News

Special Report: Policy

A review of human carcinogens—Part A: pharmaceuticals
In October, 2008, 21 scientists
from nine countries met at the
International Agency for Research
on Cancer (IARC) and reaffirmed the
Group 1 classification “carcinogenic to
humans” of 20 pharmaceutical agents
(tables 1 and 2).
IARC is compiling a review of the
more than 100 Group 1 agents, many
of which were assessed more than
20 years ago, before mechanistic
studies were prominent tools in
assessments. Furthermore, additional
tumour sites and exposure scenarios
might be identified in the new review.
For example, tobacco was first
identified as a cause of lung cancer in
smokers, and has since been shown to
cause cancer at more than a dozen
Mechanisms Involved in Human
Carcinogenesis. The major findings
of Volume 100 will also become the
first entries of an enhanced electronic
database of Monograph findings.
Five hormonal treatments were
reassessed (table 1), two of which
increase cancer risk at some sites
and decrease risk at others, acting
through receptor-mediated events
and genotoxic mechanisms.
The Working Group concluded
that there is sufficient evidence that
oestrogen-only menopausal therapy
increases the risk for ovarian cancer,
whereas no definite association was
identified in the IARC 1999 evalu-
ation.1 Two meta-analyses published
since then reported an increased risk
combined oestrogen-progestagen oral Published Online
contraceptives increase the risk for December 1, 2008
DOI:10.1016/S1470-
hepatocellular carcinoma,5 stressing 2045(08)70286-9
that in populations where hepatitis B
virus (HBV) infection is endemic, the
risk is presumably masked by the higher
risk associated with HBV infection.
A further 15 agents were reassessed,
including some mixtures (table 2).
The Working Group identified the
specific component most likely to
be responsible for cancer risk in Upcoming meetings
February 24–March 3, 2009
three mixtures, although it is not an
Biological Agents
expressed intent of Volume 100 to
March 17–24, 2009
identify new carcinogenic agents. Metals, Particles, and Fibres
The Working Group reaffirmed the June 2–9, 2009
Group 1 classification of analgesic Radiation
mixtures containing phenacetin, and September 29–October 6, 2009
further classified phenacetin itself Lifestyle Factors

sites, through smoking and smokeless
forms.
The assessments will be published as
Volume 100 of the IARC Monographs,
to be developed in six parts. Volume
100 will include information on tumour
sites and mechanisms of carcinogen-
esis, although this does not preclude
the possibility that an agent might
cause cancer at other sites or by other
mechanisms. Volume 100 will provide
information for two subsequent pub-
lications: Tumour Site Concordance
between Humans and Animals and
for ovarian cancer among women
who used oestrogen-only therapy:
the relative risks (RRs) for ever use
were significant and ranged from
1·19 to 1·51.2,3 Furthermore, a dose-
dependent increase in risk was noted
per year of use of oestrogen-only
therapy (RR 1·07 [95% CI 1·06–1·08]).3
The Working Group also highlighted
the decrease in breast cancer incidence
after the widespread reduction in the use
of combined oestrogen-progestagen
menopausal therapy since 2003.4
Additionally, the Group confirmed that
in Group 1 (previously classified as October 20–27, 2009
Chemical Agents and Related
“probably carcinogenic to humans” Occupations
Group 2A, in 1987). The Group reached http://monographs.iarc.fr/
this decision because increased risks
for cancers of the renal pelvis and the
ureter could not be explained by other
components of the analgesic mixtures
(ie, aspirin, codeine phosphate, and
caffeine) and noted that phenazone
(sometimes added to these mixtures)
was not a component of those mix-
tures assessed in an influential study.6
When reviewing antineoplastic
drugs, the Working Group noted that

Group 1 agent Cancer on which sufficient evidence in Sites where cancer Established mechanistic Other likely
humans is based risk is reduced events mechanistic events
Diethylstilbestrol Breast (exposure during pregnancy), vagina ·· Oestrogen receptor- Epigenetic
and cervix (exposure in utero) mediated events (vagina, programming
Limited evidence: testis (exposure in utero), cervix), genotoxicity
endometrium
Oestrogen-only menopausal Endometrium, ovary ·· Oestrogen receptor- Genotoxicity
therapy Limited evidence: breast mediated events
Combined oestrogen– Endometrium (risk decreases with number ·· Receptor-mediated events Oestrogen genotoxicity
progestagen menopausal therapy of days/month of progestogen use), breast
Combined oestrogen– Breast, cervix, liver Endometrium, Receptor-mediated events Oestrogen genotoxicity,
progestagen oral contraceptives ovary hormone-stimulated
expression of human
papillomavirus genes
Tamoxifen Endometrium Breast Oestrogen receptor- ··
mediated events,
genotoxicity

Table 1: Hormonal treatments assessed by the IARC Monograph Working Group xx

www.thelancet.com/oncology Vol 10 January 2009 13

 News
Monograph Working Group
Members
A B Miller—Co-Chair (Canada),
D H Phillips—Co-Chair (UK);
J Kaldor (Australia); J H Olsen
(Denmark); M R Berger,
H H Schmeiser (Germany);
H Tsuda (Japan); S H Kim (unable
to attend, Republic of Korea);
B C Baguley (New Zealand);
M Marques (Portugal); P Karran
(UK); E Barrett-Connor,
F A Beland, J L Bolton (unable to
attend), M C Bosland, J F Buell,
D Eastmond, C J Jameson,
D G Kaufman, A A Molinolo,
C A Schiffer, L Titus-Ernstoff,
D B Thomas (USA)
Conflicts of interest
DE has previously received
funding from, and acted as
consultant to, Johnson &
Johnson. He currently receives
funding from Pfizer. Both of
these companies manufacture
hormone-based contraceptives.
JK is deputy director of the Centre
in HIV Epidemiology and Clinical
Research, University of New
South Wales, Australia, which
receives partial funding from
Hoffman-La Roche, Bristol-Myers
Squibb, Pfizer, and Johnson &
Johnson. All of these companies
manufacture drugs, or
alternatives to drugs, mentioned
in this article
Invited Specialists
None
Representatives
None
Observers
M G Bird (ExxonMobil Corp, USA)
14
This shows how mechanistic data
Group 1 agent Cancer on which sufficient Established mechanistic events
evidence in humans is based can help identify carcinogenic hazards.
It is encouraging to think that other
Busulfan Acute myeloid leukaemia Genotoxicity (alkylating agent)
Chlorambucil Acute myeloid leukaemia Genotoxicity (alkylating agent)
environmental or occupational cancers
Cyclophosphamide Acute myeloid leukaemia, Genotoxicity (metabolism to alkylating
might be investigated and resolved
bladder agents) with similar confidence.
Melphalan Acute myeloid leukaemia Genotoxicity (alkylating agent)
Semustine Acute myeloid leukaemia Genotoxicity (alkylating agent) Yann Grosse, Robert Baan,
(methyl-CCNU) Kurt Straif, Béatrice Secretan,
Thiotepa Leukaemia Genotoxicity (alkylating agent) Fatiha El Ghissassi, Véronique Bouvard,
Treosulfan Acute myeloid leukaemia Genotoxicity (alkylating agent) Lamia Benbrahim-Tallaa, Neela Guha,
MOPP combined Acute myeloid leukaemia, lung Genotoxicity Laurent Galichet, Vincent Cogliano, on
chemotherapy
behalf of the WHO International Agency
Etoposide in combination Acute myeloid leukaemia Genotoxicity; translocations involving
with cisplatin and MLL gene (etoposide) for Research on Cancer Monograph
bleomycin Working Group
Etoposide (Group 2A in ·· Genotoxicity, translocations involving International Agency for Research on
2000) MLL gene
Cancer, Lyon, France
Chlornaphazine Bladder Genotoxicity (alkylating agent,
metabolism to 2-naphthylamine The IARC authors declared no conflicts of interest.
derivatives) 1 IARC. IARC Monographs on the evaluation of
Azathioprine Non-Hodgkin lymphoma, skin Genotoxicity, immunosuppression carcinogenic risks to humans. Volume 72.
Hormonal contraception and post-menopausal
Ciclosporin Non-Hodgkin lymphoma, skin, Immunosuppression hormonal therapy. Lyon: International Agency
multiple other sites for Research on Cancer 1999.
Methoxsalen+ultraviolet Skin Genotoxicity following photo-activation 2 Zhou B, Sun Q, Cong R, et al. Hormone
light replacement therapy and ovarian cancer risk:
a meta-analysis. Gynecol Oncol 2008;
Plants containing Renal pelvis, ureter Genotoxicity, DNA adducts in humans,
108: 641–51.
aristolochic acid A:T→T:A transversions in TP53 in
3 Greiser CM, Greiser EM, Dören M. Menopausal
human tumours
hormone therapy and risk of ovarian cancer:
Aristolochic acid ·· Genotoxicity, DNA adducts in animals systematic review and meta-analysis.
(Group 2A in 2002) are the same as those found in humans Hum Reprod Update 2007; 13: 453–63.
exposed to plants, A:T→T:A 4 Jemal A, Ward E, Thun MJ. Recent trends in
transversions in TP53, RAS activation breast cancer incidence rates by age and tumor
Analgesic mixtures Renal pelvis, ureter (See phenacetin) characteristics among U.S. women.
containing phenacetin Breast Cancer Res 2007; 9: R28.
5 IARC. IARC Monographs on the Evaluation of
Phenacetin Renal pelvis, ureter Genotoxicity, cell proliferation Carcinogenic Risks to Humans. Volume 91.
(Group 2A in 1987) Combined estrogen-progestogen contraceptives
and combined estrogen-progestogen
MOPP=chlormethine (mechlorethamine), vincristine (oncovin), procarbazine, and prednisone menopausal therapy. Lyon: International Agency
for Research on Cancer 2007.
Table 2: Antineoplastic drugs and other drugs evaluated by the IARC Monograph Working Group
6 McCredie M, Stewart JH, Day NE. Different
roles for phenacetin and paracetamol in cancer
of the kidney and renal pelvis. Int J Cancer
acute myeloid leukaemia induced by adducts and A:T→T:A transversions in 1993; 53: 245–49.
alkylating agents, such as busulfan, TP53 induced by aristolochic acid were 7 Pedersen-Bjergaard J, Christiansen DH, Desta F,
et al. Alternative genetic pathways and
frequently exhibits clonal loss (partial found in patients with nephropathy cooperating genetic abnormalities in the
or total) of either chromosome 5 or urothelial tumours after ingestion pathogenesis of therapy-related
myelodysplasia and acute myeloid leukemia.
or 7, thereby distinguishing it from of material from Aristolochia plant Leukemia 2006; 11: 1943–49.
acute myeloid leukaemia induced by species.9,10 As a result, aristolochic acid 8 WHO classification of tumours of
topoisomerase II inhibitors, such as was classified in Group 1 (previously haematopoietic and lymphoid tissues.
Swerdlow SH, Campo E, Harris NL, et al, eds.
etoposide. The latter shows clonal classified in Group 2A, in 2002). In Lyon: WHO Press, 2008.
balanced translocations involving the just 6 years, mechanistic studies 9 Lord GM, Hollstein M, Arlt VM, et al. DNA
adducts and p53 mutations in a patient with
MLL gene on chromosome 11 (11q23).7,8 convincingly showed that aristolochic aristolochic acid-associated nephropathy.
Following this line of reasoning, the acid was responsible for the high risk for Am J Kidney Dis 2004; 43: e11–17.
10 Grollman AP, Shibutani S, Moriya M, et al.
Working Group classified etoposide cancer and nephropathy in individuals
Aristolochic acid and the etiology of endemic
itself in Group 1 (previously classified who ingested material from Aristolochia (Balkan) nephropathy. Proc Natl Acad Sci USA
in Group 2A, in 2000). plants—in the form of weight-loss pills 2007; 93: 12129–34.
11 Nortier JL, Martinez MC, Schmeiser HH, et al.
When reviewing plants containing in Belgium and from cereal fields in the
Urothelial carcinoma associated with the use
aristolochic acid, the Working Group Balkans where Aristolochia plants were of a Chinese herb (Aristolochia fangchi).
reviewed new evidence that DNA growing as weeds.10,11 N Engl J Med 2000; 342: 1686–92.
www.thelancet.com/oncology Vol 10 January 2009
 News

Special Report: Policy

A review of human carcinogens—Part B: biological agents
In February, 2009, 36 scientists from
16 countries met at the International
Agency for Research on Cancer (IARC)
to reassess the carcinogenicity of
the biological agents classified as
“carcinogenic to humans” (Group 1)
and to identify additional tumour sites
and mechanisms of carcinogenesis
(tables 1 and 2). These assessments will
be published as part B of Volume 100
of the IARC Monographs.1
Hepatitis B virus (HBV) and hepatitis
C virus (HCV) infect, respectively, over
300 million and 170 million people
worldwide, mainly in Asia and Africa.
types of cancer, including naso-
pharyngeal carcinoma, one of the most
common cancers in southeastern Asia,
and Burkitt’s lymphoma in children
in Africa. New evidence points to
a role for EBV in 5–10% of gastric
carcinomas worldwide.4 EBV-positive
gastric carcinoma develops early in
life and has distinct histopathology,
therefore it might belong to a separate
clinical entity.5 In this subset of gastric
tumours, presence of the viral genome
in a monoclonal form and expression of
EBV-transforming proteins are strong
evidence for the involvement of EBV.6
that KSHV causes primary effusion
lymphoma, a rare subgroup of B-cell
non-Hodgkin lymphoma. Mechanistic
data support an oncogenic role for KSHV
in Kaposi’s sarcoma and in primary
effusion lymphoma—in individuals who
are immunocompromised and in those
apparently immunocompetent. KSHV See From the Archives page 430
is also associated with multicentric Upcoming meetings
Castleman’s disease. June 2–9, 2009
Radiation
Individuals who are infected with
September 29–October 6, 2009
HIV-1 have a high risk of cancer. HIV-1 Lifestyle Factors
infection, mainly through immuno- October 20–27, 2009
suppression, leads to increased repli- Chemical Agents and Related
cation of oncogenic viruses such as Occupations

Chronic infection with these viruses Data from 22 cohort studies and EBV and KSHV. Although antiretroviral http://monographs.iarc.fr/

is known to cause hepatocellular
carcinoma.2 Sufficient evidence is
available to conclude that chronic
infection with HCV can also cause
non-Hodgkin lymphoma, especially
B-cell lymphoma. In an intervention
study, patients with HCV infection and
splenic lymphoma who were given the
antiviral agent, interferon, showed
regression of the lymphoma.3
Epstein–Barr virus (EBV) infects
almost everyone and causes several
80 case–control studies show an
association between Kaposi’s sarcoma
herpes virus (KSHV) and Kaposi’s
sarcoma, with relative risks higher
than 10. Most studies are of transplant
recipients and people infected with
HIV-1. In both patients who are and are
not infected with HIV-1, risk of Kaposi’s
sarcoma increases relative to increasing
titre of antibodies directed against
KSHV, which are markers of the viral
load.7,8 Evidence is sufficient to show
therapy lowers the risk of many cancers
associated with HIV-1, risks remain
high.9
Cervical cancer is caused by types
of human papillomavirus (HPV) that
belong to a few phylogenetically related
“high-risk” species (alpha-5, 6, 7, 9, 11)
of the mucosotropic alpha genus.10,11 The
types found most frequently in cervical
cancer (HPV-16, 18, 31, 33, 35, 45, 52,
58) and four types less constantly found
(HPV-39, 51, 56, 59) were classified in

Group 1 agent
Epstein–Barr virus (EBV)
Hepatitis B virus (HBV)
Hepatitis C virus (HCV)
Kaposi‘s sarcoma herpes
virus (KSHV)
Human immunodeficiency
virus, type 1 (HIV-1)
Human papillomavirus
type 16 (HPV-16)†
Human T-cell lymphotrophic Adult T-cell leukaemia and lymphoma
virus, type-1 (HTLV-1)
Helicobacter pylori
Clonorchis sinensis
Opisthorchis viverrini
Schistosoma haematobium
Cancers for which there is sufficient evidence in humans Other sites with limited evidence in humans Established mechanistic events
Nasopharyngeal carcinoma, Burkitt’s lymphoma, immune- Gastric carcinoma,* lympho-epithelioma-like Cell proliferation, inhibition of apoptosis, genomic
suppression-related non-Hodgkin lymphoma, extranodal carcinoma* instability, cell migration
NK/T-cell lymphoma (nasal type), Hodgkin’s lymphoma
Hepatocellular carcinoma Cholangiocarcinoma,* non-Hodgkin lymphoma* Inflammation, liver cirrhosis, chronic hepatitis
Hepatocellular carcinoma, non-Hodgkin lymphoma* Cholangiocarcinoma* Inflammation, liver cirrhosis, liver fibrosis
Kaposi’s sarcoma,* primary effusion lymphoma* multicentric Castleman’s disease* Cell proliferation, inhibition of apoptosis, genomic
instability, cell migration
Kaposi’s sarcoma, non-Hodgkin lymphoma, Hodgkin’s Cancer of the vulva,* vagina,* penis,* non- Immunosuppression (indirect action)
lymphoma,* cancer of the cervix,* anus,* conjunctiva* melanoma skin cancer,* hepatocellular
carcinoma*
Carcinoma of the cervix, vulva, vagina, penis, anus, oral Cancer of the larynx Immortalisation, genomic instability, inhibition of
cavity, and oropharynx and tonsil DNA damage response, anti-apoptotic activity
.. Immortalisation and transformation of T cells
Non-cardia gastric carcinoma, low-grade B-cell mucosa- .. Inflammation, oxidative stress, altered cellular turn-
associated lymphoid tissue (MALT) gastric lymphoma* over and gene expression, methylation, mutation
Cholangiocarcinoma* .. ..
Cholangiocarcinoma .. Inflammation, oxidative stress, cell proliferation
Urinary bladder cancer .. Inflammation, oxidative stress

*Newly identified link between virus and cancer. †For other types, see table 2.

Table 1: Biological agents assessed by the IARC Monograph Working Group

www.thelancet.com/oncology Vol 10 April 2009 321

 News
Group HPV types
Alpha HPV types
1 16
1 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59
2A 68
2B 26, 53, 66, 67, 70, 73, 82
2B 30, 34, 69, 85, 97
3 6, 11
Beta HPV types
2B 5 and 8
3 Other beta and gamma types
Table 2: Human papillomavirus (HPV) types assessed by the IARC Monograph Working Group
Monograph Working Group
Members
T F Schulz—Co-Chair (Germany),
N Mueller—Co-Chair (USA);
A Grulich, F Sitas (Australia);
K Polman (Belgium); C J Chen,
Y Y Fang (China); R Herrero (Costa
Rica); B J Vennervald (Denmark);
R Mahieux, F Mégraud, F Zoulim
(France); H Blum, H zur Hausen
(both unable to attend)
(Germany); L Banks, A Carbone,
D Serraino (Italy); M Matsuoka
(Japan); S T Hong (South Korea);
M C Kew (South Africa);
S de Sanjosé (Spain); I Ernberg
(Sweden); B Sripa (Thailand);
A Hall, D Forman, R Newton (UK);
E Cesarman, D Dittmer,
E T H Fontham, P F Lambert,
S Moss, E Murphy, M Schiffman,
S Stuver, D Whitby (USA)
Conflicts of interest
SDS receives funding from Merck
and Sanofi-Pasteur. AG has
received funding from and is an
advisor for CSL. RM has acted as a
consultant for MP Biomedicals.
SM served on a speaker’s bureau
for Otsuka Pharmaceuticals and
was a consultant for Altana.
NuM is a member of steering
committees and a speaker’s
bureau for Merck and Sanofi-
Pasteur. EM owns stock in
Genentech. CJC received funding
from Bristol-Myer-Squibb.
Invited Specialists
N Muñoz (IARC, France; retired)
322
Comments
Most potent HPV type, known to cause cancer at several sites
Sufficient evidence for cervical cancer
Limited evidence in humans and strong mechanistic evidence for cervical cancer
Limited evidence in humans for cervical cancer
Classified by phylogenetic analogy to HPV types with sufficient or limited evidence in
humans
··
Limited evidence for skin cancer in patients with epidermodysplasia verruciformis
··
Group 1 (table 2). The risk of cancer may
be an order of magnitude higher for
HPV-16 infection than for other high-
risk HPV types. HPV-68 was classified
as “probably carcinogenic to humans”
(Group 2A) with limited evidence
in humans and strong mechanistic
evidence. The remaining types of HPV
in the high-risk alpha species were
classified as “possibly carcinogenic”
(Group 2B; table 2). Finally, HPV-6 and
HPV-11, which belong to the alpha-
10 species, were “not classifiable as
to its carcinogenicity to humans”
(Group 3) on the basis of inadequate
epidemiological evidence and absence
of carcinogenic potential in mechanistic
studies.
The Working Group recognises the
need for further research of cutaneous
HPV types of the beta and gamma
genera. These widespread HPV types
were classified in Group 3 on the basis
of inconclusive evidence of causing
skin cancer in humans and limited
mechanistic data. Exceptions were the
beta types HPV-5 and HPV-8, which
are “possibly carcinogenic” in patients
with epidermodysplasia verruciformis
(Group 2B).
Helicobacter pylori infection is
associated with gastric cancer,12 one of
the most prevalent cancers worldwide.
Prospective epidemiological studies
and eradication trials show that
H pylori infection causes non-cardia
gastric cancer.13 H pylori infection
also causes B-cell mucosa-associated
lymphoid tissue (MALT) gastric
lymphoma; eradication treatment
leads to remission of these low-grade
lymphomas.14 Several studies show
that individuals with H pylori infection
have a reduced risk of oesophageal
adenocarcinoma compared with those
without the infection.15
Opisthorchis viverrini and Clonorchis
sinensis, two liver flukes of the
genus Opisthorchis, are endemic in
northeastern Thailand and many areas
of southeastern Asia, respectively. In
particular areas, prevalence of infection
with liver flukes correlates with
incidence of cholangiocarcinoma, and
several case–control studies showed a
high risk for this cancer.16,17 Therefore,
infections with O viverrini or with C
sinensis were both classified in Group 1.
Schistosoma haematobium is endemic
in most countries in Africa and the
eastern Mediterranean region; infection
with this worm, which causes urinary
bladder cancer, is classified in Group 1.
The proportion of cancers caused
by infectious agents was recently
estimated to be more than 20%.4
The identification of new cancer sites
attributed to these agents means
that more cancers are potentially
preventable.
Véronique Bouvard, Robert Baan,
Kurt Straif, Yann Grosse,
Béatrice Secretan, Fatiha El Ghissassi,
Lamia Benbrahim-Tallaa, Neela Guha,
Crystal Freeman, Laurent Galichet,
Vincent Cogliano, on behalf of the WHO
International Agency for Research on
Cancer Monograph Working Group
International Agency for Research on
Cancer, Lyon, France
The IARC authors declared no conflicts of interest.
D Blair attended as a Representative of the US
National Cancer Institute (Bethesda, MD, USA).
F Buonaguro (NCI, Napoli, Italy) and A Fiander
(Cardiff University, Cardiff, UK) attended as Observers.
1 Grosse Y, Baan R, Straif K, et al. A review of
human carcinogens—Part A: pharmaceuticals.
Lancet Oncol 2009; 10: 13–14.
2 IARC. Hepatitis viruses. IARC Monogr Eval
Carcinog Risks Hum 1994; 59: 1–255.
3 Hermine O, Lefrere F, Bronowicki JP, et al.
Regression of splenic lymphoma with villous
lymphocytes after treatment of hepatitis C
virus infection. N Engl J Med 2002; 347: 89–94.
4 Zur Hausen H. Infections causing human cancer.
2006. Weinheim: Wiley-VCH; Chichester:
John Wiley.
5 Fukayama M, Hino R, Uozaki H. Epstein-Barr
virus and gastric carcinoma: virus-host
interactions leading to carcinoma. Cancer Sci
2008; 99: 1726–33.
6 Hino R, Uozaki H, Inoue Y, et al. Survival
advantage of EBV-associated gastric
carcinoma: surviving up-regulation by viral
latent membrane protein 2A. Cancer Res 2008;
68: 1427–35.
7 Sitas F, Carrara H, Beral V, et al. Antibodies
against human herpesvirus 8 in black South
African patients with cancer. N Engl J Med
1999; 340: 1863–71.
8 Newton R, Ziegler J, Bourboulia D, et al. The sero-
epidemiology of Kaposi’s sarcoma-associated
herpesvirus (KSHV/HHV-8) in adults with cancer
in Uganda. Int J Cancer 2003; 103: 226–32.
9 International Collaboration on HIV and Cancer.
Highly active antiretroviral therapy and
incidence of cancer in human
immunodeficiency virus-infected adults.
J Natl Cancer Inst 2000; 92: 1823–30.
10 de Villiers EM, Fauquet C, Broker TR,
Bernard HU, zur Hansen. Classification of
papillomaviruses. Virology 2004; 324: 17–27.
11 IARC. Human papillomaviruses. IARC Monogr
Eval Carcinog Risks Hum 2007; 90: 1–636.
12 IARC. Schistosomes, liver flukes and
Helicobacter pylori. IARC Working Group on the
evaluation of carcinogenic risks to humans.
Lyon, 7-14 June 1994. IARC Monogr Eval
Carcinog Risks Hum 1994; 61: 1–241.
13 Helicobacter and Cancer Collaborative Group.
Gastric cancer and Helicobacter pylori: a combined
analysis of 12 case control studies nested within
prospective cohorts. Gut 2001; 49: 347–53.
14 Wundisch T, Thiede C, Morgner A, et al.
Long-term follow-up of gastric MALT
lymphoma after Helicobacter pylori eradication.
J Clin Oncol 2005; 23: 8018–24.
15 Islami F, Kamangar F. Helicobacter pylori and
esophageal cancer risk: a meta-analysis.
Cancer Prev Res (Phila Pa) 2008; 1: 329–38.
16 Honjo S, Srivatanakul P, Sriplung H, et al.
Genetic and environmental determinants of
risk for cholangiocarcinoma via Opisthorchis
viverrini in a densely infested area in Nakhon
Phanom, northeast Thailand. Int J Cancer 2005;
117: 854–60.
17 Choi D, Lim JH, Lee KT, et al.
Cholangiocarcinoma and Clonorchis sinensis
infection: a case-control study in Korea.
J Hepatol 2006; 44: 1066–73.
www.thelancet.com/oncology Vol 10 April 2009

Special Report: Policy
A review of human carcinogens—Part C: metals, arsenic, dusts,
and fibres
In March, 2009, 27 scientists from
eight countries met at the International
Agency for Research on Cancer (IARC)
to reassess the carcinogenicity of
metals, arsenic, dusts, and fibres
previously classified as “carcinogenic
to humans” (Group 1) and to
identify additional tumour sites and
mechanisms of carcinogenesis (table).
These assessments will be published
as part C of Volume 100 of the IARC
Monographs.
Inhalation is the primary route of
exposure to arsenic in the workplace
and happens in industries such as non-
ferrous smelting, arsenic production,
wood preservation, glass manufact-
uring, production and application
of arsenic-based pesticides, and elec-
tronics. Non-occupational exposure to
arsenic is mainly through food, except
in areas with high levels of arsenic
in the drinking water—eg, Taiwan,
Bangladesh, West Bengal (India),
northern Chile, and Cordoba Province
(Argentina).1 Epidemiological studies
have shown that exposure to arsenic
through inhalation or drinking-water
Group 1 agent
Arsenic and inorganic arsenic
compounds
Beryllium and beryllium compounds Lung
Cadmium and cadmium compounds Lung
Chromium (VI) compounds
Nickel compounds
Asbestos (chrysotile, crocidolite,
amosite, tremolite, actinolite, and
anthophyllite)
Erionite
Silica dust, crystalline in the form of
quartz or crystobalite
Leather dust
Wood dust
Table: Metals, arsenic, dusts, and fibres assessed by the IARC Monograph Working Group
www.thelancet.com/oncology Vol 10 May 2009
causes cancer of the lung, skin, and
urinary bladder. Evidence suggests
an association between exposure
to arsenic in drinking water and the
development of tumours at several
other sites; however, various factors
prevent a conclusion. Analytical studies
have provided only limited information
to support an association with kidney
cancer, causes of liver cancer can be
difficult to elucidate in groups that
are high-risk for hepatitis B, and
data on prostate cancer and arsenic
exposure are not consistent between
countries. Overall, the Working
Group classified arsenic and inorganic
arsenic compounds as “carcinogenic
to humans” (Group 1). The organic
arsenicals monomethylarsonic acid
(MMA) and dimethylarsinic acid
(DMA) are the active ingredients of
some herbicides and are metabolites
of inorganic arsenic. On the basis of
sufficient evidence of cancer caused
by DMA in experimental animals,
and because MMA is extensively
metabolised to DMA, both compounds
are classified as “possibly carcinogenic
Tumour sites (or types) for which Other sites with
there is sufficient evidence in limited evidence
humans in humans
Lung, skin, urinary bladder Kidney, liver,
prostate
··
Prostate, kidney
Lung Nasal cavity and
paranasal sinuses
Lung, nasal cavity, and paranasal ··
sinuses
Lung, mesothelioma, larynx, ovary Colorectum,
pharynx, stomach
Mesothelioma ··
Lung ··
Nasal cavity and paranasal sinuses ··
Nasal cavity and paranasal sinuses, ··
nasopharynx
News
to humans” (Group 2B). Arsenobetaine
and other organic arsenic compounds
that are not metabolised in humans are
“not classifiable” (Group 3).
The Working Group reaffirmed
the classification of beryllium and its
compounds, cadmium and its com-
pounds, chromium (VI) compounds, Upcoming meetings
and nickel compounds as “carcinogenic June 2–9, 2009
Radiation
to humans” (Group 1). Studies involved
September 29–October 6, 2009
complex occupational exposures to a Lifestyle Factors
metal and its compounds, making it October 20–27, 2009
impossible to separately assess their Chemical Agents and Related
carcinogenicity. Occupations
Globally, an estimated 125 million http://monographs.iarc.fr/
people are still exposed to asbestos in
the workplace.2 Although asbestos has
been banned or restricted in most of the
industrialised world, its use is increasing
in parts of Asia, South America, and
the former Soviet Union.3 Naturally
occurring sources of asbestos, its use
in brake linings, and deterioration
of asbestos-containing products all
contribute to environmental exposure
worldwide. Exposure may also come
from fibres carried home on the
clothing of asbestos workers.4
Established mechanistic events
Oxidative DNA damage, genomic instability, aneuploidy, gene amplification, epigenetic effects,
DNA-repair inhibition leading to mutagenesis
Chromosome aberrations, aneuploidy, DNA damage
DNA-repair inhibition, disturbance of tumour-suppressor proteins leading to genomic instability
Direct DNA damage after intracellular reduction to Cr(III), mutation, genomic instability,
aneuploidy, cell transformation
DNA damage, chromosome aberrations, genomic instability, micronuclei, DNA-repair inhibition,
alteration of DNA methylation, histone modification
Impaired fibre clearance leading to macrophage activation, inflammation, generation of reactive
oxygen and nitrogen species, tissue injury, genotoxicity, aneuploidy and polyploidy, epigenetic
alteration, activation of signalling pathways, resistance to apoptosis
Genotoxicity
Impaired particle clearance leading to macrophage activation and persistent inflammation
··
··
453
 News
Monograph Working Group
Members
U Heinrich—Co-Chair (Germany),
J Samet—Co-Chair (USA);
P A Demers, M Gérin,
J Siemiatycki (Canada);
P Grandjean (Denmark); A Aitio,
T Kauppinen (Finland);
M Goldberg (France); A Hartwig,
H Muhle (Germany); B Fubini,
F Merletti (Italy); M Ikeda
(Japan); M D Attfield, K P Cantor,
B A Fowler, R Henderson,
P F Infante, AB Kane,
P J Landrigan, R Lunn,
T G Rossman, L Stayner,
M P Waalkes, E M Ward, J M Ward
(USA)
Conflicts of interest
RH served as chair of the US EPA
Clean Air Seminar Advisory
Committee from 2004 to 2008,
which reviews US air standards
for noxious gases and particulate
matter. ABK is a member of the
Science Advisory Board for the
US EPA and served as chair of
their Working Group on Asbestos
in 2008.
Invited Specialists
None
454
Epidemiological evidence has in-
creasingly shown an association
of all forms of asbestos (chrysotile,
crocidolite, amosite, tremolite,
actinolite, and anthophyllite) with
an increased risk of lung cancer and
mesothelioma. Although the potency
differences with respect to lung cancer
or mesothelioma for fibres of various
types and dimensions are debated,
the fundamental conclusion is that all
forms of asbestos are “carcinogenic to
humans” (Group 1). Mineral substances
(eg, talc or vermiculite) that contain
asbestos should also be regarded as
“carcinogenic to humans”.
Sufficient evidence is now available
to show that asbestos also causes
cancer of the larynx and of the ovary.
A meta-analysis of cohort studies
reported a relative risk of cancer of the
larynx of 1·4 (95% CI 1·2–1·6) for “any”
exposure to asbestos. With different
exposure metrics, the relative risk for
“high” exposure versus “none” was at
least 2·0 (1·6–2·5).5 Cohort studies of
women who were heavily exposed to
asbestos in the workplace consistently
report increased risks of ovarian cancer,
as in a study of women in the UK who
manufactured gas masks during World
War II.6 Studies suggest that asbestos
can accumulate in the ovaries of women
who are exposed to it.7
The Working Group classified the
evidence for an association between
asbestos and colorectal cancer as
“limited”, although members were
evenly divided as to whetherx the
evidence was strong enough to warrant
classification as “sufficient”. Further,
there is “limited” evidence in humans
for cancers of the pharynx and of the
stomach.
The mechanism of the carcinogenicity
of asbestos fibres involves a complex
interaction between the crystalline
mineral fibres and target cells. The
physicochemical properties of asbestos
fibres that are most relevant to
pathogenicity are surface chemistry
and reactivity, surface area, fibre
dimensions, and biopersistence. Direct
and indirect mechanisms have been
proposed on the basis of in-vitro cellular
assays and acute and subchronic animal
bioassays (table). Respiratory responses
to inhalation of asbestos fibres are sub-
stantially different between species, and
the biological mechanisms responsible
for these differences are unknown.
The Working Group reaffirmed the
carcinogenicity of crystalline silica dust
as Group 1. An increased risk of lung
cancer was observed across various
industries and processes.8
The Working Group reviewed
evidence of epidemiological studies of
boot and shoe manufacture and repair,
and found that sinonasal cancers can
result from exposure to leather dust and
leukaemias from exposure to benzene.
A particularly high risk of sinonasal
adenocarcinoma was noted among
workers with the highest exposure to
leather dust.9 Leather dust was classified
as “carcinogenic to humans” (Group 1).
Epidemiological studies report a
strong association between exposure
to wood dust and development of
sinonasal cancer.10 Only a few studies
included details of tumour histology
and substantial risks for sinonasal
adenocarcinoma were noted. The
few studies that assessed exposure
to specific wood types found strong
evidence of carcinogenicity for
hardwood dusts. Case–control studies
that investigated exposure to softwood
dust observed a consistent but smaller
risk, compared with hardwood dust,
mainly for squamous-cell carcinoma.
For cancer of the nasopharynx,
exposure to formaldehyde is unlikely
to be responsible for the increased
risks (compared with the reference
population) that were reported in most
case–control studies and in the pooled
reanalysis of cohort studies.11 Wood
dust was reaffirmed as “carcinogenic to
humans”.
Kurt Straif, Lamia Benbrahim-Tallaa,
Robert Baan, Yann Grosse,
Béatrice Secretan, Fatiha El Ghissassi,
Véronique Bouvard, Neela Guha,
Crystal Freeman, Laurent Galichet,
Vincent Cogliano, on behalf of the WHO
International Agency for Research on
Cancer Monograph Working Group.
International Agency for Research on
Cancer, Lyon, France
The IARC authors declared no conflicts of interest.
Attending the meeting as Representatives of their
respective health agencies were P B Larsen (Danish
Environmental Protection Agency), A Huici-Montagud
(European Commission Directorate General for
Employment, Social Affairs and Equal Opportunities),
T Bateson and R Sams (US Environmental Protection
Agency), and F Rice and M Schubauer-Berigan (US
National Institute for Occupational Safety and
Health). Attending the meeting as Observers
sponsored by various organisations were J Addison
(RT Vanderbilt Co, USA), D Bernstein and J Hoskins
(American Forest and Paper Association), M G Bird
(ExxonMobil Corp, USA), F Bochmann (German Social
Accident Insurance), G Bromfield (Canadian Cancer
Society), P Crosignani (International Society of
Doctors for the Environment, Switzerland), D Deubner
(Brush Wellman Inc, USA), M Eldan (Methanearsonic
Acid Research Task Force, USA), J Gamble (National
Stone, Sand and Gravel Association, USA), J Goodman
(Eurometaux, Belgium), TK Grimsrud (Cancer Registry
of Norway), E Kovalevskiy (Russian Academy of
Medical Sciences), R A Lemen (private consultant,
USA), P Morfeld and G Oberdörster (EUROSIL,
Belgium; EUROTALC, Belgium; Industrial Minerals
Association, North America, USA), L Neumeister
(International Social Security Association, Germany),
and A Oller (Nickel Producers Environmental Research
Association Inc, USA).
1 IARC. Some drinking-water disinfectants and
contaminants, including arsenic. IARC Monogr
Eval Carcinog Risks Hum 2004; 84: 1–477.
2 WHO. Elimination of asbestos-related diseases.
http://whqlibdoc.who.int/hq/2006/WHO_SDE_
OEH_06.03_eng.pdf (accessed April 9, 2009).
3 LaDou J. The asbestos cancer epidemic.
Environ Health Perspect 2004; 112: 285–90.
4 Anderson HA, Lilis R, Daum SM, Selikoff IJ.
Asbestosis among household contacts of
asbestos factory workers. Ann N Y Acad Sci 1979;
330: 387–99.
5 Institute of Medicine, Committee on Asbestos.
Selected health effects. Asbestos: selected
cancers. Washington, DC: National Academies
Press, 2006.
6 Acheson ED, Gardner MJ, Pippard EC, Grime LP.
Mortality of two groups of women who
manufactured gas masks from chrysotile and
crocidolite asbestos: a 40-year follow-up.
Br J Ind Med 1982; 39: 344–48.
7 Heller DS, Gordon RE, Westhoff C, Gerber S.
Asbestos exposure and ovarian fiber burden.
Am J Ind Med 1996; 29: 435–39.
8 Steenland K, Mannetje A, Boffetta P, et al.
Pooled exposure-response analyses and risk
assessment for lung cancer in 10 cohorts of
silica-exposed workers: an IARC multicentre
study. Cancer Causes Control 2001; 12: 773–84.
9 ‘tMannetje A., Kogevinas M, Luce D, et al.
Sinonasal cancer, occupation, and tobacco
smoking in European women and men.
Am J Ind Med 1999; 36: 101–07.
10 Demers PA, Boffetta P, Kogevinas M, et al.
Pooled reanalysis of cancer mortality among five
cohorts of workers in wood-related industries.
Scand J Work Environ Health 21: 1995; 179–90.
www.thelancet.com/oncology Vol 10 May 2009

Special Report: Policy
A review of human carcinogens—Part D: radiation
In June 2009, 20 scientists from nine
countries met at the International
Agency for Research on Cancer (IARC)
to reassess the carcinogenicity of the
types of radiation previously classified
as “carcinogenic to humans” (Group 1)
and to identify additional tumour sites
and mechanisms of carcinogenesis
(table and panel). These assessments
will be published as part D of Volume
100 of the IARC Monographs.1
Alpha particles, consisting of two
protons and two neutrons, are a
densely ionising type of radiation
with low capacity to penetrate living
tissue (less than 0·1 mm). Beta
particles are electrons or positrons
that are less ionising, but more
penetrating (up to a few milimetres).
The health hazards resulting from
radionuclides that emit these
particles largely occur after internal
deposition. Epidemiological evidence
shows a number of radionuclides that
emit alpha or beta particles increase
cancer risks at several anatomical sites
(table). The Working Group reaffirmed
the carcinogenicity of internally
deposited radionuclides that emit
alpha or beta particles (Group 1).
Radiation type
Alpha-particle and beta-particle emitters
Radon-222 and decay products
Radium-224 and decay products
Radium-226, radium-228, and decay products
Thorium-232 and decay products
Plutonium
Phosphorus-32
Fission products, including strontium-90
Radioiodines, including iodine-131
X-radiation or gamma-radiation
Solar radiation
UV-emitting tanning devices
CLL=chronic lymphocytic leukaemia. BCC=basal-cell carcinoma. SCC=squamous-cell carcinoma.
Table: Radiation exposures with sufficient evidence in humans
www.thelancet.com/oncology Vol 10 August 2009
After the Chernobyl accident, a
sharp increase in the risk of thyroid
cancer was found with exposure to
radioiodines, particularly iodine-131,
during childhood and adolescence.2,3
This increased risk might be due to
higher milk intake per unit of body
weight among children; a higher thyroid
dose per unit of iodine-131 intake from
milk; a higher susceptibility per unit of
thyroid dose; or a combination of these.
Radon exposure occurs mainly
through contamination of indoor
air by radon released from soil and
building materials. Combined analyses
of case–control studies now estimate
that residential exposure to radon gas
is the leading cause of lung cancer after
tobacco smoke (8–15% attributable
risk in Europe and North America).4,5
X-rays and gamma-rays are
sparsely ionising electromagnetic
radiation that penetrate living tissue,
typically producing fast electrons that
deposit energy, resulting in tissue
damage. Extensive study of atomic-
bomb survivors shows increased
cancer risks at multiple anatomical
sites.6 Current evidence adds to the
list of tumours caused by x-rays
Major study populations
General population (residential exposure), underground miners
Medical patients
Radium-dial painters
Medical patients
Plutonium-production workers
Medical patients
General population, following nuclear reactor accident
Children and adolescents, following nuclear reactor accident
Atomic-bomb survivors, medical patients; in-utero exposure (offspring
of pregnant medical patients and of atomic-bomb survivors)
General population
General population
News
and gamma-rays (table), and also
establishes that in-utero exposure
increases the risk of cancer at multiple
sites.7,8 The Working Group reaffirmed
the carcinogenicity of x-radiation and
gamma-radiation (Group 1).
Neutrons are produced by nuclear
reactions and are a main component Upcoming meetings
Sept 29–Oct 6, 2009
of cosmic radiation. They are highly
Lifestyle Factors
penetrating and interact with
Oct 20–27, 2009
the traversed tissue, producing Chemical Agents and Related
protons, other charged particles, and Occupations
gamma-radiation. Epidemiological http://monographs.iarc.fr/
evidence is inadequate to assess the
carcinogenicity of neutrons, because
of co-exposures to other types of
radiation. However, the evidence
of cancer in experimental animals
is sufficient, and mechanistic data
show that neutrons transfer their
energy in clusters of ionising events—
resulting in similar, but more severe,
local damage than that induced by
x-rays or gamma-rays. On the basis
of this evidence, the Working Group
reaffirmed the carcinogenicity of
neutron radiation (Group 1).
Each type of ionising radiation
(panel) transfers energy in the
form of highly structured tracks of
Tumour sites (and types) on which sufficient evidence is based
Lung
Bone
Bone, paranasal sinus and mastoid process (radium-226 only)
Liver, extrahepatic bile ducts, gall bladder, leukaemia (excluding CLL)
Lung, liver, bone
Acute leukaemia
Solid cancers, leukaemia
Thyroid
Salivary gland, oesophagus, stomach, colon, lung, bone, skin (BCC),
female breast, urinary bladder, brain and CNS, leukaemia (excluding CLL),
thyroid, kidney (atomic-bomb survivors, medical patients); multiple sites
(in-utero exposure)
Skin (BCC, SCC, melanoma)
Skin (melanoma), eye (melanoma, particularly choroid and ciliary body)
751
 News
Monograph Working Group
Members
B Armstrong–Co-Chair
(Australia), E Cardis–Co-Chair
(Spain); A Green (Australia);
D Krewski, R Mitchel, N Priest
(Canada); L Tomašek (Czech
Republic); K Baverstock (Finland);
J-F Doré, J Hall, L Sabatier
(France); M Sokolnikov (Russian
Federation); M Hill, M Little,
M Marshall, C Muirhead,
A Riddell (UK); D Brenner [unable
to attend], R Guilmette, D Hoel,
D Richardson, R Ullrich (USA)
Conflicts of interest
NP works for, and RM is a
consultant to, Atomic Energy of
Canada Ltd. CM receives funding
from the UK Ministry of Defence.
JH receives funding from
Electricité de France. AG receives
funding from L’Oreal Recherche.
Invited Specialists
None
752
Panel: Types of radiation classified in
Group 1
• Ionising radiation
• Alpha-particle emitters
• Beta-particle emitters
• X-rays and gamma-rays
• Neutron radiation
• Solar radiation
• Ultraviolet radiation (wavelengths
100–400 nm, encompassing UVA,
UVB, and UVC)
ionisation and excitation events that
can produce a variety of molecular
lesions and clustered, complex DNA
damage.9 Subsequent processing of
this damage induces many responses
(eg, cell killing, chromosomal
aberrations, mutations, genomic
instability, cell transformation, and
bystander effects) that contribute
to carcinogenesis. Based on these
mechanistic considerations, all types
of ionising radiation were classified by
the Working Group as “carcinogenic to
humans” (Group 1).
Solar radiation is the main source of
human exposure to ultraviolet (UV)
radiation, which is further subdivided
into UVA, UVB, and UVC. The
ultraviolet component that reaches the
earth’s surface comprises around 95%
UVA and 5% UVB; UVC is blocked by
stratospheric ozone. Epidemiological
studies have established a causal
association between exposure to solar
radiation and all major types of skin
cancer (table). The Working Group
reaffirmed the carcinogenicity of solar
radiation (Group 1).
Exposure to solar radiation causes
a specific mutation fingerprint
(cytidine to thymidine transition),
as a result of cyclobutane pyrimidine
dimers in DNA. This pattern had long
been attributed to UVB.10 However,
this same cytidine to thymidine
transition has been detected in
the skin of UVA-treated mice11 and
in the Tp53 gene of UVA-induced
or UVB-induced skin tumours in
hairless mice.10 In humans, this
transition has been seen in TP53 in
premalignant solar keratosis and in
malignant skin tumours.12 Based on
these mechanistic data, the Working
Group classified UV radiation as
“carcinogenic to humans” (Group 1).
The use of UV-emitting tanning
devices is widespread in many
developed countries, especially among
young women. A comprehensive
meta-analysis concluded that the risk
of cutaneous melanoma is increased
by 75% when use of tanning devices
starts before 30 years of age.13
Additionally, several case–control
studies provide consistent evidence
of a positive association between
the use of UV-emitting tanning
devices and ocular melanoma.14,15
Therefore, the Working Group raised
the classification of the use of UV-
emitting tanning devices to Group 1,
“carcinogenic to humans”.
While reviewing the studies of
occupational UV exposure, the
Working Group concluded that there
is “sufficient evidence” for ocular
melanoma in welders.16,17 However,
because welders are also exposed to
other harmful agents, this association
could not be attributed specifically
to UV radiation. A full review of the
carcinogenic hazards of welding will
be undertaken by IARC with high
priority.
Fatiha El Ghissassi, Robert Baan, Kurt
Straif, Yann Grosse, Béatrice
Secretan, Véronique Bouvard, Lamia
Benbrahim-Tallaa, Neela Guha,
Crystal Freeman, Laurent Galichet,
Vincent Cogliano, on behalf of the
WHO International Agency for
Research on Cancer Monograph
Working Group
International Agency for Research on
Cancer, Lyon, France
The IARC authors declared no conflicts of interest.
1 Grosse Y, Baan R, Straif K, et al. A review of
human carcinogens—part A: pharmaceuticals.
Lancet Oncol 2009; 10: 13–14.
2 UN Chernobyl Forum expert group “Health”
(EGH). Health effects of the Chernobyl
accident and special health care programmes.
Geneva; 2006. http://whqlibdoc.who.int/publi
cations/2006/9241594179_eng.pdf.
www.thelancet.com/oncology Vol 10 August 2009
3 Cardis E, Howe G, Ron E, et al. Cancer
consequences of the Chernobyl accident:
20 years on. J Radiol Prot 2006; 26: 127–40.
4 Darby S, Hill D, Auvinen A, et al. Radon in
homes and risk of lung cancer: collaborative
analysis of individual data from 13 European
case–control studies. BMJ 2005; 330: 223.
5 National Research Council, Committee to
Assess Health Risks from Exposure to Low
Levels of Ionizing Radiation, Board on
Radiation Effects, and Research Division on
Earth and Life Studies. Health effects of
exposure to radon: BEIR VI. Washington:
National Academies Press; 1999.
6 National Research Council, Committee to
Assess Health Risks from Exposure to Low
Levels of Ionizing Radiation, Board on
Radiation Effects, and Research Division on
Earth and Life Studies. Health risks from
exposure to low levels of ionizing radiation:
BEIR VII, Phase 2. Washington: National
Academies Press; 2006.
7 Wakeford R, Little MP. Risk coefficients for
childhood cancer after intrauterine irradiation:
a review. Int J Radiat Biol 2003; 79: 293–309.
8 Preston DL, Cullings H, Suyama A, et al. Solid
cancer incidence in atomic bomb survivors
exposed in utero or as young children.
J Natl Cancer Inst 2008; 100: 428–36.
9 Goodhead DT. Initial events in the cellular
effects of ionizing radiations: clustered
damage in DNA. Int J Radiat Biol 1994;
65: 7–17.
10 Runger TM, Kappes UP. Mechanisms of
mutation formation with long-wave
ultraviolet light (UVA). Photodermatol
Photoimmunol Photomed 2008; 24: 2–10.
11 Ikehata H, Kawai K, Komura J, et al. UVA1
genotoxicity is mediated not by oxidative
damage but by cyclobutane pyrimidine dimers
in normal mouse skin. J Invest Dermatol 2008;
128: 2289–96.
12 Agar NS, Halliday GM, Barnetson RS,
Ananthaswamy HN, Wheeler M, Jones AM.
The basal layer in human squamous tumors
harbors more UVA than UVB fingerprint
mutations: a role for UVA in human skin
carcinogenesis. Proc Natl Acad Sci USA 2004;
101: 4954–59.
13 IARC Working Group. The association of use of
sunbeds with cutaneous malignant melanoma
and other skin cancers: a systematic review.
Int J Cancer 2006; 120: 1116–22.
14 Seddon JM, Gragoudas ES, Glynn RJ, Egan KM,
Albert DM, Blitzer PH. Host factors, UV
radiation, and risk of uveal melanoma: a
case-control study. Arch Ophthalmol 1990;
108: 1274–80.
15 Vajdic CM, Kricker A, Giblin M, et al. Artificial
ultraviolet radiation and ocular melanoma in
Australia. Int J Cancer 2004; 112: 896–900.
16 Lutz JM, Cree I, Sabroe S, et al. Occupational
risks for uveal melanoma results from a case-
control study in nine European countries.
Cancer Causes Control 2005; 16: 437–47.
17 Shah CP, Weis E, Lajous M, Shields JA,
Shields CL. Intermittent and chronic ultraviolet
light exposure and uveal melanoma: a meta-
analysis. Ophthalmology 2005; 112: 1599–607.