rr833 - the joint effect of asbestos exposure and smoking ... · exposure. stopping smoking at any...

Health and Safety Executive

The joint effect of asbestos exposure and smoking on the risk of lung cancer mortality for asbestos workers (1971-2005)

Prepared by the Health and Safety Laboratory for the Health and Safety Executive 2011

RR833 Research Report



Gillian Frost Health and Safety Laboratory Harpur Hill Buxton Derbyshire SK17 9JN

The Great Britain Asbestos Survey was established in 1971 to monitor the long-term health of asbestos workers. Descriptive statistics and mortality of the cohort have been reported previously (Harding & Wegerdt, 2006; Harding & Frost, 2009). The objectives of the analysis undertaken for this report were:

n to investigate if asbestos exposure increased lung cancer mortality risk in never smokers; n to determine if the risk of lung cancer mortality reduces following smoking cessation for asbestos

workers; and n to examine the interaction between exposure to asbestos and smoking on lung cancer mortality risk.

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 2011

First published 2011

You may reuse this information (not including logos) free of charge in any format or medium, under the terms of the Open Government Licence. To view the licence visit www.nationalarchives.gov.uk/doc/open-government-licence/, write to the Information Policy Team, The National Archives, Kew, London TW9 4DU, or email [email protected].

Some images and illustrations may not be owned by the Crown so cannot be reproduced without permission of the copyright owner. Enquiries should be sent to [email protected].

ACKNOWLEDGEMENTS

We would like to thank the staff at the Health and Safety Laboratory who work on the Asbestos Survey, in particular Anna Buttrill, Claire Collins, Rosemary Gagen-Hill and Carl Gartside. Thanks also go to Anne-Helen Harding of the Health and Safety Laboratory, and Andy Darnton of the Health and Safety Executive for their guidance and assistance during the data analysis and report preparation. We would also like to thank the staff at the National Health Service Central Register and the General Register Office for Scotland for their support.

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CONTENTS

LIST OF FIGURES............................................................................................. V

LIST OF TABLES .............................................................................................. V

LIST OF APPENDICES .................................................................................... VI

EXECUTIVE SUMMARY.................................................................................. VII

1 INTRODUCTION......................................................................................... 1

2 METHODS .................................................................................................. 2 2.1 Study population...................................................................................... 2 2.2 Survey questionnaire ............................................................................... 2 2.3 Study follow-up ........................................................................................ 2 2.4 Variable definition .................................................................................... 2

2.4.1 Smoking status ........................................................................................................ 2 2.4.2 Age started and age stopped smoking ..................................................................... 4 2.4.3 Other variables ........................................................................................................ 4

2.5 Statistical methods................................................................................... 4

3 RESULTS ................................................................................................... 6 3.1 Descriptive statistics ................................................................................ 6

3.1.1 Survey population.................................................................................................... 6 3.1.2 Distribution of workers, deaths and demographic characteristics ........................... 6

3.2 Standardised mortality ratios ................................................................... 7 3.3 Poisson regression analyses ................................................................. 16

3.3.1 Asbestos exposure ................................................................................................. 16 3.3.2 Never smokers ....................................................................................................... 17 3.3.3 Asbestos and smoking ........................................................................................... 17

3.4 Asbestos and smoking interaction ......................................................... 30 3.4.1 Attributable fraction estimation............................................................................. 32

4 DISCUSSION............................................................................................ 36 4.1 Strengths and limitations ....................................................................... 36 4.2 Descriptive statistics .............................................................................. 36 4.3 Asbestos exposure ................................................................................ 37 4.4 Never smokers ...................................................................................... 38 4.5 Asbestos and smoking........................................................................... 38 4.6 Asbestos and smoking interaction ......................................................... 39

4.6.1 Attributable fraction estimation............................................................................. 40 4.7 Conclusions ........................................................................................... 40 4.8 Recommendations................................................................................. 41

5 REFERENCES.......................................................................................... 47

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LIST OF FIGURES

Figure 1 Distribution of participants by smoking status, and age and calendar period at examination (1971-2005) ....................................................................................... 14

Figure 2 Standardised mortality ratios for lung cancer mortality among male asbestos

Figure 3 Relative risks of lung cancer mortality by asbestos exposure variables,

Figure 4 Relative risks of lung cancer mortality by smoking variables, estimated using

Figure 5 Relative risks of lung cancer mortality among former smokers by smoking

workers, by smoking status at the final examination (1971-2005) ........................ 15

estimated using Poisson regression ........................................................................ 20

Poisson regression .................................................................................................. 24

variables, estimated using Poisson regression........................................................ 29

LIST OF TABLES

Table 1 Number of participants who changed smoking status during the study period and the nature of the change (1971-2005) ................................................................ 3

Table 2 Distribution of workers, person-years at risk and deaths by country of residence, period of employment, length of time in the survey, smoking status, and industrial sector (1971-2005) ................................................................................... 8

Table 3 Distribution of workers, person-years at risk and deaths by year of birth, age at first exposure, year of first exposure, length of occupational exposure to asbestos, time since first exposure, and time since last exposure (1971-2005)....................... 9

Table 4 Distribution of current smokers, person-years at risk and deaths by age started smoking, packs smoked per day, smoking duration and total smoking exposure (1971-2005) ............................................................................................................ 11

Table 5 Distribution of former smokers, person-years at risk and deaths by age started smoking, packs smoked per day, smoking duration, total smoking exposure, age stopped smoking and time since smoking cessation (1971-2005) ......................... 12

Table 6 Standardised mortality ratios for lung cancer among asbestos workers, by smoking status at the last examination and gender (1971-2005) ........................... 15

Table 7 Standardised mortality ratios for lung cancer among male asbestos workers

Table 8 Risk of lung cancer mortality among all workers, adjusted for age, calendar

Table 9 Risk of lung cancer mortality among all asbestos workers in the final Poisson

Table 10 Risk of lung cancer mortality among never smokers, adjusted for age,

adjusted for smoking status at the last examination (1971-2005) .......................... 15

period, sex and smoking status using Poisson regression. ..................................... 19

regression model for asbestos exposure ................................................................. 21

calendar period, sex and smoking status using Poisson regression........................ 22 Table 11 Risk of lung cancer mortality among former and current smokers, adjusted for

age, calendar period, sex, smoking status and asbestos exposure using Poisson regression................................................................................................................ 23

Table 12 Risk of lung cancer mortality among former and current smokers relative to never smokers, adjusted for age, calendar period, sex, smoking status and asbestos exposure using Poisson regression ......................................................................... 25

Table 13 Risk of lung cancer mortality among former and current smokers in the final Poisson regression model for smoking exposure ................................................... 26

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Table 14 Risk of lung cancer mortality among former smokers relative to the lowest level of each variable, never smokers and current smokers, adjusted for age, calendar period, sex and asbestos exposure using Poisson regression................... 27

Table 15 Risk of lung cancer mortality among former smokers, with sick-quitters removed and adjusted for age, calendar period, sex and asbestos exposure using Poisson regression .................................................................................................. 28

Table 16 Multiplicativity index (V) and synergy index (S) estimated using relative risks adjusted by age, calendar period, sex and main occupation................................... 31

Table 17 Multiplicativity index (V) and synergy index (S) estimated combining never-smokers with former smokers who had stopped smoking for more than 40 years, using relative risks adjusted by age, calendar period, sex and main occupation.... 31

Table 18 Percentage attributable risks from smoking and asbestos exposure among the asbestos workers ..................................................................................................... 33

Table 19 Percentage attributable risks from smoking and asbestos exposure, estimated combining never smokers with former smokers who had stopped smoking for more than 40 years........................................................................................................... 34

Table 20 Estimation of the attributable fraction for lung cancer mortality due to asbestos exposure among male asbestos workers (1971-2005)............................................ 35

Table 21 Estimation of the population attributable fraction for lung cancer mortality due

Table 22 Factors to adjust expected lung cancer deaths of British males for smoking to asbestos exposure among males in Great Britain (1986-2005) .......................... 35

habits....................................................................................................................... 42 Table 23 Poisson distribution 95% confidence limits ................................................... 43 Table 24 Relative risks estimated using Poisson regression (R1, R2, R3, R4) and the

population distribution of exposure........................................................................ 45

LIST OF APPENDICES

Appendix 1 Statistical methods ..................................................................................... 42

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EXECUTIVE SUMMARY

Objectives

The Great Britain Asbestos Survey was established in 1971 to monitor the long-term health of workers in the asbestos industry. Both asbestos exposure and cigarette smoking are recognised risk factors for lung cancer mortality. However, the exact nature of the interaction between the two is still debated. The objectives of the analysis undertaken for this report were:

• To investigate if asbestos exposure increased lung cancer mortality risk in asbestos workers who have never smoked;

• To determine if the risk of lung cancer mortality reduces following smoking cessation for asbestos workers; and

• To examine the interaction between exposure to asbestos and smoking on lung cancer mortality risk.

Main Findings

• There were 1,878 deaths from lung cancer among 98,912 asbestos workers who were followed-up for a total of 1,780,233 person-years.

• Over 50% of participants were smokers at the time of their last examination, with almost 45% of current and former smokers classed as heavy smokers (smoking more than 20 cigarettes a day). Both were higher than the percentage in the national population. Even after adjustment for smoking status, the mortality due to lung cancer for male asbestos workers was significantly higher than the national population.

• Just 2% of lung cancer deaths occurred in asbestos workers who had never smoked. Overall, lung cancer mortality for never smokers who worked in the asbestos industry was higher than never smokers in the national population, but the difference was not statistically significant. Among never smokers, higher lung cancer mortality rates were seen for those first occupationally exposed to asbestos 30 to 39 years previously.

• After adjustment for the smoking status of asbestos workers, the risk of lung cancer mortality increased with length of exposure and years since first occupational exposure to asbestos. Insulation workers had the greatest risk of lung cancer mortality, together with those first occupationally exposed to asbestos before 20 years of age.

• Starting to smoke at an early age and high intensity smoking for long periods of time increased the risk of lung cancer mortality, after adjustment for the workers’ asbestos exposure. Stopping smoking at any age resulted in lung cancer mortality rates that were lower than current smokers. Asbestos workers who quit smoking remained at an increased risk for lung cancer mortality up to 40 years after smoking cessation.

• The interaction between asbestos exposure and smoking for asbestos workers was greater than additive, and the hypothesis that asbestos produces an effect proportional to the effect of smoking (multiplicative) could not be rejected. For those asbestos workers who smoked, an estimated 3% of lung cancer deaths were attributable to asbestos only, 66% to smoking only, and 28% to the interaction of asbestos and smoking.

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• Nearly 30% of lung cancer deaths among all male asbestos workers and 7% among the male national population were estimated to be attributable to asbestos exposure.

Recommendations

• The Asbestos Survey should continue to recruit asbestos workers into the survey and monitor the long-term health of participants. This will allow assessment of the effectiveness of regulations implemented to reduce occupational exposure to asbestos on the risk of mortality among this high-risk group.

• Asbestos workers who smoke should be actively encouraged to quit, thereby reducing the risk of lung cancer mortality.

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1 INTRODUCTION

Asbestos is a naturally occurring mineral made up of strong fibres that can be spun into a thread. Generally speaking, asbestos resists heat and flame, has insulating capabilities, and is flexible and strong. These properties, together with the low cost of mining and processing of asbestos, resulted in its popular usage in the early part of the 20th century. Asbestos could be found in cars, buildings, warships and many domestic products, and so a large number of people came into contact with asbestos fibres in their day-to-day working environment (Bartrip, 2004). A suspected link between asbestos exposure and lung cancer mortality began to emerge in the 1930s, but it was not until the 1950s that a causal association between the two was satisfactorily established (Bartrip, 2004).

Smoking is the major determinant of lung cancer mortality, currently estimated to account for around 90% of all lung cancer cases (Quinn et al., 2001). Asbestos workers have a high percentage of current smokers compared to the national population (Harding & Wegerdt, 2006; Lange et al., 2006), already increasing the risk of lung cancer mortality. However, the exact nature of the interaction between asbestos and cigarette smoking on lung cancer mortality is still uncertain. The two main hypotheses are that the asbestos and cigarette smoking act independently (additive) or that the asbestos produces an effect proportional to the effect of smoking (multiplicative). Other, more elaborate, hypotheses have also been suggested but are believed too extreme (Saracci, 1977; Liddell, 2001). The additive model is considered least plausible, generally resulting in the multiplicative model being taken as the accepted (Hammond et al., 1979; Doll & Peto, 1985; Lee, 2001). However, evidence is starting to accumulate against the multiplicative model, with recent reviews showing that the effect of asbestos on lung cancer is greater in non-smokers than in smokers (less than multiplicative interaction) (Liddell, 2001; Berry & Liddell, 2004).


• To investigate if asbestos exposure increased lung cancer mortality risk in never smokers;

• To determine if the risk of lung cancer mortality reduces following smoking cessation for asbestos workers; and

• To examine the interaction between exposure to asbestos and smoking on lung cancer mortality risk.

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2 METHODS

2.1 STUDY POPULATION

The cohort includes all asbestos workers in Britain who have had medical examinations because of regular work with asbestos. Subjects were initially recruited on a voluntary basis under the Asbestos Survey, which was established in 1971 to monitor mortality among workers in the asbestos products manufacturing industry. Medical examinations were carried out at two yearly intervals during the period over which subjects were working with asbestos. The cohort was later expanded to include those working with insulation (application or removal) who were required to undergo statutory medicals under the Asbestos Licensing Regulations (ALR) 1983, and later to all those exposed to asbestos above the specified ‘action limit’ as required by the Control of Asbestos at Work Regulations (CAWR) 1987.

2.2 SURVEY QUESTIONNAIRE

At each medical examination workers completed the survey questionnaire, which recorded personal information, employment history, current employment details and smoking history. After the introduction of the CAWR 1987, the questionnaire was changed in order to collect more detailed information about work activity with asbestos. Questions about smoking habits were not changed and included details of current smoking habits, the number of cigarettes smoked and the age started smoking if a current or former smoker, and the age stopped smoking if a former smoker.

2.3 STUDY FOLLOW-UP

Subjects were flagged for death registrations at the National Health Service Central Register (NHSCR) for England and Wales, or the General Register Office for Scotland (GROS). Data collected at follow-up medical examinations were used to update smoking status and job details. Deaths occurring up until December 2005 were included in the analysis. For further details, see Harding & Frost (2009).

2.4 VARIABLE DEFINITION

2.4.1 Smoking status

Most subjects who had more than one medical examination reported the same smoking habit at each, but 8% changed habit at least once (Table 1). Changes in smoking habits were included in the analyses, but some of these changes (10%) were inconsistent with previous information. Therefore, before assigning the smoking status for such individuals, data for specific medicals were changed using the following rules:

• The participant recorded a change from current to never smoker -

o If the participant recorded both an age started and stopped smoking, then the examination that had recorded never smoker was considered incorrect and changed to former smoker.

o Otherwise the participant was assumed to be a current smoker.

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• The participant recorded a change from former to never smoker -

o If the participant had recorded an age stopped smoking, then the examination that had recorded never smoker was considered incorrect and changed to former smoker.

o Otherwise the examination that had recorded never smoker was changed to current smoker.

• The participant recorded a change from never to former -

o This change was possible if the individual started and stopped smoking between examinations.

o If the age they reported to have stopped smoking was less than the age at the examination, then the examination that had recorded a never smoker was considered incorrect and changed to a former smoker.

o Otherwise the examination that had recorded never smoker was changed to current smoker.

These rules were applied four times to allow for any ‘knock-on’ effects, after which nine participants remained who were looked at individually. Changed records were randomly checked for feasibility of the changes made.

Table 1 Number of participants who changed smoking status during the study period and the nature of the change (1971-2005)

Number of participants Before cleaning After cleaning

Number of changes 0 90,738 (91.7) 91,136 (92.1) 1 6,017 (6.1) 5,787 (5.9) 2 1,625 (1.6) 1,539 (1.6) 3 398 (0.4) 345 (0.4) 4 98 (0.1) 80 (0.1) 5 26 (0.0) 18 (0.0) 6 8 (0.0) 5 (0.0) 7 1 (0.0) 1 (0.0) 8 1 (0.0) 1 (0.0)

Change in smoking status Current to former 6,224 (56.4) 6,515 (62.9) Never to current 559 (5.1) 616 (6.0) Former to current 3,187 (28.9) 3,203 (30.9)

Current to never 131 (1.2) 0 (0.0) Former to never 414 (3.8) 0 (0.0) Never to former 531 (4.8) 21 (0.2)

Data are number of participants with percentages in parenthesis

Data for medicals were not changed where subjects reported changing from never to current smoker, or from current to former smoker. However, a change from a former to current smoker was not acceptable due to the unknown effect of quitting and then returning to smoking, and

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also the difficulties it would present in calculating the duration of smoking and other such variables. Subjects were classed as ‘lost to follow-up’ from the point when any such change occurred. The smoking status reported at the last medical was taken to apply over the course of subsequent follow-up.

2.4.2 Age started and age stopped smoking

Although many children have tried cigarettes by the age of 11, fewer than 1% of 11 year olds in England are regular smokers, which rapidly grows to over a fifth of 15 year olds (Higgins, 1998). Therefore, for both the age started and age stopped smoking, ages of 11 years or below were considered incorrect and changed to ‘missing’. The age a participant stopped smoking was updated at every examination and so could vary throughout the study period. The maximum age recorded was used unless this exceeded the age at examination. For these cases, the first age recorded that was valid was considered the most accurate and used for the analysis.

For 68 former smokers, the age recorded as the age they started smoking was greater than the age they stopped smoking. The database was set up in such a way that, for participants who attended more than one examination, the age they started smoking recorded at the previous examination was overwritten by the new age. This could lead to inaccuracies in this variable and so, in these 68 cases, the age they started smoking was assumed to be incorrect and changed to ‘missing’.

2.4.3 Other variables

The number of cigarettes smoked per day was taken as the average recorded over all of the participants’ examinations and assumed to apply to the end of follow-up for current smokers. For the purpose of the analyses packs per day were used, where one pack was equivalent to 20 cigarettes. Smoking duration was calculated from the age started smoking to age at exit from the study, loss to follow-up or death for current smokers, and age stopped smoking for former smokers. Total smoking exposure (pack-years) was computed as the product of the number of packs smoked per day and smoking duration. For former smokers, the time since smoking cessation was calculated from the age they stopped smoking to the age at exit from the study, loss to follow-up or death.

For job and sector classifications, workers were allocated to the industry most often recorded on each of their survey questionnaires. In the case of a tie, the worker was allocated to the job or sector associated with the higher risk of asbestos-related disease. See Harding & Frost (2009) for further details.

2.5 STATISTICAL METHODS

Statistical methods are described in full detail in Appendix 1. Briefly, Standardised Mortality Ratios (SMRs) were used to compare mortality in the study population with the Great Britain (GB) population. Expected numbers of deaths were calculated using 5-year age, calendar period and sex-specific mortality rates for England and Wales, and for Scotland. SMRs adjusted to account for the higher prevalence of smoking in the cohort, compared with that of the general population, were also calculated using methods based on population attributable risks as described by Yu & Tse (2007).

Multivariable Poisson regression models were developed to investigate the effects of factors associated with asbestos exposure on lung cancer risk, with adjustment for smoking habits. Similarly, the effects of factors such as age started smoking were estimated with adjustment for asbestos exposure. The effects of ‘sick-quitters’ (those who stopped smoking due to illness) on the relative risks obtained for former smokers were investigated. This was achieved by

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removing those who died from lung cancer within three, five, or 10 years of stopping smoking and repeating the analysis.

The nature of the joint effect of smoking and asbestos exposure on lung cancer mortality was investigated using two indices for interaction effects: the Synergy (S) and Multiplicativity (V) indices (Rothman, 1976; Lee, 2001). A value of S greater than one indicates some degree of interaction between smoking and asbestos exposure on lung cancer mortality (which could include a multiplicative effect), with a value of S equal to one indicating no interaction (that is, the effect of the two factors on risk is additive). For the second index, a value of V equal to one indicates a multiplicative interaction, whereas a value less than one indicates a less than multiplicative interaction (including no interaction at all). Note that there is not a single statistic to test both hypotheses.

The methods used to estimate the interaction indices were also used to estimate the proportion of deaths attributable to asbestos exposure, smoking, and the interaction of the two among the asbestos workers who were current or never-smokers. An estimate of the attributable fraction due to asbestos exposure among all asbestos workers was obtained using the fact that mesothelioma is considered to be almost entirely caused by exposure to asbestos. This technique was also used to obtain an estimate of the population attributable fraction for GB over the period 1986 to 2005.

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3 RESULTS

3.1 DESCRIPTIVE STATISTICS

Detailed descriptive statistics and mortality of the cohort have been reported previously (Harding & Wegerdt, 2006; Harding & Frost, 2009). Since these reports, further survey questionnaires and death notifications relevant to the study period have been received. Therefore, the number of workers and the number of deaths in the study population differ in this report to those previously (number of previous workers 98,117, whereas it is now 98,912; the number of deaths previously was 15,496 and is 15,500 now). In addition to this, the mesothelioma register (any mention of mesothelioma on the death certificate) (HSE, 2008a) identified 53 deaths that had not been recorded and so these were also included. This report focuses on lung cancer mortality but provides descriptive statistics for other main causes of death for reference.

3.1.1 Survey population

In total, there were 208,627 records for 98,912 asbestos workers who took part in the survey between 1971 and 2005. Ninety eight percent of workers were traced for follow-up with the NHSCR and GROS.

3.1.2 Distribution of workers, deaths and demographic characteristics

By the end of 2005, there had been 15,553 deaths in the study population. This included 5,528 deaths from cancer, 653 from mesothelioma and 124 from asbestosis. Overall, lung cancer accounted for 12% (n=1,878) of all deaths (Table 2).

Table 2 shows the number of workers, the person-years at risk and the observed deaths by country of residence, period of employment, length of time in the survey, smoking status at the last medical examination, and industrial sector. Altogether 98,912 workers were followed up for a total of 1,780,233 person-years. Over 95% of workers were resident in England and Wales. The majority of participants were first occupationally exposed to asbestos before the 1983 ALR (57%) and completed just one examination (57%). Over 50% of workers were current smokers at the time of the last examination, and 24% had never smoked. Lung cancer accounted for 15% of deaths for current smokers, 8% for former smokers and 2% for never smokers. The majority of asbestos workers (56%) were employed in the stripping/removal sector.

Table 3 shows the number of workers, person-years at risk and observed deaths by year of birth, age at first exposure, year of first exposure, length of occupational exposure to asbestos, time since first exposure, and time since last exposure. The majority of the workers in the study were born in the 1950s (23%) or 1960s (22%). Nearly 40% of workers were first occupationally exposed to asbestos at 20 to 29 years of age, with a further 23% first exposed at age 30 to 39 years. The majority of workers (63%) experienced less than 10 years occupational exposure to asbestos, with a further 18% having 10 to 19 years exposure, and only 8% with more than 30 years of exposure. Over 75% of participants were first exposed to asbestos after 1970. For the majority of workers, it had been 20 to 29 years since first exposure (27%) and 10 to 19 years since the last exposure to asbestos (42%).

Table 4 and Table 5 show the number of workers, the person-years at risk, and the observed number of deaths by age started smoking, packs smoked per day, smoking duration and total smoking exposure (pack-years) for current and former smokers respectively. A large proportion of current and former smokers (50%) started smoking at 16 to 19 years of age. Over 97% of

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3.2

both former and current smokers started smoking before reaching 30 years of age. Forty-four percent of current smokers smoked 10 to 20 cigarettes a day, 41% smoked 20 to 40 cigarettes and 3% smoked more than 40 cigarettes a day. This was similar to that found for former smokers, with 37% having smoked 10 to 20 cigarettes, 40% smoked 20 to 40 cigarettes, and 8% smoked more than 40 cigarettes a day. The majority of current smokers (38%) had been smoking for over 40 years, with few smoking for less than 10 years (4%). In contrast to this, the majority of former smokers (30%) had spent less than 10 years smoking, with few having smoked for more than 40 years (4%). A large proportion of former smokers (42%) had less than 10 pack-years of smoking exposure, whereas the majority of current smokers (21%) had 10 to 19 pack-years of exposure. The majority of former smokers in the study (30%) stopped smoking at 20 to 29 years of age, with 27% stopping at an age of 30 to 39 years. Very few former smokers stopped after reaching 60 years of age (2%). For the majority of former smokers (30%), 20 to 29 years had passed since they stopped smoking.

Figure 1 shows the distribution of workers by smoking status, age and calendar period at the time of the examination. A smaller proportion of those examined at older ages than younger ages were never smokers (13% of those examined over age 60 years compared with 39% of those examined under age 20). In contrast, those examined at older ages were more likely to be former smokers than those examined at younger ages (39% of those examined over age 60 years, compared with 8% of those examined under age 20). However, the majority of participants examined at any age were current smokers, with the proportion never below 47%. This proportion remained relatively constant throughout the age bands, with a maximum of 56% of participants being current smokers at 20 to 29 and 30 to 39 years of age. The proportion of current smokers varied over calendar period. The majority of participants (65%) when examined before 1975 were current smokers. This proportion fell to a minimum during 1990 to 1994, when 48% of participants were current smokers.

STANDARDISED MORTALITY RATIOS

Table 6 shows the SMRs for lung cancer by gender and smoking status at the last recorded medical examination. Overall, asbestos workers had significantly elevated mortality from lung cancer compared to the national population (SMR 187, 95% CI 178-195). Never smokers had the lowest SMR of 22 (95% CI 16-31) and current smokers had the highest of 306 (95% CI 290-323). After adjustment for smoking habits, mortality from lung cancer for male asbestos workers was statistically significantly greater than the national population (SMR 133, 95% CI 127-140; Table 7; Figure 2).

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Table 2 Distribution of workers, person-years at risk and deaths by country of residence, period of employment, length of time in the survey, smoking status, and industrial sector (1971-2005)

Number Person- Number of deaths of

workers years at

risk All deaths All MN MN Bronchus

& lung Mesotheliomafi Circulatory

disease Respiratory

disease Asbestosis

Country Great Britain 98,912 1,780,233 15,553 5,528 1,878 653 6,174 1,561 124 England & Wales 94,980 1,712,816 15,182 5,387 1,831 635 6,057 1,537 122 Scotland 3,932 67,417 371 141 47 18 117 24 2

Period of employment Pre-ALR 56,001 1,298,148 14,364 5,143 1,775 629 5,852 1,502 123 Post-ALR 42,911 482,084 1,189 385 103 24 322 59 1

Length of time in the survey One examination 56,460 924,091 7,545 2,580 892 255 2,910 765 60 ≥ two examinations 42,452 856,142 8,008 2,948 986 398 3,2634 796 64

Smoking status Current smokers 52,828 923,347 9,636 3,456 1,474 324 3,792 1,025 65 Former smokers 19,392 371,416 3,815 1,412 314 212 1,546 377 48 Never smokers 24,137 430,996 1,650 511 35 103 659 108 10

Industrial sector Manufacturing

Textiles 29,410

3,190 714,634

79,565 8,966

800 2,869

242 1,010

84 210

15 3,633

386 993

83 43

4 Asb cement mixt, 3,848 96,282 1,264 374 141 33 558 155 9

board & pipe Asb/rubber/resin/ 5,789 131,751 1,637 527 210 23 710 181 3 bitumen mixtures

Asb board & paper 616 14,566 204 67 29 4 82 23 2 Garments 287 6,803 56 20 3 0 22 6 1 Insulation & 200 4,756 67 24 10 2 27 7 1

plastering mixes Maintenance 3,600 83,142 1,194 373 126 31 539 122 3

Insulation workers 5,255 124,721 1,633 728 286 143 545 168 43 Stripping/removal 55,426 795,028 3,547 1,405 424 231 870 252 25 ‘Other’ 8,701 145,383 1,407 526 158 69 1,094 148 13

Ship building, 1,929 44,552 707 253 81 26 298 90 6 repair & breaking Building & 1,918 34,994 289 108 32 9 100 26 1

construction Miscellaneous 3,306 78,152 893 293 95 10 373 101 2

fi Mesothelioma as defined by the mesothelioma register – any mention of mesothelioma on the death certificate

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Table 3 Distribution of workers, person-years at risk and deaths by year of birth, age at first exposure, year of first exposure, length of occupational exposure to asbestos, time since first exposure, and time since last exposure (1971-2005)


workers years at



disease Respiratory

disease Asbestosis

Year of birth < 1930 13,703 275,441 9,324 3,140 1,149 296 4,107 1,170 86

1930- 12,139 281,180 3,255 1,339 445 211 1,279 240 30 1940- 17,799 392,663 1,755 757 226 120 553 102 7 1950- 23,090 466,482 834 246 53 23 189 39 1 1960- 21,270 304,539 321 39 5 3 44 9 0 1970- 10,911 59,928 46 7 0 0 2 1 0

Age at first exposure (years) < 20 19,554 414,797 2,396 1,033 328 256 792 206 43

20- 38,806 705,705 3,461 1,193 355 174 1,244 304 33 30- 22,522 375,222 3,631 1,257 447 99 1,504 378 24 40- 12,426 203,266 3,564 1,214 451 68 1,552 370 17 50- 5,604 81,243 2,501 831 297 56 1,082 303 7

Year of first exposure < 1930 106 1,457 103 27 12 3 56 13 3

1930- 1,093 19,851 901 304 114 42 407 118 13 1940- 2,736 55,658 1,779 666 247 100 733 236 29 1950- 6,012 132,497 2,755 1,121 378 224 1,063 295 48 1960- 12,534 299,128 3,663 1,297 427 148 1,542 360 18 1970- 25,280 624,352 4,529 1,499 525 94 1,820 429 11 1980- 25,011 464,467 1,500 519 156 36 482 98 2 1990-2005 26,140 181,848 322 95 19 6 70 12 0

Length of occupational exposure (years) < 10 62,697 1,004,377 5,532 1,808 596 103 2,108 472 11

10- 17,954 387,875 3,569 1,203 429 121 1,454 383 19 20- 10,454 228,596 2,922 1,110 374 172 1,194 288 34 30- 7,807 159,385 3,530 1,407 479 257 1,418 418 60

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workers years at



disease Respiratory

disease Asbestosis

Years since first exposure < 10 19,468 89,907 1,318 410 130 30 451 63 1

10- 21,537 317,657 3,034 1,027 381 49 1,237 218 12 20- 26,508 576,248 3,864 1,334 456 120 1,582 378 17 30- 18,574 482,830 3,293 1,231 412 185 1,315 351 26 40- 8,415 202,871 2,397 982 309 188 897 297 30 50- 4,410 110,720 1,647 544 190 81 692 254 38

Years since last exposure < 10 36,347 323,007 6,736 2,543 910 337 2,680 452 53

10- 41,032 836,265 6,344 2,182 717 226 2,556 753 48 20- 20,490 586,003 2,454 797 251 89 931 353 23 30- 1,043 34,529 19 6 0 1 7 3 0


10

Table 4 Distribution of current smokers, person-years at risk and deaths by age started smoking, packs smoked per day, smoking duration and total smoking exposure (1971-2005)


workers years at



disease Respiratory

disease Asbestosis

Age started smoking (years) < 16 13,326 230,634 2,510 942 450 75 967 259 16

16- 22,016 382,497 3,891 1,396 591 146 1,559 409 29 20- 7,556 127,644 1,965 678 284 61 806 226 15 30- 641 11,393 199 63 14 6 90 24 2 40- 163 3,107 63 19 4 2 27 7 1 50- 35 648 24 5 1 0 13 2 0

Packs smoked per day < 0.5 4,807 73,314 665 189 48 18 299 67 5

0.5- 16,727 261,401 2,590 905 349 87 1,043 276 11 1.0- 15,850 278,342 3,209 1,188 554 109 1,220 364 26 2.0- 902 17,876 265 96 53 5 113 28 2 3.0- 108 2,050 34 15 11 0 12 2 0

Smoking duration (years) < 10 1,841 5,403 42 7 0 0 6 0 0

10- 5,770 40,056 206 27 8 1 47 2 0 20- 8,986 115,491 567 154 46 20 198 19 0 30- 10,399 211,283 1,456 548 209 64 564 103 17 40- 16,741 383,690 6,381 2,367 1,081 205 2,647 803 46

Total smoking exposure (pack-years) < 10 6,359 53,912 286 62 14 10 112 10 0

10- 7,827 102,185 669 186 48 18 264 50 4 20- 7,163 120,032 982 341 121 41 391 75 6 30- 5,827 116,470 1,215 443 174 38 495 117 5 40- 4,147 89,246 1,220 458 198 49 483 143 9 50- 2,488 55,980 918 355 168 26 370 112 6 60- 1,426 33,364 567 195 99 15 225 103 6 70- 801 18,562 329 136 79 10 111 48 2 80- 1,147 27,373 455 174 101 9 182 67 6


11

Table 5 Distribution of former smokers, person-years at risk and deaths by age started smoking, packs smoked per day, smoking duration, total smoking exposure, age stopped smoking and time since smoking cessation (1971-2005)


workers years at



disease Respiratory

disease Asbestosis

Age started smoking (years) < 16 4,545 88,157 882 325 79 51 352 96 9

16- 7,942 153,158 1,550 573 125 85 624 167 25 20- 3,018 57,675 904 318 63 39 403 85 10 30- 233 4,613 68 21 6 0 36 2 0 40- 70 1,579 20 6 1 0 8 3 0 50- 23 502 14 4 1 0 6 2 0

Packs smoked per day < 0.5 2,160 41,425 358 112 15 11 166 28 4

0.5- 5,093 96,755 1,024 354 65 56 434 121 10 1.0- 5,510 105,930 1,245 444 117 60 529 119 13 2.0- 886 16,711 293 111 31 12 114 38 7 3.0- 230 4,333 74 25 3 4 37 6 0

Smoking duration (years) < 10 4,700 88,359 345 133 12 21 133 28 3

10- 4,671 91,714 622 254 44 45 223 41 4 20- 3,384 66,876 919 339 63 48 379 86 10 30- 2,131 42,524 1,041 359 105 37 468 125 20 40- 672 12,400 467 141 45 19 213 72 7

Total smoking exposure (pack-years) < 10 5,632 106,229 611 214 22 28 249 46 7

10- 3,315 65,965 681 258 50 36 284 73 6 20- 1,803 36,032 505 150 32 21 240 49 4 30- 1,166 23,285 457 153 45 27 198 55 5 40- 592 11,777 270 88 25 15 123 29 4 50- 303 5,502 145 61 23 4 52 19 3 60- 189 3,653 94 39 10 3 41 10 4 70- 122 2,267 66 26 7 1 29 7 0 80- 162 2,796 106 37 10 4 43 18 1

12


workers years at



disease Respiratory

disease Asbestosis

Age stopped smoking (years) < 20 1,247 24,396 54 16 1 4 20 2 0 20- 4,975 91,865 363 148 17 24 130 30 5

30- 4,488 87,013 655 265 39 47 238 43 2 40- 3,296 66,033 994 380 79 57 409 103 15 50- 2,031 40,027 1,141 377 122 39 518 143 19 60- 354 6,438 262 70 20 7 125 38 3

Time since smoking cessation (years) < 10 2,091 14,183 390 143 57 15 158 28 5

10- 3,819 56,901 944 370 85 55 385 93 14 20- 4,931 104,333 1,090 398 83 51 465 118 12 30- 3,799 95,863 595 218 36 44 227 63 6 40- 1,751 44,492 450 127 17 13 205 57 7


13

53

8

39

56

12

32

56

18

26

54

24

22

51

33

17

47

39

13

0 20

40

60

80

10

0 P

reve

lanc

e (%

)

<20 20- 30- 40- 50- 60-Age

Pre

vela

nce

(%)

0 20

40

60

80

10

0

65

16

19

59

21

21

52

24

24

51

23

26

48

24

28

54

19

27

55

18

27

<1975 1975- 1980- 1985- 1990- 1995- 2000-2005 Calendar period

Current smokers Former smokers Never smokers

Figure 1 Distribution of participants by smoking status, and age and calendar period at examination (1971-2005)

14

Table 6 Standardised mortality ratios for lung cancer among asbestos workers, by smoking status at the last examination and gender (1971-2005)

Smoking status Never Former Current

Deaths 32

305 1,401

Male SMR

22* 95

303**

(95% CI) (15 – 31) (85 – 107) (288 – 320)

Deaths 4 5

70

Female SMR

29** 70

361**

(95% CI) (8 – 75) (23 – 164) (281 – 456)

Deaths 36

310 1,471

Total SMR

22** 95

306**

(95% CI) (16 – 31) (85 – 106) (290 – 322)

Total 1,795 186** (178 – 195) 83 198** (158 – 246) 1,878 187** (178 – 195) * significant at p≤ 0.05; ** significant at p ≤ 0.01; CI, confidence interval; SMR, standardised mortality ratio

Table 7 Standardised mortality ratios for lung cancer among male asbestos workers adjusted for smoking status at the last examination (1971-2005)

Smoking habit Never Former Current

Observed

32 305

1,401

Expected

148 320 462

Adjusted expected†

24 203

1076

Adjusted SMR 136 150** 130**

(95% CI) (93 – 192) (134 – 168) (124 – 137)

Total 1,738 930 1303 133** (127 – 140) † Expected numbers adjusted using smoking adjustment factors (Appendix 1); * significant at p≤ 0.05; ** significant at p ≤ 0.01; CI, confidence interval; SMR, standardised mortality ratio.

350

300

250

200

150

100

50

0

Sta

ndar

dise

d m

orta

lity

ratio

Current Former Never All males

Smoking status at f inal examination

SMR Adjusted for smoking status

Figure 2 Standardised mortality ratios for lung cancer mortality among male asbestos workers, by smoking status at the final examination (1971-2005)

(Error bars represent 95% confidence intervals and dashed line shows a standardised mortality ratio of 100)

15

3.3 POISSON REGRESSION ANALYSES

This section presents the results of Poisson regression analyses examining the joint effect of asbestos exposure and smoking. Investigation of associations between the risk of lung cancer mortality and the asbestos related variables, adjusting for the smoking status, and development of a multivariable model of asbestos exposure is presented in Section 3.3.1. An analysis of the same asbestos-related variables in never smokers is presented in Section 3.3.2 and in Section 3.3.3 an analysis of smoking-related variables using the multivariable model of asbestos exposure given in Section 3.3.1 to adjust for asbestos exposure is presented.

3.3.1 Asbestos exposure

Table 8 and Figure 3 show the risk of lung cancer mortality for all workers in relation to each asbestos exposure variable considered separately, and adjusted for age, calendar period, sex and smoking status using Poisson regression. Both current and former smokers had significantly elevated risk of lung cancer mortality as compared to never smokers (current: RR 14.5, 95% CI 10.4-20.3; former: RR 4.7, 95% CI 3.3-6.7), with a significant trend from never to former to current smokers. Overall, age at first occupational exposure to asbestos, year of first exposure, length of exposure, years since first exposure (both with and without excluding less than 10 years latency), time of first exposure, and main occupation were associated with lung cancer mortality.

The risk of mortality from lung cancer had a significant downward trend as age at first occupational exposure to asbestos increased. The risk associated with exposure before 20 years of age was significantly greater than the other age groups. The risk of mortality was lowest for those first exposed to asbestos in more recent years, with those first exposed during 1960 to 1969 and 1970 onwards having significantly reduced risk compared to first exposure before 1940 (1960-1969: RR 0.7, 95% CI 0.6-0.9; 1970-2005: RR 0.7, 95% CI 0.6-0.8).

The risk of mortality significantly increased as the length of occupational exposure to asbestos increased. Exposure to asbestos of less than 10 years had the lowest risk, which was significantly less than those associated with other exposure lengths. Exposure of 40 or more years had a RR of 1.5 (95% CI 1.2-1.8) compared to less than 10 years exposure.

The risk of mortality from lung cancer increased as the years since first occupational exposure to asbestos increased. This risk was significantly increased for 30 or more years since first exposure compared to less than 20 years (30-39: RR 1.2, 95% CI 1.0-1.4). Fifty or more years of exposure had the highest RR of 1.7 (95% CI 1.4-2.0) when compared to less than 20 years of exposure. Excluding participants with latency periods of less than 10 years reduced the slope of the observed trend. Fifty or more years of exposure had the highest RR of 1.6 (95% CI 1.3-1.9) when compared to less than 20 years of exposure.

There were no significant differences in risk for the time since last occupational exposure to asbestos or the length of time the worker spent in the survey. The risk of mortality from lung cancer was significantly reduced when first exposure occurred after the 1983 ALR, compared to before the ALR (RR 0.7, 95% CI 0.6-0.9). Insulation workers had the greatest risk of mortality from lung cancer of all the main occupations, with a RR of 1.9 (95% CI 1.7-2.2) compared to workers in the manufacturing sector. Workers in the asbestos stripping/removal industry also had significantly greater risk of lung cancer mortality than those in the manufacturing industry (RR 1.1, 95% CI 1.0-1.3).

Table 9 shows the final multivariable Poisson regression model for asbestos exposure, which built on the basic model of age, calendar period, sex, smoking status, main job and length of

16

occupational exposure to asbestos. Age at first exposure was the only asbestos-related variable statistically significantly associated with lung cancer mortality when added to the basic model simultaneously. The risk of lung cancer significantly increased with age, such that workers with an age of 75 years or more had a RR of 258 (95% CI 137-483) compared with less than 40 years of age. There was a significant trend of decreasing risk with calendar period. The risk of mortality was significantly reduced for 1995 to 1999 compared to before 1980 (RR 0.7, 95% CI 0.6-0.9). Females had a significantly reduced risk of mortality compared to males (RR 0.6, 95% CI 0.5-0.7). Current smokers had the greatest risk of lung cancer mortality (RR 14.7, 95% CI 10.5-20.6), followed by former smokers (RR 4.6, 95% CI 3.3-6.6), compared to never smokers. Insulation workers had a significantly elevated risk compared to those in the manufacturing sector (RR 1.8, 95% CI 1.6-2.1). There was no a significant difference between risks associated with the manufacturing and stripping/removal sector. The significant trend of increasing risk with increasing length of asbestos exposure remained in the multivariable model, with those exposed for over 40 years having a RR of 1.6 (95% CI 1.1-2.2) compared to less than 10 years of exposure. There was no longer significant trend in the risks associated with the age at first occupational exposure. A significant reduction in risk when first exposure occurred at 20 to 29 years of age rather than before the age of 20 (RR 0.7, 95% CI 0.6-0.9) was the only significant difference.

3.3.2 Never smokers

Table 10 shows the risk of lung cancer mortality in relation to each asbestos exposure variable considered separately for never smokers, and adjusted for age, calendar period and sex using Poisson regression. Due to the small number of deaths from lung cancer among never smokers, categories were combined so that each category contained at least eight deaths. Overall, there were no significant variables associated with never smokers. There was a significant increase in risk for those never smokers first exposed to asbestos 30 to 39 years ago compared to less than 30 years (RR 2.6, 95% CI 1.0-6.6). There was a statistically significant trend of decreasing risk with year of first exposure to asbestos.

3.3.3 Asbestos and smoking

Table 11 and Figure 4 show the risk of lung cancer mortality for former and current smokers in relation to each smoking variable considered separately, with adjustment for asbestos exposure made by including the asbestos exposure variables from the final model defined in Section 3.3.1 (Table 9). In each case, the reference category was taken as the lowest level of each variable. Table 12 shows the risk of lung cancer for current and former smokers in relation to each smoking variable, again considered separately and adjusted for the asbestos exposure variables, but taking never smokers as the reference category. Overall, age started smoking, packs smoked per day, smoking duration and total smoking exposure were all associated with lung cancer mortality (Table 11).

There was a significant trend of decreasing risk as the age started smoking increased. Starting to smoke before 16 years of age was associated with the greatest risk. Workers who started to smoke after reaching 40 years of age had the smallest risk. Although this was significantly lower than those who started before 16 years of age (RR 0.2, 95% CI 0.1-0.5), it was still significantly greater than the risks associated with never smokers (RR 3.1, 95% CI 1.3-7.5).

The risk of mortality from lung cancer increased as the number of packs smoked per day increased. Smoking two to three packs a day (40 to 60 cigarettes) had the greatest risk, which was significantly greater than smoking less than half a pack a day (RR 4.2, 95% CI 3.0-5.8). The risk of lung cancer was consistently greater than that of never smokers, including smoking just less than half a packet a day (RR 3.9, 95% CI 2.6-5.9).

17

As the number of years spent smoking increased, the risk of lung cancer mortality also increased. Smoking for more than 60 years was associated with the greatest risk (RR 13.0, 95% CI 6.5-25.9) compared to smoking for less than 10 years. There was no significant difference between smoking for less than 10 years and never smoking (RR 1.3, 95% CI 0.7-2.7).

The risk of mortality increased as total smoking exposure increased and was always significantly greater than never smokers. The risk associated with more than 80 pack-years of smoking exposure was significantly greater than less than 10 pack-years of exposure (RR 6.3, 95% CI 4.2-9.5).

Table 13 shows the final multivariable Poisson regression model for former and current smokers, which built on the final model for asbestos exposure defined in Section 3.3.1 (Table 9). Smoking duration and total smoking exposure were statistically significantly associated with lung cancer mortality when added to the full model for asbestos exposure simultaneously. Age started smoking and the number of packs smoked per day were not significant variables in the final model. As the smoking duration increased, so did the risk of lung cancer mortality. Mortality risk was not significantly greater than for those who had been smoking for less than 10 years, until smoking duration reached 40 or more years (40-49: RR 2.2, 95% CI 1.0-4.7). The risk of mortality again increased as total smoking exposure increased. The risk associated with more than 80 pack-years of smoking exposure was significantly greater than less than 10 pack-years of exposure (RR 4.9, 95% CI 3.1-7.8).

Table 14 and Figure 5 show the risk of lung cancer for former smokers associated with the age stopped smoking and the time since smoking cessation. Risks were adjusted for asbestos exposure by including the variables from the final model for asbestos exposure defined in Section 3.3.1 (Table 9). The estimated risks among former smokers are also presented using never and current smokers (in turn) as the reference category (Table 14). The effect of ‘sick-quitters’ (smokers who gave up smoking because of illness) in the former smoker category was assessed indirectly by excluding those participants who stopped smoking less than three, five or ten years before death (Table 15). Overall, both age stopped smoking and time since smoking cessation were associated with lung cancer mortality (Table 14).

There was a significant upward trend in risk as age stopped smoking increased. Mortality risk from lung cancer was significantly increased when cessation occurred after age 40 years, as compared to before 30 years of age (RR 2.7, 95% CI 1.5-4.6) (Table 14). Smoking cessation before 30 years of age was associated with the lowest risk, which was greater than that of never smokers (RR 1.8, 95% CI 1.0-3.3) (Table 14). Stopping smoking at any age had significantly lower risk than current smokers (Table 14). The risk of lung cancer mortality decreased as the time since smoking cessation increased. The lowest risk was associated with more than 40 years since smoking cessation, which was not significantly different to that of never smokers (RR 1.6, 95% CI 0.9-2.9).

Removal of sick-quitters had relatively small effects on the results for former smokers (Table 15). The removal of those who quit less than three years and less than five years before death resulted in time since smoking cessation of 10 to 19 years no longer being statistically significantly different to less than 10-years since cessation. However, the observed trends for both variables remained. When removing those who quit less than 10-years before death, stopping smoking after 60 years of age was not significantly different to stopping before the age of 30 years.

18

Table 8 Risk of lung cancer mortality among all workers, adjusted for age, calendar period, sex and smoking status using Poisson regression.

Deaths Person-years RR† (95% CI) LR-test (df) Trend

Age at first exposure to asbestos 43.2 (4)** p<<0.0001 < 20 fi 311 398,886 1.0

20- 344 682,764 0.7** (0.6 – 0.8) 30- 430 364,767 0.7** (0.6 – 0.8) 40- 445 198,069 0.7** (0.6 – 0.8) 50- 293 79,856 0.6** (0.5 – 0.7)

Year of first exposure 52.7 (4)** p<<0.0001 < 1940 fi 120 20,726 1.0

1940- 241 53,809 1.1 (0.9 – 1.4) 1950- 362 126,896 1.0 (0.8 – 1.2) 1960- 411 285,776 0.7** (0.6 – 0.9) 1970-2005 689 1,236,160 0.7** (0.6 – 0.8)

Length of occupational exposure (years) 38.8 (4)** p<<0.0001 < 10 fi 592 1,071,961 1.0

10- 420 344,838 1.1* (1.0 – 1.3) 20- 363 184,875 1.3** (1.1 – 1.5) 30- 296 91,176 1.5** (1.3 – 1.7) 40- 152 31,493 1.5** (1.2 – 1.8)

Years since first exposure 34.2 (4)** p<<0.0001 < 20 fi 505 1,080,861 1.0

20- 450 361,519 1.1 (0.9 – 1.2) 30- 392 179,434 1.2* (1.0 – 1.4) 40- 294 75,319 1.4** (1.2 – 1.6) 50- 182 27,210 1.7** (1.4 – 2.0)

Years since first exposure (excl. <10yrs latency) 29.7 (4)** p<<0.0001 < 20 fi 376 536,284 1.0

20- 450 361,519 1.0 (0.9 – 1.1) 30- 392 179,434 1.1 (0.9 – 1.3) 40- 294 75,319 1.3** (1.1 – 1.5) 50- 182 27,210 1.6** (1.3 – 1.9)

Years since last exposure 5.8 (4) p=0.547 < 5 fi 479 555,541 1.0

5- 395 333,247 1.0 (0.9 – 1.2) 10- 374 270,581 0.9 (0.8 – 1.1) 15- 328 169,946 1.1 (0.9 – 1.3) 20- 247 117,015 0.9 (0.7 – 1.1)

Length of time in survey 0.04 (1) One examination fi 892 924,091 1.0

≥ two examinations 931 800,251 1.0 (0.9 – 1.1)

Time of first exposure 10.1 (1)** Pre-ALR fi 1,720 1,251,681 1.0

Post-ALR 103 472,661 0.7** (0.6 – 0.9)

Main job 80.8 (3)** Manufacturing fi 981 691,683 1.0

Stripping 406 768,165 1.1* (1.0 – 1.3) Other 151 140,869 1.0 (0.8 – 1.2) Insulation 285 123,158 1.9** (1.7 – 2.2)

† Relative risk adjusted with Poisson regression for age, calendar period, sex and smoking status; * significant at p≤ 0.05; ** significant at p ≤ 0.01; LR test, Likelihood ratio test of goodness-of-fit; df, degrees of freedom; fi Reference category; CI, confidence interval; Trend, significance of continuous variable.

19

Rel

ativ

e ris

k of

lung

can

cer m

orta

lity

2.5

2.0

1.5

1.0

0.5

0.0

<20

20-

30-

40-

50-

<194

0

1940

-

1950

-

1960

-

1970

-

<10

10-

20-

30-

40-

<20

20-

30-

40-

50-

<5 5- 10-

15-

20- 1 >1

Pre

-ALR

Pos

t-ALR

Man

ufac

turin

g

Stri

ppin

g

Oth

er

Insu

latio

n

Age at first exposure Year of first exposure Length of exposure (years)

Time since first exposure (years)

Time since last exposure (years)

Number of

exams

Time of first

exposure

Main job

Figure 3 Relative risks of lung cancer mortality by asbestos exposure variables, estimated using Poisson regression (Rates are adjusted by age, calendar period, sex and smoking status; Error bars represent 95% confidence intervals; Dashed line represents the

reference category)

20

Table 9 Risk of lung cancer mortality among all asbestos workers in the final Poisson regression model for asbestos exposure


Age (years) < 40 fi

40- 45-50-55-60-65- 70- 75-

14 20 73

128 244 357 378 303 306

631,118 224,586 207,494 185,034 157,948 126,014

90,640 56,071 45,437

1.0 3.6** (1.8 – 7.2)

13.9** (7.7 – 24.9) 25.3** (14.2 – 45.0) 52.4** (29.4 – 93.2) 96.8** (54.1 – 173.3)

141.6** (78.2 – 256.3) 190.7** (103.6 – 350.9) 257.5** (137.4 – 482.5)

754.4 (8)** p<<0.0001

Period < 1980 fi

1980- 1985- 1990- 1995- 2000-

123 230 267 331 337 535

132,977 180,403 275,457 328,198 349,192 458,116

1.0 1.2 (0.9 – 1.4) 0.9 (0.7 – 1.1) 0.8 (0.7 – 1.1) 0.7** (0.6 – 0.9) 0.8* (0.6 – 1.0)

24.3 (5)** p<<0.0001

Sex Male fi Female

1,742 81

1,622,882 101,460

1.0 0.6** (0.5 – 0.7)

26.8 (1)**

Smoking status Current Former

Never fi

1,431 302 35

889,358 348,463 432,048

14.7** (10.5 – 20.6) 4.6** (3.3 – 6.6) 1.0

851.6 (2)** p<<0.0001

Main job Manufacturing fi Stripping Other Insulation

981 406 151 285

691,683 768,165 140,869 123,158

1.0 1.0 (0.9 – 1.2) 0.9 (0.8 – 1.1) 1.8** (1.6 – 2.1)

73.8 (3)**

Length of occupational exposure (yea < 10 fi 592

10- 420 20- 363 30- 296 40- 152

rs) 1,071,961

344,838 184,875

91,176 31,493

1.0 1.2* (1.0 – 1.4) 1.4** (1.2 – 1.7) 1.7** (1.3 – 2.2) 1.6* (1.1 – 2.2)

18.1 (4)** p<<0.0001

Age at first exposure to asbestos < 20 fi 311

20- 344 30- 430 40- 445 50- 293

398,886 682,764 364,767 198,069

79,856

1.0 0.7** (0.6 – 0.9) 0.9 (0.7 – 1.1) 1.0 (0.8 – 1.3) 1.0 (0.7 – 1.4)

19.1 (4)** p=0.469

† Relative risk adjusted with Poisson regression for all variables in the table; * significant at p≤ 0.05; ** significant at p ≤ 0.01; LR test, Likelihood ratio test of goodness-of-fit; df, degrees of freedom; fi Reference category; CI, confidence interval; Trend, significance of continuous variable.

21

Table 10 Risk of lung cancer mortality among never smokers, adjusted for age, calendar period, sex and smoking status using Poisson regression


Age at first exposure to asbestos < 30 fi 16

30- 9 40- 10

310,040 75,630 46,378

1.0 1.2 (0.5 – 2.8) 0.8 (0.3 – 2.0)

0.9 (2) p=0.596

Year of first exposure < 1960 fi

1960-1970-2005

12 12 11

37,280 63,976

330,791

1.0 1.3 (0.6 – 3.0) 0.5 (0.2 – 1.6)

4.4 (2) p=0.028

Length of occupational exposure (yea < 10 fi 8

10- 10 20- 9 30- 8

rs) 280,876

86,509 40,975 23,688

1.0 2.3 (0.8 – 6.2) 2.7 (0.9 – 7.9) 2.0 (0.7 – 6.3)

4.6 (3) p=0.156

Years since first exposure < 30 fi

30- 40-

14 12

9

371,535 39,804 20,709

1.0 2.6* (1.0 – 6.6) 1.5 (0.5 – 4.2)

4.9 (2) p=0.196

Years since first exposure (excl. <10y < 30 fi 13

30- 12 40- 9

rs latency) 227,562

39,804 20,709

1.0 2.4 (1.0 – 5.8) 1.4 (0.5 – 3.9)

4.9 (2) p=0.206

Years since last exposure < 10 fi

10-15-

14 8

13

237,471 68,642 70,019

1.0 0.9 (0.4 – 2.3) 1.0 (0.3 – 2.9)

0.04 (2) p=0.972

Length of time in survey One examination fi 17 226,720 1.0

0.1 (1)

≥ two examinations 18 205,328 0.9 (0.5 – 1.8)

Time of first exposure Pre-ALR fi

Post-ALR 35

0 297,796 134,252

1.0 -- (--)

Main job Manufacturing fi Stripping Other Insulation

20 7 2 6

158,562 204,750

40,758 27,907

1.0 0.5 (0.2 – 1.5) 0.5 (0.1 – 2.1) 2.0 (0.8 – 5.2)

6.1 (3)

† Relative risk adjusted with Poisson regression for age, calendar period, sex and smoking status; * significant at p≤ 0.05; ** significant at p ≤ 0.01; LR test, Likelihood ratio test of goodness-of-fit; df, degrees of freedom; fi Reference category; CI, confidence interval; Trend, significance of continuous variable.

22

Table 11 Risk of lung cancer mortality among former and current smokers, adjusted for age, calendar period, sex, smoking status and asbestos exposure

using Poisson regression


Age started smoking (years) < 16 fi 514

16- 692 20- 335 30- 19 40- 6

Packs smoked per day < 0.5 fi 59

0.5- 398 1.0- 656 2.0- 82 3.0- 13

Smoking duration (years) < 10 fi 11

10- 49 20- 106 30- 302 40- 511 50- 429 60- 151

Total smoking exposure (pack-years) < 10 fi 32

10- 94 20- 144 30- 214 40- 217 50- 187 60- 106 70- 85 80- 109

305,303 508,014 175,188

14,784 5,290

106,294 342,502 369,200

33,407 6,043

136,127 242,949 249,592 202,093 116,311

46,015 11,419

200,434 210,997 163,703 113,110

66,511 36,521 19,552 10,886 13,616

66.8 (4)** p<<0.0001 1.0 0.8** (0.7 – 0.9) 0.7** (0.6 – 0.8) 0.3** (0.2 – 0.5) 0.2** (0.1 – 0.5)

139.9 (4)** p<<0.0001 1.0 2.1** (1.6 – 2.7) 3.2** (2.5 – 4.2) 4.2** (3.0 – 5.8) 3.7** (2.0 – 6.9)

109.0 (6)** p<<0.0001 1.0 2.6** (1.3 – 5.0) 3.5** (1.9 – 6.7) 5.5** (3.0 – 10.4) 7.8** (4.1 – 14.8)

11.2** (5.8 – 21.6) 13.0** (6.5 – 25.9)

185.2 (8)** p<<0.0001 1.0 2.2** (1.4 – 3.2) 2.7** (1.8 – 4.0) 3.8** (2.6 – 5.5) 4.3** (2.9 – 6.3) 5.2** (3.5 – 7.8) 5.2** (3.4 – 7.8) 7.5** (4.9 – 11.4) 6.3** (4.2 – 9.5)

† Relative risk adjusted with Poisson regression for age, calendar period, sex, smoking status, main occupation, length of exposure and age at first exposure to asbestos; * significant at p≤ 0.05; ** significant at p ≤ 0.01; LR test, Likelihood ratio test of goodness-of-fit; df, degrees of freedom; fi Reference category; CI, confidence interval; Trend, significance of continuous variable.

23

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0 <16 16- 20- 30- 40- <0.5 0.5- 1- 2- 3- <10 10- 20- 30- 40- 50- 60- <10 10- 20- 30- 40- 50- 60- 70- 80-

Age started smoking (years) Packs smoked per day Smoking duration (years) Total smoke exposure (pack-years)

Figure 4 Relative risks of lung cancer mortality by smoking variables, estimated using Poisson regression (Rates are adjusted by age, calendar period, sex, smoking status and asbestos exposure; Error bars represent 95% confidence intervals; Dashed line

represents the reference category)

24

Table 12 Risk of lung cancer mortality among former and current smokers relative to never smokers, adjusted for age, calendar period, sex, smoking status

and asbestos exposure using Poisson regression

Deaths Person-years RR† (95% CI) LR-test (df)

Age started smoking (years) 509.3 (5)** Never smokers fi 35 432,048 1.0 < 16 514 305,303 13.8** (9.8 – 19.4)

16- 692 508,014 10.7** (7.6 – 15.0) 20- 335 175,188 9.4** (6.6 – 13.3) 30- 19 14,784 5.0** (2.8 – 8.7) 40- 6 5,290 3.2** (1.3 – 7.5)

Packs smoked per day 539.3 (5)** Never smokers fi 35 432,048 1.0 < 0.5 59 106,294 3.9** (2.6 – 5.9)

0.5- 398 342,502 8.8** (6.2 – 12.5) 1.0- 656 369,200 13.5** (9.6 – 19.0) 2.0- 82 33,407 13.1** (8.8 – 19.5) 3.0- 13 6,043 9.7** (5.1 – 18.5)

Smoking duration (years) 907.9 (7)** Never smokers fi 35 432,048 1.0 < 10 11 136,127 1.3 (0.7 – 2.7)

10- 49 242,949 3.6** (2.3 – 5.5) 20- 106 249,592 5.4** (3.7 – 7.9) 30- 302 202,093 9.5** (6.7 – 13.5) 40- 511 116,311 15.2** (10.7 – 21.7) 50- 429 46,015 24.1** (16.7 – 34.8) 60- 151 11,419 28.4** (18.7 – 43.0)

Total smoking exposure (pack-years) 802.1 (9)** Never smokers fi 35 432,048 1.0

< 10 32 200,434 2.1** (1.3 – 3.4) 10- 94 210,997 5.3** (3.6 – 7.7) 20- 144 163,703 7.8** (5.4 – 11.4) 30- 214 113,110 11.7** (8.1 – 16.7) 40- 217 66,511 14.3** (10.0 – 20.5) 50- 187 36,521 18.4** (12.8 – 26.6) 60- 106 19,552 18.0** (12.2 – 26.5) 70- 85 10,886 25.6** (17.1 – 38.1) 80- 109 13,616 21.6** (14.7 – 32.0)

† Relative risk adjusted with Poisson regression for age, calendar period, sex, smoking status, main occupation, length of exposure and age at first exposure to asbestos; fi Reference category; * significant at p≤ 0.05; ** significant at p ≤ 0.01; LR test, Likelihood ratio test of goodness-of-fit; df, degrees of freedom; CI, confidence interval; Trend, significance of continuous variable.

25

Table 13 Risk of lung cancer mortality among former and current smokers in the final Poisson regression model for smoking exposure

Deaths Person-years RR† (95% CI) LR-test (df) Trend Age (years) 181.2 (8)** p<<0.0001 < 40 fi 13 416,937 1.0

40- 19 156,543 2.6* (1.1 – 6.2) 45- 71 149,964 7.9** (3.9 – 16.3) 50- 125 139,505 10.0** (4.9 – 20.6) 55- 226 122,740 19.9** (9.6 – 41.0) 60- 344 99,539 34.4** (16.5 – 72.1) 65- 360 71,701 40.2** (18.8 – 85.7) 70- 285 44,678 47.8** (21.9 – 104.5) 75- 290 36,213 60.4** (27.0 – 135.2)

Period 23.8 (5)** p=0.002 < 1980 fi 117 101,760 1.0

1980- 220 133,889 1.2 (0.9 – 1.5) 1985- 259 200,173 1.0 (0.7 – 1.2) 1990- 311 234,637 0.8 (0.6 – 1.1) 1995- 317 246,914 0.7** (0.5 – 0.9) 2000- 509 320,449 0.8 (0.6 – 1.1)

Sex 12.0 (1)** Male fi 1,660 1,174,552 1.0 Female 73 63,269 0.7** (0.5 – 0.8)

Smoking status 18.1 (1)** Current 1,431 889,358 1.6** (1.3 – 2.0)

Former fi 302 348,463 1.0 Main job 41.4 (4)** Manufacturing fi 925 497,385 1.0

Stripping 390 553,488 1.1 (0.9 – 1.3) Other 146 95,560 1.0 (0.8 – 1.2) Insulation 272 91,254 1.7** (1.5 – 2.0)

Length of occupational exposure (years) 17.7 (4)** p=0.001 < 10 fi 534 738,510 1.0

10- 409 257,451 1.2* (1.0 – 1.5) 20- 352 143,242 1.6** (1.3 – 2.0) 30- 291 72,617 1.8** (1.3 – 2.4) 40- 147 26,001 1.6* (1.0 – 2.4)

Age at first exposure to asbestos 10.3 (4)* p=0.700 < 20 fi 300 267,832 1.0

20- 333 477,169 0.8* (0.6 – 1.0) 30- 416 276,509 1.0 (0.7 – 1.3) 40- 425 155,882 1.0 (0.8 – 1.4) 50- 259 60,430 1.0 (0.7 – 1.6)

Smoking duration (years) 17.2 (6)** p<<0.0001 < 10 11 136,127 1.0

10- 49 242,949 1.7 (0.8 – 3.4) 20- 106 249,592 1.5 (0.7 – 3.0) 30- 302 202,093 1.9 (0.9 – 3.9) 40- 511 116,311 2.2* (1.0 – 4.7) 50- 429 46,015 2.9** (1.3 – 6.3) 60- 151 11,419 3.0** (1.3 – 6.8)

Total smoking exposure (pack-years) 117.0 (8)** p<<0.0001 < 10 32 200,434 1.0

10- 94 210,997 1.9** (1.2 – 2.9) 20- 144 163,703 2.3** (1.5 – 3.6) 30- 214 113,110 3.1** (2.0 – 4.8) 40- 217 66,511 3.5** (2.3 – 5.4) 50- 187 36,521 4.1** (2.6 – 6.4) 60- 106 19,552 4.1** (2.6 – 6.4) 70- 85 10,886 5.9** (3.7 – 9.5) 80- 109 13,616 4.9** (3.1 – 7.7)

† Relative risks adjusted with Poisson regression for all variables in the table; * significant at p≤ 0.05; ** significant at p ≤ 0.01; LR test, Likelihood ratio test of goodness-of-fit; df, degrees of freedom; fi Reference category; CI, confidence interval; Trend, significance of continuous variable.

26

Table 14 Risk of lung cancer mortality among former smokers relative to the lowest level of each variable, never smokers and current smokers, adjusted for

age, calendar period, sex and asbestos exposure using Poisson regression


Former smokers only

Age stopped smoking (years) < 30 fi 17

30- 38 40- 75 50- 117 60- 19

Time since smoking cessation (years) < 10 fi 54

10- 83 20- 78 30- 35 40- 16

Former relative to never-smokers

Age stopped smoking (years) Never smokers fi 35

< 30 17 30- 38 40- 75 50- 117 60- 19

Time since smoking cessation (years) Never smokers fi 35

< 10 54 10- 83 20- 78 30- 35 40- 16

Former relative to current-smokers

Age stopped smoking (years) Current smokers fi 1,431 < 30 17

30- 38 40- 75 50- 117 60- 19

Time since smoking cessation (years) Current smokers fi 1,431 < 10 54

10- 83 20- 78 30- 35 40- 16

49.5 (4)** p<<0.0001 111,636 1.0

80,593 1.7 (0.9 – 3.0) 59,830 2.7** (1.5 – 4.6) 35,535 4.6** (2.6 – 8.1) 5,607 3.6** (1.7 – 7.3)

43.5 (4)** p<<0.0001 87,866 1.0 93,864 0.6* (0.4 – 0.9) 68,769 0.4** (0.3 – 0.7) 29,717 0.3** (0.2 – 0.5) 12,979 0.2** (0.1 – 0.3)

135.6 (5)** 432,048 1.0 111,636 1.8* (1.0 – 3.3)

80,593 3.0** (1.9 – 4.8) 59,830 4.7** (3.1 – 7.1) 35,535 7.8** (5.2 – 11.9) 5,607 6.0** (3.2 – 11.0)

133.1 (5)** 432,048 1.0

87,866 9.4** (5.8 – 15.2) 93,864 6.0** (4.0 – 9.0) 68,769 4.2** (2.8 – 6.3) 29,717 2.7** (1.7 – 4.4) 12,979 1.6 (0.9 – 2.9)

434.8 (5)** 889,358 1.0 111,636 0.1** (0.1 – 0.2)

80,593 0.2** (0.1 – 0.3) 59,830 0.3** (0.2 – 0.4) 35,535 0.5** (0.4 – 0.6) 5,607 0.4** (0.2 – 0.6)

415.2 (5)** 889,358 1.0

87,866 0.5** (0.4 – 0.7) 93,864 0.4** (0.3 – 0.5) 68,769 0.3** (0.2 – 0.4) 29,717 0.2** (0.2 – 0.3) 12,979 0.1** (0.1 – 0.2)

† Relative risk adjusted with Poisson regression for age, calendar period, sex, main occupation, length of exposure and age at first exposure to asbestos; * significant at p≤ 0.05; ** significant at p ≤ 0.01; LR test, Likelihood ratio test of goodness-of-fit; df, degrees of freedom; fi Reference category; CI, confidence interval; Trend, significance of continuous variable.

27

Table 15 Risk of lung cancer mortality among former smokers, with sick-quitters removed and adjusted for age, calendar period, sex and asbestos exposure

using Poisson regression


Quit less than 3-years before death removed


30- 37 40- 74 50- 114 60- 17

111,636 80,589 59,827 35,524 5,597

1.0 1.6 (0.9 – 2.9) 2.5** (1.5 – 4.4) 4.3** (2.5 – 7.5) 3.0** (1.4 – 6.4)

45.9 (4)** p<<0.0001


10- 83 20- 78 30- 35 40- 16

87,838 93,864 68,769 29,717 12,979

1.0 0.7 (0.5 – 1.0) 0.5** (0.3 – 0.8) 0.3** (0.2 – 0.5) 0.2** (0.1 – 0.3)

40.0 (4)** p<<0.0001



30- 37 40- 73 50- 105 60- 17

111,636 80,589 59,822 35,498 5,597

1.0 1.6 (0.9 – 2.9) 2.5** (1.5 – 4.4) 4.0** (2.3 – 7.1) 3.1** (1.5 – 6.5)

39.2 (4)** p<<0.0001


10- 83 20- 78 30- 35 40- 16

87,808 93,864 68,769 29,717 12,979

1.0 0.9 (0.6 – 1.3) 0.6* (0.4 – 1.0) 0.4** (0.2 – 0.6) 0.2** (0.1 – 0.4)

34.8 (4)** p<<0.0001


Age stopped smoking (years) < 30 fi

30-40-50-60-

17 35 70 80 10

111,636 80,579 59,804 35,330 5,544

1.0 1.5 (0.8 – 2.7) 2.3** (1.3 – 3.9) 2.8** (1.6 – 4.9) 1.6 (0.7 – 3.8)

20.7 (4)** p<<0.0001


20- 78 30- 35 40- 16

181,423 68,769 29,717 12,979

1.0 0.9 (0.6 – 1.3) 0.6** (0.4 – 0.9) 0.3** (0.2 – 0.6)

24.2 (3)** p<<0.0001

† Relative risk adjusted with Poisson regression for age, calendar period, sex, main occupation, length of exposure and age at first exposure to asbestos; fi Reference category; * significant at p≤ 0.05; ** significant at p ≤ 0.01; LR test, Likelihood ratio test of goodness-of-fit; df, degrees of freedom; CI, confidence interval; Trend, significance of continuous variable.

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0 <30 30- 40- 50- 60- <10 10- 20- 30- 40-

Age stopped smoking (years) Time since smoking cessation (years)

Figure 5 Relative risks of lung cancer mortality among former smokers by smoking variables, estimated using Poisson regression

(Rates are adjusted by age, calendar period, sex, smoking status and asbestos exposure; Error bars represent 95% confidence intervals; Dashed line represents the reference category)

29

3.4 ASBESTOS AND SMOKING INTERACTION

Table 16 shows the estimated relative risks with corresponding multiplicativity (V) and synergy (S) indices estimated using Poisson regression. Workers were classified as having ‘low’ or ‘high’ asbestos exposure based on their length of occupational exposure. Since the number of deaths among never smokers was small, particularly among those with the shortest asbestos exposure durations, the analysis was carried out using three different duration cut-offs: 1) low exposure defined as less than three years duration and high exposure as more than 40 years; 2) low exposure as less than five years, high exposure as more than 35 years; and 3) low exposure as less than seven years, high exposure as more than 30 years.

Although the risk of mortality from lung cancer for never smokers with high exposure was greater than never smokers with low exposure, this was not statistically significant in any of the classifications used (< three years vs. > 40 years: RR 2.6, 95% CI 0.6-11.7) as shown in Table 16. Index V was less than one for all the classifications used, but not statistically significantly so. Index S was statistically significantly greater than one for all but the most restrictive classification used (< three years vs. > 40 years: S 1.2, 95% CI 0.8-1.7).

In Section 3.3.3, former smokers who had stopped smoking for more than 40 years were found to have risks of lung cancer mortality that were not statistically significantly different to never smokers. In order to further increase the number of never smokers, the analysis was repeated classifying these former smokers as never smokers. The resulting RRs and values for V and S were similar to those obtained using purely never smokers (Table 17). Index V was again not statistically significantly different to a value of one, with S statistically significantly greater than one for all but the most restrictive classification used.

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Table 16 Multiplicativity index (V) and synergy index (S) estimated using relative risks adjusted by age, calendar period, sex and main occupation

Smoking Asbestos Person-status exposure Deaths years RR† (95% CI) V (95% CI) S (95% CI)

Low: < 3 years; High: > 40 years 0.5 (0.1 – 2.2) 1.2 (0.8 – 1.7) Never Low 3 139,155 1.0

High 4 5,432 2.6 (0.6 – 11.7) Current Low 153 299,977 18.9** (6.0 – 59.3)

High 94 12,485 23.8** (7.2 – 78.9)

Low: < 5 years; High: > 35 years 0.5 (0.1 – 1.7) 1.3* (1.0 – 1.7) Never Low 4 195,749 1.0

High 7 12,546 2.8 (0.8 – 9.5) Current Low 272 413,801 22.6** (8.4 – 60.8)

High 192 26,870 31.5** (11.5 – 86.4)

Low: < 7 years; High: > 30 years 0.7 (0.2 – 2.2) 1.4** (1.2 – 1.7) Never Low 5 236,851 1.0

High 8 23,688 2.1 (0.7 – 6.4) Current Low 357 492,584 23.4** (9.7 – 56.6)

High 322 50,590 33.9** (13.8 – 83.0) † Relative risks adjusted for age, calendar period, sex and main occupation using Poisson regression; CI, confidence interval; * significant at p≤ 0.05; ** significant at p ≤ 0.01.

Table 17 Multiplicativity index (V) and synergy index (S) estimated combining never-smokers with former smokers who had stopped smoking for more than 40

years, using relative risks adjusted by age, calendar period, sex and main occupation

Asbestos Person-Smoking status exposure Deaths years RR† (95% CI) V (95% CI) S (95% CI)

Low: < 3 years; High: > 40 years 0.5 (0.2 – 1.6) 1.1 (0.8 – 1.6) Never‡ Low 5 139,918 1.0

High 8 6,759 2.5 (0.8 – 7.7) Current Low 153 299,977 12.5** (5.1 – 30.0)

High 94 12,485 15.4** (6.0 – 39.9)

Low: < 5 years; High: > 35 years 0.8 (0.3 – 2.0) 1.3* (1.0 – 1.7) Never‡ Low 8 197,207 1.0

High 11 15,002 1.8 (0.7 – 4.5) Current Low 272 413,801 12.4** (6.2 – 25.1)

High 192 26,870 17.2** (8.3 – 35.7)

Low: < 7 years; High: > 30 years 0.9 (0.4 – 2.1) 1.4** (1.2 – 1.7) Never‡ Low 9 238,964 1.0

High 13 27,497 1.6 (0.7 – 3.8) Current Low 357 492,584 14.4** (7.4 – 27.9)

High 322 50,590 20.8** (10.6 – 40.8) † Relative risks adjusted for age, calendar period, sex and main occupation using Poisson regression; ‡ Never smokers plus former smokers who stopped smoking for more than 40 years; CI, confidence interval; * significant at p≤ 0.05; ** significant at p ≤ 0.01.

31

3.4.1 Attributable fraction estimation

The RRs obtained from the above Poisson regression were used to estimate the proportion of deaths attributable to asbestos, smoking, and the interaction of the two among the asbestos workers (see Appendix 1 for full methodology). The classification of workers into ‘unexposed’ and ‘exposed’ groups for the calculation of the attributable fraction therefore followed the previous classifications of “low” and “high” asbestos exposure: 1) unexposed defined as less than three years duration and exposed as more than 40 years, 2) unexposed as less than five years, exposed as more than 35 years, and 3) unexposed as less than seven years, exposed as more than 30 years.

Table 18 shows the percentage of lung cancer deaths attributable to asbestos and smoking among the asbestos workers. All results discussed correspond to the classification of ‘unexposed’ as less than seven years of exposure and ‘exposed’ as more than 30 years of exposure, since all groups in this classification observed at least five deaths. For those exposed to both smoking and asbestos, an estimated 28% (95% CI 15-41%) of lung cancer deaths were attributable to the interaction between asbestos and smoking ( Table 18). There were more deaths attributable to smoking only than asbestos exposure only (66% versus 3%).

The inclusion of former smokers who had stopped smoking for more than 40 years did not affect the estimated proportion of lung cancer deaths due to the interaction of asbestos and smoking (Table 19 ). However, the background rate of lung cancer mortality increased with the inclusion of former smokers, and the proportion attributable to asbestos only and smoking only decreased ( Table 19).

Among male asbestos workers, there were around 435 lung cancer deaths and 584 mesothelioma deaths observed in excess of expected numbers, as calculated using British population rates (and adjusted for smoking in the case of lung cancer) (Table 20 ). The ratio of excess lung cancer deaths to mesothelioma was therefore 0.75. If all the excess lung cancers were caused by asbestos, it would suggest that 27% of total lung cancer deaths among the male asbestos workers were attributable to asbestos exposure ( Table 20). If a ratio of asbestos-related lung cancer to mesothelioma of 0.75 applied to the entire British male population, it would suggest that about 4% of lung cancer deaths in British men over the last 20 years were attributable to asbestos exposure (Table 21).

32

Table 18 Percentage attributable risks from smoking and asbestos exposureamong the asbestos workers

Smoking Asbestos Deaths Person- % Attributable to †

status exposure years Background Asbestos only Smoking only Both factors

Unexposed: < 3 years; Exposed: > 40 years Never Unexposed 3 139,155 100% --- --- ---

Exposed 4 5,432 38% 62% --- ---(-20 – 96%) (4 – 120%)

Current Unexposed 153 299,977 5% --- 95% ---(-1 – 11%) (89 – 101%)

Exposed 94 12,485 4% 7% 75% 14% (-1 – 9%) (-5 – 18%) (50 – 100.3%) (-15 – 44%)


Exposed 7 12,546 36% 64% --- ---(-9 – 81%) (19 – 109%)

Current Unexposed 272 413,801 4% --- 96% ---(0.04 – 9%) (91 – 99.96%)

Exposed 192 26,870 3% 6% 68% 23% (-0.03 – 6%) (-2 – 13%) (53 – 84%) (5 – 41%)


Exposed 8 23,688 48% 52% --- ---(-6 – 103%) (-3 – 106%)

Current Unexposed 357 492,584 4% --- 96% ---(0.5 – 8%) (92 – 99.5%)

Exposed 322 50,590 3% 3% 66% 28% (0.3 – 6%) (-2 – 8%) (54 – 78%) (15 – 41%)

Values in parenthesis show 95% confidence intervals † Calculated using RRs estimated from Poisson regression (Table 16);

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Table 19 Percentage attributable risks from smoking and asbestos exposure,estimated combining never smokers with former smokers who had stopped

smoking for more than 40 years Smoking Asbestos Deaths Person- % Attributable to †

status exposure years Background Asbestos only Smoking only Both factors

Unexposed: < 3 years; Exposed: > 40 years Never ‡ Unexposed 5 139,918 100% --- --- ---

Exposed 8 6,759 41% 59% --- ---(-6 – 87%) (13 – 106%)

Current Unexposed 153 299,977 8% --- 92% ---(1 – 15%) (85 – 99%)

Exposed 94 12,485 6% 10% 74% 10% (0.3 – 13%) (-3 – 22%) (49 – 98%) (-19 – 40%)


Exposed 11 15,002 56% 44% --- ---(4 – 108%) (-8 – 96%)


Exposed 192 26,870 6% 5% 67% 23% (2 – 10%) (-3 – 12%) (51 – 82%) (5 – 41%)


Exposed 13 23,688 63% 37% --- ---(9 – 117%) (-17 – 91%)


Exposed 322 50,590 5% 3% 65% 28% (2 – 8%) (-2 – 8%) (53 – 76%) (15 – 41%)

Values in parenthesis show 95% confidence intervals † Calculated using RRs estimated from Poisson regression (Table 17); ‡ Never smokers plus former smokers who stopped smoking for more than 40 years.

34

Table 20 Estimation of the attributable fraction for lung cancer mortality due to asbestos exposure among male asbestos workers (1971-2005)

Observed Expected Excess Ratio of Attributable Attributable excess number fraction

Lung cancer 1,738 1,303‡ 435 0.75 470 27% Mesothelioma† 631 47 584

† Mesothelioma as defined by the mesothelioma register – any mention of mesothelioma on the death certificate (HSE, 2008a); ‡ Adjusted for smoking habits of the asbestos workers (see Table 7)

Table 21 Estimation of the population attributable fraction for lung cancer mortality due to asbestos exposure among males in Great Britain (1986-2005)

Observed Attributable Population number attributable

fraction Lung cancer 462,032† 17,837 4% Mesothelioma 23,924‡

† Sources: Office for National Statistics (ONS, 2006) for England and Wales, and General Register Office for Scotland (GROS, 1997; GROS, 2006); ‡ Source: Health & Safety Executive (HSE, 2008b)

35

4 DISCUSSION

4.1 STRENGTHS AND LIMITATIONS

The strengths and limitations of the survey have been discussed in detail elsewhere (Harding & Wegerdt, 2006; Harding & Frost, 2009) and are summarised below.

The GB Asbestos Survey is an important study set up to monitor the long-term health and mortality of workers occupationally exposed to asbestos. Since 1971 it has been successful in recruiting and following a large number of these workers, and continues to do so today. The survey not only collects personal details and information regarding occupational exposure to asbestos, but also asks questions about current smoking habits.

The criteria for inclusion in the survey have changed according to the regulations in force at different times. The nature of the British asbestos industry has also changed considerably with progressively stringent regulation and banning of the importation of asbestos and use of asbestos products. Thus, at the start of the survey, the majority of asbestos workers were employed in the asbestos product manufacturing industry, but in more recent years the vast majority have been employed in the stripping/removal sector (Harding & Wegerdt, 2006).

One of the main limitations of the survey is the lack of detailed exposure measurements and information about the type of asbestos fibres. There is evidence that different forms of asbestos pose different health risks, though the evidence for a differential between the carcinogenic potency of chrysotile and amphibole is less clear cut in the case of lung cancer than mesothelioma. A recent review suggested that the risk differential may range from between 1:10 and 1:50 (Hodgson & Darnton, 2000). Workers employed in different sectors of the asbestos industry were likely to come into contact with different forms of asbestos. Variations in risk by occupation in this study are therefore likely to reflect to some extent differences in the type of asbestos workers were exposed to. Cumulative exposure is also related to lung cancer risk, displaying an increase in risk with increasing exposure (Boffetta, 1998; Henderson et al., 2004). Length of occupational exposure was used as a proxy for cumulative exposure in this study.

Participants completed a questionnaire at every medical examination attended, which enabled details such as smoking status to remain up-to-date. However, the database was set up in such a way that the age started smoking recorded at the previous examination was overwritten by the new age. This could potentially lead to inaccuracies not only in the age started smoking but also the smoking duration and total smoking exposure.

The latency period for asbestos related diseases is 10 to 40 or more years (Levin et al., 1998; Henderson et al., 2004; Yarborough, 2006). With first occupational exposure to asbestos occurring in the 1970s or later for the majority of subjects (77%), this cohort is still relatively young. Any diseases related to exposure are thus still only just beginning to emerge. A longer follow-up period would begin to capture the full extent of the asbestos-related disease.

4.2 DESCRIPTIVE STATISTICS

Lung cancer is currently the most common cancer in the world. In the UK, it is the first and third most common cancer for males and females respectively. Trends in incidence and mortality are generally close due to low survival rates. For England and Wales in 1986 to 1990, only around 20% of people with lung cancer were still alive one year after diagnosis and 5% after five years. There have been some improvement in survival since the 1970s for one year rates, but on the whole survival remains poor (Quinn et al., 2001).

36

4.3

In 2003 in England and Wales, lung cancer accounted for an estimated 28,765 deaths, which was about 21% of all cancers and 5% of all deaths (ONS, 2004). The proportion of lung cancer deaths among the asbestos workers was greater than this, with lung cancer accounting for 34% of all cancers and 12% of all deaths. This difference is, in part, due to the smoking habits of the asbestos workers. Tobacco smoke is an established determinant of lung cancer, causing an estimated 90% of lung cancer cases (Quinn et al., 2001). A large proportion of the participants were current smokers (53%). This was consistently greater than the national population, where just 45% of persons aged 16 and over were current smokers in 1974, dropping to a minimum of around 28% in the 1990s (Walker et al., 2002).

In 2006, almost two fifths of the GB population who were either current or former smokers had started to smoke before reaching 16 years of age (Goddard, 2008). Just 30% of participants in this study recorded starting to smoke before the age of 16. The difference between the two could be due to the potential error in this variable discussed above, or perhaps people felt less able to admit starting to smoke before the age at which cigarettes could legally be bought. However, the number of participants who reported starting to smoke regularly in their teens (80%) was comparable with the GB population, approximately 81% (Goddard, 2008).

Current smokers in the GB population in 2001 were more likely to be light smokers, with approximately 70% smoking less than 20 cigarettes a day (Walker et al., 2002). Although the majority of current smokers in this study also smoked less than 20 cigarettes a day (one pack), there were a larger proportion of heavy smokers (greater than 20 cigarettes) than the national population (44% versus 30%).

ASBESTOS EXPOSURE

Asbestos exposure is an established risk factor for lung cancer mortality (Samet, 1993; Steenland et al., 1999), with asbestos-related lung cancer estimated to account for 2-3% of all lung cancer deaths in Britain over the period 1980-2000 (Darnton et al., 2006). As the main determinant of lung cancer mortality, it is important that the smoking habits of the study population are taken into account. Few asbestos studies have information on smoking status, with some attempting to adjust for this by using birth cohort as a proxy for smoking history (Hein et al., 2007). The recent detailed mortality analysis on this cohort reported proportional mortality ratios (PMR) alongside SMRs in order to informally assess the potential extent of confounding by tobacco smoke and other possible factors. The PMR for lung cancer mortality was statistically significantly elevated (PMR 129, 95% 123-134) as well as the SMR (SMR 187, 95% CI 179-186), suggesting that occupational exposure to asbestos was associated with lung cancer risk (Harding & Frost, 2009). Another study found that the relative risk of lung cancer associated with asbestos exposure was 2.41 (p<0.05), after controlling for age and smoking history (Minowa et al., 1991).

In this study, the SMRs were adjusted for the smoking habits of the asbestos workers using the population attributable risk percent of smoking for lung cancer mortality and the smoking habits of the general population. Even after this adjustment, the overall SMR for male asbestos workers remained statistically significantly elevated (SMR 133, 95% CI 127-140). This suggested that it was not only the smoking habits of the asbestos workers that increased mortality from lung cancer, but also the exposure to asbestos.

In the recent study of the asbestos workers cohort (Harding & Frost, 2009), multivariable Poisson regression analyses were restricted to those in the stripping/removal sector and first exposed to asbestos after implementation of the ALR (1983), resulting in just 49 deaths from lung cancer being included. Smoking status was the only variable significantly associated with an increased lung cancer risk after adjustment for age, calendar period and sex. The current

37

study included all asbestos workers and, as a result, many more lung cancer deaths (n=1,878). A statistically significant association was observed between lung cancer mortality and all the asbestos-related variables, except for the time since last exposure to asbestos and the length of time in the survey. The final multivariable model for asbestos exposure included main occupation, length of exposure and age at first occupational exposure adjusted for age, period, sex, and smoking status. Workers in the insulation sector had a risk of 1.8 (95% CI 1.6-2.1) compared to those in the manufacturing industry. Insulation workers are at a high risk of exposure to asbestos and therefore asbestos-related diseases (Niklinski et al., 2004), which has resulted in a large number of studies in this area (Elmes & Simpson, 1971; Selikoff, 1979; Selikoff et al., 1980; Jarvholm & Sanden, 1998). However, there were no significant differences between the other asbestos sectors. There was a significant upward trend for risk of lung cancer mortality with increasing length of exposure. This is in agreement with previous studies, where direct relationships with duration of exposure (Pira et al., 2005; Magnani et al., 2008) and cumulative exposure (Sullivan, 2007) have been found. The risk of mortality from lung cancer decreased as age at first exposure increased. However, this trend no longer existed once included in the multivariable model. This could be due to possible confounding with the length of occupational exposure.

4.4 NEVER SMOKERS

One approach to assess the impact of asbestos exposure on lung cancer mortality would be to consider only never smokers, removing the majority of cases due to smoking tobacco. However, few never smokers develop lung cancer, resulting in small sample sizes and lack of power. Despite these issues there is still evidence that asbestos exposure increases the risk of lung cancer for non-smokers. A recent review of the literature on occupational lung cancer in non-smokers (never smokers and former smokers) concluded that occupational exposure to asbestos was a “probable” cause of lung cancer (Neuberger & Field, 2003). Evidence has also been found that the risk of lung cancer increases with increased duration of exposure to asbestos, where the highest risks were seen in never smokers with more than 10 years of exposure to asbestos (Morabia et al., 1992).

An attempt to overcome the problem of small numbers was made by combining categories with few deaths in the Poisson regression analyses, but the number of cases were still somewhat limited. However, there were indications in this study that asbestos exposure increased the risk of lung cancer mortality among never smokers. The risk for never smokers was greatest 30 to 39 years after first occupational exposure to asbestos. This coincided with the findings of Selikoff et al. (1980), where lung cancer peaked at 30 to 35 years since first exposure for insulation workers in the United States and Canada, although this study was not restricted to never smokers. Also, the smoking adjusted SMR for male never smokers was greater than 100, although this was not statistically significant (SMR 136, 95% CI 93-192).

4.5 ASBESTOS AND SMOKING

The relationship between smoking and lung cancer is well documented. However, there are few studies that examine the risk of lung cancer associated with smoking for asbestos workers. Lung cancer risk was greatest among those who smoked the most cigarettes over the longest period of time, and also for those with greater total smoking exposure (pack-years). These results mirror investigations into smoking without asbestos exposure (Doll & Peto, 1978; Rogot & Murray, 1980; Zang & Wynder, 1992; Lubin & Caporaso, 2006). Starting to smoke at an early age also increased the risk of lung cancer. Wiencke et al. (1999) suggested that young smokers may be more susceptible to smoking-related DNA damage.

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4.6

Duration of smoking is considered the strongest determinant of lung cancer risk, with the number of cigarettes smoked per day also an important factor (Doll & Peto, 1978; Flanders et al., 2003). The final multivariable model for smoking exposure developed in this study included smoking duration and total smoking exposure, but the number of packs smoked per day did not make a significant contribution to the model fit.

Smoking cessation has major and immediate health benefits, with the risk of all cause mortality returning nearly to that of never smokers after around 10 to 15 years of smoking cessation (US DHHS, 1990). Stopping at any age reduces the risk of lung cancer compared with continued smoking (Doll et al., 1994; IARC, 2004). However, the younger the age at cessation and the greater the length of time since smoking cessation, the greater the benefit (Rogot & Murray, 1980; Peto et al., 2000). A reduced risk of lung cancer is usually evident within five years of cessation, but convergence towards the lung cancer rates of never smokers for former smokers has been inconsistent among those not knowingly exposed to asbestos (US DHHS, 1990). For asbestos workers, de Klerk et al. (1991) and Reid et al. (2006) reported a convergence to near never smoking rates of lung cancer incidence among those who had ceased smoking for 10 or more years (OR 1.30, 95% CI 0.25-6.90) and 20 or more years (OR 1.9, 95% CI 0.5-7.2) respectively. These values are much less than found in this study, where convergence was not seen until 40 or more years after smoking cessation (RR 1.6, 95% CI 0.9-2.9).

ASBESTOS AND SMOKING INTERACTION

Multiplicativity and synergy indices were used to test for multiplicative and additive interaction (respectively) between asbestos exposure and smoking. There was no control group of workers unexposed to asbestos in this study. Current and never smokers were therefore subdivided into low and high exposure using the length of occupational exposure to asbestos. The value of the muliplicativity index ranged from 0.5 (95% CI 0.1-2.2) to 0.7 (95% CI 0.2-2.2) depending on the cut-off points used to define low and high exposure. Although the index was consistently less than one, it was not statistically significant and so the hypothesis of a multiplicative interaction between asbestos and smoking could not be rejected. The synergy index ranged from 1.2 (95% CI 0.8-1.7) to 1.4 (95% CI 1.2-1.7) and was statistically significantly greater than one in two of the three classifications used, suggesting that the interaction between asbestos exposure and smoking was greater than additive.

As discussed above, this study found that the risk of lung cancer mortality was not statistically significantly different to never smokers for those who stopped smoking for 40 or more years. Therefore, in order to increase the number of deaths in the never smoker categories and increase the power of the results, these former smokers were included with the never smokers. Despite the fact that the mixing of former smokers with never smokers can lead to bias (Liddell, 2001), the estimates of the multiplicativity and synergy indices were similar, ranging from 0.5 (95% CI 0.2-1.6) to 0.9 (95% CI 0.4-2.1) and 1.1 (0.8-1.6) to 1.4 (1.2-1.7) respectively.

The results of this study indicated that the interaction between asbestos exposure and smoking was closer to multiplicative than additive. This is consistent with recent reviews of the literature. Wraith & Mengersen (2007) used a bayesian meta-analysis approach to obtain overall estimates of the multiplicativity and synergy indices. An estimate of 0.86 (95% credible interval 0.52-1.41) was found for the multiplicativity index and 1.70 (95% credible interval 1.09-2.67) for the synergy index. None of the studies reviewed had an observed estimate for the multiplicativity index that was statistically significantly different to one. Liddell (2001), however, reviewed similar literature and found evidence that, on average, the interaction between smoking and asbestos exposure was less than multiplicative with a “best estimate” of the average relative asbestos effect of 2.04 (95% CI 1.28-3.25), which corresponds to a multiplicativity index of 0.49 (95% CI 0.31-0.78).

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4.6.1 Attributable fraction estimation

The attributable proportion due to interaction is very closely related to the value of the synergy index. The fact that the estimate of the synergy obtained in this study was consistent with the literature means that this would also be the case for the attributable proportion due to interaction. This study estimated that, among asbestos workers who smoked, around 28% (95% CI 15-41%) of lung cancer deaths were attributable to the interaction between asbestos and smoking. The estimate of the attributable proportion corresponding to the synergy index obtained in Wraith & Mengersen (2007) above was 41% (95% credible interval 8-63%). Erren et al. (1999) calculated a weighted average synergy index across 12 studies of 1.64 (95% CI 1.33-2.03), which corresponded to an estimated attributable proportion of 33% (95% CI 22-45%). Also, Lee (2001) found a mean attributable proportion of 36% (no confidence given) for seven cohort studies that did not use external comparisons.

The estimate of excess lung cancer to mesothelioma deaths for male asbestos workers of around three quarters led to an estimated 4% of lung cancer deaths for males in GB attributable to asbestos exposure (1986-2005). Darnton et al. (2006) estimated the ratio to be ~0.7 for GB males during 1980-2000, leading to an estimated 2-3% of total lung cancers attributable to asbestos exposure during this period. These proportions are lower than previously estimated, where ratios of asbestos related lung cancer to mesothelioma deaths have typically been in excess of 1:1. Albin et al. (1999) reviewed the relationship of occupational exposure to asbestos and occurrence of mesothelioma and lung cancer in Europe. Here it was estimated that around 10 to 20% of total lung cancers among males were attributable to occupational asbestos exposure. However, a recent study looking into asbestos-related lung cancer in Italy found a ratio of 1:1, with 3% of all male lung cancers estimated to be asbestos-related (Marinaccio et al., 2008).

4.7 CONCLUSIONS

The GB asbestos workers experienced significantly higher mortality from lung cancer than the national population. There was a high smoking prevalence among the asbestos workers and also a greater prevalence of heavy smokers than the national population.

There were very few deaths from lung cancer for those who had never smoked, so statistical power to detect any effect of asbestos exposure was limited among this group. Based on standardised mortality ratios adjusted to account for the higher smoking prevalence among asbestos workers, never smokers who worked in the asbestos industry had a higher lung cancer mortality than was expected, but this was not statistically significant. Among never smokers, higher mortality rates were seen for those first occupationally exposed to asbestos 30 to 39 years before.

The risk of mortality from lung cancer for asbestos workers was highest among those who were first exposed to asbestos at a young age, were exposed for a long period of time, and were employed in the insulation sector. Starting to smoke at an early age and high intensity smoking for long periods of time also increased the risk of lung cancer mortality. However, stopping smoking at any age resulted in lung cancer mortality rates that were lower than current smokers. Asbestos workers who stopped smoking remained at an increased risk of lung cancer mortality up to 40 years after smoking cessation.

There was evidence of an interaction between asbestos exposure and smoking, and there was no evidence that the interaction between asbestos and smoking was not multiplicative. For those asbestos workers who smoked, an estimated 3% of lung cancer deaths were attributable to asbestos only, 66% to smoking only and 28% to the interaction of asbestos and smoking.

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4.8

Nearly 30% of lung cancer deaths among all male asbestos workers and 4% among the male GB population were estimated to be attributable to asbestos exposure.

RECOMMENDATIONS

The main aim of the GB Asbestos Survey is to monitor the long-term health of asbestos workers covered by the regulations. The GB Asbestos Survey should therefore continue to recruit workers from the asbestos industry into the survey and monitor the mortality of survey participants. This will allow assessment of the effectiveness of regulations implemented to reduce occupational exposure to asbestos on the risk of mortality among these workers.

Smoking is not only associated with lung cancer, but also other diseases such as cerebrovascular disease, respiratory disease and other cancers. Those who both smoke and have been exposed to asbestos have the highest risk of lung cancer mortality. However, almost immediate benefits can be seen by stopping smoking compared to those who continue to smoke. This study emphasises the importance of smoking prevention and cessation within this high-risk cohort.

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Appendix 1 Statistical methods

A1.1 STANDARDISED MORTALITY RATIOS

When comparing mortality rates between different groups of people (in this case the group of British asbestos workers with the British population), it is important to take into account the differing age structures. The standardised mortality ratio (SMR) is a commonly used method to adjust mortality rates for such differences. It allows comparison of the number of observed deaths in the study population with the number of expected deaths if the age-specific death rates were the same as the standard population. An SMR equal to 100 implies that the mortality rate is the same as the standard mortality rate. If the SMR is greater than 100 then above average mortality is implied, with a value less than 100 suggesting below average mortality.

In this analysis, the expected number of deaths was calculated using the 5-year age-, period- and sex-specific mortality rates for England and Wales, and for Scotland. Person-years at risk were calculated from the date of first medical examination (entry into the study) as the starting date, and date of death, loss to follow-up or the end of the study period as the ending date. The ratio of the observed number of deaths to expected was multiplied by 100 to give the SMR. All SMRs were calculated using OCMAP-PLUS V4.00 (Release 01e) (Marsh et al., 2004).

A1.1.1 Smoking adjustment

Tobacco smoking is an important cause of lung cancer. The SMRs calculated as described above compare the age-, period- and sex-specific mortality rates of the asbestos workers to those observed in the general population, but do not take into account differences in smoking habits. As the risk of lung cancer for smokers is much higher than that for non-smokers, the calculated number of expected deaths due to lung cancer will be potentially substantially underestimated for smokers and overestimated for non-smokers. This can be taken into account by calculating a smoking adjustment factor for each smoking category using an estimate of the population attributable-risk percent (PAR%) of smoking for lung cancer and the relative risk of lung cancer for smokers (RRS) and former smokers (RRF) compared to non-smokers. The smoking PAR% of the general population was obtained using mortality according to smoking habits of British male doctors (Doll et al., 2004), with the prevalence of current smokers (PS) and former smokers (PF) for the male national population taken as the average from 1974 to 1998 (Walker et al., 2002) (Table 22 ). The PAR% of 84% was calculated using the formula for multicategory exposures, given by PAR% = 1 – 1/(PS RRS + PF RRF) (Rockhill et al., 1998). The smoking adjustment factors were then calculated as (1 – PAR%) for non-smokers, (1 – PAR%)RRS for current smokers and (1 – PAR%)RRF for former smokers (Yu & Tse, 2007) (Table 22). The adjusted SMRs were obtained by multiplying the expected numbers by the smoking adjustment factor for each smoking category.

Table 22 Factors to adjust expected lung cancer deaths of British males for smoking habits

Smoking habit Never Former Current

Relative rate of lung cancer mortality †

Proportion in national population ‡ 1.0

35% 4.0

30% 14.6 35%

Smoking adjustment factor 0.16 0.64 2.33 † Mortality from lung cancer according to smoking habits of male British doctors (Doll et al., 2004); ‡ Average for British males over 1974 to 1998 (Walker et al., 2002)

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The following methods of Breslow & Day (1987) were used to test the significance of the adjusted SMRs and construct 95% confidence intervals. Let O be the observed number of deaths and E the number expected then SMR =100× O / E , lower limit =100× μL / E and upper limit =100 × μU / E , where

⎡ 1 z ⎤3

α / 2μ = O 1− − ,L ⎢ ⎥⎣ 9 ⋅ O 3 O ⎦

⎡ 1 zα / 2 ⎤3

μU = (O +1)⎢1− − ⎣ 9 ⋅ (O +1) 3

and zα / 2 denotes the 100(1-α/2) percentile of the unit normal distribution (1.96 used for 95% confidence intervals). If the number of observed deaths was less than 100, then the Poisson distribution was used to calculate the lower μL and upper μU limits for the observed number of deaths, and then calculating the confidence interval for the SMR as above. Table 23 shows exact 95% limits using the Poisson distribution for selected values of O. The significance of the SMR was calculated using the test statistic χ = 2( and comparing this to the standard normal deviate.

Table 23 Poisson distribution 95% confidence limits

1 ⎥⎦+O

)EO −

Observed Lower Upper Observed Lower Upper O limit μL limit μU O limit μL limit μU

0 0.00 3.00 20 12.22 30.89 1 0.03 5.57 21 13.00 32.10 2 0.24 7.22 22 13.79 33.31 3 0.62 8.77 23 14.58 34.51 4 1.09 10.24 24 15.38 35.71 5 1.62 11.67 25 16.18 36.90 6 2.20 13.06 26 16.98 38.10 7 2.81 14.42 27 17.79 39.28 8 3.45 15.76 28 18.61 40.47 9 4.12 17.08 29 19.42 41.65

10 4.80 18.39 30 20.24 42.83 11 5.49 19.68 35 24.38 48.68 12 6.20 20.96 40 28.58 54.47 13 6.92 22.23 45 32.82 60.21 14 7.65 23.49 50 37.11 65.92 15 8.40 24.74 60 45.79 77.23 16 9.15 25.98 70 54.57 88.44 17 9.90 27.22 80 63.44 99.57 18 10.67 28.45 90 72.37 110.63 19 11.44 29.67 99 80.46 120.53

Source: Washington State Department of Health (2007)

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A1.2 POISSON REGRESSION

Poisson regression is a form of analysis used to model count data. This technique not only allows for unequal follow-up times (included as an ‘offset’ variable) but also for adjustment of multiple confounding variables such as sex, smoking status, and age (McNamee, 2005). In this analysis, the dependent variable was the number of deaths from lung cancer, with the person-years at risk as an offset variable.

Relative risks were calculated for asbestos related variables with adjustment for smoking status (three groups: current, former, never smokers), age (5-year classes, 40-75+ years), calendar period (5-year period, 1980-2000+) and sex. The covariates of interest were age at first occupational exposure to asbestos, year of first exposure, length of time spent in the study, the time of first exposure (pre- or post-ALR) and main occupation. The length of occupational exposure to asbestos, years since first exposure and years since last exposure were entered as time-dependent covariates.

All variables that were associated with lung cancer mortality were considered for the multivariable model of asbestos exposure. Linear relations between variables reduce the number that may be used simultaneously in the regression model. For example, time since first exposure minus the time since last exposure would give the length of occupational exposure to asbestos, and so all three could not be included in the model at the same time. Smoking status, age, calendar period and sex were adjusted for as risk factors for lung cancer. Main occupation and length of occupational exposure were included as proxies for type of asbestos exposure and cumulative exposure respectively.

The above model of asbestos exposure was used to adjust the relative risks of lung cancer mortality associated with smoking-related variables. The covariates of interest for both current and former smokers were the age started smoking, packs smoked per day, smoking duration and total smoking exposure (pack-years). The covariates associated only with former smokers were the age stopped smoking and time since smoking cessation. Smoking duration and time since smoking cessation were considered time-dependent covariates.

All variables were entered as a series of indicator variables, the significance of which was tested using the likelihood-ratio test of goodness-of-fit (significance, p≤0.05). The observed relationships were tested for trend by including the covariates as continuous rather than categorical variables where appropriate. All analyses were carried out in Stata 10 (StataCorp, 2007).

A1.3 THE ASBESTOS AND SMOKING INTERACTION

There is no single statistic that can test for both multiplicative and additive interactions. Therefore, in order to investigate the nature of the joint effect of asbestos exposure and smoking on lung cancer mortality, both the multiplicativity index (V) and the synergy index (S) were used.

The Relative Asbestos Effect (RAE) is a term that was first used by Berry et al. (1985) to describe the ratio of the relative risk due to asbestos exposure in non-smokers to that in smokers. RAE equal to one means that the asbestos effect is the same for non-smokers as for smokers, which is equivalent to there being a multiplicative interaction between the two factors. RAE greater than one implies less synergism (including potentially no interaction) and RAE less than one implies a more than multiplicative interaction. In this report the multiplicativity index (V) is presented, which is the reciprocal of the RAE. This has a more intuitive

44

interpretation than the RAE, with V greater than one corresponding to an interaction that is more than multiplicative and V less than one corresponding to less than multiplicative.

Rothman (1976) presented the synergy index (S) as a means of testing for the presence of an interaction between two factors, using the ratio of the joint effect of exposure to the two agents to the sum of the separate effects. Under the additive hypothesis (no interaction) S equals one, whereas for a more than additive effect S is greater than one, and for a less than additive effect S is less than one.

There was no control group of workers unexposed to asbestos in the study and so indices were calculated based on comparisons of risks for those with ‘low asbestos exposure’ versus ‘high exposure’ for never and current smokers. Workers were assigned to the low or high asbestos exposure categories based on their length of occupational asbestos exposure, repeating the analysis using three different duration cut-offs. Poisson regression was used to obtain the risk of lung cancer mortality for never smokers with high exposure (R2), current smokers with low exposure (R3) and current smokers with high exposure (R4) relative to never smokers with low asbestos exposure (R1=1.0). Adjustment was again made for age, calendar period, sex and main occupation. The multiplicativity index (V) is then given by R1R4/R2R3 and the synergy index (S) by (R4 – R1)/(R2 + R3 – 2R1). 95% confidence intervals of V were calculated assuming the relative risk is log normally distributed. Confidence intervals for S were obtained by using the delta method to form confidence intervals for ln(S) and exponentiating its limits (Hosmer & Lemeshow, 1992; Rongling & Chambless, 2007). All analyses were carried out in Stata 10 (StataCorp, 2007), with the delta method for estimating confidence intervals implemented using the nlcom command.

A1.3.1 Attributable fraction estimation

The Attributable Fraction (AF) is the proportion of cases that would not have occurred in the absence of a particular exposure. The relative risks obtained from the above model can be used to estimate the proportion of deaths attributable to asbestos exposure, smoking, and the interaction of the two among the asbestos workers. Table 24 shows how the deaths would be divided (Lee, 2001). Confidence intervals were calculated from the variance of the AF estimated using the delta method (Hosmer & Lemeshow, 1992; Rongling & Chambless, 2007), calculated in Stata 10 (StataCorp, 2007) using the nlcom command.

Table 24 Relative risks estimated using Poisson regression (R1, R2, R3, R4) and the population distribution of exposure

Smoking Asbestos Proportion of deaths attributable to status exposure Background Asbestos only Smoking only Both factors Never Unexposed 1 --- --- ---

Exposed 1/R2 (R2 – 1)/R2 --- --- Current Unexposed 1/R3 --- (R3 – 1)/R3 ---

Exposed 1/R4 (R2 – 1)/R4 (R3 – 1)/R4 (1 – R2 – R3 + R4)/R4

Adapted with permission of the BMJ Publishing Group Limited from Lee (2001)

The AF for lung cancer due to asbestos exposure among all the asbestos workers was calculated by estimating the number of excess deaths for lung cancer and for mesothelioma in the study population compared to the national population. Mesothelioma is considered uniquely to be caused by exposure to asbestos, and so the ratio of excess lung cancers to mesotheliomas was taken as an indication of the numbers of lung cancers that were attributable to the exposure.

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Before the 10th revision of the International Classification of Disease Codes (ICD-10) in 2001, there was no specific ICD code for mesothelioma. Therefore a case of mesothelioma was defined by any mention of mesothelioma on the death certificate. The expected number of deaths for lung cancer and mesothelioma were calculated using the 5-year age-, period- and sex-specific mortality rates for England and Wales, and for Scotland. The expected number of lung cancer deaths were then adjusted for smoking habits using the adjustment factors previously calculated (Appendix A1.1.1). The ratio of excess deaths was applied to the count of mesothelioma deaths for the survey participants to estimate the number of lung cancers that could be attributable to asbestos exposure. The AF among the asbestos workers was derived as the attributable number of lung cancers divided by the total number of lung cancers observed in the study population.

If the ratio of excess deaths calculated from the study population was applied to the count of mesothelioma and lung cancer deaths observed in the general population, then this would result in the population attributable fraction (AFp). The ratio calculated above was applied to the number of mesothelioma (HSE, 2008b) and lung cancer deaths (GROS, 1997; GROS, 2006; ONS, 2006) in GB during 1986 to 2005 to obtain an estimate of the AFp.

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5 REFERENCES

Albin, M., C. Magnani, S. Krstev, E. Rapiti and I. Shefer (1999). "Asbestos and cancer: an overview of current trends in Europe." Environ Health Perspect 107(Suppl 2): 289-298.

Bartrip, P. W. (2004). "History of asbestos related disease." Postgrad Med J 80(940): 72-6.

Berry, G. and F. D. K. Liddell (2004). "The interaction of asbestos and smoking in lung cancer: a modified measure of effect." Ann Occup Hyg 48(5): 459-462.

Berry, G., M. L. Newhouse and P. Antonis (1985). "Combined effect of asbestos and smoking on mortality from lung cancer and mesothelioma in factory workers." Br J Ind Med 42: 12-18.

Boffetta, P. (1998). "Health effects of asbestos exposure in humans: a quantitative assessment." Med Lav 89: 471-480.

Breslow, N. E. and N. E. Day (1987). Statistical methods in cancer research: Vol II - The design and analysis of cohort studies. Lyon, International Agency for Research on Cancer.

Darnton, A. J., D. M. McElvenny and J. T. Hodgson (2006). "Estimating the number of asbestos-related lung cancer deaths in Great Britain from 1980 to 2000." Ann Occup Hyg 50(1): 29-38.

de Klerk, N. H., A. W. Musk, B. K. Armstrong and M. S. T. Hobbs (1991). "Smoking, exposure to crocidolite, and the incidence of lung cancer and asbestosis." Br J Ind Med 48: 412-417.

Doll, R. and J. Peto (1985). Effects on health of exposure to asbestos. London, Health and Safety Commission.

Doll, R. and R. Peto (1978). "Cigarette smoking and bronchial carcinoma: dose and time relationships among regular smokers and lifelong non-smokers." J Epidemiol Commun Health 32: 303-313.

Doll, R., R. Peto, J. Boreham and I. Sutherland (2004). "Mortality in relation to smoking: 50 years' observations on male British doctors." BMJ 328(7455): 1519-.

Doll, R., R. Peto, K. Wheatley, R. Gray and I. Sutherland (1994). "Mortality in relation to smoking: 40 years' observations on male British doctors." BMJ 309: 901-911.

Elmes, P. C. and M. J. C. Simpson (1971). "Insulation workers in Belfast." Br J Ind Med 28: 226-36.

Erren, T. C., M. Jacobsen and C. Piekarski (1999). "Synergy between asbestos and smoking on lung cancer risks." Epidemiology 10(4): 405-11.

Flanders, W. D., C. A. Lally, B.-P. Zhu, S. J. Henley and M. J. Thun (2003). "Lung cancer mortality in relation to age, duration of smoking, and daily cigarette consumption: results from Cancer Prevention Study II." Canc Res 63: 6556-6562.

Goddard, E. (2008). General Household Survey 2006: smoking and drinking among adults, 2006, Office for National Statistics.

47

GROS (1997). Registrar General's Annual Report 1996. Edinburgh, General Register Office for Scotland.

GROS. (2006). "Vital events reference tables 2005." Retrieved June, 2008, from http://www.gro-scotland.gov.uk/statistics/publications-and-data/annual-report-publications/index.html.

Hammond, E. C., I. J. Selikoff and H. Seidman (1979). "Asbestos exposure, cigarette smoking and death rates." Ann N Y Acad Sci 330(1): 473-790.

Harding, A.-H. and G. Frost (2009). "The Asbestos Survey: mortality among asbestos workers 1971-2005." HSE Research Report MSU/2007/13: 135.

Harding, A.-H. and J. Wegerdt (2006). "Asbestos Workers Database: summary statistics." HSE Research Report MSU/2007/05: 45.

Hein, M. J., L. Stayner, E. Lehman and J. M. Dement (2007). "Follow-up study of chrysotile textile workers: cohort mortality and exposure-response." Occup Environ Med 64(9): 616-24.

Henderson, D. W., K. Rodelsperger, H.-J. Woitowitz and J. Leigh (2004). "After Helsinki: a multidisciplinary review of the relationship between asbestos exposure and lung cancer, with emphasis on studies published during 1997-2004." Pathology 36(6): 517-550.

Higgins, V. (1998). Young teenagers and smoking in 1998: a report of the key findings from the Teenage Smoking Attitudes survey carried out in England in 1998. London, ONS Social Survey Division.

Hodgson, J. T. and A. J. Darnton (2000). "The quantitative risks of mesothelioma and lung cancer in relation to asbestos exposure." Ann Occup Hyg 44(8): 565-601.

Hosmer, D. W. and S. Lemeshow (1992). "Confidence interval estimation of interaction." Epidemiology 3(5): 452-456.

HSE. (2008a). "Data sources: Death certificates as a source of deaths from asbestos-related and other occupational lung diseases." Retrieved January, 2009, from http://www.hse.gov.uk/statistics/sources.htm.

HSE. (2008b). "Mesothelioma statistics: death certificates mentioning mesothelioma, 1968-2005." Retrieved June, 2008, from http://www.hse.gov.uk/statistics/causdis/mesothelioma/index.htm.

IARC (2004). IARC monographs on the evaluation of carcinogenic risks to humans: tobacco smoke and involuntary smoking. Lyon, IARCPress.

Jarvholm, B. and A. Sanden (1998). "Lung cancer and mesothelioma in the pleura and peritoneum among Swedish insulation workers." Occup Environ Med 55: 766-770.

Lange, J. H., G. Mastrangelo and A. Buja (2006). "Smoking and alcohol use in asbestos abatement workers." Bull Environ Contam Toxicol 77(3): 338-42.

Lee, P. N. (2001). "Relation between exposure to asbestos and smoking jointly and the risk of lung cancer." Occup Environ Med 58: 145-153.

48

Levin, J. L., J. W. McLarty, G. A. Hurst, A. N. Smith and A. L. Frank (1998). "Tyler asbestos workers: mortality experience in a cohort exposed to amosite." Occup Environ Med 55(3): 155-60.

Liddell, F. D. K. (2001). "The interaction of asbestos and smoking in lung cancer." Ann Occup Hyg 45(5): 341-356.

Lubin, J. H. and N. E. Caporaso (2006). "Cigarette smoking and lung cancer: modeling total exposure and intensity." Cancer Epidemiol Biomarkers Prev 15(3): 519-23.

Magnani, C., D. Ferrante, F. B. Adesi, M. Bertolotti, A. Todesco, D. Mirabelli and B. Terracini (2008). "Cancer risk after cessation of asbestos exposure. A cohort study of Italian asbestos cement workers." Occup Environ Med 65: 164-170.

Marinaccio, A., A. Scarselli, A. Binazzi, M. Mastrantonio, P. Ferrante and S. Iavicoli (2008). "Magnitude of asbestos-related lung cancer mortality in Italy." Br J Canc 99(1): 173-175.

Marsh, G. M., A. O. Youk, S. T. Sefcik and C. W. Alcorn (2004). Occupational Cohort Mortality Analysis Program. Pittsburgh, Department of Biostatistics, University of Pittsburgh.

McNamee, R. (2005). "Regression modelling and other methods to control confounding." Occup Environ Med 62: 500-506.

Minowa, M., S. Hatano, M. Ashizawa, H. Oquro, H. Naruhashi, M. Suzuki, K. Mitoku, M. Miwa, C. Wakamatsu, Y. Yasuda, K. Shirai and H. Miura (1991). "A case-control study of lung cancer with special reference to asbestos exposure." Environ Health Perspect 94: 39-42.

Morabia, A., S. Markowitz, K. Garibaldi and E. L. Wynder (1992). "Lung cancer and occupation: results of a multicentre case-control study." Br J Ind Med 49: 721-727.

Neuberger, J. S. and R. W. Field (2003). "Occupation and lung cancer in nonsmokers." Rev Environ Health 18(4): 251-267.

Niklinski, J., W. Niklinska, E. Chyczewska, J. Laudanski, W. Naumnik, L. Chyczewski and E. Pluygers (2004). "The epidemiology of asbestos-related diseases." Lung Cancer 45: S7-S15.

ONS (2004). Mortality statistics: cause 2003. London, Office for National Statistics.

ONS (2006). Mortality statistics: cause 2005. London, Office for National Statistics.

Peto, R., S. Darby, H. Deo, P. Silcocks, E. Whitley and R. Doll (2000). "Smoking, smoking cessation, and lung cancer in the UK since 1950: combination of national statistics with two case-control studies." BMJ 321: 323-329.

Pira, E., C. Pelucchi, L. Buffoni, A. Palmas, M. Turbiglio, E. Negri, P. G. Piolatto and C. La Vecchia (2005). "Cancer mortality in a cohort of asbestos textile workers." Br J Cancer 92(3): 580-6.

Quinn, M., P. Babb, A. Brock, L. Kirby and J. Jones (2001). Cancer trends in England and Wales 1950-1999. London, The Stationery Office.

49

Reid, A., N. H. de Klerk, G. L. Ambrosini, G. Berry and A. W. Musk (2006). "The risk of lung cancer with increasing time since ceasing exposure to asbestos and quitting smoking." Occup Environ Med 63: 509-512.

Rockhill, B., B. Newman and C. Weinberg (1998). "Use and misuse of population attributable fractions." Am J Public Health 88(1): 15-19.

Rogot, E. and J. L. Murray (1980). "Smoking and causes of death among US veterans: 16 years of observation." Public Health Rep 95(3): 213-222.

Rongling, L. and L. Chambless (2007). "Test for additive interaction in proportional hazards models." Ann Epidemiol 17(3): 227-236.

Rothman, K. J. (1976). "The estimation of synergy or antagonism." Am J Epidemiol 103: 506-511.

Samet, J. M. (1993). "The epidemiology of lung cancer." Chest 103: 20-29.

Saracci, R. (1977). "Asbestos and lung cancer: an analysis of the epidemiological evidence on the asbestos-smoking interaction." Int J Cancer 20(3): 323-31.

Selikoff, I. J. (1979). "Mortality experience of insulation workers in the United States and Canada, 1943-1976." Ann N Y Acad Sci 330(1): 91-116.

Selikoff, I. J., E. C. Hammond and H. Seidman (1980). "Latency of asbestos disease among insulation workers in the United-States and Canada." Cancer 46(12): 2736-2740.

StataCorp (2007). Stata Statistical Software: Release 10, College Station, TX: StataCorp LP.

Steenland, K., D. Loomis, C. Shy and N. Simonsen (1999). "Review of occupational lung carcinogens." Am J Ind Med 29(5): 474-490.

Sullivan, P. A. (2007). "Vermiculite, respiratory disease, and asbestos exposure in Libby, Montana: update of a cohort mortality study." Environ Health Perspect 115: 579-585.

US DHHS (1990). The health benefits of smoking cessation. A report of the Surgeon General. Department of Health and Human Services Publication No. (CDC) 89-8416. Atlanta, Georgia, US Department of Health and Human Services, Public Health Service, Centers for Disease Control, Center for Chronic Disease Prevention and Health Promotion, Office on Smoking and Health.

Walker, A., M. O'Brien, J. Traynor, K. Fox, E. Goddard and K. Foster (2002). Living in Britain: results from the 2001 General Household Survey. London, The Stationery Office.

Washington State Department of Health. (2007). "Guidelines for using confidence intervals for public health assessment." Retrieved June, 2008, from http://www.doh.wa.gov/data/guidelines/guidelines.htm.

Wiencke, J. K., S. W. Thurston, K. T. Kelsey, A. Verkonyi, J. C. Wain, E. J. Mark and D. C. Christiani (1999). "Early age at smoking initiation and tobacco carcinogen DNA damage in the lung." J Natl Cancer Inst 91: 614-9.

Wraith, D. and K. Mengersen (2007). "Assessing the combined effect of asbestos exposure and smoking on lung cancer: a Bayesian approach." Stat Med 26(5): 1150-69.

50

Yarborough, C. M. (2006). "Chrysotile as a cause of mesothelioma: an assessment based on epidemiology." Crit Rev Toxicol 36(2): 165-187.

Yu, I. T.-S. and L. A. Tse (2007). "Exploring the joint effects of silicosis and smoking on lung cancer risks." Int J Cancer 120(1): 133-139.

Zang, E. A. and E. L. Wynder (1992). "A new index for estimating lung cancer risk among cigarette smokers." Cancer 70(1): 69-76.

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Published by the Health and Safety Executive 01/11




n to investigate if asbestos exposure increased lung cancer mortality risk in never smokers;

n to determine if the risk of lung cancer mortality reduces following smoking cessation for asbestos workers; and

n to examine the interaction between exposure to asbestos and smoking on lung cancer mortality risk.

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.

RR833

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rr833 - the joint effect of asbestos exposure and smoking ... · exposure. stopping smoking at any...

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