Recent advances in understanding/assessing toxicity to the epigenome

Area of Science:

• Toxicology
• Genetics
• Epigenetics
• Drug Safety Evaluation

Background:

• Non-genotoxic agents are increasingly recognized for their potential to induce cancer, challenging traditional safety assessment models.
• Current drug safety testing predominantly relies on genetic toxicology assays focused on DNA damage and mutations.
• The evolving pharmaceutical landscape includes biologics and peptides, which may not be adequately assessed by standard genotoxicity tests.

Purpose of the Study:

• To highlight the limitations of existing genetic toxicology testing batteries in detecting non-genotoxic carcinogens.
• To emphasize the need for reassessing safety testing strategies in light of epigenetic mechanisms of carcinogenesis.
• To advocate for the development of new testing paradigms that incorporate epigenetic endpoints for comprehensive risk assessment.

Main Methods:

• Review of existing literature on non-genotoxic carcinogens and epigenetic mechanisms.
• Analysis of the suitability of current genetic toxicology testing batteries for novel therapeutic modalities.
• Discussion of the implications of epigenetic modifications in chemical and biomolecule safety evaluation.

Main Results:

• Documented evidence shows non-genotoxic agents can induce cancer, indicating a gap in current safety testing.
• Standard genetic toxicology tests are insufficient for identifying compounds that exert effects through epigenetic pathways.
• The shift towards biologics and peptides necessitates a broader approach beyond genotoxicity.

Conclusions:

• A fundamental reassessment of environmental and human safety testing is required.
• Existing testing paradigms must be updated to include the evaluation of epigenetic mechanisms.
• Future safety testing must evolve to predict long-term downstream effects mediated by epigenetic changes for both chemicals and biomolecules.