Objectives The present study was conducted to investigate the relationship between occupational chemical exposure and incidence of cholangiocarcinoma among workers in the offset colour proof-printing section of a small printing company in Osaka, Japan.
Methods We identified 51 men who had worked in the proof-printing room, and 11 men who had worked in the front room for at least 1 year between 1991 and 2006. We interviewed them about the chemicals they used, and estimated their levels of exposure to chemicals. We also investigated the medical records of 11 cholangiocarcinoma patients, and calculated the standardised mortality ratio (SMR) from 1991 to 2011.
Results Workers used 1,2-dichloropropane (1,2-DCP) from approximately 1985 to 2006, and dichloromethane (DCM) from approximately 1985 to 1997/1998. Exposure concentrations were estimated to be 100–670 ppm for 1,2-DCP and 80–540 ppm for DCM among the proof-printing workers. All 11 patients were pathologically diagnosed with cholangiocarcinoma. Ages at diagnosis were 25–45 years, and ages at death were 27–46 years among the six deceased individuals. The primary cancer site was the intrahepatic bile duct for five patients, and the extrahepatic bile ducts for six. All patients were exposed to 1,2-DCP for 7–17 years and diagnosed with cholangiocarcinoma 7–20 years after their first exposure. Ten patients were also exposed to DCM for 1–13 years. The SMR for cholangiocarcinoma was 2900 (expected deaths: 0.00204, 95% CI 1100 to 6400) for all workers combined.
Conclusions These findings suggest that 1,2-DCP and/or DCM may cause cholangiocarcinoma in humans.
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What this paper adds
Carcinogenicity of 1,2-dichloropropane (1,2-DCP) and dichloromethane (DCM) against humans is not known prior to this study.
The present study found that 1,2-DCP and/or DCM may cause cholangiocarcinoma in humans.
Occupational exposure to these chemicals should be controlled so as to be minimal.
We encountered 11 patients with intrahepatic or extrahepatic bile duct cancer (cholangiocarcinoma) among workers employed at a small printing company in Osaka, Japan. All patients were men who had worked in the offset colour proof-printing section of the company, which suggests that cholangiocarcinoma is a new occupational cancer. The present study aimed to investigate the relationship between occupational chemical exposure and cholangiocarcinoma among workers at this company. This study was approved by the ethics committee of the University of Occupational and Environmental Health.
The printing company was established in 1969, and the present company building was constructed in 1991. The proof-printing room was located in the first basement of the present building, and had seven single-colour printing machines. The proof-printing workers printed approximately 10 sheets for each set of proofs using red, blue, black and yellow ink sequentially. To change colours, they removed ink from the ink-roller using kerosene, and from the transcription rubber roller (referred to as the ‘blanket’ hereafter) using highly volatile organic solvents including 1,2-dichloropropane (1,2-DCP) and/or dichloromethane (DCM). The ink-removal operation was repeated 300–800 times over the course of 16 h (two shifts). The front room was adjacent to the proof-printing room, where other workers of the proof-printing section (hereafter, ‘front room workers’) supervised the progress of proof-printing, made printing plates and/or prepared printing paper.
There seemed to be very little ventilation because of the basement location and the low capacity of the installed ventilation equipment. Proof-printing workers wore plastic gloves during ink-removal operations, but neither proof-printing workers nor front room workers used respiratory protection while working.
Identification of workers
Based on old employee lists and workers’ memories, we identified 62 men and 11 women who had worked in the offset colour proof-printing section for at least 1 year between 1991 and 2006. Because we did not find cholangiocarcinoma patients among the female workers, we focused on the male workers in this paper. Fifty-one of the 62 men were proof-printing workers, and the remaining 11 men were front room workers.
Chemical identification and exposure level estimation
To identify the chemicals used, we conducted detailed interviews with 12 proof-printing workers and four front room workers. Chemical components were identified by certificates provided from the companies that sold them.
After our preliminary report that described five patients with cholangiocarcinoma at this company,1 the Japanese National Institute of Occupational Safety and Health (JNIOSH) conducted an experiment to reproduce the working environment of the proof-printing room of this company and measured exposure concentrations of 1,2-DCP and DCM for the proof-printing workers.2 Assuming that exposure concentration was proportional to the amount of chemicals used, we estimated exposure concentrations for the proof-printing workers using the JNIOSH data.
Confirmation of patients and mortality estimation
We confirmed medical records for the 11 cholangiocarcinoma patients, and interviewed the patients and/or their relatives about the occupational histories and lifestyles.
We computed the standardised mortality ratio (SMR) for cholangiocarcinoma (codes 155.1 and 156.1 in the ICD-9 and codes C22.1 and C24.0 in the ICD-10) from 1 January 1991 to 31 December 2011, using sex, age, calendar year and cause-specific mortality rates among the Japanese population. Because we could not identify vital status for 11 of the proof-printing workers and three of the front room workers due to their being untraceable, we assumed that they were alive at the end of 2011.
The inks used at the company were those typically used for offset printing. Ink removal from the ink-roller required approximately 35 litres of kerosene per day, and the same amount of ink-roller cleaner (mixture of kerosene and water with a surface-active agent) in the 1990s, which decreased to 25 litres per day in the 2000s. Ink removal from the blanket required approximately 45 litres of blanket cleaner in the 1990s, which decreased to 35 litres in the 2000s. Figure 1 shows the chemical components of blanket cleaners used from 1985 to 2011.
The 51 proof-printing workers were exposed to 1,2-DCP for 1–17 years (mean, 6 years) and 27 of the workers were also exposed to DCM for 1–12 years (mean, 4 years). Exposure concentrations were estimated to be 120–430 ppm (mean, 220 ppm) for 1,2-DCP and 80–210 ppm (mean, 140 ppm) for DCM from 1991 to 1992/1993, 100–360 ppm (mean, 190 ppm) for 1,2-DCP and 190–540 ppm (mean, 360 ppm) for DCM from 1992/1993 to 1997/1998, and 150–670 ppm (mean, 310 ppm) for 1,2-DCP from 1997/1998 to 2006.
The 11 front room workers were exposed to 1,2-DCP for 1–17 years (mean, 7 years), and 8 of the workers were also exposed to DCM for 1–11 years (mean, 6 years). Airborne concentrations in the front room were estimated to be 80 ppm for 1,2-DCP and 50 ppm for DCM from 1991 to 1992/1993, 70 ppm for 1,2-DCP and 130 ppm for DCM from 1992/1993 to 1997/1998, and 110 ppm for 1,2-DCP from 1997/1998 to 2006.
Figure 1 also illustrates demographic features, times of cholangiocarcinoma diagnosis and death, primary cancer site, duration of employment at the company, and duration of exposure to 1,2-DCP and/or DCM in the 11 patients. Ages at diagnosis were 25–45 years (mean, 36 years), and ages at death were 27–46 years (mean, 37 years) among the six deceased individuals. Primary cancer sites were the intrahepatic bile duct for five patients and the extrahepatic bile ducts for six. Histological type was adenocarcinoma in all patients. Tests for hepatitis B surface antigen and for hepatitis C virus antibody were negative for all patients. None of the patients were heavy drinkers.
Only patient 3 was a front room worker, but he also conducted proof-printing for 1–2 h for 2–3 days/week. All patients were exposed to 1,2-DCP for 7–17 years (mean, 10 years) and were diagnosed with cholangiocarcinoma 7–20 years (mean, 14 years) after their first exposure (figure 1). All patients except patient 11 were also exposed to DCM for 1–13 years (mean, 7 years). SMRs for cholangiocarcinoma were 5000 (expected deaths (E): 0.00100, 95% CI 1600–12 000) and 960 (E: 0.00104, 95% CI 24 to 5400), respectively, for proof-printing and front room workers, and 2900 (E: 0.00204, 95% CI 1100 to 6400) for all workers combined.
We identified the 62 male workers based on old employee lists and fellow worker memories, but we could have overlooked some workers. When we were unable to identify vital status, we assumed that they were alive, which may have underestimated the mortality risk. Consequently, SMR of 2900 is a crude estimate, but the incidence of cholangiocarcinoma among our proof-printing workers was unquestionably high.
Known risk factors for cholangiocarcinoma are primary sclerosing cholangitis, liver fluke infestation, biliary stones, fibropolycystic liver disease, chemical carcinogen exposure including thorotrast, and heavy drinking and smoking.3 A silent biliary stone was noted in patient 3. No other risk factors were found in the other patients.
A cancer epidemiological study, or cancer case report of 1,2-DCP exposed workers, has not been published. There have been four cohort studies of DCM exposed workers in two cellulose triacetate-film production plants, and two cellulose triacetate-fibre production plants.4–7 Of these, Lane's original study of 1271 employees in one of the fibre production plants found a significantly increased mortality risk for biliary tract cancer (three deaths compared with 0.15 expected deaths; SMR=20 (95% CI 5.2 to 56)).8 In their updated study,6 no additional cases were reported during the additional observation period, and the authors did not recalculate biliary tract cancer SMR. However, we surmise that the mortality risk would remain significantly elevated because expected deaths from biliary tract cancer would be only double that of the original study (0.15), based on the fact that the combined expected deaths of liver and biliary tract cancer increased from 0.7 to 1.37. DCM exposure levels were 140, 280 and 475 ppm in the three main working areas of the plant. Our proof-printing workers were estimated to be exposed to DCM at similar levels with additional exposure to high levels of 1,2-DCP.
Both DCM and 1,2-DCP cause hepatocellular tumours in mice,9 ,10 and metabolic activation by glutathione S-transferase T1-1 (GST T1-1) is thought to play a significant role in this process.11 Though glutathione-dependent DCM metabolism in the human liver is much less active than that in the mouse liver, GST T1-1 is detected at the highest levels in bile duct epithelial cells rather than hepatic cells in humans.11 This finding is an important suggestion that these chemicals may cause cholangiocarcinoma in humans.
Pigments or synthetic-resins included in the inks used at the company might be carcinogenic. However, the inks were those typically used for offset printing, and the quantity used was less than that used in the general offset printing industry. Consequently, the inks are not thought to cause cholangiocarcinoma.
The International Agency for Research on Cancer classifies 1,2-DCP as a group 3 and DCM as a group 2B chemical.12 The present study encourages further epidemiological and experimental studies on their carcinogenicity.
The authors deeply thank all the interviewees for responding to the long interview. The authors thank Akihiko Kataoka for acting as intermediary between the interviewees and the authors.
Contributors SK planned and conducted this investigation, and described this article. SK is responsible for the conduct of this study and the overall content of this article. NK supported this investigation from the epidemiological aspect. AA is the attending doctor for two of our patients and supported this investigation from the hepatology aspect. GI supported this investigation from the toxicological aspect.
Competing interests None.
Patient consent Obtained.
Ethics approval The ethics approval was provided by the Ethics Committee of the University of Occupational and Environmental Health, Kitakyushu, Japan.
Provenance and peer review Not commissioned; externally peer reviewed.