Mortality patterns among industrial workers exposed to chloroprene and other substances. I. General mortality patterns

We conducted an historical cohort study to investigate the mortality experience of industrial workers potentially exposed to chloroprene (CD) and other substances, including vinyl chloride (VC), with emphasis on cancer mortality, including respiratory system (RSC) and liver. In 1999, the International Agency for Research on Cancer (IARC) classified CD as a possible carcinogen (Group 2B); VC was classified in 1987 as a known human carcinogen (Group 1). Subjects were 12,430 workers ever employed at one of two U.S. industrial sites (Louisville, KY (n=5507) and Pontchartrain, LA (n=1357)) or two European sites (Maydown, Northern Ireland (n=4849) and Grenoble, France (n=717)), with earliest CD production dates ranging from 1942 (L) to 1969 (P). Two sites (L and M) synthesized CD with the acetylene process that produced VC exposures. We determined vital status through 2000 for 95% of subjects and cause of death for 95% of the deaths. Historical exposures for individual workers were estimated quantitatively for CD and VC. Workers ever exposed to CD ranged from 92.3% (M) to 100% (G); to VC from 5.5% (M) to 22.7% (L). We computed standardized mortality ratios (SMRs) (using national and regional standard populations) in relation to selected demographic, work history and exposure factors. We used worker pay type (white or blue collar) as a rough surrogate for lifetime smoking history. For the combined cohort, SMRs (95% CIs) for all causes combined, all cancers combined, RSC and liver cancer were, respectively, 0.72 (0.69-0.74), 0.73 (0.68-0.78), 0.75 (0.67-0.84) and 0.72 (0.43-1.13). Site-specific (L, M, P and G, respectively) SMRs were: for all cancers combined: 0.75 (0.69-0.80), 0.68 (0.56-0.80), 0.68 (0.47-0.95) and 0.59 (0.36-0.91); for RSC: 0.75 (0.66-0.85), 0.79 (0.58-1.05), 0.62 (0.32-1.09) and 0.85 (0.41-1.56); for liver cancer: 0.90 (0.53-1.44) (17 deaths), 0.24 (0.01-1.34) (1 death), 0.0 (0-2.39) (no deaths) and 0.56 (0.01-3.12) (1 death). Among all workers ever exposed to CD, SMRs were: for all cancers combined: 0.71 (0.66-0.76); for RSC: 0.75 (0.67-0.84); for liver cancer: 0.71 (0.42-1.14). We also observed no increased mortality risks among cohort subgroups defined by race, gender, worker pay type, worker service type (short/long term), time period, year of hire, age at hire, duration of employment, the time since first employment, and CD or VC exposure status (never/ever exposed). In summary, our study has many strengths and is the most definitive study of the human carcinogenic potential of exposure to CD conducted to date. We conclude that persons exposed to chloroprene or vinyl chloride at the levels encountered in the four study sites did not have elevated risks of mortality from any of the causes of death examined, including all cancers combined and lung and liver cancer, the cancer sites of a priori interest. This conclusion is corroborated by our detailed analyses of mortality in relation to qualitative and quantitative exposures to CD and VC at each of the four study sites, reported in our companion paper (Marsh et al., submitted for publication).     

Chemical process-based reconstruction of exposures for an epidemiological study. Part II. Estimated exposures to chloroprene and vinyl chloride

In a four-facility occupational epidemiology study of chloroprene monomer and polymer production workers, the chloroprene (CD) and vinyl chloride monomer (VCM) exposures were modeled for plant specific job title classes. In two facilities an acetylene-based process was used and in the other two plants only a butadiene-based process was used in the monomer synthesis. In the Acetylene process VCM was an undesirable by-product to be removed. In the newer butadiene-based process, VCM was not involved and the exposures to CD were considerably lower than they were in the earlier years. One of the limiting factors was the operator rotation within a number of job titles. This rotation and inability to differentiate between job titles subsumed in job classifications recorded in the work histories required an exposure classification scheme based on an order of magnitude separation of exposure classes. In the four facilities with considerable variation in the mix of the production methods, the CD exposures were remarkably similar in both calculated and measured values. The reductions in exposures were much more dependent upon the improvement of the production methods, rather than deliberate exposure control for occupational hygiene considerations. This is reasonable since the exposures were generally lower than the coeval exposure limits and/or guidelines. The estimated exposures were less than 100 ppm in the pre-1960 era and less than 10 ppm in the 1960-1980 era, less than 1 ppm 1980-1990 era and less than 0.5 ppm thereafter. The exposures were categorized in four classes for VCM and six classes for CD. The characteristic class exposure values were used to cumulate individual exposures over time with a quantification of the potential range for exposures that are reasonably certain to ascribe correct ranking to job classes.     

Mortality of workers at the Sellafield plant of British Nuclear Fuels.

The mortality of all 14,327 people who were known to have been employed at the Sellafield plant of British Nuclear Fuels at any time between the opening of the site in 1947 and 31 December 1975 was studied up to the end of 1983. The vital state of 96% of the workers was traced satisfactorily and 2277 were found to have died, 572 (25%) from cancer. On average the workers suffered a mortality from all causes that was 2% less than that of the general population of England and Wales and 9% less than that of the population of Cumberland (the area in which the plant is sited). Their mortality from cancers of all kinds was 5% less than that of England and Wales and 3% less than that of Cumberland. In the five years after their first employment Sellafield workers had an overall mortality that was 70% of that of England and Wales, probably due to healthier members of the population being selected for employment. Raised death rates from cancers of several specific sites were found, but only for those of ill defined and secondary sites was the excess statistically significant (30 observed, 19.7 expected). For cancers of the liver and gall bladder there was a significant deficit of deaths (four observed, 10.5 expected). Workers in areas of the plant where radiation exposure was likely were issued with dosimeters to measure their external exposure to ionising radiations. Personal dose records were maintained for workers who entered such areas other than infrequently. Workers with personal dose records ("radiation" workers) had lower death rates from all causes combined than other workers but the death rates from cancer in the two groups were similar. Compared with the general population radiation workers had statistically significant deficits of liver and gall bladder cancer, lung cancer, and Hodgkin''s disease. There were excesses of deaths from myeloma (seven observed, 4.2 expected) and prostatic cancer (19 observed, 15.8 expected) but these were not significant and there was no evidence of an excess of leukaemia (10 deaths observed, 12.2 expected) or cancer of the pancreas (15 observed, 17.8 expected). Non-radiation workers had a significant deficit of leukaemia (one death observed, 5.1 expected) and a significant excess of cancers of ill defined and secondary sites (13 deaths observed, 5.8 expected). For no type of cancer was the ratio of observed to expected deaths significantly different between radiation and non-radiation workers.(ABSTRACT TRUNCATED AT 400 WORDS)     

Mortality of employees of the Atomic Weapons Establishment, 1951-82.

A total of 22,552 workers employed by the Atomic Weapons Establishment between 1951 and 1982 were followed up for an average of 18.6 years. Of the 3115 who died, 865 (28%) died of cancer. Mortality was 23% lower than the national average for all causes of death and 18% lower for cancer. These low rates were consistent with the findings in other workforces in the nuclear industry and reflect, at least in part, the selection of healthy people to work in the industry and the disproportionate recruitment of people from the higher social classes. At some time during their employment 9389 (42%) of the workers were monitored for exposure to radiation, the average cumulative whole body exposure to external radiation being 7.8 mSv. Their mortality was generally similar to that of other employees, even when exposures were lagged by 10 years. The rate ratio after a 10 year lag in workers with a radiation record compared with other workers was 1.01 (95% confidence interval 0.92 to 1.10) for all causes of death and 1.06 (0.89 to 1.27) for all malignant neoplasms. The only significant differences were for prostatic cancer (rate ratio 2.23; 95% confidence interval 1.13 to 4.40) and for cancers of ill defined and secondary sites (rate ratio 2.37; 1.23 to 4.56). Cancers of lymphatic and haemopoietic tissues were notable for their low occurrence in the study population, with only four deaths from leukaemia and two from multiple myeloma in workers with a radiation record, 9.16 and 3.55 deaths respectively being expected on the basis of national rates. Among workers who had a radiation record 3742 (40%) were also monitored for possible internal exposure to plutonium, 3044 (32%) to uranium, 1562 (17%) to tritium, 638 (7%) to polonium, and 281 (3%) to actinium. In these workers mortality from malignant neoplasms as a whole was not increased, but after a 10 year lag death rates from prostatic and renal cancers were generally more than twice the national average, these excesses arising in a small group of workers monitored for exposure to multiple radionuclides. Though mortality from lung cancer in workers monitored for exposure to plutonium was below the national average, it was some two thirds higher than in other radiation workers, the excess being of borderline statistical significance. Mortality from malignant neoplasms as a whole showed a weak and non-significant increasing trend with increasing level of cumulative whole body exposure to external radiation. When the exposures were lagged by 10 years the trend became stronger and significant, the estimated increase in relative risk per 10 mSv being 7.6% (95% confidence interval 0.4% to 15.3%). This trend was confined almost entirely to workers who were also monitored for exposure to radionuclides (p<0.001), the main contributions coming from lung cancer and prostatic cancer. Exposures of the lung and prostate from internal sources of radiation were not quantified, except for the contribution from tritium. It was therefore not possible to assess the extent to which the associations were due to internally deposited radionuclides rather than external exposure. The finding for prostatic cancer taken in conjunction with the results of other studies suggest a specific occupational hazard in a small group of workers in the nuclear industry who had comparatively high exposures to external radiation and who were also monitored for internal exposure to multiple radionuclides. Research is needed to discover whether any of the radionuclides and other substances concerned are concentrated in the prostate. The occurrence of lung cancer in this workforce requires further investigation taking into account smoking habits and tissue doses from inhaled radionuclides.     

Mortality (1950-1999) and cancer incidence (1969-1999) in the cohort of Eldorado uranium workers

This study assessed the relationship between radon decay product (RDP) exposure and mortality and cancer incidence in a cohort of 17,660 Eldorado uranium workers first employed in 1932-1980 and followed up through 1999. The analysis was based on substantially revised identifying information and dosimetry for workers from the Beaverlodge and Port Radium uranium mines and for the first time includes workers from a radium and uranium refinery and processing facility in Port Hope, Canada. Overall, male workers had lower mortality rates of all causes and all cancers and lower incidence rates of all cancers compared with the general Canadian male population, a likely healthy worker effect. Individual cancer rates were also reduced except for lung cancer mortality (SMR = 1.31, P < 0.001) and incidence (SIR = 1.23, P < 0.001). The excess relative risk per 100 WLM (ERR/100 WLM) of lung cancer mortality (N = 618, ERR/100 WLM = 0.55, 95% CI: 0.37, 0.78, P < 0.01) and incidence (N = 626, ERR/100 WLM = 0.55, 95% CI: 0.37, 0.81, P < 0.001) increased linearly with increasing RDP exposure. Adjustment for effect modification by time since exposure, exposure rate and age at risk resulted in comparable estimates of risk of lung cancer for all three uranium worksites. RDP exposures and γ-ray doses were not associated with any other cancer site or other cause of death. The risk estimates are in agreement with the results of the pooled analysis of 11 miner cohorts and more recent studies of uranium workers. The current analysis provides more precise risk estimates and compares the findings from the mortality study with the incidence study. Future follow-up of the cohort and joint analysis with other uranium miners' studies should shed more light on the effects of low RDP exposures as experienced by current workers as well as help to understand and address the health risks associated with residential radon.     

Radiation Effects on Mortality from Solid Cancers Other than Lung,Liver, and Bone Cancer in the Mayak Worker Cohort: 1948–2008

Radiation effects on mortality from solid cancers other than lung, liver, and bone cancer in the Mayak worker cohort: 1948–2008. The cohort of Mayak Production Association (PA) workers in Russia offers a unique opportunity to study the effects of prolonged low dose rate external gamma exposures and exposure to plutonium in a working age population. We examined radiation effects on the risk of mortality from solid cancers excluding sites of primary plutonium deposition (lung, liver, and bone surface) among 25,757 workers who were first employed in 1948–1982. During the period 1948–2008, there were 1,825 deaths from cancers other than lung, liver and bone. Using colon dose as a representative external dose, a linear dose response model described the data well. The excess relative risk per Gray for external gamma exposure was 0.16 (95% CI: 0.07 – 0.26) when unadjusted for plutonium exposure and 0.12 (95% CI 0.03 – 0.21) when adjusted for plutonium dose and monitoring status. There was no significant effect modification by sex or attained age. Plutonium exposure was not significantly associated with the group of cancers analyzed after adjusting for monitoring status. Site-specific risks were uncertainly estimated but positive for 13 of the 15 sites evaluated with a statistically significant estimate only for esophageal cancer. Comparison with estimates based on the acute exposures in atomic bomb survivors suggests that the excess relative risk per Gray for prolonged external exposure in Mayak workers may be lower than that for acute exposure but, given the uncertainties, the possibility of equal effects cannot be dismissed.     

Chemical process based reconstruction of exposures for an epidemiological study. III. Analysis of industrial hygiene samples

As part of an historical cohort study to investigate the mortality experience of industrial workers exposed to chloroprene (beta-CD) and other substances, all available industrial hygiene exposure monitoring data were collected and summarized. From discussions with on-site industrial hygiene personnel, it was apparent that these data were not collected for epidemiological purposes and, therefore, their use in characterization of exposures was problematic as the data mostly pertained to samples collected to investigate the performance of specific tasks. These data were, however, informative for validating the exposure modeling process used to estimate historical exposures. The data summarized below clearly indicate that exposures to beta-CD were lowered across the time period of this study. Typically, the exposures recorded were less than the occupational exposure limits of the periods in which the exposures were recorded. Additionally, exposure measurements recorded in the recent past do not represent the exposure actually experienced by the worker as a strict personal protective equipment use program has been in place for the facilities studied since the mid-1980s.     

Carcinogenic,mutagenic and teratogenic risks associated with vinyl chloride

The data presented demonstrate clearly that vinyl chloride (VC) is related to a significant excess of mortality from cancer of the liver, lung and brain among workers occupationally exposed to VC. The risk of dying from cancer of the lymphatic and hematopoietic system also appears to increase with an increase in latency. These cancer sites could have been predicted by the animal bioassay conducted by Maltoni. With regard to the liver, even the histopathologic type of cancer (angiosarcoma) was observed first in experimental animals. A sutdy of cancer mortality among populations residing proximate to VC polymerization facilities also demonstrated an increased risk of dying from CNS and lymphatic cancer. These latter findings raise cause for concern about out-plant emisssions of VC, but without further study these cancers obviously cannot be interpreted as being related to out-plant exposure to VC.Various test systems now have been elicited a positive mutagenic response to VC. Thus, our observations of a significant excess of fetal mortality among the wives of males, who were occupationally exposed to VC, raise public health concern that VC may be mutagenic in humas.With regard to the teratogenicity of VC, observations of a significant excess of children born with birth defects were reported among populations residing proximate to VC polymerization facilities. Additional epidemiologic study is needed to determine whether a repeated pattern of excessive numbers of children born with birth defects can be observed in other communities with VC polymerization facilities.     

Mortality and occupational exposure to radiation: first analysis of the National Registry for Radiation Workers.

OBJECTIVE--To study cause specific mortality of radiation workers with particular reference to associations between fatal neoplasms and level of exposure to radiation. DESIGN--Cohort study. SETTING--United Kingdom. SUBJECTS--95,217 radiation workers at major sites of the nuclear industry. MAIN OUTCOME MEASURE--Cause of death. RESULTS--Most standardised mortality ratios were below 100: 83 unlagged, 85 with a 10 year lag for all causes; 84 unlagged, 86 lagged for all cancers; and 80 for all known other causes, indicating a "healthy worker effect." The deficit of lung cancer (75 unlagged, 76 lagged) was significant at the 0.1% level. Standardised mortality ratios were significantly raised (214 unlagged, 303 lagged) for thyroid cancer, but there was no evidence for any trend with external recorded radiation dose. Dose of external radiation and mortality from all cancers were weakly correlated (p = 0.10), and multiple myeloma was more strongly correlated (p = 0.06); for leukaemia, excluding chronic lymphatic, the trend was significant (p = 0.03; all tests one tailed). The central estimates of lifetime risk derived from these data were 10.0% per Sv (90% confidence interval less than 0 to 24%) for all cancers and 0.76% per Sv (0.07 to 2.4%) for leukaemia (excluding chronic lymphatic leukaemia). These are, respectively, 2.5 times and 1.9 times the risk estimates recommended by the International Commission on Radiological Protection, but 90% confidence intervals are large and the commission''s risk factors fall well within the range. The positive trend with dose for all cancers, from which the risk estimate was derived, was not significant. The positive association between leukaemia (except chronic lymphatic leukaemia) was significant and robust in subsidiary analyses. This study showed no association between radiation exposure and prostatic cancer. CONCLUSION--There is evidence for an association between radiation exposure and mortality from cancer, in particular leukaemia (excluding chronic lymphatic leukaemia) and multiple myeloma, although mortality from these diseases in the study population overall was below that in the general population. The central estimates of risk from this study lie above the most recent estimates of the International Commission on Radiological Protection for leukaemia (excluding chronic lymphatic leukaemia) and for all malignancies. However, the commission''s risk estimates are well within the 90% confidence intervals from this study. Analysis of combined cohorts of radiation workers in the United States indicated lower risk estimates than the commission recommends, and when the American data are combined with our analysis the overall risks are close to those estimated by the commission. This first analysis of the National Registry for Radiation Workers does not provide sufficient evidence to justify a revision in risk estimates for radiological protection purposes.     

Cancer Mortality in Chinese Chrysotile Asbestos Miners: Exposure-Response Relationships

Objective

This study was conducted to assess the relationship of mortality from lung cancer and other selected causes to asbestos exposure levels.

Methods

A cohort of 1539 male workers from a chrysotile mine in China was followed for 26 years. Data on vital status, occupation and smoking were collected from the mine records and individual contacts. Causes and dates of death were further verified from the local death registry. Individual cumulative fibre exposures (f-yr/ml) were estimated based on converted dust measurements and working years at specific workshops. Standardized mortality ratios (SMRs) for lung cancer, gastrointestinal (GI) cancer, all cancers and nonmalignant respiratory diseases (NMRD) stratified by employment years, estimated cumulative fibre exposures, and smoking, were calculated. Poisson models were fitted to determine exposure-response relationships between estimated fibre exposures and cause-specific mortality, adjusting for age and smoking.

Results

SMRs for lung cancer increased with employment years at entry to the study, by 3.5-fold in ≥10 years and 5.3-fold in ≥20 years compared with <10 years. A similar trend was seen for NMRD. Smokers had greater mortality from all causes than nonsmokers, but the latter also had slightly increased SMR for lung cancer. No excess lung cancer mortality was observed in cumulative exposures of <20 f-yrs/ml. However, significantly increased mortality was observed in smokers at the levels of ≥20 f-yrs/ml and above, and in nonsmokers at ≥100 f-yrs/ml and above. A similarly clear gradient was also displayed for NMRD. The exposure-response relationships with lung cancer and NMRD persisted in multivariate analysis. Moreover, a clear gradient was shown in GI cancer mortality when age and smoking were adjusted for.

Conclusion

There were clear exposure-response relationships in this cohort, which imply a causal link between chrysotile asbestos exposure and lung cancer and nonmalignant respiratory diseases, and possibly to gastrointestinal cancer, at least for smokers.     

Evaluation of long-term occupational exposure to styrene vapor on olfactory function

The primary sensory neurons of the olfactory system are chronically exposed to the ambient environment and may therefore be susceptible to damage from occupational exposure to many volatile chemicals. To investigate whether occupational exposure to styrene was associated with olfactory impairment, we examined olfactory function in 2 groups: workers in a German reinforced-plastics boat-manufacturing facility having a minimum of 2 years of styrene exposure (15-25 ppm as calculated from urinary metabolite concentrations, with historical exposures up to 85 ppm) and a group of age-matched workers from the same facility with lower styrene exposures. The results were also compared with normative data previously collected from healthy, unexposed individuals. Multiple measures of olfactory function were evaluated using a standardized battery of clinical assessments from the Monell-Jefferson Chemosensory Clinical Research Center that included tests of threshold sensitivity for phenylethyl alcohol (PEA) and odor identification ability. Thresholds for styrene were also obtained as a measure of occupational olfactory adaptation. Styrene exposure history was calculated through the use of past biological monitoring results for urinary metabolites of styrene (mandelic acid [MA], phenylglyoxylic acid [PGA]); current exposure was determined for each individual using passive air sampling for styrene and biological monitoring for styrene urinary metabolites. Current mean effective styrene exposure during the day of olfactory testing for the group of workers who worked directly with styrene resins was 18 ppm styrene (standard deviation [SD] = 14), 371 g/g creatinine MA + PGA (SD = 289) and that of the group of workers with lower exposures was 4.8 ppm (SD = 5.2), 93 g/g creatinine MA+PGA (SD = 100). Historic annual average exposures for all workers were greater by a factor of up to 6x. No differences unequivocally attributable to exposure status were observed between the Exposed and Comparison groups or between performance of either group and normative population values on thresholds for PEA or odor identification. Although odor identification performance was lower among workers with higher ongoing exposures, performance on this test is not a pure measure of olfactory ability and is influenced by familiarity with the stimuli and their sources. Consistent with exposure-induced sensory adaptation, however, elevated styrene thresholds were significantly associated with higher occupational exposures to styrene. In summary, the present study found no evidence among a cross-section of reinforced-plastics workers that current or historical exposure to styrene was associated with a general impairment of olfactory function. When taken together with prior studies of styrene-exposed workers, these results suggest that styrene is not a significant olfactory toxicant in humans at current exposure levels.     

Comparison of standardized mortality ratios (SMRs) obtained from use of reference populations based on a company-wide registry cohort to SMRs calculated against local and national rates

The DuPont Company has maintained a mortality registry for all active and pensioned U.S. employees since 1957. Standardized mortality ratios (SMRs) for each plant site in the U.S. can be calculated based on the comparison with the entire U.S. DuPont population or with a regional subset of DuPont employees. We compared the SMRs derived from a large, international cohort mortality study of chloroprene workers (IISRP study) with those derived from the entire DuPont Registry and appropriate subpopulations of the registry for two U.S. neoprene plants--Louisville (Kentucky) and Pontchartrain (Louisiana). SMRs from the IISRP study for the Louisville cohort based on national rates for all causes of death, all cancers, respiratory cancer, and liver cancer are higher than those based on local mortality rates. Both the national and local comparisons (several counties surrounding each plant) for all-cancer SMRs are lower than 1.0, the local comparison being statistically significantly reduced. In contrast, the SMRs based on the total U.S. DuPont worker mortality rates for all causes of death (1.13), all cancers (1.11), and respiratory cancers (1.37) are statistically significantly increased. The SMR for liver cancer (1.27), although elevated, is not statistically significant. SMRs based on DuPont Region 1 were closer to 1.0, and the SMR for all cancers was no longer significant. Stratification of the Louisville subcohort of males using the same cumulative exposure categories used in the IISRP study yielded SMRs calculated against DuPont Region 1 that were generally higher than those calculated against U.S. and local rates. Only the third exposure category showed SMRs statistically significantly above 1.0 for all cancers and for cancer of bronchus, trachea, and lung. However, there does not appear to be an exposure-response trend. The SMRs from the IISRP study for the Pontchartrain cohort based on national rates are higher than those based on local rates for all causes of death, but all are less than 1.0. The all-cause SMRs for both local and national comparisons are significantly reduced. There were no deaths from liver cancers observed in this cohort. Comparisons of the Pontchartrain cohort against the total U.S. DuPont worker mortality rates resulted in higher SMRs for all causes of death (0.98), all cancers (1.03), and respiratory cancer (1.08), but none were statistically significant. SMRs based on DuPont Region 2 showed very little change from those based on the total registry. The use of reference rates based on regional workers in the same large company produces SMRs lower than those based on the entire company population (regional socio-cultural effects) but higher than those based on geographically closer local general populations (healthy worker effect). The healthy worker effect is seen in cancer mortality rates as well as in other chronic diseases.     

Molecular epidemiological studies in 1,3-butadiene exposed Czech workers: female-male comparisons

Results of a recent molecular epidemiological study of 1,3-butadiene (BD) exposed Czech workers, conducted to compare female to male responses, have confirmed and extended the findings of a previously reported males only study (HEI Research Report 116, 2003). The initial study found that urine concentrations of the metabolites 1,2-dihydroxy-4-(acetyl) butane (M1) and 1-dihydroxy-2-(N-acetylcysteinyl)-3-butene (M2) and blood concentrations of the hemoglobin adducts N-[2-hydroxy-3-butenyl] valine (HB-Val) and N-[2,3,4-trihydroxy-butyl] valine (THB-Val) constitute excellent biomarkers of exposure, both being highly correlated with BD exposure levels, and that GST genotypes modulate at least one metabolic pathway, but that irreversible genotoxic effects such as chromosome aberrations and HPRT gene mutations are neither associated with BD exposure levels nor with worker genotypes (GST [glutathione-S-transferase]-M1, GSTT1, CYP2E1 (5' promoter), CYP2E1 (intron 6), EH [epoxide hydrolase] 113, EH139, ADH [alcohol dehydrogenase]2 and ADH3). The no observed adverse effect level (NOAEL) for chromosome aberrations and HPRT mutations was 1.794 mg/m(3) (0.812 ppm)--the mean exposure level for the highest exposed worker group in this initial study. The second Czech study, reported here, initiated in 2003, included 26 female control workers, 23 female BD exposed workers, 25 male control workers and 30 male BD exposed workers (some repeats from the first study). Multiple external exposure measurements (10 full 8-h shift measures by personal monitoring per worker) over a 4-month period before biological sample collections showed that BD workplace levels were lower than in the first study. Mean 8-h TWA exposure levels were 0.008 mg/m(3) (0.0035 ppm) and 0.397 mg/m(3) (0.180 ppm) for female controls and exposed, respectively, but with individual single 8-h TWA values up to 9.793 mg/m(3) (4.45 ppm) in the exposed group. Mean male 8-h TWA exposure levels were 0.007 mg/m(3) (0.0032 ppm) and 0.808 mg/m(3) (0.370 ppm) for controls and exposed, respectively; however, the individual single 8-h TWA values up to 12.583 mg/m(3) (5.72 ppm) in the exposed group. While the urine metabolite concentrations for both M1 and M2 were elevated in exposed compared to control females, the differences were not significant, possibly due to the relatively low BD exposure levels. For males, with greater BD exposures, the concentrations of both metabolites were significantly elevated in urine from exposed compared to control workers. As in the first study, urine metabolite excretion patterns in both sexes revealed conjugation to be the minor detoxification pathway (yielding the M2 metabolite) but both M1 and M2 concentration values were lower in males in this second study compared to their concentrations in the first, reflecting the lower external exposures of males in this second study compared to the first. Of note, females showed lower concentrations of both M1 and M2 metabolites in the urine per unit of BD exposure than did males while exhibiting the same M1/(M1+M2) ratio, reflecting the same relative utilization of the hydrolytic (producing M1) and the conjugation (producing M2) detoxification pathways as males. Assays for the N,N-(2,3-dihydroxy-1,4-butadyl) valine (pyr-Val) hemoglobin (Hb) adduct, which is specific for the highly genotoxic 1,2,3,4-diepoxybutane (DEB) metabolite of BD, have been conducted on blood samples from all participants in this second Czech study. Any adduct that may have been present was below the limits of quantitation (LOQ) for this assay for all samples, indicating that production of this important BD metabolite in humans is below levels produced in both mice and rats exposed to as little as 1.0 ppm BD by inhalation (J.A. Swenberg, M.G. Bird, R.J. Lewis, Future directions in butadiene risk assessment, Chem. Biol. Int. (2006), this issue). Results of assays for the HB-Val and THB-Val hemoglobin adducts are pending. HPRT mutations, determined by cloning assays, and multiple measures of chromosome level changes (sister-chromatid exchanges [SCE], aberrations determined by conventional methods and FISH) again showed no associations with BD exposures, confirming the findings of the initial study that these irreversible genotoxic changes do not arise in humans occupationally exposed to low levels of BD. Except for lower production of both urine metabolites in females, no female-male differences in response to BD exposures were detected in this study. As in the initial study, there were no significant genotype associations with the irreversible genotoxic endpoints. However, as in the first, differences in the metabolic detoxification of BD as reflected in relative amounts of the M1 and M2 urinary metabolites were associated with genotypes, this time both GST and EH.     

Cancer mortality risk among workers at the Mayak nuclear complex

At present, direct data on risk from protracted or fractionated radiation exposure at low dose rates have been limited largely to studies of populations exposed to low cumulative doses with resulting low statistical power. We evaluated the cancer risks associated with protracted exposure to external whole-body gamma radiation at high cumulative doses (the average dose is 0.8 Gy and the highest doses exceed 10 Gy) in Russian nuclear workers. Cancer deaths in a cohort of about 21,500 nuclear workers who began working at the Mayak complex between 1948 and 1972 were ascertained from death certificates and autopsy reports with follow-up through December 1997. Excess relative risk models were used to estimate solid cancer and leukemia risks associated with external gamma-radiation dose with adjustment for effects of plutonium exposures. Both solid cancer and leukemia death rates increased significantly with increasing gamma-ray dose (P < 0.001). Under a linear dose-response model, the excess relative risk for lung, liver and skeletal cancers as a group (668 deaths) adjusted for plutonium exposure is 0.30 per gray (P < 0.001) and 0.08 per gray (P < 0.001) for all other solid cancers (1062 deaths). The solid cancer dose-response functions appear to be nonlinear, with the excess risk estimates at doses of less than 3 Gy being about twice those predicted by the linear model. Plutonium exposure was associated with increased risks both for lung, liver and skeletal cancers (the sites of primary plutonium deposition) and for other solid cancers as a group. A significant dose response, with no indication of plutonium exposure effects, was found for leukemia. Excess risks for leukemia exhibited a significant dependence on the time since the dose was received. For doses received within 3 to 5 years of death the excess relative risk per gray was estimated to be about 7 (P < 0.001), but this risk was only 0.45 (P = 0.02) for doses received 5 to 45 years prior to death. External gamma-ray exposures significantly increased risks of both solid cancers and leukemia in this large cohort of men and women with occupational radiation exposures. Risks at doses of less than 1 Gy may be slightly lower than those seen for doses arising from acute exposures in the atomic bomb survivors. As dose estimates for the Mayak workers are improved, it should be possible to obtain more precise estimates of solid cancer and leukemia risks from protracted external radiation exposure in this cohort.     

Occupational exposure to genotoxic agents.

Millions of workers in the United States are potentially exposed each year to hazardous chemicals, dusts, or fibers in occupational settings. Some of these agents are genotoxic and may cause genetic alterations in the somatic or germ cells of exposed workers. Such alterations, if they occur in proto-oncogenes or tumor suppressor genes, which are involved in controlling cell growth or differentiation, may lead to the development of cancer. Genetic alterations in germ cells may also lead to reproductive failure or genetic disorders in subsequent generations. It has been estimated that occupational exposure accounts for 4% of all human cancers and up to 30% of cancer among blue-collar workers. Approximately 20,000 cancer deaths each year are attributable to occupational exposure in the United States. Occupational cancer and reproductive abnormalities have been listed on the National Occupational Research Agenda master list of research priorities as major occupational diseases and injuries.     

Long-Term Exposure to Silica Dust and Risk of Total and Cause-Specific Mortality in Chinese Workers: A Cohort Study

Background

Human exposure to silica dust is very common in both working and living environments. However, the potential long-term health effects have not been well established across different exposure situations.

Methods and Findings

We studied 74,040 workers who worked at 29 metal mines and pottery factories in China for 1 y or more between January 1, 1960, and December 31, 1974, with follow-up until December 31, 2003 (median follow-up of 33 y). We estimated the cumulative silica dust exposure (CDE) for each worker by linking work history to a job–exposure matrix. We calculated standardized mortality ratios for underlying causes of death based on Chinese national mortality rates. Hazard ratios (HRs) for selected causes of death associated with CDE were estimated using the Cox proportional hazards model. The population attributable risks were estimated based on the prevalence of workers with silica dust exposure and HRs. The number of deaths attributable to silica dust exposure among Chinese workers was then calculated using the population attributable risk and the national mortality rate. We observed 19,516 deaths during 2,306,428 person-years of follow-up. Mortality from all causes was higher among workers exposed to silica dust than among non-exposed workers (993 versus 551 per 100,000 person-years). We observed significant positive exposure–response relationships between CDE (measured in milligrams/cubic meter–years, i.e., the sum of silica dust concentrations multiplied by the years of silica exposure) and mortality from all causes (HR 1.026, 95% confidence interval 1.023–1.029), respiratory diseases (1.069, 1.064–1.074), respiratory tuberculosis (1.065, 1.059–1.071), and cardiovascular disease (1.031, 1.025–1.036). Significantly elevated standardized mortality ratios were observed for all causes (1.06, 95% confidence interval 1.01–1.11), ischemic heart disease (1.65, 1.35–1.99), and pneumoconiosis (11.01, 7.67–14.95) among workers exposed to respirable silica concentrations equal to or lower than 0.1 mg/m³. After adjustment for potential confounders, including smoking, silica dust exposure accounted for 15.2% of all deaths in this study. We estimated that 4.2% of deaths (231,104 cases) among Chinese workers were attributable to silica dust exposure. The limitations of this study included a lack of data on dietary patterns and leisure time physical activity, possible underestimation of silica dust exposure for individuals who worked at the mines/factories before 1950, and a small number of deaths (4.3%) where the cause of death was based on oral reports from relatives.

Conclusions

Long-term silica dust exposure was associated with substantially increased mortality among Chinese workers. The increased risk was observed not only for deaths due to respiratory diseases and lung cancer, but also for deaths due to cardiovascular disease. Please see later in the article for the Editors'' Summary     

Mortality of plastic-ware workers exposed to radiofrequencies

The mortality experience of a cohort of Italian plastic-ware workers exposed to radiofrequency (RF)-electromagnetic fields generated by dielectric heat sealers was investigated. Follow-up extended from 1962 to 1992. The standardised mortality ratio (SMR) analysis was restricted to 481 women workers, representing 78% of the total person-years at risk. Mortality from malignant neoplasms was slightly elevated, and increased risks of leukemia and accidents were detected. The all-cancer SMR was higher among women employed in the sealing department, where exposure to RF occurred, than in the whole cohort. This study raises interest in a possible association between exposure to RF radiation and cancer risk. However, the study power was very small, and the possible confounding effects of exposure to solvents and vinyl chloride monomer (VCM) could not be ruled out. The hypothesis of an increased risk of cancer after radiofrequency exposure should be further explored by means of analytical studies characterised by adequate power and more accurate exposure assessment. Bioelectromagnetics 18:418–421, 1997. © 1997 Wiley-Liss, Inc.     

Updated Mortality Analyses of Pernis Epidemiological Data on Human Exposures to Aldrin and Dieldrin

An extensive clinical and epidemiological study of workers engaged in the manufacturing and formulation of aldrin and dieldrin, the Pernis study, provides occupational hygiene and biological monitoring data on individual exposures over the years of employment and provides the opportunity to investigate dose response relationships for these chemicals. The human epide miological mortality data on these workers, who were exposed to fairly substan tial lifetime average daily doses of aldrin and dieldrin, suggest that low dose exposures do not significantly increase human mortality and may even de crease the human mortality hazard rate. While hormesis from low dose expo sure to aldrin and dieldrin is not statistically significant, it is observed in the raw data and in the best fitting dose response models. The decrease in risk suggests increased survival time at low doses of aldrin and dieldrin. Using an upper bound on cancer potency based on mouse liver tumors, the U.S. Environmental Protection Agency (EPA) estimated that lifetime average daily doses (LADDs) of 0.0000625 and 0.00625?µg/kg body weight/day would correspond to increased cancer risks of 0.000001 and 0.0001, respectively. However, the best estimate from the Pernis epidemiological data is that LADDs of 0.0000625 and 0.00625?µg/kg body weight/day correspond to no increase in cancer risk and a decrease in the probability of mortality from all causes by the age of 70 years. At low doses of aldrin and dieldrin, the estimated decrease in mortality in a reference period of 70 years is more than 1000 times larger than the U.S. EPA's upper bound on the increase in the lifetime probability of cancer.     

Solid cancer mortality associated with chronic external radiation exposure at the French atomic energy commission and nuclear fuel company

Studies of nuclear workers make it possible to directly quantify the risks associated with ionizing radiation exposure at low doses and low dose rates. Studies of the CEA (Commissariat à l'Energie Atomique) and AREVA Nuclear Cycle (AREVA NC) cohort, currently the most informative such group in France, describe the long-term risk to nuclear workers associated with external exposure. Our aim is to assess the risk of mortality from solid cancers among CEA and AREVA NC nuclear workers and its association with external radiation exposure. Standardized mortality ratios (SMRs) were calculated and internal Poisson regressions were conducted, controlling for the main confounding factors [sex, attained age, calendar period, company and socioeconomic status (SES)]. During the period 1968-2004, there were 2,035 solid cancers among the 36,769 CEA-AREVA NC workers. Cumulative external radiation exposure was assessed for the period 1950-2004, and the mean cumulative dose was 12.1 mSv. Mortality rates for all causes and all solid cancers were both significantly lower in this cohort than in the general population. A significant excess of deaths from pleural cancer, not associated with cumulative external dose, was observed, probably due to past asbestos exposure. We observed a significant excess of melanoma, also unassociated with dose. Although cumulative external dose was not associated with mortality from all solid cancers, the central estimated excess relative risk (ERR) per Sv of 0.46 for solid cancer mortality was higher than the 0.26 calculated for male Hiroshima and Nagasaki A-bomb survivors 50 years or older and exposed at the age of 30 years or older. The modification of our results after stratification for SES demonstrates the importance of this characteristic in occupational studies, because it makes it possible to take class-based lifestyle differences into account, at least partly. These results show the great potential of a further joint international study of nuclear workers, which should improve knowledge about the risks associated with chronic low doses and provide useful risk estimates for radiation protection.     

Repeated inhalation exposure of rats to aerosols of 144CeO2. II. Effects on survival and lung, liver, and skeletal neoplasms.

Groups of 94-day-old F344/Crl rats were exposed repeatedly to aerosols of 144CeO2 to reestablish desired lung burdens of 1.9, 9.2, 46, or 230 kBq of 144Ce every 60 days for 1 year (seven exposures). Other 94-day-old rats were exposed once to achieve similar desired initial lung burdens of 144Ce. Older rats were exposed once to achieve desired initial lung burdens of 46 or 230 kBq when 500 days of age, the same age at which rats had the last of the repeated exposures. Control rats were either unexposed, sham-exposed once or repeatedly, or exposed once or repeatedly to stable CeO2. Approximately equal numbers of male and female rats were used. The median survival time and cumulative percentage survival curves were significantly decreased only in male and female rats exposed repeatedly to reestablish a 230-kBq lung burden and among the 94-day-old male rats exposed once to achieve a 230-kBq lung burden of 144Ce. The crude incidences of primary lung cancers (well described by a single Weibull distribution function), time to death with lung tumors, and risk of lung cancer per unit of beta-radiation dose to the lungs were correlated with the cumulative beta-radiation dose rather than the rate at which the dose was accumulated. A linear function, 70 (+/- 7.3) + -0.15 (+/- 0.056) x dose (+/- SD), adequately described the excess numbers of rats with lung cancers over a beta-radiation dose range to the lungs of 6.8 to 250 Gy for two groups of rats with the highest doses to the lungs after a single exposure and for two groups with the highest doses after repeated exposure.