Attention-deficit/hyperactivity disorder (ADHD) is a common neurodevelopmental condition with multifactorial etiology involving genetic, neurobiological, and environmental determinants. Emerging evidence suggests that environmental exposures may influence neurodevelopmental pathways relevant to ADHD pathophysiology. Manganese is an essential trace element required for normal brain development; however, excessive or dysregulated exposure has been associated with neurotoxic effects. This systematic review aimed to synthesize human evidence on the association between manganese exposure and ADHD or ADHD-related neurobehavioral outcomes in children.
Methods:
Four electronic databases were systematically searched according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Observational studies meeting predefined Population, Exposure, Comparison, Outcomes, and Study Design criteria were included. Methodological quality was assessed using Joanna Briggs Institute appraisal tools, and certainty of evidence was evaluated using the Grading of Recommendations, Assessment, Development, and Evaluation framework.
Results:
Thirty studies met the inclusion criteria. Elevated manganese exposure was more frequently associated with increased risk or severity of ADHD or ADHD-related neurobehavioral symptoms, although inverse and nonlinear (U-shaped) associations were also reported.
Conclusions:
The available evidence indicates a complex and potentially nonlinear relationship between manganese exposure and child neurobehavioral outcomes. These findings identify manganese exposure as a potentially modifiable environmental factor influencing neurodevelopmental mechanisms relevant to ADHD and highlight the need for longitudinal studies integrating exposure biomarkers with neurobiological and clinical outcomes to clarify causal pathways and therapeutic implications.
AtkinsD, BestD, BrissPA, et al.; GRADE Working Group. Grading quality of evidence and strength of recommendations. BMJ2004;328(7454):1490; doi: 10.1136/bmj.328.7454.1490
2.
AylwardLL, HaysSM, SmoldersR, et al.Sources of variability in biomarker concentrations. J Toxicol Environ Health B Crit Rev2014;17(1):45–61; doi: 10.1080/10937404.2013.864250
3.
BalachandranRC, MukhopadhyayS, McBrideD, et al.Brain manganese and the balance between essential roles and neurotoxicity. J Biol Chem2020;295(19):6312–6329; doi: 10.1074/jbc.REV119.009453
4.
BauerJA, Claus HennB, AustinC, et al.Manganese in teeth and neurobehavior: Sex-specific windows of susceptibility. Environ Int2017;108:299–308; doi: 10.1016/j.envint.2017.08.013
5.
BeaudinSA, StruppBJ, UribeW, et al.Methylphenidate alleviates manganese-induced impulsivity but not distractibility. Neurotoxicol Teratol2017;61:17–28; doi: 10.1016/j.ntt.2017.03.005
6.
BhangSY, ChoSC, KimJW, et al.Relationship between blood manganese levels and children’s attention, cognition, behavior, and academic performance–a nationwide cross-sectional study. Environ Res2013;126:9–16; doi: 10.1016/j.envres.2013.05.006
7.
BonviciniC, FaraoneSV, ScassellatiC. Attention-deficit hyperactivity disorder in adults: A systematic review and meta-analysis of genetic, pharmacogenetic and biochemical studies. Mol Psychiatry2016;21(11):1643; doi: 10.1038/mp.2016.74
8.
BouchardM, LaforestF, VandelacL, et al.Hair manganese and hyperactive behaviors: Pilot study of school-age children exposed through tap water. Environ Health Perspect2007;115(1):122–127; doi: 10.1289/ehp.9504
9.
BraunJM, KahnRS, FroehlichT, et al.Exposures to environmental toxicants and attention deficit hyperactivity disorder in U.S. children. Environ Health Perspect2006;114(12):1904–1909; doi: 10.1289/ehp.9478
10.
BrobergK, TajT, GuazzettiS, et al.Manganese transporter genetics and sex modify the association between environmental manganese exposure and neurobehavioral outcomes in children. Environ Int2019;130:104908; doi: 10.1016/j.envint.2019.104908
11.
CanfieldRL, GendleMH, Cory-SlechtaDA. Impaired neuropsychological functioning in lead-exposed children. Dev Neuropsychol2004;26(1):513–540; doi: 10.1207/s15326942dn2601_8
12.
CarvalhoCF, Menezes-FilhoJA, de MatosVP, et al.Elevated airborne manganese and low executive function in school-aged children in Brazil. Neurotoxicology2014;45:301–308; doi: 10.1016/j.neuro.2013.11.006
13.
ChanTJ, GutierrezC, OgunseitanOA. Metallic burden of deciduous teeth and childhood behavioral deficits. Int J Environ Res Public Health2015;12(6):6771–6787; doi: 10.3390/ijerph120606771
14.
de CamposEG, da CostaBRB, Dos SantosFS, et al.Alternative matrices in forensic toxicology: A critical review. Forensic Toxicol2022;40(1):1–18; doi: 10.1007/s11419-021-00596-5
15.
De FeliceA, RicceriL, VenerosiA, et al.Multifactorial origin of neurodevelopmental disorders: Approaches to understanding complex etiologies. Toxics2015;3(1):89–129; doi: 10.3390/toxics3010089
16.
DegremontA, JainR, PhilippouE, et al.Brain iron concentrations in the pathophysiology of children with attention deficit/hyperactivity disorder: A systematic review. Nutr Rev2021;79(5):615–626; doi: 10.1093/nutrit/nuaa065
17.
DormanDC. The role of oxidative stress in manganese neurotoxicity: A literature review focused on contributions made by Professor Michael Aschner. Biomolecules2023;13(8):1176; doi: 10.3390/biom13081176
18.
FaraoneSV, PerlisRH, DoyleAE, et al.Molecular genetics of attention-deficit/hyperactivity disorder. Biol Psychiatry2005;57(11):1313–1323; doi: 10.1016/j.biopsych.2004.11.024
19.
FariasAC, CunhaA, BenkoCR, et al.Manganese in children with attention-deficit/hyperactivity disorder: Relationship with methylphenidate exposure. J Child Adolesc Psychopharmacol2010;20(2):113–118; doi: 10.1089/cap.2009.0073
20.
GadeM, ComfortN, ReDB. Sex-specific neurotoxic effects of heavy metal pollutants: Epidemiological, experimental evidence and candidate mechanisms. Environ Res2021;201:111558; doi: 10.1016/j.envres.2021.111558
21.
GędekA, ModrzejewskiS, GędekM, et al.Neutrophil to lymphocyte ratio, platelet to lymphocyte ratio, and monocyte to lymphocyte ratio in ADHD: A systematic review and meta-analysis. Front Psychiatry2023;14:1258868; doi: 10.3389/fpsyt.2023.1258868
22.
GizerIR, FicksC, WaldmanID. Candidate gene studies of ADHD: A meta-analytic review. Hum Genet2009;126(1):51–90; doi: 10.1007/s00439-009-0694-x
23.
GuilarteTR. Manganese and Parkinson’s disease: A critical review and new findings. Environ Health Perspect2010;118(8):1071–1080; doi: 10.1590/s1413-81232011001200028
24.
GuptaK, MuthuMS, SaikiaA, et al.Association of exposures to environmental chemicals estimated through primary teeth biomatrix and health outcomes in children and adolescents - A systematic review. Sci Total Environ2024;928:172032; doi: 10.1016/j.scitotenv.2024.172032
25.
HarischandraDS, GhaisasS, ZenitskyG, et al.Manganese-Induced neurotoxicity: New insights into the triad of protein misfolding, mitochondrial impairment, and neuroinflammation. Front Neurosci2019;13:654; doi: 10.3389/fnins.2019.00654
26.
HawariI, EskandarMB, AlzeerS. The role of lead, manganese, and zinc in Autism Spectrum Disorders (ASDs) and Attention-Deficient Hyperactivity Disorder (ADHD): A Case-Control Study on Syrian Children Affected by the Syrian Crisis. Biol Trace Elem Res2020;197(1):107–114; doi: 10.1007/s12011-020-02146-3
27.
HeB, WangY, LiS, et al.A cross-sectional survey of preschool children: Exploring heavy metal exposure, neurotransmitters, and neurobehavioural relationships and mediation effects. Ecotoxicol Environ Saf2021;220:112391; doi: 10.1016/j.ecoenv.2021.112391
HongSB, ImMH, KimJW, et al.Environmental lead exposure and attention deficit/hyperactivity disorder symptom domains in a community sample of South Korean school-age children. Environ Health Perspect2015;123(3):271–276; doi: 10.3390/ijerph120606771
30.
HongSB, KimJW, ChoiBS, et al.Blood manganese levels in relation to comorbid behavioral and emotional problems in children with attention-deficit/hyperactivity disorder. Psychiatry Res2014;220(1–2):418–425; doi: 10.1016/j.psychres.2014.05.049
31.
HuangCC, PanSC, ChinWS, et al.Urinary heavy metals and attention-deficit/hyperactivity symptoms of preschool children: A mixed-exposure analysis. Ecotoxicol Environ Saf2023;268:115714; doi: 10.1016/j.ecoenv.2023.115714
32.
HusseinRA, RefaiRH, El-ZokaAH, et al.Association between some environmental risk factors and attention-deficit hyperactivity disorder among children in Egypt: A case-control study. Ital J Pediatr2025;51(1):19; doi: 10.1186/s13052-025-01843-w
33.
IjomoneOM, OlungNF, AkingbadeGT, et al.Environmental influence on neurodevelopmental disorders: Potential association of heavy metal exposure and autism. J Trace Elem Med Biol2020;62:126638; doi: 10.1016/j.jtemb.2020.126638
KernCH, StanwoodGD, SmithDR. Preweaning manganese exposure causes hyperactivity, disinhibition, and spatial learning and memory deficits associated with altered dopamine receptor and transporter levels. Synapse2010;64(5):363–378; doi: 10.1002/syn.20736
36.
LaneJM, LiuSH, Cory-SlechtaDA, et al.Sexual dimorphism in the programming effects of prenatal manganese multi-media biomarker on temporal cognition in school-aged children. Sci Rep2026;16(1):13219; doi: 10.1038/s41598-026-44007-4
37.
LiY, ChaC, LvX, et al.Association between 10 urinary heavy metal exposure and attention deficit hyperactivity disorder for children. Environ Sci Pollut Res Int2020;27(25):31233–31242; doi: 10.1007/s11356-020-09421-9
38.
LiaoSL, LaiSH, HsuYT, et al.Early postnatal and concurrent exposure to metals and neurobehavioral outcomes at 5 years: Associations with individual environmental exposures and mixtures. Neurotoxicology2024;105:58–66; doi: 10.1016/j.neuro.2024.08.006
39.
LinM, Colon-PerezLM, SamboDO, et al.Mechanism of manganese dysregulation of dopamine neuronal activity. J Neurosci2020;40(30):5871–5891; doi: 10.1523/JNEUROSCI.2830-19.2020
40.
LiuW, HuoX, LiuD, et al.S100β in heavy metal-related child attention-deficit hyperactivity disorder in an informal e-waste recycling area. Neurotoxicology2014;45:185–191; doi: 10.1016/j.neuro.2014.10.013
41.
LucchiniR, PlacidiD, CagnaG, et al.Manganese and developmental neurotoxicity. Adv Neurobiol2017;18:13–34; doi: 10.1007/978-3-319-60189-2_2
42.
MahoneEM, DencklaMB. Attention-Deficit/hyperactivity disorder: A historical neuropsychological perspective. J Int Neuropsychol Soc2017;23(9–10):916–929; doi: 10.1017/S1355617717000807
43.
ManorI, TyanoS, EisenbergME, et al.Family-based and case–control studies of the serotonin transporter gene polymorphism in attention-deficit hyperactivity disorder (ADHD): A meta-analysis. Psychiatr Genet2001;11(4):231–235; doi: 10.1002/1096-8628(20010108)105:1≤91::AID-AJMG1069≥3.0.CO;2-V
44.
MoherD, LiberatiA, TetzlaffJ, et al.; PRISMA Group. Preferred reporting items for systematic reviews and meta-analyses: The PRISMA statement. PLoS Med2009;6(7):e1000097; doi: 10.1371/journal.pmed.1000097
National Toxicology Program (US). NTP research report on the scoping review of prenatal exposure to progestogens and adverse health outcomes. Research Triangle Park (NC): National Toxicology Program; 2020. (NTP Research Report No.: 17); doi: 10.22427/NTP-RR-17
47.
Nyarko-DanquahI, PajarilloE, DigmanA, et al.Manganese accumulation in the brain via various transporters and its neurotoxicity mechanisms. Molecules2020;25(24):5880; doi: 10.3390/molecules25245880
48.
OdeA, RylanderL, GustafssonP, et al.Manganese and selenium concentrations in umbilical cord serum and attention deficit hyperactivity disorder in childhood. Environ Res2015;137:373–381; doi: 10.1016/j.envres.2015.01.001
49.
OulhoteY, MerglerD, BarbeauB, et al.Neurobehavioral function in school-age children exposed to manganese in drinking water. Environ Health Perspect2014;122(12):1343–1350; doi: 10.1289/ehp.1307918
RobinsonDM, EdwardsKL, WilloughbyMT, et al.Increased risk of attention-deficit/hyperactivity disorder in adolescents with high salivary levels of copper, manganese, and zinc. Eur Child Adolesc Psychiatry2024;33(9):3091–3099; doi: 10.1007/s00787-024-02381-2
52.
SchildrothS, BauerJA, FriedmanA, et al.Early life manganese exposure and reported attention-related behaviors in Italian adolescents. Environ Epidemiol2023;7(6):e274; doi: 10.1097/EE9.0000000000000274
53.
SchildrothS, KordasK, WhiteRF, et al.An industry-relevant metal mixture, iron status, and reported attention-related behaviors in Italian adolescents. Environ Health Perspect2024;132(2):27008; doi: 10.1289/EHP12988
54.
SchullehnerJ, ThygesenM, KristiansenSM, et al.Exposure to manganese in drinking water during childhood and association with attention-deficit hyperactivity disorder: A nationwide cohort study. Environ Health Perspect2020;128(9):97004; doi: 10.1289/EHP6391
55.
SextonK, NeedhamLL, PirkleJL. Human biomonitoring of environmental chemicals: Measuring chemicals in human tissue is the “gold standard” for assessing people’s exposure to pollution. Am Sci2004;92(1):38–45.
56.
ShihJH, ZengBY, LinPY, et al.Association between peripheral manganese levels and attention-deficit/hyperactivity disorder: a preliminary meta-analysis. Neuropsychiatr Dis Treat2018;14:1831–1842; doi: 10.2147/NDT.S165378
57.
ShinDW, KimEJ, LimSW, et al.Association of hair manganese level with symptoms in attention-deficit/hyperactivity disorder. Psychiatry Investig2015;12(1):66–72; doi: 10.4306/pi.2015.12.1.66
58.
SkalnyAV, MazaletskayaAL, AjsuvakovaOP, et al.Hair trace element concentrations in autism spectrum disorder (ASD) and attention deficit/hyperactivity disorder (ADHD). J Trace Elem Med Biol2020;61:126539; doi: 10.1016/j.jtemb.2020.126539
59.
SkogheimTS, WeydeKVF, EngelSM, et al.Metal and essential element concentrations during pregnancy and associations with autism spectrum disorder and attention-deficit/hyperactivity disorder in children. Environ Int2021;152:106468; doi: 10.1016/j.envint.2021.106468
60.
SmithDR, StruppBJ. Animal models of childhood exposure to lead or manganese: Evidence for impaired attention, impulse control, and affect regulation and assessment of potential therapies. Neurotherapeutics2023;20(1):3–21; doi: 10.1007/s13311-023-01345-9
61.
SteinCR, WuH, BellingerDC, et al.Exposure to metal mixtures and neuropsychological functioning in middle childhood. Neurotoxicology2022;93:84–91; doi: 10.1016/j.neuro.2022.09.003
62.
Substance Abuse and Mental Health Services Administration (SAMHSA). DSM-5 Changes: Implications for Child Serious Emotional Disturbance [Internet]. DSM-5 Child Mental Disorder Classification. Rockville (MD): Substance Abuse and Mental Health Services Administration (US); 2016. Available from: https://www.ncbi.nlm.nih.gov/books/NBK519712/
63.
TabatadzeT, KherkheulidzeM, KandelakiE, et al.Attention deficit hyperactivity disorder and hair heavy metal and essential trace element concentrations. Is There a Link? Georgian Med News2018;284:88–92.
64.
TinkovAA, MazaletskayaAL, AjsuvakovaOP, et al.ICP-MS assessment of hair essential trace elements and minerals in Russian preschool and primary school children with Attention-Deficit/Hyperactivity Disorder (ADHD). Biol Trace Elem Res2020;196(2):400–409; doi: 10.1007/s12011-019-01947-5
65.
TranNQV, MiyakeK. Neurodevelopmental disorders and environmental toxicants: Epigenetics as an underlying mechanism. Int J Genomics2017;2017:7526592; doi: 10.1155/2017/7526592
66.
WilschefskiSC, BaxterMR. Inductively coupled plasma mass spectrometry: Introduction to analytical aspects. Clin Biochem Rev2019;40(3):115–133; doi: 10.33176/AACB-19-00024
67.
YalçınSS, ÇakT, YalçınS. Lower strontium in two different body matrices in neurodevelopmental disorders: A preliminary report. J Trace Elem Med Biol2020;62:126553; doi: 10.1016/j.jtemb.2020.126553
68.
YousefS, AdemA, ZoubeidiT, et al.Attention deficit hyperactivity disorder and environmental toxic metal exposure in the United Arab Emirates. J Trop Pediatr2011;57(6):457–460; doi: 10.1093/tropej/fmq121
69.
ZhouJ, TongJ, LiangC, et al.Prenatal placental metal accumulation and its association with child attention deficit/hyperactivity disorder and autism spectrum disorder symptom at 3 years of age: The role of psychosocial-environmental support in infancy. Environ Res2025;274:121294; doi: 10.1016/j.envres.2025.121294
Supplementary Material
Please find the following supplemental material available below.
For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.
For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.
