Neuropsychological and Psychiatric Functioning in Sheep Farmers Exposed to Low Levels of Organophosphate Pesticides
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Neuropsychological and psychiatric functioning in sheep farmers exposed to low levels of organophosphate pesticides Sarah Mackenzie Ross PhD Thesis University College London 1 I, Sarah Mackenzie Ross, confirm that the work presented in this thesis is my own. Where information has been derived from other sources, I confirm that this has been indicated in the thesis. Signature………………………………………………………… Sarah Mackenzie Ross June, 2011 Portions of this thesis have been published in the following journal article: Mackenzie Ross, S.J., Brewin, C., Curran, H.V., Furlong, C., Abraham, K. & Harrison, V. (2010). Neuropsychological and psychiatric functioning in sheep farmers exposed to low levels of organophosphate pesticides. Neurotoxicology and Teratology, 32 (4), 452-459 2 ACKNOWLEDGEMENTS I would like to acknowledge the support of the UK Department of Food, Environment and Rural Affairs in funding this study. I would also like to thank all participants who took part in the study (farm and police workers) without whom this research could not have been undertaken. Special thanks is also extended to a number of farming, police and support organisations for assistance with recruitment. I would further like to thank Kelly Abraham-Smith, Tessa Hughes, Julia Britton, Alison Dunevein, Gini Harrison, Professor Val Curran and Professor Chris Brewin for your contributions and support over the span of this project; and Professor Clem Furlong for undertaking the genetic analysis described within this thesis. Special thanks are due to my supervisors Dr Oliver Mason and Professor Chris McManus. Finally I would like to thank my husband, Steve Dunevein, my children, Jemma and Toby, and extended family for encouragement and support which sustained me throughout this study. 3 ABSTRACT The aim of this thesis is to determine whether exposure to low levels of organophosphate pesticides (OPs) causes neuropsychological or psychiatric impairment. The thesis is arranged in three parts. Part 1 provides an introduction to neurotoxicology, the role of the psychologist, and the toxicity of OPs; Part 2 provides a historical review of the existing scientific evidence regarding the impact on human health of low level exposure to organophosphate pesticides. A major unresolved issue in the toxicity literature is whether repeated, low level exposure to OPs, in the absence of a history of acute toxicity, is harmful to human health. Part 3 presents the findings of a four year empirical study designed to address this issue. A cross-sectional study was undertaken in which the performance on neuropsychological tests of 127 sheep farmers with a history of low level exposure to organophosphate pesticides was compared with 78 non- exposed healthy volunteers (rural police workers) matched for age, gender, years in education and level of intelligence. Methodological weaknesses of earlier studies were addressed in the study design, such as inclusion of study participants who had retired on ill health grounds to take account of the ‘healthy worker effect’; exclusion of study participants with a history of acute poisoning and those with a psychiatric or medical history that might otherwise account for ill health; and exploration of factors that may render some individuals more vulnerable to the effects of OPs than others (e.g. genetic differences in the capacity to metabolise and detoxify OPs). In the final chapter the findings are summarised and discussed, the study design is critically appraised and the implications of the findings are listed along with recommendations for future research. 4 Contents PART 1 An introduction to neurotoxicology, the role of the psychologist, and the toxicity of organophosphate pesticides. ..........................................................................17 Chapter 1 : An introduction to neuropsychological toxicology.............................................. 18 1.1 History of toxicology .............................................................................................. 18 1.2 The scale of the problem......................................................................................... 18 1.3 Toxicity testing and safety standards ...................................................................... 18 1.4 Detection and health care professionals.................................................................. 20 1.5 The role of neuropsychological research ................................................................ 20 1.6 Common issues in neuropsychological toxicology................................................. 21 1.6.1 Proving a link with exposure ....................................................................21 1.6.2 Spectrum of effects..................................................................................21 1.6.3 Acute vs chronic effects ...........................................................................22 1.6.4 Individual differences ..............................................................................22 1.7 Concluding remarks ................................................................................................ 22 Chapter 2 : Organophosphates................................................................................................ 24 2.1 Development and consumption of organophosphates............................................. 24 2.2 Organophosphate use in the UK ............................................................................. 25 2.3 Process of dipping................................................................................................... 25 2.4 Health effects .......................................................................................................... 26 2.5 Toxicology of organophosphate pesticides............................................................. 27 2.5.1 Acute poisoning – the cholinergic crisis ....................................................27 2.5.2 The Intermediate Syndrome......................................................................28 2.5.3 Organophosphate induced delayed polyneuropathy ....................................28 2.5.4 Chronic neurological and neurobehavioural changes ..................................29 2.6 Factors influencing toxicity in humans................................................................... 29 2.6.1 Measurement of exposure.........................................................................29 2.6.2 Route of exposure....................................................................................31 2.6.3 Rates of metabolism, individual differences & interactions with other chemicals ..............................................................................................................31 2.6.4 Use of protective measures and cross cultural differences ...........................33 2.6.5 Outcome measures...................................................................................33 2.7 Concluding comments............................................................................................. 34 5 PART 2 Neurobehavioural problems following low level exposure to organophosphate pesticides: A systematic & meta-analytic review. ...................................................................... 35 Chapter 3 : Neurobehavioural problems following low level exposure to organophosphate pesticides: A systematic review.............................................................................................. 36 3.1 Background ............................................................................................................. 36 3.2 Methods................................................................................................................... 37 3.2.1 Objectives ...............................................................................................37 3.2.2 Criteria for considering studies for this review...........................................37 3.2.3 Search methods for identification of relevant studies..................................38 3.2.4 Data synthesis and quality assessment.......................................................39 3.3 Results..................................................................................................................... 40 3.3.1. Numbers of articles retrieved from database searches.................................40 3.3.2 Excluded studies......................................................................................40 3.3.3 Findings of the review: Epidemiological studies that provide quantitative measures of exposure.............................................................................................42 Chapter 4 : Neurobehavioural problems following low level exposure to organophosphate pesticides: A meta-analytic investigation. .............................................................................. 54 4.1 Background ............................................................................................................. 54 4.2 Selection of studies ................................................................................................. 54 4.3 Meta-analysis .......................................................................................................... 55 4.3.1 Calculation of effect sizes and effect size formulas....................................64 4.3.2 Method of meta-analysis .........................................................................65 4.3.3 Influence of study publication date...........................................................72