Geno Toxicology - GENETIC TOXICOLOGY Dr V. Jagadeesan...

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1 GENETIC TOXICOLOGY Dr V. Jagadeesan Former Deputy Director ( Sr. Gr . ) Food and Drug Toxicol. . Res. Centre . Natl Inst . Nutrition Hyderabad Gad,S.C. : Product Safety Evalution Handbook Concepts in Toxiclogy UH PGDEM Course Materials
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2 BASIC MECHANISMS Genetic toxicology test systems measure the outcome of damage or alterations in DNA , which is the basic blueprint for transmission of hereditary information to daughter cells DNA is damaged , it may: be correctly repaired with no genetic consequences lead to cell death , again with no genetic consequences or be replicated with the damage incorrectly repaired. Only the third consequence leads to mutations , DNA alterations that are propagated thru subsequent generations of cells or individuals During regulatory submissions SCE and UDS are less frequently used since they are indirect tests . Instead other direct tests for gene and chromosome aberrations are more favoured
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3 INTRODUCTION In most developed and developing countries, it has become mandatory to evaluate chemicals, for their mutagenic and carcinogenic potential along with other toxicological effects before their introduction to public. To this effect, many international guidelines are framed to regulate such chemicals.
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4 INTRODUCTION (CONTD) Genetic changes induced by carcinogens include gene mutations , gene amplifications, chromosomal rearrangements, and aneuploidy (change in the number of chromosomes leading to chromosomal abnormalities) The development of cancer requires multiple mutations in proto oncogenes and tumour suppressor genes. Point mutations and chromosomal aberrations have been observed to activate proto oncogenes and inactivate tumour suppressor genes in many cancers. Therefore , chemicals that induce gene mutations, chromosomal aberrations and micronuclei could heritably alter a critical target gene necessary for cancer development.
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5 These observations support the use of short term mutagenicity (genotoxicity) assays in the evaluation of carcinogenic risk of chemicals before the testing by long term animal carcinogenicity testing. WHY GENETIC TOXICOLOGY TESTING?
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6 Gene Mutations About 5000 diseases in humans are now known to be due to defective genes These inherited disorders cause 20% of all infant mortalities 50% of all miscarriages 80% of all cases of mental retardation 100 different cancer genes have also been identified
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7 LIST OF OECD RECOMMENDED SHORT TERM TESTS FOR IDENTIFICATION MUTAGENIC AND CARCINOGENIC RISK TO ANIMALS AND HUMANS (OECD GUIDELINE NO.) (A) TESTS FOR GENE MUTATION 1. Ames salmonella/microsome mutagenicity test (471) 1. Reverse mutation assay in E. Coli ( 472) 1. Mouse Lymphoma cell forward mutation assay (476) 1. Gene mutation assay in S. cerevisiae (480) 1. Drosophila sex linked recessive lethal assay(477) 1. Mouse Spot test (477)
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(B) TESTS FOR CHROMOSOMAL DAMAGE 1. Analysis of chromosomal aberration in CHO cells (473) and
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Geno Toxicology - GENETIC TOXICOLOGY Dr V. Jagadeesan...

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