acute toxicity studies

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Acute toxicity studies:

1 Acute toxicity studies

CONTENTS:

2 CONTENTS Introduction Aim of acute toxicity test Initial considerations Testing procedures Methods used for acute toxicity testing Conclusion References

Introduction:

3 Introduction Acute toxicity studies in animals are usually necessary for any pharmaceutical intended for human use. The information obtained from these studies is useful in choosing doses for repeat-dose studies, providing preliminary identification of target organs of toxicity, and occasionally, revealing delayed toxicity. Acute toxicity studies may also aid in the selection of starting doses for Phase 1 human studies, and provide information relevant to acute overdosing in humans.

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4 Acute toxicity is defined as the adverse effect occurring within a short time of administration of single dose of a substance or multiple doses given within 24 hrs.

Aim of acute toxicity test:

5 Aim of acute toxicity test To define intrinsic toxicity of chemical Provides information for the design and selection of dose levels for prolonged studies Provides valuable information to clinician in prediction, diagnosis, and treatment for acute over doses of chemicals. To determine the therapeutic index,

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6 Data from the acute study may: (a) Serve as the basis for classification and labelling; (b) Provide initial information on the mode of toxic action of a substance; (c) Help arrive at a dose of a new compound; (d) Help in dose determination in animal studies; (e) Help determine LD50 values that provide many indices of potential types of drug activity

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7 The original Guideline 423 was adopted in March 1996 as the second alternative to the conventional acute toxicity test, described in Test Guideline 401. The acute toxic class method is a stepwise procedure with the use of 3 animals of a single sex per step. Depending on the mortality and/or the moribund status of the animals, on average 2-4 steps may be necessary to allow judgement on the acute toxicity of the test substance. Guideline 425 use an up-and-down procedure (UDP) for the determination of acute toxicity of chemicals.

PRINCIPLE OF THE TEST :

8 PRINCIPLE OF THE TEST The substance is administered orally to a group of animals at one of the defined doses. (normally females). Absence or presence of compound-related mortality of the animals dosed at one step will determine the next step. − no further testing is needed, − dosing of three additional animals, with the same dose − dosing of three additional animals at the next higher or the next lower dose level. Death of a proportion of the animals is the major endpoint of this test.

INITIAL CONSIDERATIONS :

9 INITIAL CONSIDERATIONS Test substances, at doses that are known to cause marked pain and distress due to corrosive or severely irritant actions, need not be administered. Moribund animals, or animals obviously in pain or showing signs of severe and enduring distress shall be humanely killed, and are considered in the interpretation of the test results in the same way as animals that died on test. The testing laboratory should consider all available information on the test substance prior to conducting the study

Description of method:

10 Description of method Preferred rodent species is the rat Females should be nulliparous and non-pregnant. The temperature in the experimental animal room should be 22ºC ( + 3ºC). The animals are randomly selected, marked to permit individual identification, and kept in their cages for at least 5 days prior to dosing to allow for acclimatisation to the laboratory conditions Animals should be fasted prior to dosing

Test procedure:

11 Test procedure The test substance was administered orally/intraperitoneally in graduated doses. Dose selection is based on the results of a range finding test. The maximum volume of liquid that can be administered at one time depends on the size of the test animal. In rodents, the volume should not normally exceed 1mL/100g of body weight maximum of 50 ml/kg. Following the period of fasting, the animals should be weighed and the test substance administered.

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12 Three animals are used for each step. The dose level to be used as the starting dose is selected from one of four fixed levels, 5, 50, 300 and 2000 mg/kg body weight. The starting dose level should be that which is most likely to produce mortality in some of the dosed animals. When available information suggests that mortality is unlikely at the highest starting dose level (2000 mg/kg body weight), then a limit test should be conducted. When there is no information on a substance to be tested, for animal welfare reasons it is recommended to use the starting dose of 300 mg/kg body weight.

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13 The time interval between treatment groups is determined by the onset, duration, and severity of toxic signs. Treatment of animals at the next dose, should be delayed until one is confident of survival of the previously dosed animals Exceptionally, and only when justified by specific regulatory needs, the use of additional upper dose level of 5000 mg/kg body weight may be considered Individual weights of animals should be determined shortly before the test substance is administered, and at least weekly thereafter

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14 Observation period : Observed individually after dosing at least once during the first 30 minutes, periodically during the first 24 hours, with special attention given during the first 4 hours, and daily thereafter, for a total of 14 days At the end of the test surviving animals were weighed and sacrificed. A gross necropsy was performed, all gross pathology changes were recounted. Necropsies must be performed no later than 16 h after death.

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15 Signs recorded during acute toxicity studies: Increased motor activity, anaesthesia, tremors, arching and rolling, clonic convulsions, tonic extension, lacrimation, Straub reaction, pilo-erection, salivation, muscle spasm, writhing, hyperesthesia, loss of righting reflex, depression, ataxia, stimulation, sedation, blanching, hypnosis, cyanosis and analgesia.

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16 All data should be summarised in tabular form, showing for each test group the number of animals used, the number of animals displaying signs of toxicity, the number of animals found dead during the test or killed for humane reasons, time of death of individual animals, a description and the time course of toxic effects and reversibility, and necropsy findings.

The test report must include the following information, as appropriate :

17 The test report must include the following information, as appropriate Test substance − physical nature, purity, physio-chemical properties − identification data, including CAS number. Test animals − species/strain used; − microbiological status of the animals, when known; − number, age, and sex of animals − source, housing conditions, diet etc.

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18 Test conditions − details of test substance formulation including details of the physical form of the material administered; − details of the administration of the test substance including dosing volumes and time of dosing; − details of food and water quality (including diet type/source, water source); − the rationale for the selection of the starting dose.

TESTING AT DOSES ABOVE 2000 MG/KG:

19 TESTING AT DOSES ABOVE 2000 MG/KG Recognising the need to protect animal welfare, testing of animals in Category 5 (5000 mg/kg) ranges is discouraged. No further testing should be conducted at higher dose levels. When testing is required a dose of 5000mg/kg, only one step (i.e. three animals) is required. If the first animal dosed dies , then dosing procedes at 2000mg/kg If the first animal survives, two further animals are dosed. If only one of the three animal dies , the LD50 value is expected to exceed 5000mg/kg. If both animals die, then dosing proceeds at 2000mg/kg.

Methods used for acute toxicity testing:

20 Methods used for acute toxicity testing Approximate lethal dose method Class method Fixed dose procedure Acute toxic class method Up and down procedure

Approximate lethal dose method :

21 Approximate lethal dose method Sequential dosing until lowest lethal dose is obtained The lethal dose thus obtained is Approximate lethal dose 6-10 animal are reqiured to achieve Approximate lethal dose

Class method :

22 Class method Diluted or undiluted test material is given to several groups A vehicle control group is included Clinical signs, morbidity and mortality is observed

Fixed dose procedure :

23 Fixed dose procedure Dosing of animal in stepwise fashion using fixed doses of 5,50,500 and 2000 mg/kg Traditional test limit - 50 mg/kg Observation- mortality,time course of signs of toxicity and necropsy findings

Acute toxic class method :

24 Acute toxic class method Fixed dose level – 5,50,300 or 2000 mg/kg Initial dose is related Based on the assumption that using minimum number of animal in step wise procedure will provide enough information on the acute toxicity of substance

Up and down procedure :

25 Up and down procedure Animals are dosed one at a time, minimum of 48 hrs interval 1 st animal survives, next one receives higher dose The spacing of dose is adjusted up or down by a factor 3.2(default factor corresponding to a gross progression of one half log unit )

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26 LD50: Median lethal dose (the dose that causes 50% mortality in a population). LC50: Median lethal concentration (inhaled drugs). LD0: Represents the dose at which no individuals are expected to die.  This is just below the threshold for lethality. LD10: Refers to the dose at which 10% of the individuals will die. EDs: Effective Doses that are used to indicate the effectiveness or harmful effect (paralysis) of substances. TI: The Therapeutic Index (is used to compare the therapeutically effective dose to the toxic dose = LD50 / ED50). Acute toxicity tests: Toxicometric studies

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27 The LD50 value depends on the route of administration. Usually the values are found to increase with the following sequences of routes: intravenous > intraperitoneal > subcutaneous > oral.

Conclusion:

28 Conclusion IN screening of drugs, determination of LD50 is usually an initial step in the assessment and evaluation of the toxic characteristics of a substance. It is an initial assessment of toxic manifestations and is one of the initial screening experiments performed with all compounds

References :

29 References Principles and methods of toxicology, A Wallace Thyes, page no: 1132-1146 Ghosh, M. N., Toxicity studies. In Fundamentals of Experimental Pharmacology, 1984, pp. 153–158. Acute Oral Toxicity (OECD Test Guideline 425) Statistical Programme (AOT 425 StatPgm) Version: 1.0, 2001. OECD Test Guidelines 423 Alternative Methods for the Median Lethal Dose (LD50) Test:The Up-and-Down Procedure for Acute Oral Toxicity Amy Rispin, David Farrar, Elizabeth Margosches Volume 43, Number 4 2002 Acute toxicity studies and determination of median lethal dose J. Shetty Akhila, Shyamjith, Deepa and M. C. Alwar current science, vol. 93, no. 7, 10 october 2007

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