News
Carcinogenicity of some industrial chemicals
In February 2016, 24 experts
from eight countries met at the
International Agency for Research
on Cancer (IARC), Lyon, France,
to assess the carcinogenicity of
seven industrial chemicals (appendix).
These assessments will be published as
volume 115 of the IARC Monographs.1
N,N-dimethylformamide has been
measured in the environment, and
personal exposure was quantified
among acrylic-fibre and synthetic-
leather workers. In a facility in the USA, a
cluster of three cases of testicular cancer
was reported among 153 workers
repairing fighter aircraft and with high
exposure to N,N-dimethylformamide.
This prompted a study at a similar
facility in which four cases of
testicular cancer (<one expected)
were reported in 680 workers using
N,N-dimethylformamide in a unit
repairing the same type of aircraft,
compared with none in a unit repairing
other aircraft and without such
exposure.2 A cluster of three cases of
testicular cancer was also reported in
workers using N,N-dimethylformamide
at a leather tannery in the USA.
A community-based case-control study
in the county where the tannery was
located supported the existence of a
cancer cluster among leather workers.
N,N-dimethylformamide caused
hepatocellular adenoma and carcinoma
after inhalation in one study of male
and female mice, and one study of male
and female rats, and after inhalation or
in drinking water (or in combination) in
a study of male rats.3
N,N-dimethylformamide is readily
absorbed. N-methylcarba moyl-
mercapturic acid, and carbamoylated
adducts with valine and lysine of
human globin and with cytosine,
have been detected after occupational
exposure. N,N-dimethylformamide
induces oxidative stress in exposed
human beings, and in experi-
mental systems in vivo and
in vitro. N,N-dimethylformamide was
classified as “probably carcinogenic
www.thelancet.com/oncology Vol 17 April 2016
to humans” (group 2A), based
on “limited evidence in humans”
that it causes testicular cancer, and
“sufficient evidence of carcinogenicity
in experimental animals”.
Exposure to 2-mercaptobenzothiazole
occurs among workers in the
chemical industry and in the general
population (through dermal contact
with rubber-containing goods), and
can also occur in workers in the rubber
or tyre-manufacturing industries.
2-mercaptobenzothiazole has also
been found as an environmental
contaminant, and detected in
crumb rubber used on playgrounds.
In a chemical plant manufacturing
2-mercaptobenzothiazole in Wales,
comparison of exposed workers with
the English and Welsh population
showed a significant excess of incident
cases of urinary bladder cancer,
and a non-statistically significant
trend with increasing cumulative
exposure.4 A study5 in a chemical plant
in the USA reported a statistically
significant four-times excess of
mortality from bladder cancer, and
a significant trend with increasing
cumulative exposure. In gavage
studies, 2-mercaptobenzothiazole
increased the incidence of hepato-
cellular adenoma or carcinoma
(combined) in female mice, and also
increased the incidence of benign or
malignant (combined) adrenal gland
pheochromocytoma, preputial gland
adenoma or carcinoma (combined),
mononuclear cell leukaemia, and
benign or malignant (combined)
skin tumours in male rats.6 No data
were available on toxicokinetics or
mechanisms in exposed human beings.
In rodents, 2-mercaptobenzothiazole
is well absorbed, widely distri-
buted, and excreted in the urine.
2-mercaptobenzothiazole was
classified as group 2A, based on
“limited evidence in humans” that
it causes urinary bladder cancer, and
“sufficient evidence of carcinogenicity
in experimental animals”.
Exposure to hydrazine is mainly
occupational, with the highest expo-
sures in facilities where hydrazine is
handled as rocket propellant or aircraft
fuel. Cancer risks among rocket-testing
workers were investigated in
two overlapping cohort studies at the
same facility.7,8 One study considered
only mortality8 whereas the other also
presented incidence data,7 and each
study used different eligibility criteria
and exposure definitions. Both studies
showed an excess incidence of lung
cancer among workers estimated to
have had elevated exposure to hydrazine
early in the facility’s history. Incidence
of lung cancer showed a statistically
significant positive exposure–response
relationship. 7 In mice, hydrazine
caused lung adenoma and carcinoma
in multiple gavage, drinking water,
and intraperitoneal studies;9 and also
caused hepatocellular adenoma and
carcinoma in three oral administration
studies.9,10 In rats, hydrazine in drinking
water caused hepatocellular adenoma
and carcinoma in two studies, and lung
tumours in one study.10 In hamsters,
hydrazine in drinking water induced
hepatocellular adenoma or carcinoma
in two studies.11 In human beings,
hydrazine is absorbed rapidly and
metabolised. In experimental systems,
hydrazine induces oxidative stress, is
genotoxic, and alters nutrient supply
(inducing hepatic steatosis in rats).
Hydrazine was classified as group
2A, based on “limited evidence in
humans” that it causes lung cancer, and
“sufficient evidence of carcinogenicity in
experimental animals”.
Tetrabromobisphenol A, a widely used
flame retardant, is detected in almost
all biotic and abiotic compartments
worldwide. Occupational exposures
were measured in facilities man-
ufacturing electronic products, and
in recycling facilities. The general
population, including babies and young
children, is exposed through mothers’
milk, diet, and ingestion of indoor dust.
In gavage studies, tetrabromobisphenol
Published Online
February 23, 2016
http://dx.doi.org/10.1016/
S1470-2045(16)00137-6
For more on the IARC
Monographs see http://
monographs.iarc.fr/
Upcoming meetings
May 24–31, 2016, Volume 116:
Coffee and some other hot
beverages; Oct 4–11, 2016,
Volume 117: Pentachlorophenol
and some related compounds
Monograph Working Group
Members
C W Jameson (USA–Meeting
Chair); I Linhart
(Czech Republic); H U Käfferlein
(Germany); G Ichihara (Japan);
T Nomiyama (Japan); K Ogawa
(Japan); H Kromhout
(Netherlands); M van den Berg
(Netherlands); M M Marques
(Portugal); M A Abdallah (UK);
R C Cattley (USA); A Ducatman
(USA); J K Dunnick (USA);
K W Hanley (USA); K Houck
(USA); R Melnick (USA);
F E Mirer (USA); S Nesnow
(USA); A M Ruder (USA);
J M Sanders (USA); K Steenland
(USA); R T Zoeller (USA)
Declaration of interests
RM was involved in litigation on
bladder cancer and exposure to
p-cresidine and D-toluidine; KO
is an employee of the Japanese
Government; all other Working
Group Members declare no
competing interests
Invited specialists
D C Glass (Australia); T Sorahan
(UK)
Declaration of interests
DCG has received funding from
the Australian Institute of
Petroleum; TS has received
research awards from the rubber
industry and the petroleum
industry
Representatives
M Bisson (National Competence
Centre for Industrial Safety and
Environmental Protection; France)
419
 News
Declaration of interests
All representatives declare no
competing interests
Observers
S Borghoff (American Chemistry
Council’s North American Flame
Retardant Alliance; USA);
W Dekant (Bromine Science and
Environmental Forum; Belgium);
P Erkekoglu (Hacettepe
University; Turkey); S Jacobi
(Albemarle Europe SPRL;
Belgium); O Manor
(ICL-Industrial Products; Israel);
V Thomas (University Paris
Dauphine; France)
Declaration of interests
SB has provided research and
consulting services for the North
American Flame Retardant
Alliance panel of the American
Chemistry Council; WD has
received financial support from
the Bromine Science and
Environmental Forum for a
report on tetrabromobisphenol
A and from the American
Chemistry Council. All other
observers declare no competing
interests
IARC/WHO secretariat
L Benbrahim-Tallaa; V Bouvard;
R Carel; F El Ghissassi; Y Grosse;
K Z Guyton; D Loomis;
H Mattock; K Straif
Declaration of interests
All members of the secretariat
declare no competing interests
For the Preamble to the IARC
Monographs see http://
monographs.iarc.fr/ENG/
Preamble/index.php
For IARC declarations of
interests see
http://monographs.iarc.fr/ENG/
Meetings/vol115-participants.pdf
See Online for appendix
420
A caused an increase in the incidence
of hepatoblastoma, hepatocellular
carcinoma or hepatoblastoma (com-
bined), haemangiosarcoma, and large
intestine tumours in male mice, and
induced uterine adenocarcinomas
and rare malignant mixed Müllerian
uterine tumours in female rats.12
Tetrabromobisphenol A interacts with
human nuclear receptors, including
thyroid-hormone receptor and
PPAR-γ.13 It modulates enzymes relevant
to the endocrine system, including
aromatase, and is a potent inhibitor
of oestrogen sulfotransferase. 14,15
Tetrabromobisphenol A induces
oxidative stress in human cells in
vitro and in multiple species in vivo,
and has immunosuppressive effects
in human natural killer cells in vitro
and in mice in vivo.16 A majority of
Working Group members supported
a group 2A classification based on
“sufficient evidence of carcinogenicity
in experimental animals”, and strong
mechanistic evidence.
Occupational exposures to 1-bromo-
propane have been reported in chemical
manufacturing, production and use of
spray adhesives, vapour degreasing,
and fabric dry-cleaning. In inhalation
studies, 1-bromopropane increased
the incidence of bronchioloalveolar
adenoma or carcinoma in female mice,
and of benign or malignant (combined)
skin tumours and mesothelioma
of the tunica vaginalis in male
rats.17 1-bromopropane metabolites
have been detected in the urine of
occupationally exposed workers.
Occupational or environmental
exposure to technical-grade
3-chloro-2-methylpropene can
result from uses in the chemical
industry and as a seed fumigant.
In gavage studies,18 technical-grade
3-chloro-2-methylpropene increased
the incidence of forestomach
carcinoma in male mice, forestomach
papilloma or carcinoma (combined)
in female mice and male rats, and
forestomach papilloma in female rats.
In inhalation studies, technical-grade
3-chloro-2-methylpropene induced
forestomach papillomas in male and
female mice and male rats; Harderian
gland adenomas in female mice, and
thyroid follicular cell tumours in male
rats were also reported.
Health professionals, nail-salon
workers, industrial-glue users,
and chemical-production workers
can be occupationally exposed to
N,N-dimethyl-p-toluidine; and the
general population can be exposed
via dental material, bone cement,
and nail polish. In rodents exposed
orally, N,N-dimethyl-p-toluidine is
readily absorbed, widely distributed,
rapidly metabolised, and excreted
primarily in the urine. In gavage
studies,19 N,N-dimethyl-p-toluidine
induced hepatocellular carcinoma and
hepatoblastoma in male and female
mice, and hepatocellular carcinoma in
male and female rats.
1-bromopropane, 3-chloro-2-
methylpropene, and N,N-dimethyl-
p-toluidine were classified as
“possibly carcinogenic to humans”
(group 2B), based on “sufficient
evidence of carcinogenicity in
experimental animals”.
We declare no competing interests.
Yann Grosse, Dana Loomis,
Kathryn Z Guyton, Fatiha El Ghissassi,
Véronique Bouvard,
Lamia Benbrahim-Tallaa,
Heidi Mattock, Kurt Straif; on behalf of
the International Agency for Research
on Cancer Monograph Working Group
International Agency for Research on Cancer,
Lyon, France
1 International Agency for Research on Cancer.
IARC monographs on the evaluation of
carcinogenic risks to humans. Volume 115. Some
industrial chemicals. Lyon, France; February, 2016.
IARC Monogr Eval Carcinog Risks Hum (in press).
2 Ducatman AM, Conwill DE, Crawl J. Germ cell
tumours of the testicle among aircraft
repairmen. J Urol 1986; 136: 834–36.
3 Senoh H, Aiso S, Arito H, et al. Carcinogenicity
and chronic toxicity after inhalation exposure
of rats and mice to N,N-dimethylformamide.
J Occup Health 2004; 46: 429–39.
4 Sorahan T. Bladder cancer risks in workers
manufacturing chemicals for the rubber
industry. Occup Med (Lond) 2008;
58: 496–501.
5 Collins JJ, Strauss ME, Riordan SG. Mortalities of
workers at the Nitro plant with exposure to
2-mercaptobenzothialzole. Occup Environ Med
1999; 56: 667–71.
6 NTP. NTP toxicology and carcinogenesis
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(CAS No. 149–30–4) in F344/N rats and
B6C3F1 mice (gavage studies).
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7 Ritz B, Zhao Y, Krishnadasan A, Kennedy N,
Morgenstern H. Estimated effects of hydrazine
exposure on cancer incidence and mortality in
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8 Boice JD Jr, Marano DE, Cohen SS, et al.
Mortality among Rocketdyne workers who
tested rocket engines, 1948–1999.
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9 Biancifiori C. Pulmonary and hepatic
tumors caused by hydrazine sulfate in
reduced doses in BALB-c-Cb-Se mice.
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30: 89–99.
10 Matsumoto M, Kano H, Suzuki M, Katagiri T,
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rats and mice by two-year drinking water
treatment. Regul Toxicol Pharmacol 2016;
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11 Bosan WS, Shank RC, MacEwen JD, Gaworski CL,
Newberne PM. Methylation of DNA guanine
during the course of induction of liver cancer in
hamsters by hydrazine or dimethylnitrosamine.
Carcinogenesis 1987; 8: 439–44.
12 NTP. Toxicology studies of tetrabromobisphenol
A (CAS No. 79-94-7) in F344/NTac rats and
B6C3F1/N mice and toxicology and
carcinogenesis studies of tetrabromobisphenol
A in wistar han [Crl:WI(Han)] rats and B6C3F1/N
mice (gavage studies). http://ntp.niehs.nih.gov/
ntp/about_ntp/trpanel/2013/october/draft_tr-
587.pdf (accessed Feb 19, 2016).
13 Hofmann PJ, Schomburg L, Köhrle J.
Interference of endocrine disrupters with
thyroid hormone receptor-dependent
transactivation. Toxicol Sci 2009; 110: 125–37.
14 Honkisz E, Wójtowicz AK. Modulation of
estradiol synthesis and aromatase activity in
human choriocarcinoma JEG-3 cells exposed to
tetrabromobisphenol A. Toxicol In Vitro 2015;
29: 44–50.
15 Gosavi RA, Knudsen GA, Birnbaum LS,
Pedersen LC. Mimicking of estradiol binding by
flame retardants and their metabolites:
a crystallographic analysis.
Environ Health Perspect 2013; 121: 1194–99.
16 Watanabe W, Shimizu T, Sawamura R, et al.
Effects of tetrabromobisphenol A, a brominated
flame retardant, on the immune response to
respiratory syncytial virus infection in mice.
Int Immunopharmacol 2010; 10: 393–97.
17 NTP. Toxicology and carcinogenesis studies of
1-bromopropane (CAS No. 106–94–5) in
F344/N rats and B6C3F1 mice (inhalation
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564: 1–190.
18 National Toxicology Program. NTP toxicology
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www.thelancet.com/oncology Vol 17 April 2016