News
centres in the USA, up from 11 in the base of skull, hepatocellular
2013. “Nine more centres are under
construction, Warwick said. Four of
the six most recently constructed
centres were single-room facilities,
he said. Cost assessments should
account for long-term costs and
proton therapy equipment’s longer
life span”, he added.
However, investors badly over­
estimated regional demand and
referral rates. The $200 million
Maryland Proton Treatment Center
in Baltimore (MD, USA), which
opened in 2016, in affiliation with the
University of Maryland Medical Center,
is restructuring its debt. The Scripps
Proton Treatment Center (San Diego,
CA, USA) declared bankruptcy and
parted ways with Scripp and is now
under new management. In the
absence of definitive evidence that
more expensive proton treatments
offer superior outcomes, many private
insurers resist paying for proton
treatment.
The ASTRO model policy for proton
beam therapy supports proton
therapy use for ocular tumours,
chordomas and other tumours at
Carcinogenicity of isobutyl nitrite, β-picoline, and some
acrylates
Published Online In June 2018, 14 experts from
June 28, 2018 eight countries met at the
http://dx.doi.org/10.1016/
S1470-2045(18)30491-1 International Agency for Research
For more on the IARC on Cancer (IARC) in Lyon, France,
Monographs see http:// to finalise their evaluation of the
monographs.iarc.fr/ carcinogenicity of methyl acrylate,
Upcoming meetings ethyl acrylate, 2-ethylhexyl acrylate,
Oct 9–16, 2018, volume 123:
Some nitrobenzenes and other
trimethylolpropane triacrylate
industrial chemicals (TMPTA), isobutyl nitrite, and
Nov 12–14, 2018, Advisory β-picoline. These assessments will be
Group to Recommend an Update published in volume 122 of the IARC
to the Preamble
Monographs.1
March 25–27, 2019, Advisory
Group to Recommend Priorities
Methyl acrylate, ethyl acrylate,
for the IARC Monographs during 2-ethylhexyl acrylate, technical-grade
2020–2024 TMPTA, and isobutyl nit­rite were
IARC Monograph Working classified as “possibly carcinogenic
Group Members
to humans” (Group 2B), based on
H Kromhout (Netherlands)—
Meeting Chair; G Benke “sufficient evidence” of carcinogenicity
1020 www.thelancet.com/oncology Vol 19 August 2018
toxicities and erectile disfunction
cancer, primary central nervous
system tumours, advanced or
unresectable head and neck cancers,
non-metastatic retroperitoneal sar­
comas, some spinal tumours, cancers
of the accessory sinuses, and certain
paediatric and re-irradiation cases,
Kavanagh said.
However, most adults in the USA
treated with proton therapy to date
have been men with prostate cancer.
Many privately-operated US proton
centres emphasise prostate cancer
treatment in patient-directed online
marketing, without reference to age.
“But prostate cancer is a common
diagnosis, and the desire to take
advantage of any available tool that
may help to minimise toxicities is
understandable, particularly for
younger prostate cancer patients in
their 40s or 50s, lifetime exposure to
radiation and the risk of secondary
malignancies can be important
considerations”, noted Neha Vapiwala
(University of Pennsylvania,
Philadelphia, PA, USA).
A recent prospective study showed
that the risk of composite urinary
in experimental animals and no data
or inadequate evidence in humans.
β-picoline was evaluated as “not
classifiable as to its carcinogenicity
to humans” (Group 3) based on
“limited evidence” of carcinogenicity
in experimental animals and no data
in humans.
All four acrylates evaluated are
high-production-volume chemicals
that are produced worldwide.
Methyl acrylate is used in the
production of acrylic fibres and
fire-retardant fabrics. It is also used
to produce coatings, adhesives,
prostheses, and as an intermediate
in the synthesis of other compounds.
Human exposure occurs primarily
2 years after treatment was lower
in patients with prostate cancer
treated with proton therapy than
those treated with IMRT (33% vs
42%; p<0.001 for urinary toxicity
and 21% vs 28%; p<0.001 for
erectile dysfunction). “It is difficult
to determine exactly why proton
treatment was associated with lower
urinary toxicity risk”, cautioned
coauthor Benjamin Smith (M.D.
Anderson Cancer Center, Houston,
TX, USA). “Is it something to do with
proton dosimetry, or the way patients
are treated—perhaps with more
precise immobilisation or tighter
margins at proton centres?”, Smith
said.
“Everybody recognises that
radiation delivered to non-target
tissue does not benefit patients
and may cause harm—we all agree
that radiation oncologists should
strive to minimise that”, Smith said.
“Fundamentally, this is about the
Hippocratic Oath: primum non nocere.
First, do no harm.”
Bryant Furlow
through inhalation and dermal
contact during production and use
as an intermediate. In humans, the
development of allergic contact
dermatitis has been reported. In
rodents, methyl acrylate is readily
absorbed, widely distributed,
metabolised via hydrolysis by
carboxylesterases to acrylic acid
and methanol, and excreted
mainly as CO 2 in expired air and
as mercapturic acid conjugates in
the urine. In one inhalation study
in rats, 2 methyl acrylate increased
the incidence of soft tissue sarcoma
and leukaemia, and lymphoma
or lymphosarcoma (combined)
in male rats, and pituitary gland

adenoma in female rats. In another
inhalation study, 3 methyl acrylate
caused squamous cell carcinoma of
the nasal cavity in male and female
rats, and pheochromocytoma of the
adrenal gland (benign and malignant
tumours combined) in female rats.
Data on cancer mechanisms were
sparse.
Ethyl acrylate is used to produce
polymers for water-based paints,
resins, plastics, and synthetic rubber.
It is one of the principal monomers
used worldwide to manufacture
styrene-based polymers, used for
medical and dental items. Ethyl
acrylate is also used in surface
coatings for textiles, paper, leather,
and food contact materials, and as a
food flavouring agent. Occupational
exposure can occur in chemical and
paint manufacturing workers, nail
salon workers, and dental technicians.
Exposure of the general population
occurs through food and from
materials containing ethyl acrylate.
A small number of occupational
epidemiological studies with non-
specific exposure assessment were
considered inadequate for the
evaluation of carcinogenicity in
humans. The development of allergic
contact dermatitis has been described
in humans. In rats, ethyl acrylate is
rapidly absorbed, widely distributed,
and extensively metabolised by
carboxylesterases to yield acrylic acid
and ethanol, and subsequently CO2.
Covalent binding to glutathione
and proteins was demonstrated.
In mice and rats, exposure to ethyl
acrylate by gavage increased the
incidence of forestomach squamous
cell papilloma and carci­ n oma. 4,5
Although agents that only produce
tumours in the forestomach after
prolonged treatment through non-
DNA-reactive mechanisms might
have less relevance to humans, 6
ethyl acrylate also increased the
incidence of thyroid follicular cell
adenoma in male mice, and thyroid
follicular cell adenoma or carcinoma
(combined) in male rats exposed
www.thelancet.com/oncology Vol 19 August 2018 1021
through inhalation. 7 Furthermore,
ethyl acrylate gave positive results in
some rodent assays for genotoxicity
in vivo and in vitro, but overall
the findings were equivocal due
to inconsistencies and lack of
reproducibility. Ethyl acrylate induced
chronic inflammation and altered cell
proliferation, cell death or nutrient
supply, inducing hyperplasia and
inflammation in the forestomach of
rats and mice when administered for
2 years by gavage.4
2-ethylhexyl acrylate is used
as a plasticising comonomer
in the production of resins for
pressure-sensitive adhesives, latex
paints, reactive diluent or cross-
linking agents, textile and leather
finishes, and coatings for paper.
Occupational exposure occurs
during the manufacturing process.
The development of allergic
contact dermatitis after exposure
to 2-ethylhexyl acrylate in artificial
sculptured nails has been described.
In rats, 2-ethylhexyl acrylate is readily
absorbed, widely distributed, and
mainly excreted as CO2 in expired air
and as mercapturic acid conjugates
in the urine. 2-ethylhexyl acrylate
undergoes carboxylesterase-catalysed
metabolism and conjugation with
glutathione. In dermal studies with
male mice, 8,9 2-ethylhexyl acrylate
increased the incidence of squamous
cell papilloma, squamous cell
papilloma or carcinoma (combined),
cornified squamous cell carcinoma,
and malignant melanoma and
fibrosarcoma. Overall, mechanistic
data were scarce, with negative
results for genotoxicity in the
available studies.
TMPTA is available as a technical-
grade product of 70–90% purity
that contains incomplete reaction
products. It is used primarily to
produce ultraviolet-curable inks,
paint additives, coatings, and
adhesives. Occupational exposure
occurs during manufacture or use
of TMPTA. Exposure of the general
population can occur through the
use of consumer products (eg, latex
paints), and furniture and floor
polishes containing TMPTA. In
dermal studies in rodents, technical-
grade TMPTA increased the inci­
dence of hepatocellular carcinoma,
hepatoblastoma, hepato­cholangio­
carcinoma, uterine stromal polyp,
and uterine stromal polyp or stromal
sarcoma (combined) in female mice,
and of malignant mesothelioma of
the tunica vaginalis in male rats.10
In one dermal study in transgenic
mice,11 TMPTA caused skin squamous
cell papillomas in male and female
mice, and forestomach squamous
cell papillomas in female mice. In
rats, urinary excretion is the primary
elimination pathway, followed
by CO 2 exhalation, whereas the
two pathways occur to similar
extents in mice. Dermal hyperplasia
in multiple cell types was seen
in chronically exposed rodents.
Few other mechanistic data were
available.
The primary source of human
exposure to isobutyl nitrite is as a
recreational drug. Isobutyl nitrite
is also used as an intermediate
in the synthesis of solvents and
fuels. Methaemoglobinaemia and
vasodilation with isobutyl nitrite are
observed in humans, demonstrating
absorption. In rodents, isobutyl
nitrite is rapidly metabolised
to nitrite and isobutyl alcohol.
Nitric oxide has been identified in
exhaled air from exposed rabbits.
Results of genotoxicity tests were
generally positive, but few studies
were available. Dose-dependent
suppression of antigen-specific
antibody production was shown
in multiple studies in mice. 12 In
inhalation studies in rodents, 13
isobutyl nitrite increased the
incidence of bronchioloalveolar
adenoma and carcinoma in male
rats, bronchioloalveolar adenoma or
carcinoma (combined) in male and
female mice and female rats, and
thyroid follicular cell adenoma or
carcinoma (combined) in male mice.
News
(Australia); C M Sergi (Canada);
G Ichihara; J Kanno (Japan);
C Svendsen (Norway);
M Marques (Portugal);
M Abdallah (UK); M Cesta,
M Friesen, D Germolec, K Houck,
C W Jameson, I Pogribny (USA)
Declaration of interests
All working group members
declare no competing interests.
Invited Specialists
None
Representatives
S Charles, E Pasquier, for the
French Agency for Food,
Environmental and Occupational
Health and Safety (ANSES),
France
Declaration of interests
All representatives declare no
competing interests.
Observers
R G Ellis-Hutchings, for the Basic
Acrylic Monomer Manufacturers,
USA; L Finch, for Arkema, USA;
K Wiench, for the European
Chemicals Industry Council,
Belgium
Declaration of interests
R G Ellis-Hutchings is currently
employed by and holds stocks
from the Dow Chemical
Company. L Finch is employed by
Arkema. K Wiench is currently
employed by and holds stocks
from BASF, Germany.
IARC Secretariat
L Benbrahim-Tallaa; V Bouvard;
F El Ghissassi; Y Grosse;
K Z Guyton; A Hall; C Jaillet;
H Mattock; K Straif
Declaration of interests
All 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/vol122-participants.
pdf
 News
β-picoline, a methyl pyridine, is
widely used as a starting material
for pesticides (eg, chlorpyrifos) and
pharmaceuticals (eg, vitamin B3).
It is also used as a solvent and
intermediate in rubber accelerators,
waterproofing agents, dyes and
resins, and as a flavouring substance
in food and beverages. Occupational
exposure occurs primarily through
inhalation or dermal contact during
its production and use. β-picoline
is released into the environment
through industrial waste water and
from cigarette smoke; it also occurs
naturally at low concentrations in
beer, coffee, and whiskey. The general
population can also be exposed via use
of products containing β-picoline. In
rodents, β-picoline is readily absorbed
and metabolised by cytochrome
P450-mediated oxidation, but
data on cancer mechanisms were
sparse. When administered in
drinking water, β-picoline increased
the incidence of hepatocellular
carcinoma, hepatocellular carcinoma
or hepatoblastoma (combined),
and bronchioloalveolar adenoma
or carcinoma (combined) in female
mice, and bronchioloalveolar aden­
oma in male mice and female rats.14
We declare no competing interests.
Hans Kromhout, Melissa Friesen,
M Mathilde Marques,
Consolato Maria Sergi ,
Mohamed Abdallah, Geza Benke,
Mark Cesta, Dori Germolec,
1022 www.thelancet.com/oncology Vol 19 August 2018
Keith Houck, Gaku Ichihara,
Charles William Jameson, Jun Kanno,
Igor Pogribny, Camilla Svendsen,
Lamia Benbrahim-Tallaa,
Kathryn Z Guyton, Yann Grosse,
Fatiha El Ghissassi,
Véronique Bouvard, Amy Hall,
Corentin Jaillet, 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
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