Elsevier

NeuroToxicology

Volume 41, March 2014, Pages 44-53
NeuroToxicology

Effects of occupational exposure to chlorpyrifos on neuropsychological function: A prospective longitudinal study

https://doi.org/10.1016/j.neuro.2013.12.010Get rights and content

Highlights

  • We studied neurobehavioral function in workers exposed to chlorpyrifos (CPF).

  • Workers had higher CPF exposures than referents, before and during the study.

  • No impairment was observed at baseline or repeat examinations in CPF exposed group.

  • Verbal memory domain higher in exposed at baseline but no group–time interactions.

  • Results may not apply to applicators with high exposure or to low educated workers.

Abstract

Background

Exposure to chlorpyrifos (CPF), an organophosphorus (OP) anticholinesterase insecticide, occurs typically in settings where multiple agents are present (e.g., agriculture) and quantitative dose measures may be absent (e.g., pesticide application). Such exposures allow few opportunities to study potential neurobehavioral effects of CPF alone. We studied the relationship between CPF exposure and behavioral function among CPF manufacturing workers, which allowed identification, measurement, and estimation of exposure and important non-exposure variables that potentially could affect study findings.

Methods

A prospective longitudinal study design was used to compare neurobehavioral function over a one-year period among 53 CPF workers and 60 referent workers. Quantitative and qualitative measures were used, and potential confounders were identified and tested for possible inclusion in our statistical models. Neurobehavioral function was assessed by neuropsychological tests covering various behavioral domains that may be adversely affected by exposure to CPF in sufficient amount.

Results

CPF workers had significantly greater CPF exposures during the study period than did referents at levels where physiologic effects on plasma butyrylcholinesterase (BuChE) activity were apparent and with higher 3,5,6-trichloro-2-pyridinol (TCPy/Cr) urinary excretion (p < 0.0001) and lower average BuChE activity (p < 0.01). No evidence for impaired neurobehavioral domains by either group of workers was observed at baseline, on repeat examination, or between examinations. CPF workers scored higher than referent workers on the verbal memory domain score (p = 0.03) at baseline, but there were no significant changes in verbal memory over time and no significant group-by-time interactions.

Conclusions

The study provides important information about CPF exposure in the workplace by not supporting our working hypothesis that CPF exposure associated with various aspects of the manufacturing process would be accompanied by adverse neurobehavioral effects detectable by quantitative neurobehavioral testing. Some aspects making this workplace site attractive for study and also present limitations for the generalization of results to other situations that might have exposures that vary widely between and within different facilities and locations. For example, these results might not apply to occupations such as applicators with higher exposure or to workers with low educational levels.

Introduction

Adverse cognitive and other neurobehavioral findings have been observed in acute and chronic, high level pesticide exposures (Kamel et al., 2005, Savage et al., 1988, Starks et al., 2012). A variety of cognitive (e.g., memory, attention, concentration, and alertness), psychomotor, and emotional (e.g., depression, anxiety, and irritability) impairments have also been reported to result from 20 or more chronic, low level organophosphorus (OP) exposures studies (Ismail et al., 2012). Ismail and colleagues, for instance, identified 17 studies in their meta-analytic study of agricultural workers and pesticide applicators (Ismail et al., 2012), and they concluded “decrements in neurobehavioral performance” in the pesticide exposed group in comparison to the control group. Work in these areas, however, has proven to be challenging from a scientific perspective. Such challenges are likely due to a host of factors, many outside a given investigators control as is often acknowledged by the authors of a given study (Blain, 2001, Clegg and van Gemert, 1999, Kamel et al., 2005, Pilkington, 2001, Starks et al., 2012, Woods et al., 1999). The settings in which exposures to OP compounds are likely to occur, for instance, frequently challenge good experimental control of important variables, such as specific exposure details and other factors that are known to affect study outcomes and other aspects of methodology. These settings often involve exposure to multiple types of compounds aside from OP compounds. Determining levels of exposure is often difficult to accomplish, and potential confounders may be difficult to identify and control. Studies that target a specific compound, e.g., chlorpyrifos (CPF), must attempt to identify and control factors with the potential for causal contribution to results, including the presence of alternative exposures. At the same time, knowing that a particular setting may be associated with measurable impairments is important from a public health viewpoint even when causality has not yet been specified completely (Farahat et al., 2003, Hogstedt et al., 1984, Rosenstock et al., 1991, Rothlein et al., 2006, Starks et al., 2012, Stephens et al., 1996).

Recognizing the importance of arriving at scientifically objective answers to questions surrounding the potential toxic effects of chronic, low-level OP exposures, a committee was convened by the United Kingdom Department of Health (Woods et al., 1999). The committee reviewed existing evidence that associated chronic, low-level exposures to OP insecticides with adverse effects on neurological or neuropsychological performance. They determined that the evidence did not scientifically support a causal association, but recommended further investigation to establish whether the risk of neurological dysfunction is increased by low-level OP exposures. Other reports have made similar recommendations (Albers et al., 1999, Clegg and van Gemert, 1999). In response to these recommendations, we sought to address the question of adverse effects of chronic, low-level OP exposure on neurobehavioral function by studying individuals involved in the manufacture of these compounds. CPF manufacturing workers are a suitable population to study for a number of reasons. The most important reasons include their potential for chronic exposure, the opportunity to measure exposures reliably, their availability in a single geographic location in which standardized medical and neurobehavioral testing can be performed, the ability to control potential confounders that might influence the test performance and the availability of these workers for repeat study over time.

Our working hypothesis was that workers with chronic occupational exposure to CPF develop dose-related subclinical or clinically evident adverse neurobehavioral effects demonstrable by quantitative neurobehavioral testing.

Section snippets

Study design

The prospective longitudinal study design employed here has been described previously (Albers et al., 2004a, Albers et al., 2004b). Briefly, we evaluated two groups of workers at the Dow Chemical Company in Midland, Michigan, on two occasions, baseline and one year later. As previously reported (Albers et al., 2010), the CPF workers averaged almost a decade of exposure to chlorpyrifos, and there was no evident movement of workers from chlorpyrifos-related jobs. The referent group included

Demographic and other subject-related details

As seen in Table 2, CPF subjects were comparable to referents at study baseline in terms of age, sex, body mass index (BMI), and anxiety level. The subjects were early middle age, mostly male, and mostly Caucasian. The two groups were comparable at baseline in terms of general aptitude, as measured by the NART-R index, and in terms of general mental status, as determined by clinical interview and formal testing. The overall frequency of medical problems as reported on questionnaires did not

Discussion

Our earlier publications focused on the effects of CPF exposure on findings from neurological examination of CNS and peripheral nervous system function (Albers et al., 2004a, Albers et al., 2004b). In the present report, we focused on quantitative examination of neuropsychological function. Our working hypothesis that workers with chronic occupational exposure to CPF develop dose-related sub-clinical or clinically evident adverse neurobehavioral effects demonstrable by quantitative

Conflict of interest statement

In addition to funding from governmental and private industrial sources for research and related activities, some of the authors have at times been retained as consultants or served as expert witnesses in litigation for firms, agencies, or companies, including Dow Chemical Company and Dow AgroSciences, concerned with the manufacture or use of insecticides. Support of these activities has included both personal and institutional remuneration.

Activities by individual authors have included the

Acknowledgments

This study was supported financially by Dow AgroSciences, Indianapolis, Indiana, USA, with additional support from Dow Chemical Company and Dow Chemical Company Foundation. Aspects of this study also were presented in a talk at the 10th International Symposium on Neurobehavioral Methods and Effects in Environmental and Occupational Health (NEUREOH) (Berent et al., 2008).

We acknowledge the additional investigators who worked at some point on this project, including Brenda Gillespie, PhD, Alison

References (48)

  • J.W. Albers et al.

    The effects of occupational exposure to chlorpyrifos on the neurologic examination of central nervous system function: a prospective cohort study

    JOEM

    (2004)
  • J.W. Albers et al.

    Analysis of chlorpyrifos exposure and human health: expert panel report

    J Toxicol Environ Health B: Crit Rev

    (1999)
  • J.W. Albers et al.

    Paraoxonase status and plasma butyrylcholinesterase activity in chlorpyrifos manufacturing workers

    J Exp Anal Environ Epidemiol

    (2010)
  • J.W. Albers et al.

    The effects of occupational exposure to chlorpyrifos on the peripheral nervous system: a prospective cohort study

    Occup Environ Med

    (2004)
  • American Conference of Governmental Industrial Hygienists

    TLVs and BEIs based on the documentation of the threshold limit values for chemical substances and physical agents and biological exposure indices

    (2013)
  • W.K. Anger

    Neurobehavioural tests and systems to assess neurotoxic exposures in the workplace and community

    Occup Environ Med

    (2003)
  • I. Baldi et al.

    Neuropsychologic effects of long-term exposure to pesticides: results from the French Phytoner study

    EHP

    (2001)
  • R.M. Bauer et al.

    Computerized neuropsychological assessment devices: joint position paper of the American Academy of Clinical Neuropsychology and the National Academy of Neuropsychology

    Clin Neuropsychol

    (2012)
  • S. Berent et al.

    Neurobehavioral toxicology: neurological and neuropsychological perspectives, Volume. I, Foundations and methods

    (2005)
  • S. Berent et al.

    Occupational chlorpyrifos exposure and neurobehavioral functioning in pesticide manufacturing workers

  • S. Berent et al.

    Human neuropsychological testing and evaluation

  • J. Blair et al.

    Predicting premorbid IQ: a revision of the North American Adult Reading Test

    Clin Neuropsychol

    (1989)
  • M.L. Bleecker et al.

    The interaction of education and cumulative lead exposure on the Mini-Mental State Examination

    JOEM

    (2002)
  • C.J. Burns et al.

    Update of the morbidity experience of employees potentially exposed to chlorpyrifos

    Occup Environ Med

    (1998)
  • Cited by (20)

    • Organophosphate pesticides an emerging environmental contaminant: Pollution, toxicity, bioremediation progress, and remaining challenges

      2023, Journal of Environmental Sciences (China)
      Citation Excerpt :

      Victims of OPs poisoning typically die because of a shortage of breath (Chambers and Levi, 1992; Pundir et al., 2019). OPs not only act as inhibitors of acetylcholinesterase but also bind to other proteins and enzymes and inhibit by covalently binding with serine containing enzymes such as proteases, esterases, carboxylesterases, neuropathy target esterase (NTE), plasma pseudocholinesterase, and A-esterases (Berent et al., 2014; Naughton and Terry, 2018). Along with these, a few non-cholinesterase targets of OPs and their downstream effects have been listed in Appendix A Table S1.

    • Identifying and preventing the neurotoxic effects of pesticides

      2022, Advances in Neurotoxicology
      Citation Excerpt :

      Moreover, most studies have examined only a single time point. Those that have addressed multiple time points have primarily focused only on pre- and post-application comparisons (Bazylewicz-Walczak et al., 1999; Daniell et al., 1992; Nguyen et al., 2015), while few studies have examined exposure across multiple years (Baldi et al., 2011; Berent et al., 2014; Roldan-Tapia et al., 2005, 2006). Furthermore, these previous studies were conducted with adult workers and not adolescents.

    • Pesticides, cognitive functions and dementia: A review

      2020, Toxicology Letters
      Citation Excerpt :

      Sometimes the delayed neuropathies can manifest outside of the timeline of the study. For example, the study of Daniel et al. (Daniell et al., 1992), that could not show any evidence of clinically significant adverse neuropsychological effects, evaluated the pesticide applicators before the spraying season and at 1 month after the end of the spraying system, while in the studies that showed a significant correlation between worse neurological performance and pesticide exposure, the follow-up period was usually more than 1 year (Baldi et al., 2011, 2003; Berent et al., 2014; Bosma et al., 2000; Helmer et al., 2006; Lee et al., 2016; Tyas et al., 2001). In fact, the studies that reported a positive association, when compared to those that did not, seemed to include larger populations and larger periods of time, ranging from months to even 10 years.

    • Acute exposure to chlorpyrifos caused NADPH oxidase mediated oxidative stress and neurotoxicity in a striatal cell model of Huntington's disease

      2017, NeuroToxicology
      Citation Excerpt :

      However, epidemiological studies have demonstrated that individuals who come into regular occupational exposure to CPF have high concentrations of this chemical in their urine. For example, Berent et al. estimated that CPF manufacturing workers are exposed to approximately 600 μg CPF or 1.71 mM per day (Berent et al., 2014). Other occupational studies have estimated a range of 97 to 275 μg TCP/person (Geer et al., 2004).

    • Enhanced degradation of chlorpyrifos in rice (Oryza sativa L.) by five strains of endophytic bacteria and their plant growth promotional ability

      2017, Chemosphere
      Citation Excerpt :

      It has been proposed that the accumulation of CP in living tissues may pose a potential risk to humans and other organisms (Landrigan et al., 1999; Varó et al., 2002). Some studies showed that CP has adverse impacts on human beings' genital system and nervous system, hepatic and renal function as well as causing congenital defect in infants (Andreadis et al., 2014; Berent et al., 2014; Meeker et al., 2004; Rauh et al., 2006). Hence, reducing or eliminating CP in foodstuff is urgent.

    View all citing articles on Scopus
    View full text