Abstract
An approach to systematically describe the uncertainties and complexity of the standard animal testing and assessment approach for carcinogenicity is explored by using a OECD Guidance Document that was originally developed for reporting defined in vitro approaches to testing and assessment. The format is suitable for this re-purposing and it appears that the potential multitude of approaches for integrating and interpreting data from standard animal testing may ultimately be conceptually similar to the challenge of integrating relevant in vitro and in silico data. This structured approach shall allow 1) fostering interest in developing improved defined in silico and in vitro approaches; 2) the definition of what type of effects should be predicted by the new approach; 3) selection of the most suitable reference data and assessments; 4) definition of the weight that the standard animal reference data should have compared to human reference data and mechanistic information in the context of assessing the fitness of the new in vitro and in silico approach; 5) definition of a benchmark for the minimum performance of the new approach, based on a conceptual recognition that correlation of alternative assessment results with reference animal results is limited by the uncertainties and complexity of the latter. A longer term perspective is indicated for evolving the definition of adversity for classification and regulatory purposes. This work will be further discussed and developed within the OECD expert group on non-genotoxic carcinogenicity IATA development.
Highlights
1.1 History of the rodent cancer bioassay Experimental carcinogenesis was initiated in the first part of the 20th century, when Yamagiwa and Ichikawa first developed an experimental model to study the pathogenesis of carcinoma and used it to confirm the causal effect between exposure and cancer (Yamagiwa and Ichikawa, 1918)
Are genotoxic chemicals more likely to show multiple site carcinogenicity? How much do we lose of the value added of the carcinogenicity study if we require multiple strains, species, multiple studies, multiple site neoplasms, rare neoplasms seen for species being tested? (And when developing new in vitro NGTxC IATAs – should we focus on reference chemicals showing these multiple effect characteristics? (Gray et al, 1995))
Do non-monotonic dose-response (NMDR) relationships exist and would they be identified by the rodent carcinogenicity bioassay (RCB)? Reproducible NMDRs may be observed with non-monotonic kinetics, e.g., if uptake is reduced due to agglomeration at high concentrations; or if at higher concentrations high cytotoxicity or general toxicity covers the more specific effects; or where more than one mechanism operates at differing dose levels resulting in the same mode of action of the endpoint being affected due to different mechanisms within that MoA; or due to experimental variability in the low dose range
Summary
Uncertainties of Testing Methods: What Do We (Want to) Know About Carcinogenicity?. Summary An approach to systematically describe the uncertainties and complexity of the standard animal testing and assessment approach for carcinogenicity is explored by using a OECD Guidance Document that was originally developed for reporting defined in vitro approaches to testing and assessment. The format is suitable for this re-purposing and it appears that the potential multitude of approaches for integrating and interpreting data from standard animal testing may be conceptually similar to the challenge of integrating relevant in vitro and in silico data This structured approach shall allow 1) fostering interest in developing improved defined in silico and in vitro approaches; 2) the definition of what type of effects should be predicted by the new approach; 3) selection of the most suitable reference data and assessments; 4) definition of the weight that the standard animal reference data should have compared to human reference data and mechanistic information in the context of assessing the fitness of the new in vitro and in silico approach; 5) definition of a benchmark for the minimum performance of the new approach, based on a conceptual recognition that correlation of alternative assessment results with reference animal results is limited by the uncertainties and complexity of the latter.
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