RR833. The joint effect of asbestos exposure and smoking on the risk of lung cancer mortality for asbestos workers ( )

Transcription

1 Health and Safety Executive The joint effect of asbestos exposure and smoking on the risk of lung cancer mortality for asbestos workers ( ) Prepared by the Health and Safety Laboratory for the Health and Safety Executive 2011 RR833 Research Report

2 Health and Safety Executive The joint effect of asbestos exposure and smoking on the risk of lung cancer mortality for asbestos workers ( ) 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 n n 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. 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

3 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 write to the Information Policy Team, The National Archives, Kew, London TW9 4DU, or 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 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. ii

4 CONTENTS LIST OF FIGURES... V LIST OF TABLES... V LIST OF APPENDICES... VI EXECUTIVE SUMMARY... VII 1 INTRODUCTION METHODS Study population Survey questionnaire Study follow-up Variable definition Smoking status Age started and age stopped smoking Other variables Statistical methods RESULTS Descriptive statistics Survey population Distribution of workers, deaths and demographic characteristics Standardised mortality ratios Poisson regression analyses Asbestos exposure Never smokers Asbestos and smoking Asbestos and smoking interaction Attributable fraction estimation DISCUSSION Strengths and limitations Descriptive statistics Asbestos exposure Never smokers Asbestos and smoking Asbestos and smoking interaction Attributable fraction estimation Conclusions Recommendations REFERENCES iii

5 LIST OF FIGURES Figure 1 Distribution of participants by smoking status, and age and calendar period at examination ( ) Figure 2 Standardised mortality ratios for lung cancer mortality among male asbestos workers, by smoking status at the final examination ( ) Figure 3 Relative risks of lung cancer mortality by asbestos exposure variables, estimated using Poisson regression Figure 4 Relative risks of lung cancer mortality by smoking variables, estimated using Poisson regression Figure 5 Relative risks of lung cancer mortality among former smokers by smoking variables, estimated using Poisson regression LIST OF TABLES Table 1 Number of participants who changed smoking status during the study period and the nature of the change ( )... 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 ( )... 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 ( )... 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 ( ) 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 ( ) Table 6 Standardised mortality ratios for lung cancer among asbestos workers, by smoking status at the last examination and gender ( ) Table 7 Standardised mortality ratios for lung cancer among male asbestos workers adjusted for smoking status at the last examination ( ) Table 8 Risk of lung cancer mortality among all workers, adjusted for age, calendar period, sex and smoking status using Poisson regression Table 9 Risk of lung cancer mortality among all asbestos workers in the final Poisson regression model for asbestos exposure Table 10 Risk of lung cancer mortality among never smokers, adjusted for age, calendar period, sex and smoking status using Poisson regression 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 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 Table 13 Risk of lung cancer mortality among former and current smokers in the final Poisson regression model for smoking exposure iv

6 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 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 Table 16 Multiplicativity index (V) and synergy index (S) estimated using relative risks adjusted by age, calendar period, sex and main occupation 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 Table 18 Percentage attributable risks from smoking and asbestos exposure among the asbestos workers 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 Table 20 Estimation of the attributable fraction for lung cancer mortality due to asbestos exposure among male asbestos workers ( ) Table 21 Estimation of the population attributable fraction for lung cancer mortality due to asbestos exposure among males in Great Britain ( ) Table 22 Factors to adjust expected lung cancer deaths of British males for smoking habits Table 23 Poisson distribution 95% confidence limits Table 24 Relative risks estimated using Poisson regression (R 1, R 2, R 3, R 4 ) and the population distribution of exposure LIST OF APPENDICES Appendix 1 Statistical methods v

7 vi

8 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. vii

9 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. viii

10 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 20 th 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). 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: 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. 1

11 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) 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 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 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. Otherwise the participant was assumed to be a current smoker. 2

12 The participant recorded a change from former to never smoker - o 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. Otherwise the examination that had recorded never smoker was changed to current smoker. The participant recorded a change from never to former - o o o This change was possible if the individual started and stopped smoking between examinations. 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. 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 ( ) 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) (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 3

13 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 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 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 4

14 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

15 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 Survey population In total, there were 208,627 records for 98,912 asbestos workers who took part in the survey between 1971 and Ninety eight percent of workers were traced for follow-up with the NHSCR and GROS 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 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 6

16 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. 3.2 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 ). Never smokers had the lowest SMR of 22 (95% CI 16-31) and current smokers had the highest of 306 (95% CI ). 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 ; Table 7; Figure 2). 7

17 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 ( ) Number Person- Number of deaths of years at All deaths All MN MN Bronchus Mesothelioma fi workers risk & lung Circulatory disease Respiratory disease Asbestosis Country Great Britain 98,912 1,780,233 15,553 5,528 1, ,174 1, England & Wales 94,980 1,712,816 15,182 5,387 1, ,057 1, Scotland 3,932 67, Period of employment Pre-ALR 56,001 1,298,148 14,364 5,143 1, ,852 1, Post-ALR 42, ,084 1, Length of time in the survey One examination 56, ,091 7,545 2, , two examinations 42, ,142 8,008 2, , Smoking status Current smokers 52, ,347 9,636 3,456 1, ,792 1, Former smokers 19, ,416 3,815 1, , Never smokers 24, ,996 1, Industrial sector Manufacturing Textiles 29,410 3, ,634 79,565 8, , , , Asb cement mixt, 3,848 96,282 1, board & pipe Asb/rubber/resin/ 5, ,751 1, bitumen mixtures Asb board & paper , Garments 287 6, Insulation & 200 4, plastering mixes Maintenance 3,600 83,142 1, Insulation workers 5, ,721 1, Stripping/removal 55, ,028 3,547 1, Other 8, ,383 1, , Ship building, 1,929 44, repair & breaking Building & 1,918 34, construction Miscellaneous 3,306 78, fi Mesothelioma as defined by the mesothelioma register any mention of mesothelioma on the death certificate 8

18 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 ( ) Number Person- Number of deaths of years at All deaths All MN MN Bronchus Mesothelioma fi workers risk & lung Circulatory disease Respiratory disease Asbestosis Year of birth < , ,441 9,324 3,140 1, ,107 1, , ,180 3,255 1, , , ,663 1, , , , , ,911 59, Age at first exposure (years) < 20 19, ,797 2,396 1, , ,705 3,461 1, , , ,222 3,631 1, , , ,266 3,564 1, , ,604 81,243 2, , Year of first exposure < , ,093 19, ,736 55,658 1, , ,497 2,755 1, , , ,128 3,663 1, , , ,352 4,529 1, , , ,467 1, , , Length of occupational exposure (years) < 10 62,697 1,004,377 5,532 1, , , ,875 3,569 1, , , ,596 2,922 1, , , ,385 3,530 1, ,

19 Number Person- Number of deaths of years at All deaths All MN MN Bronchus Mesothelioma fi workers risk & lung Circulatory disease Respiratory disease Asbestosis Years since first exposure < 10 19,468 89,907 1, , ,657 3,034 1, , , ,248 3,864 1, , , ,830 3,293 1, , , ,871 2, , ,720 1, Years since last exposure < 10 36, ,007 6,736 2, , , ,265 6,344 2, , , ,003 2, ,043 34, fi Mesothelioma as defined by the mesothelioma register any mention of mesothelioma on the death certificate 10

20 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 ( ) Number Person- Number of deaths of years at All deaths All MN MN Bronchus Mesothelioma fi workers risk & lung Circulatory disease Respiratory disease Asbestosis Age started smoking (years) < 16 13, ,634 2, , ,497 3,891 1, , , ,644 1, , , Packs smoked per day < 0.5 4,807 73, , ,401 2, , , ,342 3,209 1, , , , Smoking duration (years) < 10 1,841 5, ,770 40, , , , ,283 1, , ,690 6,381 2,367 1, , Total smoking exposure (pack-years) < 10 6,359 53, , , , , , ,470 1, ,147 89,246 1, ,488 55, ,426 33, , ,147 27, fi Mesothelioma as defined by the mesothelioma register any mention of mesothelioma on the death certificate 11

21 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 ( ) Number Person- Number of deaths of years at All deaths All MN MN Bronchus Mesothelioma fi workers risk & lung Circulatory disease Respiratory disease Asbestosis Age started smoking (years) < 16 4,545 88, , ,158 1, ,018 57, , , Packs smoked per day < 0.5 2,160 41, ,093 96,755 1, , ,930 1, , , Smoking duration (years) < 10 4,700 88, ,671 91, ,384 66, ,131 42,524 1, , Total smoking exposure (pack-years) < 10 5, , ,315 65, ,803 36, ,166 23, , , , , ,

22 Number Person- Number of deaths of workers years at risk All deaths All MN MN Bronchus & lung Mesothelioma fi Age stopped smoking (years) Circulatory disease Respiratory disease Asbestosis < 20 1,247 24, ,975 91, ,488 87, ,296 66, ,031 40,027 1, , Time since smoking cessation (years) < 10 2,091 14, ,819 56, , ,333 1, ,799 95, ,751 44, fi Mesothelioma as defined by the mesothelioma register any mention of mesothelioma on the death certificate 13

23 Prevelance (%) < Age Prevelance (%) < Calendar period Current smokers Former smokers Never smokers Figure 1 Distribution of participants by smoking status, and age and calendar period at examination ( ) 14

24 Smoking status Never Former Current Table 6 Standardised mortality ratios for lung cancer among asbestos workers, by smoking status at the last examination and gender ( ) Deaths ,401 Male SMR 22* ** (95% CI) (15 31) (85 107) ( ) Deaths Female SMR 29** ** (95% CI) (8 75) (23 164) ( ) Deaths ,471 Total SMR 22** ** (95% CI) (16 31) (85 106) ( ) Total 1, ** ( ) ** ( ) 1, ** ( ) * 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 ( ) Smoking habit Never Former Current Observed ,401 Expected Adjusted expected Adjusted SMR ** 130** (95% CI) (93 192) ( ) ( ) Total 1, ** ( ) 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 Standardised mortality ratio Current Former Never All males Smoking status at final 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 ( ) (Error bars represent 95% confidence intervals and dashed line shows a standardised mortality ratio of 100) 15

25 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 An analysis of the same asbestos-related variables in never smokers is presented in Section and in Section an analysis of smoking-related variables using the multivariable model of asbestos exposure given in Section to adjust for asbestos exposure is presented 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 ; former: RR 4.7, 95% CI ), 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 ( : RR 0.7, 95% CI ; : RR 0.7, 95% CI ). 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 ) 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 ). Fifty or more years of exposure had the highest RR of 1.7 (95% CI ) 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 ) 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 ). Insulation workers had the greatest risk of mortality from lung cancer of all the main occupations, with a RR of 1.9 (95% CI ) 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 ). 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

26 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 ) 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 ). Females had a significantly reduced risk of mortality compared to males (RR 0.6, 95% CI ). Current smokers had the greatest risk of lung cancer mortality (RR 14.7, 95% CI ), followed by former smokers (RR 4.6, 95% CI ), compared to never smokers. Insulation workers had a significantly elevated risk compared to those in the manufacturing sector (RR 1.8, 95% CI ). 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 ) 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 ) was the only significant difference 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 ). There was a statistically significant trend of decreasing risk with year of first exposure to asbestos 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 (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 ), it was still significantly greater than the risks associated with never smokers (RR 3.1, 95% CI ). 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 ). 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 ). 17

27 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 ) 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 ). 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 ). 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 (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 ). 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 ). 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 (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 sickquitters (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 ) (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 ) (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 ). 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