Introduction

1. Prostate Cancer is the most common cancer in men in the UK, with over 24,700 new cases a year (2000 data). Prostate Cancer is the second largest cause of death from cancer in the UK. There were 9,900 deaths reported in 2002 accounting for around 13% of cancer deaths in men. Around 70% of these deaths are in men aged over 70 years. The mortality rate for Prostate Cancer peaked in the early 1990s and has now fallen to 25 per 100,000 population at risk. The lifetime risk for being diagnosed with Prostate Cancer is 1 in 14. The cancer develops from cells within the prostate gland. The majority of Prostate Cancers are slow growing and many men are unaware that they have this cancer. However, a small number of Prostate Cancers grow more quickly and may spread to other parts of the body. Cancer Research UK reported a 57% increase in Prostate Cancer incidence in Great Britain between 1991 and 2000.^1-3

2. The Committee was asked to review the available epidemiological and other research to identify if there were any potential chemical exposures which might be associated with Prostate Cancer.

3. The Committee initially considered the evidence for an increasing incidence of Prostate Cancer in order to elucidate if there were diagnostic and registration changes which might be important in interpreting the documented increased incidence of Prostate Cancer. The second phase of the review concerned an evaluation of the epidemiological and other data regarding occupational groups (such as farmers/farm workers) and chemical exposures which have been proposed as being associated with Prostate Cancer.

4. The Committee considered an overview drafted by the DH Toxicology Unit http://www.advisorybodies.doh.gov.uk/pdfs/annex1cc0335.pdf and evaluated additional commissioned papers published studies. The DH Toxicology Unit overview and additional commissioned papers list the full set of references considered during the COC discussions. The Committee considered the evidence regarding chemical causation of Prostate Cancer at its November 2003 and April 2004 meetings. The additional discussion papers on prostate cancer from the DH Toxicology Unit on the evidence regarding a possible association between PAH exposure (http://www.advisorybodies.doh.gov.uk/pdfs/Cc0412.pdf) and occupation in the rubber industry (http://www.advisorybodies.doh.gov.uk/pdfs/Cc0413.pdf)
were reviewed at the June 2004 meeting.

Trends in Prostate Cancer in the UK

5. Age-adjusted rates for Prostate Cancer increased in all age groups in England and Wales during the 1970s and 1980s. A marked increase occurred after this, rates peaked in 1994 and subsequently decreased in some, but not all, age groups.⁴ The Committee agreed that increased use of trans-urethral resection of the prostate (TURP) for benign prostatic hyperplasia accounted in part for increased reporting of Prostate Cancer during the 1970-80s. The adoption of Prostate-Specific Antigen (PSA) testing during the 1990s partly explained the subsequent increased reporting of Prostate Cancer. Similar patterns were observed in Scotland, where the increases in incidence were closely correlated with rates of TURP (up to 1988) and, subsequently, PSA testing (1989-1996).⁵

6. The Committee reviewed a Small Area Health Statistics Unit (SAHSU) study on geographical variation in the incidence of Prostate Cancer in the UK at the June 2002 meeting.⁶ The Committee agreed that the study showed no evidence for significant geographical variation in Prostate Cancer in the UK. This would suggest there were no major environmental factors affecting incidence of Prostate Cancer in the UK.

7. The Committee agreed that the impact of screening for Prostate Cancer using Prostate Specific Antigen (PSA) on recording of incidence and to a lesser degree mortality data severely complicated the interpretation of epidemiological studies and time trends in incidence in particular.

Risk factors associated with Prostate Cancer

8. There are a number of suspected risk factors for Prostate Cancer. The most important two are age and family history. Clinical prostate cancer is rare in men under 40 years of age.⁷ The risk of Prostate Cancer increases by 2-3 fold in men who have a first-degree relative with the disease.⁸ It is estimated that high penetrance familial Prostate Cancer accounts for 5-10% of all cases and a higher proportion of cases identified before the age of 55 years.^9,10

9. A number of other risk factors have been suggested including vasectomy^12,16 sexual activity^12,16 viral exposure¹⁷ and physical activity.¹⁸ However, the evidence for these factors is uncertain and no conclusions can be drawn. There is some limited evidence that smoking is associated with Prostate Cancer^11,12,16 but no convincing evidence regarding alcohol consumption.¹⁹

10. The evidence for an association between diet and risk of Prostate Cancer was reviewed fully by the Working Group on Diet and Cancer of the Committee on Medical Aspects of Food and Nutrition Policy in 1998.¹⁵ The Working Group concluded that the limited data were weakly consistent with the hypothesis that higher total fat intakes are associated with higher risks of Prostate Cancer. The Working Group also concluded that the limited evidence was moderately consistent that higher vegetable consumption, especially raw and salad vegetables, is associated with a lower risk of Prostate Cancer. The evidence for an association between consumption of fruit and risk of Prostate Cancer was inconsistent. There were insufficient data on intakes of soya products to reach a conclusion on the association of soya products with risk of Prostate Cancer. Advice on nutritional factors is the responsibility of the Scientific Advisory Committee on Nutrition (http://www.sacn.gov.uk/).

11. Other potential risk factors include ethnicity,^11,12 a number of genetic polymorphisms (for example genes involved in androgen metabolism and signalling pathways),¹² and endocrine factors (such as low testosterone levels, and elevated IGF-1 levels).^11,13,14 These observations have led to the suggestion that androgenicity may influence Prostate Cancer risk.

Chemical exposures associated with Prostate Cancer

Cadmium

12. Occupational exposure to cadmium was associated with an increased incidence of lung cancer and was considered by the World Health Organisation's International Agency for Research on Cancer (IARC) to be carcinogenic to humans (ie Group 1).²⁰ Chronic dietary administration of 50 ppm cadmium in the diet to rats has been reported to be associated with proliferative responses of the prostate (eg hyperplasia and adenoma).²¹ The finding of increased incidence of Prostate Cancer in rats given a single subcutaneous injection of cadmium²² was considered by members to be dependent on functioning of the testes and androgen production. Subcutaneous administration of higher cadmium doses, which induced testicular toxicity and thus reduced androgen production, resulted in no evidence for Prostate Cancer. It was noted that Prostate Cancer had been induced following direct injection of cadmium into the prostate of rats but members considered that this route of administration was of limited relevance.²³

13. The Committee considered one published paper²⁴ which reported evidence that low concentrations of cadmium chloride could interact with androgen receptor in-vitro and could also produce an androgenic response (eg increased prostate weight) in-vivo in rats given relatively low intraperitoneal doses. This suggests a plausible mechanism by which cadmium might be associated with prostate tumours in rats.

14. However the evidence from occupational studies regarding Prostate Cancer showed no association in the majority of studies including relatively large cohort studies. Thus overall there was no evidence to associate occupational exposure to cadmium with cancer of the prostate. The Committee was aware of a relatively old study of residual exposure which reported 40 years of mortality follow-up of the residents of Shipham, Somerset, England where there were high soil-levels of cadmium. No evidence for an excess mortality from Prostate Cancer was found, though this was only based on 2 cases.²⁵ The possibility that cadmium might induce androgen imbalance and thus might potentially be associated with Prostate Cancer should be monitored and any relevant information considered in the future.

Pesticides and endocrine disrupting chemicals

15. There is evidence from a variety of in-vitro studies that a number of pesticides (such as certain organochlorine insecticides (o,p'DDT, p,p'DDT, ß-hexachlorocyclohexane (ß-HCH) and the fungicide chlorothalonil) can produce androgenic effects.^26,27 However it has been noted that some of these pesticides can also induce anti-androgenic effects (eg vinclozolin).²⁷

16. The Committee agreed that any potential androgenic effect in-vivo following environmental exposure to pesticides and other endocrine disrupting chemicals was likely to be minimal. The Committee noted that there was some epidemiological evidence suggesting a weak association between herbicide exposure and Prostate Cancer^27-29 The Committee considered the evidence for an association between farmers, farm workers and pesticide applicators and increased risk of Prostate Cancer. These studies are considered below in paragraphs 24-30.

17. The Committee was aware that the development of appropriate biomarker approaches to the determination of exposure might aid in the evaluation of exposure to pesticides. There was however, comparatively limited information available where biomonitoring data had been used to evaluate exposure in epidemiological studies of Prostate Cancer. The only retrieved publication was in abstract form.³⁰

Genotoxic chemicals

18. A number of genotoxic chemicals including the polycyclic aromatic hydrocarbon benzo(a)pyrene have been found to induce prostate tumours in experimental animals (http://www.advisorybodies.doh.gov.uk/pdfs/cc0335.pdf). Co-administration of testosterone enhanced the tumourigenicity in experimental animals. Epidemiology studies investigating occupational exposure to polycyclic aromatic hydrocarbons have reported an association with Prostate Cancer in a number of studies.^31,32

19. A further discussion paper which presented a detailed review of the epidemiology studies of the potential association between occupational exposure to PAHs and increased risk of prostate cancer was provided by the DH Toxicology Unit. (http://www.advisorybodies.doh.gov.uk/pdfs/Cc0412.pdf)

20. The overall conclusion reached in the additional review prepared by the DH Toxicology Unit was that there are several occupational groups where relatively high exposures to PAHs could be anticipated, eg truck drivers, foundry workers, chimney sweeps and to a lesser extent fire-fighters. There have been a number of epidemiological investigations of the potential association between exposure to PAHs in these occupational groups and risk of Prostate Cancer. This has included several cohort studies in coke oven workers, fire-fighters and chimney sweeps. The adequacy of exposure data documented is very limited in most of the reports reviewed in the DH Toxicology Unit paper. Where exposure data or information on the duration of occupational exposure were available, there was evidence from some studies of both greater exposure to PAHs and slightly higher risks of Prostate Cancer, but there was no compelling evidence for an increased risk of Prostate Cancer in any of the PAH exposed occupational groups studied.

21. The Committee agreed that overall the available studies do not provide evidence that is convincing for an association between occupations with exposure to PAHs and an increased risk of Prostate Cancer.

Vitamin supplements (zinc)

22. The Committee was asked to comment on the recent paper by Leiztmann M et al which investigated approximately 47,000 individuals as part of the USA based Health Professionals Follow-up study.³³ Members considered that the study had been adequately undertaken by a well respected group using the Health Professionals cohort established in the USA in 1986. There was a statistically significant increase in relative risk for advanced Prostate Cancer in men consuming ³ 100 mg/day supplemental zinc (RR = 2.29, 95% Confidence Interval (CI) 1.06-4.95). There was limited evidence for a dose-response relationship which was not statistically significant. There was a statistically significant association with taking supplemental zinc for ³ 10 years (RR = 2.37, 95% CI 1.42-3.95). Members were uncertain as to whether individuals who consumed high amounts of supplemental zinc would be more likely to seek PSA testing. However it was noted that the authors had considered routine screening for PSA up to the year 2000 in their evaluation. Members felt that the arguments presented by Leitzmann and colleagues regarding the role of intracellular concentrations of zinc in prostate tissue were inconsistent with the existing information on zinc and it was not possible to derive a biologically plausible hypothesis from the information reported. It was noted that a number of comments regarding the approach to statistical analysis of the data, the small number of cancer patients who reported intakes of zinc over 100 mg/day, and the limited evidence to support a biologically plausible hypothesis concerning dietary supplements containing zinc and increased risk of Prostate Cancer, had been raised in published correspondence commenting on the paper by Leiztmann M et al.^34-37

23. The Committee considered that the study results could not be dismissed. However, members heard that dietary supplements available in the UK each contained up to 50 mg of zinc. The Expert Group on Vitamins and Minerals had recently established a Safe Upper Level for dietary supplementation of 25 mg zinc/day based on evidence that consumption of 50 mg/day might reduce the absorption of copper across the gastrointestinal tract (http://www.foodstandards.gov.uk/multimedia/pdfs/evm_zinc.pdf).³⁸ Information from the EPIC-Norfolk cohort (for first 1860 individuals entering the cohort in 1993/4) reported that 5% of subjects were consuming zinc supplements (the intake from supplements was 4.9 (± 4.1 mg/d). Thus the number of individuals consuming more than 50 mg zinc/day from supplements was likely to be very small. The Committee agreed that it was not possible to identify sufficient numbers of individuals for study from the EPIC cohort, and that therefore that it was not feasible to undertake any further epidemiological investigation of dietary zinc intake and Prostate Cancer in the UK.

Occupations associated with Prostate Cancer

Farmers, farm workers and pesticide applicators

24. A number of studies have indicated a small excess of Prostate Cancer amongst farmers and farm-related workers and pesticide applicators, although other studies have failed to confirm this observation. Several reviews and meta-analyses of the epidemiological literature have been published. These generally described a slight excess of Prostate Cancer.^39-47

25. The COC considered a systematic review on occupational related pesticide exposure and cancer by Van Maele-Fabry and Willems⁴⁷ in detail. This meta-analysis produced an overall relative risk of 1.13 (95% C.I. 1.04-1.22) for Prostate Cancer in workers exposed to pesticides in pesticide related occupations (from 11 cohort, 4 Proportional Mortality Ratio, and 7 case control studies). Members noted that for all studies (excluding proportional mortality ratio Studies) the relative risk was 1.09 (95% C. I. 1.00 - 1.19) and that the risk estimates were for all farming occupations and not just for pesticide applicators. North American studies tended to show higher Prostate Cancer risk than European studies. The Committee considered that pesticide exposure was likely to be lower in Europe. The separate risk ratio for pesticide applicators (Relative risk 1.64 95% C.I. 1.23 - 2.38) was greater than the overall risk ratio for all studies.

26. The Committee also considered the large retrospective cohort study reported by Morrison et al²⁹ in detail. This study comprised male farmers aged 45 or more in 1971 identified through the Canadian National Mortality Database during the period of June 1971 up to the end of 1987. A total of 1,148 Prostate Cancer deaths and over two million person years were observed. The analyses reported were based on a one third sample from this cohort who had completed the more extensive census questionnaire thus allowing for better classification of exposure. A relative risk of 2.23 (95% C.I. 1.30-3.84) for Prostate Cancer was reported for farmers (aged 45-69 years) who sprayed herbicides on to 250 or more acres (p<0.01 test for trend). The Committee noted this analysis was based on younger farmers who were more likely to have applied the herbicides themselves. A subsequent analysis using data for mortality from 1981-1987 reported no evidence for a dose-related effect of herbicide use on Prostate Cancer.²⁹ It was possible that changes in herbicides used by Canadian farmers may account for this finding.

27. The Committee agreed that these two studies provided some evidence for increased Prostate Cancer risk for farm workers most exposed to pesticides and with some evidence suggesting an association between increased risk of Prostate Cancer and exposure to pesticides and in particular herbicides.

28. The COC also noted two separate cohort studies of cancer incidence from the USA (a retrospective analysis of licensed pesticide applicators in Florida and a prospective analysis of pesticide applicators from Iowa/North Carolina).^48,49 The Florida study showed no association between Prostate Cancer and year of first licence ( a proxy measure for duration of exposure). The Iowa/North Carolina study found no evidence for a trend with increasing exposure to herbicides, fumigants and fungicides but did report a trend regarding organochlorine pesticides and older age. No trend was documented for individual organochlorine pesticides in this study. Overall these two studies provided some limited evidence for an association between pesticide exposure and Prostate Cancer but provided no convincing evidence regarding any specific pesticide exposures.

29. The Committee was aware of a review of Prostate Cancer undertaken by the Health and Safety Executive⁵⁰ published in 1998 which had concluded that the potential association between farmers/farm workers and Prostate Cancer merited further monitoring of the literature.

30. Overall the Committee agreed there was some evidence to suggest an association between farmers/farm workers, exposure to pesticides and increased risk of Prostate Cancer. The possibility of such an association could not be discounted and the published literature should continue to be monitored for further studies. Members commented on the need for improved measures of exposure to pesticides and in particular herbicides. It was considered that the potential association between herbicide use by farmers and farm workers should be kept under review.

Rubber workers

31. The further review undertaken by the DH Toxicology Unit at the request of the COC identified epidemiological studies undertaken at rubber manufacturing plants in the USA, Europe and the UK as well as two studies where the location of the rubber manufacturing plant was not reported. (http://www.advisorybodies.doh.gov.uk/pdfs/Cc0413.pdf)

32. Overall there was no convincing evidence to associate employment in the rubber industry with Prostate Cancer. A number of the studies investigated the association between employment in particular jobs and Prostate Cancer. The suggestion for such an association came from studies in rubber manufacturing plants in the USA where the task of compounding and mixing was highlighted, but no definite conclusions could be drawn. On the basis of the limited available studies, there was no convincing evidence to associate Prostate Cancer with any particular chemical exposure at rubber plants.

33. The Committee concluded that the information from the available epidemiological studies are consistent with the view that overall, there is no evidence convincing of an increased risk of Prostate Cancer in rubber workers as a whole.

Other occupations

34. The Committee agreed that the evidence regarding other occupations and Prostate Cancer did not suggest any hypotheses that required further investigation.

COC conclusions

35. The Committee agreed the following overall conclusions:

i. The increase in incidence of Prostate Cancer reported over the past 2-3 decades is largely accounted for by improved identification of cases due to increased numbers of individuals undergoing surgery for benign prostatic conditions and the use of Prostate Specific Antigen Screening.

ii. The Committee concluded that there was some limited evidence to suggest an association between farmers/farm workers, exposure to pesticides and increased risk of Prostate Cancer. The possibility of such an association being causal could not be discounted and the published literature should continue to be monitored for further studies. Members commented on the need for improved measures of exposure to pesticides and in particular herbicides. It was considered that the potential association between herbicide use by farmers and farm workers should be kept under review.

iii. The information from the available epidemiological studies are consistent with the view that overall, there is no convincing evidence of an increased risk of Prostate Cancer in rubber workers as a whole.

iv. There is no convincing evidence to associate other occupations with Prostate Cancer.

v. There is no convincing evidence to associate occupational exposure to cadmium with cancer of the prostate. The possibility that cadmium might induce androgen imbalance and thus might potentially be associated with Prostate Cancer should be monitored and relevant new information considered in the future.

vi. The one available epidemiological study on dietary zinc supplementation and risk of Prostate Cancer dose found increased risk of Prostate Cancer at high levels of supplementation (>100 mg/day). Further epidemiology studies are unlikely to provide sufficient numbers of individuals regularly consuming high doses of supplements for a study to be undertaken in the UK. The Committee agreed that it could not identify a biologically plausible rationale as to why zinc should be associated with Prostate Cancer.

December 2004

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