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epidemiological data
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
1946 - 2006
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Well-documented publication.

Data source

Reference Type:
Coronary Artery Disease and Cancer Mortality in a Cohort of Workers Exposed to Vinyl Chloride, Carbon Disulfide, Rotating Shift Work, and o-Toluidine at a Chemical Manufacturing Plant
Tania Carreón, Misty J. Hein, Kevin W. Hanley, Susan M. Viet, and Avima M. Ruder
Bibliographic source:

Materials and methods

Study type:
cohort study (retrospective)
Endpoint addressed:
repeated dose toxicity: inhalation
Test guideline
no guideline available
GLP compliance:
not specified

Test material

Constituent 1
Chemical structure
Reference substance name:
Carbon disulphide
EC Number:
EC Name:
Carbon disulphide
Cas Number:
Molecular formula:


Type of population:
Details on study design:
- Details: Vital status was ascetained by linking records of the National Center for Health Statistics' National Death Index. Causes of death were
Coronary Artery Disease and Cancer Mortality in a Chemical Manufacturing Plant obtained by National Death Index Plus, and a special request
was submitted to the Florida Department of Health for deaths that occurred in that state.

- STUDY PERIOD: 1946 and 2006

- Selection criteria: Any worker assigned to the Rubber Chemicals department from 1954 to 1994 were conidered. Multiple jobs assigned to other departments (i.e., Shipping, Packaging & Warehouse, Quality Control, Laboratory and Research & Development; see Hanley et al. [2012] for the rationale) and departments whose work was conducted throughout the plant (i.e., Maintenance, Yard/Janitor) were also considered exposed to carbon disulfide. Some jobs in the PVC, Vinyl department as exposed to carbon disulfide when the job title specifically indicated work in the Rubber Chemicals department. Furthermore guards, nurses, engineers, yardmen, co-op employees, workers on temporary assignment from company headquarters, and other jobs with no assigned department from 1954 to 1994 were considered exposed to carbon disulfide, because they moved around the plant.

- Total number of subjects participating in study: 1874

- Workers were considered unexposed to the agents analyzed in this study during employment at other company locations and after separation from the company.

- Disease(s): coronary artery disease mortality

Exposure assessment:
not specified
Details on exposure:
EXPOSURE PERIOD: ranged from less than 1 year to 40 years or longer

Statistical methods:
NIOSH Life Table Analysis System. Standardized mortality ratios, adjusted for gender, race, age (in 5-year categories), and calendar year (in 5-year categories), were based on US mortality rates (beginning in 1960) for 119 underlying cause of death categories [Robinson et al., 2006]. Additional analyses used New York State (excluding New York City) underlying cause mortality rates or US multiple cause of death rates (i.e., considering all causes of death listed on the death certificate). For all analyses, person-years-at-risk began on the later of January 1, 1960 (the rate file begin date) or the 400 Carreón et al. date of first employment at the plant. Person-years-at-risk ended at the earliest of the date of death (for deceased cohort members), the date last observed (for cohort members lost to follow-up), or December 31, 2007. Estimated 95% confidence intervals (CIs) for the SMRs were based on the Poisson distribution. Life table analyses were conducted for the total cohort and separately for those employed less than 90 days and 90 days or more. Directly standardized rate ratios (SRR) for internal analyses with 95% CIs estimated using approximate methods we used [Rothman and Greenland, 1998]. Linear trend tests using the Rothman trend test [Rothman and
Greenland, 1998] for all a priori outcomes using quartiles of employment duration (or duration of exposure to vinyl chloride, carbon disulfide, and/or shift work) defined by the distribution of the metric among decedents were conducted.

Results and discussion

- Sixty-seven percent of workers were classified as ever exposed (greater or equal 1 day) to carbon disulfide, and a larger percentage (77%) had performed some frame shift work (greater or equal 1 day)

- Compared to the US population, statistically significant increases in mortality were observed among workers with both exposures for 90 days or more, and among workers with fewer than 90 days of both exposures. Using cutpoints of 4 years (median exposure duration among longterm cases), the results were no longer statistically significant. The elevation in coronary artery diseasemortality among workers exposed 90 days or more to both shift work and
carbon disulfide (SMR 1.36, 95% CI: 1.03–1.76) was adjusted for gender, race, age, and calendar year, but not for smoking. The distribution of smoking was 26.9% never, 29.0% former, and 44.1% current among similarly exposed workers in the cohort with all sources of smoking data and 35.3% never, 31.8% former, and 32.9% current among US males in 1987 (age-adjusted to the exposed). The smoking-adjusted SMR was 1.28 with 95% Monte
Carlo limits of 1.03–1.11 for the bias factor and 0.98–1.66 for the smoking-adjusted SMR. Similar results were observed when only source 1 of the smoking data was used (estimated median bias factor 1.09, bias-adjusted SMR 1.24, and 95% Monte Carlo limits 0.96–1.62).
Coronary artery disease mortality was significantly higher among workers with more than 4 years of exposure to both shift work and carbon disulfide compared to workers with less than 4 years of exposure to both shift work and carbon disulfide, but only when short-term workers were excluded. Compared to the same referent group, mortality was not higher among workers with 4 years or more of just one of these exposures.

Applicant's summary and conclusion

Coronary artery disease mortality was increased in human workers by CS2 long-term exposure.
Executive summary:

Through 2007 the mortality experience of 1874 workers employed at a New York chemical manufacturing plant between 1946 and 2006 was updated. For the update a company-provided electronic work history database (complete as to April 2006) was merged with the exisiting NIOSH database. In addition to documented exposures to o-toluidine, aniline, and nitrobenzene, exposures at the plant included vinyl chloride, carbon disulfide and rotating shift work. Coronary artery disease was investigated as the outcome of interest for carbon disulfide. As many workers exposed to carbon disulfide also performed shift work, the risk of coronary artery disease mortality in groups defined by duration of exposure to these agents were evaluated. Internal comparisons showed increased coronary artery disease mortality among long-term workers exposed to carbon disulfide and shift work for 4 years or more.