RE: "DOES ARSENIC EXPOSURE INCREASE THE RISK FOR CIRCULATORY DISEASE?"
Jay H. Lubin and
Joseph F. Fraumeni, Jr.
Division of Cancer Epidemiology and Genetics National Cancer Institute National Institutes of Health Bethesda, MD 20892
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INTRODUCTION
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High levels of ingested inorganic arsenic in drinking water have been linked to arsenical dermatosis and to elevated risks of cancers of the skin, bladder, kidney, liver, and lung (1
), as well as to diabetes mellitus (2
, 3
) and peripheral vascular and cardiovascular disease, but not cerebrovascular disease (4
6
). Recently, Hertz-Picciotto et al. (7
) observed that while high levels of arsenic in drinking water increase risk for a variety of diseases, most occupational studies of arsenic, in which inhalation is the primary route of exposure, have shown excess mortality only for respiratory cancer. This observation agrees with our summarization of 11 occupational studies of arsenic-exposed workers that showed consistent excesses only for respiratory cancer (8
). Despite results to date, the hypothesis of a deleterious effect of inhaled arsenic for diseases other than respiratory cancer remains credible. Inhaled arsenic-containing dusts increase systemic arsenic, as demonstrated by elevated urinary arsenic in workers, to levels comparable with those found in populations consuming contaminated drinking water (9
). Thus, one could posit that occupationally exposed cohorts should experience excess mortality for cancers of the kidney, bladder, and liver and for diseases of the circulatory system, particularly cardiovascular disease.
Hertz-Picciotto et al. (7
) suggested that the absence of an excess mortality for circulatory diseases in occupational studies is due to a healthy worker survivor effect (HWSE), whereby exposure-related disorders result in early retirement or less hazardous jobs and, thus, in reduced total exposure. With data from a study of smelter workers in Tacoma, Washington, and adjustment for age and year of hire, there were no apparent arsenic-related trends in the relative risks for circulatory diseases, cardiovascular disease, or cerebrovascular disease. To account for the HWSE, the authors then added an adjustment for employment status (current or former worker) and determined exposures based on 10- and 20-year lag intervals. Although p values for tests of trend were not provided, there was a suggestive increase in the relative risk with arsenic exposure for circulatory diseases and for cardiovascular disease, but not for cerebrovascular disease. However, results were ambiguous, as there was no association between arsenic exposure and circulatory diseases using a G-null analysis (10
), an alternative method for HWSE adjustment.
The paper by Hertz-Picciotto et al. (7
) prompted a reexamination of our cohort of 8,014 Montana copper smelter workers (8
). The study included all workers who were employed for 12 months or more prior to 1957, with follow-up starting on January 1, 1938, or 1 year after the start of employment and continuing through December 31, 1989. Because we had no information on exposures received after employment at the smelter ended, we restrict our analyses to person-years accrued by current workers and former workers last employed at age 50 years or older. A total of 6,885 workers contributed 120,900 person-years, with 1,615 deaths from all circulatory diseases (International Classification of Diseases, Eight Revision (11
) (ICD-8) codes 390459), including 1,115 deaths from cardiovascular disease (ICD-8 codes 410414 and 420429), 260 deaths from cerebrovascular disease (ICD-8 codes 430438), and 45 deaths from peripheral vascular disease (ICD-8 codes 440448). Exposure was expressed as years working in areas with heavy (mean, 11.3 mg/m3), medium (mean, 0.58 mg/m3), and light (mean, 0.29 mg/m3) arsenic levels. Unspecified or unknown work areas were classified as work areas with light exposure. There were no indications of increasing risks with greater duration of exposure in work areas with light, medium, or heavy arsenic exposure, using the baseline model or after additional adjustment for the HWSE for cardiovascular disease (table 1) or for cerebrovascular disease (table 2). All tests of linear trends were not significant. Results for all circulatory diseases and peripheral vascular disease were similar (not shown). We also analyzed morality from diabetes mellitus (ICD-8 code 250), with 54 deaths and 27 deaths in the restricted data, and found no association with arsenic exposure.
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TABLE 1. Relative risks and 95% confidence intervals for cardiovascular disease (ICD-8* codes 410414 and 420429), Montana, 19381989
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TABLE 2. Relative risks and 95% confidence intervals for cardiovascular disease (ICD-8* codes 430439), Montana, 19381989
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The disease experience of former workers whose last employment at the smelter occurred before age 50 years was omitted in our analysis because there were sufficient cases only to analyze cardiovascular disease. There were no significant trends in the relative risks with the various measures of cumulative arsenic exposure. However, relative risks for 514, 1524, and 25 years and more after cessation of employment were 0.80, 0.66, and 0.41, respectively, compared with 14 years after cessation of employment. These results do not suggest a relation between cardiovascular disease and cumulative arsenic exposure, but do suggest that cardiovascular disease "caused the retirement."
Along with most other occupational studies, we were unable to detect associations of inhaled arsenic with mortality from circulatory diseases or from cancer sites other than the respiratory tract. The more limited effect of inhaled arsenic stands in contrast to the excess of circulatory diseases and various cancers reported in populations exposed to arsenic-contaminated drinking water, despite equivalent levels of urinary arsenic. While an HWSE may indeed tend to obscure associations in occupational studies, the more systemic effects of ingested versus inhaled arsenic suggest different mechanisms of action that remain to be clarified.
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REFERENCES
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Lai MK, Hsueh YM, Chen CJ, et al. Ingested inorganic arsenic and prevalence of diabetes mellitus. Am J Epidemiol 1994;139:48492.[Abstract]
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Engel RR, Smith AH. Arsenic in drinking water and mortality from vascular disease: an ecologic analysis in 30 counties in the United States. Arch Environ Health 1994;49:41827.[ISI][Medline]
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Hertz-Picciotto I, Arrighi HM, Hu SW. Does arsenic exposure increase the risk for circulatory disease? Am J Epidemiol 2000;151:17481.[Abstract]
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Lubin JH, Pottern LM, Stone BJ, et al. Respiratory cancer in a cohort of copper smelter workers: results from more than 50 years of follow-up. Am J Epidemiol 2000;151:55465.[Abstract]
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Hopenhayn-Rich C, Smith AH, Goeden HM. Human studies do not support the methylation threshold hypothesis for the toxicity of inorganic arsenic. Environ Res 1993;60:16177.[ISI][Medline]
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Robins J. A general approach to the identification and estimation of causal parameters in mortality studies with sustained exposure periods. J Chronic Dis 1987;40 (Suppl. 2):139S61S.
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International Agency for Research on Cancer. International classification of diseases. Adapted. USPHS publication no.1693. Washington, DC: US GPO, 1976.
The Authors Reply
Irva Hertz-Picciotto,
Suh-Woah Hu and
H. M. Arrighi
Department of Epidemiology School of Public Health University of North Carolina Chapel Hill, NC 275997400
School of Dentistry Chung Shan Medical and Dental College Taichung, Taiwan 402
Amgen Thousand Oaks, CA 913201789
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INTRODUCTION
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In response to our recent paper (1
) suggesting an association between circulatory disease mortality and occupational arsenic exposure that is seen only after adjustment for the healthy worker survivor effect, Lubin and Fraumeni (2
) have reanalyzed data from the Anaconda smelter worker cohort. They are in agreement that there is biologic plausibility to this association, based largely on studies in populations with ingestion exposure, and despite their finding of no significant trend between duration of exposure and circulatory disease mortality, they and we believe that the data to date are not conclusive.
As discussed in an earlier paper (3
), a complete adjustment for the differences in underlying health status between those who remain on a job and those who leave employment at that site is quite complex. The methods used by us and by Lubin and Fraumenilagging exposure and controlling for work statusprovide only a partial adjustment. The problem is that any measure of cumulative exposure incurs the potential for this survivorship bias, since it is a function of length of employment. Nonetheless, the greater the association between the measure used and the duration of employment, the lower the chance of successfully controlling this bias through lagging and work status adjustment. Thus, it would have been more informative if Lubin and Fraumeni had compared different intensities of exposure among workers of similar duration rather than different durations among workers of similar intensity of exposure. From the results shown, no inferences can be drawn about intensity.
If there is an association between circulatory disease and some function of cumulative arsenic exposure, then the observed exposure response relation will reflect these two opposing phenomena: a declining risk with increasing length of employment due to the healthy worker survivor effect and an increasing risk with longer duration of employment due to greater accumulated exposure. In this circumstance, the healthy worker survivor effect can easily distort the dose-response relation, and therefore, even if exposure caused a linear increase in mortality, a nonlinear dose response might well be observed. For this reason, the test for linear trend would not be of interest (4
). The results of Lubin and Fraumeni for cardiovascular disease (2
, table 1) show consistent, although unstable, elevations in mortality relative risks among those with the longest durations of exposure in every analysis except that based on a 20-year lag among workers from medium airborne arsenic areas. Considering these observations and the lack of association with cerebrovascular disease, their findings are remarkably similar to ours.
Finally, the monotonically declining risk ratios for increasing years since leaving employment among workers who left the smelter prior to reaching age 50 years are interpreted by Lubin and Fraumeni as suggesting that cardiovascular disease "caused the retirement" (2
, p. 000). This is an excellent description of how the healthy survivor effect operates; indeed, the findings seem to indicate that this bias also may not be well-controlled in the reported analysis for those who left employment at the smelter after age 50.
As previously discussed, G-estimation (5
7
) provides the potential for a more complete and valid adjustment for the healthy worker effect without the problem of low statistical power that plagued our analysis based on the G-null test. We are currently conducting analyses on the Tacoma smelter worker cohort using G-estimation.
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REFERENCES
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Hertz-Picciotto I, Arrighi HM, Hu SW. Does arsenic exposure increase the risk for circulatory disease? Am J Epidemiol 2000;151:17481.[Abstract]
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Lubin JH, Fraumeni JF. Re: "Does arsenic exposure increase the risk for circulatory disease?" Am J Epidemiol 2000;152:290-3.[Free Full Text]
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Arrighi HM, Hertz-Picciotto I. The evolving concept of the healthy worker survivor effect. Epidemiology 1994;5:18996.[ISI][Medline]
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MacClure M, Greenland S. Tests for trend and dose response: misinterpretations and alternatives. Am J Epidemiol 1992;135:96104.[Abstract]
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Robins J. A new approach to causal inference in mortality studies with an sustained exposure periodapplication to control of the healthy worker survivor effect. Math Modeling 1986;7:1393512.
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Robins JM, Blevins D, Ritter G, et al. G-Estimation of the effect of prophylaxis therapy for Pneumocystis carinii pneumonia (PCP) on the survival of AIDS patients. Epidemiology 1992;3:31936.[ISI][Medline]
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Witteman JCM, D'Agostina RB, Stijnen T, et al. G-Estimation of causal effects: isolated systolic hypertension and cardiovascular death in the Framingham Heart Study. Am J Epidemiol 1998;148:390401.[Abstract]