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Design and Conduct Safety Pharmacology & Toxicology Study for Pharmaceuticals

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Title: Design and Conduct Safety Pharmacology & Toxicology Study for Pharmaceuticals


1
Design and Conduct Safety Pharmacology
Toxicology Study for Pharmaceuticals
  • Dr. Basavaraj K. Nanjwade M.Pharm., Ph.D
  • Professor of Pharmaceutics
  • Department of Pharmaceutics, KLE University,
  • BELGAUM 590010, Karnataka, India
  • E-mail bknanjwade_at_yahoo.co.in
  • Cell No 919742431000

2
R D Pharmacology and Toxicology
  • PHARMACOLOGY
  • Oncology
  • Pain Inflammation
  • Metabolic Disorders
  • Respiratory Diseases
  • Psychopharmacology
  • models
  • IN-VITRO TOXICOLOGY
  • In-vitro toxicity assays
  • In-vitro genotoxicity
  • assays
  • DRUG METABOLISM PHARMACOKINETICS STUDIES
  • In-Vivo DMPK
  • studies
  • In-vitro DMPK
  • studies
  • Plasma Protein
  • Binding studies
  • Drug Drug
  • interaction studies
  • Bioanalysis
  • Special Analytical
  • studies

HISTOPATHOLOGICAL AND BIOCHEMISTRY STUDIES
  • SAFETY PHARMACOLOGY
  • CNS studies
  • CVS studies
  • Respiratory evaluations/
  • system
  • IN-VIVO TOXICOLOGY
  • General toxicology
  • In-vivo Genotoxicity studies
  • Carcinogenicity
  • Development and reproductive
  • studies
  • Special toxicity studies

3
  • PHARMACOLOGY

4
Oncology
  • i. Xenograft model
  • This model provides consistent and reproducible
    cell growth and permits easy access to the tumor
    for treatment and calliper measurement
  • Cell implant subcutaneously into
    immuno-compromised animals
  • Tumors measured during growth phase
  • Animals treated with vehicle, test article and
    positive control
  • Various protocol-specified parameters/markers
    assessed ex vivo or in vivo assays
  • Report preparation

5
Oncology
  • ii. In vivo targeted inhibition model
  • In PK/PD studies the tumors are from the test
    article treated mice group along with respective
    control groups.
  • Then the effect of test article at molecular
    level is investigated in different cell based
    assays
  • The MTD of the compound is also analysed

6
Pain and Inflammation
  • 1. Chemical Induced
  • Capsaicin induced Hyperalgesia in rats
  • FCA induced Hyperalgesia
  • Carrageenan induced paw edema
  • Acetic acid/Formalin induced pain in mice
  • Mouse Ear Edema
  • Adjuvant-Induced Arthritis (AIA)
  • Collagen-Induced Arthritis (CIA)

7
Pain and Inflammation
  • 2. Thermal Mechanical Induced Hyperalgesia
  • Tail flick model of Hyperalgesia
  • Hot plate model of Hyperalgesia
  • Neuropathic Pain (PSL and CCI induced PAIN)
  • Diabetic neuropathic pain model (DNP)
  • Post operative pain model

8
Pain and Inflammation
  • 3. Miscellaneous
  • Novel technique to quantitatively assess
    Inflammatory mediators-In Vitro assay measuring
    cytokine production/inhibition in rat/mice
  • Mouse LPS model-LPS-stimulated inflammation in
    mice

9
Metabolic Disorder
  • 1. Acute Model
  • OGITT/IPGTT Model
  • 2. Chronic Model
  • STZ induced Diabetes in mice/rats
  • STZ induced Diabetes in neonatal rats
  • Sucrose Fed Diet induced Diabetes
  • High-Fat/carbohydrate Fed Diet and STZ treated
    Mice model for Diabetes
  • Glucose and Insulin estimation
  • ob/ob mouse
  • db/db mouse
  • ZDF rats

10
Respiratory Diseases
  • Antigen-induced Airway Hyper responsiveness in
    mice/rats
  • Antigent-induced Pulmonary eosinophilia in
    mice/rats
  • Passive Cutaneous Anaphylaxis
  • Active Cutaneous Anaphylaxis
  • LPS-induced Meutrophilia in rats/mice

11
Psychopharmacology Models
  • 1. Muscle Relaxation
  • Rota-rod test
  • Inclined screen test
  • Grip Strength test
  • 2. Behavioral test
  • Irwin test

12
  • IN-VIVO TOXICOLOGY

13
General Toxicology
  • Single dose studies
  • Repeated dose sub-acute and sub-chronic studies
    (14, 28 90 days)
  • Chronic toxicology studies (6, 9 12 months)
  • Carcinogenicity studies
  • Toxicokinetics
  • Pathology

14
In-Vivo Genotoxicity Studies
  • Micronucleus test in mouse or rat bone marrow
    (OECD 474)
  • Mammalian bone marrow chromosome aberration test
    in rats or mice (OECD)
  • Unscheduled DNA synthesis (UDS) with rat
    hepatocytes (OECD 486)

15
Development Reproduction toxicology
  • Fertility (Segment I)
  • Embryo-fetal development (Segment II)
  • Perinatal and postnatal development, including
    maternal function (Segment III)
  • Multigenerational studies
  • Endocrine disruptors
  • Selected neurobehavioral tests
  • Juvenile dosing studies (rodent, dog)
  • Sample collection (TK/PK and absorption analysis,
    maternal and fetal blood, amniotic fluid, milk)
  • Spermatogenesis evaluations of cellular endpoint
    (morphology, motility, spermatid head count) via
    the IVOS system
  • Vaginal cytology evaluations

16
Special Toxicity Studies
  • The potential, adverse effects of human
    pharmaceuticals and biotech products on the
    immune system is acknowledged as an important
    issue.
  • According to the FDA, evaluation of potential
    immunotoxic effects should be incorporated into
    standard drug development
  • It incorporates immunotoxicology assays using
    standard rodent species (Wistar rat and CD-1
    mouse)

17
  • IN VITRO TOXICOLOGY

18
In Vitro Toxicology
  • Human skin corrosion assay (OECD 431)
  • Human skin irritation assay (draft proposal for a
    new guideline OECD)
  • Hen Egg Test-Chorioallantoic Membrane (HET-CAM)
    test

19
In-Vitro Genotoxicity Studies
  • Bacterial reverse mutation (Ames) test with
    salmonella typhimurium and Escherichia coli (OECD
    471)
  • Chromosome aberration test (CAT) with human
    lymphocytes (OECD 473)
  • Mammalian gene mutation test (MLA) with mouse
    lymphoma cells (TK-locus) (OECD 476)
  • Unscheduled DNA synthesis (UDS) with isolated rat
    hepatocytes (OECD 482)
  • Micronucleus test with human lymphocytes (draft
    OECD 487)
  • Single cell gel electrophoresis (COMET) Assay

20
  • SAFETY PHARMACOLOGY

21
Scope and Principle
  • Design and conduct safety pharmacology study can
    be applied to marketed pharmaceuticals when
    appropriate
  • e.g.
  • 1. When adverse clinical events
  • 2. A new patient population
  • 3. A new route of administration raises concerns
    not previously addressed.
  • Some safety pharmacology endpoint can be
    incorporated in the design of toxicology, kinetic
    and clinical studies

29/12/2009
21
Nepal Pharmaceuticals Ltd., Birgunj, Nepal.
22
Definition of Safety Pharmacology
  • Pharmacology studies can be divided into three
    categories
  • 1. Primary pharmacodynamic
  • 2. Secondary pharmacodynamic
  • 3. Safety Pharmacology studies

23
Objectives of Studies
  • To identify undesirable pharmacodynamic
    properties of a substance that may have relevance
    to its human safety
  • To evaluate adverse pharmacodynamic and/or
    pathophysiological effects of a substance
    observed in toxicology and /or clinical studies
  • To investigate the mechanism of the adverse
    pharmacodynamic effects observed and/or suspected

24
General Considerations in Selection and Design of
Safety Pharmacology
  • Effects related to the therapeutic class of the
    test substance, since the mechanism of action may
    suggest specific adverse effects
  • Adverse effects associated with members of the
    chemical or therapeutic class, but independent of
    the primary pharmacodynamics effects

25
General Considerations in Selection and Design of
Safety Pharmacology
  • Ligand binding or enzyme assay data suggesting a
    potential for adverse effects
  • Results from previous safety pharmacology
    studies, from secondary pharmacodynamic studies,
    from toxicology studies, or from human use that
    warrant further investigation to establish and
    characterize the relevance of these findings to
    potential adverse effects in humans.

26
Test Systems
  • 1. General Considerations on Test Systems
  • 2. Use of In Vivo and In Vitro Studies
  • 3. Experimental Design
  • a. Sample Size and Use of Controls
  • b. Route of Administration

27
General Considerations on Test Systems
  • Consideration should be given to the selection of
    relevant animal model or other test systems so
    that scientifically valid information can be
    derived.
  • Selection factors can include the pharmacodynamic
    responsiveness of the model, pharmacokinetic
    profile, species, strain, gender and age of the
    experimental animals, the susceptibility,
    sensitivity, and reproducibility of the test
    system and available background data on the
    substance.

28
Use of In Vivo and in Vitro Studies
  • Animal models as well as ex vivo and in citro
    preparations can be used as test systems.
  • Ex vivo and vitro systems can include, but are
    not limited to isolated organs and tissues, cell
    cultures, cellular fragments, subcellular
    organelles, receptors, ion channels, transporters
    and enzymes.
  • In vitro systems can be used in supportive
    studies
  • In conducting in vivo studies, it is preferable
    to use anaesthetized

29
Sample Size and Use of Controls
  • The sample size should take into consideration
    the size of the biological effect that is of
    concern for humans
  • Appropriate negative and positive control group
    should be included in the experimental design
  • In well-characterized in vivo test systems,
    positive controls may not be necessary.
  • The exclusion of control from studies should be
    justified

30
Route of Administration
  • In general, the expected clinical route of
    administration should be used when feasible.
  • Regardless of the route of administration,
    exposure to the parent substance and its major
    metabolites should be similar to or greater than
    that achieved in humans hen such information is
    available.
  • Assessment of effects by more than one route may
    be appropriate if the test substance is intended
    for clinical use by more than one route of
    administration

31
Dose Levels or Concentrations of test Substance
  • In Vivo Studies
  • In Vitro Studies

32
In Vivo Studies
  • In vivo safety pharmacology studies should be
    designed to define the dose-response relationship
    of the adverse effect observed.
  • The time course of the adverse effect should be
    investigated, when feasible.
  • Generally, the doses eliciting the adverse effect
    should be compared to the doses eliciting the
    primary pharmacodynamic effect in the test
    species or the proposed therapeutic effect in
    humans, if feasible.

33
In Vitro Studies
  • In vitro studies should be designed to establish
    a concentration-effect relationship.
  • The range of concentrations used should be
    selected to increase the likelihood of detecting
    an effect on the test system.
  • The upper limit of this range may be influenced
    by physico-chemical properties of the test
    substance and other assay specific factors.
  • In the absence of an effect, the range of
    concentrations selected should be justified.

34
Duration of Studies
  • Safety pharmacology studies are generally
    performed by single-dose administration
  • When pharmacodynamic effects occur only after a
    certain duration of treatment, or when results
    from repeat dose non-clinical studies or results
    from use in humans give rise to concerns about
    safety pharmacological effects, the duration of
    the safety pharmacology studies to address these
    effects should be rationally based.

35
Studies on Metabolites, Isomers and Finished
Products
  • Metabolites from humans are known to
    substantially contribute to the pharmacological
    actions of the therapeutic agent, it could be
    important to test such active metabolites.
  • When the in vivo studies on the parent compound
    have not adequately assessed metabolites, as
    discussed above, the tests of metabolites can use
    in vitro systems based on practical
    considerations.

36
Studies on Metabolites, Isomers and Finished
Products
  • In vitro or in vivo testing of the individual
    isomers should also be considered when the
    product contains an isomeric mixture
  • Finished product formulations should be conducted
    only for formulations that substantially alter
    the pharmacokinetics and/or pharmacodynamics of
    the active substance in comparison to
    formulations previously tested

37
Safety Pharmacology Core Battery
  • 1. Central Nervous System
  • 2. Cardiovascular System
  • 3. Respiratory System

38
Central Nervous System
  • Effects of the test substance on the central
    nervous system should be assessed appropriately.
  • Motor activity, behavioral changes, coordination,
    sensory/motor reflex responses and body
    temperature should be evaluated.

39
Cardiovascular System
  • Effect of the test substance on the
    cardiovascular system should be assessed
    appropriately.
  • Blood pressure, heart rate and the
    electrocardiogram should be evaluated
  • In vivo, in vitro and /or ex vivo evaluations,
    including methods for repolarzation and
    conductance abnormalities, should also be
    considered.

40
Respiratory System
  • Effects of the test substance on the respiratory
    system should be assessed appropriately
  • Respiratory rate and other measures of
    respiratory function should be evaluated.
  • Clinical observation of animals is generally not
    adequate to assess respiratory function, and thus
    these parameters should be quantified by using
    appropriate methodologies.

41
Follow-up and Supplemental Safety Pharmacology
Studies
  • Follow-up Studies For Safety Pharmacology Core
    Battery
  • Central Nervous System
  • Cardiovascular System
  • Respiratory System

42
Central Nervous System, Cardiovascular System
Respiratory System
  • Behavioral pharmacology, learning and memory,
    ligand-specific binding, neurochemistry, visual,
    auditory, and/or electrophysiology examination
  • Cardiac output, ventricular contractility,
    vascular resistant, the effects of endogenous
    and/or exogenous substances on the cardiovascular
    responses
  • Airway resistance, compliance, pulmonary arterial
    pressure, blood gases, blood pH

43
Follow-up and Supplemental Safety Pharmacology
Studies
  • 2. Supplemental Safety Pharmacology Studies
  • Renal/Urinary System
  • Autonomic Nervous System
  • Gastrointestinal System
  • Other Organ Systems

44
Renal/Urinary System
  • Effect of the test substance on renal parameters
    should be assessed.
  • e.g
  • Urinary volume, specific gravity, osmolality,
    pH, fluid/electrolyte balance, protein, cytology,
    and blood chemistry determinations such as blood
    urea nitrogen, creatinine, and plasma proteins
    can be used

45
Autonomic Nervous System
  • Effects of the test substance on the autonomic
    nervous system should be assessed.
  • e.g
  • Binding to receptors relevant for the autonomic
    nervous system, functional responses to agonists
    or antagonists in vivo or in vitro, direct
    stimulation of autonomic nerves and measurement
    of cardiovascular responses, baroreflex testing,
    and heart rate variability can be used.

46
Gastrointestinal System
  • Effects of the test substance on the
    gastrointestinal system should be assessed.
  • e.g
  • Gastric secretion, gastrointestinal injury
    potential, bile secretion, transit time in vivo,
    ileal contraction in vitro, gastric pH
    measurement and pooling can be used

47
Other Organ Systems
  • Effects of the test substance on organ systems
    not investigated elsewhere should be assessed
    when there is a reason for concern.
  • e.g.
  • Dependency potential or skeletal muscle, immune
    and endocrine functions can be investigated.

48
Conditions Under Which Studies are Not Necessary
  • Safety pharmacology studies may not be needed for
    locally applied
  • Safety pharmacology studies prior to the first
    administration in human may not be needed for
    cytotoxic agents for treatment of end-stage
    cancer patients.
  • There may be additional exceptions where safety
    pharmacology testing is not needed
  • e.g
  • Case of a new salt having similar
    pharmacokinetics and pharmacodynamics

49
Timing of Safety Pharmacology Studies in Relation
to Clinical Development
  • Studies Prior to First Administration in Humans
  • Studies During Clinical Development
  • Studies Before Approval

50
Studies prior to First Administration in Human
  • The effects of a test substance on the functions
    listed in the safety pharmacology core battery
    should be investigated prior to first
    administration in humans
  • Any follow-up or supplemental studies identified
    as appropriate, based on a cause for concern,
    should also be conducted.
  • Information from toxicology studies adequately
    designed and conducted to address safety
    pharmacology endpoint can result in reduction or
    elimination of separate safety pharmacology
    studies.

51
Studies During Clinical Development
  • Additional studies may be warranted to clarify
    observed or suspected adverse effects in animals
    and humans during clinical development

52
Studies Before Approval
  • Safety pharmacology effects should be assessed
    prior to product approval, unless not warranted,
    in which case this should be justified.
  • Available information from toxicology studies
    adequately designed and conducted to address
    safety pharmacology endpoint, or information from
    clinical studies, can support this assessment and
    replace safety pharmacology studies

53
Application of Good Laboratory Practice (GLP)
  • This is normally accomplished through the conduct
    of the studies in compliance with GLP.
  • Due to the unique design of and practical
    considerations for, some safety pharmacology
    studies, it may not be feasible to conduct these
    in compliance with GLP
  • The safety pharmacology core battery should
    ordinarily be conducted in compliance with GLP

54
Application of Good Laboratory Practice (GLP)
  • Follow-up and supplemental studies should be
    conducted in compliance with GLP to the greatest
    extent feasible.
  • Safety pharmacology investigations can be part of
    toxicology studies in such cases, these studies
    would be conducted in compliance with GLP
  • Primary pharmacodynamic studies do not need to be
    conducted in compliance with GLP

55
Application of Good Laboratory Practice (GLP)
  • Generally, secondary pharmacodynamic studies do
    not need to be conduct in compliance with GLP
  • In some circumstances, results of secondary
    pharmacodynamics studies may make a pivotal
    contribution to the safety evaluation for
    potential adverse effects in humans, and these
    are normally conducted in compliance with GLP

56
  • DRUG METABOLISM PHARMACOKINETIC STUDIES

57
In-vivo DMPK Studies
  • In vivo preclinical ADME studies are routinely
    performed in rat and dog with radiolabeled
    compounds usually using carbon-14 or tritium
    isotopes
  • However, all other animal species or isotopes can
    be considered
  • These studies are performed using all common
    routes of administration
  • This includes mass balance, tissue distribution,
    bile cannulation and dermal absorption studies
  • Pharmacokinetic evaluation using validated
    WinNonLin software is performed in house

58
In-vitro DMPK Studies
  • Cytochrome P450 studies
  • Metabolite Profiling metabolite Identification
    Metabolic Stability Studies
  • Blood Distribution Studies
  • Drug Transport Using Caco-2 cell and skin
    Absortion, transport and Metabolism studies

59
Plasma Protein Binding
  • The plasma protein binding of a drug is
    determined in plasma of different species
    (including human) using either equilibrium
    dialysis or ultrafiltration
  • In addition, the stability of the drug in plasma
    is investigated
  • These studies are performed using radiolabeled
    and non-labeled compounds

60
Drug Drug Interaction Studies
  • Using pooled human liver microsomes or other in
    vitro metabolism models
  • The interaction of a drug on the metabolism of
    another drug is determined

61
Special Analytical Studies
  • Metabolite Identification/Elucidation
  • This provides metabolite identification in sample
    available from in vitro and in vivo studies, as
    well as from environmental fate studies
  • The method is then adapted for the specific
    compound
  • Generally method development is finished within
    three days
  • Data are generated using LC-PDA-MS analysis with
    data-dependent MS-MS
  • Additional MS analysis is possible, as well as
    accurate mass determination

62
  • HISTOPATHOLOGICAL BIOCHEMISTRY STUDIES

63
Hematology
  • Complete Blood Count (CBC) with no Differential
    (WBC, RBC, HCT, HGB, MCV, MCH, MCHC, MPV, RDW,
    CHCM)
  • Platelet (automated count), Reticulocytes
  • Differential Count
  • Complete Blood Count (CBC) with Differential

64
Clinical Chemistry
  • Alanine Aminotransferase
  • Albumin
  • Alkaline Phosphatase
  • Aspartate Aminotrasferase
  • Calcium
  • Chloride
  • Cholesterol
  • Creatinine
  • Glucose
  • Prealbumin
  • A/G/ Ratio
  • Globulin,
  • Phosphorous
  • Potassium
  • Sodium
  • Total Bilirubin
  • Total Protein
  • Triglycerides
  • Urea
  • Nitrogen
  • Osmolality
  • Anion Gap

65
Biomarkers
  • Advanced Lipid biomarkers
  • HDL-C
  • LDL-C
  • VLDL
  • Cardiac risk ratio
  • Apo A1
  • Apo B
  • FFA
  • Cardiac biomarkers
  • BNP
  • Troponin I
  • Myoglobin
  • CK
  • CK-MB
  • Homocysteine
  • Hs-CRP
  • D-Dimer

66
  • LIST OF EQUIPMENTS

67
General Pharmacology Equipments
  • Auto analyzer (semi-automated)
  • Blood cell counter
  • UV Spectrophotometer
  • HPLC
  • CO2 incubator with air jacket
  • ELISA microplate reader
  • Inverted microscopes
  • Non Invasive BP Measurements (Tail cuff) 
  • Physiograph
  • Polygraph

68
General Pharmacology Equipments
  • Deep freezer (420 L)
  • Electrophoresis
  • Cooling microcentrifuge
  • CNS Pharmacology related instruments
  • Student kymographs
  • Respiratory pumps
  • Langendorffs apparatus
  • UGO Basile plethysmometer
  • UGO Basile analgesiometer
  • UGO Basile ECT

69
List of Critical Equipment for Pharmacology
  • IVC units
  • Boyles apparatus
  • Hot plate
  • Plethysmometer
  • Automated cell counter (Mythic 18)
  • Plate reader (Biotech)
  • Plantar Aesthesiometer

70
List of Critical Equipments for ADME and PK
  • HPLCs (Water, Agilent)
  • LC/MS/MS (API 3000, Applied Biosciences)
  • Spectramax-Quartz plate reader (Molecular
    Devices)
  • Zymark Evaporator (Caliper)
  • Vacuum manifield (Whatman)
  • Apricot
  • Centrifuge (Hettich)
  • Shaker incubator (Jeotech)

71
List of Critical Equipment for Assay Development
  • FLIPR (Molecular Devices)
  • Janus Liquid Handaling system (PerkinElmer)
  • Novostar-single channel robotic plate reader (BMG
    Labtech)
  • Fluostar-single channel robotic plate reader (BMG
    Labtech)
  • Victor (PerkinElmer)
  • Cell Harvesters (Tomtec, Skatron)

72
List of Critical Equipment for Assay Development
  • Wallac Beta and Gamma counter (PerkinElmer)
  • Inverted fluorescence microscope (Nikon TE 200U)
  • CO2 incubator (Thermo)
  • Ultracentrifuge (Beckman coulter)
  • Cold centrifuge (Beckman coulter)
  • Cryopreservation Equipment (Thermo)
  • Hydra (Matrix)
  • Lyophilizer

73
List of Critical Equipments for Molecular Biology
and Gene Expression
  • Gradient PCR machines (Biometra, Applied
    Biosciences)
  • Gel Imaging System Bio-Rad)
  • Shaker incubators (VWR, Zhicheng)
  • DNA Electrophoresis system (Owl)
  • UV-Vis Spectrophotometer (Beckman Coulter)
  • Electroporator (Bio-Rad)

74
List of Critical Equipments for Molecular Biology
and Gene Expression
  • FPLC (Bio-Rad)
  • Gel dryer (Bio-Rad)
  • Southern/Northern blot chamber (Amersham
    Biosciences)
  • Western transfer apparatus (Bio-Rad)
  • Table-top refrigerated centrifuges (Beckman
    Coulter, Eppendroff)
  • Protein Electrophoresis (Bio-Rad)

75
PHARMACOLOGY LAB LAY OUT (ANIMAL HOUSE)
Sterile room for exchange of clothes, belongings
etc
Library
Quarantine room

Animal House for MICE
Animal house for RATS
Entrance
Dosing Room
Senior and Junior Research Officers
Restricted Entry
Restricted Entrance
HODs Office
Well equipped Samples Analysis Room
Operation Room for invasive procedures
Animal House for Rabbits
Dosing Room
Mating Room for Rats and Mice
Animal House for Guinea Pigs
Discussion/Meeting Room
76
Rodent Facility
  • Preclinical research facility encompasses a
    state-of-art building with a total built up area
    of 33,000 sq. ft. with 32 Rodent experimental
    rooms (200 sq. ft) and separate provision of
    rooms for quarantine of animals and 5 procedure
    rooms wherein different pharmacological studies
    are carried out as on need basis
  • The facility is registered with the CPCSEA
    (Committee for the Purpose of Control and
    Supervision of Experiments on Animals)

77
International Guidelines
  • ICH www.ich.og
  • International Conference on Harmonization
  • FDA www.fda.org
  • Food and Drug Administration
  • EPA www.epa.org
  • Environmental Protection Agency
  • OECD www.oecd.org
  • Organization for Economic Co-operation
    Development
  • CPCSEA www.cpcsea.com
  • Committee for the Purpose of Control and
    Supervision of Experiments on Animals

78
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