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animal toxicity studies


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animal toxicolgy studies

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animal toxicity studies

  1. 1. ANIMAL TOXICITY STUDIES Dr.k.vishnuvardhan babu
  2. 2. Why study toxicology??? Benefit –risk ratio can be calculated Prediction of therapeutic index Therapeutic index= Maximum tolerated dose Minimum curative dose Smaller ratio, better safety of the drug
  3. 3. why do we require non clinical studies IN ANIMALS before ADMINISTERED to man??  Pharmacological effects are same in man as in animals  Toxic effect in species will predict adverse effects in man  Giving high doses in animals improves predictability to man  Risk assessment can be made by comparison of toxic doses in test species with predicted therapeutic dose in man
  4. 4. Relevant Test Models  Pharmacodynamic responses  Pharmacokinetic profile  Species, sex, age of experimental animals  Susceptibility, sensitivity and reproducibility of test system  In vitro: Isolated organs, tissues cell-cultures  Mechanism of effect in vivo
  5. 5. Types of toxicology studies Systemic toxicology studies Single dose studies Repeated dose studies Reproductive toxicology studies Male fertility Female reproduction & Developmental studies Local toxicity studies Hypersensitivity studies Genotoxicity studies Carcinogenicity studies
  6. 6. A. Systemic toxicology studies Preliminary Definitive • Maximum Non Lethal dose (MNLD) determined • MTD and MLD determined • Evaluate effects • Target organ of toxicity may be determined a) SINGLE DOSE STUDIES/ ACUTE TOXICITY
  7. 7. Preliminary studies METHOD  Single dose tested in 2 rodent species  2 routes of administration  Oral dosing of 2g/kg or 10 times of normal human dose  Observation for 14 days after dosing  MNLD established  Symptoms , signs reported  Microscopic and Macroscopic evaluation
  8. 8. Definitive studies METHOD  Group of 20 animals of either sex dosed at MNLD  5 animals of each sex are observed for 48 hr and conduct autopsy for early pathological changes  Remaining 5 of each sex are observed for 14 days  MTD and MLD established  Signs of intoxication or recovery, changes in body weight, pathological changes  Complete macroscopic and microscopic examination  Target organs can be identified
  9. 9.  Two mammalian species(one should be non-rodent)  Long duration studies (30-180 days)  Dose is dependent on dose-escalating studies  Drug administered by clinical route  Parameters monitored and recorded are:  Behavioral  Physiological  Biochemical  Microscopic observations b) REPEATED DOSE STUDIES/SUB-ACUTE OR CHRONIC TOXICITY
  10. 10. Chronic toxicity  Objectives  To evaluate the cumulative toxicity of chemicals.  To assess carcinogenic potential.  Duration Rodents - 6 to 24 months; non-rodents - 12 months or longer or up to 15 to 20% of species’ lifespan.  Test System/Animal System 2 species required. Rodents, non rodents.  Parameters  Mortality  Pathology and histopathology  Weight change  Clinical pathology of all animals (mortalities and survivors)
  11. 11. B. Reproductive toxicology studies a) MALE FERTILITY METHOD One rodent species(rat) 3 dose groups taken (each with 6 adult males), 1 control Drug treatment by clinical route for 28-72 days
  12. 12. Mated with females in 1:2 ratio Females getting pregnant should be examined After 13 days of gestation All male animals sacrificed •Weights of testis, epididymus recorded & examined for their histology •Sperms examined for motility & morphology
  13. 13. Segment I 13 Fertility and general reproductive performance study Segment II Teratogenicity Segment III Perinatal and post-natal study Fertility and early embryonic development (rat) Embryo- foetal development (rat & rabbit) Post natal development (rat) (post natal survival of offspring), growth parameters, vital senses, behavioral effects b) FEMALE FETILITY Drug administered to both males (28days) and females (14 days) before mating Implantation Embryogenesis
  14. 14. C. Local toxicity studies  Required when drug is administered by special route (other than oral) in humans  Study design:  2 species along with control used  Dose dependent on dose escalating studies  3 dose levels
  15. 15. Types of local toxicity studies Dermal toxicity studies  Dermal photo-toxicity studies Vaginal toxicity studies Rectal tolerance studies Rats & Rabbit Local signs (erythema, oedema), histological examination Guinea pig Used in treatment of leucoderma Examination of erythema & oedema formation Rabbit or Dog Observation of swelling, histopathology of vaginal wall Rabbit or Dog Signs of pain, blood or mucous, histology examination of rectal mucosa
  16. 16. Ocular toxicity studies Parenteral drugs Inhalation toxicity studies Albino Rabbit Changes in cornea ,Iris & aqueous humor, histological examination of eye For intravenous/ intramuscular/ subcutaneous/ intra-dermal injection Sites of injection examined grossly and microscopically One rodent and non rodent species Acute , sub-acute and chronic studies performed Observation of respiratory rate Histological examination of respiratory passages, lung tissue
  17. 17. D. Allergenicity/hypersensitivity toxicology studies Guinea Pig Maximization test Local lymph node assay Determination of Maximum non irritant or minimum irritant dose Evaluation of Erythema and oedema Mice of one sex(either male or female) Drug treatment given on ear skin Auricular lymph node dissection after 5 days Increase in 3h-thymidine used for evaluation
  18. 18. E. Genotoxicity studies To detect early tumorigenic effects in cases of chronic illness In vitro tests: Test for gene mutation in Bacteria Cytogenetic evaluation of chromosomal damage in mammalian cells E.g.; Ames’s Salmonella Assay detects increased number of aberrations in metaphase chromosomes DNA strand breaks, DNA repair or recombination, Measurements of DNA adductsIn vivo tests: Chromosome damage in rodent hematopoietic cells E.g.; Micronucleus Assay
  19. 19. f. Carcinogenicity/ oncogenicity studies Life-time Bioassays Carcinogenicity studies are performed on: Drug used for >6 months or frequent intermittent use for chronic diseases Chemical structure of drug indicates carcinogenic potential Therapeutic class of drugs which have produced positive carcinogenicity
  20. 20. Group sizes of 50 animals/sex at each of 3 dose levels Control group is of double size Record for onset of tumor development Usually carried out for 24 months in rats and 18 months in mice (life span studies) CONDUCT OF STUDY
  21. 21. EVALUATION OF RESULT Incidence of cancers in control and test  Trend towards increasing incidence with increasing doses Number of animals with single/multiple tumors Macroscopic changes observed by autopsy  Histopathology of organs and tissues
  22. 22. Thank you