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

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.

Auditory memory decrements, without dissimulation, among patients with major depressive disorder.

Questions have been raised about whether poor performance on memory tasks by individuals with major depressive disorder (MDD) might be the result of poor or variable effort or disease-related disruption of neural circuits supporting memory functions. The present study examined performance on a measure of task engagement and on an auditory memory task among 45 patients with MDD (M age = 47.82, SD = 19.55) relative to 32 healthy controls (HC; M age = 51.03, SD = 22.09). One-hundred percent of HC and MDD volunteers performed above the threshold for adequate effort on a formal measure of task engagement. The MDD subjects performed significantly more poorly than the HC subjects on an auditory learning and memory test. The present results suggest that auditory memory difficulties do occur among those with MDD and that decrements in performance in this group may be related to factors other than lack of effort.

Paraoxonase status and plasma butyrylcholinesterase activity in chlorpyrifos manufacturing workers.

Chlorpyrifos is an organophosphorus (OP) anticholinesterase insecticide. Paraoxonase (PON1) is an enzyme found in liver and plasma that hydrolyzes a number of OP compounds. PON1 polymorphisms include a glutamine (Q)/arginine (R) substitution at position 192 (PON1(Q192R)) that affects hydrolysis of OP substrates, with the PON1(192Q) allotype hydrolyzing chlorpyrifos oxon less efficiently than the PON1(192R) allotype, a variation potentially important in determining susceptibility to chlorpyrifos. We studied 53 chlorpyrifos workers and 60 referents during 1 year and estimated chlorpyrifos exposure using industrial hygiene and employment records and excretion of the chlorpyrifos metabolite 3,5,6-trichloro-2-pyridinol (TCP). Plasma butyrylcholinesterase (BuChE) activity, which may by inhibited by chlorpyrifos exposure, was measured monthly. In addition, plasma samples were assayed for paraoxonase (PONase), diazoxonase (DZOase), and chlorpyrifosoxonase (CPOase) activity to determine PON1 status (inferred genotypes and their functional activity). Linear regression analyses modeled BuChE activity as a function of chlorpyrifos exposure and covariates. We postulated that the level of CPOase activity and the inferred PON1(192) genotype (together reflecting PON1 status) would differ between groups and that PON1 status would modify the models of chlorpyrifos exposure on BuChE activity. Chlorpyrifos workers and referents had a 100-fold difference in cumulative chlorpyrifos exposure. Contrary to our hypotheses, mean CPOase activity was similar in both groups (P=0.58) and PON1(192Q) showed a slight overrepresentation, not an underrepresentation, in the chlorpyrifos group compared with referents (PON1(192QQ), 51% chlorpyrifos, 40% referent; PON(192QR), 43% chlorpyrifos, 40% referent; PON(192RR), 6% chlorpyrifos, 20% referent, P=0.08). In our models, BuChE activity was significantly inversely associated with measures of interim chlorpyrifos exposure, but the biological effects of chlorpyrifos exposure on BuChE activity were not modified by PON1 inferred genotype or CPOase activity.

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

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 microg TCPy/g creatinine (Cr). Plasma BuChE activity, a non-adverse biomarker of exposure, was negatively related to urinary TCPy concentrations above approximately 110 microg 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 microg/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.

The sensitivity and psychometric properties of a brief computer-based cognitive screening battery in a depression clinic.

At present, there is poor accuracy in assessing cognitive and vegetative symptoms in depression using clinician or self-rated measures, suggesting the need for development of standardized tasks to assess these functions. The current study assessed the psychometric properties and diagnostic specificity of a brief neuropsychological screening battery designed to assess core signs of depression; psychomotor retardation, attention and executive functioning difficulties, and impaired emotion perception within an outpatient psychiatry setting. Three hundred eighty-four patients with mood disorders and 77 healthy volunteers participated. A large percentage of patients met diagnostic criteria for Major Depressive Disorder alone (49%) or with another comorbid psychiatric disorder (24%). A brief, 25-min battery of computer-based tests was administered to control participants and patients measuring the constructs of inhibitory control, attention, visual perception, and both executive and visual processing speed. The patient groups performed significantly worse than the control group regardless of diagnosis on visual perception and attention accuracy and processing speed factors. Surprisingly, the anxiety disorder group performed better than several other psychiatric disorder groups in inhibitory control accuracy. Developing valid and reliable measures of cognitive signs in mood disorders creates excellent opportunities for tracking cognitive status prior to initiation of treatment, and allows for reliable retest following treatment.

Dose-effect analyses of occupational chlorpyrifos exposure and peripheral nerve electrophysiology.

We performed nerve conduction studies (NCSs) on 113 chemical workers, many of whom had occupational exposure to the organophosphorus insecticide chlorpyrifos (O,O-diethyl-O-[3,5,6-trichloro-2-pyridyl]-phosphorothioate), to identify dose effects of subclinical neuropathy. In this masked longitudinal study, we estimated historic and interim chlorpyrifos exposures and measured excretion of 3,5,6 trichloro-2-pyridinol (TCP), a chlorpyrifos metabolite. TCP excretion among exposed workers suggested an estimated daily chlorpyrifos exposure averaging about 576-627 microg/day and indicated levels approximately 30% (range 0-250%) of the internal dose received by a typical subject exposed during a working day at the threshold limit value of 200 microg/m3. We modeled NCS results using linear mixed models with repeated measures. Although we found no consistent associations between interim chlorpyrifos exposure and NCS results, we identified several significant associations involving historic chlorpyrifos exposure. Most associations, however, reflected effects at low-exposure levels (< 20 mg/m3 x days) without further effects as exposure increased over a 10-fold range (20-220 mg/m3 x days). This suggested small differences among subjects with low or no chlorpyrifos exposure, rather than a dose-related deterioration among subjects with higher exposures. Two NCS results demonstrating apparent subclinical adverse dose effects showed significant but unexplained interaction with education level. The overall results provide little support for the hypothesis that chronic chlorpyrifos exposures at levels in the range associated with appreciable inhibition of B-esterases produce adverse dose effects on peripheral nerve electrophysiology suggestive of subclinical neuropathy.

The potential adverse health effects of dental amalgam.

There is significant public concern about the potential health effects of exposure to mercury vapour (Hg(0)) released from dental amalgam restorations. The purpose of this article is to provide information about the toxicokinetics of Hg(0), evaluate the findings from the recent scientific and medical literature, and identify research gaps that when filled may definitively support or refute the hypothesis that dental amalgam causes adverse health effects. Dental amalgam is a widely used restorative dental material that was introduced over 150 years ago. Most standard dental amalgam formulations contain approximately 50% elemental mercury. Experimental evidence consistently demonstrates that Hg(0) is released from dental amalgam restorations and is absorbed by the human body. Numerous studies report positive correlations between the number of dental amalgam restorations or surfaces and urine mercury concentrations in non-occupationally exposed individuals. Although of public concern, it is currently unclear what adverse health effects are caused by the levels of Hg(0) released from this restoration material. Historically, studies of occupationally exposed individuals have provided consistent information about the relationship between exposure to Hg(0) and adverse effects reflecting both nervous system and renal dysfunction. Workers are usually exposed to substantially higher Hg(0) levels than individuals with dental amalgam restorations and are typically exposed 8 hours per day for 20-30 years, whereas persons with dental amalgam restorations are exposed 24 hours per day over some portion of a lifetime. This review has uncovered no convincing evidence pointing to any adverse health effects that are attributable to dental amalgam restorations besides hypersensitivity in some individuals.

Face emotion perception and executive functioning deficits in depression.

Frontal, limbic and temporal regions of the brain important in emotion perception and executive functioning also have been implicated in the etiology and maintenance of depression; yet, the relationships among these topics remain poorly understood. The present study evaluated emotion perception and executive functioning among 21 depressed women and 20 nondepressed women controls. Depressed women performed significantly worse than controls in emotion perception accuracy and in inhibitory control, an aspect of executive functioning, whereas the groups did not differ in other cognitive tests assessing memory, visual-spatial, motor, and attention skills. The findings suggest that emotion perception and executive functioning are disproportionately negatively affected relative to other cognitive functions, even in a high-functioning group of mildly depressed women. Measures of emotion perception and executive functioning may be of assistance in objectively measuring functional capability of the ventral and dorsal neural systems, respectively, as well as in the diagnosis of depression.

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

Questions persist about adverse effects such as impaired cognition and attention, incoordination, spasticity, or parkinsonism from chronic, low-level exposures to organophosphate (OP) compounds. In a prospective cohort study, we evaluated chlorpyrifos-manufacturing workers and a referent group on 2 occasions, 1 year apart, to determine whether occupational exposure to chlorpyrifos produced clinically evident central nervous system (CNS) dysfunction. Chlorpyrifos subjects had significantly higher TCP excretion and lower average BuChE activity than referents in a range in which physiological effects on B-esterases exist. Few subjects had neurologic symptoms or signs, and there were no significant group differences in terms of signs at baseline or second examinations. Chronic chlorpyrifos exposure produced no clinical evidence of cortical, pyramidal tract, extrapyramidal, or other CNS dysfunction among chlorpyrifos subjects compared with referents, either at baseline or after 1 year of additional chlorpyrifos exposure.

Absence of sensory neuropathy among workers with occupational exposure to chlorpyrifos.

Several studies have reported the occurrence of sensory neuropathy with exposure to chlorpyrifos and other organophosphorus insecticides, at levels not associated with overt toxicity. We evaluated 113 chemical workers, including 53 of 66 (80%) eligible chlorpyrifos workers and 60 of 74 (81%) randomly selected referent workers, to identify evidence of sensory neuropathy or subclinical neuropathy. Compared to referents, chlorpyrifos subjects had significantly longer duration of work in chlorpyrifos-exposed areas (9.72 vs. 0.01 years; P < 0.0001), greater cumulative chlorpyrifos exposure (64.16 vs. 0.69 mg/m(3). day; P < 0.0001), higher urine 3,5,6-trichloro-2-pyridinol (TCP) excretion (108.6 vs. 4.3 microg/g creatinine; P < 0.0001), and lower plasma butyrylcholinesterase (BuChE) activity (7281 vs. 8176 mU/ml; P = 0.003). Despite exposures among chlorpyrifos subjects to levels at which well-described physiological effects on B-esterases exist, the frequency of symptoms or signs of neuropathy did not differ significantly between groups, and the only 2 subjects fulfilling criteria for confirmed neuropathy were both in the referent group. Mean nerve conduction study results were comparable to established control values and did not differ significantly between groups. We found no evidence of sensory neuropathy or isolated peripheral abnormalities among subjects with long-term chlorpyrifos exposure at levels known to be associated with the manufacturing process.

Varying patterns of verbal recall, recognition, and response bias with progression of alzheimer's disease.

Aspects of performance on verbal list learning tasks, such as recall, recognition, and response bias, may vary with severity in Alzheimer's disease (AD). We administered a 10-item, single-category word list learning test using selective reminding procedures to 188 patients with probable AD and 36 healthy normal controls with equivalent age and education. We analyzed the total number of words recalled as well as discrimination and response bias indexes derived from signal detection theory. Recall and discrimination were impaired in patients with probable AD compared to controls, and recall scores were more sensitive to dementia severity than discrimination. While many AD patients showed a liberal response bias, their response bias varied considerably within patient groups and did not correlate with disease severity.

Spurious WAIS-R cholinergic profiles in schizophrenia.

The Fuld (1984) cholinergic profile based on the WAIS and WAIS-R age scaled scores has been shown to have moderate sensitivity and varying degrees of specificity in identifying dementia of the Alzheimer's type. The utility of this algorithm has increasingly been in doubt. The present study used young, well-diagnosed schizophrenic inpatients, a nondemented population with known cognitive deficits, to examine the specificity of the Fuld profile and its relationship to demographic and neuropsychological indices. The results found that the subjects who demonstrated a positive cholinergic profile (15%) did not differ neuropsychologically from the remaining sample. In the absence of other discriminating neuropsychological functions, the index is merely an artifact of relatively higher verbal abilities in the context of lower performance skills.