A Framework for Human Relevance Analysis of Information on Carcinogenic Modes of Action

Health Canada, Ottawa, Ontario, Canada.
Critical Reviews in Toxicology (Impact Factor: 5.1). 02/2003; 33(6):591-653. DOI: 10.1080/713608373
Source: PubMed


The human relevance framework (HRF) outlines a four-part process, beginning with data on the mode of action (MOA) in laboratory animals, for evaluating the human relevance of animal tumors. Drawing on U.S. EPA and IPCS proposals for animal MOA analysis, the HRF expands those analyses to include a systematic evaluation of comparability, or lack of comparability, between the postulated animal MOA and related information from human data sources. The HRF evolved through a series of case studies representing several different MOAs. HRF analyses produced divergent outcomes, some leading to complete risk assessment and others discontinuing the process, according to the data available from animal and human sources. Two case examples call for complete risk assessments. One is the default: When data are insufficient to confidently postulate a MOA for test animals, the animal tumor data are presumed to be relevant for risk assessment and a complete risk assessment is necessary. The other is the product of a data-based finding that the animal MOA is relevant to humans. For the specific MOA and endpoint combinations studied for this article, full risk assessments are necessary for potentially relevant MOAs involving cytotoxicity and cell proliferation in animals and humans (Case Study 6, chloroform) and formation of urinary-tract calculi (Case Study 7, melamine). In other circumstances, when data-based findings for the chemical and endpoint combination studied indicate that the tumor-related animal MOA is unlikely to have a human counterpart, there is little reason to continue the risk assessment for that combination. Similarly, when qualitative considerations identify MOAs specific to the test species or quantitative considerations indicate that the animal MOA is unlikely to occur in humans, such hazard findings are generally conclusive and further risk assessment is not necessary for the endpoint-MOA combination under study. Case examples include a tumor-related protein specific to test animals (Case Study 3, d-limonene), the tumor consequences of hormone suppression typical of laboratory animals but not humans (Case Study 4, atrazine), and chemical-related enhanced hormone clearance rates in animals relative to humans (Case Study 5, phenobarbital). The human relevance analysis is highly specific for the chemical-MOA-tissue-endpoint combination under analysis in any particular case: different tissues, different endpoints, or alternative MOAs for a given chemical may result in different human relevance findings. By providing a systematic approach to using MOA data, the HRF offers a new tool for the scientific community's overall effort to enhance the predictive power, reliability and transparency of cancer risk assessment.

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    • "The two-year rat carcinogenicity bioassay, as outlined in the International Conference on Harmonization guidance documents (ICH S1, S2, S3), is used in conjunction with other assays to determine the carcinogenicity potential of compounds. Human patient safety risk (if any) is determined based on the human relevance framework [9] [10] [11]. This framework leverages two concepts to determine a statement of confidence regarding patient safety risk: (1) is the weight of evidence sufficient to establish the mode of action (MOA) in animals and (2) is the MOA plausible in humans. "
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    ABSTRACT: Ticagrelor is an orally available, direct acting and reversible P2Y12 receptor antagonist approved for treatment of acute coronary syndrome. The objectives of these studies were to 1) evaluate the Ticagrelor 2-year rat carcinogenicity bioassay data 2) investigate potential mode of action (MOA) and 3) interpret human relevance.
    Toxicology Reports 11/2014; 1. DOI:10.1016/j.toxrep.2014.11.010
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    • "This HRF evaluation for sulfoxafl or-induced hepatocellular tumors in mice and rats follows the guideline established for this process (Sonich-Mullin et al. 2001, Cohen et al. 2003, Meek et al. 2003, USEPA 2005, Holsapple et al. 2006, Boobis et al. 2006). The extensive toxicological database for sulfoxafl or, including several focused MoA studies in both mice and rats, as well as a study in genetically engineered (knockout and humanized) mice provide the necessary data to establish the CAR-mediated MoA for sulfoxafl or-induced rodent liver tumors. "
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    Critical Reviews in Toxicology 05/2014; 44 Suppl 2(S2):15-24. DOI:10.3109/10408444.2014.910751 · 5.10 Impact Factor
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    • "a mutagenic (linear at low dose) or a threshold (not linear at low dose) MOA, or to ''consider the respective contribution of each mode of action in different dose ranges.'' The MOA framework within the cancer risk assessment guidelines of the US Environmental Protection Agency (2005) is built in part on the work of Meek et al. (2003). In accordance with these guidelines, we consider whether each hypothesized MOA is sufficiently supported by the existing human or experimental animal data, and whether the available evidence suggests these MOAs are relevant to humans. "
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    ABSTRACT: 1,4-Dioxane is found in consumer products and is used as a solvent in manufacturing. Studies in rodents show liver tumors to be consistently reported after chronic oral exposure. However, there were differences in the reporting of non-neoplastic lesions in the livers of rats and mice. In order to clarify these differences, a reread of mouse liver slides from the 1978 NCI bioassay on 1,4-dioxane in drinking water was conducted. This reread clearly identified dose-related non-neoplastic changes in the liver; specifically, a dose-related increase in the hypertrophic response of hepatocytes, followed by necrosis, inflammation and hyperplastic hepatocellular foci. 1,4-Dioxane does not cause point mutations, DNA repair, or initiation. However, it appears to promote tumors and stimulate DNA synthesis. Using EPA Guidelines (2005), the weight of the evidence suggests that 1,4-dioxane causes liver tumors in rats and mice through cytotoxicity followed by regenerative hyperplasia. Specific key events in this mode of action are identified. A Reference Dose (RfD) of 0.05 mg/kg-day is proposed to protect against regenerative liver hyperplasia based on a benchmark dose (BMD) approach. Based on this RfD, a Maximum Contaminant Level Goal of 350 μg/L is proposed using a default relative source contribution for water of 20%.
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