Genotoxicity Assessment

Genotoxicity assessment is a key part of safety screening that evaluates the effects of physical and chemical agents on the genetic material (Deoxyribonucleic acid; DNA) and on the genetic processes of living cells. Genotoxicity refers to the ability of harmful substances including chemical, physical, and biological agents to damage genetic information in cells. Being exposed to biological and chemical agents can result in genomic instabilities and epigenetic alterations, which lead to a variety of diseases, including mutation, which ultimately leads to cancer progression.

The National and International regulatory agencies have used genotoxicity data as part of a weight-of-evidence (WOE) approach to assess the potential human carcinogenicity and its corresponding mode of action. The testing patterns and strategies of genotoxic substances are discussed with the purpose of identifying potential human carcinogens, as well as compounds capable of inducing heritable mutations in humans.

Health Impact of Genetic Alterations

Understanding genetic disorders and genetic factors are important in learning more about how the genes and DNA work. Also, preventing disease and promoting health. Some genetic changes have been associated with an increased risk of birth defect or developmental disability and developing diseases such as cancer or heart disease. Most genes we acquire from our parents are in the form of copies that work the same way they do in our parents. But sometimes, a gene is not a perfect copy and these changes in genes are called mutations. Some mutations work better than the original and some mutations cause problems, while many make no difference at all.

A condition that is caused by mutations in a single gene (monogenic) or multiple genes (polygenic) is called a genetic disorder. There is a group of rare diseases caused by mutations in one gene at a time called single-gene disorders. But most common diseases are caused by a combination of gene mutation, environmental factors, and by damage to chromosomes (changes in the number or structure of entire chromosomes. Genotoxicity is often confused with mutagenicity, which refers to the permanent transmissible variations in the amount and structure of genetic materials of cells or organisms that can increase the frequency of mutations. Therefore, genotoxicity encompasses mutagenicity, but not all genotoxic substances are mutagenic in nature, as they may not cause DNA alterations.

Testing Techniques in Genetic Toxicology

Genotoxicity assessment is an indispensable component in the safety assessment of potentially hazardous chemicals, aiming to prevent certain substances from affecting human health and the Environment. Since no single test can detect all relevant genotoxic endpoints, a basic battery of in vivo and in vitro testing techniques for genotoxicity is always recommended. Although the in vitro systems are more welcomed than in vivo systems due to the growing concern for animal welfare as well as reduced cost and high throughput.

At present, various in vitro methods for genetic toxicity assessment are primarily based on bacterial and mammalian cell assays, with several accepted by regulatory authorities. The most applied methods for genotoxicity assessment include the bacterial reverse Mutation test (AMES Test), DNA strand break measurements in cells, and cytogenetic assays designed to detect chemicals that induce genetic damage indirectly or directly by multiple mechanisms. These below assays can detect hazards with respect to damage to DNA and its fixation.

In Vitro Assays:

  • OECD 471: Bacterial Reverse Mutation or Ames Test (Salmonella typhimurium and E. coli test strains)
  • OECD 473: In Vitro Mammalian Chromosomal Aberration Test (Human lymphocytes, CHO, and V79 cells)
  • OECD 487: In Vitro Mammalian Cell Micronucleus Test (Human lymphocytes, CHO, and V79 cells)

In Vivo assays:

  • OECD 474: Mammalian Erythrocyte Micronucleus Test
  • OECD 475: Mammalian Bone Marrow Chromosomic Aberration Test

Genetic toxicology testing in drug discovery and optimization serves to quickly identify mutagens and weed out from further development. Also, genetic toxicology data is often used as a surrogate for long-term carcinogenicity data during early drug development. The field of genetic toxicology is evolving rapidly, and a review of its past and present state will set the stage to allow for consideration in the coming future.

We, at Dabur Research Foundation (DRF), have the expertise to undertake these toxicity studies for Pharmaceuticals, Drug product impurities, Intermediates, Agrochemicals, and Traditional Medicine for its genotoxic potential assessment.