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Toxicological screening

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Toxicological screening

  1. 1. Toxicity studies Dr. S. Parasuraman, M.Pharm., Ph.D., Senior Lecturer, Faculty of Pharmacy AIMST University
  2. 2. Toxicity studies- Introduction • Toxicology is a branch of science that deals with toxins and poisons and their effects and treatment. • Toxicological screening is very important for the development of new drugs and for the extension of the therapeutic potential of existing molecules. • The US-FDA states that it is essential to screen new molecules for pharmacological activity and toxicity potential in animals (21CFR Part 314). • Toxicity tests are mostly used to examine specific adverse events or specific end points such as cancer, cardiotoxicity, and skin/eye irritation. • Toxicity testing also helps calculate the No Observed Adverse Effect Level (NOAEL) dose and is helpful for clinical trails.
  3. 3. History of Toxicity Studies • Paracelsus (Father of Toxicology): determined specific chemicals responsible for the toxicity of plants and animals (dose-response relationship). • "All substances are poisons; there is none which is not a poison. The right dose differentiates a poison and a remedy” – Paracelsus • Mathieu Orfila, determined the relationship between poisons and their biological He is referred to as the father of modern toxicology. Paracelsus (1493-1541) Recent developments: after 1920 (introduced determine LD50 by USFDA )
  4. 4. Sources of toxic substances • Classified based on their – chemical nature – mode of action – class (exposure class and use class) • Exposure class: Food, air, water or soil. • Use class: drugs as drug of abuse, therapeutic drugs, agriculture chemicals, food additives, pesticides, plant toxins and cosmetics.
  5. 5. Biomedical ethics • Before conducting any toxicological testing in animals or collecting tissue/cell lines from animals, the study should be approved by the Institute Animal Ethics Committee (IAEC) or the protocol should satisfy the guidelines of the local governing body. • Malaysia: – http://www.animalethics.org.au/animal-ethics-committees
  6. 6. Toxicity testing methods • Acute toxicity testing • Subchronic toxicity testing (repeated dose =/ >90 day) • Chronic toxicity testing (repeated dose <90 day) • Mutagenicity testing • Carcinogenicity testing • One-generation reproduction toxicity testing • Two-generation reproduction toxicity studies • Developmental toxicity/embryotoxicity studies • Genetic toxicity testing
  7. 7. Acute toxicity studies • Acute toxicity testing- study the effect of a single dose on a particular animal species. • Acute toxicity testing be carried out with two different animal species (one rodent and one non-rodent). • In acute toxicological testing, the investigational product is administered at different dose levels, and the effect is observed for 14 days. All mortalities caused by the investigational product during the experimental period are recorded and morphological, biochemical, pathological, and histological changes in the dead animals are investigated.
  8. 8. Acute toxicity studies • The LD50 was used as an indicator of acute toxicity previously. The determination of the LD50 involves large numbers of animals, and the mortality ratio is high. (24 h testing) – Graphical method – Arithmetical method (karbers’s) method. when number of animal is small) • Because of these limitations, modified methods were developed: 1. The fixed dose procedure 2. The acute toxic category method 3. The up-and-down method Cont.,
  9. 9. Acute toxicity studies • Signs recorded during acute toxicity studies Cont., • Increases motor activity • Decreased motor activity • Tremors and ataxia • Tonic convulsion • Catatonia • loss of righting reflex • Sedation • muscle relaxation • Piloerection/ straub tail phenomenon • Cannibalism • Straub reaction • Hypnosis • Analgesia • Lacrimation • Diarrahoea • Salivation: viscid or watery • Writhing • Respiration: depression, stimulation or failure. • Skin color Piloerection PiloerectionNormal
  10. 10. Sub-acute toxicity studies • Rodents and non-rodents are used to study the subchronic toxicity of a substance. • Dose: Expected therapeutic level (daily) or expected therapeutic level to increasing dose phase-wise manner. • The test substance is administered orally for =/>90 days, and regular body weight variations, biochemical and cardiovascular parameters changes, and behavioral changes are observed. • At the end of the study, the experimental animals are sacrificed. Gross pathological changes are observed, and all the tissues are subjected to histopathological analyses. • There should be little individual variation between the animals, and the allowed weight variation range is ±20%. • Used to determine the maximum tolerable dose and nature of toxicity.
  11. 11. Chronic toxicity studies • Chronic toxicity studies are conducted with a minimum of one rodent and one nonrodent species. • The test compound is administered over more than 90 days, and the animals are observed periodically. • Dose: • A chronic toxicology study provides inferences about the long-term effect of a test substance in animals, and it may be extrapolated to the human safety of the test substance. • The report on chronic oral toxicity is essential for new drug entities. There should be little individual variation between the animals, and the allowable weight variation range is ±20%.
  12. 12. • High dose: Produce significant retardation of growth or some pathological changes (10 times the expected maximum clinical dose). • The low dose is about twice the expected maximum clinical dose • Third dose is (medium dose) fixed midway between the high and low dose Chronic toxicity studies Cont.,
  13. 13. Chronic toxicity studies • During the study period, the animals are observed for normal physiological functions, behavioral variations and alterations in biochemical parameters at regular intervals (atleast every 14 days). At the end of the study, tissues are collected from all parts of the animal and subjected to histological analyses.
  14. 14. Parasuraman S. Toxicological screening. J Pharmacol Pharmacother 2011;2:74-9. Available from: http://www.jpharmacol.com/text.asp?2011/2/2/74/81895
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