Tail of Two Carcinogens

Transcription

1 Tail of Two Carcinogens The Legacy of Asbestos and Smoking Steven Markowitz MD, DrPH City University of New York Ramazzini Days 2012 October Carpi, Italy 1

2 Irving J. Selikoff, MD, Director, Environmental Science Laboratory Mount Sinai School of Medicine, Co-Founder, Collegium Ramazzini 2

3 Acknowledgements Alfredo Morabia MD, PhD, and Al Miller, MD, Queens College Shannon Widman, MPH, Jordan Werbe Fuentes, Yan Guo, Queens College Michael Thun, MD, MS, Susan Gapstur, PhD, MPH, Yusheng Zhai, MS, MSPH, American Cancer Society Stephen Levin MD and Philip Landrigan MD, MSc, Mount Sinai School of Medicine People who worked on the North American insulator survey in , Irving Selikoff MD, Ruth Lilis, MD, Albert Miller, MD, Stephen Levin MD, and William Nicholson, PhD. 3

4 Disclosure I have provided medico-legal opinions and testimony in asbestos tort cases, mostly involving malignant mesothelioma. 4

5 Question #1 Is it asbestosis or asbestos (or both) that raises lung cancer risk? Question #2 How do asbestos, asbestosis, and smoking interact? 5

6 Causal Model of Asbestos, Asbestosis, Smoking and Lung Cancer Smoki ng Asbestosis Asbestos Lung Cancer 6

7 New significance Low-dose CT scan screening reduces lung cancer mortality (NCI 2011). Asbestos exposure was common in U.S. through 1980 s. Asbestosis is uncommon. Many asbestos-exposed workers have stopped smoking. 7

8 1.6 cm lung cancer detected by low dose CT scan, Oak Ridge DOE worker 8

9 Question #1 Is it asbestosis or asbestos (or both) that raises lung cancer risk? 9

10 American Journal of Industrial Medicine 10

11 Lung Cancer Mortality among Sheet Metal Workers, Dement J, Welch L, Haile E, Myers D Mortality among sheet metal workers participating in medical screening program. AJIM 52:

12 Irving J. Selikoff, MD, Director, Environmental Science Laboratory Mount Sinai School of Medicine

13 Chronology of Dr. Selikoff s Insulator Studies IJS initiates NA insulator study, n=17,800 IJS examines 2,907 NA insulators Publication of asbestosis mortality, 2,907 insulators IJS publishes NY/NJ insulator mortality IJS publishes 10 years of NA insulator mortality and asbestossmoking interaction IJS publishes 20 years of NA insulator mortality

14 1979 Asbestos Conference 14

15 Asbestos and Smoking Classic example of interaction Compared insulators to blue collar cohort of Cancer Prevention Study I (CPS) 15

16 60 50 Asbestos, Smoking and Lung Cancer (Hammond and Selikoff, 1979) RR = Insulators RR Lung Cancer CPS I 10 CPS I Insulators RR = 5.2 RR = 10.9 RR = 1 0 A-S- A+ S+ A+S+ Reference, not asbestos-exposed non-smokers Asbestos-exposed non-smokers Smokers (not exposed to asbestos) Asbestos-exposed smokers 16

17 60 50 Asbestos, Smoking and Lung Cancer (Hammond and Selikoff, 1979) RR= RR Lung Cancer Based on 4 lung cancer deaths 10 RR= 5.2 RR= 10.9 RR = 1 0 A-S- A+ S+ A+S+ Asbestos-exposed Reference (Insulators) Smokers Asbestos-exposed smokers 17 not exposed to asbestos Non-smokers (not exposed to asbestos) (Insulators who smoked) non-smokers

18 60 50 Asbestos, Smoking and Lung Cancer (Hammond and Selikoff, 1979) 40 RR Lung Cancer No asbestosis With asbestosis 10 RR = 1 0 A-S- A+ S+ A+S+ Reference not exposed to asbestos non-smokers Asbestos-exposed (Insulators) Smokers (not exposed to asbestos) Asbestos-exposed 18 (Insulators who smoked)

19 Chronology of Dr. Selikoff s Insulators Studies IJS initiates NA insulator study, n=17,800 IJS examines 2,907 NA insulators Publication of asbestosis mortality, 2,907 insulators IJS publishes NY/NJ insulator mortality IJS publishes 10 years of NA insulator mortality and asbestossmoking interaction IJS publishes 20 years of NA insulator mortality

20 Two Groups in Current Study of Insulators 1) Study group: North American Insulators Long term asbestos-exposed workers with known asbestosis status and smoking status (n=2,377); Examined ; mortality follow-up through ) Reference: Cancer Prevention Study II (American Cancer Society) Blue collar subset not exposed to asbestos with known smoking habits (n=54,243) Enrolled 1982; mortality follow-up through

21 Study results Baseline status of insulators (n=2,377) 1) Age at exam = mean, 58.1 years, 2) Duration of exposure = mean, 33.2 years 3) Smoking: never (19.7%), former smokers (47.2%) 4) Asbestosis: 38.6% without asbestosis 21

22 Study results Mortality follow-up of insulators ( ) 1) Death certificate diagnosis, National Death Index 2) 1,786 died (75.1%) 3) 339 lung cancer deaths (19% deaths) 18 lung cancer deaths among non-smokers 22

23 28 year follow-up of 2,377 Insulators 30,0 25,0 Lung cancer mortality rate ratios by asbestos and smoking status, Insulators vs. CPS II, RR = % CI: ( ) Lung Cancer Rate Ratio 20,0 15,0 10,0 RR = % CI: ( ) 5,0 RR = % CI: ( ) 1.0 0,0 A-S- A+S- S+A- A+S+ CPS II, nonsmokers Insulators, non-smokers CPS II, smokers Insulators, smokers 23

24 Current Study 30,0 25,0 Lung cancer mortality rate ratios by asbestos and smoking status, Insulators vs. CPS II, RR = % CI: ( ) Lung Cancer Rate Ratio 20,0 15,0 10,0 Based on 18 lung cancer deaths RR = % CI: ( ) RR = 5.2 5,0 95% CI: ( ) 1.0 0,0 A-S- A+S- S+A- A+S+ CPS II, nonsmokers Insulators, non-smokers CPS II, smokers Insulators, smokers 24

25 Question #1 Is it asbestosis or asbestos (or both) that raises lung cancer risk? 25

26 40 35 Lung cancer mortality rate ratios (95% CI) by asbestos, asbestosis and smoking status, Insulators vs. CPS II 36,8 ( ) 30 28,4 ( ) Lung Cancer Rate Ratio ,4 ( ) ,4 ( ) 5,2 ( ) 3,6 ( ) 10,3 ( ) 0 1,0 A-S- A+S-_A+Asb-S-_A+Asb-S- All A A+ A+ A-S+ A+S+ A+Asb-S+ A+Asb+S+ All A Asb- Asb+ Asb- Asb- Asb+ Non-Smokers Smokers 26

27 40 35 Lung cancer mortality rate ratios (95% CI) by asbestos, asbestosis and smoking status, Insulators vs. CPS II Lung cancer mortality rate ratios (95% CI) by asbestos, asbestosis among non-smokers, Insulators vs. CPS II 36,8 ( ) 30 28,4 Lung Cancer Rate Ratio All Insulators No asbestosis With asbestosis 14,4 ( ) Series1 Series2 Series ,4 ( ) 5,2 ( ) 3,6 ( ) n=7 10,3 ( ) n=11 1,0 0 A- All A A+ Asb- Non-Smokers A+ Asb+ A- Asb- All A Smokers A+ Asb- A+ Asb+ 27

28 Lung cancer mortality rate ratios (95% CI) by asbestos, 40 asbestosis among smokers, Insulators vs. CPS II Lung cancer mortality rate ratios by asbestos, asbestosis among smokers, Insulators vs. CPS II All Insulators 28,4 36,8 ( ) With asbestosis Lung Cancer Rate Ratio No asbestosis 14,4 ( ) Series1 Series2 Series ,4 ( ) 5,2 ( ) 3,6 ( ) 10,3 ( ) 1,0 0 A- All A A+ Asb- Non-Smokers A+ Asb+ A- Asb- All A Smokers A+ Asb- A+ Asb+ 28

29 Is increased exposure to asbestos among insulators with asbestosis responsible for their increased lung cancer rates? 29

30 30

31 Conclusions 1. Asbestos alone raises risk of lung cancer. 2. Asbestosis further doubles the risk of lung cancer in smokers and non-smokers. 31

32 Question #2 How do asbestos, asbestosis, and smoking interact? 32

33 60 50 Asbestos, Smoking and Lung Cancer (Hammond and Selikoff, 1979) RR = RR Lung Cancer RR = 5.2 RR = 10.9 RR = 1 0 A-S- A+ S+ A+S+ Reference, Asbestos-exposed not asbestos-exposed Smokers (Insulators) Asbestos-exposed smokers 33 non-smokers (not exposed to asbestos) non-smokers (Insulators who smoked)

34 28 year follow-up of 2,377 Insulators 30,0 25,0 Lung cancer mortality rate ratios by asbestos and smoking status, Insulators vs. CPS II, RR = % CI: ( ) Lung Cancer Rate Ratio 20,0 15,0 10,0 RR = % CI: ( ) 5,0 RR = % CI: ( ) 1.0 0,0 A-S- A+S- S+A- A+S+ CPS II, nonsmokers Insulators, non-smokers CPS II, smokers Insulators, smokers 34

35 37.1 Combined Effects of Asbestos and Smoking among Insulators without Asbestosis Multiplicative Model Smokers 12.9 Study Result 14.4 Insulators without asbestosis 10.3 Additive Model A- S- A +, S- S+, A- A+, S+ 35

36 Combined Effects of Asbestos and Smoking among Insulators with Asbestosis Multiplicative Model Study Result Insulators with asbestosis 7.4 Smokers 10.3 Additive Model 1 A- S- A + S- S+ A- A+ S+ 36

37 Conclusions 1. Asbestos alone and smoking raise risk of lung cancer additively. 2. Asbestosis and smoking raise lung cancer risk supra-additively. 37

38 Question #3 To what extent does smoking cessation lower lung cancer risk among asbestos workers? 38

39 Strengths of study 1. Similar, contemporaneous reference group 2. Large sample size; long-term follow-up 3. Similar follow-up method 4. Homogeneous asbestos exposure 39

40 Limitations of study 1. Homogeneous asbestos exposure; study group had heavy asbestos exposure 2. Misclassification of exposure: one-time characterization of smoking status and asbestosis status 3. Misclassification of exposure: radiographic basis for identifying asbestosis 40

41 Implications Public health: Asbestos-exposed insulators, with or without smoking or asbestosis have appreciable risk (RR> 3.0) of lung cancer and are likely to benefit from lung cancer screening with low dose CT. Biology: At least two pathways are likely to underlie asbestos-related lung carcinogenesis, one of which may be associated with inflammation. 41

42 Dr. Hammond Dr. Selikoff 42

43 Implications Public health: Asbestos-exposed insulators, with or without smoking or asbestosis have appreciable risk (RR> 3.0) of lung cancer and are likely to benefit from lung cancer screening with low dose CT. Biology: At least two pathways are likely to underlie asbestos-related lung carcinogenesis, one of which may be associated with inflammation. 43

44 Today s challenge + + = Screen for Occupational Lung Cancer 44

45 I am Dr. Irving Selikoff, and I approve this message. 45

46 Questions? Steven Markowitz MD, DrPH 46

47 Biological significance 1. There is > 1 pathway operating in asbestosrelated carcinogenesis. 2. Inflammation is likely linked to carcinogenesis. 3. Carcinogenic events during period of active smoking determine lung carcinogenic events during period following smoking cessation. 47

48 Cause of death Cancer Lung and trachea Larynx Mesothelioma* Pleura Peritoneum Other, unspecified Other Respiratory Gastrointestinal Esophagus Intestine and Rectum Stomach Pancreas Other Other Respiratory diseases Asbestosis Pneumonia Chronic obstructive pulmonary disease Other respiratory diseases Cardiovascular diseases Ischemic heart disease Other heart diseases Cerebrovascular disease and other vascular diseases Table 2.3 Causes of death, North American insulators (n=2,377), Total Period (n=1,786) (n=482) (n=769) (n=535) n % n % n % n % % % % % % % % % 2 0.1% 1 0.2% 1 0.1% 0 0.0% % % % % 6 0.3% 3 0.6% 3 0.4% 0 0.0% % % % 0 0.0% % 0 0.0% 9 1.2% % 2 0.1% 0 0.0% 0 0.0% 2 0.4% % % % % % 0 0.0% % 0 0.0% % % % 7 1.3% % 4 0.8% 6 0.8% 3 0.6% % 9 1.9% % 8 1.5% % 6 1.2% 7 0.9% 4 0.7% % % % % % % % % % % % % % % % % % % % % % 6 1.2% % % % % % % % % % % % % % % % % % % Other % % % % *Mesothelioma of the pleura, peritoneum, and other/unspecified include ICD 9 codes: 163.9, 195.2, 199.1, 235.2, 158.8, and ICD 10 codes: C45.0, C45.1, C45.7, C

49 CPS II Blue Collar Subcohort Major Job Titles (>1000 persons) Job Title Number Farmer, Fishing, Ranger 15,797 Truck, Bus Driver 5,346 Machinist 3,619 Military Personnel 3,095 Foreman 3,036 Postal Worker 2,733 Police 2,383 Lab, X-ray Technician 2,369 Janitor 2,190 Warehouse Worker 2,078 Cook 1,528 Railroad Worker 1,165 Firefighter 1,164 Welder 1,101 Manager 1,020 49

50 Overall mortality, North American Insulators, * 95% Confidence Limits Cause Observed Expected SMR Lower Upper All Causes All Cancers ** MN buccal & pharynx MN digestive & peritoneum ** MN esophagus MN stomach MN intestine MN rectum ** 0 67 MN biliary, liver, gall bladder *compared to US white male population MN pancreas MN peritoneum, other & unspec. site ,512** 1,794 3,421 MN respiratory ** MN larynx MN trachea, bronchus, lung ** MN pleura ,202** 441 2,616 MN other respiratory MN breast (major) MN male genital organs MN prostate MN urinary MN kidney MN bladder & other urinary site * MN other & unspec. site (maj.) ** MN mesothelioma ,501** 4,166 7,128 MN connective ** MN other & unspec. site (minor) MN lymphatic & hematopoietic ** **

51 Overall mortality, North American Insulators, * 95% Confidence Limits Cause Observed Expected SMR Lower Upper Benign & unspec. nature neoplasms Dis. blood & blood-forming organs Diabetes mellitus (major) ** 8 40 Mental & psych. disorders ** Alcoholism Nervous system disorders Heart diseases ** Ischemic heart disease ** Other dis. circulatory system ** Cerebrovascular disease ** Dis. respiratory system ** Influenza Pneumonia COPD * Asbestosis ,348** 16,897 24,296 Other pneumoconiosis Other respiratory diseases ** Diseases digestive system * Cirrhosis & other liver dis * Dis. skin & subcutaneous Dis. musculoskeletal & connective Diseases genito-urinary syst ** Sympt. & ill-def. cond. (maj.) * Transportation injuries ** 7 43 Falls Other injury (major) * Violence ** 9 44 Tuberculosis & HIV Other & unspec. causes (maj.) *compared to US white male population 51

52 Do smoking habits differ between the CPS II blue collar cohort and insulators? Table

53 50 Smoking Habits, CPS II and Insulators 47, , ,1 % % ,7 28,3 Insulators CPS II Never Smoked Former Smoker Current Smoker 53

54 60 Quantity Smoked (mean pack years), CPS II and Insulators Number of Pack Years Insulators CPS II 10 0 Former Smoker Current Smoker 54

55 Is increased smoking among insulators with asbestosis responsible for their increased lung cancer rates? 55

56 Lung Cancer Mortality in Asbestos-exposed Cohorts Cohort Observed Expected SM R Wittenoom miners, millers Paterson fac tory New Orleans-cement factory US/Canada- insulators Rochdale- textile factory Johns Manville-insulation factory South Carolina-textile factory Quebec miners, millers

57 Asbestos Asbestosis Lung Cancer Asbestos Asbestosis Lung Cancer Asbestosis Asbestos Lung Cancer 57

58 60 50 Asbestos, Smoking and Lung Cancer (Hammond and Selikoff, 1979) Current smoker 40 RR Lung Cancer Former smoker No asbestosis With asbestosis 10 RR = 1 0 A-S- A+ S+ A+S+ Reference not exposed to asbestos non-smokers Asbestos-exposed (Insulators) Smokers (not exposed to asbestos) Asbestos-exposed 58 (Insulators who smoked)

59 Decline in lung cancer with smoking cessation CPS II versus Insulators 59

60 Decline in lung cancer with smoking cessation CPS II versus Insulators 60

61 Does an insulator with asbestosis also benefit from smoking cessation? 61

62 Decline in lung cancer with smoking cessation CPS II versus insulators, with and without asbestosis Insulators with asbestosis Insulators without asbestosis 62

63 Decline in lung cancer with smoking cessation CPS II versus insulators without asbestosis 63

64 Decline in lung cancer with smoking cessation CPS II versus insulators with asbestosis 64