Mesothelioma among Motor Vehicle Mechanics: An Updated Review and Meta-analysis.

BACKGROUND: We published a meta-analysis of the association between work as a motor vehicle mechanic and mesothelioma in 2004. Since then, several relevant studies on this topic have been published. Thus, to update the state-of-the-science on this issue, we conducted a new systematic review and meta-analysis. METHODS: A comprehensive PubMed literature search through May 2014 was conducted to identify studies that reported relative risk estimates for mesothelioma among motor vehicle mechanics (in general), and those who were engaged in brake repair (specifically). Studies were scored and classified based on study characteristics. Random-effects meta-analyses generated summary relative risk estimates (SRREs) and corresponding 95% confidence intervals (CI). Heterogeneity of results was examined by calculating Q-test P-values (P-H) and I (2) estimates. Sub-group and sensitivity analyses were conducted for relevant study characteristics and quality measures. RESULTS: Ten case-control studies, one cohort study, and five proportionate mortality ratio (PMR)/standardized mortality odds ratio (SMOR) studies were identified and included in the quantitative assessment. Most meta-analysis models produced SRREs below 1.0, and no statistically significant increases in mesothelioma were observed. The SRRE for all studies was 0.80 (95% CI: 0.61-1.05) with significant heterogeneity (P-H <0.001, I (2) = 62.90). A similar SRRE was observed among the five Tier 1 studies with the highest quality ratings (SRRE = 0.76, 95% CI: 0.46-1.25), with no heterogeneity among studies (P-H = 0.912, I (2) = 0.00). Meta-analysis of the Tier 2 (n = 5) and Tier 3 (n = 6) studies resulted in SRREs of 1.09 (95% CI: 0.76-1.58) and 0.73 (95% CI: 0.49-1.08), respectively. Restricting the analysis to Tiers 1 and 2 combined resulted in an SRRE of 0.92 (95% CI: 0.72-1.29). The SRRE specific to brake work (n = 4) was 0.64 (95% CI: 0.38-1.09). CONCLUSIONS: This meta-analysis of the epidemiologic studies provides evidence that motor vehicle mechanics, including workers who were engaged in brake repair, are not at an increased risk of mesothelioma.

Addressing nonlinearity in the exposure-response relationship for a genotoxic carcinogen: cancer potency estimates for ethylene oxide.

Ethylene oxide (EO) has been identified as a carcinogen in laboratory animals. Although the precise mechanism of action is not known, tumors in animals exposed to EO are presumed to result from its genotoxicity. The overall weight of evidence for carcinogenicity from a large body of epidemiological data in the published literature remains limited. There is some evidence for an association between EO exposure and lympho/hematopoietic cancer mortality. Of these cancers, the evidence provided by two large cohorts with the longest follow-up is most consistent for leukemia. Together with what is known about human leukemia and EO at the molecular level, there is a body of evidence that supports a plausible mode of action for EO as a potential leukemogen. Based on a consideration of the mode of action, the events leading from EO exposure to the development of leukemia (and therefore risk) are expected to be proportional to the square of the dose. In support of this hypothesis, a quadratic dose-response model provided the best overall fit to the epidemiology data in the range of observation. Cancer dose-response assessments based on human and animal data are presented using three different assumptions for extrapolating to low doses: (1) risk is linearly proportionate to dose; (2) there is no appreciable risk at low doses (margin-of-exposure or reference dose approach); and (3) risk below the point of departure continues to be proportionate to the square of the dose. The weight of evidence for EO supports the use of a nonlinear assessment. Therefore, exposures to concentrations below 37 microg/m3 are not likely to pose an appreciable risk of leukemia in human populations. However, if quantitative estimates of risk at low doses are desired and the mode of action for EO is considered, these risks are best quantified using the quadratic estimates of cancer potency, which are approximately 3.2- to 32-fold lower, using alternative points of departure, than the linear estimates of cancer potency for EO. An approach is described for linking the selection of an appropriate point of departure to the confidence in the proposed mode of action. Despite high confidence in the proposed mode of action, a small linear component for the dose-response relationship at low concentrations cannot be ruled out conclusively. Accordingly, a unit risk value of 4.5 x 10(-8) (microg/m3)(-1) was derived for EO, with a range of unit risk values of 1.4 x 10(-8) to 1.4 x 10(-7) (microg/m3)(-1) reflecting the uncertainty associated with a theoretical linear term at low concentrations.

Ethylene oxide cancer risk assessment based on epidemiological data: application of revised regulatory guidelines.

Ethylene oxide (EO) research has significantly increased since the 1980s, when regulatory risk assessments were last completed on the basis of the animal cancer chronic bioassays. In tandem with the new scientific understanding, there have been evolutionary changes in regulatory risk assessment guidelines, that encourage flexibility and greater use of scientific information. The results of an updated meta-analysis of the findings from 10 unique EO study cohorts from five countries, including nearly 33,000 workers, and over 800 cancers are presented, indicating that EO does not cause increased risk of cancers overall or of brain, stomach or pancreatic cancers. The findings for leukemia and non-Hodgkin's lymphoma (NHL) are inconclusive. Two studies with the requisite attributes of size, individual exposure estimates and follow up are the basis for dose-response modeling and added lifetime risk predictions under environmental and occupational exposure scenarios and a variety of plausible alternative assumptions. A point of departure analysis, with various margins of exposure, is also illustrated using human data. The two datasets produce remarkably similar leukemia added risk predictions, orders of magnitude lower than prior animal-based predictions under conservative, default assumptions, with risks on the order of 1 x 10(-6) or lower for exposures in the low ppb range. Inconsistent results for "lymphoid" tumors, a non-standard grouping using histologic information from death certificates, are discussed. This assessment demonstrates the applicability of the current risk assessment paradigm to epidemiological data.

Mortality among workers at a plastics manufacturing and research and development facility: 1946-1988.

Mortality through 1988 was studied for 5,932 male employees who worked between January 1, 1946 and December 31, 1967 at a New Jersey plastics manufacturing and research and development facility. The cohort was followed for an average of 32 years and included 1,859 deaths. Potential exposures included asbestos, formaldehyde, and polyvinyl chloride (PVC). Mortality rates for the cohort were compared to both U.S. and state mortality rates, and analyses were also performed by lagging duration of employment. Based on U.S. rates, mortality among hourly males (n = 3,853) from all cancers was similar to expected [standardized mortality ratio (SMR), 102; 95% confidence interval (CI), 92-114]. Excess mortality among hourly workers was seen for pancreatic cancer (SMR, 146; 95% CI, 95-216) and "malignancies of other parts of the respiratory system" (SMR, 373; 95% CI, 121-870). The latter excess was due entirely to five deaths from pleural mesothelioma. There were no deaths identified due to nasal cavity or nasopharyngeal cancers, or angiosarcoma of the liver. Mortality from leukemia among research and development workers (n = 1,421) was significantly elevated (SMR, 265; 95% CI, 115-524) and related to assignment to process development. This study verifies the excess of pancreatic cancer among workers at the facility seen in earlier studies and observes excesses of mesothelioma due to asbestos exposure and leukemia in process development workers.

Pancreatic cancer among workers processing synthetic resins.

A nested case-control study was conducted to investigate whether an excess of pancreatic cancer, identified in a cohort mortality study with follow-up from 1946 through 1988, was associated with potential workplace exposures at a New Jersey plastics manufacturing and research and development facility. The study population included 28 male pancreatic cancer cases and 140 randomly selected controls, matched on year of birth and at risk (alive) at the time of the case death. Using plant work history records, department assignments for the two groups were compared according to duration and time since first assignment. Workers assigned to a work area that processed vinyl resins and polyethylene (PE) were shown to be at increased risk. Men assigned more than 16 years to this department had a significantly increased risk ratio of 7.15 (95% confidence intervals [CI]: 1.28-40.1). No excess was seen with shorter duration assignments. Seven of the nine cases began working in this area in the 1940s. Average latency was 32 years, and all but three cases worked 20 years or more in this unit. Over the study period, significant exposure-related process changes occurred, in addition to the use of numerous chemical additives. Although vinyl and PE processing operations could not be analyzed separately, the pancreatic cancer excess is more likely to be related to vinyl processing. Identification of a causative agent or combination of agents would require investigations with more detailed exposure information.

Mortality study of ethylene oxide workers in chemical manufacturing: a 10 year update.

Men assigned to units producing ethylene oxide by the chlorohydrin or direct oxidation processes and to other departments using ethylene oxide in two chemical plants were followed up for mortality from 1940 to 1988 (n = 1896). Based on findings from a previous study of these workers to the end of 1978, which identified confounding exposures, workers assigned to one unit with low ethylene oxide exposure potential were excluded (n = 278). Average duration of exposure was over five years and average follow up was 27 years, with all subjects at least 10 years from first exposure. The data did not support associations of ethylene oxide with all cancer types combined, leukaemia, non-Hodgkin's lymphoma, or brain, pancreatic, or stomach cancers. There were also no duration-response trends. The standardised mortality ratio (SMR) for total cancer was 86 (95% confidence interval 71-104) and did not increase for those hired the earliest and with long duration assignments. The results of this 10 year update and those of other recent studies of ethylene oxide workers do not confirm findings from animal studies and are not consistent with the earliest results reported among ethylene oxide workers.

Mortality due to pancreatic and lymphopoietic cancers in chlorohydrin production workers.

Men assigned to the chlorohydrin unit of Union Carbide's South Charleston plant in the Kanawha Valley of West Virginia were followed up for mortality from 1940 to the end of 1988. This 10 year update was conducted to verify previous findings of excesses of cancer among the 278 men assigned to the chlorohydrin unit, which primarily produced ethylene chlorohydrin from 1925 to 1957. This process produced ethylene dichloride and bischloroethyl ether as byproducts. Mean duration of assignment was 5.9 years and mean duration of follow up was 36.5 years. Standardised mortality ratios (SMRs) were calculated based on comparisons with the United States white male population. Duration-response trends were assessed by internal comparisons with two different groups of unexposed chemical workers in the Kanawha Valley. The evidence that the earlier finding of an excess of pancreatic cancer was work related is strengthened by the occurrence of two additional cases (0.9 expected). The SMR for pancreatic cancer was 492 (95% CI 158-1140), based on eight observed v 1.6 expected deaths. There were no additional deaths due to leukaemia, but the three to four-fold excess risk for lymphopoietic cancers persisted due to new cases of non-Hodgkin's lymphoma and a death from multiple myeloma. The SMR for lymphatic and haematopoietic cancers was 294 (eight observed v 2.7 expected; 95% CI 127-580). Pronounced increases in risk were seen for total cancer, pancreatic cancer, all lymphatic and haematopoietic cancers, and leukaemia with increasing durations of assignment to the chlorohydrin unit. Most of the cases were first assigned to the unit in the 1930s when chemical manufacturing was in its infancy and exposures were less controlled. These data are insufficient to identify conclusively the causative agent or agents. The weight of evidence, however, based on probable exposure, known toxicity of the chemicals, and animal responses suggest that high exposures to ethylene dichloride, perhaps in combination with other chlorinated hydrocarbons, is the most likely explanation.

Mortality study of ethanol and isopropanol production workers at two facilities.

The mortality experience of alcohol process workers (N = 1031) from two chemical plants was followed from the early 1940s to 1983. Reported associations of the production of ethanol and isopropanol by the strong-acid process with upper respiratory tract cancers, heart disease, and lympho- and reticulosarcoma were tested with both external and internal comparisons. Excesses of cancers of the larynx, buccal cavity, and pharynx, based on very small numbers, were observed. There was one death due to sinus cancer. It could not be concluded that there were work-related effects on mortality due to heart disease or lympho- or reticulosarcoma. Workers assigned to the production of isopropanol by the weak-acid method showed no evidence of excess cancer mortality (0 observed, 1.9 expected cancer deaths). The absence of major risks among strong-acid workers can be explained by the initiation of engineering controls and health monitoring that took place after the original medical observations.

Smoking habits in survivors of childhood and adolescent cancer.

Because of their increased risk for second cancers, childhood cancer survivors are people who really should not smoke, but available evidence suggests that they do. We studied the smoking habits of long-term childhood cancer survivors in data collected from 1289 adult survivors of childhood cancer and 1930 of their sibling controls. Survivors were diagnosed with cancer between 1945 and 1974 when they were less than 20 years old. Using matched analyses that controlled for the influence of family, survivors were 8% less likely than controls to be current smokers, 13% less likely to be ever-smokers, but 12% less likely to have quit smoking; these differences were not statistically significant. In a logistic regression analysis there was a significant difference by year of diagnosis for current smoking rate ratios (RR); survivors were less likely to be current smokers if diagnosed in recent years (RR = 0.76; 95% confidence intervals = 0.58-0.98, between 1965-74) and quite similar to controls if diagnosed in earlier years (RR = 1.05 between 1945 and 1954). In our group of long-term cancer survivors, the reduction in current smoking came about because survivors were more inclined never to start smoking than controls. Once addicted to tobacco, they were less likely to quit. While the fact that survivors are less likely to start smoking is encouraging, the persistence of smoking habits strongly suggests the need for continuing efforts to prevent smoking in this most vulnerable group.

An update of mortality due to brain neoplasms and other causes among employees of a petrochemical facility.

In an update of an earlier investigation of brain tumors, mortality patterns were examined for 7849 male employees who worked at a petrochemical plant from 1941 through 1983. The update added 6 years of observation (1978 to 1983). During this period, the brain tumor (BT) mortality risk declined relative to the US population, but continued to be higher than expected in hourly workers (5 observed/3.4 expected). Similar to the earlier studies, BT occurrence was not explained by patterns of production work assignments. Mortality rates for hourly and salaried workers from all causes combined, total cancer and respiratory cancer were lower than US population rates. Lower rates for these causes were also seen for white and nonwhite production and maintenance workers. Liver cancer rates were greater than expected in white production workers (3 observed/1.6 expected) and included two men assigned more than 40 years ago to vinyl chloride-related departments. Mortality rates due to malignant melanoma were elevated in white maintenance workers (5 observed/2.0 expected) and may be explained by heavy sun exposure in outdoor work.

Mortality surveillance in a large chemical company: the Union Carbide Corporation experience, 1974-1983.

The mortality experience of 88,000 Union Carbide Corporation employees from 1974 to 1983 is presented using a population-based surveillance system. The study included many long-term employees, with most deaths contributed by those retired or terminated. The total population exhibited 30% lower mortality overall and 10% lower cancer mortality, as compared with the general U.S. population. Excesses of benign neoplasms and malignant melanoma of the skin were observed in both hourly and salaried males. Mortality rates for lymphosarcoma and reticulosarcoma were significantly elevated due to higher rates among hourly male employees and a cluster in one location. This same location also exhibited an excess of liver cancer associated with vinyl chloride operations. There were no other significant excesses in the hourly male workers and fewer deaths than expected due to brain cancer, respiratory cancer, and nonmalignant respiratory diseases. Salaried, and particularly hourly, women experienced favorable mortality, although for the women, time since hire was relatively short. Location-specific findings were similar to what had been observed in the company's previously conducted cohort studies. Future value lies in the development of a database that will have greater power to address possible effects of past exposures and outcomes related to more recent lower level exposures.

Marriage and divorce after childhood and adolescent cancer.

As part of a study of long-term survivors of childhood and adolescent cancer, we interviewed 2170 survivors and 3138 sibling control subjects about their marital histories. In a proportional hazards analysis, both male and female survivors were less likely to be ever married than control subjects (rate ratio [RR] for males, 0.87; 99% confidence interval, 0.76 to 0.99; RR for females, 0.86; 99% confidence interval, 0.76 to 0.97). Survivors of brain and central nervous system tumors accounted for most of the marriage deficit, which was greater in men than in women (RRs, 0.48 and 0.73, respectively). Survivors married at the same average age as control subjects, except for survivors of central nervous system tumors, who married slightly later. The average length of first marriages was shorter in survivors than in control subjects. Men who had survived central nervous system tumors diagnosed before 10 years of age and male survivors of retinoblastoma had higher divorce rates than male control subjects (RRs, 2.9 and 1.9, respectively). In this cohort (which received less intense therapy than given in current practice), altered marriage practices are substantial only among survivors of central nervous system tumors.

Assessment of exposure to chemicals in a complex work environment.

Exposure information was evaluated for two large chemical manufacturing facilities and a research and development center in support of occupational health studies of employees assigned to these facilities. Methodology and rationale underlying the exposure categorization are provided, and descriptive exposure statistics are presented for a sample of 774 employees. Analysis of work patterns and exposure profiles revealed that 1) employee transfers among various production work areas did not follow a predictable pattern, 2) over 41% of the chemicals identified were present in multiple work areas, and 3) individuals exposed to one chemical of toxicologic interest were also likely to be exposed to other similarly toxic materials. The use of both work area and chemical-specific exposure measures is recommended, as each may be helpful in addressing etiologic questions regarding complex work environments.

Lymphatic and hematopoietic tissue cancer in a chemical manufacturing environment.

Nested case-control studies of non-Hodgkin's lymphoma (52 cases), multiple myeloma (20 cases), nonlymphocytic leukemia (39 cases), and lymphocytic leukemia (18 cases) were conducted within a cohort of employed men from two chemical manufacturing facilities and a research and development center. Exposure odds ratios were examined in relation to 111 work areas, 21 specific chemicals, and 52 chemical activity groups. Associations were observed for a maintenance and construction subgroup (non-Hodgkin's lymphoma) and a chlorohydrin production unit (nonlymphocytic leukemia). The odds ratio for the association of "foremen and others" with non-Hodgkin's lymphoma was 3.2 (CI95 = 1.47-7.2) based on 11 cases. A duration-response trend was observed for the chlorohydrin unit with three of four cases assigned 5+ years to that unit. An association between non-Hodgkin's lymphoma and assignment to strong acid alcohol production units (OR = 8.3; CI95 = 2.3-30.7) was not supported by a duration-response trend. Two highly correlated chemical groups, antioxidants (five cases) and nitriles (four cases), were over-represented among multiple myeloma cases. A duration effect was observed. However, examination of work histories did not reveal common jobs or departments among these cases.

A mortality study of a research, engineering, and metal fabrication facility in western New York State.

The mortality experience of 8,146 male employees of a research, engineering, and metal fabrication facility in Tonawanda, New York state was examined from 1946 to 1981. Potential workplace exposures included welding fumes, cutting oils, asbestos, organic solvents, and environmental ionizing radiation, as the result of disposal of wastes during the Manhattan Project of World War II. External comparisons with the US male population were supplemented by regional comparisons. For the total cohort, deficits were observed for all causes of death (standardized mortality ratio (SMR) = 87) and most non-cancer causes. The observed number of cancer deaths was close to expected (SMR = 99). There was an excess of connective and soft tissue cancer deaths, most notably in hourly employees hired prior to 1946. Among all hourly employees, there was an excess of respiratory cancer, which did not appear to be associated with length of employment. Mesothelioma was recorded as the cause of death for three decedents, two of whom were hourly employees who worked in production areas with high potential for asbestos exposure. The standardized mortality ratio for cirrhosis of the liver was elevated among long-term hourly employees hired prior to 1946. The roles of carbon tetrachloride exposure in the 1940s and alcohol consumption are discussed as possible contributory risk factors for the cirrhosis findings. The data do not provide evidence of radiation-induced cancers within this employee population.

Population based mortality surveillance in carbon products manufacturing plants.

The utility of a population based, corporate wide mortality surveillance system was evaluated after a 10 year observation period of one of the company's divisions. The subject population, 2219 white male, long term employees from Union Carbide Corporation's carbon based electrode and specialty products operations, was followed up for mortality from 1974 to 1983. External comparisons with the United States male population were supplemented with internal comparisons among subgroups of the study population, defined by broad job categories and time related variables, adjusting for important correlates of the healthy worker effect. Significant deficits of deaths were observed for all causes and the major non-cancer causes of death. The numbers of deaths due to malignant neoplasms and respiratory cancer were less than, but not statistically different from, expected. There was a non-significant excess of deaths from lymphopoietic cancer, occurring predominantly among salaried employees. When specific locations were examined, operations with potential exposure to coal tar products exhibited a mortality pattern similar to that of the total cohort. The risk for lung cancer was significantly raised (five observed, 1.4 expected) in one small, but older, location which did not involve coal tar products during the period of employment of these individuals, but which historically used asbestos materials for several unique applications. Although these findings are limited by small numbers and a short observation period, the population based surveillance strategy has provided valuable information regarding the mortality experience of the population, directions for future research, and the allocation of epidemiological resources.