IARC Monographs on the Identification ofCarcinogenic Hazards to Humans

PREAMBLE

Lyon, France
Amended January 2019

IARC Monographs Preamble

Contents
A. GENERAL PRINCIPLES AND PROCEDURES ...................................... 1
1. Background ............................................................................................................. 1
2. Objective and scope ................................................................................................ 2
3. Selection of agents for review ................................................................................. 3
4. The Working Group and other meeting participants .............................................. 4
5. Working procedures ................................................................................................ 6
6. Overview of the scientific review and evaluation process ...................................... 8
7. Responsibilities of the Working Group ................................................................ 10

B. SCIENTIFIC REVIEW AND EVALUATION ......................................... 12
1. Exposure characterization ..................................................................................... 12(a) Identification of the agent ................................................................................ 12(b) Detection and analysis...................................................................................... 13(c) Production and use ........................................................................................... 13(d) Exposure ........................................................................................................... 14(e) Regulations and guidelines............................................................................... 14(f) Critical review of exposure assessment in key epidemiological studies .......... 15
2. Studies of cancer in humans .................................................................................. 16(a) Types of study considered ................................................................................ 16(b) Identification of eligible studies of cancer in humans ..................................... 17(c) Assessment of study quality and informativeness ........................................... 17(d) Meta-analyses and pooled analyses ................................................................. 20(e) Considerations in assessing the body of epidemiological evidence................. 20
3. Studies of cancer in experimental animals ............................................................ 22(a) Types of studies considered ............................................................................. 23(b) Study evaluation ............................................................................................... 23(c) Outcomes and statistical analyses .................................................................... 24
4. Mechanistic evidence ............................................................................................ 25(a) Absorption, distribution, metabolism, and excretion ....................................... 26(b) Evidence relevant to key characteristics of carcinogens .................................. 26

IARC Monographs Preamble(c) Other relevant evidence .................................................................................... 28(d) Study quality and importance to the evaluation ............................................... 28
5. Summary of data reported ..................................................................................... 29(a) Exposure characterization ................................................................................ 29(b) Cancer in humans ............................................................................................. 29(c) Cancer in experimental animals ....................................................................... 30(d) Mechanistic evidence ....................................................................................... 30
6. Evaluation and rationale ........................................................................................ 30(a) Carcinogenicity in humans ............................................................................... 31(b) Carcinogenicity in experimental animals ......................................................... 32(c) Mechanistic evidence ....................................................................................... 33(d) Overall evaluation ............................................................................................ 35(e) Rationale ........................................................................................................... 36
References ................................................................................................................. 38

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The Preamble to the IARC Monographs describes the objective and scope of
the programme, general principles and procedures, and scientific review andevaluations. The IARC Monographs embody principles of scientific rigour,
impartial evaluation, transparency, and consistency. The Preamble should be
consulted when reading a Monograph or a summary of a Monograph’s
evaluations. Separate Instructions for Authors describe the operational
procedures for the preparation and publication of a volume of the Monographs.

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A. GENERAL PRINCIPLES AND PROCEDURES

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1. Background

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Soon after the International Agency for Research on Cancer (IARC) wasestablished in 1965, it started to receive frequent requests for advice on the
carcinogenicity of chemicals, including requests for lists of established andsuspected human carcinogens. In 1970, an IARC Advisory Committee on
Environmental Carcinogenesis recommended “that a compendium on carcinogenic
chemicals be prepared by experts. The biological activity and evaluation ofpractical importance to public health should be referenced and documented.” The
next year, the IARC Governing Council adopted a resolution that IARC should
prepare “monographs on the evaluation of carcinogenic risk of chemicals to man”,
which became the initial title of the series.
In succeeding years, the scope of the programme broadened as Monographs
were developed for complex mixtures, occupational exposures, physical agents,
biological organisms, pharmaceuticals, and other exposures. In 1988, “ofchemicals” was dropped from the title, and in 2019, “evaluation of carcinogenic
risks” became “identification of carcinogenic hazards”, in line with the objective of
the programme.
Identifying the causes of human cancer is the first step in cancer prevention.
The identification of a cancer hazard may have broad and profound implications.
National and international authorities and organizations can and do use information
on causes of cancer in support of actions to reduce exposure to carcinogens in theworkplace, in the environment, and elsewhere. Cancer prevention is needed asmuch today as it was when IARC was established, because the global burden ofcancer is high and continues to increase as a result of population growth and ageing
and upward trends in some exposures, especially in low- and middle-income
countries(http://publications.iarc.fr/Non-Series-Publications/World-CancerReports).
IARC’s process for developing Monographs, which has evolved over several
decades, involves the engagement of international, interdisciplinary Working
Groups of expert scientists, the transparent synthesis of different streams ofevidence (exposure characterization, cancer in humans, cancer in experimental
animals, and mechanisms of carcinogenesis), and the integration of these streams

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of evidence into an overall evaluation and classification according to criteria
developed and refined by IARC. Since the Monographs programme wasestablished, the understanding of carcinogenesis has greatly deepened. Scientificadvances are incorporated into the evaluation methodology. In particular, strong
mechanistic evidence has had an increasing role in the overall evaluations since
1991.
The Preamble is primarily a statement of the general principles and procedures
used in developing a Monograph, to promote transparency and consistency acrossMonographs evaluations. In addition, IARC provides Instructions for Authors(https://monographs.iarc.fr/instructions-for-authors/), which specify more detailed
working procedures. IARC routinely updates these Instructions for Authors toreflect advances in methods for cancer hazard identification and accumulated
experience, including input from experts.

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2. Objective and scope

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The objective of the programme is to prepare, with the engagement ofinternational, interdisciplinary Working Groups of experts, scientific reviews andevaluations of evidence on the carcinogenicity of a wide range of agents.
The Monographs assess the strength of the available evidence that an agent cancause cancer in humans, based on three streams of evidence: on cancer in humans(see Part B, Section 2), on cancer in experimental animals (see Part B, Section 3),
and on mechanistic evidence (see Part B, Section 4). In addition, the exposure toeach agent is characterized (see Part B, Section 1). In this Preamble, the term“agent” refers to any chemical, physical, or biological entity or exposure
circumstance (e.g. occupation as a painter) for which evidence on the
carcinogenicity is evaluated.
A cancer hazard is an agent that is capable of causing cancer, whereas a cancer
risk is an estimate of the probability that cancer will occur given some level of
exposure to a cancer hazard. The Monographs assess the strength of evidence thatan agent is a cancer hazard. The distinction between hazard and risk isfundamental. The Monographs identify cancer hazards even when risks appear to
be low in some exposure scenarios. This is because the exposure may be
widespread at low levels, and because exposure levels in many populations are notknown or documented.
Although the Monographs programme has focused on hazard identification,some epidemiological studies used to identify a cancer hazard are also used toestimate an exposure–response relationship within the range of the available data.
However, extrapolating exposure–response relationships beyond the available data
(e.g. to lower exposures, or from experimental animals to humans) is outside thescope of Monographs Working Groups (IARC, 2014). In addition, theMonographs programme does not review quantitative risk characterizations
developed by other health agencies.

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The identification of a cancer hazard should trigger some action to protect
public health, either directly as a result of the hazard identification or through theconduct of a risk assessment. Although such actions are outside the scope of the
programme, the Monographs are used by national and international authorities andorganizations to inform risk assessments, formulate decisions about preventive
measures, motivate effective cancer control programmes, and choose among
options for public health decisions. Monographs evaluations are only one part ofthe body of information on which decisions to control exposure to carcinogens
may be based. Options to prevent cancer vary from one situation to another andacross geographical regions and take many factors into account, including different
national priorities. Therefore, no recommendations are given in the Monographswith regard to regulation, legislation, or other policy approaches, which are theresponsibility of individual governments or organizations. The Monographs
programme also does not make research recommendations. However, it isimportant to note that Monographs contribute significantly to the science of
carcinogenesis by synthesizing and integrating streams of evidence aboutcarcinogenicity and pointing to critical gaps in knowledge.

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3. Selection of agents for review

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Since 1984, about every five years IARC convenes an international,
interdisciplinary Advisory Group to recommend agents for review by the
Monographs programme. IARC selects Advisory Group members who areknowledgeable about current research on carcinogens and public health priorities.
Before an Advisory Group meets, IARC solicits nominations of agents fromscientists and government agencies worldwide. Since 2003, IARC also invites
nominations from the public. IARC charges each Advisory Group with reviewing
nominations, evaluating exposure and hazard potential, and preparing a report that
documents the Advisory Group’s process for these activities and its rationale forthe recommendations.
For each new volume of the Monographs, IARC selects the agents for review
from those recommended by the most recent Advisory Group, considering theavailability of pertinent research studies and current public health priorities. On
occasion, IARC may select other agents if there is a need to rapidly evaluate an
emerging carcinogenic hazard or an urgent need to re-evaluate a previous
classification. All evaluations consider the full body of available evidence, not justinformation published after a previous review.
A Monograph may review:(a) An agent not reviewed in a previous Monograph, if there is potential human
exposure and there is evidence for assessing its carcinogenicity. A group of
related agents (e.g. metal compounds) may be reviewed together if there isevidence for assessing carcinogenicity for one or more members of thegroup.

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(b) An agent reviewed in a previous Monograph, if there is new evidence ofcancer in humans or in experimental animals, or mechanistic evidence towarrant re-evaluation of the classification. In the interests of efficiency, theliterature searches may build on previous comprehensive searches.
(c) An agent that has been established to be carcinogenic to humans and has
been reviewed in a previous Monograph, if there is new evidence of cancer
in humans that indicates new tumour sites where there might be a causal
association. In the interests of efficiency, the review may focus on these newtumour sites.
4. The Working Group and other meeting participants
Five categories of participants can be present at Monographs meetings:

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(i) Working Group members are responsible for all scientific reviews andevaluations developed in the volume of the Monographs. The Working
Group is interdisciplinary and comprises subgroups of experts in the fields of(a) exposure characterization, (b) cancer in humans, (c) cancer inexperimental animals, and (d) mechanistic evidence. IARC selects Working
Group members on the basis of expertise related to the subject matter andrelevant methodologies, and absence of conflicts of interest. Consideration is
also given to diversity in scientific approaches and views, as well as
demographic composition. Working Group members generally havepublished research related to the exposure or carcinogenicity of the agents
being reviewed, and IARC uses literature searches to identify most experts.
Since 2006, IARC also has encouraged public nominations through its Callfor Experts. IARC’s reliance on experts with knowledge of the subject matter
and/or expertise in methodological assessment is confirmed by decades ofexperience documenting that there is value in specialized expertise and thatthe overwhelming majority of Working Group members are committed to theobjective evaluation of scientific evidence and not to the narrow advancementof their own research results or a pre-determined outcome (Wild & Cogliano,2011). Working Group members are expected to serve the public healthmission of IARC, and should refrain from consulting and other activities forfinancial gain that are related to the agents under review, or the use of inside
information from the meeting, until the full volume of the Monographs ispublished.

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IARC identifies, from among Working Group members, individuals to serve
as Meeting Chair and Subgroup Chairs. At the opening of the meeting, theWorking Group is asked to endorse the selection of the Meeting Chair, withthe opportunity to propose alternatives. The Meeting Chair and Subgroup
Chairs take a leading role at all stages of the review process (see Part A,
Section 7), promote open scientific discussions that involve all Working

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Group members in accordance with normal committee procedures, andensure adherence to the Preamble.

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(ii) Invited Specialists are experts who have critical knowledge and experiencebut who also have a conflict of interest that warrants exclusion fromdeveloping or influencing the evaluations of carcinogenicity. Invited
Specialists do not draft any section of the Monograph that pertains to thedescription or interpretation of cancer data, and they do not participate in theevaluations. These experts are invited in limited numbers when necessary toassist the Working Group by contributing their unique knowledge andexperience to the discussions.

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(iii) Representatives of national and international health agencies may attend
because their agencies are interested in the subject of the meeting. They do
not draft any section of the Monograph or participate in the evaluations.

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(iv) Observers with relevant scientific credentials may be admitted in limited
numbers. Attention is given to the balance of Observers from constituencies
with differing perspectives. Observers are invited to observe the meeting andshould not attempt to influence it, and they agree to respect the Guidelines
for Observers at IARC Monographs meetings. Observers do not draft any
section of the Monograph or participate in the evaluations.

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(v) The IARC Secretariat consists of scientists who are designated by IARC andwho have relevant expertise. The IARC Secretariat coordinates andfacilitates all aspects of the evaluation and ensures adherence to thePreamble throughout development of the scientific reviews andclassifications (see Part A, Sections 5 and 6). The IARC Secretariat
organizes and announces the meeting, identifies and recruits the Working
Group members, and assesses the declared interests of all meeting
participants. The IARC Secretariat supports the activities of the Working
Group (see Part A, Section 7) by searching the literature and performing title
and abstract screening, organizing conference calls to coordinate thedevelopment of pre-meeting drafts and discuss cross-cutting issues, andreviewing drafts before and during the meeting. Members of the IARC
Secretariat serve as meeting rapporteurs, assist the Meeting Chair and
Subgroup Chairs in facilitating all discussions, and may draft text or tables
when designated by the Meeting Chair and Subgroup Chairs. Their
participation in the evaluations is restricted to the role of clarifying orinterpreting the Preamble.
All participants are listed, with their principal affiliations, in the front matter ofthe published volume of the Monographs. Working Group members and Invited
Specialists serve as individual scientists and not as representatives of any
organization, government, or industry (Cogliano et al., 2004).
The roles of the meeting participants are summarized in Table 1.

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Table 1. Roles of participants at IARC Monographs meetings
Role

Category of participant

Preparetext,
tables, andanalysesParticipate
in
discussions

Participateinevaluations

Eligible toserve asChair

Working Group members

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Invited Specialists√a√Representatives of healthagencies√b

Observers√b

IARC Secretariat

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√d

a

Only for the section on exposure characterizationb

Only at times designated by the Meeting Chair and Subgroup ChairscWhen needed or requested by the Meeting Chair and Subgroup ChairsdOnly for clarifying or interpreting the Preamble

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5. Working procedures

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A separate Working Group is responsible for developing each volume of theMonographs. A volume contains one or more Monographs, which can cover eithera single agent or several related agents. Approximately one year before the meetingof a Working Group, a preliminary list of agents to be reviewed, together with a
Call for Data and a Call for Experts, is announced on the Monographs programme
website (http://monographs.iarc.fr).
Before a meeting invitation is extended, each potential participant, including the
IARC Secretariat, completes the WHO Declaration of Interests form to reportfinancial interests, employment and consulting (including remuneration for serving
as an expert witness), individual and institutional research support, and nonfinancial interests such as public statements and positions related to the subject ofthe meeting. IARC assesses the declared interests to determine whether there is a
conflict that warrants any limitation on participation (see Table 2).
Approximately two months before a Monographs meeting, IARC publishes thenames and affiliations of all meeting participants together with a summary ofdeclared interests, in the interests of transparency and to provide an opportunity for
undeclared conflicts of interest to be brought to IARC’s attention. It is not

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acceptable for Observers or third parties to contact other participants before ameeting or to lobby them at any time. Meeting participants are asked to report all
such contacts to IARC (Cogliano et al., 2005).
The Working Group meets at IARC for approximately eight days to discuss andfinalize the scientific review and to develop summaries and evaluations. At the
opening of the meeting, all participants update their Declaration of Interests forms,
which are then reviewed by IARC. Declared interests related to the subject of themeeting are disclosed to the meeting participants during the meeting and in the
published volume (Cogliano et al., 2004). The objectives of the meeting are peer
review and consensus. During the first part of the meeting, subgroup sessions(covering exposure characterization, cancer in humans, cancer in experimental
animals, and mechanistic evidence) review the pre-meeting drafts, develop a joint
subgroup draft, and draft subgroup summaries. During the last part of the meeting,the Working Group meets in plenary session to review the subgroup drafts andsummaries and to develop the consensus evaluations. As a result, the entire volume
is the joint product of the Working Group, and there are no individually authoredsections. After the meeting, the master copy is verified by the IARC Secretariat
and is then edited and prepared for publication. The aim is to publish the volume
within approximately nine months of the Working Group meeting. A summary of
the evaluations and key supporting evidence is prepared for publication in ascientific journal or is made available on the Monographs programme website
soon after the meeting.
In the interests of transparency, IARC engages with the public throughout theprocess, as summarized in Table 2.

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Table 2. Public engagement during Monographs development
Approximate timeframe

Engagement

Every 5 years

IARC convenes an Advisory Group to recommend
high-priority agents for future review
IARC selects agents for review in a new volume of theMonographs
IARC posts on its website:~1 year before a Monographs
meeting

Preliminary List of Agents to be reviewed
Call for Data and Call for Experts
Request for Observer Status
WHO Declaration of Interests form

~8 months before a
Monographs meeting

Call for Experts closes~4 months before a
Monographs meeting

Request for Observer Status closes~2 months before a
Monographs meeting

IARC posts the names of all meeting participants
together with a summary of declared interests, and astatement discouraging contact of the Working Groupby interested parties~1 month before a
Monographs meeting

Call for Data closes~2–4 weeks after a
Monographs meeting

IARC publishes a summary of evaluations and key
supporting evidence~9 months after a
Monographs meeting

IARC Secretariat publishes the verified and edited
master copy of plenary drafts as a Monographs
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6. Overview of the scientific review and evaluation process

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The Working Group considers all pertinent epidemiological studies, cancer
bioassays in experimental animals, and mechanistic evidence, as well as pertinent
information on exposure in humans. In general, for cancer in humans, cancer inexperimental animals, and mechanistic evidence, only studies that have been
published or accepted for publication in the openly available scientific literature arereviewed. Under some circumstances, materials that are publicly available and

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whose content is final may be reviewed if there is sufficient information to permit
an evaluation of the quality of the methods and results of the studies (see Step 1,
below). Such materials may include reports and databases publicly available fromgovernment agencies, as well as doctoral theses. The reliance on published andpublicly available studies promotes transparency and protects against citation ofpremature information.
The principles of systematic review are applied to the identification, screening,
synthesis, and evaluation of the evidence related to cancer in humans, cancer inexperimental animals, and mechanistic evidence (as described in Part B,
Sections 2–4 and as detailed in the Instructions for Authors). Each Monographspecifies or references information on the conduct of the literature searches,
including search terms and inclusion/exclusion criteria that were used for eachstream of evidence.

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In brief, the steps of the review process are as follows:

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Step 1. Comprehensive and transparent identification of the relevant
information: The IARC Secretariat identifies relevant studies throughinitial comprehensive searches of literature contained in authoritative
biomedical databases (e.g. PubMed, PubChem) and through a Call for
Data. These literature searches, designed in consultation with a librarianand other technical experts, address whether the agent causes cancer inhumans, causes cancer in experimental systems, and/or exhibits key
characteristics of established human carcinogens (in humans or inexperimental systems). The Working Group provides input and advice to
IARC to refine the search strategies, and identifies literature throughother searches (e.g. from reference lists of past Monographs, retrieved
articles, and other authoritative reviews).

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For certain types of agents (e.g. regulated pesticides and pharmaceuticals),
IARC also provides an opportunity to relevant regulatory authorities, andregulated parties through such authorities, to make pertinent unpublishedstudies publicly available by the date specified in the Call for Data.
Consideration of such studies by the Working Group is dependent on the
public availability of sufficient information to permit an independent
evaluation of (a) whether there has been selective reporting (e.g. on
outcomes, or from a larger set of conducted studies), (b) study quality(e.g. design, methodology, and reporting of results), and (c) study results.

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Step 2. Screening, selection, and organization of the studies: The IARC
Secretariat screens the retrieved literature for inclusion based on title andabstract review, according to pre-defined exclusion criteria. For instance,
studies may be excluded if they were not about the agent (or a metaboliteof the agent), or if they reported no original data on epidemiological or
toxicological end-points (e.g. review articles). The Working Group9

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reviews the title and abstract screening done by IARC, and performs fulltext review. Any reasons for exclusion are recorded, and included studies
are organized according to factors pertinent to the considerations
described in Part B, Sections 2–4 (e.g. design, species, and end-point).
Inclusion of a study does not imply acceptance of the adequacy of thestudy design or of the analysis and interpretation of the results.

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Step 3. Evaluation of study quality: The Working Group evaluates the qualityof the included studies based on the considerations (e.g. design,
methodology, and reporting of results) described in Part B, Sections 2–4.
Based on these considerations, the Working Group may accord greater
weight to some of the included studies. Interpretation of the results andthe strengths and limitations of a study are clearly outlined in square
brackets at the end of study descriptions (see Part B).

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Step 4. Report characteristics of included studies, including assessment ofstudy quality: Pertinent characteristics and results of included studies arereviewed and succinctly described, as detailed in Part B, Sections 1–4.
Tabulation of data may facilitate this reporting. This step may be iterativewith Step 3.

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Step 5. Synthesis and evaluation of strength of evidence: The Working Groupsummarizes the overall strengths and limitations of the evidence from theindividual streams of evidence (cancer in humans, cancer in experimental
animals, and mechanistic evidence; see Part B, Section 5). The Working
Group then evaluates the strength of evidence from each stream ofevidence by using the transparent methods and defined descriptive terms
given in Part B, Sections 6a–c. The Working Group then develops, anddescribes the rationale for, the consensus classification of carcinogenicity
that integrates the conclusions about the strength of evidence from studies
of cancer in humans, studies of cancer in experimental animals, andmechanistic evidence (see Part B, Section 6d).

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7. Responsibilities of the Working Group

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The Working Group is responsible for identifying and evaluating the relevant
studies and developing the scientific reviews and evaluations for a volume of theMonographs. The IARC Secretariat supports these activities of the Working Group(see Part A, Section 4). Briefly, the Working Group’s tasks in developing theevaluation are, in sequence:

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(i) Before the meeting, the Working Group ascertains that all appropriate
studies have been identified and selected, and assesses the methods and quality ofeach individual study, as outlined above (see Part A, Section 6). The Working
Group members prepare pre-meeting working drafts that present accurate tabular
or textual summaries of informative studies by extracting key elements of the study

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design and results, and highlighting notable strengths and limitations. They
participate in conference calls organized by IARC to coordinate the developmentof working drafts and to discuss cross-cutting issues. Pre-meeting reviews of all
working drafts are generally performed by two or more subgroup members who
did not participate in study identification, data extraction, or study review for thedraft. Each study summary is written or reviewed by someone who is not
associated with the study.

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(ii) At the meeting, within subgroups, the Working Group members criticallyreview, discuss, and revise the pre-meeting drafts and adopt the revised versions asconsensus subgroup drafts. Subgroup Chairs ensure that someone who is not
associated with the study leads the discussion of each study summary. A proposedclassification of the strength of the evidence reviewed in the subgroup using the
IARC Monographs criteria (see Part B, Sections 6a–c) is then developed from theconsensus subgroup drafts of the evidence summaries (see Part B, Section 5).

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(iii) During the plenary session, each subgroup presents its drafts for scientificreview and discussion to the other Working Group members, who did notparticipate in study identification, data extraction, or study review for the drafts.
Subgroup Chairs ensure that someone who is not associated with the study leads
the discussion of each study summary. After review, discussion, and revisions asneeded, the subgroup drafts are adopted as a consensus Working Group product.
The summaries and classifications of the strength of the evidence, developed in thesubgroup in line with the IARC Monographs criteria (see Part B, Sections 6a–c),
are considered, revised as needed, and adopted by the full Working Group. The
Meeting Chair proposes an overall evaluation using the guidance provided inPart B, Section 6d.

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The Working Group strives to achieve consensus evaluations. Consensus
reflects broad agreement among the Working Group, but not necessarily
unanimity. The Meeting Chair may poll the Working Group to determine thediversity of scientific opinion on issues where consensus is not apparent.
Only the final product of the plenary session represents the views and expert
opinions of the Working Group. The entire Monographs volume is the joint
product of the Working Group and represents an extensive and thorough peer
review of the body of evidence (individual studies, synthesis, and evaluation) by aninterdisciplinary expert group. Initial working papers and subsequent revisions are
not released, because they would give an incomplete and possibly misleading
impression of the consensus developed by the Working Group over a full week ofdeliberation.

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B. SCIENTIFIC REVIEW AND EVALUATION

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This part of the Preamble discusses the types of evidence that are consideredand summarized in each section of a Monograph, followed by the scientific criteriathat guide the evaluations. In addition, a section of General Remarks at the front of
the volume discusses the reasons the agents were scheduled for evaluation and any
key issues encountered during the meeting.

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1. Exposure characterization

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This section identifies the agent and describes its occurrence, main uses, andproduction locations and volumes, where relevant. It also summarizes theprevalence, concentrations in relevant studies, and relevant routes of exposure in
humans worldwide. Methods of exposure measurement and analysis are described,
and methods of exposure assessment used in key epidemiological studies reviewed
by the Working Group are described and evaluated.
Over the course of the Monographs programme, concepts of exposure and dose
have evolved substantially with deepening understanding of the interactions ofagents and biological systems. The concept of exposure has broadened and become
more holistic, extending beyond chemical, physical, and biological agents tostressors as construed generally, including psychosocial stressors (National
Research Council, 2012; National Academies of Sciences, Engineering, andMedicine, 2017). Overall, this broader conceptualization supports greater
integration between exposure characterization and other sections of theMonographs. Concepts of absorption, distribution, metabolism, and excretion are
considered in the first subsection of mechanistic evidence (see Part B, Section 4a),whereas validated biomarkers of internal exposure or metabolites that are routinely
used for exposure assessment are reported on in this section (see Part B,
Section 1b).

28(a) Identification of the agent

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The agent being evaluated is unambiguously identified. Details will varydepending on the type of agent but will generally include physical and chemical
properties relevant to the agent’s identification, occurrence, and biological activity.
If the material that has been tested in experimental animals or in vitro systems isdifferent from that to which humans are exposed, these differences are noted.
For chemical agents, the Chemical Abstracts Service Registry Number isprovided, as well as the latest primary name and other names in common use,
including important trade names, along with available information on thecomposition of common mixtures or products containing the agent, and potentially
toxic and/or carcinogenic impurities. Physical properties relevant to understanding
the potential for human exposure and measures of exposure used in studies in

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humans are summarized. These might include physical state, volatility, aqueousand fat solubility, and half-life in the environment and/or in human tissues.
For biological agents, taxonomy and structure are described. Mode of
replication, life-cycle, target cells, persistence, latency, and host responses,
including morbidity and mortality through pathologies other than cancer, are alsopresented.
For foreign bodies, fibres and particles, composition, size range, relative
dimensions, and accumulation, persistence, and clearance in target organs are
summarized. Physical agents that are forms of radiation are described in terms offrequency spectrum and energy transmission.
Exposures may result from, or be influenced by, a diverse range of social andenvironmental factors, including components of diet, sleep, and physical activity
patterns. In these instances, this section will include a description of the agent, itsvariability across human populations, and its composition or characteristics
relevant to understanding its potential carcinogenic hazard to humans and toevaluating exposure assessments in epidemiological studies.

17(b) Detection and analysis

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Key methods of detection and quantification of the agent are presented, with anemphasis on those used most widely in surveillance, regulation, andepidemiological studies. Measurement methods for sample matrices that are
deemed important sources of human exposure (e.g. air, drinking-water, food,residential dust) and for validated exposure biomarkers (e.g. the agent or its
metabolites in human blood, urine, or saliva) are described. Information on
detection and quantification limits is provided when it is available and is useful forinterpreting studies in humans and in experimental animals. This is not an
exhaustive treatise but is meant to help readers understand the strengths andlimitations of the available exposure data and of the epidemiological studies that
rely on these measurements.

29(c) Production and use

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Historical and geographical patterns and trends in production and use areincluded when they are available, to help readers understand the contexts in which
exposures may occur, both within key epidemiological studies reviewed by theWorking Group and in human populations generally. Industries that produce, use,
or dispose of the agent are described, including their global distribution, whenavailable. National or international listing as a high-production-volume chemical orsimilar classification may be included. Production processes with significant
potential for occupational exposure or environmental pollution are indicated.
Trends in global production volumes, technologies, and other data relevant tounderstanding exposure potential are summarized. Minor or historical uses with

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significant exposure potential or with particular relevance to key epidemiologicalstudies are included. Particular effort may be directed towards finding data on
production in low- and middle-income countries, where rapid economic
development may lead to higher exposures than those in high-income countries.

5(d) Exposure

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A concise overview of quantitative information on sources, prevalence, andlevels of exposure in humans is provided. Representative data from researchstudies, government reports and websites, online databases, and other citable,
publicly available sources are tabulated. Data from low- and middle-income
countries are sought and included to the extent feasible; information gaps for key
regions are noted. Naturally occurring sources of exposure, if any, are noted.
Primary exposure routes (e.g. inhalation, ingestion, skin uptake) and otherconsiderations relevant to understanding the potential for cancer hazard fromexposure to the agent are reported.
For occupational settings, information on exposure prevalence and levels (e.g.
in air or human tissues) is reported by industry, occupation, region, and othercharacteristics (e.g. process, task) where feasible. Information on historicalexposure trends, protection measures to limit exposure, and potential co-exposures
to other carcinogenic agents in workplaces is provided when available.
For non-occupational settings, the occurrence of the agent is described withenvironmental monitoring or surveillance data. Information on exposure
prevalence and levels (e.g. concentrations in human tissues) as well as exposure
from and/or concentrations in food and beverages, consumer products,
consumption practices, and personal microenvironments is reported by region andother relevant characteristics. Particular importance is placed on describing
exposures in life stages or in states of disease or nutrition that may involve greater
exposure or susceptibility.
Current exposures are of primary interest; however, information on historicalexposure trends is provided when available. Historical exposures may be relevant
for interpreting epidemiological studies, and when agents are persistent or havelong-term effects. Information gaps for important time periods are noted. Exposure
data that are not deemed to have high relevance to human exposure are generally
not considered.

34(e) Regulations and guidelines

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Regulations or guidelines that have been established for the agent (e.g.
occupational exposure limits, maximum permitted levels in foods and water,
pesticide registrations) are described in brief to provide context about government
efforts to limit exposure; these may be tabulated if they are informative for theinterpretation of existing or historical exposure levels. Information on applicable

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populations, specific agents concerned, basis for regulation (e.g. human health risk,
environmental considerations), and timing of implementation may be noted.
National and international bans on production, use, and trade are also indicated.
This section aims to include major or illustrative regulations and may not becomprehensive, because of the complexity and range of regulatory processes
worldwide. An absence of information on regulatory status should not be taken to
imply that a given country or region lacks exposure to, or regulations on exposure
to, the agent.

9(f) Critical review of exposure assessment in key epidemiological studies

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Epidemiological studies evaluate cancer hazard by comparing outcomes acrossdifferently exposed groups. Therefore, the type and quality of the exposure
assessment methods used are key considerations when interpreting study findings
for hazard identification. This section summarizes and critically reviews the
exposure assessment methods used in the individual epidemiological studies that
contribute data relevant to the Monographs evaluation.
Although there is no standard set of criteria for evaluating the quality of
exposure assessment methods across all possible agents, some concepts areuniversally relevant. Regardless of the agent, all exposures have two principal
dimensions: intensity (sometimes defined as concentration or dose) and time. Timeconsiderations include duration (time from first to last exposure), pattern or
frequency (whether continuous or intermittent), and windows of susceptibility.
This section considers how each of the key epidemiological studies characterizes
these dimensions. Interpretation of exposure information may also be informed byconsideration of mechanistic evidence (e.g. as described in Part B, Section 4a),including the processes of absorption, distribution, metabolism, and excretion.
Exposure intensity and time in epidemiological studies can be characterized byusing environmental or biological monitoring data, records from workplaces orother sources, expert assessments, modelled exposures, job-exposure matrices, andsubject or proxy reports via questionnaires or interviews. Investigators use thesedata sources and methods individually or in combination to assign levels or valuesof an exposure metric (which may be quantitative, semi-quantitative, or qualitative)
to members of the population under study.
In collaboration with the Working Group members reviewing human studies (ofcancer and of mechanisms), key epidemiological studies are identified. For eachselected study, the exposure assessment approach, along with its strengths andlimitations, is summarized using text and tables. Working Group members identify
concerns about exposure assessment methods and their impacts on overall quality
for each study reviewed (see Part B, Sections 2d and 4d). In situations where theinformation provided in the study is inadequate to properly consider the exposure
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direction of bias due to error in exposure measurement, including misclassification(overestimated effects, underestimated effects, or unknown) is discussed.

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2. Studies of cancer in humans

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This section includes all pertinent epidemiological studies (see Part B,
Section 2b) that include cancer as an outcome. These studies encompass certain
types of biomarker studies, for example, studies with biomarkers as exposure
metrics (see Part B, Section 2) or those evaluating histological or tumour subtypes
and molecular signatures in tumours consistent with a given exposure (Alexandrov
et al., 2016). Studies that evaluate early biological effect biomarkers are reviewed
in Part B, Section 4.

11(a) Types of study considered

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Several types of epidemiological studies contribute to the assessment ofcarcinogenicity in humans; they typically include cohort studies (including variants
such as case–cohort and nested case–control studies), case–control studies,
ecological studies, and intervention studies. Rarely, results from randomized trials
may be available. Exceptionally, case reports and case series of cancer in humans
may also be reviewed. In addition to these designs, innovations in epidemiology
allow for many other variants that may be considered in any given Monographs
evaluation.
Cohort and case–control studies typically have the capacity to relate individual
exposures under study to the occurrence of cancer in individuals, and provide anestimate of effect (such as relative risk) as the main measure of association. Wellconducted cohort and case–control studies provide most of the evidence of cancer
in humans evaluated by Working Groups. Intervention studies are much lesscommon, but when available can provide strong evidence for making causal
inferences.
In ecological studies, the units of investigation are usually whole populations(e.g. in particular geographical areas or at particular times), and cancer frequency isrelated to a summary measure of the exposure in the population under study. In
ecological studies, data on individual exposure and outcome are not available,
which renders this type of study more prone to confounding and exposure
misclassification. In some circumstances, however, ecological studies may be
informative, especially when the unit of exposure is most accurately measured at
the population level (see, for example, the Monograph on arsenic in drinkingwater; IARC, 2004).
Exceptionally, case reports and case series may provide compelling evidence
about the carcinogenicity of an agent. In fact, many of the early discoveries ofoccupational cancer hazards came about because of observations by workers andtheir clinicians, who noted a high frequency of cancer in workers who share acommon occupation or exposure. Such observations may be the starting point for

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more structured investigations, but in exceptional circumstances, when the risk ishigh enough, the case series may in itself provide compelling evidence. This would
be especially warranted in situations where the exposure circumstance is fairly
unusual, as it was in the example of plants containing aristolochic acid (IARC,
2012a).

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The uncertainties that surround the interpretation of case reports, case series,and ecological studies typically make them inadequate, except in rare instances
as described above, to form the sole basis for inferring a causal relationship.
However, when considered together with cohort and case–control studies, thesetypes of study may support the judgement that a causal relationship exists.

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Epidemiological studies of benign neoplasms, pre-neoplastic lesions,malignant precursors, and other end-points are also reviewed when they relate
to the agents reviewed. On occasion they can strengthen inferences drawn fromstudies of cancer itself. For example, benign brain tumours may share common
risk factors with those that are malignant, and benign neoplasms (or those of
uncertain behaviour) may be part of the causal path to malignancies (e.g.
myelodysplastic syndromes, which may progress to acute myeloid leukaemia).

18(b) Identification of eligible studies of cancer in humans

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Relevant studies of cancer in humans are identified by using systematic review
principles as described in Part A, further elaborated in the Instructions for Authors,
and as detailed below. Eligible studies include all studies in humans of exposure to
the agent of interest with cancer as an outcome. Multiple publications on the same
study population are identified so that the number of independent studies is
accurately represented. Multiple publications may result, for example, fromsuccessive follow-ups of a single cohort, from analyses focused on different
aspects of an exposure–disease association, or from inclusion of overlapping
populations. Usually in such situations, only the most recent, most comprehensive,or most informative report is reviewed in detail.

29(c) Assessment of study quality and informativeness

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Epidemiological studies are potentially susceptible to several different sourcesof error, summarized briefly below. Qualities of individual studies that addressthese issues are also described below.
Study quality is assessed as part of the structured expert review process
undertaken by the Working Group. A key aspect of quality assessment is
consideration of the possible roles of chance and bias in the interpretation of
epidemiological studies. Chance, which is also called random variation, canproduce misleading study results. This variability in study results is strongly
influenced by the sample size: smaller studies are more likely than larger studies tohave effect estimates that are imprecise. Confidence intervals around a study’s

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point estimate of effect are used routinely to indicate the range of values of theestimate that could easily be produced by chance alone.
Bias is the effect of factors in study design or conduct that lead an association toerroneously appear stronger or weaker than the association that really exists
between the agent and the disease. Biases that require consideration are varied but
are usually categorized as selection bias, information bias (e.g. error inmeasurement of exposure and diseases), and confounding (or confounding bias),(Rothman et al., 2008). Selection bias in an epidemiological study occurs when
inclusion of participants from the eligible population or their follow-up in the study
is influenced by their exposure or their outcome (usually disease occurrence).
Under these conditions, the measure of association found in the study will notaccurately reflect the association that would otherwise have been found in theeligible population (Hernán et al., 2004). Information bias results from inaccuracy
in exposure or outcome measurement. Both can cause an association between
hypothesized cause and effect to appear stronger or weaker than it really is.
Confounding is a mixing of extraneous effects with the effects of interest(Rothman et al., 2008). An association between the purported causal factor andanother factor that is associated with an increase or decrease in incidence of disease
can lead to a spurious association or absence of a real association of the presumed
causal factor with the disease. When either of these occurs, confounding is present.
In assessing study quality, the Working Group consistently considers thefollowing aspects:

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• Study description: Clarity in describing the study design and its
implementation, and the completeness of reporting of all other key
information about the study and its results.

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• Study population: Whether the study population was appropriate for
evaluating the association between the agent and cancer. Whether the
study was designed and carried out to minimize selection bias. Cancer
cases in the study population must have been identified in a way that was
independent of the exposure of interest, and exposure assessed in a waythat was not related to disease (outcome) status. In these respects,
completeness of recruitment into the study from the population of interest
and completeness of follow-up for the outcome are essential measures.

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• Outcome measurement: The appropriateness of the cancer outcome
measure (e.g. mortality vs incidence) for the agent and cancer type underconsideration, outcome ascertainment methodology, and the extent towhich outcome misclassification may have led to bias in the measure(s)of association.

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40• Exposure measurement: The adequacy of the methods used to assess
exposure to the agent, and the likelihood (and direction) of bias in the18

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measure(s) of association due to error in exposure measurement,
including misclassification (as described in Part B, Section 1f).

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• Assessment of potential confounding: To what extent the authors took
into account in the study design and analysis other variables (including
co-exposures, as described in Part B, Section 1d) that can influence therisk of disease and may have been related to the exposure of interest.
Important sources of potential confounding by such variables should havebeen addressed either in the design of the study, such as by matching or
restriction, or in the analysis, by statistical adjustment. In some instances,where direct information on confounders is unavailable, use of indirect
methods to evaluate the potential impact of confounding on exposure–disease associations is appropriate (e.g. Axelson & Steenland, 1988;
Richardson et al., 2014).

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• Other potential sources of bias: Each epidemiological study is unique inits study population, its design, its data collection, and, consequently, its
potential biases. All possible sources of bias are considered for their
possible impact on the results. The possibility of reporting bias (i.e.
selective reporting of some results and the suppression of others) should
be explored.

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• Statistical methodology: Adequacy of the statistical methods used andtheir ability to obtain unbiased estimates of exposure–outcome
associations, confidence intervals, and test statistics for the significanceof measures of association. Appropriateness of methods used toinvestigate confounding, including adjusting for matching whennecessary and avoiding treatment of probable mediating variables asconfounders. Detailed analyses of cancer risks in relation to summary
measures of exposure such as cumulative exposure, or temporal variables
such as age at first exposure or time since first exposure, are reviewed
and summarized when available.

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For the sake of economy and simplicity, in this Preamble the list of possible
sources of error is referred to with the phrase “chance, bias, and confounding”, but
it should be recognized that this phrase encompasses a comprehensive set ofconcerns pertaining to study quality.
These sources of error do not constitute and should not be used as a formal
checklist of indicators of study quality. The judgement of experienced experts is
critical in determining how much weight to assign to different issues in considering
how all of these potential sources of error should be integrated and how to rate thepotential for error related to each of these considerations.
The informativeness of a study is its ability to show a true association, if there isone, between the agent and cancer, and the lack of an association, if no association
exists. Key determinants of informativeness include: having a study population of

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sufficient size to obtain precise estimates of effect; sufficient elapsed time fromexposure to measurement of outcome for an effect, if present, to be observable;
presence of an adequate exposure contrast (intensity, frequency, and/or duration);
biologically relevant definitions of exposure; and relevant and well-defined time
windows for exposure and outcome.

6(d) Meta-analyses and pooled analyses

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Independent epidemiological studies of the same agent may lead to inconsistent
results that are difficult to interpret or reconcile. Combined analyses of data frommultiple studies may be conducted as a means to address this ambiguity. There are
two types of combined analysis. The first involves combining summary statistics
such as relative risks from individual studies (meta-analysis), and the second
involves a pooled analysis of the raw data from the individual studies (pooled
analysis) (Greenland & O’Rourke, 2008).
The strengths of combined analyses are increased precision because ofincreased sample size and, in the case of pooled analyses, the opportunity to better
control for potential confounders and to explore in more detail interactions andmodifying effects that may explain heterogeneity among studies. A disadvantage
of combined analyses is the possible lack of comparability of data from various
studies, because of differences in population characteristics, subject recruitment,
procedures of data collection, methods of measurement, and effects of unmeasured
covariates that may differ among studies. These differences in study methods andquality can influence results of either meta-analyses or pooled analyses. If
published meta-analyses are to be considered by the Working Group, theiradequacy needs to be carefully evaluated, including the methods used to identify
eligible studies and the accuracy of data extracted from the individual studies.
The Working Group may conduct ad hoc meta-analyses during the course of a
Monographs meeting, when there are sufficient studies of an exposure–outcome
association to contribute to the Working Group’s assessment of the association.
The results of such unpublished original calculations, which would be specified in
the text by presentation in square brackets, might involve updates of previously
conducted analyses that incorporate the results of more recent studies, or de novo
analyses.
Irrespective of the source of data for the meta-analyses and pooled analyses, thefollowing key considerations apply: the same criteria for data quality must be
applied as for individual studies; sources of heterogeneity among studies must be
carefully considered; and the possibility of publication bias should be explored.

37(e) Considerations in assessing the body of epidemiological evidence

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The ability of the body of epidemiological evidence to inform the Working
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quality of the evidence. There is no formulaic answer to the question of how manystudies of cancer in humans are needed from which to draw inferences aboutcausality, although more than a single study in a single population will almost
always be needed. The number will depend on the considerations relating toevidence described below.
After the quality of individual epidemiological studies of cancer has beenassessed and the informativeness of the various studies on the association between
the agent and cancer has been evaluated, a judgement is made about the strength ofevidence that the agent in question is carcinogenic to humans. In making its
judgement, the Working Group considers several aspects of the body of evidence(e.g. Hill, 1965; Rothman et al., 2008; Vandenbroucke et al., 2016).
A strong association (e.g. a large relative risk) is more likely to indicate
causality than is a weak association, because it is more difficult for confounding tofalsely create a strong association. However, it is recognized that estimates ofeffect of small magnitude do not imply lack of causality and may have impact on
public health if the disease or exposure is common. Estimates of effect of small
magnitude could also contribute useful information to the assessment of causality
if level of risk is commensurate with level of exposure when compared with risk
estimates from populations with higher exposure (e.g. as seen in residential radonstudies compared with studies of radon from uranium mining).
Associations that are consistently observed in several studies of the same
design, or in studies that use different epidemiological approaches, or under
different circumstances of exposure are more likely to indicate a causal
relationship than are isolated observations from single studies. If there areinconsistent results among investigations, possible reasons are sought (e.g.
differences in study informativeness because of latency, exposure levels, orassessment methods). Results of studies that are judged to be of high quality andinformativeness are given more weight than those of studies judged to bemethodologically less sound or less informative.
Temporality of the association is an essential consideration: that is, the exposuremust precede the outcome.
An observation that cancer risk increases with increasing exposure isconsidered to be a strong indication of causality, although the absence of a graded
response is not necessarily evidence against a causal relationship, and there areseveral reasons why the shape of the exposure–response association may be nonmonotonic (e.g. Stayner et al., 2003). The demonstration of a decline in risk after
cessation of or reduction in exposure in individuals or in whole populations also
supports a causal interpretation of the findings.
Confidence in a causal interpretation of the evidence from studies of cancer inhumans is enhanced if it is coherent with physiological and biological knowledge,
including information about exposure to the target organ, latency and timing of the
exposure, and characteristics of tumour subtypes.

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The Working Group considers whether there are subpopulations withincreased susceptibility to cancer from the agent. For example, molecularepidemiology studies that identify associations between genetic polymorphisms
and inter-individual differences in cancer susceptibility to the agent(s) being
evaluated may contribute to the identification of carcinogenic hazards tohumans. Such studies may be particularly informative if polymorphisms arefound to be modifiers of the exposure–response association, because evaluationof polymorphisms may increase the ability to detect an effect in susceptible
subpopulations.
When, in the process of evaluating the studies of cancer in humans, theWorking Group identifies several high-quality, informative epidemiologicalstudies that clearly show either no positive association or an inverse association
between an exposure and a specific type of cancer, a judgement may be made that,in the aggregate, they suggest evidence of lack of carcinogenicity for that cancer
type. Such a judgement requires, first, that the studies strictly meet the standards ofdesign and analysis described above. Specifically, the possibility that bias,
confounding, or misclassification of exposure or outcome could explain theobserved results should be considered and ruled out with reasonable confidence. In
addition, all studies that are judged to be methodologically sound should (a) be
consistent with an estimate of relative effect of unity (or below unity) for any
observed level of exposure, (b) when considered together, provide a combined
estimate of relative risk that is at or below unity, and (c) have a narrow confidence
interval. Moreover, neither any individual well-designed and well-conducted study
nor the pooled results of all the studies should show any consistent tendency thatthe relative risk of cancer increases with increasing level of exposure. It must be
noted that evidence of lack of carcinogenicity obtained from several
epidemiological studies can apply only to the type(s) of cancer studied, to the
exposure levels reported and the timing and route of exposure studied, to theintervals between first exposure and disease onset observed in these studies, and to
the general population(s) studied (i.e. there may be susceptible subpopulations orlife stages). Experience from studies of cancer in humans indicates that the period
from first exposure to the development of clinical cancer is sometimes longer than
20 years; therefore, latency periods substantially shorter than about 30 years cannot
provide evidence of lack of carcinogenicity. Furthermore, there may be critical
windows of exposure, for example, as with diethylstilboestrol and clear celladenocarcinoma of the cervix and vagina (IARC, 2012a).

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3. Studies of cancer in experimental animals

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Most human carcinogens that have been studied adequately for carcinogenicity
in experimental animals have produced positive results in one or more animal
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humans. Although this observation cannot establish that all agents that cause
cancer in experimental animals also cause cancer in humans, it is biologicallyplausible that agents for which there is sufficient evidence of carcinogenicity inexperimental animals (see Part B, Section 6b) present a carcinogenic hazard tohumans. Accordingly, in the absence of additional scientific information, such as
strong evidence that a given agent causes cancer in experimental animals through aspecies-specific mechanism that does not operate in humans (see Part B, Sections 4
and 6; Capen et al., 1999; IARC, 2003), these agents are considered to pose apotential carcinogenic hazard to humans. The inference of potential carcinogenic
hazard to humans does not imply tumour site concordance across species (Baan etal., 2019).

12(a) Types of studies considered

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Relevant studies of cancer in experimental animals are identified by using
systematic review principles as described in Part A, further elaborated in theInstructions for Authors, and as detailed below. Consideration is given to all
available long-term studies of cancer in experimental animals with the agent underreview (or possibly metabolites or derivatives of the agent) (see Part A, Section 7)
after a thorough evaluation of the study features (see Part B, Section 3b). Thosestudies that are judged to be irrelevant to the evaluation or judged to be inadequate(e.g. too short a duration, too few animals, poor survival; see below) may beomitted. Guidelines for conducting long-term carcinogenicity experiments havebeen published (e.g. OECD, 2018).
In addition to conventional long-term bioassays, alternative studies (e.g. in
genetically engineered mouse models) may be considered in assessing
carcinogenicity in experimental animals, also after a critical evaluation of the study
features. For studies of certain exposures, such as viruses that typically only infecthumans, use of such specialized experimental animal models may be particularly
important; models include genetically engineered mice with targeted expression ofviral genes to tissues from which human cancers arise, as well as humanized mice
implanted with the human cells usually infected by the virus.
Other types of studies can provide supportive evidence. These include:
experiments in which the agent was administered in the presence of factors thatmodify carcinogenic effects (e.g. initiation–promotion studies); studies in which
the end-point was not cancer but a defined precancerous lesion; and studies ofcancer in non-laboratory animals (e.g. companion animals) exposed to the agent.

36(b) Study evaluation

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Considerations of importance in the interpretation and evaluation of a particularstudy include: (i) whether the agent was clearly characterized, including the natureand extent of impurities and contaminants and the stability of the agent, and, in the23

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case of mixtures, whether the sample characterization was adequately reported;(ii) whether the dose was monitored adequately, particularly in inhalation
experiments; (iii) whether the doses, duration and frequency of treatment, durationof observation, and route of exposure were appropriate; (iv) whether appropriate
experimental animal species and strains were evaluated; (v) whether there wereadequate numbers of animals per group; (vi) whether animals were allocatedrandomly to groups; (vii) whether the body weight, food and water consumption,and survival of treated animals were affected by any factors other than the test
agent; (viii) whether the histopathology review was adequate; and (ix) whether thedata were reported and analysed adequately.

11(c) Outcomes and statistical analyses

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An assessment of findings of carcinogenicity in experimental animals involves
consideration of (i) study features such as route, doses, schedule and duration of
exposure, species, strain (including genetic background where applicable), sex,age, and duration of follow-up; (ii) the spectrum of neoplastic response, from preneoplastic lesions and benign tumours to malignant neoplasms; (iii) the incidence,latency, severity, and multiplicity of neoplasms and pre-neoplastic lesions; (iv) the
consistency of the results for a specific target organ or organs across studies ofsimilar design; and (v) the possible role of modifying factors (e.g. diet, infection,
stress).
Key factors for statistical analysis include: (i) number of animals studied andnumber examined histologically, (ii) number of animals with a given tumour typeor lesion, and (iii) duration of survival.
Benign tumours may be combined with malignant tumours in the assessment oftumour incidence when (a) they occur together with and originate from the same
cell type as malignant tumours in an organ or tissue in a particular study and(b) they appear to represent a stage in the progression to malignancy (Huff et al.,1989). The occurrence of lesions presumed to be pre-neoplastic may in certain
instances aid in assessing the biological plausibility of any neoplastic response
observed.
Evidence of an increased incidence of neoplasms with increasing level of
exposure strengthens the inference of a causal association between the exposureand the development of neoplasms. The form of the dose–response relationshipcan vary widely, including non-linearity, depending on the particular agent understudy and the target organ. The dose–response relationship can also be affected bydifferences in survival among the treatment groups.
The statistical methods used should be clearly stated and should be thegenerally accepted techniques refined for this purpose (Peto et al., 1980; Gart et al.,
1986; Portier & Bailer, 1989; Bieler & Williams, 1993). The choice of the mostappropriate statistical method requires consideration of whether there aredifferences in survival among the treatment groups; for example, reduced survival

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because of non-tumour-related mortality can preclude the occurrence of tumours
later in life and a survival-adjusted analysis would be warranted. When detailed
information on survival is not available, comparisons of the proportions of tumourbearing animals among the effective number of animals (alive at the time that thefirst tumour was discovered) can be useful when significant differences in survival
occur before tumours appear. The lethality of the tumour also requiresconsideration: for rapidly fatal tumours, the time of death provides an indication of
the time of tumour onset and can be assessed using life-table methods; non-fatal orincidental tumours that do not affect survival can be assessed using methods suchas the Mantel–Haenszel test for changes in tumour prevalence. Because tumour
lethality is often difficult to determine, methods such as the poly-k test that do not
require such information can also be used. When results are available on thenumber and size of tumours seen in experimental animals (e.g. papillomas onmouse skin, liver tumours observed through nuclear magnetic resonancetomography), other, more complicated statistical procedures may be needed(Sherman et al., 1994; Dunson et al., 2003).
The concurrent control group is generally the most appropriate comparisongroup for statistical analysis; however, for uncommon tumours, the analysis may
be improved by considering historical control data, particularly when betweenstudy variability is low. Historical controls should be selected to resemble theconcurrent controls as closely as possible with respect to species, sex, and strain, as
well as other factors, such as basal diet and general laboratory environment, which
may affect tumour response rates in control animals (Haseman et al., 1984; Fung etal., 1996; Greim et al., 2003). It is generally not appropriate to discount a tumour
response that is significantly increased compared with concurrent controls by
arguing that it falls within the range of historical controls.
Meta-analyses and pooled analyses may be appropriate when the experimental
protocols are sufficiently similar.

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4. Mechanistic evidence

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Mechanistic data may provide evidence of carcinogenicity and may also help inassessing the relevance and importance of findings of cancer in experimental
animals and in humans (Guyton et al., 2009; Parkkinen et al., 2018) (see Part B,
Section 6). Mechanistic studies have gained in prominence, increasing in theirvolume, diversity, and relevance to cancer hazard evaluation, whereas studies
pertinent to other streams of evidence evaluated in the Monographs (i.e. studies ofcancer in humans and lifetime cancer bioassays in rodents) may only be available
for a fraction of agents to which humans are currently exposed (Guyton et al.,2009, 2018). Mechanistic studies and data are identified, screened, and evaluatedfor quality and importance to the evaluation by using systematic review principles
as described in Part A, further elaborated in the Instructions for Authors, and asdetailed below.

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The Working Group’s synthesis reflects the extent of available evidence,summarizing groups of included studies with an emphasis on characterizing
consistencies or differences in results within and across experimental designs.
Greater emphasis is given to informative mechanistic evidence from human-related
studies than to that from other experimental test systems, and gaps are identified.
Tabulation of data may facilitate this review. The specific topics addressed in theevidence synthesis are described below.

8(a) Absorption, distribution, metabolism, and excretion

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Studies of absorption, distribution, metabolism, and excretion in mammalian
species are addressed in a summary fashion; exposure characterization is addressed
in Part B, Section 1. The Working Group describes the metabolic fate of the agent
in mammalian species, noting the metabolites that have been identified and theirchemical reactivity. A metabolic schema may indicate the relevant metabolic
pathways and products and whether supporting evidence is from studies in humans
and/or studies in experimental animals. Evidence on other adverse effects thatindirectly confirm absorption, distribution, and/or metabolism at tumour sites isbriefly summarized when direct evidence is sparse.

18(b) Evidence relevant to key characteristics of carcinogens

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A review of Group 1 human carcinogens classified up to and including IARC
Monographs Volume 100 revealed several issues relevant to improving theevaluation of mechanistic evidence for cancer hazard identification (Smith et al.,2016). First, it was noted that human carcinogens often share one or morecharacteristics that are related to the multiple mechanisms by which agents cause
cancer. Second, different human carcinogens may exhibit a different spectrum ofthese key characteristics and operate through distinct mechanisms. Third, for many
carcinogens evaluated before Volume 100, few data were available on somemechanisms of recognized importance in carcinogenesis, such as epigenetic
alterations (Herceg et al., 2013). Fourth, there was no widely accepted method tosearch systematically for relevant mechanistic evidence, resulting in a lack of
uniformity in the scope of mechanistic topics addressed across IARC Monographs
evaluations.
To address these challenges, the key characteristics of human carcinogens wereintroduced to facilitate systematic consideration of mechanistic evidence in IARC
Monographs evaluations (Smith et al., 2016; Guyton et al., 2018). The key
characteristics described by Smith et al. (2016) (see Table 3), such as “isgenotoxic”, “is immunosuppressive”, or “modulates receptor-mediated effects”,
are based on empirical observations of the chemical and biological properties
associated with the human carcinogens identified by the IARC Monographs
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associated end-points may evolve, based on the experience of their application andas new human carcinogens are identified. Key characteristics are distinct from the“hallmarks of cancer”, which relate to the properties of cancer cells (Hanahan &Weinberg, 2000, 2011). Key characteristics are also distinct from hypothesizedmechanistic pathways, which describe a sequence of biological events postulated
to occur during carcinogenesis. As such, the evaluation approach based on key
characteristics, outlined below, “avoids a narrow focus on specific pathways andhypotheses and provides for a broad, holistic consideration of the mechanistic
evidence” (National Academies of Sciences, Engineering, and Medicine, 2017).
Table 3. The key characteristics of carcinogens described by Smith et al.
(2016)
Ten key characteristics of carcinogens
1. Is electrophilic or can be metabolically activated to an electrophile
2. Is genotoxic
3. Alters DNA repair or causes genomic instability
4. Induces epigenetic alterations
5. Induces oxidative stress
6. Induces chronic inflammation
7. Is immunosuppressive
8. Modulates receptor-mediated effects
9. Causes immortalization
10. Alters cell proliferation, cell death, or nutrient supply

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Studies in exposed humans and in human primary cells or tissues thatincorporate end-points relevant to key characteristics of carcinogens areemphasized when available. For each key characteristic with adequate evidence for
evaluation, studies are grouped according to whether they involve (a) humans orhuman primary cells or tissues or (b) experimental systems; further organization(as appropriate) is by end-point (e.g. DNA damage), duration, species, sex, strain,
and target organ as well as strength of study design. Studies investigating
susceptibility related to key characteristics of carcinogens (e.g. of genetic
polymorphisms, or in genetically engineered animals) can be highlighted and may
provide additional support for conclusions on the strength of evidence. Findings
relevant to a specific tumour type may be noted.

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Other informative evidence may be described when it is judged by the Working
Group to be relevant to an evaluation of carcinogenicity and to be of sufficientimportance to affect the overall evaluation. Quantitative structure–activity
information, such as on specific chemical and/or biological features or activities(e.g. electrophilicity, molecular docking with receptors), may be informative. In
addition, evidence that falls outside of the recognized key characteristics ofcarcinogens, reflecting emerging knowledge or important novel scientificdevelopments on carcinogen mechanisms, may also be included. Available
evidence relevant to criteria provided in authoritative publications (e.g. Capen etal., 1999; IARC, 2003) on thyroid, kidney, urinary bladder, or other tumours inexperimental animals induced by mechanisms that do not operate in humans is also
described.

14(d) Study quality and importance to the evaluation

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Based on formal considerations of the quality of the studies (e.g. design,
methodology, and reporting of results), the Working Group may give greater
weight to some included studies.
For observational and other studies in humans, the quality of study design,
exposure assessment, and assay accuracy and precision are considered, in
collaboration with the Working Group members reviewing exposure
characterization and studies of cancer in humans, as are other important factors,
including those described above for evaluation of epidemiological evidence(García-Closas et al., 2006, 2011; Vermeulen et al., 2018) (Part B, Sections 1
and 2).
In general, in experimental systems, studies of repeated doses and of chronic
exposures are accorded greater importance than are studies of a single dose or time
point. Consideration is also given to factors such as the suitability of the dosing
range, the extent of concurrent toxicity observed, and the completeness ofreporting of the study (e.g. the source and purity of the agent, the analyticalmethods, and the results). Route of exposure is generally considered to be a lessimportant factor in the evaluation of experimental studies, recognizing that the
exposures and target tissues may vary across experimental models and in exposed
human populations. Non-mammalian studies can be synthetically summarized
when they are considered to be supportive of evidence in humans or higherorganisms.
In vitro test systems can provide mechanistic insights, but importantconsiderations include the limitations of the test system (e.g. in metabolic
capabilities) as well as the suitability of a particular test article (i.e. because ofphysical and chemical characteristics) (Hopkins et al., 2004). For studies on some
end-points, such as for traditional studies of mutations in bacteria and in28

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mammalian cells, formal guidelines, including those from the Organisation for
Economic Co-operation and Development, may be informative in conducting thequality review (OECD, 1997, 2016a, b). However, existing guidelines will notgenerally cover all relevant assays, even for genotoxicity. Possible considerations
when evaluating the quality of in vitro studies encompass the methodology anddesign (e.g. the end-point and test method, the number of replicate samples, thesuitability of the concentration range, the inclusion of positive and negative
controls, and the assessment of cytotoxicity) as well as reporting (e.g. of the sourceand purity of the agent, and of the analytical methods and results). High-content
and high-throughput in vitro data can serve as an additional or supportive source of
mechanistic evidence (Chiu et al., 2018; Guyton et al., 2018), although large-scale
screening programmes measuring a variety of end-points were designed to evaluate
large chemical libraries in order to prioritize chemicals for additional toxicity
testing rather than to identify the hazard of a specific chemical or chemical group.
The synthesis is focused on the evidence that is most informative for the overall
evaluation. In this regard, it is of note that some human carcinogens exhibit asingle or primary key characteristic, evidence of which has been influential in theircancer hazard classifications. For instance, ethylene oxide is genotoxic (IARC,
1994), 2,3,7,8-tetrachlorodibenzo-para-dioxin modulates receptor-mediated effects(IARC, 1997), and etoposide alters DNA repair (IARC, 2012a). Similarly,
oncogenic viruses cause immortalization, and certain drugs are, by design,
immunosuppressive (IARC, 2012a, b). Because non-carcinogens can also induce
oxidative stress, this key characteristic should be interpreted with caution unless it
is found in combination with other key characteristics (Guyton et al., 2018).
Evidence for a group of key characteristics can strengthen mechanistic conclusions(e.g. “induces oxidative stress” together with “is electrophilic or can bemetabolically activated to an electrophile”, “induces chronic inflammation”, and“is immunosuppressive”); see, for example, 1-bromopropane (IARC, 2018).

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5. Summary of data reported30(a) Exposure characterization

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Exposure data are summarized to identify the agent and describe its production,use, and occurrence. Information on exposure prevalence and intensity in different
settings, including geographical patterns and time trends, may be included.
Exposure assessment methods used in key epidemiological studies reviewed by theWorking Group are described and evaluated.

36(b) Cancer in humans

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Results of epidemiological studies pertinent to an evaluation of carcinogenicity
in humans are summarized. The overall strengths and limitations of theepidemiological evidence base are highlighted to indicate how the evaluation wasreached. The target organ(s) or tissue(s) in which a positive association between

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the agent and cancer was observed are identified. Exposure–response and otherquantitative data may be summarized when available. When the available
epidemiological studies pertain to a mixed exposure, process, occupation, or
industry, the Working Group seeks to identify the specific agent considered to be
most likely to be responsible for any excess risk. The evaluation is focused as
narrowly as the available data permit.

7(c) Cancer in experimental animals

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Results pertinent to an evaluation of carcinogenicity in experimental animals
are summarized to indicate how the evaluation was reached. For each animal
species, study design, and route of administration, there is a statement about
whether an increased incidence, reduced latency, or increased severity or
multiplicity of neoplasms or pre-neoplastic lesions was observed, and the tumoursites are indicated. Special conditions resulting in tumours, such as prenatal
exposure or single-dose experiments, are mentioned. Negative findings, inverse
relationships, dose–response patterns, and other quantitative data are also
summarized.

17(d) Mechanistic evidence

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Results pertinent to an evaluation of the mechanistic evidence on
carcinogenicity are summarized to indicate how the evaluation was reached. The
summary encompasses the informative studies on absorption, distribution,
metabolism, and excretion; on the key characteristics with adequate evidence for
evaluation; and on any other aspects of sufficient importance to affect the overall
evaluation, including on whether the agent belongs to a class of agents for which
one or more members have been classified as carcinogenic or probably
carcinogenic to humans, and on criteria with respect to tumours in experimental
animals induced by mechanisms that do not operate in humans. For each topic
addressed, the main supporting findings are highlighted from exposed humans,
human cells or tissues, experimental animals, or in vitro systems. Whenmechanistic studies are available in exposed humans, the tumour type or target
tissue studied may be specified. Gaps in the evidence are indicated (i.e. if nostudies were available in exposed humans, in in vivo systems, etc.). Consistency ordifferences of effects across different experimental systems are emphasized.

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6. Evaluation and rationale

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Consensus evaluations of the strength of the evidence of cancer in humans, theevidence of cancer in experimental animals, and the mechanistic evidence are
made using transparent criteria and defined descriptive terms. The Working Groupthen develops a consensus overall evaluation of the strength of the evidence of
carcinogenicity for each agent under review.

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An evaluation of the strength of the evidence is limited to the agents underreview. When multiple agents being evaluated are considered by the Working
Group to be sufficiently closely related, they may be grouped together for the
purpose of a single and unified evaluation of the strength of the evidence.
The framework for these evaluations, described below, may not encompass all
factors relevant to a particular evaluation of carcinogenicity. After considering all
relevant scientific findings, the Working Group may exceptionally assign the agent
to a different category than a strict application of the framework would indicate,while providing a clear rationale for the overall evaluation.
When there are substantial differences of scientific interpretation among theWorking Group members, the overall evaluation will be based on the consensus of
the Working Group. A summary of the alternative interpretations may be provided,
together with their scientific rationale and an indication of the relative degree ofsupport for each alternative.
The categories of the classification refer to the strength of the evidence that an
exposure is carcinogenic and not to the risk of cancer from particular exposures.
The terms probably carcinogenic and possibly carcinogenic have no quantitative
significance and are used as descriptors of different strengths of evidence of
carcinogenicity in humans; probably carcinogenic signifies a greater strength ofevidence than possibly carcinogenic.

21(a) Carcinogenicity in humans

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Based on the principles outlined in Part B, Section 2, the evidence relevant tocarcinogenicity from studies in humans is classified into one of the following
categories:

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Sufficient evidence of carcinogenicity: A causal association between
exposure to the agent and human cancer has been established. That is, apositive association has been observed in the body of evidence on
exposure to the agent and cancer in studies in which chance, bias, andconfounding were ruled out with reasonable confidence.

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Limited evidence of carcinogenicity: A causal interpretation of the positive
association observed in the body of evidence on exposure to the agent andcancer is credible, but chance, bias, or confounding could not be ruled out
with reasonable confidence.

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Inadequate evidence regarding carcinogenicity: The available studies are of
insufficient quality, consistency, or statistical precision to permit aconclusion to be drawn about the presence or the absence of a causal
association between exposure and cancer, or no data on cancer in humans
are available. Common findings that lead to a determination of
inadequate evidence of carcinogenicity include: (a) there are no data
available in humans; (b) there are data available in humans, but they are

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of poor quality or informativeness; and (c) there are studies of sufficientquality available in humans, but their results are inconsistent or otherwiseinconclusive.

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Evidence suggesting lack of carcinogenicity: There are several high-quality
studies covering the full range of levels of exposure that humans are
known to encounter, which are mutually consistent in not showing a
positive association between exposure to the agent and the studied
cancers at any observed level of exposure. The results from these studies
alone or combined should have narrow confidence intervals with an upper
limit below or close to the null value (e.g. a relative risk of unity). Biasand confounding were ruled out with reasonable confidence, and thestudies were considered informative. A conclusion of evidence suggestinglack of carcinogenicity is limited to the cancer sites, populations and life
stages, conditions and levels of exposure, and length of observation
covered by the available studies. In addition, the possibility of a verysmall risk at the levels of exposure studied can never be excluded.

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When there is sufficient evidence, a separate sentence identifies thetarget organ(s) or tissue(s) for which a causal interpretation has been
established. When there is limited evidence, a separate sentence identifies
the target organ(s) or tissue(s) for which a positive association between
exposure to the agent and the cancer(s) was observed in humans. When
there is evidence suggesting lack of carcinogenicity, a separate sentence
identifies the target organ(s) or tissue(s) where evidence of lack ofcarcinogenicity was observed in humans. Identification of a specifictarget organ or tissue as having sufficient evidence or limited evidence orevidence suggesting lack of carcinogenicity does not preclude thepossibility that the agent may cause cancer at other sites.

28(b) Carcinogenicity in experimental animals

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The evidence relevant to carcinogenicity from studies in experimental animals
is classified into one of the following categories:

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Sufficient evidence of carcinogenicity: A causal relationship has been
established between exposure to the agent and cancer in experimental
animals based on an increased incidence of malignant neoplasms or of an
appropriate combination of benign and malignant neoplasms in (a) two or
more species of animals or (b) two or more independent studies in one
species carried out at different times or in different laboratories and/or
under different protocols. An increased incidence of malignant neoplasms
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conducted under Good Laboratory Practices (GLP), can also provide
sufficient evidence.

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Exceptionally, a single study in one species and sex may be considered toprovide sufficient evidence of carcinogenicity when malignant neoplasms
occur to an unusual degree with regard to incidence, site, type of tumour,or age at onset, or when there are marked findings of tumours at multiple
sites.

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Limited evidence of carcinogenicity: The data suggest a carcinogenic effectbut are limited for making a definitive evaluation because, for example,(a) the evidence of carcinogenicity is restricted to a single experiment anddoes not meet the criteria for sufficient evidence; (b) the agent increases
the incidence only of benign neoplasms or lesions of uncertain neoplastic
potential; (c) the agent increases tumour multiplicity or decreases tumour
latency but does not increase tumour incidence; (d) the evidence of
carcinogenicity is restricted to initiation–promotion studies; (e) theevidence of carcinogenicity is restricted to observational studies in nonlaboratory animals (e.g. companion animals); or (f) there are unresolved
questions about the adequacy of the design, conduct, or interpretation of
the available studies.

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Inadequate evidence regarding carcinogenicity: The studies cannot beinterpreted as showing either the presence or the absence of a
carcinogenic effect because of major qualitative or quantitative
limitations, or no data are available on cancer in experimental animals.

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Evidence suggesting lack of carcinogenicity: Well-conducted studies (e.g.
conducted under GLP) involving both sexes of at least two species areavailable showing that, within the limits of the tests used, the agent was
not carcinogenic. The conclusion of evidence suggesting lack ofcarcinogenicity is limited to the species, tumour sites, age at exposure,and conditions and levels of exposure covered by the available studies.

30(c) Mechanistic evidence

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Based on the principles outlined in Part B, Section 4, the mechanistic evidence
is classified into one of the following categories:

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Strong mechanistic evidence: Results in several different experimental systems
are consistent, and the overall mechanistic database is coherent. Further
support can be provided by studies that demonstrate experimentally that the
suppression of key mechanistic processes leads to the suppression of tumour
development. Typically, a substantial number of studies on a range of
relevant end-points are available in one or more mammalian species.
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mammalian cells, and experiments in non-mammalian species may provide
corroborating evidence but typically do not in themselves provide strong
evidence. However, consistent findings across a number of different test
systems in different species may provide strong evidence.
Of note, “strong” relates not to potency but to strength of evidence. The
classification applies to three distinct topics:

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(a) Strong evidence that the agent belongs, based on mechanistic
considerations, to a class of agents for which one or more members havebeen classified as carcinogenic or probably carcinogenic to humans. The
considerations can go beyond quantitative structure–activity relationships toincorporate similarities in biological activity relevant to common key
characteristics across dissimilar chemicals (e.g. based on molecular docking,–omics data).

1415(b) Strong evidence that the agent exhibits key characteristics of carcinogens.
In this case, three descriptors are possible:

1617(1) The strong evidence is in exposed humans. Findings relevant to a
specific tumour type may be informative in this determination.

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(2) The strong evidence is in human primary cells or tissues. Specifically,
the strong findings are from biological specimens obtained fromhumans (e.g. ex vivo exposure), from human primary cells, and/or, insome cases, from other humanized systems (e.g. a human receptor or
enzyme).

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or a few studies in human primary cells and tissues.

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(c) Strong evidence that the mechanism of carcinogenicity in experimental
animals does not operate in humans. Certain results in experimental animals(see Part B, Section 6b) would be discounted, according to relevant criteria
and considerations in authoritative publications (e.g. Capen et al., 1999;
IARC, 2003). Typically, this classification would not apply when there isstrong mechanistic evidence that the agent exhibits key characteristics ofcarcinogens.

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Limited mechanistic evidence: The evidence is suggestive, but, for example,(a) the studies cover a narrow range of experiments, relevant end-points,
and/or species; (b) there are unexplained inconsistencies in the studies ofsimilar design; and/or (c) there is unexplained incoherence across studies ofdifferent end-points or in different experimental systems.

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Inadequate mechanistic evidence: Common findings that lead to a
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the design, conduct, or interpretation of the studies; (c) the available results
are negative.

3(d) Overall evaluation

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Finally, the bodies of evidence included within each stream of evidence areconsidered as a whole, in order to reach an overall evaluation of the
carcinogenicity of the agent to humans. The three streams of evidence areintegrated and the agent is classified into one of the following categories (seeTable 4), indicating that the Working Group has established that:

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The agent is carcinogenic to humans (Group 1)
This category applies whenever there is sufficient evidence of carcinogenicity inhumans.
In addition, this category may apply when there is both strong evidence in
exposed humans that the agent exhibits key characteristics of carcinogens andsufficient evidence of carcinogenicity in experimental animals.

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The agent is probably carcinogenic to humans (Group 2A)
This category generally applies when the Working Group has made at least
two of the following evaluations, including at least one that involves either
exposed humans or human cells or tissues:• Limited evidence of carcinogenicity in humans,• Sufficient evidence of carcinogenicity in experimental animals,• Strong evidence that the agent exhibits key characteristics ofcarcinogens.
If there is inadequate evidence regarding carcinogenicity in humans, there
should be strong evidence in human cells or tissues that the agent exhibits key
characteristics of carcinogens. If there is limited evidence of carcinogenicity inhumans, then the second individual evaluation may be from experimental systems(i.e. sufficient evidence of carcinogenicity in experimental animals or strong
evidence in experimental systems that the agent exhibits key characteristics ofcarcinogens).
Additional considerations apply when there is strong evidence that themechanism of carcinogenicity in experimental animals does not operate in humans
for one or more tumour sites. Specifically, the remaining tumour sites should still
support an evaluation of sufficient evidence in experimental animals in order forthis evaluation to be used to support an overall classification in Group 2A.
Separately, this category generally applies if there is strong evidence that theagent belongs, based on mechanistic considerations, to a class of agents for which
one or more members have been classified in Group 1 or Group 2A.

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9
10
11
12
13
14
15
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17
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The agent is possibly carcinogenic to humans (Group 2B)
This category generally applies when only one of the following evaluations
has been made by the Working Group:• Limited evidence of carcinogenicity in humans,• Sufficient evidence of carcinogenicity in experimental animals,• Strong evidence that the agent exhibits key characteristics ofcarcinogens.
Because this category can be based on evidence from studies in experimental
animals alone, there is no requirement that the strong mechanistic evidence bein exposed humans or in human cells or tissues. This category may be based onstrong evidence in experimental systems that the agent exhibits key
characteristics of carcinogens.
As with Group 2A, additional considerations apply when there is strong
evidence that the mechanism of carcinogenicity in experimental animals does
not operate in humans for one or more tumour sites. Specifically, the remaining
tumour sites should still support an evaluation of sufficient evidence inexperimental animals in order for this evaluation to be used to support an
overall classification in Group 2B.

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The agent is not classifiable as to its carcinogenicity to humans (Group 3)
Agents that do not fall into any other group are generally placed in thiscategory.
This includes the case when there is strong evidence that the mechanism ofcarcinogenicity in experimental animals does not operate in humans for one ormore tumour sites in experimental animals, the remaining tumour sites do notsupport an evaluation of sufficient evidence in experimental animals, and othercategories are not supported by data from studies in humans and mechanistic
studies.
An evaluation in Group 3 is not a determination of non-carcinogenicity oroverall safety. It often means that the agent is of unknown carcinogenic potential
and that there are significant gaps in research.
If the evidence suggests that the agent exhibits no carcinogenic activity, either
through evidence suggesting lack of carcinogenicity in both humans andexperimental animals, or through evidence suggesting lack of carcinogenicity inexperimental animals complemented by strong negative mechanistic evidence inassays relevant to human cancer, then the Working Group may add a sentence tothe evaluation to characterize the agent as well-studied and without evidence of
carcinogenic activity.

38(e) Rationale

39
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The reasoning that the Working Group used to reach its evaluation issummarized so that the basis for the evaluation offered is transparent. This section

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integrates the major findings from studies of cancer in humans, cancer inexperimental animals, and mechanistic evidence. It includes concise statements ofthe principal line(s) of argument that emerged in the deliberations of the Working
Group, the conclusions of the Working Group on the strength of the evidence foreach stream of evidence, an indication of the body of evidence that was pivotal tothese conclusions, and an explanation of the reasoning of the Working Group in
making its evaluation.
Table 4. Integration of streams of evidence in reaching overall
classifications (the evidence in bold italic represents the basis of the overall
evaluation)
Stream of evidence

Classification based onstrength of evidence

Evidence ofcancer inhumansa

Evidence ofcancer inexperimental
animals

Mechanistic
evidence

Sufficient

Not necessary

Not necessary

Limited or
Inadequate

Sufficient

LimitedSufficient

Inadequate

Sufficient

Strong (b)(1)(exposed humans)
Strong (b)(2–3),
Limited, or
Inadequate
Strong (b)(2)(human cells or
tissues)

LimitedLess than
Sufficient

Strong (b)(1–3)

Limited or
Inadequate

Not necessary

Strong (a)(mechanistic class)

LimitedLess than
Sufficient

Inadequate

Sufficient

Limited or
Inadequate
Strong (b)(3),
Limited, or
Inadequate

Inadequate

Less than
Sufficient

Strong b(1–3)

LimitedSufficient

Strong (c) (does notb
operate in humans)

Inadequate

Sufficient

Strong (c) (does notb
operate in humans)

Carcinogenic to humans(Group 1)

Probably carcinogenic tohumans (Group 2A)

Possibly carcinogenic tohumans (Group 2B)

Not classifiable as to its
carcinogenicity to humans(Group 3)

All other situations not listed abovea

Human cancer(s) with highest evaluationb

The strong evidence that the mechanism of carcinogenicity in experimental animals does notoperate in humans must specifically be for the tumour sites supporting the classification of sufficientevidence in experimental animals.

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