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

University of Nebraska at Omaha, Omaha, Nebraska, United States
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.

    • "Since MOA analysis has focused on the application of mechanistic data in the assessment of specific chemicals, it addresses both toxicokinetics (in species concordance analysis) and metabolism (as a KE) (Boobis et al., 2006Boobis et al., , 2008 Meek, 2008; Meek et al., 2014a,b). Indeed, several highly cited MOA case studies include metabolic activation of the chemical (Meek et al., 2003; Seed et al., 2005) as a KE in the MOA. In contrast, consideration of ADME is not incorporated directly into an AOP description, which is intended to be applicable to any chemical that triggers a given MIE. "
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    ABSTRACT: The number of chemicals for which environmental regulatory decisions are required far exceeds the current capacity for toxicity testing. High throughput screening commonly used for drug discovery has the potential to increase this capacity. The adverse outcome pathway (AOP) concept has emerged as a framework for connecting high throughput toxicity testing (HTT) and other results to potential impacts on humans and wildlife populations. As a result of international efforts, the AOP development process is now well-defined and efforts are underway to broaden the participation through outreach and training. One key principle is that AOPs represent the chemical-agnostic portions of pathways in order to increase the generalizability of their application from early key events to overt toxicity. The closely related mode of action framework extends the AOP as needed when evaluating the potential risk of a specific chemical. This in turn enables Integrated Approaches to Testing and Assessment (IATA), which incorporate results of assays at various levels of biological organization including in silico, HTT, chemical-specific aspects including absorption, distribution, metabolism, and excretion (ADME), and an AOP describing the biological basis of toxicity. It's envisaged, then, that provision of limited information regarding both the AOP for critical effects and the ADME for any chemical associated with any adverse outcome would allow for the development of IATA and permit more detailed AOP and ADME research where a higher precision is needed based on the decision context.
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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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    • "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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    ABSTRACT: Abstract Sulfoxaflor, a novel active substance that targets sap-feeding insects, induced rodent hepatotoxicity when administered at high dietary doses. Specifically, hepatocellular adenomas and carcinomas increased after 18 months in male and female CD-1 mice at 750 and 1250 ppm, respectively, and hepatocellular adenomas increased after 2 years in male F344 rats at 500 ppm. Studies to determine the mode of action (MoA) for these liver tumors were performed in an integrated and prospective manner as part of the standard battery of toxicology studies such that the MoA data were available prior to, or by the time of, the completion of the carcinogenicity studies. Sulfoxaflor is not genotoxic and the MoA data support the following key events in the etiology of the rodent liver tumors: (1) CAR nuclear receptor activation and (2) hepatocellular proliferation. The MoA data were evaluated in a weight of evidence approach using the Bradford Hill criteria for causation and were found to align with dose and temporal concordance, biological plausibility, coherence, strength, consistency, and specificity for a CAR-mediated MoA while excluding other alternate MoAs. The available data include: activation of CAR, Cyp2b induction, hepatocellular hypertrophy and hyperplasia, absence of liver effects in KO mice, absence of proliferation in humanized mice, and exclusion of other possible mechanisms (e.g., genotoxicity, cytotoxicity, AhR, or PPAR activation), and indicate that the identified rodent liver tumor MoA for sulfoxaflor would not occur in humans. In this case, sulfoxaflor is considered not to be a potential human liver carcinogen.
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