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Appendix C
Classification Systems Used
in Evidence Reviews
363
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364 BREAST CANCER AND THE ENVIRONMENT
TABLE C-1 Compilation of Evidence Categories Used by Selected
Organizations
International Agency for Environmental
Research on Cancer Protection Agency National Toxicology
(IARC) (EPA) Program (NTP)
Overall evaluation
Finally, the body of
evidence is considered as
a whole, in order to reach
an overall evaluation of the
carcinogenicity of the agent to
humans.
An evaluation may be made
for a group of agents that have
been evaluated by the Working
Group. In addition, when
supporting data indicate that
other related agents, for which
there is no direct evidence of
their capacity to induce cancer
in humans or in animals,
may also be carcinogenic,
a statement describing the
rationale for this conclusion
is added to the evaluation
narrative; an additional
evaluation may be made for
this broader group of agents
if the strength of the evidence
warrants it.
The agent is described
according to the wording
of one of the following
categories, and the designated
group is given. The
categorization of an agent is a
matter of scientific judgement
that reflects the strength of the
evidence derived from studies
in humans and in experimental
animals and from mechanistic
and other relevant data.
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APPENDIX C
World Cancer Research Fund/
American Institute for Cancer Research
(WCRF/AICR) Institute of Medicine (IOM)
Special upgrading factors The committee relied entirely on clinical and
These are factors that form part of the human epidemiologic studies to draw its conclusions
assessment of the evidence that, when present, about the strength of evidence regarding associations
can upgrade the judgement reached. So an between deployment to the Gulf War and health
exposure that might be deemed a “limited— outcomes seen in Gulf War veterans. The committee
suggestive” causal factor in the absence, say, acknowledges, however, that animal studies might
of a biological gradient, might be upgraded to prove helpful in providing biologic understanding
“probable” in its presence. The application of of many of the effects seen in humans from specific
these factors (listed below) requires judgement, exposures, such as pesticides, solvents, and nerve
and the way in which these judgements affect agents, which have been reported by troops
the final conclusion in the matrix are stated. deployed in the Gulf War. Furthermore, information
from molecular and cellular biology, neuroimaging,
• resence of a plausible biological gradient
P and other types of human studies can be used
(“dose response”) in the association. Such to understand the biological mechanisms and
a gradient need not be linear or even in the identification of biomarkers for clinical outcomes.
same direction across the different levels of Such studies, however, are not, in general, included
exposure, so long as this can be explained in this review.
plausibly.
• particularly large summary effect size (an
A
odds ratio or relative risk of 2.0 or more,
depending on the unit of exposure) after
appropriate control for confounders.
• vidence from randomised trials in humans.
E
• vidence from appropriately controlled
E
experiments demonstrating one or more
plausible and specific mechanisms actually
operating in humans.
• obust and reproducible evidence from
R
experimental studies in appropriate animal
models showing that typical human
exposures can lead to relevant cancer
outcomes.
continued
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TABLE C-1 Continued
International Agency for Environmental
Research on Cancer Protection Agency National Toxicology
(IARC) (EPA) Program (NTP)
Group 1: The agent is Carcinogenic to humans Known to be human carcinogen
carcinogenic to humans. This descriptor indicates strong There is sufficient evidence of
This category is used when evidence of human carcinogenicity. carcinogenicity from studies in
there is sufficient evidence of It covers different combinations of humans,* which indicates a causal
carcinogenicity in humans. evidence. relationship between exposure to
Exceptionally, an agent may be the agent, substance, or mixture,
placed in this category when 1. This descriptor is appropriate and human cancer.
evidence of carcinogenicity when there is convincing epidemiologic
in humans is less than evidence of a causal association
sufficient but there is sufficient between human exposure and cancer.
2. Exceptionally, this descriptor may
evidence of carcinogenicity
in experimental animals and be equally appropriate with a lesser
strong evidence in exposed weight of epidemiologic evidence that is
humans that the agent acts strengthened by other lines of evidence.
through a relevant mechanism It can be used when all of the following
of carcinogenicity. conditions are met: (a) there is strong
evidence of an association between
human exposure and either cancer or
the key precursor events of the agent’s
mode of action but not enough for
a causal association, and (b) there is
extensive evidence of carcinogenicity
in animals, and (c) the mode(s) of
carcinogenic action and associated key
precursor events have been identified in
animals, and (d) there is strong evidence
that the key precursor events that
precede the cancer response in animals
are anticipated to occur in humans and
progress to tumors, based on available
biological information. In this case, the
narrative includes a summary of both
the experimental and epidemiologic
information on mode of action and also
an indication of the relative weight that
each source of information carries, e.g.,
based on human information, based on
limited human and extensive animal
experiments.
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APPENDIX C
World Cancer Research Fund/
American Institute for Cancer Research
(WCRF/AICR) Institute of Medicine (IOM)
Convincing Sufficient evidence of a causal relationship
These criteria are for evidence strong enough Evidence is sufficient to conclude that a causal
to support a judgement of a convincing relationship exists between being deployed to the
causal relationship, which justifies goals and Gulf War and a health outcome. The evidence
recommendations designed to reduce the fulfills the criteria for sufficient evidence of a causal
incidence of cancer. A convincing relationship association in which chance, bias, and confounding
should be robust enough to be highly unlikely can be ruled out with reasonable confidence. The
to be modified in the foreseeable future as new association is supported by several of the other
evidence accumulates. considerations used to assess causality: strength of
All of the following were generally required: association, dose–response relationship, consistency
of association, temporal relationship, specificity of
• vidence from more than one study type.
E association, and biologic plausibility.
• vidence from at least two independent
E
cohort studies.
• o substantial unexplained heterogeneity
N
within or between study types or in different
populations relating to the presence or
absence of an association, or direction of
effect.
• ood-quality studies to exclude with
G
confidence the possibility that the observed
association results from random or
systematic error, including confounding,
measurement error, and selection bias.
• resence of a plausible biological gradient
P
(“dose response”) in the association. Such
a gradient need not be linear or even in the
same direction across the different levels of
exposure, so long as this can be explained
plausibly.
• trong and plausible experimental evidence,
S
either from human studies or relevant
animal models, that typical human
exposures can lead to relevant cancer
outcomes.
continued
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TABLE C-1 Continued
International Agency for Environmental
Research on Cancer Protection Agency National Toxicology
(IARC) (EPA) Program (NTP)
Group 2:
This category includes
agents for which, at one
extreme, the degree of
evidence of carcinogenicity in
humans is almost sufficient,
as well as those for which,
at the other extreme, there
are no human data but for
which there is evidence of
carcinogenicity in experimental
animals. Agents are assigned
to either Group 2A (probably
carcinogenic to humans)
or Group 2B (possibly
carcinogenic to humans) on
the basis of epidemiological
and experimental evidence
of carcinogenicity and
mechanistic and other
relevant data. The terms
probably carcinogenic and
possibly carcinogenic have no
quantitative significance and
are used simply as descriptors
of different levels of evidence
of human carcinogenicity,
with probably carcinogenic
signifying a higher level
of evidence than possibly
carcinogenic.
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APPENDIX C
World Cancer Research Fund/
American Institute for Cancer Research
(WCRF/AICR) Institute of Medicine (IOM)
continued
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TABLE C-1 Continued
International Agency for Environmental
Research on Cancer Protection Agency National Toxicology
(IARC) (EPA) Program (NTP)
Group 2A: The agent is Likely to be carcinogenic to humans Reasonably anticipated to be
human carcinogen:
probably carcinogenic to This descriptor is appropriate when
humans. the weight of the evidence is adequate There is limited evidence of
This category is used when to demonstrate carcinogenic potential carcinogenicity from studies in
there is limited evidence of to humans but does not reach the humans,* which indicates that
carcinogenicity in humans weight of evidence for the descriptor causal interpretation is credible,
and sufficient evidence of “Carcinogenic to Humans.” Adequate but that alternative explanations,
carcinogenicity in experimental evidence consistent with this descriptor such as chance, bias, or
animals. In some cases, an covers a broad spectrum. As stated confounding factors, could not
agent may be classified in previously, the use of the term “likely” adequately be excluded,
this category when there as a weight of evidence descriptor
or
is inadequate evidence of does not correspond to a quantifiable
carcinogenicity in humans probability. The examples below are there is sufficient evidence of
and sufficient evidence of meant to represent the broad range of carcinogenicity from studies in
carcinogenicity in experimental data combinations that are covered experimental animals, which
animals and strong evidence by this descriptor; they are illustrative indicates there is an increased
that the carcinogenesis is and provide neither a checklist incidence of malignant and/or a
mediated by a mechanism nor a limitation for the data that combination of malignant and
that also operates in humans. might support use of this descriptor. benign tumors (1) in multiple
Exceptionally, an agent may be Moreover, additional information, e.g., species or at multiple tissue
classified in this category solely on mode of action, might change the sites, or (2) by multiple routes of
on the basis of limited evidence choice of descriptor for the illustrated exposure, or (3) to an unusual
of carcinogenicity in humans. examples. Supporting data for this degree with regard to incidence,
An agent may be assigned descriptor may include: site, or type of tumor, or age at
to this category if it clearly onset,
belongs, based on mechanistic • n agent demonstrating a plausible
a
or
considerations, to a class of (but not definitively causal)
agents for which one or more association between human there is less than sufficient
members have been classified exposure and cancer, in most cases evidence of carcinogenicity in
in Group 1 or Group 2A. with some supporting biological, humans or laboratory animals;
experimental evidence, though not however, the agent, substance,
necessarily carcinogenicity data or mixture belongs to a well-
from animal experiments; defined, structurally related class
• n agent that has tested positive in of substances whose members
a
animal experiments in more than are listed in a previous Report
one species, sex, strain, site, or on Carcinogens as either known
exposure route, with or without to be a human carcinogen or
evidence of carcinogenicity in reasonably anticipated to be a
humans; human carcinogen, or there is
• positive tumor study that raises convincing relevant information
a
additional biological concerns that the agent acts through
beyond that of a statistically mechanisms indicating it would
significant result, for example, a likely cause cancer in humans.
high degree of malignancy, or an
early age at onset;
• rare animal tumor response in a
a
single experiment that is assumed
to be relevant to humans; or
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371
APPENDIX C
World Cancer Research Fund/
American Institute for Cancer Research
(WCRF/AICR) Institute of Medicine (IOM)
Probable Sufficient evidence of an association
These criteria are for evidence strong enough Evidence suggests an association, in that a positive
to support a judgement of a probable causal association has been observed between deployment
relationship, which would generally justify goals to the Gulf War and a health outcome in humans;
and recommendations designed to reduce the however, there is some doubt as to the influence of
incidence of cancer. chance, bias, and confounding.
All the following were generally required:
• vidence from at least two independent
E
cohort studies, or at least five case–control
studies.
• o substantial unexplained heterogeneity
N
between or within study types in the
presence or absence of any association, or
direction of effect.
• ood quality studies to exclude with
G
confidence the possibility that the observed
association results from random or
systematic error, including confounding,
measurement error, and selection bias.
• vidence for biological plausibility.
E
continued
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TABLE C-1 Continued
International Agency for Environmental
Research on Cancer Protection Agency National Toxicology
(IARC) (EPA) Program (NTP)
• positive tumor study that is
a Conclusions regarding
strengthened by other lines of carcinogenicity in humans or
evidence, for example, either experimental animals are based
plausible (but not definitively on scientific judgment, with
causal) association between human consideration given to all relevant
exposure and cancer or evidence information. Relevant information
that the agent or an important includes, but is not limited to,
metabolite causes events generally dose response, route of exposure,
known to be associated with tumor chemical structure, metabolism,
formation (such as DNA reactivity pharmacokinetics, sensitive sub-
or effects on cell growth control) populations, genetic effects, or
likely to be related to the tumor other data relating to mechanism
response in this case. of action or factors that may be
unique to a given substance. For
example, there may be substances
for which there is evidence of
carcinogenicity in laboratory
animals, but there are compelling
data indicating that the agent
acts through mechanisms which
do not operate in humans and
would therefore not reasonably
be anticipated to cause cancer in
humans.
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APPENDIX C
World Cancer Research Fund/
American Institute for Cancer Research
(WCRF/AICR) Institute of Medicine (IOM)
continued
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TABLE C-1 Continued
International Agency for Environmental
Research on Cancer Protection Agency National Toxicology
(IARC) (EPA) Program (NTP)
• vidence of a positive response in
e
a study whose power, design, or
conduct limits the ability to draw a
confident conclusion (but does not
make the study fatally flawed), but
where the carcinogenic potential
is strengthened by other lines of
evidence (such as structure-activity
relationships); or
• statistically significant increase
a
at one dose only, but no significant
response at the other doses and no
overall trend.
Group 3: The agent is Inadequate information to assess
carcinogenic potential
not classifiable as to its
carcinogenicity to humans. This descriptor of the database is
This category is used most appropriate when available data are
commonly for agents for which judged inadequate for applying one
the evidence of carcinogenicity of the other descriptors. Additional
is inadequate in humans studies generally would be expected to
and inadequate or limited in provide further insights. Some examples
experimental animals. include:
Exceptionally, agents
for which the evidence of – little or no pertinent information;
carcinogenicity is inadequate – conflicting evidence, that is,
in humans but sufficient in some studies provide evidence of
experimental animals may carcinogenicity but other studies
be placed in this category of equal quality in the same sex
when there is strong evidence and strain are negative. Differing
that the mechanism of results, that is, positive results
carcinogenicity in experimental in some studies and negative
animals does not operate in results in one or more different
humans. experimental systems, do not
Agents that do not fall constitute conflicting evidence, as
into any other group are also the term is used here. Depending
placed in this category. on the overall weight of evidence,
An evaluation in Group differing results can be considered
3 is not a determination of either suggestive evidence or likely
non-carcinogenicity or overall evidence; or
safety. It often means that – negative results that are not
further research is needed, sufficiently robust for the
especially when exposures are descriptor, “Not Likely to Be
widespread or the cancer data Carcinogenic to Humans.”
are consistent with differing
interpretations.
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APPENDIX C
World Cancer Research Fund/
American Institute for Cancer Research
(WCRF/AICR) Institute of Medicine (IOM)
Limited—no conclusion Inadequate/insufficient evidence to determine
whether an association exists
Evidence is so limited that no firm conclusion
can be made. This category represents an entry The available studies are of insufficient quality,
level, and is intended to allow any exposure for validity, consistency, or statistical power to permit
which there are sufficient data to warrant Panel a conclusion regarding the presence or absence of
consideration, but where insufficient evidence an association between deployment to the Gulf War
exists to permit a more definitive grading. This and a health outcome in humans.
does not necessarily mean a limited quantity of
evidence. A body of evidence for a particular
exposure might be graded “limited—no
conclusion” for a number of reasons. The
evidence might be limited by the amount of
evidence in terms of the number of studies
available, by inconsistency of direction of effect,
by poor quality of studies (for example, lack of
adjustment for known confounders), or by any
combination of these factors. Exposures that are
graded “limited—no conclusion” do not appear
in the matrices presented in Chapters 4–6, but
do appear in Chapters 7 and 8.
When an exposure is graded “limited—no
conclusion”, this does not necessarily indicate
that the Panel has judged that there is evidence
of no relationship. With further good quality
research, any exposure graded in this way might
in the future be shown to increase or decrease the
risk of cancer. Where there is sufficient evidence
to give confidence that an exposure is unlikely to
have an effect on cancer risk, this exposure will
be judged “substantial effect on risk unlikely.”
There are also many exposures for which
there is such limited evidence that no judgement
is possible. In these cases, evidence is recorded
in the full SLR reports contained on the
CD included with this Report. However,
such evidence is usually not included in the
summaries and is not included in the matrices in
this printed Report.
continued
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TABLE C-1 Continued
International Agency for Environmental
Research on Cancer Protection Agency National Toxicology
(IARC) (EPA) Program (NTP)
Group 4: The agent is Not likely to be carcinogenic to humans
probably not carcinogenic to This descriptor is appropriate when
humans. the available data are considered robust
This category is used for deciding that there is no basis
for agents for which there for human hazard concern. In some
is evidence suggesting instances, there can be positive results
lack of carcinogenicity in in experimental animals when there is
humans and in experimental strong, consistent evidence that each
animals. In some instances, mode of action in experimental animals
agents for which there is does not operate in humans. In other
cases, there can be convincing evidence
inadequate evidence of
carcinogenicity in humans but in both humans and animals that the
agent is not carcinogenic. The judgment
evidence suggesting lack of
carcinogenicity in experimental may be based on data such as:
animals, consistently and
strongly supported by a broad • nimal evidence that demonstrates
a
range of mechanistic and other lack of carcinogenic effect in both
relevant data, may be classified sexes in well-designed and well-
in this group. conducted studies in at least two
appropriate animal species (in the
absence of other animal or human
data suggesting a potential for
cancer effects),
• onvincing and extensive
c
experimental evidence showing
that the only carcinogenic effects
observed in animals are not
relevant to humans,
• onvincing evidence that
c
carcinogenic effects are not likely
by a particular exposure route (see
Section 2.3), or
• onvincing evidence that
c
carcinogenic effects are not likely
below a defined dose range.
A descriptor of “not likely” applies
only to the circumstances supported by
the data. For example, an agent may
be “Not Likely to Be Carcinogenic”
by one route but not necessarily by
another. In those cases that have
positive animal experiment(s) but the
results are judged to be not relevant to
humans, the narrative discusses why the
results are not relevant.
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APPENDIX C
World Cancer Research Fund/
American Institute for Cancer Research
(WCRF/AICR) Institute of Medicine (IOM)
Substantial effect on risk unlikely Limited/suggestive evidence of no association
Evidence is strong enough to support a There are several adequate studies, covering the
judgement that a particular food, nutrition, or full range of levels of exposure that humans are
physical activity exposure is unlikely to have a known to encounter, that are consistent in not
substantial causal relation to a cancer outcome. showing an association between deployment to the
The evidence should be robust enough to be Gulf War and a health outcome. A conclusion of no
unlikely to be modified in the foreseeable future association is inevitably limited to the conditions,
as new evidence accumulates. levels of exposure, and length of observation
All of the following were generally required: covered by the available studies. In addition, the
possibility of a very small increase in risk at the
• vidence from more than one study type.
E levels of exposure studied can never be excluded.
• vidence from at least two independent
E
cohort studies.
• ummary estimate of effect close to 1.0 for
S
comparison of high versus low exposure
categories.
• o substantial unexplained heterogeneity
N
within or between study types or in different
populations.
• ood quality studies to exclude, with
G
absence of an observed association results
from random or systematic error, including
inadequate power, imprecision or error in
exposure measurement, inadequate range of
exposure, confounding, and selection bias.
• bsence of a demonstrable biological
A
gradient (“dose response”).
• bsence of strong and plausible
A
experimental evidence, either from human
studies or relevant animal models, that
typical human exposures lead to relevant
cancer outcomes.
Factors that might misleadingly imply an
absence of effect include imprecision of the
exposure assessment, an insufficient range
of exposure in the study population, and
inadequate statistical power. Defects in these
and other study design attributes might lead to a
false conclusion of no effect.
The presence of a plausible, relevant
biological mechanism does not necessarily rule
out a judgement of “substantial effect on risk
unlikely.” But the presence of robust evidence
from appropriate animal models or in humans
that a specific mechanism exists, or that typical
exposures can lead to cancer outcomes, argues
against such a judgement.
continued
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TABLE C-1 Continued
International Agency for Environmental
Research on Cancer Protection Agency National Toxicology
(IARC) (EPA) Program (NTP)
*This evidence can include traditional cancer epidemiology studies, data from clinical studies, and/or data
derived from the study of tissues or cells from humans exposed to the substance in question that can be
useful for evaluating whether a relevant cancer mechanism is operating in people.
SOURCES: EPA (2005); NTP (2005); IARC (2006, pp. 22–23), used with permission: From Monographs on
the evaluation of carcinogenic risks to humans: Preamble. Lyon, France: IARC. http://monographs.iarc.fr/
ENG/Preamble/CurrentPreamble.pdf; WCRF/AICR (2007, pp. 60–61), used with permission; IOM (2010).
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APPENDIX C
World Cancer Research Fund/
American Institute for Cancer Research
(WCRF/AICR) Institute of Medicine (IOM)
Because of the uncertainty inherent in
concluding that an exposure has no effect on
risk, the criteria used to judge an exposure
“substantial effect on risk unlikely” are roughly
equivalent to the criteria used with at least a
“probable” level of confidence. Conclusions of
“substantial effect on risk unlikely” with a lower
confidence than this would not be helpful, and
could overlap with judgements of “limited—
suggestive” or “limited—no conclusion.”
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TABLE C-2 Supplemental Criteria Used by IARC and WCRF/AICR in
Evaluation of Evidence
IARC
Human Animal
Sufficient evidence of Sufficient evidence of carcinogenicity: The
carcinogenicity: The Working Working Group considers that a causal
Group considers that a causal relationship has been established between the
relationship has been established agent and an increased incidence of malignant
between exposure to the agent and neoplasms or of an appropriate combination
human cancer. That is, a positive of benign and malignant neoplasms in (a) two
relationship has been observed or more species of animals or (b) two or more
between the exposure and cancer independent studies in one species carried out
in studies in which chance, bias at different times or in different laboratories or
and confounding could be ruled under different protocols. An increased incidence
out with reasonable confidence. A of tumours in both sexes of a single species in a
statement that there is sufficient well-conducted study, ideally conducted under
evidence is followed by a separate Good Laboratory Practices, can also provide
sentence that identifies the target sufficient evidence.
organ(s) or tissue(s) where an A single study in one species and sex might
increased risk of cancer was be considered to provide sufficient evidence of
observed in humans. Identification carcinogenicity when malignant neoplasms occur
of a specific target organ or tissue to an unusual degree with regard to incidence,
does not preclude the possibility site, type of tumour or age at onset, or when
that the agent may cause cancer at there are strong findings of tumours at multiple
other sites. sites.
Limited evidence of Limited evidence of carcinogenicity: The data
carcinogenicity: A positive suggest a carcinogenic effect but are limited for
association has been observed making a definitive evaluation because, e.g., (a)
between exposure to the agent the evidence of carcinogenicity is restricted to
and cancer for which a causal a single experiment; (b) there are unresolved
interpretation is considered by the questions regarding the adequacy of the design,
Working Group to be credible, but conduct or interpretation of the studies; (c) the
chance, bias or confounding could agent increases the incidence only of benign
not be ruled out with reasonable neoplasms or lesions of uncertain neoplastic
confidence. potential; or (d) the evidence of carcinogenicity
is restricted to studies that demonstrate only
promoting activity in a narrow range of tissues
or organs.
Inadequate evidence of Inadequate evidence of carcinogenicity: The
carcinogenicity: The available studies cannot be interpreted as showing either
studies are of insufficient quality, the presence or absence of a carcinogenic effect
consistency or statistical power to because of major qualitative or quantitative
permit a conclusion regarding the limitations, or no data on cancer in experimental
presence or absence of a causal animals are available.
association between exposure and
cancer, or no data on cancer in
humans are available.
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APPENDIX C
Mechanism
The strongest indications that a particular mechanism operates in humans derive from
data on humans or biological specimens obtained from exposed humans. The data may
be considered to be especially relevant if they show that the agent in question has caused
changes in exposed humans that are on the causal pathway to carcinogenesis. Such data
may, however, never become available, because it is at least conceivable that certain
compounds may be kept from human use solely on the basis of evidence of their toxicity
and/or carcinogenicity in experimental systems.
The conclusion that a mechanism operates in experimental animals is strengthened
by findings of consistent results in different experimental systems, by the demonstration
of biological plausibility and by coherence of the overall database. Strong support can
be obtained from studies that challenge the hypothesized mechanism experimentally, by
demonstrating that the suppression of key mechanistic processes leads to the suppression of
tumour development. The Working Group considers whether multiple mechanisms might
contribute to tumour development, whether different mechanisms might operate in different
dose ranges, whether separate mechanisms might operate in humans and experimental
animals and whether a unique mechanism might operate in a susceptible group. The
possible contribution of alternative mechanisms must be considered before concluding that
tumours observed in experimental animals are not relevant to humans. An uneven level of
experimental support for different mechanisms may reflect that disproportionate resources
have been focused on investigating a favoured mechanism.
continued
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TABLE C-2 Continued
IARC
Evidence suggesting lack of Evidence suggesting lack of carcinogenicity:
carcinogenicity: There are several Adequate studies involving at least two species
adequate studies covering the full are available which show that, within the limits
range of levels of exposure that of the tests used, the agent is not carcinogenic.
humans are known to encounter, A conclusion of evidence suggesting lack of
which are mutually consistent in carcinogenicity is inevitably limited to the
not showing a positive association species, tumour sites, age at exposure, and
between exposure to the agent and conditions and levels of exposure studied.
any studied cancer at any observed
level of exposure. The results from
these studies alone or combined
should have narrow confidence
intervals with an upper limit close
to the null value (e.g., a relative
risk of 1.0). Bias and confounding
should be ruled out with reasonable
confidence, and the studies should
have an adequate length of
follow-up. A conclusion of evidence
suggesting lack of carcinogenicity
is inevitably limited to the cancer
sites, conditions and levels of
exposure, and length of observation
covered by the available studies. In
addition, the possibility of a very
small risk at the levels of exposure
studied can never be excluded.
WCRF/AICR
Class 1 Class 2
• n vivo data from studies in
I • n vitro data from studies using human cells
I
human volunteers (controlled validated with an in vivo model; for example,
human feeding studies). a transgenic model.
• n vivo data from studies using
I • n vitro data from studies using primary
I
genetically modified animal human cells.
models related to human cancer • n vitro data from studies using human cell
I
(such as gene knockout or lines.
transgenic mouse models).
• n vivo data from studies using
I
rodent cancer models designed
to investigate modifiers of the
cancer process.
SOURCES: IARC (2006, pp. 19–21), used with permission: From Monographs on the evalua-
tion of carcinogenic risks to humans: Preamble. Lyon, France: IARC. http://monographs.iarc.
fr/ENG/Preamble/CurrentPreamble.pdf; WCRF/AICR (2007, p. 55), used with permission.
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APPENDIX C
Class 3
• n vitro data from studies on animal cells.
I
• ata from mechanistic test systems; for example, isolated enzymes or genes.
D
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REFERENCES
EPA (Environmental Protection Agency). 2005. Guidelines for carcinogen risk assessment.
Washington, DC: EPA.
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