2-chlorobuta-1,3-diene

Endpoint summary

Description of key information

Numerous epidemiological studies have investigated the association between occupational exposure to chloroprene and cancer incidence or mortality, particularly of the liver and the respiratory system. Available occupational epidemiological studies do not provide clear evidence for a causal relationship between inhalation exposure to chloroprene and cancer, but preclude a firm conclusion on causality being drawn due to inconsistencies and a lack of control for confounding factors.  Results from the large and rigerous study conducted by Marsh et al (2007a) tend to refute earlier findings of substantially increased risks for liver, respiratory and LH cancers. The four cohort studies conducted by Marsh et al., especially the rigorous investigation of the large Louisville cohort, provide the highest quality evidence and would be the most likely candidates to serve as "principal studies" for purposes of risk assessment. Although these studies are largely negative and do not provide evidence for a dose-response, the data can be used to establish a boundary for purposes of establishing a point of departure. 

Additional information

Epidemiological studies

Numerous epidemiological studies have investigated the association between occupational exposure to chloroprene and cancer incidence or mortality, particularly of the liver and the respiratory system. Occupational cohorts studied have included production workers from industrial sites in China, Armenia, France, Northern Ireland and the United States and shoe workers from a Russian site. Although earlier studies reported excess liver and lung or respiratory cancers which in some cases were statistically significant, these studies had a number of limitations including: crude exposure assessment, incomplete follow-up, uncertain baseline rates and uncontrolled confounding by factors such as smoking, drinking and co-exposure to benzene and vinyl chloride. In an evaluation of available published epidemiological studies of occupational cohorts using quality criteria developed by the US Environmental Protection Agency, Bukowski et al (2009) regarded the largest, most rigorous and comprehensive studies of the long term health effects of chloroprene exposure as two studies conducted by Marsh et al (2007a,b) based on historical cohorts covering four production plants in EU and USA. Marsh et al did not report statistically significant increases in the incidence of cancer at any site, at any of the production plants. Available occupational epidemiological studies do not provide clear evidence for a causal relationship between inhalation exposure to chloroprene and cancer, but preclude a firm conclusion on causality being drawn due to inconsistencies and a lack of control for confounding factors.  Results from the large and rigorous study conducted by Marsh et al tend to refute earlier findings of substantially increased risks for liver, respiratory and LH cancers. The four cohort studies conducted by Marsh et al, (2007a,b), especially the rigorous investigation of the large Louisville cohort, provide the highest quality evidence and would be the most likely candidates to serve as "principal studies" for purposes of risk assessment. See discussion on DMEL.

Human surveillance data

Khachatryan (1972) investigated the morbidity in a cohort of patients with primary lung cancer from Yerevan, Russia from 1956 to 1970 with a history of long-term occupational exposures to chloroprene via employments in sectors including: production, rubber product factories, shoe and fancy good productions. The study included 2934 chloroprene workers and 3 control groups from: 1. non-chloroprene type processes (n=4780); 2. non-chemical based industries (n=6045) and 3. cultural/welfare institutions (n=6220). The incidence of primary lung cancers in chloroprene-exposed workers (18/2934) was 2.97-fold, 6.3-fold and 17.5-fold higher than in controls groups 1, 2 and 3 respectively. On the basis of these findings, the authors concluded that prolonged occupational exposure to chloroprene or chloroprene derivatives leads to a marked increase in primary lung cancer morbidity. The study had a number of limitations including: lack of statistical evaluation, no adjustment for co-founding factors (e.g. smoking) and lack of details on occupational exposure controls.

Occupational cohort studies

In a historical cohort study, Marsh et al, (2007a) investigated cancer mortality patterns using all cancers combined , respiratory system cancers (RSC) and liver cancers as markers of site cancer risk in industrial workers exposed to chloroprene from 4 production sites (Plant L = Louisville, Kentucky, US (n = 5507); Plant P = Pontchartrain, Louisiana, US (n= 1357) Plant M = Maydown, Northern Ireland (n- 4849); and Plant G = Grenoble, France (n= 717). The combined cohort included 12,430 subjects (>300,000 person-years of observation) with 41% (151691 person-years) consisting of workers with more than 20 years exposure.

The major strengths of the study contributing to the rigorous and robust assessment of chloroprene-related mortality included: the diversity of location and production processes; length of observation periods; substantial proportion of worker cohort employed for >20 years; almost total cohort enumeration with cross-referencing; vital status tracing; cause of death determination; detection of two-fold or greater overall mortality excess for all cause of death categories of prime interest with powerful statistical analysis; a rigorous, innovative, chemical process-based exposure reconstruction for both chloroprene and vinyl chloride; use of national and local mortality comparisons and robust statistical modelling of internal cohort rates. Attempts to account for smoking in subjects that died from RSC were unfeasible due to poor historical data on tobacco use and confounding due to smoking was therefore adjusted on the basis of geographical variations in tobacco use and expected smoking prevalence based on education and socioeconomic status. Potential co-exposures of workers to chemicals including vinyl chloride (produced as a by-product of chloroprene production using acetylene-based processes at plants L and M) and a known human carcinogen, were also assessed in the study. In this evaluation, exposures to vinyl chloride were considered to be transient and process-specific and unlikely to impact on the long-term health of workers. 

Reference population rates were based on local mortality data. Follow-up to the year 2000, resulted in 3002 observed mortalities including 834 from all cancers combined. Of the two causes of death of primary interest, 336 and 19 cases of (RSC and liver cancer (including biliary passage cancers) respectively were observed. For the combined cohort standardised mortality ratios (SMR) and the 95% confidence interval (shown in brackets) were 0.72 (0.69-0.94), 0.73 (0.68-0.78), 0.75 (0.67-0.84) and 0.72 (0.43-1.13) for all causes combined, all cancers combined, RSC and liver cancer respectively. Site-specific (L, M, P and G respectively) SMRs were for all cancers combined: 0.75 (0.69-0.8), 0.68 (0.56-0.8), 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 chloroprene, SMRs were 0.71 (0.66-0.76) for all cancers combined; 0.75 (0.67-0.84) for RSC and 0.71 (0.42-1.14) for liver cancer. No increased cancer mortality risks were observed in sub-groups of the cohort defined on the basis of race, gender, employment characteristics or chloroprene employment status. Consistent total and cause-specific mortality patterns were observed between plants showing a statistically significant reduction in mortality risk from all causes combined, all cancers combined and for many of the other disease categories investigated. The authors proposed this may be evident of a "healthy worker effect" at the production sites influenced by favourable working conditions, long-term health care services and quality of life improvements in the workplace.

On the basis of its design and strengths, the authors proposed that the study could be regarded as the most definitive investigation of the carcinogenic potential of chloroprene in humans conducted to date. Based on the findings, it was concluded that workers occupationally exposed to chloroprene at levels encountered at the four sites did not have an elevated risk of mortality from all cancers combined, liver cancer, lung cancer or cancers of the respiratory system.

In a parallel study, Marsh et al (2007) estimated historical exposures for individual workers at the 4 production sites to chloroprene (and vinyl chloride (VC) where appropriate) using approximation models. Median chloroprene exposures (airborne concentrations) were 5.23, 0.16, 0.028 and 0.149 ppm for the plants L, M, P and G respectively whereas median cumulative exposure (ppm years) were 18.35, 0.084, 0.133 and 1.01 respectively. Potential co-exposure to VC was linked to 2 sites only: L and M. Median VC exposures were 1.54 and 0.03 ppm respectively whereas median cumulative exposures were 1.54 and 0.094 ppm years respectively.

Relative risk (RR) regression modelling was performed to investigate the relationship between chloroprene (and VC) exposures and internal cohort rates for all cancers combined, for RSC and for liver cancers. Various combinations of categories of chloroprene and/or VC exposure, with adjustments for confounding factors, were analysed. Exposure measures were categorised in approximate quartiles based on distribution of deaths from all cancers combined. Lag periods were accounted for in 5 or 15 year lag time analyses to take account of latency periods for cancer development. Some of the RR models were adjusted for worker pay type (white or blue collar) to adjust for smoking prevalence. Exposure category-specific SMR were calculated to analyse absolute mortality rates. With one exception (a statistically significant association between duration of chloroprene exposure and all cancer incidence in one plant: plant M), chloroprene exposure was not positively associated with all cancers combined, RSC or liver cancers using the lagged and unlagged measures analysed for duration, average intensity or cumulative exposure, time from first exposure and duration of chloroprene exposure with VC exposure. Any observations of elevated RRs were deemed to be due to the exeptionally low baseline death rate in the comparison categories. Smoking was proposed to be a possible confounding factor in all cancer mortalities and Plant G, but confounding was not apparent at the other sites.

The authors concluded that occupational exposures to chloroprene at airborne levels predicted for the four production sites (e.g. 0.028 – 5.23 ppm average intensity of exposure) were not associated with an increased risk of mortality from all cancers combined, cancers of the respiratory system or of the liver. The same conclusion was reached when expressed as the cumulative exposure (i.e., the number of years at each job multiplied by the average intensity of exposure), the highest of which was 164 ppm-yr.

In a critical review of the available chloroprene epidemiology studies, Bukowski et al (2009) evaluated the quality and weight of evidence associated with epidemiological studies of mortality from cancer, particularly in the liver, lungs and lymphohematopoietic system in occupational cohorts exposed to chloroprene including arsh (2007a,b). The review evaluated morbidity and mortality studies covering 7 chloroprene-exposed cohorts from 6 countries. Studies evaluated were: Li et al (1989) – Chinese production workers (n=1258); Bulbulyan et al (1998) - Russian shoe workers (n=5185); Bulbulyan et al (1999) - Armenian production workers (n=2314), Colona and Laydevant (2001), and Marsh (2007a,b) - French production workers (Grenoble; n=533); Marsh et al (2007a,b) – Irish production workers (Maydown; n=4849) and Marsh et al (2007a,b) – US elastomer production workers at Louisville, Kentucky (n=5507) and Ponchartrain, Lousianna (n=1357).

The quality of studies was evaluated using criteria established by the US Environmental Protection Agency for assessing epidemiology studies used in risk assessment : (1) clear objectives, (2) proper selection and characterisation of comparison groups (cohorts and references), (3) adequate characterisation of exposure, (4) sufficient duration of follow-up (5) valid ascertainment of cases of death or disease (6)proper consideration of bias and confounding (7) sample size (8) clear, proper and well documented methods for data collection and analysis (9) adequate response (minimal loss to follow-up) and (10) clear and well documented results.

Chinese Cohort

Li et al (1989) investigated cancer mortality in 1258 Chinese monomer or neoprene production or research workers with > 1 year of exposure between 1958 and 1980 (follow-up from 1969 to 1983) compared to local mortality rates between 1973 to 1975 were used. Average chloroprene exposure concentrations could not be determined for the cohort; high exposure jobs were identified subjectively. The SMR for all-cause cancer mortality was significantly elevated. Although the SMRs for liver, lung and malignant lymphoma were elevated, this was not statistically significant.

Russian Cohort

Bulbulyan et al (1998) investigated cancer mortality in 5185 Russian shoe workers with >2 years exposure during 1960 to 1976 (follow-on 1979 to 1976), compared to local mortality rates (Moscow) from 1979 to 1993. Chloroprene exposures could not be determined quantitatively: workers were assigned to “high”, “medium” or “no-exposure” categories based on their job title. Marginally significant SMRs were obtained for liver cancer and leukemia and an association was proposed between the duration or magnitude of exposure and the relative risk of developing these cancers.

Armenia Cohort

In a further study, Bulbulyan et al (1999) investigated cancer mortality in 2314 Armenian production workers exposed to chloroprene during 1940 – 1988 (follow-on 1979 -1993) compared to national mortality rates. Exposures could not be determined from available industrial hygiene measurements. Workers were subjectively assigned to exposure categories Significantly increased standardised incidence ratio (SIR) and SMR estimates were obtained for liver cancer, with the risk of disease increasing as a function of the duration or magnitude of exposure.

French cohort

Colona and Laydevant (2001) investigated morbidity and mortality in 533 French chloroprene workers at a production plant in Grenoble during 1966 – 1997 compared to local and national rates. Exposures were determined loosely based on industrial hygeine measurements with workers categorised into low (< 2 ppm), medium (2 -5 ppm) or high (>5 ppm) groups. The aouthors also evaluated the length of exposure and exposure before and after 1977 when protective measures imporved. SIR were elevated for liver and lung cancers but were not statistically significant. In a further study Marsh et al (2007 a,b), analysed cancer mortality in 717 workers from the site.

The Irish production worker cohort and the two US cohorts also studied by Marsh et al (2007 a,b) have been discussed previously.

Bukowski et al evaluated the quality of each of these studies against the EPA criteria for assessing epidemiological studies and ranked the studies on this basis. The main limitations of the available occupational epidemiological studies on chloroprene included crude exposure assessment, in-complete follow-up, uncertain baseline rates and uncontrolled confounding by factors such as smoking, drinking and co-exposure to benzene and vinyl chloride. These limitations were considered to apply mainly to the earlier studies with the four-cohort study by Marsh et al being regarded as the most rigorous, having the most comprehensive exposure assessment and follow-up and providing the most detailed information. The study included two of the largest cohorts and emerged as having the highest ranking against the EPA quality criteria. Bukowski noted however, that evidence of a strong healthy workers effect in this study may have masked small excess risks, however, the risk, if any, is likely to be small when compared to other company workers. Although an association between exposure and liver or lung cancer within internal worker comparison groups may indicate a slight increased risk (as reported in some earlier studies), a link to chloroprene exposure could not be confidently made since uncontrolled confounding factors (e.g. smoking, alcohol consumption and other factors) could be responsible. The authors concluded that the weight of evidence did not support a strong link with chloroprene exposure and the development of cancer and that the Marsh et al studies should serve as "principal studies" for purposes of human risk assessment.