Disabling Neuropsychiatric Disease in Farmers Exposed to Organophosphates Phase 1

DISABLING NEUROPSYCHIATRIC DISEASE IN FARMERS EXPOSED TO ORGANOPHOSPHATES: PHASE 1: THE STUDY OF HEALTH IN AGRICULTURAL WORK COHORT

Project number VM02115

Project investigators Dr AC Povey, Professor RM Agius, Occupational and Environmental Health Research Group, Faculty of Medical and Human Sciences, University of Manchester, Dr R McNamee, Biostatistics, Informatics and Health Economics Research Group, Faculty of Medical and Human Sciences, University of Manchester Professor A Burns, Professor F Creed, Psychiatry Research Group, Faculty of Medical and Human Sciences, University of Manchester Professor D Neary, Clinical Neurosciences Research Group, Faculty of Medical and Human Sciences, University of Manchester

IN CONFIDENCE TO SPONSORS DATE: 23/11/07

Foreword

This report has been prepared to provide information on the SHAW study which has examined the health effects of low dose chronic exposure to organophosphates in sheep farmers with the UK. It includes a detailed description of the study design and methodology used together with the results of the phase 1 of the study. The results from the second phase of the study will be appended as they and those questions subsequent to this report are completed.

Contents

Foreword 2 Contents 3 List of Tables 5 List of Figures 7 List of Appendices 8 Executive Summary 10 1.0 Introduction 12 1.1 Aims and objectives of the present study 13 2.0 Materials and Methods 14 2.1 Study design 14 2.2 Study population 14 2.2.1 Database entry, merging and cleaning 14 2.2.2 Addition of postcodes and telephone numbers 15 2.3 Study recruitment 15 2.3.1 Office of National Statistics 16 2.4 Screening questionnaire 16 2.5 Case Identification 17 2.5.1 Screen identified depression 17 2.5.2 Screen identified dementia 18 2.5.3 Screen identified neuropathy 18 2.5.4 Screen identified Parkinsonism 18 2.6 Ethical approval 18 2.7 Statistical analysis 19 3.0 Description of study cohort 19 3.1 Study population 19 3.2 Response rates 21 3.2.1 Adjusted response rates 23 3.3 ONS tracing 23 3.3.1 Death certificate tracing 24 4.0 Analysis of screening questionnaire 24 4.1 Demographics of population 24

4.2 Farming background and activities 24 4.3 Health status 25 4.4 Screen identified depression 26 4.5 Screen identified dementia 26 4.6 Screen identified neuropathy and Parkinsonism 27 4.7 Associations between screen identified depression and farming 27 4.8 Associations between screen identified dementia and farming 28 4.9 Associations between screen identified neuropathy and farming 29 4.10 Associations between screen identified Parkinsonism and farming 30 4.11 Associations between screen identified ill-health and sheep farming 30 4.12 Associations between screen identified ill-health and cattle farming 31 4.13 Associations between seeking medical advice for pesticide poisoning 31 and farming 4.14 Associations between seeking medical advice for pesticide poisoning 32 and screen identified ill-health 4.15 Risk of screen identified ill-health and farming factors in a population 33 restricted to those who had not sought medical advice for pesticide poisoning 5.0 Discussion 34 5.1 Strengths and weaknesses of the phase 1 study 36 5.1.1 Screen identified ill-health 39 5.1.2 Exposure assessment 40 5.2 SHAW study phases and SHAW study objectives 41 5.3 Summary 43 6.0 Acknowledgements 43 7.0 References 45 Tables 49 Figures 80 Appendices 87

List of Tables

1. Response rates in study population by source of information 49 2. Response rates in study population by geographical region 50 3. Demographics and farming variables of study population 51 4. Farming sector worked by study population 52 5. Farming activities carried out by study population 53 6. Handling of different types of concentrate by study population 54 7. Current medical problems in study population 55 8. Seeking medical advice in the study population 56 9. Current medical treatment in study population 57 10. Differences in farmers and farming variables by case status of screen 58 identified depression 11. Risk of screen identified depression by farming sector 59 12. Risk of screen identified depression by farming activity 60 13. Risk of screen identified depression by handling of pesticide 61 concentrate 14. Differences in farmers and farming variables by case status of screen 62 identified dementia 15. Risk of screen identified dementia by farming sector 63 16. Risk of screen identified dementia by farming activity 64 17. Risk of screen identified dementia by handling of pesticide 65 concentrate 18. Differences in farmers and farming variables by case status of screen 66 identified neuropathy 19. Risk of screen identified neuropathy by farming sector 67 20. Risk of screen identified neuropathy by farming activity 68 21. Risk of screen identified neuropathy by handling of pesticide 69 concentrate 22. Differences in farmers and farming variables by case status of screen 70 identified Parkinsonism 23. Risk of screen identified Parkinsonism by farming sector 71 24. Risk of screen identified Parkinsonism by farming activity 72 25. Risk of screen identified Parkinsonism by handling of pesticide 73

concentrate 26. Differences in farmers and farming variables by case status of ever 74 seeking medical advice for pesticide poisoning 27. Associations between ever seeking medical advice for pesticide 75 poisoning and farming sectors 28. Associations between ever seeking medical advice for pesticide 76 poisoning and farming activities 29. Associations between ever seeking medical advice for pesticide 77 poisoning and handling of pesticide concentrate 30. Associations between ever seeking medical advice for pesticide 78 poisoning and screen identified ill-health 31. Associations between screen identified ill-health and farming 79 variables in the whole population and a population restricted to those who had never sought medical advice for pesticide poisoning

List of Figures

1. Creation of SHAW database for mailing 80 2. Initial and final responses to SHAW mailing and telephone contact 81 3. Regional distribution of the SHAW sampling frame 82 4. Adjusted response rates by (A) Information Source and (B) 83 Geographical Region. 5. Associations between screen identified (A) depression, (B) dementia, 84 (C) neuropathy and (D) Parkinsonism and working with sheep, sheep farming activities and handling sheep dip concentrate 6. Associations between screen identified (A) depression, (B) dementia, 85 (C) neuropathy and (D) Parkinsonism and worki ng with cattle, cattle farming activities and handling cattle concentrate 7. Associations between ever seeking medical advice for pesticide 86 poisoning and (A) working with sheep, sheep farming activities, and handling sheep dip concentrate and (B) wor king with cattle, cattle farming activities and handling cattle concentrate

List of Appendices

1 Source of cohort members - NFU Ledger books 87 2 Source of cohort members - Cattle Association Records 88 3 Source of cohort members - Sheep Association Records 89 4 Source of cohort members - Shepherd’s guides 90 5 Introductory letter to cohort members 91 6 Information leaflet 92 7 Consent form 94 8 Health and Work Questionnaire 95 9 Addressee update (Blue form) 103 10 Follow-up letter (England) 104 11 Follow-up letter (Scotland) 105 12 Follow up letter (Wales) 106 13 SHAW non-responders telephone call 107 14 Telephone questionnaire 108 15 Dear occupier letter (general version) 110 16 Dear occupier letter (moved away version) 111 17 Dear occupier letter (deceased version) 112 18 Follow-up letter – retired farmer 113 19 Letter to Health Authority 114 20 Letter to doctor 115 21 Letter to subject 116 22 Number of farm workers and agricultural holdings in 1970 117 23 Geographical distribution of (A) Farmers (1970-71), (B) Regular farm 118 workers (1970-1971), (C) Agricultural holdings (1970-71) and (D) the SHAW cohort 24 Geographical distribution of cohort members identified through (A) 119 NFU ledger books, (B) Sheep associations, (C) Cattle associations and (D) Shepherd’s Guides 25 Geographical distribution of the SHAW sampling frame 120 26 Responses to further contact with initial non-responders 122 27 Responses to telephone contact of initial non-responders 123 28 Responses to “Dear Occupier” letters 124

29 Causes of death 125 30 Responses (%) to screening questionnaire (A3 questions) 126 31 Responses (%) to screening questionnaire (A4 questions) 127 32 Responses (%) to screening questionnaire (A2 questions) 128 33 Response rates of various studies in farming communities 129

Executive summary

Long term low dose exposure to organophosphates (OPs) has been associated with chronic ill-health particularly in sheep farmers. However in the absence of overt acute toxicity the epidemiological evidence linking chronic ill- health to such exposures is weak. To address this specific question, a large historically prospective cohort study of farmers from the 1970s has been carried out. One of the a priori hypotheses was that if OP exposure were a cause of neuropsychiatric disease, then any adverse ill-health would be associated with handling the sheep dip concentrate as this activity is the main determinant of OP exposure.

A cohort containing 18958 people who were farmers in the 1970s was identified through contemporaneous records held by the National Farmers’ Union, Sheep and Cattle Associations and through Shepherd’s Guides. Information on the study, a consent form and a brief screening questionnaire were sent to the identified person at the (1970s) address that had been obtained. Responses were obtained from (or about) 7691 people of whom 1380 completed the screening questionnaire (17.9%), 4635 had died (60.3%) and 1102 refused (14.3%). No response was obtained from 11,267 people of whom 5870 (51.4%) were known to have moved away from the address that had been obtained. Using as a denominator only those cohort subjects known to be still alive and to have the received the original letter, 48% of that population completed the screening questionnaire.

Potential cases (of depression, dementia, Parkinsonism and neuropathy) were identified using a priori (usually published) algorithms of the questions used for screening purposes. The frequency of working in different farming sectors, farming activity and handling the concentrate was compared in screen identified cases and controls (all participants not identified as a case). The risk associated with working in different farming sectors, undertaking different tasks and handling the concentrate was then determined by logistic regression both before and after adjustment for potential confounders.

Working in three farming sectors (glasshouse, other livestock and other work), two farming activities (working with other pesticides on the farm and slaughtering livestock) and handling the pesticide concentrate (but not that concentrate specifically used to treat arable crops, sheep or cattle) were all associated with an increased risk of screen identified dementia. Two farming activities (using fertilisers and carrying out lambing) were associated with a decreased risk of screen identified depression. Risk of screen identified neuropathy was increased with working with other pesticides on the farm, handling either sheep dip concentrate (OR adj , 95%CI = 1.58, 1.00-2.51) or the pesticide concentrate (but not that specifically used for arable, sheep or cattle treatment). Risk of screen identified Parkinsonism was increased by handling the sheep dip concentrate (OR adj , 95%CI = 1.64, 1.02-2.63) and the pesticide concentrate used to treat cattle.

Ever seeking advice for pesticide poisoning was strongly associated with screen identified depression (OR adj , 95%CI = 6.89, 3.48-13.6), dementia

(OR adj , 95%CI = 6.26, 3.24-12.1), neuropathy (OR adj , 95%CI = 4.94, 2.53-

9.64) and Parkinsonism (OR adj , 95%CI = 5.26, 2.64-10.5). These strong associations may have confounded the observed associations between handling the sheep dip concentrate and screen identified ill-health. In a population restricted to those who had never sought medical advice for pesticide poisoning, handling sheep dip concentrate was associated with an elevated but non-significant risk of neuropathy (ORadj , 95%CI = 1.44, 0.89-

2.34) and Parkinsonism (OR adj , 95%CI = 1.41, 0.86-2.32).

These results are thus consistent with the a priori hypothesis that OP exposure (via the handling of sheep dip concentrate) was associated with screen identified ill-health (namely Parkinsonism and neuropathy). At present, it is unclear whether this increased risk may have resulted from chronic low dose exposure or an episode of acute poisoning. However, the elevated risks of ill-health associated with seeking medical advice for pesticide poisoning together with the reduced risk estimates after exclusion of these advice seekers suggests that acute high dose exposure is probably an important contributory factor even if it does not necessarily account for all the effect.

1.0 Introduction

Over the past two decades there have been a number of reports of increased chronic ill-health amongst sheep farmers 1. A wide range of symptoms, often severe, have been described including headache, limb pains, sleep disturbance, poor concentration, mood changes and suicidal thoughts. An extensive review of epidemiological studies in 1999 by the Committee on Toxicity of Chemicals in Food, Consumer Products and the Environment (COT) reported that whilst there was evidence that acute high dose OP exposure caused long-term health effects, there was no conclusive evidence chronic low dose OP exposure had similar effects 2. This lack of firm evidence is at odds with the degree of concern expressed by some groups of farm workers occupationally exposed to OP pesticides, including sheep dip, who attribute distressing neuropsychiatric illness to OP exposure. Some of this disease is indeed severe, and it is worth noting that mortality from multiple sclerosis, Parkinson's disease and suicide is significantly increased for male farmers (and suicide for females 3) and that pesticide exposure, and not simply farming as an occupation, has been suggested as the causal agent in at least some of these conditions 4. Since the COT report 2 there have been additional studies in UK populations that provide additional information on exposure determinants 5 as well as further evidence of ill-health amongst those who have worked with sheep dip 6-8. Whilst, exposure to OPs can occur through a number of routes including splashes from the sheep dip itself, the main determinant of exposure has been shown to be whether the farmer handles the sheep dip concentrate itself 5. Psychiatric disorders (particularly depression) and musculoskeletal disorders (myalgia) were significantly associated with both short and long-term OP exposures in an analysis of suspected adverse reactions to OP sheep dips reported to the Veterinary Medicines Directorate 6. Members of organisations providing support to sheep farmers (and others) with self-reported OP exposure reported a wide range of symptoms with those people reporting an acute OP exposure tending to have poorer health than those without such an episode 7. In a population survey of men living in rural England and Wales, neurological symptoms (but not depression) were more common in men who were past users of sheep dip but

this not specific as there was also a higher rate of symptoms in men who had worked only with pesticides other than sheep dip or insecticides 8. Whether such associations occur through a toxic action of OPs or through psychological mechanisms is currently unclear 8.

Further research was recommended by the COT report to address a number of specific issues 2: • What are the most common patterns of exposure, clinical presentation and subsequent clinical course among people in the United Kingdom with chronic illnesses that they attribute to OPs? • How common is dipper's flu, and what causes it? • Does low-level exposure to OPs cause disabling neurological or psychiatric disease in a small subgroup of exposed persons? • Do people with chronic disabling illness that is suspected of being related to OPs differ metabolically from the general population? • Other than acetylcholinesterase inhibition, what mechanisms play an important role in the causation of adverse health effects by OPs

To address previously identified problems 2 and the specific research requirement “Does low-level exposure to OPs cause disabling neurological or psychiatric disease in a small subgroup of exposed persons?“, a large historically prospective cohort study of farmers was undertaken of subjects identified as either working with or not with sheep in the 1970s and traced to the present day to determine their current health status.

1.1 Aims and objectives of the study The objectives of this study were: 1. to determine the cumulative incidence of dementia, adult onset neurological disease, Parkinson’s disease and clinical depression in farmers 2. to establish whether an excess of such disease is apparent in those exposed to organophosphates, particularly in those farmers who handled the sheep dip concentrate

3. to estimate the size of the excess when subjects with a history of acute poisoning are excluded from the analysis 4. to determine whether diagnosed cases of dementia, Parkinson’s disease, neurological disease or depression differ in their exposure to organophosphates than randomly selected cohort members

2.0 Materials and methods

2.1 Study design The study, called the Study of Health in Agricultural Work (SHAW) has been carried out in two main phases. The first phase of the study had a cohort design and was established to objectives 1-3. The second phase of the study, a case-cohort study, was undertaken to meet objective 4. This report describes the methodology and results from the first phase of the SHAW study.

2.2 Study population The study population consisted of those people who were identified as being farmers in the 1970s through four main sources namely, the National Farmers’ Union (NFU), UK sheep associations, UK cattle associations and Shepherd’s Guides. Details of these sources are provided in appendices 1-4.

2.2.1 Database entry, merging and cleaning Records held by these organisations were all paper (and not electronic). Hence the name and address of each subject , a two digit county identifier as well as the data source, was directly entered into an Access database.

Duplicates were identified through four separate hierarchical checks by examining the database for individuals with (i) the same address, surname and forename, (ii) the same address and surname, (iii) the same address and finally the same surname. Initially these checks were carried out on a county by county basis and then finally by checking counties within a region to take into account any entries initially assigned a county code wrongly. If a duplicate entry was identified and eliminated, the remaining entry contained

information from the sources in the following order: (i) NFU ledger (tended to contain most comprehensive information), (ii) Shepherds Guide (1970) (iii) any Sheep association (1970) yearbook , (iv) any Cattle association (1970) yearbook , (v) entry from any source nearest to 1970 (between 1970 and 1975) and (vi) entry from source before 1970.

2.2.2 Addition of postcodes and telephone numbers The information obtained from these different sources rarely contained postcode or telephone information. Hence this information was obtained from different sources. The postcode was obtained by using the Royal Mail ‘Address Finder’. Each cohort member was checked and postcodes added to a matched address as well as any address amendments that needed to be made.

Telephone information on named farmers within the cohort was obtained by using computerised databases namely bt.com (both personal and business details) and 192.com (general information, business and area details) as well as google (postcode directly).

2.3 Study recruitment Each named person on the database was sent a letter describing the study (Appendix 5), an information sheet (Appendix 6), a consent form (Appendix 7), and a questionnaire asking about their health and work history, including working with sheep or cattle and the use of concentrate for treatment of pests (Appendix 8). A ‘blue’ form was also included so that those people who received the letter but were not the addressee could return information regarding the addressee to us (Appendix 9).

Non-responders were sent a reminder letter, which varied slightly according to region (England - Appendix 10; Scotland – Appendix 11; Wales – Appendix 12). A proportion of those who still did not respond were contacted by telephone to ask if they wished to participate by way of a standard script (Appendix 13). If they declined, they were asked to answer a short telephone questionnaire (Appendix 14).

A number of unopened letters were returned to Manchester for various reasons, e.g. the addressee had moved away/was deceased. A follow-up letter (general version-Appendix 15; ‘Moved away’ version – Appendix 16; Deceased – appendix 17) and ‘blue’ form was sent to the address asking the occupier to supply details of the original addressee if possible. In addition, further checks were made with local NFU offices, when possible, to try and determine whether these non-responders were still at the addresses in the database. A small proportion of farmers contacted us to say that they had retired from farming, therefore assuming that they were not eligible to participate in the study. These were sent a letter encouraging them to participate (Appendix 18).

2.3.1 Office of National Statistics The services of the Office of National Statistics (ONS) were used to try and trace cohort members who had been reported to have moved away from the address on the SHAW database. To aid in this process ONS were supplied with a letter to be sent to the health authority (Appendix 19), a letter to be send to the doctor via the health authority (Appendix 20) and a letter to be sent to the cohort member via their GP (Appendix 21).

2.4 Screening Questionnaire The screening questionnaire sent to potential study participants was developed in part from validated questionnaires used in previously published studies 9-13 . However, when this was not possible, questions were devised with the help of advice from experts in exposure assessment, clinical colleagues and also from the NFU and working farmers.

The questionnaire contained sections on health, lifestyle and work history (Appendix 8). The health section contained questions on general health status 9, neurological disease and Parkinsonism 10-12 , depression 9 and dementia 13 as well as sections on seeking medical advice ( e.g. ever sought advice for pesticide poisoning) and current medications/treatment. The

Lifestyle section contained questions on smoking and drinking history (adapted from the Scottish Reproductive Health Study).

The working history section contained questions on the respondent’s current employment status, their history of working in different sectors of the agricultural and horticultural industry, as well as brief questions on exposure (for example, had they ever dipped sheep or used the concentrate for the treatment of pests on sheep?). Questions were also asked about whether the farms were affected by BSE or Foot and Mouth (FMD) in 2001.

The questionnaire was then discussed further with the NFU and with focus groups of farmers. This resulted in the rewording of certain questions ( e.g. on the effects of BSE and FMD) and the use of more detailed questions to obtain information on the status of the farmer and the addition of further activities to the work activity tables to accommodate all types of farming.

2.5 Case identification Potential cases (of neurological disease, Parkinsonism, depression and dementia in particular) were identified using either published or a priori algorithms of the questions used for screening purposes (Appendix 8). Controls for each screen-identified ill-health were then the remaining participants who had not been identified as a case.

2.5.1 Screen identified depression Subjects were identified as a potential case of current depression if (i) their answer to A3.1 or A3.2 and four or more of A3.1 – A3.10 of the Health and Work Questionnaire (with the exception of 3.8 and 3.9, which a response to either was acceptable) were at least “More than half the days”. Question 3.10 was counted if any positive reply was present. This was based upon previously published scoring schemes9 or (ii) their cumulative score to A3.1-A3.10 was ≥10 when the answers were scored as follows: half the days or less =1, more than half the days=2,

every day or nearly every day =3. This was based upon previously published scoring schemes 9 or (iii) their answer to A6.3 was positive i.e. they had taken tablets or had any other treatment for depression in the past 4 weeks

Controls were then the remaining participants who had not been identified as a case.

2.5.2 Screen identified dementia Subjects were identified as a potential case of dementia if their answer to 4.1, 4.9 or 4.10 was positive and their cumulative score of answers to A4.1- 4.11 was ≥4 if each positive answer was scored as 1. This was based upon previously published scoring schemes 13 . Controls were then the remaining participants who had not been identified as a case.

2.5.3 Screen identified neuropathy Subjects were identified as a potential case of neuropathy if their answer to one or more of A2.2, 2.4, 2.11, 2.13, 2.14, 2.16 and 2.18 was “bothered a lot” . This was based upon clinical judgement by one of the authors of the study (DN). Controls were then the remaining participants who had not been identified as a case.

2.5.4 Screen identified Parkinsonism Subjects were identified as a potential case of Parkinsonism if their answer to one or more of A2.7, 2.8 and 2.9 was “bothered a lot”. This was based upon previously published scoring schemes 10 . Controls were then the remaining participants who had not been identified as a case.

2.6 Ethical approval Ethical approval was obtained from the West Midlands Multi-Centre Research Ethics Committee (MREC/02/7/115) and by the University of Manchester Ethics Committee (study 3156).

2.7 Statistical analysis The associations between case control status and demographic and farming factors were examined by cross tabulation, comparison of means (and medians) where appropriate and calculation of simple univariate statistics (chi square, t-tests) to compare the values in the two groups. Following this univariate analysis, multiple logistic regression was used to examine the risk (odds ratio) of being a case having taken account of other factors identified as being clinically important or found to be associated with case status in the univariate analysis .

3.0 Description of cohort

3.1 Study population The NFU maintains an electronic database of current and retired members of the NFU but did not have any centralised or computerised records of members from the 1970s. Hence, each of the 290 regional and group NFU offices in England and Wales were contacted and 6500 farmers were identified in 7 different areas with the most numbers being obtained from the Carlisle office (3,879). No records were found in the remaining NFU offices. To enlarge this cohort we obtained details of 84 UK sheep associations from the National Sheep Association and handbooks from the relevant time period traced. Of these sheep associations we obtained lists of members from 27 associations providing names of 5,301 sheep farmers; 24 associations had no records available, 18 were formed after the 1970s, 11 associations did not reply and the contact details for 4 others were out of date. Two editions of Shepherd’s Guides from the 1970s were also obtained for the Pennine and Lakeland areas of the north of England, providing a further 2,433 names of sheep farmers. Details of 31 UK cattle associations (as a possible source of unexposed or less exposed farmers) were obtained and membership lists from the 1970s were obtained for 15 associations providing a further 8,949 names. No records were available from 11 cattle associations, 3 did not response and 2 were formed after the 1970s.

Contact was also made with a number of other organisations and most did not have records from the appropriate time period. Organisations contacted included the Department of Agriculture and Rural Development in Northern Ireland, the Scottish Executive Environment and Rural Affairs Department, NFU Scotland, Farmers’ Union of Wales, Tenant Farmers Association, the Agricultural Wages Board at DEFRA, the British Wool Marketing Board, Cheshire Trading Standards Office and the Rural Payments Agency.

A total of 23,183 names of farmers were thus initially identified but there were duplicate entries due to the use of multiple sources of data. Upon removal of duplicate entries, the cohort contained 19,981 names (Figure 2). After elimination of entries from Northern Ireland the cohort contained 19,361 entries. 80% of these records had no postcodes so each address was checked for a postcode using Royal Mail software and postcodes were obtained for 17,056 entries. A further 325 subjects were eliminated as the address was not specific enough ( e.g. Mr Smith, Leyburn, Yorkshire) rendering delivery impossible.

The initial mailing was sent to 19036 cohort members (Figure 2) of which a further 78 were subsequently identified as being duplicate entries after the first mailing and subsequent contacts (Figure 3). Hence the SHAW cohort contained 18958 subjects. Approximately 87% of the farmers lived in England and Wales (the majority lived in the Northern regions of England; Figure 4) whilst the remainder (13%) lived in Scotland (Appendix 22). This distribution of people in the SHAW cohort is similar to that of the distribution of agricultural holdings and regular farm workers in England, Scotland and Wales in this time period. In 1970, approximately 87% of regular farm workers lived in England and Wales and 86% of agricultural holdings were in the same countries 14,15 (Appendix 22). A more detailed geographical distribution of farmers, farm workers and agricultural holdings (in 1970/71 14-16 ), together with the SHAW cohort is shown in Appendix 23, with the individual data sources (NFU ledger books, Sheep and Cattle Associations and Shepherd’s Guides shown in Appendix 24. The highest concentration of farmers and farm workers was in the south west and east of England (Appendix 23). The SHAW cohort

contained farmers throughout Great Britain but was concentrated in the North West of England (Appendix 24), which reflected particularly the numbers of farmers identified through the NFU ledgers and Shepherd’s Guides (Appendix 24). Members of Sheep and Cattle Associations were more widely dispersed (Appendix 24). A detailed breakdown of cohort members by region is provided in Appendix 25.

17,310 (91.3%) of the cohort were male, 1,374 (7.3%) female, and 274 (1.4%) of unknown sex. More detailed information on the demography of the cohort, most notably date of birth, was not available from the original data sources.

3.2 Response rates The initial responses to the first mailing and the overall responses to this mailing and subsequent mailing and telephone follow–up is shown in Figure 3. The non-response to the initial mailing was almost 60%. A further ~23% of letters were returned, some (2.9%) indicating that the named person had moved away. After follow-up by a further mail shot and telephone call , ~31% of subjects were reported as having moved away with a further 28% being non-responders (after two mailings and a telephone call). The screening questionnaire was completed by 1380 subjects (7.3%), the telephone questionnaire by 368 (19.3%) with 1102 (5.8%) refusing to take part. Almost one quarter of the study cohort (n=4635, 24.4%) was found to have died (Figure 2).

Final responses to the initial non-responders are shown in Appendix 26: by repeat mailing and telephone follow-up information on a further third of the cohort (31.7%) was obtained; just over 20% of the initial non-responders were identified as no longer being at the address in the study database with almost one half still providing no response. Responses to telephone contact of 2126 non-responders are shown in Appendix 27; almost one quarter of the cohort members had died and no response was obtained from a further third. Responses to the “Dear Occupier” letter i.e from people living at the address

but not the cohort member are shown in Appendix 28; 18% of the cohort members were identified as having died. Nineteen people, so contacted, completed the questionnaire but they were not included in the study as they were not part of the original cohort.

Responses were obtained from (or about) 7691 people (40.6% of the original cohort) of which 1380 (17.9%) completed the screening questionnaire and 368 (4.8%) completed the telephone questionnaire (Table 1 and Figure 2). A further 4635 subjects had died (60.3%), 1102 refused to participate (14.3%) and 206 were found to be ineligible (2.7%) e.g. by completing the screening questionnaire although they were not in the SHAW database. No response was obtained from 11267 people of whom 5870 (51.4%) were reported to have moved away from the address that had been obtained.

Response rates were examined both in terms of the original source of information (Table 1) and by geographical area (Table 2). The response rate was highest in those subjects identified through Sheep Associations (45.4%) and lowest with the Shepherd’s Guides (33.5%; Table 1). Screening questionnaire data was obtained from 17.9% of the responders with the highest rate (20.3%) from cohort members identified from the NFU ledgers and lowest (13.3%) from those identified from the Shepherd’s Guides. Approximately 60% of the responses indicated that the named person in the cohort had died with the highest rate being from those subjects in the Shepherd’s Guides. Subjects from the Shepherd’s Guides also had the lowest refusal rate (10.1%). Of the non-responders approximately half were reported to have moved away overall but only 30% of those subjects identified through the Shepherd’s Guides were reported to have moved away (Table 1).

Response rates varied with geographical location with the lowest rate in Wales (31.5%) and the highest in Scotland (48.6%; Table 2). The rate of answering the screening questionnaire was highest in the North West (20.6%) and lowest in the South East (14.0%) whereas refusal was highest in the Scotland (17.3%) and also lowest in the South East (9.6%). The percentage of cohort members identified as being deceased was highest in the South East (69.9%) and lowest in the North West (49.8%). Of the non-

responders, the percentage of those reported to have moved away was lowest in Wales (31.8%) and highest in the North West (67.2%).

Subsequent tracing (through the help of NFU offices) of those 325 subjects eliminated from the study due to inadequate address information indicated that 132 (40.6%) were reported to have died.

3.2.1 Adjusted response rates The denominator used to calculate the response rates includes those people known not to have received the original letter describing the study (namely those who had moved away and those who had died). An adjusted response rate was then calculated using as a denominator only those cohort subjects known to have the received the original letter (namely those who completed the screening or telephone questionnaire and those who refused to take part). Using this adjusted denominator, overall 48% of the population had completed the screening questionnaire, 13% the telephone questionnaire and 39% had refused.

The adjusted response rates varied little with source of information save for there being a much higher proportion of completed telephone questionnaires with people identified through the Shepherd’s Guides (Figure 4A). Similarly the adjusted response rates also varied little with geographical region (Figure 4B) except that no farmers in Wales completed the telephone questionnaire.

3.3 ONS tracing The rate of non-response was high and may affect the interpretation of the study depending upon the causes of this non-response. Hence, in a pilot study, the names and addresses (on the database) of 200 cohort members subjects who had been reported to have moved away were sent to ONS for tracing. Of these, ONS were unable to trace 142 subjects, 36 subjects had died, 21 were traced and had registered with a GP, and 1 had been traced but was not registered with a GP.

3.3.1 Death certificate tracing Information on cause of death was received for 2017 deceased farmers with the vast majority dying from old age/natural causes (Appendix 29). The details of 200 farmers who were reported to have died but for whom the cause of death was missing were sent to the ONS. 149 (74.9%) were traced, and copies of the death certificates obtained. One person was found to be alive.

4.0 Analysis of screening questionnaire

Though the screening questionnaire was completed by 1380 individuals, analysis of the completed data has been restricted to those individuals who were 13 or over in 1970 ( i.e. born before or in 1957) as individuals aged 13 or over are legally allowed to do agricultural or horticultural work.

4.1 Demographics of population Information on 1338 subjects aged 13 or over in 1970 was obtained (Table 3). The population was distributed over all of Great Britain but most responses were obtained from farmers in the North and North West (47.2%) and fewest from Wales (7.7%). Most of the population were men (95%) and the mean age was 69.6 years. Approximately 52% of the population drunk alcohol on more than one day per week and 16% were current smokers but 37% had been a smoker at one point.

Almost 71% had left school before the age of 16, 64% were still working and 3.6% had retired due to ill-health. More than two thirds of farmers worked on family farms. Whereas less than one third had been affected by BSE, almost half of the farms had been affected by Foot and Mouth disease (FMD) in 2001.

4.2 Farming background and activities Most of the farmers had worked at some point with either sheep (83.4%) or with cattle (94.8%) but fewer had work with combinable crops (53.6%) or with other livestock (34.7%: Table 4). Approximately 25% of farmers had worked in the outdoor vegetable/potato sector or had carried out other non-farming

work. Few farmers had either worked in glasshouse production (2.5%) or with top and soft fruit (4.0%). Just over a quarter of respondents indicated that they had carried out work outside farming.

The mean duration of working in the sheep, cattle or combinable crops sectors was approximately 40 years (Table 4). In the other sectors, the duration of working was lower with the lowest duration being for farmers who worked with top and soft fruit (21 years).

Self-reported farming activities are shown in Table 5. Most farmers had either carried out lambing or calving (93.6%), sheep dipping (82.8%) or sheep shearing (74.3%) or had been involved in worming (92.6%), carried out teat disinfection (72.1%) or applied treatment for warble fly infestation (88.2%). Only one third of farmers had slaughtered livestock. Most farmers had used fertilisers (93.3%) or had applied insecticides (64.8%) or other chemicals to crops (66.3%). Approximately half reported using pesticides for other work (52.4%) and 12.9 % reported using pesticides in any job that they had carried out. Approximately one third (38.1%) of farmers had treated or fumigated grain.

Most farmers reported handling the concentrated for the treatment of any pests on sheep (79.6%) or cattle (85.7%) but only half (51.6%) for arable treatment. Approximately 20% of farmers reported the handling of other types of concentrated pesticide (Table 6).

4.3 Health status Self-reported current health problems are shown in Table 7. The most prevalent problem was pain in arms, legs or joints (23.1% of farmers were bothered a lot during the previous four weeks), followed by back pain (12.3%). Other problems, except for shortness of breath (7.2%) were reported by less than 5% of the farmers.

Table 8 provides data on whether the farmers ever sought medical advice (as an adult) for health problems. Almost one third of farmers had sought advice

for high blood pressure (29.2%). More than 10% of farmers also sought advice for heart disease (20.9%), allergy (18.9%) and asthma (11.5%). Forty three farmers (3.4%) had sought advice for pesticide poisoning.

Current medical treatment is shown in Table 9. The most common medical treatments were for high blood pressure (25.3%) or heart disease (17.7%). Forty farmers reported taken treatment for depression (3.1%) and 19 for Parkinson’s disease (1.5%).

4.4 Screen identified depression Responses to individual questions (A3 of the screening questionnaire: Appendix 27) are provided in Appendix 30. Almost one half of farmers had been bothered by “feeling tired or having little energy” (question A3.4): of those 8% of farmers were feeling tired every day or nearly every day. In contrast, less than 10% of farmers were bothered by “poor appetite or overeating” (question A3.5), “moving or speaking so slowly that other people could have noticed “ (question A 3.8), “ being so fidgety or restless that you have been moving around a lot more than usual (question A3.9), or “thoughts that life is not worth living (question A3.10).

Responses to these individual questions were then used to identify potential cases of depression as described in Section 2.5.1: 111 farmers were classified as a screen identified case of depression.

4.5 Screen identified dementia Responses to individual questions (A4 of the screening questionnaire: Appendix 28) are provided in Appendix 31. Approximately 50% of respondents felt that “they were more forgetful and having trouble with their short-term memory” (question A4.2) and that “they were having trouble finding the words that they wanted to say or naming people or things” (question A4.11). In contrast fewer than 10% of subjects were “sad or down in the dumps” (question A4.5), or “had started to have trouble doing calculations” (question A4.6), or “had lost interest in their usual activities” (question A4.7), or “had started needing help with eating or dressing” (question A4.8), or “were

becoming irritable” (question A4.9) or “were concerned about their driving “ (question A4.10) or “had trouble with their nerves” (question A4.12).

Responses to these individual questions were then used to identify potential cases of dementia as described in Section 2.5.2: 148 farmers were classified as a screen identified case of depression.

4.6 Screen identified neuropathy and Parkinsonism Responses to individual questions (A2 of the screening questionnaire: Appendix 29) are provided in Appendix 32. More than 50% of respondents were bothered by “moving more slowly or stiffly” (question A2.7) and by “slowing down physically” (question A2.10) with approximately 1 in 10 farmers reporting that they had been bothered a lot by either problem. Less than 10% of farmers were bothered by “slurring their words” (question A2.4), problems when “using the telephone or cooking a meal” (question A2.6), or “feeling drunk when they haven’t had much to drink” (question A2.15).

Responses to these individual questions were then used to identify potential cases of neuropathy and Parkinsonism (section 2.5.3); 167 farmers were classified as a screen identified case of neuropathy and 160 were classified as a screen identified case of Parkinsonism.

4.7 Associations between screen identified depression and farming The demographic and farming variables of both farmers with screen identified depression (“cases”) and all other farmers not so identified (“controls”) are shown in Table 10. Cases and controls were of similar age and had a similar proportion of men. Compared to the controls, cases were more likely to come from Wales and the South East and less likely from Scotland and the Midlands/East Anglia. Cases were less likely than controls to drink alcohol on more than one day per week (35.1% vs 54.3%) but were more likely to have retired due to ill-health than controls (17.3% vs 2.4%). There were no detectable associations between case status and whether the farm and farmers’ livelihood had been affected BSE but there was some evidence that

case status was associated with how severe the farmers’ livelihood was affected by FMD in 2001 (Table 10).

Associations between screen identified depression and working in a specific farming sector are shown in Table 11. There were no significant associations between case status and working in any particular farming sector. Working in the glasshouse sector was associated with an elevated but non significant risk

(OR adj, 95%CI = 1.81, 0.64-5.14).

Associations between screen identified depression and specific farming activities are shown in Table 12. No farming activities were associated with an increased risk for screen identified depression. However, both the use of fertilisers and carrying out lambing was associated with significantly decreased risk ; the OR adj (95%CI) associated with the use of fertilisers was 0.42 (0.20-0.88) and with carrying out lambing was 0.48 (0.23-0.99).

There were no associations detected between screen identified depression and handling pesticide concentrate (Table 13); the OR adj (95%CI) associated with handling the concentrate for treatment of pests on sheep was 1.25 (0.69- 2.29).

4.8 Associations between screen identified dementia and farming. The demographic and farming variables of both screen identified cases of dementia and controls are shown in Table 14. Cases were older than controls (71.1±10.6 vs 69.4±9.6 years respectively) and were more likely to have been an ever smoker (49.7% vs 36.9%), retired due to ill-health (8.8% vs 3.0%) and less likely to have worked on a family farm (72.3% vs 83.4%).

Associations between screen identified dementia and working in a specific farming sector are shown in Table 15. Working in the glasshouse sector or with other livestock or carrying out other non-farming work was significantly associated with case status. The OR adj (95%CI) associated with the glasshouse sector was 2.44 (1.08-5.51), with working with other livestock 1.61 (1.13-2.29) and carrying out other work 1.50 (1.03-2.17). Working with cattle

was associated with a decreased risk that was of borderline significance after adjustment (OR adj , 95%CI =0.55,0.28-1.06).

Associations between screen identified dementia and specific farming activities are shown in Table 16. Risk of being a screen identified case of dementia was associated with the use of other pesticides on the farm (OR adj ,

95%CI = 2.10, 1.43-3.09) and with slaughtering livestock (OR adj , 95%CI = 1.94, 1.35-2.79).

Associations detected between screen identified dementia and handling pesticide concentrate for treating pests are shown in Table 17. Working with other (non arable, non sheep and non cattle) concentrate for use on pests was associated with an increased risk (OR adj , 95%CI = 2.45, 1.46-4.10). Handling cattle concentrate was associated with an elevated but non- significant , risk (OR adj , 95%CI =1.69, 0.95-3.03).

4.9 Associations between screen identified neuropathy and farming The demographic and farming variables of both screen identified cases of neuropathy and controls are shown in Table 18. Cases were older than controls (72.7±9.8 vs 69.1±9.6 years respectively) and were less likely to drink alcohol than controls (37.7% vs 54.9% drank on more than one day per week), and to have retired due to ill-health (16.4% vs 1.8%). There was also evidence that case status was associated with how severe the farmer’s livelihood was affected by FMD in 2001 or not.

Associations between screen identified neuropathy and working in a specific farming sector are shown in Table 19. Working in the sheep and other livestock sectors were associated with an elevated but non-significant risk; the

OR adj (95%CI) associated with working with sheep was 1.53 (0.94-2.51) and with other livestock 1.38 (0.98-1.94).

Associations between screen identified neuropathy and specific farming activities are shown in Table 20. Use of other (non-arable, non cattle and non- sheep) pesticides was associated with an increased risk (OR adj, 95%CI =

1.52, 1.06-2.18). No other farming activities were associated with increased risk.

Associations between screen identified neuropathy and handling pesticide concentrate are shown in Table 21. Increased risk was found for handling the concentrate for treatment of pests on sheep (OR adj, 95%CI = 1.58,1.00-2.51) and handling other (non sheep, non cattle and non arable) concentrate (OR adj, 95%CI = 1.76,1.05-2.94).

4.10 Associations between screen identified Parkinsonism and farming The demographic and farming variables of both screen identified cases of Parkinsonism and controls are shown in Table 22. Cases were less likely to be men (91.9% vs 95.5%), but were older than controls (73.8±10.1 vs 68.7±9.8 years) and were more likely to have retired due to ill-health (17.0 % vs 1.8%). Case status was also associated with whether livelihood was severely affected by FMD in 2001. There was some evidence that the geographical distribution of cases and controls varied with the proportion of cases being lower in Scotland and Midlands/East Anglia and higher in the North/North West.

There were no detectable associations between screen identified Parkinsonism and working in a specific farming sector (Table 23) or with any specific farming activites (Table 24). Associations between screen identified Parkinsonism and handling pesticide concentrate are shown in Table 25. Increased risk was observed with handling the concentrate for treatment of pests on sheep (OR adj, 95%CI = 1.64,1.02-2.63) and cattle (OR adj, 95%CI = 1.90,1.07-3.38).

4. 11 Associations between screen identified ill-health and sheep farming Associations between screen identified ill health and sheep farming activities are summarised in Figure 5. Working with sheep was not associated with screen identified depression, dementia and Parkinsonism, but there was an elevated but non significant risk of neuropathy. There was little evidence to

suggest that those activities (such as carrying out lambing or shearing sheep) less likely to result in exposure to pesticides including OPs resulted in an increase in ill-health. However, there was evidence that handling the sheep dip concentrate (an important determinant of sheep dip exposure) was associated with an increased risk of screen identified neuropathy and Parkinsonism: dipping sheep per se was not associated with any ill-health.

4.12 Associations between screen identified ill-health and cattle farming Associations between screen identified ill-health and cattle farming activities are shown in Figure 6. Working with cattle was not associated with screen identified ill-health. Activities (such as worming or disinfecting cattle) less likely to result in pesticide exposure also did not result in any increased risk. Handling the concentrate for treating cattle pests was associated with an increase risk of screen identified Parkinsonism and there were elevated but non significant risks of screen identified neuropathy and dementia. Warble fly treatment (an activity which may have resulted in OP exposure) was not associated with any ill health.

4.13 Associations between seeking medical advice for pesticide poisoning and farming The demographic and farming variables of those farmers who self-reported seeking medical advice for pesticide poisoning and controls are shown in Table 26. Those who sought medical advice were more likely to be retired (14.0% vs 3.0%) and had their livelihood more severely affected by BSE. There was also evidence that those who had sought medical advice were more likely to be current smokers but were less likely to drink alcohol more than 1 day per week.

Ever seeking medical advice for pesticide poisoning was not associated with working in any farming sector, though there was an elevated but non significant risk associated with working with sheep (OR adj , 95%CI = 2.54, 0.78-8.34; Table 27).

Ever seeking medical advice for pesticide poisoning was significantly associated with a number of farming activities (Table 28). Specifically risk was increased with shearing sheep (OR adj , 95%CI = 3.35,1.78-9.49), dipping sheep (OR adj , 95%CI = 8.63, 1.18-63.1) and with the use of other pesticides on the farm (OR adj , 95%CI = 3.44 , 1.62-7.29).

Ever seeking medical advice for pesticide poisoning was significantly associated with handling the concentrate for treating pests on sheep (OR adj, 95%CI =10.2, 1.39-74.8; Table 29). There was an elevated but non- significant increased risk associated with handling the concentrate for treating pests on cattle (OR adj , 95%CI = 6.64, 0.90-48.8).

Overall, an increased risk of ever seeking medical advice for pesticide poisoning was significantly associated with a number of aspects of sheep farming but particularly with sheep dipping and handling the sheep dip concentrate (Figure 7). In contrast, the risks associated with cattle farming activities were not significant, although the risk associated with handling the concentrate was elevated (Figure 7).

4.14 Associations between seeking medical advice for pesticide poisoning and screen identified ill-health Given the reported associations between pesticide poisoning and subsequent chronic ill-health, the associations between seeking medical advice for pesticide poisoning and screen identified ill-health were examined (Table 30).

Seeking medical advice for pesticide poisoning was significantly associated with all screen identified ill-health, notably depression (OR adj , 95%CI = 6.89,

3.48-13.6), dementia (OR adj , 95%CI = 6.26, 3.24-12.1), neuropathy (OR adj ,

95%CI = 4.94, 2.53-9.64) and Parkinsonism (OR adj , 95%CI = 5.26, 2.64-10.5).

4.15 Risk of screen identified ill-health and farming factors in a population restricted to those who had not sought medical advice for pesticide poisoning. Given the increased risk of screen identified ill health in those who had sought medical advice for pesticide poisoning, those associations between screen identified ill health and farming factors were re-examined in a population restricted to those who had not sought medical advice for pesticide poisoning, by excluding those who had sought medical advice and those who did not know the answer to the question (Table 31).

In this restricted population, a number of previously significant associations were found to be no longer significant. The risks associated with handling the concentrate for treatment of pests on sheep remained elevated but non- significant for both neuropathy (OR adj , 95%CI = 1.44, 0.89-2.34) and

Parkinsonism (OR adj , 95%CI 1.41, 0.86-2.32). Similarly, the risk associated with handling the concentrate for the treatment of pests on cattle remained elevated and was of borderline significance for Parkinsonism (OR adj , 95%CI = 1.78, 0.97-3.29). The association between handling the concentrate (non- arable, non-sheep and non-cattle concentrate) and neuropathy remained significant (OR adj , 95%CI 1.81, 1.04-3.17).

A number of associations between screen identified dementia and farming sectors, activities and concentrate handling remained elevated and significant even after exclusion of those farmers who had sought medical advice for pesticide poisoning (Table 31); specifically these risk factors included working with other livestock (OR adj , 95%CI = 1.80, 1.22-2.67), other non farming work

(OR adj , 95%CI = 1.51, 1.00-2.29), livestock slaughtering (OR adj , 95%CI =

1.92, 1.28-2.89), the use of other pesticides on farm (OR adj , 95%CI = 1.78, 1.18-2.70) and the handling of other (non-sheep/non-cattle/non-arable) concentrate for treating pests (OR adj, 95%CI = 2.35, 1.31-4.22).

5.0 Discussion

The present study was designed to investigate whether chronic low-dose OP exposure resulted in any adverse neuropsychiatric disease in farming populations, and sheep farmers in particular. One of the a priori hypotheses of this study was that if OP exposure were a cause, then any adverse ill-health would be associated with handling the sheep dip concentrate as this activity has been reported to be the main determinant of OP exposure 5. However if such an increased risk were found, this does not necessarily implicate specifically chronic low-dose exposure (rather than high dose exposure) as it is known that there are long-term sequelae of acute OP poisoning. However, if the association between OP exposure and adverse ill-health were still to be found, after the exclusion of those who had been acutely poisoned, then this would provide evidence that chronic low dose OP exposure had cause ill- health in the population studied.

The risk of screen identified depression, dementia, neuropathy or Parkinsonism was not significantly increased in those farmers who worked with sheep nor with any farming activity associated with working with sheep such as shearing sheep, dipping sheep or carrying out lambing. The handling of concentrate for the treatment of pests on sheep was however significantly associated with screen identified neuropathy and with screen identified Parkinsonism but not with screen identified depression or dementia. This is of particular interest as it confirms the a priori hypothesis that as handling the concentrate is a major determinant of exposure 5 it would be the exposure variable most likely to be associated with self-reported ill-health. To exclude acute OP poisoning as a cause, the associations between the screen- identified health outcomes and ever sought advice for pesticide poisoning (used as a surrogate for pesticide poisoning) were examined. Risk of seeking advice for pesticide poisoning was not increased in those farmers working with sheep but was increased in those farmers who had sheared sheep, dipped sheep or handled the sheep dip concentrate. Furthermore, ever seeking advice for pesticide poisoning was strongly associated with screen- identified depression, dementia, neuropathy and Parkinsonism. Whilst these

associations may reflect a causative relationship between a high dose exposure and subsequent ill-health it may also simply reflect a recall bias. Whatever the cause, these strong associations may have confounded the observed associations between handling the sheep dip concentrate and screen identified ill-health. Initial analyses were then repeated after excluding those subjects who had reported seeking medical advice for pesticide poisoning. In this re-analysis, handling sheep dip concentrate was associated with an elevated but non-significant risk of neuropathy and Parkinsonism.

Results are thus consistent with the a priori hypothesis that OP exposure ( via the handling of sheep dip concentrate) was associated with self-reported ill- health (namely screen identified neuropathy and Parkinsonism). The exclusion of subjects who had sought medical advice for pesticide poisoning resulted in the risks associated with handling the sheep dip concentrate remaining elevated, but not significantly so. Whilst it is possible that there is differential recall of handling concentrate due to the different perceptions of cases and controls, the farmers in this study would be unaware of the methods used to categorise the population into cases and controls. Hence this would suggest that elevated risk associated with handling the concentrate may then have arisen from an acute high dose exposure rather than chronic low dose exposure, particularly if some subjects had an unrecognised past history of acute poisoning.

In addition to the specific focus of screen identified ill-health and sheep farming activities, analysis of phase 1 data has further identified significant associations between screen identified ill-health and other farming activities. Risks associated with other non sheep farming activities should be interpreted with a degree of caution due to the lack of a priori hypotheses and the potential of false positive associations. Screen identified dementia was associated with seven work related factors, neuropathy three, depression two and Parkinsonism with only one factor. In particular, handling the concentrate for the treatment of pests on arable crops was not associated with screen- identified ill health whereas handling the concentrate for the treatment of pests on cattle was associated with an elevated risk of screen identified

Parkinsonism. Handling the concentrate for the treatment of pests (other than those on sheep, cattle or arable crops) was associated with screen identified dementia and neuropathy. As the associations with screen identified dementia were still elevated and significant after exclusion of those farmers who had sought medical advice for pesticide poisoning, these associations may then merit further study.

5.1 Strengths and weaknesses of the phase 1 study As noted by the Committee on Toxicity of Chemicals in Food, Consumer Products and the Environment 2, published epidemiological studies that have examined associations between chronic ill-health and OP exposure have had a number of limitations, including 1. participation bias in that subjects who suspected they were suffering ill- health as a result of exposure to OPs were more likely to take part 2. small sample size resulting in low power 3. the exclusion of those individuals too ill to continue working as studies focussed on those individuals currently or recently exposed to OPs 4. insufficient adjustment of potential confounding factors which could account for differences between exposed and unexposed groups 5. the possible inclusion of those with an unrecognised past history of acute poisoning.

To address, in particular problems (1), (2) and (3), the SHAW study was designed as a large historically prospective cohort study of farmers who could be identified as working (or not working) with sheep in the 1970s. A large, cohort, containing almost 19,000 farmers, was identified through a number of different sources and by tracing these farmers to the present day, irrespective of ill-health or exposure status, then those 1970 farmers who were no longer working due to ill-health would still be included in the study. Furthermore, the risks associated with participation bias would potentially be minimised. To be included in the cohort, the subject had to have been a farmer in 1970. In the 1970s, the use of organochlorines in sheep dips was declining whilst that of OPs was increasing. Hence, the potential confounding effects of organochlorine exposure was limited by this inclusion criteria.

In the phase 1 study information about pesticide poisoning (in terms of “ever seeking medical advice for pesticide poisoning”) was also collected to address problem (5). These subjects who had reported seeking medical advice and hence may have suffered from acute poisoning could then be excluded from the analysis and changes in the risk estimates assessed. Information on confounding exposures, problem (4), collected in phase 1 of this study was rather more limited and restricted to variables which were easily collected in a self-completed questionnaire such age, sex, age left school, smoking and whether the farm had been affected by BSE or FMD. More detailed information on confounders has been collected in the phase 2 study.

There are some limitations to the study that are worthy of further discussion. It had been anticipated that there was an electronic database of farmers who were NFU members in the 1970s. Unfortunately, it was found that this database consisted only of current NFU members and hence the use of this database would have resulted in a study of those farmers currently or recently exposed to OPs and would have excluded those farmers who been too ill to continue working (perhaps as a result of exposure to OPs) and had retired from the NFU. To avoid this healthy worker bias, contemporaneous records that would identify farmers from the 1970s were sought. These records were identified from a number of different sources including paper records held by local NFU offices, Sheep and Cattle Associations and Shepherd’s Guides. Whilst these records provided an invaluable source of names and addresses the quality of information was limited in two particular areas. Firstly, the address was of that location where the cohort member lived in the 1970s. Given the continuing loss of farms over this period and the potential for population movement, there was the possibility that either the address was no longer in existence or that the farmer had moved. This would then directly impact on the response rate. Secondly, there was no information as to the age of the farmer from these sources and hence it was not possible to predict the proportion of farmers who would have died over the thirty year follow up period of the study. This lack of information contributed to both the high proportion of the study cohort who were known to have died and also to the

high proportion of those farmers who had moved away from the address in the study database. In addition, there was also a high rate of non-response due to unknown reasons ( i.e. not known to have died or moved away). Upon trying to contact a proportion of these non-responders by telephone, both death and the subject having moved away was found to contribute significantly to non-response.

Using the study cohort as a denominator the response rate ( i.e. receiving completed questionnaires) was ~18% but if the denominator was taken as those cohort members known to have received the questionnaire the response rate was 48%. Whilst the first estimate is likely to underestimate the response rate, the second is likely to be an overestimate. Available evidence (from telephone calls to non-responders: Appendix 27) suggests that a significant proportion of non-responders (for which no cause could be attributed such as death or moving away) may still have died or have moved away, but it was beyond the scope of this work to be able to trace further these non-responders.

The response rate amongst farming communities to epidemiological studies (either via postal questionnaire or by telephone interviews) can be quite low in comparison to studies in other populations. In a number of studies over the past decade or so the response rate amongst farmers using current addresses and phone numbers ranged from 19 to 98 % 17-26 (Appendix 33). The highest response being obtained from members of OP support groups using the telephone 7 but the same study also reported the lowest response rate (19%) when contact was made by letter. Given that the SHAW study used addresses from the 1970s (and it was found that a considerable proportion of the cohort were no longer at this address), the response rate for the SHAW study is thus broadly consistent with these other studies.

This low response rate can be ascribed to a number of reasons including the pressure of work, the perceived burden of forms to complete from both the Government and scientific researchers, and disillusionment with progress in the understanding of concerns of certain sections of the farming community

regarding ill-health. In addition some farmers are sceptical about whether research funded by certain organisations can be objective. Such considerations may well impact upon the generalisability of the study as the decision to participate may depend upon whether the farmer is ill or not and if ill whether their ascribe their ill-health to OP exposure. Hence it is possible that there may be a participation bias in that subjects who suspected they were suffering ill-health as a result of exposure to OPs may have been more likely to take part. However, it should be noted that the case definitions used for this study, though derived from self-report, were not self-evident and hence no individual farmer could know whether they would or would not be a case.

5.1.1 Screen identified ill health Ill-effects arising from chronic exposure to low-levels of OPs are poorly defined, particularly in the absence of any acute poisoning 2. Indeed there is no single syndrome, or agreed mechanism, associated with chronic effects. Acute nervous system effects of organophosphate (OP) poisoning are well characterised and may include 1) immediate cholinergic symptoms and signs with CNS involvement, muscle fasciculation and paralysis 2) an 'intermediate syndrome' occurring 24-96 hours after poisoning, with paralysis of distal limb and respiratory muscles and 3) a sensory motor axonopathy, occurring 7-14 days after exposure 2. Long-sequelae, such as neuropsychological abnormalities, following acute poisoning have been reported. Follow up studies of workers with known episodes of poisoning suggest that they do less well than referents in neurobehavioural tests of memory, coordination and speed of coding, and that minor neurophysiological changes may be present 27-29. There is less evidence, at present, to indicate any ill-effects following prolonged exposure to low-levels of OPs i.e. at levels that do not produce any overt toxicity. Higher exposures in sheep farmers have been associated with decreased speed on a test of reasoning 17 and reported neurological symptoms associated with the extent of handling concentrate 30,31 . Less clearly defined neuropsychiatric symptoms, such as numbness, incoordination, depression, problems with memory, are often reported by sheep farmers 1,2,7 and may form the majority of cases attributed by patients to OP exposure.

Relatively crude screening techniques were used to identify ill-health amongst this population. This is a standard procedure amongst population studies and further work, currently ongoing, will ascertain the specificity and sensitivity of the tools used to identify ill-health. It should be stressed then that the people identified in this study do not necessarily have depression, dementia, neuropathy or Parkinsonism diagnosable by clinical standards but have self- reported signs/symptoms that are consistent with such ill-health. A widely used instrument was used to define screen identified depression 9 but when the study was in the planning stages there appeared to be no such screening instruments for dementia, Parkinsonism, or neuropathy. Hence, instruments derived from the literature or from clinical practice were developed. It is possible that by using different definitions of ill-health, other associations with work-related factors may be identified.

5.1.2 Exposure assessment The focus of the present proposal was on chronic effects of low dose OP exposure. No biological measure is currently available as a marker of past or cumulative exposure to OPs so that if chronic effects were to be attributed to past exposure, then this has to be estimated in this study from self-reported exposure histories. Self-report then depends upon recall which is potentially subject to considerable error. Furthermore, associations between exposure duration and health outcome will be subject to error due to the lack of information regarding the incidence of ill-health (i.e. when the problem started).

In this analysis handling the sheep dip concentrate has been used a surrogate of cumulative exposure as it has been reported that sheep dip concentrate handling is the major determinant of OP exposure 5. However, this may result in error as both OP and non-OP products were used during the thirty year time period covered by the study. Furthermore, the use of OPs is not restricted to those farmers who work with sheep as OPs have been widely used in other sectors of the farming community ( e.g. for the treatment of warble fly on cattle). Hence it is possible that there may have been some

exposure misclassification. More detailed analysis of the type of products used and other potential determinants of exposure is also ongoing. While it seems biological plausible that increased exposure (duration and/or concentration) would be associated with increased risk of effect, the existence of a 'special sensitivity' to OPs has been advanced to account for cases with rather little documented exposure.

There remains the difficulty in identifying low dose exposure in the absence of any quantitative data. Defining low dose exposures as insufficient to cause overt acute toxicity results in a practical definition, which can be of use provided that these cases are readily identifiable. In the absence of any definitive data (such as that might be obtained from medical records), seeking medical advice for pesticide poisoning has been taken as a surrogate measure of acute poisoning. Acute pesticide poisoning is rare (3 deaths in England and Wales in 11 years 32 . The incidence of non-fatal poisoning is less well defined. Whilst it is possible that some farmers have had an unrecognised past history of acute poisoning, farmers are often perceived as stoic and do not often visit their GP or other service providers. Hence while seeking medical advice may be a good indicator of more serious acute pesticide poisoning, it might not be so good for a lesser degree of acute poisoning.

5.2 SHAW study phases and SHAW study objectives The first phase of the SHAW study has addressed the primary objectives of to determine whether there is an excess of disease in those farmers exposed to OPs (and sheep dip in particular) and to estimate the excess when subjects with a history of acute poisoning are excluded. The second phase of the SHAW study specifically addresses objective 4 (to determine whether diagnosed cases of dementia, Parkinson’s disease, neurological disease or depression differ in their exposure to organophosphates than randomly selected cohort members) but further information has also been collected to address objective 1 (to determine the cumulative incidence of dementia, adult onset neurological disease and clinical depression in farmers). Cohort members screen identified as a case and a random sample of other cohort

members have been recruited to this second phase and have undergone a structured interview with a study nurse using an occupational and exposure questionnaire, a general health questionnaire followed by one or more of health specific questionnaires. Further detailed information has been collected on their health status (i.e. whether they were a case or not), their working and exposure history) and confounders.

Health specific questionnaires were also used to obtain more detailed information on the participants’ current health. In particular, the Clinical Interview Schedule 32 , CAMCOG 33 , the activities of daily living scale 34,35 and a neuropathy questionnaire 31 were used. If appropriate, a physical examination was also undertaken so as assess symptoms associated with both neuropathy and Parkinson’s disease 34,35 . This further interview was designed to ascertain whether the screen identified case is a true case or not and hence will determine the sensitivity and specificity of the screening procedures undertaken in the phase 1 study reported here.

A detailed occupational and exposure history was taken based upon the life events approach which has been used previously to obtain material from farmers 36. In this approach, key life events in the participants’ history are identified which are then used to anchor the subsequent occupational histories. In addition, the CAMCOG instrument 33 can allow for an assessment of memory. The questionnaire focussed on activities which are potential determinants of exposure such as the method of pesticide application, the handling of concentrates, use of personal protective equipment as well as the type of products used . A detailed exposure algorithm to assess the probability of exposure to certain pesticides will be developed. Existing exposure models from previously published studies such as for sheep dipping 6,25 and for pesticide spraying 37, 38 will also be evaluated. If necessary the models will be adapted or new algorithms will be developed based on knowledge of exposure determinants and reported exposure levels. The developed algorithm will be validated by comparison with expert judgement and when possible by direct measurement of biomarkers in exposed populations. Risk of developing ill-health as a result of OP exposure will then be determined

using standard statistical techniques. Various exposure metrics will be used in the analyses, such as highest and average intensity and cumulative exposure.

5.3 Summary In summary, to address problems associated with epidemiological studies of OP exposure previously identified 2, a large historically prospective cohort study of farmers from the 1970s has been carried out. In the first stage of the study, relatively crude measures of ill-health and exposure were used and indicated that there was evidence that handling pesticide concentrate for the treatment of sheep (and cattle), the main determinant of OP exposure during sheep dipping was associated with screen identified ill-health, notably neuropathy and Parkinsonism, possibly as a result of unrecognised acute rather than chronic exposures. Other associations between farming activities and ill-health have been identified which merit further study. Further more detailed analysis in Phase 2 will provide additional information on the associations between OP exposure and ill-health.

6.0 Acknowledgements

This study was funded by the Department of Health and the Department of Environment, Food and Rural Affairs.

Firstly, we would like to thank all the farmers and the other respondents who provided information for the study. None of this work could have been accomplished without their participation. We would also like to thank the farmers who took part in the initial focus groups for their advice.

The research reported here was carried out with the help of a team of research co-ordinators and clerical staff. In particular we would like to thank Gillian Watkins and Jill Stocks for their help in co-ordinating and analysing the study and Priscilla Appelbe, Joanna Pope, Jude Seath and Dominic Kelly for their clerical assistance. We would also like to express gratitude to Dr Gary

Burgess and Dr Martie van Tongeren for their advice on exposure assessment and Dr David Gow for his clinical advice on neuropathy.

Finally, this work would also not have been possible without the support of various other individuals and organisations for their assistance in developing the cohort. These included the National Farmers’ Union, (particularly Roger Ward, and John Raine and numerous individuals at the group and regional offices), the National Farmers’ Union (Wales), the Farmers’ Union of Wales and the National Sheep Association (particularly John Thorley).

7.0 References

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24. Thomas HV, Lewis G, Thomas DR, Salmon RL, Chalmers RM, Coleman TJ, Kench SM, Morgan-Capner P, Meadows D, Sillis M, Softley P. Mental health of British farmers. Occup Environ Med 2003; 60: 181-186. 25. Tahmaz N, Soutar A, Cherrie JW. Chronic fatigue and organophosphate pesticides in sheep farming: a retrospective study amongst people reporting to a UK pharmacovigilance scheme. Ann Occup Hyg 2003; 47:261-267. 26. Stephens R, Sreenivasan B. Neuropyscholgical effects of long-term low- level organophosphate exposure in orchard sprayers in England. Arch.. Environ Health 2004;59:566-574 27. Savage EP, Keefe TJ, Mounce LM, Heaton RK, Lewis JA, Burcar PJ. Chronic neurological sequelae of acute organophosphate pesticide poisoning. Arch Environ Health 1988 ;43: 38-45. 28. Rosenstock L, Keifer M and Daniell WE, McConnell R, Claypoole K, The Pesticide Health Effects Study Group. Chronic central nervous system effects of acute organophosphate pesticide intoxication. Lancet, 1991; 338: 223-227. 29. Steenland K, Jenkins B, Ames RG, O'Malley M, Chrislip D, Russo J. Chronic neurological sequelae to organophosphate pesticide poisoning. Am J Public Health, 1994; 84: 731-736. 30. Stephens R, Spurgeon A, Calvert IA, Beach J, Levy LS, Berry H, Harrington JM. Neuropsychological effects of long-term exposure to organophosphates in sheep dip. Lancet, 1995;345: 1135-1139. 31. Pilkington A, Buchanan D, Jamal GA, Kidd M, Sewell C, Donnan P, Hansen S, Tannahill SN, Robertson A, Hurley JF, Soutar CA. Epidemiological study of the relationships between exposure to organophosphate pesticides and indices of chronic peripheral neuropathy, and neuropsychological abnormalities in sheep farmers and dippers. Phase 2. Cross-sectional exposure-response study of sheep dippers. Report No. TM/99/02b, 1999. Institute of Occupational Medicine. 32. Coggon D. Work with pesticides and sheep dips. Occup Med 2002; 52:467-470.

33. Goldberg DP, Cooper B, Eastwood MR, Kedward HB, Shepherd M. A standardized psychiatric interview for use in community surveys. Brit J Prevent Social Med 1970; 24: 18-23 . 34. Roth M, Huppert FA, Mountjoy CQ, Tym E. Camdex-R. The Cambridge examination for mental disorders of the elderly – revised. Cambridge University Press, Cambridge, 2006. 35. Fahn S, Elton RL, and members of the UPDRS Development committee. Unified Parkinson’s Disease rating scale. In Recent Developments in Parkinson’s disease vol II. Florham Park, NJ: Macmillan Healthcare Information, 1987, 153-163. 36. Engel LS, Checkoway H, Keifer MC, Seixas NS, Longstreth JR, W T. Scott KC, Hudnell K, Anger WK, Camicioli, R. Parkinsonism and occupational exposure to pesticides. Occup Environ Med 2001;58:582- 589. 37. Hoppin JA, Tolbert PE, Flagg EW, Blair A, Zahm SH. Use of a life events calender approach to elicit occupational history from farmers. Am J Ind Med 1998; 34: 470-476. 38. Dosemeci M, Alavanja MCR, Rowland AS, Mage D, Zahm SH, Rothman N, Lubin JH, Hoppin JA, Sandler DP, Blair A. A quantitative approach for estimating exposure to pesticides in the agricultural health study. Annals Occup Hyg 2002; 46: 245-260 39. Hamey PY. An example to illustrate the potential use of probabilistic modelling to estimate operator exposure to pesticides. Annals Occup Hyg 2001; 45: S55-S64.

TABLE 1 Response rates in study population by source of information

Source Outcome All NFU ledger Sheep Shepherds Cattle Association Guides Association Responders 7691 (40.6) 2501 (39.8) 1773 (45.4) 595 (33.5) 2822 (40.3) Non-responders 11267 (59.4) 3777 (60.2) 2134 (54.6) 1179 (66.5) 4177 (59.7) Total number of subjects 18958 (100.0) 6278 (100.0) 3907 (100.0) 1774 (100.0) 6999 (100.0)

Screening questionnaire 1380 (17.9) 507 (20.3) 313 (17.7) 79 (13.3) 481 (17.0) Telephone questionnaire 368 (4.8) 111 (4.4) 87 (4.9) 64 (10.8) 106 (3.8) Deceased 4635 (60.3) 1451 (58.0) 1066 (60.1) 373 (62.7) 1745 (61.8) Responders Refusal 1102 (14.3) 378 (15.1) 263 (14.8) 60 (10.1) 401 (14.3) Ineligible 206 (2.7) 54 (2.2) 44 (2.5) 19 (3.2) 89 (3.2) Total Number of subjects 7691 (100.0) 2501 (100.0) 1773 (100.0) 595 (100.0) 2822 (100.0)

Moved away 5870 (51.4) 1906 (50.5) 1264 (59.2) 381 (32.3) 2319 (55.5) Non-responders Unknown 5397 (48.6) 1871 (49.5) 870 (40.8) 798 (67.7) 1858 (44.5) Total Number of subjects 11267 (100.0) 3777 (100.0) 2173 (100.0) 1216 (100.0) 4187 (100.0)

TABLE 2 Response rates in study population by geographical region

England Outcome South South Midlands North North Wales Scotland West East /East Anglia West Responders 1131 (43.3) 874 (43.2) 1042 (47.8) 223 (46.0) 2611 (35.8) 578 (31.5) 1232 (48.6) Non responders 1480 (56.7) 1148 (56.8) 1139 (52.2) 262 (54.0) 4679 (64.2) 1258 (68.5) 1301 (51.4) Total number of subjects 2611 (100) 2022 (100) 2181 (100) 485 (100) 7290 (100) 1836 (100) 2533 (100)

Screening 192 (17.0) 122 (14.0) 168 (16.1) 46 (20.6) 504 (19.3) 106 (18.3) 242 (19.6) questionnaire Telephone 53 (4.7) 35 (4.0) 59 (5.7) 23 (10.3) 146 (5.6) 0 (0.0) 52 (4.2) questionnaire Responders Deceased 674 (59.6) 611 (69.9) 634 (60.8) 111 (49.8) 1523 (58.3) 402 (69.6) 680 (55.2) Refusal 181 (16.0) 84 (9.6) 148 (14.2) 33 (14.8) 381 (14.6) 62 (10.7) 213 (17.3) Ineligible 31 (2.7) 22 (2.5) 33 (3.2) 10 (4.5) 57 (2.2) 8 (1.4) 45 (3.7) Total number 1131 (100) 874 (100) 1042 (100) 223 (100) 2611 (100) 578 (100) 1232 (100)

Moved away 975 (65.9) 751 (65.4) 739 (64.9) 176 (67.2) 1959 (41.9) 400 (31.8) 870 (66.9) Non- Unknown 505 (34.1) 397 (34.6) 400 (35.1) 86 (32.8) 2720 (58.1) 858 (68.2) 431 (33.1) responders Total number 1480 (100) 1154 (100) 1140 (100) 262 (100) 4679 (100) 1258 (100) 1301 (100)

TABLE 3 Demographics and farming variables of study population

Variable Definition N Value Sex Male/female (% male) 1338 1271/67 (95.0) Age Mean (± SD) 1338 69.6±9.7 Scotland (%) 235 (17.6) North/North West (%) 529 (47.2) Midlands/East Anglia (%) 165 (12.3) Region 1338 Wales (%) 103 (7.7) South West (%) 186 (13.9) South East (%) 120 (9.0) Ever /Never (% ever) 1298 497/801 (37.1) Smoker Current /Non-smoker (%current) 496 78/418 (15.7) Drinker Number of days per week, >1/<1 (%>1) 1324 698/626 (52.2) Schooling Leaving age <16/>16 (%<16) 1319 948/371 (70.9) Currently/Retired/ Not working due to ill health (% ill-health) 1140 727/546/48 (3.6) Working On family farm/other (% family farm) 1127 925/202 (69.1) Affected farm: yes/no (%yes) 1269 382/887 (28.6) BSE Affected livelihood slightly/moderately/severely (% severely) 365 203/79/83 (22.7) Affected farm:yes/no (% yes) 1300 632/668 (47.2) FMD a Affected livelihood: slightly/ moderately/severely (% severely) 617 118/192/307 (49.8)

a FMD = foot and mouth in 2001

TABLE 4 Farming sector worked by study population

Sector Ever/never (%) Length a Yes No Mean±SD Median Sheep 1116 (83.4) 222 (16.6) 40.3±15.4 44.0 Cattle 1269 (94.8) 69 (5.2) 40.9±16.1 45.0 Other livestock 464 (34.7) 874 (65.3) 27.6±16.4 26.0 Combinable crops 717 (53.6) 621 (46.4) 39.4±14.8 43.0 Glasshouse production 34 (2.5) 1304 (97.5) 26.2±16.7 28.0 Outdoor Vegetables or 346 (25.9) 992 (74.1) 28.8±16.7 30.0 potatoes Top & soft fruit 54 (4.0) 1284 (96.0) 21.3±17.8 15.5 Other work 349 (26.1) 989 (73.9) 26.5±17.0 26

a if ever worked in the sector

TABLE 5 Farming activities carried out by study population

Activity Self-reported activity N Yes No Applied insecticides (arable) 1291 837 (64.8) 454 (35.2) Treated or fumigated grain 1274 485 (38.1) 789 (61.9) Applied other chemicals to crops 1280 849 (66.3) 431 (33.7) Other work with pesticides 1259 660 (52.4) 599 (47.6) Used pesticides in any job 1233 159 (12.9) 1074 (87.1) Used fertilisers 1311 1223 (93.3) 88 (6.7) Carried out lambing/calving 1317 1232 (93.6) 85 (6.5) Slaughtered livestock 1265 408 (32.3) 857 (67.8) Sheared sheep 1304 969 (74.3) 335 (25.7) Dipped sheep 1313 1087 (82.8) 226 (17.2) Been involved in worming 1318 1221 (92.6) 97 (7.4) Carried out teat disinfection 1291 931 (72.1) 360 (27.9) Applied treatment warble fly 1320 1164 (88.2) 156 (11.8)

TABLE 6 Handling of different types of concentrate by study population

Type of Self-reported handling of concentrate Concentrate n Yes (%) No (%) Sheep 1267 1009 (79.6) 258 (20.4) Cattle 1281 1098 (85.7) 183 (14.3) Arable 1144 590 (51.6) 554 (48.4) Other 712 146 (20.5) 566 (79.5)

TABLE 7 Current medical problems in study population

During the last 4 weeks , how much have you been bothered by any of the following problems? Problem Not Bothered Bothered n bothered a little a lot Stomach pain 1242 1074 (86.5) 151 (12.2) 17 (1.4) Back pain 1270 682 (53.7) 432 (34.0) 156 (12.3) Pain in your arms, legs, or joints (knees, hips,) 1275 441 (34.6) 540 (42.4) 294 (23.1) Menstrual cramps or problems with periods 61 60 (98.4) 0 (0.0) 1 (1.6) Pain or problems during sexual intercourse 1166 1098 (94.2) 40 (3.4) 28 (2.4) Headaches 1250 1023 (81.8) 198 (15.8) 29 (2.3) Chest pain 1252 1113 (88.9) 119 (9.5) 20 (1.6) Dizziness 1251 1068 (85.4) 161 (12.9) 22 (1.8) Fainting spells 1242 1209 (97.3) 29 (1.8) 4 (0.3) Racing or pounding heart 1247 1053 (84.4) 169 (13.6) 25 (2.0) Shortness of breath 1269 842 (66.4) 336 (26.5) 91 (7.2) Constipation, loose bowels or diarrhoea 1260 1007 (79.9) 217 (17.2) 36 (2.9) Nausea, gas or indigestion 1256 928 (73.9) 278 (22.1) 50 (4.0) Excessive sweating 1254 1109 (88.4) 112 (8.9) 33 (2.6)

a 38 women said not applicable

TABLE 8 Seeking medical advice in the study population

Ever sought medical advice for this Problem problem n No Yes Allergy e.g. hay fever, 1285 1042 (79.2) 243 (18.9) eczema, dermatitis Alzheimer’s disease 1282 1274 (99.4) 8 (0.6) Asbestos-related disease 1276 1270 (99.5) 6 (0.5) Asthma 1283 1135 (88.5) 148 (11.5) Brucellosis 1277 1212 (94.9) 65 (5.1) Cancer 1280 1171 (91.5) 109 (8.5) Chronic bronchitis or 1277 1196 (93.7) 81 (6.3) emphysema Dementia 1272 1264 (99.4) 8 (0.6) Depressive illness 1278 1186 (92.8) 92 (7.2) Diabetes 1282 1183 (92.3) 99 (7.7) Farmer’s Lung 1272 1166 (91.7) 106 (8.3) Heart disease including 1289 1020 (79.1) 269 (20.9) angina High blood pressure 1289 913 (70.8) 376 (29.2) Kidney disease 1277 1242 (97.3) 35 (2.7) Liver disease 1276 1260 (98.8) 16 (1.3) ME/chronic fatigue 1268 1257 (99.1) 11 (0.9) syndrome Motor neurone disease 1277 1270 (99.5) 7 (0.6) Multiple sclerosis 1278 1274 (99.7) 4 (0.3) Parkinson’s Disease 1278 1260 (98.6) 18 (1.4) Pesticide poisoning 1264 1221 (96.6) 43 (3.4) Seizures or epilepsy 1279 1262 (98.7) 17 (1.3) Stroke 1281 1214 (94.8) 67 (5.2) Tuberculosis 1276 1264 (99.1) 12 (0.9)

TABLE 9 Current Medical Treatment in study population

During the last four weeks, have you had any tablets or any Problem other treatment for the following n No Yes Anxiety 1280 1253 (97.9) 27 (2.1) Asthma 1284 1184 (92.2) 100 (7.8) Depression 1281 1241 (96.9) 40 (3.1) Diabetes 1284 1213 (94.5) 71 (5.5) Heart disease 1299 1069 (82.3) 230 (17.7) including angina High blood pressure 1293 966 (74.7) 327 (25.3) Parkinson’s disease 1277 1258 (98.5) 19 (1.5) Stress 1281 1250 (97.6) 31 (2.4)

TABLE 10 Demographics and farming variables by case status of screen identified depression a

Screen identified status p Variable Definition Case Control Sex Male/female (% male) 105/6 (94.6) 1166/61 (95.0) 1.0 Age Mean (± SD) 70.3±11.2 69.5±9.5 0.40 Scotland 12 (10.8) 223 (18.2) North/North West 47 (42.3) 482 (39.3) Midlands/East Anglia 15 (3.5) 150 (12.2) Region 0.03 Wales 14 (12.6) 89 (7.3) South West 9 (8.1) 177 (14.4) South East 12 (12.6) 106 (8.6) Ever /Never (% ever) 48/60 (44.4) 449/741 (37.7) 0.20 Smoker Current /Non-smoker (%current) 10/38 (20.8) 68/380 (15.2) 0.42 Drinker Number of days per week, >1/<1 (%>1) 39/72 (35.1) 659/554 (54.3) <0.001 Schooling Leaving age <16/>16 (%<16) 79/30 (72.5) 869/341 (71.8) 0.97 Currently/Retired/ Not working due to ill health (% ill-health) 47/44/19 (17.3) 680/502/29 (2.4) <0.001 Working On family farm/other (% family farm) 77/24 (76.2) 848/178 (82.7) 0.14 Affected farm: yes/no (%yes) 33/70 (32.0) 349/817 (29.9) 0.74 BSE Affected livelihood slightly/moderately/severely (% severely) 17/6/10 (30.3) 186/73/73 (22.0) 0.54 FMD affected farm:yes/no (% yes) 56/51 (52.3) 576/671 (48.3) 0.48 FMD b FMD affected livelihood: slightly/ moderately/severely (% severely) 12/9/33 (61.1) 106/183/274 (48.7) 0.06

a As identified through published algorithm (section 2.5.1) bFMD = foot and mouth in 2001

TABLE 11 Risk of screen identified depression by farming sector a

Ever worked/Never worked (% ever) OR (95%CI) Sector Case Control Unadjusted Adjusted b Cattle 105/6 (94.6) 1164/63 (94.9) 0.95 (0.40-2.24) 0.97(0.37-2.58) Crops 59/52 (53.2) 658/569 (53.6) 0.98 (0.67-1.45) 1.02 (0.66-1.56) Fruit 7/104 (6.3) 47/1180 (3.8) 1.69 (0.75-3.83) 1.55 (0.62-3.83) Glasshouse 5/106 (4.5) 29/1198 (2.4) 1.95 (0.75-5.14) 1.81 (0.64-5.14) Other livestock 47/64 (42.3) 417/810 (34.0) 1.43 (0.96-2.12) 1.36 (0.88-2.09) Other work 34/77 (30.6) 315/912 (25.7) 1.28 (0.84-1.95) 1.38 (0.88-2.18) Sheep 93/18 (83.8) 1023/204 (83.4) 1.03 (0.61-1.74) 1.04 (0.58-1.86) Vegetables 22/89 (19.8) 324/903 (26.4) 0.69 (0.43-1.12) 0.63 (0.38-1.07)

a As identified through published algorithm (section 2.5.1) b For age,sex, age left school, employment status and whether FMD or BSE affected farm

TABLE 12 a Risk of screen identified depression by farming activity

Ever done/Never done (% ever) OR (95%CI) Activity Case Control Unadjusted Adjusted b Applied Insecticides 66/42 (61.1) 771/412 (65.2) 0.84 (0.56-1.26) 0.77 (0.49-1.20) Treated Grain 36/70 (34.0) 449/719 (38.4) 0.82 (0.54-1.25) 0.80 (0.51-1.27) Applied Other Chemicals 67/39 (63.2) 782/392 (66.6) 0.86 (0.57-1.30) 0.82 (0.52-1.30) Other Pesticides on Farm 63/42 (60.0) 597/557 (51.7) 1.40 (0.93-2.10) 1.42 (0.91-2.22) Used Pesticides Other Job 12/89 (11.9) 147/985 (13.0) 0.90 (0.48-1.69) 0.99 (0.52-1.90) Used Fertilisers 95/13 (88.0) 1128/75 (93.8) 0.49 (0.26-0.91) 0.42 (0.20-0.88) Carried Out Lambing 99/12 (89.2) 1133/73 (94.0) 0.53 (0.28-1.01) 0.48 (0.23-0.99) Slaughtered Livestock 37/71 (34.3) 371/786 (32.1) 1.10 (0.73-1.67) 1.34 (0.85-2.09) Sheared Sheep 81/28 (74.3) 888/307 (74.3) 1.00 (0.64-1.57) 0.99 (0.60-1.66) Dipped Sheep 93/17 (84.6) 994/209 (82.9) 1.16 (0.67-1.97) 1.12 (0.62-2.04) Wormed Cattle 99/12 (89.2) 1122/85 (93.0) 0.63 (0.33-1.18) 0.60 (0.28-1.28) Disinfected Cattle 74/33 (69.2) 857/327 (72.4) 0.86 (0.56-1.32) 0.81 (0.50-1.31) Treated Warble Fly 97/14 (87.4) 1067 /142 (88.3) 0.92 (0.51-1.66) 0.90 (0.46-1.77)

a As identified through published algorithm (section 2.5.1) b For age, sex, age left school, employment status and whether FMD or BSE affected farm

TABLE 13 Risk of screen identified depression by concentrate handling a

Ever handled/never handled (% ever) OR (95%CI) Concentrate Case Control Unadjusted Adjusted b Arable 45/47 (48.9) 545 /507 (51.8) 0.84 (0.52-1.34) 0.89 (0.58-1.36) Sheep 89/18 (82.4) 920/239 (79.4) 1.16 (0.65-2.05) 1.22 (0.73-2.29) Cattle 96/13 (88.1) 1002 /170 (85.5) 1.31 (0.67-2.59) 1.25 (0.69-2.29) Other 17/44 (27.9) 129/522 (19.8) 1.25 (0.36-4.35) 1.56 (0.87-2.83)

a As identified through published algorithm (section 2.5.1) bFor age, sex, age left school, employment status and whether FMD or BSE affected farm

TABLE 14 Demographics and farming variables by case status of screen indentified dementia a

Screen identified status p Variable Definition Case Control Sex Male/female (% male) 140/8 (94.6) 1079/58 (94.9) 0.97 Age Mean (± SD) 71.1±10.6 69.4±9.6 0.05 Scotland 20 (13.5) 215 (18.1) North/North West 62 (41.9) 467 (39.2) Midlands/East Anglia 21 (14.2) 144 (12.1) Region 0.11 Wales 5 (3.4) 98 (8.2) South West 21 (14.2) 165 (13.9) South East 19 (12.8) 101 (8.5) Ever /Never (% ever) 72/73 (49.7) 425/728 (36.9) 0.004 Smoker Current /Non-smoker (%current) 8/64 (11.1) 70/324 (16.5) 0.32 Drinker Number of days per week, >1/<1 (%>1) 75/71 (51.4) 623/555 (52.9) 0.80 Schooling Leaving age <16/>16 (%<16) 100/45 (69.0) 848/326 (72.2) 0.47 Currently/Retired/ Not working due to ill health (% ill-health) 66/68/13 (8.8) 661/478/35 (3.0) 0.001 Working On family farm/other (% family farm) 94/36 (72.3) 831/166 (83.4) 0.003 Affected farm: yes/no (%yes) 47/93 (33.6) 335/794 (29.7) 0.40 BSE Affected livelihood slightly/moderately/severely (% severely) 21/9/16 (34.8) 182/70/67 (21.0) 0.11 FMD affected farm:yes/no (% yes) 74/71 (51.0) 558/597 (48.3) 0.60 FMD b FMD affected livelihood: slightly/ moderately/severely (% severely) 17/17/36 (51.4) 101/175/271 (49.5) 0.31

a As identified through published algorithm (section 2.5.2) b FMD = foot and mouth in 2001

TABLE 15 Risk of screen identified dementia by farming sector a

Ever worked/Never worked (% ever) OR (95%CI) Sector Case Control Unadjusted Adjusted b Cattle 135/13 (91.2) 1134/57 (95.3) 0.51 (0.27-0.96) 0.55 (0.28-1.06) Crops 73/75 (49.3) 644/546 (54.1) 0.83 (0.59-1.16) 0.81 (0.57-1.15) Fruit 6/142 (4.1) 46/1142 (4.0) 1.01 (0.42-2.39) 1.01 (0.42-2.40) Glasshouse 8/140 (5.4) 26/1164 (2.2) 2.56 (1.14-5.76) 2.44 (1.08-5.51) Other livestock 68/80 (46.0) 396/794 (33.3) 1.70 (1.21-2.41) 1.61 (1.13-2.29) Other work 50/98 (33.8) 299/891 (25.1) 1.52 (1.06-2.19) 1.50 (1.03-2.17) Sheep 116/32 (78.4) 1000/190 (84.0) 0.69 (0.45-1.05) 0.73 (0.48-1.14) Vegetables 31/117 (21.0) 315/875 (26.5) 0.74 (0.49-1.12) 0.70 (0.46-1.07)

a As identified through published algorithm (section 2.5.2) b Adjusted for age, sex and age left school

TABLE 16 Risk of screen identified dementia by farming activity a

Ever done/Never done (% ever) OR (95%CI) Activity Case Control Unadjusted Adjusted b Applied Insecticides 96/44 (68.6) 741/410 (64.4) 1.21 (0.83-1.76) 1.28 (0.87-1.89) Treated Grain 51/85 (37.5) 434/704 (38.1) 0.97 (0.67-1.41) 0.97 (0.67-1.42) Applied Other Chemicals 98/42 (70.0) 751/389 (65.9) 1.21 (0.83-1.77) 1.23 (0.83-1.83) Other Pesticides on Farm 93/47 (66.4) 567/552 (50.7) 1.93 (1.33-2.79) 2.10 (1.43-3.09) Used Pesticides Other Job 22/111 (16.5) 137/963 (12.5) 1.39 (0.85-2.28) 1.41 (0.86-2.33) Used Fertilisers 129/14 (90.2) 1094/74 (93.7) 0.62 (0.34-1.14) 0.67 (0.35-1.29) Carried Out Lambing 129/15 (89.6) 1103/70 (94.0) 0.55 (0.30-0.98) 0.64 (0.35-1.17) Slaughtered Livestock 64/75 (46.0) 344/782 (30.6) 1.94 (1.36-2.77) 1.94 (1.35-2.79) Sheared Sheep 107/34 (75.9) 862/301 (74.1) 1.10 (0.73-1.65) 1.33 (0.86-2.06) Dipped Sheep 115/29 (79.9) 972/197 (83.2) 0.80 (0.52-1.24) 0.92 (0.58-1.44) Wormed Cattle 131/14 (90.3) 1090/83 (92.9) 0.71 (0.39-1.29) 0.89 (0.47-1.69) Disinfected Cattle 101/39 (72.1) 830/321 (72.1) 1.00 (0.68-1.48) 1.04 (0.70-1.56) Treated Warble Fly 126/19 (86.9) 1038/137 (88.3) 0.88 (0.52-1.46) 1.01 (0.59-1.74)

a As identified through published algorithm (section 2.5.2) b For age, sex and age left school

TABLE 17 Risk of screen identified dementia by concentrate handling a

Ever handled/never handled (% ever) OR (95%CI) Concentrate Case Control Unadjusted Adjusted b Arable 64/56 (53.3) 526/498 (51.4) 1.08 (0.74-1.58) 1.12 (0.76-1.66) Cattle 125/15 (89.3) 973/168 (85.3) 1.44 (0.82-2.52) 1.69 (0.94-3.03) Sheep 113/25 (81.9) 896/233 (79.4) 1.18 (0.75-1.86) 1.31 (0.82-2.10) Other 28/50 (35.9) 118/516 (18.6) 2.45 (1.48-4.05) 2.45 (1.46-4.10)

a As identified through published algorithm (section 2.5.2) b For age, sex and age left school

TABLE 18 Demographics and farming variables by case status of screen identified neuropathy a

Screen identified status p Variable Definition Case Control Sex Male/female (% male) 158/9 (94.6) 1113/58 (95.0) 0.96 Age Mean (± SD) 72.7±9.8 69.1±9.6 <0.001 Scotland 24 (14.4) 211 (18.0) North/North West 74 (44.3) 455 (38.9) Midlands/East Anglia 15 (9.0) 150 (12.8) Region 0.11 Wales 20 (12.0) 83 (7.1) South West 21 (12.6) 165 (14.1) South East 13 (7.8) 107(9.1) Ever /Never (% ever) 70/91 (43.5) 407/710 (37.6) 0.17 Smoker Current /Non-smoker (%current) 11/59 (15.7) 67/359 (15.7) 1.0 Drinker Number of days per week, >1/<1 (%>1) 63/104 (37.7) 435/522 (54.9) <0.001 Schooling Leaving age <16/>16 (%<16) 126/37 (77.3) 822/334 (71.1) 0.12 Currently/Retired/ Not working due to ill health (% ill-health) 59/79/27 (16.4) 668/467/21 (1.8) <0.001 Working On family farm/other (% family farm) 115/25 (76.7) 810/167 (82.9) 0.08 Affected farm: yes/no (%yes) 43/111 (27.9) 339/736 (30.4) 0.59 BSE Affected livelihood slightly/moderately/severely (% severely) 24/4/13 (31.7) 179/75/70 (21.6) 0.09 FMD affected farm:yes/no (% yes) 82/76 (51.9) 550/592 (48.2) 0.43 FMD b FMD affected livelihood: slightly/ moderately/severely (% severely) 14/14/51 (64.6) 104/178/256 (47.6) 0.01

a As identified through a priori clinical algorithm (section 2.5.3) b FMD = foot and mouth in 2001

TABLE 19 Risk of screen identified neuropathy by farming sector a

Ever worked/Never worked (% ever) OR (95%CI) Sector Case Control Unadjusted Adjusted b Cattle 159/8 (95.2) 1110/61 (94.8) 1.09 (0.51-2.33) 1.44 (0.61-3.42) Crops 90/77 (53.9) 627/544 (53.5) 1.01 (0.73-1.40) 1.01 (0.72-1.41) Fruit 8/159 (4.8) 46/1125 (3.9) 1.23 (0.57-2.66) 1.10 (0.48-2.10) Glasshouse 8/159 (4.8) 26/1145 (2.2) 2.22 (0.99-4.98) 1.76 (0.75-4.17) Other livestock 73/94 (43.7) 391/780 (33.4) 1.55 (1.12-2.15) 1.38 (0.98-1.94) Other work 46/121 (27.5) 303/868 (25.9) 1.09 (0.76-1.57) 1.10 (0.76-1.60) Sheep 143/24 (85.6) 973/198 (83.1) 1.21 (0.77-1.92) 1.53 (0.94-2.51) Vegetables 48/119 (28.7) 298/873 (25.5) 1.18 (0.82-1.69) 1.16 (0.80-1.68)

a As identified through a priori clinical algorithm (section 2.5.3) b adjusted for age, sex and ever smoked cigarettes

TABLE 20 Risk of screen identified neuropathy by farming activity a

Ever done/Never done (% ever) OR (95%CI) Activity Case Control Unadjusted Adjusted a Applied Insecticides 94/63 (59.9) 743/391 (65.5) 0.79 (0.56-1.11) 0.81 (0.57-1.16) Treated Grain 52/101 (34.0) 433/688 (38.6) 0.82 (0.57-1.17) 0.83 (0.58-1.20) Applied Other Chemicals 103/54 (65.6) 746/377 (66.4) 0.96 (0.68-1.37) 0.96 (0.66-1.38) Other Pesticides on Farm 92/62 (59.7) 568/537 (51.4) 1.40 (1.00-1.98) 1.52 (1.06-2.18) Used Pesticides Other Job 21/128 (14.1) 138/946 (12.7) 1.13 (0.69-1.85) 1.16 (0.70-1.74) Used Fertilisers 149/13 (92.0) 1074/75 (93.5) 0.80 (0.43-1.48) 0.79 (0.41-1.53) Carried Out Lambing 154/11 (93.3) 1078/74 (93.6) 0.96 (0.50-1.85) 1.05 (0.54-2.05) Slaughtered Livestock 55/103 (34.8) 353/754 (31.9) 1.14 (0.80-1.62) 1.16 (0.81-1.67) Sheared Sheep 126/36 (77.8) 843/299 (72.8) 1.24 (0.84-1.84) 1.27 (0.85-1.91) Dipped Sheep 141/23 (86.0) 946/203 (82.3) 1.32 (0.83-2.10) 1.40 (0.87-2.24) Wormed Cattle 152/11 (93.3) 1069/86 (92.6) 1.11 (0.58-2.13) 1.22 (0.63-2.37) Disinfected Cattle 116/44 (72.5) 815/316 (72.1) 1.02 (0.71-1.48) 1.01 (0.69-1.49) Treated Warble Fly 146/19 (88.5) 1018/137 (88.1) 1.03 (0.62-1.72) 1.02 (0.60-1.71)

a As identified through a priori clinical algorithm (section 2.5.3) b For age, sex and ever smoked cigarettes

TABLE 21 Risk of screen identified neuropathy by concentrate handling a

Ever handled/never handled (% ever) OR (95%CI) Concentrate Case Control Unadjusted Adjusted b Arable 64/73 (46.7) 526/481 (52.2) 0.80 (0.56-1.15) 0.81 (0.56-1.17) Sheep 136/25 (84.5) 873/223 (78.9) 1.45 (0.93-2.28) 1.58 (1.00-2.51) Cattle 141/18 (88.7) 957/165 (85.3) 1.35 (0.81-2.27) 1.44 (0.85-2.45) Other 26/63 (29.2) 120/503 (19.3) 1.73 (1.05-2.85) 1.76 (1.05-2.94)

a As identified through a priori clinical algorithm (section 2.5.3) bFor age, sex and ever smoked cigarettes

TABLE 22 Demographics and farming variables by case status of screen identified Parkinsonism a

Screen identified status p Variable Definition Case Control Sex Male/female (% male) 147/13 (91.9) 1136/54 (95.5) 0.06 Age Mean (± SD) 73.8±10.1 68.7±9.8 <0.001 Scotland 19 (11.9) 220 (18.5) North/North West 72 (45.0) 465 (39.1) Midlands/East Anglia 12 (7.5) 153 (12.9) Region 0.07 Wales 16 (10.0) 88 (7.4) South West 26 (16.3) 159 (13.4) South East 15 (9.4) 105 (8.8) Ever /Never (% ever) 67/89 (42.9) 432/722 (37.4) 0.21 Smoker Current /Non-smoker (%current) 8/59 (11.9) 70/361 (16.2) 0.47 Drinker Number of days per week, >1/<1 (%>1) 71/87 (44.9) 635/543 (53.9) 0.04 Schooling Leaving age <16/>16 (%<16) 115/43 (72.8) 844/330 (71.9) 0.89 Currently/Retired/ Not working due to ill health (% ill-health) 51/81/27 (17.0) 688/465/21 (1.8) <0.001 Working On family farm/other (% family farm) 118/30 (79.7) 813/174 (82.4) 0.51 Affected farm: yes/no (%yes) 50/99 (33.6) 338/794 (29.9) 0.41 BSE Affected livelihood slightly/moderately/severely (% severely) 24/9/15 (31.3) 183/72/68 (21.1) 0.28 FMD affected farm:yes/no (% yes) 84/70 (54.5) 558/600 (48.2) 0.16 FMD b FMD affected livelihood: slightly/ moderately/severely (% severely) 12/17/53 (64.6) 106/178/259 (47.7) 0.02

a As identified through a published algorithm (section 2.5.4) b FMD = foot and mouth in 2001

TABLE 23 Risk of screen identified Parkinsonism by farming sector a

Ever worked/Never worked (% ever) OR (95%CI) Sector Case Control Unadjusted Adjusted b Cattle 149/11 (93.1) 1120/58 (95.1) 0.70 (0.36-1.37) 0.88 (0.42-1.86) Crops 82/78 (51.3) 635/543 (53.9) 0.90 (0.65-1.25) 0.92 (0.65-1.29) Fruit 7/153 (4.4) 47/1131 (4.0) 1.10 (0.49-2.48) 0.93 (0.38-2.24) Glasshouse 5/155 (3.1) 29/1149 (2.5) 1.28 (0.49-3.35) 0.91 (0.31-2.64) Other livestock 66/94 (41.3) 398/780 (33.8) 1.38 (0.98-1.93) 1.21 (0.85-1.71) Other work 46/114 (28.8) 303/875 (25.7) 1.17 (0.81-1.68) 1.23 (0.84-1.79) Sheep 130/29 (81.9) 985/193 (83.6) 0.89 (0.58-1.36) 1.10 (0.70-1.74) Vegetables 37/123 (23.1) 309/869 (26.2) 0.85 (0.57-1.25) 0.81 (0.54-1.21)

a As identified through a published algorithm (section 2.5.4) badjusted for age, sex and ever smoked cigarettes

TABLE 24 a Risk of screen identified Parkinsonism by farming activity

Ever done/Never done (% ever) OR (95%CI) Activity Case Control Unadjusted Adjusted b Applied Insecticides 94/57 (62.3) 743/397 (65.2) 0.88 (0.62-1.25) 0.97 (0.67-1.40) Treated Grain 50/96 (34.2) 435/693 (38.6) 0.83 (0.58-1.19) 0.86 (0.59-1.25) Applied Other Chemicals 94/55 (63.1) 755/376 (66.8) 0.85 (0.60-1.21) 0.90 (0.62-1.31) Other Pesticides on Farm 73/74 (49.7) 587/525 (52.8) 0.88 (0.63-1.25) 0.97 (0.68-1.39) Used Pesticides Other Job 14/126 (10.0) 145/948 (13.3) 0.73 (0.41-1.30) 0.72 (0.39-1.32) Used Fertilisers 141/12 (92.2) 1082/76 (93.4) 0.83 (0.44-1.56) 0.99 (0.49-2.00) Carried Out Lambing 148/10 (93.7) 1084/75 (93.5) 1.02 (0.52-2.03) 1.24 (0.61-2.50) Slaughtered Livestock 46/103 (30.9) 362/754 (32.4) 0.93 (0.64-1.35) 0.93 (0.63-1.36) Sheared Sheep 117/35 (77.0) 852/300 (74.2) 1.18 (0.79-1.76) 1.31 (0.86-1.99) Dipped Sheep 129/28 (82.2) 958/198 (82.9) 0.95 (0.62-1.47) 1.07 (0.68-1.67) Wormed Cattle 144/12 (92.3) 1077/85 (92.7) 0.95 (0.51-1.78) 1.14 (0.60-2.16) Disinfected Cattle 114/40 (74.0) 817/320 (71.9) 1.12 (0.76-1.64) 1.19 (0.80-1.77) Treated Warble Fly 140/18 (88.6) 1024/138 (88.1) 1.05 (0.62-1.77) 1.12 (0.65-1.93)

a As identified through a published algorithm (section 2.5.4) bFor age, sex and ever smoked cigarettes

TABLE 25 Risk of screen identified Parkinsonism by concentrate handling a

Ever handled/never handled (% ever) OR (95%CI) Concentrate Case Control Unadjusted Adjusted b Arable 58/67 (46.4) 532/487 (52.2) 0.79 (0.55-1.15) 0.82 (0.56-1.21) Cattle 137/15 (90.1) 961/168 (85.2) 1.60 (0.91-2.79) 1.90 (1.07-3.38) Sheep 126/24 (84.0) 883/234 (79.1) 1.39 (0.88-2.20) 1.64 (1.02-2.63) Other 17/54 (23.9) 129/512 (20.1) 1.25 (0.70-2.23) 1.26 (0.69-2.29)

a As identified through a published algorithm (section 2.5.4) b For age, sex and ever smoked cigarettes

TABLE 26 Demographics and farming variables by case status of ever seeking medical advice for pesticide poisoning

Screen identified status P Variable Definition Case Control Sex Male/female (% male) 42/1 (89.5) 1158/63 (94.8) 0.63 Age Mean (± SD) 67.6±8.5 69.4±9.7 0.23 Scotland 6 (14.0) 219 (17.9) North/North West 18 (41.9) 477 (39.1) Midlands/East Anglia 6 (14.0) 151 (12.4) Region 0.8 Wales 4 (9.3) 93 (7.6) South West 7 (16.3) 169 (13.8) South East 2 (4.7) 112 (9.2) Ever /Never (% ever) 21/21 (50.0) 445/744 (37.4) 0.14 Smoker Current /Non-smoker (%current) 7/14 (33.3) 70/374 (15.8) 0.07 Drinker Number of days per week, >1/<1 (%>1) 17/26 (39.5) 653/559 (53.9) 0.09 Schooling Leaving age <16/>16 (%<16) 34/9 (79.1) 858/348 (71.1) 0.34 Currently/Retired/ Not working due to ill health (% ill-health) 21/16/6 (14.0) 681/491/36 (3.0) <0.001 Working On family farm/other (% family farm) 31/9 (77.5) 852/172 (83.2) 0.47 Affected farm: yes/no (%yes) 12/31 (27.9) 352/810 (30.3) 0.87 BSE Affected livelihood slightly/moderately/severely (% severely) 5/1/6 (50.0) 192/74/69 (20.6) 0.05 FMD affected farm:yes/no (% yes) 22/21 (51.2) 578/610 (48.7) 0.87 FMD a FMD affected livelihood: slightly/ moderately/severely (% severely) 5/4/13 (59.1) 110/178/275 (48.8) 0.41

a FMD = foot and mouth in 2001

TABLE 27 Associations between ever seeking medical advice for pesticide poisoning and farming sectorsa

Ever worked/Never worked (% ever) OR (95%CI) Sector Case Control Unadjusted adjusted a Cattle 43/0 (100) 1159/62 (94.9) - - Crops 20/23 (46.5) 662/559 (54.2) 0.73 (0.40-1.35) 0.71 (0.38-1.30) Fruit 2/41 (4.7) 50/1171 (4.1) 1.14 (0.27-4.86) 1.20 (0.28-5.12) Glasshouse 1/42 (2.3) 31/1190 (2.5) 0.91 (0.12-6.86) 0.95 (0.13-7.16) Other livestock 14/29 (32.6) 422/799 (34.6) 0.91 (0.48-1.75) 0.98 (0.51-1.89) Other work 12/31 (27.9) 318/903 (26.0) 1.10 (0.56-2.17) 1.10 (0.56-2.16) Sheep 40/3 (93.0) 1016/205 (83.2) 2.69 (0.82-8.78) 2.54 (0.78-8.34) Vegetables 13/30 (30.2) 313/908 (25.6) 1.26 (0.65-2.44) 1.26 (0.65-2.46)

a adjusted for age and sex

TABLE 28 Associations between ever seeking medical advice for pesticide poisoning and farming activities

Ever done/Never done (% ever) OR (95%CI) Activity Case Control Unadjusted Adjusted a Applied Insecticides 28/14 (66.7) 769/424 (64.5) 1.10 (0.57-2.12) 1.03 (0.53-1.99) Treated Grain 14/27 (34.1) 436 /746 (36.9) 0.89 (0.46-1.71) 0.84 (0.44-1.63) Applied Other Chemicals 29/13 (69.0) 776/406 (65.7) 1.17 (0.60-2.27) 1.08 (0.55-2.13) Other Pesticides on Farm 33/9 (78.6) 589/578 (50.5) 3.60 (1.71-7.59) 3.44 (1.62-7.29) Used Pesticides Other Job 2/37 (5.1) 147/1000 (12.8) 0.37 (0.09-1.54) 0.35 (0.08-1.46) Used Fertilisers 37/5 (88.1) 1112/82 (93.2) 0.54 (0.21-1.41) 0.45 (0.17-1.20) Carried Out Lambing 43/0 (100) 1123/83 (93.1) - - Slaughtered Livestock 14/27 (34.1) 368/803(31.4) 1.13 (0.59-2.18) 1.10 (0.57-2.14) Sheared Sheep 38/4 (90.5) 873/322 (73.1) 3.50 (1.24-9.90) 3.35 (1.18-9.49) Dipped Sheep 41/1 (97.6) 985/216 (82.0) 9.00 (1.23-65.7) 8.63 (1.18-63.1) Wormed Cattle 42/1 (97.7) 1112/94 (92.2) 3.55 (0.48-26.1) 3.35 (0.46-24.7) Disinfected Cattle 32/8 (80.0) 848/341 (71.3) 1.61 (0.73-3.53) 1.60 (0.73-3.51) Treated Warble Fly 40/3 (93.0) 1057/150 (87.6) 1.89 (0.58-6.19) 1.83 (0.56-6.02)

a For age and sex

TABLE 29 Associations between ever seeking medical advice for pesticide poisoning and concentrate handling

Ever handled/never handled (% ever) OR (95%CI) Concentrate Case Control Unadjusted Adjusted a Arable 16/19 (45.7) 544/520 (51.1) 0.81 (0.41-1.58) 0.76 (0.38-1.50) Sheep 40/1 (97.6) 911/248 (78.6) 10.9 (1.49-79.6) 10.2 (1.39-74.8) Cattle 40/1 (97.6) 1000/179 (84.8) 7.16 (0.98-52.4) 6.64 (0.90-48.8) Other 6/22 (22.2) 130/527 (19.8) 1.16 (0.46-2.93) 1.15 (0.45-2.90)

a For age and sex

TABLE 30 Associations between ever seeking medical advice for pesticide poisoning and screen identified ill-health

Outcome Ever reported/never reported (% ever) OR (95%CI) Case Control Unadjusted Adjusted Depression 14/88 (13.7) 29/1133 (2.5) 6.22 (3.17-12.2) 6.89 (3.48-13.6) a Dementia 17/117 (12.7) 26/1104 (2.3) 6.17 (3.25-11.7) 6.26 (3.24-12.1) b Neuropathy 15/136 (9.9) 28/1085 (2.5) 4.27 (2.23-8.20) 4.94 (2.53-9.64) c Parkinsonism 14/126 (10.0) 29/1095 (2.6) 4.20 (2.16-8.15) 5.26 (2.64-10.5) c

a For age, sex, age left school, employment status and whether BSE or FMD affected farm b For age, sex and age left school c For age, sex and ever smoked

TABLE 31 Associations between screen identified ill-health and farming variables in the whole population and a population restricted to those who had never sought medical advice for pesticide poisoning

Outcome Variable type Variable OR (95%CI) a All subjects Exclude PPE Depression Activity Used fertilisers 0.42 (0.20-0.88) 0.56 (0.24-1.32) Carried out lambing 0.48 (0.23-0.99) 0.42 (0.20-0.97) Dementia Sector Glasshouse 2.44 (1.08-5.51) 2.21 (0.88-5.54) Other livestock 1.61 (1.13-2.29) 1.80 (1.22-2.67) Other work 1.50 (1.03-2.17) 1.51 (1.00-2.29) Activity Other pesticides on farm 2.10 (1.43-3.09) 1.78 (1.18-2.70) Slaughtered livestock 1.94 (1.35-2.79) 1.92 (1.28-2.89) Concentrate Other concentrate 2.45 (1.46-4.10) 2.35 (1.31-4.22) Neuropathy Activity Other pesticides on farm 1.52 (1.06-2.18) 1.38 (0.94-2.02) Concentrate Sheep concentrate 1.58 (1.00-2.51) 1.44 (0.89-2.34) Other concentrate 1.76 (1.05-2.94) 1.81 (1.04-3.17) Parkinsonism Concentrate Cattle concentrate 1.90 (1.07-3.38) 1.78 (0.97-3.24) Sheep concentrate 1.64 (1.02-2.63) 1.41 (0.86-2.32) a For depression, adjusted for age, sex, age left school, employment status and whether FMD or BSE affected farm; for dementia adjusted for age, sex and age left school; for neuropathy and Parkinsonism adjusted for age, sex and ever smoked cigarettes

NFU Ledgers Sheep Associations Cattle Associations Shepherds Guides (n=6500) (n=5301) (n=8949) (n=2433)

Merged database (n=23183)

Elimination of duplicates (n=3202) and entries from N. Ireland (n=620)

Reduced database (n=19361)

Elimination of entries with insufficient information (n=325) SHAW database for mailing (n=19036)

FIGURE 1 Study of Health in Agricultural Work (SHAW) database for mailing

SHAW database for mailing (n=19036)

Initial mailing

Q (self) Q (non-self) Deceased Refused Ineligible Duplicate Return to sender Gone away Non-response 784 (4.1) 13 (0.1) 2103 (11.1) 345 (1.8) 64 (0.3) 24 (0.1) 3620 (19.0) 546 (2.9) 11536 (59.6)

Further contact by mail and telephone

Q (self) Q (phone) Deceased Refused Ineligible Duplicate Gone away Non-response 1380 (7.3) 368 (19.3) 4635 (24.4) 1102 (5.8) 206 (1.1) 78 (0.4) 5870 (30.8) 5397 (28.4)

FIGURE 2 Initial and final responses to SHAW mailing and telephone contact

Scotland

Northern region Wales

North West

West Midlands

Yorkshire and Humberside South West East Midlands

South East East Anglia London

FIGURE 3 Regional distribution of the SHAW sampling frame

A: Information Source 100 Screening questionnaire 80 Telephone questionnaire Refused

0 All NFU Sheep Shepherds Cattle Associations Guides Associations

B: Geographical Region 100 Screening questionnaire 80 Telephone questionnaire Refused 60

0 ll t t h s A s nd glia e la W Nort t th East an Wale co th Wes th S ast Sou Sou /E Nor

idlands M

FIGURE 4 Adjusted response rates a by (A ) Information Source and (B) Geographical Region

a Denominator excludes those who did not respond, or were ineligible or had died and includes those who completed the screening or telephone questionnaire or refused to take part in the study

2.5 A: Screen ident ified Depression 2.5 B: Screen identified Dementia

2.0 2.0

1.5 OR 1.5 OR (95%CI) (95%CI) 1.0 1.0

0.5 0.5

0.0 0.0 Worked Carried out Sheared Dipped Handled Worked Carried out Sheared Dipped Handled Sheep Lambing Sheep Sheep Concentrate Sheep Lambing Sheep Sheep Concentrate

3.0 C: Screen identified Neuropathy D: Screen identified Parkinsonism 3.0 2.5 2.5 2.0 2.0 OR OR (95%CI) 1.5 1.5 (95%CI) 1.0 1.0

0.5 0.5 0.0 Worked Carried out Sheared Dipped Handled 0.0 Sheep Lambing Sheep Sheep Concentrate Worked Carried out Sheared Dipped Handled Sheep Lambing Sheep Sheep Concentrate FIGURE 5 Associations between screen identified (A) depression, (B) dementia, (C) neuropathy and (D) Parkinsonism and working with sheep, sheep farming activities and handling sheep dip concentrate

3.0 3.5 A: Screen identified Depression B: Scr een identified Dementia 2.5 3.0 2.5 2.0 OR OR 2.0 (95%CI) 1.5 (95%CI) 1.5 1.0 1.0

0.5 0.5

0.0 0.0 Worked Wormed Disinfected Treated Handled Worked Wormed Disinfected Treated Handled Cattle Cattle Cattle Warble Fly Concentrate Cattle Cattle Cattle Warble Fly Concentrate

3.5 3.5 C: Screen identified neuropathy D: Screen identified Parkinsonism 3.0 3.0

2.5 2.5

OR 2.0 OR 2.0 (95%CI) (95%CI) 1.5 1.5

1.0 1.0

0.5 0.5 0.0 0.0 Worked Wormed Disinfected Treated Handled Worked Wormed Disinfected Treated Handled Cattle Cattle Cattle Warble Fly Concentrate Cattle Cattle Cattle Warble Fly Concentrate

FIGURE 6 Associations between screen identified (A) depression, (B) dementia, (C) neuropathy and (D) Parkinsonism and working with cattle, cattle farming activities and handling cattle concentrate

Panel A: Sheep farming 100

10 OR (95%CI)

0.1

Worked Sheared Dipped Handled Sheep Sheep Sheep Concentrate

Panel B: Cattle farming 100

OR (95%CI)

0.1 Wormed Disinfected Treated Handled Cattle Cattle Warble Fly Concentrate

FIGURE 7 Associations between ever seeking medical advice for pesticide poisoning and working with sheep, sheep farming activities, and handling sheep dip concentrate (panel A) and working with cattle, cattle farming activities and handling cattle concentrate (panel B)

Appendix 1 Source of cohort members NFU Ledger books

a Source Years N NFU Bletchley Ledger 1968 onwards 155 NFU Bodmin Ledger 1968-1979 560 NFU (Carlisle) Unrevised Subscriptions Ledger 1962-1978 336 NFU Carlisle and Whitehaven Ledger 1961-1976 614 NFU Cockermouth Ledger 1961-1978 417 NFU Chipping Sodbury Ledger 1975-1989 262 NFU Dursley/Nailsworth Ledger 1973-1990 151

NFU Halesworth Ledger 1978 214 NFU Kendal/Sedbergh Ledger 1962-1978 498 NFU Newport Pagnell Ledger 1968 onwards 245 NFU North Cumberland and Wigton Ledger 1961-1979 447 NFU North Westmorland Ledger 1961-1978 516 NFU Penrith Ledger 1961-1979 528 NFU Saffron Walden Ledger 1968-1971 488

NFU Saffron Walden Ledger 1972-1981 91

NFU Tetbury Ledger 1970-1991 93 NFU Thirsk Yearbook 1974 58 NFU Whitehaven Ledger 1961-1979 496 NFU Wotton under Edge Ledger 1973-1990 109

a Number of members in final cohort (n=18958)

Appendix 2 Source of cohort members Cattle Association Records

Source Years Na Aberdeen- Angus Cattle Society Herd Book 1970 1013 Beef Shorthorn Herd Book 1974 201 British Canadian Holstein Friesian Herd Book 1970 153 British Polled Hereford Cattle 1970 97 Coates's Herd Book (Dairy Shorthorn) Vol 117 1971 621 Devon Cattle Breeders' Society Vol XCIII 1970 436 Dexter Cattle 1970 109 English Guernsey Cattle Society's Handbook 1970 92 Galloway Cattle Herd Book 1970 653 Hereford Herd Book Vol 9 1970 1697 Highland Cattle Herd Book 1970 160 Lincoln Red Cattle 1970 155 Red Poll and British Dane Herd Book 1971 251 The Sussex Herd Book 1970 260 Welsh Black Cattle Herd Book 1970 1101

a Number of members in final cohort (n=18958)

Appendix 3 Source of cohort members Sheep Association Records

Source Years Na Black Welsh Mountain Sheep Breeders Association Vol XLIX 1970 53 Bluefaced Leicester Sheep Breeders Association 1970 281 Border Leicester Flock Book Vol LXXIII 1971 286 Cheviot Sheep Flock Book Vol 79 1970 126 Clun Forest Sheep Breeders Flock Book Vol 46 1970 475 Dales-Bred Sheep Breeders' Association Flock Book 1969-70 139 Devon Closewool Flock Book Vol 49 1972 187 Devon Longwoolled Sheepbreeders' Society Vol 16 1966-70 49 Dorset Down Flock Book 1970 75 Dorset Horn Flock Book Vol 79 1970 150 Flock Book of the Rough Fell Sheep Breeders' Association 1967 60 Hampshire Down Flock Book Vol 82 1971 45 Leicester Longwool 1970 16 Lincoln Longwool Vol 80/81 1972 16 North Country Cheviot Sheep Society Flock Book( vol 25) 1970-71 273 Oxford Down Sheep Breeders Association 1970-71 60 Romney Flock Book Vol LXXVI 1970 96 Ryeland Flock Book Society Limited 1970 64 South Devon Flock Book Vol LXVII 1970 91 Southdown Flock Book Vol LXXVII 1968 45 Suffolk Sheep Society Flock Book Vol 85 1971 595 Swaledale Sheep Breeders Association Flock Book (Vol 52) 1971 431 Teeswater Sheep Association Handbook 1970 134 The Radnor Flock Book Society 1970 33 Welsh Mountain Sheep Society (council) 1970 45 Wensleydale Longwool 1975 48 Wiltshire Horn Sheep Society Flock Book Vol XLVIII 1970 34

a Number of members in final cohort (n=18958)

Appendix 4 Source of cohort members Shepherds Guide

Source Years Na Shepherds Guide (Lakeland) 1967 423 Shepherds Guide (Pennine) 1970 1351

a Number of members in final cohort (n=18958)

Appendix 5 Introductory letter to cohort members

Centre for Occupational & Environmental Health Divison of Epidemiology & Health Sciences Faculty of Medical and Human Sciences, The University of Manchester 4th Floor, ‘C’ Block, Humanities Building Oxford Road, Manchester M13 9PL +44(0)161 275 5524 www.coeh. manchester.ac.uk

Date: Study number: Dear SHAW – Study of Health in Agricultural Work

The Centre for Occupational and Environmental Health at the University of Manchester is conducting a study looking at the health of farmers with the help of the National Farmers Union and the Farmers’ Union of Wales. This study is called SHAW (Study of Health in Agricultural Work). We have identified people who were farming in the 1970s from historical records held by the National Farmer’s Union, by Sheep and Cattle Associations, and from Shepherd’s Guides, and we are writing to these farmers to ask them to participate in this study.

If you are the person named above, we would like you to participate in the study. Participation is important as it will help us to determine whether any aspects of work in farming might contribute to ill health. The results of this study may then benefit farmers in the future. Please take time to read the accompanying information sheet as it has been designed to answer any questions you may have about the study. There is also a free SHAW helpline (0800 195 1621 (9:30am to 4:30pm Monday to Friday) that you can call if you have any further questions.

If you are willing to take part, please complete the accompanying consent form and questionnaire, taking care to answer all the questions and return both to the University of Manchester study team in the pre-paid envelope provided. All the information you give will be completely confidential to the study team, and you will not be identified from any future research publications about the study.

We hope that you will be willing to participate, and we appreciate you co-operation.

Yours sincerely

Dr Andrew Povey

91 SHAW Study of

Appendix 6 Information Leaflet Health in Agricultural Work

PARTICIPANT INFORMATION SHEET

STUDY OF HEALTH IN AGRICULTURAL WORK (SHAW)

This information sheet is to explain the study and detail how you would be involved if you decided to take part. It is important for you to understand why the research is being carried out. Please read this information sheet carefully and discuss it with others if you wish. If you would like some more information about the study please contact one of the researchers whose names appear at the end of this sheet by calling the free SHAW helpline (0800 195 1621) or by sending an email. Take time to decide whether you would like to be involved in the project. Thank you for reading this.

What is the study about?

The aim of this three-year study is to document the current health status of people who were farmers in the 1970s and to examine whether the health of farmers varies with the type of work they have carried out.

Why have I been chosen?

Your name has been obtained from records provided by the National Farmers’ Union or from lists held by Sheep or Cattle Associations or in Shepherd’s Guides. We intend to involve a large number of people throughout the UK (about 12,000).

Why should I take part?

The success of the study depends on a high participation rate. Thus if a high number of farmers agree to take part, the results will be more scientifically sound and potentially of more use to people in the future. Previous studies have suffered from low response rates which have made their results less applicable to the agricultural community, so your participation will be a valuable contribution to our work. However it is entirely up to you whether you wish to participate in the study or not. Even if you agree to help, you can withdraw at any time without giving any reason. Although taking part in the study will have no direct benefit to you personally, it will be very important in helping us to establish if there is a link between farming and ill-health.

What will happen to me if I agree to take part?

If you agree to take part in the study, you will be asked to fill in a short questionnaire about your physical and psychological health, and memory and mood over the past few weeks. We would also ask questions about your past health and about your working life.

The questionnaire should take about 15 minutes to complete. The answers you give to the questions will be reviewed by doctors in the research team. Following this review, we will contact a small number of the participants again to carry out a face-to-face interview to discuss any symptoms that you have and to obtain more information about your working history. If you were one of the minorities chosen for this interview and you agreed to take part in it, we would ask you for your permission to contact your GP to obtain information about your health. However we would ask for

92 your consent once again to include you in the second stage of the study, and your participation in the first stage does not assume that we would necessarily ask to contact your GP in the future.

What will happen to my answers?

Everything you say will be kept confidential and will be analysed anonymously as part of the study. The results of the study will be published in medical journals. A summary of these results will be sent to you and you will also be given the opportunity to request a more detailed summary of the results if you so wish. You will not be identified in any report or publication.

Who do I contact for information or advice?

If you have any questions about the study, you can contact the researchers whose names appear at the bottom of this letter, either by telephoning the free SHAW helpline on 0800 195 1621 or by e- mail.

What are the advantages and disadvantages of taking part in the study?

The advantage of taking part in the study is that you would be helping the research team to understand better any association that exists between any farming activity and ill-health. The disadvantages are that asking questions about how you are feeling may be regarded as an intrusion, and would take about quarter of an hour of your time.

Who is funding the study?

The study is being funded by the UK government through the Department for Environment Food and Rural Affairs and the Department of Health. However it is being undertaken independently of the government by the University of Manchester and the people carrying out the study receive no personal benefit, and get a standard University salary for the work.

Dr Andrew Povey Gillian Watkins Lead Investigator for SHAW Research Co-ordinator for SHAW Email: [email protected] Email: [email protected]

Centre for Occupational and Environmental Health, 4th Floor Humanities Building University of Manchester, Oxford Road, Manchester M13 9PL

SHAW Free Helpline: 0800 195 1621 Website: www.coeh.man.ac.uk/research/shaw/

Consumers for Ethics in Research (CERES) publish a leaflet entitled ‘Medical Research and you’. This leaflet gives more information about medical research and looks at some questions that you may want to ask. A copy may be obtained from CERES, PO Box 1365, London N16 0BW http://www.ceres.org.uk/.

Appendix 7 Consent Form SHAW Study of Health in Agricultural Work

CONSENT FORM ID No:

STUDY OF HEALTH IN AGRICULTURAL WORK (SHAW)

I ------

Of ------

------

------confirm that: (please tick )

No Yes

(1) I have read and understood the Information Sheet.

(2) I understand that if I do not want to take part in the study, I can withdraw my consent at any stage without giving a reason.

(3) I agree to take part in the study.

Signature ------

Date ------

Appendix 8 Health and Work SHAW Study of Questionnaire Health in

ID No: Agricultural Wo rk

HEALTH AND WORK HISTORY QUESTIONNAIRE

The following pages contain questions about your physical and psychological health, memory and mood, current medication, smoking and drinking habits, and work history and practices. Please answer all the questions, even if some do not seem applicable to you, or the wording seems unusual. These questions have been used in other, similar, studies and to be able to make valid comparisons, we need to use the same questions and phrasing.

Please tick the boxes provided and answer all the questions

Name: ......

Address: ......

......

Postcode: ......

Telephone: ......

What is your date of birth? ...... day ...... month ...... year

What is your gender? Male Female

What is the current date and time? ……………………… Date ……………………….Time

A1. During the last 4 weeks , how much have you been bothered by any of the following problems? Not Bothered Bothered bothered a little a lot 1.1 Stomach pain 1.2 Back pain 1.3 Pain in your arms, legs, or joints (knees, hips, etc.) 1.4 Menstrual cramps or other problems with your periods ( Not applicable) 1.5 Pain or problems during sexual intercourse 1.6 Headaches 1.7 Chest pain 1.8 Dizziness 1.9 Fainting spells 1.10 Feeling your heart pound or race 1.11 Shortness of breath 1.12 Constipation, loose bowels, or diarrhoea 1.13 Nausea, gas, or indigestion 1.14 Excessive sweating

A2. During the last 4 weeks , how much have you been Not Bothered Bothered bothered by any of the following problems? bothered a little a lot 2.1 Doing up buttons on your clothes 2.2 Your hands shaking 2.3 Clumsiness 2.4 Slurring your words 2.5 Feeling unsteady when walking 2.6 Problems when using the telephone or cooking a meal 2.7 Moving more slowly or stiffly 2.8 Walking with a stooped posture 2.9 Not swinging your arms when you walk as much as you used to 2.10 Slowing down physically 2.11 Difficulty in turning over in bed at night 2.12 Difficulty in standing up from a chair 2.13 Losing your balance 2.14 Loss of sensation in your hands and feet 2.15 Feeling drunk when you haven’t drunk too much ( Not applicable) 2.16 Cramps or spasms in your muscles 2.17 Cold hands or feet 2.18 Having a weak feeling in your arms and legs

Half the Every day or A3. Over the last 2 weeks , how often have you been bothered Not at More days or nearly every by any of the following problems? all than half less day the days 3.1 Little interest or pleasure in doing things 3.2 Feeling down, depressed, or hopeless 3.3 Trouble with sleep: too little/too much 3.4 Feeling tired or having little energy 3.5 Poor appetite or overeating 3.6 Feeling bad about yourself - or that you are a failure or have let yourself or your family down 3.7 Trouble concentrating on things, such as reading the newspaper or watching television 3.8 Moving or speaking so slowly that other people could have noticed 3.9 Being so fidgety or restless that you have been moving around a lot more than usual 3.10 Thoughts that life is not worth living Not Some- Very Extremely difficult what difficult difficult at all difficult 3.11 How difficult have these problems made it for you to do your work, take care of things at home, or get along with other people?

A4. No Yes Don’t know 4.1 Do you often repeat yourself or ask the same question over and over? 4.2 Are you more forgetful, that is, having trouble with short-term memory? 4.3 Do you need reminders to do things like chores, shopping or taking medicine? 4.4 Do you forget appointments, family occasions or holidays? 4.5 Are you sad, down in the dumps, or cry more often than in the past? 4.6 Have you started having trouble doing calculations, managing finances or balancing the chequebook? 4.7 Have you lost interest in your usual activities such as hobbies, reading, church or other social activities?

4.8 Have you started needing help eating, dressing, bathing, or using the bathroom? 4.9 Have you become irritable, agitated or suspicious, or started seeing, hearing or believing things that are not real? 4.10 Are you concerned about your driving, for example, getting lost or driving unsafely? 4.11 Do you have trouble finding the words you want to say, or naming people or things? 4.12 Do you think you’re having trouble with your nerves?

A5 Have you (as an adult) ever had to seek medical advice for any of No Yes Don’t know m the following medical problems?

5.1 Allergy e.g. hay fever, eczema, dermatitis 5.2 Alzheimer’s disease 5.3 Asthma 5.4 Brucellosis 5.5 Cancer 5.6 Chronic bronchitis or emphysema 5.7 Dementia 5.8 Depressive illness 5.9 Diabetes 5.10 Heart disease including angina 5.11 High blood pressure 5.12 Kidney disease 5.13 Liver disease 5.14 ME/chronic fatigue syndrome 5.15 Motor neurone disease 5.16 Multiple sclerosis 5.17 Parkinson’s Disease 5.18 Pesticide poisoning 5.19 Seizures or epilepsy 5.20 Stroke 5.21 Tuberculosis

A6. During the last 4 weeks , have you had any tablets or any other treatment for No Yes the following? 6.1 Anxiety 6.2 Asthma 6.3 Depression 6.4 Diabetes 6.5 Heart disease including angina 6.6 High blood pressure 6.7 Parkinson’s disease 6.8 Stress

B1. Now we would like to ask some questions about your smoking habits: No Yes 1.1 Have you ever smoked cigarettes regularly (i.e. one a day for more than six months)? (If no, please move onto B2) 1.2 If yes, at what age did you start smoking? ……………….. 1.3 Are you still smoking? 1.4 If yes, how many per day on average? ……………….. 1.5 If no, at what age did you stop smoking? ……………….. 1.6 How many cigarettes did you smoke per day, on average? ………………..

B2. Which of the following statements best describes your drinking habits? Please tick one I drink alcohol: 2.1 Six or seven days a week 2.2 Three to five days a week 2.3 One or two days a week 2.4 One to three days a month 2.5 Less than one day a month 2.6 Never

B3. Approximately how many units of alcohol do you drink per week ? ….. (One unit = Half a pint of average strength beer, a glass of wine OR a standard pub measure of spirits)

C1. Now we would like to ask you some questions regarding your work history:

1.1 At what age did you leave school/full-time education? ……… 1.2 At what age did you start working in farming (including any time spent helping out as a child)? ……… 1.3 Before you worked/helped out on a farm, did you live on a farm? No Yes

1.4 What is your current employment status? Working full-time Not working because of ill-health/disability Working part-time Retired Unemployed but seeking work Other (please specify) ……………………………………..

1.5 If you are no longer working at what age did you stop working? ………

1.6 At your current or last farm (if no longer farming) Was it your family farm? Other Were you a tenant farmer? (Please specify)……………………………………………… Were you an employee? The following pages contain questions about your working history as a farmer since the end of the Second World War. On the first two pages, all you have to do is to put a tick or a line in the relevant boxes, as in the following example:

EXAMPLE

Other Outdoor Top & Other livestock Combinable Glasshouse work Year Sheep Cattle Vegetables Soft Please specify Crops Production Please or Potatoes Fruit specify 1980 a 1981 1982 1983 aDriver 1984 aDriver 1985 Retired

By ‘Other work’ we mean any work outside the farm either on a casual, part-time or full-time basis. In this example, this farmer started working in 1980, was a sheep farmer from 1980 to 1984 but also kept cattle in 1980, and was a driver, part-time, between 1983 and 1984. This person retired in 1985. Please only complete the years that apply to your working life. If you started working in or before 1975 please complete questions C2.1 and C2.2. If you started work after 1975 please complete questions C2.2 only. 99

C2.1 Work history questionnaire from 1946 to 1975

Outdoor Other livestock Combinable Glasshouse Top & Other work Year Sheep Cattle Vegetables Please specify Crops Production Soft Fruit Please specify or Potatoes 1946 1947 1948 1949 1950 1951 1952 1953 1954 1955 1956 1957 1958 1959 1960 1961 1962 1963 1964 1965 1966 1967 1968 1969 1970 1971 1972 1973 1974 1975

.100

C2.2 Work history questionnaire from 1976 to 2003

Other livestock Combinable Glasshouse Outdoor Vegetables Top & Soft Other work Year Sheep Cattle Please specify Crops Production or Potatoes Fruit Please specify 1976 1977 1978 1979 1980 1981 1982 1983 1984 1985 1986 1987 1988 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003

.101

C3. Have you EVER…? No Yes 3.1 Applied insecticides to arable, fodder crops, or grassland 3.2 Treated or fumigated grain or grain storage buildings 3.3 Applied other agricultural chemicals to crops 3.4 Carried out any other work with pesticides on farms 3.5 Used pesticides in any other job (e.g. forestry, road maintenance) 3.6 Used fertilisers 3.7 Carried out lambing/calving etc 3.8 Slaughtered livestock 3.9 Sheared sheep 3.10 Dipped sheep 3.11 Been involved in the worming of cattle or sheep 3.12 Carried out teat disinfection for cattle 3.13 Applied treatment for warble fly

C4. Have you ever handled the concentrate for the treatment of any pests on…? No Yes

4.1 Arable 4.2 Sheep 4.3 Cattle 4.4 Other (Please specify) ……………………………………………………………………

C5. Was your farm affected by BSE?

If No, please move onto question C6. If yes:

5.1 What approximate percentage of your livestock was slaughtered? …………………….

5.2 How did BSE affect your livelihood? Slightly Moderately Severely

No Yes C6. Was your farm affected by Foot and Mouth Disease in 2001?

If yes:

6.1 What were the restrictions on your livestock?

National movement restrictions More severe movement restrictions

6.2 What approximate percentage of your livestock was slaughtered? …………………….

6.3 How did FMD affect your livelihood? Slightly Moderately Severely

Thank you for your help. Using the accompanying self addressed envelope, please send the completed form and the top copy of the consent form to: The SHAW Research Team, Centre for Occupational and Environmental Health, 4th Floor Humanities Building, University of Manchester, Oxford Road, Manchester, M13 9PL.

.102 SHAW Study of Health in Appendix 9 Addressee update (Blue form) Agricultural Work

Please complete and return this form to the University of Manchester only if you are not the person named below :

Addressee Ref:

The addressee is unable to respond because they: (please tick appropriate box)

Do not live at the above address but I am able to contact them

If this is the case, please could you forward the accompanying documentation to them or ask them to call the SHAW research team on the free SHAW helpline 0800 195 1261

Please tick this box if you have done this

Do not live at the above address and I have no knowledge of their whereabouts

Are deceased

If this is the case, we would be most grateful if you could provide the following information if known, as it is important to account for everyone in our study group:

Full Name of the deceased: Date of Birth: Date of Death: Cause of Death (if known):

Other reason (please specify) :

Your Name (Please print): Relationship (if any) to the addressee: Signature: Date: If we require further information may we contact you again? Yes No

.103

Appendix 10 Follow-up letter (England)

Name Address

Ref: Date as postmark

Dear

SHAW – Study of Health in Agricultural Work

The University of Manchester is conducting research to examine whether certain groups of farmers have experienced ill health from their farming activities, and the results of our study will be important to both current farmers and those who have retired from the industry. The National Farmers’ Union has given us significant assistance with this work and would like to encourage farmers to participate. We recently sent you a questionnaire and information pack for this study and we have not yet received a questionnaire back from you. If you have already returned the questionnaire to us, we would like to thank you for your contribution and apologise for contacting you again. If you have not yet returned the questionnaire, could you help the study by completing the enclosed questionnaire and returning it to us as soon as possible? Your completed questionnaire would be of great value to this research, even if you are no longer an active farmer, or were only a part-time farmer or farmed for a short period. It is important that our results accurately reflect the health and work practices of farmers, which is why we would like as many farmers as possible to return the completed questionnaire to us. If you are not the person named above, we would like to apologise for any inconvenience or distress our contact may have caused. However to ensure our records are up to date, we would be grateful if you would complete the accompanying blue form and return it to us. All the information we receive is treated in the strictest confidence. Please contact myself or the research team on freephone 0800 195 1621 (Monday-Friday: 9.30am to 4.30pm) if you have any queries or problems filling in the questionnaire. The completed questionnaire, accompanying consent form and the blue form, if applicable, can be returned to us using the enclosed pre-paid envelope.

We hope that you will be willing to participate, and we appreciate your co-operation. If we do not receive anything back from you, we will try to telephone you to see if we can assist you with completing the questionnaire or blue form.

We look forward to hearing from you.

Yours sincerely,

Dr Andrew Povey Lead Investigator (SHAW)

.104

Appendix 11 Follow-up letter (Scotland)

Name Address

Ref: Date as postmark

Dear

SHAW – Study of Health in Agricultural Work

We recently sent you a questionnaire and information pack for this study and we have not yet received a questionnaire back from you. If you have already returned the questionnaire to us, we would like to thank you for your contribution and apologise for contacting you again. If you have not yet returned the questionnaire, could you help the study by completing the enclosed questionnaire and returning it to us as soon as possible? Your completed questionnaire would be of great value to this research, even if you are no longer an active farmer, or were only a part-time farmer or farmed for a short period. It is important that our results accurately reflect the health and work practices of farmers, which is why we would like as many farmers as possible to return the completed questionnaire to us.

If you are not the person named above, we would like to apologise for any inconvenience or distress our contact may have caused. However to ensure our records are up to date, we would be grateful if you would complete the accompanying blue form and return it to us.

All the information we receive is treated in the strictest confidence. Please contact myself or the research team on freephone 0800 195 1621 (Monday-Friday: 9.30am to 4.30pm) if you have any queries or problems filling in the questionnaire. The completed questionnaire, accompanying consent form and the blue form, if applicable, can be returned to us using the enclosed pre-paid envelope.

We look forward to hearing from you.

Yours sincerely,

Dr Andrew Povey Lead Investigator (SHAW)

.105

Appendix 12 Follow-up letter (Wales)

Name Address

Ref: Date as postmark Dear SHAW – Study of Health in Agricultural Work

The University of Manchester is conducting research to examine whether certain groups of farmers have experienced ill health from their farming activities, and the results of our study will be important to both current farmers and those who have retired from the industry. The National Farmers’ Union Cymru and the Farmers’ Union of Wales have given us significant assistance with this work and would like to encourage farmers to participate. We recently sent you a questionnaire and information pack for this study and we have not yet received a questionnaire back from you. If you have already returned the questionnaire to us, we would like to thank you for your contribution and apologise for contacting you again. If you have not yet returned the questionnaire, could you help the study by completing the enclosed questionnaire and returning it to us as soon as possible? Your completed questionnaire would be of great value to this research, even if you are no longer an active farmer, or were only a part-time farmer or farmed for a short period. It is important that our results accurately reflect the health and work practices of farmers, which is why we would like as many farmers as possible to return the completed questionnaire to us. If you are not the person named above, we would like to apologise for any inconvenience or distress our contact may have caused. However to ensure our records are up to date, we would be grateful if you would complete the accompanying blue form. All the information we receive is treated in the strictest confidence. Please contact myself or the research team on freephone 0800 195 1621 (Monday-Friday: 9.30am to 4.30pm) if you have any queries or problems filling in the questionnaire. The completed questionnaire, accompanying consent form and the blue form, if applicable, can be returned to us using the enclosed pre-paid envelope.

We look forward to hearing from you. Yours sincerely,

Dr Andrew Povey Lead Investigator (SHAW)

.106

Appendix 13 SHAW Non-responders telephone call

Study number Name of person in record Date when initial letter sent Date when recorded delivery sent

Good morning/afternoon/evening. Hello am I speaking to _ ?

If get the correct person

My name is ____ and I am ringing from the Centre for Occupational and Environmental Health at the University of Manchester.

I recently sent you a questionnaire from the SHAW study (Study of Health in Agricultural Work) but I have had some difficulties in getting these letters delivered so I thought I would give you a call to check whether you had received the letter and whether, if possible, you could help the study by completing the questionnaire and returning it to us?

We have had a large number of replies already but it is important that we get as many completed questionnaires as we can so that our results accurately reflect the health and work practices of all farmers. Your completed questionnaire would be of great value to this research, even if you are no longer an active farmer or were only a part-time farmer or farmed for a short period.

.107

Appendix 14 Telephone questionnaire Part 1: SHAW Non-responders Questions to Phase 1

Respondent: Self Non-self Name:…………………………………………….

Refusals: Incapacitated (comment) Retired Old age No reason given

Comments: ………………………………………………………………………………………………………………

1. What is your Date of birth? …………………………

2. At what age did you start working? …………… years

3. Are you currently working?…………………………………….Yes No

Have you retired ?………………………………………………Yes No Part-time Semi-retired

If you are not working is it because of ill-health/disability…..Yes No Specify: ………………

4. Have you ever handled or worked with the concentrate for the treatment of any pests on…?

Arable crops..………Yes No Sheep……………… Yes No Cattle………………. Yes No Other……………… .Yes No Specify: ( mole, horse, pig.) ………………………….………

5. Have you ever had to seek medical advice for any of the following medical problems: a) Dementia…………………….Yes No b) Depressive illness…………..Yes No c) Parkinson’s disease………...Yes No d) Alzheimer’s…………………..Yes No e) Pesticide Poisoning…………Yes No Specify: ……………………………………………

6a Finally, could I ask if you could think of ways we could improve our response rates with the farming community, to studies such as this? Comments: ………………………………………………………………………………………………………………………

6b Did you receive any of our previous mail outs? Yes No Don’t know 6c. If interested in study ask if they would like to take part in the full questionnaire (15 min, sent to them, free post) Yes No

.108

Part 2: Non-responders – Deceased

Full Name :……………………………………………………………………..

Date of Birth :…………………………………………………………………..

Date of Death: ………………………………………………………………..

Cause of Death :……………………………………………………………….

Farming interests:

a) Sheep:……………………Yes No b) Cattle:…………………….Yes No c) Other Livestock:…………Yes No d) Combinable crops:……….Yes No e) Glasshouse production:….Yes No f) Outdoor vegetables ……...Yes No or potatoes: g) Top & soft fruit:……………Yes No h) Other:………………………Yes No Specify: ……………………………………………

.109

Appendix 15 Dear Occupier letter (general version)

Name Address line 1 Address line 2 Address line 3 Address line 4

Ref:…………………. Date as postmark Dear Occupier SHAW – Study of Health in Agricultural Work

At this stage we are unable to determine whether the farmers, we have identified in these records, have moved away, left farming or have since died. We recently sent a letter to (name of the person) at this address but it was returned unopened. It is important for our study that we try and trace everyone who we originally identified. Would you be able to complete the accompanying blue form and return it to us using the pre-paid envelope so as to ensure that our records are up to date?

All the information we receive is treated in the strictest confidence and if our contact has caused any inconvenience or distress we would like to apologise. Please contact myself or the research team on freephone 0800 195 1621 (Monday-Friday: 9.30am to 4.30pm ) if you have any queries or problems filling in the questionnaire, or if you need another copy. The blue form can be returned to us using the enclosed pre-paid envelope.

We hope that you will be willing to help the study , and we appreciate your co-operation.

Yours sincerely,

Dr Andrew Povey Lead Investigator (SHAW)

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Appendix 16 Dear Occupier letter (moved away version)

Name Address line 1 Address line 2 Address line 3 Address line 4

Ref:…………………. Date as postmark Dear Occupier SHAW – Study of Health in Agricultural Work

The Centre for Occupational and Environmental Health at the University of Manchester is conducting a study looking at the health of farmers with the help of the National Farmers’ Union, the National Farmers’ Union Cymru and the Farmers’ Union of Wales. This study is called SHAW (Study of Health in Agricultural Work) and its aim is to see whether farmers have suffered ill-health as a result of their farming activities and thus the results may potentially be important to both current farmers and those who have retired from the industry. To do this study we have identified people who were farming in the 1970s from historical records held by the National Farmers’ Union, by Sheep or Cattle Associations and from Shepherd’s Guides and we are in the process of contacting these farmers to invite them to participate in the study.

We recently sent a letter to (name of the person) at this address and it was returned unopened to us with the envelope marked that the addressee had moved away. It is important for our study that we try and trace everyone who we originally identified. Thus we would be grateful if you could complete the accompanying blue form and return it to us so as to ensure that our records are up to date.

All the information we receive is treated in the strictest confidence and if our contact has caused any inconvenience or distress we would like to apologise. Please contact myself or the research team on freephone 0800 195 1621 (Monday-Friday: 9.30am to 4.30pm ) if you have any queries or problems completing the form. The blue form can be returned to us using the enclosed pre-paid envelope.

We hope that you will be willing to help the study and we appreciate your co-operation.

Yours sincerely,

Dr Andrew Povey Lead Investigator (SHAW)

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Appendix 17 Dear Occupier letter (deceased version)

Ref: Date as postmark Dear Occupier SHAW – Study of Health in Agricultural Work

We recently sent a letter to at this address and it was returned unopened to us with the envelope marked that the person had died. It is important for our study that we try and trace everyone who we originally identified. Thus we would be grateful if you could complete the accompanying form and return it to us so as to ensure that our records are up to date.

All the information we receive is treated in the strictest confidence and if our contact has caused any inconvenience or distress we would like to apologise. Please contact myself or the research team on freephone 0800 195 1621 (Monday-Friday: 9.30am to 4.30pm) if you have any queries or problems completing the accompanying form. This form can be returned to us using the enclosed pre-paid envelope.

We hope that you will be willing to help the study, and we appreciate your co-operation.

Yours sincerely,

Dr Andrew Povey Lead Investigator (SHAW)

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Appendix 18 Follow up letter – Retired farmer

Name Address line 1 Address line 2 Address line 3 Address line 4

Ref:…………………. Date as postmark Dear XXXX SHAW – Study of Health in Agricultural Work

Thank you very much for replying to our initial letter about the SHAW study. You mentioned in your letter that you had retired and that you did not think that you should be in the study. It is important that our results accurately reflect the health and work practices of farmers, which is why we would like as many farmers as possible to return the completed questionnaire to us. Your completed questionnaire would thus be of great value to this research, even if you are now no longer an active farmer. Given that would you be willing to participate?

All the information we receive is treated in the strictest confidence. Please contact the team on freephone 0800 195 1621 (Monday-Friday: 9.30am to 4.30pm ) if you have any queries or problems filling in the questionnaire, or if you need another copy. The blue form can be returned to us using the enclosed pre-paid envelope.

We hope that you will be willing to participate, and we appreciate your co-operation.

Yours sincerely,

Dr Andrew Povey Lead Investigator (SHAW)

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Appendix 19 Letter to Health Authority The administrator [Address 1] [Address 2] [Address 3] [Address 4]

[Date]

Dear Sir/Madam

RE: Study of Health in Agricultural Work (SHAW)

Study by Dr AC Povey and Professor R Agius from The University of Manchester in co-operation with the Office for National Statistics

Name:

Date of Birth:

NHS No:

The above named patient is a potential participant in the above-mentioned study. We have identified people who were farmers in the 1970s and are trying to trace them to the present day so as to determine whether there are any associations between ill-health and farming practices or exposures. So far we have been unable to trace the current address of this subject.

We have thus asked for help from the Office for National Statistics. The Health Authority where the patient is registered with a GP was obtained from the NHSCR, part of the General Register Office.

We are writing to seek your help in contacting the family doctor of the above named patient in your Health Authority. However, there is no obligation for him/her to take part in any research. It is entirely his/her choice. An information sheet about the study is enclosed.

We would be grateful if you would forward the attached pack to the family doctor of the patient named above and return the reply slip using the prepaid envelope provided.

If you would like further information about the study, please contact the researcher Dr Andrew Povey ([email protected] or 0161 275 5232), or call the free SHAW helpline on 0800 195 1621.

Thank you for your help.

Yours sincerely

Dr A. Povey

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Appendix 20 Letter to doctor

[Name] [Address1] [Address2] [Address 3] [Address 4]

[Date]

Dear Dr

RE: Study of Health in Agricultural Work (SHAW)

Study by Dr AC Povey and Professor R Agius from the University of Manchester in co-operation with the Office for National Statistics

We are seeking your help to contact:

Name:

Date of birth:

NHS No. who is a patient of yours.

The Health Authority were the patient is registered with a GP was obtained from the NHSCR, part of the General Register Office. The Health Authority identified you as the patient’s GP and kindly forwarded this letter to you on our behalf. A leaflet about SHAW is attached. However, there is no obligation for your patient to take part in any research. This study has been approved by the Multi-Centre Research Ethics Committee (MREC).

We would be grateful if you could forward the enclosed pack to the patient named above and return the reply slip using the prepaid envelope provided.

If you would like further information about, please contact the researcher Dr Andrew Povey ([email protected] or 0161 275 5232), or call the free SHAW helpline on 0800 195 1621.

Thank you in anticipation of your help.

Yours sincerely

Dr A.C. Povey

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Appendix 21 Letter to cohort member

[Name] [Address1] [Address2] [Address3] [Address4]

[Date]

Dear

Study in Health in Agricultural Health (SHAW)

Your GP has kindly passed this letter to you on our behalf since we do not have your current address. The General Register Office has used the National Health Service Central Register to identify the Health Authority where you are registered with a GP. The Health Authority then forwarded the letter to your GP.

The Centre for Occupational and Environmental Health at the University of Manchester is conducting research to examine whether certain groups of farmers have experienced ill health from their farming activities, and the results of our study will be important to both current farmers and those who have retired from the industry. The study is called SHAW (Study of Health in Agricultural Work). We have identified people who were farming in the 1970s from historical records held by the National Farmers’ Union, the National Farmers’ Union Cymru and the Farmers’ Union of Wales and have given us significant assistance with this work and would like to encourage farmers to participate.

Your completed questionnaire would be of great value to this research, even if you are no longer an active farmer or were only a part-time farmer or farmed for a short period. It is important that our results accurately reflect the health and work practices of farmers, which is why we would like as many farmers as possible to return the completed questionnaire to us. The results of this study may then benefit farmers in the future. Please take time to read the accompanying information sheet as it has been designed to answer any questions you may have about the study.

All the information we receive is treated in the strictest confidence and information you give us will be completely confidential to the study team, and you will not be identifiable from any future research publications about the study. Please contact myself or the research team on freephone 0800 195 1621 (Monday-Friday: 9.30am to 4.30pm) if you have any queries or problems filling in the questionnaire. The completed questionnaire, accompanying consent form and the blue form, if applicable, can be returned to us using the enclosed pre-paid envelope.

We hope that you will be willing to participate, and we appreciate your co-operation.

Yours sincerely

Dr A.C. Povey

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Appendix 22 Number of farm workers and agricultural holdings in 1970 14,15

Area Regular farm Agricultural SHAW workers holdings cohort England and Wales 280,856 (86.6) 233,408 (86.0) 16,425 (86.6) Scotland 43,301 (13.4) 37,930 (14.0) 2,533 (13.3)

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Appendix 23

Geographical distribution of (A) Farmers (1970-71)16 , (B) Regular farm workers (1970-1971) 15,16 , (C) Agricultural holdings (1970-71) 15,16 and (D) the SHAW cohort

A Farmers 16 B. Regular Farm workers 15,16 (Farmers, partners and directors) (Full time family and hired workers)

C. Agricultural Holdings 15,16 D. SHAW cohort

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Appendix 24 Geographical distribution of cohort members identified through(A) NFU ledger books, (B) Sheep associations, (C) Cattle associations and (D) Shepherd,s Guides

A NFU ledgers B Sheep Associations

C Cattle Associations D Shepherd’s Guides

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Appendix 25 Geographical distribution of the SHAW sampling frame Region N County N Northern region 6158 Tyne and Wear 20 Northumberland 349 Cumbria 50765 Durham 708 Cleveland 6 Yorkshire and 1133 North Yorkshire 970 Humberside South Yorkshire 40 West Yorkshire 86 Humberside 37 East Midlands 495 Derbyshire 86 Leicestershire 77 Northamptonshire 77 Lincolnshire 202 Nottinghamshire 53 East Anglia 611 Cambridgeshire 185 Norfolk 102 Suffolk 324 London 34 Inner London 28 Outer London 6 South East 1989 Hertfordshire 118 Buckinghamshire 459 Berkshire 90 Surrey 87 Kent 279 Essex 404 Oxfordshire 110 Hampshire 142 West Sussex 114 East Sussex 158 Bedfordshire 28 South West 2611 Gloucestershire 696 Wiltshire 116 Dorset 109 Somerset 253 Devon 584 Cornwall 775 Avon 78 West Midlands 1074 West Midlands Met. Coun. 8 Shropshire 323 Staffordshire 93 Warwickshire 136 Hereford & Worcestershire 514

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Appendix 25 (continued) Geographical distribution of the SHAW sampling frame

Region N County N North West 485 Greater Manchester 2 Merseyside 4 Cheshire 128 Lancashire/Isle of Man 351 Wales 1840 Clywd 194 Gwynedd 597 Powys 465 Dyfed 393 Gwent 105 Glamorgan West 28 Glamorgan Mid 21 Glamorgan South 37 Scotland 2528 Central Clydeside 148 Highland 405 Grampian 370 Tayside 309 Central 51 Fife 117 Lothian 119 Strathclyde 270 Borders 248 Dumfries & Galloway 491 Total 18958

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Appendix 26 Responses to further contact with initial non-responders

Non-responders 11536 (100)

Q (self) Q (phone) Deceased Refused Ineligible Duplicate Gone away Non-response 579 (5.0) 367 (3.2) 1806 (15.7) 725 (6.3) 130 (1.1) 50 (0.4) 2529 (21.9) 5350 (46.4)

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Appendix 27

Responses to telephone contact of initial non-responders

Non-responders 2126 (100)

Telephone contact

Q (self) Q (phone) Deceased Refused Ineligible Duplicate Gone away Non-response 108 (7.50) 367 (17.3) 472 (22.2) 296 (13.9) 76 (3.4) 1 (0.1) 126 (5.9) 680 (32.0)

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Appendix 28

Responses to “Dear Occupier” letters

Return to sender 3200 (100)

Dear Occupier letter

Q (self) Deceased Refused Return to sender Gone away Non-response 19 (0.6) 583 (18.2) 24 (0.8) 242 (7.6) 780 (24.4) 1552 (48.5)

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Appendix 29 Causes of death

ICD code Description Number (%) F00-F09 Organic, including symptomatic, mental disorders 11 (0.6) F30-F39 Mood [affective] disorders 1 (<0.1) G10-G13 Systemic atrophies primarily affecting CNS 12 (0.6) G20-G29 Extrapyramidal and movement disorders 19 (0.9) G30-G32 Other degenerative disorders of the nervous 20 (1.0) system G35-G37 Demyelinating diseases of the CNS 2 (0.1 G40-G47 Episodic and paroxysmal disorders 1 (<0.1) G70-G73 Diseases of the myoneural junction and muscle 1 (<0.1) X60-X84 Intentional self-harm 18 (0.9) Accidental/intentional causes of death 42 (2.1) Old age/natural causes 1890 (93.7)

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Appendix 30 Responses (%) to screening questionnaire (A3 questions)*

Feeling tired (3.4)

Trouble with sleep (3.3)

Trouble concentrating (3.7)

Moving slowly (3.8) Feeling depressed

Little interest

Feeling bad about yourself (3.6) Poor appetite (3.5)

Life not worth living (3.10)

Being fidgety (3.9)

0 20 40 60 80 100 %

Not at all Half the days or less More than half the days Every day or nearly every day

* Over the last two weeks, how often have you been bothered by any of the following problems

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Appendix 31 Responses (%) to screening questionnaire (A4 questions)

More forgetful (4.2)

Trouble finding words (4.11)

Need reminders (4.3)

Forget appointments (4.4)

Repeating yourself (4.1)

Lost interest (4.7) No Trouble doing calculations (4.6) Yes

Feeling sad (4.5)

Concerned about driving (4.10)

Trouble with nerves (4.12)

Needing help (4.8)

Become irritable (4.9)

0 20 40 60 80 100 %

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Appendix 32

Responses (%) to screening questionnaire (A2 questions)*

Slowing down (2.10) Moving slowly (2.7) Cold hands (2.17) Difficulty standing up (2.12) Feeling unsteady (2.5) Stooped posture (2.8) Weak feeling (2.18) Turning over in bed (2.11) Not bothered Arm swinging (2.9) Bothered a little Doing up buttons (2.1) Muscle cramps (2.16) Bothered a lot Losing balance (2.13) Loss of sensation (2.14) Clumsiness (2.3) Problems using telephone (2.6) Hands shaking (2.2) Slurring words (2.4) Feeling drunk (2.15)

0 20 40 60 80 100 %

*During the last 4 weeks, how much have you been bothered by any of the following problems….

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Appendix 33 Response rates of various studies in farming communities

Year Response Study Sampling frame Area Approach Published rate (%) Letter 33 Stephens 17 1995 BWMB Devon, Cumbria, North .Wales Telephone 69 Gerrard 18 1998 NFU Cumbria, Cheshire, Cambridgeshire Telephone 89 a,b,c NFU England and Wales Letter 57 b Simkin 19 1998 FUW Wales Letter 28 b Booth 20 1999 NFU Devon, Cornwall, Somerset Letter 30 Eisner 21 1998 GP lists Yorkshire Letter 78 d Yellow pages Cornwall/Devon Letter 45 Davies 22 1999 OPIN network Not specified Letter 90 Hereford, Worcester, the Borders, Pilkington 23 2001 MAFF/Scottish Office census Letter 61 Lothians and Ayrshire Remaining members of 1991 Thomas 24 2003 Hereford, Norwich, Preston Letter 91 cohort (MAFF census data) Suspected Adverse Reaction Tahmaz 25 2003 Not specified Letter 37 e Surveillance scheme database Participants of occupational Hereford, Worcester, East Anglia, Not Stephens 26 2004 68 hygiene survey Kent, Sussex specified Telephone 98 Fletcher 7 2005 4 OP support groups UK Letter 19 North Devon, the Welsh borders, Solomon 8 2007 GP lists Letter 31 south Lincolnshire

Excluding a those not listed in the telephone directory, b those no longer in farming, c those where no contact was established, d those who were ineligible, e those who had moved home

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