Lecture 13

Question 1

What is Thalidomide/Contergan?

Answer 1

It was a drug marked in the 1950s to alleviate morning sickness in pregnant woman

Question 2

What was the issue with Thalidomide/Contergan?

Answer 2

It ended up causing thousands of infants to be born with phocomelia which is the severe malformation of limbs

Question 3

When Thalidomide/Contergan withdrawn and what is it now used for?

Answer 3

-Withdrawn in 1961
-now used to treat leprosy and multiple myeloma as an orphan drug

Question 4

What is potential drug teratogenicity?

Answer 4

It is the ability of a substance to cause birth defect

Question 5

Why are animals used in toxicity testing

Answer 5

Because they are the most reliable testing source in the absence of human data

Question 6

Toxixty tests depend on?

Answer 6

-The type of substance
-Regulations of the country
-The use of the test agent

Question 7

How does tissue-specific toxicity occur?

Answer 7

Usually occurs from specific interactions between the test substance and a particular biological system

Question 8

Considerations for toxicity testing:

Answer 8

-Biological considerations
-Physio-chemical properties of test substance

Question 9

Biological considerations for toxicity testing includes:

Answer 9

-Species, strain, and sex of test animal
-Metabolic and physiological similarity to humans
-Duration of toxicity testing
-Number and diet of test animals

Question 10

Physico-chemical properties of test substance includes:

Answer 10

-Structure
-Vapour pressure
-pKa (acid dissociation constant)
-Solubility (water vs fat)
-Melting point
-Purity

Question 11

Compounds which undergo toxicity testing are divided into?

Answer 11

1. Intended for administration to humans
2. Non intended for administration to humans

Question 12

Examples of substances intended for administration to humans:

Answer 12

-Pharmaceuticals
-Food additives
-Drug additives

Question 13

Examples of substances non-intended for administration to humans:

Answer 13

-Biocides(pesticides)
-Environmental contaminants
-Industrial chemical
-Household chemical
-Natural toxins

Question 14

Preclinical testing can be done on what?

Answer 14

-Animals
-Animal models of human disease
-Isolated organs
-Cell cultures

Question 15

How does toxicity ratings work?

Answer 15

It goes from 1 to 6
1 being super toxic and 6 being practically non toxic

Question 16

Reasons tests may vary between laboratories:

Answer 16

-Differing genotype or phenotype of sample population
-Difference in tested range of animal species
-Influence of environmental factors
-Mode of drug administration

Question 17

What a slightly toxic agent?

Answer 17

-Ethanol
-Has a high LD50 value

Question 18

Chronic exposure of ethanol results in what?

Answer 18

It triggers severe side effects in various tissues based on drastic metabolic disturbances

Question 19

Example of a super toxic agent?

Answer 19

-Botulinum toxin
-Has an extremely low LD50 value

Question 20

What bacteria is botulinum toxin produced by?

Answer 20

Clostridium botulinum

Question 21

What can exposure to botulinum toxin cause?

Answer 21

Sever food poisoning called Botulism

Question 22

How does Botulinum toxin work?

Answer 22

It is a protein that binds to cholinergic nerve terminals which inhibits the release or Achieve by degrading key proteins for the vesicular docking process

Question 23

What is a dose-response curve?

Answer 23

Can determine the concentration of an agent that causes the median lethal dose

Question 24

What alternative approach can be used for reduce the number of animals in toxicity testing?

Answer 24

Fixed Dose procedure

Question 25

Traditional whole animal toxicity tests:

Answer 25

-Acute
-Sub chronic
-Chronic
-Reproductive
-Behavioural

Question 26

Pathological and histological examination:

Answer 26

Involves weight and histology of organs

Question 27

Analytical and functional tests employed in chronic toxicity tests:

Answer 27

-Hematology
-Blood chemistry
-Urine analysis

Question 28

Advantages of non-animal alternative in vitro toxicity testing

Answer 28

-Improved screening purposes
-For regulatory purposes

Question 29

Advantages of increased screening purposes:

Answer 29

-Good correlation with in vivo toxicity data
-Low incidence of false negatives
-Low incidence of false positives
-Cheap and fast

Question 30

Advantages of improved regulatory purposes:

Answer 30

-High interpretability
-Mechanistically based assay
-High predictive power
-Rapid and reliable tests

Question 31

Advantages of proper in vitro test systems?

Answer 31

-Drastic reduction of animal usage
-Smaller quantities of test chemicals needed
-Reduced variability between analytical experiments

-see slide 19 for more info

Question 32

Examples of in vitro test system:

Answer 32

-Cell culture based cytotoxicity assay
-Chicken egg CAM test
-Genotoxicity AMES test (used for Salmonella)
-Organ/Tissue-derived cell testing

Question 33

Examples of cell culture based cytotoxicity assays:

Answer 33

-Kenacid Blue total protein assay
-MTT metabolism assay
-Neutral red dye uptake assay
-Crystal violet dye assay
-ATP content assay
-LDH leakage assay

Question 34

What are AMES tests (Salmonella) used for?

Answer 34

-Initial screening of potential genotoxins
-Determins mutagenic of test chemical prior to measuring mutagenic potential in animals

Question 35

Types of salmonella strains:

Answer 35

1. Histidine positive
2. Histidine negative

Question 36

Chicken egg Het-CAM test is used to?

Answer 36

To asses membrane irritation