Other Genetic Toxicology Assays

GENETIC TOXICOLOGY SCREENING ASSAYS

Inotiv provides insights through a cost-effective, non-GLP genetic toxicology screening program that is designed to quickly determine the genotoxic potential of your substance. Our approaches include:

• Mini Ames assay (6-Well and Standard Plate)
• Microwell and mini in vitro micronucleus assay with flow cytometric or microscopic analysis
• Mini in vitro chromosome aberration assay
• In vitro high content MultiFlow^® assay for mode of action predictions

Rationale and Strategies for In Vitro Screening Assays

Early identification of potential genotoxic issues with candidate compounds is an essential part of a product development process.

Advantages of Screening Assays:

• Low(er) cost
• Quick turnaround time
• Minimal test article requirements
• Can be highly predictive
• Focus time and resources on most promising candidates
• Facilitate efficient planning for follow-up testing

Selection of Assays

When designing a screening program, various factors need to be considered including: the purpose of the testing (e.g., outcome prediction for GLP assays or investigation of mechanism of action), how the data will be used, the quantity of test article available, cost and timeline.

High Throughput (HTP) Screening Assays

Inotiv provides testing using the MultiFlow^® assay to determine mode of action (MOA) and genotoxicity. This is useful for decision-making regarding continuing compound development.

MultiFlow^® is a high-throughput 96-well assay using human TK6 cells and Litron Laboratory’s MultiFlow^® DNA Damage Kit. The assay relies on a combination of machine learning and global evaluation factor models to predict the clastogenic, aneugenic, or non-genotoxic properties of test articles based on patterns of test article-induced changes in p53, γH2AX, and Phospho-histone H3 biomarkers and polyploidy.

This is accomplished in a single assay, a feature not found in other screening assays. Moreover, the concurrent analysis of these multiple biomarkers avoids the limitations of predictions based on a single assay or biomarker.

Identification of a clastogenic MOA means that the compound is likely DNA reactive with a linear dose response. Since no exposure or, at best, very low exposure is considered safe, further product development may not be advisable.

On the other hand, an aneugenic MOA means that the compound is likely non-DNA reactive and that there may be a threshold response and a margin of safety that allows for the compound to continue in development. A classification of non-genotoxicant could mean the product is safe for further development.

The high through-put design has short turnaround times using a minimal amount of test article. The MOA information can also be used for designing GLP assays in a smarter way to avoid costly and time-consuming follow-up assays.

Genetic Toxicology Screening Assay FAQs:

QSAR IN SILICO MUTAGENICITY PREDICTION

Inotiv offers Quantitative Structure–Activity Relationship (QSAR) as an in silico method for predicting chemical substances causing adverse effects based on their chemical structures. Our expert rule and statistical-based models include:

• Leadscope
• CASE Ultra
• OECD QSAR Toolbox

QSAR involves in silico methods designed to find relationships between chemical structure and biological activity of compounds measured in in vivo and in vitro assays. This tool is a primary step in lead candidate selection and is useful in pharmaceutical development, agricultural and industrial chemical assessment, and impurity analysis. QSAR models include those for bacterial mutagenicity models for ICH M7 guidelines, carcinogenesis, and various types of organ-specific toxicities. Since in silico analyses do not require synthesis of the chemical of interest, they provide a cost and time effective approach to early screening.

CELL TRANSFORMATION AND CYTOTOXICITY ASSAYS