Determinants of Lung Cancer Risk Among Cadmium0 Exposed Workers Steven Henry Lamm, MD, Michael Parkinson, William Taylor, BS
MD, Mary Anderson,
MD, and
Workers at a cadmium recovery pIant in Globe, Colorado, showed an increased risk of lung cancer, which some investigators have attributed to cadmium exposure. We conducted a cohort mortality analysis of this work force and a case-control analysis of the lung cancer cases within this work force in order to assess the probable causes of the lung cancer excess. The Globe plant began as a lead smelter about 1886, switched to arsenic production in 1920, and became a cadmium metal production facility in 1926. Cadmium, arsenic, and cigarette smoking are three potential lung carcinogens found in this workplace. Industrial hygiene data collected from I943 onward served as the basis for the National Institute for Occupational Safety and Health (NIOSH)-derived exposure algorithm that assigned cadmium exposure estimates to employees based on their work area in the plant and calendar time. Few exposure data existed for substunces other than cadmium. Feedstock ore concentrations were used us a surrogate measure of air arsenic levels. The arsenic content of the fines used as feedstock prior to I940 was considerably higher than rhat of the fines used after 1940. Smoking histories had been obtained previously for 45% of the workers. A case-control analysis of the 25 cases of lung cancer known to have occurred among these workers through 1982 was conducted using three controls per case, matched by closest data of hire and age at hire. Porenrial causal agents for lung cancer included cadmium exposure, cigarette smoking, and arsenic exposure. Exposure variables for each case and control included estimated cumulative cadmium exposure in milligram-years per cubic meter, cigarette smoking history, and plant arsenic exposure status at the time of hire. Estimated cumuhtiwe cadmium exposures of cases and controls did not differ overall or within the date-of-hire strata. Cases were more than eight rimes more likely to have been cigarette smokers than were controls. Lung cancer risk in this workplace was more closely related to the period of hire, not to the cumulative cadmium eqosure. The period of hire appears to be a surrogate for arsenic exposure as related to feedstock. The measures used here seem to indicate that exposure to arsenic and cigarette particulates, rather than to cadmium particulates, may have caused the increased rate of lung cancer of these workers. Ann Epidemiol I992;2; 195-2 11. KEY WORDS:
Lung cancer, cadmium, arsenic, cigarette smoking, caSe control.
INTRODUCTION The lung cancer mortality
for the production workers at the Globe, Colorado cadmium smelter has been reported in numerous studies (l-5) (Table I), with some (I, 4) concluding that cadmium is a demonstrated human carcinogen and others (2, 3, 5) that it is not. This group of workers comprises the only US database for assessing mortality risks associated with employment and cadmium exposure. Nonetheless, its
From Consultants in Epidemiology and Occupational Health, Inc., Washington, DC (S.H.L., M.P., M.A., W.T.); Department of Health Policy and Management and Preventive Medicine Residency Program, Johns Hopkins School of Public Health Baltimore, MD (S.H.L., M.P., M.A.); and DataSoft, Clarksville, MD (W.-r.). Address reprint requests to: Steven H. Lamm, MD, Consultants in Epidemiology and Occupational Health, Inc., 2428 Wisconsin Avenue, N.W., Washington, DC 20007. Received September 15, 1990; revised September 20, 1991. 0 1992 Elsevier Science Publishing Co.,
Inc.
1047-2797/92/$05.00
196
Lamm et al. LUNG CANCER
TABLE 1
RISK IN CADMIUM-EXPOSED
Lung
Study
cancer
risk
in cohort studies of Globe, Colorado smelter workers Cohort
Lemen et al., 1976 (1) Vamer, 1983 (2)
292 white males employed > 2 y 625 employees
White, 1985 (3)
employed > 6 mo 646 employees
Thun et al., 1985 (4)
Lamm, 1988 (5)
AEf’ Vol. 2, No. 3 May 1992: 195-211
WORKERS
employed > 6 mo Hired pre- 1940 Hired post-1940 602 white males employed > 6 mo Hired pm-1926 Hired post-1926 Employed > 2 y Employed < 2 y 599 white males employed > 6 mo Hired pm-1926 Hired 1926-1939 Hired 1940- 1969
End of follow-llu
Results
1973 SMR = 235” 1982 SCR = 163” 1982 SCR = 244“ SCR = 078
1978 SMR = 175 SMR = 714” SMR = 147 SMR = 229” SMR = 000” 1978 SMR SMR SMR SMR
= = = =
144 492” 283” 88
= P < 0.05.
analysis is particularly problematic because of confounding from exposure to cadmium, arsenic, and cigarette smoking. The plant has a varied history of activities, serving first as a lead smelter from 1886 to 1919, then as an arsenic smelter from 1920 to 1925, and finally as a cadmium smelter since 1926. The plant’s primary function is to extract cadmium from the feedstock of precipitated dusts (fines) that are by-products of other smelters, primarily lead smelters. Additionally, other operations conducted at the plant at various times included the smelting or refining of iridium, platinum, and other fine metals. The first cohort mortality study (1) of the workers at this plant was conducted by Lemen and colleagues (1976) of the National Institute for Occupational Safety and Health (NIOSH), who studied 292 white male workers employed at least 2 years in the production processes of the plant between January 1, 1940, and December 3 1, 1969, and followed their mortality experience through 1973. They reported a statistically significant excess of respiratory cancer deaths (I2 cases, standardized mortality ratio (SMR) = 235) among the 292 workers employed for more than 2 years and also a statistically significant excess of prostate cancer deaths for those observed more than 20 years after hire. This study was later expanded by Thun and associates (1985) to include 602 white males with at least 6 months of employment and to observe mortality through 1978 (4). The lung cancer rate, reported as marginally statistically significant for the total study group (SMR = 175), was highly significant for those hired prior to 1926 (SMR = 714), but not significant for those hired after 1926 (SMR = 147). The stratification into pre- and post-1926 date-of-hire groups was performed in order to separate out those hired during the primarily arsenic-smelting period from those hired during the cadmium-smelting period of the plant. Among those hired after 1926, the lung cancer mortality rate was statistically significantly high only for those employed
Lamm et al. LUNG CANCER RISK IN CADMIUM-EXPOSED WORKERS
AEP Vol. 2, No. 3 May 1992: 19.5-21 I
197
250 200 S M 150 R 100 50 0
2920
Exposure in mg-days/m3
FIGURE 1
Lung cancer mortality risk by cumulative cadmium exposure in milligram-days per cubic meter for men hired 1926 or later. Data from Thun et al. (4).
for more
than 2 years (SMR = 229) and was statistically significantly low for those employed for less than 2 years (SMR = 000). Additionally, lung cancer risk was shown to be dose-related to their estimate of cumulative cadmium exposure (Figure 1). The results of this study were instrumental in the US Environmental Protection Agency’s decision to label cadmium as a probable human pulmonary carcinogen (6). Vamer (2) and White (3) of ASARCO, Inc., independently conducted a mortality study through 1982 of the 2702 persons who had worked at the plant for even 1 day from 1940 onward. In 1985, White (4) reported the mortality experience through 1982 for the cohort of production workers with more than 6 months’ employment between 1940 and 1969 (including black and female workers). The analysis was stratified by date of hire prior to and after 1940, that is, separating the employment period prevalence cohort (those employed between 1940 and 1969) into its two component parts of the cross-sectional or “prior” cohort (those employed at the beginning of 1940) and the employment incidence or “hire” cohort (those hired between 1940 and 1969). A significantly increased lung cancer risk was demonstrated in those hired prior to 1940 (11 cases, SMR = 244) (’i.e., the cross-sectional cohort) and no increased risk, among those hired 1940 or later (10 cases, SMR = 78). All of the cadmium exposure measurements NIOSH had relied on were obtained during the period of the hire cohort which showed no increased lung cancer risk. White concluded that NIOSH’s attribution of pulmonary carcinogenicity to inhaled cadmium was in-
correct.
Although Thun and colleagues (4) and Vamer (2) and White (3) studied essentially the same group of workers, they came to markedly different conclusions.The studies differed in a number of ways, including cohort definition, analytic method, death certificate coding, and date-of-hire stratification. In order to develop a common database, we (5) merged the NIOSH demographic and work-history data tapes (of the Thun study) and the ASARCO mortality data tapes (of Vamer and White’s study). We were able to identify 599 of the 602 men in the NIOSH cohort and all of the lung cancer deaths. We attempted to replicate the findings of each group, both with their own tape and from the other’s tapes. Using death certificate coding by National Center for Health Statistics (NCHS) nosologists, we found for lung cancer mortality that those hired prior to 1926 had an
198
AEP Voi. 2, No. 3
Lamm et al.
LUNG CANCER RISK IN CADMIUM-EXPOSED WORKERS
MD, Mary Anderson,
MD, and
Workers at a cadmium recovery pIant in Globe, Colorado, showed an increased risk of lung cancer, which some investigators have attributed to cadmium exposure. We conducted a cohort mortality analysis of this work force and a case-control analysis of the lung cancer cases within this work force in order to assess the probable causes of the lung cancer excess. The Globe plant began as a lead smelter about 1886, switched to arsenic production in 1920, and became a cadmium metal production facility in 1926. Cadmium, arsenic, and cigarette smoking are three potential lung carcinogens found in this workplace. Industrial hygiene data collected from I943 onward served as the basis for the National Institute for Occupational Safety and Health (NIOSH)-derived exposure algorithm that assigned cadmium exposure estimates to employees based on their work area in the plant and calendar time. Few exposure data existed for substunces other than cadmium. Feedstock ore concentrations were used us a surrogate measure of air arsenic levels. The arsenic content of the fines used as feedstock prior to I940 was considerably higher than rhat of the fines used after 1940. Smoking histories had been obtained previously for 45% of the workers. A case-control analysis of the 25 cases of lung cancer known to have occurred among these workers through 1982 was conducted using three controls per case, matched by closest data of hire and age at hire. Porenrial causal agents for lung cancer included cadmium exposure, cigarette smoking, and arsenic exposure. Exposure variables for each case and control included estimated cumulative cadmium exposure in milligram-years per cubic meter, cigarette smoking history, and plant arsenic exposure status at the time of hire. Estimated cumuhtiwe cadmium exposures of cases and controls did not differ overall or within the date-of-hire strata. Cases were more than eight rimes more likely to have been cigarette smokers than were controls. Lung cancer risk in this workplace was more closely related to the period of hire, not to the cumulative cadmium eqosure. The period of hire appears to be a surrogate for arsenic exposure as related to feedstock. The measures used here seem to indicate that exposure to arsenic and cigarette particulates, rather than to cadmium particulates, may have caused the increased rate of lung cancer of these workers. Ann Epidemiol I992;2; 195-2 11. KEY WORDS:
Lung cancer, cadmium, arsenic, cigarette smoking, caSe control.
INTRODUCTION The lung cancer mortality
for the production workers at the Globe, Colorado cadmium smelter has been reported in numerous studies (l-5) (Table I), with some (I, 4) concluding that cadmium is a demonstrated human carcinogen and others (2, 3, 5) that it is not. This group of workers comprises the only US database for assessing mortality risks associated with employment and cadmium exposure. Nonetheless, its
From Consultants in Epidemiology and Occupational Health, Inc., Washington, DC (S.H.L., M.P., M.A., W.T.); Department of Health Policy and Management and Preventive Medicine Residency Program, Johns Hopkins School of Public Health Baltimore, MD (S.H.L., M.P., M.A.); and DataSoft, Clarksville, MD (W.-r.). Address reprint requests to: Steven H. Lamm, MD, Consultants in Epidemiology and Occupational Health, Inc., 2428 Wisconsin Avenue, N.W., Washington, DC 20007. Received September 15, 1990; revised September 20, 1991. 0 1992 Elsevier Science Publishing Co.,
Inc.
1047-2797/92/$05.00
196
Lamm et al. LUNG CANCER
TABLE 1
RISK IN CADMIUM-EXPOSED
Lung
Study
cancer
risk
in cohort studies of Globe, Colorado smelter workers Cohort
Lemen et al., 1976 (1) Vamer, 1983 (2)
292 white males employed > 2 y 625 employees
White, 1985 (3)
employed > 6 mo 646 employees
Thun et al., 1985 (4)
Lamm, 1988 (5)
AEf’ Vol. 2, No. 3 May 1992: 195-211
WORKERS
employed > 6 mo Hired pre- 1940 Hired post-1940 602 white males employed > 6 mo Hired pm-1926 Hired post-1926 Employed > 2 y Employed < 2 y 599 white males employed > 6 mo Hired pm-1926 Hired 1926-1939 Hired 1940- 1969
End of follow-llu
Results
1973 SMR = 235” 1982 SCR = 163” 1982 SCR = 244“ SCR = 078
1978 SMR = 175 SMR = 714” SMR = 147 SMR = 229” SMR = 000” 1978 SMR SMR SMR SMR
= = = =
144 492” 283” 88
= P < 0.05.
analysis is particularly problematic because of confounding from exposure to cadmium, arsenic, and cigarette smoking. The plant has a varied history of activities, serving first as a lead smelter from 1886 to 1919, then as an arsenic smelter from 1920 to 1925, and finally as a cadmium smelter since 1926. The plant’s primary function is to extract cadmium from the feedstock of precipitated dusts (fines) that are by-products of other smelters, primarily lead smelters. Additionally, other operations conducted at the plant at various times included the smelting or refining of iridium, platinum, and other fine metals. The first cohort mortality study (1) of the workers at this plant was conducted by Lemen and colleagues (1976) of the National Institute for Occupational Safety and Health (NIOSH), who studied 292 white male workers employed at least 2 years in the production processes of the plant between January 1, 1940, and December 3 1, 1969, and followed their mortality experience through 1973. They reported a statistically significant excess of respiratory cancer deaths (I2 cases, standardized mortality ratio (SMR) = 235) among the 292 workers employed for more than 2 years and also a statistically significant excess of prostate cancer deaths for those observed more than 20 years after hire. This study was later expanded by Thun and associates (1985) to include 602 white males with at least 6 months of employment and to observe mortality through 1978 (4). The lung cancer rate, reported as marginally statistically significant for the total study group (SMR = 175), was highly significant for those hired prior to 1926 (SMR = 714), but not significant for those hired after 1926 (SMR = 147). The stratification into pre- and post-1926 date-of-hire groups was performed in order to separate out those hired during the primarily arsenic-smelting period from those hired during the cadmium-smelting period of the plant. Among those hired after 1926, the lung cancer mortality rate was statistically significantly high only for those employed
Lamm et al. LUNG CANCER RISK IN CADMIUM-EXPOSED WORKERS
AEP Vol. 2, No. 3 May 1992: 19.5-21 I
197
250 200 S M 150 R 100 50 0
2920
Exposure in mg-days/m3
FIGURE 1
Lung cancer mortality risk by cumulative cadmium exposure in milligram-days per cubic meter for men hired 1926 or later. Data from Thun et al. (4).
for more
than 2 years (SMR = 229) and was statistically significantly low for those employed for less than 2 years (SMR = 000). Additionally, lung cancer risk was shown to be dose-related to their estimate of cumulative cadmium exposure (Figure 1). The results of this study were instrumental in the US Environmental Protection Agency’s decision to label cadmium as a probable human pulmonary carcinogen (6). Vamer (2) and White (3) of ASARCO, Inc., independently conducted a mortality study through 1982 of the 2702 persons who had worked at the plant for even 1 day from 1940 onward. In 1985, White (4) reported the mortality experience through 1982 for the cohort of production workers with more than 6 months’ employment between 1940 and 1969 (including black and female workers). The analysis was stratified by date of hire prior to and after 1940, that is, separating the employment period prevalence cohort (those employed between 1940 and 1969) into its two component parts of the cross-sectional or “prior” cohort (those employed at the beginning of 1940) and the employment incidence or “hire” cohort (those hired between 1940 and 1969). A significantly increased lung cancer risk was demonstrated in those hired prior to 1940 (11 cases, SMR = 244) (’i.e., the cross-sectional cohort) and no increased risk, among those hired 1940 or later (10 cases, SMR = 78). All of the cadmium exposure measurements NIOSH had relied on were obtained during the period of the hire cohort which showed no increased lung cancer risk. White concluded that NIOSH’s attribution of pulmonary carcinogenicity to inhaled cadmium was in-
correct.
Although Thun and colleagues (4) and Vamer (2) and White (3) studied essentially the same group of workers, they came to markedly different conclusions.The studies differed in a number of ways, including cohort definition, analytic method, death certificate coding, and date-of-hire stratification. In order to develop a common database, we (5) merged the NIOSH demographic and work-history data tapes (of the Thun study) and the ASARCO mortality data tapes (of Vamer and White’s study). We were able to identify 599 of the 602 men in the NIOSH cohort and all of the lung cancer deaths. We attempted to replicate the findings of each group, both with their own tape and from the other’s tapes. Using death certificate coding by National Center for Health Statistics (NCHS) nosologists, we found for lung cancer mortality that those hired prior to 1926 had an
198
AEP Voi. 2, No. 3
Lamm et al.
LUNG CANCER RISK IN CADMIUM-EXPOSED WORKERS
