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Appendix C: Classification Systems Used in Evidence Reviews
Pages 363-386

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From page 363...
... Appendix C Classification Systems Used in Evidence Reviews 363
From page 364...
... 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.
From page 365...
... 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.
From page 366...
... 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.
From page 367...
... 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.
From page 368...
... 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)
From page 369...
... 369 APPENDIX C World Cancer Research Fund/ American Institute for Cancer Research (WCRF/AICR) Institute of Medicine (IOM)
From page 370...
... 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.
From page 371...
... 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.
From page 372...
... • 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.
From page 373...
... 373 APPENDIX C World Cancer Research Fund/ American Institute for Cancer Research (WCRF/AICR) Institute of Medicine (IOM)
From page 374...
... Group 2B: The agent is Suggestive evidence of carcinogenic potential possibly carcinogenic to humans. This descriptor of the database This category is used is appropriate when the weight for agents for which there of evidence is suggestive of is limited evidence of carcinogenicity; a concern for potential carcinogenicity in humans and carcinogenic effects in humans is less than sufficient evidence of raised, but the data are judged not carcinogenicity in experimental sufficient for a stronger conclusion.
From page 375...
... Limited -- suggestive Limited/suggestive evidence of an association These criteria are for evidence that is too Some evidence of an association between limited to permit a probable or convincing deployment to the Gulf War and a health outcome causal judgement, but where there is evidence in humans exists, but this is limited by the presence suggestive of a direction of effect. The evidence of substantial doubt regarding chance, bias, and may have methodological flaws, or be limited confounding.
From page 376...
... 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.
From page 377...
... 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.
From page 378...
... 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)
From page 379...
... 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
From page 380...
... * 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.
From page 381...
... 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."
From page 382...
... 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.
From page 383...
... 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.
From page 384...
... • 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.
From page 385...
... 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.
From page 386...
... WCRF/AICR (World Cancer Research Fund/American Institute for Cancer Research)


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