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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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365 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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366 BREAST CANCER AND THE ENVIRONMENT 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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367 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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368 BREAST CANCER AND THE ENVIRONMENT 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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369 APPENDIX C World Cancer Research Fund/ American Institute for Cancer Research (WCRF/AICR) Institute of Medicine (IOM) continued

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370 BREAST CANCER AND THE ENVIRONMENT 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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372 BREAST CANCER AND THE ENVIRONMENT 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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373 APPENDIX C World Cancer Research Fund/ American Institute for Cancer Research (WCRF/AICR) Institute of Medicine (IOM) continued

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376 BREAST CANCER AND THE ENVIRONMENT 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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377 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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378 BREAST CANCER AND THE ENVIRONMENT 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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379 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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380 BREAST CANCER AND THE ENVIRONMENT 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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381 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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382 BREAST CANCER AND THE ENVIRONMENT 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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383 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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384 BREAST CANCER AND THE ENVIRONMENT 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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385 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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386 BREAST CANCER AND THE ENVIRONMENT 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.