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Special Report: Policy

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

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

Table 1: Hormonal treatments assessed by the IARC Monograph Working Group xx Vol 10 January 2009 13


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
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
Monograph Working Group Ciclosporin Non-Hodgkin lymphoma, skin, Immunosuppression hormonal therapy. Lyon: International Agency
Members multiple other sites for Research on Cancer 1999.
A B Miller—Co-Chair (Canada), Methoxsalen+ultraviolet Skin Genotoxicity following photo-activation 2 Zhou B, Sun Q, Cong R, et al. Hormone
D H Phillips—Co-Chair (UK); light replacement therapy and ovarian cancer risk:
J Kaldor (Australia); J H Olsen a meta-analysis. Gynecol Oncol 2008;
Plants containing Renal pelvis, ureter Genotoxicity, DNA adducts in humans,
(Denmark); M R Berger, 108: 641–51.
aristolochic acid A:T→T:A transversions in TP53 in
H H Schmeiser (Germany); 3 Greiser CM, Greiser EM, Dören M. Menopausal
human tumours
H Tsuda (Japan); S H Kim (unable hormone therapy and risk of ovarian cancer:
to attend, Republic of Korea); Aristolochic acid ·· Genotoxicity, DNA adducts in animals systematic review and meta-analysis.
B C Baguley (New Zealand); (Group 2A in 2002) are the same as those found in humans Hum Reprod Update 2007; 13: 453–63.
M Marques (Portugal); P Karran exposed to plants, A:T→T:A 4 Jemal A, Ward E, Thun MJ. Recent trends in
(UK); E Barrett-Connor, transversions in TP53, RAS activation breast cancer incidence rates by age and tumor
F A Beland, J L Bolton (unable to Analgesic mixtures Renal pelvis, ureter (See phenacetin) characteristics among U.S. women.
attend), M C Bosland, J F Buell, containing phenacetin Breast Cancer Res 2007; 9: R28.
D Eastmond, C J Jameson, 5 IARC. IARC Monographs on the Evaluation of
Phenacetin Renal pelvis, ureter Genotoxicity, cell proliferation Carcinogenic Risks to Humans. Volume 91.
D G Kaufman, A A Molinolo, (Group 2A in 1987) Combined estrogen-progestogen contraceptives
C A Schiffer, L Titus-Ernstoff,
and combined estrogen-progestogen
D B Thomas (USA) MOPP=chlormethine (mechlorethamine), vincristine (oncovin), procarbazine, and prednisone menopausal therapy. Lyon: International Agency
Conflicts of interest for Research on Cancer 2007.
DE has previously received Table 2: Antineoplastic drugs and other drugs evaluated by the IARC Monograph Working Group
6 McCredie M, Stewart JH, Day NE. Different
funding from, and acted as roles for phenacetin and paracetamol in cancer
consultant to, Johnson & of the kidney and renal pelvis. Int J Cancer
Johnson. He currently receives acute myeloid leukaemia induced by adducts and A:T→T:A transversions in 1993; 53: 245–49.
funding from Pfizer. Both of alkylating agents, such as busulfan, TP53 induced by aristolochic acid were 7 Pedersen-Bjergaard J, Christiansen DH, Desta F,
these companies manufacture et al. Alternative genetic pathways and
hormone-based contraceptives.
frequently exhibits clonal loss (partial found in patients with nephropathy cooperating genetic abnormalities in the
JK is deputy director of the Centre or total) of either chromosome 5 or urothelial tumours after ingestion pathogenesis of therapy-related
myelodysplasia and acute myeloid leukemia.
in HIV Epidemiology and Clinical or 7, thereby distinguishing it from of material from Aristolochia plant Leukemia 2006; 11: 1943–49.
Research, University of New
South Wales, Australia, which
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.
receives partial funding from Swerdlow SH, Campo E, Harris NL, et al, eds.
Hoffman-La Roche, Bristol-Myers etoposide. The latter shows clonal classified in Group 2A, in 2002). In Lyon: WHO Press, 2008.
Squibb, Pfizer, and Johnson &
balanced translocations involving the just 6 years, mechanistic studies 9 Lord GM, Hollstein M, Arlt VM, et al. DNA
Johnson. All of these companies adducts and p53 mutations in a patient with
manufacture drugs, or MLL gene on chromosome 11 (11q23).7,8 convincingly showed that aristolochic aristolochic acid-associated nephropathy.
alternatives to drugs, mentioned Following this line of reasoning, the acid was responsible for the high risk for Am J Kidney Dis 2004; 43: e11–17.
in this article 10 Grollman AP, Shibutani S, Moriya M, et al.
Working Group classified etoposide cancer and nephropathy in individuals
Invited Specialists 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.
Representatives 11 Nortier JL, Martinez MC, Schmeiser HH, et al.
None When reviewing plants containing in Belgium and from cereal fields in the
Urothelial carcinoma associated with the use
Observers aristolochic acid, the Working Group Balkans where Aristolochia plants were of a Chinese herb (Aristolochia fangchi).
M G Bird (ExxonMobil Corp, USA) reviewed new evidence that DNA growing as weeds.10,11 N Engl J Med 2000; 342: 1686–92.

14 Vol 10 January 2009


Special Report: Policy

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

Chronic infection with these viruses Data from 22 cohort studies and EBV and KSHV. Although antiretroviral

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

Group 1 agent Cancers for which there is sufficient evidence in humans Other sites with limited evidence in humans Established mechanistic events
Epstein–Barr virus (EBV) 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
Hepatitis B virus (HBV) Hepatocellular carcinoma Cholangiocarcinoma,* non-Hodgkin lymphoma* Inflammation, liver cirrhosis, chronic hepatitis
Hepatitis C virus (HCV) Hepatocellular carcinoma, non-Hodgkin lymphoma* Cholangiocarcinoma* Inflammation, liver cirrhosis, liver fibrosis
Kaposi‘s sarcoma herpes Kaposi’s sarcoma,* primary effusion lymphoma* multicentric Castleman’s disease* Cell proliferation, inhibition of apoptosis, genomic
virus (KSHV) instability, cell migration
Human immunodeficiency Kaposi’s sarcoma, non-Hodgkin lymphoma, Hodgkin’s Cancer of the vulva,* vagina,* penis,* non- Immunosuppression (indirect action)
virus, type 1 (HIV-1) lymphoma,* cancer of the cervix,* anus,* conjunctiva* melanoma skin cancer,* hepatocellular
Human papillomavirus Carcinoma of the cervix, vulva, vagina, penis, anus, oral Cancer of the larynx Immortalisation, genomic instability, inhibition of
type 16 (HPV-16)† cavity, and oropharynx and tonsil DNA damage response, anti-apoptotic activity
Human T-cell lymphotrophic Adult T-cell leukaemia and lymphoma .. Immortalisation and transformation of T cells
virus, type-1 (HTLV-1)
Helicobacter pylori 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
Clonorchis sinensis Cholangiocarcinoma* .. ..
Opisthorchis viverrini Cholangiocarcinoma .. Inflammation, oxidative stress, cell proliferation
Schistosoma haematobium 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 Vol 10 April 2009 321


Group HPV types Comments

International Agency for Research on
Cancer, Lyon, France
Alpha HPV types
The IARC authors declared no conflicts of interest.
1 16 Most potent HPV type, known to cause cancer at several sites
1 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59 Sufficient evidence for cervical cancer D Blair attended as a Representative of the US
National Cancer Institute (Bethesda, MD, USA).
2A 68 Limited evidence in humans and strong mechanistic evidence for cervical cancer F Buonaguro (NCI, Napoli, Italy) and A Fiander
2B 26, 53, 66, 67, 70, 73, 82 Limited evidence in humans for cervical cancer (Cardiff University, Cardiff, UK) attended as Observers.
2B 30, 34, 69, 85, 97 Classified by phylogenetic analogy to HPV types with sufficient or limited evidence in 1 Grosse Y, Baan R, Straif K, et al. A review of
humans human carcinogens—Part A: pharmaceuticals.
3 6, 11 ·· Lancet Oncol 2009; 10: 13–14.
2 IARC. Hepatitis viruses. IARC Monogr Eval
Beta HPV types
Carcinog Risks Hum 1994; 59: 1–255.
2B 5 and 8 Limited evidence for skin cancer in patients with epidermodysplasia verruciformis 3 Hermine O, Lefrere F, Bronowicki JP, et al.
3 Other beta and gamma types ·· Regression of splenic lymphoma with villous
lymphocytes after treatment of hepatitis C
Table 2: Human papillomavirus (HPV) types assessed by the IARC Monograph Working Group 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.
Monograph Working Group Group 1 (table 2). The risk of cancer may lymphoma; eradication treatment 5 Fukayama M, Hino R, Uozaki H. Epstein-Barr
Members be an order of magnitude higher for leads to remission of these low-grade virus and gastric carcinoma: virus-host
T F Schulz—Co-Chair (Germany), interactions leading to carcinoma. Cancer Sci
N Mueller—Co-Chair (USA); HPV-16 infection than for other high- lymphomas.14 Several studies show
2008; 99: 1726–33.
A Grulich, F Sitas (Australia); risk HPV types. HPV-68 was classified that individuals with H pylori infection 6 Hino R, Uozaki H, Inoue Y, et al. Survival
K Polman (Belgium); C J Chen, as “probably carcinogenic to humans” have a reduced risk of oesophageal advantage of EBV-associated gastric
Y Y Fang (China); R Herrero (Costa carcinoma: surviving up-regulation by viral
Rica); B J Vennervald (Denmark); (Group 2A) with limited evidence adenocarcinoma compared with those latent membrane protein 2A. Cancer Res 2008;
R Mahieux, F Mégraud, F Zoulim in humans and strong mechanistic without the infection.15 68: 1427–35.
(France); H Blum, H zur Hausen evidence. The remaining types of HPV Opisthorchis viverrini and Clonorchis 7 Sitas F, Carrara H, Beral V, et al. Antibodies
(both unable to attend) against human herpesvirus 8 in black South
(Germany); L Banks, A Carbone, in the high-risk alpha species were sinensis, two liver flukes of the African patients with cancer. N Engl J Med
D Serraino (Italy); M Matsuoka classified as “possibly carcinogenic” genus Opisthorchis, are endemic in 1999; 340: 1863–71.
(Japan); S T Hong (South Korea); 8 Newton R, Ziegler J, Bourboulia D, et al. The sero-
(Group 2B; table 2). Finally, HPV-6 and northeastern Thailand and many areas
M C Kew (South Africa); epidemiology of Kaposi’s sarcoma-associated
S de Sanjosé (Spain); I Ernberg HPV-11, which belong to the alpha- of southeastern Asia, respectively. In herpesvirus (KSHV/HHV-8) in adults with cancer
(Sweden); B Sripa (Thailand); 10 species, were “not classifiable as particular areas, prevalence of infection in Uganda. Int J Cancer 2003; 103: 226–32.
A Hall, D Forman, R Newton (UK); 9 International Collaboration on HIV and Cancer.
to its carcinogenicity to humans” with liver flukes correlates with Highly active antiretroviral therapy and
E Cesarman, D Dittmer,
E T H Fontham, P F Lambert, (Group 3) on the basis of inadequate incidence of cholangiocarcinoma, and incidence of cancer in human
S Moss, E Murphy, M Schiffman, epidemiological evidence and absence several case–control studies showed a immunodeficiency virus-infected adults.
S Stuver, D Whitby (USA) J Natl Cancer Inst 2000; 92: 1823–30.
of carcinogenic potential in mechanistic high risk for this cancer.16,17 Therefore, 10 de Villiers EM, Fauquet C, Broker TR,
Conflicts of interest
studies. infections with O viverrini or with C Bernard HU, zur Hansen. Classification of
SDS receives funding from Merck papillomaviruses. Virology 2004; 324: 17–27.
and Sanofi-Pasteur. AG has The Working Group recognises the sinensis were both classified in Group 1.
11 IARC. Human papillomaviruses. IARC Monogr
received funding from and is an need for further research of cutaneous Schistosoma haematobium is endemic Eval Carcinog Risks Hum 2007; 90: 1–636.
advisor for CSL. RM has acted as a
HPV types of the beta and gamma in most countries in Africa and the 12 IARC. Schistosomes, liver flukes and
consultant for MP Biomedicals. Helicobacter pylori. IARC Working Group on the
SM served on a speaker’s bureau genera. These widespread HPV types eastern Mediterranean region; infection evaluation of carcinogenic risks to humans.
for Otsuka Pharmaceuticals and were classified in Group 3 on the basis with this worm, which causes urinary Lyon, 7-14 June 1994. IARC Monogr Eval
was a consultant for Altana. Carcinog Risks Hum 1994; 61: 1–241.
of inconclusive evidence of causing bladder cancer, is classified in Group 1.
NuM is a member of steering 13 Helicobacter and Cancer Collaborative Group.
committees and a speaker’s skin cancer in humans and limited The proportion of cancers caused Gastric cancer and Helicobacter pylori: a combined
bureau for Merck and Sanofi- mechanistic data. Exceptions were the by infectious agents was recently analysis of 12 case control studies nested within
Pasteur. EM owns stock in prospective cohorts. Gut 2001; 49: 347–53.
beta types HPV-5 and HPV-8, which estimated to be more than 20%.4
Genentech. CJC received funding 14 Wundisch T, Thiede C, Morgner A, et al.
from Bristol-Myer-Squibb. are “possibly carcinogenic” in patients The identification of new cancer sites Long-term follow-up of gastric MALT
Invited Specialists with epidermodysplasia verruciformis attributed to these agents means lymphoma after Helicobacter pylori eradication.
J Clin Oncol 2005; 23: 8018–24.
N Muñoz (IARC, France; retired) (Group 2B). that more cancers are potentially
15 Islami F, Kamangar F. Helicobacter pylori and
Helicobacter pylori infection is preventable. esophageal cancer risk: a meta-analysis.
associated with gastric cancer,12 one of Cancer Prev Res (Phila Pa) 2008; 1: 329–38.
Véronique Bouvard, Robert Baan, 16 Honjo S, Srivatanakul P, Sriplung H, et al.
the most prevalent cancers worldwide. Kurt Straif, Yann Grosse, Genetic and environmental determinants of
Prospective epidemiological studies Béatrice Secretan, Fatiha El Ghissassi, risk for cholangiocarcinoma via Opisthorchis
and eradication trials show that viverrini in a densely infested area in Nakhon
Lamia Benbrahim-Tallaa, Neela Guha, Phanom, northeast Thailand. Int J Cancer 2005;
H pylori infection causes non-cardia Crystal Freeman, Laurent Galichet, 117: 854–60.
gastric cancer.13 H pylori infection Vincent Cogliano, on behalf of the WHO 17 Choi D, Lim JH, Lee KT, et al.
Cholangiocarcinoma and Clonorchis sinensis
also causes B-cell mucosa-associated International Agency for Research on infection: a case-control study in Korea.
lymphoid tissue (MALT) gastric Cancer Monograph Working Group J Hepatol 2006; 44: 1066–73.

322 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 causes cancer of the lung, skin, and to humans” (Group 2B). Arsenobetaine
eight countries met at the International urinary bladder. Evidence suggests and other organic arsenic compounds
Agency for Research on Cancer (IARC) an association between exposure that are not metabolised in humans are
to reassess the carcinogenicity of to arsenic in drinking water and the “not classifiable” (Group 3).
metals, arsenic, dusts, and fibres development of tumours at several The Working Group reaffirmed
previously classified as “carcinogenic other sites; however, various factors the classification of beryllium and its
to humans” (Group 1) and to prevent a conclusion. Analytical studies compounds, cadmium and its com-
identify additional tumour sites and have provided only limited information pounds, chromium (VI) compounds, Upcoming meetings
mechanisms of carcinogenesis (table). to support an association with kidney and nickel compounds as “carcinogenic June 2–9, 2009
These assessments will be published cancer, causes of liver cancer can be to humans” (Group 1). Studies involved
September 29–October 6, 2009
as part C of Volume 100 of the IARC difficult to elucidate in groups that complex occupational exposures to a Lifestyle Factors
Monographs. are high-risk for hepatitis B, and metal and its compounds, making it October 20–27, 2009
Inhalation is the primary route of data on prostate cancer and arsenic impossible to separately assess their Chemical Agents and Related
exposure to arsenic in the workplace exposure are not consistent between carcinogenicity. Occupations

and happens in industries such as non- countries. Overall, the Working Globally, an estimated 125 million

ferrous smelting, arsenic production, Group classified arsenic and inorganic people are still exposed to asbestos in
wood preservation, glass manufact- arsenic compounds as “carcinogenic the workplace.2 Although asbestos has
uring, production and application to humans” (Group 1). The organic been banned or restricted in most of the
of arsenic-based pesticides, and elec- arsenicals monomethylarsonic acid industrialised world, its use is increasing
tronics. Non-occupational exposure to (MMA) and dimethylarsinic acid in parts of Asia, South America, and
arsenic is mainly through food, except (DMA) are the active ingredients of the former Soviet Union.3 Naturally
in areas with high levels of arsenic some herbicides and are metabolites occurring sources of asbestos, its use
in the drinking water—eg, Taiwan, of inorganic arsenic. On the basis of in brake linings, and deterioration
Bangladesh, West Bengal (India), sufficient evidence of cancer caused of asbestos-containing products all
northern Chile, and Cordoba Province by DMA in experimental animals, contribute to environmental exposure
(Argentina).1 Epidemiological studies and because MMA is extensively worldwide. Exposure may also come
have shown that exposure to arsenic metabolised to DMA, both compounds from fibres carried home on the
through inhalation or drinking-water are classified as “possibly carcinogenic clothing of asbestos workers.4

Group 1 agent Tumour sites (or types) for which Other sites with Established mechanistic events
there is sufficient evidence in limited evidence
humans in humans
Arsenic and inorganic arsenic Lung, skin, urinary bladder Kidney, liver, Oxidative DNA damage, genomic instability, aneuploidy, gene amplification, epigenetic effects,
compounds prostate DNA-repair inhibition leading to mutagenesis
Beryllium and beryllium compounds Lung ·· Chromosome aberrations, aneuploidy, DNA damage
Cadmium and cadmium compounds Lung Prostate, kidney DNA-repair inhibition, disturbance of tumour-suppressor proteins leading to genomic instability
Chromium (VI) compounds Lung Nasal cavity and Direct DNA damage after intracellular reduction to Cr(III), mutation, genomic instability,
paranasal sinuses aneuploidy, cell transformation
Nickel compounds Lung, nasal cavity, and paranasal ·· DNA damage, chromosome aberrations, genomic instability, micronuclei, DNA-repair inhibition,
sinuses alteration of DNA methylation, histone modification
Asbestos (chrysotile, crocidolite, Lung, mesothelioma, larynx, ovary Colorectum, Impaired fibre clearance leading to macrophage activation, inflammation, generation of reactive
amosite, tremolite, actinolite, and pharynx, stomach oxygen and nitrogen species, tissue injury, genotoxicity, aneuploidy and polyploidy, epigenetic
anthophyllite) alteration, activation of signalling pathways, resistance to apoptosis
Erionite Mesothelioma ·· Genotoxicity
Silica dust, crystalline in the form of Lung ·· Impaired particle clearance leading to macrophage activation and persistent inflammation
quartz or crystobalite
Leather dust Nasal cavity and paranasal sinuses ·· ··
Wood dust Nasal cavity and paranasal sinuses, ·· ··

Table: Metals, arsenic, dusts, and fibres assessed by the IARC Monograph Working Group Vol 10 May 2009 453


Monograph Working Group Epidemiological evidence has in- proposed on the basis of in-vitro cellular International Agency for Research on
creasingly shown an association assays and acute and subchronic animal Cancer Monograph Working Group.
U Heinrich—Co-Chair (Germany),
J Samet—Co-Chair (USA); of all forms of asbestos (chrysotile, bioassays (table). Respiratory responses International Agency for Research on
P A Demers, M Gérin, crocidolite, amosite, tremolite, to inhalation of asbestos fibres are sub- Cancer, Lyon, France
J Siemiatycki (Canada); actinolite, and anthophyllite) with stantially different between species, and The IARC authors declared no conflicts of interest.
P Grandjean (Denmark); A Aitio,
T Kauppinen (Finland); an increased risk of lung cancer and the biological mechanisms responsible Attending the meeting as Representatives of their
M Goldberg (France); A Hartwig, mesothelioma. Although the potency for these differences are unknown. respective health agencies were P B Larsen (Danish
H Muhle (Germany); B Fubini, differences with respect to lung cancer The Working Group reaffirmed the Environmental Protection Agency), A Huici-Montagud
F Merletti (Italy); M Ikeda (European Commission Directorate General for
(Japan); M D Attfield, K P Cantor,
or mesothelioma for fibres of various carcinogenicity of crystalline silica dust Employment, Social Affairs and Equal Opportunities),
B A Fowler, R Henderson, types and dimensions are debated, as Group 1. An increased risk of lung T Bateson and R Sams (US Environmental Protection
P F Infante, AB Kane, the fundamental conclusion is that all cancer was observed across various Agency), and F Rice and M Schubauer-Berigan (US
P J Landrigan, R Lunn, National Institute for Occupational Safety and
T G Rossman, L Stayner,
forms of asbestos are “carcinogenic to industries and processes.8 Health). Attending the meeting as Observers
M P Waalkes, E M Ward, J M Ward humans” (Group 1). Mineral substances The Working Group reviewed sponsored by various organisations were J Addison
(USA) (eg, talc or vermiculite) that contain evidence of epidemiological studies of (RT Vanderbilt Co, USA), D Bernstein and J Hoskins
(American Forest and Paper Association), M G Bird
Conflicts of interest asbestos should also be regarded as boot and shoe manufacture and repair, (ExxonMobil Corp, USA), F Bochmann (German Social
RH served as chair of the US EPA
“carcinogenic to humans”. and found that sinonasal cancers can Accident Insurance), G Bromfield (Canadian Cancer
Clean Air Seminar Advisory
Sufficient evidence is now available result from exposure to leather dust and Society), P Crosignani (International Society of
Committee from 2004 to 2008,
Doctors for the Environment, Switzerland), D Deubner
which reviews US air standards to show that asbestos also causes leukaemias from exposure to benzene. (Brush Wellman Inc, USA), M Eldan (Methanearsonic
for noxious gases and particulate
cancer of the larynx and of the ovary. A particularly high risk of sinonasal Acid Research Task Force, USA), J Gamble (National
matter. ABK is a member of the
Science Advisory Board for the A meta-analysis of cohort studies adenocarcinoma was noted among Stone, Sand and Gravel Association, USA), J Goodman
(Eurometaux, Belgium), TK Grimsrud (Cancer Registry
US EPA and served as chair of reported a relative risk of cancer of the workers with the highest exposure to of Norway), E Kovalevskiy (Russian Academy of
their Working Group on Asbestos larynx of 1·4 (95% CI 1·2–1·6) for “any” leather dust.9 Leather dust was classified Medical Sciences), R A Lemen (private consultant,
in 2008.
exposure to asbestos. With different as “carcinogenic to humans” (Group 1). USA), P Morfeld and G Oberdörster (EUROSIL,
Invited Specialists Belgium; EUROTALC, Belgium; Industrial Minerals
None exposure metrics, the relative risk for Epidemiological studies report a
Association, North America, USA), L Neumeister
“high” exposure versus “none” was at strong association between exposure (International Social Security Association, Germany),
least 2·0 (1·6–2·5).5 Cohort studies of to wood dust and development of and A Oller (Nickel Producers Environmental Research
women who were heavily exposed to sinonasal cancer.10 Only a few studies Association Inc, USA).

asbestos in the workplace consistently included details of tumour histology 1 IARC. Some drinking-water disinfectants and
contaminants, including arsenic. IARC Monogr
report increased risks of ovarian cancer, and substantial risks for sinonasal Eval Carcinog Risks Hum 2004; 84: 1–477.
as in a study of women in the UK who adenocarcinoma were noted. The 2 WHO. Elimination of asbestos-related diseases.
manufactured gas masks during World few studies that assessed exposure OEH_06.03_eng.pdf (accessed April 9, 2009).
War II.6 Studies suggest that asbestos to specific wood types found strong 3 LaDou J. The asbestos cancer epidemic.
can accumulate in the ovaries of women evidence of carcinogenicity for Environ Health Perspect 2004; 112: 285–90.
who are exposed to it.7 hardwood dusts. Case–control studies 4 Anderson HA, Lilis R, Daum SM, Selikoff IJ.
Asbestosis among household contacts of
The Working Group classified the that investigated exposure to softwood asbestos factory workers. Ann N Y Acad Sci 1979;
evidence for an association between dust observed a consistent but smaller 330: 387–99.
5 Institute of Medicine, Committee on Asbestos.
asbestos and colorectal cancer as risk, compared with hardwood dust, Selected health effects. Asbestos: selected
“limited”, although members were mainly for squamous-cell carcinoma. cancers. Washington, DC: National Academies
evenly divided as to whetherx the For cancer of the nasopharynx, Press, 2006.
6 Acheson ED, Gardner MJ, Pippard EC, Grime LP.
evidence was strong enough to warrant exposure to formaldehyde is unlikely Mortality of two groups of women who
classification as “sufficient”. Further, to be responsible for the increased manufactured gas masks from chrysotile and
crocidolite asbestos: a 40-year follow-up.
there is “limited” evidence in humans risks (compared with the reference Br J Ind Med 1982; 39: 344–48.
for cancers of the pharynx and of the population) that were reported in most 7 Heller DS, Gordon RE, Westhoff C, Gerber S.
stomach. case–control studies and in the pooled Asbestos exposure and ovarian fiber burden.
Am J Ind Med 1996; 29: 435–39.
The mechanism of the carcinogenicity reanalysis of cohort studies.11 Wood 8 Steenland K, Mannetje A, Boffetta P, et al.
of asbestos fibres involves a complex dust was reaffirmed as “carcinogenic to Pooled exposure-response analyses and risk
interaction between the crystalline humans”. assessment for lung cancer in 10 cohorts of
silica-exposed workers: an IARC multicentre
mineral fibres and target cells. The study. Cancer Causes Control 2001; 12: 773–84.
physicochemical properties of asbestos Kurt Straif, Lamia Benbrahim-Tallaa, 9 ‘tMannetje A., Kogevinas M, Luce D, et al.
Sinonasal cancer, occupation, and tobacco
fibres that are most relevant to Robert Baan, Yann Grosse, smoking in European women and men.
pathogenicity are surface chemistry Béatrice Secretan, Fatiha El Ghissassi, Am J Ind Med 1999; 36: 101–07.
and reactivity, surface area, fibre Véronique Bouvard, Neela Guha, 10 Demers PA, Boffetta P, Kogevinas M, et al.
Pooled reanalysis of cancer mortality among five
dimensions, and biopersistence. Direct Crystal Freeman, Laurent Galichet, cohorts of workers in wood-related industries.
and indirect mechanisms have been Vincent Cogliano, on behalf of the WHO Scand J Work Environ Health 21: 1995; 179–90.

454 Vol 10 May 2009


Special Report: Policy

A review of human carcinogens—Part D: radiation
In June 2009, 20 scientists from nine After the Chernobyl accident, a and gamma-rays (table), and also
countries met at the International sharp increase in the risk of thyroid establishes that in-utero exposure
Agency for Research on Cancer (IARC) cancer was found with exposure to increases the risk of cancer at multiple
to reassess the carcinogenicity of the radioiodines, particularly iodine-131, sites.7,8 The Working Group reaffirmed
types of radiation previously classified during childhood and adolescence.2,3 the carcinogenicity of x-radiation and
as “carcinogenic to humans” (Group 1) This increased risk might be due to gamma-radiation (Group 1).
and to identify additional tumour sites higher milk intake per unit of body Neutrons are produced by nuclear
and mechanisms of carcinogenesis weight among children; a higher thyroid reactions and are a main component Upcoming meetings
Sept 29–Oct 6, 2009
(table and panel). These assessments dose per unit of iodine-131 intake from of cosmic radiation. They are highly
Lifestyle Factors
will be published as part D of Volume milk; a higher susceptibility per unit of penetrating and interact with
Oct 20–27, 2009
100 of the IARC Monographs.1 thyroid dose; or a combination of these. the traversed tissue, producing Chemical Agents and Related
Alpha particles, consisting of two Radon exposure occurs mainly protons, other charged particles, and Occupations
protons and two neutrons, are a through contamination of indoor gamma-radiation. Epidemiological
densely ionising type of radiation air by radon released from soil and evidence is inadequate to assess the
with low capacity to penetrate living building materials. Combined analyses carcinogenicity of neutrons, because
tissue (less than 0·1 mm). Beta of case–control studies now estimate of co-exposures to other types of
particles are electrons or positrons that residential exposure to radon gas radiation. However, the evidence
that are less ionising, but more is the leading cause of lung cancer after of cancer in experimental animals
penetrating (up to a few milimetres). tobacco smoke (8–15% attributable is sufficient, and mechanistic data
The health hazards resulting from risk in Europe and North America).4,5 show that neutrons transfer their
radionuclides that emit these X-rays and gamma-rays are energy in clusters of ionising events—
particles largely occur after internal sparsely ionising electromagnetic resulting in similar, but more severe,
deposition. Epidemiological evidence radiation that penetrate living tissue, local damage than that induced by
shows a number of radionuclides that typically producing fast electrons that x-rays or gamma-rays. On the basis
emit alpha or beta particles increase deposit energy, resulting in tissue of this evidence, the Working Group
cancer risks at several anatomical sites damage. Extensive study of atomic- reaffirmed the carcinogenicity of
(table). The Working Group reaffirmed bomb survivors shows increased neutron radiation (Group 1).
the carcinogenicity of internally cancer risks at multiple anatomical Each type of ionising radiation
deposited radionuclides that emit sites.6 Current evidence adds to the (panel) transfers energy in the
alpha or beta particles (Group 1). list of tumours caused by x-rays form of highly structured tracks of

Radiation type Major study populations Tumour sites (and types) on which sufficient evidence is based
Alpha-particle and beta-particle emitters
Radon-222 and decay products General population (residential exposure), underground miners Lung
Radium-224 and decay products Medical patients Bone
Radium-226, radium-228, and decay products Radium-dial painters Bone, paranasal sinus and mastoid process (radium-226 only)
Thorium-232 and decay products Medical patients Liver, extrahepatic bile ducts, gall bladder, leukaemia (excluding CLL)
Plutonium Plutonium-production workers Lung, liver, bone
Phosphorus-32 Medical patients Acute leukaemia
Fission products, including strontium-90 General population, following nuclear reactor accident Solid cancers, leukaemia
Radioiodines, including iodine-131 Children and adolescents, following nuclear reactor accident Thyroid
X-radiation or gamma-radiation Atomic-bomb survivors, medical patients; in-utero exposure (offspring Salivary gland, oesophagus, stomach, colon, lung, bone, skin (BCC),
of pregnant medical patients and of atomic-bomb survivors) female breast, urinary bladder, brain and CNS, leukaemia (excluding CLL),
thyroid, kidney (atomic-bomb survivors, medical patients); multiple sites
(in-utero exposure)
Solar radiation General population Skin (BCC, SCC, melanoma)
UV-emitting tanning devices General population Skin (melanoma), eye (melanoma, particularly choroid and ciliary body)

CLL=chronic lymphocytic leukaemia. BCC=basal-cell carcinoma. SCC=squamous-cell carcinoma.

Table: Radiation exposures with sufficient evidence in humans Vol 10 August 2009 751


Monograph Working Group transition has been seen in TP53 in 3 Cardis E, Howe G, Ron E, et al. Cancer
Members Panel: Types of radiation classified in consequences of the Chernobyl accident:
premalignant solar keratosis and in 20 years on. J Radiol Prot 2006; 26: 127–40.
B Armstrong–Co-Chair Group 1
(Australia), E Cardis–Co-Chair malignant skin tumours.12 Based on 4 Darby S, Hill D, Auvinen A, et al. Radon in
(Spain); A Green (Australia); • Ionising radiation these mechanistic data, the Working homes and risk of lung cancer: collaborative
D Krewski, R Mitchel, N Priest analysis of individual data from 13 European
• Alpha-particle emitters Group classified UV radiation as case–control studies. BMJ 2005; 330: 223.
(Canada); L Tomašek (Czech
• Beta-particle emitters “carcinogenic to humans” (Group 1). 5 National Research Council, Committee to
Republic); K Baverstock (Finland);
• X-rays and gamma-rays The use of UV-emitting tanning Assess Health Risks from Exposure to Low
J-F Doré, J Hall, L Sabatier
Levels of Ionizing Radiation, Board on
(France); M Sokolnikov (Russian • Neutron radiation devices is widespread in many Radiation Effects, and Research Division on
Federation); M Hill, M Little, Earth and Life Studies. Health effects of
M Marshall, C Muirhead, • Solar radiation developed countries, especially among
exposure to radon: BEIR VI. Washington:
A Riddell (UK); D Brenner [unable young women. A comprehensive National Academies Press; 1999.
to attend], R Guilmette, D Hoel, • Ultraviolet radiation (wavelengths meta-analysis concluded that the risk 6 National Research Council, Committee to
D Richardson, R Ullrich (USA) 100–400 nm, encompassing UVA, of cutaneous melanoma is increased Assess Health Risks from Exposure to Low
Conflicts of interest UVB, and UVC) Levels of Ionizing Radiation, Board on
NP works for, and RM is a
by 75% when use of tanning devices Radiation Effects, and Research Division on
starts before 30 years of age.13 Earth and Life Studies. Health risks from
consultant to, Atomic Energy of
exposure to low levels of ionizing radiation:
Canada Ltd. CM receives funding ionisation and excitation events that Additionally, several case–control BEIR VII, Phase 2. Washington: National
from the UK Ministry of Defence.
can produce a variety of molecular studies provide consistent evidence Academies Press; 2006.
JH receives funding from
lesions and clustered, complex DNA of a positive association between 7 Wakeford R, Little MP. Risk coefficients for
Electricité de France. AG receives childhood cancer after intrauterine irradiation:
funding from L’Oreal Recherche. damage.9 Subsequent processing of the use of UV-emitting tanning a review. Int J Radiat Biol 2003; 79: 293–309.
Invited Specialists this damage induces many responses devices and ocular melanoma.14,15 8 Preston DL, Cullings H, Suyama A, et al. Solid
None cancer incidence in atomic bomb survivors
(eg, cell killing, chromosomal Therefore, the Working Group raised exposed in utero or as young children.
aberrations, mutations, genomic the classification of the use of UV- J Natl Cancer Inst 2008; 100: 428–36.
instability, cell transformation, and emitting tanning devices to Group 1, 9 Goodhead DT. Initial events in the cellular
effects of ionizing radiations: clustered
bystander effects) that contribute “carcinogenic to humans”. damage in DNA. Int J Radiat Biol 1994;
to carcinogenesis. Based on these While reviewing the studies of 65: 7–17.
mechanistic considerations, all types occupational UV exposure, the 10 Runger TM, Kappes UP. Mechanisms of
mutation formation with long-wave
of ionising radiation were classified by Working Group concluded that there ultraviolet light (UVA). Photodermatol
the Working Group as “carcinogenic to is “sufficient evidence” for ocular Photoimmunol Photomed 2008; 24: 2–10.
11 Ikehata H, Kawai K, Komura J, et al. UVA1
humans” (Group 1). melanoma in welders.16,17 However, genotoxicity is mediated not by oxidative
Solar radiation is the main source of because welders are also exposed to damage but by cyclobutane pyrimidine dimers
human exposure to ultraviolet (UV) other harmful agents, this association in normal mouse skin. J Invest Dermatol 2008;
128: 2289–96.
radiation, which is further subdivided could not be attributed specifically 12 Agar NS, Halliday GM, Barnetson RS,
into UVA, UVB, and UVC. The to UV radiation. A full review of the Ananthaswamy HN, Wheeler M, Jones AM.
The basal layer in human squamous tumors
ultraviolet component that reaches the carcinogenic hazards of welding will harbors more UVA than UVB fingerprint
earth’s surface comprises around 95% be undertaken by IARC with high mutations: a role for UVA in human skin
UVA and 5% UVB; UVC is blocked by priority. carcinogenesis. Proc Natl Acad Sci USA 2004;
101: 4954–59.
stratospheric ozone. Epidemiological 13 IARC Working Group. The association of use of
studies have established a causal Fatiha El Ghissassi, Robert Baan, Kurt sunbeds with cutaneous malignant melanoma
and other skin cancers: a systematic review.
association between exposure to solar Straif, Yann Grosse, Béatrice Int J Cancer 2006; 120: 1116–22.
radiation and all major types of skin Secretan, Véronique Bouvard, Lamia 14 Seddon JM, Gragoudas ES, Glynn RJ, Egan KM,
cancer (table). The Working Group Benbrahim-Tallaa, Neela Guha, Albert DM, Blitzer PH. Host factors, UV
radiation, and risk of uveal melanoma: a
reaffirmed the carcinogenicity of solar Crystal Freeman, Laurent Galichet, case-control study. Arch Ophthalmol 1990;
radiation (Group 1). Vincent Cogliano, on behalf of the 108: 1274–80.
Exposure to solar radiation causes WHO International Agency for 15 Vajdic CM, Kricker A, Giblin M, et al. Artificial
ultraviolet radiation and ocular melanoma in
a specific mutation fingerprint Research on Cancer Monograph Australia. Int J Cancer 2004; 112: 896–900.
(cytidine to thymidine transition), Working Group 16 Lutz JM, Cree I, Sabroe S, et al. Occupational
risks for uveal melanoma results from a case-
as a result of cyclobutane pyrimidine International Agency for Research on control study in nine European countries.
dimers in DNA. This pattern had long Cancer, Lyon, France Cancer Causes Control 2005; 16: 437–47.
been attributed to UVB.10 However, The IARC authors declared no conflicts of interest. 17 Shah CP, Weis E, Lajous M, Shields JA,
Shields CL. Intermittent and chronic ultraviolet
this same cytidine to thymidine 1 Grosse Y, Baan R, Straif K, et al. A review of light exposure and uveal melanoma: a meta-
transition has been detected in human carcinogens—part A: pharmaceuticals. analysis. Ophthalmology 2005; 112: 1599–607.
Lancet Oncol 2009; 10: 13–14.
the skin of UVA-treated mice11 and 2 UN Chernobyl Forum expert group “Health”
in the Tp53 gene of UVA-induced (EGH). Health effects of the Chernobyl
or UVB-induced skin tumours in accident and special health care programmes.
Geneva; 2006.
hairless mice.10 In humans, this cations/2006/9241594179_eng.pdf.

752 Vol 10 August 2009