Principles of toxicology -II-SAURABH DUBEY

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PRINCIPLES OF TOXICOLOGY:

PRINCIPLES OF TOXICOLOGY R.Vadivelan M.Pharm (PhD) Assistant Professor Department of Pharmacology JSS College of Pharmacy, Ooty 1

OUTLINE:

OUTLINE Definition of poison General principles of treatment of poisoning. Heavy metals and heavy metal antagonists. Definition for acute, sub acute and chronic toxicity, genotoxicity, carcinogenicity, teratogenicity and mutagenicity studies 2

Definition for Acute, sub acute and chronic toxicity, Genotoxicity, Carcinogenicity, Teratogenicity and Mutagenicity studies :

Definition for Acute, sub acute and chronic toxicity, Genotoxicity, Carcinogenicity, Teratogenicity and Mutagenicity studies 3

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Acute toxicity study (OECD 401,402,420,423,425) Skin irritation/eye irritation (OECD 404/405) Sensibilization by skin contact (OECD 406) Sub acute toxicity study(14 or 28 days) (OECD 407) Sub chronic toxicity study (90 days rodent) (OECD 408/409) Chronic toxicity study (2 yr rodent) (OECD 452) Carcinogenicity study (OECD 453) Genotoxicity studies (OECD 471-486) Developmental toxicity (OECD 414) Reproduction toxicity (OECD 415,416) Neurotoxicity (OECD 424) Delayed neurotoxicity (OECD 418, 419) Developmental neurotoxicity (OECD 426) Toxicokinetic studies(ADME) (OECD 417) OVERVIEW OF TOXICITY STUDIES 4

ACUTE TOXICITY :

ACUTE TOXICITY It describes the adverse effects of a substance which result either from a single exposure or from multiple exposures in a short space of time (usually less than 24 hours). To be described as acute toxicity, the adverse effects should occur within 14 days of the administration of the substance. Acute toxicity is distinguished from chronic toxicity , which describes the adverse health effects from repeated exposures, often at lower levels, to a substance over a longer time period ( months or years).

ACUTE ORAL TOXICITY-GENERAL SET UP:

ACUTE ORAL TOXICITY-GENERAL SET UP Introduction with purpose of the test Description of test procedure Principle of the test Preparations Experimental animals Selection of species Number and sex Housing and feeding conditions Testing conditions Dose levels ,Limit test Observation period Procedure Clinical examinations Pathology Assessment of toxicity in other sex Data and reporting Treatment of results Evaluation of report Test report 6

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S.No . Parameters 0 min 30 hour 1 hour 2 hour 4 hour 24 hour 1 Hyperactivity 2 Piloerection 3 Twitching 4 Rigidity 5 Irritability 6 Jumping 7 Clonic convulsions 8 Tonic convulsion 9 Ptosis 10 Sedation 11 Sleep(Loss of R.R) 12 Loss of traction 13 Loss of pinna reflex 14 Catatonia 15 Ataxia 16 Loss of muscle tone 17 Analgesia 18 Straub’s tail 19 Labored respiration 20 Cyanosis 21 Blanching 22 Reddening 23 Abnormal secretion 24 Death 7

Subacute toxicity:

Subacute toxicity This tests are usually carried out for at least the amount of time proposed for human application, that is for 2-4 weeks.

28 DAYS REPEATED ORAL TOXICITY (OECD 407):

28 DAYS REPEATED ORAL TOXICITY (OECD 407)

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PURPOSE OF THE STUDY In the assessment and evaluation of the toxic characteristics of a chemical, the determination of oral toxicity using repeated doses may be carried out after initial information on toxicity has been obtained by acute testing. PRINCIPLE OF THE STUDY The test substance is orally administered daily in graduated doses to several groups of experimental animals, one dose level per group for a period of 28 days. During the period of administration the animals are observed closely, each day for signs of toxicity. Animals which die or are killed during the test are necropsied and at the conclusion of the test surviving animals are killed and necropsied.

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DETAILS OECD-407 1. Age of animals After weaning not more than 8 weeks. 2. Acclimatization At least 5 days 3. No. of animals 10/sex/group 4. Body weight range ± 20% of the mean weight 5. No. of groups At least 2dose group 1 control/vehicle, 1 high dose recovery group 6. Recovery period Not less than 28 days 7.Clinical observations Once a day 8.Physical examination Not mentioned 9. Body weight, Feed, Water Weekly 10. Functional observation Not mentioned 11. Haematology 1. Haemotocrit 2. Red Blood Corpuscles 3. Haemoglobin 4. White Blood Corpuscles 5. Differential Leucocyte Count 6. Clotting time 7. Prothrombine time 8. Thromboplastine time 9. Platelet Count 28-DAYS TOXICITY STUDY 11

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12 Clinical Chemistry 1Potassium (k), 2. Sodium (Na) 3. Fasting Glucose 4. Total cholestrol 5. Creatinine 6. Total Protein 7. Albumin 8. Alanine aminotransferase, 9 Aspartate aminotransferase, 10Alkaline phosphatase, 11gamma glutamyl transpeptidase 12 sorbitol dehydrogenase. 13. Potassium 14. Calcium 15. Total bilirubine Optional: 16. Cholinesterase 17. Methaemoglobin 18. Lipids, Hormones, acid/base balance 13. Organ weights 1. Liver 2. Kidneys 3. Adrenals 4. Testes 5. Ovaries 12

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14. Tissue collection Digestive system: 1. Salivary glands 2. Oesophagus 3. Stomach 4. Duodenum 5. Jejunum 6. Ileum 7. Caecum 8. Colon 9. Rectum 10. Liver 11. Pancreas 12. Gallbladder (when present) 13. Brain (Medulla/Pons, Cerebellum, Cerebrum) 14. Pituitary 15. Peripheral nerve (Sciatic/ tibial) 16. Spinal cord (Three levels) 17. Eyes (Retina optic nerve) Glandular system: 18. Adrenals 19. Parathyroid 20. Thyroid Respiratory system: 21. Trachea 22. Lungs 23. Pharynx 24. Larynx 25. Nose 13

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15. Tissue collection contd. Cardiovascular/ hemopoietic system: 26 . Aorta 27. Heart 28. Bone marrow 29. Lymph nodes 30. Spleen 31. Thymus Urogenital system: 32. Kidneys, 33. Urinary bladder 34. Prostate 35. Testes 36. Epididymises 37. Seminal vesicle(s) 38. Uterus 39. Ovaries 40. Female mammary glands Others : All gross lesions & Masses skin 16. Histopathology Gross lesions Control & high dose Lungs in low and mid dose Liver & Kidney in low and mid dose 14

CHRONIC TOXICITY:

CHRONIC TOXICITY Chronic toxicity is a property of a substance that has toxic effects on a living organism , when that organism is exposed to the substance. Adverse effects resulting from repeated doses of or exposures t o a substance over a long period of time. Chronic toxicity is the ability of a substance or mixture of substances to cause harmful effects over an extended period, usually upon repeated or continuous exposure, sometimes lasting for the entire life of the exposed organism.

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90-DAYS REPEATED DOSE 90-DAY ORAL TOXICITY STUDY IN RODENTS

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PURPOSE OF THE TEST It provides information on the possible health hazards likely to arise repeated exposure over a prolonged period of time . The study will provide information on the major toxic effects, indicate target organs and the possibility of accumulation, and can provide an estimate of a NOAEL of exposure which can be used in selecting dose levels for chronic studies and for establishing safety criteria for human exposure. PRINCIPLE OF THE TEST The test substance is orally administered daily in graduated doses to several groups of experimental animals, one dose level per group for a period of 90 days. During the period of administration the animals are observed closely for signs of toxicity. Animals which die or are killed during the test are necropsied and, at the conclusion of the test, surviving animals are also killed and necropsied.

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DETAILS OECD-408 (12.05.1981) 1. Age of animals After weaning not more than 9 weeks. 2. Acclimatization At least 5 days 3. No. of animals 20 animals (10 male 10 female) 4. Body weight range ± 20% of the mean weight 5. No. of groups At least 3dose group 1 control/vehicle, 1 high dose recovery group , concurrent control 7.Clinical observations Once a day 8.Physical examination Not mentioned 9. Body weight, Feed, Water Weekly 10. Functional observation Not mentioned 12. Haematology 1. Haemotocrit 2 . Haemoglobin concentration 3 .Erythrocyte count 4.Total and differential leukocyte count 5.Platelet count 6.Blood clotting time 90-DAYS TOXICITY STUDY 18

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13. Clinical Chemistry 1. Potassium (k),2. Sodium (Na) 3. Fasting Glucose 4. Blood Urea Nitrogen 5. Creatinine 6. Total Protein 7. Albumin 8. Aspartate aminotransferase 9. Alanine aminotransferase 10. Gamma Glutamyl ranspeptidase 11.Sorbitol dehydrogenase 12. Potassium 13. Calcium 14. Total bilirubine Optional: 15. Cholinesterase 16. Methaemoglobin 14. Urinalysis Optional 15. Organ weights 1. Liver 2. Kidneys 3. Adrenals 4. Testes 5. Ovaries 19

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16. Tissue collection Digestive system: 1. Salivary glands 2. Oesophagus 3. Stomach 4. Duodenum 5. Jejunum 6. Ileum 7. Cecum 8. Colon 9. Rectum 10. Liver 11. Pancreas 12. Gallbladder (when present) 13. Brain (Medulla/Pons, Cerebellum, Cerebrum) 14. Pituitary 15. Peripheral nerve (Sciatic/ tibial) 16. Spinal cord (Three levels) 17. Eyes (Retina optic nerve) Glandular system: 18. Adrenals 19. Parathyroid 20. Thyroid Respiratory system: 21. Trachea 22. Lungs 23. Pharynx 24. Larynx 25. Nose 20

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16. Tissue collection contd. Cardiovascular/ hemopoietic system: 26. Aorta 27. Heart 28. Bone marrow 29. Lymph nodes 30. Spleen 31. Thymus Urogenital system: 32. Kidneys, 33. Urinary bladder 34. Prostate 35. Testes 36. Epididymises 37. Seminal vesicle(s) 38. Uterus 39. Ovaries 40. Female mammary glands Others : All gross lesions & Masses skin 17. Histopathology Gross lesions Control & high dose Lungs in low and mid dose Liver & Kidney in low and mid dose 21

GENOTOXICITY:

GENOTOXICITY [ Latin geno-, gene (from greek genos, race, offspring ; + toxin.] Genotoxicity describes a deleterious action on a cell's genetic material affecting its integrity. Genotoxic substances are known to be potentially mutagenic or carcinogenic, specifically those capable of causing genetic mutation and of contributing to the development of tumors. Genotoxic - Capable of damaging genetic m aterial such as DNA , and thus causing mutations or possibly cancer.

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Typical genotoxins like aromatic ami nes are believed to cause mutations because they are nucleophilic and form strong covalent bonds with DNA resulting with the formation of Aromatic Amine-DNA Adducts, preventing accurate replication . Genotoxins affecting sperm and eggs can pass genetic changes down to descendants who have never been exposed to the genotoxin.

CARCINOGENICITY :

CARCINOGENICITY Car·ci·no·ge·nic·i·ty; the ability or tendency to produce cancer A carcinogen is any substance, radionuclide or radiation, that is an agent directly involved in the exacerbation of cancer or in the increase of its propagation . This may be due to the ability to damage the genome or to the disruption of cellular metabolic processes.

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There are many natural carcinogens. Aflatoxin B 1 , which is produced by the fungus Aspergillus flavus growing on stored grains, nuts and peanut butter, is an example of a potent, naturally-occurring microbial carcinogen. Certain viruses such as Hepatitis B and human papilloma viruses have been found to cause cancer in humans. The first one shown to cause cancer in animals is Rous sarcoma virus Co-carcinogens are chemicals that do not necessarily cause cancer on their own, but promote the activity of other carcinogens in causing cancer.

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Carcinogen Associated cancer sites or types Arsenic and its compounds Lung Skin Hemangiosarcoma Asbestos Lungs Mesothelioma Gastrointestinal tract Benzene Leukemia Hodgkin lymphoma Beryllium and its compounds Lung Cadmium and its compounds Prostate Hexavalent chromium (VI) compounds Lung Carcinogens

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Studies on Benzene Carcinogenicity in Rats and Mice,

MUTAGENICITY :

MUTAGENICITY Mu·ta·gen, an agent, such as a chemical, ultraviolet light, or a radioactive element, that can induce or increase the frequency of mutation in an organism In biology, a mutagen (Latin, literally origin of change) is a physical or chemical agent that changes the genetic material, usually DNA , of an organism and thus increases the frequency of mutations above the natural background level.

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29

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Examples Ionizing radiation , for example X-rays, gamma rays and alpha particles Ultraviolet , electromagnetic radiation with a wavelength shorter than that of visible light but longer than x-rays Base analog , which can substitute for DNA bases and cause copying errors Deaminating agents such as nitrous acid Intercalating agents such as ethidium bromide Alkylating agents such as ethylnitrosourea Transposon , a section of DNA that undergoes autonomous fragment relocation/multiplication Alkaloid plants, such as those from Vinca species Bromine and some compounds that contain bromine in their chemical structure Sodium azide , an azide salt that is a common reagent in organic synthesis and a component in many car airbag systems Psoralen combined with ultraviolet radiation causes DNA cross-linking and hence chromosome breakage Benzene , an industrial solvent and precursor in the production of drugs, plastics, synthetic rubber and dyes

TERATOGENICITY :

TERATOGENICITY Ter·a·to·ge·nic·i·ty] the capability of producing fetal malformation Teratology is the study of abnormalities of physiological development . It is often thought of as the study of birth defects , but it is much broader than that, taking in other developmental stages, such as puberty; and other life forms, such as plants. Teratogeni c - drugs given to the mother that can cross the placental barrier to the unborn child. They are capable of interfering with the development of the fetus, causing birth defects.

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32 Marijuana as a Teratogen

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33 Growth and development of featal

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Teratogenesis signifies the production of gross structural malformations during fetal development , in distinction from other kinds of drug-induced fetal damage such as growth retardation, dysplasia (e.g. iodide-associated goitre), or the asymmetrical limb reduction resulting from vasoconstriction

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Agent Effect(s) Thalidomide Phocomelia , heart defects, gut atresia , etc. Penicillamine Loose skin etc. Warfarin Saddle nose; retarded growth; defects of limbs, eyes, central nervous system Corticosteroids Cleft palate and congenital cataract-rare Androgens Masculinisation in female Oestrogens Testicular atrophy in male Stilbestrol Vaginal adenosis in female fetus, also vaginal or cervical cancer Phenytoin Cleft lip/palate, microcephaly , mental retardation Valproate Neural tube defects (e.g. spina bifida) Carbamazepine Retardation of fetal head growth Cytotoxic drugs (especially folate antagonists) Hydrocephalus, cleft palate, neural tube defects, etc. Some drugs reported to have adverse effects on human fetal development

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36 Phecomelia defect

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Thalidomide birth deffect

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