Cognitive deficits associated with long-term, low-level exposure to organophosphate pesticides: a small group study

Organophosphate (OPs) pesticides were derived from World War II nerve gas agents and are being increasingly used around the world for a variety of agricultural, industrial and domestic purposes. Concerns have been expressed about the effects of these chemicals on human health. Chronic ill health may follow recovery from acute organophosphate poisoning, but the possibility that repeated low level exposure may cause ill health is controversial as previous research has yielded inconsistent results. As an occupational group, farmers are considered to be at risk of low level exposure only.METHOD: The present study compared neuropsychological performance of 25 agricultural workers, exposed to organophosphate pesticides in the course of their work with 22 nonexposed healthy volunteers (controls) who were matched to the exposed group for age, gender, years spent in education and level of intelligence. All ofthe agricultural workers were involved in litigation.OBJECTIVE: To establish whether agricultural workers with a history of prolonged exposure to OPs show evidence of cognitive impairment and to determine whether the pattern of cognitive deficit relates to exposure history.FINDINGS: A range of cognitive and emotional problems were identified in agricultural workers. Although general intellectual ability was relatively well preserved in the exposed cohort, they obtained lower scores on tests of auditory verbal memory span, verbal learning, verbal fluency, mental flexibility, reading, visuo-spatial skill and information processing speed, than non-exposed controls. In addition, over 70% of the exposed cohort complained of clinically significant levels of anxiety and depression. They also reported a range of physical symptoms, the most prominent being fatigue, aching muscles and joints, headaches, sleep disturbance and irritability. Exposure history varied enormously amongst individuals who seemed to have similar jobs and many appeared to have a history of undiagnosed acute poisoning. This highlights the importance of taking an adequate exposure history.CONCLUSIONS: The question of whether low level exposure to OPs causes ill health will never be resolved without agreed definitions of acute versus low level exposure, adequate assessment of exposure history and consideration of individual vulnerability factors or synergistic effects of chemical combinations that may mediate the dose-response relationship

Reflections on the process of using systematic review techniques to evaluate the literature regarding the neurotoxicity of low level exposure to organophosphate pesticides

We undertook a systematic review (incorporating meta-analysis) of the literature concerning the neurotoxicity of cumulative low level occupational exposure to organophosphate pesticides, which was published online by the journal Critical Reviews in Toxicology in 2012. As far as we are aware, we were the first research team to attempt quantitative evaluation of study findings on this topic, using meta-analysis. We wish to encourage others to apply systematic review techniques in chemical risk assessment to reduce bias, increase transparency and better inform public policy. We thought it would be useful to share our experience of undertaking a systematic review in the hope of dispelling misconceptions about the complexity, time and resource issues involved along with the view that meta-analysis is meaningless when studies are not homogeneous. In this commentary paper we reflect on aspects of the process which were relatively straightforward; aspects which were more challenging; the advantages of using systematic review techniques; and the advantages and limitations of using statistical techniques such as meta-analysis in this context

Neurobehavioral problems following low-level exposure to organophosphate pesticides: a systematic and meta-analytic review

Meta-analysis was carried out to determine the neurotoxic effects of long-term exposure to low levels of organophosphates (OPs) in occupational settings. Concern about the effects of OPs on human health has been growing as they are increasingly used throughout the world for a variety of agricultural, industrial and domestic purposes. The neurotoxic effects of acute poisoning are well established but the possibility that low-level exposure causes ill health is controversial. It is important to get a clear answer to this question as more individuals are at risk of low-level exposure than acute poisoning. Although a number of reviews on this topic have been published in the past, authors have come to conflicting conclusions. To date, none of these reviews have attempted quantitative evaluation of study findings using meta-analysis. This paper reviews the available evidence concerning the neurotoxicity of low-level occupational exposure to OPs and goes on to report the results of a meta-analysis of 14 studies which fulfilled criteria for this type of statistical analysis (means and standard deviations of dependant variables reported). Data were assimilated from more than 1600 participants. The majority of well designed studies found a significant association between low-level exposure to OPs and impaired neurobehavioral function which is consistent, small to moderate in magnitude and concerned primarily with cognitive functions such as psychomotor speed, executive function, visuospatial ability, working and visual memory. Unresolved issues in the literature which should become the focus of further studies are highlighted and discussed

Anxiety and depression following cumulative low-level exposure to organophosphate pesticides

Previous research suggests that individuals with a prior history of pesticide poisoning are at increased risk of psychiatric disorder (Freire and Koifman, 2013), but findings regarding the impact of cumulative low-level exposure are inconsistent. The aim of the current study was to investigate whether sheep farmers with a history of low-level exposure to organophosphate pesticides (1) report a higher level of psychological distress on subjective symptom questionnaires, compared to unexposed controls (2) also meet internationally agreed diagnostic criteria for a psychiatric disorder more often than unexposed controls. 127 sheep farmers were evaluated and compared to 78 unexposed controls, matched in terms of gender, education, level of intelligence, working status and area of residence. Both self-report measures and structured clinical interviews were used to assess mental health. The exposed cohort reported significantly higher rates of anxiety and depression when self-report questionnaires were used to evaluate mood, even when stressful life events, demographic and physical health factors were taken into account. However, when diagnostic interviews were used to assess mood, this pattern only held true for anxiety

Neuropsychological and psychiatric functioning in sheep farmers exposed to low levels of organophosphate pesticides

The study aim was to determine whether low level exposure to organophosphate pesticides (OPs) causes neuropsychological or psychiatric impairment. Methodological weaknesses of earlier studies were addressed by: recruiting participants who had retired on ill health grounds; excluding participants with a history of acute poisoning, medical or psychiatric conditions that might account for ill health; and exploring factors which may render some individuals more vulnerable to the effects of OPs than others. Performance on tests of cognition and mood of 127 exposed sheep farmers (67 working, 60 retired) was compared with 78 unexposed controls (38 working, 40 retired) and published test norms derived from a cross section of several thousand adults in the general population. Over 40% of the exposed cohort reported clinically significant levels of anxiety and depression compared to less than 23% of controls. Exposed subjects performed significantly worse than controls and standardisation samples on tests of memory, response speed, fine motor control, mental flexibility and strategy making, even after controlling for the effects of mood. The pattern was similar for both working and retired groups. The cognitive deficits identified cannot be attributed to mood disorder, malingering, a history of acute exposure or genetic vulnerability in terms of PON1(192) polymorphisms. Results suggest a relationship may exist between low level exposure to organophosphates and impaired neurobehavioural functioning and these findings have implications for working practice and for other occupational groups exposed to OPs such as aviation workers and Gulf War veterans

Phenotypic Characterization of EIF2AK4 Mutation Carriers in a Large Cohort of Patients Diagnosed Clinically With Pulmonary Arterial Hypertension.

BACKGROUND: Pulmonary arterial hypertension (PAH) is a rare disease with an emerging genetic basis. Heterozygous mutations in the gene encoding the bone morphogenetic protein receptor type 2 (BMPR2) are the commonest genetic cause of PAH, whereas biallelic mutations in the eukaryotic translation initiation factor 2 alpha kinase 4 gene (EIF2AK4) are described in pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis. Here, we determine the frequency of these mutations and define the genotype-phenotype characteristics in a large cohort of patients diagnosed clinically with PAH. METHODS: Whole-genome sequencing was performed on DNA from patients with idiopathic and heritable PAH and with pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis recruited to the National Institute of Health Research BioResource-Rare Diseases study. Heterozygous variants in BMPR2 and biallelic EIF2AK4 variants with a minor allele frequency of <1:10 000 in control data sets and predicted to be deleterious (by combined annotation-dependent depletion, PolyPhen-2, and sorting intolerant from tolerant predictions) were identified as potentially causal. Phenotype data from the time of diagnosis were also captured. RESULTS: Eight hundred sixty-four patients with idiopathic or heritable PAH and 16 with pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis were recruited. Mutations in BMPR2 were identified in 130 patients (14.8%). Biallelic mutations in EIF2AK4 were identified in 5 patients with a clinical diagnosis of pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis. Furthermore, 9 patients with a clinical diagnosis of PAH carried biallelic EIF2AK4 mutations. These patients had a reduced transfer coefficient for carbon monoxide (Kco; 33% [interquartile range, 30%-35%] predicted) and younger age at diagnosis (29 years; interquartile range, 23-38 years) and more interlobular septal thickening and mediastinal lymphadenopathy on computed tomography of the chest compared with patients with PAH without EIF2AK4 mutations. However, radiological assessment alone could not accurately identify biallelic EIF2AK4 mutation carriers. Patients with PAH with biallelic EIF2AK4 mutations had a shorter survival. CONCLUSIONS: Biallelic EIF2AK4 mutations are found in patients classified clinically as having idiopathic and heritable PAH. These patients cannot be identified reliably by computed tomography, but a low Kco and a young age at diagnosis suggests the underlying molecular diagnosis. Genetic testing can identify these misclassified patients, allowing appropriate management and early referral for lung transplantation

Comprehensive Cancer-Predisposition Gene Testing in an Adult Multiple Primary Tumor Series Shows a Broad Range of Deleterious Variants and Atypical Tumor Phenotypes.

Multiple primary tumors (MPTs) affect a substantial proportion of cancer survivors and can result from various causes, including inherited predisposition. Currently, germline genetic testing of MPT-affected individuals for variants in cancer-predisposition genes (CPGs) is mostly targeted by tumor type. We ascertained pre-assessed MPT individuals (with at least two primary tumors by age 60 years or at least three by 70 years) from genetics centers and performed whole-genome sequencing (WGS) on 460 individuals from 440 families. Despite previous negative genetic assessment and molecular investigations, pathogenic variants in moderate- and high-risk CPGs were detected in 67/440 (15.2%) probands. WGS detected variants that would not be (or were not) detected by targeted resequencing strategies, including low-frequency structural variants (6/440 [1.4%] probands). In most individuals with a germline variant assessed as pathogenic or likely pathogenic (P/LP), at least one of their tumor types was characteristic of variants in the relevant CPG. However, in 29 probands (42.2% of those with a P/LP variant), the tumor phenotype appeared discordant. The frequency of individuals with truncating or splice-site CPG variants and at least one discordant tumor type was significantly higher than in a control population (χ2 = 43.642; p ≤ 0.0001). 2/67 (3%) probands with P/LP variants had evidence of multiple inherited neoplasia allele syndrome (MINAS) with deleterious variants in two CPGs. Together with variant detection rates from a previous series of similarly ascertained MPT-affected individuals, the present results suggest that first-line comprehensive CPG analysis in an MPT cohort referred to clinical genetics services would detect a deleterious variant in about a third of individuals.JW is supported by a Cancer Research UK Cambridge Cancer Centre Clinical Research Training Fellowship. Funding for the NIHR BioResource – Rare diseases project was provided by the National Institute for Health Research (NIHR, grant number RG65966). ERM acknowledges support from the European Research Council (Advanced Researcher Award), NIHR (Senior Investigator Award and Cambridge NIHR Biomedical Research Centre), Cancer Research UK Cambridge Cancer Centre and Medical Research Council Infrastructure Award. The University of Cambridge has received salary support in respect of EM from the NHS in the East of England through the Clinical Academic Reserve. The views expressed are those of the authors and not necessarily those of the NHS or Department of Health. DGE is an NIHR Senior Investigator and is supported by the all Manchester NIHR Biomedical Research Centre