Affiliation of authors: Medical Research Council Environmental Epidemiology Unit, University of Southampton, Southampton, United Kingdom.
Correspondence to: Professor David Coggon, DM, Medical Research Council Environmental Epidemiology Unit, Southampton General Hospital, Southampton SO16 6YD U.K. (e-mail: dnc{at}mrc.soton.ac.uk).
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ABSTRACT |
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INTRODUCTION |
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Formaldehyde is mutagenic in vitro, and exposures in vivo by gavage and inhalation have been shown to induce cytogenetic damage in tissues that are in direct contact with the chemical (1). When rats inhaled formaldehyde at concentrations of 14 ppm or higher, they developed cancer of the nose (1,2), but it is unclear whether these tumors arose through a genotoxic mechanism or as a consequence of cytotoxicity. Epidemiologic studies of occupational exposure to formaldehyde (3-5) have suggested elevated risks of cancer at various sites, including the nose and nasal sinuses, nasopharynx, lung, and brain. However, the evidence that formaldehyde is carcinogenic in humans has been inconsistent, and when last reviewed by the International Agency for Research on Cancer in 1995, the evidence was classed as limited
(1).
To address the continuing uncertainties in risk assessment for formaldehyde, there is a need for further epidemiologic data, particularly from the chemical industry, where occupational exposures have historically tended to be highest. In Britain, a large cohort of such workers was identified by Acheson et al. (6) in the early 1980s. A previous analysis of this cohort (7) indicated an excess of lung cancer, but it was unclear whether this excess resulted from exposure to formaldehyde or from confounding by nonoccupational risk factors. Here, we have extended follow-up of the cohort by 11 years, during which almost 2000 additional deaths occurred.
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SUBJECTS AND METHODS |
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In addition to formaldehyde, other hazardous materials, including styrene, ethylene oxide, epichlorhydrin, various solvents, asbestos, chromium salts, and cadmium, were handled at some of the factories. In most cases, however, any exposures to these substances would have been relatively low.
The cohort was followed for mortality and cancer incidence through December 31, 2000, principally through the National Health Service Central Register (NHSCR). For the few members of the cohort for whom tracing proved difficult, supplementary information on vital status was obtained from Social Security records. Deaths were coded according to the ninth revision of the International Classification of Diseases (ICD-9). Person-year analyses were conducted using Stata 7.0 software to derive standardized mortality ratios (SMRs), with associated 95% confidence intervals (CIs) based on the Poisson distribution. Expected numbers of deaths were calculated from national rates for England and Wales in 5-year age bands and 5-year calendar periods. As in previous reports (6,7), some analyses also included an adjustment for local geographical variations in mortality. This adjustment involved multiplying the expected numbers of deaths from national rates by SMRs for the local authority areas in which each factory was located. The adjustment factors that were used for each factory in different time periods are shown in Table 2. The relevant local authority areas changed over time because of reorganizations of local government. Poisson regression was used for tests for trend across ordered exposure categories. All statistical tests were two-sided.
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The number of men (14 014) included in our analysis differed slightly from that in a previous report of this cohort (14 017) (7). In our analysis, two workers previously miscoded as male were excluded, and four had previously been double-counted because they had been employed a second time by the same factory or by another factory in the study, and their records had not been linked. These losses were partially offset by the inclusion of three additional men whose date of birth (two) or sex (one) had before been unknown.
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RESULTS |
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The overall mortality among members of the cohort was slightly higher than expected from national death rates (SMR = 1.04, 95% CI = 1.02 to 1.07), as was mortality from all cancers (SMR = 1.10, 95% CI = 1.04 to 1.16), respiratory disease (SMR = 1.12, 95% CI = 1.04 to 1.21), digestive disease (SMR = 1.19, 95% CI = 1.02 to 1.38), and injury and poisoning (SMR = 1.09, 95% CI = 0.96 to 1.24) (Table 3). A similar pattern was observed when analysis was restricted to the 1919 deaths that had occurred during the 11 years of added follow-up (data not shown). Among men who had worked in jobs with high exposure to formaldehyde (1995 deaths, overall SMR = 1.15, 95% CI = 1.10 to 1.20), the increase in mortality was greater than that in the total cohort for the diagnostic categories of cancer, respiratory disease, and digestive disease, but not for deaths from injury and poisoning. In men who had never been recorded as working in a job where formaldehyde exposure was high, mortality from all causes and from all cancers was close to that expected (SMR = 0.99 for each).
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Review of cancer registrations and of the contributing causes of death reported on death certificates revealed two additional cases of sino-nasal cancer (both in individuals with high exposure to formaldehyde) but no further cancers of the nasopharynx that had not been included as causes of death in the analysis of mortality.
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DISCUSSION |
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The major strength of this investigation was its prolonged follow-up of a large population of workers with relatively high exposures to formaldehyde. No occupational hygiene measurements were available for the early years in which these men worked, but from descriptions of working conditions and practices, it seems likely that airborne concentrations of the compound were substantially higher than those encountered in industry today. At the factory where the largest number of heavily exposed workers was employed (BIP), formaldehyde-based resins were used in the manufacture of Mosquito aircraft during World War II, and productivity was likely to have been a higher priority than occupational hygiene.
Our study has several limitations, however. First, when follow-up of a cohort is so long (almost 60 years for some of our subjects), unrecognized losses to follow-up with missed deaths can sometimes lead to an underestimation of risks. However, when analyses were repeated with follow-up censored at age 85 years, there was no indication that bias of this sort had occurred. Second, the workers in our cohort may have been exposed to various other hazards in addition to formaldehyde in the course of their work, including asbestos and several other known or suspected carcinogens. However, the extent of such exposures is unlikely to have been sufficient to cause substantial confounding. In support of this view, among employees at the BIP factory, where the main excess of lung cancer occurred, there were only two deaths from mesothelioma, a tumor which is commonly associated with asbestos exposure. More important is the potential for confounding by non-occupational factors. Unfortunately, no information was available on aspects of individual lifestyle such as smoking habits, and the possible impact of such confounding could only be addressed indirectly.
Among the human cancers that have been linked previously with formaldehyde, tumors of the nose and nasal sinuses and of the nasopharynx have been under the most suspicion. Evidence for an association with sino-nasal cancer comes mainly from case-control studies. In a meta-analysis reported in 1997, Collins et al. (5) derived a summary relative risk estimate of 1.8 (95% CI = 1.4 to 2.3) from 11 case-control studies and of 0.3 (95% CI = 0.1 to 0.9) from nine cohort studies of industrial populations, pathologists, and embalmers. Additional results published since those analyses have followed a similar pattern. For example, one new case of sino-nasal cancer has been described in an extended follow-up of 6039 workers at a U.S. chemical plant in Connnecticut (8), and none were observed among 111 men who were exposed to formaldehyde at a plastics facility in New Jersey (9). However, an analysis of proportional cancer incidence in Denmark indicated a 2.3-fold increased risk of sino-nasal cancer in employees at 265 companies that had used or manufactured formaldehyde (10).
In our study, there was one death from sino-nasal cancer during the additional period of follow-up, but the man who died had only background exposure to formaldehyde and, over the full duration of follow-up, mortality from the disease was close to that expected. Two other cases of sino-nasal cancer were registered in men whose deaths were ascribed to other causes (melanoma and cerebrovascular disease). Both of these men had worked in jobs with high exposure to formaldehyde. Because of uncertainties about the completeness of cancer registration in the United Kingdom during the follow-up period, we do not have reliable expected numbers against which to assess this observation. However, given that the expected number of deaths from sino-nasal cancer was 2.3, a total of four observed cases, both fatal and nonfatal, is unremarkable.
The disparity between cohort and case-control studies in risk estimates for sino-nasal cancer is unlikely to reflect differences in levels of exposure to formaldehyde because, in general, exposures have been higher in the cohort studies. The discrepancy may be attributable in part to unadjusted or residual confounding by exposure to wood dust, which is strongly associated with exposure to formaldehyde in some occupations. However, in the Danish analysis of proportional cancer incidence (10), risk of sino-nasal cancer was statistically significantly increased, even in workers who were unlikely to have been exposed to wood dust. Whatever the explanation for the discrepancy, any excess risk of sino-nasal cancer from exposures to formaldehyde at the concentrations that occur in industry today is likely to be extremely small.
The suspicion that formaldehyde exposure causes nasopharyngeal cancer stems in part from a study of workers at 10 chemical plants in the United States (11), in which an SMR of 3.0 was derived based on six observed cases [although a subsequent investigation showed that one of the individuals in fact had cancer of the tonsillar fossa, and the cause of death had been misclassified on his death certificate (12)]. In addition, positive associations between formaldehyde exposure and nasopharyngeal cancers have been reported in several case-control studies (13-17). However, other investigations have given little support to these findings (5,9,10,18) and, in our study, the only death from nasopharyngeal cancer was in a man whose exposure to formaldehyde was classified as low. Overall, the epidemiologic evidence now available indicates that if formaldehyde does cause nasopharyngeal cancer, then the increased risk is small.
The last analysis of mortality in our cohort showed that, although there were 21% more deaths from lung cancer (ICD-9 codes 162-164) than expected from national rates, the excess was reduced to 12% after adjustment for local variations in mortality and was not clearly related to formaldehyde exposure (7). With extended follow-up, a similar pattern is apparent. Mortality from lung tumors (ICD-9 code 162) was increased in the cohort overall (SMR based on national rates = 1.22), and particularly among men who had worked in jobs with high levels of exposure (SMR = 1.58). However, most of the high-level exposures occurred at one factory (BIP), which was located in an area with high background rates of lung cancer. Thus, when expected numbers were adjusted for local differences in mortality, the SMR for the high-exposure category was reduced to 1.28. Moreover, the locally adjusted SMRs for lung cancer were also elevated in men with only background (SMR = 1.12) or low exposure to formaldehyde (SMR = 1.15). There was no consistent increase in risk with duration of employment in jobs with high levels of exposure or with time since first carrying out work of this sort. Mortality was highest in those who had worked in jobs with high levels of exposure for less than 1 year (locally adjusted SMR = 1.40).
These observations suggest residual confounding by non-occupational causes of lung cancer that were more common in short-term employees. The presence of residual confounding would not be surprising, given that our method of adjusting for geographic variation in mortality was, by necessity, somewhat crude, and that such adjustment, even if more refined, would not account fully for individual differences in exposure to risk factors such as smoking. The increased mortality from respiratory disease (Table 4) is also consistent with an unusually high prevalence of smoking in the cohort, and it is notable that, at BIP, the SMR for respiratory disease was again reduced substantially after adjustment for local differences in mortality. However, the SMR for lung cancer in men with high levels of exposure (SMR = 1.28 after local adjustment) is rather large to be explained simply by a confounding effect of smoking, particularly as the prevalence of smoking in the comparison population is likely to have been high. Also, at the BIP factory, where most of the high-level exposure occurred, mortality from respiratory disease was highest for jobs with low exposures, whereas mortality from lung cancer was highest for those with high exposure. Thus, confounding by smoking may not be the full explanation for the observed excess of lung cancer deaths in the cohort.
The other major cohort study of formaldehyde exposure in the chemical and plastics industry, which was carried out in the United States, also found an increase in mortality from lung cancer (11,19), although the increase was smaller than that in our investigation. In a re-analysis of the U.S. study, one group has claimed that the risk of lung tumors increased with cumulative exposure to formaldehyde (20). However, this was not a finding in the original analysis (11,19) and has not been confirmed by others who have examined the same data (21). Several other studies of industrial populations (22,23) have also suggested an increased rate of lung cancer in workers exposed to formaldehyde, but this has not been a universal observation (10,18) and, where present, the excess has generally been small. Anatomists and pathologists who are also exposed to formaldehyde have been found to experience unusually low mortality from lung cancer (5), but this almost certainly reflects low rates of smoking.
Our cohort also had increased mortality from stomach cancer, although again the excess was reduced after adjustment for local differences in death rates. A hazard of stomach cancer from inhalation of formaldehyde is less plausible than an effect on tissues in the respiratory tract that come into direct contact with the chemical. Moreover, increased rates of stomach cancer have not been found in other cohort studies of formaldehyde workers. Therefore, it seems more likely that the excess in our study was a consequence of confounding by non-occupational factors.
Recent analysis of data from an extended follow-up of a cohort of industrial workers in the United States has suggested an association between formaldehyde and lymphatic and hematopoietic cancer, and particularly between formaldehyde and leukemia (24). Although mortality from these diseases was not increased in exposed workers overall and showed no relation to cumulative exposure, risk of death increased statistically significantly with higher peak and average intensities of exposure. In our study, however, mortality from leukemia and other lymphatic and hematopoietic cancer was lower than expected from national rates, both in the full cohort and in the subset of men with high levels of exposure (Table 5). There is no obvious explanation for this discrepancy in findings, other than that it occurred by chance.
Overall, we conclude that the evidence for human carcinogenicity of formaldehyde remains unconvincing. Whether formaldehyde exposure is associated with a small increase in the risk of sino-nasal and/or nasopharyngeal cancer cannot be ruled out from the results of our study. However, lung cancer is a much more common disease, and the possibility of a marginally elevated relative risk of lung cancer from formaldehyde exposure is of greater concern. Further follow-up of industrial cohorts, particularly those with relatively high levels of exposure to formaldehyde, may help to resolve the outstanding uncertainties. In addition, clarification may come from the study of biomarkers for tissue and DNA damage in exposed workers.
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NOTES |
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We thank the staff of the National Health Service Central Register for their help with the follow-up, Holly Syddall for her advice on the statistical analysis, and Patsy Coakley for assistance with computing and data management.
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REFERENCES |
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Manuscript received March 20, 2003; revised June 30, 2003; accepted July 11, 2003.
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