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SID 5 Research Project Final Report

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NoteIn line with the Freedom of Information Act 2000, Defra aims to place the results of its completed research projects in the public domain wherever possible. The SID 5 (Research Project Final Report) is designed to capture the information on the results and outputs of Defra-funded research in a format that is easily publishable through the Defra website. A SID 5 must be completed for all projects.

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Project identification

1. Defra Project code PS2609

2. Project title

Desk Study on Prostate Cancer and Pesticide Exposure

3. Contractororganisation(s)

Institute of Occupational Medicine, Edinburgh

54. Total Defra project costs £ 24,109(agreed fixed price)

5. Project: start date................ 01 September 2005

end date................. 28 February 2006

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6. It is Defra’s intention to publish this form. Please confirm your agreement to do so...................................................................................YES NO (a) When preparing SID 5s contractors should bear in mind that Defra intends that they be made public. They

should be written in a clear and concise manner and represent a full account of the research project which someone not closely associated with the project can follow.Defra recognises that in a small minority of cases there may be information, such as intellectual property or commercially confidential data, used in or generated by the research project, which should not be disclosed. In these cases, such information should be detailed in a separate annex (not to be published) so that the SID 5 can be placed in the public domain. Where it is impossible to complete the Final Report without including references to any sensitive or confidential data, the information should be included and section (b) completed. NB: only in exceptional circumstances will Defra expect contractors to give a "No" answer.In all cases, reasons for withholding information must be fully in line with exemptions under the Environmental Information Regulations or the Freedom of Information Act 2000.

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Executive Summary7. The executive summary must not exceed 2 sides in total of A4 and should be understandable to the

intelligent non-scientist. It should cover the main objectives, methods and findings of the research, together with any other significant events and options for new work.

Summary

The aim of this study was to review the published literature on pesticide exposure and the risk of prostate cancer. The study involved two components:

A literature review of the epidemiology on pesticide exposure and prostate cancer;A review of the potential mechanisms that might underlie any link between pesticide exposure and prostate cancer.

The initial brief for the epidemiological review was to examine cohorts of workers involved in pesticide manufacture. This brief was subsequently expanded, with the agreement of DEFRA, to include pesticide users, as there were too few data available from the studies of manufacturing workers to assess whether or not an excess risk of prostate cancer exists.

Prostate cancer is the most commonly diagnosed cancer in UK males and its incidence is rising. The introduction and widespread use of the prostate-specific antigen (PSA) test has had a substantial impact on the apparent incidence of prostate cancer through enabling detection at a much earlier stage in disease development. It is likely that the incidence of prostate cancer in studies undertaken prior to PSA testing was under-estimated relative to that found in more recent studies. Although detection rates for prostate cancer in earlier studies could be reasonably assumed to be equivalent in the exposed and control populations, a smaller number of cases would have weakened the power of studies to detect a small excess risk.

Epidemiological studies of manufacturing workers exposed to pesticides have not reported an excess risk of prostate cancer. The carcinogenicity of phenoxy herbicides has been extensively investigated in manufacturing workers (and users) and it seems unlikely that any important prostate cancer risk has remained undetected. Investigations of other compounds have been limited and most of the relevant studies have had only limited power to detect effects because of the relatively small numbers of exposed workers and/or relatively short follow up times. It is possible that the power of epidemiological studies to detect effects has been further limited by the generally low levels of exposure that may be experienced by the majority of manufacturing workers. If pesticides are largely synthesised within closed system processes with automated packaging or containerisation, exposure may be limited to a small number of

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maintenance tasks.

The results of studies of pesticide users have been inconsistent. It is probable that exposures to pesticides during use are much less controlled than during manufacture and some users may experience relatively high levels of exposure. Many of the studies reviewed here were negative or inconclusive, with a few showing positive results.

Excess risks of prostate cancer have been most commonly reported in US farmers, particularly in more recent studies, including the Agricultural Health Study (AHS). The AHS was a large, well-conducted study that reported associations between a number of pesticide compounds and prostate cancer. These relationships appeared to be strongly influenced by familial factors suggesting that genetic susceptibility has an important modifying effect on the relationship between specific pesticides and prostate cancer risk. Excess risks have not been found in most studies of European farmers or other applicators elsewhere. This may reflect differences in pesticide use (quantities used, frequency of use or compounds used), other differences in farming practice (such as the routine use of antibiotics) or lifestyle factors. It may also partly reflect deficiencies in study design that may have limited the power of studies to detect increased risks of prostate cancer, particularly if these risks were relatively small. Factors that may have contributed to the failure of epidemiological studies to consistently detect an excess cancer risk include:

The possibility that there is no real excess risk;The wide range of unrelated substances to which workers have been exposed;Poor exposure characterisation;Classification of workers with extremely low levels of exposure as being “exposed”;Small study populations and/or short follow up times in over half of the available studies;A failure to specifically investigate prostate cancer risk in some earlier studies; andThe substantial change in diagnostic practice in recent years.

Several studies have suggested an increased excess risk of prostate cancers in pesticide users in old age that may reflect a substantial latency period between first exposure and disease development, although this has not been extensively investigated. It is also possible that the pattern of exposure in older workers has been substantially different than in younger workers (different compounds, differences in handling and attitudes towards exposure). There has been very little investigation of prostate cancer risks by age in pesticide workers. A few studies report a possible link between pesticides and prostate cancer in younger men, but the associations were not statistically significant.

Overall there are considerable epidemiological data that suggest that it is unlikely that phenoxy herbicides or aldrin are associated with an excess risk of prostate cancer. The evidence for other chlorinated pesticides is less consistent. Most applicators are likely to have been exposed to a range of pesticides and exposures have typically been poorly characterised in epidemiological studies. Pesticides that appear to be associated with prostate cancer in more than one study are methyl bromide, DDT and heptachlor. Two studies also reported an association for atrazine that failed to reach statistical significance. Given that these compounds represent only a small proportion (less than 5%) of the large number of different compounds that have been used, these apparent positive associations may have arisen by chance. There is little evidence from other sources that methyl bromide is carcinogenic but atrazine, DDT and heptachlor cause cancer in animals and some further investigation of effects in humans may be appropriate, although it should be noted that DDT and heptachlor are not currently approved in the UK and the current limited ‘essential uses’ for atrazine will be revoked in the UK in 2007. The possible association of prostate cancer with organophosphate compounds is not specific to particular compounds.

A number of recent mechanistic studies have demonstrated that pesticides might induce androgen imbalance by interfering with the action of natural hormones at both the peripheral and intracellular levels. The possible effects on the prostate have not yet been investigated, even though the gland is a target tissue for androgens and the growth and function of the prostate is dependent on the continuous supply of hormones controlled by the hypothalamic-pituitary-gonadal axis. Any disruptor that suppressed the normal workings of this axis could interfere with hormone synthesis and curtail the flow of testosterone and other hormones into the prostate. Additionally pesticides may target the prostate directly, influence steroid metabolism, receptor binding activity or degradation and trigger the sequence of events leading to the onset of abnormal tissue growth. The mechanisms that may be involved at both the cellular and molecular levels have yet to be identified.

In conclusion, there is insufficient evidence to conclude that pesticide exposure is associated with an increased prostate cancer risk. There is, however, also insufficient evidence to be certain that such a risk does not exist, although the failure to consistently detect a risk suggests that typical levels of pesticide exposure among pesticide workers do not have an important influence on prostate cancer risk. There is a need for further investigations into the mechanisms by which exposure to pesticides may lead to increased

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prostate cancer risk

Project Report to Defra8. As a guide this report should be no longer than 20 sides of A4. This report is to provide Defra with

details of the outputs of the research project for internal purposes; to meet the terms of the contract; and to allow Defra to publish details of the outputs to meet Environmental Information Regulation or Freedom of Information obligations. This short report to Defra does not preclude contractors from also seeking to publish a full, formal scientific report/paper in an appropriate scientific or other journal/publication. Indeed, Defra actively encourages such publications as part of the contract terms. The report to Defra should include: the scientific objectives as set out in the contract; the extent to which the objectives set out in the contract have been met; details of methods used and the results obtained, including statistical analysis (if appropriate); a discussion of the results and their reliability; the main implications of the findings; possible future work; and any action resulting from the research (e.g. IP, Knowledge Transfer).

Literature review of prostate cancer and pesticide exposure

Alison Searl1, Fouad K Habib2, Hilary Cowie1

1Institute of Occupational Medicine, Edinburgh2Prostate Research Group, Edinburgh Cancer Research Centre, Edinburgh

Introduction

The aim of this study was to review the published literature on pesticide exposure and the risk of prostate cancer. The study involved two components:

A literature review of the epidemiology on pesticide exposure and prostate cancer; A review of the potential mechanisms that might underlie any link between pesticide exposure and

prostate cancer.

The term pesticide is used to describe any substance or mixture of substances intended for preventing, destroying, repelling, or mitigating any pest. Pests include insects, mice and other animals, unwanted plants (weeds), including algae, fungi, or microorganisms like bacteria and viruses. The term may also include any substance or mixture of substances intended for use as a plant regulator, defoliant, or desiccant. The term includes biologically-based pesticides, such as pheromones and microbial pesticides but excludes biological control agents in the form of beneficial predators such as ladybirds that eat aphids. A large number of different terms are used to describe pesticides with different functions (Table 1). An extremely wide range of chemicals is used as pesticides and there is no simple chemical classification available.

Table 1Examples of terms used to describe pesticides with different functions

Type of pesticide FunctionAlgicides Control algae, for example, in water tanksAntifouling agents Kill or repel organisms that attach to underwater surfacesAntimicrobials (or biocides) Kill microorganisms (such as bacteria and viruses)Attractants Attract pests (for example, to lure an insect or rodent to a trap)Disinfectants and sanitizers Kill or inactivate microorganisms on inanimate objectsFungicides Kill fungi (including blights, mildews, molds, and rusts)Fumigants Produce gas or vapor intended to destroy pests in buildings or soil.Herbicides Kill plantsInsecticides Kill insects and other arthropods.Miticides (or acaricides) Kill mites that feed on plants and animalsMolluscicides Kill snails and slugsNematicides Kill nematodes (microscopic, worm-like organisms)Ovicides Kill eggs of insects and mites.Pheromones Biochemicals used to disrupt the mating behavior of insects.

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http://www.epa.gov/oppad001/ad_info.htm

Repellents Repel pests, including insects (such as mosquitoes) and birdsRodenticides Control mice and other rodents

The initial brief for the epidemiological review was to examine cohorts of workers involved in pesticide manufacture, as exposures were likely to be better characterised than in user industries and workers were likely to be exposed to fewer substances than typical users. The brief was subsequently expanded, with the agreement of the study sponsor, to include pesticide users as there were too few data available from the studies of manufacturing workers to assess whether an excess risk of prostate cancer exists. The literature search terms and methods used are detailed in the Appendix.

Some background information about prostate cancer

INCIDENCE OF PROSTATE CANCER

Prostate cancer is the most common diagnosed cancer in UK males with almost 32,000 cases diagnosed in 2002 (Cancer Research UK, 2005). Mortality from this disease is second only to that from lung cancer in western society (Cancer Research UK, 2005). Prostate cancer is most common in older men, with an incidence of almost 1% in men aged over 85 in the UK. Less than 0.5% of cases arise in men under 50.

The incidence of prostate cancer is rising. In the UK, the incidence rate for 2001-3 was 89.8 per 100 000 population and the mortality rate was 27.1 per 100 000 (www.statistics.gov.uk). The incidence rate rose sharply (by 86%) during the late 1980s as a result of improved methods of detection. The mortality rate has also risen slightly since the 1960s and 1970s, when the mortality rate was about 20 per 100 000. The death rate from prostate cancer in the UK is similar to that for the EU as a whole but slightly lower than in the Netherlands and Scandinavia (www.statistics.gov.uk).

The introduction and widespread use of the prostate-specific antigen (PSA) test has had a substantial impact on the apparent incidence of prostate cancer through enabling detection at a much earlier stage in disease development (McDavid et al, 2004). It is likely that the incidence of prostate cancer in studies undertaken prior to PSA testing was under-estimated relative to that found in more recent studies. Although detection rates for prostate cancer in earlier studies could be reasonably assumed to be equivalent in the exposed and control populations, a smaller number of cases would have weakened the power of studies to detect a small excess risk.

Both the aetiology and the mechanism(s) involved in the progression of prostate cancer continue to be extensively investigated but to date the causes of this disease remain largely unknown.

RISK FACTORS ASSOCIATED WITH PROSTATE CANCER

Cancer of the prostate follows a single consistent biological process that is characterised by an unusually slow, although generally constant, rate of growth. This rate of growth can be enhanced by genetic instability of the cancer and epidemiological data suggest that there is a significant genetic component to prostate cancer risk that underlies the processes leading to malignant transformation and tumour progression (Foster et al, 2005). However it remains possible that this is not the sole route by which a prostate cell develops the potential to become malignant: prostate cancer does not occur in the pre-pubertally castrated male suggesting that androgens are implicated in the pathogenesis of the disease (Wilson & McPhaul, 1994). Furthermore, a high incidence of prostate cancer has been found in men taking anabolic steroids (Roberts & Essenhigh,1986; Jackson et al, 1989), thus confirming the view that abnormal androgen levels are associated with tumour development.

There are a number of other aetiological factors linked to prostate cancer including age and race/ethnicity. Prostate cancers are extremely rare in men under 40 years of age but the rate of increase with aging is greater than for any other cancer (Peehl, 1999). Likewise epidemiological studies have highlighted the large variations in incidence of prostate cancer amongst the different ethnic groups in the USA: highest in African Americans, intermediate in Caucasians and Latinos and lowest in Asian-Americans (Ross et al, 1999). However, irrespective of the ethnic grouping, the risk of prostate cancer increases by 2 to 3 fold in men who have a first degree relative with the disease (Cussenot, 2004). High penetrance familial prostate cancer accounts for approximately 9% of all prostate cancers (Cussenot, 2004). Increased risks have also been reported for men with close relatives with breast cancer, although there is no evidence of a common hormonal factor affecting breast cancer and prostate cancer risk. In particular, there is no evidence of a link between oestrogen exposure and prostate cancer.

There are also reports linking the incidence of prostate cancer to a western diet including high levels of red meat, saturated fat and dietary products (Coffey, 2001; Bostwick et al, 2004). The molecular basis for these epidemiological relationships is obscure but an unknown constituent of dietary fat has recently been suggested to be a potential contributor to a progression mechanism (Freeman et al, 2004). Other risk factors include employment in farming and possibly exposure to pesticides (Bostwick et al, 2004).

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To date there are no convincing data linking environmental risk factors, such as exposure to pesticides, to the onset of prostate cancer even though there may be a strong biological basis for such a link.

Previous reviews of the role of pesticide exposure in the development of prostate cancer1

Van Maele-Fabry and Willems (2003, 2004) analysed data from peer-reviewed, case-referent and cohort studies, of prostate cancer in pesticide applicators (2004) and more generally in occupational groups potentially exposed to pesticides (2003). The meta-rate ratio for more general occupational exposure to pesticides was 1.13 (95% confidence interval (CI) 1.04, 1.22), based on 22 estimates of relative risk, with a higher pooled estimate for pesticide applicators (1.64; 95% CI 1.13,2.38), based on four studies, than farmers (0.97). Pesticide applicators were investigated in more detail in the 2004 paper where an analysis of 22 studies gave a meta rate-ratio of 1.24 (95% CI 1.06-1.45) indicating a significant elevation in risk. Pooled risk estimates for pesticide applicators in European studies were lower than for USA/Canadian studies (1.12 compared with 1.40) and the rate ratio in cohort mortality studies was 1.21 compared with 1.37 in incidence studies. No consistent evidence of an exposure-response relationship was found for applicators, although this may have been due to poor exposure characterisation. The inclusion of a wide range of chemically distinct pesticides may have weakened the power of the study to detect effects. The study did not examine apparent risks of prostate cancer by age or length of follow up. The authors concluded that the study reinforced the evidence for a relationship between pesticide exposure and cancer of the prostate but that the underlying data were insufficient to draw firm conclusions about pesticide exposure as an independent risk factor. Previously Sathiakumar and Delzell (1997) had reported that there were insufficient published data to assess prostate cancer risk. Two reviews and meta-analyses of cancer in farmers (Blair et al, 1992; Keller-Byrne, 1997) reported excess risks of prostate cancer but neither study was able to investigate cancer risk by age group or in relation to specific exposures.

In a more general review of cancer risk among pesticide manufacturers and applicators sponsored by the chemical industry, Burns (2005) concluded that there was little indication of an increased risk of any cancers. The available studies generally had little power to demonstrate the presence or absence of effect as a result of poor exposure characterisation. Many studies were limited by a small sample population and there were too few studies of individual pesticides or classes of pesticides to undertake a credible meta-analysis for individual compounds or classes of compounds.

Earlier reviews of cancer risk failed to report an excess risk of prostate cancer. It is possible that small excess risks went unreported in some studies that were focussed on cancers at other sites, particularly lymphomas and soft tissue sarcomas (Maroni and Fait 1993; Morrison et al, 1992; Johnson, 1990; Johnson et al, 1990; Bond et al, 1989). The studies available for review in these earlier studies would have preceded the introduction of PSA testing. The absence of an excess of prostate cancer in these earlier studies does not provide complete reassurance that, if modern diagnostic methods had been available, a small excess risk would not have been detected.

Studies of workers in plants manufacturing pesticides

The results of a number of studies of pesticide manufacturing workers have failed to demonstrate a consistent association between pesticide exposure and prostate cancer.

Atrazine: MacLennan et al (2002) reported a possible association between prostate cancer incidence and atrazine in a study of 2045 US manufacturing workers. The excess was postulated to have arisen as a result of improved screening and was not confirmed in a later mortality study (MacLennan et al, 2003). A short follow-up period, however, had limited the power of the study to confirm an absence of effects. Sass (2003) expressed concern that the choice of follow up period had excluded 6 of 17 possible cases, which had been due to the unavailability of general population rates at the time the study was done. An excess of prostate cancer in younger men and a relationship with duration of exposure suggested a causal link with atrazine. In a subsequent nested case-control study, however, no relationship was found between cancer risk and average or cumulative levels of exposure (Hessel et al, 2004). The additional analyses included the cases occurring later in the follow-up period.

Phenoxyherbicides: The results of a number of large studies of manufacturing workers exposed to phenoxy herbicides do not suggest a link with prostate cancer. These include an IARC co-ordinated study of 21, 863 workers in 36 cohorts exposed to phenoxy herbicides, chlorophenols and dioxins in 12 countries outside of the

1 Since this review was undertaken in early 2006, Van Maele-Fabry et al have published a review and meta-analysis of prostate cancer risks in pesticide manufacturing workers. They found an increased risk of prostate cancer in each of the chemical classes that they examined. The increase in risk was only significant, however, for exposure to phenoxy herbicides contaminated with dioxins and furans (van Maele-Fabry, Libotte V, Willems J, Lison D (2006) Review and meta-analysis of risk estimates for prostate cancer in pesticide manufacturing workers. Cancer Causes Control 17, 353-373).

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USA (Kogevinas et al, 1997) who were followed from 1939 to 1992. Other European studies included Coggon et al (1991; 1986), Bueno de Mesquita et al (1993), Lynge (1993, 1998) and Saracci et al (1991). Studies of US workers were reported by Fingerhut et al (1991), Bloemen et al (1993) and Burns et al (2001). All of these phenoxy herbicide studies were undertaken before the introduction of modern diagnostic methods for prostate cancer and were influenced by concerns about possible risks of lymphoma and soft tissue sarcoma. Although the power of these studies to detect an excess risk would have been lower than in more recent studies, the size of the studies and length of follow-up suggest it is unlikely that an important excess risk of prostate cancer remained undetected.

Other pesticides: A study of 770 workers exposed to pentachlorophenol between 1940 and 1989 found no excess of prostate cancer, although the number of workers and length of follow up time may have been insufficient to detect a small excess risk (Ramlow, 1996). A study of mortality rates between 1968 and 1999 and cancer incidence between 1969 and 1999 in 1206 US alachlor manufacturing workers, employed for at least a year between 1961 and 1991, found no increase in cancer risks (Acquavella et al, 2004). Other studies of workers exposed to chlordane (Shindell and Ulrich, 1986; Wang and MacMahon, 1979), various chlorinated pesticides (Ditraglia et al, 1981; Brown et al, 1992), DDT (Garabrant et al, 1992), and aldrin, dieldrin, endrin and telodrin (Ribbens, 1985) have not reported excess risks of prostate cancer. All of these studies predated modern diagnostic methods for prostate cancer and were also too small and/or had insufficient length of follow up to have reliably detected a small excess risk of prostate cancer.

Overall, the available data are inconclusive regarding any association between exposure to pesticides during manufacture and prostate cancer. The data do suggest that there is no important prostate cancer risk associated with the manufacture of phenoxy herbicides. There is some evidence of an excess risk associated with manufacture of atrazine, but this may be due to improved screening; no exposure-response association was apparent. There was little evidence of an excess risk associated with other pesticide formulations, but most studies of these were small and/or had short follow-up times.

Pesticide exposure in agriculture

There have been a large number of studies of agricultural workers exposed to pesticides. The Agricultural Health Study (AHS) provided limited evidence of an association between pesticide exposure and prostate cancer in US farmers (Alavanja et al, 2003). The exposure of 55323 pesticide applicators to 45 different pesticides was assessed through the use of a self-administered questionnaire. Cancer incidence was determined from 1993 to the end of 1999. One of the strengths of the AHS is that the diagnosis of prostate cancer is likely to have employed modern methods. A prostate cancer standardised incidence ratio of 1.14 (95% CI: 1.05, 1.24) was observed. An updated analysis with follow-up extended to 2002 confirmed the overall excess of prostate cancer in this group of pesticide applicators (Alavanja et al, 2005).

In the earlier study, statistically significant exposure response relationships were found for prostate cancer risk in relation to use of the fungicide methyl bromide and, among applicators over 50 years of age, for the use of chlorinated pesticide. Significantly raised risks of prostate cancer were found for applicators who ever used chlorinated pesticides including aldrin, DDT or heptachlor compared to those who had never used them. No exposure response relationships were observed for alachlor, atrazine, carbofuran, chlorpyrifos, permethrin, aldrin, DDT, heptachlor or captan. Small non-significantly raised risks of prostate cancer were found for carbofuran, permethrin and phorate among those with no family history of prostate cancer. For those with a family history of prostate cancer, statistically significant raised risks were found for butylate (thiocarbamate), carbofuran, coumaphos, 2,2-dichlorethenyl dimethylphostate, fonofos, permethrin and phorate and nonsignificantly raised risks were found for alachlor, atrazine, dicamba, EPTC, aldicarb, chlorpyfrifos, terbufos and methyl bromide. The strong familial influence on apparent prostate cancer risk suggests genetic susceptibility could be an important modifying factor in the relationship between pesticides and prostate cancer. Although the agricultural study involved a large number of workers, it looked at a relatively short period in time and the method of exposure assessment may not have fully captured cumulative exposure or the influence of working methods on exposure levels. The large number of different pesticides considered and difficulties in assessing exposure may have weakened the power of the study to detect effects. Factors that suggest that apparent relationships may not be causal include:

An absence of exposure-response relationships; andNone of the studies of individual pesticides that were used in relatively large quantities demonstrated an increased prostate cancer risk.

The absence of exposure-response relationships could reflect inadequacies in exposure assessment or the metric of exposure used. For example, occasional very high exposures may not have been fully accounted for, although there was no evidence that more cases than controls had experienced a high pesticide exposure event. Life expectancy for the cohort as a whole was greater than for the general population. Blair et al (2005) reported standardised mortality ratios (SMRs) for total mortality, cardiovascular disease, diabetes, chronic obstructive

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pulmonary disease, total cancer, and cancers of the oesophagus, stomach, and lung of 0.6 or less in these agricultural workers.

The results of other studies of prostate cancer in agricultural workers handling pesticides are inconsistent. Most of the positive findings have been in more recent studies. This may indicate that prostate cancer is associated with more modern pesticide formulations and/or much longer periods of exposure than was typical of previously studied workers. It may also reflect a greater sensitivity in the detection of prostate cancer. Few studies have reported evidence of exposure-response relationships between pesticide exposure and prostate cancer, but this may reflect the difficulties in exposure estimation (Kromhout and Heederik, 2005). In a Canadian study, Morrison et al (1993) found an association between the number of acres sprayed with herbicide and prostate cancer risk. Few studies have reported risks by age group. Dich and Wiklund (1998) found a possibly greater excess of prostate cancer in younger men than in older men in a large study, although this was not statistically significant and was based on only 7 of a total of 410 cases for all ages.

Different studies have found different pesticides to be most strongly associated with increased risks. In a US study, Mills and Yang (2003) reported that prostate cancer risks were raised in Hispanic farm workers with relatively high levels of exposure to organochlorine pesticides (lindane and hepatachlor), organophosphate pesticides (dichlorvos), fumigants (methyl bromide), or triazine herbicides (simazine) when compared to less exposed workers. In a relatively small Italian study that may therefore have lacked power to reliably detect effects, Settimi et al (2003) reported increased prostate risks associated with organochlorine insecticides and acaricides, particularly DDT and dicofol. Nonsignificant increases in risk were associated with exposure (ever) to carbamates, ziram, nitrofenoles, dithiophosphates, thiophosphates and triftalates. No increase in risk was associated with copper and sulphur compounds, dithiocarbamates generally or organophosphates generally. There was no evidence that risk increased with duration of exposure.

Overall the studies of prostate cancer in pesticide applicators in agriculture provide weak evidence of a possible link with pesticide exposure. However, the inconsistencies between studies may indicate that some of the apparent associations have arisen by chance or reflect some confounding exposure/factor associated with pesticide application.

Other studies of agricultural workers

A number of studies reported an excess of prostate cancer among farmers in North America prior to more recent investigations into a specific link to pesticide exposure (Fincham et al, 1992; Delzell and Grufferman, 1985; Saftlas et al, 1987, Parker et al, 1999 and Burmeister et al, 1983). In contrast Stubbs et al (1984) and Gallagher et al (1985) found no excess prostate cancer risk in US farmers. In a recent review of risk factors for prostate cancer, Bostwick et al (2004) suggested that farmers may eat a relatively high fat diet which would be a risk factor for prostate cancer, but did not dismiss the possible role of pesticides and the role of genetic susceptibility and/or age in modifying the potential impacts of pesticide exposure on cancer risk. Farm animals, zoonotic viruses and farm chemicals, but not specifically pesticides, were also suggested as causes. Both Parker et al (1999) and Burmeister et al (1983) highlighted a greater excess prostate cancer risk in older farmers but there has been little investigation of prostate cancer risks in younger men.

There is a marked discrepancy between the findings of studies of farmers undertaken in North American and those undertaken in Europe. Most European studies have not found an excess of prostate cancer (Wiklund and Dich, 1995; Torchio et al, 1994; Levi et al, 1988; Ronco et al, 1992; Kristensen et al, 1996; Forastiere et al, 1993; Faustini et al, 1993; Rafnsson and Gunnarsdottir, 1989). This may reflect differences in chemical usage or other differences in farming practice (eg the use of artificial hormones or antibiotics in livestock) and/or differences in lifestyle including diet, alcohol consumption and smoking. In a study of Italian farmers, Forastiere et al (1993) did report a non-significant excess of prostate cancer among farmers licensed as pesticide users (based on only 5 cases) with a higher excess among those who had farmed for more than 10 years. There was also an association between wheat and prostate cancer in farmers, but the significance of this finding is unclear.

In a single study from the developing world, Meyer et al (2003) reported a non-significant excess risk of prostate cancer in Brazilian agricultural workers of 30-49 years in age. Given that this excess was due to a single case, it is of doubtful significance. Workers were exposed to a variety of pesticides with paraquat, methamidophos and mancozeb being the most widely used. It was acknowledged that risk factors such as micro-organisms, fertilisers and malnutrition could have contributed to the observed effects together with the confounding effects of smoking and alcohol. Pesticide exposure was likely to have started in childhood and could plausibly have given rise to the observed excess risk in younger men.

Overall, results of these other studies of prostate cancer in farmers show little or no evidence of a link to pesticide exposure.

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Other studies of pesticide applicators

Fleming et al (1999ab) found a significantly increased prostate cancer risk among 33,658 licensed pesticide applicators in Florida followed up from 1975 to 1993, before the introduction of modern diagnostic methods, with higher SIRs among those licensed before 1990, but lower SMRs among those who had held licences for longer periods. Zahm (1997) found no excess of prostate cancer in a study of 32,600 US lawn care workers exposed to the herbicide 2,4-dichlorophenoxyacetic acid. The cohort was, however, generally young with short duration of employment and follow-up. A smaller US proportionate mortality study of 686 deceased golf course superintendents did find a significantly raised risk of prostate cancer, but the authors were unable to attribute this to pesticides as opposed to lifestyle factors (an excess of smoking related disease was found) or other occupational exposures (Kross et al, 1996). The excess of deaths from cardiovascular mortality would suggest that the observed excess of prostate cancer was not due to a deficit of deaths from other causes, but does not exclude the possibility that the lifestyle factors influencing risk of both causes of death were similar. A US study of 9677 aerial pesticide applicators reported a non-significantly raised risk of prostate cancers (Cantor and Booze, 1991; Cantor and Silberman, 1999). Earlier US studies failed to find an association between pesticides and prostate cancer (Blair et al, 1983; Wang and MacMahon, 1979; MacMahon et al, 1988). These studies predated modern diagnostic methods and were also too small and/or had insufficient follow up to be certain that no excess risk of prostate cancer existed.

European studies have not generally found an association between pesticide use and prostate cancer with the exception of Swaen et al (1992) who reported a nonsignificantly raised risk of prostate cancer in 1341 Dutch herbicide applicators, despite a relatively short follow up time. This was, however, due to a single death and was of doubtful importance. No excess risk of prostate cancer was found in a subsequent follow up study (Swaen et al, 2004). Other studies have typically been small with short follow up periods (Settimi et al, 1998; Figa-Talamanca, 1993; Figa-Talamanca, 1994, Axelson et al, 1980) and most may have lacked the power to detect a small excess risk of prostate cancer. Larger studies with longer follow up times have, however, also failed to find an excess risk of prostate cancer (Asp et al, 1994). A large Australian study of insecticide applicators with a 30 year follow up period, found a nonsignificant deficit of prostate cancer (Beard et al, 2003).

Overall, the available data do not preclude a possible association between pesticide use and a small increase in prostate cancer risk. The single study that found a convincing, although small, excess risk (Fleming et al, 1999ab) was also the study that had the greatest power to detect an effect, even in the absence of modern diagnostic methods. The striking difference in apparent risks in studies performed in the US compared with those from elsewhere in the world might reflect substantial differences in the way that pesticides are used, the formulation of pesticides or some confounding factor unrelated to pesticide use.

Agent orange

The results of several studies suggest an excess risk of prostate cancer among US veterans exposed to Agent Orange (Akhtar et al, 2004; Giri et al, 2004). Other studies have not, however, detected a specific link between Agent Orange and prostate cancer (Zafar and Terris, 2001). Pavuk et al (2005, 2006) found an association between prostate cancer and time served in south-east Asia but not Agent Orange. It seems likely that other factors associated with service in Asia may have contributed to the excess risk observed in some studies. Pavuk et al (2006) suggested that dietary exposure to organochlorines may have played a role in increasing prostate cancer risk in veterans, as a result of the extensive anti-malarial measures that were taken in Asia at that time.

Studies of prostate cancer risk by occupation

In studies of the employment history of prostate cancer cases, some studies have found that farmers are among the occupational groups with elevated risks (Buxton et al, 1999; Band et al, 1999; Brownson et al, 1988; Krstev et al, 1998a; Mallin et al, 1989; Sharma-Wagner et al, 2000; van der Gulden et al, 1995). Potti et al (2003) specifically reported a link with pesticides. Other similar studies did not find a link with farming or pesticides (Krstev et al, 1998b; Elghany et al, 1990; Fincham et al, 1990; Aronson et al, 1996; Boers et al, 2005; Zeegers et al, 2004; Heiskel et al, 1998; Ilic et al, 1996; Pearce et al, 1987; Frith et al, 1996). The interpretation of the findings of these studies is unclear as there is an inconsistency in the “at risk” groups identified by different studies. There has been no marked difference between the findings of European and North American studies.

Other relevant studies of prostate cancer in relation to pesticide exposure

In a small hospital-based US case control study of the relationship between serum levels of 18 organochlorine pesticides and prostate cancer risk, Ritchie et al (2003) reported a possible association with oxychordane. Serum concentrations of 11 of the 18 compounds were below the limits of detection. In another US study, Cocco and Benichou (1998) found no association between increased prostate cancer risk within individual states and

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exposure to DDT as assessed by adipose concentrations of p,p’-DDE from individuals residing in that state (not specifically individuals with prostate cancer). In a study of prostate cancer mortality in 589 Belgian municipal areas, Jannsens et al (2001) found that prostate cancer was more common in regions where potatoes were grown, and/or defoliants used. In a study of county cancer incidence rates versus pesticide use in California, Mills (1998) found possible relationships between atrazine and/or captan use and prostate cancer in black males who worked principally in the cotton industry. However, individual exposures to pesticides were not investigated in this study, which looked at the association between prostate cancer and pesticide use at the county level only. Overall these studies are not informative about the potential association between pesticides and prostate cancer.

Methyl bromide, atrazine, heptachlor, DDT and organophosphates

Where information is available about the types of pesticide applied, four substances that appear to be associated with prostate cancer in more than one study are methyl bromide (AHS, Mills and Yang, 2003), atrazine (AHS, Mills, 1998), heptachlor (AHS, Mills and Yang, 2003) and DDT (AHS, Settimi et al, 2003). The relationship for atrazine was not significant in either study. Given the large number of different compounds that have been used, and the likelihood that many applicators have been exposed to a mixture of substances, these positive associations may have arisen by chance. Organophosphates are also implicated in more than one study, but no individual compound is named in more than one study.

IARC (1999a) concluded that methyl bromide is not classifiable as to its carcinogenicity in humans (IARC Group 3). There were two deaths from testicular cancer (0.11 expected) in methyl bromide exposed workers who were part of a subcohort of 665 workers at three chemical manufacturing exposed to bromine chemicals (Wong et al, 1984). Two studies in exposed workers have found limited evidence of possible genotoxic effects in lymphocytes and oropharyngeal cells (Pletsa et al, 2002; Calvert et al, 1998). There was limited evidence for carcinogenicity in animal experiments, although the results of different studies were highly inconsistent. Methyl bromide does, however, display genotoxic properties in a number of assays (IARC, 1999). The main noncancer effect of methyl bromide that has been reported in exposed workers and in animal experiments is neurotoxicity (eg studies by Hustinx et al, 1993; Anger et al, 1981, Eustis et al, 1988; Kishi et al, 1991). Testicular damage was reported in one animal experiment (Eustis et al, 1988).

IARC (1999b) determined that atrazine is not classifiable as to its carcinogenicity in humans (Group 3). Although there is sufficient evidence for carcinogenicity in animals (mammary tumours in one strain of laboratory rats), the mechanisms giving rise to tumours were not believed to be relevant to man. IARC (1991, 2001) have determined that both DDT and heptachlor may possibly cause cancer in humans. The human data for both substances are inadequate and more recent studies have failed to confirm associations between these substances and cancer. In particular, a very large number of studies have failed to demonstrate a consistent relationship between serum or tissue levels of DDT or its metabolites and cancer. Both substances give rise to cancers in animals.

There is limited information to suggest some organophosphate compounds may interfere with androgens. A

limited number of organophosphate compounds have been shown to bind to the androgen receptor and interfere with its normal function (Tamura et al, 2003) and there have been reports of lowered levels of testosterone in organophosphate manufacturing workers (Padungtod et al, 1998) and sprayers (Kamijima et al, 2004).

Mechanism(s) by which pesticides may cause an increased prostate cancer risk

The potential for developing prostate cancer in man following exposure to pesticides, including those currently on the market, is poorly understood. Most of these pesticides have been inadequately evaluated and previous investigations have been generally targeted at assessing risk rather than identifying the mechanism(s) involved. Additionally there are few anomalies in the published epidemiological literature for prostate cancer including:-

Unreliability of studies performed prior to 1987 when detection and screening procedures were not as rigorous and PSA was not standard.

Discrepancy between outcome for “Manufacturing Workers” and “Agricultural Workers” underlying the possibility that other factors might be involved.

The limitations of some of the earlier studies because stringent criteria for inclusion/exclusion were not observed.

Many of the reported studies focused on the endocrine/reproductive organs but did not specifically study the prostate.

Conflicting data showing different patterns when comparing American with European studies.

Nonetheless, there is a wealth of information demonstrating that pesticides maintain a wide range of activities which permit them to copy/counteract the actions of hormones in target tissues. Prostate is dependant for its normal growth and function on a continuous supply of steroid hormones. Pesticides as endocrine disruptors

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could interfere with these processes and lead to abnormal growth of the prostate. The biological plausibility for a link between pesticides and prostate cancer is therefore real and worthy of consideration.

Mode of action of androgens and other hormones

The model for the mechanism of action of androgens in the prostate follows an integrated sequence of events, as previously described (Habib, 1994). Initially the entering steroid molecule, testosterone, is metabolised to dihydrotestosterone (DHT) in a reaction catalysed by a nuclear-membrane-bound steroid 5α-reductase enzyme. After binding of the ligand (androgens), the receptor (AR) is phosphorylated, homodimerised and transformed into a transcription factor that interacts with the so called hormone responsive elements in the DNA. The binding of the receptors to DNA, in turn, induces transcription of the androgen-regulated genes including prostate specific antigen (PSA) and the mitogenenic regulators (Koivisto et al, 1998). Following androgen ablation or anti-androgen treatment for prostate cancer, AR transcriptional activity is blocked. However, with time the tumour cells develop resistance to the treatment and androgen signalling is re-activated despite continuation of therapy.

Although testosterone also binds to the androgen receptor, the importance of DHT to the action of androgen in the human prostate is highlighted by the fact that no development of the prostate gland occurs in males with inherited 5α-reductase deficiency syndrome (Imperato-McGinley et al, 1999). Prostate tissue concentrations of DHT are therefore critical to the growth of the prostate.

Steroid receptors other than AR may also be involved in prostate cancer biology. Analysis of oestrogen receptor (ER)-α and –β in normal prostate, cancer and hormone refractory prostate cancer (HRPC) has demonstrated expression of ER-β in HRPC (Leave et al, 2001). Whether this is a consequence of the midlife change in the endocrine status of the aging male that invokes an enhanced oestrogenic status is not very clear. Declining testicular function after the age of fifty leads to decreasing concentrations of plasma testosterone. But the levels of plasma oestrogen are, however, sustained in the older man by enhanced peripheral aromatisation of adrenal androgens. The aromatase enzyme converts androgens to oestrogens (Bosland, 2000).

Peptide hormones such as prolactin, growth hormone and luteinizing hormone (LH) acting alone or in concert with androgens are also known to regulate normal physiological function of the prostate (Reiter et al, 1999). Recent experimental and clinical reports show that these peptide hormones may play an important role in prostate cancer development and progression (Leave et al, 1999).

Future investigations evaluating the role of pesticides as aetiological factors in prostate cancer will need to assess the impact of these chemicals on all stages of hormonal regulation including hormone synthesis, release, transport, storage, receptor recognition and transcriptional activity at both the peripheral level as well as at the target tissue.

ENDOCRINE-DISRUPTING PESTICIDES

Many pesticides are now suspected of being endocrine disruptors because they can cause adverse effects by interfering with the endocrine glands that secrete the hormones (Giusi et al, 2006). Endocrine disruptors can exert their effects either by binding to the hormone receptor and mimicking the hormone (Daxenberger, 2002; Monosson et al 1999) or by blocking the action of the hormone (Monosson et al 1999; Keice et al, 1995). Alternatively, they can stimulate or inhibit the enzymes responsible for the synthesis or clearance of a hormone (Sanderson et al, 2000, 2001). The bulk of these pesticides have been found to have either oestrogenic (Tollefsen et al, 2002) or antiandrogenic activity and they mediate their action by interacting either with oestrogen or androgen receptors (Daxenberger, 2002; Monosson et al 1999; Keice et al, 1995; Tollefsen et al, 2002). However the processes involved may also be far more complex than originally indicated. Indeed, merely binding to a receptor or inhibiting the metabolism of a hormone will not necessarily result in an immediate in vivo effect. The identification of the signalling pathways activated by the many hormones acting on the prostate will offer alternative targets for pesticides. Of particular interest are the downstream signalling molecules because of their potential role in cancer but these remain to be determined. Moreover, there is the added factor that target organs are generally integrated within a complex feedback system as witnessed by the hypothalamic-pituitary-gonadal axis in which the cumulative hormonal activities acting on a target cell is dependent on the inter-relationship between the various organs within the axis. Likewise the interplay between the neurological, reproductive and immune systems within man may also be critical to the control of the hormonal milieu.

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Figure 1 – Schematic diagram illustrating the adverse effects arising from the interplay between the Endocrine disruptors and the various organ systems. (Adapted from Kavlock et al, 1996)Abbreviations used: PCB, polychlorinated biphenyls.

Earlier studies on endocrine disrupting pesticides have included studies of organochlorines and organophosphates (Fig 1; Kavlock et al, 1996). Adverse health effects have been reported in experimental animals following relatively high exposure to these agents (Alavanja & Bonner, 2005). Although reported changes were primarily associated with the endocrine system, anatomical and morphological changes have also been noted in various organ systems including those of the male reproductive tract (Alavanja & Bonner, 2005; Fig. 1). However, there is a dearth of information regarding the impact of these endocrine disruptors on the prostate at both the experimental level as well as in humans. Atrazine and its metabolites, DIA (deisopropyl-atrazine), DACT (diaminochlorotriazine ) and DEA (deethylatrazine) have been found to reduce ventral and lateral prostate, seminal vesicle and epididymal weight when administered to male rats during puberty (Stoker et al 2002; Table 2). Furthermore when atrazine was administered to peripubertal male rats (22-47 days of age) doses of 1/200mg/kg/day, serum and intratesticular testosterone levels were reduced in the 100 and 200 mg/kg/d groups, as were seminal vesicle and ventral prostate weights (Trentacoste et al 2001; Table 2). In the same study, serum LH was also reduced, suggesting an effect on the hypothalamus, the pituitary gland or both. Deprivation of prolactin during the early post-natal stage in the male offspring of dams receiving less than 25mg/kg/d atrazine resulted in an increased incidence and severity of prostate inflammation (Stoker et al 1999; Table 2).

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Endocrine Disruptors

Organophosphates(e.g. Chlorpyrifos)

Organochlorines(e.g. PCB)

Triazines(e.g. Atrazine)

Target Organs (Laboratory animals, wildlife species, humans ?)

Neurological System

Immune System

Reproductive System

Adverse Effects

Table 2 – Summary of Reported Changes in the Male Reproductive System Of Rats Administered Atrazine or Metabolites

Abbreviations used: SD, Sprague-Dawley rats; PRL, prolactin; PND, postnatal day; DEA, deethylatrazine; DIA, deisopropyl-atrazine; DACT, diaminochloratriazine

In summary, exposure of male rats to endocrine disruptors during critical periods of development can impair differentiation of reproductive organs and sexual function. Although no specific mechanism(s) of action has, so far, been identified , these adverse effects may be triggered by the lack of a central nervous system control of the pituitary /gonadal axis. Down regulation of the neuropeptide GnRH induces the suppression of LH secretion and a reduction in circulating testosterone levels thereby causing the loss of weight seen in the ventral and lateral prostate. None of the studies so far reported have demonstrated that atrazine or any other endocrine disruptor was instrumental in the induction of prostate cancer in animal models. However, because of the significant physiological differences between human and rat prostate, caution should be observed when results in animal models, that have important implications for risk assessment, are extrapolated to humans.

Discussion

Epidemiological studies of workers exposed to pesticides have not consistently demonstrated the presence or absence of an excess risk of prostate cancer. The increase in incidence of prostate cancer reported over the last 20 years is largely due to the increase in PSA testing. Factors that may have contributed to the failure of epidemiological studies to detect a consistent excess cancer risk include:

The possibility that no excess exists;The wide range of unrelated substances to which workers have been exposed;Poor exposure characterisation;Classification of workers with extremely low levels of exposure as being “exposed”;Small study populations and/or short follow up times in over half of the available studies;A failure to specifically investigate prostate cancer risk in some earlier studies; andThe substantial change in diagnostic practice in recent years.

None of the studies of pesticide production workers demonstrated a link between pesticides and prostate cancer, although in some cases study populations were small, follow up times short, and the detection rates for prostate cancer would have been much lower than now. The available studies may not have detected an excess prostate cancer risk, if there was a long latency between first exposure and the onset of disease. It is also possible that levels of exposure to pesticides during manufacture have been typically very low. If pesticides are largely manufactured using closed system processes with automated packing or containerisation of the final product, exposures will be limited to those occurring during occasional maintenance tasks. The numbers of manufacturing workers exposed to significant quantities of pesticide may be very small, and the exposures may be infrequent. Under such circumstances, it is highly unlikely that epidemiological studies would be able to detect an excess risk of prostate cancer, even if such a risk existed.

Some, but not all, studies of pesticide-exposed agricultural workers appear to show excess risks of prostate cancer, particularly in more recent studies conducted in North America. These excess risks appear to be greatest in older men. It seems plausible that exposures to pesticides during use would be much less controlled than during manufacture, giving rise to much greater levels of exposure than would be found in manufacturing plants. It is not possible, however, to prove that these possible excess risks of prostate cancer are not associated with some other aspect of agricultural work or rural lifestyle. The results of most studies have shown that farmers generally have lower mortality risks than typical of the general population. It is possible that the survival of a greater proportion of men into old age and lower risks of death from other causes than is typical of the general

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Response Rat Strain Exposure Period Dose (mg/kg/day) Reference Decreased LH SD PND 22-47 100/200 (atrazine) Trentacoste

et al 2001Decreased testosterone and prostate weight

SD PND 22-47 50/100 (atrazine) Trentacoste et al 2001

Delayed preputial separation Decreased LH PRL and prostate weight

Wistar PND 23-53 12.5/50 (DEA)12.5/25 (DIA)6.25/100 (DACT)

Wistar PND 23-53 <12.5/25 (atrazine)Increased incidence and prostatitis in offspring

Wistar PND 1-4 13/25 (atrazine) Stoker et al 1999

Increased incidence and severity of prostatitis in offspring

Wistar PND 1-4 25/50 (atrazine) Stoker et al 1999

population may influence the apparent risks of prostate cancer diagnosis and death in farmers. Given that virtually all men would eventually develop prostate cancer in the absence of death from other causes, the apparent excess of prostate cancer in older farmers may be partly related to a deficit of deaths from other causes, in an age group where the risks of death are greatly increased in comparison with younger men. Men of a similar age in a comparison population may be at equal risk of developing prostate cancer but may die from other causes marginally earlier than they would have died from prostate cancer. It is also possible that the increased excess risks of prostate cancer in old age may reflect long latencies between exposure and effects and/or the pattern of exposure in older workers may be different from that in younger workers. Increasing awareness of pesticide safety issues is likely to have led to an overall reduction in pesticide exposure through time, but older workers may have modified their work practices to a lesser extent than younger men, giving rise to higher levels of exposure over comparable calendar time periods.

Only three studies of pesticide users present evidence of a possible link between pesticides and prostate cancer in younger men that would be consistent with a causal association, but none of these studies found a statistically significant risk in younger men. In two of these studies, the apparent excess risk was based on a single case and is likely to have arisen by chance. Another study in golf course superintendents reported an excess in prostate cancer in a population where lifestyle factors did not appear to have given rise to a deficit of deaths from other causes.

Pesticide workers are exposed to a very wide range of compounds, both as a group, and, in many cases, as individuals. These compounds will have very different modes of toxic action and it is inconceivable that all compounds used as pesticides would give rise to an increased risk in prostate cancer risk. The data do not preclude the possibility that a small proportion of pesticide compounds could be associated with a prostate cancer risk.

There are considerable epidemiological data that suggest that it is highly unlikely that phenoxy herbicides are associated with an excess risk of prostate cancer. It is also unlikely that aldrin is associated with prostate cancer. The evidence for other chlorinated pesticides is less consistent. Pesticides that appear to be associated with prostate cancer in more than one study are methyl bromide (AHS, Mills and Yang, 2003), DDT (AHS, Settimi et al, 2003) and heptachlor (AHS, Mills and Yang, 2003). Two studies also reported an association for atrazine that failed to reach statistical significance (AHS, Mills, 1998). Given the large number of different compounds that have been used, and the likelihood that many applicators have been exposed to a mixture of substances, these positive associations may have arisen by chance. There is little evidence from other sources that methyl bromide is carcinogenic and given that it is being phased out of use, the issue is of limited relevance to future risk management. There is evidence that atrazine, DDT and heptachlor cause cancer in animals and some further investigation of effects in humans may be appropriate. However, as the use of DDT and heptachlor is banned within the UK and the use of atrazine will cease in 2007, the carcinogenic potential of these particular compounds will be of limited value in future risk assessment except in relation to consideration of any closely related chemicals. There is a possible association of prostate cancer with some organophosphate compounds but specific organophosphate compounds have not been identified as possible causes of prostate cancer.

A number of recent mechanistic studies have demonstrated that pesticides might induce androgen imbalance by interfering with the action of natural hormones at both the peripheral and intracellular levels (Giusi etal, 2006; Hayes, 2004; Timms et al, 2005; Wozniak et al, 2005; Meeker et al, 2006). The possible effects on the prostate have not yet been investigated, even though the gland is a target tissue for androgens and the growth and function of the prostate is dependant on the continuous supply of hormones controlled by the hypothalamic-pituitary-gonadal axis. Any disruptor that suppressed the normal workings of this axis could interfere with hormone synthesis and curtail the flow of testosterone and other hormones into the prostate. Additionally pesticides may target the prostate directly, influence steroid metabolism, receptor binding activity or degradation and trigger the sequence of events leading to the onset of neoplasia. There is a need for studies to be undertaken that will lead to the identification of the mechanisms that may be involved at both the cellular and molecular levels.

Extent to which study goals were achieved

The two principal study aims have been achieved. A comprehensive review of the literature on pesticide use and prostate cancer has been carried out. Early literature searches showed that there was relatively little information available on workers in the pesticide manufacturing industry and, with the agreement of the sponsor, the scope of the study was extended to include workers exposed to pesticides in other occupations. Over 140 relevant publications were identified (from many more possibly-relevant publications identified during early wide-ranging searches of the literature) and reviewed in detail. These included both epidemiological studies of pesticide use and prostate cancer, and investigations of potential mechanisms underlying any link between them.

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Conclusions to be drawn from the study are limited, however, by the range and scope of the studies reported in the literature. There are insufficient epidemiological or mechanistic data to determine the relationship between pesticide exposure and prostate cancer risk. The vast number of very different chemical compounds that are or have been used as pesticides has proved a major limitation in understanding the potential link between pesticides and prostate cancer. There were no published investigations of the mechanisms that may link the androgen-disrupting properties of some pesticides to prostate cancer available for review.

Conclusions and recommendations

There is insufficient evidence to conclude that pesticide exposure is associated with an increased prostate cancer risk. There is, however, also insufficient evidence to be certain that such a risk does not exist, although the failure to consistently detect a risk suggests that typical levels of pesticide exposure among pesticide workers do not have an important influence on prostate cancer risk. Epidemiological evidence that is suggestive of a possible effect is strongest for methyl bromide, atrazine, DDT, heptachlor and some (unspecified) organophosphate compounds. Possible excess risks appear to be confined to pesticide applicators rather than manufacturers, possibly because applicators experience greater levels of exposure, or possibly because the apparent risks are due to some confounding factor associated with pesticide application. Increased risks of prostate cancer have been more consistently reported in North American studies than in European studies. This may reflect differences in pesticide use, some other aspect of agricultural practice or lifestyle factors. Increased risks have also been more consistently reported in recent studies than in older studies, possibly reflecting improvements in diagnostic practice or changes in the pattern of pesticide use through time.

Several studies have suggested an increased excess risk of prostate cancers in pesticide users in old age that may reflect a substantial latency period between first exposure and disease development, although this has not been extensively investigated. It is also possible that the pattern of exposure in older workers has been substantially different than in younger workers (different compounds, differences in handling and attitudes towards exposure). There has been very little investigation of prostate cancer risks by age in pesticide workers and other studies have reported a greater excess risk in younger men, although this has not been statistically significant.

There has been little investigation of the mechanisms by which exposure to pesticides may lead to increased prostate cancer risk and several research topics were identified including:-

1. Potential role of hormonal disruption in giving rise to an increased prostate cancer risk; 2. Genetic susceptibility.

Given there is some evidence of a relationship between the ratio of oestrogen to androgen and susceptibility to prostate cancer, there would be value in further investigation of this relationship in humans. A future review of the results from human studies on the ratio of hormones among people with prostate cancer and those without may be informative as to the potential importance of this ratio. There is also a requirement for an improved mechanistic understanding of how this ratio may affect prostate cancer risk and also the potential mechanisms by which pesticide exposure could affect this ratio. The potential impact of pesticides on this ratio could be assessed through a review of any existing studies and by undertaking animal studies to specifically examine hormonal changes in animals exposed to pesticides. In addition, in vitro/human tissue studies could be undertaken in order to better understand the potential effects of pesticides and pesticide metabolites on the metabolism of androgens in the prostate. Integration of the results of such studies with existing knowledge on the role of androgens in prostate cancer may provide an understanding of the mechanisms by which pesticides may or may not give rise to increased prostate cancer risks.

There appears to be a familial link between occurrence of prostate cancer and of breast cancer that suggests the possibility of a common genetic factor. If a common gene for these susceptibilities could be identified then studies could be carried out to investigate whether exposure to pesticides could cause mutation of these genes.

It is difficult to make recommendations for future epidemiological investigations at this time, although it would be worth updating this review in five years time when the mechanisms underlying prostate cancer may be better understood and there may be fresh epidemiological evidence to examine.

If any future epidemiological studies are undertaken, we would recommend specific examination of the risks of prostate cancer in younger men and also specific investigations of the role of latency. We would also recommend better characterisation of exposure and the use of study designs that are able to assess the risks for specific groups of pesticides rather than pesticides more broadly. It would be worth considering excluding workers with very low exposures from the “exposed” population to ensure an adequate contrast between the “exposed” population and any “unexposed” comparison group. Study populations need to be large enough and follow up long enough to provide confidence that any absence of observed risk is real. Given that modern production methods in both the chemical and agricultural industries employ relatively few workers, it may be difficult to

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identify suitable study populations. Changing patterns of pesticide production and use may be another difficulty. Older pesticide formulations are likely to be phased out as they become ineffective or are recognised as posing unacceptable environmental or health hazards.

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Annex to final report on DEFRA project PS2609

Appendix to “Literature review of prostate cancer and pesticide exposure”

A1 Introduction

This review includes consideration of:

Previous reviews and meta-analyses of the possible links between pesticide exposure and prostate cancer;Studies of cancers in workers involved in pesticide manufacture (not limited to specific studies of prostate cancer);Studies of cancer in pesticide users;Studies of prostate cancer risk by occupation;Studies of prostate cancer risk by markers of population exposure;Studies of prostate cancer risk in US veterans exposed to agent orange.

The studies of cancer in pesticide users includes studies in agriculture workers using pesticides, studies in farmers not specific to pesticide exposure and studies in other professional groups exposed to pesticides.

The conclusions of this review are outlined in the final section.

A2 Methods

A number of searches were made of the on-line database PubMed.

Prostate + cancer + pesticide/ pesticides (also checked herbicide(s) and biocide(s))

Prostate + cancer + occupation/occupational

Pesticide + manufacture + exposure

Pesticide + exposure + production

Pesticide + manufacture (limited to humans)

Pesticide + production (limited to humans)

Pesticide + cancer (limited to humans)

In addition lists of “related articles” were checked for the manufacturing and production studies found. Other references were identified from earlier reviews and meta-analyses including the discussion sections of some of the primary studies. A number of studies identified by these means had not appeared in the original PubMed searches and it is therefore difficult to be certain that all relevant studies have been identified.

The abstracts of all the identified studies were assembled, organised by topic, reviewed and summarised. Copies of the studies of populations exposed during pesticide manufacture and production, the earlier reviews and meta-analyses and most of the studies of pesticide applicators were obtained. These were reviewed and an assessment made of the strength of evidence underlying the reported results. Information derived from reviews of the full reports was integrated into the summaries of the studies. For many cancer studies, the term prostate was not included in the abstract and it was necessary to obtain the full study in order to determine whether prostate cancer had been considered.

A3 Some background information about prostate cancer

Prostate cancer is a relatively common disease in older men affecting almost 1% of men aged over 85 in the UK. It has been suggested that all men with circulating androgens will develop microscopic prostate cancer if they live long enough (Bostwick et al, 2004). This implies that, if the risk of death from other causes is reduced, the incidence of prostate cancer is likely to increase. A number of potential risk factors for prostate cancer have been investigated but the results of different studies are generally highly inconsistent. There is some evidence to suggest that risks of prostate cancer are increased by the consumption of animal fat, employment in farming and possibly pesticides (Bostwick et al, 2004). Many other factors such as body mass index, exercise, vasectomy and

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exposure to cadmium have been shown to be associated with increased prostate cancer risks in some studies but not in others.

The incidence of prostate cancer is rising. In the UK, the incident rate for 2001-3 was 89.8 per 100 000 population and the mortality rate was 27.1 per 100 000 (www.statistics.gov.uk). The incidence rate rose sharply (by 86%) during the late 1980s as a result of improved detection. The mortality rate has also risen slightly since the 1960s and 1970s, when the mortality rate was about 20 per 100 000. Less than 0.5% of cases arise in men under 50. The death rate from prostate cancer are in the UK is similar to that for the EU as a whole but slightly lower than in the Netherlands and Scandinavia (www.statistics.gov.uk).

The incidence of prostate cancer has also risen in North America (McDavid et al, 2004). The 2002 US incidence rate was 161.2 per 100,000 and the mortality rate 28.1 (www.cdc.gov/cancer/npcr/uscs/pdf/2002_USCS.pdf). In Canada and the U.S. the growth in age-adjusted incidence from 1969-90 and 1973-85, respectively was 3.0% and 2.5%. U.S. rates accelerated in the mid- to late 1980s. Similar patterns occurred in Canada with a one-year lag. Annual age-adjusted mortality rates in Canada increased by 1.4% per year from 1977-93 then fell by 2.7% per year from 1993-99. In the U.S., annual age-adjusted mortality rates for white males increased by 0.7% from 1969-1987 and by 3.0% from 1987-91, then decreased by 1.2% and 4.5% during the 1991-94 and 1994-99 periods, respectively. McDavid et al (2004) concluded that the introduction and widespread use of the prostate-specific antigen (PSA) test use had had a substantial impact on the apparent incidence of disease though enabling detection at a much earlier stage in disease development.

The introduction of PSA has implications for the interpretation of epidemiological investigations of prostate cancer incidence, particularly those undertaken in North America. In studies published prior to the widespread use of PSA, it is likely that some of the control subjects would have had pre-clinical cancers that would now be detected by PSA. It is also likely that in a given cohort over a given time period, a higher incidence of prostate cancer would be detected now than would have been detected thirty years ago, as more men are likely to develop pre-clinical disease than clinical disease within a given time frame. The increased number of cases in both “exposed” and “unexposed” populations is likely to have increased the power of studies to detect effects. The incidence of prostate cancer in past studies was probably under-estimated relative to that which would have been found in studies undertaken since the mid 1990s. An absence of prostate cancer in earlier studies would not necessarily be re-assuring as to an absence of risk, although the detection rates for prostate cancer could be reasonably assumed to be at least as good in the exposed populations as for the control population. In some circumstances, the detection rate might have been better, if workers were subject to route medical screening as part of their terms of employment. Platz et al (2004) raise concerns that the pre-clinical disease detected by PSA may not lead to the same kind of disease as would have been detected purely through clinical means. They also raise concerns about the imperfection of the PSA test as it does not detect all prostate cancers either because some men have prostate cancers in the absence of raised levels of PSA or because biopsy sampling may fail to detect the presence of a tumour following PSA testing.

A4 Previous reviews of the role of pesticide exposure in the development of prostate cancer

Van Maele-Fabry and Willems (2003, 2004) analysed data from peer-reviewed, case-referent and cohort studies, on the occurrence of prostate cancer in pesticide applicators and in some other, related, occupational categories. Studies were identified using a Medline search for the years between 1966 and 2003, and relevant studies were identified from 1986 onwards. They conducted a meta-analysis of 22 studies complying with their inclusion criteria. Studies were excluded if they included subjects in studies updated by more recent studies, less than five exposed cases, did not report original results or only reported proportionate mortality ratios. Length of follow up was not specifically considered. The study authors considered that there was no evidence of publication bias. The meta-rate ratio, based on 22 estimates of relative risk (RR), was 1.24 [95% confidence interval (CI)) 1.06-1.45]. Pooled risk estimates for studies derived from Europe were lower than those derived from the USA/Canada (1.12 compared with 1.40). Apparent risk also varied by study design with the rate ratio in cohort mortality studies being 1.21 compared with 1.37 in incidence studies. In case control studies, pooled estimates of risk were 2.13 for mortality studies and 1.10 for incidence studies. Risk estimates also varied by occupation with a significant increase in risk being observed for pesticide applicators (rate ratio 1.64) whereas no significant increase was observed for farmers (rate ratio 0.97). No evidence of exposure-response relationships (eg increasing risk with increasing duration of exposure) was found for applicators but it was acknowledged that the pattern of exposures were likely to be very variable. It would seem plausible that pesticide applicators would experience higher levels of exposure to pesticides than farmers such that the higher risk for applicators could be related to higher levels of exposure. The authors concluded that there was an increased meta-rate ratio for prostate cancer in different pesticide related occupations but that the underlying data were insufficient to confirm pesticide exposure as an independent risk factor for prostate cancer because of the absence of good exposure information and the wide range of compounds considered. The inclusion of a wide range of different compounds classified as pesticides may have weakened the power of the study to detect effects. The study did not examine apparent risks of prostate cancer by age or length of follow up.

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In a more general chemical industry funded review of pesticide manufacturers and applicators, Burns (2005) concluded that there was little indication of an increased cancer risk. Poor exposure characterisation meant that the available studies generally had little power to demonstrate the presence or absence of effect. A further limitation in many studies was a small sample population. There were too few studies of individual pesticides or classes of pesticides to undertake a credible meta-analysis for individual compounds or classes or compounds.

Dich and Wiklund (1998) provide a useful summary table of the findings of earlier cohort studies that had investigated exposure to pesticides and prostate cancer risks that highlights the inconsistencies between different studies.

A number of earlier reviews of the links between pesticide exposure and cancer failed to detect an excess risk of prostate cancer as described in more detail below. The studies available for review in these studies would have preceded the introduction of PSA testing and there may have been an underestimation of the incidence of prostate cancer in both “exposed” and comparison “unexposed” populations. The absence of an excess of prostate cancer in these earlier studies does not provide complete reassurance that, if modern diagnostic methods had been available, an excess risk would not have been detected.

Sathiakumar and Delzell (1997) reviewed the carcinogenic potential of triazine herbicides in general and of atrazine, the most common triazine, in humans. Available epidemiological data included non-Hodgkin's lymphoma, Hodgkin's disease, leukaemia, multiple myeloma, soft tissue sarcoma, colon cancer, and ovarian cancer. Methodological limitations of the investigations included lack of detailed exposure measurements and small numbers of subjects with the heavy exposure and/or with many years since starting exposure, that may be required for the induction of cancer. A pooled analysis of the studies that reported excess risks of non-Hodgkin's lymphoma did not demonstrate the types of dose-response or induction time patterns that would be expected if triazines were causal factors. There were insufficient data to determine whether cancers at other sites, including the prostate, were associated with triazine exposure.

Maroni and Fait (1993) reviewed the scientific literature published over the period 1975-1991 on long-term health effects arising from prolonged exposure to pesticides. A total of 440 papers were identified including 97 reviews, a small number of case reports, 108 case-control, 10 proportionate mortality, 66 cohort and 51 cross-sectional studies. These were carried out in pesticide applicators (48 studies), agricultural workers (26 studies) or people employed in the pesticide manufacturing industry (50 studies). Most of the case-control studies related to cases of cancer particularly myelolymphoproliferative disorders and soft-tissue sarcomas. When compared to the general population total mortality was found to be consistently lower among pesticide manufacturers as well as other pesticide-exposed workers. This was attributed to the 'healthy worker effect' or, in the case of agricultural workers, to the healthier lifestyle of farm families. There was no consistent evidence that cancer mortality was greater in pesticide manufacturers or applicators than in the general population.

Morrison et al (1993) concluded from a review of the literature that there was reasonable evidence to suggest that occupational exposure to phenoxy herbicides results in increased risk of developing non-Hodgkin's lymphoma. Several of the reviewed studies reported large increases in risk of soft-tissue sarcomas with phenoxy herbicide exposure. In contrast, others failed to observe increased risks, and no evidence of an exposure-response relationship was detected. There was insufficient evidence to determine whether herbicide exposure could be linked to cancers of the colon, lung, nose, prostate, and ovary as well as to leukaemia and multiple myeloma, although such associations had been reported in some studies. Poor characterisation of exposure in most studies had limited their power to detect exposure-response relationships.

Johnson (1990) reviewed the epidemiological evidence for a significant association between occupational use of phenoxy herbicides and chlorophenols and soft-tissue sarcomas and malignant lymphomas. Case-control studies that had reported potential associations had generally failed to control for exposure to other potentially carcinogenic chemicals and oncogenic viruses. The evidence from occupational cohort studies also did not provide unequivocal evidence of a link between phenoxy herbicides and chlorophenols and these cancers, although the apparent absence of effects may have been due to inadequate follow up periods in the source studies. In a meta-analysis of epidemiological studies published between 1979-1987, Johnson et al (1990) further investigated the relationship between phenoxy acid herbicides and chlorophenols and the occurrence of soft tissue sarcoma. They derived a proportional mortality ratio of 3.5 (95% CI 0.7-10.3) from cohort studies. The selected case-control studies had homogeneous risk estimates with a summary odds ratio of 1.1 (95% CI 0.9-1.4). The authors concluded that there was no strong evidence for an association between the specified herbicides and soft tissue sarcoma. Prostate cancer was not investigated as a potential outcome of exposure in either of these studies.

Bond et al (1989) reviewed the carcinogenicity of phenoxy herbicides in humans. Graphs of the individual probability densities for the odds ratios from the eight case-control studies of soft-tissue sarcoma, Hodgkin's disease, or non-Hodgkin's lymphoma demonstrated gross inconsistencies that were not likely to be attributable to

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chance. Early studies, conducted in Sweden, had indicated strong associations, but later studies in New Zealand and the United States failed to substantiate those findings. Bond et al suggest the earlier studies may have been subject to methodological problems. Retrospective cohort studies that had examined occupational groups believed to have had the highest exposures were individually too small to assess the risks of rarer forms of cancer. Consideration of the combined cohort studies of workers exposed to the phenoxy herbicides per se provided little or no evidence of carcinogenicity. The authors concluded the available evidence did not indicate that the phenoxy herbicides present a carcinogenic hazard to humans.

Garabrant and Philbert (2002) reviewed the toxicity of 2,4-dichlorophenoxyacetic acid (2,4-D) and concluded that the available evidence from epidemiologic studies was not adequate to conclude that any form of cancer is causally associated with 2,4-D exposure.

In a review and meta-analysis of cancer in farmers, Blair et al (1992) found statistically significant excess risks of death from a range of cancers including prostate cancer (meta-risk 1.08, 95% CI 1.06-1.11). Overall mortality risks in farmers and risks of death from all cancers were however found to be much lower than for the general population. Blair et al were unable to investigate cancer risk by age group or in relation to potential specific exposures that may have given rise to a raised cancer risk. Keller-Byrne (1997) undertook meta-analyses of articles published in peer-reviewed journals between January 1983 and June 1994 to investigate the risks of prostate cancer in farmers. Three analyses were performed: (1) an analysis including all articles written during the specified time period that listed an estimate of the relative risk of prostate cancer in farmers: (2) an analysis that included only retrospective studies; and (3) an analysis that included only studies reporting a standardized mortality ratio. Positive associations between prostate cancer and farming were found by the analysis including all studies and the analysis limited to the retrospective studies. No association was found with the analysis that included only studies reporting a standard mortality ratio. The author suggested that the positive association between prostate cancer and farming is due to exposure to hormonally active agricultural chemicals.

In conclusion, the results of the meta-analysis published by Van MaeleFbary and Willems (2003,2004) indicate that pesticide applicators have an increased risk of prostate cancer, although it was not possible to establish that this was solely due to pesticide exposure. Other, earlier reviews had failed to identify a link between pesticides and prostate cancer. The populations in the source studies of earlier reviews are likely to have been exposed to different pesticides from those in more recent studies and also the follow up times in many of the earlier studies was relatively short, particularly in relation to the development of cancer in old age. The short follow up times may have limited the power of many of the earlier studies to detect an excess of prostate cancer. In addition, poor detection of prostate cancer prior to the mid 1990s may have led to an under-estimation of incidence in earlier studies. It is also possible that higher levels of exposure in earlier studies may have given rise to different disease outcomes than those found in later studies. For example, many of the earlier studies found excesses of lymphoma and soft tissue sarcomas. Publication bias may have played a role as many of the earlier studies were actively investigating possible links with lymphoma and soft tissue sarcomas whereas more recent studies have actively investigated prostate cancer risks.

A5 Studies of workers in plants manufacturing pesticides

A5.1 ATRAZINE

Following an earlier study by Sathiakumar et al (1998) that had reported a possible small excess of non-Hodgkins lymphoma in workers exposed to triazine herbicides, MacLennan et al (2002) evaluated cancer incidence and PSA testing among workers at a plant in Louisiana (LA) that made atrazine and other triazine herbicides. The study covered the time period 1985 through 1997 and included 2045 subjects, of whom 757 worked for the company that owned the plant and 1288 were contract employees. Cancer cases were identified through linkage with a population-based cancer registry and review of death certificates and plant medical records. Incidence rates in workers were compared with those of the regional general population. Plant medical records provided data on the proportion receiving PSA tests among male company employees. Among subjects there were 46 observed cases of all cancers combined compared with 40 expected (Standard Incidence Ratio (SIR) = 114, 95% CI = 83-152) and there were 11 prostate cancers versus 6.3 expected (SIR = 175, CI = 87-312). The prostate cancer excess was greater in actively working company employees (5/1.3, SIR = 394, CI = 128-920) than in contract employees or inactive company employees (6/5.0, SIR = 119, CI = 44-260) and was limited to men under 60 years of age. Given that prostate cancer is typically a disease of old age, this excess in younger men is suggestive of a potential link with workplace exposure, although the availability of PSA testing for active company employees may have substantially increased detection rates in these men compared with the two other groups. Of the 11 prostate cancer cases, nine were diagnosed at an early clinical stage. From 1993 to 1999, the proportion of male company employees who had at least one PSA test was 86% for those who reached 40 years of age while actively working and was 98% for those who reached 45 years of age. The authors suggested that the observed prostate cancer increase may have been due to the frequent PSA testing of actively working company employees. No evidence was found of causal relation between atrazine and prostate cancer. Sass (2003), however, noted that by limiting the time period of interest to 1985-1997 (which was governed by the

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availability of comparison rates for the general population) the authors had restricted the number of prostate cancer cases to 11 whereas if the study had been extended to 1999, the number of cases would have been 14. This greater level of excess risk would have been more difficult to explain in terms of improved screening. Subsequently, MacLennan et al (2003) evaluated mortality patterns among 2213 people employed for at least 6 months in operations related to the manufacture or formulation of atrazine and other triazine herbicides in the same plant over the time period 1970-1997. All cause mortality was less than expected and the cancer mortality was similar to expected. There were 4 deaths from non-Hodgkin's lymphoma compared with the 1.1 expected (standardised mortality ratio (SMR) = 372, CI = 101-952); but the risk was not associated with duration of employment or time of first employment. There were small statistically nonsignificant excesses of digestive and lung cancer deaths. Data on other forms of cancer were sparse. This study was limited by its small size, by the relatively young age and short follow-up of its subjects, and by the lack of exposure data. Although these two studies do not provide clear evidence linking triazine pesticides to cancers in humans, their limited power to detect effects means that they also do not provide strong evidence for an absence of effect.

Hessel et al (2004) in a follow up to the studies undertaken by MacLennan et al (2004, 2003), and Sathiakumar et al (1996) investigated the relationship among atrazine exposure, prostate cancer, and the screening program. Twelve cases and 130 control subjects were selected from the original cohort studied by MacLennan et al. Controls were matched by age and race. Prostate screening and occupational histories were abstracted from company records. Atrazine exposures were estimated from the combination of job title and department by four industrial hygienists. Each combination of job title and department was assigned to one of five qualitative exposure levels. The exposure assessment was partly based on 1368 total dust measurements made between 1970 and 1991 and 194 measurements of airborne atrazine made between 1989 and 1999. Dust levels generally fell from mean levels between 10 and 15 mgm -3 in the late 1970s to less than 5 mgm -3 in the mid 1980s and thereafter remained stable. Atrazine concentrations were less than 1 mgm-3. The relationship between dust concentrations and the subsequent measurements of atrazine was not investigated. The cases and control subjects were hired at comparable dates, but nearly half of the control subjects left before the prostate-specific antigen (PSA) screening program was initiated compared with none of the cases. Cases were therefore more likely to have undergone PSA tests than control subjects (odds ratio 8.54; 95% CI, 1.69-82.20). When all cases and controls were considered, there was no association between the average or cumulative exposure to atrazine between cases and controls but the length of exposure was significantly higher among cases. When only subjects who had undergone at least one PSA test were considered, there was no evidence for an association between atrazine and prostate cancer.

In conclusion, the results of the Louisiana studies suggest that the apparent association between prostate cancer and atrazine reported in earlier studies had arisen as a consequence of the introduction of an intensive screening programme at the plant. The authors believed that although the number of subjects studied was small, the absence of any suggestive relationships between atrazine and prostate cancer suggests that it was unlikely that they had missed an important effect. The excess of prostate cancer in younger men and relationship with duration of exposure are, however, suggestive of an effect and the limited follow up times employed in the studies may have weakened their power to detect effects.

A5.2 PHENOXY ACID HERBICIDES

There have been a number of studies of workers involved in the manufacture of phenoxy acid herbicides. In the past, some phenoxy acid herbicides were heavily contaminated with dioxin and there has been uncertainty as to whether the increased cancer risk seen in some studies was due to exposure to dioxin or to phenoxy acids. Many of the published studies from outside of the US were undertaken within an IARC coordinated international collaborative study.

Coggon et al (1991) recruited four British cohorts of chemical manufacturers. They comprised a total of 2239 men employed during 1963-85. These subjects were traced to 31 December 1987 through the National Health Service Central Register and the National Insurance Index, and their mortality compared with that in the national population. Two deaths from non-Hodgkin's lymphoma compared with 0.87 expected. Both deaths occurred more than 10 years after first exposure to phenoxy compounds. One further non-Hodgkin's lymphoma was registered in a living subject with probable exposure to phenoxy compounds. A nonsignificant excess of lung cancer (19 deaths observed, 14.2 expected) was probably attributable to chance or a confounding effect of smoking. In one cohort only there was increased mortality from circulatory disease (34 deaths observed, 20.4 expected). A nested case-control study did not point to any occupational cause for this excess. There was no evidence for an excess risk of prostate cancer.

Previously, Coggon et al (1986) had examined the mortality and cancer incidence of employees at a company that manufactured, formulated, and sprayed 2 methyl-4 chlorophenoxyacetic acid (MCPA) and other phenoxy acid herbicides. Ninety-eight percent of the 5,784 men employed by the company during 1947-1975 were traced to the end of 1983. The overall mortality of the cohort was less than that of the national population, as was

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mortality from cancer. When allowance was made for rural residence, the deficit of cancer deaths became a slight excess, but was not statistically significant. Among workers whose jobs entailed potential exposure to MCPA, there was one death from soft tissue sarcoma (0.6 expected). No further cases of soft tissue sarcoma were registered among living members of the cohort. Three potentially exposed workers died from nasal carcinoma, but this tumour had not previously been associated with phenoxy herbicides and the cluster of cases may have occurred by chance. The authors suggested that any risk of soft tissue sarcoma was less than that indicated by earlier studies of 2,4,5-trichlorophenoxyacetic acid (2,4,5-T) and 2,4,5-trichlorophenol. No evidence was found to suggest an excess risk of prostate cancer.

Bueno de Mesquita et al (1993) followed up 2,310 workers from two plants in the Netherlands, during the periods 1955-1985 and 1965-1986, respectively. Loss to follow-up was 3%. In 1963, there had been an industrial accident in one factory with concomitant release of dioxin into the environment. Compared with national rates, there was no significant increase in all cause or cancer mortality. A statistically insignificant increase was observed for non-Hodgkin's lymphoma. No increased risk of prostate cancer was reported. The relatively short follow up period may have limited the power of the study to detect effects.

Lynge (1985, 1993, 1998) studied 2119 workers at two Danish plants manufacturing 2,4-dichlorophenol and 4-chloro-ortho-cresol based phenoxy herbicides since 1947 and 1951, respectively. Contamination by 2,3,7,8-tetrachlorodibenzo-p-dioxin (2,3,7,8-TCDD) was thought unlikely. The 1998 study covered the period 1947-93. The predominant product was MCPA and only a very limited amount of 2,4,5-T was processed in one of the factories. The overall cancer incidence in herbicide-exposed workers was slightly lower than in the Danish general population. A small excess of soft-tissue sarcoma cases was observed but no significantly elevated risk of other cancers were observed. A small excess of lung cancer found in the first study was not confirmed by the later studies.

Saracci et al (1991) undertook a historical cohort study of mortality in an international register of 18,910 production workers or sprayers from ten countries. Exposure was reconstructed through questionnaires, factory or spraying records, and job histories. Cause-specific national death rates were used as reference. No excess was observed in all-cause mortality, for all neoplasms, for the most common epithelial cancers, or for lymphomas. A statistically non-significant two-fold excess risk, based on 4 observed deaths, was noted for soft-tissue sarcoma (SMR = 196, 95% CI 53-502). This was concentrated as a six-fold statistically significant excess, occurring 10-19 years from first exposure in the cohort as a whole (SMR = 606 95% CI 165-1552) and, for the same time period, as a nine-fold excess among sprayers (SMR = 882 95% CI 182-2579). Risks appeared to be increased for cancers of the testicle, thyroid, other endocrine glands, and nose and nasal cavity, based on small numbers of deaths. No significant excess of prostate cancer deaths was reported (SMR in exposed workers 111, 95% CI 75-158).

In an overall analysis of the IARC-coordinated study, Kogevinas et al (1997) examined cancer mortality in a historical cohort study of 21,863 male and female workers in 36 cohorts exposed to phenoxy herbicides, chlorophenols, and dioxins in 12 countries. Workers were followed from 1939 to 1992. Exposure was reconstructed using job records, company exposure questionnaires, and serum and adipose tissue dioxin levels. Among workers exposed to phenoxy herbicides contaminated with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) or higher chlorinated dioxins, there was increased mortality from soft-tissue sarcoma, all malignant neoplasms, non-Hodgkin's lymphoma and lung cancer. In workers exposed to phenoxy herbicides with minimal or no contamination by TCDD and higher chlorinated dioxins, mortality from soft-tissue sarcoma was slightly elevated but there was no significant excess of other cancers. No excess of prostate cancer was reported in either group. Previously Kogevinas et al (1995) had investigated the effects of exposure to chemicals present in the production and spraying of phenoxy herbicides or chlorophenols in two nested case-control studies of soft tissue sarcoma and non-Hodgkin's lymphoma. They found evidence that workers exposed to phenoxy herbicides and their contaminants are at a higher risk of soft tissue sarcoma.

Fingerhut et al (1991) conducted a retrospective cohort study of mortality among the 5172 workers at 12 plants in the United States that had produced chemicals contaminated with TCDD. Occupational exposure was documented by reviewing job descriptions and by measuring TCDD in serum from a sample of 253 workers. Although there was a small, but statistically significant excess of deaths from “all cancers”, there was no excess mortality from several cancers previously associated with TCDD (stomach, liver, and nasal cancers, Hodgkin's disease, and non-Hodgkin's lymphoma). There was a nonsignificant increase in mortality from soft-tissue sarcoma in the cohort as a whole that became significant in the subcohort of 1520 workers with at least one year of exposure and twenty years of latency. Conclusions about an increase in the risk of soft-tissue sarcoma were, however, limited by small numbers and misclassification on death certificates. In an earlier study, Ott et al (1987) evaluated mortality from 1940 through 1982, in 2,192 US chemical workers who had potentially been exposed to chlorinated dioxins during the manufacture of higher chlorinated phenols and derivative products. In comparison with US white males, there was no excess of deaths from all causes, total malignant neoplasms, or specific malignancies of particular interest: stomach cancer, liver cancer, connective and other soft-tissue cancer, the lymphomas, or nasal and nasopharyngeal cancer. No excess of prostate cancer was reported.

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Bond et al (1988) studied 878 US chemical workers potentially exposed to the herbicide 2,4-dichlorophenoxyacetic acid (2,4-D) at any time between 1945 and 1983. No excess risk was found for any particular cause of death. The study was focussed on brain cancer risks and this may have affected outcomes. In addition, the small study size and limited follow up may have limited its power to detect an excess of prostate cancer (SMR 104, 95% CI 1-576). Measured personal exposure concentrations ranged from <0.04 – 7 mgm -3. In an update of this study, Bloemen et al (1993) reported standardised mortality ratios for all causes and for malignant neoplasms of 92 and 91, respectively for the period up to 1988. No excess of prostate cancer was reported.

Burns et al (2001) undertook a study of 1567 US workers manufacturing the herbicide 2,4-D any time from 1945 to the end of 1994. The time since first exposure for 725 of the workers was more than 30 years. Their mortality experience was compared with national rates and with more than 40 000 other company employees who worked at the same location. There were no significantly increased SMRs for any of the causes of death analyzed. There was a small nonsignificant excess of prostate cancer (SMR 1.34, 95% CI 0.54-2.77). The study was primarily undertaken to investigate lymphoma and no data were presented that relate apparent prostate cancer risk to cumulative exposure.

In a recent New Zealand study, Mannetje et al (2004) found a nonsignificant deficit of prostate cancer in a cohort of 1025 phenoxy herbicide production workers and 703 sprayers who were followed up from 1st January 1969 and the 1st January 1973 respectively, until 31 December 2000. It seems likely that this study would have detected a substantial excess risk of prostate cancer, had such a risk existed.

Overall, the available studies of workers exposed to phenoxy herbicides during manufacturing do not suggest a link with prostate cancer, although most studies of these workers predated the widespread introduction of PSA testing. The IARC co-ordinated studies involved a large number of workers and long follow up periods such that it is unlikely that an important excess risk of prostate cancer would have remained undetected. It is not possible to exclude the possibility that, if modern diagnostic methods had been available, a small excess of prostate cancer might have been found. The efficiency of detection should have been similar in both exposed and unexposed comparison groups.

A5.3 CHLOROPHENOLS

Ramlow et al (1996) investigated mortality in a cohort of 770 workers with potential pentachlorophenol (PCP) exposure from 1940 through to the end of 1989. Total mortality and cancer mortality were slightly lower than expected in comparison to the US white male population and similar to expected when compared with unexposed employees. A small excess of other and unspecified lymphohaemomatopoietic cancer deaths did not appear to be related to exposure. Excesses of deaths due to cancer of the kidney, gastric and duodenal ulcer and cirrhosis of the liver were observed in comparison with the US white male population and with unexposed employees. These were associated with increasing estimated cumulative exposure after lagging exposures by 5 and 15 years. No excess of prostate cancer was reported. The cohort was relatively small and the study may have lacked the power to detect a small excess of prostate cancer.

The review and meta-analyses reported by Johnson (1990) and Johnson et al (1990) did not find strong evidence of an association between chlorophenols and the occurrence of soft tissue sarcoma. There was no suggestion of excess risks for other types of cancer.

The limited available data do not suggest an association between the manufacture of chlorophenols and prostate cancer, but the studies were performed before modern diagnostic methods for prostate cancer were available.

A5.4 ALACHLOR

Acquavella et al (2004) evaluated mortality rates from 1968 to 1999 and cancer incidence rates from 1969 to 1999 for 1206 alachlor manufacturing workers employed for at least a year at anytime between 1961 and 1999 at a plant in Muscatine, Iowa. When compared with the general population in Iowa, no increased cancer risks were found in exposed workers. Arguably the follow-up period may have been insufficient to fully evaluate potential cancer risks. The main route of exposure to alachlor was thought to be through skin contact. Airborne concentrations were less than 100 ppb. Modern diagnostic methods for prostate cancer were only available for the later part of the follow-up and it is possible that cases may have gone undetected during the early years of the study.

A5.5 OTHER CHLORINATED PESTICIDES

Shindell and Ulrich (1986) conducted a prospective mortality study of 800 employees who worked 3 months or more during the period January 1946 through June 1985, in the only plant in the US where the termiticide chlordane was produced. Production workers with higher pesticide blood levels had lower standardised mortality

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ratios for cancer than nonproduction employees, and there appeared to be an inverse relationship of cancer mortality to length of employment. No excess of prostate cancer was reported, although the study may not have been large enough to have reliably detected an excess risk.

Ditraglia et al (1981) conducted a retrospective cohort study to examine the mortality of workers employed in the manufacture of the chlorinated hydrocarbon pesticides, chlordane, heptachlor, dichloro-diphenyl-trichloro-ethane (DDT) and aldrin/dieldrin/endrin at four manufacturing plants in the US. Each cohort included all workers employed for at least six months prior to January 1964. The entire study group totalled approximately 2,100 individuals. Vital status ascertainment for these cohorts ranged from 90 to 97% complete; the cut-off date for follow-up was 31 December 1976. The authors concluded that there had been too few deaths in this study on which to base any meaningful conclusions. Overall levels of all-cause and cancer mortality were less than expected. Brown (1992) updated this study through to the end of 1987. The mortality for all causes and all malignant neoplasms at each of the plants was lower than expected. There was a statistically significant increase in liver and biliary tract cancer among workers at one plant. However, the deaths were due to a mixture of intra- and extra-hepatic tumours, and the dose-response analysis was limited because of the small number of deaths and lack of exposure data. No specific information about prostate cancer was reported.

Wang and MacMahon (1979) performed a retrospective mortality study on 1403 male workers employed in the manufacture of chlordane and heptachlor at two US plants between 1946 and 1976. They found no overall excess of deaths from cancer, even among workers followed twenty or more years after starting work, although there was a nonsignificant increase in lung cancer. No evidence of an excess risk of prostate cancer was reported. It is possible that the follow up period was insufficient to reliably detect any excess of prostate cancer.

A cohort mortality study among 5886 chemical manufacturing workers found a possible association between DDT and pancreatic cancer that was confirmed in a subsequent nested case-control study (Garabrant et al, 1992). In a small study of 232 of a group of 233 workers engaged in the manufacturing and formulation of aldrin, dieldrin, endrin and (for a limited period) telodrin, Ribbens (1985) identified no specific cancer risks.

In conclusion there is no evidence from studies of manufacturing workers of an association between chlorinated pesticides and prostate cancer. All of the studies were, however, performed before modern diagnostic methods were available such that the incidence of prostate cancer may have been underestimated relative to current levels in both exposed and unexposed control groups. This would have weakened the power of studies to detect any excess risk.

A5.6 OVERALL ASSESSMENT OF PROSTATE CANCER RISK IN PESTICIDE MANUFACTURING WORKERS

Studies of pesticide manufacturing workers have failed to detect a clear excess risk of prostate cancer. Early studies of phenoxy herbicides and a range of other chlorinated compounds may have had inadequate power to detect an excess, due to the small size of the investigated populations, short follow up and the use of less sophisticated methods for detecting prostate cancer. More recent studies involving large numbers of workers and extended follow-up periods have also failed to detect an excess risk of prostate cancer. Recent studies of atrazine-exposed workers in a plant in Louisiana have also not demonstrated a convincing excess risk of prostate cancer. The results of these studies do not wholly exclude the possibility that an excess risk may be present, as some data were suggestive of an increased risk and the follow up periods were fairly short which would have precluded the detection of effects with a long latency.

A6 Studies of workers using pesticides

A6.1 INTRODUCTION

A general problem in the interpretation of studies of pesticide users rather than manufacturers is that exposures in these studies have generally been poorly characterised. Kromhout and Heederik (2005) noted that agricultural workers have intermittent exposures to a wide range of agents and individuals vary widely in how they handle agricultural chemicals. Exposure by the dermal route is likely to be generally more important than inhalation, although absorption may be less efficient.

A6.2 THE AGRICULTURAL HEALTH STUDY

The Agricultural Health Study (AHS) was a large prospective cohort study initiated in North Carolina and Iowa (Alavanja et al, 1996). Its objectives were to: 1) identify and quantify cancer risks among men, women, whites, and minorities associated with direct exposure to pesticides and other agricultural agents; 2) evaluate noncancer health risks including neurotoxicity reproductive effects, immunologic effects, nonmalignant respiratory disease,

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kidney disease, and growth and development among children; 3) evaluate disease risks among spouses and children of farmers that may arise from direct contact with pesticides and agricultural chemicals used in the home or garden, and from indirect contact, such as spray drift, laundering work clothes, or contaminated food or water; 4) assess current and past occupational and nonoccupational agricultural exposures using periodic interviews and environmental and biologic monitoring; 5) study the relationship between agricultural exposures, biomarkers of exposure, biologic effect, and genetic susceptibility factors relevant to carcinogenesis; and 6) identify and quantify cancer and other disease risks associated with lifestyle factors such as diet, cooking practices, physical activity, smoking and alcohol consumption, and hair dye use.

Alavanja et al (2003) examined the relationship between 45 common agricultural pesticides and prostate cancer incidence in a prospective cohort study of 55,332 male pesticide applicators from Iowa and North Carolina with no prior history of prostate cancer. A self-administered questionnaire completed at enrolment (1993-1997) was used to collect information on the use of 50 pesticides, crops grown, livestock raised, personal protective equipment used, application methods used, other agricultural and non agricultural exposures, smoking alcohol diet, medical conditions in first degree relatives and basic demographic data. A literature review was used as the basis of exposure assessment and the study was heavily dependent on the accurate recall and recording of exposure factors by those completing the questionnaire. Dosemeci et al (2002) reported that in addition to the enrolment questionnaire, further intensity-related exposure information such as maintenance or repair of mixing and application equipment, work practices and personal hygiene was collected for more than 40% of the enrolled applicators. Two algorithms were developed to identify applicators' exposure scenarios using information from the enrolment and take-home questionnaires separately in the calculation of subject-specific intensity of exposure score to individual pesticides. The 'general algorithm' used four basic variables (i.e. mixing status, application method, equipment repair status and personal protective equipment use) from the enrolment questionnaire and measurement data from the published pesticide exposure literature to calculate estimated intensity of exposure to individual pesticides for each applicator. The 'detailed' algorithm was based on variables in the general algorithm plus additional exposure information from the take-home questionnaire, including types of mixing system used (i.e. enclosed or open), having a tractor with enclosed cab and/or charcoal filter, frequency of washing equipment after application, frequency of replacing old gloves, personal hygiene and changing clothes after a spill. Weighting factors applied in both algorithms were estimated using measurement data from the published pesticide exposure literature and professional judgement. For each study subject, chemical-specific lifetime cumulative pesticide exposure levels were derived by combining intensity of pesticide exposure as calculated by the two algorithms independently and duration/frequency of pesticide use from the questionnaire. The distribution patterns of all basic exposure indices by state, gender, age and applicator type were almost identical in two study populations, indicating that the take-home questionnaire sub-cohort of applicators was representative of the entire cohort in terms of exposure.

The majority of the farmers enrolled in the AHS (55%) reported that they mixed or applied pesticides on 10 or more days per year and 58% reported performing routine maintenance of pesticide equipment at least once a month (Cobble et al, 2002). Farmers also experienced a range of other exposures including solvents (25%), metals (68%), grain dusts (65%), diesel exhaust fumes (935) and the majority of farmers (74% in North Carolina; 59% in Iowa) reported holding nonfarm jobs, of which the most frequent were construction and transportation (Cobble et al, 2002). Calculated confounding risk ratios for these exposures and activities were reported to suggest that the magnitude of bias due to confounding was likely to be minimal. Pesticide exposures in the AHS did not correlate with lifestyle characteristics such as race, smoking status or education (Saramaic et al, 2005).

In a separate study of Iowa residents, Curwin et al (2002) found atrazine was the agricultural pesticide used most by farmers. Most farmers applied pesticides themselves but only 10 (59%) used tractors with enclosed cabs, and they typically wore little personal protective equipment. More than one agricultural pesticide was applied on almost every farm. The majority of farmers changed from their work clothes and shoes in the home, and when they changed outside or in the garage, they usually brought their clothes and shoes inside. Almost half of the 66 farm children less than 16 years of age were engaged in some form of farm chores, with 6 (9%) potentially directly exposed to pesticides, while only 2 (4%) of the 52 non-farm children less than 16 years of age had farm chores, and none were directly exposed to pesticides. Non-agricultural pesticides were used more in and around farm homes than non-farm homes.

Cancer incidence in the AHS was determined through population-based cancer registries from enrolment through December 31, 1999. Cases diagnosed before 1993 were excluded. A total of 566 prostate cancers were observed and less than 0.4% of the cohort was lost to follow up. A prostate cancer standardised incidence ratio of 1.14 (95% CI: 1.05, 1.24) was observed. Factor analysis was used to calculate odds ratios for individual pesticides and for pesticide use patterns.

Statistically significant exposure response relationships were found for prostate cancer risk in relation to use of the fungicide methyl bromide and, among applicators over 50 years of age, for the use of chlorinated pesticide and applicators who ever used aldrin, DDT or heptachlor. No exposure response relationships were observed for

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alachlor, atrazine, carbofuran, chlorpyrifos, permethrin, aldrin, DDT, heptachlor or captan. Small nonsignficantly raised risks of prostate cancer were found for carbofuran, permethrin (animal use) and phorate among those with no family history of prostate cancer. For those with a family history of prostate cancer, statistically significant raised risks were found for butylate (thiocarbamate), carbofuran, coumaphos, 2,2-chloroethenyl dimethyl phosphate, fonofos, permethrin, phorate and nonsignificantly raised risks were found for alachlor, atrazine, dicamba, EPTC, aldicarb, chlorpyfrifos, terbufos and methyl bromide.

Cigarette smoking had a near to significant association with prostate cancer.

The results of this study are suggestive of a strong familial influence on prostate cancer risk and of a possible role for pesticide exposure (Alavanja et al, 2003, Blair et al, 2005). Uncertainties about the importance of pesticide exposure arise because of the general absence of exposure-response relationships, other than for methyl bromide and chlorinated pesticides, and also because of the very broad spectrum of substances involved. It seems unlikely that these widely disparate substances would have a similar biological effect, although as the authors point out, the extent to which familial factors influence prostate cancer risk does vary by pesticide group which would be consistent with slightly different mechanisms underlying the prostate cancer risk in each case. Although the positive finding for an exposure response relationship with methyl bromide could have been a chance finding, given the large number of pesticides investigated, the authors noted that evidence of genotoxicity has been reported in methyl bromide exposed workers (Calvert et al, 1998).

Although the agricultural study involved a very large number of workers, it only looked at a relatively short period in time and the method of exposure assessment may not have fully captured cumulative exposure or the influence of working methods on actual levels of exposure experienced by the cohort.

There is some evidence that participants in the Agricultural Health Study had a much lower mortality rate than for the general population (Blair et al, 2005). Standardised mortality ratios (SMRs) for total mortality, cardiovascular disease, diabetes, chronic obstructive pulmonary disease (COPD), total cancer, and cancers of the oesophagus, stomach, and lung were 0.6 or lower for both farmers and spouses. These deficits varied little by farm size, type of crops or livestock on the farm, years of handling pesticides, holding a non-farm job, or length of follow up. SMRs among ever smokers were higher than among never smokers, but were still less than 1.0 for all smoking-related causes of death. No statistically significant excesses occurred, but slightly elevated SMRs, or those near 1.0, were noted for diseases that have been associated with farming in previous studies. The low overall mortality rate means that a greater proportion of men within the AHS may have lived to an age where they developed prostate cancer than would be typical of the general population. It is also possible that men in the AHS may have been less susceptible to cardiovascular disease than others in the general population, even in old age.

It is unclear whether prostate cancer risk would be expected to increase as a simple linear function of cumulative exposure or whether other exposure metrics might be relevant. Single incidents involving accidental exposure to a relatively large quantity of pesticide might have an undue influence on risk or might be of importance because their impact on cumulative exposure may not have been fully taken into account during the analysis of exposure-response relationships. Mage et al (2000) reported that 14% of the applicators enrolled in the AHS reported "an incident or experience while using any pesticide which caused an unusually high exposure”. They found that the probability of such an event increased with the cumulative number of days of pesticide application reported by the applicator. The three main factors leading to these events were believed to be failure to carefully follow all the pesticide manufacturer's label requirements, inexperience, and random events (i.e., breaking hose). Alavanja et al (1999) found that work practices that were more common among applicators who experienced a high exposure event than in others included delay in changing clothing or washing after pesticide application, mixing pesticide application clothing with the family wash, washing up inside the house after application, applying pesticides within 50 yards of their well, and storing pesticides in the home. Job characteristics associated with high exposure included self-repair of application equipment and first pesticide use more than 10 years in the past. Keim and Alavanja (2001) reported that generally, pesticides with greater acute toxicity were more frequently involved with reported high pesticide exposure events than other pesticides (which might indicate reporting bias).

The Agricultural Health Study led to a number of papers that describe cancer risk associated with individual types and classes of pesticides.

Beane Freeman et al (2005) reported that 301 incident cancer cases were diagnosed among 4,961 applicators who reported using the insecticide diazinon during the follow-up period ending December 2002 compared with 968 cases among 18,145 participants who reported no use. Poisson regression was used to calculate rate ratios and 95% confidence intervals. Increased risks of lung cancer and leukaemia were observed for the highest tertile of exposure as assessed from lifetime exposure days. When the exposure metric was adjusted to take account of the probable intensity of exposure, however, these relationships were less apparent.

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Bonner et al (2005) investigated Carbofuran, a carbamate insecticide registered for use on a variety of food crops including corn, alfalfa, rice, and tobacco. Nitrosated carbofuran has demonstrated mutagenic properties. Lung cancer risk was 3-fold higher for those with > 109 days of lifetime exposure to carbofuran (Rate ratio = 3.05; 95% CI, 0.94-9.87) compared with those with < 9 lifetime exposure days, with a significant dose-response trend for both days of use per year and total years of use. However, carbofuran use was not associated with lung cancer risk when nonexposed persons were used as the referent. In addition, carbofuran exposure was not associated with any other cancer site examined.

De Roos et al (2005) reported that exposure to the broad spectrum herbicide glyphosate was not associated with cancer incidence overall or with most of the cancer subtypes studied. There was a suggested association with multiple myeloma incidence.

Lee et al (2004a) reported that the rate ratio for all cancers combined among chlorpyrifos-exposed applicators compared with nonexposed applicators was 0.97 (95% CI 0.87, 1.08). For most cancers analysed, there was no evidence of an exposure-response relationship. The incidence of lung cancer, however, showed statistically significant associations with both chlorpyrifos lifetime exposure-days and chlorpyrifos intensity-weighted exposure-days. After adjustment for other pesticide exposures and demographic factors, individuals in the highest quartile of chlorpyrifos lifetime exposure-days (>56 days) had a relative risk of lung cancer that was 2.18 (95% CI = 1.31, 3.64) times that of those with no chlorpyrifos exposure.

Russiecki et al (2004) found no excess of overall cancer incidence in the 36,513 (68%) applicators who reported ever using atrazine. Comparison of cancer incidence in applicators with the highest atrazine exposure and those with the lowest exposure, assessed by lifetime days and intensity-weighted lifetime days found no relationship for prostate cancer and nonsignificant relationships for cancer of the lung and bladder, non-Hodgkin lymphoma, and multiple myeloma.

Lee et al (2004b) evaluated the exposure-response relations between alachlor and cancer incidence after controlling for the effects of potential confounding factors. A total of 1,466 incident malignant neoplasms were diagnosed during the study period, 1993-2000. Among alachlor-exposed applicators, the authors found a significant increasing trend for incidence of all lymphopoietic cancers associated with lifetime exposure-days and intensity-weighted exposure-days to alachlor. The risks of leukaemia (rate ratio = 2.83, 95% CI 0.74, 10.9) and multiple myeloma (rate ratio = 5.66, 95% CI 0.70, 45.7) were increased among applicators in the highest alachlor exposure category.

In conclusion, the results of the AHS provided limited evidence of a possible association between pesticide exposure and prostate cancer. The large number of different pesticides considered and difficulties in assessing exposure may have weakened the power of the study to detect effects. Factors that suggest that the apparent relationship may not be causal include:

An absence of exposure response relationships;None of the studies of individual pesticides that were used in relatively large quantities demonstrated an increased prostate cancer risk.

The absence of exposure-response relationships could possibly reflect inadequacies in exposure assessment or the metric of exposure used. For example, occasional very high exposures may not have been fully accounted for.

The increased risks associated with specific pesticides in some families suggests genetic susceptibility may have an important modifying influence on cancer risk. One of the strengths of the AHS is that modern methods of diagnosis of prostate cancer would have been employed.

A6.4 OTHER STUDIES OF PESTICIDE APPLICATORS IN AGRICULTURE

North America

Mills and Yang (2003) conducted a nested case-control study of prostate cancer within a large cohort of a predominantly Hispanic labour union in California, the United Farm Workers of America. By conducting an electronic record linkage between a roster of the union members and the California Cancer Registry for the years 1988 through 1999, newly diagnosed cases of prostate cancer were identified within the union. Age-matched controls were randomly selected from the remainder of the cancer-free cohort. Risk for prostate cancer was examined by examining the type of crops and commodities cultivated by the farm workers as well as by the date of first union activity and duration of union affiliation. In addition, the risk of prostate cancer was evaluated in association with use of several pesticides recorded by the California Department of Pesticide Regulation. Between 1988 and 1999, 222 newly diagnosed prostate cancer cases were identified for analysis and 1110 age-matched controls were selected. The risk of prostate cancer was not associated with patterns of employment in

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any crop/commodity. Increasing duration of union affiliation was associated with decreasing prostate cancer risk. Risk was not associated with total pounds of pesticides applied in the years or counties where farm workers were employed. The study, however, would have had only limited power to detect effects using such broad categorisations of exposure. Risk was found to be significantly increased with increasing exposure to specific chemicals, including simazine, lindane, and heptachlor, and statistically nonsignificant increases were observed with dichlorvos and methyl bromide. No clear excess risks were observed with diazinon, dichlropropene, dicofol, malthion, mancozeb, maneb, propargite, propyzamide or triflualin. The authors concluded that Hispanic farm workers with relatively high levels of exposure to organochlorine pesticides (lindane and hepatachlor), organophosphate pesticides (dichlorvos), fumigants (methyl bromide), or triazine herbicides (simazine) experienced elevated risk of prostate cancer compared to workers with lower levels of exposure. The study provides some evidence of variability in effect between different herbicides. The pesticides identified as being possibly associated with prostate cancer, however, differ to some extent from those identified by the AHS. Both studies did, however, identify potential associations with methyl bromide and with heptachlor. Previously Mills and Kwong (2001) had found no excess risk of prostate cancer in the cohort on comparison with the Californian Hispanic population, although small statistically significant excess risks were found for leukaemia, stomach cancer, uterine cervix cancer and uterine corpus cancer. There was a nonsignificant risk for brain cancer.

Morrison et al (1993) studied a retrospectively assembled cohort of male farmers aged 45 years or older identified in the 1971 Canadian censuses of population and agriculture. The cohort was linked to the Canadian National Mortality Database using an iterative computer record linkage system for the period June 1971 to the end of 1987. A total of 1,148 prostate cancer deaths and 2,213,478 person-years were observed. Using Poisson regression, the study examined the relationship between the risk of dying from prostate cancer and various farm practices as identified by the 1971 Census of Agriculture, including exposure to chickens, cattle, pesticides, and fuels. A weak, but statistically significant, association was found between number of acres sprayed with herbicides in 1970 and risk of prostate cancer mortality. When the analysis was restricted to farmers believed to be subject to the least amount of misclassification, the risk associated with acres sprayed with herbicides increased (rate ratio = 2.23 for 250 or more acres sprayed; 95% CI 1.30-3.84; test for trend, p < 0.01). No other farm exposure examined was associated with any detectable pattern of increased or decreased risk.

Europe

Wiklund et al (1989) studied a cohort of 20,245 licensed pesticide applicators in agriculture who had licences issued between 1965 and 1976. Most were men (99%) and about 50% had been born in 1935 or later. The cohort was followed up in the Swedish Cancer Register from date of licence until death or 31 December 1982. The mean follow up time was 12.2 years. Average time since first exposure was longer, however, since one fifth of the cohort was exposed in the 1950s. The overall cancer risk was lower than expected (SIR 0.86 95% CI 0.79-0.93). For those born in 1935 or later a non-significant increased overall risk of cancer was observed (SIR = 1.07, 95% CI: 0.82-1.37). Significantly decreased risks of cancer were found for liver, pancreas, lung and kidney and there was a nonsignificant increase in testicular cancer risk (SIR = 1.55, 95% CI: 0.92-2.45) that increased with period since licence. When compared against agricultural workers, rather than the general population, higher risks for pesticide applicators were found for testicular cancer, tumours of the nervous system and endocrine glands, and Hodgkin's disease. In an update to this study, Dich and Wiklund (1998) extended the follow up until December 31, 1991 and found a statistically raised prostate cancer risk. The mean follow-up time was 21.3 years and 401 cases of prostate cancer were observed compared to 355 expected (SIR 1.13 95% CI 1.02-1.24). Among those born in 1935 or later, the SIR was 2.03 (0.82-4.19) based on 7 cases. For those born earlier than 1935 the SIR was 1.12 (1.01-1.24). No information was available on individual exposure within this cohort and an assessment of probable levels of exposure to pesticides was based on a random sample of 268 pesticides applicators. Exposure was described in terms of pesticide trade name, number of application days in year, number of years of exposure, protective clothing, tobacco habits and occupational history. Pesticides had been used for 1 day or more between 1950 and 1979 by 92% of the applicators. The lower bound of exposure seems very low and allows for the potential for misclassification if individuals had forgotten about an isolated task that involved pesticide exposure. The most commonly used compounds were phenoxy acetic acid herbicides, organochlorine compounds (DDT, Lindane, pentachlophenols), mercury and organophosphorous compounds. The conclusions that can be drawn from Dich and Wiklund’s study are limited in that it is not certain whether the prostate cancer cases had comparable exposure and it was not possible to investigate any possible dose response relationships or relationships between prostate cancer and specific pesticides. The study was also undertaken before modern diagnostic methods were available and the detection of prostate cancer would have been less reliable than in more recent studies. The excess of prostate cancer among younger men is suggestive of an effect that could be attributed to workplace exposure to pesticides or other risk factors, rather than being due to a deficit of deaths from other causes. However, as the apparent excess lacked statistical significance and was based on only 7 out of 401 cases, it is likely to have been a chance finding.

In a study of mortality in 4,580 male farmers licensed to buy and use pesticides in Northern Italy, Alberghini et al (1991) reported deficits in mortality from all causes, all neoplasms and most malignancies with the exception of brain cancer. More recently Sperati et al (1999) reported an increased leukaemia risk in licensed pesticide users

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in central Italy although the risks of death from all causes and all cancers were lower than expected. The cohort consisted of 2978 male farmers licensed for buying and handling toxic pesticides during the period 1971-1973 and 2586 farmers' wives. No excess risk was found for prostate cancer.

Settimi et al (2003) undertook a hospital-based multi-site case-control study in 5 rural areas in Italy between 1990-92 in which 124 new cases of prostate cancer were ascertained and interviewed, along with 659 cancer controls. Past exposure to pesticides was determined by using a checklist of 100 chemical families and 217 compounds applied from 1950-85 in the areas considered. In addition to subjects own recall of use of different products, agricultural experts made exposure assessments based on individual’s memories of crops grown and disease problems. This may have led to some attribution of unexposed individuals to exposed groups. The association between prostate cancer and different occupational risk factors was measured by maximum likelihood estimation of the odds ratio, controlling for potential confounders. "Ever been employed in agriculture" was associated with a 40% increased risk (OR = 1.4, 95% CI = 0.9-2.0). Prostate cancer was also related positively to food and tobacco (OR= 2.1, 95% CI = 1.1-4.1), and chemical products (OR = 2.2, 95% CI = 0.7-7.2) industries. The analyses carried out to estimate the association between different types of pesticides and prostate cancer showed increased risks among farmers exposed to organochlorine insecticides and acaricides (OR = 2.5, 95% CI = 1.4-4.2), more specifically to the often contemporary used compounds DDT (OR = 2.1, 95% CI = 1.2-3.8), and dicofol (OR = 2.8, 95% CI = 1.5-5.0), whose effects could not be well separated. Nonsignificant increases in risk were associated with exposure (ever) to carbamates, ziram, nitrofenoles, dithiophosphates, thiophosphates and triftalates. No increase in risk was associated with copper and sulphur compounds, dithiocarbamates generally or organophosphates generally. There was no evidence that risk increased with duration of exposure. The method used to assess exposures to pesticides in this study did provide estimated exposures at an individual level but did assume a high level of homogeneity in agriculture practice which may or may not have existed. Given that the study was not large and a wide range of pesticides was involved, the significance of Settimi et al’s findings is questionable. The identification of organochlorine compounds as a potential cause is consistent with the findings of other studies (AHS, Mills and Yang, 2003), although the individual pesticides identified are not consistent with those identified in other studies.

In a German study of 1791 pesticide-exposed agricultural technicians, Barthel (1981) reported an increased incidence of bronchial carcinoma relative to the general GDR population, but no increase in cancers at other sites including the prostate.

In conclusion, the results of studies of prostate cancer in agricultural workers handling pesticides are inconsistent. Several, but not all, studies have reported apparently increased risks of prostate cancer. Different studies have found different pesticides to be most strongly associated with increased risks. It is possible that some of the apparent associations have arisen by chance or by some confounding exposure/factor associated with pesticide application. It is notable, however, that most of the positive findings have been in more recent studies. This may indicate that prostate cancer is associated with more modern pesticide formulations and/or much longer periods of exposure than would have been typical of workers considered in earlier studies. It may also simply reflect a greater sensitivity in the detection of prostate cancer. The finding of a greater excess of prostate cancer in younger men than in older men by Dich and Wiklund (1998) may have arisen by chance, but is suggestive of a causal between prostate cancer and pesticide exposure.

A6.5 STUDIES OF CANCERS IN FARMERS (NOT SPECIFICALLY PESTICIDE APPLICATORS)

North America

Fincham et al (1992) investigated cancer patterns and risks in cancer patients in Alberta. All farmers were abstracted and compared with nonfarmers in the database, using case-control analysis. Controls were patients with cancer at any site except the index site. Significantly elevated odds ratio (OR), adjusted for age and smoking, were found among the farmers for cancers of the lip (OR = 3.22, 95% CI = 2.14 to 4.84) and prostate (OR = 1.31, 95% CI = 1.11 to 1.55). The crude risk for lung cancer was significantly lower in farmers, but statistical significance disappeared when risk was adjusted for smoking (OR = 0.81, 95% CI = 0.65 to 1.02). Farmers were at considerably lower risk of malignant melanoma of the skin, than nonfarmers (OR = 0.57, 95% CI = 0.36 to 0.91).

Delzell and Grufferman (1985) used death certificate information to identify 9,245 white and 3,508 nonwhite men who died in North Carolina during 1976-1978 who had been farmers. Proportional mortality ratios (PMRs) were elevated for tuberculosis, diseases of the skin and subcutaneous tissue, and external causes, and were decreased for cancers of the oesophagus and large intestine. Increased risks of melanoma and other skin cancer were found in white farmers, while nonwhite farmers had an increased relative frequency of brain cancer and leukaemia. In addition, among decedents under 65 years of age, both white and nonwhite farmers had an elevated proportional mortality ratio for prostate cancer.

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In a proportionate mortality study Gallgaher et al (1985) reported that farmers in British Columbia appeared to have excess risks of stomach and liver cancer. No excess of prostate cancer was reported.

In a study of Winsconsin farmers, Saftlas et al (1987) reported significantly decreased PMRs for tobacco- and alcohol-related causes of death, and increased PMRs for accidental causes, asthma, and cancer of the stomach, prostate, eye, and lymphatic and haematopoietic systems. Elevated proportionate cancer mortality ratios (PCMRs) for leukaemia and all lymphopoietic cancer, and cancers of the stomach, rectum and eye occurred in farmers born 1905-1958, while deficits were observed for cancer of the pancreas and the category, "all other cancers." Certain agricultural exposures were also positively associated with deaths due to cancers of the prostate, brain, lymphosarcoma and reticulosarcoma, and all lymphopoietic cancers.

Stubbs et al (1984) conducted a proportionate mortality analysis of all deaths recorded during 1978-1979 among California farm workers and farm owner/managers. They reported slightly increased PCMRs for cancer of the stomach and cancer of other lymphatic tissue but no increase in prostate cancer.

Parker et al (1999) followed a population-based cohort of 1,177 cancer-free men in Iowa for up to 9 years and identified 81 incident prostate cancers. Men whose usual occupation was farmer were at an increased risk of prostate cancer after adjustment for age, smoking, alcohol, and dietary factors (RR = 1.7; 95% CI = 1.0-2.7). Exclusion of well-differentiated, localized tumours slightly strengthened the association (RR = 2.0; 95% CI = 1.1-3.6). Risk was confined to older (age 70+ years) farmers (RR = 2.2; 95% CI = 1.1-4.3. No evidence of an effect was found among younger farmers (RR = 1.0; 95% CI = 0.4-2.1). In a much earlier study, Burmeister et al (1983) analysed the death certificates of white male Iowans over age 30 who died of multiple myeloma, non-Hodgkin's lymphoma, prostate cancer or stomach cancer between 1964 and 1978. Each case was matched to two controls on age (within two years) at death, county of residence, and year of death. Statistically significant increased risks were found for multiple myeloma, non-Hodgkin's lymphoma, prostate cancer, and stomach cancer in farmers. Although prostate cancer was elevated in those born before 1901, it was not associated with any agricultural practice.

Europe

A number of studies have been undertaken in Scandinavia and in Italy.

Wiklund and Dich (1995) conducted a cohort study of 140,208 Swedish farmers and compared their cancer risks with those of the general male population. There were no individual exposure data for agricultural chemicals and the effects of differential exposure were considered by dividing the data into time periods, year-of-birth cohorts and geographical areas. The cohort was followed-up in the Cancer Environment Register from 1 January 1971 either until death or until 31 December 1987. A statistically significant decreased SIR was found for all cancers (SIR 0.80 95% CI 0.78-0.81). The SIR was significantly decreased for several cancer sites, and the lowest value was found for tongue, lung, oesophagus, liver and urinary organs. Other major cancer sites with decreased SIRs were the colon, rectum, pancreas and kidney. Lip cancer and multiple myeloma showed statistically significant increased risks. SIRs for stomach cancer, prostate cancer, skin carcinoma, malignant melanoma, tumours in connective tissue or muscle, malignant lymphomas and leukaemia were all close to unity. For malignant lymphomas the SIR increased over time, though not significantly, and was highest among younger farmers. The SIR for non-Hodgkin lymphoma was lowest in the northernmost region. The authors claimed that the study findings gave some support to the hypothesis that there is an association between non-Hodgkin lymphoma and exposure to pesticides and other agricultural chemicals. It was of note, however, that the SIR for multiple myeloma was significantly increased in those parts of Sweden where the use of pesticides has been less frequent and in lower amounts.

Torchio et al (1994) investigated mortality in a cohort of 23,401 farmers, residing in southern Piedmont, Italy, and licensed to use pesticides. From 1970 to 1986 the cohort included 340,794 person-years and 2683 deaths were observed. Fewer deaths than expected were observed for all causes and for all cancers, although raised risks were found for melanomas and eye tumours. Raised risks of lymphoma and tumours of the connective tissue were found in a subcohort of subjects living in villages with mainly arable land.

In a Swiss study, Levi et al (1988) reported decreased risks in agricultural workers for cancers of the lung (MOR = 0.75), cervix uteri (MOR = 0.72) and prostate (MOR = 0.80). Excess mortality was reported for cancers of the upper digestive and respiratory sites (MOR = 1.22), stomach (MOR = 1.18), testis (MOR = 2.05) and lympho-haematopoietic neoplasms, particularly myeloma (MOR = 2.14).

The linkage of occupational census data with incidence of cancer in Denmark and with cancer mortality in Italy by Ronco et al (1992) demonstrated that, farmers in the two countries had a reduced risk for cancer of the lung, bladder, small intestine, colon, rectum, and prostate. The risk of brain cancer was significantly reduced among Italian farmers. There was a significant reduction in risk for Hodgkin's disease and no excess for non-Hodgkin's lymphoma in Denmark, whereas in Italy a statistically significant excess risk was found for Hodgkin's disease and

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a slight excess risk for non-Hodgkin's lymphoma. Specific occupations in agriculture showing a high risk for cancers of the lymphopoietic system in Denmark mostly entailed contact with animals. The per capita consumption of phenoxy-herbicides between 1950 and 1970 was lower in Italy than in Denmark but treatments were performed mainly by professional applicators in Denmark compared with by the farmers themselves in Italy.

Kristensen et al (1996) examined cancer incidence among subjects born in 1925-1971 and engaged in agricultural activities in Norway and found possible relationships between acute leukaemia and animal contact and between multiple myeloma and pesticides in potato cultivation.

Forastiere et al (1993) undertook a case-referent study among farmers in central Italy. Farmers had a decreased risk of lung and bladder cancer and melanoma and nonsignificant excess risks for stomach, rectal, kidney, and nonmelanoma skin cancer. Stomach and kidney cancer were significantly increased among the farmers with > 10 years' experience, and stomach, rectal, and pancreatic cancer were increased among licensed pesticide users with > 10 years' experience. Possible relationships emerged between specific crops and cancer: fruit and colon and bladder cancer, wheat and prostate cancer, olives and kidney cancer, and potato and kidney cancer.

Faustini et al (1993) studied the mortality experience of 1701 male and 426 female farm workers (Aprilia, Italy) during the period 1972-1988. All cause and cancer mortality was less than expected but they reported possible increased risks of gastric cancer, renal cancer, skin cancer and leukaemia, mainly of the myeloid type. For those under 65 years, excess deaths were found for all cancer sites investigated except cancer of the lymphatic and haemopoietic tissues

Rafnsson and Gunnarsdottir (1989) performed a retrospective cohort study in 5923 farmers in Iceland for deaths occurring between 1977 and 1985.The number of deaths from all causes, malignant neoplasms, lung cancer, ischaemic heart disease, respiratory diseases and accidents was lower than expected. Nonsignificant excess risks were however observed for skin cancer, Hodgkin's disease leukaemia and for brain cancer. The short study time weakened the power of the study to detect effects. No excess of prostate cancer was reported.

Elsewhere

Meyer et al (2003)) undertook an ecological analysis of cancer mortality among agricultural workers in an important agricultural area of the Rio de Janeiro State, Brazil. All causes of death for male workers 30-69 years old provided by the National Mortality Information System between 1979 and 1998 were evaluated. Information on employment was obtained from death certificates so some misclassification is likely, although the authors state agriculture was generally a lifetime occupation. Mortality odds ratios (MOR) were calculated in comparison to three reference populations. In agricultural workers 50-69 years old, increased mortality risks from oesophagus, stomach, and larynx cancer were observed for the period from 1979 to 1988 and from oesophagus and stomach cancer for 1989 to 1998. Agricultural workers 30-49 years old showed nonsignificantly raised risks of mortality from stomach, oesophagus, liver, testis, and prostate cancer (one case), and soft-tissue sarcoma in the period of 1979-1988, and from testis and penis cancer, leukaemia, and soft-tissue sarcoma in the period of 1989-1998. Workers in the region were stated to use a variety of pesticides with paraquat, methamidophos and mancozeb being the most widely used. Children usually help with agricultural work and thus exposure to pesticides is initiated at an early age. It was acknowledged that risk factors such as micro-organisms, fertilisers and malnutrition could have contributed to the observed effects together with the confounding effects of smoking and alcohol which were not investigated. The detection of a possible prostate cancer risk in younger men is of potential significance in determining the impacts of pesticide exposure, but as only a single case was reported, it may have been a chance finding. The identified pesticides differ from those shown to have a potential link to prostate cancer in US studies (the AHS, Mills and Yang, 2003).

Conclusions

There has been a long history of reports of an excess of prostate cancer among farmers in North America that predates the more recent investigation of a specific link to pesticide exposure. This excess also predates the introduction of modern diagnostic methods for prostate cancer such that the incidence of prostate cancer in farmers and in comparison populations may have been substantially underestimated.

The results of most studies have shown that farmers generally have lower mortality risks than typical of the general population. There has been little specific investigation of prostate cancer risks in younger men but several studies have reported that the excess risk of prostate cancer is greater in older agricultural workers.

There is a marked discrepancy between the findings of studies undertaken in North American and those undertaken in Europe. Whereas the North American studies have generally found an excess of prostate cancer, a similar excess has not been observed in the European studies. This may reflect differences in chemical usage or other differences in farming practice (eg the use of artificial hormones or antibiotics in livestock) and/or

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differences in lifestyle including diet, alcohol consumption and smoking. It should be noted, however, that an exhaustive search for studies of prostate cancer in farmers was not conducted.

In a recent review of risk factors for prostate cancer, Bostwick et al (2004) concluded that there was evidence for a modest increase in risk for farmers, although they could not find a clear explanation for this increase. It was suggested that farmers eat a relatively high fat diet which would be a risk factor whereas increased levels of exposure to ultraviolet light and increased levels of exercise compared with the general population would be expected to be protective. Some studies were reported to implicate farm animals and zoonotic viruses and farm chemicals were also suggested as causes. Bostwick et al did not identify pesticides as the major cause of the observed excess risk in farmers.

In conclusion, some but not all studies of farmers undertaken in North America have reported excess risks of prostate cancer, particularly in older men, although few studies have specifically investigated prostate cancer risks in younger men. A clear association with pesticides has not been demonstrated in these studies and some authors have suggested that other factors such as exposure to animals and infections might influence prostate cancer risk. None of the European studies reviewed here identified an excess risk of prostate cancer.

A6.7 OTHER STUDIES OF PESTICIDE APPLICATORS

Cantor and Booze (1991) conducted a cohort mortality study was of 9677 male aerial pesticide applicators and 9727 flight instructors identified from computerized Federal Aviation Administration medical examination records from 1965-1979. Cantor and Silberman (1999) extended the follow up to December 31, 1988. Among applicator pilots, there were 1,441 deaths, and among instructors, 1,045 deaths. In both groups, aircraft accidents were the major cause of death (446 applicators; 234 instructors). Compared with flight instructors, aerial applicator pilots were at significantly elevated risk for all causes of death (risk ratio = 1.34) and for malignant neoplasms (1.18), non-motor vehicle accidents (1.71), motor vehicle accidents (1.69), and stroke (1.91). Pancreatic cancer (2.71) and leukaemia (3.35) were significantly elevated. Applicators were at lower risk of colon cancer (0.51) and multiple myeloma (0.23) mortality. Based on U.S. rates, the SMR for all causes of death among applicators was 111 (95% CI 105-117) and among instructors, 81 (95%CI 76-85). Applicators had a nonsignificantly raised risk of prostate cancer (SMR 136, 95% CI 44-317).

Fleming et al (1999a) undertook a retrospective cohort study of 33,658 (10% female) licensed pesticide applicators in Florida compared with the general population of Florida. Among male applicators, prostate cancer mortality (SMR 2.38; 95% CI 1.83 - 3.04) was significantly increased. No cases of soft tissue sarcoma were confirmed in this cohort, and non-Hodgkin's lymphoma was not increased. In a companion study, Fleming et al (1999b) investigated cancer incidence from January 1, 1975, to December 31, 1993. Among males, prostate cancer (SIR = 1.91; 95% CI 1.72-2.13) and testicular cancer (SIR 2.48; 95% CI 1.57-3.72) were significantly elevated. No confirmed cases of soft tissue sarcoma were found, and the incidence of non-Hodgkin's lymphoma was not increased. There were few female applicators; nevertheless, cervical cancer incidence (SIR 3.69; 95% CI, 1.84-6.61) was significantly increased, while the incidence of breast cancer was significantly decreased.

Zahm (1997) undertook a retrospective cohort mortality study of 32,600 employees of a lawn care company who were exposed to the herbicide 2,4-dichlorophenoxyacetic acid. The cohort was generally young with short duration of employment and follow-up. In comparison to the US population, the cohort had significantly decreased mortality from all causes of death. There were 45 cancer deaths (SMR 0.76; 95% CI: 0.55, 1.01). Bladder cancer mortality was significantly increased, but two of the three observed deaths had no direct occupational contact with pesticides. There was also a nonsignificant increase in risk of non-Hodgkin’s lymphoma. No excess of prostate cancer was observed, but the study may have lacked sufficient power to detect a small excess risk.

In a mortality study of a cohort of 3,827 white men licensed to apply pesticides in Florida, Blair et al (1983) reported increased risks of death from leukaemia, lung cancer and brain cancers but not of prostate cancer.

Wang and MacMahon (1979) and MacMahon et al (1988) studied a cohort of 16,124 male pesticide applicators in which 1,082 deaths had occurred by the end of 1982 with death certificates available for 994. The SMR for all causes of death was 98 and no excess of prostate cancer was reported.

Kross et al (1996) undertook a proportionate mortality study of a cohort of golf course superintendents using death certificates for 686 deceased members of the Golf Course Superintendents Association of America who died from 1970 to 1992. The proportionate mortality ratio (PMR) for all types of cancer was 136 (95%C 121 - 152) and a significantly raised risk was reported for prostate cancer (PMR 293, 95% CI 121-454). Significant excess mortality from smoking-related diseases was also observed. Significantly raised PMRs were also reported for brain cancer, non-Hodgkin's lymphoma and cancer of the large intestine. The study was relatively small and the excess of prostate cancer may have been associated with lifestyle factors such as smoking rather than pesticide exposure. The study reported raised risks of cardiovascular mortality suggesting that it was unlikely that the apparent excess of prostate cancer was due to a deficit of deaths from other causes. No information was

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provided about the pesticides that golf course superintendents are likely to have used. They are also likely to have been exposed to fertilisers and fuels.

Figa-Talamanca (1993) undertook a small mortality study of a cohort of 168 pesticide applicators employed in the disinfestation service of the city of Rome for an average of 20 years and found an increased risk of liver cancer in those exposed to organochlorine pesticides between 1960 and 1965. No significant increased risks were reported for prostate cancer, but the small size of the study would have limited its power to detect effects.

Figa-Talamanca (1994) investigated the mortality of a cohort of 2310 male workers who obtained a licence to handle pesticides in the period 1973-1979 in the province of Rome. The cohort contributed 26,846 person-years of exposure. The vital status of the cohort was determined up to the end of 1988. Overall mortality and mortality from all cancers was lower than expected although a statistically significant excess was noted for brain cancer. The relatively short follow up period would have limited the power of this study to detect effects.

Swaen et al (1992) undertook a retrospective cohort study of 1341 Dutch herbicide applicators licensed before 1 January 1980. Follow up was until 1988. About a third of the pesticide use by weight was simazine and about a third quartz granulates composed of chlrothiamide, dalapon, dichlobenil, diuron, simazine or their combinations. Although total mortality was lower than expected when compared with the total male Dutch population, the total number of cancer deaths was slightly higher. There was a nonsignificant excess of prostate cancer (SMR 131, 95% CI 2-632). A significant excess was found for multiple myeloma. The short follow up period limited the power of the study to detect effects. Swaen et al (2004) updated the follow-up of the cohort, adding 13 years to the follow-up and found a significantly raised risk of skin cancer although it was unclear whether this was due to pesticide exposure or exposure to sunlight.

Zhong and Rafnsson (1996) followed a cohort of 2449 licensed pesticide users, students from a horticultural college and members of a pension fund for market gardeners, horticulturists and vegetable farmers up until the end of 1993 in the Icelandic Cancer Registry of cancer incidence. The SIR for all cancer sites was 0.80. Among females the increased incidence for cancer of lymphatic and haematopoietic tissue was significant (SIR 5.56, 95% CI 1.12-16.23). The incidence of rectal cancer was three times that expected (SIR 2.94, 95% CI: 1.07-6.40), and this cancer was even more predominant among the licensed pesticides users (SIR 4.63, 95% CI: 1.49-10.80). No association with prostate cancer was reported.

In a pilot study of the mortality of a group who had owned greenhouses between1965-1993, Settimi et al (1998) found no evidence of an excess cancer risk or of a specific risk of prostate cancer. There was a nonsignificantly raised risk of leukaemia. The study was, however, small (178 greenhouse owners) and would have had very limited power to detect an excess of prostate cancer.

Beard et al (2003) compared mortality of 1,999 outdoor staff working as part of an insecticide application program during 1935-1996 with that of 1,984 outdoor workers not occupationally exposed to insecticides, and with the Australian population. Prior to 1955, treatments had been arsenic based, between 1955 and 1962, DDT was used and between 1962 and 1976, courmaphos, carbophenothian, carbaryl, chloropyrifos, bromphos ethyl dioxothion, ethion, chlordimform and cymyzazole were used. Since 1976, workers were exposed to amitraz, promacyl, cypermethrin, chlorfenvinphos and flumethrin. Mortality was significantly higher in both exposed and control subjects compared with the Australian population. The major cause was mortality from smoking-related diseases. Compared with the general Australian population, mortality over the total study period was increased for asthma and diabetes. Mortality from pancreatic cancer was more frequent in subjects exposed to 1,1,1-trichloro-2,2-bis(p-chlorophenyl) and mortality from leukaemia was increased in subjects working with more modern chemicals. There was a nonsignificant deficit in prostate cancer. Lifestyle factors, particularly smoking, had an important influence on the outcome of this study, but it is notable that the pesticides to which workers were exposed were generally rather different from those used by workers in the various agricultural studies reviewed in preceding sections.

Rijhimaki et al (1982) examined mortality in a cohort of 1,926 men who had sprayed 2,4-dichlorophenoxyacetic acid (2,4-D) and 2,4,5-trichlorophenoxyacetic acid (2,4,5-T) during 1955-1971 that was followed prospectively from 1972 to 1980. The total phenoxy acid exposure was generally low because the duration of work had mostly been less than two months. Overall mortality was low, no increase in cancer mortality was detected, and the distribution of cancer types was unremarkable. Subsequently Asp et al (1994) extended the follow up to 18 years. No excess of cancers was detected.

Axelson et al (1980) analysed mortality in a cohort of 348 railroad workers exposed to amitrol and phenoxy acids and found evidence of a slight excess of cancer deaths but no clear association with cancer at any one site.

Overall these studies do not provide strong evidence of a link between pesticides and prostate cancer. There is some evidence of a possible excess risk of prostate cancer among some groups of pesticide users in the US but only one of European studies of pesticide applicators reported an excess of prostate cancer and this excess was

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not statistically significant. Many of the studies were, however, too small and/or had insufficient follow up to be certain that no excess risk of prostate cancer existed. Reported excesses of prostate cancer were not confirmed to the most recent studies, implying that the inconsistent results of different studies were not simply due to changes in diagnostic practice through time.

A6.8 PESTICIDES REPORTED TO BE ASSOCIATED WITH PROSTATE CANCER IN MORE THAN ONE STUDY OF APPLICATORS

Overview

Where information is available about the types of pesticide applied, substances that appear to be associated with prostate cancer in more than one study are methyl bromide (HAS, Mills and Yang, 2003), atrazine (AHS, Mills, 1998), DDT (AHS, Settimi et al, 2003) and heptachlor (AHS, Mills and Yang, 2003). The relationship for atrazine was not significant in either study. Given the large number of different compounds that have been used, and the likelihood that many applicators have been exposed to a mixture of substances, these positive associations may have arisen by chance. Organophosphates are also implicated in more than one study, but no individual compound is named in more than one study. The remainder of this section examines information from studies other than those of pesticide users in order to determine whether there are other types of evidence that would support a possible association with prostate cancer.

Methyl bromide

IARC (1999a) concluded that methyl bromide is not classifiable as to its carcinogenicity in humans (IARC Group 3). There were two deaths from testicular cancer (0.11 expected) in methyl bromide exposed workers who were part of a subcohort of 665 workers at three chemical manufacturing exposed to bromine chemicals (Wong et al, 1984). Two studies in exposed workers have found limited evidence of possible genotoxic effects in lymphocytes and oropharyngeal cells (Pletsa et al, 2002; Calvert et al, 1998). There was limited evidence for carcinogenicity in animal experiments, although the results of different studies were highly inconsistent. Methyl bromide does, however, display genotoxic properties in a number of assays (IARC, 1999a). The main noncancer effects of methyl bromide that have been reported in exposed workers and in animal experiments are neurotoxicity (eg studies by Hustinx et al, 1993; Anger et al, 1981, Eustis et al, 1988; Kishi et al, 1991). Testicular damage was reported in one animal experiment (Eustis et al, 1988).

Atrazine

IARC (1999b) determined that atrazine is not classifiable as to its carcinogenicity in humans (Group 3). A combined analysis of the results of two cohort studies of agricultural chemical production workers in the United States showed decreased mortality from cancers at all sites combined among workers who had had definite or probable exposure to triazine. Based on a very few cases, a non-significant increase in the number of deaths from non-Hodgkin lymphoma was seen, but no excess risks were observed for cancers at other sites. A pooled analysis of the results of three population-based case–control studies of US showed no excess risk for non-Hodgkin lymphoma among farmers who had used atrazine for at least 15 years, after adjustment for use of other pesticides. In a case–control study of non-Hodgkin lymphoma among women in eastern Nebraska, a slight, nonsignificant increase in risk was seen. In all these studies, farmers tended to have an increased risk for non-Hodgkin lymphoma, but the excess could not be attributed to atrazine. Other studies of Hodgkin’s disease in Kansas, leukaemia in Iowa–Minnesota and multiple myeloma from Iowa gave no indication of excess risk among persons handling triazine herbicides. In a population-based study in Italy, definite exposure to triazines was associated with a two- to threefold increase of borderline significance in the risk for ovarian cancer. The study was small, and potential confounding by exposure to other herbicides was not controlled for in the analysis. Overall, IARC considered the data to be insufficient to determine the cancer risk in humans exposed to atrazine. More recently Hopenhayn-Rich et al (2002) reported that there was no association between atrazine exposure at a regional level and the incidence of breast and ovarian cancer in Kentucky.

Following oral administration, mammary tumours were observed in one strain of laboratory rats, but not in mice or two other strains of rat. Following intraperitoneal injection, an increased incidence of lymphomas was reported. IARC considered that there was sufficient evidence for carcinogenicity in animals but that the mechanisms giving rise to mammary tumours were not relevant to humans. The mammary tumours seen in rats were believed to arise from the onset of reproductive senescence in one particularly susceptible strain of rat, resulting in an earlier onset of persistent oestrus and tissue changes characteristic of long-term exposure to elevated oestrogen levels. There is weak evidence that atrazine is genotoxic in mammalian cells in vivo and in vitro. Atrazine was mutagenic in Drosophila, yeast and plant cells but was not mutagenic to bacteria. Atrazine does not have intrinsic oestrogenic activity (IARC, 1999b). More recently Kandori et al (2005) have reported that atrazine appears to suppress prostate carcinogenesis in transgenic rats. Their data suggest that the effect was probably caused by the decrease in calorie intake, rather than by atrazine-related endocrine disruption. Testosterone levels were not affected by atrazine administration or dietary restriction.

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DDT

In the studies reviewed by IARC (1991), slight excess risks for lung cancer were observed among workers at two US DDT production facilities. A nested case-control study in one of these investigations found a slight deficit of respiratory cancer. Results from case-control studies of soft-tissue sarcoma do not point to an association, but two studies have found possible associations with for non-Hodgkin's lymphoma. The only study available found no association between exposure to DDT and primary liver cancer. In the USA, a slight increase in the risk for leukaemia occurred among farmers who reported use of DDT and many other agricultural exposures. A large number of investigators have compared serum or tissue levels of DDT and/or its metabolite DDE among individuals with and without cancer, with inconsistent results (IARC, 1991). There has been a particular interest in a postulated relationship between body burden of DDT/DDE and breast cancer. No convincing evidence of a significant association between DDT/DDE and breast cancer has however been reported (Romieu et al, 2000; Hoyer et al, 2000; Zheng et al, 1999; Helzlsouer et al, 1999; Guttes et al, 1998; Schecter et al, 1997; Hunter et al, 1997; Lopez-Carrillo et al, 1998; van’t Veer et al, 1997). Other cancers that have been investigated include lymphoma, leukaemia and cancers of the pancreas and lung (Baris et al, 1998; Cocco et al, 1997; Rothman et al, 1997; Fryzek et al, 1997; Garabrant et al, 1992). Overall, however, no clear association has been found between measures of body burden of DDT and its metabolites and cancer risk. IARC concluded that there was inadequate evidence in humans for the carcinogenicity of DDT and more recent epidemiological data do not support an association between DDT and cancer. IARC (1991) did find sufficient evidence of carcinogenicity in animals. Liver tumours have been observed following oral administration to rats, mice and hamsters. The results of genotoxicity assays have been mixed. IARC concluded that DDT is possibly carcinogenic to humans (Group 2B).

Heptachlor

A number of epidemiological studies of production workers have been undertaken and also studies of cancer risk in relation to blood or tissue concentrations. No clear relationships have been reported with cancers at any site, although some study results have suggested a possible link with non-Hodgkins lymphoma (IARC, 2001). IARC (2001) determined that there is inadequate evidence in humans for the carcinogenicity of heptachlor but that is sufficient evidence in experimental animals for the carcinogenicity of heptachlor. Oral administration in mice gave rise to increased incidences of hepatocellular neoplasms (including carcinomas and increased incidences of thyroid follicular-cell adenomas and carcinomas were seen in rats following oral administration. Heptachlor gave positive results in some genotoxicity assays but was not mutagenic to bacteria. The overall evaluation was that heptachlor is possibly carcinogenic to humans (Group 2B).

Organophosphates

Several studies of pesticide exposure, particularly exposure to organophosphates have demonstrated a link with reduced serum levels of testosterone. Most of these studies have also demonstrated an associated link with reduced semen quality. There is a well established link between prostate cancer and testosterone, with prostate cancer risks being reduced in the absence of testosterone. Kamijima et al (2004), for example, found evidence of reduced semen quality and increased serum testosterone concentrations in insecticide sprayers exposed mainly to organophosphorus and pyrethroid insecticides. Padungtod et al (1998) measured serum follicle-stimulating hormone (FSH), luteinizing hormone (LH), and testosterone levels, as well as urinary levels of FSH, LH, and E1C, a metabolite of testosterone, in Chinese factory workers who were occupationally exposed to ethylparathion and methamidophos. Thirty-four exposed workers were randomly chosen and 44 unexposed workers were selected from a nearby textile factory. A significant negative correlation was found among the exposed group between urinary FSH level and sperm count and between urinary FSH level and sperm concentration. Pesticide exposure alone was significantly associated with serum LH level but not with serum FSH or testosterone or with any urinary hormone levels. With adjustment for age, rotating shift work, current cigarette smoking, and current alcohol consumption, exposure significantly increased the serum LH level by 1.1 mIU/mL. Meanwhile, the serum FSH level was slightly elevated and the serum testosterone level was decreased with increased pesticide exposure. Age and rotating shift work appeared to act as confounders. Tamura et al (2003) demonstrated that the organophosphate (OP) pesticide fenitrothion and structurally related chemicals were capable of binding to the androgen receptor and interfering with its normal function.

Several other studies have demonstrated associations between exposure to pesticides and adverse effects on male fertility.

Meeker et al (2004) assessed environmental exposures to 1-naphthol (1N), a metabolite of carbaryl and naphthalene, and 3,5,6-trichloro-2-pyridinol (TCPY), a metabolite of chlorpyrifos and chlorpyrifos-methyl from spot urinary concentrations of 1N and TCPY in men recruited through a Massachusetts infertility clinic. For increasing 1N tertiles, adjusted odds ratios (ORs) were significantly elevated for below-reference sperm concentration (OR for low, medium, and high tertiles = 1.0, 4.2, 4.2, respectively; p-value for trend =0.01) and percent motile sperm (1.0, 2.5, 2.4; p-value for trend = 0.01). The sperm motion parameter most strongly associated with 1N was

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straight-line velocity. There were suggestive, borderline-significant associations for TCPY with sperm concentration and motility, whereas sperm morphology was weakly and nonsignificantly associated with both TCPY and 1N. The observed associations between altered semen quality and 1N are consistent with previous studies of carbaryl exposure, although suggestive associations with TCPY are difficult to interpret because human and animal data are currently limited.

Abell et al (2000) found median values of sperm concentration and the proportion of normal spermatozoa were 60% and 14% lower, respectively, in the greenhouse workers with high levels of exposure than in less exposed workers. The adjusted differences between the high-level and low-level exposure groups were statistically significant, while no differences were observed for the viability and velocity of sperm and sexual hormones. The median sperm concentration was 40% lower for the men with > 10 years' experience in a greenhouse than for those with < 5 years' experience. The age-adjusted testosterone/sex-hormone-binding globulin ratio declined 1.9% (95% CI 0.4-3.4%) per year of work.

Conclusions

Evidence from a wider range of studies did not suggest that methyl bromide or atrazine are likely to be carcinogenic in humans. It is possible that DDT and/or heptachlor cause cancer in humans but no evidence that either of these substances is a highly potent carcinogen at typical levels of workplace exposure. There is some evidence that organophosphates and other pesticides may disrupt testosterone activity in men. The effect, however, is to reduce serum testosterone levels which would not be expected to lead to an increased cancer risk.

A7 Prostate cancer and occupation

A number of studies have looked at the employment history of prostate cancer cases.

A7.1 STUDIES REPORTING AN ASSOCIATION WITH PESTICIDES OR FARMING

North America

Buxton et al (1999) calculated age standardized proportional mortality ratios (PMR) for prostate cancer for 216 occupations and 88 industries in British Columbia. Separate calculations were done for all male deaths age 20 and up and for deaths that occurred during men's working lifetime (age 20-65). Elevated mortality from prostate cancer was seen among business owners and managers (PMR 110; 95% CI 101-118), brokers (PMR 184; 95% CI 122-266), farmers and farm managers (PMR 112; 95% CI 105-120), and school teachers (PMR 133; 95% CI 101-174). Evaluation by industry shows elevated prostate cancer mortality in agriculture (PMR 110; 95% CI103-118), financial institutions (PMR 138, 95% CI 112-170), and transportation equipment manufacture (PMR 136; 95% CI 109-168). These results provide no useful new information about the potential role of pesticides.

Band et al (1999) collected lifetime occupational histories from 15,643 incident cancer cases, of whom 1519 had a diagnosis of prostate cancer. Occupational risks for prostate cancer included farming.

Brownson et al (1988) conducted a US cancer registry-based case-control study to investigate possible associations between various occupations and the risk of prostate cancer among 1,239 cases and 3,717 age-matched control subjects. Elevated relative risk estimates were observed for farmers, mechanics, sheet metal workers, separating machine operators, and for men employed in several manufacturing industries.

Krstev et al (1998a) studied 981 new pathologically confirmed prostate cancer cases (479 blacks and 502 whites) diagnosed between 1986 and 1989, and 1,315 population controls (594 blacks and 721 whites) who resided in Atlanta, Detroit, and 10 countries in New Jersey, covered by population-based cancer registries. Information on occupation, including a lifetime work history, was collected by in-person interview. No clear patterns of risk were found for U.S. whites versus blacks, nor for white-collar versus blue-collar jobs. Farming was related to prostate cancer (OR 2.17; 95% CI 1.18-3.98). Risk was restricted, however, to short-term workers and workers in crop production but was not restricted to those farming after 1950, when widespread use of pesticides started. Risks increased with increasing years of employment in firefighting and power plant operations and were elevated among long-term railroad line-haulers; jobs with potential polycyclic aromatic hydrocarbon (PAH) exposures and athletes. Overall it was concluded that occupation is not a major determinant of prostate cancer risk.

In a death certificate mortality odds ratio study of seven cancer sites conducted using 1979-1984 data on Illinois deaths in white and black males, Mallin et al (1989) found excess risks of prostate cancer in farmers and mechanics and repairers, especially auto mechanics. There were substantial gaps in data availability for black males.

Potti et al (2003) undertook a preliminary retrospective study was performed on young males 50 years or under) with a biopsy-proven diagnosis of carcinoma of the prostate. The records of all patients aged less than/equal to

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50 years, with a diagnosis of adenocarcinoma of the prostate, from January 1991 through December 2001 were reviewed and a pesticide exposure index was calculated for each interviewed subject. Over half of the patients (66.1%) were judged to have had 'significant' exposure and their mean survival following diagnosis was shorter than for patients without exposure. It is not clear how prevalent pesticide exposure was among young males in the local community who did not develop prostate cancer.

Europe

Sharma-Wagner et al (2000) linked 36,269 prostate cancer cases reported to the Swedish National Cancer Registry during 1961 to 1979 with employment information from the 1960 National Census. Standardized incidence ratios for prostate cancer, within major (1-digit), general (2-digit), and specific (3-digit) industries and occupations, were calculated. Significant excess risks were seen for agriculture-related industries (SIR 1.05, 95% CI 1.03-1.07), soap and perfume manufacture, and leather processing industries. Significantly elevated standardized incidence ratios were also seen for the following occupations: farmers (SIR 1.04, 95% CI 1.02-1.10), leather workers, and white-collar occupations. The authors suggest that farmers; certain occupations and industries with exposures to cadmium, herbicides, and fertilizers; and men with low occupational physical activity levels have elevated prostate cancer risks. The study provides no clear evidence of a link between pesticide exposure and raised prostate cancer risks.

In a Dutch case-referent study of 345 prostate cancer cases and 1,346 referents, van der Gulden et al (1995) found significantly elevated risks of prostate cancer associated with work in food manufacturing and for bookkeepers. Significantly elevated odds ratios (OR) were also observed for jobs held between 1960 and 1970 in administration, in storage, or as farm labourer. In addition, a statistically significant excess risk was found for subjects who reported frequent occupational exposure to cadmium. Cases who worked in farming applied pesticides during significantly more days per year than the referents did. A nonsignificantly elevated OR was found for maintenance of tractors and agricultural machinery. Among metal workers, mechanics, and repairmen, nonsignificantly increased ORs were observed with regard to the use of acids, solvents, iron, and steel, and for welding and maintenance of machinery.

A7.2 STUDIES THAT FAILED TO FIND AN ASSOCIATION WITH PESTICIDES OR FARMING

North America

Krstev et al (1998b) undertook a case control study based on information on occupation and industry on death certificates from 24 states between 1984 to 1993. A total of 60,878 men with prostate cancer as underlying cause of death was selected and matched with controls who died of all other causes except cancer. Excess risks were observed for some white-collar occupations, such as administrators, managers, teachers, engineers, and sales occupations. However, some blue-collar occupations, such as power plant operators and stationary engineers, brickmasons, machinery maintenance workers, airplane pilots, longshoreman, railroad industry workers, and other occupations with potential exposure to PAH also showed risk of excess prostate cancer. Risk was significantly decreased for blue-collar occupations, including farm workers, commercial fishermen, mechanics and repairers, structural metal workers, mining, printing, winding, dry cleaning, textile machine operators, cooks, bakers, and bartenders.

Elghany et al (1990) found no increased risk of prostate cancer in agriculture workers in a population-based case-control study although an increased relative risk for aggressive tumours was detected among younger men (OR 2.6, CI 0.6-12.1). The study included 358 men with newly diagnosed prostate cancer and 679 control men identified from the Utah population. The study specifically investigated cadmium exposures and found that cadmium exposure appeared to result in a small increased relative risk for prostate cancer, most apparent for aggressive tumours. Cases were more likely to have worked in the following industries: mining, paper and wood, medicine and science, and entertainment and recreation. Among men younger than 67, cases were also more likely to have worked in the food and tobacco industries. Cases were less likely to have worked in industries involved with glass, clay and stone, or rubber, plastics, and synthetics. Agricultural occupations did not appear to be related to prostate cancer,

In a population-based case-control study of prostatic cancer in Alberta, Fincham et al (1990) compared 382 newly diagnosed prostatic cancer patients to 625 controls, group-matched to the anticipated age distribution of the cases, chosen at random from the health insurance roster. Prostatic cancer was found to be associated with ethnic group (British high, Ukrainian low), education (elementary high, university low), age at first marriage (early high, late low), family history (high risk for those with relatives with prostatic cancer), and increased masculinity among the children of cases. Smoking, occupation, medical history, birthplace, residence, water supply, and diet did not appear to be important risk factors.

Aronson et al (1996) performed a population-based case-control study of cancer and occupation in Montreal, Canada. Between 1979 and 1986, 449 pathologically confirmed cases of prostate cancer were interviewed, as

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well as 1,550 cancer controls and 533 population controls. Job histories were evaluated by a team of chemist/hygienists using a checklist of 294 workplace chemicals. After preliminary evaluation, 17 occupations, 11 industries, and 27 substances were selected for multivariate logistic regression analyses to estimate the odds ratio between each occupational circumstance and prostate cancer with control for potential confounders. Moderate evidence was found of increased risks for electrical power workers, water transport workers, aircraft fabricators, metal product fabricators, structural metal erectors and railway transport workers. Moderately strong associations were found for metallic dust, liquid fuel combustion products, lubricating oils and greases, and polyaromatic hydrocarbons from coal. The population attributable risk was estimated to be between 12% and 21% for these occupational exposures, although the authors admit that this was likely to have been an over-estimate.

Europe

Boers et al (2005) and Zeegers et al (2004) reported on a prospective cohort study among 58,279 men in the Netherlands. The results of their studies do not support an association between pesticide exposure or farming and prostate cancer. Cohort members (55-69 years) completed a self-administered questionnaire in September 1986 on potential cancer risk factors, including job history. Follow up for prostate cancer incidence in the Boers et al study was established by linkage to cancer registries until December 1995 (9.3 years of follow up). The analyses included 1386 cases of prostate cancer and 2335 subcohort members. A blinded case-by-case expert exposure assessment was carried out to assign cases and subcohort members a cumulative probability of exposure for each potential carcinogenic exposure. In multivariate analyses, Boers et al found a significant negative association for pesticides (RR 0.60; 95% CI 0.37- 0.95) when comparing the highest tertile of exposure to pesticides with no exposure. No association was found for occupational exposure to PAHs (RR 0.75; 95% CI 0.42 - 1.31), diesel exhaust (RR 0.81; 95% CI 0.62 - 1.06), metal dust (RR 1.01; 95% CI 0.72 - 1.40), metal fumes (RR 1.11; 95% CI 0.80 - 1.54), or mineral oil (RR 0.99; 95% CI 0.66 - 1.48) when comparing the highest tertile of exposure with no exposure. In subgroup analysis, with respect to tumour invasiveness and morphology, null results were found for occupational exposure to pesticides, PAH, diesel exhaust, metal dust, metal fumes, and mineral oil. In their analysis, Zeegers et al (2004) clustered job codes into professional groups that were investigated in 3 time windows: 1) profession ever performed, 2) longest profession ever held, and 3) last profession held at baseline. Follow up for incident prostate cancer was established by linkage to cancer registries until December 1993. A case-cohort approach was used based on 830 cases and 1525 subcohort members. Moderately decreased prostate cancer risks were found for electricians, farmers, firefighters, woodworkers, textile workers, butchers, salesmen, teachers, and clerical workers, but the relative risks for these groups were not statistically significant. Moderately increased relative risks for railway workers, mechanics, welders, chemists, painters, and cooks were also not statistically significant. In contrast, a substantially increased, but not statistically significant, prostate cancer risk was found in men who reported to have ever worked in the rubber industry. The lack of statistical significance could be caused by the scarcity of rubber workers in this cohort. For road transporters, metal workers, and managers, no association with prostate cancer risk was found. The only group in which a statistically significant raised risk was found was in policemen. The statistical analysis took account of family history of prostate cancer, diet, alcohol, smoking and level of education.

In a German study, Heiskel et al (1998) reported a positive association between having worked in transportation/communication and having prostate cancer. Work in other occupational groups was not associated with an increased risk for prostate cancer.

In a study of 101 prostate cancer patients and 202 hospital controls individually matched by age (+/- 2 years), hospital admittance and place of residence, Ilic et al (1996) found significant associations between prostate cancer and occupational physical activity during the year preceding the disease. They also reported associations with occupational exposure to asbestos, steel, dyes and lacquers, bitumen, pitch, iron, nickel, lead, fertiliser and certain other agents, nephrolithiasis, 'other' diseases including chronic bronchitis, chronic rheumatic diseases, hypertension, cardiomyopathy, diabetes mellitus, renal diseases, eye diseases and tuberculosis and large numbers of sexual partners. Marital status, age at first marriage, educational level, age at first sexual intercourse, frequency of sexual intercourse, venereal diseases, tonsillectomy, appendectomy, hernia inguinale and hydrocele, anthropometric characteristics, smoking history, sport and recreational activities and family history of prostatic neoplasms were not found to be independently related to prostate cancer.

Elsewhere

A New Zealand Cancer Registry based case-control study involved 617 male patients with prostate cancer registered during 1979 and aged 20 years or more at the time of registration (Pearce et al 1987). Controls were also males chosen from the Cancer Registry with two controls per case, matched on age and year of registration. There was an elevated risk in the upper social class groupings. No evidence was found of elevated risks in agricultural workers (OR 1.08, 90% CI 0.86-1.36). The only occupational groups showing elevated risks were sales and service workers (OR 1.29, 90% CI 0.99-1.69) and teachers (OR 2.44, 90% CI 1.05-5.70). Frith et al (1996) analysed the incidence of cancer for the period 1972-1984 in New Zealand. No specific excess of cancer

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in farmers was reported. It seems probable that farming practice would be generally very different in New Zealand from that in Europe and North America and the pattern of pesticide exposure would be similarly different.

A7.3 CONCLUSIONS

In conclusion, some, but not most studies that have examined prostate cancer risk by occupation have found that farmers are among a number of occupational groups that appear to have higher risks than other occupations. Some of these studies have also suggested a link with pesticides. The significance of the findings of these studies is unclear given the lack of consistency in the “at risk” groups identified by different studies. There has been no marked difference between the findings of European and North American studies. There is no clear trend with date of study that could relate to changes in diagnostic practice.

A8 Studies based on markers of population exposure to pesticides

In a hospital based case control study, Ritchie et al (2003) examined the relationships of serum levels of organochlorine pesticides (OCPs) and polychlorinated biphenyls (PCBs) with prostate cancer. Ninety-nine controls drawn from men receiving treatment for other conditions were frequency matched by age in 5-year increments to 58 prostate cancer patients. Four of the controls had been diagnosed with prostatic hyperplasia. There were no significant differences in the prevalence of self-reported exposures to solvents, dusts, pesticides, fumigants, wood preservatives, metals, dyes and adhesives or radiation between the cases and the controls. Of 30 PCBs and 18 OCPs measured in serum, 7 organochlorines, dieldrin, p,p'-DDE, trans-nonachlor, oxychlordane, heptachlor epoxide, and PCBs 153 and 180 were detected in at least 20% of all study participants. Adjusting for age, body mass index, and a history of prostatitis, multiple logistic regression showed that oxychlordane and PCB 180 were associated with an increased risk of prostate cancer. Serum levels of the other compounds were not significantly different between cases and controls. The authors noted that PCB180 had been associated with raised risks for breast cancer in some studies but not in others. It was concluded that it was possible that long-term, low-dose exposure to specific OCPs and PCBs in the general population may contribute to an increased risk of prostate cancer. One substantial weakness in the study is that the risks of prostate cancer appeared to be greater for middle exposure category rather than high exposure category for both oxychlodane and PCB180. This issue is not addressed by the authors. Although it could have been an artefact arising from the relatively small number of more highly exposed cases and controls, it does shed some doubt on the reliability of the findings for the middle exposure groups. It is plausible that the apparently raised risks of prostate cancer associated with oxychlodane and PCB180 arose by chance.

Cocco and Benichou (1998) used multiple linear regression to investigate the association of prostate cancer mortality and testicular cancer mortality with environmental exposure to the anti-androgen DDT derivative p,p'-dichlorodiphenyldichloroethylene (p,p'-DDE) in the USA in the period 1971-1994. Environmental p,p'-DDE contamination was estimated at State level from the p,p'-DDE concentrations in the subcutaneous fat of population samples (1968) and from measurements of p,p'-DDE in tree bark (thought to be related to spray drift, 1992-5) and compared with cancer mortality for 1971-90 On average, African Americans had adipose p,p'-DDE levels that were 74% higher than in Whites (8.49 vs. 4.88 ug/g; p < 0.001). Neither prostate cancer mortality nor testicular cancer mortality showed a positive association with either indicator of p,p'-DDE environmental contamination. The regression coefficient for prostate cancer was constantly inverse for adipose p,p'-DDE along the period of study, although it approached statistical significance only for African Americans in 1981-1985 (P=-0.755; 0.10 > p > 0.05). The variability of individual exposure to DDT was not considered and overall power of the study to determine dose-response relationships was limited by considering exposure only in terms of average state wide exposure. The variability of average exposure at State level through time was also not considered so that potential variability in cumulative or maximum levels of exposure was not investigated.

Janssens et al (2001) collected the mortality statistics for breast and prostate cancer between 1985-1994 for each of the 589 Belgian municipalities together with data on crops and pesticides (1998) and possible confounders such as population density, degree of urbanization, industrial activity and the presence of an incinerator. The authors were particularly interested in the possible effects of endocrine disrupting chemicals in the environment on breast and prostate cancer risks. It was considered that agricultural practice in different parts of Belgium is relatively stable and that recent crop information was relevant to understanding historical exposures that may have given rise to the observed cancers. There was a large variation in crops and pesticide exposure among the municipalities, the highest exposure being seen in the fruit production area where up to 27 kg per hectare may be applied. Univariate analysis demonstrated a relationship between prostate cancer mortality and potatoes, defoliants, presence of an incinerator (presumed source of dioxin), detection of dioxin, industrial activity (potential source of a range of endocrine distruptors including dioxin) and a degree of urbanisation of 5%. Similar factors were reported for breast cancer. The results of multivariate analysis suggested that exposure to acaricides, industrial activity and dioxin were not correlated with prostate cancer mortality. A relationship was found between mortality and growth regulators, defoliants and degree of urbanisation. Using the same procedure for crops, prostate cancer mortality was found to be unrelated to corn, apples, vegetables, dioxin, incinerators and industrial

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activity, but a significant relationship was found with cereals and potatoes. The association with potatoes was consistent with the relationship with defoliants as these are largely used in the potato industry. It was noted that potato growing areas are likely to be affected by historical DDT contamination arising from its use to combat the Colorado beetle. Overall, the study results did not demonstrate a relationship between total and class-related pesticide use and breast and prostate cancer mortality, but it did demonstrate a relationship with potatoes and, by inference with defoliants and/or exposure to DDT. The use of spatial data to assess individual exposure to pesticides and other agents meant that the exposure classification of individuals was relatively imprecise and this is likely to have weakened the power of the study to detect effects.

Mills (1998) obtained average annual age-adjusted cancer incidence rates (1988-1992), on a county-, sex-, and race/ethnicity-specific basis from the California Cancer Registry (and pesticide use data from the California Department of Pesticide Regulation for 1993. Pearson product-moment correlation coefficients (r) were used to correlate age-adjusted incidence rates for selected cancers with the use data for selected pesticides. For most sex- and race/ethnicity-specific groups, there was no correlation between pesticide use and cancer incidence. There were, however, several exceptions, particularly in Hispanic males for whom the following correlations were observed: leukaemia and atrazine (r=0.40), leukaemia and 2,4-dichlorophenoxyacetic acid (r=0.41), leukaemia and captan (r=0.46), atrazine and brain cancer (r=0.54), and atrazine and testicular cancer (r=0.41). For black males, relationships were observed between atrazine and prostate cancer (r=0.67) and between Captan and prostate cancer (r=0.49). The author notes that no data about exposure to pesticides at the individual level were available for analysis. In addition, no latency period was allowed between potential exposure and diagnosis with cancer. The absence of linkage between cases and individual exposure to pesticides meant that this study had very limited power to detect an effect and there is no evidence that any of the cases were actually exposed to pesticides.

None of the limited number of studies of population exposure to pesticides provide strong support for an association with prostate cancer.

A9 Exposure of military personnel to Agent Orange

Agent Orange was a herbicide sprayed in Vietnam that was composed of a 1:1 mixture of 2,4-dichlorophenoxyacetic acid and 2,4,5-trichlorophenoxyacetic acid. The trichlophenoxyacetic acid was contaminated by 2,3,7,8-tetrachlroodibenzo-p-dioxin. It has been assumed that any potential cancer would be primarily associated with exposure to dioxin.

Giri et al (2004) conducted a case-control study at the Department of Veterans Affairs Medical Center in Ann Arbor, Michigan. Cases of pathologically diagnosed prostate cancer were identified and age matched in a 1:3 ratio with controls. Exposure to Agent Orange was assessed by reviewing the administrative portion of the computerized medical records. A subanalysis of the cases was conducted to examine the clinical features of prostate cancer in men reporting exposure to Agent Orange versus those who did not report exposure. A total of 47 military veterans with prostate cancer and 142 control men without prostate cancer were selected. After adjusting for age and race, men with prostate cancer were approximately two times more likely to report previous exposure to Agent Orange than the controls (OR 2.06; 95% CI 0.81 - 5.23). The number of cases was however fairly small (47) and only 11 of the cases had been exposed to Agent Orange compared with 17 of the 142 controls. The exposure assessment was limited to questioning men as to whether they had been exposed to Agent Orange and the authors make no comment as to the probable accuracy of the response given. The family history of prostate cancer in cases and controls, an important determinant of prostate cancer risk, was not considered in the analysis.

Zafar and Terris (2001) compared the rate of prostate cancer in veterans referred for prostate biopsy who reported a history of Agent Orange exposure compared to the rate in veterans who denied such exposure. A total of 400 consecutive veterans referred for prostate needle biopsy in a 30-month period completed a survey regarding Agent Orange exposure. Of these 400 patients 32 (8%) reported previous exposure to Agent Orange. From the remaining 368 patients who denied Agent Orange exposure, three consecutive age matched controls were selected per each patient reporting exposure for a total of 96 age-matched controls. Prostate specific antigen, prostate cancer, cancer grade and length of cancer in the biopsy cores were compared in Agent Orange exposed patients and unexposed controls. Of the 32 Agent Orange exposed patients, 13 (41%) had prostate cancer, while 33 of the 96 controls (34.4%) had cancer. There was no correlation of Agent Orange exposure with cancer (r = 0.06). There was also no statistically significant difference in the 2 groups in regard to PSA (p = 0.90), cancer (p = 0.15), proportion of well differentiated cancers (p = 0.41) or length of cancer in the biopsy cores (p = 0.34). Compared with the total adult male veteran population followed on an outpatient basis at the authors’ facility in California, an average of 1.07% of those with a history of Agent Orange exposure were referred for

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prostate biopsy yearly versus 1.33% of unexposed patients. Overall, there was no significant relationship of prostate cancer with Agent Orange exposure in patients referred for prostate biopsy.

More recently Pavuk et al (2005) examined cancer incidence in 1482 Air Force veterans who served in Southeast Asia (SEA) and who were not occupationally exposed to herbicides. Cancer incidence between 1982 and 2003 was determined by record review and Cox proportional hazards models were used to estimate risk ratios across serum 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and years served in SEA categories. All sites cancer risk increased with TCDD (RR 1.6; 95% CI 1.2-2.2) and also with time served in SEA whereas the risk of prostate cancer increased with years of SEA service but not with TCDD. In an extension to the study, Pavuk et al (2006) examined prostate cancer in 2516 veterans of whom 1019 had been involved in spraying agent orange. No increased prostate cancer risk was found in veterans who had sprayed agent orange, except in men who had served prior to 1969, when the levels of TCDD contamination in herbicides were considerably higher than subsequently. In the comparison group, prostate cancer risk was found to increase with increasing length of service in SEA. This was attributed to possible organochlorine contamination of food as a result of the widespread use of DDT for mosquito control as part of malaria control measures.

In contrast Akhtar et al (2004) reported that operation Ranch Hand veterans who sprayed 2,3,7,8 tetrachlorodibenzo-p-dioxin (dioxin)-contaminated herbicides in Vietnam had increased cancer risks. Among veterans who spent at most 2 years in SEA, the risk of cancer at any site, of prostate cancer and of melanoma was increased in the highest dioxin exposure category. These results appear consistent with an association between cancer and dioxin exposure.

In conclusion, the studies of US veterans do not provide consistent evidence for an association between Agent Orange and prostate cancer. Other factors associated with service in Asia may have contributed to the excess risks observed in some studies. It seems plausible that military veterans may receive more medical surveillance than others in the population and this may have contributed to an apparently increased incidence of prostate cancer.

A10 Environmental Contamination

Pavuk et al (2003) reported a raised incidence of cancers of the tongue, stomach, lung, testis and kidneys and a lower than expected incidence of prostate cancer in male residents of an area of eastern Slovakia contaminated by PCBs. Biomonitoring provided evidence of higher levels of PCB exposure than in a reference population, although exposure to the pesticides DDT, DDE and HCB was similar in the two regions.

A11 Discussion and Conclusions

A11.1 PESTICIDE PRODUCTION WORKERS

The results of a number of studies of pesticide manufacturing workers have failed to demonstrate a consistent association between pesticide exposure and prostate cancer. A possible association between prostate cancer and atrazine in manufacturing workers was postulated by the authors to have arisen as a result of improved screening and the excess was not confirmed in a case-control study. An excess of prostate cancer in younger men and relationship with duration of exposure in these studies were, however, suggestive of an effect and limited follow up may have weakened the power to detect effects. The results of a number of large studies of workers exposed to phenoxy herbicides during manufacturing do not suggest a link with prostate cancer. Given the size of the studies and the length of follow-up, it is unlikely that an important excess risk of prostate cancer would have remained undetected. The studies were undertaken before the introduction of modern diagnostic methods for prostate cancer, such that the power of these studies to detect an excess risk would have been less than in more recent studies, although diagnostic practice would have been the same for populations who were exposed or unexposed to pesticides. There is no evidence from studies of manufacturing workers of an association between chlorinated pesticides and prostate cancer and the limited available data do not suggest an association between the manufacture of chlorophenols and prostate cancer. Although the available data are insufficient to conclude that exposure to pesticides during manufacture is not associated with prostate cancer for all pesticide formulations, there is an apparent absence of risk for phenoxy herbicides and little evidence of an excess risk associated with other pesticide formulations.

Most of the studies of manufacturing workers have not included a quantitative evaluation of exposure. Given, however, that these compounds are likely to be typically manufactured within closed system processes and that packaging or containerisation is likely to be automated, it is possible that potential exposure to these compounds is limited to occasional maintenance activities. Levels of exposure to pesticides may be very much lower than in some groups of pesticide applicators.

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A11.2 AGRICULTURAL WORKERS AND OTHER PESTICIDE APPLICATORS

There have been a large number of studies of agricultural workers exposed to pesticides. The Agricultural Health Study (AHS) undertaken in the US provided limited evidence of a possible association between pesticide exposure and prostate cancer in farmers. One of the strengths of the AHS is that the diagnosis of prostate cancer is likely to have employed modern methods. The large number of different pesticides considered and difficulties in assessing exposure may, however, have weakened the power of the study to detect effects. Factors that suggest that apparent relationships may not be causal include:

An absence of exposure response relationships;None of the studies of individual pesticides that were used in relatively large quantities demonstrated an increased prostate cancer risk.

The absence of exposure-response relationships could possibly reflect inadequacies in exposure assessment or the metric of exposure used. For example, occasional very high exposures may not have been fully accounted for, although there was no evidence that more cases than controls experienced high exposure events. The strong familial influence on prostate cancer risk with some, but not all, pesticide formulations suggests that genetic susceptibility may influence prostate cancer risk arising from pesticide exposure.

The results of other studies of prostate cancer in agricultural workers handling pesticides are inconsistent. Several, but not all, studies have reported apparently increased risks of prostate cancer. Different studies have found different pesticides to be most strongly associated with increased risks. It is possible that some of the apparent associations have arisen by chance or by some confounding exposure/factor associated with pesticide application. It is notable, however, that most of the positive findings have been in more recent studies. This may indicate that prostate cancer is associated with more modern pesticide formulations and/or much longer periods of exposure than would have been typical of workers considered in earlier studies. It may also simply reflect a greater sensitivity in the detection of prostate cancer. The absence of a consistent trend in findings through time, however, suggests that changes in diagnostic practice have not had an important influence on determining whether or not individual studies have detected an excess prostate cancer risk. A number of studies of farmers in North America have identified an excess risk of prostate cancer. In a recent review of risk factors for prostate cancer, Bostwick et al (2004) suggested that farmers may eat a relative high fat diet which would be a risk factor for prostate cancer. Farm animals, zoonotic viruses and farm chemicals, but not specifically pesticides, were also suggested as causes. There is a marked discrepancy between the findings of studies undertaken in North American and those undertaken in Europe, and most European studies have failed to find an excess risk of prostate cancer in farmers. This may reflect differences in chemical usage or other differences in farming practice (eg the use of artificial hormones or antibiotics in livestock) and/or differences in lifestyle including diet, alcohol consumption and smoking. It should be noted, however, that an exhaustive search for studies of prostate cancer in farmers was not conducted.

The results of most studies have shown that farmers generally have lower mortality risks than typical of the general population. It is possible that the survival of a greater proportion of men into old age and lower risks of death from other causes than is typical of the general population may influence the apparent risks of prostate cancer diagnosis and death in farmers. Given that virtually all men would eventually develop prostate cancer in the absence of death from other causes, the apparent excess of prostate cancer in older farmers may be partly related to a deficit of deaths from other causes, in an age group where the risks of death are greatly increased in comparison with younger men. Men of a similar age in a comparison population may be at equal risk of developing prostate cancer but may die from other causes marginally earlier than they would have died from prostate cancer. It is notable, however, that some studies of other groups of outdoor workers such as golf course superintendents (Kross et al, 1996) and Australian pesticide applicators (Beard et al, 2003) have found an excess of deaths from smoking-related causes, suggesting that they are marked differences in lifestyle-related risk factors for cancer among different groups of pesticide users.

Most studies of pesticides and prostate cancer have not reported risks by age group and there has been little investigation of latency. Several studies of agricultural workers have reported a greater excess of prostate cancer in older men exposed to pesticides and farmers than in younger men although one large study reported a larger excess risk in younger men that was not statistically significant. It is possible that the apparently increased excess risks of prostate cancer in old age may reflect long latencies between exposure and effects and/or the pattern of exposure in older workers may be different from that in younger workers. Increasing awareness of pesticide safety issues is likely to have led to an overall reduction in pesticide exposure through time, but older workers may have modified their work practices to a lesser extent than younger men, giving rise to higher levels of exposure over comparable calendar time periods.

The results of studies of pesticide applicators outside of the farming industry do not provide strong evidence of a link between pesticides and prostate cancer. There is some evidence of a possible excess risk of prostate cancer among some groups of pesticide users in the US but only one of European studies of pesticide applicators

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reported an excess of prostate cancer and this excess was not statistically significant. Many of the studies were, however, too small and/or had insufficient follow up to be certain that no excess risk of prostate cancer existed. Many of the studies also predated the introduction of modern diagnostic methods for prostate cancer which would have weakened their power to detect an effect.

A11.3 SPECIFIC COMPOUNDS LINKED TO PROSTATE CANCER

Many of the studies of pesticide users (agricultural and nonagricultural users) have not detailed which pesticides applicators were exposed to. Where information is available about the types of pesticide applied, four substances appear to be associated with prostate cancer in more than one study: methyl bromide, atrazine, DDT and heptachlor. Other studies have reported negative relationships for all of these substances except methyl bromide. Where positive associations have been found for other substances, other studies have been published that indicate an absence of association. Given the very large number of different compounds that have been used, and the likelihood that many agricultural applicators are likely to have been exposed to a mixture of substances, the positive findings for methyl bromide may have arisen by chance. There are no common factors among the pesticides identified to be associated with prostate cancer in different studies (Table). The compounds span a wide range of chemical structures and are used in a variety of ways.

Pesticide StudySignificant association Type Use

methyl bromideAHS, Mills & Yang 2003 yes fungicide

aldrin AHS yesCyclodiene (organochlorine) insecticide

carbofuran AHS No carbamateacaricide, insecticide, nematacide

permethrin AHS No pyrethroid acaricide

phorate AHS Noaliphatic organothiophosphate

acaricide, insecticide, nematacide

butylate AHS Yes (+ family)* thiocarbamate herbicide

carbofuran AHS Yes (+ family)* carbamateacaricide, insecticide, nematacide

coumaphos AHS Yes (+ family)*heterocyclic organothiophosphate acaricide, insecticide

2,2-chloroethenyl dimethyl phosphate AHS Yes (+ family)*fonofos AHS Yes (+ family)* phosphonothioate insecticidealachlor AHS No (+family)* chloroacetanilide herbicideatrazine AHS, Mills (1998) No (+family)* chlorotriazine herbicidedicamba AHS No (+family)* benzoic acid herbicideEPTC AHS No (+family)* thiocarbamate herbicide

aldicarb AHS No (+family)*oxime carbamate acaricide, insecticide,

nematacide

chlorpyrifos AHS No (+family)*pyridine organothiophosphate

insecticide, nematacide

terbufos AHS No (+family)*aliphatic organothiophosphate

acaricide, insecticide, rodentacide

lindane Mills&Yang 2003 Yes organochlorineacaricide, insecticide, nematacide

heptachlorAHS, Mills&Yang 2003 Yes

Cyclodiene (organochlorine) insecticide

simazine Mills&Yang 2003 Yes chlorotriazine herbicidedichlorvos Mills&Yang 2003 No organophosphate acaricide, insecticide

DDTAHS, Settimi et al 2003 Yes organochlorine acaricide, insecticide

dicofol Settimi et al 2003 Yes bridged diphenyl acaricide

Captan Mills, 1998 Nophthalimide (dicarboximide) fungicide

oxychlordane Ritchie et al 2003 No organochlorine insecticide*relationship observed only for men with a family history of prostate cancer

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A11.4 ASSOCIATION BETWEEN PROSTATE CANCER AND SPECIFIC OCCUPATIONS

In more general investigations of possible links between occupation and prostate cancer risk, some, but not most studies have found that farmers are among a number of occupational groups that appear to have higher risks than other occupations. Some of these studies have also suggested a link with pesticides. The significance of the findings of these studies is unclear as there is a marked lack of consistency in the “at risk” groups identified by different studies. There has been no marked difference between the findings of European and North American studies.

A11.5 AGENT ORANGE

The results of studies of US veterans are suggestive of an excess risk of prostate cancer among veterans but do not provide consistent evidence for an association between Agent Orange and prostate cancer. Other factors associated with service in Asia, such as more frequent subsequent medical examination than for others in the population, may have contributed to the excess risks observed in some studies.

A11.6 GENERAL POPULATION STUDIES

A limited number of studies have investigated prostate cancer risk in relation to markers of population exposure to pesticides including biomarkers, pesticides sales and regional patterns of agricultural practice. In most of these studies, exposure was not determined at an individual level and thus the power of these studies to detect an effect was limited. The one study that did investigate individual exposure and effects was too small to reliably assess prostate cancer risk. Overall the results of these studies are not informative about the potential association between pesticides and prostate cancer.

A11.7CONCLUSIONS

Overall, there is insufficient evidence to conclusively link pesticide exposure with an increased prostate cancer risk, particularly in studies of manufacturing workers. There is, however, also insufficient evidence to be certain that such a risk does not exist, although the failure to consistently detect an excess risk, suggests that any risk is likely to be relatively small in comparison to other influences on health. These findings are consistent with those of earlier reviews. In a review and meta-analysis, Van MaeleFbary and Willems (2003,2004) found that, although pesticide applicators appear to have an increased risk of prostate cancer, it was not possible to establish that this was solely due to pesticide exposure. Other, earlier reviews failed to identify a link between pesticides and prostate cancer. The populations in the source studies of earlier reviews are likely to have been exposed to different pesticides from those in more recent studies and also the follow up times in many of the earlier studies was relatively short, particularly in relation to the development of cancer in old age. The short follow up times and less sensitive diagnostic methods for prostate cancer, may have limited the power of many of the earlier studies to detect an excess of prostate cancer. It is also possible that higher levels of exposure in earlier studies may have given rise to different disease outcomes than those found in later studies. For example, many of the earlier studies found excesses of lymphoma and soft tissue sarcomas. Publication bias may have played a role as many of the earlier studies actively investigated possible links with lymphoma and soft tissue sarcomas whereas more recent studies have actively investigated prostate cancer risks.

Several studies have suggested an increased excess risk of prostate cancers in pesticide users in old age that may reflect a substantial latency period between first exposure and disease development, although this has not been extensively investigated. It is also possible that the pattern of exposure in older has been substantially different than in younger workers (different compounds, differences in handling and attitudes towards exposure). There has been very little investigation of prostate cancer risks by age in pesticide workers and other studies have reported a greater excess risk in younger men, although this has not been statistically significant.

Most of the studies that have reported a possible link between pesticide exposure and prostate cancer have been in users rather than manufacturing workers. It seems probable that exposure among pesticide users is much less well controlled than during manufacture. Mean levels of exposure during manufacturing may be very much lower than for some users. It is possible, therefore, that some of the differences in the findings of studies of workers in manufacturing versus user industries arise from differences in the level of exposure. A factor that is likely to have given rise to differences between different user groups is that a very wide range of different substances are classified as pesticides and it seems highly unlikely that all of these compounds would have a similar potential to cause prostate cancer.

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