News
www.thelancet.com/oncology Vol 17 July 2016 877
In May, 2016, a Working Group of
23 scientists from ten countries met at
the International Agency for Research
on Cancer (IARC) in Lyon, France, to
evaluatethe carcinogenicityofdrinking
coffee, mate, and very hot beverages.
These assessments will be published in
volume 116 ofthe IARC Monographs.1
Coffee is one of the world’s
most widely consumed beverages.
It contains many different compounds
and its composition varies depending
on how it is produced and prepared
for drinking. After consumption,
caffeine, chlorogenic acids, and other
compounds contained in coffee are
absorbed and distributed throughout
the body.
The carcinogenicity of coffee drinking
was last assessed by IARC in 1991.2
At that time coffee was classified as
“possibly carcinogenic to humans“
(Group2B)basedonlimitedevidenceof
anassociationwithcanceroftheurinary
bladder from case-control studies, and
inadequate evidence of carcinogenicity
in experimental animals. However,
there was also evidence suggesting a
lackof carcinogenicity for cancersofthe
female breast andthe large intestine.
For this re-evaluation, a much
larger database of more than
1000 observational and experimental
studies was available. In assessing
the accumulated epidemiological
evidence, the current Working
Group gave the greatest weight to
well-conducted prospective cohort
and population-based case-control
studies that controlled adequately
for important potential confounders,
including tobacco and alcohol
consumption. For bladder cancer,
there was no consistent evidence of
an association with drinking coffee,
or of an exposure–response gradient
from ten cohort studies and several
population-based case-control studies
in Europe, the USA, and Japan.3–5
In several studies, relative risks were
increased in men but were null or
decreased in women, consistent with
residual confounding from smoking
or occupational exposures among
men. The Working Group concluded
that positive associations reported
in some studies could have been due
to inadequate control for tobacco
smoking, which can be strongly
associated with heavy coffee drinking.
By contrast, for endometrial cancer,
the five largest cohort studies showed
mostly inverse associations with coffee
drinking. These results were supported
by the findings of several case-control
studies and a meta-analysis.6
Inverse
associations with coffee drinking were
alsoobservedincohortandcase-control
studies of liver cancer in Asia, Europe,
and North America. A meta-analysis of
prospective cohort studies estimated
that the risk of liver cancer decreases
15% for each 1 cup per day increment.7
More than 40 cohort and case-control
studies and a meta-analysis8
including
nearly 1 million women consistently
indicated either no association or
a modest inverse association for
cancer of the female breast and
coffee drinking. Similarly, numerous
cohort and case-control studies of
cancers of the pancreas and prostate
consistently indicated no association
between these cancers and coffee
drinking. Data were also available
for more than 20 other cancers,
including lung, colorectal, stomach,
oesophageal, oral cavity, ovarian,
and brain cancers, and childhood
leukaemia. Although the volume of
data for some of these cancers was
substantial, the Working Group judged
the evidence to be inadequate for all of
the other cancers reviewed for reasons
including inconsistency of findings
across studies, inadequate control
for potential confounding, potential
for measurement error, selection bias
or recall bias, or insufficient numbers
of studies.
The combination of evidence
suggesting lack of carcinogenicity for
cancers of the female breast, pancreas,
prostate, uterine endometrium, and
liver, with inverse associations for the
latter two and inadequate evidence
for all the other sites reviewed
led to the conclusion that there is
inadequate evidence in humans forthe
carcinogenicity of coffee drinking.
Coffee has been evaluated for
carcinogenicity in several long-term
studies in mice and rats, and has been
tested for both tumour-promoting
and cancer-preventing activity in a
number of co-carcinogenicity studies
in rats and hamsters. The Working
Group concluded that these studies
provided inadequate evidence
in experimental animals for the
carcinogenicity of coffee.
Coffee drinking exhibited strong
antioxidant effects in studies in
humans, including in randomised
controlled trials.9
Results for
genotoxicity from studies in humans
were inconsistent, and coffee did
not induce chromosomal damage
in rodents. Nonetheless, coffee gave
positive results in bacterial mutagenesis
assays, but only without metabolic
activation. Coffee promoted apoptosis
in human cancer cell lines.10
Moderate
evidence of an association of coffee
drinking with reduced risk of colorectal
adenoma was noted. Coffee has also
been associated with beneficial effects
on liver fibrosis and cirrhosis.
Overall coffee drinking was
evaluated as unclassifiable as to its
carcinogenicity to humans (Group 3).
Mate is an infusion made from
dried leaves of Ilex paraguariensis. It is
consumed mainly in South America
and to a lesser extent in the Middle
East, Europe, and North America. Mate
is traditionally drunk very hot (>65°C),
but it can also be consumed warm or
cold. The carcinogenicity of mate was
previously evaluated in 1991,2
when
Carcinogenicity of drinking coffee, mate, and very hot
beverages
Published Online
June 15, 2016
http://dx.doi.org/10.1016/
S1470-2045(16)30239-X
For more on the IARC
Monographs see http://
monographs.iarc.fr
Upcoming meetings
October 4–11, 2016,Volume 117:
Pentachlorophenol and some
related compounds;
March 21–28, 2017,Volume 118:
Welding, welding fumes and
some related chemicals
IARC MonographWorking
Group Members
LT Stayner (USA)—meeting
chair; E Milne (Australia);
S Knasmüller (Austria); A Farah,
L F Ribeiro Pinto (Brazil);
DW Lachenmeier (Germany);
C Bamia (Greece); ATavani
(Italy); M Inoue (Japan);
N Djordjevic (Serbia);
P C H Hollman,
P A van den Brandt
(Netherlands); J A Baron,
E Gonzalez de Mejia, F Islami
(unable to attend); CW Jameson,
F Kamangar, D L McCormick,
I Pogribny, I I Rusyn, R Sinha,
M C Stern, K MWilson (USA)
Declaration of interests
MI is the beneficiary of a financial
contribution from AXA Research
fund as chair holder of the AXA
Department of Health and
Human Security, Graduate
School of Medicine,The
University ofTokyo from
Nov 1, 2012. AXA Research has
no role in this work. All other
working group members declare
no competing interests.
Invited Specialists
None
Representatives
A Morise, for the French Agency
for Food, Environmental and
Occupational Health and Safety
(ANSES), France
News
878 www.thelancet.com/oncology Vol 17 July 2016
hot mate drinking was classified as
“probably carcinogenic to humans”
(Group 2A).
Evidence on the carcinogenicity of
matecomesmainlyfromhospital-based
case-control studies on cancer of the
oesophagus in SouthAmerica.A pooled
analysis11
of most of the available
studies showed the risk of oesophageal
cancer increasing with the quantity of
mate consumed. However, the trend
was statistically significant only for
mate consumed “hot” or “very hot”,
and a significant trend was observed
withdrinkingtemperatureindependent
of the amount consumed. The single
study that examined cold mate
drinking showed no association with
oesophageal cancer.
To further assess the effect of
beverage temperature, the Working
Group reviewed studies that reported
on the association of oesophageal
cancer with the drinking temperature
of other beverages. Another pooled
analysis12
of South American
case-control studies on oesophageal
cancer showed significantly increased
relative risks for drinking very hot tea
and very hot beverages other than
mate similar in magnitude to that
for drinking very hot mate. A large
cohort study and several case-control
studies13
showed an increased risk of
oesophageal cancer when drinking tea
very hot or hot, compared with lower
temperatures. Similar results have been
reported in other studies evaluating
combinations of very hot drinks.
From these data, the Working
Group concluded that there is
limited evidence in humans for the
carcinogenicity of drinking very hot
beverages, and inadequate evidence
in humans for the carcinogenicity of
drinking mate that is not very hot.
In experimental animals, the
carcinogenicityofmateandofbeverage
temperature has only been assessed in
a few co-carcinogenicity studies. Locally
instilled very hot water (at 65–70°C)
increasedthe incidenceof nitrosamineinduced
oesophageal tumours in one
study in mice14
and one study in rats.15
By contrast, cold mate administered
as drinking fluid in rats reduced the
incidence of oesophageal and liver
tumours induced by nitrosamine and
hot water combined. The Working
Group concluded that there is limited
evidence in experimental animals for
the carcinogenicity of very hot water
at 65°C or above, and inadequate
evidence in experimental animals
for the carcinogenicity of mate as a
drinking fluid.
Pharmacokinetic and mechanistic
data for mate drinking are sparse.
Studies in humans and animals given
orally administered mate did not
report genotoxicity or other cancer
related effects.
The Working Group noted that the
epidemiological evidence for very
hot beverages and human cancer has
strengthened over time, with positive
associations and trends in studies that
considered qualitative gradations of
temperature. Additionally, new studies
in experimental animals show that hot
water above 65°C can act as a tumour
promoter. Although the mechanistic
andother relevant evidence for very hot
beverages is scant, biological plausibility
exists for an association between very
hot beverages and cell injury and the
sequelae that might lead to cancer.
Onthebasisoftheseconsiderationsand
on the totality of the evidence, drinking
very hot beverages at above 65°C was
classified as “probably carcinogenic to
humans” (Group 2A). This evaluation
of very hot beverages includes drinking
of very hot mate. Drinking mate that
is not very hot was evaluated as “not
classifiable as to its carcinogenicity to
humans” (Group 3).
We declare no competing interests.
Dana Loomis, Kathryn Z Guyton,
Yann Grosse, Béatrice Lauby-Secretan,
Fatiha El Ghissassi,Véronique Bouvard,
Lamia Benbrahim-Tallaa, Neela Guha,
Heidi Mattock, Kurt Straif, on behalf of
the International Agency for Research
on Cancer MonographWorking Group
International Agency for Research on Cancer,
Lyon, France
1 International Agency for Research on Cancer.
Volume 116: coffee, mate and very hot
beverages. IARCWorking Group. Lyon,
France; 24–31 May, 2016.
IARC Monogr Eval Carcinog Risks Hum (in press).
2 International Agency for Research on
Cancer. Coffee, tea, mate, methylxanthines
and methylglyoxal.
IARC Monogr Eval Carcinog Risks Hum 1991;
51: 1–513.
3 Zeegers MP, Dorant E, Goldbohm RA,
van den Brandt PA. Are coffee, tea, and total
fluid consumption associated with bladder
cancer risk? Results from the Netherlands
Cohort Study. Cancer Causes Control 2001;
12: 231–38.
4 Michaud DS, Spiegelman D, Clinton SK, et al.
Fluid intake and the risk of bladder cancer in
men. N Engl J Med 1999; 340: 1390–97.
5 Nagano J, Kono S, Preston DL, et al.
Bladder-cancer incidence in relation to
vegetable and fruit consumption:
a prospective study of atomic-bomb
survivors. Int J Cancer 2000; 86: 132–38.
6 JeY, Giovannucci E. Coffee consumption and
risk of endometrial cancer: findings from a
large up-to-date meta-analysis. Int J Cancer
2012; 131: 1700–10.
7 Bravi F, Tavani A, Bosetti C, Boffetta P,
La Vecchia C. Coffee and the risk of
hepatocellular carcinoma and chronic liver
disease: a systematic review and
meta-analysis of prospective studies.
Eur J Cancer Prev (in press).
8 JiangW,WuY, Jiang X. Coffee and caffeine
intake and breast cancer risk: an updated
dose-response meta-analysis of 37 published
studies. Gynecol Oncol 2013; 129: 620–29.
9 CorrêaTA, Monteiro MP, MendesTM, et al.
Medium light and medium roast paper-filtered
coffee increased antioxidant capacity in
healthy volunteers: results of a randomized
trial. Plant Foods Hum Nutr 2012; 67: 277–82.
10 Tai J, Cheung S, Chan E, Hasman D.
Antiproliferation effect of commercially
brewed coffees on human ovarian cancer cells
in vitro. Nutr Cancer 2010; 62: 1044–57.
11 Lubin JH, De Stefani E, Abnet CC, et al.
Maté drinking and esophageal squamous cell
carcinoma in South America: pooled results
from two large multicenter case-control
studies. Cancer Epidemiol Biomarkers Prev 2014;
23: 107–16.
12 Castellsagué X, Muñoz N, De Stefani E,
Victora CG, Castelletto R, Rolón PA. Influence
of mate drinking, hot beverages and diet on
esophageal cancer risk in South America.
Int J Cancer 2000; 88: 658–64.
13 Islami F, Pourshams A, Nasrollahzadeh D, et al.
Tea drinking habits and oesophageal cancer in
a high risk area in northern Iran: population
based case-control study. BMJ 2009;
338: b929.
14 Rapozo DC, Blanco TC, Reis BB, et al.
Recurrent acute thermal lesion induces
esophageal hyper proliferative premalignant
lesions in mice esophagus. Exp Mol Pathol
2016; 1: 1–10.
15 Li ZG, ShimadaY, Sato F, et al. Promotion
effects of hot water on N-nitrosomethylbenzylamine-induced
esophageal
tumorigenesis in F344 rats. Oncol Rep 2003;
10: 421–26.
Declaration of interests
All representatives declare no
competing interests.
Observers
V Guercio, for the Mario Negri
Institute of Pharmacological
Research, Italy;T Hatzold, for the
Institute for Scientific
Organization on Coffee (ISIC),
Switzerland; A Leviton, for the
National Coffee Association,
USA; F Phillips, Freelance
Dietitian and Nutrition
Consultant, UK;VThomas, for
the University Paris Dauphine,
France; CWallmann, for the
University of Kent, UK; MWilde,
for the University of Kent, UK
Declaration of interests
TH was an employee of Modelez
International until November,
2015, holds stock options for
Modelez International, and is a
consultant to the Institute for
Scientific Information on coffee.
AL represents the National
Coffee Association of the USA.
All other observers declare no
competing interests.
IARC/WHO Secretariat
B Abedi-Ardekani;
L Benbrahim-Tallaa;V Bouvard;
F El Ghissassi;Y Grosse; N Guha;
K Z Guyton; I Huybrechts;
B Lauby-Secretan; D Loomis;
H Mattock; H Noh; S Pisanu;
J Rothwell; A Scalbert; K Straif;
M Zhivagui
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/vol116-
participants.pdf