Evaluation of acute sensory–motor effects and test sensitivity using termiticide workers exposed to chlorpyrifos

Abstract

Sensory and motor testing was performed on a group of termiticide workers primarily using chlorpyrifos-containing products to evaluate both the acute effects from current exposure and sensitivity of the measures to detect effects. The study group comprised 106 applicators and 52 nonexposed participants. Current exposure was measured by urinary concentrations of 3,5,6-trichloro-2-pyridinol (TCP) collected the morning of testing. The mean TCP value for the 106 applicators was 200 μg/g creatinine. Participants received 4–5 h of testing and were evaluated using a sensory–motor test battery recommended by a National Institute for Occupational Safety and Health (NIOSH)-sponsored advisory panel to be appropriate for testing effects from pesticide exposures. Measurements testing olfactory dysfunction, visual acuity, contrast sensitivity, color vision, vibrotactile sensitivity, tremor, manual dexterity, eye–hand coordination, and postural stability were analyzed. Study results indicated limited acute effects from exposure to chlorpyrifos using urinary TCP as a measure of current exposure. The effects occurred primarily on measures of postural sway in the eyes closed and soft-surface conditions, which suggests a possible subclinical effect involving the proprioceptive and vestibular systems. Several other tests of motor and sensory functions did not show any evidence of acute exposure effects, although statistically significant effects of urinary TCP on the Lanthony color vision test scores and one contrast sensitivity test score were found. The visual measures, however, were not significant when a step-down Bonferroni correction was applied. Information also is presented on the sensitivity of the measures to detect effects in an occupationally exposed population using standard error of the parameter estimates.

Introduction

Conducting research on the health effects of organophosphorus pesticides in humans presents difficult problems. Controlled exposure laboratory studies or independent group studies with double-blind procedures are usually prohibitive because of ethical concerns and if a field study is conducted, securing a worker population exposed to one pesticide is difficult. Another problem is the separation of acute and chronic effects in active workers, because at the time the research is conducted, the participants will have both a current exposure body burden and a past exposure history. Additionally, the selection of tests that have sufficient statistical power and specificity to detect effects at typical occupational exposure levels (i.e., nonpoisoned) is important.

The National Institute for Occupational Safety and Health (NIOSH), with the cooperation of the State of North Carolina and the U.S. Environmental Protection Agency recruited a population of 191 current and former termiticide workers primarily applying chlorpyrifos and 189 controls for a cross-sectional study [52]. From this population of termiticide applicators and controls, a subgroup of applicators who indicated through phone interviews current use of chlorpyrifos-containing products, and a subgroup of controls were preselected to provide urine samples for an assessment of acute effects using a chlorpyrifos-specific urinary metabolite, 3,5,6-trichloro-2-pyridinol (TCP), and to evaluate the sensitivity of a battery of sensory–motor tests to detect effects on the nervous system from exposures to organophosphate (OP) compounds.

Chlorpyrifos is a widely available OP pesticide used for both residential and agricultural pest control. The chemical formula is O,O-diethyl O-3,5,6-trichloro-2-pyridyl phosphorothioate. An estimated 18.5 million pounds of the active ingredient chlorpyrifos were consumed in the US in 1995 [51]. The historical use of chlorpyrifos in both agricultural and nonagricultural environments is attributed to its moderate acute toxicity in mammalian species, broad spectrum insecticidal action, and as a replacement for other compounds that were no longer used because of lack of effectiveness or regulatory action [43]. Usage of chlorpyrifos-containing products, however, will drop markedly in the US because of recent pronouncements by the U.S. Environmental Protection Agency to phase out/eliminate the chemical for termiticide, residential indoor, and lawn uses [61].

The signs and symptoms of acute toxic effects from exposure to chlorpyrifos are similar to other OP or cholinesterase-inhibiting compounds and are listed in standard toxicological sources [1], [23], [28]. Reported long-term nervous system effects from acute poisoning or repeated exposures to OP compounds include impaired memory, attention and concentration, depression, irritability, confusion, speech difficulties, nightmares, mood disorders, delayed reaction times, increased vibrotactile sensitivity, and sensory and motor impairments [5], [36], [43], [53], [54], [56].

Some OP compounds, may also cause OP-induced delayed neurotoxicity (OPIDN), a neurodegenerative disorder 1 to 4 weeks following a poisoning episode [1], [43]. Animal studies, however, show low potential for OPIDN at maximum tolerated doses, and chlorpyrifos is not a potent inhibitor of neurotoxic esterase, which is associated with the occurrence of OPIDN [43]. There have, however, been reports in the literature of possible OPIDN among individuals who received near-lethal doses of chlorpyrifos [2], [40]. Whether or not OPIDN can occur in humans from repeated subchronic exposures to chlorpyrifos needs further research [43]. There is some evidence that acute poisoning episodes from exposure to OP compounds, which do not inhibit neuropathy target esterase or produce the classic OPIDN symptoms, may lead to a persistent peripheral neuropathy detectable by neurophysiological tests [53], [57].

Upon exposure (e.g., ingestion, inhalation, dermal), the compound is metabolically activated in the liver to the active metabolite, chlorpyrifos oxon, which produces neurotoxicity by inhibiting target esterases in the peripheral and central nervous system. Chlorpyrifos oxon is also detoxified in the liver and plasma to diethyl phosphate and TCP [43]. The main target enzyme is acetylcholinesterase. Similar to other OP compounds, chlorpyrifos binds to the esteratic site causing accumulation of the chemical transmitter acetylcholine at the muscarinic receptors (e.g., parasympathetic autonomic nervous system) and the nicotinic receptors (e.g., parasympathic and sympathetic nervous system and neuromuscular junctions) which results in excess cholinergic stimulation [23]. Acetylcholine is also a neurotransmitter in the brain and chlorpyrifos readily crosses the blood–brain barrier with effects on this structure.

Nolan et al. [41] studied the kinetics of chlorpyrifos in human volunteers using both oral and dermal dosages and determined that urinary TCP was the principle metabolite present in blood and urine with a half-life of 27 h after administration. Fenske and Elkner [24] in a study of five urban pesticide applicators applying chlorpyrifos in subslab and soil injection to houses confirmed that TCP was the principle indicator found in measurable quantities that reflected total absorbed dose from both dermal and inhalation exposures. Preexposure and complete 72-h urine samples demonstrated considerable interindividual variability, but urinary metabolite concentrations collected 24–48 h postexposures were the most highly correlated with total absorbed dose estimates.

Although chlorpyrifos has been marketed since the late 1960s and is in widespread use, human studies of both acute and chronic effects on the nervous system are sparse. One difficulty has been finding populations exclusively exposed to chlorpyrifos. The relevant studies either reported some limited health effects [3], [36], [53] or no significant health effects [10], [11] associated with exposures to chlorpyrifos. None of these studies were very comprehensive in evaluating the effects on the nervous system from exposures to chlorpyrifos and all lacked current measures of exposure and internal dose at the time of testing.

This research is part of a large effort by NIOSH to study the effects of pesticide exposures. The report of the cross-sectional study is available in Steenland et al. [52]. The purpose of this report is to evaluate the sensitivity of several specifically selected measures of sensory and motor functions using urinary TCP as a measure of current exposure to chlorpyrifos. The TCP concentrations provide a measurement of the chlorpyrifos body burden for each participant and by including nonexposed controls with both low- and high-exposed workers, a dose–response range for the detection of acute effects is possible. This paper also presents more detailed analysis and discussion of the acute effects of chlorpyrifos (using TCP measurements) for the sensory and motor outcomes than is available in Steenland et al. [52].