TABLE I.

Session 1 SWOT Analyses: Alternative Experimental Models to Improve Genetic Toxicity Testing

Test/system	Strengths	Weaknesses	Opportunities	Threats
Three- Dimensional Tissue Constructs	Closer (than 2-D) to “in vivo” conditions. Technology is well- developed and 3-D models are commercially available. Cells are of human origin and function more organ- like in terms of cell viability, proliferation, differentiation, morphology, gene and protein expression. Large interest in assay, used by increasing number of laboratories in various locations. (Pre)validation exercise ongoing for 3-D skin.	More difficult to handle than 2-D. High throughput possible only for low-complexity models. Various levels of supporting data available, minimal to moderate. Used in limited number of labortories. Some models in early stage of development. Validation is needed for most models. Cost.	3-D constructs have the potential to serve as follow-up assays based on results in the traditional 2- D tests, especially when 2-D models cannot be used. Collaborative efforts recommended for relevant tissues for which such efforts are not currently ongoing (liver, lung). May be useful to bridge gap between in vitro and in vivo for quantitative risk assessment.	Validation of methods is very resource intense. Limited availability of tissue constructs. Potential issues with patents.
Stem cell-derived hepatocytes	Theoretically unlimited supply of human hepatocytes. Use of hepatocytes with different genetic back- grounds. Use of hepatocytes from patients suffering specific diseases. Simultaneous analysis of multiple drug metabolism cascade in one cell.	Complexity of differentiation process of stem cells into hepatocytes. Low reproducibility of differentiation process. Interlaboratory reproducibility needs to be defined. Early stage of development. Cost.	Replacement of human primary hepatocytes. Replacement/reduction of animal toxicity testing. Improvement of hepatotoxicity prediction. Evaluation of hepatotoxicity, prediction of metabolites, of induction of drug metabolism-related enzymes, and of drug- drug interaction. Supply of metabolites for other testing.	Complexity of differentiation process. Requirements of higher maturation of hepatocyte activities. Establishment of standards for hepatocyte qualification. Hepatocyte progenitor cell line: HepaRG. Ethical and regulatory issues if from human origin.
Humanized animal models	Allows for better characterization of human hazard and risk potential. Relevant to humans. Provides data on mode/ mechanism of action. Allows comparison of rodent vs. human metabolism and toxicity pathways.	Involves animal use. Expensive to create and maintain. Low-throughput. Models human gene product in mouse environment.	Refinement of hazard and risk assessments: decreased uncertainty increased human relevance New technologies are decreasing the cost and expanding the model species. Can be used to further define “toxicity pathways” thereby facilitating development of in vitro assays based on MoA. Can be used to validate in vitro hypotheses.	Models not widely available. Models using different technologies may generate different results. Lack of acceptance of this technology for advancing human health risk assessments.