The Pesticide Users Health Study 2013 UK Low Cancer Rates

Health and Safety Executive
The Pesticide Users Health Study
An analysis of mortality (1987-2005)
Prepared by the Health and Safety Laboratory for the Health and Safety Executive 2013
RR958 Research Report
Terry Brown Anne-Helen Harding Gillian Frost Harpur Hill Buxton Derbyshire SK17 9JN
The Pesticide Users Health Study (PUHS) was established so as to monitor the health of men and women who are certified to apply pesticides on a commercial basis under the 1986 Control of Pesticides Regulations. An analysis of deaths occurring between 1987 and 2005 among members of the PUHS is presented in this report. There were 1,628 deaths among 59,085 male and 3,875 female pesticide users during the follow-up period. Compared with the population of Great Britain, the pesticide users had lower than expected mortality from all causes, and in particular from all cancers combined, cancers of the digestive organs, cancers of the respiratory system, and non-malignant diseases of the nervous system and sense organs, and of the circulatory, respiratory, and digestive systems. There was some evidence of excess deaths from multiple myeloma in men and women, and possibly also from testicular cancer. Deaths from all external causes (accidents and injuries) combined were lower than expected when compared with the general population. However in men, deaths from injury by machinery were higher than expected. Continuing recruitment into the PUHS will enable HSE to monitor the health of these pesticide users as regulations and exposures change over time. This report and the work it describes were funded by the Health and Safety Executive (HSE). Its contents, including any opinions and/or conclusions expressed, are those of the authors alone and do not necessarily reflect HSE policy.
HSE Books
Crown copyright 2013 First published 2013 You may reuse this information (not including logos) free of charge in any format or medium, under the terms of the Open Government Licence. To view the licence visit www.nationalarchives.gov.uk/doc/open-government-licence/, write to the Information Policy Team, The National Archives, Kew, London TW9 4DU, or email psi@nationalarchives.gsi.gov.uk. Some images and illustrations may not be owned by the Crown so cannot be reproduced without permission of the copyright owner. Enquiries should be sent to copyright@hse.gsi.gov.uk.
ACKNOWLEDGEMENTS Acknowledgements go to Steve Hewitt and Kate Hopkins at City & Guilds Land Based Services for their advice and support for the database. The authors would also like to thank Paul Buckley, John Osman, and John Hodgson at the Health and Safety Executive for their assistance on how the study was established and previous work that had been carried out. The authors would also like to thank Adrian Cassidy and Yiqun Chen of the Health & Safety Executive for their contributions. Lastly, the authors wish to thank the staff at the National Health Service Information Centre for their support.
ii
KEY MESSAGES
Overall, men and women in the Pesticide Users Health Study (PUHS) had statistically significantly lower than expected mortality from all causes, all cancers combined, cancers of the lip, oral cavity and pharynx, of the digestive organs, and of the respiratory system, non malignant diseases of the nervous system and sense organs, and non-malignant diseases of the circulatory, respiratory and digestive systems, when compared with the GB population. There was some evidence of excess deaths from multiple myeloma among men and women, and possibly also some excess of testicular cancer deaths. With the limited data available, it was not possible to investigate whether these were linked with particular jobs, working practices or pesticides. There was lower than expected mortality from all external causes (accidents and injuries) combined in both men and women. In men only, there was an excess of deaths due to injury by machinery. It is recommended that recruitment into the PUHS cohort and follow-up of the PUHS cohort be continued, so that this system for monitoring the health of workers exposed to pesticides through their work is maintained.
iii
iv
EXECUTIVE SUMMARY
Objectives The overall objective of this report was to describe mortality among participants of the Pesticide Users Health Study (PUHS). Study participants were men and women who have been certified to apply pesticides on a commercial basis in Great Britain under the 1986 Control of Pesticides Regulations and who agreed to take part in HSEs research into their health. These men and women therefore represent a cohort of individuals who were likely to have been occupationally exposed to pesticides. Main findings There were 1,628 deaths among 59,085 male and 3,875 female pesticide users during the follow-up period, 1987-2005. The mean age at first certification was 32 years (sd 11), with women on average nearly 4 years younger than men at entry. At the end of the study, the mean length of time since first certification was 13 years, with a range of less than one year to 18.7 years. The mean age at first certification for those who died was 46 years for men and 36 years for women. For those who died, the mean length of time since first certification was 9 years. All cause mortality was substantially lower among the pesticide users than in the general population (standardised mortality ratio (SMR) 0.58, 95% CI 0.55-0.61), as was mortality for a number of the major disease groups: o All cancers combined (SMR 0.72, 95% CI 0.66-0.78), o Cancers of the lip, oral cavity and pharynx (SMR 0.18, 95% CI 0.07-0.48), o Cancers of the digestive organs (SMR 0.78, 95% CI 0.68-0.90), o Cancers of the respiratory system (SMR 0.55, 95% CI 0.46-0.65), o Non-malignant diseases of the nervous system and sense organs (SMR 0.39, 95% CI 0.27-0.57), o Non-malignant diseases of the circulatory system (SMR 0.58, 95% CI 0.52 0.63) o Non-malignant diseases of the respiratory system (SMR 0.39, 95% CI 0.31 0.49) o Non-malignant diseases of the digestive system (SMR 0.24, 95% CI 0.18-0.32) The healthy worker effect, together with higher occupational physical activity levels and lower smoking rates in this group of workers, to some degree may explain these lower than expected mortality rates.
The SMRs for some causes of death were higher than expected, though relatively small numbers of deaths, wide confidence intervals and statistical non-significance for some SMRs, mean that these need to be interpreted with caution. Only those causes of death with raised SMRs in this analysis and statistically significantly higher than expected cancer incidence in the parallel analysis of cancer incidence a in the PUHS cohort are listed here: o There was some evidence that mortality from multiple myeloma (SMR 1.28, 95% CI 0.77-2.12 for men and SMR 10.8, 95% CI 2.70-43.2 for women) was higher than expected in this cohort. o There may be some evidence of an excess of deaths from testicular cancer (SMR 1.95, 95% CI 0.93-4.09).
Mortality from all external causes (accidents and injuries) combined was significantly lower than expected in men (SMR 0.69, 95% CI 0.62-1.78), but for women it was not significantly different from the general population. Among men injury by machinery was statistically significantly higher than expected (SMR 4.21, 95% CI 2.11-8.42).
Recommendations The PUHS is an important resource, but the information currently held on the PUHS database is limited. As it stands, it is not possible to investigate whether occupational exposures at any level industry, job, specific pesticide or working practice are associated with an increased risk of mortality. In addition, information on factors that may affect mortality, such as diet and lifestyle, would permit an analysis to take these into account before investigating the associations with occupational exposures. It is recommended that this type of information be collected on the pesticide users in future research. At present only information on mortality and cancer incidence among the pesticide users is available. Concern has been raised in the published literature about possible links between pesticide exposure and non-malignant conditions, such as neurological and respiratory symptoms and diseases, which are not always fatal. A general health survey of the pesticide users is recommended, in order to determine the occurrence and the associated risk factors of these health conditions among the pesticide users. It is recommended that recruitment into the PUHS cohort and follow-up of the PUHS cohort be continued, so that this system for monitoring the health of workers exposed to pesticides through their work is maintained.
a Frost, G. The Pesticide Users Health Study: an analysis of cancer incidence (1987-2004). 2011. HSE Research Report (in preparation)
vi
CONTENTS PAGE
1 2 INTRODUCTION......................................................................................... 2
IMPLICATIONS .......................................................................................... 5
3 METHODOLOGY........................................................................................ 6
3.1 The Cohort............................................................................................... 6
3.2 The Pesticide Users Health Study Database........................................... 7
3.3 Follow-Up ................................................................................................ 7
3.4 Case definition......................................................................................... 7
3.5 Data Analysis........................................................................................... 7
4 RESULTS ................................................................................................... 9
4.1 The Cohort............................................................................................... 9
4.2 Results from the Mortality Analysis........................................................ 12
4.3 Discussion of results.............................................................................. 15
5 REFERENCES.......................................................................................... 18
6 APPENDICES........................................................................................... 20
6.1 Causes of death selected for analysis ................................................... 20
6.2 City & Guilds Land Based Services certificates of competence............. 22
6.3 Stratified tables of results ...................................................................... 23
6.4 Review of the literature .......................................................................... 33
6.5 References cited in the appendices....................................................... 45
INTRODUCTION
A pesticide is any physical, chemical or biological agent that will kill an undesirable plant, fungal or animal pest. Therefore, pesticides are almost as diverse as their targets. Pesticides have been used for centuries: the first recorded use was by the Sumerians who were using sulphur as an insecticide in 2500 BC1. The Chinese were using pyrethrum as an insecticide by 1200 BC and sulphur as a fumigant by 1000 BC. Arsenic-containing compounds were used as insecticides in the 16th century and as a weed killer in the late 19th century. By the 1920s the extensive use of arsenicals caused public concern because some fruit and vegetables were found to contain toxic residues. The use of chemicals for pest control in crops began in the 19th century with, firstly, the introduction of lime-based fungicides and insecticides and, secondly, the use of copper sulphate in fungicide mixtures2. The 1930s saw the development of a variety of synthetic pesticides such as alkyl thiocyanate insecticides, dithiocarbamates and ethylene dibromide, some of which have been superseded by numerous new compounds developed in the post-war era. Pesticide use increased with the introduction of the insecticide DDT (Dichloro-DiphenylTrichloroethane) and growth-regulating herbicides in the 1940s. Organomercury has been used since the 1950s to control seed and soil-borne fungal diseases, while the use of foliar fungicides on cereals began in the 1970s. At the same time, the use of organochlorines (OCs), organophosphates (OPs) and later, carbamates for insect pest control became more widespread. Since the late 1970s, control of insects in arable crops via chemicals has become commonplace, helped by the introduction of synthetic pyrethroids. Potential associations between pesticide exposure and human diseases are increasingly the focus of epidemiological investigations. This increased concern for human toxicity, potential addresses differing levels of exposure occurring through various routes (food, air, water, soil). The process of identifying causes of disease within pesticide-exposed populations is complex, primarily because pesticides are merely one of many environmental exposures that people may encounter. Therefore, to say that a pesticide is associated with increased adverse health effects cancer, respiratory problems, immune disorders, birth defects, etc. requires the determination of a positive association between pesticide exposure and a specific disease; and that other known causes can be ruled out. For instance, farmers are not only exposed to pesticides, but also to other potential risk factors such as fertilisers, nitrates, fuels and engine exhausts, solvents, organic and inorganic dusts, electromagnetic and ultraviolet radiation, and animal pathogens. Behavioural, dietary, and genetic factors may also have a bearing on their risk of disease. The acute health effects of pesticides in humans are well documented; common symptoms include headache, aching limbs, runny nose, giddiness, muscle weakness, and fevers/chills, plus others3. In a study of 4,108 individuals who had at some time used pesticides occupationally, the risk of pesticide-related symptoms increased with somatizing tendency b (somatic symptoms include: faintness or dizziness, pains in the heart or chest, nausea or upset stomach, trouble getting breath, hot or cold spells, numbness and tingling in parts of the body, and feeling weak in parts of the body). The risk was also higher in men who had used pesticides more often and who had worked with concentrates. The relative frequency of symptoms was similar for all categories of pesticide (sheep dip, other insecticides, herbicides, fungicides and wood preservatives). However, in many cases the symptoms may have arisen through psychological rather than toxic mechanisms. Existing reporting systems in the UK that collect data on incident illness associated with exposure to pesticides, focus on acute episodes of ill health such as poisonings, caused by either misuse or abuse. Much less is known about the incidence of ill health due to low-levels of
b
Somatization is the tendency to express psychological factors such as anxiety or stress through bodily symptoms.
pesticides and in the UK there is currently no surveillance scheme within primary care. A recent study to estimate the prevalence and incidence of pesticide-related illness presenting to GPs in Great Britain, suggested the former to be 0.07% and latter 0.04% of consultations, because of concern about pesticide exposure4. Estimates of prevalence and incidence of possible pesticiderelated symptoms were 2.7% and 1.6% respectively. Although small, these estimates translate to relatively large numbers of consultations annually. Chronic health effects, such as cancer, and adverse reproductive outcomes, have been
investigated extensively5-12. Results have been interpreted in various ways as evidence that
pesticides are safe or that they are a cause for concern because they can be detrimental to human
health13. Genotoxicity studies and some recent epidemiological studies in occupationally
exposed populations, point to the real possibility of carcinogenic health effects in humans
exposed to pesticides 5-7 9 10 12 14-16.
The Occupational Health Decennial Supplement showed that farmers had high death rates from various accidental injuries, from several occupationally related respiratory disorders, from hernias (which may result from the extremely heavy lifting in agriculture, especially in the past), and from suicide (Table 1)17. The highest Proportional Mortality Ratio (PMR) (1455) was seen for pesticide poisoning. A more detailed review of the published literature on epidemiological studies, which investigate the association between occupational exposure to pesticides and morbidity or mortality, is given in Appendix 6.4.
Table 1 Mortality from selected causes in farmers: men aged 20-74,

England and Wales, 1979-80 and 1982-90 (Source Drever et al, 1995)17 and 19912000 (Source Coggan et al, 2009)18
Cause of death 1979-80 and 1982-90 Deaths Farmers lung disease (495.0) Other and unspecified allergic pneumonitis (495.1, 495.3-495.9) Inguinal hernia (550) Other hernia (551-553) Infections of skin, joints and bone (680-686, 711, 730) Off-road motor vehicle accidents (E820-E825) Animal transport accidents (E827-E828) Pesticide poisoning (E863) Poisoning by other gases (E869) Slipping and tripping (E885) Injury by animals and plants (E905-E906) Injury by falling object (E916) Injury by machinery (E919) Injury by firearms (E922) Injury by electric current (E925) Suicide (E950-E959) 56 7 41 41 36 38 15 4 7 17 21 35 147 23 29 1215 PMR 10.1 7.87 1.91 1.49 1.81 2.55 4.68 14.6 4.17 1.93 7.75 1.56 4.57 6.70 2.13 1.56 95% CI 8.23-14.2 3.17-16.2 1.37-2.59 1.07-2.02 1.27-2.51 1.80-3.50 2.62-7.73 3.96-37.24 1.68-8.59 1.12-3.09 4.79-11.9 1.09-2.17 3.86-5.38 4.24-10.2 1.43-3.07 1.47-1.65 Deaths 31 3 29 24 1991-2000 PMR 14.6 2.89 2.37 1.57 95% CI 9.89-20.7 0.60-8.44 1.59-3.41 1.01-2.34
23 9 4 3 4 16 17 50 12 18 908
2.80 9.64 13.5 2.38 1.54 10.3 2.20 4.17 8.13 2.38 1.37
1.78-4.20 4.41-18.3 3.68-34.6 0.49-6.97 0.42-3.93 5.90-16.8 1.28-3.52 3.09-5.50 4.20-14.2 1.41-3.76 1.29-1.47
The most obvious groups in which to study the chronic effects of pesticides in humans are those occupational groups or workers who apply pesticides in high doses as part of their daily activities. Individuals working with pesticides can be categorised into a number of groups, depending on their place of work and/or activity with the active ingredients: Pesticide sprayers and applicators: Those involved directly in the preparation and application of pesticides to crops and who potentially represent the most exposed group of workers. However, as the potential for direct contact with pesticides is anticipated during these activities, the use of personal protective equipment (PPE) is frequently a condition of use and is thought to be more commonplace than in those working with the sprayed crops, which may impact on outcomes 19 20. Floriculturists and greenhouse workers: Those involved in the production of flowers and ornamental plants that are commonly sprayed with pesticides in greenhouses. It has been suggested that these groups of workers may potentially have an increased risk of cytogenetic damage due to working in small confined areas, humid conditions and a potential continuous exposure through re-entry activities such as cutting and potting, all militating against the regular use of PPE 21 22. Additionally, compared to other classes of workers, floriculturists may be relatively highly exposed to pesticides during loading, mixing and application as well as during manual activities following regular contact with flowers and ornamental plants. Furthermore, the climatic conditions within greenhouses allow for the continuous production of fruits, vegetables and flowers, requiring a regular application of pesticides throughout the year, resulting in potentially continuous exposure. Agricultural workers and farmers: Those involved in the production of crops, fruits and vegetables and hence indirectly exposed to pesticides. In most instances, such workers are also involved in the mixing and loading of the pesticides. Exposure to pesticides may be lower than in other groups due to the seasonal application of pesticides and the working environment, i.e. outdoors. Forestry workers: Those involved in the spraying of trees and shrubs. In general, compared with other occupational groups, forestry workers use fewer active ingredients. Production workers: Those involved in the manufacture of pesticides. The production of pesticides is undertaken throughout the year, as opposed to pesticide applications, which in general, occur seasonally. Workers are therefore potentially exposed to pesticides continuously, as well as to the raw materials such as formaldehyde, toluene and benzene, some of which also have genotoxic activity.
The overall objective of this report was to describe mortality up to the end of 2005 among participants of the Pesticide Users Health Study. Study participants were men and women, who have taken certificates of competence in the use of agricultural pesticides and who therefore represent a cohort of individuals who were likely to have been occupationally exposed to pesticides.
IMPLICATIONS
The Pesticide Users Health Study (PUHS) is the only national study monitoring the health of men and women who are chronically exposed to pesticides as a part of their work. As such, and in the absence of a requirement for health surveillance of these workers, the PUHS is the principle means by which HSE can assess whether occupational exposure to pesticides is linked to ill health. The findings of the mortality analysis thus provide an important insight into the health of commercial pesticide users in Great Britain, and represent the first step in the investigation of the health effects of occupational exposure to pesticides. Men and women in the PUHS had significantly lower mortality rates than the GB population during the period 1987-2005. Mortality from all causes, and from major disease groups, including all cancers combined, cancers of the lip, oral cavity and pharynx, cancers of the digestive organs, cancers of the respiratory system, non-malignant diseases of the nervous system and sense organs, and non-malignant diseases of the circulatory, respiratory and digestive systems, were statistically significantly lower than mortality in the GB population, after taking age, year of death and sex into account. The healthy worker effect, and higher occupational physical activity levels and lower smoking rates in this group of workers, may explain these lower than expected mortality rates to some degree. There was some evidence that there were excess deaths from multiple myeloma in both men and women, and possibly also an excess of testicular cancer deaths. The evidence from the mortality analysis for these excess deaths was relatively weak, but is strengthened when combined with the reported statistically significant excess in the number of incident cases of multiple myeloma and testicular cancer in the PUHS cohort during the period 1987-200423. The published evidence for a link between pesticide use and multiple myeloma is conflicting; more accurate measurement of exposure to specific pesticides may help clarify whether there is a causal association. An association between blood levels of a metabolite of the organochlorine pesticide DDT and testicular germ cell tumours has been reported in the literature24. Further research into the observed excess of these cancers in the PUHS cohort may be warranted, particularly with respect to occupational exposures and other potential explanatory factors. Reported statistics for farmers, the occupational group most closely representative of the PUHS cohort in official Standard Occupational Classifications, indicate that farmers are at increased risk of mortality from a range of external causes, including transport, falling from height, struck by moving or falling objects, asphyxiation/drowning, trapped by something collapsing or overturning, contact with machinery, livestock related fatalities, and contact with electricity. The HSE focused on safe working practices among farmers in their 2009 Agriculture Campaign and it regularly runs Farm Safety Health Awareness Days in an attempt to reduce the disproportionately high number of deaths from accidents and injuries in agriculture. There was a statistically significantly lower risk of mortality from all external causes (accidents and injuries) combined in the PUHS cohort than expected when compared with the GB population. In the PUHS, the only statistically significant increased risk of mortality from external causes was observed for injury by machinery in men. This self-selected cohort of workers trained in the safe use of pesticides may be more health and safety aware than the wider group of farmers. Alternatively, as only a proportion of the cohort are farmers, non-farming cohort members may not be exposed to the same range of risks as farmers.
3
3.1 THE COHORT
METHODOLOGY
Since 1986, anyone applying pesticides on a commercial basis in the UK must first gain a certificate of competence in their safe use. The City & Guilds Land Based Services (formerly the National Proficiency Test Council (NPTC)), in Stoneleigh, has been at the forefront of developments for craftsmen awards under the Agricultural Wages Order, statutory and code of practice qualifications for the safe use of pesticides, sheep dipping, chainsaw operation and transport of livestock, required by the Chemicals Regulation Directorate (CRD), the Veterinary Medicines Directorate (VMD), Department for Environment Food and Rural Affairs (Defra), the Health and Safety Executive (HSE) and other government agencies and national bodies. The City & Guilds Land Based Services maintains a database of individuals who hold a certificate of competence in the use of agricultural pesticides. At the time of their training, individuals were invited to participate in a programme of medical research on the health effects of pesticide usage conducted by HSE. In 1998, the HSEs Epidemiology and Medical Statistics Unit (EMSU) conducted a feasibility study into using the City & Guilds Land Based Services database, both for following up cancer incidence and mortality, and for collecting other data on health and on pesticide usage. They concluded that the database was an excellent tool . but could be enhanced, and committed HSE to a programme of work to achieve this. In February 2005, the database was transferred from EMSU to the Health and Safety Laboratory (HSL) in Buxton, and the programme of work continues at HSL. The Pesticide Users Health Study (PUHS) cohort consists of those individuals on the City & Guilds Land Based Services database who consented to taking part in HSEs medical research programme. The overall objectives of the work involving the PUHS were to fill the gaps in knowledge about the extent and nature of pesticide-related ill health, especially chronic pesticide-related ill health, which is not the focus of current surveillance schemes. To achieve this, the overall aims of the study are: To augment the information stored in the City & Guilds Land Based Services database, by conducting surveys to collect data on: o The extent and nature of current and historical pesticide usage; o The health of cohort members; and o Other relevant factors (but not health outcomes), e.g. work practices. To maintain the cohort so that it remains available for future research, by adopting procedures to optimise: o Recruitment to the study; o Retention and tracking of study members; and o Good survey practice.
3.2
THE PESTICIDE USERS HEALTH STUDY DATABASE
The PUHS database contains personal details of all 65,910 individuals who agreed to take part in HSEs programme of medical research into the health of pesticide users. The first test date included in the database was May 1987. Data for those who agreed to take part before March 2003 were available for this analysis. The details include: Full name Maiden/previous name Sex Date of birth Address Employer name, background and address Test details: certificate received, date, centre name, county National insurance number National health service number Death details Cancer registration details Although the database contains the employers name and background, the job of each individual or the industry in which they worked cannot be ascertained from this information. 3.3 FOLLOW-UP
A request to flag the 65,910 men and women in the PUHS for cancer and death registrations was made to the National Health Service Central Register (NHSCR) or the General Register Office for Scotland (GROS) for those based in Scotland. For individuals not immediately traced by NHSCR or GROS, further information was requested from the National Insurance office in Newcastle-upon-Tyne, and passed back to NHSCR. A total of 63,493 individuals were eventually traced, a rate of 96.3%. The NHSCR and GROS notify HSL, on a quarterly basis, of any cancer or death registrations among the PUHS participants who were successfully traced. 3.4 CASE DEFINITION
The causes of death selected for the analysis were determined from a comprehensive review of the literature. A list of the diseases or conditions considered in previous studies of pesticide users or pesticide manufacturing workers was compiled and used as the outcomes for this analysis. The underlying cause of death reported on death certificates was used to define a case in this analysis. A full list of the causes selected and their associated International Classification of Diseases (ICD) revisions 9 and 10 codes is given in Appendix 6.1. 3.5 DATA ANALYSIS
The outcome for the mortality analysis was the underlying cause of death recorded on the death certificate, coded according to ICD-9 or ICD-10. Person-years at risk and standardised mortality ratios (SMR) were calculated using Stata SE v11.125 26. The start date for the cohort was the date members sat for their first certificate of competence, irrespective of what type it was. Person years at risk accrued until the end of the study period (31 December 2005), or when an individual died or emigrated. Individuals were excluded from the analysis if they were not successfully traced by the NHSCR or GROS, they were not resident in Great Britain, they had withdrawn from the study, or had
missing or invalid information recorded in the database on date of birth, date of first test, date of death (if applicable), and region. Standard methods for analysing cohort studies were used. Standardised mortality ratios, which compare mortality in the cohort with national mortality, were calculated. The SMRs were calculated by sex-specific 5-year age and calendar periods. National mortality rates were obtained from the Office for National Statistics (England and Wales) and from the General Register Officer for Scotland. If an SMR is greater than 1, there is an excess of deaths among the pesticide users, and if the SMR is less than 1, there are fewer deaths than expected among the pesticide users when compared with the national population. Potential trends within the overall SMRs were examined by stratifying the SMRs by year of birth, year of the first test, age at the first test, and the modules for which an individual had received a certificate of competence (Appendix 6.2). The number of years since an individual was first certified was treated as a time dependent variable in the analysis. SMRs were also stratified in relation to the region where an individual lived. The regions were based on Government Office Regions, defined as: Scotland North: Durham, Cleveland, Cheshire, Lancashire, Humberside, Northumberland, Yorkshire, Cumbria, Yorkshire, Tyne & Wear, Merseyside Midlands: Leicestershire, Derbyshire, Nottinghamshire, Lincolnshire, Northamptonshire, Hereford, Worcester, Shropshire, Staffordshire, Warwickshire, West Midlands Eastern: Norfolk, Suffolk, Essex, Hertfordshire, Bedfordshire, Cambridgeshire South East: Sussex, Surrey, Hampshire, Berkshire, Buckinghamshire, Isle of Wight, Kent, Oxfordshire, London c South West: Cornwall, Devon, Dorset, Somerset, Gloucestershire, Avon, Wiltshire Wales
London is a separate Government Office Region; for the purpose of this analysis it was combined with South-East because there was a comparatively small number of pesticide users in London.
4
4.1 THE COHORT
RESULTS
Altogether 63,493 of the 65,910 men and women on the PUHS database, were successfully traced. Of these, a further 533 individuals were excluded from the analysis: 182 did not have a date on which they took the first test, 344 lived outside the boundaries of England, Wales and Scotland, and 7 emigrated before the first test date. Men and women who only held a Foundation Module were included in the analysis, because they are permitted to apply pesticides under the supervision of an individual who is fully qualified to apply pesticides on a commercial basis. Thus, 62,960 members of the cohort were included in the analysis: 59,085 (93.8%) men and 3,875 (6.2%) women. Table 2 gives numbers of individuals in the different regions of the country.
Table 2
Region East South East South West Midlands North Scotland Wales Total
Regional distribution of the cohort

Women Number (%) 600 (1.0) 1,156 (1.8) 543 (0.9) 584 (0.9) 615 (1.0) 252 (0.4) 125 (0.2) (100) 3,875 Total Number (%) 8,943 (14.2) 13,028 (20.7) 8,000 (12.7) 11,015 (17.5) 12,965 (20.6) 6,323 (10.0) 2,686 (4.3) 62,960 (100)
Men Number (%) 8,343 (13.2) 11,872 (18.9) 7,457 (11.8) 10,431 (16.6) 12,350 (19.6) 6,071 (9.6) 2,561 (4.1) 59,085 (100)
Table 3 gives information about the year of birth of the cohort as a whole (men and women). The majority of the cohort was born in the 1950s and 1960s, though the majority of women were born in the 1960s and 1970s.
Table 3
Year of Birth Before 1930 1930-1939 1940-1949 1950-1959 1960-1969 1970-1979 1980-
Cohort distribution by year of birth

% (1.0) (5.6) (13.2) (21.1) (33.9) (16.8) (2.2) Women Number % 4 (0.01) 48 (0.1) 290 (0.5) 598 (1.0) 1,698 (2.7) 1,157 (1.8) 80 (0.1) Total Number % 622 (1.0) 3,580 (5.7) 8,634 (13.7) 13,862 (22.0) 23,045 (36.6) 11,764 (18.7) 1,453 (2.3)
Men Number 618 3,532 8,344 13,264 21,347 10,607 1,373
Table 4 gives details of the year in which individuals were first given a certificate of competence and the age they were when issued the certificate. As expected, the majority of certificates were first issued in the 1980s when the certification scheme was established. In each
year group, the mean age of men was significantly greater than the mean age of women. The
average age of the cohort at the date they received their first certificate of competence was 32.3
years (standard deviation: 11.0; range: 16.2-74.3), and almost 50% were under the age of 30
years. At the end of follow-up, the mean age for men was 45.7 years (standard deviation (sd)
11.7), compared to 40.8 years (sd 9.3) for women.
Table 4
Year of first test 1987-1990 1991-1994 1996-2000 2001-2003 Age at first test <25 25-29 30-34 35-39 40-44 45-49 50Mean age at first test
Cohort distribution by year of and age at the first test date

Men Number (%) 29,742 16,465 10,149 2,729 (50.3) (27.9) (17.2) (4.6) Mean age 33.4 31.1 32.1 33.7 Women Number (%) Mean age 1,366 (35.3) 28.3 1,419 (36.6) 27.9 835 (21.5) 29.6 255 (6.6) 32.5 Total Number (%) 31,108 17,884 10,984 2,984 (49.4) (28.4) (17.4) (4.7) Mean age 33.1 30.8 31.9 33.6
18,696 10,428 8,520 6,692 5,498 3,975 5,276
(29.7) (16.6) (13.5) (10.6) (8.7) (6.3) (8.4)
1,689 876 479 314 261 141 115
(2.7) (1.4) (0.8) (0.5) (0.4) (0.2) (0.2)
20,385 11,304 8,999 7,006 5,759 4,116 5,391
(32.4) (18.0) (14.3) (11.1) (9.2) (6.5) (8.6)
32.5 (11.0)
28.7 (8.8)
32.3 (11.0)
As outlined in section 3.2, job information was lacking on the PUHS database, although a total of 8,270 were known to be definitely self-employed and 16,934 not. Table 5 gives information of the modules passed by the cohort: 6,969 individuals completed only the foundation module, while 48,249 completed the foundation module and either the ground crop sprayer or the hand held operator module. The table also shows the length of time a certificate had been held by the end of the study (31 December 2005). The overall mean was 13.2 years (sd 4.2), with a range from less than one month to 18.7 years.
10
Table 5
Cohort distribution by City & Guilds Land Based Services modules taken and number of years certified
Men Women (%) (10.7) (28.2) (48.6) (4.6) (8.0) Number 676 207 2,709 73 210 (%) (17.5) (5.3) (69.9) (1.9) (5.4) Total Number 6,969 16,847 31,402 2,784 4,958 (%) (11.1)
(26.8) (49.9) (4.4)
(7.9)

Modules taken Foundation Module (FM) FM + Ground Crop Sprayer, unspec.

FM + Hand Held Applicators, unspec.
All Three All others
Number 6,293 16,640 28,693 2,711 4,748
Total
Years since first certification$ <=5 5-9 10-14 15+ Total Mean number of years certified
$
59,085
(100)
3,875
(100)
62,960
(100)
5,814 10,605 19,681 22,985 59,085 13.3
(9.8) (18.0) (33.3) (38.9) (100) (sd 4.2)
533 889 1,546 907 3,875 12.2
(13.8) (22.9) (39.9) (23.4) (100) (sd 4.2)
6,347 11,494 21,227 23,892 62,960 13.2
(10.1) (18.3) (33.7) (38.0) (100) (sd 4.2)
Equivalent to length of follow-up
11
4.2
RESULTS FROM THE MORTALITY ANALYSIS
Altogether there were 829,709 person years at risk and 1,628 deaths among the cohort (1,591 men, 37 women). The mean age at which those individuals who died took their first test was 45.3 years, approximately 13 years older than the cohort average. The mean age of men was approximately ten years greater than that for women. The number of years those individuals, who died during follow-up, had held a certificate (9.4 years, sd 4.6) was some four years less than the cohort average. The mean age at death was 54.6 years (sd 13.7), with that for men (54.8 years) being significantly greater than that for women (44.9 years) (Table 6).
Table 6
Mean age at death, age at first test and number of years certified by sex for individuals who died during follow-up
Men 45.5 (12.5) 9.4 (4.6) 54.8 (13.6) Women 36.1 (11.0) 8.8 (4.4) 44.9 (13.0) Total 45.3 (12.6) 9.4 (4.6) 54.6 (13.7) p<0.001$ p = 0.43$ p<0.001$
Age at first test Number of years certified Age at death
$ Difference between men and women
Table 7 shows the mortality pattern for men and women and the cohort as a whole. All-cause mortality (SMR 0.58, 95% CI 0.55-0.61) and mortality from all cancers (SMR 0.72, 95% CI 0.66-0.78) were significantly less than expected when compared with the GB population. In addition, cancers of the lip, oral cavity, pharynx, digestive organs, and respiratory system, and diseases of the nervous system, sense organs, circulatory system, respiratory system, and digestive system were all statistically significantly lower than expected. In men, the SMRs for the majority of causes of death were less than one. There was no statististically significant excess of deaths from any of the individual causes of death analysed. There were statistically non-significantly raised SMRs for pancreatic cancer (observed deaths = 38, SMR 1.02), non-melanoma skin cancer (observed deaths = 2, SMR 1.92), breast cancer (observed deaths = 1, SMR 1.24), testicular cancer (observed deaths = 7, SMR 1.95), cancer of the central nervous system (observed deaths = 1, SMR 3.32), and multiple myeloma (observed deaths = 15, SMR 1.28). These statistically non-significant excesses should not be overinterpreted in the absence of other supporting evidence, particularly where the number of deaths is small, the excess is small, and/or the confidence interval is very wide. On the whole, no real patterns could be discerned for women because of the small number of deaths and the resulting wide confidence intervals for many SMRs (Table 7). There was a statistically significant excess of connective and soft tissue cancers (observed deaths = 1; SMR 8.77, 95% CI 1.24-62.3) and the SMRs for lymphohaematopoietic cancers suggested there was some evidence of an excess of deaths from this group of cancers in women. The SMR for lymphohaematopoietic cancers was 3.48 (95% CI 1.56-7.74), with a statistically significant excess of multiple myelomas (observed deaths = 2, SMR 10.8, 95% CI 2.70-43.2) and non significant excesses of non-Hodgkins lymphoma (observed deaths = 2, SMR 3.03) and leukaemia (observed deaths = 2, SMR 2.83). The small number of deaths for each of these cancers means that the results should be treated with caution, and the role of chance cannot be excluded. The SMR for mortality from all external causes was also statistically significantly lower than expected when compared with the GB population (SMR 0.70, 95% CI 0.62-0.79) (Table 8). In
12
men only, there was a statistically significant excess of the external cause of death injury by machinery (observed deaths = 8; SMR 4.21, 95% CI 2.11-8.42) and in women there was an excess of deaths caused by slips, trips or stumbling (observed deaths = 1; SMR 123, 95% CI 17.3-873). The latter, based on one death, should be interpreted with caution. External causes accounted for 82% of deaths from all causes among those aged under 25-years at death. The proportion declined steadily with age at death to the extent that in the over 50-year old age group, external causes accounted for 4% of deaths from all causes. Overall, suicide and selfinflicted injuries dominated the external cause of death category (39%), although the proportion varied by age at death. In individuals aged less than 25 years at death, 18% of external causes of death were suicides or self-inflicted injuries, whereas the proportion was 59% in those aged 35 39 years. Among those aged less than 25 years at death, 48% of deaths from external causes were due to transport accidents, whereas this proportion was less than 25% in those aged over 30 years at death. The SMRs for men, stratified by region of residence, year of birth, age at first certification, length of time since first certification, and type(s) of certificate held, are shown in Table 9 to Table 13 in Appendix 6.3. Overall there were no discernable trends in mortality with any of these possible explanatory variables.
13
Table 7
Cause of Death All causes
Mortality in the Pesticide Users Health Study, 1987-2005

Obs 1,591 583 580 4 192 46 30 38 22 8 38 126 3 118 15 12 3 3 1 40 33 7 34 18 14 34 0 20 1 1 73 4 26 15 26 Men SMR (95% CI) 0.58 (0.55-0.60) 0.71 0.71 0.18 0.78 0.89 0.88 0.72 0.64 0.42 1.02 0.55 0.34 0.55 0.79 0.72 1.34 0.93 1.24 (0.66-0.77) (0.66-0.77) (0.07-0.49) (0.68-0.90) (0.66-1.18) (0.61-1.26) (0.53-1.00) (0.42-0.97) (0.21-0.85) (0.74-1.40) (0.46-0.66) (0.11-1.05) (0.46-0.66) (0.48-1.32) (0.41-1.27) (0.43-4.15) (0.30-2.87) (0.17-8.82) Obs 37 19 19 0 2 0 1 0 0 0 1 1 0 1 0 0 0 1 6 2 1 0 0 0 1 0 0 0 0 6 0 2 2 2 Women SMR (95% CI) 0.71 (0.52-0.98) 0.85 0.85 0.58 2.33 (0.54-1.34) (0.54-1.34) (0.14-2.30) (0.33-16.5) SMR 0.58 0.72 0.71 0.18 0.78 0.88 0.90 0.71 0.63 0.42 1.03 0.55 0.34 0.55 0.77 0.70 1.33 1.19 0.97 0.60 0.60 0.86 0.80 1.95 0.71 0.71 0.65 0.82 0.77 1.84 0.69 1.00 0.80 0.81 1.42 1.01 All (95% CI) (0.55-0.61) (0.66-0.78) (0.66-0.77) (0.07-0.48) (0.68-0.90) (0.66-1.18) (0.63-1.28) (0.52-0.98) (0.41-0.95) (0.21-0.84) (0.75-1.40) (0.46-0.65) (0.11-1.05) (0.46-0.66) (0.46-1.28) (0.40-1.23) (0.43-4.11) (0.44-3.18) (0.46-2.03) (0.15-2.40) (0.08-4.22) (0.63-1.18) (0.57-1.12) (0.93-4.09) (0.51-1.00) (0.45-1.13) (0.38-1.10) (0.59-1.14) (0.49-1.19) (0.26-13.0) (0.10-4.93) (0.80-1.24) (0.30-2.12) (0.56-1.18) (0.89-2.30) (0.70-1.47)
Malignant neoplasms Malignant neoplasms (excl. NMSC) Lip, oral cavity & pharynx Digestive organs Oesophagus Stomach Colon Rectum & anus Liver & gall bladder Pancreas Respiratory system Larynx Trachea, bronchus & lung Skin Malignant melanoma Non-melanoma skin cancer Connective & soft tissue Breast Female genital system Ovarian & other uterine adnexa Male genital system Prostate Testis Urinary system Kidney Bladder Eye, brain & central nervous system Eye Brain Central nervous system & meninges Thyroid Lymphohaematopoietic Hodgkins disease Non-Hodgkins lymphoma Multiple myeloma Leukaemia Diseases of the: Nervous system & sense organs Parkinsons disease Motor neuron disease Alzheimers disease Circulatory system Ischaemic heart disease Cerebrovascular disease Respiratory system COPD Asthma Farmers Lung Digestive System
1.55 0.34 0.35
(0.22-11.0) (0.05-2.42) (0.05-2.51)
8.77 0.94 0.60 0.60
(1.24-62.3) (0.42-2.08) (0.15-2.40) (0.08-4.22)
0.86 0.80 1.95 0.72 0.72 0.66 0.82 0.78 1.89 0.72 0.94 0.82 0.77 1.28 0.96
(0.63-1.18) (0.57-1.12) (0.93-4.09) (0.51-1.00) (0.45-1.15) (0.39-1.11) (0.58-1.14) (0.51-1.22) (0.27-13.4) (0.10-5.09) (0.75-1.18) (0.31-2.20) (0.53-1.14) (0.77-2.12) (0.66-1.42)
0.98
(0.14-6.95)
3.48 3.03 10.8 2.83
(1.56-7.74) (0.76-12.1) (2.70-43.2) (0.71-11.3)
28 0 9 3 530 335 89 75 15 4 0 39
0.40 0.81 0.95 0.58 0.54 0.66 0.39 0.30 0.41 0.23
(0.28-0.59) (0.42-1.56) (0.31-2.94) (0.53-0.63) (0.48-0.60) (0.54-0.82) (0.32-0.49) (0.18-0.49) (0.15-1.08) (0.17-0.32)
0 0 0 0 4 1 2 1 0 0 0 2
0.39 0.80 0.93 0.58 0.54 0.66 0.39 0.29 0.39 0.24
(0.27-0.57) (0.41-1.53) (0.30-2.89) (0.52-0.63) (0.48-0.60) (0.54-0.82) (0.31-0.49) (0.18-0.49) (0.15-1.04) (0.18-0.32)
0.43 0.27 0.71 0.32
(0.16-1.14) (0.04-1.90) (0.18-2.85) (0.04-2.26)
0.56
(0.14-2.25)
Number of deaths observed; Standardised mortality ratio; 95% Confidence intervals
14
Table 8
External causes of mortality among men and women in the

Pesticide Users Health Study database, 1987-2005
Obs 264 67 17 1 3 8 1 6 2 6 101 25 Men SMR 0.69 0.74 0.74 1.66 1.78 4.21 5.03 0.45 1.33 0.34 0.80 0.43 (95% CI) (0.62-0.78) (0.58-0.94) (0.46-1.20) (0.23-11.8) (0.57-5.51) (2.11-8.42) (0.71-35.8) (0.20-1.00) (0.33-5.31) (0.15-0.75) (0.66-0.97) (0.29-0.64) Obs 6 1 1 1 0 0 0 0 0 0 4 0 Women SMR (95% CI) 0.96 (0.43-2.14) 0.74 (0.10-5.29) 3.14 (0.44-22.3) 123 (17.3-873) SMR 0.70 0.74 0.78 3.28 1.77 4.21 5.03 0.44 1.32 0.33 0.82 0.43 All (95% CI) (0.62-0.79) (0.58-0.93) (0.49-1.23) (0.82-13.1) (0.57-5.49) (2.11-8.42) (0.71-35.7) (0.20-0.98) (0.33-5.29) (0.15-0.74) (0.68-0.99) (0.29-0.63)
Cause of Death External causes Transport accidents Accidental falls Slips, trips or stumbling Injury by falling object Injury by machinery Injury by firearm Accidents by submersion, suffocation & foreign bodies Injury by electric current Accidental poisoning Suicide & self-inflicted injury Injury, undetermined intent
2.23
(0.84-5.93)
4.3
DISCUSSION OF RESULTS
This analysis of mortality among 62,960 pesticide users in the GB Pesticide Users Health Study during the period 1987-2005 demonstrated that all cause mortality, and mortality from all cancers combined, respiratory disease, circulatory disease, and non-malignant diseases of the digestive system of the pesticide users were statistically significantly lower than expected when compared with the GB population. In men, all cause mortality was 42% lower than expected and in women it was 29% lower than expected. This may in part reflect the well-known healthy worker effect, but it may also reflect relatively higher occupational physical activity levels and lower tobacco consumption among these workers. A survey of the members of the PUHS undertaken in 2004-2006 showed that 14% of the 8,073 respondents were current smokers1. Although this represents only 13% of the whole cohort of pesticide users, it does suggest that smoking is less prevalent in the cohort than in the GB population, where approximately 24% of the population were current smokers in 20052. Consequently, the lower mortality rates among the pesticide users will be at least partially attributable to differences in smoking rates in the cohort and the reference population. These findings are consistent with the published literature on farmers and pesticide applicators, which indicates that these workers tend to be healthier than the general population, especially with respect to cardiovascular disease and diseases associated with heavy tobacco and alcohol use3 4. For example, in the US Agricultural Health Study of 52,394 pesticide applicators followed up from 1993 to 2007, the SMR was 0.54 (95% CI 0.52-0.55) for all cause mortality, 0.61 (95% CI 0.58-0.64) for all cancers, 0.43 (95% CI 0.39-0.47) for lung cancer, 0.54 (95% CI 0.51-0.56) for heart diseases, 0.52 (95% CI 0.45-0.59) for cerebrovascular disease, and 0.60 (95% CI 0.32-0.46) for non-malignant diseases of the digestive system5. Overall, 17% of these pesticide applicators were current smokers compared with 25% of the US population in 19956. Although SMRs are generally not directly comparable between different populations, the similarities observed between the Agricultural Health Survey and the PUHS results does provide evidence of consistency in their reported associations. In men there were a number of statistically non-significantly raised SMRs, which on their own do not provide evidence of an increased risk of mortality. However, a parallel analysis of cancer incidence in this cohort was undertaken, and this analysis found statistically significantly raised incidence of testicular cancer (observed cases = 102; Standardised Incidence Rate (SIR) 1.26,
15
95 % CI 1.04-1.53) and multiple myeloma (observed cases = 31; SIR 1.49, 95% CI 1.05-2.13)7. Taken together, the significant excess in the number of incident cancers and the statistically non-significant excess of deaths from testicular cancer and from multiple myeloma suggest that there may be some increase in the risk of these two cancers in men. In women there were statistically significantly raised SMRs for connective and soft tissue cancers and lymphohaematopoietic cancers, and within the group of lymphohaematopoietic cancers for multiple myeloma. The small number of deaths for each of these causes means that these excesses must be treated with caution. In the analysis of cancer incidence in this cohort, no soft tissue cancers were observed in women, and the raised SIR for lymphohaematopoietic cancers was not statistically significant7. However, there were four cases of multiple myeloma, and the SIR of 10.0 (95% CI 2.72-25.6) was statistically significant (p < 0.01). Despite the small numbers involved, the consistency of the findings in the incidence and the mortality analysis provides some evidence of an increased risk of multiple myeloma in these women. Few studies have investigated the association between pesticides and the risk of testicular germ cell tumours (TGCT). A case-control study of 739 cases with TGCT and 915 matched controls reported a significantly increased risk of TGCT associated with exposure to a metabolite (p,p' DDE) of the organochlorine pesticide DDT (odds ratio 1.71, 95% CI 1.23-2.38 for 4th quartile vs 1st quartile)8. An earlier case-control study of 61 cases with TGCT and 58 matched controls reported a statistically non-significantly raised odds ratio of 1.7 for blood p,p'-DDE levels higher than the median compared with those less than the median9. There is substantial literature on the association between agricultural work or pesticide-related occupations and the risk of multiple myeloma, but the evidence in the literature is not conclusive. Meta-analyses have been undertaken, with the meta-relative risk estimates ranging from 1.09-1.26, though many of these were not statistically significantly elevated (see Appendix 6.4). As with all studies investigating occupational groups such as farmers or pesticide users, the ability to identify particular exposures that may be causal is limited given the broad range of activities, and hence the exposures connected with these occupations. Reported associations between specific exposures and a disease, such as multiple myeloma, may be more consistent if it were possible to classify the exposures more accurately. In official publications reporting occupational health statistics for the periods 1979-1980 and 1982-199010 and for the period 1991-200011, the proportional mortality ratios (PMR) for a number of external causes of death, including intentional suicide and self-inflicted injury, were significantly elevated. These external causes of death were investigated in the cohort of pesticide users, but the SMR for all external causes of death and for most individual external causes were either below one or not statistically significantly elevated. The only external cause of death with a significantly raised SMR in men was injury by machinery (SMR 4.21, 95% CI 2.11-8.42) and in women was slips, trips and falls (SMR 123, 95% CI 17.3-873). The latter was based on one death and the confidence interval was very wide. The Agricultural Health Study reported a similarly raised SMR for injury by machine in men (SMR 4.15, 95% CI 3.18-5.31), but for most external causes the SMRs were less than one5. There are significant drawbacks with the information stored on the database. Only four causes of death (underlying cause plus up to three other contributory causes) are recorded for each death. Thus, for any death where more causes are recorded, in either section one or two of the death certificate, the other causes are not recorded. This is especially important for causes that are not directly related to the underlying cause of death. This may include asthma, farmers lung disease and other respiratory diseases, and neurological conditions such as Parkinsons and Alzheimers Diseases. However, there are no national data for the rates of death from contributory causes of death, although these data could be useful in an internal analysis,
16
especially where cancer is mentioned as a contributory cause of death and there is no registration for it. In the current analysis it was only possible to examine mortality within the cohort. A significant number of diseases, however, are not life threatening but may be associated with pesticide exposure and agricultural work where most exposure occurs. These include respiratory diseases, including a decrease in lung function; non-fatal accidents/injuries; incidence of acute symptoms following exposure; musculoskeletal problems; and health in general. These health outcomes could be examined by means of a general health survey of the PUHS cohort members. The most important information that is lacking on the PUHS database is some indication of the job/industry in which each individual was employed. This reflects the fact that the data are secondary data, not collected for research purposes. Although the employers address was available, it provided little information about actual occupation. Death certificates contained information about occupation but the occupations of those who were still alive were unknown. Thus, it was not possible to present any analysis by occupation. Related to the lack of information on the individuals job and industry, there was no information available on exposure to specific pesticides or on working practices, which would help in the interpretation of individual findings. The cohort includes a substantial number of men and women who applied pesticides on a commercial basis before the introduction of the 1986 Control of Pesticides Regulations, and the types of pesticides in use have changed over time. Consequently it would not be possible to rule out exposure to certain pesticides by the first date of certification. Availability of exposure data is critical when investigating causality. This information, in addition to information on other factors potentially associated with disease such as diet, smoking, and alcohol intake, could be gathered as part of a general health survey of the PUHS cohort. The cohort offers the opportunity to investigate actual exposures to pesticides. Laboratory volunteer studies have been undertaken of exposure to various pesticides12-14, however, these have not been validated in the field. Biological sampling following pesticide spraying would allow us to determine whether individuals have been significantly exposed to pesticides, or whether working practices, e.g. use of personal protective equipment, have prevented them being exposed. The work would also allow exposure models that have been developed in the laboratory to be validated. The PUHS cohort includes all those who hold a certificate of competency in the use of pesticides and who agreed to take part in HSEs programme of research into the health of these workers. Consequently, members of the cohort are distributed geographically across the whole of Great Britain, and represent men and women working in a broad range of jobs and industries. However, the cohort is self-selected, and it is possible that those who agreed to participate in the research are not fully representative in terms of age, sex, attitudes towards health and safety, and other attributes. As a consequence of their training, the men and women in this cohort are likely to understand the risks associated with pesticide use and employ best practice when applying pesticides. Those who apply pesticides without a certificate of competence, for example under grandfather rights, may be at greater risk of any harmful effects associated with pesticide use. The PUHS database is an important resource that needs to be utilised, and cohort members should be encouraged to take part in further studies to help investigate the association between the health of pesticide users in Great Britain and the pesticides they use. This is the only national study of men and women chronically exposed to pesticides as part of their work in Great Britain. The findings from PUHS will make a substantial contribution to the scientific evidence base about the role of pesticides in human health, and complement the results of other studies such as the US Agricultural Health Study.
17
REFERENCES
1. USACHPPM. Entomological science programs. Pesticide timeline: US Army Center for Health Promotion and Preventive Medicine, 2010. 2. Mellanby K. The New Naturalist. London: Collins, 1981. 3. Solomon C, Poole J, Palmer KT, Peveler R, Coggon D. Acute symptoms following work with pesticides. Occupational Medicine-Oxford 2007;57:505-511. 4. Rushton L, Mann V. Estimating the prevalence and incidence of pesticide-related illness presented to General Practitioners in Great Britain. Research Report 608: HSE Books, 2008. 5. Fleming LE, Bean JA, Rudolph M, Hamilton K. Mortality in a cohort of licenced pesticide applicators in Florida. Occupational and Environmental Medicine 1999;56(1):14-21. 6. IARC. Occupational exposure in insecticide application and some pesticides, volume 53. IARC Monograph on Evaluating the Carcinogenic Risks to Humans. Lyon: International Agency for Research on Cancer, 1991:1-587. 7. Jeyaratnam J. Health problems of pesticide usage in the Third World. British Journal of Industrial Medicine 1985;42:505-506. 8. Levine RS, Doull J. Global estimates of acute pesticide morbidity and mortality. Reviews of Environmental Contamination and Toxicology 1992;129:29-50. 9. Maroni M, Fait A. Health effects in a man from long-term exposure to pesticides. A review of the 1975-1991 literature. Toxicology 1993;78(1-3):1-180. 10. Moses M, Johnson ES, Anger WK, Burse VW, Horstman SW, Jackson RJ, et al. Environmental equity and pesticide exposure. Toxicology and Industrial Health 1993;9(5):913-959. 11. O'Malley M. Clinical evaluation of pesticide exposure and poisonings. Lancet 1997;349(9059):1161-1166. 12. WHO. Public health impact of pesticides used in agriculture. Geneva: World Health Organization, 1990. 13. Sanborn M, Kerr KJ, Sanin LH, Cole DC, Bassil KL, Vakil C. Non-cancer health effects of pesticides: systematic review and implications for family doctors. Can Fam Physician 2007;53(10):1712-20. 14. Blair A, Malker H, Cantor KP, Burmeister L, Wiklund K. Cancer among farmers: A review. Scandinavian Journal of Work Environment & Health 1985;11(6):397-407. 15. CSA. Cancer risk of pesticides in agricultural workers. Council on Scientific Affairs. Journal of the American Medical Association 1988;260(7):959-966. 16. Zheng TZ, Blair A, Zhang YW, Weisenburger DD, Zahm SH. Occupation and risk of non Hodgkin's lymphoma and chronic lymphocytic leukemia. Journal of Occupational and Environmental Medicine 2002;44(5):469-474.
18
17. Drever F. Occupational Health Decennial Supplement: The Registrar General's Decennial Supplement for England and Wales. London: HMSO, 1995. 18. Coggan D, Harris EC, Brown TB, Rice S, Palmer KT. Occupational mortality in England and Wales, 1991-2000. Newport: Office for National Statistics, 2009:52. 19. Lander F, Ronne M. Frequency of sister chromatid exchange and hematological effects in pesticide-exposed greenhouse sprayers. Scandinavian Journal of Work & Environmental Health 1995;21(4):283-288. 20. Undeger U, Basaran N. Assessment of DNA damage in workers occupationally exposed to pesticide mixtures by the alkaline comet assay. Archives of Toxicology 2002;76(7):430 436. 21. Bolognesi C, Landini E, Perrone E, Roggieri P. Cytogenetic biomonitoring of a floriculturist population in Italy: micronucleus analysis by fluorescence insitu hybridization (FISH) with an all-chromosome centromeric probe. Mutation Research 2004;557(2):109-117. 22. Scarpato R, Migliore L, Angotzi G, Fedi A, Miligi L, Loprieno N. Cytogenetic monitoring of a group of Italian floriculturists: no evidence of DNA damage related to pesticide exposure. Mutation Research 1996;367(2):73-82. 23. Frost G. The Pesticide Users Health Study: an analysis of cancer incidence (1987-2004). Bootle: Health & Safety Executive, 2011 (under review). 24. McGlynn KA, Quraishi SM, Graubard BI, Weber JP, Rubertone MV, Erickson RL. Persistent organochlorine pesticides and risk of testicular germ cell tumors. J Natl Cancer Inst 2008;100(9):663-71. 25. Stata statistical software SE version: Release 11.1 [program]: College Station, TX: StataCorp LP, 2010. 26. Juul S. An Introduction to Stata for Health Researchers. Texas: Stata Press, 2006.
19
6
6.1
APPENDICES
CAUSES OF DEATH SELECTED FOR ANALYSIS
ICD-9 codes 1400-2089 1400-1499 1500-1599 1500-1509 1510-1519 1530-1539 1540-1548 1550-1569 1570-1579 1600-1659 1610-1619 1620-1629 1720-1739 1720-1729 1730-1732 1710-1713 1740-1759 1790-1849 1830-1839 1850-1879 1850-1850 1860-1869 1880-1899 1890-1890 1880-1889 1900-1929 1903-1904 1910-1916 1920-1929 1930-1939 2000-2089 2014-2019
ICD-10 codes C000-C970 C000-C148 C150-C260 C150-C159 C160-C169 C180-C189 C190-C218 C220-C249 C250-C259 C300-C399 C320-C329 C330-C349 C430-C449 C430-C439 C440-C449 C490-C499 C500-C509 C510-C589 C560-C579 C600-C639 C610-C610 C620-C629 C640-C689 C640-C640 C670-C679 C690-C729 C690-C699 C710-C719 C700-C709 C730-C739 C810-C969 C810-C819
Cause of death group Malignant neoplasms MN of lip, oral cavity and pharynx MN digestive organs MN of oesophagus MN of stomach MN of colon MN of rectum and anus MN of liver and gall bladder MN of pancreas MN respiratory system MN of larynx MN of trachea, bronchus and lung MN skin Malignant melanoma of skin Non melanoma skin cancer (NMSC) MN other connective and soft tissue MN of breast MN female genital organs MN of ovarian and uterine adnexa MN male genital system MN of prostate MN testis MN urinary system MN of kidney, except renal pelvis MN of bladder MN eye, meninges, brain & central nervous system MN of eye and adnexa MN of brain
0010-7999 E800-E999 A000-R990 V010-Y899 All causes 1400-1729 1740-2089 C000-C439 C450-C979 Malignant neoplasms excl NMSC
C720-C729 MN of central nervous system and meninges MN thyroid MN of lymphoid, haematopoietic and related tissue Hodgkin's disease Non-Hodgkin's lymphoma 20
2020-2029 2000-2009 C820-C859
ICD-9 codes 2030-2039 2040-2089 2900-3190 3200-3899 3352-3352 3320-3320 3310-3310 3200-3790 3900-4599 4100-4149 4300-4380 4600-5199 4900-4929 4930-4939 4950-4950 5200-5799 E800-E999 E800-E848 E880-E888 E885-E885 E916-E916 E919-E919 E922-E922 E910-E915 E925-E925 E850-E863 E950-E959 E980-E989
ICD-10 codes C900-C900 C910-C959 F000-F999 G000-H959 G122-G122 G200-G209 G300-G309 H000-H599 I000-I990 I200-I259 I390-I528 I600-I698 J000-J998 J400-J449 J450-J460 J670-J670 K000-K938 V010-Y980 V010-V999 W000-W199 W010-W010 W200-W209 W300-W319 W320-W339 W650-W849 W850-W879 X480-X499 X600-X840 Y100-Y349
Cause of death group Multiple myeloma Leukaemia Mental and behavioural disorders Diseases of the nervous system and the sense organs Motor neuron disease Parkinson's disease Alzheimer's disease Diseases of eye and adnexa Diseases of the circulatory system Ischaemic heart diseases Other heart diseases Cerebrovascular diseases Diseases of the respiratory system Bronchitis, emphysema and other COPD Asthma Farmer's lung disease Diseases of the digestive system External causes of morbidity and mortality Transport accidents Accidental falls Slips, trips or stumbling Injury by falling object Injury by machinery Injury by firearm Accidents by submersion, suffocation & foreign bodies Injury by electric current Accidental poisoning Suicide & self-inflicted injury Injury, undetermined intent
4200-4239 4250-4299 I300-I339
21
6.2
CITY & GUILDS LAND BASED SERVICES CERTIFICATES OF COMPETENCE
The following table shows the City & Guilds Land Based Services certificates of competence, which are recorded in the PUHS database.
Certificate PA01 PA02 PA02A PA02B PA02C PA02D PA02E PA02F PA02AR PA02BR PA02ST PA03 PA03A PA03B PA03C PA04 PA05A PA05B PA05C PA06 PA06A PA06AW PA06B PA06C PA06CW PA06D PA07 PA07A PA07B PA08 PA09 PA10 PA11 PA11A PA11B PA12 PA13 Module Foundation Ground crop sprayer unspecified Ground crop sprayer boom type hydraulic nozzle Ground crop sprayer boom type rotary atomiser Ground crop sprayer boom type twin fluid nozzle Ground crop sprayer electro-statically charged Ground crop sprayer boom type fitted with downward air assistance Wick applicator boom or frame type Vehicle mounted kerb sprayer hydraulic nozzle type Vehicle mounted kerb sprayer rotary atomiser type Spray trains hydraulic nozzle and rotary atomiser Air sprayer unspecified Broadcast air blast sprayer mounted or trailed Variable geometry boom air assisted sprayer mounted or trailed Variable geometry boom sprayer without air assistance Granule applicatory mounted or trailed Boat mounted applicator hydraulic nozzle boom Hand held applicators application to water using viscous gel applicators Boat mounted applicator viscous gel applicator Hand-held applicators unspecified Hand held applicators hydraulic nozzle and/or rotary atomiser types Hand held applicators application to water using hydraulic nozzle or rotary atom Hand held applicators application to water using viscous gel applicators Handheld applications granule applicator Hand held applicators application to water using granule applicators Hand held applicators requiring minimal calibration Aerial application Aerial applicator pilot Aerial applicator fieldsman/ground marker Mixer/loader Fogging, misting and smokes Dipping, bulbs, corms, plant material or containers Seed treating equipment unspecified Seed treating equipment mobile equipment Seed treating equipment static equipment Application of pesticides to material as a continuous or batch process Sub surface liquid applicator Grouping Foundation Ground crop sprayer Ground crop sprayer Ground crop sprayer Ground crop sprayer Ground crop sprayer Ground crop sprayer Ground crop sprayer Ground crop sprayer Ground crop sprayer Ground crop sprayer Other Other Other Other Other Other Other Other Hand-held operator Hand-held operator Hand-held operator Hand-held operator Hand-held operator Hand-held operator Hand-held operator Other Other Other Other Other Other Other Other Other Other Other
22
6.3
STRATIFIED TABLES OF RESULTS
Standardised mortality ratios, stratified by a number of possible explanatory variables, were calculated. The number of deaths among women was small, so stratified analyses are presented only for men. In order to reduce the number of very small counts and empty cells within the stratified tables, SMRs are presented by grouped causes of death rather than individual causes. Table 9 shows the mortality pattern among men by region of residence, Table 10 gives mortality in men by year of birth, Table 11 gives mortality patterns by age at the first test, Table 12 presents mortality by length of time since the first licence, and Table 13 shows mortality by the type(s) of module for which each cohort member had received a certificate of competence. Overall, there were no obvious associations between mortality and the possible explanatory variables. The majority of SMRs were not statistically significantly different to 1.00; some indicated that the number of deaths was statistically significantly smaller than expected when compared with the GB population. In these stratified tables, only one statistically significantly raised SMR was observed: SMR 1.51 (95% CI 1.09-2.11) for lymphohaematopoietic cancers among men who had held a licence for 5-9 years. In the context of the number of statistical tests presented, and without further evidence of an excess of these cancers in men, this statistically significant SMR should be interpreted with caution.
23
Table 9
Mortality amongst men by region, 1987-2005

North SMR 0.63 (0.56-0.70) 0.81 1.08 0.55 1.08 0.49 0.58 0.99 1.13 (0.68-0.97) (0.82-1.44) (0.36-0.84) (0.40-2.87) (0.18-1.31) (0.24-1.41) (0.50-1.98) (0.71-1.82) Midlands SMR 0.50 (0.44-0.57) 0.54 0.55 0.58 0.92 0.67 0.39 0.28 0.38 (0.43-0.69) (0.36-0.83) (0.38-0.89) (0.30-2.86) (0.28-1.61) (0.12-1.20) 90.07-1.13) (0.16-0.90) Eastern SMR 0.52 (0.46-0.60) 0.61 0.60 0.48 1.35 0.99 1.02 0.62 0.71 (0.49-0.76) (0.40-0.89) (0.30-0.76) (0.51-3.60) (0.50-1.98) (0.51-2.03) (0.23-1.65) (0.37-1.37)
Cause of Death All causes Malignant neoplasms (all) Digestive organs Respiratory system Skin Male genital system Urinary system Eye, brain & CNS Lymphohaematopoietic Diseases of the: Nervous system & sense organs Circulatory system Respiratory system Digestive system External causes
Obs 208 84 21 26 1 4 6 3 12
Scotland SMR 0.56 (0.49-0.64) 0.83 0.69 0.79 0.51 0.76 1.09 0.64 1.60 (0.67-1.02) (0.45-1.06) (0.54-1.16) (0.07-3.62) (0.29-2.03) (0.49-2.42) (0.21-1.98) (0.91-2.81)
Obs 318 120 48 22 4 4 5 8 17
Obs 226 73 22 21 3 5 3 2 5
Obs 227 82 24 18 4 8 8 4 9
5 60 9 6 36
0.61 0.49 0.38 0.21
(0.25-1.46) (0.38-0.64) (0.20-0.73) (0.09-0.47)
5 110 16 11 45
0.37 0.67 0.47 0.36
(0.16-0.90) (0.56-0.81) (0.29-0.77) (0.20-0.65)
5 86 7 7 38
0.43 0.58 0.23 0.26
(0.18-1.03) (0.47-0.72) (0.11-0.48) (0.12-0.55)
5 77 11 2 36
0.47 0.51 0.34 0.08
(0.20-1.13) (0.41-0.64) (0.19-0.62) (0.02-0.33)
0.67 (0.48-0.93)
0.59 (0.44-0.79)
0.58 (0.42-0.80)
0.69 (0.50-0.96)
24
Table 9 (continued)
Obs 372 135 47 21 0 15 9 9 18
South East SMR 0.66 (0.60-0.73) 0.79 (0.67-0.94) 0.92 (0.69-1.22) 0.45 (0.29-0.68) 1.50 0.90 1.05 1.10 (0.90-2.49) (0.47-1.74) (0.55-2.01) (0.69-1.74)
Obs 170 63 19 14 2 3 3 6 8
South West SMR 0.53 (45-0.61) 0.66 0.66 0.54 0.88 0.54 0.54 1.21 0.85 (0.51-0.84) (0.42-1.04) (0.32-0.91) (0.22-3.52) (0.18-1.69) (0.17-1.68) (0.54-2.70) (0.42-1.70)
Obs 70 26 11 4 1 1 0 2 4
Wales SMR 0.61 (0.49-0.78) 0.76 1.07 0.43 1.24 0.51 (0.52-1.11) (0.59-1.93) (0.16-1.14) (0.17-8.78) (0.07-3.63)
1.14 (0.28-4.54) 1.20 (0.45-3.20)
6 119 19 11 62
0.43 0.62 0.47 0.34
(0.19-0.95) (0.52-0.75) (0.30-0.74) (0.19-0.61)
2 52 11 1 33
0.24 0.49 0.49 0.05
(0.06-0.96) (0.37-0.64) (0.27-0.89) (0.01-0.38)
0 26 2 1 14
0.68 (0.46-1.00) 0.25 (0.06-1.00) 0.15 (0.02-1.06) 0.92 (0.54-1.55)
0.86 (0.67-1.10)
0.72 (0.51-1.01)
25
Table 10
Mortality in men by year of birth, 1987-2005

Before 1930 SMR 0.58 (0.50-0.67) 0.65 0.62 0.32 1.92 0.65 0.60 0.50 1.42 (0.51-0.83) (0.40-0.97) (0.18-0.58) (0.48-7.69) (0.31-1.36) (0.23-1.61) (0.07-3.52) (0.77-2.64) 1930-1939 SMR 0.59 (0.54-0.65) 0.77 0.94 0.61 1.01 1.08 0.65 0.88 0.76 (0.67-0.87) (0.77-1.17) (0.48-0.79) (0.38-2.69) (0.72-1.62) (0.37-1.14) (0.44-1.75) (0.47-1.22) 1940-1949 SMR 0.56 (0.51-0.62) 0.66 0.70 0.55 0.55 0.32 0.84 0.81 1.14 (0.57-0.77) (0.54-0.92) (0.40-0.75) (0.18-1.70) (0.10-1.00) (0.48-1.47) (0.43-1.50) (0.76-1.70)
Obs 184 68 19 11 2 7 4 1 10
Obs 489 232 88 59 4 23 12 8 17
Obs 391 163 54 39 3 3 12 10 24
4 96 11 1 2
0.71 0.70 0.30 0.10
(0.27-1.90) (0.57-0.85) (0.17-0.54) (0.01-0.69)
7 172 36 8 11
0.50 0.51 0.50 0.24
(0.24-1.05) (0.44-0.59) (0.36-0.69) (0.12-0.47)
5 149 12 20 27
0.34 0.59 0.27 0.41
(0.14-0.81) (0.50-0.69) (0.16-0.48) (0.27-0.64)
0.40 (0.10-1.61)
0.50 (0.28-0.91)
0.54 (0.37-0.79)
26
Table 10 (continued)
Obs 278 81 24 14 4 2 5 9 12
1950-1959 SMR 0.62 (0.55-0.70) 0.75 0.73 0.61 0.90 0.75 0.86 0.93 0.92 (0.60-0.93) (0.49-1.09) (0.36-1.03) (0.34-2.39) (0.19-3.01) (0.36-2.05) (0.48-1.79) (0.52-1.61)
Obs 180 32 6 3 0 4 1 6 8
1960-1969 SMR 0.49 (0.43-0.57) 0.66 (0.47-0.94) 0.56 (0.25-1.24) 0.65 (0.21-2.01) 2.34 0.60 0.87 0.73 (0.84-5.96) (0.08-1.28) (0.39-1.94) (0.36-1.46)
Obs 66 7 1 0 2 1 0 0 2
1970-1979 SMR 0.62 (0.48-0.78) 0.77 (0.37-1.62) 0.84 (0.12-6.00) 3.29 (0.82-13.2) 2.30 (0.32-16.3)
Obs 3 0 0 0 0 0 0 0 0
1980SMR 0.52 (0.17-1.60)
0.70 (0.18-2.82)
7 82 13 7 72
0.49 0.65 0.61 0.15
(0.23-1.02) (0.52-0.81) (0.35-1.05) (0.07-0.32)
4 25 3 3 103
0.26 0.47 0.22 0.11
(0.10-0.69) (0.32-0.70) (0.07-0.68) (0.04-0.36)
0 6 0 0 47
0.76 (0.35-1.73)
1 0 0 0 2
3.32 (0.49-23.6)
0.84 (0.67-1.06)
0.67 (0.55-0.81)
0.78 (0.58-1.03)
0.56 (0.14-2.22)
27
Table 11
Mortality in men by age at first test, 1987-2005
25-29 SMR 0.54 (0.44-0.65) 0.72 (0.46-1.12) 0.63 (0.24-1.68) 0.69 (0.17-2.74) 3.21 1.00 0.82 0.90 (1.04-9.95) (0.14-7.10) (0.26-2.53) (0.37-2.16) 30-34 SMR 0.62 (0.52-0.74) 0.77 0.61 0.29 1.43 (0.54-1.09) (0.29-1.27) (0.07-1.15) (0.46-4.43) 35-39 SMR 0.60 (51-0.70) 0.76 0.72 0.77 0.42 1.30 0.57 0.77 0.99 (0.57-1.01) (0.43-1.22) (0.42-1.39) (0.06-3.00) (0.32-5.18) (0.14-2.29) (0.29-2.06) (0.47-2.07)
Obs 138 15 2 1 2 2 0 2 3
<25 SMR 0.54 (0.46-0.64) 0.60 0.49 0.69 1.12 1.75 (0.36-0.99) (0.12-1.97) (0.10-4.93) (0.28-4.46) (0.44-7.01)
Obs 99 19 4 2 0 3 1 3 5
Obs 127 31 7 2 3 0 3 4 8
Obs 143 48 14 11 1 2 2 4 7
0.51 (0.13-2.05) 0.41 (0.13-1.27)
1.51 (0.49-4.69) 0.90 (0.34-2.40) 1.32 (0.66-2.64)
2 14 0 0 93
0.18 (0.05-0.73) 0.60 (0.35-1.01)
3 14 4 1 56
0.39 0.46 0.55 0.07
(0.13-1.21) (0.28-0.78) (0.21-1.46) (0.01-0.49)
6 33 4 5 43
0.78 0.68 0.44 0.24
(0.35-1.75) (0.48-0.95) (0.17-1.18) (0.10-0.58)
1 44 7 6 27
0.14 0.61 0.59 0.25
(0.02-0.98) (0.45-0.82) (0.28-1.24) (0.11-0.55)
0.70 (0.57-0.86)
0.79 (0.61-1.03)
0.80 (0.59-1.08)
0.68 (0.46-0.99)
28
Obs 179 78 26 18 2 1 5 7 11
40-44 SMR 0.56 (0.48-0.64) 0.75 0.79 0.64 0.70 0.31 0.83 1.11 1.13 (0.60-0.93) (0.54-1.16) (0.40-1.02) (0.17-2.79) (0.04-2.23) (0.34-1.98) (0.53-2.33) (0.62-2.03)
Obs 205 85 31 21 0 2 4 4 13
45-49 SMR 0.55 (0.48-0.63) 0.63 (0.51-0.78) 0.73 (0.52-1.16) 0.52 (0.34-0.80) 0.35 0.50 0.65 1.18 (0.09-1.40) (0.19-1.34) (0.24-1.72) (0.68-2.02)
50+ Obs 700 307 108 71 7 30 19 10 26 SMR 0.59 (0.55-0.64) 0.73 0.84 0.53 1.31 0.92 0.73 0.84 0.85 (0.65-0.81) (0.69-1.01) (0.42-0.66) (0.62-2.75) (0.64-1.31) (0.46-1.14) (0.45-1.56) (0.58-1.24)
2 54 5 12 19
0.26 0.48 0.28 0.45
(0.06-1.03) (0.37-0.63) (0.12-0.66) (0.26-0.80)
3 85 9 5 11
0.41 0.61 0.36 0.21
(0.13-1.26) (0.49-0.75) (0.19-0.70) (0.09-0.51)
11 286 46 10 15
0.53 0.58 0.41 0.21
(0.30-0.96) (0.52-0.65) (0.31-0.55) (0.11-0.38)
0.60 (0.38-0.94)
0.51 (0.28-0.92)
0.51 (0.31-0.85)
29
Table 12
Mortality in men by length of time since first licensed, 1987-2005

5-9 years SMR 0.60 (0.55-0.66) 0.76 0.79 0.54 0.34 0.99 0.80 0.47 1.51 (0.65-0.87) (0.61-1.02) (0.39-0.75) (0.09-1.38) (0.56-1.74) 90.44-1.44) (0.21-1.04) (1.09-2.11) 10-14 years SMR 0.62 (0.57-0.67) 0.75 0.86 0.68 1.16 0.92 0.59 0.99 0.84 (0.66-0.86) (0.68-1.07) (0.52-0.88) (0.55-2.44) (0.57-1.47) (0.32-1.09) (0.58-1.71) (0.55-1.29) 15+ years SMR 0.56 (0.48-0.65) 0.69 0.53 0.56 0.97 0.71 0.90 0.92 0.66 (0.55-0.86) (0.34-0.85) (0.35-0.90) (0.24-3.87) (0.32-1.59) (0.40-2.00) (0.34-2.46) (0.30-1.47)
Obs 341 108 42 18 4 5 7 11 11
<5 years SMR 0.49 (0.44-0.55) 0.60 0.81 0.36 0.80 0.69 0.72 0.97 0.54 (0.50-0.73) (0.60-1.10) (0.23-0.57) (0.30-2.13) (0.29-1.66) (0.34-1.51) (0.54-1.75) (0.30-0.97)
Obs 501 182 57 37 2 12 11 6 35
Obs 563 217 75 54 7 17 10 13 21
Obs 186 76 18 17 2 6 6 4 6
3 114 12 6 88
0.16 0.53 0.33 0.18
(0.05-0.50) (0.44-0.63) (0.19-0.58) (0.08-0.40)
5 169 22 9 93
0.25 0.61 0.39 0.18
(0.10-0.60) (0.53-0.71) (0.26-0.59) (0.09-0.35)
13 187 30 19 61
0.58 0.61 0.43 0.30
(0.34-1.00) (0.53-0.70) (0.30-0.61) (0.19-0.48)
7 60 11 5 22
0.83 0.51 0.39 0.22
(0.40-1.75) (0.40-0.66) (0.22-0.70) (0.09-0.53)
0.59 (0.48-0.73)
0.76 (0.62-0.93)
0.70 (0.54-0.89)
0.99 (0.65-1.50)
30
Table 13
Foundation only SMR 0.75 (0.67-0.84) 0.85 0.90 0.72 0.82 0.90 0.83 0.56 1.11 (0.70-1.02) (0.64-1.26) (0.49-1.06) (0.21-3.29) (0.42-1.89) (0.37-1.86) (0.18-1.74) (0.63-1.96)
Mortality in men by modules taken, 1987-2005
Foundation + Ground crop sprayer Obs SMR 332 0.47 (0.42-0.52) 121 35 23 3 12 7 12 18 0.60 0.59 0.42 0.59 1.12 0.61 1.08 0.89 (0.50-0.72) (0.42-0.82) (0.28-0.64) (0.19-1.83) (0.64-1.97) (0.29-1.29) (0.61-1.89) (0.56-1.41) Foundation + Hand-held operator Obs SMR 854 0.62 (0.58-0.66) 319 113 69 10 21 18 16 35 0.76 0.90 0.58 1.06 0.89 0.74 0.77 0.91 (0.68-0.85) (0.75-1.08) (0.46-0.74) (0.57-1.98) (0.58-1.36) 90.47-1.18) (0.47-1.26) (0.65-1.26) All three SMR 0.44 (0.31-0.65) 0.62 (0.32-1.20) 0.48 (0.12-1.91)
Obs 297 104 33 26 2 7 6 3 12
Obs 27 9 2 0 0 0 1 1 3
1.30 (0.18-9.25) 0.94 (0.13-6.70) 1.74 (0.56-5.38)
3 107 19 7 47
0.33 0.76 0.63 0.32
(0.11-1.02) (0.63-0.92) (0.40-0.99) (0.15-0.68)
8 97 11 3 80
0.42 0.43 0.24 0.07
(0.21-0.85) (0.36-0.53) (0.13-0.43) (0.02-0.21)
12 291 43 27 115
0.36 0.62 0.44 0.32
(0.20-0.63) (0.55-0.70) (0.33-0.60) (0.22-0.46)
2 8 1 0 7
1.05 (0.26-4.21) 0.51 (0.25-1.02) 0.32 (0.04-2.27)
1.06 (0.80-1.41)
0.69 (0.55-0.86)
0.66 (0.55-0.80)
0.48 (0.23-1.00)
31
Obs 81 30 9 8 0 0 2 2 5
Other Modules SMR 0.38 (0.30-0.47) 0.48 (0.33-0.68) 0.90 (0.75-1.08) 0.46 (0.23-0.93)
0.56 (0.14-2.22) 0.61 (0.15-2.43) 0.82 (0.34-1.97)
3 27 1 2 15
0.54 0.38 0.07 0.15
(0.17-1.67) (0.26-0.56) (0.01-0.48) (0.04-0.61)
0.47 (0.29-0.79)
32
6.4
REVIEW OF THE LITERATURE
The body of evidence from studies of chronic disease in pesticide-exposed worker populations generally report consistent findings in mortality patterns, despite a variety of methodological issues15-21. Exposure data is frequently unavailable, but where it is, demonstrating a causal relationship with a specific pesticide may still present difficulties: the data may lack detail, many pesticide applicators use a variety of pesticides and work practices, and hence exposure may vary widely between applicators. Farmers and other agricultural workers, pesticide manufacturers and applicators, the main worker groups that have been studied, tend to be healthier compared with the general population, especially with respect to cardiovascular disease and the diseases associated with heavy tobacco and alcohol use. They are, however, at an increased risk from accidents and fatal injuries 22, some of this possibly pesticide-related (e.g. aerial sprayers). Farmers are also more likely to die of infectious and non-malignant respiratory disease; to the extent that certain pesticides have immunologic effects, pesticide exposure may contribute toward these risks, although this aspect has not been studied rigorously 3 4 16 21 23-27. Exposure to pesticides has been linked to increased risk of incidence/mortality from a number of diseases and also a number of cancers. The diseases include respiratory (e.g. chronic bronchitis and asthma), neurological (e.g. Parkinsons and Alzheimers disease), and poisonings. Cancers include brain, breast, pancreas, prostate, non-Hodgkins lymphoma (NHL), leukaemia and multiple myeloma. A review of the major findings in the published literature follows. 6.4.1 6.4.1.1 Respiratory Diseases Farmers lung disease
Farmers lung disease, or hypersensitivity pneumonitis, is an important source of respiratory morbidity among farmers. There have typically been around five or fewer new assessed cases for disablement benefit each year over the last few years, though in 2007 there were 20 cases d . Farmers lung disease was recorded as the underlying cause of death typically between 5-10 times per year over the last few years e . The prevalence of farmers lung disease in the United Kingdom has been reported to be 420-3,000 cases per 100,000 at risk persons, and incidence between 8-540 cases per 100,000. Incidence is highly variable and depends on multiple factors, such as intensity, frequency, and duration of exposure, type of farming, and climate. It is also more common in the northern latitudes and among dairy farmers. Farmers lung disease rarely progresses to a life-threatening level, which suggests that there are substantially more cases than those receiving compensation. Evidence from SWORD/OPRA suggests the number of new cases varied between about 20 and 50 per year over the last ten years with no obvious trendsd. A significant number of farmers develop mild chronic lung impairment, which is predominantly obstructive airflow disease associated with mild emphysematous changes. Farmers lung disease is an immune complex hypersensitivity (Type III hypersensitivity): thermoactinomycetes and other bacteria in mouldy hay are well-established causes of hypersensitivity pneumonitis28 29. Other factors, such as isocyanates, have also been hypothesised to influence the development of hypersensitivity pneumonitis28. Pesticides have been suggested as a risk factor but this hypothesis has rarely been explored. The disease was recognised as a significant cause of death among farmers in the last published Occupational Health Decennial Supplement (PMR=1089, 95% CI=823-1416)30. Analysis of data by region showed a more than 20-fold variation with particularly high proportions in
d e
http://www.hse.gov.uk/statistics/causdis/respiratory http://www.statistics.gov.uk/statbase/Product.asp?vlnk=618
33
farmers from Wales and the North-east of England. These areas have extensive hill farming and a relatively damp climate predisposing the formation of the moulds in hay that cause the disease. The US Agricultural Health Study (AHS) is a prospective cohort study of farmers and their spouses in Iowa and North Carolina 31. Hoppin et al 32 analysed cross-sectional enrolment data between 1993-7 from the AHS, and observed 427 cases of farmers lung disease among farmers in the study and 38 cases among spouses. Compared to 17,952 and 26,011 controls, respectively, these cases were more likely to be exposed to pesticides over their lifetime, in particular among the farmers, a history of a high pesticide exposure event (OR=1.75, 95% CI=1.39-2.21), use ever of organochlorine (OC) pesticides (OR=1.34, 95% CI=1.04-1.74) and use ever of carbamate pesticides (OR=1.32, 95% CI=1.03-1.68). Analysis of individual pesticides showed variable results. Two organochlorine pesticides associated with farmers lung disease were lindane (OR=1.25, 95% CI 0.98-1.60) and dichlorodiphenyl trichloroethan (DDT) (OR=1.25, 95% CI 0.95-1.65), although these results were not statistically significant. Also, two carbamate pesticides were associated with farmers lung disease, but in opposite directions; aldicarb, an insecticide, had a positive association (OR=1.65, 95% CI 1.04-2.61), whereas benomyl, a fungicide, had an inverse association (OR=0.60, 95% CI 0.33-1.07). Although these risks were observed, confounding by historic farm activities could not be ruled out. 6.4.1.2 Chronic obstructive pulmonary disease
Studies have suggested that pesticide use may increase the risk of chronic bronchitis. Pesticides have been associated with cough and phlegm among participants in the Singapore Chinese Health Study33. Also, in a study of non-smoking women in the AHS, chronic bronchitis was associated with exposure to dichlorvos, dichlorodiphenyl thrichloroethane (DDT), cyanazine, paraquat and methyl bromide after multivariate adjustment34. A study of the baseline data collected for the AHS reported that 11 pesticides were significantly associated with chronic bronchitis, after adjustment for correlated pesticides and confounders35. These included carbamates, OCs, organophosphates (OPs) and pyrethroid insecticides, and herbicides (2,4,5-T; 2,4,5-TP; chlorimuron-ethyl (CME), petroleum oil). However, farmers undertake a variety of activities that potentially put them at risk of chronic bronchitis, including confinement farming 36 37 , grain handling38, and livestock production39 40. A recent population-based survey of 1,258 men and women in Austria found that 23% had any type of farming experience, and that farming was the only occupation with increased prevalence of chronic obstructive pulmonary disease (COPD)41. Substantially more farmers had at least mild COPD compared to non-farmers (30% compared to 22%), and proportionally they also exhibited more severe COPD symptoms (14% compared to 8%). 6.4.1.3 Other respiratory symptoms
In the US, applying pesticides to livestock has been found to be associated with a high prevalence of respiratory symptoms42, and there is some evidence of an association between working with pesticides and prevalence of cough and chronic phlegm43. In Saskatchewan, Canada, farmers working with carbamates and OPs have reported a higher prevalence of asthma than other farmers44. In the US AHS an increased odds of wheeze was associated with 11 of 40 pesticides among more than 20,000 farmer pesticide applicators45. Pesticides associated with increased wheeze included the herbicides paraquat, atrazine, alachlor and chlorimuron-ethyl (CME) and the OP insecticides parathion and chlorpyrifos. Significant dose-response relationships were also demonstrated for chlorpyrifos, s-ethyl-dipropylthiocarbamate (EPTC), paraquat and parathion. Later work showed a dose-response trend for CME and phorate46.
34
6.4.2 6.4.2.1
Neurological Diseases Neurological symptoms
The neurological consequences of high-level exposure to pesticides are well established47 and symptoms can result from exposure to most types of compounds (for example, OPs, carbamates, OCs, fungicides and fumigants)48. However, only OPs have been studied in detail. Mild exposures lead to symptoms including dizziness, headache, nausea and vomiting, papillary constriction, and excessive sweating, tearing and salivation. High exposures can lead to muscle weakness and twitches, changes in heart rate, and bronchospasm and can progress to convulsions and coma. Some patients may develop OP-induced delayed neuropathy two to five weeks after exposure, which involves sensory abnormalities, muscle cramps, weakness and even paralysis. In some cases of acute OP poisoning, neurological effects were observed ten or more years after poisoning49, suggesting that the residual damage is permanent. In a recent study, the prevalence and pattern of neuropsychiatric symptoms were consistently more common in past users of sheep dip and other pesticides than in those who had never worked with pesticides50. A study of applicators in the AHS observed an association between the number of neurological symptoms experienced and cumulative lifetime days of insecticide use, fumigant use, and weaker relationships for cumulative lifetime days of herbicide use and fungicide use51. Beseler et al 52 noted that depression was significantly associated with a history of pesticide poisoning in female spouses of applicators in the AHS. Chronic low-level exposure is associated with a broad range of non-specific symptoms, including headache, dizziness, insomnia, confusion, and difficulty concentrating47. Men and women who applied OPs, including greenhouse workers53, farmers and pesticide applicators54, commercial termiticide applicators55 and sheep dippers56, all reported higher symptom prevalence than non-exposed. In a review of the health effects of chronic exposure to pesticides, 39 out of 41 studies showed a positive increase in one or more neurological abnormalities (including malaise, depression, mood changes, cognitive dysfunction) with pesticide exposure57. 6.4.2.2 Parkinsons disease
There is extensive literature suggesting that pesticide exposure may increase the risk of Parkinsons disease58-61. Numerous case-control studies have suggested an association between pesticide exposure and Parkinsons disease with ORs ranging from 1.6 to 7.062. However, many of the studies defined exposure as ever exposed to any pesticide, a broad definition that could give rise to significant misclassification, which might weaken the association. The results of cohort studies indicate that employment in certain occupations involving pesticide exposure may increase the risk of Parkinsons disease51 60 63 64. However, findings have been inconsistent, and a number of methodological difficulties were identified that might account for them65 66. These include: variation in diagnostic criteria for Parkinsons disease, limitations in exposure assessment and variable adjustment for other potential risk factors. In particular, Parkinsons disease risk is related to living in rural areas, drinking well water and pesticide exposure. With regards to the latter, and the wide range of compounds subsumed under the title pesticide, the biological implausibility of all pesticides having a similar toxicological action was noted. In a case-control study in four European centres (Scotland, Sweden, Italy, Romania), 649 cases and 1,587 controls were recruited, and their lifetime occupational histories collected 67. Scottish data showed a non-significant increased risk for agriculture (Dictionary of Occupational Titles [DOT]: OR= 1.32, 95% CI=0.81-2.16; International Standard Industrial Classification [ISIC]: OR=1.30, 95% CI=0.84-2.02). Analysis of information from all four centres resulted in a
35
reduced risk (DOT: OR=1.02, 95% CI=0.82-1.28; ISIC: OR=1.05, 95% CI=0.85-1.31). In a further analysis these data were added to cases from Malta68, giving a total of 959 cases with parkinsonism, 767 with Parkinsons disease, and 1,989 controls. Logistic regression analysis of all cases noted a significant risk with any exposure to pesticides (OR=1.29, 95% CI=1.02-1.63), and an exposure-response when average annual intensity of exposure was the metric (low vs. no exposure: OR=1.13, 95% CI=0.82-1.57; high vs. no exposure: OR=1.41, 95% CI=1.06-1.88). When only Parkinsons disease cases were considered, similar but slightly lower risks were observed (any exposure: OR=1.25, 95% CI=0.97-1.61; low vs. no exposure: OR=1.09, 95% CI=0.77-1.55; high vs. no exposure: OR=1.39, 95% CI=1.02-1.89). In a case-control study from the US, 319 cases and 296 relative and other controls were examined69. Overall, individuals with Parkinsons disease were significantly more likely to report direct pesticide application than their unaffected relatives (OR=1.61, 95% CI=1.13-2.29). Significant exposure-response relationships with frequency and duration of pesticide use, and cumulative exposure were reported. Excess risk was observed in individuals exposed to insecticides and herbicides, and specifically OC and organophosphorous compounds. Among male farmers in the Occupational Health Decennial Supplement, a significant excess of Parkinsons disease was observed (PMR=125, 95% CI=110-142)10. 6.4.2.3 Amyotrophic lateral sclerosis
Information on the association between pesticide exposure and the risk of other neurological disease is sparser. Several studies have suggested that the risk of amyotrophic lateral sclerosis is related to farming as an occupation, although the evidence for an increased risk with pesticide exposure is inconclusive 70-74. 6.4.2.4 Alzheimers disease
Alzheimers disease is the most common cause of dementia in the elderly. Several risk factors have been identified including head injury, low serum levels of folate and vitamin B12, raised plasma and total homocysteine levels, a family history of Alzheimers disease or dementia, fewer years of education, lower income and lower occupational status75. The evidence for an increased risk of Alzheimers disease for occupational exposures, including pesticides, is generally not consistent61 76-78. A recent review of both case-control and cohort studies published up to June 2003 found that for pesticides, studies of greater quality and prospective design found increased and statistically significant associations79. 6.4.3 Cancer
The International Agency for Research on Cancer (IARC) has classified occupational exposures in spraying and application of non-arsenical insecticides as probable human carcinogens (Group 2A)16. However, epidemiological studies relating pesticide exposure and human cancer have been inconsistent, and the evidence probably cannot be considered to establish a causal relationship for any single pesticide at the present time16. According to IARC and the US Environment Protection Agency (EPA) the weight of evidence suggests that although occupational exposure to other insecticides is probably associated with human cancer, the relationship is not considered causal because of the lack of high-quality evidence. The sites where evidence supports an association with pesticides include: non-Hodgkins lymphoma, leukaemia, multiple myeloma, soft-tissue sarcoma, prostate, pancreas and lung3 15 16 26 27 80 81. Cancers less frequently associated with pesticide exposures include: breast, testis, Hodgkins disease, liver, kidney, rectum, brain and neurological systems.
36
6.4.3.1
Non-Hodgkins Lymphoma
Non-Hodgkins lymphoma is among the most widely studied cancers in relation to pesticide use. The last published Occupational Health Decennial Supplement did not show any excess risk among farmers10. They also plotted the rates of phenoxy herbicide usage by Ministry of Agriculture (now Defra) region against the mortality from Non-Hodgkins lymphoma, but could not find a significant correlation thus concluding the data provided little support for the hypothesised association 30. Many studies have shown farmers to be at an increased risk of Non-Hodgkins lymphoma82. However, the specific practices associated with the risk vary. In addition, pesticides have been suggested as risk factors for Non-Hodgkins lymphoma based on findings from studies of pesticide applicators, pesticide manufacturers, chemical production workers, and military veterans who served in Vietnam83. Findings from studies of humans have been inconsistent, and collectively the epidemiological data do not provide powerful evidence for a causal association between pesticides and NHL. A recent review of the literature listed over 100 papers reporting an Non-Hodgkins lymphoma risk with pesticide exposure83. The study populations included agriculture and applicators, producers and manufacturers, case-control (incident) and cohort (incident) studies, proportional mortality analyses, accidents and environmental exposures. The relative risks ranged from 0.3 to 10.0, however, no summary statistic was estimated. Blair and Zahm3 reviewed the literature and reported that Non-Hodgkins lymphoma has been linked with exposure to phenoxyacetic acid herbicides, OC and OP pesticides. In 18 of 29 studies, farmers were observed to show excesses of Non-Hodgkins lymphoma compared to the general population, but no excess was greater than twofold84. Population-based case-control studies have observed NHL risk with self-reported agricultural exposures to specific pesticide groups23 85 86. A Canadian multi-centre population-based incident case-control study found the risk of Non-Hodgkins lymphoma was increased with exposure to phenoxy and benzoic acid (dicamba) herbicides, to carbamate and OP insecticides, to amide fungicides, and to the fumigant carbon tetrachloride 87. However, the AHS has not observed any excess Non-Hodgkins lymphoma risk in the cohort as a whole88 89, and a similar study of licensed pesticide applicators in Florida also did not observe an increased Non-Hodgkins lymphoma risk4. Cohort and case-control studies that evaluated specific pesticides or classes of pesticides generally have reported inconsistent findings. This may be due, in part, to studies investigating different exposure scenarios and using different variables to classify the exposures. As examples, reports from the US AHS that evaluated specific pesticides found no increased Non Hodgkins lymphoma risk 90-95. Various meta-analyses have examined the risk of Non-Hodgkins lymphoma among farmers and shown associations to be weak. In an analysis of 14 studies of farmers no significant association between farming and Non-Hodgkins lymphoma risk was reported (meta-RR=1.05, 95% CI=0.98-1.12)96, whereas in an analysis of six studies among farmers in the central United States a weak but significant increase in risk was obtained (meta-RR=1.34, 95% CI=1.17 1.55)97. The most comprehensive review, which looked at 36 studies published between 1982 and 1997, reported a significant positive association (meta-RR=1.10, 95% CI=1.03-1.19)98. However, findings across studies were heterogeneous, and when studies were analysed according to study design, only the results from case-control studies produced a significant summary estimate (meta-RR=1.19, 95% CI=1.06-1.33). The summary estimate based on cohort studies was 0.95 (95% CI=0.85-1.07). Another meta-analysis on a smaller number of studies
37
obtained similar summary estimates for eight case-control studies of farmers, although the summary RR was only marginally significant (meta-RR=1.13, 95% CI=1.00-1.27). In contrast, the association based on eight cohort studies was inverse (meta-RR=0.95, 95% CI=0.90-1.00)99. A more recent meta-analysis of 13 case-control studies observed a meta-OR of 1.35 (95% CI=1.17-1.55), but found significant heterogeneity and detected publication bias100. Meta regression showed that a long period of exposure (>10 years) was associated with an increase in the odds for Non-Hodgkins lymphoma of 1.65 (95% CI=1.08-2.51). Boffetta & De Vocht101 obtained a pooled RR (from 50 studies of farmers) of 1.11 (95% CI=1.05-1.17). No association was seen between crop farming and Non-Hodgkins lymphoma risk, but a greater risk was observed amongst livestock workers (meta-RR 1.31, 95% CI 1.08-1.60). Diagnostic analyses did not indicate the presence of publication bias, but there was significant heterogeneity. The authors concluded, Overall, the available evidence supports the hypothesis of a weak association between farming and Non-Hodgkins lymphoma risk. Although the quantitative summary estimate of the strength of the association is uncertain given the heterogeneity in exposure circumstances, it is unlikely that the excess risk in farmers is higher than 10% to 15%. Findings from studies of occupationally exposed pesticide production/manufacturing workers, including studies among phenoxy or chlorophenol production and manufacturing workers102-104, triazine manufacturing workers 105, and alachlor manufacturing workers 106 have generally been mixed. Studies of pesticide applicators have generally shown no excess risk 107 108. In a multinational study of workers enrolled in the IARC cohort, no significant excess of Non Hodgkins lymphoma mortality was observed among workers exposed to phenoxy herbicides or chlorophenols (SMR=1.27, 95% CI=0.88-1.78), with no exposure-response relationship based on duration of exposure109. However, a recently published systematic review and meta-analysis of mortality in crop protection product manufacturing workers identified 26 studies that investigated NHL risk110. The pooled estimate was 1.98 (95% CI=1.45-2.69), whereas in studies of phenoxy-herbicide workers the estimate was 2.01 (95% CI=1.38-2.93). 6.4.3.2 Leukaemia
Investigations have shown some negative, but mainly positive associations between farming and leukaemia111. Leukaemia types linked with farming include acute lymphoid112, chronic lymphoid113 114, acute myeloid115 and chronic myeloid116, with pesticide exposure suggested as the likely cause. A number of meta-analyses have been undertaken. Keller-Byrne et al 117 investigated 19 studies that examined the association between leukaemia and farming. A random-effects meta-analysis yielded a relative risk of 1.09 (95% CI= 0.997-1.19). The meta-RR of 10 case-control studies was 1.23 (95% CI=1.17-1.29). Another meta-analysis of 27 studies obtained a meta-RR of 1.10 (95% CI=1.02-1.18) for white male farmers99. There was a small difference in the meta-RR by study type: in cohort studies it was 1.00 (95% CI=0.91-1.11); in PMR studies it was 1.17 (95% CI=1.07-1.28); whilst in case-control studies it was 1.11 (95% CI=0.96-1.27). In a comprehensive review, 14 of 16 studies showed an association between pesticide exposure and leukaemia, all but one with statistical significance118. Exposure to specific pesticides, including mancozeb and toxaphane119, have been associated with excess mortality from leukaemia. Evidence from a few studies of workers exposed to DDT provide limited support for an association with leukaemia113, and chronic lymphoid leukaemia120. Exposure to dichlorvos and other pesticides like nicotine and pyrethrins gave, after a 20-year latency, significant excesses of leukaemia 113.
38
Findings from studies of occupationally exposed pesticide production/manufacturing workers, including studies among phenoxy or chlorophenol production and manufacturing workers102 104, triazine manufacturing workers105 121, and alachlor manufacturing workers122 have generally been mixed. Studies of pesticide applicators have generally shown no excess risk107 123. A study by Jones et al 110 reviewed 30 studies of crop protection product manufacturing workers from Europe, USA and China, and obtained a pooled estimate of 1.08 (95% CI=0.81-1.44). In a sub-group of 20 cohorts of workers involved in the manufacture of phenoxy herbicides the summary risk estimate was 1.02 (95% CI=0.71-1.46). In contrast to this, a recent meta-analysis of 12 cohort studies published between 1984 and 2004 obtained a fixed effects meta-RR of 1.43 (95% CI=1.05-1.94) for pesticide manufacturing workers124. Also, a systematic review and meta-analysis of 17 cohort and 16 case-control studies published between 1979 and 2005 examining the association between myeloid leukaemia and occupational pesticide exposure estimated a meta-rate ratio for cohort studies of 1.21 (95% CI=0.99-1.48)125. The meta-RR was 6.32 (95% CI=1.90-21.01) for manufacturing workers and 2.14 (95% CI=1.39-3.31) for pesticide applicators. Among case-control studies a meta-RR of 1.39 was obtained (95% CI=1.03-1.88) for men, and 1.38 (95% CI=1.06-1.79) for farmers and agricultural workers. 6.4.3.3 Multiple Myeloma
The Occupational Health Decennial Supplement did not show an increased mortality from myeloma among farmers but did show an increased risk of contracting myeloma among male farmers (PRR=126, 95% CI=105-151)10. Many epidemiological studies, both cohort and case-control, have investigated the relationship between agricultural work and myeloma126 127. Studies that have reported a risk for myeloma have generally reported estimates exceeding 1.0 overall and for specific subgroups, although these were not always statistically significant96 128-136. However, interpretation of the results from studies examining the link between farming and myeloma is limited by the broad exposure classification of farming as an occupational group. Farmers also perform activities such as machine repair, carpentry, welding, painting, equipment operating, pesticide and fertiliser mixing and application, and livestock handling. These activities may involve contact with multiple chemicals and microorganisms, including solvents, fuels and oils, lubricants, wood preservatives, engine exhausts, dusts, zoonotic viruses and other microbes. A number of meta-analyses have been carried out. In one that included 12 studies published between 1977 and 1990 with farmers as an occupational group, RR estimates ranged from 0.4 to 2.5, with a summary RR of 1.12 (95% CI=1.04-1.21)96. In a second analysis of 32 studies published between 1981 and 1996, a random-effects summary RR of 1.23 (95% CI=1.14-1.32) was obtained137. In a third analysis of 22 studies (16 follow-up; 11 PMR; 7 case-control, and 1 other) published through 1994, a summary RR of 1.09 (95% CI=0.99-1.19) was recorded, and the risk was greater than 1.0 irrespective of the study design99. No heterogeneity was observed. The authors also re-analysed the information using 10 studies examined by Blair et al 96, and obtained a summary RR of 1.10 (95% CI=1.01-1.21). A recent study of 13 case-control studies that examined pesticide-related occupations observed a non-significant increase in myeloma risk (OR=1.16, 95% CI=0.99-1.36)100. Although there was no sign of heterogeneity there was an indication that publication bias existed. The authors undertook a process to correct for this with the result of a decrease in the OR to 1.12 (95% CI=0.96-1.30). Nevertheless, only two studies were included in their analysis. A meta-analysis of 25 cohorts from Europe, USA, China and New Zealand of pesticide production workers obtained a pooled estimate of 1.26 (95% CI=0.89-1.77)110. In a sub-group of 20 cohorts of
39
workers involved in the manufacture of phenoxy-herbicides the summary risk estimate was 1.24 (95% CI=0.82-1.86). 6.4.3.4 Soft Tissue Sarcoma
Soft tissue sarcoma is a rare heterogeneous group of tumours that show a broad range of differentiation that may reflect aetiologic distinction138 139. However, it is difficult to study the aetiology of soft tissue sarcoma because of their relatively low incidence and inherent misclassification of histology139. Also, because of the rarity, any study usually groups all the different histological subtypes into one, resulting in a loss of specificity and possibly masking the behaviour of the different subtypes. Soft tissue sarcoma are made up of a heterogeneous mix of cancer subtypes and it has been suggested that occupational risk factors are not uniform across subtypes140. A number of factors have been implicated in the aetiology of soft tissue sarcomas. Viruses have long been suspected as causal in their development, and the association of Karposis and AIDS is supportive of this hypothesis. Tobacco use has been inconsistently associated with soft tissue sarcoma, and diet has been little studied. The role of therapeutic radiation in inducing soft tissue sarcomas is well established 139.
144
A number of studies have found an association between herbicide use and soft tissue sarcoma141 , although, others have not 85 145 146. However, in most of these studies the assumed aetiologic agent is dioxin. The problem with histological subtypes was highlighted by Hoppin and colleagues140, who observed self-reported herbicide use was associated with malignant fibrohistiocytic sarcoma (OR=2.9, 95% CI=1.1-7.3) but not with liposarcoma. 6.4.3.5 Prostate Cancer
In the previous Occupational Health Decennial Supplement, mortality from prostate cancer was significantly increased (PMR=112, 95% CI=106-118) among farmers10. Prostate cancer risk among farmers and other pesticide users has been examined in a large number of studies in Europe and US, with relative risks generally less than two4 84 99 147 148. A recent analysis of the AHS cohort observed an SIR of 1.14 (95% CI=1.05-1.24)149. The study showed use of chlorinated pesticides over 50 years of age and methyl bromide use were significantly associated with prostate cancer risk. Several other pesticides also showed a significantly increased risk, especially among subjects with a family history of prostate cancer, including carbofuran, coumaphos, fonofos, permethrin and phorate. A previous literature review of prostate cancer and occupation found the evidence to be inconclusive150. Various reports have, however, shown small excesses among exposed workers. A meta-analysis of 24 studies, published between 1983 and 1994, estimated the relative risk to be 1.12 (95% CI=1.01-1.24)148, whereas a meta-analysis of 30 studies of farmers obtained a combined RR of 1.07 (95% CI=1.02-1.13)99. In another analysis of 22 studies published between 1995 and 2001 an estimated RR of 1.13 (95% CI=1.04-1.22) was obtained151. Significant heterogeneity was observed and the major sources were geographic location, study design and the healthy worker effect. A stratified analysis revealed a significant increase in the rate ratio of pesticide applicators (RR=1.64, 95% CI=1.13-2.38), whereas this was not the case for farmers (RR=0.97, 95% CI=0.92-1.03). In a review of 18 studies of pesticide manufacturers published between 1984 and 2004, the meta-RR estimate for all studies was 1.28 (95% CI=1.05 1.58)152. In analyses stratified by specific chemical class, increases in prostate cancer risk were seen in all groups, but statistical significance was only found for accidental or non-accidental exposure to phenoxy herbicide contaminated with dioxins and furans. A more recent meta analysis of manufacturers obtained a pooled estimate of 1.03 (95% CI=0.80-1.33; 29 studies) for all cohorts, and 1.16 (95% CI=0.85-1.57; 20 studies) for cohorts exposed to phenoxy herbicides 110.
40
6.4.3.6
Pancreatic Cancer
The risk of pancreatic cancer and exposure to pesticides has been found to be elevated, but rarely statistically significant, in a number of occupational studies of agricultural workers and pesticide users including: farmers153, agricultural pesticide applicators123 154 155, and production workers110. However, a meta-analysis of 28 studies of farmers obtained a summary RR of 0.94 (95% CI=0.86-1.02)99. 6.4.3.7 Lung Cancer
The Occupational Health Decennial Supplement noted a significantly decreased mortality from lung cancer among male farmers (PMR=88, 95% CI=86-91)10. Lung cancer is causally associated with exposure to arsenical compounds156, and an excess risk has been observed among vineyard workers157, arsenical pesticide manufacturers158 159 and general pesticide manufacturers110. Increased risk has also been observed amongst licensed pesticide applicators in the US and rose with the number of years licensed160 161. Similar findings were also seen in Germany162. Studies have observed excesses with exposure to OP and carbamate insecticides and phenoxyacetic acid herbicides160, phenoxy herbicides and/or contaminants (dioxins/furans)109, and evidence of exposure response for others163. However, in a review of studies published in 1992-1997 (19 case-control & 21 cohort, not all investigating lung cancer)108, only one case-control study160 reported an excess risk of lung cancer. Farmers have not been seen to be at risk of lung cancer99, and neither have pesticide applicators studied in the AHS89 or from Florida4. However, lung cancer risk was increased with exposure to some OC insecticides164, diazinon90 and chlorpyrifos165. A recent systematic review and meta-analysis of mortality in crop production product manufacturing workers, reported a pooled risk estimate of 1.22 (95% CI=1.05-1.41) in 32 studies, and of 1.28 (95% CI=1.08-1.52) in 20 studies of phenoxy herbicide exposed cohorts 110. 6.4.3.8 Ovarian Cancer
Two Italian case-control studies have shown an excess risk among women exposed to herbicides166 167. Previous analysis of the AHS cohort of pesticide applicators showed increased mortality of ovarian cancer among female private applicators, but not among spouses of male private applicators89. However, the study of Florida applicators did not provide any data4. The Occupational Health Decennial Supplement reported a 23% increase in mortality (PMR=123, 95% CI=100-151)10. However, the meta-analysis of production workers by Jones et al 110 used 10 studies and did not observe any excess risk (meta-RR=0.93, 95% CI=0.52-1.68), and the meta-analysis by Acquavella et al 99 did not provide any data. 6.4.3.9 Brain Cancer
In the Occupational Health Decennial Supplement no excess deaths from brain cancer were observed among farmers10. The aetiology of brain cancer is still poorly understood. Brain tumours have been associated with several occupational and environmental exposures, including farming168-170 and pesticides171. A review of studies published before 1995 concluded that existing data were insufficient to demonstrate that exposure to pesticides is a clear risk factor for brain tumours172. The authors suggested that it seemed more plausible that exposure to multiple agents and/or other factors are most relevant with respect to brain tumour pathogenesis. A meta-analysis of 33 studies, published between 1981 and 1996, examining the association between brain cancer and farming, yielded a summary RR of 1.30 (95% CI=1.09-1.56)173, which the authors suggested was evidence for a weak association that may be at least partially caused by pesticides and also microorganisms. In the AHS, there was no excess in brain cancer incidence or mortality89 174. A
41
second meta-analysis of 28 studies of farmers reported a summary RR of 1.06 (95% CI=1.02 1.11)99, which was similar to that obtained in an earlier analysis96. A meta-analysis of 30 studies of pesticide production workers reported a pooled estimate of 1.01 (95% CI=0.75-1.36)110, however, the pooled risk for phenoxy-herbicide cohorts was 0.93 (95% CI=.0.64-1.36). 6.4.3.10 Breast Cancer
The Occupational Health Decennial Supplement reported breast cancer mortality was lower than expected among female farmers, with a PMR of 85 (95% CI=74-98)10. However, it has been suggested that some pesticides have an oestrogenic effect thus increasing the risk of breast cancer. Studies that have analysed the association between pesticide exposure and breast cancer have mostly supported an association175. In the AHS, private applicators were seen to have a raised incidence, although this was not statistically significant174, and mortality was below that expected89. Pesticide manufacturers were seen to be at a 14% greater risk of breast cancer (meta-SMR=1.14, 95% CI=0.81-1.61)110. 6.4.3.11 Skin Cancer
Proportional cancer mortality analysis of the Decennial Supplement data (1979-90 and 1982-90) observed no significant excess of melanoma among male farmers (PCMR=0.94, 95% CI=0.78 1.13) or female farmers (PCMR=1.01, 95% CI=0.48-1.85)169. In contrast, there were excesses of non-melanoma skin cancer (male farmers: 1.27, 95% CI=0.95-1.66; female farmers: 4.22, 95% CI=1.70-8.70). The main cause of melanoma is sun exposure. A number of occupations (airline flight crews, polyvinyl chloride manufacture, employment in the oil industry) or occupational exposures (ionising radiation, extremely low frequency electromagnetic fields, polychlorinated biphenyls) have been linked with melanoma but most cohort studies in these areas have been unable to adequately deal with potential confounding by sun exposure176. Case-control studies177 178 and studies on the incidence and/or mortality caused by cutaneous melanoma amongst agricultural workers and farmers or those otherwise exposed to pesticides (e.g. vets), found indication for an increased risk147 179-182, although another showed a decrease154. Similarly, the main cause of non-melanoma skin cancer is sun exposure, in particular ultraviolet radiation183, and exposure to ionising radiation has been shown to increase risk. Exposure to arsenic contaminated drinking water has be shown to increase the risk of non-melanoma skin cancer184 185. However, in industries where arsenic exposure may occur, including the manufacture of glass and nonferrous alloys, smelting and where wood preservatives are used, the risk of non-melanoma skin cancer is rarely presented as in the majority of cases it is rarely fatal. Studies of farmers have generally shown them to be at an increased risk84 99 186 187, and others have reported an association with agricultural chemicals including paraquat188. However, several studies have not included non-melanoma skin cancer in their reports 88 105. The use of arsenic in sheep dip, and other pesticides, has long since disappeared in farming and the use of these chemicals was also intermittent, but due to the long latency, cases may still be the result of exposure. Agricultural workers are also exposed regularly to UV radiation that must be taken into account in any interpretation of results. 6.4.4 Accidents, Injuries and Poisonings
Agriculture has higher rates of occupational accidents than most industries in the UK. The most common fatal accidents in agriculture are those involving vehicles and machinery, falls from height and electrocution189, and according to the HSE, the main causes of death continue to be f :
f
http:/www.hse.gov.uk/statistics/industry/hsagriculture.htm#fatal
42
Transport (being run over or vehicle overturns); Falling from height (through fragile roofs, trees, etc.); Struck by moving or falling objects (bales, trees, etc.); Asphyxiation/drowning; Trapped by something collapsing or overturning; Contact with machinery; Livestock related fatalities; Contact with electricity.
According to reports submitted under the Reporting of Injuries, Disease and Dangerous Occurrences Regulations (RIDDOR), the most frequent categories of fatal accident were those involving vehicles and machinery and falls from height. In addition, electrical injuries account for a relatively high proportion of deaths. Other less common accidents are asphyxiation and injury by an animal22. The Occupational Health Decennial Supplement also confirms these figures, with the highest risk being from pesticide poisoning (PMR=1455, 95% CI=396-3724), injury by animals and plants (PMR=775, 95% CI 479-1186), injury by firearms (PMR=670, 95% CI=424-1006), and animal transport accidents (PMR=468, 95% CI=262-773)10. Farmers have, for a long time, been under considerable financial pressures especially as most are running their own businesses, and it has been widely agreed that because of this the suicide rates are much higher among the group. Among self-employed farmers, the PMR was 193 (415 deaths), whereas among employees it was 136 (498 deaths), and managers/foremen it was 134 (70 deaths). In addition to financial constraints other factors may include ready access to means of successful suicide such as guns and poisons30. The rate of occupational accidents in British agriculture is higher than in most other industries. According to the HSE, the rate of fatal injury to workers in 2006/7 was 8.1 deaths per 100,000 g , the numbers fluctuating over the last decade with no overall trend. In 2006/7, the number of reported major injuries to employees decreased by 6% to 437 from 465 in 2005/6 (a decrease in rate of 11% to 191.1), slips and trips accounted for 20% (86) of major injuries. The next most common cause of major injuries were being hit by a moving or falling object at 17% (76) followed by falls from height 14% (63). The rate of reportable non-fatal injury was 2000 per 100,000 workers in 2005/6, double that of the average for all industries. In farmers under 45 years, the second most common cause of death (after accidents) was suicide. They are twice as likely to commit suicide as the average member of the public190. Suicide among farmers is not just because they have easy access to the means, they are also independent, and decisive. Although there is good information about suicide in farmers, the data are poor on agricultural workers, geographical and sectoral variations, and about other physical, psychological and behavioural effects, and requires further investigation190. 6.4.5 Retinal Degeneration
Retinal degeneration is the leading cause of visual impairment in older adults, but its aetiology is not well known. Non-occupational risk factors include light eye colour, hypertension, history of cardiovascular disease, diabetes, sun exposure, and low antioxidant levels, but studies have produced inconsistent results. Genetic susceptibility may play a role because familial aggregation has been demonstrated191. Little is known about its relationship to occupational or environmental neurotoxic exposures, although the available evidence mainly concerns exposure to pesticides, primarily OP insecticides. In the AHS, retinal degeneration was associated with fungicide use (OR=1.8, 95% CI=1.3-2.6)192. Risk was seen to increase with cumulative day of fungicide use and was greater when application methods involving greater personal exposure
g
http://www.hse.gov.uk/statistics/industry/agriculture.htm
43
were used. Retinal degeneration was also related to a lesser extent with use of OC or carbamate insecticides. However, because retinal degeneration is very rarely fatal, it has not been possible to study this disease in the current analysis, and a more general survey is required.
44
6.5
REFERENCES CITED IN THE APPENDICES
1. Holmes EM. The Pesticide Users' Health Study: Survey of Pesticide Usage: HSE, 2011. 2. Robinson S, Lader D. Smoking and drinking among adults, 2007. General Household Survey 2007. Newport: Office for National Statistics, 2007:62. 3. Blair A, Zahm SH. Agricultural exposures and cancer. Environmental Health Perspectives 1995;103(suppl 8):205-208. 4. Fleming LE, Bean JA, Rudolph M, Hamilton K. Mortality in a cohort of licenced pesticide applicators in Florida. Occupational and Environmental Medicine 1999;56(1):14-21. 5. Waggoner JK, Kullman GJ, Henneberger PK, Umbach DM, Blair A, Alavanja MC, et al. Mortality in the Agricultural Health Study, 1993-2007. Am J Epidemiol;173(1):71-83. 6. Centers for Disease Control and Prevention. Cigarette smoking among adults - United States, 1995. Morbidity and Mortality Weekly Report 1997;46(51):1217-1220. 7. Frost G. The Pesticide Users Health Study: an analysis of cancer incidence (1987-2004). Bootle: Health & Safety Executive, 2011 (under review). 8. McGlynn KA, Quraishi SM, Graubard BI, Weber JP, Rubertone MV, Erickson RL. Persistent organochlorine pesticides and risk of testicular germ cell tumors. J Natl Cancer Inst 2008;100(9):663-71. 9. Hardell L, van Bavel B, Lindstrom G, Carlberg M, Dreifaldt AC, Wijkstrom H, et al. Increased concentrations of polychlorinated biphenyls, hexachlorobenzene, and chlordanes in mothers of men with testicular cancer. Environ Health Perspect 2003;111(7):930-4. 10. Drever F. Occupational Health Decennial Supplement: The Registrar General's Decennial Supplement for England and Wales. London: HMSO, 1995. 11. Coggan D, Harris EC, Brown TB, Rice S, Palmer KT. Occupational mortality in England and Wales, 1991-2000. Newport: Office for National Statistics, 2009:52. 12. Garfitt SJ, Jones K, Mason HJ, Cocker J. Oral and dermal exposure to propetamphos: a human volunteer study. Toxicol Lett 2002;134(1-3):115-8. 13. Garfitt SJ, Jones K, Mason HJ, Cocker J. Exposure to the organophosphate diazinon: data from a human volunteer study with oral and dermal doses. Toxicol Lett 2002;134(1 3):105-13. 14. Griffin P, Mason H, Heywood K, Cocker J. Oral and dermal absorption of chlorpyrifos: a human volunteer study. Occup Environ Med 1999;56(1):10-3. 15. Doe JE, Paddle GM. The Evaluation of Carcinogenic Risk to Humans - Occupational Exposures in the Spraying and Application of Insecticides. Regulatory Toxicology and Pharmacology 1994;19(3):297-308. 16. IARC. Occupational exposure in insecticide application and some pesticides, volume 53. IARC Monograph on Evaluating the Carcinogenic Risks to Humans. Lyon: International Agency for Research on Cancer, 1991:1-587.
45
17. Blair A, Zahm SH. Herbicides and cancer: A review and discussion of methodologic issues. Recent Results in Cancer Research 1990;120:132-145. 18. Blair A, Zahm SH. Methodologic issues in exposure assessment for case-control studies of cancer and herbicides. American Journal of Industrial Medicine 1990;18(3):285-293. 19. Blondell JM. Problems encountered in the design of epidemiologic studies of cancer in pesticide users. La Medicina del Lavoro 1990;81(6):524-529. 20. Cordes DH, Rea DF. Farming: a hazardous occupation. Occupational Medicine - State of the Art Reviews 1991;6(3):327-334. 21. CSA. Cancer risk of pesticides in agricultural workers. Council on Scientific Affairs. Journal of the American Medical Association 1988;260(7):959-966. 22. HSE. Fatal injuries in farming, forestry horticulture and associated industries 2007/2008. 2008. 23. Cantor KP, Blair A, Everett GD, Gibson R, Burmeister LF, Brown LM, et al. Pesticides and other agricultural risk factors for non-Hodgkin's Lymphoma among men in Iowa and Minnesota. Cancer Research 1992;52(9):2447-2455. 24. WHO. Public health impact of pesticides used in agriculture. Geneva: World Health Organization, 1990. 25. Zheng TZ, Blair A, Zhang YW, Weisenburger DD, Zahm SH. Occupation and risk of non Hodgkin's lymphoma and chronic lymphocytic leukemia. Journal of Occupational and Environmental Medicine 2002;44(5):469-474. 26. Moses M, Johnson ES, Anger WK, Burse VW, Horstman SW, Jackson RJ, et al. Environmental equity and pesticide exposure. Toxicology and Industrial Health 1993;9(5):913-959. 27. Maroni M, Fait A. Health effects in a man from long-term exposure to pesticides. A review of the 1975-1991 literature. Toxicology 1993;78(1-3):1-180. 28. Schenker MB, Christiani D, Cormier Y, Dimich-Ward H, Doekes G, Dosman J, et al. Respiratory health hazards in agriculture. American Journal of Respiratory and Critical Care Medicine 1998;158(5):S1-S76. 29. Fink JN, Ortega HG, Reynolds HY, Cormier YF, Fan LL, Franks TJ, et al. Needs and opportunities for research in hypersensitivity pneumonitis. American Journal of Respiratory and Critical Care Medicine 2005;171(7):792-798. 30. Coggon D, Inskip H, Winter P, Pannett B. Occupational mortality of men. In: Drever F, editor. Occupational Health, Decennial Supplement. The Registrar General's Decennial Supplement for England and Wales. London: HMSO, 1995:23-43. 31. Alavanja MC, Sandler DP, McMaster SB, Zahm SH, McDonnell CJ, Lynch CF, et al. The Agricultural Health Study. Environmental Health Perspectives 1996;104(4):362-369. 32. Hoppin JA, Umbach DM, Kullman GJ, Henneberger PK, London SJ, Alavanja MCR, et al. Pesticides and other agricultural factors associated with self-reported farmer's lung among farm residents in the Agricultural Health Study. Occupational and Environmental Medicine 2007;64(5):334-342.
46
33. LeVan TD, Koh WP, Lee HP, Koh D, Yu MC, London SJ. Vapor, dust, and smoke exposure in relation to adult-onset asthma and chronic respiratory symptoms - The Singapore Chinese Health Study. American Journal of Epidemiology 2006;163(12):1118-1128. 34. Valcin M, Henneberger PK, Kullman GJ, Umbach DM, London SJ, Alavanja MCR, et al. Chronic bronchitis among nonsmoking farm women in the agricultural health study. Journal of Occupational and Environmental Medicine 2007;49(5):574-583. 35. Hoppin JA, Valcin M, Henneberger PK, Kullman GJ, Umbach DM, London SJ, et al. Pesticide use and chronic bronchitis among farmers in the Agricultural Health Study. American Journal of Industrial Medicine 2007;50:969-979. 36. Von Essen S, Romberger DJ. The respiratory inflammatory response to the swine confinement building environment: The adaptation to respiratory exposures in the chronically exposed worker. Journal of Agricultural Safety and Health 2003;9(3):185 196. 37. Monso M, Riu E, Radon K, Magarolas R, Danuser B, Iversen M, et al. Chronic obstructive pulmonary disease in never-smoking animal farmers working inside confinement buildings. American Journal of Industrial Medicine 2004;46(4):357-362. 38. Chen Y, Horne SL, McDuffie HH, Dosman JA. Combined effect of grain farming and smoking on lung function and the prevalence of chronic bronchitis. International Journal of Epidemiology 1991;20(2):416-423. 39. Melbostad E, Wijnand E, Magnus P. Chronic bronchitis in farmers. Scandinavian Journal of Work, Environment & Health 1997;23(4):271-280. 40. Vohlonen I, Tupi K, Terho EO, Husman K. Prevalence and incidence of chronic bronchitis and farmers lung with respect to the geographical location of the farm and the work of farmers. European Journal of Respiratory Diseases Supplement 1987;152:37-46. 41. Lamprecht B, Schirnhofer L, Kaiser B, Studnicka M, Buist AS. Farming and the prevalence of non-reversible airways obstruction results from a population-based study. American Journal of Industrial Medicine 2007;50(6):421-426. 42. Sprince NL, Lewis MQ, Whitten PS, Reynolds SJ, Zwerling C. Respiratory symptoms: Associations with pesticides, silos, and animal confinement in the Iowa Farm Family Health and Hazard Surveillance Project. American Journal of Industrial Medicine 2000;38(4):455-462. 43. Wilkins JR, Engelhardt HL, Rublaitus SM, Crawford JM, Fisher JL, Bean TL. Prevalence of chronic respiratory symptoms among Ohio cash grain farmers. American Journal of Industrial Medicine 1999;35(2):150-163. 44. Senthilselvan A, McDuffie HH, Dosman JA. Association of asthma with use of pesticides. Results of a cross-sectional survey of farmers. American Review of Respiratory Diseases 1992;146(4):884-887. 45. Hoppin JA, Umbach DM, London SJ, Alavanja MCR, Sandler DP. Chemical predictors of wheeze among farmer pesticide applicators in the Agricultural Health Study. American Journal of Respiratory and Critical Care Medicine 2002;165(5):683-689.
47
46. Hoppin JA, Umbach DM, London SJ, Lynch CF, Alavanja MCR, Sandler DP. Pesticides associated with wheeze among commercial pesticide applicators in the agricultural health study. American Journal of Epidemiology 2006;161(11):S85-S85. 47. Alavanja MCR, Hoppin JA, Kamel F. Health effects of chronic pesticide exposure: Cancer and neurotoxicity. Annual Review of Public Health 2004;25:155-197. 48. Keifer M C, Mahurin RK. Chronic neurologic effects of pesticide overexposure. Occupational Medicine - State of the Art Reviews 1997;12(2):291-304. 49. Savage EP, Keefe TJ, Mounce LM, Heaton RK, Lewis JA, Burcar PJ. Chronic neurological sequelae of acute organophosphate pesticide poisoning. Archives of Environmental Health 1988;43(1):38-45. 50. Solomon C, Poole J, Palmer KT, Peveler R, Coggon D. Neuropsychiatric symptoms in past users of sheep dip and other pesticides. Occupational and Environmental Medicine 2007;64(4):259-266. 51. Kamel F, Engel LS, Gladen BC, Hoppin JA, Alavanja MCR, Sandler DP. Neurologic symptoms in licensed private pesticide applicators in the Agricultural Health Study. Environmental Health Perspectives 2005;113(7):877-882. 52. Beseler C, Stallones L, Hoppin JA, Alavanja MCR, Blair A, Keefe T, et al. Depression and pesticide exposures in female spouses of licensed pesticide applicators in the Agricultural Health Study cohort. Journal of Occupational and Environmental Medicine 2006;48(10):1005-1013. 53. Bazylewicz-Walczak B, Majczakowa W, Szymczak M. Behavioural effects of occupational exposure to organophosphorous pesticides in females greenhouse planting workers. Neurotoxicology 1999;20(5):819-826. 54. Stokes L, Stark A, Marshall E, Narang A. Neurotoxicity among pesticide applicators exposed to organophosphates. Occupational and Environmental Medicine 1995;52(10):648-653. 55. Steenland K, Dick RB, Howell RJ, Chrislip DW, Hines CJ, Reid TM, et al. Neurologic function among termiticide applicators exposed to chlorpyrifos. Environmental Health Perspectives 2000;108:293-300. 56. Pilkington A, Buchanan D, Jamal GA, Gillham R, Hansen S, Kidd M, et al. An epidemiological study of the relations between exposure to organophosphate pesticides and indices of chronic peripheral neuropathy and neuropsychological abnormalities in sheep farmers and dippers. Occupational and Environmental Medicine 2001;58(11):702-710. 57. Sanborn M, Kerr KJ, Sanin LH, Cole DC, Bassil KL, Vakil C. Non-cancer health effects of pesticides: systematic review and implications for family doctors. Can Fam Physician 2007;53(10):1712-20. 58. Hoogenraad TU. Dithiocarbamates and Parkinsons disease. Lancet 1988;1(8588):767. 59. Priyadarshi A, Khuder SA, Schaub EA, Priyadarshi SS. Environmental risk factors and Parkinson's disease: a metaanalysis. Environmental Research Section A 2001;86(2):122 7.
48
60. Kamel F, Tanner C, Umbach D, Hoppin J, Alavanja M, Blair A, et al. Pesticide exposure and self-reported Parkinson's disease in the Agricultural Health Study. American Journal of Epidemiology 2007;165(4):364-74. 61. Baldi I, Lebailly P, Mohammed-Brahim B, Letenneur L, Dartiigues J-F, Brochard P. Neurodegenerative diseases and exposure to pesticides in the elderly. American Journal of Epidemiology 2003;157(5):409-414. 62. Le Couteur DG, McLean AJ, Taylor MC, Woodham BL, Board PG. Pesticides and Parkinsons disease. Biomedicine & Pharmacotherapy 1999;53(3):122-130. 63. Ascherio A, Chen H, Weisskopf MG, O'Reilly E, McCullough ML, Calle EE, et al. Pesticide exposure and risk for Parkinson's disease. Annals of Neurology 2006;60(2):197-203. 64. Tchsen F, Jensen AA. Agricultural work and the risk of Parkinsons disease in Denmark, 1981-1993. Scandinavian Journal of Work Environment & Health 2000;26(4):359-362. 65. Brown T, Rumsby P, Capleton A, Rushton L, Levy L. Pesticides and Parkinson's disease - is there a link? Environmental Health Perspectives 2006;114(2):156-64. 66. Li AA, Mink PJ, McIntosh LJ, Teta MJ, Finley B. Evaluation of epidemiologic and animal data associating pesticides with Parkinson's disease. Journal of Occupational and Environmental Medicine 2005;47(10):1059-1087. 67. Dick S, Semple S, Dick F, Seaton A. Occupational titles as risk factors for Parkinson's disease. Occupational Medicine 2007;57(1):50-56. 68. Dick FD, De Palma G, Ahmadi A, Scott NW, Prescott GJ, Bennett J, et al. Environmental risk factors for Parkinson's disease and parkinsonism: the Geoparkinson study. Occupational and Environmental Medicine 2007;64(10):666-672. 69. Hancock DB, Martin ER, Mayhew GM, Stajich JM, Jewett R, Stacy MA, et al. Pesticide exposure and risk of Parkinson's disease: A family-based case-control study. BMC Neurology 2008;8:6. 70. Chancellor AM, Slattery JM, Fraser H, Warlow CP. Risk factors for motor neuron disease: a case-control study based on patients from the Scottish Motor Neuron Disease Register. Journal of Neurology, Neurosurgery and Psychiatry 1993;56(11):1200-1206. 71. Gunnarsson LG, Bodin L, Soderfeldt B, Axelson O. A case-control study of motor neuron disease: its relation to heritability, and occupational exposures, particularly to solvents. British Journal of Industrial Medicine 1992;49(11):791-798. 72. Granieri E, Carreras M, Tola R, Paolino E, Tralli G, Eleopra R, et al. Motor neuron disease in the province of Ferrara, Italy, in 1964-1982. Neurology 1988;38(10):1604-1608. 73. McGuire V, Longstreth WT, Nelson LM, Koepsell TD, Checkoway H, Morgan MS, et al. Occupational exposures and amyotrophic lateral sclerosis - A population-based casecontrol study. American Journal of Epidemiology 1997;145(12):1076-1088. 74. Savettieri G, Salemi G, Arcara A, Cassata M, Castiglione MG, Fierro B. A case-control study of amyotrophic lateral sclerosis. Neuroepidemiology 1991;10(5-6):242-245.
49
75. Cummings JL, Cole G. Alzheimer disease. Journal of the American Medical Association 2002;287(18):2335-2338. 76. McDowell I, Hill G, Lindsay J, Helliwell B, Costa L. The Canadian study of health and aging: risk factors for Alzheimers disease in Canada. Neurology 1994;44:2073-2080. 77. Gauthier E, Fortier I, Courchesne F, Pepin P, Mortimer J, Gauvreau D. Environmental pesticide exposure as a risk factor for Alzheimer's disease: A case-control study. Environmental Research Section A 2001;86(1):37-45. 78. Van Duijn CM. Epidemiology of the dementias: Recent developments and new approaches. Journal of Neurology, Neusurgery,a dn Psychiatry 1996;60(5):478-488. 79. Santibanez M, Bolumar F, Garcia AM. Occupational risk factors in Alzheimer's disease: a review assessing the quality of published epidemiological studies. Occupational and Environmental Medicine 2007;64:723-732. 80. Alavanja MCR, Bonner MR. Pesticides and human cancers. Cancer Investigation 2005;23(8):700-711. 81. Munro IC, Carlo GL, Orr JC, Sund KG, Wilson RM, Kennepohl E, et al. A comprehensive, integrated review and evaluation of the scientific evidence relating to the safety of the herbicide 2,4-D. International Journal of Toxicology 1992;11(5):559-664. 82. Descatha A, Jenabian A, Conso F, Ameille J. Occupational exposures and haematological malignancies: overview on human recent data. Cancer Causes & Control 2005;16(8):939-953. 83. Alexander D, Mink PJ, Adami HO, Chang ET, Cole P, Mandel JS, et al. The non-Hodgkin lymphomas: a review of the epidemiologic literature. International Journal of Cancer 2007;120(suppl 23):1-39. 84. Blair A, Zahm SH. Cancer among farmers. Occupation Medicine - State of the Art Reviews 1991;6:335-354. 85. Woods JS, Polissar L, Severson RK, Heuser LS, Kulander BG. Soft tissue sarcoma and non Hodgkins lymphoma in relation to phenoxyherbicide and chlorinated phenol exposure in western Washington. Journal of the National Cancer Institute 1987;78(5):899-910. 86. Zahm SH, Weisenburger DD, Babbit PA, Saal RC, Vaught JB, Cantor KP, et al. A casecontrol study of non-Hodgkins lymphoma and the herbicide 2,4-dichlorophenoxyacetic acid (2,4-D) in eastern Nebraska. Epidemiology 1990;1(5):349-356. 87. McDuffie HH, Pahwa P, McLaughlin JR, Spinelli JJ, Fincham S, Dosman JA, et al. Non Hodgkins lymphoma and specific pesticide exposures in men: cross-Canada study of pesticides and health. Cancer Epidemiology, Biomarkers & Prevention 2001;10(11):1155-1163. 88. Alavanja MCR, Sandler DP, Lynch CF, Knott C, Lubin JH, Tarone R, et al. Cancer incidence in the Agricultural Health Study. Scandinavian Journal of Work Environment & Health 2005;31(suppl 1):39-45.
50
89. Blair A, Sandler DP, Tarone R, Lubin J, Thomas K, Hoppin JA, et al. Mortality among participants in the Agricultural Health Study. Annals of Epidemiology 2005;15(4):279 285. 90. Beane Freeman LE, Bonner MR, Blair A, Hoppin JA, Sandler DP, Lubin JH, et al. Cancer incidence among male pesticide applicators in the Agricultural Health Study cohort exposed to diazinon. American Journal of Epidemiology 2005;162(11):1070-1079. 91. Bonner MR, Coble J, Blair A, Beane Freeman LE, Hoppin JA, Sandler DP, et al. Malathion exposure and the incidence of cancer in the Agricultural Health Study. American Journal of Epidemiology 2007;166(9):1023-1034. 92. Bonner MR, Lee WJ, Sandler DA, Hoppin JA, Dosemeci M, Alavanja MCR. Occupational exposure to carbofuran and the incidence of cancer in the Agricultural Health Study. Environmental Health Perspectives 2005;113(3):285-289. 93. Rusiecki JA, De Roos A, Lee WJ, Dosemeci M, Lubin JH, Hoppin JA, et al. Cancer incidence among pesticide applicators exposed to atrazine in the Agricultural Health Study. Journal of the National Cancer Institute 2004;96(18):1375-1382. 94. Rusiecki JA, Hou LF, Lee WJ, Blair A, Dosemeci M, Lubin JH, et al. Cancer incidence among pesticide applicators exposed to metolachlor in the Agricultural Health Study. International Journal of Cancer 2006;118(12):3118-3123. 95. Rusiecki JA, Patel R, Koutros S, Beane-Freeman L, Landgren O, Bonner MR, et al. Cancer incidence among pesticide applicators exposed to permethrin in the Agricultural Health Study. Environmental Health Perspectives 2009;117(4):581-586. 96. Blair A, Zahm SH, Pearce N, Heineman EF, Fraumeni Jr JF. Clues to cancer etiology from studies of farmers. Scandinavian Journal of Work Environment & Health 1992;18(4):209-215. 97. Keller-Byrne J, Khuder SA, Schaub EA, McAfee O. A meta-analysis of non-Hodgkin lymphoma among farmers in the Central United States. American Journal of Industrial Medicine 1997;31:442-4. 98. Khuder SA, Schaub EA, Keller-Byrne J. Meta-analyses of non-Hodgkin lymphoma and farming. Scandinavian Journal of Work Environment & Health 1998;24(4):255-261. 99. Acquavella J, Olsen G, Cole P, Ireland B, Kaneene J, Schuman S, et al. Cancer among farmers: A meta-analysis. Annals of Epidemiology 1998;8(1):64-74. 100. Merhi M, Raynal H, Cahuzac E, Vinson F, Cravedi JP, Gamet-Payrastre L. Occupational exposure to pesticides and risk of hematopoietic cancers: meta-analysis of case-control studies. Cancer Causes & Control 2007;18:1209-1226. 101. Boffetta P, de Vocht F. Occupation and the risk of non-Hodgkin lymphoma. C ancer Epidemiology, Biomarkers & Prevention 2007;16(3):369-372. 102. Burns CJ, Beard KK, Cartmill JB. Mortality in chemical workers potentially exposed to 2,4-dichlorophenoxyacetic acid (2,4-D) 1945-94: an update. Occupational and Environmental Medicine 2001;58(1):24-30.
51
103. Coggon D, Pannett B, Winter PD. Mortality and incidence of cancer at four factories making phenoxy herbicides. British Journal of Industrial Medicine 1991;48(3):173 178. 104. Hooiveld M, Heederik DJJ, Kogevinas M, Boffetta P, Needham LL, Patterson DG, et al. Second follow-up of a Dutch cohort occupationally exposed to phenoxy herbicides, chlorophenols, and contaminants. American Journal of Epidemiology 1998;147(9):891 901. 105. MacLennan PA, Delzell E, Sathiakumar N, Myers SL. Mortality among triazine herbicide manufacturing workers. Journal of Toxicology and Environmental Health-Part aCurrent Issues 2003;66(6):501-517. 106. Leet T, Acquavella J, Lynch C, Anne M, Weiss N, Vaugn T, et al. Cancer incidence among alachlor manufacturing workers. American Journal of Industrial Medicine 1996;30(3):300-306. 107. Swaen GMH, van Amelsvoort L, Slangen JJM, Mohren DCL. Cancer mortality in a cohort of licensed herbicide applicators. International Archives of Occupational and Environmental Health 2004;77(4):293-295. 108. Dich J, Zahm SH, Hanberg A, Adami HO. Pesticides and cancer. C ancer Causes & Control 1997;8(3):420-443. 109. Kogevinas M, Becher H, Benn T, Bertazzi PA, Boffetta P, BuenodeMesquita HB, et al. Cancer mortality in workers exposed to phenoxy herbicides, chlorophenols, and dioxins - An expanded and updated international cohort study. American Journal of Epidemiology 1997;145(12):1061-1075. 110. Jones DR, Sutton AJ, Abrams KR, Fenty J, Warren F, Rushton L. Systematic review and meta-analysis of mortality in crop protection product manufacturing workers. Occupational and Environmental Medicine 2009;66(1):7-15. 111. Linet MS, Devesa S, Morgan GJ. The Leukaemias. In: Schottenfeld D, Fraumeni Jr JF, editors. Cancer Epidemiology and Prevention. Oxford: Oxford University Press, 2006:841-871. 112. Donham KJ, Berg JW, Sawin RS. Epidemiologic relationships of the bovine population and human leukemia in Iowa. Am J Epidemiol 1980;112(1):80-92. 113. Brown LM, Blair A, Gibson R, Everett GD, Cantor KP, Schuman LM, et al. Pesticide exposures and other agricultural risk factors for leukemia among men in Iowa and Minnesota. Cancer Research 1990;50(20):6585-6591. 114. Blair A, White DW. Leukemia cell types and agricultural practices in Nebraska. Archives of Environmental Health 1985;40(4):211-214. 115. Pearce NE, Sheppard RA, Howard JK, Fraser J, Lilley BM. Leukemia among New Zealand agricultural workers. A cancer registry-based study. American Journal of Epidemiology 1986;124(3):402-409. 116. Blair A, White DW. Death certificate study of leukemia among farmers from Wisconsin. Journal of the National Cancer Institute 1981;66(6):1027-1030.
52
117. Keller-Byrne JE, Khuder SA, Schaub EA. Meta-analysis of leukemia and farming. Environmental Research 1995;71(1):1-10. 118. Sanborn M, Cole D, Kerr K, Vakil C, Sanin LH, Bassil K. Pesticides literature review: The Ontario College of Family Physicians, 2004. 119. Mills PK, Yang R, Riordan D. Lymphohematopoietic cancers in the United Farm Workers of America (UFW), 1988-2001. Cancer Causes & Control 2005;16(7):823-830. 120. Flodin U, Fredrisksson M, Persson B, Axelson O. Chronic lymphatic leukaemia and engine exhausts, fresh wood, and DDT: a case-referent study. British Journal of Industrial Medicine 1988;45(1):33-38. 121. Sathiakumar N, Delzell E. A review of epidemiologic studies of triazine herbicides and cancer. Critical Reviews in Toxicology 1997;27(6):599-612. 122. Acquavella JF, Delzell E, Cheng H, Lynch CF, Johnson G. Mortality and cancer incidence among alachlor manufacturing workers 1968-99. Occupational and Environmental Medicine 2004;61(8):680-685. 123. Figa-Talamanca I, Mearelli I, Valente P, Bascherini S. Cancer mortality in a cohort of rural licensed pesticide users in the province of Rome. International Journal of Epidemiology 1993;22(4):579-583. 124. Van Maele-Fabry G, Duhayon S, Mertens C, Lison D. Risk of leukaemia among pesticide manufacturing workers: A review and meta-analysis of cohort studies. Environmental Research 2008;106(1):121-137. 125. Van Maele-Fabry G, Duhayon S, Lison D. A systematic review of myeloid leukemias and occupational pesticide exposure. Cancer Causes & Control 2007;18(5):457-478. 126. Alexander D, Mink PJ, Adami HO, Cole P, Mandel JS, Oken MM, et al. Multiple myeloma: A review of the epidemiologic literature. International Journal of Cancer 2007;120(suppl12):40-61. 127. De Roos AJ, Baris D, Weiss NS, Herrinton LJ. Multiple myeloma. In: Schottenfeld D, Fraumeni Jr JF, editors. Cancer Epidemiology and Prevention. Oxford: Oxford University Press, 2006:919-945. 128. Cuzick J, De Stavola B. Multiple myeloma a case-control study. British Journal of Cancer 1988;57(5):516-520. 129. La Vecchia C, Negri E, D'Avanzo B, Franceschi S. Occupation and lymphoid neoplasms. British Journal of Cancer 1989;60(3):385-388. 130. Reif J, Pearce N, Fraser J. Cancer risks in New Zealand farmers. International Journal of Epidemiology 1989;18(4):768-774. 131. Heineman EF, Olsen JH, Pottern LM, Gomez M, Raffin E, Blair A. Occupational risk factors for multiple myeloma among Danish men. Cancer Causes & Control 1992;3(6):555-568. 132. Franceschi S, Barbone F, Bidoli E, Guarneri S, Serraino D, Talamini R, et al. Cancer risk in farmers: results from a multi-site case-control study in north-eastern Italy. International Journal of Cancer 1993;53(5):740-745.
53
133. Keller JE, Howe HL. Case-control studies of cancer in Illinois farmers using data from the Illinois State Cancer Registry and the U.S. Census of Agriculture. European Journal of Cancer 1994;30A(4):469-473. 134. Lee E, Burnett CA, Lalich N, Cameron LL, Sestito JP. Proportionate mortality of crop and livestock farmers in the United States, 1984-1993. American Journal of Industrial Medicine 2002;42(5):410-420. 135. Baris D, Silverman DT, Brown LM, Swanson GM, Hayes RB, Schwartz AG, et al. Occupation, pesticide exposure and risk of multiple myeloma. Scandinavian Journal of Work Environment & Health 2004;30(3):215-222. 136. Cantor KP, Blair A. Farming and mortality from multiple myeloma: a case-control study with the use of death certificates. Journal of the National Cancer Institute 1984;72(2):251-255. 137. Khuder SA, Mutgi AB. Meta-analyses of multiple myeloma and farming. American Journal of Industrial Medicine 1997;32(5):510-516. 138. Toro JR, Travis LB, Wu HJ, Zhu K, Fletcher CDM, Devesa S. Incidence patterns of soft tissue sarcomas, regardless of primary site, in the Surveillance, Epidemiology and End Results program, 1978-2001: an analysis of 26,758 cases. International Journal of Cancer 2006;119(12):2922-2930. 139. Berwick M. Soft tissue sarcoma. In: Schottenfeld D, Fraumeni Jr JF, editors. C ancer Epidemiology and Prevention. Oxford: Oxford University Press, 2006:959-974. 140. Hoppin JA, Tolbert PE, Flanders WD, Zhang RH, Daniels DS, Ragsdale BD, et al. Occupational risk factors for sarcoma subtypes. Epidemiology 1999;10(3):300-306. 141. Hardell L, Sandstrom A. Case-control study: soft-tissue sarcomas and exposure to phenoxyacetic acids or chlorophenols. British Journal of Cancer 1979;39:711-717. 142. Eriksson M, Hardell L, Berg NO, Moller T, Axelson O. Soft-tissue sarcomas and exposure to chemical substances: a case-referent study. British Journal of Industrial Medicine 1981;38(1):27-33. 143. Hardell L, Eriksson M. The association between soft-tissue sarcoma and exposure to phenoxyacetic acids: a case-referent study. Cancer 1988;62(3):652-656. 144. Wingren G, Fredrikson M, Brage H, Nordenskjold B, Axelson O. Soft tissue sarcoma and occupational exposures. Cancer 1990;66:806-811. 145. Hoar SK, Blair A, Holmes FF, Boysen CD, Robel RJ, Hoover R, et al. Agricultural herbicide use and risk of lymphoma and soft tissue sarcoma. Journal of the American Medical Association 1986;256(9):1141-1147. 146. Smith AH, Pearce NE, Fisher DO, Giles HJ, Teague CA, Howard JK. Soft tissue sarcoma and exposure to phenoxyherbicides and chlorophenols in New Zealand. Journal of the National Cancer Institute 1984;73(5):1111-1117. 147. Cerhan JR, Cantor KP, Williamson K, Lynch CF, Torner JC, Burmeister LF. Cancer mortality among Iowa farmers: Recent results, time trends, and lifestyle factors (United States). Cancer Causes & Control 1998;9(3):311-319.
54
148. Keller-Byrne JE, Khuder SA, Schaub EA. Meta-analyses of prostate cancer and farming. American Journal of Industrial Medicine 1997;31(5):580-586. 149. Alavanja MCR, Samanic C, Dosemeci M, Lubin J, Tarone R, Lynch CF, et al. Use of agricultural pesticides and prostate cancer risk in the Agricultural Health Study cohort. American Journal of Epidemiology 2003;157(9):800-814. 150. Muir KR, Harriss C. Prostate cancer and occupation: A literature review. Contract Research Report 191/1998: HSE Books, 1998. 151. Van Maele-Fabry G, Willems JL. Occupation related pesticide exposure and cancer of the prostate: a meta-analysis. Occupational and Environmental Medicine 2003;60(9):634 642. 152. Van Maele-Fabry G, Libotte V, Willems J, Lison D. Review and meta-analysis of risk estimates for prostate cancer in pesticide manufacturing workers. Cancer Causes & Control 2006;17(4):353-373. 153. Falk RT, Pickle LW, Fontham ET, Correa P, Morse A, Chen V, et al. Occupation and pancreatic cancer in Louisiana. American Journal of Industrial Medicine 1990;18(5):565-576. 154. Forastiere F, Quercia A, Miceli M, Settimi L, Terenzoni B, Rapiti E, et al. Cancer among farmers in central Italy. Scandinavian Journal of Work Environment & Health 1993;19(6):382-389. 155. Zhong JP, Rafnsson V. Cancer incidence among Icelandic pesticide users. A merican Journal of Respiratory and Critical Care Medicine 1996;25:1117-1124. 156. IARC. Overall evaluations of carcinogenicity: An updating of IARC Monographs volumes 1 to 42. Lyon: International Agency for Research on Cancer, 1987. 157. Lchtrath H. The consequences of chronic arsenic poisoning among Moselle wine growers. Pathoanatomical investigations of post-mortem examinations between 1960 and 1977. Journal of Cancer Research and Clinical Oncology 1983;105(2):173-182. 158. Mabuchi K, Lilienfeld AM, Snell LM. Lung cancer among pesticide workers exposed to inorganic arsenicals. Archives of Environmental Health 1979;34(5):312-320. 159. Mabuchi K, Lilienfeld AM, Snell LM. Cancer and occupational exposure to arsenic: a study of pesticide workers. Preventative Medicine 1980;9(1):51-77. 160. Pesatori AC, Sontag JM, Lubin JH, Consonni D, Blair A. Cohort mortality and nested case-control study of lung cancer among structural pest control workers in Florida (United States). Cancer Causes & Control 1994;5(4):310-318. 161. Blair A, Grauman DJ, Lubin JH, Fraumeni Jr JF. Lung cancer and other causes of death among licensed pesticide applicators. Journal of the National Cancer Institute 1983;71(1):31-37. 162. Barthel E. Increased risk of lung cancer in pesticide-exposed male agricultural workers. Journal of Toxicology and Environmental Health 1981;8(5-6):1027-1040.
55
163. Alavanja MCR, Dosemeci M, Samanic C, Lubin J, Lynch CF, Knott C, et al. Pesticides and lung cancer risk in the Agricultural Health Study cohort. American Journal of Epidemiology 2004;160(9):876-885. 164. Purdue MP, Hoppin JA, Blair A, Dosemeci M, Alavanja MCR. Occupational exposure to organochlorine insecticides and cancer incidence in the Agricultural Health Study. International Journal of Cancer 2007;120(3):642-649. 165. Lee WJ, Blair A, Hoppin JA, Lubin JH, Rusiecki JA, Sandler DP, et al. Cancer incidence among pesticide applicators exposed to chlorpyrifos in the agricultural health study. Journal of the National Cancer Institute 2004;96(23):1781-1789. 166. Donna A, Betta P, Robutti F, Crosignani P, Berrino F, Bellingeri D. Ovarian mesothelial tumors and herbicides: a case-control study. Carcinogenesis 1984;5(7):941-942. 167. Donna A, Cosignani P, Robutti F, Betta PG, Bocca R, Mariana N, et al. Triazine herbicides and ovarian epithelial neoplasms. Scandinavian Journal of Work Environment & Health 1989;15(1):47-53. 168. Firth HM, Cooke KR, Herbison GP. Male cancer incidence by occupation: New Zealand, 1972-1984. International Journal of Epidemiology 1996;15(1):14-21. 169. Inskip H, Coggon D, Winter P, Pannett B. Mortality of farmers and farmers' wives in England and Wales 1979-80, 1982-90. Occupational and Environmental Medicine 1996;53(11):730-735. 170. De Roos AJ, Stewart PA, Linet MS, Heineman EF, Dosemeci M, Wilcosky T, et al. Occupation and the risk of adult glioma in the United States. Cancer Causes & Control 2003;14(2):139-150. 171. Musicco M, Sant M, Molinari S, Filippini G, Gatta G, Berrino F. A case-control study of brain gliomas and occupational exposure to chemical carcinogens: the risk to farmers. American Journal of Epidemiology 1988;128(4):778-785. 172. Bohnen NI, Kurland LT. Brain tumor and exposure to pesticides in humans: a review of the epidemiologic data. Journal of the Neurological Sciences 1995;132(2):110-121. 173. Khuder SA, Mutgi AB, Schaub EA. Meta-analyses of brain cancer and farming. American Journal of Industrial Medicine 1998;34(3):252-260. 174. Alavanja MC, Sandler DP, Lynch CF, Knott C, Lubin JH, Tarone R, et al. Cancer incidence in the agricultural health study. Scandinavian Journal of Work & Environmental Health 2005;31(suppl 1):39-45; discussion 5-7. 175. Bassil KL, Vakil C, Sanborn M, Cole DC, Kaur JS, Kerr KJ. Cancer health effects of pesticides - Systematic review. Canadian Family Physician 2007;53(10):1705-1711. 176. Gruber SB, Armstrong BK. Cutaneous and ocular melanoma. In: Schottenfeld D, Fraumeni Jr JF, editors. Cancer Epidemiology and Prevention. Oxford: Oxford University Press, 2006:1196-1229. 177. Green A, McCredie M, MacKie RM, Giles G, Young P, Morton C, et al. A c ase-control study of melanomas of the soles and palms (Australia and Scotland). Cancer Causes & Control 1999;10(1):21-25.
56
178. Settimi L, Comba P, Carrieri P, Boffetta P, Magnani C, Terracini B, et al. Cancer risk among female agricultural workers: A multi-center case-control study. American Journal of Industrial Medicine 1999;36(1):135-141. 179. Corrao G, Calleri M, Carle F, Russo R, Bosia S, Piccioni P. Cancer risk in a cohort of licensed pesticide users. Scandinavian Journal of Work Environment & Health 1989;15(3):203-209. 180. Pukkala E, Notkola V. Cancer incidence among Finnish farmers, 1979-93. Cancer Causes & Control 1997;8(1):25-33. 181. Travier N, Gridley G, Blair A, Dosemeci M, Boffetta P. Cancer incidence among male Swedish veterinarians and other workers of the veterinary industry: a record-linkage study. Cancer Causes & Control 2003;14(6):587-593. 182. Wesseling C, Ahlbom A, Antich D, Rodriguez AC, Castro R. Cancer in banana plantation workers in Costa Rica. International Journal of Epidemiology 1996;25(6):1125-1131. 183. Karagas MR, Weinstock MA, Nelson HH. Keratinocyte carcinomas (basal and squamous cell carcinomas of the skin). In: Schottenfeld D, Fraumeni Jr JF, editors. Cancer Epidemiology and Prevention. Oxford: Oxford University Press, 2006:1230-1250. 184. Cantor KP. Drinking water and cancer. Cancer Causes & Control 1997;8:292-308. 185. IARC. Volume 84: Some drinking-water disinfectants and contaminants, including arsenic related nitrosamines. IARC Monographs on the Evaluation of Carcinogenic Risks to Humans. Lyon: International Agency for Research on Cancer, 2004. 186. Hogan DJ, To T, Gran L, Wong D, Lane PR. Risk factors for basal cell carcinoma. International Journal of Dermatology 1989;28(9):591-594. 187. Hogan DJ, Lane PR, Gran L, Wong D. Risk factors for squamous cell carcinoma of the skin in Saskatchewan, Canada. Journal of Dermatological Science 1990;1(2):97-101. 188. Jee SH, Kuo HW, Su WP, Chang CH, Sun CC, Wang JD. Photodamage and skin cancer among paraquat workers. International Journal of Dermatology 1995;34(7):466-469. 189. Solomon C. Accidental injuries in agriculture in the UK. Occupational Medicine-Oxford 2002;52(8):461-466. 190. HSC. Report of a conference on occupational health in agriculture. London,: Health & Safety Commission, 2001. 191. Scholl HPN, Fleckenstein M, Issa PC, Keilhauer C, Holz FG, Weber BHF. An update on the genetics of age-related macular degeneration. Molecular Vision 2007;13:196-205. 192. Kamel F, Boyes WK, Gladen BC, Rowland AS, Alavanja MC, Blair A, et al. Retinal degeneration in licensed pesticide applicators. American Journal of Industrial Medicine 2000;37(6):618-628.
57
58
59
Published by the Health and Safety Executive
03/13
The Pesticide Users Health Study (PUHS) was established so as to monitor the health of men and women who are certified to apply pesticides on a commercial basis under the 1986 Control of Pesticides Regulations. An analysis of deaths occurring between 1987 and 2005 among members of the PUHS is presented in this report. There were 1,628 deaths among 59,085 male and 3,875 female pesticide users during the followup period. Compared with the population of Great Britain, the pesticide users had lower than expected mortality from all causes, and in particular from all cancers combined, cancers of the digestive organs, cancers of the respiratory system, and non-malignant diseases of the nervous system and sense organs, and of the circulatory, respiratory, and digestive systems. There was some evidence of excess deaths from multiple myeloma in men and women, and possibly also from testicular cancer. Deaths from all external causes (accidents and injuries) combined were lower than expected when compared with the general population. However in men, deaths from injury by machinery were higher than expected. Continuing recruitment into the PUHS will enable HSE to monitor the health of these pesticide users as regulations and exposures change over time. This report and the work it describes were funded by the Health and Safety Executive (HSE). Its contents, including any opinions and/or conclusions expressed, are those of the authors alone and do not necessarily reflect HSE policy.
RR958
www.hse.gov.uk

The Pesticide Users Health Study 2013 UK Low Cancer Rates

Uploaded by

Document Information

Original Description:

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

The Pesticide Users Health Study 2013 UK Low Cancer Rates

Uploaded by

Copyright:

Available Formats

Health and Safety Executive

The Pesticide Users Health Study

An analysis of mortality (1987-2005)

RR958 Research Report

Health and Safety Executive

The Pesticide Users Health Study

An analysis of mortality (1987-2005)

Table 1 Mortality from selected causes in farmers: men aged 20-74,

THE PESTICIDE USERS HEALTH STUDY DATABASE

Regional distribution of the cohort

Cohort distribution by year of birth

Men Number 618 3,532 8,344 13,264 21,347 10,607 1,373

Cohort distribution by year of and age at the first test date

18,696 10,428 8,520 6,692 5,498 3,975 5,276

(29.7) (16.6) (13.5) (10.6) (8.7) (6.3) (8.4)

1,689 876 479 314 261 141 115

(2.7) (1.4) (0.8) (0.5) (0.4) (0.2) (0.2)

20,385 11,304 8,999 7,006 5,759 4,116 5,391

(32.4) (18.0) (14.3) (11.1) (9.2) (6.5) (8.6)

Modules taken Foundation Module (FM) FM + Ground Crop Sprayer, unspec.

Number 6,293 16,640 28,693 2,711 4,748

5,814 10,605 19,681 22,985 59,085 13.3

(9.8) (18.0) (33.3) (38.9) (100) (sd 4.2)

533 889 1,546 907 3,875 12.2

(13.8) (22.9) (39.9) (23.4) (100) (sd 4.2)

6,347 11,494 21,227 23,892 62,960 13.2

(10.1) (18.3) (33.7) (38.0) (100) (sd 4.2)

Equivalent to length of follow-up

RESULTS FROM THE MORTALITY ANALYSIS

Age at first test Number of years certified Age at death

$ Difference between men and women

Mortality in the Pesticide Users Health Study, 1987-2005

1.55 0.34 0.35

(0.22-11.0) (0.05-2.42) (0.05-2.51)

8.77 0.94 0.60 0.60

(1.24-62.3) (0.42-2.08) (0.15-2.40) (0.08-4.22)

3.48 3.03 10.8 2.83

(1.56-7.74) (0.76-12.1) (2.70-43.2) (0.71-11.3)

0.43 0.27 0.71 0.32

(0.16-1.14) (0.04-1.90) (0.18-2.85) (0.04-2.26)

Number of deaths observed; Standardised mortality ratio; 95% Confidence intervals

External causes of mortality among men and women in the

Number of deaths observed; Standardised mortality ratio; 95% Confidence intervals

CAUSES OF DEATH SELECTED FOR ANALYSIS

2020-2029 2000-2009 C820-C859

4200-4239 4250-4299 I300-I339

CITY & GUILDS LAND BASED SERVICES CERTIFICATES OF COMPETENCE

STRATIFIED TABLES OF RESULTS

Mortality amongst men by region, 1987-2005

Obs 318 120 48 22 4 4 5 8 17

0.61 0.49 0.38 0.21

(0.25-1.46) (0.38-0.64) (0.20-0.73) (0.09-0.47)

0.37 0.67 0.47 0.36

(0.16-0.90) (0.56-0.81) (0.29-0.77) (0.20-0.65)

0.43 0.58 0.23 0.26

(0.18-1.03) (0.47-0.72) (0.11-0.48) (0.12-0.55)

0.47 0.51 0.34 0.08

(0.20-1.13) (0.41-0.64) (0.19-0.62) (0.02-0.33)

Number of deaths observed; Standardised mortality ratio; 95% Confidence intervals

Obs 372 135 47 21 0 15 9 9 18

1.14 (0.28-4.54) 1.20 (0.45-3.20)

0.43 0.62 0.47 0.34