"Riesgo cancerígeno" esta expresión de la serie Monografías de la IARC se entiende que un agente que es capaz de causar cáncer. EstasMonografías evaluan los riesgos de cáncer, a pesar de la presencia histórica de los «riesgos» que figuran en el título.
La inclusión de un agente en las monografías no implica que se trata de un carcinógeno, sólo que los datos publicados han sido examinados. Igualmente, el hecho de que un agente aún no ha sido evaluado en una
Monografía no significa que no es cancerígeno. Del mismo modo, la identificación de los tipos de cáncer con pruebas suficientes o evidencia limitada en humanos no debe considerarse como excluyente de la posibilidad de que un agente puede causar cáncer en otros sitios.
Las evaluaciones de riesgo de cáncer son realizados por grupos de trabajo internacionales de científicos independientes y no son de naturaleza cualitativa. Ninguna recomendación se da para la regulación o legislación.
Cualquier persona que es consciente de los datos publicados que pueden alterar la evaluación del riesgo cancerígeno de un agente para el ser humano se le anima a hacer esta información disponible a la Sección de Monografías del IARC, Agencia Internacional para la Investigación del Cáncer, 150 cours Albert Thomas, 69372 Lyon Cedex 08 de Francia, con el fin de que el agente puede ser considerado para la re-evaluación de un futuro grupo de trabajo.
Aunque no se escatiman esfuerzos para preparar las monografías con la mayor precisión posible, los errores pueden ocurrir. Los lectores deben comunicar los errores a la Sección de Monografías del IARC, por lo que las correcciones pueden ser reportados en los volúmenes futuros.
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IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
1. WORLD HEALTH ORGANIZATION
INTERNATIONAL AGENCY FOR RESEARCH ON CANCER
IARC Monographs on the Evaluation of
Carcinogenic Risks to Humans
VOLUME 100
A Review of Human Carcinogens
Part D: Radiation
LYON, FRANCE
2.
3. WORLD HEALTH ORGANIZATION
INTERNATIONAL AGENCY FOR RESEARCH ON CANCER
IARC Monographs on the Evaluation of
Carcinogenic Risks to Humans
Volume 100
A Review of Human Carcinogens
Part D: Radiation
This publication represents the views and expert opinions
of an IARC Working Group on the
Evaluation of Carcinogenic Risks to Humans,
which met in Lyon,
2–9 June 2009
11. NOTE TO THE READER
The term ‘carcinogenic risk’ in the IARC Monographs series is taken to mean that an agent is
capable of causing cancer. The Monographs evaluate cancer hazards, despite the historical presence
of the word ‘risks’ in the title.
Inclusion of an agent in the Monographs does not imply that it is a carcinogen, only that the
published data have been examined. Equally, the fact that an agent has not yet been evaluated in a
Monograph does not mean that it is not carcinogenic. Similarly, identification of cancer sites with
sufficient evidence or limited evidence in humans should not be viewed as precluding the possibility
that an agent may cause cancer at other sites.
The evaluations of carcinogenic risk are made by international working groups of independent
scientists and are qualitative in nature. No recommendation is given for regulation or legislation.
Anyone who is aware of published data that may alter the evaluation of the carcinogenic risk
of an agent to humans is encouraged to make this information available to the Section of IARC
Monographs, International Agency for Research on Cancer, 150 cours Albert Thomas, 69372 Lyon
Cedex 08, France, in order that the agent may be considered for re-evaluation by a future Working
Group.
Although every effort is made to prepare the monographs as accurately as possible, mistakes may
occur. Readers are requested to communicate any errors to the Section of IARC Monographs, so that
corrections can be reported in future volumes.
1
12.
13. List of Participants
Members1
Bruce Armstrong David J. Brenner (unable to attend)
School of Public Health Center for Radiological Research
University of Sydney Columbia University
NSW 2006 New York, NY 10043
Australia USA
Keith Baverstock Elisabeth Cardis
Faculty of Natural and Environmental Center for Research in Environmental
Sciences Epidemiology (CREAL)
University of Eastern Finland E-08003 Barcelona
FI-70211 Kuopio Spain
Finland
1
Working Group Members and Invited Specialists serve in their individual capacities as scientists and not as representa-
tives of their government or any organization with which they are affiliated. Affiliations are provided for identification
purposes only. Invited specialists are marked by an asterisk.
Each participant was asked to disclose pertinent research, employment, and financial interests. Current financial
interests and research and employment interests during the past 3 years or anticipated in the future are identified here.
Minor pertinent interests are not listed and include stock valued at no more than US$10 000 overall, grants that provide
no more than 5% of the research budget of the expert’s organization and that do not support the expert’s research or
position, and consulting or speaking on matters not before a court or government agency that does not exceed 2% of
total professional time or compensation. All grants that support the expert’s research or position and all consulting or
speaking on behalf of an interested party on matters before a court or government agency are listed as significant perti-
nent interests.
3
14. IARC MONOGRAPHS – 100D
Adele Green2 David Hoel4
Cancer & Population Studies Group College of Medicine
Queensland Institute of Medical Research Medical University of South Carolina
Queensland 4029 Charleston, SC 29401
Australia USA
Raymond A. Guilmette
Daniel Krewski
Lovelace Respiratory Research Institute
Albuquerque, NM 87108-5127 McLaughlin Centre for Population
USA Health Risk Assessment
University of Ottawa
Ottawa, Ontario K1N 6N5
Janet Hall3 Canada
Institut Curie Research Center
INSERM Unit 612
University Centre Mark P. Little5
91405 Orsay Division of Epidemiology, Public Health
France and Primary Care
Imperial College Faculty of Medicine
London W2 1PG
Mark A. Hill United Kingdom
Gray Institute for Radiation Oncology &
Biology
University of Oxford
Oxford OX3 7DQ
United Kingdom
2
Dr Green receives research funds (not exceeding 5% of total research support) from L’Oréal which makes products
intended to reduce the dose from solar radiation.
3
Dr Hall’s research unit receives funds (not exceeding 5% of total research support) from Electricité de France, an elec-
tric power company.
4
Dr Hoel is providing assistance to Exxon Corp in court cases involving personal injury claimed to be related to radia-
tion. He owns stock in Duke Energy Corp, an electric power company. His university salary is supported in part by
grants from the U.S. National Aeronautics and Space Administration (NASA) and the U.S. Department of Energy.
5
Dr Little wrote software for the British Nuclear Group to calculate risks for workers in the nuclear industry. This
represented less than 5% of his annual total professional compensation for 2006 and 2007, when the activity ceased. He
also advised the International Epidemiology Institute (USA) and Westlakes Research Institute (UK) on epidemiological
matters. This represented less than 5% of total professional income, and work ceased in 2007 for both contracts.
New address: Radiation Epidemiology Branch, National Cancer Institute, Rockville MD, USA
4
15. Participants
Michael Marshall (retired)6 David B. Richardson10
UK Atomic Energy Authority School of Public Health
Blewbury, Didcot University of North Carolina at Chapel Hill
Oxon OX11 9NW Chapel Hill, NC 27599-7435
United Kingdom USA
Ronald E. J. Mitchel (retired)7 Anthony E. Riddell11
Atomic Energy of Canada Limited Westlakes Scientific Consulting Ltd
Chalk River, Ontario K0J 1J0 University of Central Lancashire
Canada Cumbria CA24 3JY
United Kingdom
Colin R. Muirhead8
Laure Sabatier
Centre for Radiation, Chemical and
Environmental Hazards Radiobiology and Oncology Unit
Health Protection Agency French Alternative Energies and Atomic
Chilton, Didcot Energy Commission
Oxon OX11 0RQ 92265 Fontenay-aux-Roses
United Kingdom France
Nicholas D. Priest9 Mikhail E. Sokolnikov
Radiation Biology and Health Physics Southern Urals Biophysics Institute
Atomic Energy of Canada Limited Ozyorsk, 456780
Chalk River, Ontario K0J 1P0 Russian Federation
Canada
6
Dr Marshall is retired from the United Kingdom Atomic Energy Authority (UKAEA).
7
Dr Mitchel is retired from, and continues to consult for, Atomic Energy of Canada Ltd, a Crown corporation of Canada
whose mandate is to sustain and enhance nuclear technology, to manage nuclear wastes, and to maximize return on
investment in nuclear technology. The corporation also produces more than half of the world’s medical isotopes.
8
Dr Muirhead manages a section at the Health Protection Agency that receives partial funding from the UK Ministry of
Defence to maintain an epidemiological database of nuclear test veterans.
New address: Institute of Health and Society, Newcastle University, UK.
9
Dr Priest is a manager at Atomic Energy of Canada Ltd, a Crown corporation of Canada whose mandate is to sustain
and enhance nuclear technology, to manage nuclear wastes, and to maximize return on investment in nuclear technol-
ogy. The corporation also produces a significant fraction of the world’s medical isotopes.
10
Dr Richardson provided written testimony on behalf of four persons seeking compensation for diseases claimed to be
related to X-rays. He reports receiving no compensation for this case.
11
Dr Riddell is employed by Westlakes Scientific Consulting Ltd, a consulting firm specializing in the nuclear industry.
5
16. IARC MONOGRAPHS – 100D
Ladislav Tomasek Andrei Karotki
National Radiation Protection Institute Ausra Kesminiene
140 00 Prague 4 Béatrice Lauby-Secretan (Rapporteur,
Czech Republic Cancer in Humans)
Ferid Shannoun (WHO geneva)
Kurt Straif (Rapporteur, Cancer in Humans)
Isabelle Thierry-Chef
Robert L. Ullrich12
UTMB Cancer Center
University of Texas Medical Branch Post-meeting Scientific Assistance
Galveston, TX 77555-1048
USA Farhad Islami
Administrative Assistance
IARC Secretariat
Sandrine Egraz
Philippe Autier Michel Javin
Robert Baan (Co-Responsible Officer; Brigitte Kajo
Rapporteur, Mechanistic and Other Relevant Helene Lorenzen-Augros
Data) Karine Racinoux
Lamia Benbrahim-Tallaa (Rapporteur,
Cancer in Experimental Animals)
Véronique Bouvard (Rapporteur, Reproduction of Graphics
Mechanistic and Other Relevant Data)
Rafael Carel (Visiting Scientist) Arthur Bouvard
Vincent Cogliano (Head of Programme)
Emilie van Deventer (WHO geneva)
Jean-François Doré (Visiting Scientist)
Fatiha El Ghissassi (Responsible
Production Team
Officer; Rapporteur, Mechanistic and
Other Relevant Data) Elisabeth Elbers
Crystal Freeman (Rapporteur, Cancer in Anne-Sophie Hameau
Humans) Sylvia Moutinho
Laurent Galichet (Editor) Dorothy Russell
Yann Grosse (Rapporteur, Cancer in
Experimental Animals)
Neela Guha (Rapporteur, Cancer in Humans)
12
Dr Ullrich provided assistance to Raytheon Co in a court case involving thyroid and kidney cancer claimed to be
related to X-rays.
6
17. PREAMBLE
The Preamble to the IARC Monographs describes the objective and scope of the programme,
the scientific principles and procedures used in developing a Monograph, the types of
evidence considered and the scientific criteria that guide the evaluations. The Preamble
should be consulted when reading a Monograph or list of evaluations.
A. GENERAL PRINCIPLES AND risk of chemicals to man, which became the ini-
PROCEDURES tial title of the series.
In the succeeding years, the scope of the pro-
gramme broadened as Monographs were devel-
1. Background oped for groups of related chemicals, complex
Soon after IARC was established in 1965, it mixtures, occupational exposures, physical and
received frequent requests for advice on the car- biological agents and lifestyle factors. In 1988,
cinogenic risk of chemicals, including requests the phrase ‘of chemicals’ was dropped from
for lists of known and suspected human carcino- the title, which assumed its present form, IARC
gens. It was clear that it would not be a simple Monographs on the Evaluation of Carcinogenic
task to summarize adequately the complexity of Risks to Humans.
the information that was available, and IARC Through the Monographs programme, IARC
began to consider means of obtaining interna- seeks to identify the causes of human cancer. This
tional expert opinion on this topic. In 1970, the is the first step in cancer prevention, which is
IARC Advisory Committee on Environmental needed as much today as when IARC was estab-
Carcinogenesis recommended ‘...that a com- lished. The global burden of cancer is high and
pendium on carcinogenic chemicals be pre- continues to increase: the annual number of new
pared by experts. The biological activity and cases was estimated at 10.1 million in 2000 and
evaluation of practical importance to public is expected to reach 15 million by 2020 (Stewart
health should be referenced and documented.’ & Kleihues, 2003). With current trends in demo-
The IARC Governing Council adopted a resolu- graphics and exposure, the cancer burden has
tion concerning the role of IARC in providing been shifting from high-resource countries to
government authorities with expert, independ- low- and medium-resource countries. As a result
ent, scientific opinion on environmental carcino- of Monographs evaluations, national health agen-
genesis. As one means to that end, the Governing cies have been able, on scientific grounds, to take
Council recommended that IARC should prepare measures to reduce human exposure to carcino-
monographs on the evaluation of carcinogenic gens in the workplace and in the environment.
7
18. IARC MONOGRAPHS – 100D
The criteria established in 1971 to evaluate causation of, and susceptibility to, malignant
carcinogenic risks to humans were adopted by the disease become more fully understood.
Working Groups whose deliberations resulted in A cancer ‘hazard’ is an agent that is capable
the first 16 volumes of the Monographs series. of causing cancer under some circumstances,
Those criteria were subsequently updated by fur- while a cancer ‘risk’ is an estimate of the carci-
ther ad hoc Advisory Groups (IARC, 1977, 1978, nogenic effects expected from exposure to a can-
1979, 1982, 1983, 1987, 1988, 1991; Vainio et al., cer hazard. The Monographs are an exercise in
1992; IARC, 2005, 2006). evaluating cancer hazards, despite the historical
The Preamble is primarily a statement of sci- presence of the word ‘risks’ in the title. The dis-
entific principles, rather than a specification of tinction between hazard and risk is important,
working procedures. The procedures through and the Monographs identify cancer hazards
which a Working Group implements these prin- even when risks are very low at current exposure
ciples are not specified in detail. They usually levels, because new uses or unforeseen exposures
involve operations that have been established could engender risks that are significantly higher.
as being effective during previous Monograph In the Monographs, an agent is termed ‘car-
meetings but remain, predominantly, the pre- cinogenic’ if it is capable of increasing the inci-
rogative of each individual Working Group. dence of malignant neoplasms, reducing their
latency, or increasing their severity or multiplic-
ity. The induction of benign neoplasms may in
2. Objective and scope some circumstances (see Part B, Section 3a) con-
The objective of the programme is to pre- tribute to the judgement that the agent is carci-
pare, with the help of international Working nogenic. The terms ‘neoplasm’ and ‘tumour’ are
Groups of experts, and to publish in the form of used interchangeably.
Monographs, critical reviews and evaluations of The Preamble continues the previous usage
evidence on the carcinogenicity of a wide range of the phrase ‘strength of evidence’ as a matter
of human exposures. The Monographs repre- of historical continuity, although it should be
sent the first step in carcinogen risk assessment, understood that Monographs evaluations con-
which involves examination of all relevant infor- sider studies that support a finding of a cancer
mation to assess the strength of the available evi- hazard as well as studies that do not.
dence that an agent could alter the age-specific Some epidemiological and experimental
incidence of cancer in humans. The Monographs studies indicate that different agents may act at
may also indicate where additional research different stages in the carcinogenic process, and
efforts are needed, specifically when data imme- several different mechanisms may be involved.
diately relevant to an evaluation are not available. The aim of the Monographs has been, from their
In this Preamble, the term ‘agent’ refers to inception, to evaluate evidence of carcinogenic-
any entity or circumstance that is subject to ity at any stage in the carcinogenesis process,
evaluation in a Monograph. As the scope of the independently of the underlying mechanisms.
programme has broadened, categories of agents Information on mechanisms may, however, be
now include specific chemicals, groups of related used in making the overall evaluation (IARC,
chemicals, complex mixtures, occupational or 1991; Vainio et al., 1992; IARC, 2005, 2006; see
environmental exposures, cultural or behav- also Part B, Sections 4 and 6). As mechanisms
ioural practices, biological organisms and physi- of carcinogenesis are elucidated, IARC convenes
cal agents. This list of categories may expand as international scientific conferences to determine
whether a broad-based consensus has emerged
8
19. Preamble
on how specific mechanistic data can be used exposure and (b) there is some evidence or sus-
in an evaluation of human carcinogenicity. The picion of carcinogenicity. Mixed exposures may
results of such conferences are reported in IARC occur in occupational and environmental set-
Scientific Publications, which, as long as they still tings and as a result of individual and cultural
reflect the current state of scientific knowledge, habits (such as tobacco smoking and dietary
may guide subsequent Working Groups. practices). Chemical analogues and compounds
Although the Monographs have emphasized with biological or physical characteristics simi-
hazard identification, important issues may also lar to those of suspected carcinogens may also
involve dose–response assessment. In many be considered, even in the absence of data on a
cases, the same epidemiological and experimen- possible carcinogenic effect in humans or experi-
tal studies used to evaluate a cancer hazard can mental animals.
also be used to estimate a dose–response relation- The scientific literature is surveyed for pub-
ship. A Monograph may undertake to estimate lished data relevant to an assessment of carci-
dose–response relationships within the range nogenicity. Ad hoc Advisory Groups convened
of the available epidemiological data, or it may by IARC in 1984, 1989, 1991, 1993, 1998 and
compare the dose–response information from 2003 made recommendations as to which
experimental and epidemiological studies. In agents should be evaluated in the Monographs
some cases, a subsequent publication may be pre- series. Recent recommendations are avail-
pared by a separate Working Group with exper- able on the Monographs programme web site
tise in quantitative dose–response assessment. (http://monographs.iarc.fr). IARC may schedule
The Monographs are used by national and other agents for review as it becomes aware of
international authorities to make risk assess- new scientific information or as national health
ments, formulate decisions concerning preventive agencies identify an urgent public health need
measures, provide effective cancer control pro- related to cancer.
grammes and decide among alternative options As significant new data become available
for public health decisions. The evaluations of on an agent for which a Monograph exists, a re-
IARC Working Groups are scientific, qualita- evaluation may be made at a subsequent meeting,
tive judgements on the evidence for or against and a new Monograph published. In some cases it
carcinogenicity provided by the available data. may be appropriate to review only the data pub-
These evaluations represent only one part of the lished since a prior evaluation. This can be useful
body of information on which public health deci- for updating a database, reviewing new data to
sions may be based. Public health options vary resolve a previously open question or identifying
from one situation to another and from country new tumour sites associated with a carcinogenic
to country and relate to many factors, including agent. Major changes in an evaluation (e.g. a new
different socioeconomic and national priorities. classification in Group 1 or a determination that a
Therefore, no recommendation is given with mechanism does not operate in humans, see Part
regard to regulation or legislation, which are B, Section 6) are more appropriately addressed by
the responsibility of individual governments or a full review.
other international organizations.
4. Data for the Monographs
3. Selection of agents for review
Each Monograph reviews all pertinent epi-
Agents are selected for review on the basis of demiological studies and cancer bioassays in
two main criteria: (a) there is evidence of human experimental animals. Those judged inadequate
9
20. IARC MONOGRAPHS – 100D
or irrelevant to the evaluation may be cited but (a) The Working Group
not summarized. If a group of similar studies is
not reviewed, the reasons are indicated. The Working Group is responsible for the crit-
Mechanistic and other relevant data are also ical reviews and evaluations that are developed
reviewed. A Monograph does not necessarily during the meeting. The tasks of Working Group
cite all the mechanistic literature concerning Members are: (i) to ascertain that all appropriate
the agent being evaluated (see Part B, Section data have been collected; (ii) to select the data rel-
4). Only those data considered by the Working evant for the evaluation on the basis of scientific
Group to be relevant to making the evaluation merit; (iii) to prepare accurate summaries of the
are included. data to enable the reader to follow the reasoning
With regard to epidemiological studies, can- of the Working Group; (iv) to evaluate the results
cer bioassays, and mechanistic and other relevant of epidemiological and experimental studies on
data, only reports that have been published or cancer; (v) to evaluate data relevant to the under-
accepted for publication in the openly available standing of mechanisms of carcinogenesis; and
scientific literature are reviewed. The same publi- (vi) to make an overall evaluation of the carci-
cation requirement applies to studies originating nogenicity of the exposure to humans. Working
from IARC, including meta-analyses or pooled Group Members generally have published sig-
analyses commissioned by IARC in advance of a nificant research related to the carcinogenicity of
meeting (see Part B, Section 2c). Data from gov- the agents being reviewed, and IARC uses litera-
ernment agency reports that are publicly avail- ture searches to identify most experts. Working
able are also considered. Exceptionally, doctoral Group Members are selected on the basis of (a)
theses and other material that are in their final knowledge and experience and (b) absence of real
form and publicly available may be reviewed. or apparent conflicts of interests. Consideration
Exposure data and other information on an is also given to demographic diversity and bal-
agent under consideration are also reviewed. In ance of scientific findings and views.
the sections on chemical and physical proper-
ties, on analysis, on production and use and on (b) Invited Specialists
occurrence, published and unpublished sources Invited Specialists are experts who also have
of information may be considered. critical knowledge and experience but have
Inclusion of a study does not imply accept- a real or apparent conflict of interests. These
ance of the adequacy of the study design or of experts are invited when necessary to assist in
the analysis and interpretation of the results, and the Working Group by contributing their unique
limitations are clearly outlined in square brack- knowledge and experience during subgroup and
ets at the end of each study description (see Part plenary discussions. They may also contribute
B). The reasons for not giving further considera- text on non-influential issues in the section on
tion to an individual study also are indicated in exposure, such as a general description of data
the square brackets. on production and use (see Part B, Section 1).
Invited Specialists do not serve as meeting chair
5. Meeting participants or subgroup chair, draft text that pertains to the
description or interpretation of cancer data, or
Five categories of participant can be present participate in the evaluations.
at Monograph meetings.
10
21. Preamble
(c) Representatives of national and whether there is a conflict that warrants some
international health agencies limitation on participation. The declarations are
updated and reviewed again at the opening of
Representatives of national and interna- the meeting. Interests related to the subject of
tional health agencies often attend meetings the meeting are disclosed to the meeting par-
because their agencies sponsor the programme ticipants and in the published volume (Cogliano
or are interested in the subject of a meeting. et al., 2004).
Representatives do not serve as meeting chair or The names and principal affiliations of par-
subgroup chair, draft any part of a Monograph, ticipants are available on the Monographs pro-
or participate in the evaluations. gramme web site (http://monographs.iarc.fr)
approximately two months before each meeting.
(d) Observers with relevant scientific
It is not acceptable for Observers or third parties
credentials to contact other participants before a meeting or
Observers with relevant scientific credentials to lobby them at any time. Meeting participants
may be admitted to a meeting by IARC in limited are asked to report all such contacts to IARC
numbers. Attention will be given to achieving a (Cogliano et al., 2005).
balance of Observers from constituencies with All participants are listed, with their princi-
differing perspectives. They are invited to observe pal affiliations, at the beginning of each volume.
the meeting and should not attempt to influence Each participant who is a Member of a Working
it. Observers do not serve as meeting chair or Group serves as an individual scientist and not as
subgroup chair, draft any part of a Monograph, a representative of any organization, government
or participate in the evaluations. At the meeting, or industry.
the meeting chair and subgroup chairs may grant
Observers an opportunity to speak, generally 6. Working procedures
after they have observed a discussion. Observers
agree to respect the Guidelines for Observers A separate Working Group is responsible for
at IARC Monographs meetings (available at developing each volume of Monographs. A vol-
http://monographs.iarc.fr). ume contains one or more Monographs, which
can cover either a single agent or several related
(e) The IARC Secretariat agents. Approximately one year in advance of the
The IARC Secretariat consists of scientists meeting of a Working Group, the agents to be
who are designated by IARC and who have rel- reviewed are announced on the Monographs pro-
evant expertise. They serve as rapporteurs and gramme web site (http://monographs.iarc.fr) and
participate in all discussions. When requested by participants are selected by IARC staff in consul-
the meeting chair or subgroup chair, they may tation with other experts. Subsequently, relevant
also draft text or prepare tables and analyses. biological and epidemiological data are collected
Before an invitation is extended, each poten- by IARC from recognized sources of information
tial participant, including the IARC Secretariat, on carcinogenesis, including data storage and
completes the WHO Declaration of Interests to retrieval systems such as PubMed. Meeting par-
report financial interests, employment and con- ticipants who are asked to prepare preliminary
sulting, and individual and institutional research working papers for specific sections are expected
support related to the subject of the meeting. to supplement the IARC literature searches with
IARC assesses these interests to determine their own searches.
11
22. IARC MONOGRAPHS – 100D
For most chemicals and some complex mix- the entire volume is the joint product of the
tures, the major collection of data and the prep- Working Group, and there are no individually
aration of working papers for the sections on authored sections.
chemical and physical properties, on analysis, on IARC Working Groups strive to achieve a
production and use, and on occurrence are car- consensus evaluation. Consensus reflects broad
ried out under a separate contract funded by the agreement among Working Group Members, but
US National Cancer Institute. Industrial associ- not necessarily unanimity. The chair may elect
ations, labour unions and other knowledgeable to poll Working Group Members to determine
organizations may be asked to provide input to the diversity of scientific opinion on issues where
the sections on production and use, although consensus is not readily apparent.
this involvement is not required as a general rule. After the meeting, the master copy is verified
Information on production and trade is obtained by consulting the original literature, edited and
from governmental, trade and market research prepared for publication. The aim is to publish
publications and, in some cases, by direct con- the volume within six months of the Working
tact with industries. Separate production data Group meeting. A summary of the outcome is
on some agents may not be available for a vari- available on the Monographs programme web
ety of reasons (e.g. not collected or made public site soon after the meeting.
in all producing countries, production is small).
Information on uses may be obtained from pub-
lished sources but is often complemented by B. SCIENTIFIC REVIEW AND
direct contact with manufacturers. Efforts are EVALUATION
made to supplement this information with data
from other national and international sources. The available studies are summarized by the
Six months before the meeting, the mate- Working Group, with particular regard to the
rial obtained is sent to meeting participants to qualitative aspects discussed below. In general,
prepare preliminary working papers. The work- numerical findings are indicated as they appear
ing papers are compiled by IARC staff and sent, in the original report; units are converted when
before the meeting, to Working Group Members necessary for easier comparison. The Working
and Invited Specialists for review. Group may conduct additional analyses of the
The Working Group meets at IARC for seven published data and use them in their assessment
to eight days to discuss and finalize the texts of the evidence; the results of such supplemen-
and to formulate the evaluations. The objectives tary analyses are given in square brackets. When
of the meeting are peer review and consensus. an important aspect of a study that directly
During the first few days, four subgroups (cov- impinges on its interpretation should be brought
ering exposure data, cancer in humans, cancer to the attention of the reader, a Working Group
in experimental animals, and mechanistic and comment is given in square brackets.
other relevant data) review the working papers, The scope of the IARC Monographs pro-
develop a joint subgroup draft and write sum- gramme has expanded beyond chemicals to
maries. Care is taken to ensure that each study include complex mixtures, occupational expo-
summary is written or reviewed by someone sures, physical and biological agents, lifestyle
not associated with the study being considered. factors and other potentially carcinogenic expo-
During the last few days, the Working Group sures. Over time, the structure of a Monograph
meets in plenary session to review the subgroup has evolved to include the following sections:
drafts and develop the evaluations. As a result,
12
23. Preamble
Exposure data which the agent being evaluated is only one of
Studies of cancer in humans the ingredients.
Studies of cancer in experimental animals For biological agents, taxonomy, struc-
Mechanistic and other relevant data ture and biology are described, and the degree
Summary of variability is indicated. Mode of replication,
Evaluation and rationale life cycle, target cells, persistence, latency, host
In addition, a section of General Remarks at response and clinical disease other than cancer
the front of the volume discusses the reasons the are also presented.
agents were scheduled for evaluation and some For physical agents that are forms of radia-
key issues the Working Group encountered dur- tion, energy and range of the radiation are
ing the meeting. included. For foreign bodies, fibres and respir-
This part of the Preamble discusses the types able particles, size range and relative dimensions
of evidence considered and summarized in each are indicated.
section of a Monograph, followed by the scientific For agents such as mixtures, drugs or lifestyle
criteria that guide the evaluations. factors, a description of the agent, including its
composition, is given.
Whenever appropriate, other information,
1. Exposure data such as historical perspectives or the description
Each Monograph includes general informa- of an industry or habit, may be included.
tion on the agent: this information may vary sub-
stantially between agents and must be adapted (b) Analysis and detection
accordingly. Also included is information on
An overview of methods of analysis and
production and use (when appropriate), meth-
detection of the agent is presented, including
ods of analysis and detection, occurrence, and
their sensitivity, specificity and reproducibility.
sources and routes of human occupational and
Methods widely used for regulatory purposes
environmental exposures. Depending on the
are emphasized. Methods for monitoring human
agent, regulations and guidelines for use may be
exposure are also given. No critical evaluation
presented.
or recommendation of any method is meant or
implied.
(a) General information on the agent
For chemical agents, sections on chemical (c) Production and use
and physical data are included: the Chemical
The dates of first synthesis and of first com-
Abstracts Service Registry Number, the latest pri-
mercial production of a chemical, mixture or
mary name and the IUPAC systematic name are
other agent are provided when available; for
recorded; other synonyms are given, but the list
agents that do not occur naturally, this informa-
is not necessarily comprehensive. Information
tion may allow a reasonable estimate to be made
on chemical and physical properties that are rel-
of the date before which no human exposure to
evant to identification, occurrence and biologi-
the agent could have occurred. The dates of first
cal activity is included. A description of technical
reported occurrence of an exposure are also pro-
products of chemicals includes trade names, rel-
vided when available. In addition, methods of
evant specifications and available information
synthesis used in past and present commercial
on composition and impurities. Some of the
production and different methods of production,
trade names given may be those of mixtures in
13
24. IARC MONOGRAPHS – 100D
which may give rise to different impurities, are place. For biological agents, the epidemiology of
described. infection is described.
The countries where companies report pro-
duction of the agent, and the number of compa- (e) Regulations and guidelines
nies in each country, are identified. Available data
on production, international trade and uses are Statements concerning regulations and
obtained for representative regions. It should not, guidelines (e.g. occupational exposure limits,
however, be inferred that those areas or nations maximal levels permitted in foods and water,
are necessarily the sole or major sources or users pesticide registrations) are included, but they
of the agent. Some identified uses may not be may not reflect the most recent situation, since
current or major applications, and the coverage such limits are continuously reviewed and modi-
is not necessarily comprehensive. In the case of fied. The absence of information on regulatory
drugs, mention of their therapeutic uses does not status for a country should not be taken to imply
necessarily represent current practice nor does it that that country does not have regulations with
imply judgement as to their therapeutic efficacy. regard to the exposure. For biological agents, leg-
islation and control, including vaccination and
therapy, are described.
(d) Occurrence and exposure
Information on the occurrence of an agent in
the environment is obtained from data derived
2. Studies of cancer in humans
from the monitoring and surveillance of levels This section includes all pertinent epidemio-
in occupational environments, air, water, soil, logical studies (see Part A, Section 4). Studies of
plants, foods and animal and human tissues. biomarkers are included when they are relevant
When available, data on the generation, per- to an evaluation of carcinogenicity to humans.
sistence and bioaccumulation of the agent are
also included. Such data may be available from (a) Types of study considered
national databases.
Data that indicate the extent of past and pre- Several types of epidemiological study con-
sent human exposure, the sources of exposure, tribute to the assessment of carcinogenicity in
the people most likely to be exposed and the fac- humans — cohort studies, case–control studies,
tors that contribute to the exposure are reported. correlation (or ecological) studies and interven-
Information is presented on the range of human tion studies. Rarely, results from randomized tri-
exposure, including occupational and environ- als may be available. Case reports and case series
mental exposures. This includes relevant findings of cancer in humans may also be reviewed.
from both developed and developing countries. Cohort and case–control studies relate indi-
Some of these data are not distributed widely and vidual exposures under study to the occurrence of
may be available from government reports and cancer in individuals and provide an estimate of
other sources. In the case of mixtures, indus- effect (such as relative risk) as the main measure
tries, occupations or processes, information is of association. Intervention studies may provide
given about all agents known to be present. For strong evidence for making causal inferences, as
processes, industries and occupations, a histori- exemplified by cessation of smoking and the sub-
cal description is also given, noting variations in sequent decrease in risk for lung cancer.
chemical composition, physical properties and In correlation studies, the units of inves-
levels of occupational exposure with date and tigation are usually whole populations (e.g. in
14
25. Preamble
particular geographical areas or at particular Bias is the effect of factors in study design or
times), and cancer frequency is related to a sum- execution that lead erroneously to a stronger or
mary measure of the exposure of the population weaker association than in fact exists between an
to the agent under study. In correlation studies, agent and disease. Confounding is a form of bias
individual exposure is not documented, which that occurs when the relationship with disease is
renders this kind of study more prone to con- made to appear stronger or weaker than it truly is
founding. In some circumstances, however, cor- as a result of an association between the apparent
relation studies may be more informative than causal factor and another factor that is associated
analytical study designs (see, for example, the with either an increase or decrease in the inci-
Monograph on arsenic in drinking-water; IARC, dence of the disease. The role of chance is related
2004). to biological variability and the influence of sam-
In some instances, case reports and case series ple size on the precision of estimates of effect.
have provided important information about the In evaluating the extent to which these fac-
carcinogenicity of an agent. These types of study tors have been minimized in an individual study,
generally arise from a suspicion, based on clinical consideration is given to several aspects of design
experience, that the concurrence of two events — and analysis as described in the report of the
that is, a particular exposure and occurrence of study. For example, when suspicion of carcino-
a cancer — has happened rather more frequently genicity arises largely from a single small study,
than would be expected by chance. Case reports careful consideration is given when interpreting
and case series usually lack complete ascertain- subsequent studies that included these data in an
ment of cases in any population, definition or enlarged population. Most of these considera-
enumeration of the population at risk and esti- tions apply equally to case–control, cohort and
mation of the expected number of cases in the correlation studies. Lack of clarity of any of these
absence of exposure. aspects in the reporting of a study can decrease
The uncertainties that surround the inter- its credibility and the weight given to it in the
pretation of case reports, case series and corre- final evaluation of the exposure.
lation studies make them inadequate, except in First, the study population, disease (or dis-
rare instances, to form the sole basis for inferring eases) and exposure should have been well
a causal relationship. When taken together with defined by the authors. Cases of disease in the
case–control and cohort studies, however, these study population should have been identified in
types of study may add materially to the judge- a way that was independent of the exposure of
ment that a causal relationship exists. interest, and exposure should have been assessed
Epidemiological studies of benign neo- in a way that was not related to disease status.
plasms, presumed preneoplastic lesions and Second, the authors should have taken into
other end-points thought to be relevant to cancer account — in the study design and analysis —
are also reviewed. They may, in some instances, other variables that can influence the risk of dis-
strengthen inferences drawn from studies of ease and may have been related to the exposure
cancer itself. of interest. Potential confounding by such vari-
ables should have been dealt with either in the
(b) Quality of studies considered design of the study, such as by matching, or in
the analysis, by statistical adjustment. In cohort
It is necessary to take into account the pos- studies, comparisons with local rates of disease
sible roles of bias, confounding and chance in may or may not be more appropriate than those
the interpretation of epidemiological studies. with national rates. Internal comparisons of
15
26. IARC MONOGRAPHS – 100D
frequency of disease among individuals at differ- The advantages of combined analyses are
ent levels of exposure are also desirable in cohort increased precision due to increased sample size
studies, since they minimize the potential for and the opportunity to explore potential con-
confounding related to the difference in risk fac- founders, interactions and modifying effects
tors between an external reference group and the that may explain heterogeneity among studies in
study population. more detail. A disadvantage of combined analy-
Third, the authors should have reported the ses is the possible lack of compatibility of data
basic data on which the conclusions are founded, from various studies due to differences in sub-
even if sophisticated statistical analyses were ject recruitment, procedures of data collection,
employed. At the very least, they should have methods of measurement and effects of unmeas-
given the numbers of exposed and unexposed ured co-variates that may differ among studies.
cases and controls in a case–control study and Despite these limitations, well conducted com-
the numbers of cases observed and expected in bined analyses may provide a firmer basis than
a cohort study. Further tabulations by time since individual studies for drawing conclusions about
exposure began and other temporal factors are the potential carcinogenicity of agents.
also important. In a cohort study, data on all IARC may commission a meta-analysis or
cancer sites and all causes of death should have pooled analysis that is pertinent to a particular
been given, to reveal the possibility of reporting Monograph (see Part A, Section 4). Additionally,
bias. In a case–control study, the effects of inves- as a means of gaining insight from the results of
tigated factors other than the exposure of interest multiple individual studies, ad hoc calculations
should have been reported. that combine data from different studies may
Finally, the statistical methods used to obtain be conducted by the Working Group during
estimates of relative risk, absolute rates of can- the course of a Monograph meeting. The results
cer, confidence intervals and significance tests, of such original calculations, which would be
and to adjust for confounding should have been specified in the text by presentation in square
clearly stated by the authors. These methods have brackets, might involve updates of previously
been reviewed for case–control studies (Breslow conducted analyses that incorporate the results
& Day, 1980) and for cohort studies (Breslow & of more recent studies or de-novo analyses.
Day, 1987). Irrespective of the source of data for the meta-
analyses and pooled analyses, it is important that
(c) Meta-analyses and pooled analyses the same criteria for data quality be applied as
those that would be applied to individual studies
Independent epidemiological studies of the and to ensure also that sources of heterogeneity
same agent may lead to results that are difficult between studies be taken into account.
to interpret. Combined analyses of data from
multiple studies are a means of resolving this
(d) Temporal effects
ambiguity, and well conducted analyses can be
considered. There are two types of combined Detailed analyses of both relative and abso-
analysis. The first involves combining summary lute risks in relation to temporal variables, such
statistics such as relative risks from individual as age at first exposure, time since first exposure,
studies (meta-analysis) and the second involves a duration of exposure, cumulative exposure, peak
pooled analysis of the raw data from the individ- exposure (when appropriate) and time since
ual studies (pooled analysis) (Greenland, 1998). cessation of exposure, are reviewed and sum-
marized when available. Analyses of temporal
16
27. Preamble
relationships may be useful in making causal of the agent being evaluated, data on this pheno-
inferences. In addition, such analyses may sug- type may be useful in making causal inferences.
gest whether a carcinogen acts early or late in the
process of carcinogenesis, although, at best, they (f) Criteria for causality
allow only indirect inferences about mechanisms
of carcinogenesis. After the quality of individual epidemiologi-
cal studies of cancer has been summarized and
assessed, a judgement is made concerning the
(e) Use of biomarkers in epidemiological
strength of evidence that the agent in question
studies is carcinogenic to humans. In making its judge-
Biomarkers indicate molecular, cellular or ment, the Working Group considers several crite-
other biological changes and are increasingly ria for causality (Hill, 1965). A strong association
used in epidemiological studies for various pur- (e.g. a large relative risk) is more likely to indicate
poses (IARC, 1991; Vainio et al., 1992; Toniolo causality than a weak association, although it is
et al., 1997; Vineis et al., 1999; Buffler et al., 2004). recognized that estimates of effect of small mag-
These may include evidence of exposure, of early nitude do not imply lack of causality and may be
effects, of cellular, tissue or organism responses, important if the disease or exposure is common.
of individual susceptibility or host responses, Associations that are replicated in several studies
and inference of a mechanism (see Part B, Section of the same design or that use different epidemi-
4b). This is a rapidly evolving field that encom- ological approaches or under different circum-
passes developments in genomics, epigenomics stances of exposure are more likely to represent
and other emerging technologies. a causal relationship than isolated observations
Molecular epidemiological data that identify from single studies. If there are inconsistent
associations between genetic polymorphisms results among investigations, possible reasons
and interindividual differences in susceptibility are sought (such as differences in exposure), and
to the agent(s) being evaluated may contribute results of studies that are judged to be of high
to the identification of carcinogenic hazards to quality are given more weight than those of stud-
humans. If the polymorphism has been demon- ies that are judged to be methodologically less
strated experimentally to modify the functional sound.
activity of the gene product in a manner that is If the risk increases with the exposure, this is
consistent with increased susceptibility, these considered to be a strong indication of causality,
data may be useful in making causal inferences. although the absence of a graded response is not
Similarly, molecular epidemiological studies that necessarily evidence against a causal relation-
measure cell functions, enzymes or metabolites ship. The demonstration of a decline in risk after
that are thought to be the basis of susceptibil- cessation of or reduction in exposure in indi-
ity may provide evidence that reinforces biologi- viduals or in whole populations also supports a
cal plausibility. It should be noted, however, that causal interpretation of the findings.
when data on genetic susceptibility originate Several scenarios may increase confidence in
from multiple comparisons that arise from sub- a causal relationship. On the one hand, an agent
group analyses, this can generate false-positive may be specific in causing tumours at one site or
results and inconsistencies across studies, and of one morphological type. On the other, carci-
such data therefore require careful evaluation. nogenicity may be evident through the causation
If the known phenotype of a genetic polymor- of multiple tumour types. Temporality, precision
phism can explain the carcinogenic mechanism of estimates of effect, biological plausibility and
17
28. IARC MONOGRAPHS – 100D
coherence of the overall database are consid- 3. Studies of cancer in experimental
ered. Data on biomarkers may be employed in animals
an assessment of the biological plausibility of epi-
demiological observations. All known human carcinogens that have been
Although rarely available, results from rand- studied adequately for carcinogenicity in experi-
omized trials that show different rates of cancer mental animals have produced positive results
among exposed and unexposed individuals pro- in one or more animal species (Wilbourn et al.,
vide particularly strong evidence for causality. 1986; Tomatis et al., 1989). For several agents
When several epidemiological studies show (e.g. aflatoxins, diethylstilbestrol, solar radiation,
little or no indication of an association between vinyl chloride), carcinogenicity in experimen-
an exposure and cancer, a judgement may be made tal animals was established or highly suspected
that, in the aggregate, they show evidence of lack before epidemiological studies confirmed their
of carcinogenicity. Such a judgement requires carcinogenicity in humans (Vainio et al., 1995).
first that the studies meet, to a sufficient degree, Although this association cannot establish that
the standards of design and analysis described all agents that cause cancer in experimental ani-
above. Specifically, the possibility that bias, con- mals also cause cancer in humans, it is biologically
founding or misclassification of exposure or out- plausible that agents for which there is sufficient
come could explain the observed results should evidence of carcinogenicity in experimental ani-
be considered and excluded with reasonable cer- mals (see Part B, Section 6b) also present a car-
tainty. In addition, all studies that are judged to cinogenic hazard to humans. Accordingly, in
be methodologically sound should (a) be con- the absence of additional scientific information,
sistent with an estimate of effect of unity for any these agents are considered to pose a carcinogenic
observed level of exposure, (b) when considered hazard to humans. Examples of additional scien-
together, provide a pooled estimate of relative tific information are data that demonstrate that
risk that is at or near to unity, and (c) have a nar- a given agent causes cancer in animals through
row confidence interval, due to sufficient popula- a species-specific mechanism that does not oper-
tion size. Moreover, no individual study nor the ate in humans or data that demonstrate that the
pooled results of all the studies should show any mechanism in experimental animals also oper-
consistent tendency that the relative risk of can- ates in humans (see Part B, Section 6).
cer increases with increasing level of exposure. Consideration is given to all available long-
It is important to note that evidence of lack of term studies of cancer in experimental animals
carcinogenicity obtained from several epidemio- with the agent under review (see Part A, Section
logical studies can apply only to the type(s) of 4). In all experimental settings, the nature and
cancer studied, to the dose levels reported, and to extent of impurities or contaminants present in
the intervals between first exposure and disease the agent being evaluated are given when avail-
onset observed in these studies. Experience with able. Animal species, strain (including genetic
human cancer indicates that the period from first background where applicable), sex, numbers per
exposure to the development of clinical cancer is group, age at start of treatment, route of expo-
sometimes longer than 20 years; latent periods sure, dose levels, duration of exposure, survival
substantially shorter than 30 years cannot pro- and information on tumours (incidence, latency,
vide evidence for lack of carcinogenicity. severity or multiplicity of neoplasms or prene-
oplastic lesions) are reported. Those studies in
experimental animals that are judged to be irrel-
evant to the evaluation or judged to be inadequate
18
29. Preamble
(e.g. too short a duration, too few animals, poor (a) Qualitative aspects
survival; see below) may be omitted. Guidelines
for conducting long-term carcinogenicity exper- An assessment of carcinogenicity involves
iments have been published (e.g. OECD, 2002). several considerations of qualitative impor-
Other studies considered may include: exper- tance, including (i) the experimental conditions
iments in which the agent was administered in under which the test was performed, including
the presence of factors that modify carcinogenic route, schedule and duration of exposure, spe-
effects (e.g. initiation–promotion studies, co- cies, strain (including genetic background where
carcinogenicity studies and studies in geneti- applicable), sex, age and duration of follow-up;
cally modified animals); studies in which the (ii) the consistency of the results, for example,
end-point was not cancer but a defined precan- across species and target organ(s); (iii) the spec-
cerous lesion; experiments on the carcinogenic- trum of neoplastic response, from preneoplastic
ity of known metabolites and derivatives; and lesions and benign tumours to malignant neo-
studies of cancer in non-laboratory animals (e.g. plasms; and (iv) the possible role of modifying
livestock and companion animals) exposed to factors.
the agent. Considerations of importance in the inter-
For studies of mixtures, consideration is pretation and evaluation of a particular study
given to the possibility that changes in the phys- include: (i) how clearly the agent was defined and,
icochemical properties of the individual sub- in the case of mixtures, how adequately the sam-
stances may occur during collection, storage, ple characterization was reported; (ii) whether
extraction, concentration and delivery. Another the dose was monitored adequately, particu-
consideration is that chemical and toxicological larly in inhalation experiments; (iii) whether the
interactions of components in a mixture may doses, duration of treatment and route of expo-
alter dose–response relationships. The relevance sure were appropriate; (iv) whether the survival
to human exposure of the test mixture adminis- of treated animals was similar to that of con-
tered in the animal experiment is also assessed. trols; (v) whether there were adequate numbers
This may involve consideration of the following of animals per group; (vi) whether both male and
aspects of the mixture tested: (i) physical and female animals were used; (vii) whether animals
chemical characteristics, (ii) identified constitu- were allocated randomly to groups; (viii) whether
ents that may indicate the presence of a class of the duration of observation was adequate; and
substances and (iii) the results of genetic toxicity (ix) whether the data were reported and analysed
and related tests. adequately.
The relevance of results obtained with an When benign tumours (a) occur together
agent that is analogous (e.g. similar in structure with and originate from the same cell type as
or of a similar virus genus) to that being evalu- malignant tumours in an organ or tissue in a
ated is also considered. Such results may provide particular study and (b) appear to represent a
biological and mechanistic information that is stage in the progression to malignancy, they are
relevant to the understanding of the process of usually combined in the assessment of tumour
carcinogenesis in humans and may strengthen incidence (Huff et al., 1989). The occurrence of
the biological plausibility that the agent being lesions presumed to be preneoplastic may in cer-
evaluated is carcinogenic to humans (see Part B, tain instances aid in assessing the biological plau-
Section 2f). sibility of any neoplastic response observed. If an
agent induces only benign neoplasms that appear
to be end-points that do not readily undergo
19