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Cholinesterase inhibition in chlorpyrifos workers: Characterization of biomarkers of exposure and response in relation to urinary TCPy

Journal of Exposure Science & Environmental Epidemiology volume 19, pages 634–642 (2009)Cite this article

Abstract

The objective of this study was to evaluate the quantitative relation between measured red blood cell acetylcholinesterase (RBC AChE) and plasma butyrylcholinesterase (BuChE) activities with exposure to chlorpyrifos (CPF) as assessed by measurement of urinary 3,5,6-trichloro-2-pyridinol (TCPy) in a study group of workers occupationally exposed in the manufacture of CPF and a referent group of chemical manufacturing workers. Measures of plasma BuChE and RBC AChE activity and urinary TCPy concentration collected over a year-long study (1999–2000) in CPF-exposed workers (n=53) and referents (n=60) were analyzed using linear mixed models to characterize exposure–response relationships. Intraindividual variability in cholinesterase measures was compared between CPF-exposed workers and referents. Urinary TCPy concentrations in CPF workers were substantially elevated compared to referents, with median and 95th percentile concentrations during typical employment conditions 10-fold and more than 30-fold higher, respectively, than corresponding measures in the referents. Intraindividual variability in cholinesterase activities was substantial, with 17% of unexposed referents experiencing one or more plasma BuChE measures more than 20% below baseline over a year of repeated, periodic measurements. RBC AChE activity, an early biomarker of effect, was unrelated to urinary TCPy concentration over the entire range of exposure, up to 1000 μg TCPy/g creatinine (Cr). Plasma BuChE activity, a non-adverse biomarker of exposure, was negatively related to urinary TCPy concentrations above approximately 110 μg TCPy/g Cr. No-effect levels for inhibition of plasma BuChE and RBC AChE corresponding to absorbed doses of CPF of approximately 5 and greater than 50 μg/kg/day, respectively, were identified. These findings are consistent with previous no-effect level determinations for ChE inhibition in humans and suggest that general population CPF exposure levels are substantially below the identified no-effect levels. The dose–response relationships observed in this study are consistent with predictions from the previously published physiologically based pharmacokinetic/pharmacodynamic model for CPF. Intraindividual variability in measured cholinesterase activities in referents was substantial, suggesting that ongoing monitoring programs may have a substantial rate of false positives.

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Acknowledgements

Additional investigators on this project included Richard P. Garrison, Brenda Gillespie, Bruno Giordani, Jonathon Raz (deceased), Sarah S. Cohen, Camelia Sima and other members of the Neurobehavioral Toxicology Program Chlorpyrifos Study team including Jennifer N. Baughman, Nathan Bradshaw and Zhuolin Li. We acknowledge the Dow and Dow AgroSciences employees who assisted at various points in supporting this research. Finally, we are indebted to the Dow employees who volunteered their time as subjects in this study.

Research support: This study was financially supported by Dow Agrosciences, Indianapolis, Indiana, with additional support from The Dow Chemical Company and Dow Chemical Company Foundation, which included a SPHERE (Supporting Public Health and Environmental Research Efforts) Award. Model simulations were supported by grants R01 OH003629 and R01 OH008173 from the Centers for Disease Control and Prevention (CDC). The contents of this article are solely the responsibility of the authors and have not been subject to review by CDC and therefore do not necessarily represent the official view of CDC, and no official endorsement should be inferred.

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Authors and Affiliations

  1. Risk Science Center, School of Public Health, University of Michigan, Ann Arbor, MI, USA

    David H Garabrant

  2. Department of Environmental Health Sciences, School of Public Health, University of Michigan, Ann Arbor, MI, USA

    David H Garabrant

  3. Summit Toxicology, LLP, Falls Church, VA, USA

    Lesa L Aylward

  4. Department of Psychiatry, University of Michigan School of Medicine, Ann Arbor, MI, USA

    Stanley Berent

  5. Department of Biostatistics, School of Public Health, University of Michigan, Ann Arbor, MI, USA

    Qixuan Chen

  6. Battelle Pacific Northwest Division, Richland, WA, USA

    Charles Timchalk

  7. The Dow Chemical Company, Midland, MI, USA

    Carol J Burns

  8. Summit Toxicology, LLP, Lyons, CO, USA

    Sean M Hays

  9. Department of Neurology, University of Michigan School of Medicine, Ann Arbor, MI, USA

    James W Albers

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  1. David H Garabrant
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Correspondence to Lesa L Aylward.

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Some of the authors have received research support and at times been retained as consultants or served as expert witnesses in litigation for firms or companies, including Dow and Dow AgroSciences, concerned with the manufacture or use of insecticides. Support of these activities has included both personal and institutional remuneration.

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Garabrant, D., Aylward, L., Berent, S. et al. Cholinesterase inhibition in chlorpyrifos workers: Characterization of biomarkers of exposure and response in relation to urinary TCPy. J Expo Sci Environ Epidemiol 19, 634–642 (2009). https://doi.org/10.1038/jes.2008.51

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