Effects of occupational exposure to chlorpyrifos on neuropsychological function: A prospective longitudinal study
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)
- et al.
Effects of occupational pesticide exposure on children applying pesticides
Neurotoxicology
(2008) Effects of insecticides
Lancet
(2001)- et al.
Human red blood cell acetylcholinesterase inhibition as the appropriate and conservative surrogate endpoint for establishing chlorpyrifos reference dose
Regul Toxicol Pharmacol
(1999) - et al.
Mini-mental state. A practical method for grading the cognitive state of patients for the clinician
J Psychiatr Res
(1975) - et al.
Pesticide residues in urine of adults living in the United States: reference range concentrations
Environ Res
(1995) Continuing challenges for computer-based neuropsychological tests
Neurotoxicology
(2003)- et al.
Long-term monoamine changes in the striatum and nucleus accumbens after acute chlorpyrifos exposure
Toxicol Lett
(2008) - et al.
Chronic central nervous system effects of acute organophosphate pesticide intoxication. The Pesticide Health Effects Study Group
Lancet
(1991) - et al.
Neurobehavioral function and organophosphate insecticide use among pesticide applicators in the Agricultural Health Study
Neurotoxicol Teratol
(2012) - et al.
Organophosphates: the relationship between chronic and acute exposure effects
Neurotoxicol Teratol
(1996)
The effects of occupational exposure to chlorpyrifos on the neurologic examination of central nervous system function: a prospective cohort study
JOEM
Analysis of chlorpyrifos exposure and human health: expert panel report
J Toxicol Environ Health B: Crit Rev
Paraoxonase status and plasma butyrylcholinesterase activity in chlorpyrifos manufacturing workers
J Exp Anal Environ Epidemiol
The effects of occupational exposure to chlorpyrifos on the peripheral nervous system: a prospective cohort study
Occup Environ Med
TLVs and BEIs based on the documentation of the threshold limit values for chemical substances and physical agents and biological exposure indices
Neurobehavioural tests and systems to assess neurotoxic exposures in the workplace and community
Occup Environ Med
Neuropsychologic effects of long-term exposure to pesticides: results from the French Phytoner study
EHP
Computerized neuropsychological assessment devices: joint position paper of the American Academy of Clinical Neuropsychology and the National Academy of Neuropsychology
Clin Neuropsychol
Neurobehavioral toxicology: neurological and neuropsychological perspectives, Volume. I, Foundations and methods
Occupational chlorpyrifos exposure and neurobehavioral functioning in pesticide manufacturing workers
Human neuropsychological testing and evaluation
Predicting premorbid IQ: a revision of the North American Adult Reading Test
Clin Neuropsychol
The interaction of education and cumulative lead exposure on the Mini-Mental State Examination
JOEM
Update of the morbidity experience of employees potentially exposed to chlorpyrifos
Occup Environ Med
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 NeurotoxicologyCitation 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 LettersCitation 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, NeuroToxicologyCitation 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, ChemosphereCitation 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.