164
J Occup Health, Vol. 56, 2014
Journal of
Occupational Health
J Occup Health 2014; 56: 164–168
Case Study
Two Offset Printing Workers with Cholangiocarcinoma
Shinji Kumagai
Department of Management of Occupational Safety and Health, University of Occupational and Environmental
Health, Japan
Abstract: Two Offset Printing Workers with Cholangiocarcinoma: Shinji KUMAGAI. Department of
Management of Occupational Safety and Health,
University of Occupational and Environmental
Health, Japan—Objectives: Previously, the author
reported a cluster of 11 cholangiocarcinoma cases
exposed to 1,2-dichloropropane (1,2-DCP) and/or
dichloromethane (DCM) in an offset proof-printing
company. Before that report, the association between
the two chemicals and cholangiocarcinoma had not
been known. The current study describes two cholangiocarcinoma patients exposed to 1,2-DCP or DCM in
different offset printing companies. Methods: The
author obtained medical records for the patients, and
interviewed the surviving patient and a relative of the
deceased patient about their occupational history.
Results: Case 1 was a man born in 1950. He worked
in the printing section in a proof-printing company for
26 years. He was diagnosed as cholangiocarcinoma in
1998 and died in 2000. In proof-printing operations, he
used gasoline for 14 years and 1,2-DCP for 11 years to
remove ink from a rubber transcription roller (blanket).
The exposure concentration of 1,2-DCP was estimated
to be between 72 and 5,200 ppm. Case 2 was a man
born in 1963. He worked in the printing section in a
general offset printing company for 11 years. He was
diagnosed with cholangiocarcinoma in 2007. In printing
operations, he used both kerosene and a mixture of
50% DCM and 50% 1,1,1-trichloroethane (1,1,1-TCE)
for 11 years to remove ink from a blanket. The exposure
concentration of DCM was estimated to be between 240
and 6,100 ppm. He was simultaneously exposed to
similar levels of 1,1,1-TCE. Conclusions: Because
the offset printing process may cause cholangiocarcinoma, occupational history should be examined for
patients with this cancer.
(J Occup Health 2014; 56: 164–168)
Key words: 1,2-Dichloropropane, Cholangiocarcinoma,
Dichloromethane, Printing
Previously, I found a cluster of 11 cholangiocarcinoma cases among 62 employees in the proof-printing
section of a printing company in Osaka, Japan, and
reported a standardized mortality ratio (SMR) of
2,900 as a crude estimate 1). The frequent occurrence of cholangiocarcinoma could not be explained
by known risk factors for this cancer1). Up to now,
17 employees have developed cholangiocarcinoma in
the company, and all patients had been exposed to
high concentrations of 1,2-dichloropropane (1,2-DCP)
over a long-term period, including 12 who had also
been exposed to high concentrations of dichloromethane (DCM)2). The Ministry of Health, Labour and
Welfare recognized cholangiocarcinoma in the cases
to be an occupational cancer, probably caused by the
long-term exposure to high concentrations of 1,2-DCP2).
Other than the above study 1), no cancer epidemiological study or cancer case report of 1,2-DCP
exposed workers has been published. There have
been four cohort studies of DCM exposed workers
in two cellulose triacetate-film production plants3, 4)
and two cellulose triacetate-fiber production plants5, 6),
but of these, only Lane’s original study found a
significantly increased mortality risk for biliary tract
cancer7). Consequently, the association between these
chemicals and cholangiocarcinoma should be studied
further. This report concerns two cholangiocarcinoma
patients who were exposed to 1,2-DCP or DCM in
small printing companies. The surviving patient and
a relative of the deceased patient provided informed
consent regarding study publication.
Case 1
Received Nov 11, 2013; Accepted Jan 10, 2014
Published online in J-STAGE Feb 19, 2014
Correspondence to: S. Kumagai, Department of Management of
Occupational Safety and Health, University of Occupational and
Environmental Health, Japan (e-mail: [email protected].
jp)
1) Patient characteristics and occupational and medical histories
The patient was a man born in July 1950 with no
drinking history. He smoked 20 cigarettes a day from
19 to 47 years old. He worked in the color proofprinting section of an offset proof-printing company
165
Shinji KUMAGAI: Two Offset Printing Workers with Cholangiocarcinoma
in Fukuoka, Japan, from 1970 to 1973. He then
worked for a construction company, operating a crane
truck, from 1973 to 1975. He was subsequently
re-employed by the same offset proof-printing company and worked from 1975 to 1998.
In March 1998, he visited a nearby hospital due
to epigastric pain and back pain. Abdominal CT and
abdominal ultrasonic echo revealed neoplastic lesions
in the S6 and S8 segments of the liver. In the same
month, he visited a university hospital and received a
diagnosis of intrahepatic bile duct cancer. The blood
test at diagnosis showed increased levels of biliary enzymes γ -GTP (294 IU/l) and ALP (1,017 IU/l)
and a high level of tumor marker CEA (11.2 ng/ml).
Tests for hepatitis B and for hepatitis C were negative. Moreover, lymph node metastasis in the pancreatic head was observed. He was transferred to a
municipal hospital, where he received chemotherapy
and underwent hepatic trisegmentectomy in May.
However, due to a recurrence, he underwent partial
hepatectomy in November. Thereafter, he continued
to receive chemotherapy but died in March 2000.
2) Operations at the offset proof-printing company
The proof-printing room was 10.5 m × 7.4 m with
a ceiling height of 2.7 m and was located on the first
floor of the building; two offset color proof-printing
machines were located in the room. The windows
in the room were always closed. The room was
equipped with three ventilators; all three were running
during summer, while two of the three were used
during winter. One printing worker and one assistant (e.g., for plate exchange) were allocated to each
proof-printing machine, i.e., a total of four workers in
the room. The workers printed color proofs for catalogs and brochures. Color proofs are a set of a few
preprinted sheets used to show how the colors will
look in final printing.
The color proof-printing procedure was as follows:
1) A sheet of paper and a plate were set on the
machine. 2) The ink roller was charged with red
ink and rotated so that the ink was rolled in. 3)
The plate surface was wet with a sponge soaked
in tap water. 4) The ink was spread over the plate
by the rolling motion of the ink roller on the plate
surface. 5) The rubber transcription roller (blanket)
was rolled over the plate surface as well as the paper
surface to print a proof, with this procedure repeated
about 10 times. 6) The ink roller was wiped off with
ink-roller cleaner (a mixture of kerosene and water
with surfactant) and with white gasoline. 7) Finally,
the blanket was wiped off with blanket cleaner. The
same procedure was repeated for blue ink, yellow ink
and then black ink. After black ink was used, cleaning was sometimes repeated twice in order to remove
the ink completely. Accordingly, to print one set, the
ink-removal operation was repeated four to five times.
One proof-printing machine produced about two
sets of four-color prints per hour, and thus, the blanket was cleaned eight to 10 times. Because the actual
working hours was 10 hours, the total number of
cleaning operation reached 160−200 times for the two
machines.
White gasoline was used as the blanket cleaner
from 1971 to 1973 and from 1975 to around 1986.
Subsequently, 95−100% 1,2-DCP (cleaning agent I)
was used until 1998. The amount of blanket cleaner
used was about 9 liters (half an 18-liter square can)
per day. Workers used plastic gloves while cleaning, but they were not provided with any respiratory
protection. No working environment measurements
had been conducted.
3) Estimation of exposure level of 1,2-DCP
The installed ventilators had a blade diameter
of 30 cm, a voltage of 100 V and electric power
consumption of 46 W. According to an electronics
manufacturer catalog, a ventilator with these specifications generates 1,300−2,000 m3/hour of air flow; therefore, three ventilators generate 3,900−6,000 m3/hour.
However, as there was no outside air intake, the actual
amount of ventilation was unclear. Assuming that the
amount of blanket cleaner used over the course of 10
hours was 10 kg (9 liters), and that the air volume of
the printing room was 210 m3, the 1,2-DCP concentration was estimated to be 5,200 ppm as a shift timeweighted average with no ventilation at all. If the
room was ventilated with fresh air at 6,000 m3/hour,
the 1,2-DCP concentration was estimated to be
36 ppm as a steady state level, based on the complete
mixing model8). However, exposure concentrations
for workers near the source would be actually higher.
According to the results of a reproductive experiment
at the offset proof-printing company in Osaka, the
concentrations of 1,2-DCP and DCM in the breathing
zone were approximately twice those of the workroom
environmental concentrations9). Thus, the exposure
concentration for the worker was estimated to be
72 ppm. These calculations suggest that the exposure
concentration was between 72 and 5,200 ppm. Given
that two of the three ventilators were operating during
winter, by similar estimation, the exposure concentration of 1,2-DCP was between 110 and 5,200 ppm.
Case 2
1) Patient characteristics and occupational and medical histories
The patient was a man born in November 1963.
He drank a can of beer (350 ml) two or three times a
week and smoked four cigarettes a day from 20 to 30
166
years old.
He worked at a restaurant for one year from
1982. He then worked in a termite extermination
company for about one month, going under the floors
of standard homes to spray termiticide (component
unknown). From 1984 to 1995, he worked for a
general offset printing company (non proof-printing)
in Nagoya, Japan, and engaged in printing operations.
From 1995 up to the present, he has been working for
a semiconductor manufacturing company. He served
as a clean-room operator for the first two years, but
no chemical use was involved. He has been engaged
in computer-based work since then.
In January 2006, abnormal liver function (γ -GTP,
1,150 IU/l; ALP, 773 IU/l; AST, 52 IU/l; ALT, 113 UI/l)
was observed in a periodic health examination at the
semiconductor manufacturing company. He received
treatment with oral medication at a nearby clinic, but
as there was no sign of improvement, he visited a
municipal hospital in March 2007. Abdominal CT
and magnetic resonance cholangiopancreatography
revealed a neoplastic lesion at the anterior segmental
branch of the bile duct. In April 2007, he received
a definitive diagnosis of hilar cholangiocarcinoma
(adenocarcinoma) by liver biopsy. Tests for hepatitis
B and for hepatitis C were negative. He received
ion beam radiotherapy for one month starting in May
2007 at an ion beam medical center.
In January 2010, an increase in the level of tumor
marker C19-9 was noted, and as the follow-up examination revealed lymph node metastasis, he was started
on chemotherapy. In June 2012, with relapse of
lymph node metastasis, he underwent lymph node
resection. At present, he receives regular follow-up.
2) Operations at the offset printing company
The printing room was about 17 m × 14 m with a
ceiling height of about 3 m and was located in the
first floor of the building; 3 four-color sheet-fed offset
press machines and 2 one-color sheet-fed offset press
machines were located in the room. The windows in
the room were always closed, and two or three ventilators installed in the room were used. For each of
the four-color press machines, two printing workers
were allocated, totaling 6 or 7 workers for the entire
room, including those who were allocated to one-color
press machines that were not always in use. Prints
included flyers, catalogs and brochures.
The printing procedure was as follows: 1) Sheets
of paper and a plate were set on the machine. 2)
Four color inks were placed in each ink fountain,
and the ink roller was rotated to roll-in the inks. 3)
While feeding about 30 sheets of papers, the supplied
amounts of ink and dampening solution and the position of the plate were adjusted. 4) Once adjustment
J Occup Health, Vol. 56, 2014
was complete, the blanket was wiped off with a cloth
soaked in kerosene and then with a cloth soaked in a
mixture of 50% DCM and 50% 1,1,1-trichloroethane
(1,1,1-TCE) (cleaning agent II). 5) Final printing was
then performed. 6) The blanket was cleaned every
printing about 3,000 sheets.
The four-color press machine was equipped with
eight blankets for two-sided printing. Since two
workers operated the machine, one person performed
four ink removal operations each time. It took about
four hours to print 10,000 sheets, and during this
time, cleaning was usually performed four times
(including cleaning at the end of printing); therefore,
each worker performed 16 ink removal operations.
Given that the actual working hours were 12 hours,
the number of ink removal operations performed by
one worker was 48. This means that in the printing room as a whole, the ink removal operation was
repeated about 300 times.
The plate was cleaned using the same cleaner
(cleaning agent II), sometimes simultaneously with
the blanket, or only once at the end of printing.
Moreover, at the end of daily operations, the ink roller
and ink fountains were cleaned using cleaning agent
II, and the whole press machine was also cleaned
using kerosene and cleaning agent II.
About 54 liters of cleaning agent II was used each
day for the entire printing room. Workers wore plastic gloves during cleaning, but they were not provided
with any respiratory protection. No working environment measurements had been conducted.
3) Estimation of exposure level of DCM
The printing room was equipped with two or three
ventilators; however, the specifications were unknown.
Moreover, with no outside air intake, the actual ventilation effect is unclear. Assuming that the amount
of blanket cleaner used over the course of 12 hours
was about 60 kg (54 liters, 30 kg DCM and 30 kg
1,1,1-TCE) and that the air volume of the printing
room was 710 m3, DCM concentration was estimated
to be 6,100 ppm as a shift time-weighted average with
no ventilation at all. If the room was ventilated with
flesh air at 6,000 m3/hour (three ventilators, each at
2,000 m3/hour), the concentration of DCM was estimated to be 120 ppm as a steady state level, based on
the complete mixing model8). The exposure concentration for a worker was estimated to be 240 ppm,
assuming that the value was twice the workroom
environmental concentration. Based on the above
calculations, the exposure concentration of DCM was
estimated to be between 240 and 6,100 ppm. This
patient was simultaneously exposed to similar levels
of 1,1,1-TCE.
167
Shinji KUMAGAI: Two Offset Printing Workers with Cholangiocarcinoma
Discussion
The two patients were younger than the peak age
(50 years or older) of cholangiocarcinoma onset10, 11).
The risk factors for cholangiocarcinoma include liver
fluke infection, primary sclerosing cholangitis, biliary malformation, biliary stone, viral hepatitis, heavy
drinking and smoking, and exposure to chemicals such
as thorotrast12). The two patients, however, did not
have any of these risk factors. Therefore, no known
risk factors applied to the patients, and thus, chemicals used at their work were possibly associated with
the pathogenesis.
Case 1 was exposed to white gasoline and 1,2-DCP
for 13 years and 12 years, respectively. Case 2 was
exposed to both DCM and 1,1,1-TCE for 11 years.
Of these chemicals, 1,2-DCP and DCM were also
used in the color proof-printing company in Osaka at
which 17 workers developed cholangiocarcinoma2).
Both 1,2-DCP and DCM cause hepatocellular
tumors in mice but not in rats13, 14). DCM metabolism proceeds through two pathways: a high affinity/
low capacity oxidation pathway catalyzed by cytochrome (CYP) P450 and a low affinity/high capacity conjugation pathway mediated by glutathione-Stransferase (GST)15). DCM is mainly metabolized
through the CYP pathway at low concentrations, and
when this pathway becomes saturated, the GST pathway becomes active. Development of hepatocellular
tumors is thought to be associated with S-chlorome
thylglutathione, a putative genotoxic intermediate of
DCM, in the GST pathway16, 17). Because GST activity in the liver is much lower in rats than in mice18),
DCM might not be a likely cause of hepatocellular
tumors in rats. The expression of GST T1-1, which
plays the most important role in glutathione conjugation of DCM, is highest in the nucleus of hepatic
cells in mice and the nucleus of bile duct epithelial
cells in humans19). It is therefore highly likely that
workers exposed to high levels of DCM would develop cholangiocarcinoma. 1,2-DCP is also metabolized
by CYP and GST20) and has a species difference in
sensitivity to developing hepatocellular tumors similar
to DCM, which suggests that hepatocellular tumors
may be related to an intermediate metabolite of 1,2-DCP
in the GST pathway. If GST T1-1 plays the largest
role in glutathione conjugation of 1,2-DCP, exposed
workers would develop cholangiocarcinoma.
In humans, the exposure concentration at which
saturation of the CYP pathway occurs is thought to be
in the range of 400−500 ppm for DCM21). The corresponding concentration for 1,2-DCP is thought to be
in the range of 150−250 ppm22), by analogizing from
saturated concentration for 1,2-dichloroethane23). The
estimated 1,2-DCP exposure concentration in Case 1
is 72−5,200 ppm, and the estimated DCM exposure
concentration in Case 2 is 240−6,100 ppm. These
values indicate that the exposure concentrations for
the two patients were possibly approaching levels high
enough to saturate the CYP pathway.
This study suggests that the incident at the proofprinting company in Osaka was not a specific case,
and it is certainly possible that long-term exposure
to high concentrations of 1,2-DCP or DCM would
lead to the development of cholangiocarcinoma.
Consequently, occupational history should be examined for cholangiocarcinoma patients.
References
1) Kumagai S, Kurumatani N, Arimoto A, et al.
Cholangiocarcinoma among offset colour proofprinting workers exposed to 1,2-dichloropropane
and/or dichloromethane. Occup Environ Med 2013;
70: 508−10.
2) Kamae K. Biliary tract cancer cases at printing
plants in Japan (1 October 2013/Ver.12 Since 10
August 2012). Ministry of Health, Labour and
Welfare, Tokyo, Japan. [Online]. 2013 [cited 2013
Nov 30]. Available from; URL: http://www.jisha.
or.jp/english/pdf/Biliary_tract_cancer_cases_at_printi
ng_plants_in_Japan.pdf#search='Biliary+tract+cancer
+cases+at+printing+plants+in+Japan'
3) Tomenson JA. Update of a cohort mortality study of
workers exposed to methylene chloride employed at
a plant producing cellulose triacetate film base. Int
Arch Occup Environ Health 2011; 84: 889−97.
4) Hearne FT, Pifer JW. Mortality study of two overlapping cohorts of photographic film base manufacturing employees exposed to methylene chloride. J
Occup Einviron Med 1999; 41: 1154−69.
5) Lanes SF, Rothman KJ, Dreyer NA, et al. Mortality
update of cellulose fiber production workers. Scand
J Work Environ Health 1993; 19: 426−8.
6) Gibbs GW, Amsel J, Soden K. A cohort mortality
study of cellulose triacetate-fiber workers exposed
to methylene chloride. J Occup Einviron Med 1996;
38: 693−7.
7) Lanes SF, Cohen A, Rothman KJ, et al. Mortality
of cellulose fiber production workers. Scand J Work
Environ Health 1990; 16: 247−51.
8) Hara K, Kumagai S, Nakaaki K. Application of
mathematical models predicting the exposure levels
of vapor and gas of chemicals used at the workplace. The Journal of Science of Labor 2001; 77:
439−61 (in Japanese).
9) National Institute of Occupational Safety and Health,
Japan (JNIOSH). Disaster in a printing company
in Osaka Prefecture (in Japanese). JNIOSH Report
A-2012-02, Kawasaki, Japan: JNIOSH, 2012.
10) Matsuba T, Qiu D, Kurosawa M, et al. Overview of
Epidemiology of Bile Duct and Gallbladder Cancer
Focusing on the JACC Study. J Epidemiol 2005; 15:
168
S150−6.
11) Hai-Rim Shin, Jin-Kyoung Oh, Eric Masuyer, et
al. Comparison of incidence of intrahepatic and
extrahepatic cholangiocarcinoma - Focus on East
and South-eastern Asia. Asian Pacific J Cancer Prev
2010; 11: 1159−66.
12) Khan SA, Thomas HC, Davidson BR, et al.
Cholangiocarcinoma. Lancet 2005; 366: 1303−14.
13) NTP (National Toxicology Program). Toxicology
and carcinogenesis studies of 1,2-dichloropropane
in F344/N rats and B6C3Fi mice (gavage studies).
NTP Technical Report 263, U.S. Dept. Health and
Human Services. Washington, DC. 1986.
14) NTP (National Toxicology Program). Toxicology
and carcinogenesis studies of dichloromethane in
F344/N rats and B6C3Fi mice (inhalation studies).
NTP Technical Report 306, U.S. Dept. Health and
Human Services. Washington, DC. 1986.
15) Gargas ML, Clewell HJ, Anderson M E. Metabolism
of inhaled dihalomethanes in vivo: Differentiation
of kinetic constants for two independent pathways.
Toxicol Appl Pharmacol 1986; 82: 211−23.
16) Graves RJ, Callander RD, Green T. The role of
formaldehyde and S -chloromethylglutathione in the
bacterial mutagenicity of methylene chloride. Mutat
Res 1994; 320: 235−43.
17) Green T. Methylene chloride induced mouse liver
and lung tumours: an overview of the role of mechanistic studies in human safety assessment. Hum
Exp Toxicol 1997; 16: 3−13.
J Occup Health, Vol. 56, 2014
18) Reitz RH, Mendrala AL, Guengerich FP. In vitro
metabolism of methylene chloride in human and
animal tissues: use in physiologically based pharmacokinetic models. Toxicol Appl Pharmacol 1989; 97:
230−46.
19) Sherratt PJ, Williams S, Foster J, Kernohan N,
Green T, Hayes JD. Direct comparison of the nature
of mouse and human GST T1-1 and the implications on dichloromethane carcinogenicity. Toxicol
Appl Pharmacol 2002; 179: 89−97.
20) Timchalk C, Dryzga MD, Smith FA, Bartels
MJ. Disposition and metabolism of [14C]1,2dichloropropane following oral and inhalation
exposure in Fischer 344 rats. Toxicology 1991; 68:
291−306.
21) U.S. Environmental Protection Agency (EPA).
Toxicological review of dichloromethane (methylene
chloride) (CAS No.75-09-2): In support of summary
information on the Intergrated Risk Information
System (IRIS). EPA/635/R-10/003F. Washington,
DC, EPA. 2011.
22) The worker compensation panel of the Ministry of
Health, Labour and Welfare. Report of the worker
compensation panel on cholangiocarginoma among
printing workers. 2013 (in Japanese).
23) U.S. Department of Health and Human Services,
Agency for Toxic Substances and Disease Registry
(ATSDR). Toxicological Profile for 1,2-dichloroethane. Atlanta (GA): ATSDR; 2001.