW. The 2016 World Health Organization Classification of Tumors of the Central Nervous System: a summary. Acta Neuropathol 2016; 131(6):803-820..

The identification of risk factors associated with the development of CNS tumors in children has become an epidemiological imperative to guide prevention and treatment. Studies investigating direct exposure to pesticides (use for home pest control) and indirect exposure (related to parental occupation) conducted in recent years have shown a possible link between exposure and CNS tumors⁶6 Maele-Fabry GV, Hoet P, Lison D. Parental occupational exposure to pesticides as risk factor for childhood and young adults brain tumors: a systematic review and meta-analysis. Environ Int 2013; 56:19-31..

Pesticides include herbicides (weed killers), insecticides (used to control insects), ant killers, acaricides (used to control spider mites and animal ticks), larvicides (used to control insect larvae), fungicides (used against fungi), rodenticides (used to kill rodents, particularly mice and rats), and avicides (used to kill seed-eating birds)⁷7 Almeida W, Fiúza J, Magalhães CM, Junger CM. Agrotóxicos. Cad Saude Publica 1985; 1(2):220-249..

The National Cancer Institute (INCA)⁸8 Brasil. Ministério da Saúde (MS). Instituto Nacional de Câncer (INCA). Coordenação de Prevenção e Vigilância. Vigilância do câncer relacionado ao trabalho e ao ambiente. 2ª ed. rev. atual. Rio de Janeiro: INCA; 2010. underlines that occupational exposure to pesticides poses a risk not only to workers, but also other individuals, such as family members and residents living close to pesticide use sites. Other forms of exposure can contribute to poisoning among the general population, including eating pesticide residues in food, drinking contaminated water, and using insecticides in the home.

The investigation of environmental risk factors is therefore important to gain a deeper understanding of the possible relationship between the use of pesticides and CNS tumors and help shape health promotion and prevention policies.

The metanalyses available in the literature address these factors in an isolated manner, focus on adolescents and young adults, or were conducted more than five years ago⁶6 Maele-Fabry GV, Hoet P, Lison D. Parental occupational exposure to pesticides as risk factor for childhood and young adults brain tumors: a systematic review and meta-analysis. Environ Int 2013; 56:19-31.^,99 Maele-Fabry GV, Gamet-Payrastre L, Lison D. Residential exposure to pesticides as risk factor for childhood and young adult brain tumors: A systematic review and meta-analysis. Environ Int 2017; 106:69-90.

10 Zumel-Marne A, Castano-Vinyals G, Kundi M, Alguacil J, Cardis E. Environmental Factors and the Risk of Brain Tumours in Young People: Systematic. Neuroepidemiology 2019; 53(3-4):121-141.^-1111 Vinson F, Merhi M, Baldi I, Raynal H, Gamet-Payrastre L. Exposure to pesticides and risk of childhood cancer: a meta-analysis of recent epidemiological studies. Occup Environ Med 2011; 68(9):694-702.. A systematic review of the literature on the topic was therefore undertaken to consolidate knowledge on exposure to pesticides and CNS tumors in children. The latest INCA report on cancer incidence, morbidity, and mortality specifies the following age groups: children (0-14 years), adolescents (15-19 years), and young adults (20-29 years)¹²12 Brasil. Ministério da Saúde (MS). Instituto Nacional de Câncer (INCA). Incidência, mortalidade e morbidade hospitalar por câncer em crianças, adolescentes e adultos jovens no Brasil: informações dos registros de câncer do sistema de mortalidade. Rio de Janeiro: INCA; 2016.. The present study focused on CNS tumors in children (0-14 years) because the incidence rate in this group differs from that among adolescents and young adults.

The aim of this literature review is therefore to determine the relationship between environmental exposure to pesticides and the development of CNS tumors in children.

Method

We conducted a systematic review and meta-analysis following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA-P) guidelines¹³13 Moher D. Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015 statement. Syst Rev 2015; 4(1):1. and recommendations set out in the Cochrane Manual¹⁴14 The Cocrhane Colaboration. Cochrane handbook for systematic reviews of interventions [Internet]. [acessado 2021 abr 20]. Disponível em: https://training.cochrane.org/handbook.
https://training.cochrane.org/handbook... . The review protocol was registered on the International Prospective Register of Systematic Reviews (PROSPERO)¹⁵15 PROSPERO. Registro prospectivo internacional de revisões sistemáticas [Internet]. [acessado 2021 dez 28]. Disponível em: https://www.crd.york.ac.uk/PROSPERO/.
https://www.crd.york.ac.uk/PROSPERO... under identification number CRD42021209354.

Formulation of the research question

The research question was formulated using the PECOS acronym¹⁶16 Brasil. Ministério da Saúde (MS). Secretaria de Ciência, Tecnologia e Insumos Estratégicos. Departamento de Ciência e Tecnologia. Diretrizes metodológicas: elaboração de revisão sistemática e metanálise de estudos observacionais comparativos sobre fatores de risco e prognóstico. Brasília: MS; 2014. (P: population; E: exposure; C: comparison; O: outcome; S: study design), recommended for observational studies, as follows:

Based on the above elements, the following research question was formulated: what environmental risk factors (environmental exposure to pesticides, including herbicides, insecticides, and others) may be related to the development of CNS tumors in children?

Eligibility

The following studies were considered eligible for the review: 1) studies assessing the relationship between exposure to all types of pesticides (insecticides, herbicides, fungicides, and others) and the development of CNS tumors in children; 2) cohort and case-control studies. No restrictions were applied in relation to language and data of publication.

The following exclusion criteria were used: studies including histological types not included in group III (tumors of the central nervous system) of the World Health Organization Classification of Childhood Cancer⁵5 Louis DN, Perry A, Reifenberger G, Deimling AV, Figarella-Branger D, Cavenee WK, Ohgaki H, Wiestler OD, Kleihues P, Ellison DW. The 2016 World Health Organization Classification of Tumors of the Central Nervous System: a summary. Acta Neuropathol 2016; 131(6):803-820..

Data sources and search strategies

Searches were performed of six major databases: PubMed (MEDLINE), Embase, Web of Science, Scopus, Engineering Village, and the Cumulative Index to Nursing and Allied Health Literature (CINAHL). We also searched the following grey literature sources: Google Scholar, OpenGrey, ProQuest Dissertations and Theses, and the periodicals platform of the Coordination for the Improvement of Higher Education Personnel (CAPES Periodicals).

The searches were performed using controlled Health Sciences Descriptors (DeCS), Medical Subjects Headings (MeSH), and Embase Subject Headings (Emtree) health vocabularies and one engineering controlled vocabulary (Engineering Village - Elsevier), specific to each database. We also used ordinary language terms (keywords) to complement the searches and increase the number of retrieved articles on the study topic¹⁷17 Araújo WCO. Recuperação da informação em saúde: construção, modelos e estratégias. Conver Cien Info 2020; 3(2):100-134.^,1818 Siddaway AP, Madeira AM, Hedges LV. How to do a Systematic Review: A Best Practice Guide for Conducting and Reporting Narrative Reviews, Meta-Analyses, and Meta-Syntheses. Annu Rev Psychol 2019; 70:747-770.. The search strategy included specific terms for types of pesticides and general terms for environmental exposure factors (Chart 1).

Data collection

The review strategies were tested on each database by the systematic review team (reviewers and librarian) to identify inconsistencies and feasibility. The team was made up of professionals with knowledge of the topic and/or method, exploiting the specific skills and competencies of each member. The group was composed as follows:

The retrieved data were saved in a RIS file on the same day at one-hour intervals. The metadata file was then exported to the Mendeley reference manager to check for inconsistencies and correct errors. Duplicate references were excluded using the relevant reference manager and Microsoft Excel (2020 update) tools and by checking the article titles, since many author’s names and titles were different on the databases. A blind pairwise comparison of the results was performed by the reviewers. The search and definitive extraction of data was performed in November 2021.

Study selection involved three stages: screening of the titles and abstracts of the studies included after excluding the duplicates; screening of the full version of the articles that met the eligibility criteria (exposure to pesticides in children aged 0-14 years and cohort and case-control studies); and reading of the references of the articles included in the previous stage to identify other studies that met the inclusion criteria.

Data analysis

The following study information was recorded: author name, country of origin, study design, age group, sample size (case-controls and cohorts), histological type of CNS tumors, type of environmental exposure, exposure setting, and main results.

The methodological quality of the individual studies was assessed using the Newcastle-Ottawa (NOS) Quality Assessment Scale for Case-Control and Cohort Studies, developed by the Ottawa Hospital Research Institute and used for assessing the quality of nonrandomized (observational) studies. The studies were scored based on the following three criteria: selection (0-4 points), comparability (0-2 points), outcome/exposure (0-3 points). Based on the overall score across the three criteria, the studies were classified as follows: high quality and low risk of bias (greater than or equal to 7 points), intermediate quality and risk of bias (6 points), and low quality and high risk of bias (less than or equal to 5 points)¹⁹19 Wells GA, Wells G, Shea B, Shea B, O'Connell D, Peterson J, Welch Losos M, Tugwell P, Ga SW, Zello GA, Petersen JA. The Newcastle-Ottawa Scale (NOS) for Assessing the Quality of Nonrandomised Studies in Meta-analyses [Internet]. 2021 [cited 2021 dez 28]. Available from: https://www.ohri.ca/programs/clinical_epidemiology/oxford.asp.
https://www.ohri.ca/programs/clinical_ep... . The quality assessment was performed by reviewers 1, 2 and 3.

Heterogeneity was assessed using Cochran’s Q test (p-value) and inconsistency Index (I²) and classified as follows: low (0-40%), moderate (30-60%), and high (50-90%)¹⁴14 The Cocrhane Colaboration. Cochrane handbook for systematic reviews of interventions [Internet]. [acessado 2021 abr 20]. Disponível em: https://training.cochrane.org/handbook.
https://training.cochrane.org/handbook... . The meta-analysis included only outcomes with low heterogeneity and not classified as having a high risk of bias.

The meta-analysis was performed using a random effects model and the Mantel-Haenszel method¹⁶16 Brasil. Ministério da Saúde (MS). Secretaria de Ciência, Tecnologia e Insumos Estratégicos. Departamento de Ciência e Tecnologia. Diretrizes metodológicas: elaboração de revisão sistemática e metanálise de estudos observacionais comparativos sobre fatores de risco e prognóstico. Brasília: MS; 2014.. Odds ratios (OR) were used to measure association, adopting a 95% confidence interval. The meta-analysis was performed using The Cochrane Collaboration’s Review Manager 5® (RevMan 5).

Ethical aspects

The study did not require ethical approval as it analyzed evidence from primary studies using secondary data.

Results

The searches identified 1,158 studies, 14 of which were found to be eligible for analysis after screening²⁰20 Bagazgoitia NV, Bailey HD, Orsi L, Lacour B, Guerrini-Rousseau L, Bertozzi AI, Leblond P, Faure-Conter C, Pellier I, Freycon C, Doz F, Puget S, Ducassou S, Clavel J. Maternal residential pesticide use during pregnancy and risk of malignant childhood brain tumors: A pooled analysis of the ESCALE and ESTELLE studies (SFCE). Int J Cancer 2018; 142(3):489-497.

21 Bunin GR, Buckley JD, Boesel CP, Rorke LB, Meadows AT. Risk factors for astrocytic glioma and primitive neuroectodermal tumor of the brain in young children: a report from the children's cancer group. Cancer Epidemiol Biomarkers Prev 1994; 3(3):197-204.

22 Davis JR, Brownson RC, Garcia R, Bentz BJ, Turner A. Family Pesticide Use and Childhood Brain Cancer. Arch Environ Contam Toxicol 1993; 24(1):87-92.

23 Febvey O, Schüz J, Bailey HD, Clavel J, Lacour B, Orsi L, Lightfoot T, Roman E, Vermeulen R, Kromhout H, Olsson A. Risk of Central Nervous System Tumors in Children Related to Parental Occupational Pesticide Exposures in three European Case-Control Studies. J Occup Environ Med 2016; 58(10):1046-1052.

24 Greenop K, Peters S, Bailey HD, Fritschi L, Attia J, Scott RJ, Glass DC, Klerk NH, Alvaro F, Armstrong BK, Milne E. Exposure to pesticides and the risk of childhood brain tumors. Cancer Causes Control 2013; 24(7):1269-1278.

25 Searles Nielsen SS, Mueller BA, De Roos AJ, Viernes HM, Farin FM, Checkoway H. Risk of Brain Tumors in Children and Susceptibility to Organophosphorus Insecticides: The Potential Role of Paraoxonase (PON1). Environ Health Perspect 2005; 113(7):909-913.

26 Searles Nielsen S, McKean-Cowdin R, Farin FM, Holly EA, Preston-Martin S, Mueller BA. Childhood Brain Tumors, Residential Insecticide Exposure, and Pesticide Metabolism Genes. Environ Health Perspect 2010; 118(1):144-149.

27 Reynolds P, Von Behren J, Gunier RB, Goldberg DE, Harnly M, Hertz A. Agricultural Pesticide Use and Childhood Cancer in California. Epidemiology 2005; 16(1):93-100.

28 Rosso AL, Hovinga ME, Rorke-Adams LB, Spector LG, Bunin GR. A case-control study of childhood brain tumors and fathers' hobbies - a children's oncology group study. Cancer Causes Control 2008; 19(10):1201-1207.

29 Shim YK, Mlynarek SP, van Wijngaarden E. Parental Exposure to Pesticides and Childhood Brain Cancer: U.S. Atlantic Coast Childhood Brain Cancer Study. Environ Health Perspect 2009; 117(6):1002-1006.

30 Shutz J, Kaletsch U, Kaatsch P, Meinert R, Michaelis J. Risk Factors for Pediatric Tumors of the Central Nervous System: Results from a German Population-Based Case-Control Study. Med Pediatr Oncol 2001; 36(2):274-282.

31 Spix C, Schulze-Rath R, Kaatsch P, Blettner M. Case-Control Study on Risk Factors for Leukaemia and Brain Tumours in Children under 5 Years in Germany. Klin Padiatr 2009; 221(6):362-368.

32 Walker K, Carozza S, Cooper S, Elgethun K. Childhood Cancer in Texas Counties with Moderate to Intense Agricultural Activity. J Agric Saf Health 2007; 13(1):9-24.^-3333 Wijingaarden EV, Stewart PA, Olshan AF, Savitz DA, Bunin GR. Parental Occupational Exposure to Pesticides and Childhood Brain Cancer. Am J Epidemiol 2003; 157(11):989-997.. Figure 1 shows the study selection process.

Epidemiological and clinical characteristics

The general study characteristics are presented in Chart 2. The selected articles were published between 1993 and 2018, with two studies being published in 2005²⁵25 Searles Nielsen SS, Mueller BA, De Roos AJ, Viernes HM, Farin FM, Checkoway H. Risk of Brain Tumors in Children and Susceptibility to Organophosphorus Insecticides: The Potential Role of Paraoxonase (PON1). Environ Health Perspect 2005; 113(7):909-913.^,2727 Reynolds P, Von Behren J, Gunier RB, Goldberg DE, Harnly M, Hertz A. Agricultural Pesticide Use and Childhood Cancer in California. Epidemiology 2005; 16(1):93-100. (studies 6 and 9) and 2009²⁹29 Shim YK, Mlynarek SP, van Wijngaarden E. Parental Exposure to Pesticides and Childhood Brain Cancer: U.S. Atlantic Coast Childhood Brain Cancer Study. Environ Health Perspect 2009; 117(6):1002-1006.^,3131 Spix C, Schulze-Rath R, Kaatsch P, Blettner M. Case-Control Study on Risk Factors for Leukaemia and Brain Tumours in Children under 5 Years in Germany. Klin Padiatr 2009; 221(6):362-368. (studies 12 and 14) and two (14%) annual publications. With regard country, most of the studies were conducted in the United States, accounting for nine (64%) publications²¹21 Bunin GR, Buckley JD, Boesel CP, Rorke LB, Meadows AT. Risk factors for astrocytic glioma and primitive neuroectodermal tumor of the brain in young children: a report from the children's cancer group. Cancer Epidemiol Biomarkers Prev 1994; 3(3):197-204.^,2222 Davis JR, Brownson RC, Garcia R, Bentz BJ, Turner A. Family Pesticide Use and Childhood Brain Cancer. Arch Environ Contam Toxicol 1993; 24(1):87-92.^,2525 Searles Nielsen SS, Mueller BA, De Roos AJ, Viernes HM, Farin FM, Checkoway H. Risk of Brain Tumors in Children and Susceptibility to Organophosphorus Insecticides: The Potential Role of Paraoxonase (PON1). Environ Health Perspect 2005; 113(7):909-913.^,2626 Searles Nielsen S, McKean-Cowdin R, Farin FM, Holly EA, Preston-Martin S, Mueller BA. Childhood Brain Tumors, Residential Insecticide Exposure, and Pesticide Metabolism Genes. Environ Health Perspect 2010; 118(1):144-149.

27 Reynolds P, Von Behren J, Gunier RB, Goldberg DE, Harnly M, Hertz A. Agricultural Pesticide Use and Childhood Cancer in California. Epidemiology 2005; 16(1):93-100.

28 Rosso AL, Hovinga ME, Rorke-Adams LB, Spector LG, Bunin GR. A case-control study of childhood brain tumors and fathers' hobbies - a children's oncology group study. Cancer Causes Control 2008; 19(10):1201-1207.^-2929 Shim YK, Mlynarek SP, van Wijngaarden E. Parental Exposure to Pesticides and Childhood Brain Cancer: U.S. Atlantic Coast Childhood Brain Cancer Study. Environ Health Perspect 2009; 117(6):1002-1006.^,3232 Walker K, Carozza S, Cooper S, Elgethun K. Childhood Cancer in Texas Counties with Moderate to Intense Agricultural Activity. J Agric Saf Health 2007; 13(1):9-24.^,3333 Wijingaarden EV, Stewart PA, Olshan AF, Savitz DA, Bunin GR. Parental Occupational Exposure to Pesticides and Childhood Brain Cancer. Am J Epidemiol 2003; 157(11):989-997.. All the studies were case-control studies²⁰20 Bagazgoitia NV, Bailey HD, Orsi L, Lacour B, Guerrini-Rousseau L, Bertozzi AI, Leblond P, Faure-Conter C, Pellier I, Freycon C, Doz F, Puget S, Ducassou S, Clavel J. Maternal residential pesticide use during pregnancy and risk of malignant childhood brain tumors: A pooled analysis of the ESCALE and ESTELLE studies (SFCE). Int J Cancer 2018; 142(3):489-497.

21 Bunin GR, Buckley JD, Boesel CP, Rorke LB, Meadows AT. Risk factors for astrocytic glioma and primitive neuroectodermal tumor of the brain in young children: a report from the children's cancer group. Cancer Epidemiol Biomarkers Prev 1994; 3(3):197-204.

22 Davis JR, Brownson RC, Garcia R, Bentz BJ, Turner A. Family Pesticide Use and Childhood Brain Cancer. Arch Environ Contam Toxicol 1993; 24(1):87-92.

23 Febvey O, Schüz J, Bailey HD, Clavel J, Lacour B, Orsi L, Lightfoot T, Roman E, Vermeulen R, Kromhout H, Olsson A. Risk of Central Nervous System Tumors in Children Related to Parental Occupational Pesticide Exposures in three European Case-Control Studies. J Occup Environ Med 2016; 58(10):1046-1052.

24 Greenop K, Peters S, Bailey HD, Fritschi L, Attia J, Scott RJ, Glass DC, Klerk NH, Alvaro F, Armstrong BK, Milne E. Exposure to pesticides and the risk of childhood brain tumors. Cancer Causes Control 2013; 24(7):1269-1278.

25 Searles Nielsen SS, Mueller BA, De Roos AJ, Viernes HM, Farin FM, Checkoway H. Risk of Brain Tumors in Children and Susceptibility to Organophosphorus Insecticides: The Potential Role of Paraoxonase (PON1). Environ Health Perspect 2005; 113(7):909-913.

26 Searles Nielsen S, McKean-Cowdin R, Farin FM, Holly EA, Preston-Martin S, Mueller BA. Childhood Brain Tumors, Residential Insecticide Exposure, and Pesticide Metabolism Genes. Environ Health Perspect 2010; 118(1):144-149.

27 Reynolds P, Von Behren J, Gunier RB, Goldberg DE, Harnly M, Hertz A. Agricultural Pesticide Use and Childhood Cancer in California. Epidemiology 2005; 16(1):93-100.

28 Rosso AL, Hovinga ME, Rorke-Adams LB, Spector LG, Bunin GR. A case-control study of childhood brain tumors and fathers' hobbies - a children's oncology group study. Cancer Causes Control 2008; 19(10):1201-1207.

29 Shim YK, Mlynarek SP, van Wijngaarden E. Parental Exposure to Pesticides and Childhood Brain Cancer: U.S. Atlantic Coast Childhood Brain Cancer Study. Environ Health Perspect 2009; 117(6):1002-1006.

30 Shutz J, Kaletsch U, Kaatsch P, Meinert R, Michaelis J. Risk Factors for Pediatric Tumors of the Central Nervous System: Results from a German Population-Based Case-Control Study. Med Pediatr Oncol 2001; 36(2):274-282.

31 Spix C, Schulze-Rath R, Kaatsch P, Blettner M. Case-Control Study on Risk Factors for Leukaemia and Brain Tumours in Children under 5 Years in Germany. Klin Padiatr 2009; 221(6):362-368.

32 Walker K, Carozza S, Cooper S, Elgethun K. Childhood Cancer in Texas Counties with Moderate to Intense Agricultural Activity. J Agric Saf Health 2007; 13(1):9-24.^-3333 Wijingaarden EV, Stewart PA, Olshan AF, Savitz DA, Bunin GR. Parental Occupational Exposure to Pesticides and Childhood Brain Cancer. Am J Epidemiol 2003; 157(11):989-997.. The most investigated age group was 0-14 years, accounting for five (36%) studies²⁰20 Bagazgoitia NV, Bailey HD, Orsi L, Lacour B, Guerrini-Rousseau L, Bertozzi AI, Leblond P, Faure-Conter C, Pellier I, Freycon C, Doz F, Puget S, Ducassou S, Clavel J. Maternal residential pesticide use during pregnancy and risk of malignant childhood brain tumors: A pooled analysis of the ESCALE and ESTELLE studies (SFCE). Int J Cancer 2018; 142(3):489-497.^,2323 Febvey O, Schüz J, Bailey HD, Clavel J, Lacour B, Orsi L, Lightfoot T, Roman E, Vermeulen R, Kromhout H, Olsson A. Risk of Central Nervous System Tumors in Children Related to Parental Occupational Pesticide Exposures in three European Case-Control Studies. J Occup Environ Med 2016; 58(10):1046-1052.^,3030 Shutz J, Kaletsch U, Kaatsch P, Meinert R, Michaelis J. Risk Factors for Pediatric Tumors of the Central Nervous System: Results from a German Population-Based Case-Control Study. Med Pediatr Oncol 2001; 36(2):274-282.^,3333 Wijingaarden EV, Stewart PA, Olshan AF, Savitz DA, Bunin GR. Parental Occupational Exposure to Pesticides and Childhood Brain Cancer. Am J Epidemiol 2003; 157(11):989-997.. The most commonly studied histological type was astrocytomas, present in eight (57%) of the studies²⁰20 Bagazgoitia NV, Bailey HD, Orsi L, Lacour B, Guerrini-Rousseau L, Bertozzi AI, Leblond P, Faure-Conter C, Pellier I, Freycon C, Doz F, Puget S, Ducassou S, Clavel J. Maternal residential pesticide use during pregnancy and risk of malignant childhood brain tumors: A pooled analysis of the ESCALE and ESTELLE studies (SFCE). Int J Cancer 2018; 142(3):489-497.

21 Bunin GR, Buckley JD, Boesel CP, Rorke LB, Meadows AT. Risk factors for astrocytic glioma and primitive neuroectodermal tumor of the brain in young children: a report from the children's cancer group. Cancer Epidemiol Biomarkers Prev 1994; 3(3):197-204.

22 Davis JR, Brownson RC, Garcia R, Bentz BJ, Turner A. Family Pesticide Use and Childhood Brain Cancer. Arch Environ Contam Toxicol 1993; 24(1):87-92.^-2323 Febvey O, Schüz J, Bailey HD, Clavel J, Lacour B, Orsi L, Lightfoot T, Roman E, Vermeulen R, Kromhout H, Olsson A. Risk of Central Nervous System Tumors in Children Related to Parental Occupational Pesticide Exposures in three European Case-Control Studies. J Occup Environ Med 2016; 58(10):1046-1052.^,2929 Shim YK, Mlynarek SP, van Wijngaarden E. Parental Exposure to Pesticides and Childhood Brain Cancer: U.S. Atlantic Coast Childhood Brain Cancer Study. Environ Health Perspect 2009; 117(6):1002-1006.^,3030 Shutz J, Kaletsch U, Kaatsch P, Meinert R, Michaelis J. Risk Factors for Pediatric Tumors of the Central Nervous System: Results from a German Population-Based Case-Control Study. Med Pediatr Oncol 2001; 36(2):274-282.^,3232 Walker K, Carozza S, Cooper S, Elgethun K. Childhood Cancer in Texas Counties with Moderate to Intense Agricultural Activity. J Agric Saf Health 2007; 13(1):9-24.^,3333 Wijingaarden EV, Stewart PA, Olshan AF, Savitz DA, Bunin GR. Parental Occupational Exposure to Pesticides and Childhood Brain Cancer. Am J Epidemiol 2003; 157(11):989-997. (Chart 2).

Features of environmental exposure

The environmental risk factor exposure to all pesticide classes was found in all the studies. The most common exposure setting was the home, identified in 10 (71%) of the articles²⁰20 Bagazgoitia NV, Bailey HD, Orsi L, Lacour B, Guerrini-Rousseau L, Bertozzi AI, Leblond P, Faure-Conter C, Pellier I, Freycon C, Doz F, Puget S, Ducassou S, Clavel J. Maternal residential pesticide use during pregnancy and risk of malignant childhood brain tumors: A pooled analysis of the ESCALE and ESTELLE studies (SFCE). Int J Cancer 2018; 142(3):489-497.

21 Bunin GR, Buckley JD, Boesel CP, Rorke LB, Meadows AT. Risk factors for astrocytic glioma and primitive neuroectodermal tumor of the brain in young children: a report from the children's cancer group. Cancer Epidemiol Biomarkers Prev 1994; 3(3):197-204.

22 Davis JR, Brownson RC, Garcia R, Bentz BJ, Turner A. Family Pesticide Use and Childhood Brain Cancer. Arch Environ Contam Toxicol 1993; 24(1):87-92.

23 Febvey O, Schüz J, Bailey HD, Clavel J, Lacour B, Orsi L, Lightfoot T, Roman E, Vermeulen R, Kromhout H, Olsson A. Risk of Central Nervous System Tumors in Children Related to Parental Occupational Pesticide Exposures in three European Case-Control Studies. J Occup Environ Med 2016; 58(10):1046-1052.

24 Greenop K, Peters S, Bailey HD, Fritschi L, Attia J, Scott RJ, Glass DC, Klerk NH, Alvaro F, Armstrong BK, Milne E. Exposure to pesticides and the risk of childhood brain tumors. Cancer Causes Control 2013; 24(7):1269-1278.

25 Searles Nielsen SS, Mueller BA, De Roos AJ, Viernes HM, Farin FM, Checkoway H. Risk of Brain Tumors in Children and Susceptibility to Organophosphorus Insecticides: The Potential Role of Paraoxonase (PON1). Environ Health Perspect 2005; 113(7):909-913.^-2626 Searles Nielsen S, McKean-Cowdin R, Farin FM, Holly EA, Preston-Martin S, Mueller BA. Childhood Brain Tumors, Residential Insecticide Exposure, and Pesticide Metabolism Genes. Environ Health Perspect 2010; 118(1):144-149.^,2828 Rosso AL, Hovinga ME, Rorke-Adams LB, Spector LG, Bunin GR. A case-control study of childhood brain tumors and fathers' hobbies - a children's oncology group study. Cancer Causes Control 2008; 19(10):1201-1207.

29 Shim YK, Mlynarek SP, van Wijngaarden E. Parental Exposure to Pesticides and Childhood Brain Cancer: U.S. Atlantic Coast Childhood Brain Cancer Study. Environ Health Perspect 2009; 117(6):1002-1006.

30 Shutz J, Kaletsch U, Kaatsch P, Meinert R, Michaelis J. Risk Factors for Pediatric Tumors of the Central Nervous System: Results from a German Population-Based Case-Control Study. Med Pediatr Oncol 2001; 36(2):274-282.^-3131 Spix C, Schulze-Rath R, Kaatsch P, Blettner M. Case-Control Study on Risk Factors for Leukaemia and Brain Tumours in Children under 5 Years in Germany. Klin Padiatr 2009; 221(6):362-368. (Chart 3).

Only one study (7%) reported a possible association between exposure to pesticides the year before pregnancy and CNS tumors²⁴24 Greenop K, Peters S, Bailey HD, Fritschi L, Attia J, Scott RJ, Glass DC, Klerk NH, Alvaro F, Armstrong BK, Milne E. Exposure to pesticides and the risk of childhood brain tumors. Cancer Causes Control 2013; 24(7):1269-1278.. Exposure to pesticides during pregnancy was associated with an increased risk of cancer in four (28%) studies²⁰20 Bagazgoitia NV, Bailey HD, Orsi L, Lacour B, Guerrini-Rousseau L, Bertozzi AI, Leblond P, Faure-Conter C, Pellier I, Freycon C, Doz F, Puget S, Ducassou S, Clavel J. Maternal residential pesticide use during pregnancy and risk of malignant childhood brain tumors: A pooled analysis of the ESCALE and ESTELLE studies (SFCE). Int J Cancer 2018; 142(3):489-497.^,2424 Greenop K, Peters S, Bailey HD, Fritschi L, Attia J, Scott RJ, Glass DC, Klerk NH, Alvaro F, Armstrong BK, Milne E. Exposure to pesticides and the risk of childhood brain tumors. Cancer Causes Control 2013; 24(7):1269-1278.^,2525 Searles Nielsen SS, Mueller BA, De Roos AJ, Viernes HM, Farin FM, Checkoway H. Risk of Brain Tumors in Children and Susceptibility to Organophosphorus Insecticides: The Potential Role of Paraoxonase (PON1). Environ Health Perspect 2005; 113(7):909-913.^,2828 Rosso AL, Hovinga ME, Rorke-Adams LB, Spector LG, Bunin GR. A case-control study of childhood brain tumors and fathers' hobbies - a children's oncology group study. Cancer Causes Control 2008; 19(10):1201-1207.. One study (7%) found a higher odds ratio for the outcome after birth²⁸28 Rosso AL, Hovinga ME, Rorke-Adams LB, Spector LG, Bunin GR. A case-control study of childhood brain tumors and fathers' hobbies - a children's oncology group study. Cancer Causes Control 2008; 19(10):1201-1207..

Two studies (14%) reported an association between exposure to all groups of pesticides and astrocytomas²¹21 Bunin GR, Buckley JD, Boesel CP, Rorke LB, Meadows AT. Risk factors for astrocytic glioma and primitive neuroectodermal tumor of the brain in young children: a report from the children's cancer group. Cancer Epidemiol Biomarkers Prev 1994; 3(3):197-204.^,3232 Walker K, Carozza S, Cooper S, Elgethun K. Childhood Cancer in Texas Counties with Moderate to Intense Agricultural Activity. J Agric Saf Health 2007; 13(1):9-24.. One study (7%) found an elevated risk of astrocytoma for both maternal and paternal exposure to insecticides³³33 Wijingaarden EV, Stewart PA, Olshan AF, Savitz DA, Bunin GR. Parental Occupational Exposure to Pesticides and Childhood Brain Cancer. Am J Epidemiol 2003; 157(11):989-997.. Two studies (14%) showed an increased chance of astrocytoma for exposure to herbicides/fungicides²⁹29 Shim YK, Mlynarek SP, van Wijngaarden E. Parental Exposure to Pesticides and Childhood Brain Cancer: U.S. Atlantic Coast Childhood Brain Cancer Study. Environ Health Perspect 2009; 117(6):1002-1006.^,3333 Wijingaarden EV, Stewart PA, Olshan AF, Savitz DA, Bunin GR. Parental Occupational Exposure to Pesticides and Childhood Brain Cancer. Am J Epidemiol 2003; 157(11):989-997.. Increased risk of PNET was observed for exposure to all pesticides³²32 Walker K, Carozza S, Cooper S, Elgethun K. Childhood Cancer in Texas Counties with Moderate to Intense Agricultural Activity. J Agric Saf Health 2007; 13(1):9-24., especially herbicides³³33 Wijingaarden EV, Stewart PA, Olshan AF, Savitz DA, Bunin GR. Parental Occupational Exposure to Pesticides and Childhood Brain Cancer. Am J Epidemiol 2003; 157(11):989-997..

One study (7%) observed an association between use of pesticides to control pests in the home, garden, or orchard and CNS tumors²²22 Davis JR, Brownson RC, Garcia R, Bentz BJ, Turner A. Family Pesticide Use and Childhood Brain Cancer. Arch Environ Contam Toxicol 1993; 24(1):87-92.. Another study examining the association between genetic polymorphisms and childhood brain tumors showed increased risk of tumors with exposure any time from 1 month before conception and birth²⁶26 Searles Nielsen S, McKean-Cowdin R, Farin FM, Holly EA, Preston-Martin S, Mueller BA. Childhood Brain Tumors, Residential Insecticide Exposure, and Pesticide Metabolism Genes. Environ Health Perspect 2010; 118(1):144-149.. Two specific pesticides (methyl bromide and chlorothalonil) showed an association with cancer in one (7%) of the studies²⁷27 Reynolds P, Von Behren J, Gunier RB, Goldberg DE, Harnly M, Hertz A. Agricultural Pesticide Use and Childhood Cancer in California. Epidemiology 2005; 16(1):93-100..

Risk bias analysis (methodological quality)

Eight of the 14 studies scored seven points (high quality and low risk of bias)²⁰20 Bagazgoitia NV, Bailey HD, Orsi L, Lacour B, Guerrini-Rousseau L, Bertozzi AI, Leblond P, Faure-Conter C, Pellier I, Freycon C, Doz F, Puget S, Ducassou S, Clavel J. Maternal residential pesticide use during pregnancy and risk of malignant childhood brain tumors: A pooled analysis of the ESCALE and ESTELLE studies (SFCE). Int J Cancer 2018; 142(3):489-497.^,2525 Searles Nielsen SS, Mueller BA, De Roos AJ, Viernes HM, Farin FM, Checkoway H. Risk of Brain Tumors in Children and Susceptibility to Organophosphorus Insecticides: The Potential Role of Paraoxonase (PON1). Environ Health Perspect 2005; 113(7):909-913.

26 Searles Nielsen S, McKean-Cowdin R, Farin FM, Holly EA, Preston-Martin S, Mueller BA. Childhood Brain Tumors, Residential Insecticide Exposure, and Pesticide Metabolism Genes. Environ Health Perspect 2010; 118(1):144-149.^-2727 Reynolds P, Von Behren J, Gunier RB, Goldberg DE, Harnly M, Hertz A. Agricultural Pesticide Use and Childhood Cancer in California. Epidemiology 2005; 16(1):93-100.^,3232 Walker K, Carozza S, Cooper S, Elgethun K. Childhood Cancer in Texas Counties with Moderate to Intense Agricultural Activity. J Agric Saf Health 2007; 13(1):9-24.

33 Wijingaarden EV, Stewart PA, Olshan AF, Savitz DA, Bunin GR. Parental Occupational Exposure to Pesticides and Childhood Brain Cancer. Am J Epidemiol 2003; 157(11):989-997.^-3434 Kunkle B, Bae S, Singh KP, Roy D. Increased risk of childhood brain tumors among children whose parents had farm-related pesticide exposures during pregnancy. JP J Biostat 2014; 11(2):89-101., five scored six (intermediate quality and risk of bias)²¹21 Bunin GR, Buckley JD, Boesel CP, Rorke LB, Meadows AT. Risk factors for astrocytic glioma and primitive neuroectodermal tumor of the brain in young children: a report from the children's cancer group. Cancer Epidemiol Biomarkers Prev 1994; 3(3):197-204.^,2323 Febvey O, Schüz J, Bailey HD, Clavel J, Lacour B, Orsi L, Lightfoot T, Roman E, Vermeulen R, Kromhout H, Olsson A. Risk of Central Nervous System Tumors in Children Related to Parental Occupational Pesticide Exposures in three European Case-Control Studies. J Occup Environ Med 2016; 58(10):1046-1052.^,2828 Rosso AL, Hovinga ME, Rorke-Adams LB, Spector LG, Bunin GR. A case-control study of childhood brain tumors and fathers' hobbies - a children's oncology group study. Cancer Causes Control 2008; 19(10):1201-1207.^,3030 Shutz J, Kaletsch U, Kaatsch P, Meinert R, Michaelis J. Risk Factors for Pediatric Tumors of the Central Nervous System: Results from a German Population-Based Case-Control Study. Med Pediatr Oncol 2001; 36(2):274-282.^,3131 Spix C, Schulze-Rath R, Kaatsch P, Blettner M. Case-Control Study on Risk Factors for Leukaemia and Brain Tumours in Children under 5 Years in Germany. Klin Padiatr 2009; 221(6):362-368., and one scored four (low quality and high risk of bias)²³23 Febvey O, Schüz J, Bailey HD, Clavel J, Lacour B, Orsi L, Lightfoot T, Roman E, Vermeulen R, Kromhout H, Olsson A. Risk of Central Nervous System Tumors in Children Related to Parental Occupational Pesticide Exposures in three European Case-Control Studies. J Occup Environ Med 2016; 58(10):1046-1052..

Metanalysis

For the meta-analysis, the studies were divided into two subgroups based on histological type. First, an analysis was performed of all the tumor groups, resulting in high heterogeneity among studies (I²=88%). We therefore analyzed the data for two groups of CNS tumors: astrocytomas and PNET.

The first analysis (exposure to pesticides and astrocytomas) included five studies²¹21 Bunin GR, Buckley JD, Boesel CP, Rorke LB, Meadows AT. Risk factors for astrocytic glioma and primitive neuroectodermal tumor of the brain in young children: a report from the children's cancer group. Cancer Epidemiol Biomarkers Prev 1994; 3(3):197-204.^,2929 Shim YK, Mlynarek SP, van Wijngaarden E. Parental Exposure to Pesticides and Childhood Brain Cancer: U.S. Atlantic Coast Childhood Brain Cancer Study. Environ Health Perspect 2009; 117(6):1002-1006.^,3030 Shutz J, Kaletsch U, Kaatsch P, Meinert R, Michaelis J. Risk Factors for Pediatric Tumors of the Central Nervous System: Results from a German Population-Based Case-Control Study. Med Pediatr Oncol 2001; 36(2):274-282.^,3232 Walker K, Carozza S, Cooper S, Elgethun K. Childhood Cancer in Texas Counties with Moderate to Intense Agricultural Activity. J Agric Saf Health 2007; 13(1):9-24.^,3333 Wijingaarden EV, Stewart PA, Olshan AF, Savitz DA, Bunin GR. Parental Occupational Exposure to Pesticides and Childhood Brain Cancer. Am J Epidemiol 2003; 157(11):989-997., which showed low heterogeneity (I²=26%). There was evidence of an association between exposure to all pesticide classes and astrocytomas (OR 1.50; 95%CI: 1.15-1.96; p=0.03) (Figure 2A).

The analysis of exposure to pesticides and PNET included four studies²¹21 Bunin GR, Buckley JD, Boesel CP, Rorke LB, Meadows AT. Risk factors for astrocytic glioma and primitive neuroectodermal tumor of the brain in young children: a report from the children's cancer group. Cancer Epidemiol Biomarkers Prev 1994; 3(3):197-204.^,2929 Shim YK, Mlynarek SP, van Wijngaarden E. Parental Exposure to Pesticides and Childhood Brain Cancer: U.S. Atlantic Coast Childhood Brain Cancer Study. Environ Health Perspect 2009; 117(6):1002-1006.^,3232 Walker K, Carozza S, Cooper S, Elgethun K. Childhood Cancer in Texas Counties with Moderate to Intense Agricultural Activity. J Agric Saf Health 2007; 13(1):9-24.^,3333 Wijingaarden EV, Stewart PA, Olshan AF, Savitz DA, Bunin GR. Parental Occupational Exposure to Pesticides and Childhood Brain Cancer. Am J Epidemiol 2003; 157(11):989-997. without presence of heterogeneity (I²=0). There was no evidence of an association between exposure to pesticides and development of PNET (OR 1.09; 95%CI: 0.82-1.44; p=0.55) (Figure 2B).

Discussion

Study synthesis

The individual findings of the studies included in this review point to an association between exposure to all pesticide classes and CNS tumors under certain circumstances, including exposure before and during pregnancy²⁰20 Bagazgoitia NV, Bailey HD, Orsi L, Lacour B, Guerrini-Rousseau L, Bertozzi AI, Leblond P, Faure-Conter C, Pellier I, Freycon C, Doz F, Puget S, Ducassou S, Clavel J. Maternal residential pesticide use during pregnancy and risk of malignant childhood brain tumors: A pooled analysis of the ESCALE and ESTELLE studies (SFCE). Int J Cancer 2018; 142(3):489-497.^,2424 Greenop K, Peters S, Bailey HD, Fritschi L, Attia J, Scott RJ, Glass DC, Klerk NH, Alvaro F, Armstrong BK, Milne E. Exposure to pesticides and the risk of childhood brain tumors. Cancer Causes Control 2013; 24(7):1269-1278.^,2525 Searles Nielsen SS, Mueller BA, De Roos AJ, Viernes HM, Farin FM, Checkoway H. Risk of Brain Tumors in Children and Susceptibility to Organophosphorus Insecticides: The Potential Role of Paraoxonase (PON1). Environ Health Perspect 2005; 113(7):909-913.^,2828 Rosso AL, Hovinga ME, Rorke-Adams LB, Spector LG, Bunin GR. A case-control study of childhood brain tumors and fathers' hobbies - a children's oncology group study. Cancer Causes Control 2008; 19(10):1201-1207. and residential pesticide use²⁰20 Bagazgoitia NV, Bailey HD, Orsi L, Lacour B, Guerrini-Rousseau L, Bertozzi AI, Leblond P, Faure-Conter C, Pellier I, Freycon C, Doz F, Puget S, Ducassou S, Clavel J. Maternal residential pesticide use during pregnancy and risk of malignant childhood brain tumors: A pooled analysis of the ESCALE and ESTELLE studies (SFCE). Int J Cancer 2018; 142(3):489-497.

21 Bunin GR, Buckley JD, Boesel CP, Rorke LB, Meadows AT. Risk factors for astrocytic glioma and primitive neuroectodermal tumor of the brain in young children: a report from the children's cancer group. Cancer Epidemiol Biomarkers Prev 1994; 3(3):197-204.^-2222 Davis JR, Brownson RC, Garcia R, Bentz BJ, Turner A. Family Pesticide Use and Childhood Brain Cancer. Arch Environ Contam Toxicol 1993; 24(1):87-92.^,2424 Greenop K, Peters S, Bailey HD, Fritschi L, Attia J, Scott RJ, Glass DC, Klerk NH, Alvaro F, Armstrong BK, Milne E. Exposure to pesticides and the risk of childhood brain tumors. Cancer Causes Control 2013; 24(7):1269-1278.

25 Searles Nielsen SS, Mueller BA, De Roos AJ, Viernes HM, Farin FM, Checkoway H. Risk of Brain Tumors in Children and Susceptibility to Organophosphorus Insecticides: The Potential Role of Paraoxonase (PON1). Environ Health Perspect 2005; 113(7):909-913.^-2626 Searles Nielsen S, McKean-Cowdin R, Farin FM, Holly EA, Preston-Martin S, Mueller BA. Childhood Brain Tumors, Residential Insecticide Exposure, and Pesticide Metabolism Genes. Environ Health Perspect 2010; 118(1):144-149.^,2828 Rosso AL, Hovinga ME, Rorke-Adams LB, Spector LG, Bunin GR. A case-control study of childhood brain tumors and fathers' hobbies - a children's oncology group study. Cancer Causes Control 2008; 19(10):1201-1207.. Two meta-analyses showed increased risk for occupational exposure or maternal exposure during pregnancy in the home¹²12 Brasil. Ministério da Saúde (MS). Instituto Nacional de Câncer (INCA). Incidência, mortalidade e morbidade hospitalar por câncer em crianças, adolescentes e adultos jovens no Brasil: informações dos registros de câncer do sistema de mortalidade. Rio de Janeiro: INCA; 2016.^,3434 Kunkle B, Bae S, Singh KP, Roy D. Increased risk of childhood brain tumors among children whose parents had farm-related pesticide exposures during pregnancy. JP J Biostat 2014; 11(2):89-101..

Pesticides are classified as potentially carcinogenic substances, particularly insecticides used for residential insect control³⁵35 Guyton KZ, Loomis D, Grosse Y, El Ghissassi F, Benbrahim-Tallaa L, Guha N, Scoccianti C, Mattock H, Straif K. Carcinogenicity of tetrachlorvinphos, parathion, malathion, diazinon, and glyphosate. Lancet Oncol 2015; 16(5):490-491.. Carbamates and organophosphates are able to cross the placental barrier and can therefore be readily transferred from the mother to fetus³⁶36 Whyatt RM, Barr DB, Camann DE, Kinney PL, Barr JR, Andrews HF, Hoepner LA, Garfinkel R, Hazi Y, Reyes A, Ramirez J, Cosme Y, Perera FP. Contemporary-use pesticides in personal air samples during pregnancy and blood samples at delivery among urban minority mothers and newborns. Environ Health Perspect 2003; 111(5):749-756.^,3737 Ostrea EM, Bielawski DM, Posecion Jr. NC, Corrion M, Villanueva-Uy E, Bernardo RC, Jin Y, Janisse JJ, Ager JW. Combined analysis of prenatal (maternal hair and blood) and neonatal (infant hair, cord blood and meconium) matrices to detect fetal exposure to environmental pesticides. Environ Res 2009; 109(1):116-122.. Fetuses and children are more vulnerable to exposure to these types of pesticides because they have an immature nervous system and their cells divide more rapidly³⁸38 Koob M, Girard N. Cerebral tumors: specific features in children. Diagn Interv Imaging 2014; 95(10):965-983.. The synthesized findings of this review showing that exposure before and especially during pregnancy increases risk of CNS tumors in children corroborate pathophysiological evidence of the carcinogenicity of these chemicals.

Some studies indicate that proximity to industrial sites and urban areas (exposure to chemical pollutants) can contribute to higher incidence of CNS tumors in children³⁹39 Brender JD, Maantay JA, Chakraborty J. Residential proximity to environmental hazards and adverse health outcomes. Am J Public Health 2011; 101(Supl. 1):S37-S52.^,4040 Danysh HE, Mitchell LE, Zhang K, Scheurer ME, Lupo PJ. Traffic-related air pollution and the incidence of childhood central nervous system tumors: Texas, 2001-2009. Pediatr Blood Cancer 2015; 62(9):1572-1578.. Other studies investigating the use of agrichemicals close to residential areas found differing results, reporting excess risk among children living within a 1 km radius of crops⁴¹41 Gomez-Barroso D, García-Pérez J, López-Abente G, Tamayo-Uria I, Morales-Piga A, Pardo Romaguera E, Ramis R. Agricultural crop exposure and risk of childhood cancer: new findings from a case-control study in Spain. Int J Health Geogr 2016; 15(1):18., but not in counties with harvested acreage of crops⁴²42 Both BJ, Ward MH, Turyk ME, Stayner LT. Agricultural crop density and risk of childhood cancer in the midwestern United states: an ecologic study. Environ Health 2015; 14:82..

Comparison with other literature reviews

The astrocytoma subgroup meta-analysis showed increased risk and moderate heterogeneity. Two of the studies that found elevated risk investigated the association between parental occupational exposure to pesticides and risk of CNS tumors. The odds ratios reported by these studies (2.26; 95%CI: 1.36-3.75 and 1.79; 95%CI: 1.08-2.95) show that exposure to pesticides may be an important factor in the etiology of childhood astrocytomas²⁹29 Shim YK, Mlynarek SP, van Wijngaarden E. Parental Exposure to Pesticides and Childhood Brain Cancer: U.S. Atlantic Coast Childhood Brain Cancer Study. Environ Health Perspect 2009; 117(6):1002-1006.^,3333 Wijingaarden EV, Stewart PA, Olshan AF, Savitz DA, Bunin GR. Parental Occupational Exposure to Pesticides and Childhood Brain Cancer. Am J Epidemiol 2003; 157(11):989-997..

Studies investigating the association between exposure to all pesticide classes and PNET in groups with and without CNS tumors found similar results. Two studies observed a strong association (OR 1.32; 95%CI: 0.70-2.48 and OR 1.32; 95%CI: 0.81-2.14)³³33 Wijingaarden EV, Stewart PA, Olshan AF, Savitz DA, Bunin GR. Parental Occupational Exposure to Pesticides and Childhood Brain Cancer. Am J Epidemiol 2003; 157(11):989-997.^,3434 Kunkle B, Bae S, Singh KP, Roy D. Increased risk of childhood brain tumors among children whose parents had farm-related pesticide exposures during pregnancy. JP J Biostat 2014; 11(2):89-101., while one study suggested that exposure to pesticides was a protective factor for PNET²¹21 Bunin GR, Buckley JD, Boesel CP, Rorke LB, Meadows AT. Risk factors for astrocytic glioma and primitive neuroectodermal tumor of the brain in young children: a report from the children's cancer group. Cancer Epidemiol Biomarkers Prev 1994; 3(3):197-204..

The most recent meta-analyses investigating residential or occupational exposure to pesticides involved children and adolescents (0-19 year) and young adults (<25 years). One found a significantly increased effect of 1.34 (95%CI 1.15-1.56) for exposure to pesticides during childhood with moderate heterogeneity (I²=60%)¹⁰10 Zumel-Marne A, Castano-Vinyals G, Kundi M, Alguacil J, Cardis E. Environmental Factors and the Risk of Brain Tumours in Young People: Systematic. Neuroepidemiology 2019; 53(3-4):121-141.. These results suggest that increased risk of astrocytomas and PNET with exposure to pesticides may be similar across all age groups up to young adults (<25 years). However, it is worth highlighting that the two histological types were part of the same subgroup, unlike our meta-analysis.

Heterogeneity among the studies included in this review hampered the analyses of all the histological type and exposure subgroups. We considered presenting results with moderate to low heterogeneity to make the findings representative of reality. Observational studies already incur considerable risk of bias and it is therefore important to consider these difficulties in the evidence summary.

One of the limitations of this review is therefore the heterogeneity of the observational studies included in the meta-analysis and the limited number of studies that met the inclusion criteria for statistical analysis, bearing in mind that Cochran’s Q test should be used with caution when the number of studies is less than 20⁴³43 Huedo-Medina TB, Sánchez-Meca J, Marín-Martínez F, Botella J. Assessing heterogeneity in meta-analysis: Q statistic or I² index? Psychol Methods 2006; 11(2):193-206.. In addition, the odds ratios found in the present study may have been affected by publication bias, which can prevent the collection of all existing evidence and means that data published in the studies are often not fully representative of all outcomes (both positive and negative) related to exposure factors⁴⁴44 Martín-Moro JG. La crisis de reproducibilidad de la ciencia y la necesidad de publicar los resultados negativos. Arch Soc Esp Oftalmol 2017; 92(12):e75-e77..

This review sought to ascertain whether there is an association between exposure to pesticides and living in industrial or rural areas and CNS tumors. We found a large amount of evidence in the literature for exposure to pesticides, with individual study findings pointing to a possible association with childhood CNS tumors. However, the synthesis of the evidence only included two histological types of tumors: astrocytomas and PNET. The results suggest an increased risk of astrocytomas in children exposed to all pesticide classes.

Individual studies observed that place of residence was a factor in increased risk; however, it was not possible to synthesize the evidence due to the limited number of studies retrieved. Further research is therefore required to investigate this type of exposure.

To strengthen the body of evidence on exposure to pesticides, including exposure to industrial and agricultural activities, and CNS tumors, studies need to be more specific, especially in relation to histological type and the chemical substance. Associated studies are also required to investigate genetic and environmental aspects, both of which are key factors in the etiology of cancer.

The investigation of factors related to the risks of using pesticides is vital to inform environmental policy and curb the indiscriminate use of these substances in agriculture. In recent years, the Brazilian government has approved the use of more than 86 highly hazardous pesticides and their derivatives⁴⁵45 Brasil. Projeto de Lei nº 6.299, de 2002. Altera os arts 3º e 9º da Lei nº 7.802, de 11 de julho de 1989, que dispõe sobre a pesquisa, a experimentação, a produção, a embalagem e rotulagem, o transporte, o armazenamento, a comercialização, a propaganda comercial, a utilização, a importação, a exportação, o destino final dos resíduos e embalagens, o registro, a classificação, o controle, a inspeção e a fiscalização de agrotóxicos, seus componentes e afins, e dá outras providências. Brasília: Câmara dos Deputados; 2002. [acessado 2022 dez 26]. Disponível em: https://www.camara.leg.br/proposicoesWeb/prop_mostrarintegra?codteor=1654426..

A package of measures are therefore required, including public policies, effective environmental protection, and educational initiatives in primary health care services. The latter should address the residential use of potentially harmful chemicals, encourage healthy eating based on the consumption of organic foods, promote the use of personal protective equipment by parents employed in agriculture, and provide guidance to avoid the use of pesticides in the home before and during pregnancy.

References

Publication Dates

History