Health and Safety Executive

The burden of occupational cancer in Great Britain Technical Annex 5: Bladder cancer

Prepared by Imperial College London and the Health and Safety Laboratory for the Health and Safety Executive 2007

RR595 Technical Annex 5 Health and Safety Executive

The burden of occupational cancer in Great Britain Technical Annex 5: Bladder cancer

Lesley Rushton & Sally Hutchings Imperial College London Department of Epidemiology and Public Health Faculty of Medicine St Mary’s Campus Norfolk Place London W2 1PG

Terry Brown Health and Safety Laboratory Harpur Hill Buxton SK17 9JN

The aim of this project was to produce an updated estimate of the current burden of occupational cancer specifically for Great Britain. The primary measure of the burden of cancer used was the attributable fraction (AF), ie the proportion of cases that would not have occurred in the absence of exposure. Data on the risk of the disease due to the exposures of interest, taking into account confounding factors and overlapping exposures, were combined with data on the proportion of the target population exposed over the period in which relevant exposure occurred. Estimation was carried out for carcinogenic agents or exposure circumstances that were classified by the International Agency for Research on Cancer (IARC) as Group 1 or 2A carcinogens with strong or suggestive human evidence. Estimation was carried out for 2004 for mortality and 2003 for cancer incidence for cancer of the bladder, leukaemia, cancer of the lung, mesothelioma, non­ melanoma skin cancer (NMSC), and sinonasal cancer.

The proportion of cancer deaths in 2004 attributable to occupation was estimated to be 8.0% in men and 1.5% in women with an overall estimate of 4.9% for men plus women. Estimated numbers of deaths attributable to occupation were 6,259 for men and 1,058 for women giving a total of 7,317. The total number of cancer registrations in 2003 attributable to occupational causes was 13,338 for men plus women. Asbestos contributed the largest numbers of deaths and registrations (mesothelioma and lung cancer), followed by mineral oils (mainly NMSC), solar radiation (NMSC), silica (lung cancer) and diesel engine exhaust (lung and bladder cancer). Large numbers of workers were potentially exposed to several carcinogenic agents over the risk exposure periods, particularly in the construction industry, as farmers or as other agricultural workers, and as workers in manufacture of machinery and other equipment, manufacture of wood products, land transport, metal working, painting, welding and textiles. There are several sources of uncertainty in the estimates, including exclusion of other potential carcinogenic agents, potentially inaccurate or approximate data and methodological issues. On balance, the estimates are likely to be a conservative estimate of the true risk. Future work will address estimation for the remaining cancers that have yet to be examined, together with development of methodology for predicting future estimates of the occupational cancers due to more recent exposures. This report and the work it describes were funded by the Health and Safety Executive (HSE). Its contents, including any opinions and/or conclusions expressed, are those of the authors alone and do not necessarily reflect HSE policy.

HSE Books © Crown copyright 2007

First published 2007

All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form or by any means (electronic, mechanical, photocopying, recording or otherwise) without the prior written permission of the copyright owner.

Applications for reproduction should be made in writing to: Licensing Division, Her Majesty’s Stationery Office, St Clements House, 2­16 Colegate, Norwich NR3 1BQ or by e­mail to hmsolicensing@cabinet­office.x.gsi.gov.uk

ii ACKNOWLEDGEMENTS

We would like to thank Damien McElvenny for initiating the project and Gareth Evans for his management role. Andy Darnton from the HSE was responsible for the work on mesothelioma. The contributions to the project and advice received from many other HSE and HSL staff is gratefully acknowledged. Two workshops were held during the project bringing together experts from the UK and around the world. We would like to thank all those who participated and have continued to give advice and comment on the project.

iii iv CONTENTS Acknowledgements iii

1. Incidence and Trends 1

2. Overview of Aetiology 5 2.1. Introduction 5 2.2. Exposures 9

3. Attributable Fraction Estimation 18 3.1. General Considerations 18 3.2. Mineral oils 21 3.3. Aromatic amines 24 3.4. Painters 28 3.5. Rubber industry 29 3.6. Polycyclic aromatic hydrocarbons (PAH) 30 3.7. Diesel engine exhaust 34 3.8. Hairdressers and barbers 38

4. Overall attributable fraction 40 4.1 Comparison of exposure AFs 40 4.2 Exposure Map 40 4.3 Overall AF 42 4.4 Summary of results 43 4.5 Exposures in construction 44 4.6 Higher versus lower level exposures 45

5. References 47

6. Annexes 57 Annex 1 57 Annex 2 59

v vi 1. INCIDENCE AND TRENDS

Bladder cancer (ICD-10 C67; ICD-9 188) refers to any of several types of malignant growths of the urinary bladder. About 90-95% of bladder cancers are transitional cell carcinomas; the remainder are squamous cell carcinomas and adenocarcinomas (Quinn et al., 2001). Seventy-five per cent are superficial, limited to the mucose, sub-mucosa or lamina propria (de Braud et al., 2002); the rest are invasive into the muscle.

Every year in the UK, almost 10,200 people are diagnosed with bladder cancer, causing more than 4,800 deaths each year. In the UK and Ireland, bladder cancer accounted for around 1 in 20 of all cancer registrations and 1 in 30 cancer deaths in the 1990s (Quinn et al., 2005). Bladder cancer is the 5th most commonly diagnosed cancer for all population groups combined (21.0/100,000) (Clapp et al., 2005) and is the 4th commonest cancer affecting men and the 10th commonest cancer affecting women (excluding non melanoma skin cancer)(Cancer Research UK, 2002). In Great Britain, the age-standardised incidence rates rose throughout the 1970s and 1980s to reach a peak in the late 1980s of around 31 per 100,000 males and 9 per 100,000 females. Over the last 2 decades, mortality has shown downward trends in several western European countries (albeit 10-15 years later than similar trends in the US), but is still increasing in some eastern European countries (Pelucchi et al., 2006).

The annual number of deaths for males and females in the UK and its constituent countries, together with the rates for the year 2004 are shown in Table 1. Incidence and mortality rates in women in England and Wales were high by international standards. England had the highest number of deaths, but Scotland had the highest rates (per 100,000 population). Within the UK, geographical patterns in incidence are obscured by known differences among counties and regions of England in the classification and registration of bladder tumours. Mortality in both males and females was higher than average in Scotland and in a band across the north of England and noticeably lower in Northern Ireland and Ireland (Quinn et al., 2005). Occupational exposure to chemicals, predominantly in male workers in the dye and rubber industries, may explain some of the observed geographical patterns (Quinn et al., 2005).

Table 1: Number of deaths and mortality rates of bladder cancer, UK, 2004 England Wales Scotland N.Ireland UK

Number of Deaths Males 2,688 150 275 49 3,162 Females 1,377 84 168 25 1,654 Persons 4,065 234 443 74 4,816 Crude rate per 100,000 population

Males 11.0 10.5 11.3 5.9 10.8 Females 5.4 5.5 6.4 2.9 5.4 Persons 8.1 7.9 8.7 4.3 8.1 Age-standardised rate (European) per 100,000 population

Males 8.5 (8.2,8.8) 7.3 (6.2,8.5) 9.0 (7.9,10.0) 5.6 (4.0,7.2) 8.4 (8.1,8.7) Females 2.9 (2.7,3.0) 2.5 (2.0,3.0) 3.4 (2.9,4.0) 1.8 (1.1,2.5) 2.9 (2.7,3.0) Persons 5.2 (5.0,5..3) 4.4 (3.9,5.0) 5.7 (5.2,6.2) 3.3 (2.6,4.1) 5.1 (5.0,5.3) Source: (Cancer Research UK, 2002)

1 In most European countries, including England and Wales, bladder cancer is at least three times less frequent in women than in men (worldwide ratio is about 3.5:1), which has been seen as an indication for an occupational origin (Lilienfeld and Lilienfeld, 1980; Parkin and Muir, 1992). Whilst female rates have changed little from around 3.3 in the early 1970s to 2.9 in 2004, the male rates have shown a consistent fall since 1992, from 12.2 to 8.4 per 100,000 in the year 2004, a fall of around 30%. The male:female ratio of age-standardised rates has consequently changed, from 4.0:1 in 1975 to 1.9:1 in 2004 (Cancer Research UK, 2002). The higher incidence among men can be attributed, in part, to the differences in smoking habits, with occupational exposures the second most important risk factor in men.

Few cases of bladder cancer occur under the age of 50, but thereafter the rates rise with age to reach a peak in the oldest age groups. When mortality rates are examined by age, the largest falls in mortality have been in the younger (50-59) age group and the all-age rate for women masked substantial changes within different age-groups. Between 1979 and 2000 the mortality rates for 50-59 year old men fell by 53% from 10 to 4.7 per 100,000 and for women of the same age by 44% from 3.6 to 2 per 100,000. Eighty-eight percent of male deaths and 90% of female deaths occur after the age of 65 years (Cancer Research UK, 2002). Socio-economic differences in incidence and mortality rates are not large but show a tendency for slightly higher incidence and mortality in the more deprived populations.

In 2002, approximately 356,600 people worldwide were diagnosed with bladder cancer and it accounted for 3% of all cancer cases. In the same year, bladder cancer was the 12th most common cause of death from cancer accounting for 2% (145,000 people) of all deaths from cancer worldwide (Ferlay et al., 1999).

Internationally, incidence rates of bladder cancer vary almost 10-fold (Parkin and Muir, 1992). In general, the highest incidence is found in developed countries including North America and Europe, with approximately 200,000 new cases worldwide annually (Parkin et al., 1994; Cancer Research UK, 2002). Relatively low rates are found in Eastern Europe and several areas of Asia. Bladder cancer is the fifth most commonly diagnosed cancer in the EU, preceded by bowel, female breast, lung and prostate cancer (Cancer Research UK, 2002). Some of the geographic variation may be the result of ordering practices regarding the registration of “benign” tumours or “papillomas” as cancer.

Southern Europe is a high-risk area, with Italy exhibiting one of the highest incidences in the world (Ferlay et al., 2001). Applying IARC data to population projections, Bray and co-workers (Bray et al., 2002) derived the best estimates of the burden of cancer, in terms of incidence and mortality for Europe in 2004. They reported the results for three areas: the 25 Member States of the European Union (EU); the European Economic Area (EEA) (the 25 European Union countries plus Iceland, Liechtenstein and Norway) plus Switzerland; and Europe1. Their results for bladder cancer are summarised in Table 2. They were unable to estimate figures with adequate precision for Europe due to coding classification used in some countries. In the EU, bladder cancer was the fourth most common cancer, with 91,000 (8.2%) new cases. However, due to differences in coding practices between European countries, the rubric ‘bladder cancer’ includes non-invasive tumours.

Table 2: Estimated number of incident cases and deaths for bladder cancer in 2004 (thousands) and cumulative risk (aged 0 – 74 years) (percent) EEA European Union Incident Cases Risk Incident Cases Risk Men 93.2 2.81 91.0 2.82 Women 25.8 0.52 25.1 0.52

2 Deaths Risk Deaths Risk Men 27.5 0.60 26.9 0.61 Women 9.9 0.12 9.6 0.12

1 European Economic Area plus Bulgaria, Belarus, Moldova, Romania, Russian Federation, Ukraine, Albania, Bosnia and Herzegovina, Macedonia, Serbia, Montenegro and Switzerland.

Cancer survival depends on the prognostic factors, such as depth of tumour penetration, whether it is superficial or other factors such as multiple tumour foci, grade and tumour type. Patients with superficial tumours have an excellent prognosis with 5-year survival rates between 80-90%. Patients with muscle- invasive bladder cancer have 5-year survival rates of less than 50%. Population-based bladder cancer survival rates have risen from just over 40% in the early 1970s to between 58-67% in the late 1990s (Cancer Research UK, 2002; Coleman et al., 2004). Although the survival rate is high, two-thirds of patients develop tumour recurrence within 5 years, sometimes even with higher levels of malignancy and aggressiveness (Hung et al., 2004).

Bladder cancer is one of the few cancers in which men have a substantial survival advantage over women. Relative 5-year survival is 90% for men diagnosed when aged under 40, and just under 80% for women of the same age. Survival then falls with age and is below 50% for men aged 80 or over at diagnosis and less than 40% for elderly women (Quinn et al., 2001). Some bladder tumours – transitional cell papillomas – are recorded as malignant by some cancer registries and as non-malignant by others in England. Survival rates for transitional cell papillomas are very high, so where cancer registries define these as malignant, this results in an apparently higher overall survival rate for bladder cancer (ONS, 2004). International comparisons of survival are especially difficult because of different registration practice with regard to papillomas.

Bladder cancer is generally described as a malignancy with a very long latency (Matanoski and Elliott, 1981), an observation that probably arises from the fact that bladder cancer is a disease of the elderly with the diagnosis being made in people in their sixties or seventies. In occupational studies the latency period from first exposure to detection of the cancer is variable, mean or median values ranging from 15 to 40 years (Cohen et al., 2000), and a large range, up to 50 years (Matsumoto et al., 2005). This is important because the risk of bladder cancer due to smoking shows decreasing risks if the person has stopped smoking and declines with longer time since smoking cessation (Dresler et al., 2006). Interestingly, an increased bladder cancer risk due to aromatic amines is also seen when the occupational exposure ended decades previously (Golka et al., 2004).

It is hypothesized that the genetic polymorphisms involved in the metabolism of PAHs and aromatic amines can determine the individual susceptibility to bladder cancer in particular following relevant environmental exposures. Results from a hospital based case-control study among men in Northern Italy (Hung et al., 2004) suggested that individual susceptibility to bladder cancer may be modulated by glutathione S-transferase (GST) M1, T1 and NAT2 polymorphisms. They conclude that although the effect observed is moderate, these genetic variations could be responsible for a substantial proportion of bladder cancer cases due to their high prevalence. In addition, the results from Gago-Dominguez and co- workers study (2001) showed an over-representation of slow NAT2 acetylators among diseased female users. This genetic trait is a well-known additional risk factor for bladder cancer if exposure to aromatic amines has occurred (Golka et al., 2002; Vineis and Pirastu, 1997).

Table 3 shows UK registration of newly diagnosed cases of bladder cancer from 1994 to 2004 and Table 4 summarises the mortality trends in the UK for bladder cancer between 1998 and 2004. Overall numbers

3 have remained steady in recent years for both incidence and mortality. However, bladder cancer rates dropped between 2002 and 2003 from 100 to 87 for incidence and from 54 to 30 for mortality.

Table 2: Bladder cancer registration trends (>18 years) in England

Males Females Year Total Cancer % Total Rate Total Cancer % Rate Registrations Registrations /100000 Registrations Total /100000 1994 112145 8513 7.6 33.3 112175 3285 2.9 12.4 1995 103986 8019 7.7 33.2 105151 3188 3.0 12.8 1996 104103 7626 7.3 31.0 105461 2984 2.8 11.2 1997 104335 7291 7.0 30.0 107289 3093 2.9 12.0 1998 106745 7528 7.1 30.8 109957 2998 2.7 11.6 1999 108827 7451 6.8 30.0 112237 3070 2.7 12.2 2000 111543 6584 5.9 27.4 112066 2634 2.4 10.5 2001 112516 6314 5.6 26.2 112134 2515 2.2 10.0 2002 112579 5724 5.1 23.6 112210 2296 2.0 9.1 2003 112732 5883 5.2 23.7 114740 2390 2.1 9.4

Average 108951 7093 6.5 28.9 110342 2845 2.6 11.1 Source: (ONS)

Table 3: Bladder cancer (C67 and 188) mortality trends in England and Wales

Males Females Year Total Bladder % Bladder Total Bladder Cancer % Bladder Deaths (UK) Cancer Total Cancer Deaths (UK) Deaths, UK (N) Total Cancer Deaths, UK Death Rate, Death Rate, (N) UK UK (per (per million) million) 1999 300368 2861 0.95 103 331694 1458 0.44 54 2000 290186 2881 0.99 103 318180 1532 0.48 56 2001 286757 2958 1.03 102 315511 1470 0.47 54 2002 287835 2919 1.01 100 318381 1501 0.47 54 2003 288604 2884 1.00 87 322584 1507 0.47 30 2004 244130 2840 1.16 84 268411 1461 0.54 28 Average 282980 2891 1.02 97 312460 1488 0.48 46

Source: (ONS)

4 2. OVERVIEW OF AETIOLOGY

2.1. Introduction

Bladder cancer has often been reported to be associated with occupational exposures (Schottenfeld and Fraumeni, 2006). As early as the late 19th century, doctors reported unusual incidences in industry (Rehn, 1895). The study of occupational causes gained momentum in the 1950s with the identification of hazards in the British dyestuffs and rubber industries (Case and Hosker, 1954; Case et al., 1954). They were some of the first epidemiologists to apply a retrospective cohort design to investigate the effect of occupational exposure to a possible carcinogen. In their classic study, Case and Hosker reported an exceptionally high incidence in the British rubber industry. Since then, many studies have suggested approximately 40 potentially high-risk occupations (Silverman et al., 2006). Despite this, the relationship of many of these occupations to bladder cancer risk are unclear, with strong evidence of an association reported for only a few occupational groups: aromatic amine manufacturing workers, dyestuffs workers and dye users, painters, leather workers, aluminium workers and truck drivers (Silverman et al., 2006). Findings related to other occupations have tended to be based on small numbers of exposed subjects and have been inconsistent.

Tobacco smoking and occupational exposure to aromatic amines are the two major established environmental risk factors for bladder cancer. Controlling exposure to these factors has been an important contributor to the reduction in mortality, particularly among men (Pelucchi et al., 2006). Substantial epidemiological evidence supports a relationship between bladder cancer and cigarette smoking. Aromatic amines are formed as combustion products and are present in both mainstream and side stream tobacco smoke, and so tobacco smoke is the most common and widespread source of exposure to aromatic amines (Talaska, 2003). It has been suggested that up to 40 per cent of all male and 10 per cent of female cases might be ascribable to this exposure (Cooper and Cartwright, 2005). In the US, cigarette smoking has been estimated to account for about 40% of bladder cancer deaths each year (about 50% of male deaths and 28% of female deaths) (Fellows et al., 2002). IARC have stated that the proportion of bladder cancer cases attributable in most countries with a history of prolonged cigarette use is of the order of 50% in men and 25% in women (IARC, 1986). The relative risks are around 2-4 fold (Ross et al., 1988; Vineis et al., 1995; Cooper and Cartwright, 2005).

Environmental factors, in addition to tobacco smoke, that are suspected of playing an important role in the development of bladder cancer include the presence of arsenic and disinfection by-products in drinking water, fluid intake, dietary factors (coffee and alcohol intake, artificial sweeteners), drugs (analgesics, cyclophosphamide and chlornaphazine), hair dyes and a number of urologic conditions (Silverman et al., 2006).

The Occupational Health Decennial Supplement (Drever, 1995) examined mortality (1979-1980, 1982- 1990) and cancer incidence (1981-1987) in men and women aged 20-74 years in England and Wales. It concluded, for many diseases, differences in mortality between job groups appeared to be determined mainly by non-occupational influences. Occupations that had a high proportional mortality rate (PMR) for bladder cancer generally entailed exposure to known bladder carcinogens (Table 5). Rubber manufacturers have the highest proportional registration rate (PRR) of all job groups in men, and brewery workers for women, followed by rubber manufacturers according to Drever (1995). The PRRs for men and women engaged in rubber manufacture are 226 (58 registrations) and 350 (7 registrations) respectively. The data further suggest that other occupations potentially exposed to chemical compounds, such as aromatic amines (used in the manufacture of dyes, pigments, rubber, etc) may also be at increased risk. The risk for men described as plastic goods makers, which is nearly twice that expected at 187 (19 registrations), is particularly noteworthy.

5 Table 5: Job codes with significantly high PRRs and PMRs for bladder cancer. Men and women aged 20-74 years, England, 1981-87 Job group n PRR 95%CI PMR 95%CI SIC code Description Men 006 Sales managers 168 117 100-137 122 106-140 018 Pharmacists 35 146 102-203 023 Driving instructors 36 161 113-224 054 Postal workers 222 114 100-131 131 116-146 063 Railway station workers 90 126 102-156 085 Rubber manufacturers 58 226 172-293 093 Plastic goods makers 19 187 113-293 097 Printers 115 123 102-148 124 Machine tool operators 735 112 105-121 158 Coach painters 12 198 103-347 166 Masons and stonecutters 23 164 104-247 184 Other motor drivers 112 125 103-151 Women 017 Nurses 138 120 101-142 072 Knitters 14 193 106-324 077 Brewery workers 3 589 122- 1723 085 Rubber manufacturers 7 350 141-723 * p≤0.05, based on at least three registrations. Adjusted for age, social class and region of registration. Adapted from Drever (1995)

IARC have classified a number of agents and occupational circumstances as carcinogenic for the bladder (Tables 6a and 6b).

6 Table 6a: Occupational agents, groups of agents, mixtures, and exposure circumstances classified by the IARC Monographs, Vols 1-96 (IARC, 1972-2007), into Group 1, which have the bladder as the target organ. Agents, Mixture, Circumstance Main industry, Use Evidence of Strength Other carcinogenicity of target in humans* evidence$ organs Group 1: Carcinogenic to Humans Agents, groups of agents Aromatic amine dyes Production: dyestuffs and pigment Sufficient Strong - 4-aminobipheyl manufacture - Benzidine - 2-naphthylamine Coal tars and pitches Production of refined chemicals and Sufficient Suggestive Skin, Lung coal tar products (patent-fuel); coke production; coal gasification; aluminium production; foundries; road paving and construction (roofers and slaters) Polyaromatic hydrocarbons§: Work involving combustion of organic Epidemiological Suggestive Lung, - Benzo[a]pyrene matter; foundries; steel mills; fire- evidence - not Skin fighters; vehicle mechanics available

Mineral oils, untreated and mildly Production; used as lubricant by metal Sufficient Suggestive Skin, Lung, treated workers, machinists, engineers; Nasal sinuses printing industry (ink formulation); used in cosmetics, medicinal and pharmaceutical preparations Exposure circumstances Suspected substance Aluminium production Pitch volatiles; aromatic amines Sufficient Strong Lung Auramine manufacture 2-Naphthylamine; auramine; other Sufficient Strong chemicals Magenta manufacture Magenta; ortho-toluidine; 4,4’- Sufficient Strong methylene bis(2-methylaniline); ortho- nitrotoluene Rubber industry Aromatic amines; solvents Sufficient Strong Stomach, Larynx, Leukaemia, Lung Boot and shoe manufacture and repair Leather dust; benzene and other Sufficient Suggestive Leukaemia, solvents nose, paranasal sinuses Coal gasification Coal tar; coal-tar fumes; PAHs Sufficient Suggestive Skin (including scrotum) Lung Coke production Coal-tar fumes Sufficient Suggestive Skin (including scrotum), Lung, Kidney Painters Sufficient Suggestive Lung, Stomach * Evidence according to the IARC monograph evaluation; $ taken from Siemiatycki et al., (2004)

7 Table 6b: Occupational agents, groups of agents, mixtures, and exposure circumstances classified by the IARC Monographs, Vols 1-96 (IARC, 1972-2007), into Group 2A, which have the bladder as the target organ. Agents, Mixture, Circumstance Main industry, Use Evidence of Strength Other carcinogenicity of target in humans* evidence$ organs Group 2A: Probably Carcinogenic to Humans Agents & groups of agents Polyaromatic hydrocarbons§: Work involving combustion of organic Suggestive Lung, - Dibenz[a,h]anthracene matter; foundries; steel mills; fire- Skin fighters; vehicle mechanics - Cyclopenta[cd]pyrene, - dibenzo[a,l]pyrene Diesel engine exhaust Railroad, professional drivers; dock Limited Suggestive Lung workers; mechanics Intermediates in plastics and rubber manufacturing§ - 4,4’-methylene bis(2-chloroaniline) Production; curing agent for roofing and Inadequate Suggestive wood sealing - Styrene-7,8-oxide Production; styrene glycol production; Inadequate Suggestive perfume preparation; reactive diluent in epoxy resin formulations; as chemical intermediate for cosmetics, surface coating, and agricultural and biological chemicals; used for treatment of fibres and textiles; in fabricated rubber products Aromatic amine dyes - Benzidine-based dyes§ Production; used in textile, paper, Inadequate Suggestive leather, rubber, plastics, printing, paint, and lacquer industries - 4-chloro-ortho-toluidine Dye and pigment manufacture; textile Limited Suggestive industry - Ortho-toluidine Production; manufacture of dyestuffs, Limited Suggestive pigments, optical brightener, pharmaceuticals, and pesticides; rubber vulcanising; clinical laboratory reagent; cleaners and janitors Exposure circumstances Suspected substance Hairdressers and barbers Dyes (aromatic amines, amino-phenols Limited Suggestive Lung, non- with hydrogen peroxide); solvents, Hodgkin propellants; aerosols lymphoma, Ovary Petroleum refining PAHs Limited Suggestive * Evidence for bladder cancer according to the IARC monograph evaluation; $ taken from Siemiatycki et al. (2004); § Grading based on mechanistic evidence

8 2.2. Exposures

Mineral Oils, untreated and mildly treated Mineral oils are complex mixtures of aliphatic hydrocarbons, naphthenics, and aromatics, the relative distribution of which depends on the source of the oil and the method of refinement. End-use products contain a variety of additives, and contamination by other agents generally occurs during use (Tolbert, 1997). There are several occupational environments in which an oil mist is generated and in these situations the opportunities for exposure are great. Such occupations include metalworking, print press operating, and cotton and jute spinning. A number of bladder cancer case-control studies have noted an association with work as a machinist, with studies of workers using metalworking fluids and mineral oils offering strong evidence for an association with bladder cancer (Siemiatycki et al., 1994; Tolbert, 1997; Calvert et al., 1998; Mirer, 2003).

Aromatic Amines Exposure to aromatic amines (arylamines) occurs in different industrial and agricultural activities. Aromatic amines have been used as antioxidants in the production of rubber and in cutting oils, as intermediates in azo dye manufacturing, and as pesticides. They are a common contaminant in several working environments, including the chemical and mechanic industries and aluminium transformation. Arylamine-based dyes are used widely, particularly in the textile industry. Arylamines contaminate the ambient air where smokers are present (Maclure et al., 1989).

Occupational exposures to aromatic amines explain up to 25% of bladder cancers in some areas of Western countries; these estimates might be higher in limited areas of developing countries (Vineis and Pirastu, 1997; Vineis and Simonato, 1991). Aromatic amines including 2-naphthylamine (β- naphthylamine), benzidine, 4-aminobipheyl, chlornaphazine (a derivative of 2-naphthylamine previously used in the treatment of polycythemia), as well as the manufacturing of auramine and magenta dye are well-established causes of bladder cancer, and one of the first carcinogens to be associated with an occupational exposure (IARC, 1987; Vineis and Pirastu, 1997; Siemiatycki et al., 2004; Clapp et al., 2005). Studies of several other aromatic amines including o-toluidine and aniline have demonstrated elevated risks associated with bladder cancer.

However, some of the exposures have ceased (Swerdlow et al., 2001). Exposures to carcinogenic intermediates in the dyestuffs industry decreased from about 1935 and especially after 1945, and the use of 1- and 2-naphthylamine in the rubber industry stopped in 1949. A year later in 1950 the use of 2- naphthylamine was banned (Carcinogenic Substances Regulation) (IARC, 1974), as was the use of benzidine in about 1962. The only plant making α-naphthylamine and one making benzidine in Britain were closed in 1965. Carcinogenic arylamines such as 2-naphthylamine have been banned in other Western countries after 1969 (OSHA, 1973).

A cohort study by Ouellet-Hellstrom and Rench (1996) investigated a plant that produced a variety of chemicals, including arylamines. The study reported that the observed association between bladder cancer cases and exposure to arylamines increased with increasing exposure. Vineis reviewed some other studies that reported considerable increased risk of bladder cancer in workers exposed to 2-naphthylamine, benzidine, and 4-aminobiphenyl, but found some were poorly designed and/or based on very small numbers (Vineis and Pirastu, 1997; Vineis and Simonato, 1991). Kogevinas and co-workers (2003) analysed combined data from 11 case-control studies from six European countries. They concluded that about 5-10% of bladder cancers in European men could be attributed to occupational exposures, including but not specifically aromatic amines, and that the results indicated that improvement in working conditions during the last decades in western Europe have been effective in preventing a significant number of bladder cancer cases caused by exposure to occupational carcinogens, particularly aromatic

9 amines. Other studies have reported considerable increased risks of bladder cancer in workers exposed to 2-naphthylamine, benzidine, and 4-aminobipheyl. Table 7 shows a selection of these studies.

Table 7: Arylamines with clear evidence of carcinogenicity to humans Study Number of observed deaths O/E

2-Naphthylamine Case et al. (1954) 26/29.9 87 Mancuso and El-Attar (1967) 18/60 30 Schulte et al. (1985) 13/333.3 3.9 Rubino et al. (1982) 6/4 150 Benzidine Case et al. (1954) 10/71.4 14 Mancuso and el-Attar (1967) 16/53.3 30 Zavon et al. (1973) 13 - Tsuchiya et al. (1975) 72 -

Rubino et al. (1982) 5/6.0 83 Hayes (1992) 31/124 25 Adapted from Vineis (1994)

Recent evidence suggests o-toluidine is a bladder carcinogen. In their study, Rubino and co-workers (1982) found a 62-fold increase in bladder cancer risk in workers exposed jointly to o-toluidine and 4,4’- methylene bis (2-methylaniline). Stasik (1988) reported a 72-fold increase and a more recent study conducted by the National Institute for Occupational Safety and Health (NIOSH, 1998), found high relative risks. Ward’s cohort study (1991) reported a 6.5-fold excess incidence of bladder cancer in a chemical plant that used o-toluidine. An up-date of the cohort reported more cases of bladder cancer after exposure to o-toluidine. The study concluded that potentially confounding occupational exposures other than o-toluidine were not responsible for the observed excess bladder cancer (Markowitz and Levin, 2004).

Toxicologically, benzidine has been the most important carcinogenic aromatic amine directed towards the human bladder (Golka et al., 2004). It has been produced on a very large scale and used primarily in dye production and to a much lesser extent, as a hardener in the rubber industry. One of the most important industrial facilities in Europe for benzidine production was in Leverkusen, Germany, where 92 of 331 workers ever exposed to benzidine production before 1967 suffered from bladder cancer (Lewalter and Miksche, 1992; Golka et al., 1996). A similar picture was seen in China among a cohort of benzidine- exposed workers (Bi et al., 1992; Ma et al., 2003; You et al., 1990). The high carcinogenic potential of benzidine to the urinary bladder is also fundamental to elevations of bladder cancer risks in workers exposed to benzidine-based dyes and colourants with much lower exposures.

4-Chloro-o-toluidine production is highly carcinogenic and is associated with increased bladder cancer risk (Stasik, 1988). Subsequent studies (Popp et al., 1992) have shown increases in bladder cancer showing increased risks of between 38 and 90 fold.

Listed in Group 2A by IARC are 4,4’-methylene bis(2-chloroaniline), or MOCA, and styrene-7,8-oxide (based on mechanistic evidence). MOCA is probably carcinogenic to humans based on sufficient

10 evidence of carcinogenicity in experimental animals (IARC, 1974, IARC, 1987, IARC, 1993). There is inadequate evidence for the carcinogenicity of 4,4’-methylene bis(2-chloroaniline) in humans (IARC, 1993). In a review, a higher than expected incidence of urinary bladder cancer was reported among workers in a UK facility that manufactured 4,4’-methylene bis(2-chloroaniline). An earlier study of workers manufacturing this compound in the United States, who were followed up for fewer than 16 years, failed to reveal any urinary bladder tumours (IARC, 1987). Occupational exposure to styrene oxide occurs most often to workers in the fabricated rubber products, paints and allied products. Evidence for styrene-7,8-oxide (1,2-epoxyethylbenzene) to be considered a human carcinogen is based on evidence of carcinogenic activity at multiple tissue sites in multiple species of experimental animals (IARC, 1994). However, no adequate human studies of the relationship between exposure to styrene oxide and human cancer have been reported.

Magenta manufacture IARC have classified the manufacture of magenta as Group 1. The responsible carcinogens are not known; however for magenta, an arylamine, the carcinogens are suspected to be ortho-toluidine and 4’,4’- methylene bis (2-methylaniline) (IARC, 1987; Vineis and Pirastu, 1997). Most estimates refer to the developed countries; however the major producers of magenta are India, Mexico and Brazil, where production is increasing.

Aluminium production In some instances, it is known that a cluster of people experience excess risk of bladder cancer, but the causative agent is unknown or at least unproven, for example high risks of bladder cancer among workers in the aluminium industry (IARC, 1987). Epidemiological studies have indicated an increased risk of urinary bladder cancer among workers exposed to coal tar pitch volatiles for long periods in the aluminium industry (Tremblay et al., 1995; Armstrong et al., 1994; Spinelli et al., 1991). PAH exposure in the aluminium industry originates mainly from the evaporation of carbon electrode materials used in the electrolysis process. Anodes and the lining materials usually are made from coal tar pitch and coke, with PAH exposure particularly high (typical benzo[a]pyrene levels in the range of 1-10 mg/m3) (IARC, 1984). Large epidemiological studies of aluminium workers have been conducted in Canada, Norway, France and the United States. Norwegian studies have found a positive association between exposure to PAHs and bladder cancer when the cumulative exposure index was restricted to exposure received thirty or more years before observation (Romundstad et al., 2000). A case-control study nested in a large Canadian cohort (Tremblay et al., 1995) found an association between bladder cancer risk with increased exposure to coal tar pitch volatiles, measured either as benzene soluble matter or as benzo[a]pyrene, the latter being a better predictor of risk in a linear model with 10 years of lag. Bladder cancer risk increased by 1.7 percent for each year of exposure to benzo[a]pyrene at a concentration of 1µg/m3.

Auramine manufacture Auramine is a diarylmethane dye used as a fluorescent stain. It is an arylamine and its manufacture has been classified by IARC as Group 1, although the single responsible carcinogen is not known. IARC mentions one epidemiological study, which indicates that the open manufacture of auramine presents an occupational bladder cancer risk (IARC, 1972). The presence of aromatic amines with different degrees of evidence of carcinogenicity is documented in some cosmetic products, such as auramine (2B) in brilliantines, CI Disperse Blue 1 (2B) and HC Blue No. 1 in semi-permanent hair dyes used in the past (Vineis and Pirastu, 1997).

Boot and shoe manufacture and repair There are several studies which suggest that excess risks of urothelial cancer are associated with textile and leather work (IARC, 1990; IARC, 1981; IARC, 1987; Marret et al., 1986). The relevant exposures

11 have not been identified confidently, but exposure to dyes (including some benzidine-based dyes) is a likely explanation (Sorahan et al., 1998). Studies have revealed that inert azo dyes can be cleaved to their toxicologically relevant amino components, which had been used to synthesise the respective azo dye. Several professions in which azo dyes based on carcinogenic aromatic amines had been used have revealed increased bladder cancer risks in different studies (Golka et al., 2004). Among these, due to intensive dermal contact and inhalation exposure, have been dyers in the textile and leather industries (Frumin et al., 1990). IARC (1981) report that in England and Wales, SMRs for ‘leather workers’ in 1961 and for ‘leather’ in 1971 were 122 (based on 8 cases) and 151, respectively. An association between work in the leather industry and bladder cancer is supported by three US case-control studies, with relative risks in the order of 2-6 (IARC, 1981). However, there were weaknesses in all these studies. In Costantini’s and co-workers cancer mortality study in Italy of male tannery workers (1989), they reported an SMR of 150 (95% CI 48-349) for bladder cancer.

Coal gasification Town gas and industrial gases derived from the destructive distillation of coal are produced in thousands of plants throughout the world. Substantial exposures to airborne polynuclear aromatic compounds have been measured in retort houses (a place where gas is manufactured by heating coal in the absence of air) (IARC, 1984). PAHs from coal tar are the most plausible explanation for the increased risk of bladder cancer among coal gasification workers (Boffetta et al., 1997), in particular, those employed in coal distillation and purification using old types of gasifiers such as horizontal, vertical and continuous vertical retorts. In Doll’s studies (Doll, 1952; Doll et al., 1965) that looked at eight gas boards in the UK, a twofold increased risk of bladder cancer was reported among workers employed in coal carbonisation, while no such excess was reported among other groups of workers.

Coke production Coke is a solid carbonaceous residue derived from low-ash, low-sulphur bituminous coal. The volatile constituents of the coal (including water, coal-gas and coal-tar) are driven off by baking in an airless oven at temperatures as high as 1,000 degrees. Coke is used as a fuel.

Coke oven workers are exposed to extremely high concentrations of combustion products. Doll and co- workers (1972) reported an elevated bladder cancer mortality for coke oven workers in a prospective study, that was significantly higher than the national rate (p=0.003). For the time period of 1961-1965, the death rate from bladder cancer was described as 2.5 times higher than the national incidence (Golka et al., 2004).

Substantial airborne exposure to PAHs has been measured in various occupations in coke production (IARC, 1984). Exposure to PAHs is highest in coke oven operations, in particular at the top of the oven. The most important epidemiological study to date on coke oven workers has been conducted since the 1960s in the US and Canada (Lloyd et al., 1970; Costantino et al., 1995). In Boffetta’s review (1997), no evidence of an increased risk of bladder cancer was present in any study.

Polycyclic aromatic hydrocarbons and petroleum refining PAHs are formed by the incomplete combustion of carbon-containing fuels such as wood, coal, diesel, fat, or tobacco. Workers are exposed by inhalation, ingestion and skin contact, the main route of exposure being inhalation. PAHs are produced in a number of occupational settings including coal gasification, coke production, coal-tar distillation, chimney sweeping (soots), coal tar and pitches, creosotes, and others (IARC, 1984; IARC, 1984; IARC, 1984; IARC, 1985), most of which have been classified by IARC as Group 1 carcinogenic situations (creosote is Group 2A) (IARC, In preparation). Because PAHs are common in many occupational exposures, including soot and tar, untreated and mildly treated mineral

12 oils, coke or iron steel foundries, findings of an association should be considered to be indirect evidence of the carcinogenic effects of PAHs (Mastrangelo et al., 1996; IARC, 1987).

Occupations in which PAH exposure is associated with an excess bladder cancer risk include painters, machinists, aluminium processing, other metal workers, workers in the textile industry, leather workers and shoemakers, printers, hairdressers and transport workers (Kogevinas et al., 2003). A number of epidemiological studies have documented an increased risk of bladder cancer among workers exposed to petrochemicals and combustion products in different industries suggesting an association with PAHs, their nitro-derivatives as well as diesel exhausts (Siemiatycki et al., 2004; Pirastu et al., 1996). An increase of bladder cancer risk, although inconsistent, is also found among industries with high exposure to PAHs from coal tars and pitches (Boffetta et al., 1997; Clapp et al., 2005). In their meta-analysis, Kogevinas and co-workers (Kogevinas et al., 2003) reported an increased risk for exposure to PAHs (OR for highest exposure tertile = 1.23, 95% CI = 1.07-1.4). The risk attributable to occupation ranged from 4.2 to 7.4%, with an estimated 4.3% for exposure to PAHs. In their review, Mastrangelo and co-workers (1996, 2002) reported that after 40 years of exposure to benzene soluble matter (which indicated PAH exposure), there was a relative risk of 2.2 for bladder cancer.

Approximately 3000 million tonnes of petroleum fuels, solvents, lubricants, bitumen and other products are produced annually from crude oil. Process operators and maintenance workers may be exposed to a large number of substances, which occur in crude oil, process streams, intermediates, catalysts, additives and final products (IARC, 1998). A large number of epidemiological studies of workers in the petroleum industry have been conducted to address the issue of carcinogenicity of petroleum chemicals. Because exposure to petroleum chemicals has been steadily reduced over the years, historical exposures were much higher (e.g. before 1950) when compared to current exposures. In their review of cancer epidemiology in the petroleum industry, Wong and Raabe (2000) concluded that there was no increased mortality from bladder cancer, as all summary standardized mortality ratios were below unity.

Diesel engine exhaust Diesel engine exhaust comprises a particulate and gaseous phase, the former being important for a possible carcinogenic effect. Exposure to diesel engine emissions occurs in many occupational settings, and it is often difficult to separate this agent from other combustion fumes, notably gasoline engine emissions. Levels of PAHs are highest in emissions from heavy-duty diesel engines and lower (and comparable) in emissions from light-duty diesel engines and gasoline engines without catalytic converters (Boffetta et al., 1997). Professional drivers, mechanics, and other professions are exposed to elevated levels of emissions from combustion engines. An effect of diesel engine exhaust on bladder cancer is plausible because metabolites of PAH present in diesel exhaust are concentrated in the urine and may interact with the urothelium of the bladder (Silverman et al., 1986).

Drivers are an important group of workers exposed to diesel engine exhaust although results of studies on bus drivers do not consistently show an excess of lung and bladder cancer. Mortality from bladder cancer does not increase in studies of railroad workers and no pattern of excess of bladder cancer risk emerges from cohort studies of workers exposed to diesel engine exhaust (Boffetta et al., 1997). Olsen and Jensen (1987) observed an elevated risk only after exposures for more than 20 years. Golka (2004) surmises that it is doubtful that exposures to combustion exhausts are nowadays a significant risk of human bladder cancer.

Several studies have found an elevated risk of bladder cancer related to diesel engine exhaust, except Boffetta and co-workers (2001). Guo and co-workers (2004) followed a cohort of economically active Finns born between 1906 and 1945. They found a slight elevation of relative risk for bladder cancer at the lowest exposure level of diesel engine exhaust. A case-control study by Colt and co-workers (2004) reported an elevated risk for bladder cancer for male drivers of tractors/trucks, typically fuelled by diesel

13 (OR = 2.4, 95% CI 1.4-4.1), with a significant positive trend in risk with increasing duration of employment (Ptrend = 0.0003). This was higher than among drivers of other types of trucks and there was no increase for taxicab or bus drivers. Soll-Johanning and co-workers (2003) reported no differences in bladder cancer rates in Copenhagen even after 20 years of employment. After introducing a lag period of 10 years, they saw a positive tendency to an increase in cancer risk with increasing time of employment; however, there was no positive trend (RR=1.00, 95% CI 0.98-1.02). Finally, a population based, case- control study in Iowa (Zheng et al., 2002) reported an excess risk of bladder cancer for in the automobile mechanics (OR=1.6, 95% CI 1.0-2.6) industry. However, Boffetta and co-workers (2001) found no increased risk of bladder cancer in either gender from exposure to diesel emissions in a cohort from the Swedish Cancer Environment Register. In their meta-analysis, Boffetta and Silverman (2001) estimated a RR of 1.44 (95% CI 1.18-1.76) for high diesel engine exhaust exposure. Their review suggested that exposure to diesel exhaust may increase the occurrence of bladder cancer but the effects of misclassification, publication bias and confounding could not be fully taken into account.

Intermediates in plastics and rubber manufacturing There is independent support for the hypothesis that working with plastics may present excess risks of bladder cancer (Najem et al., 1982), as the plastics industry covers a wide range of chemical processes. However, if urothelial carcinogens have been or are being used in this industries it does not follow that they will have been used in all parts of the industry (Sorahan et al., 1998).

Zahm and co-workers (1987) conducted a case-control study using data from The National Bladder Cancer Study (U.S.). They found that women who had worked in the plastics industry had a 3.3-fold increased bladder cancer risk. Within the plastics and rubber industries, increased risk for bladder cancer was found for men in mixing, filtering, grinding, and other dusty operations (OR=4.6, 95% CI 0.5-15.3). In the US, NIOSH maintains the National Occupational Mortality Surveillance (NOMS) database of death certificate data with coded occupation and industry information. The results of a PMR analysis of the NOMS data are used to identify industries with high proportions of deaths due to selected cancers. The results reported are restricted to cancer causes of death in the US manufacturing industries. The highest proportionate mortality ratio for bladder cancer was in plastics, synthetics and resins industries with a PMR of 1.7 (95% CI 1.0-2.6) for men and was the highest for women (PMR=2.8, 95% CI 1.0-6.0) (Ward et al., 1997).

Occupations Painters The profession of a painter and varnisher was classified as an occupation associated with sufficient evidence of carcinogenicity (IARC, 1989). Thousands of chemicals are used in paint products as pigments, extenders, binders, solvents and additives. Painters are commonly exposed by inhalation to solvents and other volatile paint components; inhalation of less volatile and non-volatile compounds is common during spray painting (IARC, 1989). Titanium dioxide and chromium and iron compounds are used widely as paint pigments. Between 2002 and 2004 the LFS estimates gave an average 24,906 workers employed as vehicle spray painters and 138,212 as painters and decorators 2.

However, paint technology has changed over the last 50 years, as has exposure. Since the introduction of water-based-paints, the inhalation of solvents (i.e. toluene, xylene, ketones, alcohols, esters and glycol ethers) has been reduced. Bladder cancer risk for painters and varnishers is also very dependent on the individual exposure, which is determined by a broad spectrum of working materials and techniques. Due

2 http://www.statistics.gov.uk/StatBase/tsdataset.asp?vlnk=429&More=Y

14 to these differences in past exposure conditions, it is understandable that a number of studies did not show a significant bladder cancer risk for painters (IARC, 1989).

A cohort study of more than 42,000 American painters, based on union records, confirmed that risks of bladder cancer were high compared to the US population (SMR 1.23, 95% CI 1.05-1.43) and also when compared with more than 14,000 organised non-painters (SMR 1.77, 95% CI 1.13-2.77) (Steenland and Palu, 1999). In a meta-analysis of 13 case-control studies, Chen and Seaton (1998), found a standardised mortality ratio of 1.3.

A population based, case-control study in Iowa (Zheng et al., 2002) reported an excess risk of bladder cancer for the painting industry (OR=2.7, 95% CI 1.0-7.7). Another case-control study by Jensen and co- workers (1987) found an association for employment in trades undertaking painting (RR=1.4 for 10 years employment) and a significant trend emerged for duration of employment.

Rubber industry Antioxidants containing 2-naphthylamine were used in the rubber and electric-cable manufacturing industries in Great Britain. Beta-naphthylamine was also used in the British rubber industry up to the end of 1949, when it was withdrawn because it was deemed to have caused an excess of bladder tumours both in product manufacture and use (Veys, 2004a; IARC, 1982). In addition, since the 1970s, further health and safety measures have been widely applied in the rubber industry by substituting some chemical agents and controlling exposure to others (Kromhout et al., 1994).

Some epidemiological studies showed strong evidence that demonstrated workers in the rubber industry had elevated risks for bladder cancer (Siemiatycki et al., 1994; Kogevinas et al., 1998a; Ward et al., 1997; Clapp et al., 2005). Case and Hosker (1954) had forewarned this link between urothelial tract cancer and the UK rubber industry, and Veys (1969) and IARC (1982) reviewed cancer in the rubber industry. However, this excess was observed only among rubber workers employed before 1950. These studies do not give a picture of exposure as it is today.

Recent studies still show excess risk of bladder cancer in workers in the rubber industry with no recorded exposure to 2-naphthylamine (Quinn et al., 2005). Kogevinas (1998a) reviewed papers, published after 1982, on the rubber industry including the British Rubber Manufacturer’s Association (BRMA) study (Sorahan et al., 1986; Sorahan et al., 1989) (34,000 workers), the Health and Safety Executive study (40,000 workers) (Baxter and Werner, 1980), and the Veys studies (14,000 workers) (Veys, 1992; 1995), thus presenting a picture of 80 years of cancer experience in the industry, which is not the same as the situation that exists today (Straughan, 1998).

Other studies have reported that occupational bladder cancer in (former) rubber workers is still an issue (Golka et al., 2004). In 1993, Bolm-Audorff and co-workers (1993) reported on elevated bladder cancer risks, adjusted for smoking, for “rubber manufacturing and curing”. These results were subsequently confirmed by Straif et al., (1998), who studied more than 11,000 workers in the rubber industry; elevated SMRs for bladder cancer were observed for “storage and shipment” (SMR 253, 95% CI 93-551) and for “general work” in this industry (SMR 159, 95% CI 92-279). In addition, a population based, case-control study in Iowa (Zheng et al., 2002) reported an excess risk of bladder cancer for the rubber and plastics industry (OR=3.1, 95% CI 1.2-8.5).

Hairdressers and barbers Elevated risk of bladder cancer has been observed among occupations exposed to hair dyes (La Vecchia and Tavani, 1995). Since the early twentieth century, hairdressers have made use of a wide range of products, including hair colourants and bleaches, shampoos and conditioners. Several thousand chemicals

15 are found in formulations of these products. Hair colourants are classified as permanent (primarily aromatic amines and aminophenols with hydrogen peroxide), semi-permanent (nitro-substituted aromatic amines, aminophenols, aminoanthraquinones and azo dyes), and temporary (high-molecular-weight or insoluble complexes and metal salts, such as lead acetate). The numerous individual chemicals used in hair colourants have varied over time. Only permanent and semi-permanent hair colourants are used to a significant extent by hairdressers (IARC, 1993).

In 1993, IARC categorised the profession of hairdressers in group 2A (IARC, 1993) despite debates of the risk of bladder cancer due to exposure to hair dyes. There is however, also evidence of occupational exposure to permanent hair dyes and bladder cancer. In a large population-based case-control study (Gago-Dominguez et al., 2001), it was claimed that subjects applying permanent hair dyes at least once a month had an increased risk of bladder cancer, which increased for those who had been applying permanent hair dyes at least once a month for 15 years. However, most estimates are based on occupational exposures from decades ago, when the controls of carcinogenic substances in hair dyes and the working processes were less strict. La Vechia and Tavani (2001) reviewed the evidence and concluded that the estimated relative risks, as well as the overall pooled estimates, are only moderately above unity, and hence compatible with potential errors and biases, such as not controlling for smoking.

A follow-up study of a cohort of male hairdressers from Sweden found that male hairdressers working in 1960 had an increased risk for urinary bladder cancer, which was highest in the 1960s with a standardized incidence ratio of 2.56 (95% C.I. 1.36-4.39) (Czene et al., 2003). It also found that bladder cancer did not increase among hairdressers in recent decades and, therefore, modern hair dyes are unlikely to be associated. In a Danish cohort, hairdressers had a relative risk of 2.05 (men) and RR=1.75 (women) in 1970-1980 and RR = 1.17 (men) and RR = 0.88 (women) in 1981 – 1987 (Skov and Lynge, 1994). A statistically significant increase risk for bladder cancer was found among male hairdressers in Norway and Sweden using collaborative data from Sweden, Norway and Finland (Skov et al., 1990).

Dyestuffs workers and dye users An association between the manufacture of aniline-based dyes and bladder cancer was first reported in the late 1800s by Rehn (1895). However, not until the 1950s did epidemiological studies of dye manufacturing workers confirm that benzidine was at least one of the causal agents (Zavon et al., 1973; Wendel et al., 1974; Piolatto et al., 1991; Bi et al., 1992; Bulbulyan et al., 1995; Naito and Kumazawa, 1989; Tsuchiya et al., 1975). IARC classified benzidine as a human carcinogen in 1982 (IARC, 1982). An early study of dyestuffs workers in England and Wales found a 10- to 50- fold increased risk of death from bladder cancer due to exposure to two aromatic amines, 2-naphthylamine and benzidine (Case et al., 1954). The majority of workers in some cohorts have been reported to develop bladder cancer (Zavon et al., 1973; Decarli et al., 1985; Delzell et al., 1989; Piolatto et al., 1991).

In their cohort of workers potentially exposed to benzidine from a single chemical manufacturing facility, Rosenman and Reilly (2004) confirmed a high risk of bladder cancer among benzidine exposed workers even years after exposure had ceased. This association with benzidine dyes and bladder cancer has been reported elsewhere. Zavon and co-workers (1973) reported that more than 50% of the benzidine dye workers in a plant in Cincinnati, Ohio, developed urinary bladder cancer during their employment. Bi and co-workers (1992) also report similar exposures, and disease rates remain relatively common in China, where benzidine and perhaps other aromatic amines are used with impunity.

The increased risk among dyestuffs workers also has been observed in case-control studies (la Vecchia et al., 1990; Najem et al., 1982; Vineis and Magnani, 1985; Morrison et al., 1985; Risch et al., 1988; Boyko et al., 1985) with relative risks ranging from 1.7 to 8.8. Data from the UK indicate that bladder cancer risk among dyestuffs workers has been reduced since the introduction of protective measures and the

16 subsequent banning of the industrial use of 2-naphthylamine and benzidine in 1950 and 1962 respectively (Schottenfeld and Fraumeni, 2006).

17 3. ATTRIBUTABLE FRACTION ESTIMATION

3.1. General Considerations

Substances and Occupations The substances considered in the estimation of the attributable fraction (AF) for bladder cancer are those outlined in Table 8. PAHs and aromatic amines have been considered the primary exposure. For PAH these are found in aluminium production, coal gasification, coke production and exposure to coal tar pitches, coal tars and soots, and aromatic amines are in dyes, auramine manufacture, and magenta manufacture.

With the exception of PAHs, diesel engine exhaust and aromatic amines still in use after 1962, the exposure scenarios relevant to bladder cancer have been defined by industry or occupation within each exposure, to avoid double counting of numbers of workers exposed. Diesel engine exhaust exposure for drivers has also been excluded from the estimates for PAHs for this reason.

Table 8: Substances considered in the estimation of the attributable fraction for bladder cancer. Agents, Mixture, Circumstance AF Comments Strength of Established calculation evidence $ or uncertain carcinogen

Group 1: Carcinogenic to Humans Agents, groups of agents Coal tars and pitches N Included with PAHs Suggestive

Mineral oils, untreated and mildly Y Suggestive U treated Aromatic amine dyes Y Strong E - 4-aminobipheyl - Benzidine - 2-naphthylamine Polyaromatic hydrocarbons: Y E - Benzo[a]pyrene Exposure circumstances Aluminium production N Included with PAHs Strong

Auramine manufacture N Included in aromatic amine Strong

Boot and shoe manufacture and N Exposure up to 1962 included with Suggestive repair aromatic amines

Coal gasification N Included with PAHs Strong

Coke production N Included with PAHs Suggestive

Magenta manufacture N Included in aromatic amine Strong

Painters Y Suggestive U

18 Agents, Mixture, Circumstance AF Comments Strength of Established calculation evidence$ or uncertain carcinogen

Group 1: Carcinogenic to Humans Rubber industry N Risk confined to pre 1950 in UK Strong

Agents, Mixture, Circumstance AF Comments Strength of Established calculation evidence $ or uncertain carcinogen Group 2A: Probably Carcinogenic to Humans Agents & groups of agents Polyaromatic hydrocarbons: Y Included with PAHs – benzo[a]pyrene Suggestive - Dibenz[a,h]anthracene above - Cyclopenta[cd]pyrene, - Dibenzo[a,l]pyrene Diesel engine exhaust Y Suggestive U Intermediates in plastics and N No human evidence Suggestive rubber manufacturing - 4,4’-methylene bis(2- chloroaniline) - Styrene-7,8-oxide Aromatic amine dyes Y Included in aromatic amine Suggestive - Benzidine-based dyes - 4-chloro-ortho-toluidine - Ortho-toluidine Exposure circumstances Hairdressers and barbers Y Suggestive U Petroleum refining N Included with PAHs Suggestive

$ taken from Siemiatycki et al., (2004)

Established and Uncertain carcinogens ‘Established’ carcinogens for bladder cancer are those recognised by IARC as Group 1 carcinogens and with ‘strong’ evidence of an association with the particular site of interest, as judged by Siemiatycki et al., (2004). ‘Uncertain’ carcinogens for bladder cancer are those recognised by IARC as in Groups 1 or 2A, and judged by Siemiatycki to have ‘suggestive’ evidence of an association with the particular site of interest. Other exposures from sources other than Siemiatycki will normally be included in the ‘uncertain’ group, unless there is ‘strong’ evidence to the contrary, probably founded in UK experience. None have been identified for bladder cancer.

Only the aromatic amine dyes, and the recently upgraded PAHs, may for the overall AF estimation be considered in the ‘established’ group of occupational carcinogens. Mineral oils and diesel engine exhaust, and occupation as a painter, hairdresser or barber are considered in the ‘uncertain’ group.

19 Latency A minimum of 20 years has been assumed an acceptable period for latency (Norpoth and Woitowitz, 1991). Sorahan et al., (2000) note an excess of bladder cancers in those employed in manufacturing chemicals for the rubber industry before 1955, with at least 20 years elapsed from first exposure. Veys (2004b) noted a mean latency of 32.4 years and range of 4 – 55 years for bladder cancer, with only 4 found with <10 years latency, and 5 over 50 years. This was in a cohort exposed to the recognised carcinogen beta-naphthylamine in the rubber industry prior to its banning in 1949.

Relevant Exposure Period (REP) Based on the above observations on latency, the standard solid tumour REP of 1955 to 1994, for a target year of 2004 (2003 for registrations) is used, with the highest number of bladder cancers leading to current deaths or registrations likely to relate to exposures in the early 1970s.

Calculation of AF The two data elements required are an estimate of relative risk (RR), and either (1) an estimate of the proportion of the population exposed (Pr(E)) from independent data for Great Britain, or (2) an estimate of the proportion of cases exposed (Pr(E|D)) (and to assess portability an estimate of Pr(E) from the proportion of controls exposed) from population based study data. In the case of the bladder cancer AF estimates independent data (1) has been used throughout.

The RR chosen from a ‘best study’ source is described for each exposure, with justification of its suitability.

In the absence of more precise knowledge of cancer latency, it is assumed that exposure at any time between 1955 and 1994 can result in a cancer being recorded in 2004 as a registration or underlying cause of death. For an independent estimate of the proportion of the population exposed, numbers of workers ever exposed during this period are counted using a point estimate of exposed workers taken from the period. If this is from CAREX relating to 1990-93, an adjustment is made to take account of gross changes in employment levels which have occurred particularly in manufacturing industry and the service sector across the REP. Otherwise a point estimate that represents numbers employed as close as possible to about 35 years before the target year of 2004 is used, as this is thought to represent a ‘peak’ latency for the solid tumours, and is also close to the mid-point of the REP for estimating numbers ever exposed across the period (for which a linear change in employment levels is implicitly assumed). Where the Census of Employment is used, the data are for 1971. Where the LFS is used, the first year available and therefore used is 1979. A turnover factor is applied to estimate numbers ever exposed during the REP, determined mainly by the estimate of staff turnover per year during the period. For each exposure therefore, if an AF has been based on independent estimates of numbers exposed, the table of results includes the point estimate of numbers employed, the adjustment factor for CAREX if applicable, the staff turnover estimate, and the resulting estimate of numbers ever exposed during the REP. Other estimates used in the calculations that remain constant across exposures (unless otherwise stated) are given below:

(1) Number of years in REP = 40 (2) Proportion in the workplace ever exposed is set to one, i.e. all are assumed to be exposed, in the absence of more detailed information. Where sources other than CAREX are used for the point estimate of numbers exposed, such as the LFS or Census of Employment, a precise as possible definition of workers exposed is sought. (3) Numbers ever of working age during the target REP = 19.2 million men, 20.9 million women. This is the denominator for the proportion of the population exposed, and is based on population estimates by age cohort in the target year. (4) Total deaths from bladder cancer, GB, 2004 = 3,113 for men, 1,629 for women

20 (5) Total registrations for bladder cancer, GB, 2003 = 7,022 for men, 2,891 for women. 2003 is the most recent year for which data is available.

For each agent where data on worker numbers are only available for men and women combined (CAREX data), the assumed percentage of men is given in addition to the numbers exposed. The allocation to high and low, and occasionally negligible, exposure level categories, or division into separate exposure scenarios, is also usually included in these tables.

Full details of the derivation of the above factors and the methods of calculating AF are published separately. Unless otherwise stated, Levin’s formula is used for independent estimates of numbers exposed, and Miettinen’s formula is used for study-based estimates.

3.2. Mineral oils

(a) Risk estimate: Tolbert (1997) reviews the relationship between mineral oil and cancer, covering metal machining, print press operating, and cotton and jute spinning. He notes a number of case-control studies that show a positive association between bladder cancer and work as a machinist.

NIOSH conclude in their review (NIOSH, 1998) that the association between bladder cancer and metalworking fluids exposure is well supported by one large and well designed case-control study (Silverman et al., 1989a; Silverman et al., 1989b) as well as several other studies conducted in different geographical locations, all of which controlled for smoking. Although none of the cohort studies found a significantly increased risk for bladder cancer, it has been observed that mortality studies may not be suitable for detecting elevated risks for cancers with high survival rates (Schulte et al., 1985; Steenland et al., 1998).

An overall RR for bladder cancer from exposure to mineral oils, taken as a weighted average across the case-control and population based studies (from Tolbert’s review which will reflect incidence as well as mortality due to bladder plus other urinary organ cancers (Annex 1)), is 1.39 (1.20-1.61). This assumes a random effects model due to significant heterogeneity across study results (using the test for heterogeneity Q = 98.24, p < 0.0001). An RR of 1 was assumed for jobs considered to have low or no exposure to MWF.

A recent case-control study of bladder cancer cases in Spain did not support an increased risk in the textile industry (Serra et al., 2000). A meta-analysis of epidemiological studies for industry workers published after 1990 indicated that after inclusion of more recent studies, the PRR for bladder cancer remained significant only in dyers (Mastrangelo et al., 2002). IARC have concluded there is limited evidence that working in the textile manufacturing industry entails a carcinogenic risk, the evaluation being based mainly on findings among dyers (IARC, 1990).

(b) Numbers exposed: NIOSH list the following industries as having the largest number of exposed workers in the US, with their SIC codes: 35 Machinery, (except electrical), 34 Fabricated metal products, 37 Transportation equipment. The numbers of machinists exposed to mineral oils (metal working fluids) in Great Britain are shown in Table 9. ‘Low’ (L) and ‘low or background’ (B) exposure levels are indicated as such. Exposure level (H) indicates jobs with known exposure to soluble MWF in large droplet form. Printers are thought not normally to be exposed to mineral oils, and as noted above, any risk for textile workers is limited to dyers exposed to aromatic amines, covered under that exposure.

21 Table 9: Numbers of workers exposed to mineral oils according to LFS 1979 SIC code Description Male Female Total Exposure Level LFS 1979 111.1 Foremen of press and machine tool setters 2,164 - 2,164 H 111.2 Foremen of other centre lathe turners 736 - 736 H 111.3 Foremen of machine tool setter operators 581 - 581 H 111.4 Foremen of machine tool operators 8,947 252 9,199 H 111.5 Foremen of press stamping and automatic machine operators 1,498 - 1,498 H 111.6 Foremen of metal polishers 265 - 265 B 111.7 Foremen of fettlers dressers - - - B 111.8 Foremen of shot blasters - - - B 112.1 Press and machine tool setters 64,157 740 64,897 H 112.2 Other centre lathe turners 49,774 - 49,774 H 112.3 Machine tool setter operators 10,818 232 11,050 H 112.4 Machine tool operators 335,097 50,424 385,521 H 113.1 Press stamping and automatic machine operators 34,002 18,281 52,283 H 113.2 Metal polishers 11,112 1,425 12,537 B 113.3 Fettlers dressers 12,391 1,619 14,010 B 114.1 Foremen of toolmakers tool fitters markers-out 4,319 - 4,319 H 114.2 Foremen of precision instrument makers and repairers 969 - 969 L 114.3 Foremen of watch and chronometer makers and repairers - - - L 114.4 Foremen of metal working production fitters and 27,544 - 27,544 H fitter/achinists 114.5 Foremen of motor mechanics auto engineers 13,825 - 13,825 - 114.6 Foremen of maintenance fitters (aircraft engines) 522 - 522 - 114.7 Foremen of office machinery mechanics - - - - 115.0 Toolmakers tool fitters markers-out 92,886 510 93,396 H 116.1 Precision instrument makers and repairers 28,071 1,667 29,738 L 116.2 Watch and chronometer makers and repairers 6,527 225 6,752 L 117.0 Metal working production fitters and fitter/machinists 546,544 6,933 553,477 H 118.1 Motor mechanics auto engineers 269,925 1,271 271,196 - 118.2 Maintenance fitters (aircraft engines) 3,957 - 3,957 - 119.0 Office machinery mechanics 11,506 - 11,506 - 131.8 Shot lasters 6,049 - 6,049 B 160.5 Labourers and other unskilled workers in foundries in 15,469 567 16,036 H engineering 160.6 Labourers and other unskilled workers in engineering and 21,276 259 21,535 H allied trades TOTAL 1,580,931 84, 405 1,665,336

(c) AF calculation: The estimated AF was 7.8% (4% - 12%) for men and 0.8% (0.4% - 1.3%) for women, resulting in 548 and 23 registrations for bladder cancer respectively (against 2003 totals) and 243 and 13 occupationally attributable deaths in 2004 (see Table 10)

.

22 Table 10: Attributable fraction for mineral oils (Talbert, 1979) Occupational exposure Mineral oils

'Best study' for RR Reference Tolbert (1979) estimate Type of study Review Sex Male Female Exposure level Higher Lower & Total Higher Lower & Total Background Background exposure exposure Independent data: Industry Sectors C-E Metal machinists only C-E Metal machinists only LFS 1979 numbers exposed 1,215,812 65,384 1,281,196 78,198 4,936 83,134 Annual employment turnover 0.09 0.09 0.14 0.14 Numbers exposed in the REP (1955- 1994) 4,200,677 225,904 4,426,581 438,568 27,683 466,252 Proportion of the population exposed 0.22 0.01 0.23 0.021 0.001 0.026 Proportion of cases exposed Relative risks 1.39 1.00 1.39 1.00 Attributable fraction 0.078 0.000 0.078 0.008 0.000 0.008 ‘Random error’ 95% confidence interval [0.04 - 0.12] [0.04 - 0.12] [0.004 - 0.013] [0.004 - 0.013] Attributable deaths 243 0 243 13 0 13 Attributable registrations 548 0 548 23 0 23

Industry sectors: A-B = Agriculture, hunting and forestry, fishing C-E = Mining and quarrying, electricity, gas and water, manufacturing industry F = Construction G-Q = Service industries

23 3.3. Aromatic amines

(a) Risk estimate: There are several studies which suggest that excess risks of urothelial cancer are associated with textile and leatherwork. Their relevant exposures have not been identified confidently, but exposure to dyes (including some benzidine-based dyes) is a likely explanation. Sorahan and co-workers (1998) investigated the role of occupational exposures in the risk of developing urothelial cancer, in a hospital based case-control study in the West Midlands. Smoking-adjusted RRs of >2.0 were obtained for seven occupations, including manufacture of dyestuffs (D, 2.61, 0.98-7.00), leather work (L, 2.51, 1.44- 4.35), cable manufacturing industry (C, 2.46, 1.20-5.04), and textile printing and dyeing (T, 2.32, 0.98- 5.45). Sorahan’s RR estimates for the manufacture of rubber products (R, 1.89, 1.34-2.66), plastics (P, 1.73, 1.17-2.55) and organic chemicals (O, 1.70, 1.05-2.76) are used for industrial exposure to MOCA.

Sorahan et al (1998) also give an estimate of RR for medical and nursing occupations (MN in table 13 below, 1.62, 1.03-2.55) and laboratory technicians (LT, 1.05, 0.60-1.86), which will be used for the lower level exposures in the CAREX data below.

(b) Numbers exposed: The numbers exposed to benzidine-based dyes and 2-naphthylamine, benzidine, chloro-ortho-toluidine and MOCA, substances covered by CAREX, are shown in Table 11. The estimated proportion of men to women in the CAREX data for the service industry sectors is taken as that for ‘associate professional and technical occupations’ in the 1991 Census. Table 12 shows the number of people employed in the cable, dyestuffs, textile and leather industries where there is historical exposure to aromatic amines. These occupations were identified by Sorahan and colleagues (1998). Exposure in the rubber industry, painters, hairdressers and barbers are dealt with separately below. For the calculation of AF, CAREX numbers exposed were used for the limited remaining industrial exposures (to MOCA and benzidine based dyes), and for laboratory technicians and medical and nursing occupations. Employment estimates from the 1971 Census of Employment were used for the other historical exposures in manufacturing industry. It has been assumed that exposure in manufacturing industry for chemicals not covered in CAREX ceased in 1962, when industrial use of benzidine was banned in the UK (Quinn et al., 2005), so that the number exposed was estimated for 1955-1962 only. 2-naphthylamine was banned in 1949.

Table 11: Numbers of workers exposed to benzidine-based dyes and 2-naphthylamine, benzidine, chloro- ortho-toluidine and MOCA according to CAREX in 1990-1993 Industry CAREX Data 1990-1993

Number Number in % Male RR used Exposed Industry Benzidine-based dyes

Other manufacturing industries 18 59,375 76% D

Research and scientific institutes 1,760 91,100 44% LT

2-Naphthylamine

Education services 244 1,455,875 44% LT

Research and scientific institutes 88 91,100 44% LT Medical, dental, other health and veterinary services 67 1,435,675 44% MN Benzidine Education services 609 1,455,875 44% LT

24 Industry CAREX Data 1990-1993

Number Number in % Male RR used Exposed Industry Research and scientific institutes 352 91,100 44% LT Medical, dental, other health and veterinary services 247 1,435,675 44% MN Para-chloro-ortho-toluidine and its strong acid salts Education services 30 1,455,875 44% LT Research and scientific institutes 22 91,100 44% LT Medical, dental, other health and veterinary services 30 1,435,675 44% MN 4,4'-Methylene bis(2-chloroaniline) (MOCA) Manufacture of industrial chemicals 13 130,000 76% O Manufacture of rubber products 221 53,025 76% R Manufacture of plastic products not elsewhere classified 202 136,900 76% P Research and scientific institutes 88 91,100 44% LT Total 3,991

Table 12: Number of workers employed in jobs exposing them to aromatic amines for 1971 (source: Census of Employment), 1979 and 2003 (source: LFS) SIC Code Description Numbers Men Women Total Exposure level, RR used 1971 362 Insulated wires and cables 34,325 12,132 46,457 C 277 Dyestuffs and pigments 16,576 3,138 19,714 D 893 Dry cleaning, job dyeing etc 7,665 24,295 31,960 D 412-429 Textile industry 276,964 265,804 542,768 423 Textile finishing 35,584 15,317 50,901 T 429 Other textile industries 17,258 6,,365 23,623 T 431 Leather (tanning and dressing) 16,449 4,364 20,813 L Total 127,857 65,611 2002-2004 5243 Line repairers and cable joiners 13,053 0 13,053 31.30 Insulated cable manufacture 12,680 4,398 17,078 24.12 Dye pigment manufacture 3,327 1,949 5,276 17.17 Other textile preparation 450 516 966 17.25 Other textile weaving 2,087 353 2,440 17.30 Textile finishing 6,095 3,834 9,929 17.403 Household textiles manufacture 7,664 5,622 13,286 17.543 Other textiles manufacture 2,170 903 3,073 29.54 Textile etc leather machine manufacturing 3,629 1,829 5,458 93.01 Washing dry cleaning textiles furs 26,404 23,763 50,167 Total 120,726

25 Table 13: Attributable fraction for aromatic amines based on Sorahan et al., (1998)

Occupational Aromatic amines exposure 'Best study' Reference Sorahan et al (1998) for RR estimate Type of study W Midlands hospital-based case-control studies Sex Male Exposure period 1955-1962 1955-1994 Exposure level Dyestuffs Leather Cable Textile Benzidine- MOCA - MOCA - MOCA - Medical Laborator TOTAL work manufact printing based dye industrial rubber plastic and y uring and manufacture chemicals products products nursing technician industry dyeing occupati s ons Independent data: Industry Sectors C-E C-E C-E C-E Total C-E C-E C-E C-E Total G-Q G-Q Total

CoE 1971 numbers exposed 24,241 16,449 34,325 52,842 127,857 CAREX numbers exposed 14 10 168 154 345 151 1,405 1,556 CAREX adjustment factor 1.4 1.4 1.4 1.4 0.9 0.9 Annual employment turnover 0.09 0.09 0.09 0.09 0.09 0.09 0.09 0.09 0.11 0.11

Numbers exposed 1,66 in the REP 17,847 12,110 25,271 38,904 94,133 66 48 812 743 9 569 5,283 5,852 101,654 Proportion of the population 0.00 exposed 0.001 0.001 0.001 0.002 0.005 0.00000 0.00000 0.00004 0.00004 0 0.00003 0.00028 0.0003 0.005

Relative risks 2.61 2.51 2.46 2.32 2.32 1.70 1.89 1.73 1.62 1.05 Attributable 0.00 fraction Levin's 0.001 0.001 0.002 0.003 0.007 0.00000 0.00000 0.00004 0.00003 0 0.00002 0.00001 0.00003 0.007 ‘Random error’ [0.00001 [0.00000 95% confidence [0.000 - [0.000 - [0.000 - [0.000 - [0.00000 - [0.00000 - - [0.00001 - - [-0.0001 - interval 0.006] 0.002] 0.005] 0.009] 0.00002] 0.00000] 0.00007] 0.00006] 0.00005] 0.0002] Attributable deaths 5 3 6 8 22 0 0 0 0 0 0 0 0 22

Attributable registrations 10 7 13 19 49 0 0 0 0 1 0 0 0 50

26 Occupational exposure Aromatic amines

'Best study' Reference Sorahan et al (1998) for RR Estimate Type of study W Midlands hospital-based case-control studies

Sex Female

Exposure period 1955-1962 1955-1994

Exposure level Dyestuff Leathe Cable Textile Benzidine- MOCA - MOCA - MOCA - Medical Laboratory TOTA s r work manufac printing based dye industrial rubber plastic and technicians L turing and manufacture chemicals products products nursing industry dyeing occupation s Independent data: Industry Sectors C-E C-E C-E C-E Total C-E C-E C-E C-E Total G-Q G-Q Total CoE 1971 numbers exposed 27,433 4,364 12,132 21,682 65,611 CAREX numbers exposed 4 3 53 48 109 193 1,739 1,931 CAREX adjustment factor 1.5 1.5 1.5 1.5 0.8 0.8 Annual employment turnover 0.14 0.14 0.14 0.14 0.14 0.14 0.14 0.14 0.15 0.15

Numbers exposed in the REP 35,025 5,572 15,490 27,682 83,769 36 26 446 408 917 922 8,326 9,249 93,934 Proportion of the population exposed 0.002 0.000 0.001 0.001 0.004 0.0000017 0.0000013 0.0000213 0.0000195 0.0000439 0.0000 0.0004 0.0004 0.004

Relative risks 2.61 2.51 2.46 2.32 2.32 1.70 1.89 1.73 1.62 1.05 Attributable 0.0000 fraction Levin's 0.003 0.000 0.001 0.002 0.006 0.000002 0.000001 0.000019 0.000014 0.000036 0.000027 0.00002 5 0.006 ‘Random error’ [0.000 [0.000000 [0.000007 [0.000003 95% confidence [0.000 - - [0.000 - [0.000 - [0.000000 - - - - [0.000 - [0.000 - interval 0.010] 0.001] 0.003] 0.006] 0.000008] 0.000002] 0.000035] 0.000030] 0.0001] 0.0003] Attributable deaths 4 1 2 3 10 0 0 0 0 0 0 0 0 10

Attributable registrations 8 1 3 5 17 0 0 0 0 0 0 0 0 17

27 (c) AF calculation: As the use of benzidine ceased in 1962, the relevant exposure period in the cable manufacturing, dyestuffs, textile printing and dyeing and leatherwork industries is taken to be 1955-1962 only; for the other exposures included in the CAREX data the period 1955-1994 was used. The estimated AF was 0.7% for men and 0.6% for women, resulting in 50 and 17 registrations for bladder cancer (against 2003 totals) and 22 and 10 occupationally attributable deaths in 2004 (Table 13).

3.4. Painters

(a) Risk estimate: Bosetti and co-workers (2005) systematically reviewed all epidemiological studies on bladder cancer in painters published since the IARC monograph (1989), since when paint technology and its exposure has changed. They reviewed all original cohort and case-control investigations on bladder cancer risk in painters between 1989 and 2004. Four cohort studies on the incidence of bladder cancer among painters gave a pooled relative risk (RR) of 1.10 (95% CI 1.03-1.18), based on 893 cases observed. For mortality, the pooled RR was 1.23 (95% CI 1.11-1.37), based on 370 deaths. The pooled RR from 14 case-control studies and a pooled-analysis of other 11 case-control studies was 1.35 (95% 1.19-1.53) based on 465 cases exposed. Overall, the RR from all epidemiological studies was 1.17 (95% CI 1.11- 1.27). Thus, recent epidemiological evidence indicates a moderate excess risk for bladder cancer in painters. The overall RR is used for the estimation of AF.

(b) Numbers exposed: The number of painters employed in the UK according to the LFS is given in Table 14.

Table 14: Numbers of workers employed as painters in the UK according to the Labour Force Survey (1979 and 2003) SIC Code Description Numbers Men Women Total Grand total 1979 1332.2 Foremen of coach painters (so described) 0 0 0 132.3 Foremen of other spray painters 1,219 0 1,219 132.4 Foremen of painters & decorators 5,066 277 5,343 133.2 Coach painters 5,131 0 5,131 133.3 Other spray painters 44,660 3,027 47,687 133.4 Painters & decorators 194,706 2,291 196,997 138.12 Painting assembling & related occupations, nec 10,346 17,524 27,870 Total 284,247 2002-2004 5234 Vehicle spray painters 25,272 325 25,597 5323 Painters & decorators 144,429 2,562 146,991 24.301&3 Paint, varnish, mastic, sealant manufacture 15,452 4,255 19,707 Total 192,295

(c) AF calculation: The estimated AF for bladder cancer was 1.04% (95% CI 0.7% - 1.6%) for men and 0.11% (0.07% - 0.17%) for women (Table 15).

28 Table 15: Attributable fraction for Painters mortality and incidence, using Bosetti et al., (2005)

Occupational exposure Painters

'Best study' for RR estimate Reference Bosetti et al., (2005) Type of study Quantitative review - all studies Sex Male Female

Exposure level High High Independent data: Industry Sectors C-E F (Painters Total C-E F (Painters Total (Coach and (Coach and & spray decorators) & spray decorators) painters painters etc) etc) LFS 1979 61,356 199,772 261,128 20,551 2,568 23,119 numbers exposed Annual 0.09 0.13 0.14 0.16 employment turnover Numbers 211,987 979,028 1,191,015 115,259 16,339 131,598 exposed in the REP (1955-1994)

Proportion of the population exposed 0.011 0.051 0.062 0.006 0.001 0.006 Relative risks 1.17 1.17 1.17 1.17 1.17 1.17 Attributable fraction 0.0019 0.0086 0.0104 0.0009 0.0001 0.0011 ‘Random error’ [0.001 - [0.006 - [0.007 - [0.0006 - [0.0001 - [0.0007 - 95% confidence 0.003] 0.014] 0.016] 0.0015] 0.0002] 0.0017] interval Attributable deaths 6 27 32 2 0 2 Attributable registrations 13 60 73 3 0 3

3.5. Rubber industry

(a) Risk estimate: Veys study (2004b) followed a composite cohort of 6450 men employed at a large tyre factory either during inadvertent exposure to the human bladder carcinogen beta-naphthylamine, or just after it. A statistically significant elevated risk of bladder cancer for the exposed workforce was evident, but this reversed when the carcinogen was removed from processing in October 1949.

The Kogevinas study (1998a) reviews studies published after 1982, including 12 cohort studies in nine countries that examined distinct populations of workers in the rubber industry, seven industry based nested case-control studies, 48 community based case-control studies in 16 countries, and 23 studies based on administrative data that reported risks for employment in the rubber industry. They found excess risk of bladder cancer in seven cohort studies (Holmberg et al., 1983; Norseth et al., 1983; Negri et al., 1989; Szeszenia-Dabrowska et al., 1991; Gustavsson et al., 1986; Bernardinelli et al., 1987; Solionova and Smulevich, 1993; Weiland et al., 1996). Risk of workers first employed after the 1960s was examined in three studies. A twofold excess risk was found in the largest study (SMR 2.14, 95% CI 1.07 to 3.84, 11 deaths). Excess risks with odds ratios ranging from 1.5 to 5.7, after adjustment for potential confounding factors such as smoking, were found in 11 case-control studies.

A cohort of 2160 male production workers at a factory manufacturing chemicals for the rubber industry (Sorahan et al., 2000) found significant excess mortality from cancer of the bladder in the 605 study subjects potentially exposed to one or more of four pre-specified chemicals investigated (SMR 277, 95%

29 CI 127-526). However, interpretation is difficult because of small numbers in the exposed sub-cohort, relatively crude measures of exposure assessment for the four chemicals under study, and presence of unconsidered potential chemical confounders.

(b) Numbers exposed: The number of workers employed in the UK rubber industry according to the Census of Employment and the LFS is given in Table 16.

Table 16: Numbers of workers employed in rubber industry in the UK according to the Census of Employment (1971) and the Labour Force Survey (1979 and 2003) SIC Code Description Numbers Men Women Total Grand total 1971 Rubber 86,882 28,883 115,765 2002-2004 24.17 Primary synthetic rubber 734 53 787 25.11 Rubber tyres etc manufacture 9,012 1,764 10,776 25.12 Rubber tyres retreading etc 2,021 343 2,364 25.13 Other rubber products manufacture 18,741 4,489 23,230 8115 Rubber process operatives 11,531 1,995 13,526 Total 50,683

(c) AF calculation: The evidence suggests that the risk ceased in the UK rubber industry after 1950. Therefore no attributable fraction has been calculated.

3.6. Polycyclic aromatic hydrocarbons (PAHs):

(a) Risk estimate: In their population-based case-control study, Bonassi and co-workers (1989) created a job-exposure matrix to assess potential lifetime occupational exposure to PAHs. It grouped occupations together based on IARC (IARC, 1984; IARC, 1984; IARC, 1985) and Lindstedt’s review (1982) of occupational exposure to PAHs, which were considered as sharing a definite exposure to PAH. They were coke workers (general), mechanics, railroad workers (machinists), glass workers (foundry), road menders, stokers (in distillery), welders, coalmen, and masons (in a kiln). Therefore, based on this, the PAH risk estimate includes workers employed in coal tars and pitches, aluminium production, coal gasification, and coke production. Their findings suggested a clear confounding effect associated with occupational exposure to aromatic amines (AA) and a weak confounding effect due to differences in smoking habits. Subjects considered as sharing a “definite exposure to PAH” showed an increased risk even after adjustment for cigarette smoking and exposure to AA (OR = 2.14, 95% CI 0.82-5.60). No elevation in risk was found for the category “possible exposure to PAH” (OR= 1.05, 95% CI 0.45-2.44), thus indicating that PAHs are a risk factor for bladder cancer.

Kogevinas and co-workers (2003) combined data from 11 case-control studies conducted between 1976 and 1996 in six European countries. They ranked occupations: industries entailing a high risk included salt mining, manufacture of carpets, paints, plastics and industrial chemicals. An increased risk was found for exposure to PAHs (OR for highest exposure tertile = 1.23, 95% CI 1.07 – 1.4, just above 1 in the lowest exposure tertile).

30 Boffetta et al., (1997) reviewed the cancer risk from occupational and environmental exposure to PAHs, in aluminium production, coal gasification, coke production, iron and steel foundry, diesel engine exhaust exposure, and workers exposed to coal tars and related products, which included tar distillation, shale oil extraction, creosote exposure, carbon black manufacture, carbon and graphite electrode manufacture, chimney sweeps, and calcium carbide production. Results from all these sectors, with the exception of diesel engine exhaust exposure (for which AFs are calculated separately), and coke production (for which no evidence was found for a raised risk of bladder cancer), have been used to calculate an inverse variance weighted combined estimate of RR (random effects model; Q test indicated significant heterogeneity, Q = 48.75, p < 0.0001). Our estimate of the resulting RR based on 26 studies is 1.4 (95% CI 1.2 – 1.7), which is used for the ‘high exposed’ group in manufacturing industry from the CAREX data. The combined RR for only those studies (10) where incident cases were taken into account was lower, at 1.3 (1.1 – 1.6), which is surprising. The RR based on mortality plus incidence studies has been used. It is not stated whether the review RRs were adjusted for smoking.

Estimates of a combined OR from a large population-based case control study in Montreal covered in the same review (again excluding diesel engine exhaust exposures and drivers, and mineral oils (cutting fluids)) resulted in lower relative risks for broader based definitions of workplace exposure, of 0.9 (0.8 – 1.1), and 1.2 (1.1 - 1.4) for a range of other smaller studies (both random effects model). The RR for the ‘low exposed’ group has been set to 1 to reflect these results, and the lowest tertile group from Kogevinas et al., (2003).

(b) Numbers exposed: Table 17 gives the numbers of workers exposed to PAHs by industry according to CAREX for 1990-1993. All exposed workers in mining and manufacturing are assumed to be male. Numbers are allocated between men and women in construction and in jobs in the service sector assuming that all the exposed were employed in “blue collar” occupations (SOC major groups 5, 8 and 9).

Table 17: Numbers of workers exposed to PAHs according to CAREX in 1990-1993 Industry CAREX Data 1990-1993 Number Number in Exposure Exposed Industry Level Crude petroleum and natural gas production 888 53,300 H Metal ore mining 103 1,225 H Other mining 217 28,150 H Food manufacturing 970 414,150 H Tobacco manufacture 102 9,950 H Manufacture of wearing apparel, except footwear 8,444 189,500 H Manufacture of leather and products of leather or of its substitutes 214 16,825 H Manufacture of footwear 130 38,500 H Manufacture of wood and wood and cork products, except furniture 515 132,975 H Manufacture of paper and paper products 289 119,050 H Printing, publishing and allied industries 105 354,750 H Manufacture of industrial chemicals 1,006 130,000 H Petroleum refineries 536 18,075 H Manufacture of miscellaneous products of petroleum and coal 82 1,125 H Manufacture of rubber products 3,848 53,025 H Manufacture of pottery, china and earthenware 1,362 54,450 H Manufacture of glass and glass products 818 43,275 H Manufacture of other non-metallic mineral products 2,073 70,875 H

31 Industry CAREX Data 1990-1993 Number Number in Exposure Exposed Industry Level Iron and steel basic industries 4,913 48,425 H Non-ferrous metal basic industries 1,626 79,325 H Manufacture of fabricated metal products, except machinery and equipment 6,108 292,200 H Manufacture of machinery except electrical 4,106 692,275 H Manufacture of transport equipment 9,292 456,900 H Electricity, gas and steam 4,996 140,975 H Construction 4,511 1,753,450 L Wholesale and retail trade and restaurants and hotels 4,855 4,459,525 L Land transport 9,348 671,050 L Water transport 171 68,175 L Services allied to transport 692 180,725 L Public administration and defence 250 1,557,875 L Sanitary and similar services 9,442 274,225 L Personal and household services 24,273 686,750 L Total 106,285 13,091,075 Main Industry Sector % Male Agriculture, hunting and forestry; fishing High 0 Low 0 Mining/quarrying, electricity/gas/steam, High 52743 100% manufacturing industry Low 0 Construction High 0 Low 4511 99% Service industries High 0 Low 49031 65%

(c) AF calculation: Workers employed in ‘manufacture of wearing apparel, except footwear’ in the period 1955 – 1962 have been excluded from the estimate of numbers ever exposed to avoid overlap with aromatic amines to which they may also have been exposed during this period (see Section 3.3).

The estimated AF was 0.6% for men (95% CI 0.3% - 0.9%), resulting in 40 attributable registrations in 2003, and 0% for women (Table 18).

32 Table 18: Attributable fraction for PAHs using Boffetta et al., (1997) Occupational PAHs exposure 'Best study' for RR Reference Boffetta et al., (1997) estimate Type of study Quantitative review Sex Male Female Exposure level High Low TOTAL Low Independent data: Industry Sectors C-E F G-Q Total 0 F G-Q Total CAREX numbers exposed 52,743 4,466 31,870 36,336 89,079 45 17,161 17,206 CAREX adjustment factor 1.4 1.0 0.9 0.7 0.8

Annual employment turnover 0.09 0.13 0.11 0.16 0.15

Numbers exposed in the REP (1955-1994) 246,417 21,886 119,835 141,721 388,138 192 82,173 82,365 Proportion of the population exposed 0.013 0.001 0.006 0.007 0.020 0.000 0.004 0.004 Proportion of cases exposed Relative risks 1.44 1.00 1.00 Attributable 0.0057 0 0.0057 0 fraction ‘Random error’ 95% [0.003 - [0.003 - confidence interval 0.009] 0.009] Attributable deaths 18 0 18 0 Attributable registrations 40 0 40 0

33 3.7. Diesel engine exhaust

(a) Risk estimate: Boffetta and Silverman (2001) reviewed 35 epidemiological studies that provided information on bladder cancer occurrence associated with exposure to diesel exhaust. Various types of exposure to diesel exhaust have been investigated, ranging from groups of highly exposed workers, such as drivers, to workers who were probably exposed. The study concentrated on five occupational groups: railroad workers, garage maintenance workers, truck drivers, and drivers and operators of heavy machines in ground and road construction. They also considered studies providing a classification of exposure to diesel exhaust based on a job-exposure matrix or on experts’ assessment of individual occupational histories. All but one of the 7 cohort studies included did not control for smoking; all but two of the 16 case-control studies controlled for smoking, and all of the 6 studies based on routinely collected data were assumed to have adjusted for smoking. They did not carry out an overall meta-analysis because of the heterogeneity of the results, mainly due to the different definitions of exposure used in the studies. The summary relative risk for ten studies that considered diesel exhaust exposure (based on a job exposure matrix or a similar approach) was 1.13 (95% CI= 1.00-1.27). A positive dose-response relation was suggested by 10 of the 12 studies that provided relevant information. The summary RR for high diesel exposure was 1.44 (95% CI – 1.18-1.76). For any exposure in the subset of studies from which the high diesel engine exhaust exposure estimate was obtained, the summary RR was 1.23 (1.12 – 1.36).

For our estimate of a suitable RR for the calculation of AF, an overall inverse variance weighted average of all RRs from the studies included in Boffetta and Silverman’s review (that were based on cancer incidence, excluding those for overlapping categories) was calculated as 1.24 (95% CI 1.10 – 1.41) (random effects model, Q = 48.3, p = 0.002), which is the value used for the ‘high exposed’ group. Although Boffetta and Silverman did not offer an overall summary RR, due to the heterogeneity between studies with different definitions of diesel exhaust exposure, the value calculated for all studies (1.18, 1.08 – 1.28) is in line with their observation of an overall RR in the range 1.1 – 1.3. For the low exposure group, Boffetta and Silverman’s meta-analysis RR for 10 studies that classified exposure according to a JEM (or similar) were used. They note that although there were a few positive results (three above RR=1.1), most were close to unity. An attempt to reproduce their result from the data provided gave a summary RR (fixed effects model) of 1.04 (0.9 – 1.2) rather than 1.13, and of 1.03 (0.84 – 1.26) when only the 6 incidence studies were taken into account. This lower result is the one that will be used.

Two of the 45 results contributing to the overall RRs were for women, and a further 4 were for men and women combined. However, the overall RR will be applied to women as well as men.

(b) Numbers exposed: The numbers of workers exposed to diesel engine exhaust according to CAREX in 1990 to 1993 are given in Table 19. Numbers are allocated between men and women in mining and manufacturing and in construction, and in low exposed jobs in the service sector, assuming that all the exposed were employed in “blue collar” occupations (SOC major groups 5, 8 and 9). However for the service sector, as the large numbers exposed at a high level are all in land transport and its allied services, the numbers have been allocated between men and women only on the basis of those employed as plant and machine operatives (SOC major group 8), which specifically covers those employed as road and other transport operatives.

34 Table 19: Numbers of workers exposed to diesel engine exhaust according to CAREX in 1990-1993 Industry CAREX Data 1990-1993 Exposure Level Number Number in Exposed Industry Crude petroleum and natural gas production 7,530 53,300 L Metal ore mining 645 1,225 H Other mining 14,075 28,150 H Food manufacturing 3,860 414,150 L Beverage industries 4,660 88,100 L Tobacco manufacture 12 9,950 L Manufacture of textiles 1,009 182,000 L Manufacture of wearing apparel, except footwear 1,120 189,500 L Manufacture of wood and wood and cork products, except furniture 4,016 132,975 L Manufacture of furniture and fixture, except primary of metal 504 144,325 L Manufacture of paper and paper products 1,144 119,050 L Printing, publishing and allied industries 595 354,750 L Manufacture of industrial chemicals 1,587 130,000 L Manufacture of other chemical products 1,387 175,175 L Petroleum refineries 826 18,075 L Manufacture of miscellaneous products of petroleum and coal 39 1,125 L Manufacture of plastic products nec 293 136,900 L Manufacture of glass and glass products 105 43,275 L Manufacture of other non-metallic mineral products 11,613 70,875 L Iron and steel basic industries 957 48,425 L Non-ferrous metal basic industries 2,653 79,325 L Manufacture of fabricated metal products, except machinery and 3,920 292,200 L equipment Manufacture of machinery except electrical 3,156 692,275 L Manufacture of electrical machinery, apparatus, appliances and supplies 1,224 473,750 L Manufacture of transport equipment 2,574 456,900 L Manufacture of instruments, photographic and optical goods 154 86,225 L Other manufacturing industries 326 59,375 L Electricity, gas and steam 3,795 140,975 L Water works and supply 4,095 45,175 L Construction 106,658 1,753,450 H Wholesale and retail trade and restaurants and hotels 13,487 4,459,525 L Land transport 158,534 671,050 H Water transport 12,993 68,175 L Air transport 6,772 95,700 L Services allied to transport 14,778 180,725 H Communication 6,277 459,425 L Public administration and defence 2,504 1,557,875 L Sanitary and similar services 4,229 274,225 L Personal and household services 68,956 686,750 L Total 473,062 14,874,425 Main Industry Sector %Male

35 Industry CAREX Data 1990-1993 Exposure Level Number Number in Exposed Industry Agriculture, hunting and forestry; fishing High 0 Low 0 Mining/quarrying, electricity/gas/steam, High 14,720 76% manufacturing industry Low 62,197 76%

Construction High 106,658 99% Low 0 Service industries High 173,312 88% Low 115,218 65%

(c) AF calculation: Workers employed in ‘manufacture of textiles’ and ‘manufacture of wearing apparel, except footwear’ in the period 1955 – 1962 have been excluded from the estimate of numbers ever exposed to avoid overlap with aromatic amines to which they also may have been exposed during this period (see Section 3.3).

The estimated AF was 1.5% for men based on cancer incidence, resulting in 107 bladder cancer registrations and 47 deaths in the target year (2004, 2003 for registrations), and 0.2% for women, resulting in 6 registrations and 3 deaths, for women (Table 20).

36 Table 20: Attributable fraction for diesel engine exhaust using Boffetta and Silverman (2001)

Occupational exposure Diesel engine exhaust 'Best study' for Reference Boffetta and Silverman (2001) RR estimate Type of study Meta-analysis - incidence studies only Sex Male Exposure level High Low TOTAL

Independent Industry Sectors C-E F G-Q Total C-E G-Q Total data: CAREX numbers exposed 11,187 105,591 152,515 269,293 47,997 74,892 122,889 392,182 CAREX adjustment factor 1.4 1.0 0.9 1.4 0.9

Annual employment turnover 0.09 0.13 0.11 0.09 0.11

Numbers exposed in the REP (1955 – 1994) 46,287 517,475 573,469 1,143,389 231,164 281,600 513,764 1,657,153 Proportion of the population exposed 0.002 0.027 0.030 0.060 0.012 0.015 0.027 0.086 Relative risks 1.24 1.03 Attributable 0.014 0.001 0.015 fraction ‘Random error’ 95% [0.006 - [-0.004 - confidence interval 0.024] 0.007] Attributable deaths 45 3 47 Attributable registrations 101 6 107

Occupational exposure Diesel engine exhaust 'Best study' Reference Boffetta and Silverman (2001) for RR Type of study Meta-analysis - incidence studies only estimate Sex Female Exposure level High Low TOTAL

Independent Industry Sectors C-E F G-Q Total C-E G-Q Total data: CAREX numbers exposed 3,533 1,067 20,797 25,397 15,157 40,326 55,483 80,880 CAREX adjustment factor 1.5 0.7 0.8 1.5 0.8

Annual employment turnover 0.14 0.16 0.15 0.14 0.15

Numbers exposed in the REP (1955 - 1994) 25,422 4,547 99,586 132,875 127,510 193,098 320,609 453,483 Proportion of the population exposed 0.001 0.000 0.005 0.006 0.006 0.009 0.015 0.022 Relative risks 1.24 1.03 Attributable 0.002 0.000 0.002 fraction [0.0006 [-0.0024 ‘Random error’ 95% - - confidence interval 0.0026] 0.0040] Attributable deaths 3 1 3 Attributable registrations 4 1 6

37 3.8. Hairdressers and barbers

(a) Risk estimate: Czene and co-workers (2003) conducted a follow-up study of a cohort of 45,690 hairdressers from Sweden and analysed all of their malignancies over a period of 39 years. As the formulae of hair dye products has changed over the course of time, it is difficult to assess whether modern hair dyes or gels are still related to some excess risk or the selective elimination of carcinogenic compounds has reduced or eliminated any such risk. In their study, Czene reports that the highest risk was an SIR of 2.56 for urinary bladder cancer in male hairdressers working in 1960 and followed up during 1960 to 1969. The risk decreased to 1.25 when these hairdressers were followed for the whole period of 1960 to 1998. The decrease of risk over time in men together with no association with urinary bladder cancer in women suggests that the use of brilliantine was the likely cause. The SIR for men recorded as a hairdresser at any decennial census between 1960 and 1990 was 1.22 (95% CI 0.98 – 1.51), and 1.09 (0.81 – 1.43) for women, not adjusted for smoking. These are the estimates used to calculate AF.

(b) Numbers exposed: The numbers of hairdressers and barbers according to the LFS for 2003 are given in Table 21. The numbers for 1979 are used in the estimate of AF.

Table 21: Number of workers employed as hairdressers and barbers in 1979 and in 2002-2004 (source: LFS) Description Male Female Number 1979 Hairdressers and barbers managers 487 2080 2567 Hairdressers barbers 22,501 103,498 125,999 Total 128,566 2002-2004 Hairdressers & beauty salon managers/proprietors 29,558 Hairdressers & barbers 150,974 Hairdressing other beauty treatment 223,084 Total 403,616

(c) AF calculation: The AF was 0.1% for men (0 – 0.3%) and 0.3% for women (0 – 1.3%).

38 Table 22: Attributable fraction using Czene et al., (2003) Occupational exposure Hairdressers and barbers 'Best study' for RR estimate Reference Czene et al., (2003) Type of study Swedish cohort study Sex Male Female Exposure level Independent data: Industry Sectors LFS 1979 numbers exposed 22,988 105,578 Annual employment turnover 0.11 0.15 Numbers exposed in the REP (1955- 1994) 96,041 631,937 Proportion of the population exposed 0.005 0.030 Proportion of cases exposed Relative risks 1.22 1.09 Attributable fraction 0.001 0.003 [0.000 - ‘Random error’ 95% confidence interval 0.003] [-0.006 - 0.013] Attributable deaths 3 4 Attributable registrations 8 8

39 4.OVERALL ATTRIBUTABLE FRACTION

4.1 Comparison of exposure AFs

Figure 1 below shows proportion of the population exposed for each exposure, and Figure 2 shows the attributable fraction estimated for each exposure for men and for women.

Figure 1:

Proportion of the population exposed

Mineral oils

Aromatic amines

Painters

e PAHs r

u M s Diesel engine exhaust o F p

x Hairdressers and barbers E

Established carcinogens

Established + uncertain carcinogens

0.00 0.05 0.10 0.15 0.20 0.25 0.30 0.35 0.40 0.45 Pr(E)

Figure 2:

Occupational attributable fraction

Mineral oils Aromatic amines

Painters

PAHs e r

u M s Diesel engine exhaust o

p F x

E Hairdressers and barbers

Established carcinogens

Established + uncertain carcinogens

0.00 0.02 0.04 0.06 0.08 0.10 0.12 0.14 AF

4.2 Exposure Map

The exposure map (Figure 3) gives an indication of how exposures overlap in the working population. It illustrates the potential for double counting of the exposed population to occur when an overall AF is

40 calculated, and facilitates strategies to avoid this. For a given cancer, the map entries consist of either an agent (or group of agents such as PAHs), or an exposure scenario (i.e. an industry or occupation in which such exposure occurs). Agents are in plain type, exposure scenarios in italics, from Table 6. Lines joining boxes then indicate where overlap would occur were all the entries in the map simply considered separately – for example, if PAHs and coal tars/pitches were considered separately, overlap would occur within foundries and steelmills (these exposure scenarios are indicated in the smaller print, again based on information in Table 6). For substances and occupations shown in dotted boxes, a separate AF has not been estimated, as these exposure scenarios are included with another exposure (see Table 9). In addition a separate AF has not been estimated for substances and occupations not shown in bold as these exposure scenarios are included within another exposure.

Figure 3: Bladder cancer exposure map.

Intermediates in plastics and rubber Aromatic amine dyes: manufacturing: 1. 4-aminobiphenyl Aromatic amine dyes: Benzidine 1. 4,4 ’-methylenebis(2 - 2-naphthylamine Coal tars and pitches ) Coke production chloroaniline 2. Benzidine -based dyes 2. Styrene -7,8 –oxide Coal gasificati on 3. -chloro ––ortho toluidine Magenta manufacture 4 Aluminium producti on 4. Ortho –toluidine Aluminium production Auramine manufacture Aluminium production Magentamanufacture

Paint andlaquer Foundries; steel mills industries

Painters PAHs Leather i ndustry Print ing i ndustry (ink formulat i on ): Coal gasi fication used i n cosmet i cs, medic inal and Petroleum pharmaceuti ca l preparat i ons: Refining textile i ndustry dyers Boot and shoe manufacture and repair

Vehicle mechani cs, drivers

Rubber industry Mineral oils Hairdressers Diesel engine and barbers exhaust

There is no overlap in the exposed populations, as estimated here from CoE and LFS data, between exposures to mineral oils and work as painters, and hairdressers and barbers. These AFs may therefore be summed directly. There may be overlap in some workers exposed to PAHs as identified by CAREX and the machinists exposed to mineral oils. It is unlikely that many workers identified in CAREX as exposed to diesel engine exhaust (mostly in construction and transport), would be exposed to PAHs, with minimal overlap with the other exposures considered. However exposure to aromatic amine dyes may overlap with most of the other exposures.

If it is known that a set of overlapping exposures are independent and their joint effect on initiating or promoting cancer is multiplicative, the AFs for each exposure in the overlapping set are combined into an overall AF for the set by taking the complement of the product of complements:

AFoverall = 1 – Πk(1-AFk) for the k exposures in the set.

41 4.3 Overall AF

Where possible, the AFs for all the bladder cancer exposures have been estimated on RRs for cancer incidence, as bladder cancer has a relatively good survival rate so that RR estimates for mortality alone would underestimate AF. However, in the case of PAHs and painters, this was not feasible and risk estimates derived from mortality as well as incidence studies have been used.

Aromatic amines and PAHs are now considered to have strong evidence for site-specific carcinogenicity for bladder cancer. The calculation for the overall AF for Established (‘strong evidence’) exposures is therefore:

AFOverall = 1- (1-AFAA) * (1- AFPAH)

= 1.3% for men and 0.6% for women, as for the aromatic amines.

As noted above, it is possible to sum directly the AFs for Mineral Oils, Diesel engine exhaust, and Occupation as a Painter and Occupation as a Hairdresser or Barber. However mineral oils and diesel overlap with PAHs, and Aromatic Amines overlap with all exposures except diesel engine exhaust. The calculation is therefore:

AFOverall = 1- (1-AFAA) * {1-[(1- (1-(AFMO + AFDiesel))*(1- AFPAH)) + (AFOP + AFOHB)]}

= 11.6% for men and 2.0% for women.

This is the overall AF for the established plus uncertain carcinogens. Taking a straight sum of all the exposure AFs, assuming no overlap, the result is nearly identical (11.7% for men and 2.0% for women).

Other authors’ estimates of overall attributable fraction for bladder cancer are in Table 23.

Table 23: Other estimates of occupational attributable fraction for bladder cancer Reference Location Men M & F Women

Doll and Peto (1981) US 10% 5% Silverman (1989a, 1989b) US 21 – 25% Vineis and Simonato (1991) 0-24% Dreyer et al. (1997) Nordic countries 2% <1% Leigh et al. (1997) US 21% - 27% Nurminen and Karjalainen (2001) Finland 14% 1% Steenland et al. (2003) US 7 – 19% 3-19% Kogevinas et al. (1998b) Europe 4-10%* 0-9%* Mannetje et al. (1999) Europe 8%* Kogevinas et al. (2003) Europe 5-10%*

* based on same pooled studies

42 4.4 Summary of results

Source data – Enlarged in Annex 2 in Table 24. Table 25: Results Established Exposure Numbers exposed Pr(E) AF (and 95% CI) Attributable Attributable /uncertain (1955-94) deaths registrations evidence for carcinogenicity M F M F M F M F M F

U Mineral oils 4,426,58 466,252 0.231 0.022 0.078 [0.04 - 0.008 [0.004 - 243 13 548 23 1 0.12] 0.013] E Aromatic amines 101,654 93,934 0.005 0.004 0.007 0.006 22 10 50 17

U Painters 1,191,01 131,598 0.062 0.006 0.010 [0.007 0.001 [0.0007 32 2 73 3 5 - - 0.016] 0.0017] U PAHs 388,138 82,365 0.020 0.004 0.006 [0.003 0 18 0 40 0 - 0.009] U Diesel engine 1,657,15 453,483 0.086 0.022 0.015 0.002 47 3 107 6 exhaust 3 U Hairdressers and 96,041 631,937 0.005 0.030 0.001 [0.000 0.003 [-0.006 3 4 8 8 barbers - - 0.013] 0.003] Combined AF All Industry Established 0.013 0.006 40 10 89 17 sectors carcinogens Established + 0.116 0.020 362 32 816 57 uncertain carcinogens

Exposures in Established + 0.015 0.002 47 0 106 1 construction only uncertain carcinogens

43 4.5 Exposures in construction Figure 4 shows the estimated number of bladder cancer registrations attributable to exposures in the construction industry only, as a proportion of total bladder cancer registrations attributable to occupation. Construction overall accounted for an estimated 106 (13%) of all occupation attributable bladder cancer registrations in 2003.

Figure 4: Bladder Cancer Registration attributes to work in construction, 2003 Male

Bladder Cancer Registrations attributable to work in Construction, 2003, Male

Mineral oils

Aromatic amines

Painters

PAHs e r u

s Construction only

o Diesel engine exhaust

p Other Sectors x

E Hairdressers and barbers

Overall AF:

Established carcinogens

Established + uncertain carcinogens

0 100 200 300 400 500 600 700 800 900

Number of registrations

*Exposures by industry/job Figure 5 shows those industry categories from CAREX and the CoE, and job categories from the LFS, which accounted for the highest numbers of workers exposed during the period 1955-1994 to an occupational bladder cancer carcinogen. Construction workers and those employed in land transport and personal and household services were exposed to PAHs and diesel engine exhaust, the other occupations all had single exposures, as indicated in Figure 5.

44 Figure 5:

Industry /Occupation classes with over 150,000 ever exposed 1955-1994 ' CAREX , l Construction s e s H

e Land transport i A

P D Personal and household services s '

s LFS 1979 g a n l i t

c 133.3 Other Spray Painters

n i n

a 133.4 Painters & Decorators

o Males i P t 112.1 Press and Machine Tool Setters a Females p

u 112.2 Other Centre Lathe Turners c

c 112.4 Machine Tool Operators O /

113.1 Press Stamping and Automatic Machine Operators y r t

Mineral oils 115.0 Toolmakers Tool Fitters Markers-Out s

u 117.0 Metal Working Production Fitters and Fitter/Machinists d ' n

I Hairdressers Barbers ' CoE 1971

s 362 Insulated wires and cables e n i 893 Dry cleaning, job dyeing etc m

a 423 Textile finishing Aromatic 0 500,000 1,000,000 1,500,000 2,000,000 Numbers ever exposed 1955-1994

4.6 Higher versus lower level exposures Table 26 shows the relative numbers of men and women ever exposed in the period 1955-1994 to an occupational carcinogen for bladder cancer at a high and a low level, and the occupational attributable registrations for the high versus low plus background level exposures. See Section 3 for definition of the high and low exposed for each exposure considered. The overwhelming majority of bladder cancers were found amongst higher level exposed workers (99.3% for men and 97.5% for women).

Table 26: Number ever exposed to an occupational carcinogen for bladder cancer in the period 1955- 1994, and attributable registrations, by level of exposure Exposure Higher Level exposure Lower and Background Level exposure Numbers exposed (1955-94) Attributable Numbers exposed (1955-94) Attributable and age<85 in 2004 registrations and age<85 in 2004 registrations M F M F M F M F Mineral oils 4,200,677 438,568 548 23 225,904 27,683 0 0 Aromatic amines 101,654 93,934 50 17 Painters 1,191,015 131,598 73 3 PAHs 246,417 40 141,721 82,365 0 0 Diesel engine 1,143,389 132,875 101 4 513,764 320,609 6 1 exhaust Hairdressers and 96,041 631,937 8 8 barbers Combined exposures: Established 89 17 0 0 carcinogens Established + 810 56 6 1 uncertain carcinogens

45 46 5. REFERENCES

ARMSTRONG, B., TREMBLAY, C., BARIS, D. & THERIAULT, G. (1994) Lung-cancer mortality and polynuclear aromatic-hydrocarbons - a case-cohort study of aluminum production workers in Arvida, Quebec, Canada. American Journal Of Epidemiology, 139, 250-262. BAXTER, P. & WERNER, J. B. (1980) Mortality in the British rubber industries, 1967-76. IN EXECUTIVE, H. A. S. (Ed.) London, Health and Safety Executive. BERNARDINELLI, L., DE MARCO, R. & TINELLI, C. (1987) Cancer mortality in an Italian rubber factory. Br J Ind Med, 44, 187-91. BI, W., HAYES, R. B., FENG, P., QI, Y., YOU, X., ZHEN, J., ZHANG, M., QU, B., FU, Z., CHEN, M. & ET AL. (1992) Mortality and incidence of bladder cancer in benzidine-exposed workers in China. Am J Ind Med, 21, 481-9. BOFFETTA, P., DOSEMECI, M., GRIDLEY, G., BATH, H., MORADI, T. & SILVERMAN, D. (2001) Occupational exposure to diesel engine emissions and risk of cancer in Swedish men and women. Cancer Causes Control, 12, 365-74. BOFFETTA, P., JOURENKOVA, N. & GUSTAVSSON, P. (1997) Cancer risk from occupational and environmental exposure to polycyclic aromatic hydrocarbons. Cancer Causes and Control, 8, 444-72. BOFFETTA, P. & SILVERMAN, D. (2001) A meta-analysis of bladder cancer and diesel exhaust exposure. Epidemiology, 12, 125-130. BOLM-AUDORFF, U., JÖCKEL, K., KILGUSS, B., POHLABELN, H. & SIEPENKOTHEN, T. (1993) Bösartige Tumoren der ableitenden Harnwege und Risiken am Arbeitsplatz. Wirtshaftsverlag NW, Bremerhaven, Dortmund, Forschung. BONASSI, S., MERLO, F., PEARCE, N. & PUNTONI, R. (1989) Bladder cancer and occupational exposure to polycyclic aromatic hydrocarbons. Int J Cancer, 44, 648-51. BOSETTI, C., PIRA, E. & LA VECCHIA, C. (2005) Bladder cancer risk in painters: a review of the epidemiological evidence, 1989-2004. Cancer Causes & Control, 16, 997-1008. BOYKO, R. W., CARTWRIGHT, R. A. & GLASHAN, R. W. (1985) Bladder cancer in dye manufacturing workers. J Occup Med, 27, 799-803. BRAY, F., SANKILA, R., FERLAY, J. & PARKIN, D. M. (2002) Estimates of cancer incidence and mortality in Europe in 1995. Eur J Cancer, 38, 99-166. BULBULYAN, M. A., FIGGS, L. W., ZAHM, S. H., SAVITSKAYA, T., GOLDFARB, A., ASTASHEVSKY, S. & ZARIDZE, D. (1995) Cancer incidence and mortality among beta-naphthylamine and benzidine dye workers in Moscow. Int J Epidemiol, 24, 266-75. CALVERT, G. M., WARD, E., SCHNORR, T. M. & FINE, L. J. (1998) Cancer risks among workers exposed to metalworking fluids: a systematic review. Am J Ind Med, 33, 282-92. CANCER RESEARCH UK (2002) UK Bladder Cancer Statistics. http://info.cancerresearchuk.org/cancerstats/types/bladder/?a=5441. London, Access Date October 2006. CASE, R. & HOSKER, M. (1954) Tumour of the urinary bladder as an occupational disease in the rubber industry in England and Wales. Br J Prev Soc Med, 8, 39-50. CASE, R., HOSKER, M., MCDONALD, D. & AL., E. (1954) Tumours of the urinary bladder in workmen engaged in the manufacture and use of certain dyestuff intermediates in the British chemical industry. Br J Prev Soc Med, 11, 75-104.

47 CHEN, R. & SEATON, A. (1998) A meta-analysis of painting exposure and cancer mortality. Cancer Detection And Prevention, 22, 533-539. CLAPP, R. W., HOWE, G. K. & JACOBS, M. M. (2005) Environmental and Occupational Causes of Cancer. Lowell, University of Massachusetts. COHEN, S.M., SHIRAI, T. & STEINECK, G. (2000) Epidemiology and etiology of premalignant and malignant urothelial changes. Scand J Urol Nephrol, Supple 205, 105-115. COLEMAN, M. P., RACHET, B., WOODS, L. M., MITRY, E., RIGA, M., COOPER, N., QUINN, M. J., BRENNER, H. & ESTEVE, J. (2004) Trends and socioeconomic inequalities in cancer survival in England and Wales up to 2001. Br J Cancer, 90, 1367-73. COLT, J. S., BARIS, D., STEWART, P. A., SCHNED, A. R., HEANEY, J. A., MOTT, L. A., SILVERMAN, D. & KARAGAS, M. (2004) Occupation and bladder cancer risk in a population-based case-control study in New Hampshire. Cancer Causes & Control, 15, 759-769. COOPER, N. & CARTWRIGHT, R. (2005) Bladder. In: Quinn, M., Wood, A., Cooper, N. & Rowan, S. (eds). Cancer Atlas ofd the United Kingdom and Ireland 1991-2000. ONS Studies on Medical and Population Subjects No. 68, pp39-50. COSTANTINI, A. S., PACI, E., MILIGI, L., BUIATTI, E., MARTELLI, C. & LENZI, S. (1989) Cancer mortality among workers in the Tuscan tanning industry. Br J Ind Med, 46, 384-8. COSTANTINO, J. P., REDMOND, C. K. & BEARDEN, A. (1995) Occupationally related cancer risk among coke oven workers: 30 years of follow-up. J Occup Environ Med, 37, 597-604. CZENE, K., TIIKKAJA, S. & HEMMINKI, K. (2003) Cancer risks in hairdressers: assessment of carcinogenicity of hair dyes and gels. Int J Cancer, 105, 108-12. DE BRAUD, F., MAFFEZZINI, M., VITALE, V., BRUZZI, P., GATTA, G., HENDRY, W.F. & STERNBERG, C.N. (2002) Bladder cancer. Critical Reviews in Oncology/Hematology, 21, 89-106. DECARLI, A., PETO, J., PIOLATTO, G. & LA VECCHIA, C. (1985) Bladder cancer mortality of workers exposed to aromatic amines: analysis of models of carcinogenesis. British Journal of Cancer, 51, 707-712. DELZELL, E., MACALUSO, M. & COLE, P. (1989) A follow-up study of workers at a dye and resin manufacturing plant. Journal of Occupational Medicine, 31, 273-278. DOLL, R. (1952) The causes of death among gas-workes with special reference to cancer of the lung. British Journal of Industrial Medicine, 9, 180-185. DOLL, R., FISHER, R. E., GAMMON, E. J., GUNN, W., HUGHES, G. O., TYRER, F. H. & WILSON, W. (1965) Mortality of Gasworkers with Special Reference to Cancers of the Lung and Bladder, Chronic Bronchitis, and Pneumoconiosis. Br J Ind Med, 22, 1-12. DOLL, R. & PETO, R. (1981) The cause of cancer. Oxford, Oxford University Press. DOLL, R., VESSEY, M. P., BEASLEY, R. W., BUCKLEY, A. R., FEAR, E. C., FISHER, R. E., GAMMON, E. J., GUNN, W., HUGHES, G. O., LEE, K. & NORMAN-SMITH, B. (1972) Mortality of gasworkers - final report of a prospective study. Br J Ind Med, 29, 394-406. DRESLER, C.M., LEON, M.E., STRAIF, K., BAAN, R. & SECRETAN, B. (2006) Reversal of risk upon quitting smoking. Lancet, 368, 348-349. DREVER, F. (1995) Occupational Health Decennial Supplement, London, HMSO. DREYER, L., ANDERSEN, A. & PUKKALA, E. (1997) Avoidable cancers in the Nordic countries. Occupation. APMIS Suppl, 76, 68-79.

48 FELLOWS, J.L., TROSCLAIR, A., ADAMS, E.K. & RIVERA, C.C. (2002) Annual smoking-attributable mortality, years of potential life lost, and economic costs - United States, 1996-1999. Mortality and Morbidity Weekly Report, 51(14), 300-303. FERLAY, J., BRAY, F., PISANI, P. & PARKIN, D. M. (2001) GLOBOCAN 2000: Cancer incidence, mortality and prevalence worldwide. (1.0) No. 5. Cancer Base. Lyon, IARC. FERLAY, J., BRAY, F., SANKILA, R. & PARKIN, D. M. (1999) GLOBOCAN 2002 EUCAN: Cancer Incidence, Mortality and prevalence in the European Union in 1998, version 5.0. IN NO.4, I. C. (Ed.) Lyon, IARCPress. FRUMIN, E., VELEZ, H., BINGHAM, E., GILLEN, M., BRATHWAITE, M. & LABARCK, R. (1990) Occupational bladder cancer in textile dyeing and printing workers: six cases and their significance for screening programs. J Occup Med, 32, 887-90. GAGO-DOMINGUEZ, M., CASTELAO, J. E., YUAN, J. M., YU, M. C. & ROSS, R. K. (2001) Use of permanent hair dyes and bladder-cancer risk. Int J Cancer, 91, 575-9. GOLKA, K., PRIOR, V., BLASZKEWICZ, M. & BOLT, H. M. (2002) The enhanced bladder cancer susceptibility of NAT2 slow acetylators towards aromatic amines: a review considering ethnic differences. Toxicol Lett, 128, 229-41. GOLKA, K., PRIOR, V., BLASZKEWICZ, M., CASCORBI, I., SCHOPS, W., KIERFELD, G., ROOTS, I. & BOLT, H. M. (1996) Occupational history and genetic N-acetyltransferase polymorphism in urothelial cancer patients of Leverkusen, Germany. Scand J Work Environ Health, 22, 332-8. GOLKA, K., WIESE, A., ASSENNATO, G. & BOLT, H. M. (2004) Occupational exposure and urological cancer. World J Urol, 21, 382-91. GUO, J., KAUPPINEN, T., KYYRONEN, P., HEIKKILA, P., LINDBOHM, M. L. & PUKKALA, E. (2004) Risk of esophageal, ovarian, testicular, kidney and bladder cancers and leukemia among Finnish workers exposed to diesel or gasoline engine exhaust. International Journal of Cancer, 111, 286-92. GUSTAVSSON, P., HOGSTEDT, C. & HOLMBERG, B. (1986) Mortality and incidence of cancer among Swedish rubber workers, 1952-1981. Scand J Work Environ Health, 12, 538-44. HAYES, R. B. (1992) Biomarkers in occupational cancer epidemiology: considerations in study design. Environ Health Perspect, 98, 149-54. HOLMBERG, B., WESTERHOLM, P., MAASING, R., KESTRUP, L., GUMAELIUS, K., HOLMLUND, L. & ENGLUND, A. (1983) Retrospective cohort study of two plants in the Swedish rubber industry. Scand J Work Environ Health, 9 Suppl 2, 59-68. HUNG, R. J., BOFFETTA, P., BRENNAN, P., MALAVEILLE, C., HAUTEFEUILLE, A., DONATO, F., GELATTI, U., SPALIVIERO, M., PLACIDI, D., CARTA, A., SCOTTO DI CARLO, A. & PORRU, S. (2004) GST, NAT, SULT1A1, CYP1B1 genetic polymorphisms, interactions with environmental exposures and bladder cancer risk in a high-risk population. Int J Cancer, 110, 598-604. IARC (1972) Volume 1: Some Inorganic Substances, Chlorinated Hydrocarbons, Aromatic Amines, N- Nitroso Compounds and Natural Products. IARC Monographs on the Evaluation of Carcinogenic Risks to Humans. Lyon, France. IARC (1974) Some Aromatic Amines, Hydrazine and Related Substances, N-Nitroso Compounds and Miscellaneous Alkylating Agents. Monog Eval Risks Humans. Lyon, International Agency for Research on Cancer. IARC (1981) Volume 25: The Leather Goods Manufacturing Industry (Other Than Boot and Shoe Manufacture and Tanning). IARC Monograph Evaluation Carcinogenic Risk to Humans. Lyon, France.

49 IARC (1981) Volume: 25: Boot and Shoe Manufacture and Repair. IARC Monograph Evaluation Carcinogenic Risk to Humans. Lyon, France. IARC (1981) Wood, Leather and Some Associated Industries. IARC Monograph Evaluation Carcinogenic Risk to Humans. Lyon, France. IARC (1982) Vol. 29. Some industrial chemicals and dyestuffs. IARC Monograph Evaluation Carcinogenic Risk to Humans. Lyon, France, IARC. IARC (1982) Volume 28: The Rubber Industry. IARC Monograph Evaluation Carcinogenic Risk to Humans. Lyon, International Agency for Research on Cancer. IARC (1984) Volume 32: Polynuclear Aromatic Hydrocarbons, Part 1: Chemical, Environmental and Experimental Data. IARC Monograph Evaluation Carcinogenic Risk to Humans. Lyon, International Agency for Research on Cancer. IARC (1984) Volume 33: Polynuclear Aromatic Hydrocarbons, Part 2: Carbon Blacks, Mineral Oils (Lubricant Base Oils and Derived Products) and Some Nitroarenes. IARC Monograph Evaluation Carcinogenic Risk to Humans. Lyon, International Agency for Research on Cancer. IARC (1984) Volume 34: Polynuclear Aromatic Hydrocarbons, Part 3: Industrial Exposures in Aluminium Production, Coal Gasification, Coke Production, and Iron and Steel Founding. IARC Monograph Evaluation Carcinogenic Risk to Humans. Lyon, International Agency for Research on Cancer. IARC (1985) Volume 35: Polynuclear Aromatic Hydrocarbons, Part 4: Bitumens, Coal-Tars and Derived Products, Shale-Oils and Soots. IARC Monograph Evaluation Carcinogenic Risk to Humans. Lyon, International Agency for Research on Cancer. IARC (1986) Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans: Tobacco Smoking No. 38. IARC Monograph Evaluation Carcinogenic Risk to Humans. Lyon, France, World Health Organization. IARC (1987) Overall Evaluations of Carcinogenicity: an updating of IARC monographs Vols 1 to 42. IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. IARC Monograph Evaluation Carcinogenic Risk to Humans. Lyon, International Agency for Research on Cancer. IARC (1989) Volume 47: Some Organic Solvents, Resin Monomers and Related Compounds, Pigments and Occupational Exposures in Paint Manufacture and Painting. IARC Monograph Evaluation Carcinogenic Risk to Humans. Lyon, International Agency for Research on Cancer. IARC (1990) Volume 48. Monographs on the evaluation of the carcinogenic risk of chemicals to humans. Some flame retardants and textile chemicals and exposures in the textile manufacturing industry. IN IARC (Ed.) IARC Monograph Evaluation Carcinogenic Risk to Humans. Lyon, France, IARC. IARC (1993) Volume 57: IARC Monographs on the evaluation of the carcinogenic risk of chemicals to humans: Occupational Exposures of Hairdressers and Barbers and Personal Use of Hair Colourants, some hair dyes, cosmetic colourants, industrial dyestuffs and aromatic amines. IARC Scientific Publications. Lyon, IARC. IARC (1994) Some industrial chemicals. IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to humans, vol. 60. IARC Monograph Evaluation Carcinogenic Risk to Humans. Lyon, France, IARC. IARC (1998) Volume 45: Occupational Exposure in Petroleum Refining; Crude Oil and Major Petroleum Fuels. IARC Monograph Evaluation Carcinogenic Risk to Humans. Lyons, France, IARC.

50 IARC (In preparation) Volume 92: Polycyclic Aromatic Hydrocarbons. IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. Lyon, International Agency for Research on Cancer. JENSEN, O. M., WAHRENDORF, J., KNUDSEN, J. B. & SORENSEN, B. L. (1987) The Copenhagen case-referent study on bladder cancer. Risks among drivers, painters and certain other occupations. Scand J Work Environ Health, 13, 129-34. KOGEVINAS, M., SALA, M., BOFFETTA, P., KAZEROUNI, N., KROMHOUT, H. & HOAR-ZAHM, S. (1998a) Cancer risk in the rubber industry: a review of the recent epidemiological evidence. Occupational and Environmental Medicine, 55, 1-12. KOGEVINAS, M., KAUPPINEN, T., BOFFETTA, P. & SARACCI, R. (1998b) Estimation of the burden of occupational cancer in Europe. Final report to the European Commission of a Project funded by the Programme “Europe Against Cancer”. Barcelona, IMIM. KOGEVINAS, M., T MANNETJE, A., CORDIER, S., RANFT, U., GONZALEZ, C. A., VINEIS, P., CHANG-CLAUDE, J., LYNGE, E., WAHRENDORF, J., TZONOU, A., JOCKEL, K. H., SERRA, C., PORRU, S., HOURS, M., GREISER, E. & BOFFETTA, P. (2003) Occupation and bladder cancer among men in Western Europe. Cancer Causes & Control, 14, 907-914. KROMHOUT, H., SWUSTE, P. & BOLEIJ, J. S. (1994) Empirical modelling of chemical exposure in the rubber-manufacturing industry. Ann Occup Hyg, 38, 3-22. LA VECCHIA, C., NEGRI, E., D'AVANZO, B. & FRANCESCHI, S. (1990) Occupation and the risk of bladder cancer. Int J Epidemiol, 19, 264-8. LA VECCHIA, C. & TAVANI, A. (1995) Epidemiological evidence on hair dyes and the risk of cancer in humans. Eur J Cancer Prev, 4, 31-43. LA VECCHIA, C. & TAVANI, A. (2001) Hair dyes and bladder cancer: an update. Eur J Cancer Prev, 10, 205-8. LEIGH, J. P., MARKOWITZ, S. B., FAHS, M., SHIN, C. & LANDRIGAN, P. J. (1997) Occupational injury and illness in the United States. Archives of Internal Medicine, 157, 1557-1568. LEWALTER, J. & MIKSCHE, L. (1992) Empfehlungen zur arbeitsmedizinischen Prävention expositions- und dispositions-bedingter Arbeitsstoff-Beanspruchungen. Verh Dt Ges Arbeitsmed, 31, 135-139. LILIENFELD, A. M. & LILIENFELD, D. E. (1980) Foundations of Epidemiology, New York Oxford, Oxford University Press. LINDSTEDT, G. & SOLLENBERG, J. (1982) Polycyclic aromatic hydrocarbons in the occupational environment: with special reference to benzo[a]pyrene measurements in Swedish industry. Scand J Work Environ Health, 8, 1-19. LLOYD, J. W., LUNDIN, F. E., JR., REDMOND, C. K. & GEISER, P. B. (1970) Long-term mortality study of steelworkers. IV. Mortality by work area. J Occup Med, 12, 151-7. MA, Q., LIN, G., QIN, Y., LU, D., GOLKA, K., GELLER, F., CHEN, J. & SHEN, J. (2003) GSTP1 A1578G (Ile105Val) polymorphism in benzidine-exposed workers: an association with cytological grading of exfoliated urothelial cells. Pharmacogenetics, 13, 409-15. MACLURE, M., KATZ, R. B., BRYANT, M. S., SKIPPER, P. L. & TANNENBAUM, S. R. (1989) Elevated blood levels of carcinogens in passive smokers. Am J Public Health, 79, 1381-4. MANCUSO, T. F. & EL-ATTAR, A. A. (1967) Cohort study of workers exposed to betanaphthylamine and benzidine. J Occup Med, 9, 277-85.

51 MANNETJE, A., KOGEVINAS, M., CHANG-CLAUDE, J., CORDIER, S., GONZALEZ, C. A., HOURS, M., JOCKEL, K. H., BOLM-AUDORFF, U., LYNGE, E., PORRU, S., DONATO, F., RANFT, U., SERRA, C., TZONOU, A., VINEIS, P., WAHRENDORF, J. & BOFFETTA, P. (1999) Occupation and bladder cancer in European women. Cancer Causes Control, 10, 209-17. MARKOWITZ, S. B. & LEVIN, K. (2004) Continued epidemic of bladder cancer in workers exposed to ortho-toluidine in a chemical factory. J Occup Environ Med, 46, 154-60. MARRET, L., HARTGE, P. & MEIGS, J. (1986) Bladder cancer and occupational exposure to leather. Br J Ind Med, 43, 96-100. MASTRANGELO, G., FADDA, E. & MARZIA, V. (1996) Polycyclic aromatic hydrocarbons and cancer in man. Environmental Health Perspectives, 104, 1166-1170. MASTRANGELO, G., FEDELI, U., FADDA, E., MILAN, G. & LANGE, J. H. (2002) Epidemiologic evidence of cancer risk in textile industry workers: a review and update. Toxicology and Industrial Health, 18, 171-181. MATANOSKI, G.M. & ELLIOTT, E.A. (1981) Bladder cancer epidemiology. Epidemiologic Reviews, 3, 203-229. MATSUMOTO, K., IRIE, A., SATOH, T., KURUMA, H., ARAKAWA, T. & BABA, S. (2005) Occupational bladder cancer: from cohort study to biologic molecular marker. Medical Science Monitor, 11(10), RA311-RA315. MIRER, F. (2003) Updated epidemiology of workers exposed to metalworking fluids provides sufficient evidence for carcinogenicity. Appl Occup Environ Hyg, 18, 902-12. MORRISON, A. S., AHLBOM, A., VERHOEK, W. G., AOKI, K., LECK, I., OHNO, Y. & OBATA, K. (1985) Occupation and bladder cancer in Boston, USA, Manchester, UK, and Nagoya, Japan. J Epidemiol Community Health, 39, 294-300. NAITO, S. & KUMAZAWA, J. (1989) [Urothelial carcinoma related to exposure to aromatic amines]. Hinyokika Kiyo, 35, 2023-31. NAJEM, G. R., LOURIA, D. B., SEEBODE, J. J., THIND, I. S., PRUSAKOWSKI, J. M., AMBROSE, R. B. & FERNICOLA, A. R. (1982) Life time occupation, smoking, caffeine, saccharine, hair dyes and bladder carcinogenesis. Int J Epidemiol, 11, 212-7. NEGRI, E., PIOLATTO, G., PIRA, E., DECARLI, A., KALDOR, J. & LA VECCHIA, C. (1989) Cancer mortality in a northern Italian cohort of rubber workers. Br J Ind Med, 46, 624-8. NIOSH (1998) Occupational Exposure to Metalworking Fluids. Criteria for a Recommended Standard. Cincinnati, Ohio, National Institute for Occupational Safety and Health. NORPOTH, K. & WOITOWITZ, H. J. (1991) Beruflich verursachte Tumoren. Grundlagen der Entscheidung zur BK-Verdachtsanzeige, Köln. NORSETH, T., ANDERSEN, A. & GILTVEDT, J. (1983) Cancer incidence in the rubber industry in Norway. Scandinavian Journal of Work and Environmental Health, 9, 69-71. NURMINEN, M. M. & KARJALAINEN, A. (2001) Epidemiologic estimate of the proportion of fatalities related to occupational factors in Finland. Scandinavian Journal of Work and Environmental Health, 27, 161-213. OLSEN, J. H. & JENSEN, O. M. (1987) Occupation and risk of cancer in Denmark. An analysis of 93,810 cancer cases, 1970-1979. Scand J Work Environ Health, 13 Suppl 1, 1-91. ONS Cancer Statistics: Registrations. Series MB1., Available at http://www.statistics.gov.uk/statbase/Product.asp?vlnk=8843.

52 ONS Mortality statistics: Cause. Series DH2. Available at http://www.statistics.gov.uk/statbase/Product.asp?vlnk=618. ONS (2004) Cancer Survival in England by Strategic Health Authority. Available at http://www.statistics.gov.uk/StatBase/Product.asp?vlnk=11991&Pos=1&ColRank=1&Rank=272. OSHA (1973) Carcinogens. IN DEPARTMENT OF LABOR (Ed.), Occupational Safety & Health Administration. Fed Register No. 38:10929. Standard No. 1910.93. OUELLET-HELLSTROM, R. & RENCH, J. D. (1996) Bladder cancer incidence in arylamine workers. J Occup Environ Med, 38, 1239-47. PARKIN, D. M. & MUIR, C. S. (1992) Cancer Incidence in Five Continents. Comparability and quality of data. IARC Sci Publ, 45-173. PARKIN, D. M., VIZCAINO, A. P., SKINNER, M. E. & NDHLOVU, A. (1994) Cancer patterns and risk factors in the African population of southwestern Zimbabwe, 1963-1977. Cancer Epidemiol Biomarkers Prev, 3, 537-47. PELUCCHI, C., BOSETTI, C., NEGRI, E., MALVEZZI, M. & LA VECCHIA, C. (2006) Mechanisms of disease: The epidemiology of bladder cancer. Nat Clin Pract Urol, 3, 327-40. PIOLATTO, G., NEGRI, E., LA VECCHIA, C., PIRA, E., DECARLI, A. & PETO, J. (1991) Bladder cancer mortality of workers exposed to aromatic amines: an updated analysis. Br J Cancer, 63, 457-9. PIRASTU, R., IAVARONE, I. & COMBA, P. (1996) Bladder cancer: a selected review of the epidemiological literature. Ann Ist Super Sanita, 32, 3-20. POPP, W., SCHMIEDING, W., SPECK, M., VAHRENHOLZ, C. & NORPOTH, K. (1992) Incidence of bladder cancer in a cohort of workers exposed to 4-chloro-o-toluidine while synthesising chlordimeform. Br J Ind Med, 49, 529-31. QUINN, M., BABB, P., BROCK, A., KIRBY, L. & JONES, J. (2001) Cancer Trends in England and Wales 1950-1999. Series on Medical and Population Subjects No. 66. London, Office for National Statistics. QUINN, M., WOOD, H., COOPER, N. & ROWAN, S. (2005) Cancer Atlas of the United Kingdom and Ireland 1991-2000. Series on Medical and Population Subjects No. 68. London, Office for National Statistics. REHN, L. (1895) Blasengeschwuelste bei Fushsin-arbeitern. Arch Klin Chir, 50, 588-600. RISCH, H. A., BURCH, J. D., MILLER, A. B., HILL, G. B., STEELE, R. & HOWE, G. R. (1988) Occupational factors and the incidence of cancer of the bladder in Canada. Br J Ind Med, 45, 361-7. ROMUNDSTAD, P., HALDORSEN, T. & ANDERSEN, A. (2000) Lung and bladder cancer among workers in a Norwegian aluminium reduction plant. Occupational and Environmental Medicine, 57, 495- 499. ROSENMAN, K. D. & REILLY, M. J. (2004) Cancer mortality and incidence among a cohort of benzidine and dichlorobenzidine dye manufacturing workers. Am J Ind Med, 46, 505-12. ROSS, R., PAGANINI-HILL, A. & HENDERSON, B. (1988) Epidemiology of bladder cancer: In Diagnosis and Management of Genitourinary Cancer, Philadelphia. pp. 32-39, W.B. Saunders & Co. RUBINO, G. F., SCANSETTI, G., PIOLATTO, G. & PIRA, E. (1982) The carcinogenic effect of aromatic amines: an epidemiological study on the role of o-toluidine and 4,4'-methylene bis (2- methylaniline) in inducing bladder cancer in man. Environ Res, 27, 241-54.

53 SCHOTTENFELD, D. & FRAUMENI, J. (2006) Cancer Epidemiology and Prevention (3rd Ed), Oxford University Press. SCHULTE, P. A., RINGEN, K., HEMSTREET, G. P., ALTEKRUSE, E. B., GULLEN, W. H., PATTON, M. G., ALLSBROOK, W. C., JR., CROSBY, J. H., WEST, S. S., WITHERINGTON, R. et al. (1985) Risk assessment of a cohort exposed to aromatic amines. Initial results. J Occup Med, 27, 115-21. SERRA, C., X. BONFILL, ET AL. (2000). Bladder cancer in the textile industry. Scandinavian Journal of Work and Environmental Health, 26(6), 476-481. SIEMIATYCKI, J., RICHARDSON, L., STRAIF, K., LATREILLE, B., LAKHANI, R., CAMPBELL, S., ROUSSEAU, M.-C. & BOFFETTA, P. (2004) Listing occupational carcinogens. Environmental Health Perspectives, 112, 1447-1459. SILVERMAN, D.T., DEVESA, S. S., MOORE, L.E. & ROTHMAN, N. (2006) Bladder cancer. IN SCHOTTENFELD, D. & FRAUMENI JR, J. F. (Eds.) Cancer Epidemiology and Prevention. 3rd Ed. Oxford, Oxford University Press, pp1101-1127. SILVERMAN, D. T., HOOVER, R. N., MASON, T. J. & SWANSON, G. M. (1986) Motor exhaust- related occupations and bladder cancer. Cancer Res, 46, 2113-6. SILVERMAN, D. T., LEVIN, L. I. & HOOVER, R. N. (1989a) Occupational risks of bladder cancer in the United States: II Nonwhite men. J Natl Cancer Inst, 81, 1480-3. SILVERMAN, D. T., LEVIN, L. I., HOOVER, R. N. & HARTGE, P. (1989b) Occupational risks of bladder cancer in the United States: I. White men. J Natl Cancer Inst, 81, 1472-80. SKOV, T., ANDERSEN, A., MALKER, H., PUKKALA, E., WEINER, J. & LYNGE, E. (1990) Risk for cancer of the urinary bladder among hairdressers in the Nordic countries. Am J Ind Med, 17, 217-23. SKOV, T. & LYNGE, E. (1994) Cancer risk and exposures to carcinogens in hairdressers. Skin Pharmacol, 7, 94-100. SOLIONOVA, L. G. & SMULEVICH, V. B. (1993) Mortality and cancer incidence in a cohort of rubber workers in Moscow. Scand J Work Environ Health, 19, 96-101. SOLL-JOHANNING, H., BACH, E. & JENSEN, S. S. (2003) Lung and bladder cancer among Danish urban bus drivers and tramway employees: a nested case-control study. Occupational Medicine, 53, 25-33. SORAHAN, T., HAMILTON, L. & JACKSON, J. R. (2000) A further cohort study of workers employed at a factory manufacturing chemicals for the rubber industry, with special reference to the chemicals 2- mercaptobenzothiazole (MBT), aniline, phenyl-beta-naphthylamine and o-toluidine. Occup Environ Med, 57, 106-15. SORAHAN, T., HAMILTON, L., WALLACE, D. M., BATHERS, S., GARDINER, K. & HARRINGTON, J. M. (1998) Occupational urothelial tumours: a regional case-control study. Br J Urol, 82, 25-32. SORAHAN, T., PARKES, H. G., VEYS, C. A. & WATERHOUSE, J. A. (1986) Cancer mortality in the British rubber industry: 1946-80. Br J Ind Med, 43, 363-73. SORAHAN, T., PARKES, H. G., VEYS, C. A., WATERHOUSE, J. A., STRAUGHAN, J. K. & NUTT, A. (1989) Mortality in the British rubber industry 1946-85. Br J Ind Med, 46, 1-10. SPINELLI, J. J., BAND, P. R., SVIRCHEV, L. M. & GALLAGHER, R. P. (1991) Mortality and cancer incidence in aluminum reduction plant workers. J Occup Med, 33, 1150-5. STASIK, M. J. (1988) Carcinomas of the urinary bladder in a 4-chloro-o-toluidine cohort. Int Arch Occup Environ Health, 60, 21-4.

54 STEENLAND, K., BURNETT, C., LALICH, N., WARD, E. & HURRELL, J. (2003) Dying for work: The magnitude of US mortality from selected causes of death associated with occupation. Am J Ind Med, 43, 461-82. STEENLAND, K., DEDDENS, J. & STAYNER, L. (1998) Diesel exhaust and lung cancer in the trucking industry: exposure-response analyses and risk assessment. American Journal of Industrial Medicine, 34, 220-228. STEENLAND, K. & PALU, S. (1999) Cohort mortality study of 57,000 painters and other union members: a 15 year update. Occupational and Environmental Medicine, 56, 315-321. STRAIF, K., WEILAND, S. K., WERNER, B., CHAMBLESS, L., MUNDT, K. A. & KEIL, U. (1998) Workplace risk factors for cancer in the German rubber industry: Part 2. Mortality from non-respiratory cancers. Occup Environ Med, 55, 325-32. STRAUGHAN, J. K. (1998) Cancer risk in the rubber industry: a review of recent epidemiological evidence. Occup Environ Med, 55, 646-7. SWERDLOW, A., DOS SANTOS SILVA, I. & DOLL, R. (2001) Cancer Incidence and Mortality in England and Wales: Trends and Risk Factors, New York, Oxford University Press Inc. SZESZENIA-DABROWSKA, N., WILCZYNSKA, U., KACZMAREK, T. & SZYMCZAK, W. (1991) Cancer mortality among male workers in the Polish rubber industry. Pol J Occup Med Environ Health, 4, 149-57. TALASKA, G. (2003) Aromatic amines and human urinary bladder cancer: exposure sources and epidemiology. J Environ Sci Health C Environ Carcinog Ecotoxicol Rev, 21, 29-43. TOLBERT, P. E. (1997) Oils and cancer. Cancer Causes and Control, 8, 386-405. TREMBLAY, C., ARMSTRONG, B., THERIAULT, G. & BRODEUR, J. (1995) Estimation of risk of developing bladder cancer among workers exposed to coal tar pitch volatiles in the primary aluminum industry. Am J Ind Med, 27, 335-48. TSUCHIYA, K., OKUBO, T. & ISHIZU, S. (1975) An epidemiological study of occupational bladder tumours in the dye industry of Japan. Br J Ind Med, 32, 203-9. VEYS, C. A. (1969) Two epidemiological inquiries into the incidence of bladder tumors in industrial workers. J Natl Cancer Inst, 43, 219-26. VEYS, C. A. (1992) Bladder cancer as an occupational disease in the rubber industry: an in-depth factory study to show the past extent of the risk and confirmation of its subsequent disappearance. Progress in Plastics and Rubber Technology, 8, 1-14 VEYS, C. A. (1995) Bladder cancer in rubber workers. Progress in Plastics and Rubber Technology, 11, 86-87 VEYS, C. A. (2004a) A study of mortality patterns at a tyre factory 1951-1985: a reference statistic dilemma. Occup Med (Lond), 54, 330-5. VEYS, C. A. (2004b) Bladder tumours in rubber workers: a factory study 1946-1995. Occupational Medicine, 54, 322-329. VINEIS, P. (1994) Epidemiology of cancer from exposure to arylamines. Environ Health Perspect, 102 Suppl 6, 7-10. VINEIS, P. & MAGNANI, C. (1985) Occupation and bladder cancer in males: a case-control study. Int J Cancer, 35, 599-606.

55 VINEIS, P., MARTONE, T. & RANDONE, D. (1995) Molecular epidemiology of bladder cancer: Known chemical causes of bladder cancer: Occupation and smoking. Urologic Oncology: Seminars and Original Investigations, 1, 137-143. VINEIS, P. & PIRASTU, R. (1997) Aromatic amines and cancer. Cancer Causes & Control, 8, 346-355. VINEIS, P. & SIMONATO, L. (1991) Proportion of lung and bladder cancers in males resulting from occupation: a systematic approach. Archives Of Environmental Health, 46, 6-15. WARD, E., CARPENTER, A., MARKOWITZ, S., ROBERTS, D. & HALPERIN, W. (1991) Excess number of bladder cancers in workers exposed to ortho-toluidine and aniline. J Natl Cancer Inst, 83, 501- 6. WARD, E. M., BURNETT, C. A., RUDER, A. & DAVIS-KING, K. (1997) Industries and cancer. Cancer Causes and Control, 8, 356-370. WEILAND, S. K., MUNDT, K. A., KEIL, U., KRAEMER, B., BIRK, T., PERSON, M., BUCHER, A. M., STRAIF, K., SCHUMANN, J. & CHAMBLESS, L. (1996) Cancer mortality among workers in the German rubber industry: 1981-91. Occup Environ Med, 53, 289-98. WENDEL, R. G., HOEGG, U. R. & ZAVON, M. R. (1974) Benzidine: a bladder carcinogen. J Urol, 111, 607-10. WONG, O. & RAABE, G. K. (2000) A critical review of cancer epidemiology in the petroleum industry, with a meta-analysis of a combined database of more than 350,000 workers. Regul Toxicol Pharmacol, 32, 78-98. YOU, X. Y., CHEN, J. G. & HU, Y. N. (1990) Studies on the relation between bladder cancer and benzidine or its derived dyes in Shanghai. Br J Ind Med, 47, 544-52. ZAHM, S. H., HARTGE, P. & HOOVER, R. (1987) The National Bladder Cancer Study: employment in the chemical industry. J Natl Cancer Inst, 79, 217-22. ZAVON, M. R., HOEGG, U. & BINGHAM, E. (1973) Benzidine exposure as a cause of bladder tumors. Arch Environ Health, 27, 1-7. ZHENG, T., CANTOR, K. P., ZHANG, Y. & LYNCH, C. F. (2002) Occupation and bladder cancer: a population-based, case-control study in Iowa. J Occup Environ Med, 44, 685-91.

56 6. Annex 1

Table 9 taken from Tolbert et al., (1997)

57 58 Annex 2 Table 24: Source data Agent Level of exposure Source study data Data for proportion of the population exposed Reference Study Male Mortality Exposure RR (95% CI) * Source Grouped Industry /Occupation classes type /Femal /Cancer scenario main e incidence industry sector Numbers: Male Numbe: Female Numbers: Total Minera High Tolbert Review M+F 1.39 LFS C-E 111.1 Foremen of Press and 2,164 - 2,164 l oils (1979) (1.20,1.61) 1979 Machine Tool Setters Mortality Metal Random and machining, effects model Incidence print press average# of operating case-control and cotton and and jute population- spinning based studies 111.2 Foremen of other Centre 736 - 736 Lathe Turners 111.3 Foremen of Machine Tool 581 - 581 Setter Operators 111.4 Foremen of Machine Tool 8,947 252 9,199 Operators 111.5 Foremen of Press Stamping 1,498 - 1,498 and Automatic Machine Operators 112.1 Press and Machine Tool 64,157 740 64,897 Setters 112.2 Other Centre Lathe Turners 49,774 - 49,774

112.3 Machine Tool Setter 10,818 232 11,050 Operators 112.4 Machine Tool Operators 335,097 50,424 385,521

113.1 Press Stamping and 34,002 18,281 52,283 Automatic Machine Operators 114.1 Foremen of Toolmakers Tool 4,319 - 4,319 Fitters Markers-Out 114.4 Foremen of Metal Working 27,544 - 27,544 Production Fitters and Fitter/Machinists 115.0 Toolmakers Tool Fitters 92,886 510 93,396 Markers-Out 117.0 Metal Working Production 546,544 6,933 553,477 Fitters and Fitter/Machinists 160.5 Labourers and Other 15,469 567 16,036 Unskilled Workers in Foundries in Engineering 160.6 Labourers and Other 21,276 259 21,535 Unskilled Workers in Engineering and Allied T High Total 1,215,812 78,198 1,294,010

Low & 1.00 114.2 Foremen of Precision 969 - 969 Backgrou Instrument Makers and Repairers nd exposure 114.3 Foremen of Watch and - - - Chronometer Makers and Repairers 116.1 Precision Instrument Makers 28,071 1,667 29,738 and Repairers

59 116.2 Watch and Chronometer 6,527 225 6,752 Makers and Repairers 111.6 Foremen of Metal Polishers 265 - 265

111.7 Foremen of Fettlers Dressers - - -

111.8 Foremen of Shot Blasters - - -

113.2 Metal Polishers 11,112 1,425 12,537

113.3 Fettlers Dressers 12,391 1,619 14,010

131.8 Shot Blasters 6,049 - 6,049

Low Total 65,384 4,936 70,320

TOTAL 1,580,931 84,405 1,665,336

Agent Level of exposure Source study data Data for proportion of the population exposed Reference Study Male Mortalit Exposure RR (95% CI) Source Groupe Industry /Occupation classes type /Fema y scenario * d main le /Cancer industry incidenc sector Numbers: e Male Numbers: Female Numbers: Total High Sorahan et W M+F Incidenc Cable 2.46 (1.20, CoE C-E 362 Insulated wires and cables al (1998) Midlan e manufacturi 5.04) [A] 1971 ds ng industry hospital -based Aromat case- ic control amines studies 34,325 12,132 46,457 Dyestuffs 2.61 (0.98, 277 Dyestuffs and pigments 7.00) [A] 16,576 3,138 19,714 893 Dry cleaning, job dyeing etc 7,665 24,295 31,960 Textile 2.32 (0.98, 423 Textile finishing printing and 5.45) [A] dyeing 35,584 15,317 50,901 429 Other textile industries 17,258 6,365 23,623 Leather 2.51 (1.44, 431 Leather (tanning and work 1.53) [A] dressing) 16,449 4,364 20,813 TOTAL 127,857 65,611 193,468 High MOCA: 1.70 (1.05, CAREX C-E Manufacture of industrial Industrial 2.76) [A] chemicals chemicals 10 3 13 Rubber 1.89 (1.34, Manufacture of rubber products products 2.66) [A] 168 53 221 Plastic 1.73 (1.17, Manufacture of plastic products products 2.55) [A] nec 154 48 202 Benzidine- 2.32 (0.98, Other manufacturing industries based dye 5.45) [A] manufactur e 14 4 18

60 Sub-total 345 109 454 High Laboratory 1.05 (0.60, G-Q Education services technicians 1.86) [A] 389 494 883 Research and scientific institutes 1,016 1,294 2,310 Medical 1.62 (1.03, Medical, dental, other health and and nursing 2.55) [A] veterinary services occupations 151 193 344 Sub-total 1,556 1,981 3,537 TOTAL 1,901 2,090 3,991 Painter High Bosetti et al Quantit M+F Mortalit Painters, 1.17 (1.11- LFS C-E 132.2 Foremen of Coach Painters s (2005) ative y and artistic 1.23) [A] 1979 (So Described) review Incidenc painters, - all e spray studies, painters industr y based 0 0 0 132.3 Foremen of Other Spray Painters 1,219 0 1,219 133.2 Coach Painters 5,131 0 5,131 133.3 Other Spray Painters 44,660 3,027 47,687 138.12 Painting Assembling & Related Occupations, Nec 10,346 17,524 27,870 Sub-total 61,356 20,551 81,907 F 132.4 Foremen of Painters & Decorators 5,066 277 5,343 133.4 Painters & Decorators 194,706 2,291 196,997 Sub-total 199,772 2,568 202,340 TOTAL 261,128 23,119 284,247

Agent Level of exposure Source study data Data for proportion of the population exposed Reference Study Male Mortalit Exposure RR (95% CI) Source Groupe Industry /Occupation classes type /Femal y scenario * d main e /Cancer industry incidenc sector Numbers: e Male Numbers: Female Numbers: Total PAHs High Boffetta Narativ M Mortalit Alluminium 1.44 CAREX C-E Crude petroleum and natural gas et al e y and production (1.20,1.74), production (1997) review Incidenc random e effects model average# of industry cohorts, men only 888 0 888 Coal Metal ore mining gasification 103 0 103

61 Coke Other mining production 217 0 217 Coal tar Food manufacturing production 970 0 970 Shale oil Tobacco manufacture extraction 102 0 102 Roofers and Manufacture of wearing apparel, ashphalt except footwear workers 8,444 0 8,444 Creosote Manufacture of leather and exposed products of leather or of its wood substitutes workers 214 0 214 Carbon Manufacture of footwear black 130 0 130 Carbon Manufacture of wood and wood electrodes and cork products, except furniture 515 0 515 Chimney Manufacture of paper and paper sweep products 289 0 289 Printing, publishing and allied industries 105 0 105 Manufacture of industrial chemicals 1,006 0 1,006 Petroleum refineries 536 0 536 Manufacture of miscellaneous products of petroleum and coal 82 0 82 Manufacture of rubber products 3,848 0 3,848 Manufacture of pottery, china and earthenware 1,362 0 1,362 Manufacture of glass and glass products 818 0 818 Manufacture of other non- metallic mineral products 2,073 0 2,073 Iron and steel basic industries 4,913 0 4,913 Non-ferrous metal basic industries 1,626 0 1,626 Manufacture of fabricated metal products, except machinery and equipment 6,108 0 6,108 Manufacture of machinery except electrical 4,106 0 4,106 Manufacture of transport equipment 9,292 0 9,292 Electricity, gas and steam 4,996 0 4,996 High Total 52,743 0 52,743 Low RR set to 1, CAREX F Construction based on pop- based studies with broader exposure definition 4,466 45 4,511 G-Q Wholesale and retail trade and 3,156 1,699 4,855

62 restaurants and hotels Land transport 6,076 3,272 9,348 Water transport 111 60 171 Services allied to transport 450 242 692 Public administration and defence 163 88 250 Sanitary and similar services 6,137 3,305 9,442 Personal and household services 15,777 8,496 24,273 Sub-total 31,870 17,161 49,031 Low Total 36,336 17,206 53,542 TOTAL 89,079 17,206 106,285 Agent Level of exposure Source study data Data for proportion of the population exposed Reference Study Male Mortalit Exposure RR (95% CI) Source Groupe Industry /Occupation classes type /Femal y scenario * d main e /Cancer industr incidenc y sector e Numbers: Male Numbers: Female Numbers: Total Diesel High Boffetta Meta- M Incidenc Truck, 1.24 (1.10, CAREX C-E Metal ore mining and analysi e railroad, bus 1.41) [PA], Silverman s of drivers random (2001) indusrt effects model y average#, all cohorts incidence studies 490 155 645 Other mining 10,697 3,378 14,075 Sub-total 11,187 3,533 14,720 F Construction 105,591 1,067 106,658 G-Q Land transport 139,510 19,024 158,534 Services allied to transport 13,005 1,773 14,778 Sub-total 152,515 20,797 173,312 High Total 269,293 25,397 294,690 Low 1.03 (0.84, CAREX C-E Crude petroleum and natural gas 1.26), fixed production effects model average#, JEM studies 5,723 1,807 7,530 Food manufacturing 2,934 926 3,860 Beverage industries 3,542 1,118 4,660 Tobacco manufacture 9 3 12 Manufacture of textiles 767 242 1,009 Manufacture of wearing apparel, except footwear 851 269 1,120 Manufacture of wood and wood 3,052 964 4,016

63 and cork products, except furniture Manufacture of furniture and fixture, except primary of metal 383 121 504 Manufacture of paper and paper products 869 275 1,144 Printing, publishing and allied industries 452 143 595 Manufacture of industrial chemicals 1,206 381 1,587 Manufacture of other chemical products 1,054 333 1,387 Petroleum refineries 628 198 826 Manufacture of miscellaneous products of petroleum and coal 30 9 39 Manufacture of plastic products nec 223 70 293 Manufacture of glass and glass products 80 25 105 Manufacture of other non- metallic mineral products 8,826 2,787 11,613 Iron and steel basic industries 727 230 957 Non-ferrous metal basic industries 2,016 637 2,653 Manufacture of fabricated metal products, except machinery and equipment 2,979 941 3,920 Manufacture of machinery except electrical 2,399 757 3,156 Manufacture of electrical machinery, apparatus, appliances and supplies 930 294 1,224 Manufacture of transport equipment 1,956 618 2,574 Manufacture of instruments, photographic and optical goods 117 37 154 Other manufacturing industries 248 78 326 Electricity, gas and steam 2,884 911 3,795 Water works and supply 3,112 983 4,095 Sub-total 47,997 15,157 63,154 G-Q Wholesale and retail trade and restaurants and hotels 8,767 4,720 13,487 Water transport 8,445 4,548 12,993 Air transport 4,402 2,370 6,772 Communication 4,080 2,197 6,277 Public administration and defence 1,628 876 2,504 Sanitary and similar services 2,749 1,480 4,229 Personal and household services 44,821 24,135 68,956

64 Sub-total 74,892 40,326 115,218 Low Total 122,889 55,483 178,372 TOTAL 392,182 80,880 473,062 Hairdres Czene et Swedis M+F Incidenc Hairdressers LFS G-Q Hairdressers and barbers sers and al (2003) h e and barbers 1.22 (0.98- 1979 managers Barbers cohort 1.51) for men; study 1.09 (0.81- 1.43) for women [NA] 487 2,080 2,567 Hairdressers Barbers 22,501 103,498 125,999 TOTAL 22,988 105,578 22,988

* Male and Female, unless otherwise stated [A] Adjusted for smoking [PA] Partially adjusted for smoking [NA] Not adjusted for smoking # minimum variance weighted average calculated by the study team

Industry sectors: A-B = Agriculture, hunting and forestry; fishing C-E = Mining and quarrying, electricity, gas and water; manufacturing industry F = Construction G-Q = Service industries

65 Published by the Health and Safety Executive 10/07 Health and Safety Executive

The burden of occupational cancer in Great Britain Technical Annex 5: Bladder cancer

The aim of this project was to produce an updated estimate of the current burden of occupational cancer specifically for Great Britain. The primary measure of the burden of cancer used was the attributable fraction (AF), ie the proportion of cases that would not have occurred in the absence of exposure. Data on the risk of the disease due to the exposures of interest, taking into account confounding factors and overlapping exposures, were combined with data on the proportion of the target population exposed over the period in which relevant exposure occurred. Estimation was carried out for carcinogenic agents or exposure circumstances that were classified by the International Agency for Research on Cancer (IARC) as Group 1 or 2A carcinogens with strong or suggestive human evidence. Estimation was carried out for 2004 for mortality and 2003 for cancer incidence for cancer of the bladder, leukaemia, cancer of the lung, mesoth elioma, non­melanoma skin cancer (NMSC), and sinonasal cancer.

The proportion of cancer deaths in 2004 attributable to occupation was estimated to be 8.0% in men and 1.5% in women with an overall estimate of 4.9% for men plus women. Estimated numbers of deaths attributable to occupation were 6,259 for men and 1,058 for women giving a total of 7,317. The total number of cancer registrations in 2003 attributable to occupational causes was 13,338 for men plus women. Asbestos contributed the largest numbers of deaths and registrations (mesothelioma and lung cancer), followed by mineral oils (mainly NMSC), solar radiation (NMSC), silica (lung cancer) and diesel engine exhaust (lung and bladder cancer). Large numbers of workers were potentially exposed to several carcinogenic agents over the risk exposure periods, particularly in the construction industry, as farmers or as other agricultural workers, and as workers in manufacture of machinery and other equipment, manufacture of wood products, land transport, metal working, painting, welding and textiles. There are several sources of uncertainty in the estimates, including exclusion of other potential carcinogenic agents, potentially inaccurate or approximate data and methodological issues. On balance, the estimates are likely to be a conservative estimate of the true risk. Future work will address estimation for the remaining cancers that have yet to be examined, together with development of methodology for predicting future estimates of the occupational cancers due to more recent exposures.

This report and the work it describes were funded by the Health and Safety Executive (HSE). Its contents, including any opinions and/or conclusions expressed, are those of the authors alone and do not necessarily reflect HSE policy.

RR595 www.hse.gov.uk