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Module 8-Hazard Characterization

Terms in this set (11)

IN HUMANS
Sufficient evidence of carcinogenicity -"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."
Limited evidence of carcinogenicity -"A positive association has been observed between exposure to the agent and cancer for which causal interpretation is considered by the Working Group to be credible, but chance, bias or confounding could not be ruled out.
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."
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

IN ANIMALS:
Sufficient evidence of carcinogenicity -"... 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 tumors 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 tumor or age at onset, or when there are strong findings of tumors at multiple sites."
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 is restricted to studies that demonstrate only promoting activity in a narrow range of tissues or organs."
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 is available."
Evidence suggesting a 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.
Carcinogenic to Humans -"This descriptor is appropriate when there is convincing epidemiologic evidence of a causal association between human exposure and cancer. Exceptionally, this descriptor may be equally appropriate with lesser weight of epidemiologic evidence that is strengthened by other lines of evidence. It can be used when all of the following are met:
•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.
•There is extensive evidence of carcinogenicity in animals
•The mode of carcinogenic action and associated key precursor events have been identified in animals
•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 upon all biological information
Likely to be carcinogenic to humans -" ... when the weight of evidence is adequate to demonstrate carcinogenic potential to humans but does not reach the weight of evidence for the descriptor "Carcinogenic to Humans."
•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 early age at onset.
•A rare tumor response in a single experiment that is assumed to be relevant to humans.
•A positive tumor study that is strengthened by other lines of evidence, for example, a plausible but not definitively causal association in humans or evidence that the agent causes events generally known to be associated with cancer.
Suggestive evidence of carcinogenic potential -when evidence is suggestive of carcinogenicity but the data are not sufficient for a stronger conclusion.
•A small and possibly not statistically significant increase in tumor incidence observed in a single animal or human study. The study would generally not be contradicted by other studies of equal quality in the same population group or experimental system.
•Evidence of a positive response in a study whose power, design, or conduct limits the ability to draw a confident conclusion.
•A significant response at one dose only, but no significant response at other doses and no trend.
Inadequate Information to Assess Carcinogenic Potential -when data are judged to be inadequate for applying one of the other descriptors.
Examples include little or no pertinent information
•Conflicting information -some studies provide evidence but other studies of equal quality in the same sex and strain are negative. Differing results in different experimental systems do not constitute conflicting evidence as the term is used here.
•Negative results that are not sufficiently robust for the descriptor "Not Likely to Be Carcinogenic to Humans."
Not Likely to be Carcinogenic to Humans -Appropriate when available data are considered robust for deciding that there is no basis for human hazard concern. Examples include:
•Animal evidence for a lack of carcinogenicity in both sexes in well designed and conducted studies in at least two appropriate animal species.
•There is convincing and extensive evidence showing that the only carcinogenic effects observed in animals are not relevant to humans.
From EPA Guidelines for Carcinogen Risk Assessment:
Consistency of the observed association -The pattern of elevated risk is observed across several independent studies
Strength of the observed association -The finding of large risks increases confidence that the association is not likely due to chance, bias, or other factors. A modest risk does not preclude a causal association and may reflect a lower level of exposure, an agent of lower potency, or a common disease with a high background level.
Specificity of the observed association -Originally intended to refer to causality if one cause is associated with a single disease or effect. For cancer (with multiple causes and sites), this is now considered one of the weaker guidelines.
Temporal relationship of the observed association-Causal interpretation is strengthened when exposure is known to precede the disease. For cancer, latency must be considered. This is one of the strongest criteria for inference of causality
Biological gradient (exposure-response relationship) -A clear exposure-response relationship (e.g., increasing effects associated with greater exposure) strongly suggests cause and effect, especially when such relationships are also observed for the duration of exposure. This relationship may be difficult to detect in an epidemiologic study for several reasons, and the absence of an exposure-response relationship does not exclude a causal relationship
Biological plausibility -Inference of causality is strengthened by consistency with data from experimental studies or other sources demonstrating plausible biological mechanisms. A lack of mechanistic data is not a reason to reject causality, however.
Coherence -Inference of causality is strengthened by other lines of evidence that support a cause-and-effect relationship interpretation of the association, e.g., information from animal bioassays, toxicokinetic studies, and short-term studies.
Experimental evidence (from human populations)-Strong evidence for causality can be provided when a change in exposure brings about a change in disease frequency.
Analogy-SARs and information on the agent's structural analogues can provide insight whether a relationship is causal. Information on mode of action can also inform decisions on causality