Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Exposome of attention deficit hyperactivity disorder in Taiwanese children: exploring risks of endocrine-disrupting chemicals



Attention-deficit hyperactivity disorder (ADHD) is diagnosed in ~7% of school-aged children. The role of endocrine-disrupting chemicals (EDC) and oxidative stress in ADHD etiology are not clear.


Assessment of the associations between simultaneous exposure to multiple compounds and ADHD in children.


The case-control study included 76 clinically diagnosed ADHD cases and 98 controls, aged 4–15 years old. Concentrations quartiles of urinary metabolites of acrylamide, acrolein, nonylphenol, phthalates, and organophosphate pesticides and biomarkers of oxidative stress were used to fit logistic regressions for each compound and weighted quantiles sum (WQS) regression for the mixture.


Positive dose-response relationships with ADHD were observed for 4-hydroxy-2-nonenal-mercapturic acid (HNE-MA) (odds ratio(OR)Q4 = 3.73, 95%CI [1.32, 11.04], ptrend = 0.003), dimethyl phosphate (DMP) (ORQ4 = 4.04, 95%CI [1.34, 12.94], ptrend = 0.014) and diethyl phosphate (ORQ4 = 2.61, 95%CI = [0.93, 7.66], ptrend = 0.030), and for the mixture of compounds (ORWQS = 3.82, 95%CI = [1.78, 8.19]) with the main contributions from HNE-MA (28.9%) and DMP (18.4%).


The dose-response relationship suggests enhanced susceptibility to EDC burden in children even at lower levels, whereas the main risk is likely from organophosphate pesticides. HNE-MA is recommended as a sensitive biomarker of lipid peroxidation in the further elucidation of the oxidative stress role in ADHD etiology.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Get just this article for as long as you need it


Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Correlation matrix of urinary metabolites and biomarkers (N = 174).
Fig. 2: Index weights from the weighted quantiles sum regression model.
Fig. 3: Predicted probability of attention-deficit hyperactivity disorder as a function of weighted quantiles sum index (WQS).


  1. Thomas R, Sanders S, Doust J, Beller E, Glasziou P. Prevalence of attention-deficit/hyperactivity disorder: a systematic review and meta-analysis. Pediatrics. 2015;135:e994–1001.

    Article  PubMed  Google Scholar 

  2. American Psychiatric Association. Diagnostic and statistical manual of mental disorders 5th ed. Washington DC 2013.

  3. Sharma A, Couture J. A review of the pathophysiology, etiology, and treatment of attention-deficit hyperactivity disorder (ADHD). Ann Pharmacother. 2014;48:209–25.

    Article  PubMed  Google Scholar 

  4. Nilsen FM, Tulve NS. A systematic review and meta-analysis examining the interrelationships between chemical and non-chemical stressors and inherent characteristics in children with ADHD. Environ Res. 2020;180:108884.

    Article  CAS  PubMed  Google Scholar 

  5. Froehlich TE, Anixt JS, Loe IM, Chirdkiatgumchai V, Kuan L, Gilman RC. Update on environmental risk factors for attention-deficit/hyperactivity disorder. Curr Psychiatry Rep. 2011;13:333–44.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Joseph N, Zhang-James Y, Perl A, Faraone SV. Oxidative stress and ADHD: a meta-analysis. J Atten Disord. 2015;19:915–24.

    Article  PubMed  Google Scholar 

  7. Alvarez-Arellano L, Gonzalez-Garcia N, Salazar-Garcia M, Corona JC. Antioxidants as a potential target against inflammation and oxidative stress in attention-deficit/hyperactivity disorder. Antioxidants (Basel). 2020;9.

  8. Wu C, Chen ST, Peng KH, Cheng TJ, Wu KY. Concurrent quantification of multiple biomarkers indicative of oxidative stress status using liquid chromatography-tandem mass spectrometry. Anal Biochem. 2016;512:26–35.

    Article  CAS  PubMed  Google Scholar 

  9. Chang CH, Yu CJ, Du JC, Chiou HC, Chen HC, Yang W, et al. The interactions among organophosphate pesticide exposure, oxidative stress, and genetic polymorphisms of dopamine receptor D4 increase the risk of attention deficit/hyperactivity disorder in children. Environ Res. 2018;160:339–46.

    Article  CAS  PubMed  Google Scholar 

  10. Verlaet AAJ, Breynaert A, Ceulemans B, De Bruyne T, Fransen E, Pieters L, et al. Oxidative stress and immune aberrancies in attention-deficit/hyperactivity disorder (ADHD): a case-control comparison. Eur Child Adolesc Psychiatry. 2019;28:719–29.

    Article  PubMed  Google Scholar 

  11. Ceylan M, Sener S, Bayraktar AC, Kavutcu M. Oxidative imbalance in child and adolescent patients with attention-deficit/hyperactivity disorder. Prog Neuropsychopharmacol Biol Psychiatry. 2010;34:1491–4.

    Article  CAS  PubMed  Google Scholar 

  12. Oztop D, Altun H, Baskol G, Ozsoy S. Oxidative stress in children with attention deficit hyperactivity disorder. Clin Biochem. 2012;45:745–8.

    Article  CAS  PubMed  Google Scholar 

  13. Bellanger M, Demeneix B, Grandjean P, Zoeller RT, Trasande L. Neurobehavioral deficits, diseases, and associated costs of exposure to endocrine-disrupting chemicals in the European Union. J Clin Endocrinol Metab. 2015;100:1256–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Lin C-Y, Lee H-L, Chen Y-C, Lien G-W, Lin L-Y, Wen L-L, et al. Positive association between urinary levels of 8-hydroxydeoxyguanosine and the acrylamide metabolite N-acetyl-S-(propionamide)-cysteine in adolescents and young adults. J Hazard Mater. 2013;261:372–7.

    Article  CAS  PubMed  Google Scholar 

  15. Lin CY, Chen PC, Hsieh CJ, Chen CY, Hu A, Sung FC, et al. Positive association between urinary concentration of phthalate metabolites and oxidation of DNA and lipid in adolescents and young adults. Sci Rep. 2017;7:44318.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Huang P-C, Waits A, Chen H-C, Chang W-T, Jaakkola JJ, Huang H-B. Mediating role of oxidative/nitrosative stress biomarkers in the associations between phthalate exposure and thyroid function in Taiwanese adults. Environ Int. 2020;140:105751.

    Article  CAS  PubMed  Google Scholar 

  17. Rohlman DS, Ismail A, Bonner MR, Abdel Rasoul G, Hendy O, Ortega Dickey L, et al. Occupational pesticide exposure and symptoms of attention deficit hyperactivity disorder in adolescent pesticide applicators in Egypt. Neurotoxicology. 2019;74:1–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Yu C-J, Du J-C, Chiou H-C, Chung M-Y, Yang W, Chen Y-S, et al. Increased risk of attention‐deficit/hyperactivity disorder associated with exposure to organophosphate pesticide in Taiwanese children. Andrology. 2016;4:695–705.

    Article  CAS  PubMed  Google Scholar 

  19. van Wendel de Joode B, Mora AM, Lindh CH, Hernández-Bonilla D, Córdoba L, Wesseling C, et al. Pesticide exposure and neurodevelopment in children aged 6–9 years from Talamanca, Costa Rica. Cortex. 2016;85:137–50.

    Article  PubMed  Google Scholar 

  20. Bouchard MF, Bellinger DC, Wright RO, Weisskopf MG. Attention-deficit/hyperactivity disorder and urinary metabolites of organophosphate pesticides. Pediatrics 2010;125:e1270–e7.

    Article  PubMed  Google Scholar 

  21. Radke EG, Braun JM, Nachman RM, Cooper GS. Phthalate exposure and neurodevelopment: a systematic review and meta-analysis of human epidemiological evidence. Environ Int. 2020;137:105408.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Lu Y-Y, Chen M-L, Sung F-C, Wang PS-G, Mao I-F. Daily intake of 4-nonylphenol in Taiwanese. Environ Int. 2007;33:903–10.

    Article  CAS  PubMed  Google Scholar 

  23. Masuo Y, Morita M, Oka S, Ishido M. Motor hyperactivity caused by a deficit in dopaminergic neurons and the effects of endocrine disruptors: a study inspired by the physiological roles of PACAP in the brain. Regulatory Pept. 2004;123:225–34.

    Article  CAS  Google Scholar 

  24. Yu C-J, Du J-C, Chiou H-C, Yang S-H, Liao K-W, Yang W, et al. Attention deficit/hyperactivity disorder and urinary nonylphenol levels: a case-control study in Taiwanese Children. PLoS ONE. 2016;11.

  25. Semla M, Goc Z, Martiniakova M, Omelka R, Formicki G. Acrylamide: a common food toxin related to physiological functions and health. Physiol Res. 2017;66:205–17.

    Article  CAS  PubMed  Google Scholar 

  26. Moghe A, Ghare S, Lamoreau B, Mohammad M, Barve S, McClain C, et al. Molecular mechanisms of acrolein toxicity: relevance to human disease. Toxicol Sci. 2015;143:242–55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Kawatani M, Tsukahara H, Mayumi M. Evaluation of oxidative stress status in children with pervasive developmental disorder and attention deficit hyperactivity disorder using urinary-specific biomarkers. Redox Rep. 2011;16:45–6.

    Article  CAS  PubMed  Google Scholar 

  28. Erkekoglu P, Baydar T. Acrylamide neurotoxicity. Nutr Neurosci. 2014;17:49–57.

    Article  CAS  PubMed  Google Scholar 

  29. Yousef MI, El-Demerdash FM. Acrylamide-induced oxidative stress and biochemical perturbations in rats. Toxicology. 2006;219:133–41.

    Article  CAS  PubMed  Google Scholar 

  30. Catalgol B, Özhan G, Alpertunga B. Acrylamide-induced oxidative stress in human erythrocytes. Hum Exp Toxicol. 2009;28:611–7.

    Article  CAS  PubMed  Google Scholar 

  31. Rappaport SM, Smith MT. Environment and disease risks. Science. 2010;330:460–1.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Sille FCM, Karakitsios S, Kleensang A, Koehler K, Maertens A, Miller GW, et al. The exposome—a new approach for risk assessment. Altex. 2020;37:3–23.

    Article  PubMed  Google Scholar 

  33. Gau SSF, Shang CY, Liu SK, Lin CH, Swanson JM, Liu YC, et al. Psychometric properties of the Chinese version of the Swanson, Nolan, and Pelham, version IV scale–parent form. Int J Methods Psychiatr Res. 2008;17:35–44.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Eckert E, Schmid K, Schaller B, Hiddemann-Koca K, Drexler H, Göen T. Mercapturic acids as metabolites of alkylating substances in urine samples of German inhabitants. Int J Hyg Environ Health. 2011;214:196–204.

    Article  CAS  PubMed  Google Scholar 

  35. Carrico C, Gennings C, Wheeler DC, Factor-Litvak P. Characterization of weighted quantile sum regression for highly correlated data in a risk analysis setting. J Agric Biol Environ Stat. 2015;20:100–20.

    Article  PubMed  Google Scholar 

  36. Renzetti S, Curtin P, Just AC, Bello G, Gennings C. How to use gWQS package. 2021, May 20 [cited 2021 July 14]. In: The Comprehensive R Archive Network [Internet].

  37. Yu C-J, Du J-C, Chiou H-C, Feng C-C, Chung M-Y, Yang W, et al. Sugar-sweetened beverage consumption is adversely associated with childhood attention deficit/hyperactivity disorder. Int J Environ Res Public Health. 2016;13:678.

    Article  PubMed Central  Google Scholar 

  38. Rana J, Paul J. Health motive and the purchase of organic food: a meta‐analytic review. Int J Consum Stud. 2020;44:162–71.

    Article  Google Scholar 

  39. Bulut M, Selek S, Gergerlioglu HS, Savas HA, Yilmaz HR, Yuce M, et al. Malondialdehyde levels in adult attention-deficit hyperactivity disorder. J Psychiatry Neurosci. 2007;32:435–8.

    PubMed  PubMed Central  Google Scholar 

  40. Bulut M, Selek S, Bez Y, Kaya MC, Gunes M, Karababa F, et al. Lipid peroxidation markers in adult attention deficit hyperactivity disorder: new findings for oxidative stress. Psychiatry Res. 2013;209:638–42.

    Article  CAS  PubMed  Google Scholar 

  41. Ito Y, Tomizawa M, Suzuki K, Shirakawa Y, Ono H, Adachi K, et al. Organophosphate agent induces ADHD-like behaviors via inhibition of brain endocannabinoid-hydrolyzing enzyme(s) in adolescent male rats. J Agric Food Chem. 2020;68:2547–53.

    Article  CAS  PubMed  Google Scholar 

  42. Leffa DT, Bellaver B, de Oliveira C, de Macedo IC, de Freitas JS, Grevet EH, et al. Increased oxidative parameters and decreased cytokine levels in an animal model of attention-deficit/hyperactivity disorder. Neurochem Res. 2017;42:3084–92.

    Article  CAS  PubMed  Google Scholar 

  43. Kuiper HC, Miranda CL, Sowell JD, Stevens JF. Mercapturic acid conjugates of 4-hydroxy-2-nonenal and 4-oxo-2-nonenal metabolites are in vivo markers of oxidative stress. J Biol Chem. 2008;283:17131–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Popa-Wagner A, Mitran S, Sivanesan S, Chang E, Buga AM. ROS and brain diseases: the good, the bad, and the ugly. Oxid Med Cell Longev. 2013;2013:963520.

    Article  PubMed  PubMed Central  Google Scholar 

  45. Jaganjac M, Milkovic L, Gegotek A, Cindric M, Zarkovic K, Skrzydlewska E, et al. The relevance of pathophysiological alterations in redox signaling of 4-hydroxynonenal for pharmacological therapies of major stress-associated diseases. Free Rad Biol Med. 2019;157:128–53.

  46. Ceylan MF, Sener S, Bayraktar AC, Kavutcu M. Changes in oxidative stress and cellular immunity serum markers in attention-deficit/hyperactivity disorder. Psychiatry Clin Neurosci. 2012;66:220–6.

    Article  CAS  PubMed  Google Scholar 

  47. Middlemore-Risher M-L, Buccafusco J, Terry A Jr. Repeated exposures to low-level chlorpyrifos results in impairments in sustained attention and increased impulsivity in rats. Neurotoxicology Teratol. 2010;32:415–24.

    Article  CAS  Google Scholar 

  48. Elten M, Benchimol EI, Fell DB, Kuenzig ME, Smith G, Chen H, et al. Ambient air pollution and the risk of pediatric-onset inflammatory bowel disease: a population-based cohort study. Environ Int. 2020;138:105676.

    Article  CAS  PubMed  Google Scholar 

  49. Faraone SV, Perlis RH, Doyle AE, Smoller JW, Goralnick JJ, Holmgren MA, et al. Molecular genetics of attention-deficit/hyperactivity disorder. Biol Psychiatry. 2005;57:1313–23.

    Article  CAS  PubMed  Google Scholar 

Download references


We would like to express our gratitude to the little patients of Taipei City Hospital, their parents, the medical and laboratory personnel, who devoted their time, efforts, and goodwill to make this study happen.



This study was financially supported by the Ministry of Science and Technology of the Republic of China (MOST 105-2314-B-010-019-, MOST107-2314-B-010-051-MY2) and the Department of Health, Taipei City Government (10301-62-004).

Author information

Authors and Affiliations


Corresponding author

Correspondence to Mei-Lien Chen.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Waits, A., Chang, CH., Yu, CJ. et al. Exposome of attention deficit hyperactivity disorder in Taiwanese children: exploring risks of endocrine-disrupting chemicals. J Expo Sci Environ Epidemiol 32, 169–176 (2022).

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:


  • Endocrine-disrupting chemicals
  • Attention deficit hyperactivity disorder
  • Weighted quantiles sum regression
  • Oxidative stress

This article is cited by


Quick links