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Health Risks from Dioxin and Related Compounds: Evaluation of the EPA Reassessment B EPA’s 2005 Guidelines for Carcinogen Risk Assessment “CARCINOGENIC TO HUMANS” This descriptor indicates strong evidence of human carcinogenicity. It covers different combinations of evidence. 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 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.
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Health Risks from Dioxin and Related Compounds: Evaluation of the EPA Reassessment “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 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. “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
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Health Risks from Dioxin and Related Compounds: Evaluation of the EPA Reassessment 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; 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. “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.”
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Health Risks from Dioxin and Related Compounds: Evaluation of the EPA Reassessment “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. MULTIPLE DESCRIPTORS More than one descriptor can be used when an agent’s effects differ by dose or exposure route. For example, an agent may be “Carcinogenic to Humans” by one exposure route but “Not Likely to Be Carcinogenic” by a route by which it is not absorbed. Also, an agent could be “Likely to Be Carcinogenic” above a specified dose but “Not Likely to Be Carcinogenic” below that dose because a key event in tumor formation does not occur below that dose.
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