Presentation Overview

• Review COPD and Risk Factors
• Present Research Design & Methods
• Review Study Results
• Discuss Implications for Prevention

COPD vs. ASTHMA

Asthma	COPD
Drop in airflow that reverses with inhalers	Drop in airflow that does not reverse with inhalers
Onset early in life, often childhood	Onset in midlife, typically after age 50
Accompanied by allergies, rhinitis	Stongly linked to smoking history
May be without any symptoms between attacks	Symptoms are persistent: chronic cough sputum production shortness of breath

Clinical COPD Diagnosis

Symptoms:

• Chronic cough, sputum production, shortness of breath on exertion.

Spirometry (Lung Function):

• Post bronchodilator FEV₁ < 80% predicted
  and
• FEV₁/FVC ratio <0.70.

(FEV₁ is a measure of air flow on lung function testing, FVC is a measure of lung volume)

COPD Disease in US

• 13 million people in U.S. have diagnosed COPD.
• >133,000 U.S. deaths due to COPD in 2010. Third leading cause of death in U.S.
• COPD costs ~ $37.2 billion in 2004.
  • $20.9 billion in health care expenditures.
  • $7.4 billion indirect morbidity costs.
  • $8.9 billion indirect mortality costs.

Many cases of COPD may go undiagnosed for many years.
Some estimates suggest that only about 50% of actual cases in the US population have received a physician diagnosis.

COPD Risk Factors

• Hereditary deficiency in α1-antitrypsin (ATT), a protein made in the liver.
  • Less than 1% of COPD patients have an ATT deficiency, so the population attributable risk (PAR) <1%.
• Cigarette Smoking
  • 80-90% of COPD cases caused by smoking
  • Only 15-20% of smokers develop COPD and 10% of COPD deaths occur in lifetime non-smokers.
• Occupational Exposures
  • 15-30% of COPD cases are estimated caused by occupational exposures overall.
  • Among never smokers, up to 50% of COPD cases estimated to be caused by occupational exposures.

Among non-smokers the occupational attributable fraction ranges from about 30-50%

Occupational Exposures and COPD Risk

• General exposure to ‘vapors, gases, dusts, and fumes’ (VGDF)
• Specific exposures known to cause COPD:
  • Coal dust
  • Welding
  • Silica
  • Diesel exhausts
  • Cement dust
  • Spray painting with isocyanate-based paints
  • Wood dust
  • Cadmium

Cigarette smoking is a major risk factor for COPD.

15-30% of COPD cases are estimated to be caused by smoking.

Most studies have considered the combination of all vapors, gases, dusts, and fumes in accessing the risk of COPD.

Some studies have looked at specific exposures and COPD. The materials in this slide show associations with specific agents from the literature.

Case-Control Study Design

This was a case-control study design. Begins with identification of workers with COPD (cases) and those who don’t have COPD (controls). Lifetime exposures are then assessed through various means including records, questionnaires, etc. The outcome measure and the measure of risk is called the odds-ratio. An odds-ratio measures the probability of exposure for cases versus controls. A value of 1.0 means the cases have the same risk as controls and values greater than 1.0 shows increased risk.

Building Trades National Medical Screening Program

The study population for this study was drawn from workers participating in the Building Trades National Medical Screening (BTMed). The Center for Construction Research and Training(CPWR) operates and manages the BTMed program which is funded by the U.S. Department of Energy. The primary objective of BTMed is to provide well designed occupational health examinations former construction trades workers at Department of Energy sites across the US. BTMed has expanded since starting in in 1996 and currently includes over 20 sites across the US.

Study Population and Case Definition

• Study Base: Workers with medical exams through the Building Trades National Medical Screening Program (BTMed) through December 2013.
• COPD Cases: Workers with a FEV₁/FVC ratio below the lower limit of normal (LLN) using the prediction equations of Hankinson et al. [1999].

Selection of Controls

• Controls were drawn from the same BTMed population as COPD cases but without COPD by the spirometry case definition.
• Controls were randomly selected and frequency matched to the distribution of cases by gender, age (± 5 years), race, and DOE site.
• Controls were over sampled in order to increase study statistical power.

Controls were not matched on trade as trade is a strong predictor of exposures. Controls were frequency matched by DOE site to allow control for local environmental conditions that might contribute to COPD risk. Statistical power is the ability of a study to detect increased risks that actually exists and takes into consideration random error.

Exposure Assessment Questionnaire

• Individuals volunteered and participated after giving informed consent.
• The telephone interview collected information concerning:
  • Jobs held more than 6 months.
  • Frequency (none to daily) of performing 90 construction-related tasks producing exposures to VGDF.
  • Exposures to VGDF in non-construction jobs, in military service, and as a bystander to other worker’s tasks.
  • Frequency of exposure to other materials associated with respiratory diseases from the literature (i.e. coal dust, pesticides, etc.).

The exposure questionnaire was developed an pilot tested in several ways including focus groups for worker input. Cases and controls were randomly assigned to trained interviewers. Interviewers were blind as to case or control status.

Cumulative Exposure Indices

• Data from the questionnaire were used to develop lifetime cumulative indices for 15 exposures known to cause COPD, plus VGDF.
• Indices included task frequency, job duration, work hours per week, and task exposure intensity.
• Task exposure intensity was developed based on scores by 3 experienced industrial hygienists.
• Indices included construction, non-construction, military, and bystander exposures.

Exposure indices should be considered qualitative estimates of lifetime exposures.

Lifetime Exposures Assessed

Agent or exposure	Reference concentration for intensity scoring
Asbestos	2 f/cc
Silica	0.1 mg/m3 respirable
Cement dust	5 mg/m3 respirable
Man-made-mineral-fibers	1f/cc
Engine Exhausts	100 µg/m3 respirable elemental carbon
Acids	Ceiling 5 ppm as HCL
Caustics	Ceiling 2 mg/m3 as sodium hydroxide
Welding, thermal cutting, soldering, or brazing	5 mg/m3 as total aerosol
Metal cutting, grinding, and machining aerosol	5 mg/m3 as total aerosol
Paint-related aerosols	1 mg/m3 as total aerosol
Isocyanates	0.02ppm
Organic solvents	100 ppm as toluene
Wood dust	1 mg/m3 as total aerosol
Molds and spores	Exposure above typical background
Particulates not otherwise regulated (PNOR)	10 mg/m3 as total aerosol

A cumulative measure of all VGDF exposures was developed as the sum of the exposure indices for the 15 a priori agents. Reference concentrations were used to better standardize scoring of exposure intensities by industrial hygienists.

COPD Study Participation Summary

Participation measure	Cases		Controls
Sent invitation letters	1612		2129
Contacted, completed interview	83		1245
Contacted, declined interview	130		200
Not contacted	648		684
Reason for no contact
Deceased	238		137
No Telephone contact1	410		547
Overall participation rate among living	60.6%		62.5%
Overall participation rate among those contacted	86.5%		86.3%
1Case and control distribution by site not significantly different, Chi-Square= 7.47, p=0.76

The overall participation rate for workers contacted was over 86%.

COPD Cases and Controls by DOE Site

DOE Site Description1	Cases (n=834)	Controls (n=1243)	Total (n=2077)2
Brookhaven National Laboratory	19	29	48
Fernald Feed Materials Production Center (FMPC)	137	18	320
General Electric Company, Cincinnati	23	39	62
Hanford	167	224	391
Idaho National Engineering and Environmental Laboratory	55	66	121
Kansas City Plant	37	53	90
Mallinckrodt Chemical/Weldon Spring	10	14	24
Oak Ridge (All Sites)	114	195	309
Paducah Gaseous Diffusion Plant	44	58	102
Portsmouth Gaseous Diffusion Plant	54	92	146
Rocky Flats Plant	62	101	163
Savannah River Site	112	189	301
1Case and control distribution by site not significantly different, Chi-Square= 7.47, p=0.76 2Two workers were not included in the analyses due to missing data on key a variable.

Cases and controls were drawn from many DOE sites.  As cases and controls were matched by DOE site, the distribution by case of control status among the study participants was similar and not statistically different.

COPD Cases and Controls by Trade

Trade Group or Job1	Cases (n=834)	Controls (n=1243	Total (n=2077)
Asbestos Worker or Insulator	25	37	62
Boilermaker	16	27	43
Carpenter	55	77	132
Cement Mason/Brick Mason/Plasterer	23	12	35
Electrician	128	226	354
Elevator Constructor	1	5	6
Ironworker	50	64	114
Laborer	115	152	267
Machinist	3	6	9
Mechanical Trades	7	8	15
Millwright	14	19	33
Operating Engineer	53	81	134
Painter	29	30	59
Plumber, Steamfitter, Pipefitter	130	200	330
Roofer	13	9	22
Security	4	5	9
Sheetmetal Worker	45	82	127
Sprinkler Fitter	8	8	16
Teamster	32	34	66
Welder	1	13	14
All Other Construction and Non-Construction	82	148	230
1Case and control distribution by trade significantly different, Chi-Square=33.09, p=0.033

The study included many construction trades, which provided workers with varied exposures. This was important and allowed us to observe exposure contrasts when cases and controls were compared.

Characteristics of Cases and Controls

Characteristic	Cases (n=834)	Controls (n=1243)2
Mean age (SE)	62.3 (0.37)	62.7 (0.30)
Male sex (%)	764 (91.6)	1152 (92.7)
Non-white race or Hispanic ethnicity (%)	76 (9.1)	118 (9.5)
History of Physician Diagnosed Respiratory Conditions(%)
Asthma (N=2076)	192 (23.1)*	114 (9.2)
Chronic bronchitis (N=2076)	169 (20.3)*	103 (8.3)
Emphysema (N=2076)	185 (22.2)*	49 (3.9)
Pneumonia (N=2076)	242 (29.1)*	241 (19.4)
Respiratory symptoms (%)
Cough (N=2074)	418 (50.1)*	353 (28.4)
Phlegm (N=2074)	393 (47.1)*	337 (27.2)
Shortness of Breath (N=2074)	469 (56.3)*	386 (31.1)
Spirometry, Mean (SE)
% Predicted FVC	81.3 (0.70)*	87.7 (0.46)
% Predicted FEV1	62.9 (0.67)*	89.7 (0.49)
FEV1/FVC ratio	0.58 (0.003)*	0.77 (0.002)
Chest X-ray B-Reader prevalence (%)(N=2057)
Pleural changes only	120 (14.6)	179 (14.5)
Parenchymal changes only (Profusion ≥1/0	20 (2.4)	23 (1.9)
Both Pleural and Parenchymal	23 (2.8)	28 (2.3)
History of hypertension (%) (N=2076)	262 (31.5)*	331 (26.6)
History of congestive heart disease (%) (N=2074)	27 (2.8)*	23 (2.1)
History of severe childhood pneumonia (%)	31 (3.7)	47 (3.8)
Smoking Status (%)
Current smoker	236 (28.3)**	138 (11.1)
Past smoker	462 (55.4)	632 (50.8)
Never smoker	136 (16.3)	473 (38.1)
Mean Cigarrette pack-years (SE)	31.3 (0.88)*	15.6 (0.56)
Mean Body Mass Index (SE)	29.2 (0.20)*	30.5 (0.15)
Family history of COPD (%)	212 (25.4)*	230 (15.5)
*Cases and controls significantly different, p<0.05 **Chi square overall measure of association across categories

Cases and controls did not differ significantly with respect to matching variables (age, gender, race/ethnicity).
As expected, controls had a significantly greater history respiratory conditions including asthma, chronic bronchitis, emphysema, and pneumonia as well as respiratory symptoms associated with COPD.
Spirometry followed the COPD case definition.

Study Results – Overall Associations

• Logistic regression models adjusted for age, gender, race/ethnicity, smoking, BMI, and having a blood relative with COPD.
• Smoking was a strong risk factor for COPD.
• Exposures to the 13 of the 15 materials previously reported to cause COPD, and all VGDF combined, were significantly associated with COPD.
  • Exposures to man-made mineral fibers and paint-related aerosols did not reach statistical significance.
• Workers who entered construction work after 1980 continued to experience increased COPD risk related to the exposures evaluated.

All analyses were based on unconditional logistic regression.

COPD Odds-Ratios Exposure Index

	Odds-ratio (95%CI) by fraction of upper 95th percentile d
Cumulative Exposure Index	0.25	0.50	0.75	1.00
Asbestos	1.15	1.31	1.50	1.72
Silica	1.21	1.46	1.77	2.13
Cement dust	1.16	1.31	1.51	1.73
Man-made -mineral- fibers	1.06	1.13	1.20	1.28
Engine exhausts	1.15	1.33	1.53	1.76
Acids and caustics	1.46	1.49	1.51	1.54
Welding, thermal cutting, soldering, brazing	1.11	1.23	1.36	1.50
Metal cutting, grinding, and machining aerosol	1.09	1.20	1.31	1.43
Paint-related aerosols	1.05	1.10	1.15	1.21
Isocyanates	1.09	1.22	1.36	1.52
Organic solvents	1.16	1.34	1.55	1.80
Wood dust	1.36	1.46	1.36	1.17
Molds and spores	1.12	1.25	1.40	1.57
Particulates not otherwise regulated (PNOR)	1.21	1.47	1.78	2.15
All VGDF	1.19	1.42	1.70	2.03
Logistic regression model adjusted for age, gender, race/ethnicity, smoking status (Current, Past, Never), cigarette pack-years, family history of COPD, and BMI.

Odds-ratios are a measure of risk. A value of 1.0 means no increased risk and values >1.0 indicate increased risk.
All a priori exposures except man-made mineral fibers and paint-related aerosols were significantly associated with COPD risk.
The relationships in the models were best described and linear except for acids and caustics and wood dust. These materials suggested a flattening the of the exposure response at higher cumulative exposures.
All VGDF exposures combined was a strong and consistent predictor of COPD risk.
PNOR exposures were strongly predictive of risk.

Occupational Attributable COPD

• Overall, 18% (95% CI=2-24%) was attributable to occupational VGDF exposures.
• Among never smokers 32% (95% CI=6-42%) was attributable to occupational VGDF exposures.
• Cigarette smoking and occupational exposures were approximately additive.

Conclusions

• Construction workers are at significantly increased risk of COPD.
• Workers employed after 1980 continue to be at risk.
• Construction exposures are complex and COPD risk is strongly related to exposure to all VGDF combined.
• 18% of COPD cases overall and 32% among never smokers is attributable to VGDF exposures.
• Regulatory approaches need to consider combined effects of all VGDF exposures.
• Exposures to PNOR, while correlated with other exposures, increase the risk of COPD.
• Current regulatory standards in the US for respirable PNOR (5 mg/m³) may not be sufficient to prevent COPD.

Publication Availability

This study is published in the American Journal of Industrial Medicine and is available as an open access (free) publication.

Dement J, Welch L, Ringen K, Quinn P, Chen A, Haas S. 2015. A case-control study of airways obstruction among construction workers. Am J Ind Med. 58:1083-1097.

http://onlinelibrary.wiley.com/doi/10.1002/ajim.22495/epdf

John Dement, PhD,¹
Laura Welch, MD,² Knut Ringen, Dr. PH,²,³ Patricia Quinn, BA,² Anna Chen, BS,⁴ and Scott Haas, MJ⁴

¹ Division of Occupational & Environmental Medicine, Duke University Medical Center
² The Center for Construction Research and Training(CPWR)
³ Stoneturn Consultants
⁴ Zenith American Solutions

This study was funded by the National Institute for Occupational Safety and Health (NIOSH)

Grant Number: 5R01OH009943
PI: John M. Dement

Acknowledgements

We greatly appreciate the many individuals who contributed to this study.

• Participants who gave of their time to further knowledge of COPD and causes.
• Our interviewers Ron Bush, Andy Noel, Johnny Ballinger, and Dan Obray.
• Drs. Carol Rice and Robert Herrick for their assistance with the exposure intensity scoring.
• Patricia Worthington (DOE) and Mary Fields (DOE) for their support of this project.