Mortality patterns among industrial workers exposed to chloroprene and other substances: II. Mortality in relation to exposure

doi:10.1016/j.cbi.2006.08.012

Chemico-Biological Interactions

Volume 166, Issues 1–3, 20 March 2007, Pages 301-316

https://doi.org/10.1016/j.cbi.2006.08.012 Get rights and content

Abstract

As part of an historical cohort study to investigate the mortality experience of industrial workers exposed to chloroprene (CD) and other substances, including vinyl chloride monomer (VC), we analyzed mortality from all cancers combined, respiratory system (RSC) and liver cancer in relation to CD and VC exposures. Subjects were 12,430 workers ever employed at one of two U.S. sites (Louisville, KY (n = 5507) and Pontchartrain, LA (n = 1357)) or two European sites (Maydown, Northern Ireland (n = 4849) and Grenoble, France (n = 717)).

Historical exposures for individual workers were estimated quantitatively for CD and VC. For sites L, M, P and G, respectively, average intensity of CD exposures (median value of exposed workers in ppm) were 5.23, 0.16, 0.028 and 0.149 and median cumulative exposures (ppm years) were 18.35, 0.084, 0.133 and 1.01. For sites L and M, respectively, average intensity of VC exposures (median value of exposed workers in ppm) was 1.54 and 0.03 and median cumulative exposures (ppm years) were 1.54 and 0.094.

We performed relative risk (RR) regression modeling to investigate the dependence of the internal cohort rates for all cancers combined, RSC and liver cancer on combinations of the categorical CD or VC exposure measures with adjustment for potential confounding factors. We categorized exposure measures into approximate quartiles based on the distribution of deaths from all cancers combined. We also considered 5- and 15-year lagged exposure measures and adjusted some RR models for worker pay type (white/blue collar) as a rough surrogate for lifetime smoking history. All modeling was site-specific to account for exposure heterogeneity. We also computed exposure category-specific standardized mortality ratios (SMRs) to assess absolute mortality rates.

With the exception of a one statistically significant association with duration of exposure to CD and all cancers combined in plant M, we observed no evidence of a positive association with all cancers, RSC or liver cancer and exposure to CD and/or VC using both the unlagged and lagged exposure measures: duration, average intensity or cumulative exposure to CD or VC; time since first CD or VC exposure; and duration of CD exposure or time since first CD exposure in presence or absence of VC exposure. We observed elevated and statistically significantly elevated RRs for some analysis subgroups, but these were due to inordinately low death rates in the baseline categories. With the possible exception of all cancer mortality in plant G, our additional adjustment of RRs for pay type revealed no evidence of positive confounding by smoking.

We conclude that exposures to CD or VC at the levels encountered in the four study sites do not elevate mortality risks from all cancers, RSC or liver cancer. This conclusion is corroborated by our analysis of general mortality patterns among the CD cohort reported in our companion paper [G. Marsh, A. Youk, J. Buchanich, M. Cunningham, N. Esmen, T. Hall, M. Phillips, Mortality patterns among industrial workers exposed to chloroprene and other substances. I. General mortality patterns, Chem.-Biol. Interact., submitted for publication].

Introduction

Chloroprene (2-chloro-1,3 butadiene) (CD) is a monomer used almost exclusively for the production of synthetic rubber and latexes [1]. The chemical structure of CD is similar to that of vinyl chloride, a known human carcinogen [2]. CD is classified by the International Agency for Research on Cancer as a possible human carcinogen (group 2B) based on sufficient evidence of carcinogenicity in experimental animals [3]. Epidemiological data on the carcinogenicity of CD are available from five cohort studies of chloroprene production workers in the U.S. [4], China [5], Armenia [6] and France [7], and the study of shoe manufacturing workers in Russia [8]. An increased risk of liver [5], [6], [8], [9] and lung cancer [7] has been suggested by some of these studies. The inherent methodological limitations in the previous epidemiology studies raise questions; however, about their significance regarding human cancer risks [10], [11].

To provide more definitive and comprehensive epidemiological evidence regarding the long-term health effects of exposure to CD, a four-plant, multi-national epidemiologic study of workers with potential exposure to CD was commissioned in 1999 by the International Institute of Synthetic Rubber Producers (IISRP). The exposure assessment component of the study was conducted at the University of Oklahoma (UOk) and the University of Illinois at Chicago (UIC); the epidemiology and biostatistics component was conducted at the University of Pittsburgh (UPitt). Our analysis of general mortality patterns among the CD cohort, reported in a companion paper [12], found no evidence of elevated mortality risks from any of the causes of death examined, including all cancers combined and lung and liver cancer, the sites of a priori interest. We report here the results of our detailed analysis of mortality from all cancers combined, lung and liver cancer in relation to quantitative measures of CD and VC exposure.

Section snippets

Study sites and subjects

The chloroprene (CD) cohort included all workers (n = 12,430) with potential CD exposure at one of four CD production sites from plant start-up date through the end of 2000 (1999 for one site). The sites include two DuPont/Dow Elastomers LLC (DDE) plants in the U.S. (Louisville, KY and Pontchartrain, LA), one DDE plant in Maydown, Northern Ireland (NI) and one Enichem Elastomers France plant in Grenoble, France (FR) (called here plants L, P, M and G). CD production dates for each plant were: L

Results

Table 4, Table 5, Table 6, Table 7, Table 8 show for plants L, M, P and G, respectively, the results of our exposure-response analyses based on internal and external comparisons. Results for the internal comparisons include for each category of the exposure measures considered, the number of observed deaths (cases) and associated non-cases summed across individual risk sets. The external comparisons include the number of person-years accumulated in each exposure category. For plant L (Table 4),

Discussion and conclusions

As described in detail in our analysis of general mortality patterns [12], our historical cohort study of workers from four CD production sites in the U.S. and Europe represents the largest and the most comprehensive and rigorous investigation of the long-term health effects of exposure to CD conducted to date. It overcomes most of the shortcomings and uncertainties noted by Rice and Bofetta [10] and Acquavella and Leonard [11] that have limited the interpretation of findings from the five

Acknowledgements

The International Institute of Synthetic Rubber Producers (IISRP) sponsored this research, but the design, conduct, analysis and conclusions are those of the authors. Sponsoring companies were DuPont Dow Elastomers LLC and Enichem Elastomers France. We would like to acknowledge the cooperation and support of the representatives and consultants of IISRP and its member companies, in particular, Sheila Jones, Robin Leonard, Mike Lynch, Stuart Pollard and Paul Poullet. Our special thanks to Dr.

References (35)

J. Lynch
BD monomer and elastomer production processes
Chem.-Biol. Interact.
(2001)
M. Colonna et al.
A cohort study of workers exposed to chloroprene in the department of Isere, France
Chem.-Biol. Interact.
(2001)
D. Zaridze et al.
Cohort studies of chloroprene-exposed workers in Russia
Chem.-Biol. Interact.
(2001)
J. Rice et al.
1,3-Butadiene, isoprene and chloroprene: reviews by the IARC monographs programme, outstanding issues, and research priorities in epidemiology
Chem.-Biol. Interact.
(2001)
J. Acquavella et al.
A review of the epidemiology of 1,3-butadiene and chloroprene
Chem.-Biol. Interact.
(2001)
G. Marsh et al.
Mortality patterns among industrial workers exposed to chloroprene and other substances. I. General mortality patterns
Chem. -Biol. Interact.
(2007)
N. Esmen et al.
Classification of worker exposures
Chem. -Biol. Interact.
(2007)
N. Esmen et al.
Chemical process based reconstruction of exposures for an epidemiological study. I. Theoretical and methodological issues
Chem. -Biol. Interact.
(2007)
N. Esmen et al.
Chemical process based reconstruction of exposures for an epidemiological study. II. Estimated exposures to chloroprene and vinyl chloride
Chem. -Biol. Interact.
(2007)
T. Hall et al.
Chemical process based reconstruction of exposures for an epidemiological study. III. Analysis of industrial hygiene samples
Chem. -Biol. Interact.
(2007)

G. Marsh et al.

Reevaluation of mortality risks from leukemia in the formaldehyde cohort study of the National Cancer Institute

Regul. Toxicol. Pharm.

(2004)

G. Marsh et al.

Reevaluation of mortality risks from nasopharyngeal cancer in the formaldehyde cohort study of the National Cancer Institute

Regul. Toxicol. Pharm.

(2005)

IARC Monographs, Suppl. 7, Vinyl Chloride, Lyon, France,...

IARC Monographs, vol. 71, Chloroprene: Re-evaluation of Some Organic Chemicals, Hydrazine and Hydrogen Peroxide, Lyon,...

S. Pell

Mortality of workers exposed to chloroprene

J. Occup. Med.

(1978)

L. Shouqi et al.

Epidemiologic study of cancer mortality among chloroprene workers

Biomed. Environ. Sci.

(1989)

M. Bulbulyan et al.

Cancer incidence and mortality in a cohort of chloroprene workers from Armenia

Int. J. Cancer

(1999)

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The resulting cancer unit risk is driven by the most sensitive endpoint in animals, the incidence of lung tumors in female mice. Integration of the epidemiological studies does not provide compelling evidence for an increased risk of mortality from total cancers of the lung following inhalation exposure to chloroprene (Marsh et al., 2007a,b). Previous studies have examined differences in toxicokinetics between animals and humans to determine if this is potentially the contributing factor to the differences in response between animals and humans.
β-Chloroprene (2-chloro-1,3-butadiene, CD) is used in the manufacture of polychloroprene rubber. Chronic inhalation studies have demonstrated that CD is carcinogenic in B6C3F1 mice and Fischer 344 rats. However, epidemiological studies do not provide compelling evidence for an increased risk of mortality from total cancers of the lung. Differences between the responses observed in animals and humans may be related to differences in toxicokinetics, the metabolism and detoxification of potentially active metabolites, as well as species differences in sensitivity. The purpose of this study was to develop and apply a novel method that combines the results from available physiologically based kinetic (PBK) models for chloroprene with a statistical maximum likelihood approach to test commonality of low-dose risk across species. This method allows for the combined evaluation of human and animal cancer study results to evaluate the difference between predicted risks using both external and internal dose metrics. The method applied to mouse and human CD data supports the hypothesis that a PBK-based metric reconciles the differences in mouse and human low-dose risk estimates and further suggests that, after PBK metric exposure adjustment, humans are equally or less sensitive than mice to low levels of CD exposure.
Kinetic modeling of β-chloroprene metabolism: Probabilistic in vitro-in vivo extrapolation of metabolism in the lung, liver and kidneys of mice, rats and humans
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A fatal intoxication by chloroprene
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Objective Chloroprene, 2-chloro-1,3 butadiene, is a volatile synthetic liquid. The chloroprene monomer is extremely reactive and is used for the production of latexes and synthetic rubber such as Neoprene^®. Up to now an acute lethal human exposure has been described only once in the literature [19]. The intoxication is associated with nervous system depression, pulmonary edema, narcosis, and respiratory arrest. Case report A 29-year-old chemistry company worker was found unconscious in an empty vessel (depth: 3 m) used for chloroprene. The man was dressed in shoes, trousers, a helmet and a respiratory mask. The upper part of the body was unclothed. In spite of reanimation, the man died three hours later in a hospital. Material and methods: All analyses were performed by headspace gas chromatography (HS/GC/FID). In addition, brain, muscle and myocardial muscle were analysed by headspace GC–MS. Results and discussion Autopsy findings: The cause of death could not be determined as the macromorphological findings were unspecific. Toxicology findings The calibration curve of chloroprene in serum shows linearity from 1.0 to 200 μg/ml (r² = 0.9999) using benzene as internal standard. The LOD is 0.28 μg/ml, the LLOQ is 0.99 μg/ml. Tissues and body fluids were stored at −20 °C till the analysis. Chloroprene was quantified after addition of benzene as the internal standard. It was found in nearly all tissues and body fluids except in the urine and lung. The highest concentrations were detected in the kidney, liver, myocardial muscle and especially in the brain. Furthermore, hexanal was found in all samples except in the urine. The amount of hexanal in some specimens is high, especially in the lung, bile, gastric content and myocardial muscle. Conclusion We assume that a significant amount of chloroprene was not only inhaled but also absorbed through the skin because the man wore a respiratory mask. Presumably the accident would not have happened if the works safety protocols had been followed. The reason why high concentrations of hexanal were found in the tissues could not be clarified.
Mortality patterns among industrial workers exposed to chloroprene and other substances. I. General mortality patterns
2007, Chemico-Biological Interactions
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
2007, Chemico-Biological Interactions
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.
Chemical process based reconstruction of exposures for an epidemiological study. I. Theoretical and methodological issues
2007, Chemico-Biological Interactions
Citation Excerpt :
In addition, results of these models are almost impossible to validate with existing measured exposure data due to the inter and intra personal variability of performing the same task and the non-epidemiological purposes behind collecting exposure data [3]. The worker classification data and the worker identification data used for selecting tasks came from the data collected for the epidemiological study reported elsewhere [1,2]. In general, input to mathematical models requires process diagrams, process flow characteristics, physical and chemical properties of the contaminants modeled, specific steps of performing the tasks, and specific durations necessary for the performance of the tasks.
In the occupational hygiene component of occupational epidemiological studies the goal is to assign group average exposure levels that can be used to compute individual cumulative exposures. This task requires the availability of sufficient amounts of proper individual exposure level data. Typically, the required data are either sparse, completely lacking or happenstance data collected for purposes not suitable for the aims of the study. In the epidemiological study of mortality patterns among industrial workers exposed to chloroprene and other substances, we developed and used a process analysis and modeling based exposure reconstruction to augment, extrapolate, or interpolate the available exposure data.
The models developed utilize equations based on the engineering principles and chemistry associated with the processes as determined from the process documentation and task performance habits as determined from interviews of knowledgeable personnel. The resulting equations are tractable and provide a general basis for calculating exposure levels for vapors. The validation of the results with available exposure measurements suggests that comprehensive process analysis and modeling may be used to reconstruct exposures or to evaluate exposure potential with scientifically defensible methods. Furthermore, even in the absence of validating data, the methodology developed has potentially very useful applications in predicting exposure levels to newly synthesized substances. Properly interpreted, the limitations of modeling can be minimized to obtain scientifically reasonable results

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Mortality patterns among industrial workers exposed to chloroprene and other substances: II. Mortality in relation to exposure

Abstract

Introduction

Section snippets

Study sites and subjects

Results

Discussion and conclusions

Acknowledgements

Chem.-Biol. Interact.

Chem.-Biol. Interact.

Chem.-Biol. Interact.

Chem.-Biol. Interact.

Chem.-Biol. Interact.

Chem. -Biol. Interact.

Chem. -Biol. Interact.

Chem. -Biol. Interact.

Chem. -Biol. Interact.

Chem. -Biol. Interact.

Regul. Toxicol. Pharm.

Regul. Toxicol. Pharm.

Mortality of workers exposed to chloroprene

J. Occup. Med.

Epidemiologic study of cancer mortality among chloroprene workers

Biomed. Environ. Sci.

Cancer incidence and mortality in a cohort of chloroprene workers from Armenia

Int. J. Cancer