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Association between 2,4-dichlorophenoxyacetic acid and cognitive impairment in older adults: a cross-sectional study from NHANES 2001–2002 and 2011–2014

Journal of Exposure Science & Environmental Epidemiology (2023)Cite this article

Abstract

Background

2,4-Dichlorophenoxyacetic acid (2,4-D) is reported to be the most widely used herbicide in home and garden environments, rendering it commonly encountered in daily life. Despite being ubiquitous, there is a scarcity of studies that have comprehensively assessed the relationship between 2,4-D exposure and cognition using multiple models.

Objective

To explore the association between 2,4-D exposure and cognition among older American people.

Methods

This was a cross-sectional study that included 3 cycles of data from the National Health and Nutrition Examination Survey. Generalized linear models (GLMs), restricted cubic spline (RCS) regression, and generalized additive models (GAMs) were used to assess the relationship between exposure to 2,4-D and cognitive performance by the Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) word learning sub-test, Digit Symbol Substitution Test (DSST), and Animal Fluency Test (AFT).

Results

A total of 1364 older U.S. adults (60+ years) were included in the study. The GLMs revealed a negative association between median high levels (0.315–0.566 μg/L) of 2,4-D and cognitive impairment on the DSST and AFT, with multivariate-adjusted ORs of 0.403 (95% CI: 0.208–0.781, P = 0.009) and 0.396 (95% CI: 0.159–0.986, P = 0.047); the RCS regression and GAMs revealed a “U” shaped curve, the left part of which is consistent with the result of the GLMs.

Impact statement

There is a U-shaped relationship between human urinary 2,4-D concentrations and cognitive impairment in older U.S. adults, especially in males, so controlling 2,4-D exposure within an appropriate range is particularly important for cognitive function.

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Fig. 1: Forest plot showing the association between 2,4-D and cognitive impairment, as assessed by the CERAD test, DSST, and AFT in males and females.
Fig. 2: Analysis of the association between ln(2,4-D) and cognitive performance, as assessed by the CERAD test, DSST, and AFT in all participants, males only, and females only using the RCS.
Fig. 3: Plots of the estimated smoothing spline function of 2,4-D exposure with 95% confidence intervals for the generalized additive model when the response variable was low cognitive performance on the DSST in all participants, males only, and females only.

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Data availability

The datasets generated for this study are available from https://www.cdc.gov/nchs/nhanes.

References

  1. Peterson MA, McMaster SA, Riechers DE, Skelton J, Stahlman PW. 2,4-D past, present, and future: a review. Weed Technol. 2017;30:303–345.

    Article  Google Scholar 

  2. Aquino AJA, Tunega D, Habephauer G, Gerzabek MH, Lischka H. Interaction of the 2.4-dichlorophenoxyacetic acid herbicide with soil organic matter moieties: a theoretical study. Eur J Soil Sci. 2007;58:889–99.

    Article  CAS  Google Scholar 

  3. Freisthler MS, Robbins CR, Benbrook CM, Young HA, Haas DM, Winchester PD, et al. Association between increasing agricultural use of 2,4-D and population biomarkers of exposure: findings from the National Health and Nutrition Examination Survey, 2001-2014. Environ Health. 2022;21:23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. USEP Agency. Pesticides industry sales and usage 2008–2012 market estimates. 2015. Available from: https://www.epa.gov/pesticides/pesticides-industry-sales-and-usage-2008-2012-market-estimates.

  5. Favreault MM, Johnson RW. The risk and costs of severe cognitive impairment at older ages: key findings from our literature review and projection analyses. ASPE. 2021. https://aspe.hhs.gov/reports/risk-costs-severe-cognitive-impairment-older-ages-key-findings-our-literature-review-projection.

  6. Centers for Disease Control and Prevention. The healthy brain initiative: the public health road map for state and national partnerships, 2013–2018, Interim Progress Report. Atlanta, GA: CDC; 2015.

  7. Anton BJ, Dehnert GK, Karasov WH. Subchronic impacts of 2,4-D herbicide Weedestroy (R) AM40 on associative learning in juvenile yellow perch (Perca flavescens). Aquat Toxicol. 2021;237:105909.

    Article  CAS  PubMed  Google Scholar 

  8. Ueda RMR, de Souza VM, Magalhaes LR, Chagas PHN, Veras ASC, Teixeira GR, et al. Neurotoxicity associated with chronic exposure to dichlorophenoxyacetic acid (2,4-D) - a simulation of environmental exposure in adult rats. J Environ Sci Health Part B Pesticides Food Contam Agric Wastes. 2021;56:695–705.

    Article  CAS  Google Scholar 

  9. National Center for Health Statistics, National Health and Nutrition Examination Survey (NHANES). Questionnaires, datasets, and related documentation. 2015. www.cdc.gov/nchs/nhanes/nhanes_questionnaires.htm.

  10. Centers for Disease Control and Prevention, National Center for Health Statistics, National Health and Nutrition Examination Survey 2011–2012, Data Documentation, Codebook, and Frequencies, Cognitive Functioning (CFQ_G). 2017. https://wwwn.cdc.gov/Nchs/Nhanes/2011-2012/CFQ_G.htm.

  11. Centers for Disease Control and Prevention, National Center for Health Statistics, National Health and Nutrition Examination Survey, 2013–2014 Data Documentation, Codebook, and Frequencies, Cognitive Functioning (CFQ_H). 2017. https://wwwn.cdc.gov/Nchs/Nhanes/2013-2014/CFQ_H.htm.

  12. Brody DJ, Kramarow EA, Taylor CA, McGuire LC. Cognitive performance in adults aged 60 and over: National Health and Nutrition Examination Survey, 2011-2014. Natl Health Stat Rep. 2019;2019:1–23.

    Google Scholar 

  13. Jaeger J. Digit symbol substitution test: the case for sensitivity over specificity in neuropsychological testing. J Clin Psychopharmacol. 2018;38:513–9.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Amaresha AC, Danivas V, Shivakumar V, Agarwal SM, Kalmady SV, Narayanaswamy JC, et al. Clinical correlates of parametric digit-symbol substitution test in schizophrenia. Asian J Psychiatry. 2014;10:45–50.

    Article  Google Scholar 

  15. Morris JC, Heyman A, Mohs RC, Hughes JP, van Belle G, Fillenbaum G. et al., The Consortium to Establish a Registry for Alzheimer’s Disease (CERAD). Part I. Clinical and neuropsychological assessment of Alzheimer’s disease. Neurology. 1989;39:1159–65.

    Article  CAS  PubMed  Google Scholar 

  16. Canning SJD, Leach L, Stuss D, Ngo L, Black SE. Diagnostic utility of abbreviated fluency measures in Alzheimer disease and vascular dementia. Neurology. 2004;62:556–62.

    Article  PubMed  Google Scholar 

  17. Sotaniemi M, Pulliainen V, Hokkanen L, Pirttila T, Hallikainen I, Soininen H, et al. CERAD-neuropsychological battery in screening mild Alzheimer’s disease. Acta Neurologica Scandinavica. 2012;125:16–23.

    Article  CAS  PubMed  Google Scholar 

  18. Dong X, Li SR, Sun J, Li Y, Zhang DF. Association of Coffee, Decaffeinated Coffee and Caffeine Intake from Coffee with Cognitive Performance in Older Adults: National Health and Nutrition Examination Survey (NHANES) 2011-2014. Nutrients. 2020, 12. https://doi.org/10.3390/nu12030840.

  19. Chen SP, Bhattacharya J, Pershing S. Association of vision loss with cognition in older adults. JAMA Ophthalmol. 2017;135:963–70.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Li SY, Sun WJ, Zhang DF. Association of zinc, iron, copper, and selenium intakes with low cognitive performance in older adults: a cross-sectional study from National Health and Nutrition Examination Survey (NHANES). J Alzheimers Dis. 2019;72:1145–57.

    Article  PubMed  Google Scholar 

  21. Sauerhoff MW, Braun WH, Blau GE, Gehring PJ. Fate of 2,4-Dichlorophenoxyacetic Acid (2,4-d) following oral-administration to man. Toxicology. 1977;8:3–11.

    Article  CAS  PubMed  Google Scholar 

  22. Hill RH, Shealy DB, Head SL, Williams CC, Bailey SL, Gregg M, et al. Determination of pesticide metabolites in human urine using an isotope-dilution technique and tandem mass-spectrometry. J Anal Toxicol. 1995;19:323–9.

    Article  CAS  PubMed  Google Scholar 

  23. Cole SR, Chu HT, Nie L, Schisterman EF. Estimating the odds ratio when exposure has a limit of detection. Int J Epidemiol. 2009;38:1674–80.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Wang W, Ma Y, Chen J, Peng L, Gao X, Lin L, et al. The association between 2, 4-Dichlorophenoxyacetic acid and erectile dysfunction. Front Public Health. 2022;10:910251.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Dinu M, Colombini B, Pagliai G, Vannetti F, Pasquini G, Molino Lova R, et al. BMI, functional and cognitive status in a cohort of nonagenarians: results from the Mugello study. Eur Geriatr Med. 2021;12:379–86.

    Article  PubMed  Google Scholar 

  26. Topiwala A, Ebmeier KP. Effects of drinking on late-life brain and cognition. Evid Based Ment Health. 2018;21:12–15.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Swan GE, Lessov-Schlaggar CN. The effects of tobacco smoke and nicotine on cognition and the brain. Neuropsychol Rev. 2007;17:259–73.

    Article  PubMed  Google Scholar 

  28. Dove A, Shang Y, Xu WL, Grande G, Laukka EJ, Fratiglioni L, et al. The impact of diabetes on cognitive impairment and its progression to dementia. Alzheimers Dement. 2021;17:1769–78.

    Article  PubMed  Google Scholar 

  29. Iadecola C, Gottesman RF. Neurovascular and cognitive dysfunction in hypertension epidemiology, pathobiology, and treatment. Circ Res. 2019;124:1025–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Walker KA, Power MC, Gottesman RF. Defining the relationship between hypertension, cognitive decline, and dementia: a review. Curr Hypertens Rep. 2017;19. https://doi.org/10.1007/s11906-017-0724-3.

  31. Lo Coco D, Lopez G, Corrao S. Cognitive impairment and stroke in elderly patients. Vasc Health Risk Manag. 2016;12:105–16.

    PubMed  PubMed Central  Google Scholar 

  32. van Vliet P. Cholesterol and late-life cognitive decline. J Alzheimers Dis. 2012;30:S147–S162.

    Article  PubMed  Google Scholar 

  33. Tana C, Ticinesi A, Prati B, Nouvenne A, Meschi T. Uric acid and cognitive function in older individuals. Nutrients. 2018, 10. https://doi.org/10.3390/nu10080975.

  34. Llewellyn DJ, Langa KM, Friedland RP, Lang IA. Serum albumin concentration and cognitive impairment. Curr Alzheimer Res. 2010;7:91–96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Prevention CfDCa. NHANES Survey Methods and Analytic Guidelines. 2020. https://wwwn.cdc.gov/nchs/nhanes/analyticguidelines.aspx. Accessed 26 Oct 2021.

  36. Lusa L, Ahlin Č. Restricted cubic splines for modelling periodic data. PloS One. 2020;15:e0241364.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Lin X, Zhang D. Inference in generalized additive mixed modelsby using smoothing splines. J R Stat Soc. 1999;61:381–400.

    Article  Google Scholar 

  38. Conolly RB, Lutz WK. Nonmonotonic dose-response relationships: mechanistic basis, kinetic modeling, and implications for risk assessment. Toxicological Sci. 2004;77:151–7.

    Article  CAS  Google Scholar 

  39. Kohn M, Melnick R. Biochemical origins of the non-monotonic receptor-mediated dose-response. J Mol Endocrinol. 2002;29:113–23.

    Article  CAS  PubMed  Google Scholar 

  40. Park SK, Ding N, Han D. Perfluoroalkyl substances and cognitive function in older adults: should we consider non-monotonic dose-responses and chronic kidney disease? Environ Res. 2021;192:110346.

    Article  CAS  PubMed  Google Scholar 

  41. Freitas LM, Valadares LA, Camozzi M, de Oliveira PG, Ferreira Machado MR, Lima FC, et al. Animal models in the neurotoxicology of 2,4-D. Hum Exp Toxicol. 2019;38:1178–82.

    Article  CAS  PubMed  Google Scholar 

  42. Elo HA, MacDonald E. Effects of 2,4-dichlorophenoxyacetic acid (2,4-D) on biogenic amines and their acidic metabolites in brain and cerebrospinal fluid of rats. Arch Toxicol. 1989;63:127–30.

    Article  CAS  PubMed  Google Scholar 

  43. Cifariello A, Pompili A, Gasbarri A. 5-HT(7) receptors in the modulation of cognitive processes. Behav Brain Res. 2008;195:171–9.

    Article  CAS  PubMed  Google Scholar 

  44. Zafeiridou G, Geronikaki A, Papaefthimiou C, Tryfonos M, Kosmidis EK, Theophilidis G, et al. Assessing the effects of the three herbicides acetochlor, 2,4,5-trichlorophenoxyacetic acid (2,4,5-T) and 2,4-dichlorophenoxyacetic acid on the compound action potential of the sciatic nerve of the frog (Rana ridibunda). Chemosphere. 2006;65:1040–8.

    Article  CAS  PubMed  Google Scholar 

  45. Sharifi Pasandi M, Hosseini Shirazi F, Gholami MR, Salehi H, Najafzadeh N, Mazani M, et al. Epi/perineural and Schwann cells as well as perineural sheath integrity are affected following 2,4-D exposure. Neurotox Res. 2017;32:624–38.

    Article  CAS  PubMed  Google Scholar 

  46. Kadekar S, Peddada S, Silins I, French JE, Högberg J, Stenius U. Gender differences in chemical carcinogenesis in National Toxicology Program 2-year bioassays. Toxicol Pathol. 2012;40:1160–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Barahona AJ, Bursac Z, Veledar E, Lucchini R, Tieu K, Richardson JR. Relationship of blood and urinary manganese levels with cognitive function in elderly individuals in the United States by race/ethnicity, NHANES 2011-2014. Toxics. 2022;10. https://doi.org/10.3390/toxics10040191.

  48. Sasaki N, Carpenter DO. Associations between metal exposures and cognitive function in American older adults. Int J Environ Res Public Health. 2022;19. https://doi.org/10.3390/ijerph19042327.

  49. Krieg EF Jr. The relationships between pesticide metabolites and neurobehavioral test performance in the third National Health and Nutrition Examination Survey. Arch Environ Occup Health. 2013;68:39–46.

    Article  CAS  PubMed  Google Scholar 

  50. National Academies of Sciences, Engineering, and Medicine; Health and Medicine Division; Board on Population Health and Public Health Practice; Committee to Review the Health Effects in Vietnam Veterans of Exposure to Herbicides (Eleventh Biennial Update). Veterans and Agent Orange: Update 11 (2018). Washington (DC): National Academies Press (US); 2018.

  51. Sauerhoff MW, Braun WH, Blau GE, Gehring PJ. The fate of 2,4-dichlorophenoxyacetic acid (2,4-D) following oral administration to man. Toxicology. 1977;8:3–11.

    Article  CAS  PubMed  Google Scholar 

  52. Ye X, Pierik FH, Hauser R, Duty S, Angerer J, Park MM, et al. Urinary metabolite concentrations of organophosphorous pesticides, bisphenol A, and phthalates among pregnant women in Rotterdam, the Netherlands: the Generation R study. Environ Res. 2008;108:260–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Trasande L, Liu B, Bao W. Phthalates and attributable mortality: A population-based longitudinal cohort study and cost analysis. Environ Pollut. 2022;292:118021.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank all the researchers who participated in this study.

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Author notes

  1. These authors contributed equally: Xinyang Zou, Yisen Shi.

Authors and Affiliations

  1. Department of Neurology, Union Hospital, Institute of Neuroscience, Institute of Clinical Neurology, Fujian Medical University, Fuzhou, 350001, China

    Xinyang Zou, Yisen Shi, Qinyong Ye & Guoen Cai

  2. Fujian Medical University, Fuzhou, 35001, China

    Xinyang Zou, Yisen Shi & Jiaqi Su

  3. Department of Neurosurgery, Fujian Medical University Union Hospital, Fuzhou, 350001, China

    Fabin Lin

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Contributions

XZ: Conceptualization, Methodology, Formal analysis, Writing original draft. YS: Methodology, Formal analysis. JS: Writing original draft. QY: Validation, Supervision. FL: Conceptualization, Supervision, Interpreted the data, Reviewed and improved the draft manuscript. GC: Conceptualization, Supervision, Interpreted the data, Reviewed and improved the draft manuscript.

Corresponding authors

Correspondence to Fabin Lin or Guoen Cai.

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The authors declare no competing interests.

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The consent form was signed by participants in the survey, and participants consented to storing specimens of their blood for future research. The CDC/NCHS Ethics Review Board (ERB) approved the NHANES study and gave approval for public dissemination.

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Zou, X., Shi, Y., Su, J. et al. Association between 2,4-dichlorophenoxyacetic acid and cognitive impairment in older adults: a cross-sectional study from NHANES 2001–2002 and 2011–2014. J Expo Sci Environ Epidemiol (2023). https://doi.org/10.1038/s41370-023-00628-9

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