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    Toxicity Studies

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    Hema Krishna
    Toxicity studies are conducted before any potential new medicine can be administered to humans. They investigate safety in animals to define safe human doses. There are five criteria for defining the high dose in toxicity studies: maximum tolerated dose, limit dose, saturation of exposure, maximum feasible dose, and a dose providing a 50-fold margin of exposure. The maximum tolerated dose is the highest dose animals can tolerate without significant health effects. The limit dose is generally accepted as 1000mg/kg. Saturation of exposure refers to the maximum absorption level of a substance. The maximum feasible dose is limited by formulation practicalities. A 50-fold margin of exposure dose provides adequate safety based on substance exposure levels.

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    Toxicity Studies

    Uploaded by

    Hema Krishna
    269 views8 pages
    Toxicity studies are conducted before any potential new medicine can be administered to humans. They investigate safety in animals to define safe human doses. There are five criteria for defining the high dose in toxicity studies: maximum tolerated dose, limit dose, saturation of exposure, maximum feasible dose, and a dose providing a 50-fold margin of exposure. The maximum tolerated dose is the highest dose animals can tolerate without significant health effects. The limit dose is generally accepted as 1000mg/kg. Saturation of exposure refers to the maximum absorption level of a substance. The maximum feasible dose is limited by formulation practicalities. A 50-fold margin of exposure dose provides adequate safety based on substance exposure levels.

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    TOXICITY STUDIES

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    Toxicity studies are conducted before any potential new medicine can be administered to humans. They investigate safety in animals to define safe human doses. There are five criteria for defining the high dose in toxicity studies: maximum tolerated dose, limit dose, saturation of exposure, maximum feasible dose, and a dose providing a 50-fold margin of exposure. The maximum tolerated dose is the highest dose animals can tolerate without significant health effects. The limit dose is generally accepted as 1000mg/kg. Saturation of exposure refers to the maximum absorption level of a substance. The maximum feasible dose is limited by formulation practicalities. A 50-fold margin of exposure dose provides adequate safety based on substance exposure levels.

    Copyright:

    © All Rights Reserved
    Download as PPTX, PDF, TXT or read online from Scribd
    Download as pptx, pdf, or txt
    269 views8 pages

    Toxicity Studies

    Uploaded by

    Hema Krishna
    Toxicity studies are conducted before any potential new medicine can be administered to humans. They investigate safety in animals to define safe human doses. There are five criteria for defining the high dose in toxicity studies: maximum tolerated dose, limit dose, saturation of exposure, maximum feasible dose, and a dose providing a 50-fold margin of exposure. The maximum tolerated dose is the highest dose animals can tolerate without significant health effects. The limit dose is generally accepted as 1000mg/kg. Saturation of exposure refers to the maximum absorption level of a substance. The maximum feasible dose is limited by formulation practicalities. A 50-fold margin of exposure dose provides adequate safety based on substance exposure levels.

    Copyright:

    © All Rights Reserved
    Download as PPTX, PDF, TXT or read online from Scribd
    Download as pptx, pdf, or txt
    of 8

    TOXICITY STUDIES

    Before any potential new medicine can be


    administered to man its safety must be
    investigated in animals in order to define
    safe human doses.

    Five general criteria for defining the high dose in a toxicology study:

     Maximum tolerated dose


     Limit dose
     Top dose based on saturation of exposure
     Maximum feasible/practical dose
     Dose providing a 50-fold margin of exposure
    Maximum Tolerated Dose

    • Highest dose that will be tolerated for the study duration


    • A dose where target organ toxicity is likely to be observed but where the
    dose is not so high that the study is jeopardized by morbidity or
    mortality.
    Limit dose

    The limit dose defines the highest dose that should be used in the
    absence of a demonstrable MTD. The limit dose is generally accepted as
    1000mg/kg in both rodents and non-rodents.
    Toxicokinetics and saturation of exposure

    • Describes the systemic exposure achieved in animals and its relationship


    to the dose, sex, species and the time course of the toxicity study.
    • Blood samples are taken from animals on toxicity studies and the
    plasma/serum or blood concentrations of the test item or its metabolites
    are measured
    • Where toxicokinetic data indicate that absorption limits exposure to the
    test item or its metabolites, the lowest dose which achieves maximum
    exposure should be used as the high dose in the absence of other dose
    limiting constraints. This is often referred to as saturation of exposure.
    Maximum Feasible Dose
    • Practicalities, such as formulation, can mean the high dose is
    limited by what is technically feasible based upon the maximum
    possible concentration of the test item in the formulation.

    Doses providing a 50-fold margin of exposure.


    • Based on the group mean of the area under the curve (AUC)
    values of the test item.
    • Generally acceptable as the maximum
    dose for acute and repeated dose toxicity
    studies in any species.
    Important Terms
     The Globally Harmonized System (GHS)

     Maximum Tolerated Dose (MTD)

     No Observable Effect Level (NOEL)

     Organization for Economic Cooperation and Development


    (OECD)

     Committee for the Purpose of Control and Supervision of


    Experiments on Animals (CPCSEA)

     Institutional Animal Ethics Committee (IAEC)

     Indian Council of Medical Reasearch(ICMR)


    Acute Toxicity Sub-acute Toxicity Sub-chronic Chronic Exposure
    (Repeated Dose)

    Objectives To determine the To determine toxicity To establish (NOAEL), To evaluate the


    Median Lethal Dose after repeated characterize dose- cumulative toxicity
    (LD50), (NOEL), administration of the response relationships of chemicals and
    (MTD)after a single test material and following repeated doses assess carcinogenic
    dose administered. establish doses for sub- and predict dose for potential.
    chronic studies. chronic exposure studies.

    Duration 14 days after single dose 14 days 90 days 6-24 months

    Species 2 species required. 2 species required. 2 species required. 2 species required.


    Mice, rats, sometimes Mice, rats, rabbits, Rodents, dogs. Rodents, dogs.
    rabbits or dogs. guinea pigs, dogs.
    Dose 3 to 4 doses given by At least 3 doses given by As in sub-acute/ sub-
    the same routes as the same routes as chronic toxicity
    previous toxicity tests. previous toxicity tests; studies.
    the lowest producing no
    apparent toxicity and the
    highest producing
    toxicity but less than or
    equal to 10% mortality.
    Parameters 1. Mortality 1. Mortality 1. Mortality 1. Mortality
    2. Clinical pathology 2. Signs of toxicity 2. Weight change 2. Pathology and
    3. Gross necropsy 3. Pathology and 3. Signs of toxicity histopathology
    4. Weight change histopathology 4. Clinical pathology 3. Weight change
    5. Signs of toxicity 4. Weight change 5. Pathology and 4. Clinical
    5. Clinical pathology histopathology pathology of all
    animals (mortalities
    and survivors)

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