TABLE II.

Session 2 SWOT Analyses: Biomarkers of Epigenetic Changes and their Applicability to Genetic Toxicology

Test/System	Strengths	Weaknesses	Opportunities	Threats
Epigenetic control of cell phenotype	Assay is predictive of chemical exposures, including genotoxins. Analysis of RNA modification spectra provides insights into mechanisms of toxicity. Possible complementation to transcriptional and proteomic data for identifying genotoxic and nongenotoxic carcinogens. Relatively straightforward method for practitioners of analytical chemistry.	Analysis of RNA modification spectra in very early stages of development. Very limited data for toxicants. Relatively specialized method at this point. Probably not entirely predictive of carcinogenicity of a chemical or drug candi- date. Interlaboratory validation will be needed.	Possible coordination of RNA modification analysis with other ‘omic data sets. Application to in vitro screening for hazard assessment. Provides insights into mechanisms of action of toxicants. Possible biomarkers that are specific for non-genotoxic carcinogens. Allow distinction between genotoxic and nongenotoxic carcinogens.	Analysis of RNA modification reprogramming is in the earliest stages of scientific acceptance and application. Translation to a high- throughput method. Relating RNA modification patterns to specific toxicities.
Epigenetics	Provides comprehensive view of modifications or changes that may precede events that lead to phenotypic change or toxicity. Rich biomarker resource. Potential for assessment of species-specific responses in vivo and in vitro.	Large and complex datasets; need for customized bioinformatic tools. Huge number of changes observed many possible. mechanisms/outcomes High probability for nonspecific or irrelevant responses. Distinguishing stress responses from chemical- specific responses.	Biomarkers for use in acute and subchronic toxicity studies. Early prediction of genotoxic risk; inform or replace 2-year bioassay. Drug-induced vs. non-drug- induced tumors. Provide or support carcinogen mode-of-action determinations. May allow identification of pre- neoplastic changes.	Tremendous complexity with possibility of compound- specific effects rather than class-effects amenable to generalized biomarkers generation. Translation of findings from preclinical models/results to humans.
Epigenetic traits as biomarkers of carcinogenesis	Early appearance of epigenetic carcinogen-alterations. Target tissue specificity. Specificity for genotoxic and nongenotoxic carcinogens.	Cellular epigenome individual and dynamic variability not completely characterized. Models for safety assessment not yet developed. Endpoints and techniques for use in safety assessment not established. Interlaboratory reproducibility not determined.	Early prediction and identification of hazardous compounds before their dissemination into environment. Provide or support carcinogen mode-of-action determinations.	Complexity of cellular epi- genomic landscape and epigenetic regulatory mechanisms. Correlating epigenomic changes between test animal species and humans.
MicroRNA analysis with lentivirus platform	This analysis provides data to progress towards more clinically relevant therapeutic applications. The lentivirus system used is commercially available and serves as a proof-of- concept to move forward.	Lentivirus platform explored may not be the best plat- form for human patient delivery.	Provides background for developing and evaluating better and more clinically relevant miRNA delivery mechanisms.	Lack of approval for use of lentivirus in humans for ethical reasons. Advancement of better, clinically relevant delivery agents needed. Multiple companies on board with the development phase. Patent protection and confidentiality agreements limit access.