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PHAR 303 (toxicology) > toxicity testing > Flashcards

toxicity testing Flashcards

in vivo and in vitro

1
Q

what is the goal of ICH?

A

to ensure that safe, effective, high quality
medicines are developed and registered

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2
Q

how does ICH guidelines achieve “harmonization”?

A

via scientific consensus of regulatory agencies and the industry experts

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3
Q

what is ICH?

A

International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use

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4
Q

what is the purpose of ICH?

A

promotion of public health through international harmonization that contributes to:
- prevention of unnecessary duplication of clinical trials and post market clinical evaluations
- development and manufacturing of new medicines
- registration and supervision of new medicines
- reduction of unnecessary animal testing without compromising safety and effectiveness

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5
Q

what are the different ICH guidelines?

A
  • Quality
  • efficacy
  • safety
  • multidisciplinary
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6
Q

what are different studies that must be done under the ICH safety guidelines?

A
  • carcinogenicity
  • genotoxicity
  • toxico/pharmacokinetics
  • reproductive
  • immunotoxicology
  • toxicology
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7
Q

what organization is responsible for the safety of chemicals in consumer products?

A

Canada consumer product safety act (similar one in USA)

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8
Q

what is the OECD?

A

Organization for Economic Co-operation and
Development:
A collection of the most relevant, internationally agreed, testing methods used by government, industry and independent laboratories to identify and characterize potential hazards of new and existing chemical substances, chemical preparations and chemical mixtures.

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9
Q

where are OECD guidelines used?

A
  • in regulatory safety testing and subsequent chemical and chemical product notification and chemical registration
  • to select and rank candidate chemicals during the
    development of new chemicals and products and in
    toxicology research
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10
Q

what are the different sections of the OECD?

A
  1. Section 1 Physical Chemical Properties
  2. Section 2 Effects on Biotic Systems
  3. Section 3 Environmental Fate and Behaviour
  4. Section 4 Health Effects - about 150 of the most relevant internationally agreed testing methods used by government, industry and independent laboratories to identify and characterize potential hazards of chemicals.
  5. Section 5 Other Test Guidelines
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11
Q

which animal is commonly used in toxicity testing?

A

rodent

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12
Q

why are animal tests used?

A
  • chemical exposure can be precisely controlled
  • environmental conditions can be well-controlled
  • virtually any type of toxic effect can be evaluated
  • the mechanism by which toxicity occurs can be studied
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13
Q

what are the different systemic toxicity studies (in animals)?

A
  • single dose
  • short terms repeated dose (subacute)
  • repeated dose: 10% life-span (subchronic)
  • repeated dose: >10% life-span (chronic)
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14
Q

what is the Screening Information Dataset (SDS) strategy?

A
  • Focus on High Production Volume Chemicals (HPV)
  • Countries agreed to “sponsor” the assessment for a proportion of these HPV chemicals
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15
Q

It was agreed that the minimum screening information dataset (SIDS) should include __ tests

A

6

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16
Q

what are the SIDS that were agreed?

A
  • acute toxicity
  • chronic toxicity
  • developmental and reproductive toxicity
  • mutagenicity
  • ecotoxicity
  • environmental fate
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17
Q

acute toxicity test:
- species
- age
- number of animals
- dosage/route of exposure
- observation period

A
  • rate for oral/inhalation; rabbits for dermal
  • young adults
  • 5 of each sex per dose level
  • 3 dose levels; exposures are single or fractional doses up to 24hr for oral/dermal and 4hrs for inhalation (route same as general population)
  • 14 days
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18
Q

chronic toxicity tests:
- species
- age
- number of animals
- dosage/route of exposure
- observation period

A
  • 2 species; rodent and non-rodent
  • young adult
  • 20 of each sex rodent; 4 of each sex non-rodent
  • 3 dose levels; including 1 NOAEL and 1 above toxic dose; maximum chronic test duration about 6 for rodent and 9 for non-rodent
  • 12-24 months
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19
Q

what are the different developmental and reproductive toxicity tests?

A
  1. Single Generation Developmental/Reproductive
    Toxicity Studies – test before/during/after mating, during pregnancy (days 6-15), prenatal/postnatal
  2. Teratology Study – look at Rat fetuses after in utero exposure to increasing doses of a DNA damaging agent
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20
Q

what are the mutagenicity tests?

A
  • Micronucleus Test – DNA damage (if fragmentation, then there is DNA damage)
  • Bacterial mutagenicity tests – Ames test
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21
Q

which species are used for ecotoxicity tests? why?

A

Drosophila, Round worms, Zebrafish, etc since want to test the impact on everything else in the environment

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22
Q

what does topical toxicology evaluate and how?

A

evaluates the effects of chemicals on skin, eyes, and sometimes oral/vaginal mucous membrane

done by placing compound on a membrane, which is examined for reddening, blistering, or corrosion

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23
Q

what do behavioral tests test for?

A

monitor the effect of a chemical on cognitive function during development and in the adult

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24
Q

what do carcinogenicity tests study? how are they done and how often?

A

measures the potential for a compound to produce tumors. in theory, animals are exposed to compound throughout their lifetime and resulting tumors are evaluated (but they are rare since is expensive)

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25
Q

what is the difference between the old/present way of Chemical Toxicity Testing and the new vision?

A
  • old: test all on animal, then look at mechanism in vivo/in vitro, then look at cellular/molecular mode of action
  • new: start with all testing in vitro, then define toxicity pathway, then animal testing of select few
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26
Q

what are key questions that are asked in Chemical Toxicity Testing?

A
  • which pathways?
  • which pathway interactions?
  • link of pathway(s) and adverse effects?
  • exposure timing?
  • chronicity effects?
  • particular effects on life stages?
  • low dose (additive) effects?
  • human variability modelling?
27
Q

what are some key challenges of in vivo toxicology?

A
  • price
  • whether it can transfer between species
  • ethical issue (so have to consider what type of data we can get)
  • time consuming
  • high doses (extrapolations over a wide range)
  • low throughput
  • large number of animals needed
  • little focus on mode of action
28
Q

what does in vitro mean (in practice)?

A

studies are performed outside the normal biological context

29
Q

what motivated the use of in vitro toxicology?

A
  • social concerns
  • ethics
  • knowledge
  • speed
  • efficiency
  • money
30
Q

what is the first key event for in vitro toxicology?

A

the creation of Society for the Prevention of Cruelty to Animals (SPCA) in UK

31
Q

what did Hall do?

A

proposed 5 principles that should govern animal experimentation

32
Q

what are Hall’s 5 principles?

A
  1. Experiment should not be done if the information can be obtained by observation
  2. Experiment must have a clearly defined and obtainable objective
  3. Prevent duplication
  4. Experiments should be done with least infliction of suffering and use of least sentient
    animals
  5. Do experiment to provide clearest possible results
33
Q

what is considered not sentient? what about low sentient?

A
  • Beings that have no centralized nervous systems are not sentient. This includes bacteria, archaea, protists, fungi, plants and certain animals
  • So for our purposes, less sentient = “lower” on the phylogenetic tree
34
Q

what did Russell and Burch do?

A

propose the 3 Rs

35
Q

who proposed the 3 Rs?

A

Russell and Burch

36
Q

what did Henry Spira do?

A

campaign against cosmetic companies

37
Q

John Hopkins University created what? (key event for in vitro toxicology)

A

Centre for Alternatives to Animal Testing

38
Q

what is the act that controls animal testing?

A

Health Research Extension Act

39
Q

what is ECVAM?

A

European Centre for the Validation of Alternative Methods

40
Q

what is ICCVAM?

A

Interagency Coordinating Committee on the Validation of Alternative Methods

41
Q

what are the 3 Rs?

A
  1. Refinement
  2. Reduction
  3. Replacement
42
Q

explain the 3 Rs.

A
  1. Refine experimental techniques to lessen pain or distress
  2. Reduce the number of animals necessary for a particular test
  3. Replace animals with other models
43
Q

what are things that can be done for refinement?

A
  • modification of a procedure that decreases potential pain or distress
  • Procedure that uses animals lower in a phylogenetic category
44
Q

what is an alternative for the Guinea pig maximization test?

A

Mouse local lymph node assay

45
Q

what was the goal of the Guinea pig maximization test and how was it done?

A
  • to screen for substances that cause human skin sensitization (contact allergy)
  • Step 1: Intradermal injection of substance + immunological adjuvant
  • Step 2: Exposed to lower concentration and tested for allergic reaction (record after 24, 48, and 72 hrs)
46
Q

how does the Mouse local lymph node assay (LLNA) work?

A
  • Scientific principle of test: sensitizers induce growth of lymphocytes
  • Lymphocyte proliferation can be measured by radiolabeling (quantifying tritiaded thymidine) or other methods
47
Q

what are different types of transgenic animals?

A
  • gene knock down/specific mutations
  • knock in (human gene; reporter gene)
48
Q

what are pros and cons of using transgenic animals?

A

Pros
- Specific target yields decrease in number of
animals
- Decreases necessity for companion species
or higher species

Cons
- Most transgenics require additional care

49
Q

transgenic animals are often used for what type of testing? give some examples of common transgenic animal types?

A
  • for carcinogenicity testing
  • P53 +/- : = heterozygous knockdown
  • TG.AC: Ha-ras transgene (oncogene) added-in. Thus, behaves as a genetically initiated model for skin carcinogenesis
50
Q

what are some non-invasive monitoring techniques?

A
  • Magnetic Resonance Imaging (MRI)
  • Ultrasound Imaging
  • Computer Assisted Tomography (CT)
  • Positron Emission Tomography (PET)
  • Transgenic animals for fluorescent imaging
51
Q

what is the use of Computer Assisted Tomography (CT) and how does it work?

A
  • anatomic information
  • 3D X-ray technique
  • Contrast generated by difference in tissue absorption
  • 3D reconstruction and computer analysis
  • 3D images with a resolution of 100 x 100 x 100 microns obtained in a few minutes
52
Q

how does Positron Emission Tomography (PET) work and what is its use?

A
  • metabolic information
  • gamma rays emitted by a positron-emitting radionuclide
  • commonly fluorine-18
  • introduced into the body on a biologically active molecule-usually fludeoxyglucose (18F)
53
Q

how do we make Transgenic animals for fluorescent imaging and what are their use?

A
  • Fluorescent-fusion proteins
  • Image a protein’s distribution, dynamics
54
Q

what should we look out for when trying to apply reduction for in vivo testing?

A
  • Careful experimental design
  • Appropriate statistical analysis
  • Use existing published data
  • Pilot studies
55
Q

what are some alternative models to animals?

A
  • Non-animal models (in vitro, etc.)
  • Less sentient species (e.g., invertebrates)
  • Computer modelling
56
Q

what is a Replacement alternative to a skin irritancy test? why is this a good option (other than the fact we are replacing animals)?

A

EpiSkin
- Reproducible (within and among laboratories)
- Distinguishes corrosive and non-corrosive chemicals
- ECVAM concluded that the EpiSkin is scientifically validated as a replacement for the animal test to distinguish chemicals

57
Q

what are stem cells

A

immature cells that can develop into any cell

58
Q

what are some Benefits of embryonic stem cells?

A
  • study embryonic and developmental toxicity
  • access to all cell types which may be difficult to obtain (and therefore study functional toxicity, reproductive toxicity, cytotoxicity)
59
Q

what are some advantages of in vitro toxicology?

A
  • controlled testing conditions
  • reduction of variability between experiments
  • reduction of systemic effects
  • testing is fast and cheap
  • time-dependent studies can be done and samples taken
  • small amount of test material is required
  • limited amount of toxic waste produced
  • human cells and tissues can be used
  • transgenic cells carrying human genes can be easily made
    -reduction of testing on animals
60
Q

what are some limitations of in vitro testing?

A
  • general side effects cannot be assessed
  • systemic effects cannot be evaluated
  • interactions between tissues/organs cannot be tested
  • pharmacokinetic effects cannot be evaluated
  • chronic effects cannot be (easily) tested
61
Q

How is toxicity evaluated?

A

apical and pathology endpoints
(e.g., death, breeding behaviours, reproductive failure)

62
Q

What endpoints (as a marker of toxicity) are used for in vitro tests?

A
  • General cytotoxicity or cell proliferation
    1. Breakdown of cellular permeability barrier
    2. Changes in cell replication
    3. Reduced mitochondrial function
    4. Changes in protein synthesis
  • Cellular responses
    1. Genotoxicity (DNA damage and mutation)
    2. Oxidative stress
    3. Heat shock proteins
    4. Stress-activated protein kinase
63
Q

what are ways to get Better data; more data; modelling data?

A

a) High-throughput screening
b) High-content cellular response (e.g., genomics, proteomics)
c) Organ-on-a-chip
d) Bioinformatics and machine learning

64
Q

what was the first organ-on-a-chip?

A

EVATAR: female menstrual cycle in a dish

PHAR 303 (toxicology) (14 decks)

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