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Breast Cancer and the Environment: A Life Course Approach (2012)

Chapter:Appendix C: Classification Systems Used in Evidence Reviews

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Suggested Citation:"Appendix C: Classification Systems Used in Evidence Reviews." Institute of Medicine. 2012. Breast Cancer and the Environment: A Life Course Approach. Washington, DC: The National Academies Press. doi: 10.17226/13263.
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Suggested Citation:"Appendix C: Classification Systems Used in Evidence Reviews." Institute of Medicine. 2012. Breast Cancer and the Environment: A Life Course Approach. Washington, DC: The National Academies Press. doi: 10.17226/13263.
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TABLE C-1 Compilation of Evidence Categories Used by Selected Organizations

International Agency for Research on Cancer (IARC) Environmental Protection Agency (EPA) National Toxicology 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.
Suggested Citation:"Appendix C: Classification Systems Used in Evidence Reviews." Institute of Medicine. 2012. Breast Cancer and the Environment: A Life Course Approach. Washington, DC: The National Academies Press. doi: 10.17226/13263.
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World Cancer Research Fund/American Institute for Cancer Research(WCRF/AICR) Institute of Medicine (IOM)

Special upgrading factors

These are factors that form part of the assessment of the evidence that, when present, can upgrade the judgement reached. So an exposure that might be deemed a “limited—suggestive” causal factor in the absence, say, of a biological gradient, might be upgraded to “probable” in its presence. The application of these factors (listed below) requires judgement, and the way in which these judgements affect the final conclusion in the matrix are stated.

• Presence of a plausible biological gradient (“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.

• A particularly large summary effect size (an odds ratio or relative risk of 2.0 or more, depending on the unit of exposure) after appropriate control for confounders.

• Evidence from randomised trials in humans.

• Evidence from appropriately controlled experiments demonstrating one or more plausible and specific mechanisms actually operating in humans.

• Robust and reproducible evidence from experimental studies in appropriate animal models showing that typical human exposures can lead to relevant cancer outcomes.

   The committee relied entirely on clinical and human epidemiologic studies to draw its conclusions about the strength of evidence regarding associations between deployment to the Gulf War and health outcomes seen in Gulf War veterans. The committee acknowledges, however, that animal studies might prove helpful in providing biologic understanding of many of the effects seen in humans from specific exposures, such as pesticides, solvents, and nerve agents, which have been reported by troops deployed in the Gulf War. Furthermore, information from molecular and cellular biology, neuroimaging, and other types of human studies can be used to understand the biological mechanisms and identification of biomarkers for clinical outcomes. Such studies, however, are not, in general, included in this review.
Suggested Citation:"Appendix C: Classification Systems Used in Evidence Reviews." Institute of Medicine. 2012. Breast Cancer and the Environment: A Life Course Approach. Washington, DC: The National Academies Press. doi: 10.17226/13263.
×
International Agency for Research on Cancer (IARC) Environmental Protection Agency (EPA) National Toxicology Program (NTP)
Group 1: The agent is carcinogenic to humans.
   This category is used when there is sufficient evidence of carcinogenicity in humans. Exceptionally, an agent may be placed in this category when evidence of carcinogenicity in humans is less than sufficient but there is sufficient evidence of carcinogenicity in experimental animals and strong evidence in exposed humans that the agent acts through a relevant mechanism of carcinogenicity.
Carcinogenic to humans
   This descriptor indicates strong evidence of human carcinogenicity. It covers different combinations of evidence.

   1. This descriptor is appropriate when there is convincing epidemiologic evidence of a causal association between human exposure and cancer.
   2. Exceptionally, this descriptor may be equally appropriate with a lesser weight of epidemiologic evidence that is strengthened by other lines of evidence. It can be used when all of the following 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.
Known to be human carcinogen
   There is sufficient evidence of carcinogenicity from studies in humans,* which indicates a causal relationship between exposure to the agent, substance, or mixture, and human cancer.
Suggested Citation:"Appendix C: Classification Systems Used in Evidence Reviews." Institute of Medicine. 2012. Breast Cancer and the Environment: A Life Course Approach. Washington, DC: The National Academies Press. doi: 10.17226/13263.
×
World Cancer Research Fund/ American Institute for Cancer Research (WCRF/AICR) Institute of Medicine (IOM)

Convincing

These criteria are for evidence strong enough to support a judgement of a convincing causal relationship, which justifies goals and recommendations designed to reduce the incidence of cancer. A convincing relationship should be robust enough to be highly unlikely to be modified in the foreseeable future as new evidence accumulates.

All of the following were generally required:

• Evidence from more than one study type.

• Evidence from at least two independent cohort studies.

• No substantial unexplained heterogeneity within or between study types or in different populations relating to the presence or absence of an association, or direction of effect.

• Good-quality studies to exclude with confidence the possibility that the observed association results from random or systematic error, including confounding, measurement error, and selection bias.

• Presence of a plausible biological gradient (“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.

• Strong and plausible experimental evidence, either from human studies or relevant animal models, that typical human exposures can lead to relevant cancer outcomes.

Sufficient evidence of a causal relationship

Evidence is sufficient to conclude that a causal relationship exists between being deployed to the Gulf War and a health outcome. The evidence fulfills the criteria for sufficient evidence of a causal association in which chance, bias, and confounding can be ruled out with reasonable confidence. The association is supported by several of the other considerations used to assess causality: strength of association, dose-response relationship, consistency of association, temporal relationship, specificity of association, and biologic plausibility.

Suggested Citation:"Appendix C: Classification Systems Used in Evidence Reviews." Institute of Medicine. 2012. Breast Cancer and the Environment: A Life Course Approach. Washington, DC: The National Academies Press. doi: 10.17226/13263.
×
International Agency for Research on Cancer (IARC) Environmental Protection Agency (EPA) National Toxicology 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.
Suggested Citation:"Appendix C: Classification Systems Used in Evidence Reviews." Institute of Medicine. 2012. Breast Cancer and the Environment: A Life Course Approach. Washington, DC: The National Academies Press. doi: 10.17226/13263.
×
World Cancer Research Fund/ American Institute for Cancer Research (WCRF/AICR) Institute of Medicine (IOM)
     
Suggested Citation:"Appendix C: Classification Systems Used in Evidence Reviews." Institute of Medicine. 2012. Breast Cancer and the Environment: A Life Course Approach. Washington, DC: The National Academies Press. doi: 10.17226/13263.
×
International Agency for Research on Cancer (IARC) Environmental Protection Agency (EPA) National Toxicology Program (NTP)

Group 2A: The agent is probably carcinogenic to humans.

This category is used when there is limited evidence of carcinogenicity in humans and sufficient evidence of carcinogenicity in experimental animals. In some cases, an agent may be classified in this category when there is inadequate evidence of carcinogenicity in humans and sufficient evidence of carcinogenicity in experimental animals and strong evidence that the carcinogenesis is mediated by a mechanism that also operates in humans. Exceptionally, an agent may be classified in this category solely on the basis of limited evidence of carcinogenicity in humans. An agent may be assigned to this category if it clearly 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.

Likely to be carcinogenic to humans

This descriptor is appropriate when the weight of the evidence is adequate to demonstrate carcinogenic potential to humans but does not reach the weight of evidence for the descriptor “Carcinogenic to Humans.” Adequate evidence consistent with this descriptor covers a broad spectrum. As stated previously, the use of the term “likely” as a weight of evidence descriptor does not correspond to a quantifiable probability. The examples below are meant to represent the broad range of data combinations that are covered by this descriptor; they are illustrative and provide neither a checklist nor a limitation for the data that might support use of this descriptor. Moreover, additional information, e.g., on mode of action, might change the choice of descriptor for the illustrated examples. Supporting data for this descriptor may include:

• an agent demonstrating a plausible (but not definitively causal) association between human exposure and cancer, in most cases with some supporting biological, experimental evidence, though not necessarily carcinogenicity data from animal experiments;

• an agent that has tested positive in animal experiments in more than one species, sex, strain, site, or exposure route, with or without evidence of carcinogenicity in humans;

• a positive tumor study that raises additional biological concerns beyond that of a statistically significant result, for example, a high degree of malignancy, or an early age at onset;

• a rare animal tumor response in a single experiment that is assumed to be relevant to humans; or

Reasonably anticipated to be human carcinogen:

There is limited evidence of carcinogenicity from studies in humans,* which indicates that causal interpretation is credible, but that alternative explanations, such as chance, bias, or confounding factors, could not adequately be excluded,

or

there is sufficient evidence of carcinogenicity from studies in experimental animals, which indicates there is an increased incidence of malignant and/or a combination of malignant and benign tumors (1) in multiple species or at multiple tissue sites, or (2) by multiple routes of exposure, or (3) to an unusual degree with regard to incidence, site, or type of tumor, or age at onset,

or

there is less than sufficient evidence of carcinogenicity in humans or laboratory animals; however, the agent, substance, or mixture belongs to a well-defined, structurally related class of substances whose members are listed in a previous Report on Carcinogens as either known to be a human carcinogen or reasonably anticipated to be a human carcinogen, or there is convincing relevant information that the agent acts through mechanisms indicating it would likely cause cancer in humans.

Suggested Citation:"Appendix C: Classification Systems Used in Evidence Reviews." Institute of Medicine. 2012. Breast Cancer and the Environment: A Life Course Approach. Washington, DC: The National Academies Press. doi: 10.17226/13263.
×
World Cancer Research Fund/ American Institute for Cancer Research (WCRF/AICR) Institute of Medicine (IOM)

Probable

These criteria are for evidence strong enough to support a judgement of a probable causal relationship, which would generally justify goals and recommendations designed to reduce the incidence of cancer.

All the following were generally required:

• Evidence from at least two independent cohort studies, or at least five case-control studies.

• No substantial unexplained heterogeneity between or within study types in the presence or absence of any association, or direction of effect.

• Good quality studies to exclude with confidence the possibility that the observed association results from random or systematic error, including confounding, measurement error, and selection bias.

• Evidence for biological plausibility.

Sufficient evidence of an association

Evidence suggests an association, in that a positive association has been observed between deployment to the Gulf War and a health outcome in humans; however, there is some doubt as to the influence of chance, bias, and confounding.

Suggested Citation:"Appendix C: Classification Systems Used in Evidence Reviews." Institute of Medicine. 2012. Breast Cancer and the Environment: A Life Course Approach. Washington, DC: The National Academies Press. doi: 10.17226/13263.
×
International Agency for Research on Cancer (IARC) Environmental Protection Agency (EPA) National Toxicology Program (NTP)

• a positive tumor study that is strengthened by other lines of evidence, for example, either plausible (but not definitively causal) association between human exposure and cancer or evidence that the agent or an important metabolite causes events generally known to be associated with tumor formation (such as DNA reactivity or effects on cell growth control) likely to be related to the tumor response in this case.

Conclusions regarding carcinogenicity in humans or experimental animals are based on scientific judgment, with consideration given to all relevant information. Relevant information includes, but is not limited to, dose response, route of exposure, chemical structure, metabolism, pharmacokinetics, sensitive sub-populations, genetic effects, or other data relating to mechanism 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.

Suggested Citation:"Appendix C: Classification Systems Used in Evidence Reviews." Institute of Medicine. 2012. Breast Cancer and the Environment: A Life Course Approach. Washington, DC: The National Academies Press. doi: 10.17226/13263.
×
World Cancer Research Fund/ American Institute for Cancer Research (WCRF/AICR) Institute of Medicine (IOM)
     
Suggested Citation:"Appendix C: Classification Systems Used in Evidence Reviews." Institute of Medicine. 2012. Breast Cancer and the Environment: A Life Course Approach. Washington, DC: The National Academies Press. doi: 10.17226/13263.
×
International Agency for Research on Cancer (IARC) Environmental Protection Agency (EPA) National Toxicology Program (NTP)

Group 2B: The agent is possibly carcinogenic to humans.

This category is used for agents for which there is limited evidence of carcinogenicity in humans and less than sufficient evidence of carcinogenicity in experimental animals. It may also be used when there is inadequate evidence of carcinogenicity in humans but there is sufficient evidence of carcinogenicity in experimental animals. In some instances, an agent for which there is inadequate evidence of carcinogenicity in humans and less than sufficient evidence of carcinogenicity in experimental animals together with supporting evidence from mechanistic and other relevant data may be placed in this group. An agent may be classified in this category solely on the basis of strong evidence from mechanistic and other relevant data.

Suggestive evidence of carcinogenic potential

This descriptor of the database is appropriate when the weight of evidence is suggestive of carcinogenicity; a concern for potential carcinogenic effects in humans is raised, but the data are judged not sufficient for a stronger conclusion. This descriptor covers a spectrum of evidence associated with varying levels of concern for carcinogenicity, ranging from a positive cancer result in the only study on an agent to a single positive cancer result in an extensive database that includes negative studies in other species. Depending on the extent of the database, additional studies may or may not provide further insights. Some examples include:

• a small, and possibly not statistically significant, increase in tumor incidence observed in a single animal or human study that does not reach the weight of evidence for the descriptor “Likely to Be Carcinogenic to Humans.” The study generally would not be contradicted by other studies of equal quality in the same population group or experimental system (see discussions of conflicting evidence and differing results, below);

• a small increase in a tumor with a high background rate in that sex and strain, when there is some but insufficient evidence that the observed tumors may be due to intrinsic factors that cause background tumors and not due to the agent being assessed. (When there is a high background rate of a specific tumor in animals of a particular sex and strain, then there may be biological factors operating independently of the agent being assessed that could be responsible for the development of the observed tumors.) In this case, the reasons for determining that the tumors are not due to the agent are explained;

Suggested Citation:"Appendix C: Classification Systems Used in Evidence Reviews." Institute of Medicine. 2012. Breast Cancer and the Environment: A Life Course Approach. Washington, DC: The National Academies Press. doi: 10.17226/13263.
×
World Cancer Research Fund/ American Institute for Cancer Research (WCRF/AICR) Institute of Medicine (IOM)

Limited—suggestive

These criteria are for evidence that is too limited to permit a probable or convincing causal judgement, but where there is evidence suggestive of a direction of effect. The evidence may have methodological flaws, or be limited in amount, but shows a generally consistent direction of effect. This almost always does not justify recommendations designed to reduce the incidence of cancer. Any exceptions to this require special explicit justification. All the following were generally required:

• Evidence from at least two independent cohort studies or at least five case-control studies.

• The direction of effect is generally consistent though some unexplained heterogeneity may be present.

• Evidence for biological plausibility.

Limited/suggestive evidence of an association

Some evidence of an association between deployment to the Gulf War and a health outcome in humans exists, but this is limited by the presence of substantial doubt regarding chance, bias, and confounding.

Suggested Citation:"Appendix C: Classification Systems Used in Evidence Reviews." Institute of Medicine. 2012. Breast Cancer and the Environment: A Life Course Approach. Washington, DC: The National Academies Press. doi: 10.17226/13263.
×
International Agency for Research on Cancer (IARC) Environmental Protection Agency (EPA) National Toxicology Program (NTP)

• evidence of a positive response in 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

• a statistically significant increase at one dose only, but no significant response at the other doses and no overall trend.

 

Group 3: The agent is not classifiable as to its carcinogenicity to humans.

This category is used most commonly for agents for which the evidence of carcinogenicity is inadequate in humans and inadequate or limited in experimental animals.

Exceptionally, agents for which the evidence of carcinogenicity is inadequate in humans but sufficient in experimental animals may be placed in this category when there is strong evidence that the mechanism of carcinogenicity in experimental animals does not operate in humans.

Agents that do not fall into any other group are also placed in this category.

An evaluation in Group 3 is not a determination of non-carcinogenicity or overall safety. It often means that further research is needed, especially when exposures are widespread or the cancer data are consistent with differing interpretations.

Inadequate information to assess carcinogenic potential

This descriptor of the database is appropriate when available data are judged inadequate for applying one of the other descriptors. Additional studies generally would be expected to provide further insights. Some examples include:

— little or no pertinent information;

— conflicting evidence, that is, some studies provide evidence of carcinogenicity but other studies of equal quality in the same sex and strain are negative. Differing results, that is, positive results in some studies and negative results in one or more different experimental systems, do not constitute conflicting evidence, as the term is used here. Depending on the overall weight of evidence, differing results can be considered either suggestive evidence or likely evidence; or

— negative results that are not sufficiently robust for the descriptor, “Not Likely to Be Carcinogenic to Humans.”

 
Suggested Citation:"Appendix C: Classification Systems Used in Evidence Reviews." Institute of Medicine. 2012. Breast Cancer and the Environment: A Life Course Approach. Washington, DC: The National Academies Press. doi: 10.17226/13263.
×
World Cancer Research Fund/ American Institute for Cancer Research (WCRF/AICR) Institute of Medicine (IOM)
     

Limited—no conclusion

Evidence is so limited that no firm conclusion can be made. This category represents an entry level, and is intended to allow any exposure for which there are sufficient data to warrant Panel consideration, but where insufficient evidence exists to permit a more definitive grading. This 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.

Inadequate/insufficient evidence to determine whether an association exists

The available studies are of insufficient quality, validity, consistency, or statistical power to permit a conclusion regarding the presence or absence of an association between deployment to the Gulf War and a health outcome in humans.

Suggested Citation:"Appendix C: Classification Systems Used in Evidence Reviews." Institute of Medicine. 2012. Breast Cancer and the Environment: A Life Course Approach. Washington, DC: The National Academies Press. doi: 10.17226/13263.
×
International Agency for Research on Cancer (IARC) Environmental Protection Agency (EPA) National Toxicology Program (NTP)

Group 4: The agent is probably not carcinogenic to humans.

This category is used for agents for which there is evidence suggesting lack of carcinogenicity in humans and in experimental animals. In some instances, agents for which there is inadequate evidence of carcinogenicity in humans but evidence suggesting lack of carcinogenicity in experimental animals, consistently and strongly supported by a broad range of mechanistic and other relevant data, may be classified in this group.

Not likely to be carcinogenic to humans

This descriptor is appropriate when the available data are considered robust for deciding that there is no basis for human hazard concern. In some instances, there can be positive results in experimental animals when there is strong, consistent evidence that each mode of action in experimental animals does not operate in humans. In other cases, there can be convincing evidence in both humans and animals that the agent is not carcinogenic. The judgment may be based on data such as:

• animal evidence that demonstrates lack of carcinogenic effect in both sexes in well-designed and well-conducted studies in at least two appropriate animal species (in the absence of other animal or human data suggesting a potential for cancer effects),

• convincing and extensive experimental evidence showing that the only carcinogenic effects observed in animals are not relevant to humans,

• convincing evidence that carcinogenic effects are not likely by a particular exposure route (see Section 2.3), or

• convincing evidence that 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.

Suggested Citation:"Appendix C: Classification Systems Used in Evidence Reviews." Institute of Medicine. 2012. Breast Cancer and the Environment: A Life Course Approach. Washington, DC: The National Academies Press. doi: 10.17226/13263.
×
World Cancer Research Fund/ American Institute for Cancer Research (WCRF/AICR) Institute of Medicine (IOM)

Substantial effect on risk unlikely

Evidence is strong enough to support a judgement that a particular food, nutrition, or physical activity exposure is unlikely to have a substantial causal relation to a cancer outcome. The evidence should be robust enough to be unlikely to be modified in the foreseeable future as new evidence accumulates.

All of the following were generally required:

• Evidence from more than one study type.

• Evidence from at least two independent cohort studies.

• Summary estimate of effect close to 1.0 for comparison of high versus low exposure categories.

• No substantial unexplained heterogeneity within or between study types or in different populations.

• Good quality studies to exclude, with 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.

• Absence of a demonstrable biological gradient (“dose response”).

• Absence of strong and plausible 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.

Limited/suggestive evidence of no association

There are several adequate studies, covering the full range of levels of exposure that humans are known to encounter, that are consistent in not showing an association between deployment to the Gulf War and a health outcome. A conclusion of no association is inevitably limited to the conditions, levels of exposure, and length of observation covered by the available studies. In addition, the possibility of a very small increase in risk at the levels of exposure studied can never be excluded.

Suggested Citation:"Appendix C: Classification Systems Used in Evidence Reviews." Institute of Medicine. 2012. Breast Cancer and the Environment: A Life Course Approach. Washington, DC: The National Academies Press. doi: 10.17226/13263.
×
International Agency for Research on Cancer (IARC) Environmental Protection Agency (EPA) National Toxicology 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).

Suggested Citation:"Appendix C: Classification Systems Used in Evidence Reviews." Institute of Medicine. 2012. Breast Cancer and the Environment: A Life Course Approach. Washington, DC: The National Academies Press. doi: 10.17226/13263.
×

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.”
Suggested Citation:"Appendix C: Classification Systems Used in Evidence Reviews." Institute of Medicine. 2012. Breast Cancer and the Environment: A Life Course Approach. Washington, DC: The National Academies Press. doi: 10.17226/13263.
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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 carcinogenicity: The Working Group considers that a causal relationship has been established between exposure to the agent and human cancer. That is, a positive relationship has been observed between the exposure and cancer in studies in which chance, bias and confounding could be ruled out with reasonable confidence. A statement that there is sufficient evidence is followed by a separate sentence that identifies the target organ(s) or tissue(s) where an increased risk of cancer was observed in humans. Identification of a specific target organ or tissue does not preclude the possibility that the agent may cause cancer at other sites. Sufficient evidence of carcinogenicity:The Working Group considers that a causal relationship has been established between the agent and 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 or under different protocols. An increased incidence of tumours in both sexes of a single species in a well-conducted study, ideally conducted under Good Laboratory Practices, can also provide sufficient evidence.
   A single study in one species and sex might be considered to provide 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 strong findings of tumours at multiple sites.
Limited evidence of carcinogenicity:A positive association has been observed between exposure to the agent and cancer for which a causal interpretation is considered by the Working Group to be credible, but chance, bias or confounding could not be ruled out with reasonable confidence. Limited evidence of carcinogenicity:The data suggest a carcinogenic effect but are limited for making a definitive evaluation because, e.g., (a) the evidence of carcinogenicity is restricted to a single experiment; (b) there are unresolved questions regarding the adequacy of the design, conduct or interpretation of the studies; (c) the agent increases the incidence only of benign neoplasms or lesions of uncertain neoplastic 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 carcinogenicity:The available studies are of insufficient quality, consistency or statistical power to permit a conclusion regarding the presence or absence of a causal association between exposure and cancer, or no data on cancer in humans are available. Inadequate evidence of carcinogenicity:The studies cannot be interpreted as showing either the presence or absence of a carcinogenic effect because of major qualitative or quantitative limitations, or no data on cancer in experimental animals are available.
Suggested Citation:"Appendix C: Classification Systems Used in Evidence Reviews." Institute of Medicine. 2012. Breast Cancer and the Environment: A Life Course Approach. Washington, DC: The National Academies Press. doi: 10.17226/13263.
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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.

Suggested Citation:"Appendix C: Classification Systems Used in Evidence Reviews." Institute of Medicine. 2012. Breast Cancer and the Environment: A Life Course Approach. Washington, DC: The National Academies Press. doi: 10.17226/13263.
×
IARC
Evidence suggesting lack of carcinogenicity:There are several adequate 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 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. Evidence suggesting lack of carcinogenicity:Adequate studies involving at least two species are available which show that, within the limits of the tests used, the agent is not carcinogenic. A conclusion of evidence suggesting lack of carcinogenicity is inevitably limited to the species, tumour sites, age at exposure, and conditions and levels of exposure studied.
WCRF/AICR

Class 1

• In vivo data from studies in human volunteers (controlled human feeding studies).

• In vivo data from studies using genetically modified animal models related to human cancer (such as gene knockout or transgenic mouse models).

• In vivo data from studies using rodent cancer models designed to investigate modifiers of the cancer process.

Class 2

• In vitro data from studies using human cells validated with an in vivo model; for example, a transgenic model.

• In vitro data from studies using primary human cells.

• In vitro data from studies using human cell lines.

SOURCES: IARC (2006, pp. 19-21), 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, p. 55), used with permission.

Suggested Citation:"Appendix C: Classification Systems Used in Evidence Reviews." Institute of Medicine. 2012. Breast Cancer and the Environment: A Life Course Approach. Washington, DC: The National Academies Press. doi: 10.17226/13263.
×

 
     

Class 3

• In vitro data from studies on animal cells.

• Data from mechanistic test systems; for example, isolated enzymes or genes.

Suggested Citation:"Appendix C: Classification Systems Used in Evidence Reviews." Institute of Medicine. 2012. Breast Cancer and the Environment: A Life Course Approach. Washington, DC: The National Academies Press. doi: 10.17226/13263.
×

REFERENCES

EPA (Environmental Protection Agency). 2005. Guidelines for carcinogen risk assessment. Washington, DC: EPA.

IARC (International Agency for Research on Cancer). 2006. Monographs on the evaluation of carcinogenic risks to humans: Preamble. Lyon, France: IARC. http://monographs.iarc.fr/ENG/Preamble/CurrentPreamble.pdf (accessed November 18, 2011).

IOM (Institute of Medicine). 2010. Gulf War and health: Update of health effects of serving in the Gulf War. Washington, DC: The National Academies Press.

NTP (National Toxicology Program). 2005. Report on carcinogens, 11th ed. Washington, DC: U.S. Department of Health and Human Services.

WCRF/AICR (World Cancer Research Fund/American Institute for Cancer Research). 2007. Food, nutrition, physical activity, and the prevention of cancer: A global perspective. Washington, DC: AICR.

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Breast cancer remains the most common invasive cancer among women. The primary patients of breast cancer are adult women who are approaching or have reached menopause; 90 percent of new cases in U.S. women in 2009 were diagnosed at age 45 or older. Growing knowledge of the complexity of breast cancer stimulated a transition in breast cancer research toward elucidating how external factors may influence the etiology of breast cancer.

Breast Cancer and the Environment reviews the current evidence on a selection of environmental risk factors for breast cancer, considers gene-environment interactions in breast cancer, and explores evidence-based actions that might reduce the risk of breast cancer. The book also recommends further integrative research into the elements of the biology of breast development and carcinogenesis, including the influence of exposure to a variety of environmental factors during potential windows of susceptibility during the full life course, potential interventions to reduce risk, and better tools for assessing the carcinogenicity of environmental factors. For a limited set of risk factors, evidence suggests that action can be taken in ways that may reduce risk for breast cancer for many women: avoiding unnecessary medical radiation throughout life, avoiding the use of some forms of postmenopausal hormone therapy, avoiding smoking, limiting alcohol consumption, increasing physical activity, and minimizing weight gain.

Breast Cancer and the Environment sets a direction and a focus for future research efforts. The book will be of special interest to medical researchers, patient advocacy groups, and public health professionals.

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