Considerable attention has been given to the potential health risks to employees in chemical manufacturing and related industries. During the past several decades, hundreds of morbidity or mortality studies of chemical workers have been published, with most focused on the potential cancer risks associated with chemical exposure.
Although many chemicals in general use have exhibited positive responses in cancer or noncancer rodent bioassays when tested at high doses, relatively few workplace exposures have been established as causes of cancer or other diseases in humans. Most epidemiologic studies of the workplace have documented a deficit in mortality caused by cardiovascular disease, accidents, and several other disease categories. These favorable outcomes typically are attributed to the “healthy worker effect.” Notable exceptions are the relations of bladder cancer with aromatic amines and certain dyes, liver angiosarcoma with vinyl chloride, and lung cancer with hexavalent chromium. Each of these causal associations was established because exposure to the specific chemicals was substantial and well documented.
Few comprehensive studies, however, have evaluated the overall health of individuals employed in chemical manufacturing. The meta-analyses that we report herein evaluate the cause-specific mortality and cancer incidence of chemical workers in the United States and western Europe as they have been reported in the peer-reviewed literature between 1966 and 1997. These analyses do not identify specific chemicals, nor rule out their effects. Rather, they provide a general overview of the mortality and cancer incidence experience of persons employed in the chemical industry as reported in cohort studies and indicate several specific areas for future research.
Subject and Methods
Our starting point was the database developed by M.D. Whorton et al (1998; available from the American Chemistry Council), a comprehensive inventory of published peer-reviewed mortality and cancer incidence studies of workers engaged in the manufacture or application of chemical products. They identified articles by searching online databases (for example, Medline, Cancerlit, NIOSHTIC, Toxline, Embase, and Current Contents), reviewing yearly indices of selected journals, and reviewing references of identified studies and relevant review articles. Studies were included if they reported on employees working in companies that would qualify for membership in the U.S. American Chemistry Council. Eligible companies included those involved in the production of chemicals and the manufacture of products involving a substantial chemical operation such as chemical synthesis, formulation, or extraction. Studies also had to be published in English in peer-reviewed journals between 1966 and 1997, to have reported on cohorts in the U.S. or western Europe, and to have included information on mortality or cancer incidence.
We excluded from our review nested case-control studies because they are nearly always initiated after some preliminary observation of an increased risk of disease or mortality that is potentially work-related; therefore, we believe that they are less likely to be useful indicators of the general health and mortality of workers throughout the large and diverse chemical industry. Furthermore, we did not include population-based case-control studies because our goal was to evaluate the general health of chemical-industry workers and not risks related to specific chemical exposures.
We independently assessed the completeness and accuracy of the Whorton et al database by comparing it with the literature citations in recent reviews of chemical-specific epidemiologic investigations, such as International Agency on Cancer Research Monographs, as well as with results from additional online literature searches. Few discrepancies were identified, and they were all satisfactorily resolved.
To prevent multiple appearances of the same cohort in our meta-analysis, studies were grouped so that specific populations could be traced from the earliest to the most recently published report. Generally we chose the most recent publication for data abstraction because it provided the longest follow-up and the most up-to-date information. Exceptions included earlier studies that reported on specific subgroups (for example, women, salary vs hourly) not included in the most recent publication.
For studies reporting multiple standardized mortality ratios (SMRs) based on different comparison populations, such as state and national rates, “local” comparison groups were selected because local populations more directly reflect the source populations from which the workers arose and, therefore, should provide a less biased comparison. Although a few of the studies in the Whorton et al database reported risk ratios resulting from internal comparisons, the only effect estimates selected for use in this analysis were SMRs based on external comparison. We found little consistency in the type of internal group used in these studies (for example, workers from a different plant or workers from the same plant assumed to be unexposed), and the number of studies reporting these results was extremely small relative to the studies using general population comparison groups. Only one study reported risk ratios for employee populations that were not included in SMR results elsewhere in the database.
One of the primary reviewers (R. S. G., J. S. M., or H. P.) reviewed each study and, using a priori quality criteria, assigned a quality score of 1 to 3 for each study, as follows:
1. Satisfactory: The study addressed the methodologic issues in a manner consistent with generally accepted epidemiologic standards.
2. Limited adequacy: The study addressed a methodologic attribute incompletely, or in a manner that might have been appropriate, but provided too few details to allow a definitive assessment.
3. Unsatisfactory: The study either failed to address the methodologic attributes or addressed them in a manner that was inappropriate or inadequate.
We deliberately set the threshold for inclusion low so that only studies with serious deficiencies in methodology, design, or analysis would be excluded.
If one of us judged a study “unsatisfactory,” it was subsequently assessed by all three reviewers. Unanimous accord was required to exclude a study. As a check of reviewer reliability, a sample of one-third of the studies was reassessed by a different reviewer. Greater than 95% concordance was reached initially and, after discussion, unanimous accord was reached on all those studies for which initial quality scores differed.
Of the 461 studies in the database, 69 (15.0%) were ineligible for one of the following reasons: noncohort study design (40 studies, 8.7%), geographical location (27 studies, 5.9%), or employers ineligible for membership in the American Chemistry Council (2 studies, 0.4%). Only seven (1.5%) studies were excluded as unsatisfactory by virtue of inadequacies in design, description, or analysis. For the remaining 385 studies, data were abstracted from the 181 studies representing the most recent report for a cohort, or the earlier study of the same cohort that provided relevant data according to the selection criteria. 1–50, 51–100, 101–150, 151–181 Of these, 156 reported only mortality data, 2–6,8,10–19,21–37,39–47, 51–62,64,67–77,79–81,82–87,89–90,92–102, 104–112,114,116–118,120,123–128,130–138,140–144, 146,148–168,170–181 10 reported only incidence data, 7,20,50,78,88,103,121,129,139,169 and 15 reported both mortality and incidence data. 1,9,38,48,49,63,65,66,82,91,113,115,119,145,147 Sixty-nine per cent of the studies reporting mortality data 1,8–19,21–24,26–29,32–35,37,39,40,42,43,46–49, 51,52,55–61,62–65,67,68,72,74–76,79–87,90,91,94,95,97,99, 101,106,108,113–117,119,120,122–125,128,131,134–138,141–146,148–151, 154,156,158–160,162,164,165,168,170,172–174,176,179–181 and 64% of the studies reporting incidence data 1,9,20,48–50,63,65,82,92,103,113,115,119,139,145 received “satisfactory” quality scores. This selection process is illustrated in Figure 1.
We abstracted and entered into an electronic database the observed and expected numbers of cases of each endpoint reported in the selected studies. 1–50, 51–100, 101–150, 151–181 These data were then used to generate SMRs or standardized incidence ratios (SIRs) and corresponding 95% confidence intervals as appropriate. For each disease endpoint, meta-analyses of the data were undertaken from all studies reporting that endpoint (meta command, Stata Corp). We also performed additional meta-analyses for selected subcohorts on the basis of gender, latency (time since first employment to death or diagnosis), or duration of exposure (employment).
Pooled effect estimates were generated using both fixed- and random-effects models. In fixed-effects models, study-specific contributions to the pooled estimates were weighted inversely in proportion to their estimated “within-study” variance estimates. In the random-effects models, we permitted the study-specific effects estimates to have a zero mean normal random component of which the additional variance was determined by a “between-studies” variance estimate. We also routinely conducted tests for heterogeneity of the study-specific estimates. Because the large number of studies included in the meta-analyses led to extremely high precision in the effects estimates, heterogeneity among results was routinely observed, and thus we elected to present only the random-effects model estimates. There were, however, only four causes of death (that is, bronchitis, esophageal cancer, laryngeal cancer, and Hodgkin’s lymphoma) exhibiting sufficient heterogeneity to lead to qualitatively different interpretations based on the model used. We therefore re-examined data evaluated in the meta-analyses of these outcomes to identify potential outliers and/or possible errors in data abstraction or entry.
The population evaluated in these mortality meta-analyses includes more than 1 million chemical workers (>15 million person-years) (Table 1), of whom approximately 85% were male. More than 35,000 workers (>3 million person-years) were included in the meta-analyses of cancer incidence; approximately 62% of these were male.
Results of the meta-analyses are presented in Tables 2–6;Table 7 presents the incidence meta-analyses. The rows of each table represent the categories of health outcomes (deaths or incident cases). The first column indicates the health outcome; the second column provides the corresponding codes from the International Classification of Diseases, 8th revision; the third column represents the number of studies included in each meta-analysis; the fourth column provides the total number of observed events; and the last two columns provide the point estimate and 95% confidence interval for either the meta-SMR (Tables 2–6) or the meta-SIR (Table 7). Because the fixed-effects and random-effects models produced results that were generally in close agreement, we have only presented the random-effects model estimates here.
As shown in Table 2, the number of studies reporting quantitative data varied markedly according to the mortality outcome considered. Of the 168 full-cohort mortality studies eligible for inclusion, 1–6,8–19,21–49,51–77,79–87,89–102,104–120,122–129,130–138,140–165,167,168,170–179,181 the most commonly reported outcomes were all causes of death (154 studies, 90.6%) 1–6,8–19,21–25,27–31,33–49,53–60,62,63,65–68,70–77,79,80,82–87,90–94,96–102,104–112,114,116–120,122–128,130,131,133–138,140–143,145–148,150–165,167,168,170–179,181 and all malignancies (150 studies, 88.2%). 1–4,8–19,21–25,27–31,33,35–47,49,51–53,56–60,62,63,65–77,79–81,83–87,91–94,96–102,104–111,113–120,122–127,130–138,140–143,145–154,156–165,167,168,170–172,174–179,181 Some mortality outcomes were much less commonly reported, such as thyroid cancer (11 studies, 6.5%) 12,18,29,46,58,83,84,141,145,153 and homicide (5 studies, 2.9%). 24,54,76,138,154
For each mortality outcome, the number of studies and the corresponding total number of events for all persons combined were very similar to those for men (see Tables 2 and 3). The number of studies reporting mortality for women was small, 4,6,15,17,39,46,59–61,76,77,81,84,113,114,118,136–138,140,145,159,179 with all types of cancer combined (18 studies), 4,15,17,39,46,59,60,76,77,81,84,113,114,136,137,145,159,179 all causes of mortality, and breast cancer (17 studies each) 4,6,15,17,39,46,59,60,76,77,84,113,114,118,136–138,140,145,159,179 the outcomes most likely to be reported (Table 4). Information on latency (10 years or more) was available in a modest number of studies for some outcomes, such as cancer of the bronchus, trachea, and lung (49 studies), 2,10,13,14,17,18,22,24,33,34,41,42,43,46,47,51,63–65,68–70,75,84,85,100,106,107,109,114,117,122,127,131,134,136,138,141,149,153,162,164,167,172,174,176,177,179,180 and all malignant neoplasms (46 studies) 2,4,9,10,13,14,17–19,22,38,43,47,51,63–66,68–70,75,83,84,94,100,106,109,114,117,127,130,136,139,141,142,146,152,162,164,172,174,176,177,179,180 (Table 5). This information was infrequently available for other outcomes, such as breast cancer (three studies), 17,138,173 multiple myeloma (two studies), 51,83 thyroid cancer (one study), 18 and homicide (no studies). Information related to workers employed 10 or more years was available most frequently for all malignancies combined (27 studies) 4,12–14,18,23,38,43,51,72,73,80,81,84,100,120,130,132,136,138,156,164,165,170,176,177,180; bronchus, trachea, and lung cancer (23 studies) 13,14,18,24,33,37,41,42,51,84,92,107,108,136,138,149,163,170,176,177,180; and all causes of mortality (23 studies) 4,12,14,38,43,48,54,63,72,73,80,92,100,120,130,136,156,164,170,171,176,177,180 (Table 6). It was available in two or fewer studies for laryngeal cancer, 14,18 breast cancer, 138,173 thyroid cancer, 18 multiple myeloma, bronchitis, emphysema and asthma, 173 suicides, 136,180 and homicides.
Of the 25 eligible studies with incidence data, 1,7,9,20,38,48–50,63,65,66,78,82,88,91,103,113,115,119,121,129,139,145,147,169 19 provided information on all types of cancer combined, 1,7,9,20,38,48–50,63,65,66,82,91,103,113,115,119,121,145 and an equal number presented data on bladder cancer 7,9,20,38,48–50,63,65,82,103,113,115,121,129,139,145,147,169 (Table 7). For cancers of the larynx, 7,63,113,115,145 breast, 1,7,66,113,145 thyroid, 7,113,145 and multiple myeloma, 7,48,66,91,145 five or fewer studies provided incidence data.
A total of 154 studies provided data on 143,927 deaths from all causes (Table 2). Overall, there were 10% fewer deaths observed than expected (meta-SMR = 0.90, 95% CI = 0.87–0.92). When only the 119 mortality studies judged to be of the highest quality were evaluated, the meta-SMR was unchanged (data not shown); we therefore evaluated the larger group to maximize the opportunity to detect potential effects. Risk was not elevated after accounting for latency (meta-SMR = 0.92, 95% CI = 0.88–0.96) or duration of employment (meta-SMR = 0.85, 95% CI = 0.79–0.91).
There were 41,914 deaths from cancer reported in 150 studies (Table 2). The observed number of cancer deaths among chemical workers was virtually identical to the expected number (meta-SMR = 0.99, 95% CI = 0.94–1.04). The results for men paralleled those for the overall worker population (Table 3). For women, however, there was a 9% reduction from expected levels in observed cancer mortality (meta-SMR = 0.91, 95% CI = 0.85–0.97) (Table 4).
A slight increase in cancer mortality was observed for all workers after 10 or more years of induction time (meta-SMR = 1.04, 95% CI = 0.99–1.09) (Table 5). In contrast, fewer cancer deaths than expected were observed for employees who worked 10 or more years (meta-SMR = 0.97, 95% CI = 0.91–1.05) (Table 6).
We found no notable difference between observed and expected numbers of deaths in the full cohort for cancers of the buccal cavity and pharynx, esophagus, stomach, large intestine, pancreas, prostate, kidney, and multiple myeloma (Table 2). There were more deaths observed than expected for cancers of the trachea, bronchus and lung (meta-SMR = 1.12, 95% CI = 1.05–1.19), bladder (meta-SMR = 1.29, 95% CI = 1.01–1.65), thyroid (meta-SMR = 1.62, 95% CI = 1.05–2.51), lymphatic and hematopoietic systems (meta-SMR = 1.09, 95% CI = 1.02–1.15), leukemia (meta-SMR = 1.07, 95% CI = 1.01–1.13), larynx (meta-SMR = 1.17, 95% CI = 0.99–1.40), skin (meta-SMR = 1.13, 95% CI = 0.98 = 1.30), lymphomas (meta-SMR = 1.09, 95% CI = 0.97–1.23), liver and biliary passages (meta-SMR = 1.08, 95% CI = 0.92–1.28), respiratory system (meta-SMR = 1.06, 95% CI = 0.97–1.15), Hodgkin’s disease (meta-SMR = 1.06, 95% CI = 0.90–1.23), and brain and other areas of the central nervous system (meta-SMR = 1.05, 95% CI = 0.96–1.16). There were fewer deaths observed than expected for cancers of the digestive organs and peritoneum (meta-SMR = 0.93, 95% CI = 0.89–0.98) and of the breast (meta-SMR = 0.90, 95% CI = 0.83–0.98).
When we considered the analyses by latency (Table 5), length of employment (Table 6), gender (Tables 3 and 4), and study quality (data not presented), some consistency in elevated findings was observed for cancers of the bronchus, trachea and lung, the bladder, lymphatic/hematopoietic systems, and the brain and central nervous system. A list of all studies with SMRs of 2.0 or greater for these cancers is provided in Tables 8–11, respectively. For cancers of the bronchus, trachea, and lung, 5 of the 10 studies with SMRs of 2.0 or greater related to chromium or chromate exposure. 42,55,67,85,95 Three of the studies 97,128,134 on bladder cancer involved aromatic amines and reported SMRs of about 30. There were seven studies with SMRs of 2.0 or greater for lymphatic and hematopoietic cancers. 11,14,36,72,91,125,144 Two of these investigations related to benzene exposure, 36,125 and two related to ethylene oxide exposure. 14,72 The studies reporting brain and central nervous system cancer excesses of 2.0 or more included two each in which the workers were exposed to acrylonitrile 100,174 and vinyl chloride 154,171; these were not, however, the studies reporting the highest SMRs. 3,147
Cancer incidence data were available from only 25 studies 1,7,9,20,38,48,49,50,63,65,66,78,82,88,91,103,113,115,119,121,129,139,145,147,169 (Table 7). For all cancers combined, the results were essentially the same as those obtained with the mortality data (meta-SIR = 1.0, 95% CI = 0.92–1.08). Fewer cases were observed than expected for cancers of the digestive organs and peritoneum (meta-SIR = 0.86, 95% CI = 0.82–0.91) and for esophageal cancer (meta-SIR = 0.67, 95% CI = 0.49–0.92); excesses were found for bladder cancer (meta-SIR = 2.21, 95% CI = 1.18–4.15), multiple myeloma (meta-SIR = 2.19, 95% CI = 1.27–3.78), respiratory cancers (meta-SIR = 1.16, 95% CI = 0.98–1.37), and cancers of the lymphatic and hematopoietic systems (meta-SIR = 1.24, 95% CI = 0.96–1.61).
As shown in Table 2, there were 33 studies in which mortality from diabetes mellitus was reported, 5,6,17,18,21–25,38,43,46,54,60,63,98,102,114,136–138,149,163–165,168,172,174,175,177–179,181 with more than 750 deaths and a small reduction from the expected level (meta-SMR = 0.96, 95% CI = 0.84–1.10). The 36,421 observed deaths from cardiovascular diseases reported in 99 studies 9,10,12–14,17–19,21–23,25,27,30,32,33,35,36,38,39,42,44,46–49,52,53,56,60,62,63,65–68,70,71,73,74,76,77,79,80,85,87,90–94,96,98,100,104,105,107,110,114,116,117–120,122,124,127,133–138,140,141,145,146,149,150,152–154,157,160,161,163,164,167,168,170,172,174–179,181 represented 14% fewer deaths than expected (meta-SMR = 0.86, 95% CI = 0.83–0.89). Results were similar for deaths from coronary heart disease and cerebrovascular disease in which the meta-SMRs for the full cohort were 0.87 (95% CI = 0.83–0.91) and 0.85 (95% CI = 0.80–0.90), respectively. When we pooled results over 94 studies, 2,4,9,10,13,14,17–19,21–25,27,28,33–39,42–44,46–49,52,56,58,60,65–68,70,71,76,83,85,86,93,98,99,104,105,107–110,114,116,119,120,123,126,127,130,134–138,141,145,146,149–154, 157,158,159–165,167,168,170,172–179,181 the 5,974 observed deaths from noncancer respiratory disease were 23% lower than expected (meta-SMR = 0.77, 95% CI = 0.72–0.83). There was no increase in deaths from bronchitis, emphysema, and asthma. When we confined our analysis to the studies judged to be of quality criterion 1, however, there was a 22% risk increase (meta-SMR = 1.22, 95% CI = 1.01–1.47). The risk was also elevated in the studies of women, but that increase was based on only 25 observed deaths reported in two studies 6,46 (Table 4). The long latency subcohort, with 44 observed deaths in seven stud-ies, 47,63–66,174,177 revealed a 35% increase in deaths (meta-SMR = 1.35, 95% CI = 0.97–1.86) (Table 5). We observed fewer deaths than expected from cirrhosis of the liver (meta-SMR = 0.74, 95% CI = 0.62–0.88) (Table 2) and noted similar results when we confined our analyses to only the studies judged to meet quality criterion 1 (data not presented), as well as those limited to men 4,5,15,18,21,22,25,43,44,46,47,62,63,76,77,91,97–99,102,107,114,134,136,137,141,158,163–165,172,175,178,179,181 (Table 5) or women 6,15,17,46,76,77,114,136,137,179 (Table 4), or the long-latency 17,18,22,47,63,64,114,136,141,164,173,180 (Table 5) and long-duration 43,136,177,180 (Table 6) subcohorts.
When we pooled results of 83 studies, 2,4–6,12–14,19,21,23–25,27,28,30,32,36,38,39,42–44,46–49,53,54,62,65–68,74,76,77,79,80,83,85,87,91–94,98,102,104,105,107,118–120,124,125,127,130,133–137,140,141,149–153,159–163,167,170,172,175,176–179,181 6,773 observed deaths were reported from external causes, which was 16% lower than expected (meta-SMR = 0.84, 95% CI = 0.78–0.91) (Table 2), with similar results in the subgroup analyses (Tables 3–6). The observed numbers of deaths from accidents, suicides, and homicides were all lower than expected (Table 2).
This is the first comprehensive analysis of the mortality and cancer incidence of workers in the chemical industry. Based on an exhaustive review of the published literature, it has included an assessment of the methodologic quality of the individual studies. Furthermore, the extremely large size of the aggregated cohort study samples provided sufficient numbers to detect even small differences in health outcomes. We undertook meta-analyses of 35 mortality endpoints and 23 cancer incidence endpoints using data from the full cohort and, in addition, examined the mortality of several subgroups (males; females; workers first employed at least 10 years before their death, incident cancer, or the end of follow-up; and workers with at least 10 years of employment).
The observed cause-specific mortality and site-specific cancer incidence of the workers included in this study were, with few exceptions, largely reassuring, as we observed similar outcomes among the vast majority of chemical workers and comparison populations. Fewer than expected deaths were observed among chemical workers from all causes, cardiovascular disease, noncancer respiratory disease, cirrhosis of the liver, and external causes including accidents, suicide, and homicide. Although some, and perhaps most, of these deficits may be attributed to the healthy worker effect, there nevertheless appears to be no generalized increased risk for mortality or cancer incidence among workers employed in chemical manufacturing.
The only consistently positive findings across the full cohort and the long-latency, long-employment duration, and incidence subgroups were those for cancers of the bronchus, trachea, and lung; the bladder; and the lymphatic/hematopoietic systems. The excesses for these three endpoints appear to be attributable, at least in part, to previously reported associations with specific chemical exposures: lung cancer with chromates, 182 bladder cancer with aromatic amines, 183 and lymphatic/hematopoietic system cancers with ethylene oxide 184 or benzene. 185 From a methodologic standpoint, the detection of these positive associations implies that the analyses had sufficient power to detect increases in risk, despite the fact that small proportions of the chemical workers included in this study were exposed to the specific implicated chemicals.
Limitations of the Meta-analyses
Several issues influence the interpretation of these results. Some issues are common to all occupational cohort studies; others relate to combining studies conducted for a variety of purposes and with varying methods and reporting practices. These are discussed below.
The “Healthy Worker Effect”
The “healthy worker effect” results from generally low relative mortality from selected diseases in an employed population 186 and is caused by the selection process whereby persons with evidence of disease or at increased risk of disease are less likely to gain and to keep jobs. In general, the “healthy worker effect” is more prominent for cardiovascular diseases and certain musculoskeletal conditions than for cancer, and is also more prominent in settings that have rigorous pre-employment testing or fitness requirements. It is difficult, however, to estimate quantitatively the extent of this bias among the pooled cohorts analyzed in this study. The reduced total mortality and cardiovascular disease mortality relative to the general population observed in this analysis is likely attributable, at least in part, to the healthy worker effect.
A concern common to virtually all occupational cohort studies is the lack of information about potentially important confounding variables. Age, gender, and time period of observation were accounted for by the authors in nearly all of the original studies; however, race or salaried vs hourly pay status were available in too few studies to be useful in constructing meaningful subgroup meta-analyses (≤15 studies reported data for nonwhite workers and ≤12 studies for salaried workers).
Another confounder of potential importance was smoking. Differential smoking patterns between study and comparison populations might have affected the SMRs for lung and other smoking-related diseases and could account for part of the significant excess of respiratory tract cancers. It is unlikely, however, that smoking prevalence varies enough between chemical workers and the general population to be able to account for the observed 29% excess of bladder cancer (Tsai SP, Wendt JK, Hunter RB. Trends in cigarette smoking among refinery and petrochemical plant employees. In preparation).
The Assumption of Exposure
An important assumption that underlies our analyses is that all members of the included cohorts were exposed to one or more chemicals in their workplaces. This level of information on exposure is adequate for a comparison of the mortality and cancer incidence experience of persons employed in the chemical industry to those not employed in this industry. On the other hand, the relative paucity of information on worker exposures makes it difficult to infer whether any observed associations with mortality or cancer incidence were attributable to chemical exposures per se. For causal inference, it is important to be able to examine the risk of disease according to the amount of exposure. Only a weak surrogate measure of dose of exposure, that is, length of employment, was possible in the present analysis.
These meta-analyses were conducted only on studies that were published in the peer-reviewed literature. Not all of the studies ever conducted have been published, nor have all results obtained been reported in the published studies. There are a number of reasons that some completed occupational cohort studies have not been published. For example, mortality surveillance programs performed either by individual industries, trade associations, regulatory agencies, or the academic community can be performed for specific purposes (for example, corporate stewardship, academic research, or legislatively mandated population surveillance) without publishing the results. Within the private sector, even when elevated SMRs are observed, companies can disclose data, either voluntarily or by mandate, to the appropriate government agencies without publication of the results in peer-reviewed journals. Furthermore, studies with negative or null results may have difficulty gaining acceptance in peer-reviewed journals. Thus, the number of unpublished studies that would be relevant to these meta-analyses is not known.
For studies that were included, the authors generally gave two reasons for undertaking the studies: (1) there was evidence for, or suspicion of, an adverse health risk, or (2) the study was conducted as part of a general health surveillance program. Studies conducted for the former reason might be more likely to produce positive findings; this is especially true for case-control studies of industrial populations. When available, we abstracted the authors’ rationale for initiating the studies, but the explanation was often incomplete or insufficient, making it impractical to conduct meta-analyses stratified by “reason for study.” Nevertheless, occupational groups for which there is little suspicion of increased risk of disease are not as likely to be studied or reported as those with suspected health concerns. Thus, in general the published literature, and hence our meta-analyses, are weighted with cohorts at higher suspicion for elevated morbidity or mortality rates. This weighting would have been even higher had case-control studies been included.
By limiting this review to studies published in the English language, conducted in North America and western Europe, and published in peer-reviewed journals since 1966, the population base was restricted. Although these restrictions may limit the ability to extrapolate results to other time periods and countries, they should not affect the validity for the populations considered.
The studies included in this review had to meet certain eligibility criteria and therefore do not include all the studies on specific chemicals. Therefore, conclusions regarding specific disease-chemical relationships cannot be made without considering all of the available data.
Variability in Reporting
Individual studies exhibited considerable variability in the amount of information reported in tables and texts, with many authors choosing to report, selectively, analyses that resulted in elevated SMRs and not to report many SMRs that were presumably not elevated. For example, of the 168 full-cohort mortality studies evaluated in this meta-analysis, 1–6,8–19,21–49,51–77,79–87,89–102,104–120,122–138,140–165,167,168,170–179,181 150 studies presented SMRs for all malignant neoplasms, 1–4,8–19,21–25,27–31,33,35–47,49,51–53,56–60,62,63,65–77,79–81,83–87,91–94,96–102,104–111,113–120,122–127,130–138,140–143,145–154,156–165,167,168,170–172,174–179,181 99 for cardiovascular diseases, 9,10,12–14,17–19,21–23,25,27,30,32,33,35,36,38,39,42,44,46–49,52,53,56,60,62,63,65–68,70,71,73,74,76,77,79,80,85,87,90–94,96,98,100,104,105,107,110,114,116,117–120,122,124,127,133–138,140,141,145,146,149,150,152–154,157,160,161,163,164,167,168,170,172,174–179,181 83 for external causes of death, 2,4–6,12–14,19,21,23–25,27,28,30,32,36,38,39,42–44,46–49,53,54,62,65–68,74,76,77,79,80,83,85,87,91–94,98,102,104,105,107,118–120,124,125,127,130,133–137,140,141,149–153,159–163,167,170,172,175,176–179,181 120 for lung cancer, 1–6,8,10,12–15,17–19,21–24,28–31,33–39,41–47,51–55,57–60,62,63,65,67–71,74–77,83–87,89,91,92,95,96,98–101,104,106–110,112,113–117,122,124,127,130,131,134–138,141,143,145,146,149–151,153,154,161–165,167,168,170,172,176–179,181 and 77 for brain cancer. 3–6,10–12,15,17–19,21,23–25,27–29,33,37,39,41–44,46,47,51,52,56,58,68,76,83,84,87,99,100,102,104,105,107,108,112–114,116,117,120,126,127,131,135–137,141,142,145–147,151,153,154,158,159,162–165,170–172,174,175,177,178,181 This selective reporting also occurred in the cancer incidence studies, in which, of the 25 studies analyzed, 1,7,9,20,38,48,49,50,63,65,66,78,82,88,91,103,113,115,119,121,129,139,145,147,169 19 studies provided data on all malignant neoplasms, 1,7,9,20,38,48–50,63,65,66,82,91,103,113,115,119,121,145 17 on lung cancer, 1,7,9,20,38,48,40,63,65,66,82,88,103,113,115,119,145 14 on prostate cancer, 7,9,20,38,48,63,66,82,103,113,115,119,121,145 and only 5 on multiple myeloma. 7,48,66,91,145
For the reasons just discussed, it is likely that the selective underreporting of subgroup analyses in the original studies resulted in a reporting bias toward elevated or statistically significant results.
Independence of Cohorts
We made every effort to avoid duplicate observations of individual cohort members by abstracting results primarily from the most recently updated publication regarding a cohort. Still, the possibility remains that we inadvertently included cohorts containing overlapping populations reported in multiple publications in the meta-analyses, and thus, the mortality and morbidity experience of such populations would be inappropriately overrepresented in the results.
In summary, in this investigation we reviewed and analyzed a large number of published studies of workers in the chemical industry and found that, with a few exceptions, their mortality and cancer morbidity experience is similar to or better than that of the general population. We observed excesses of bronchus, trachea, and lung cancers and bladder cancer that were consistent with exposure to known chemical carcinogens. A few unanswered questions remain with respect to some of the apparent excesses, such as the somewhat consistently elevated findings for brain and central nervous system cancers, and especially the observation of elevated SMRs and an elevated SIR for lymphatic and hematopoietic cancers. This category is difficult to evaluate for a number of reasons. Approximately half the studies provided data on lymphatic and hematopoietic cancers, with the classifications used across studies varying considerably. We found it was often difficult to group subcategories on the basis of the limited information provided in the study, and virtually impossible to distinguish among specific types of leukemias or lymphomas. As the diseases that constitute lymphatic and hematopoietic cancers probably have different etiologies, it is important to have a more precise breakdown of these data to properly assess the results. Important difficulties with disease nomenclature and with coding, as well as the limited reporting in these published studies, hamper a clear assessment of which specific cancers within this general category are in excess among chemical workers.
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