Toxicology

Question 1

List studies that investigate toxicology.

Answer 1

• Single Dose Toxicity (Acute)
• Repeat Dose Toxicity (Chronic
• Genotoxicity
• Carcinogenicity
• Reproductive Toxicity
• Safety Pharmacology
• Pharmacokinetics Studies

Question 2

Compare information gleaned from acute toxicology vs chronic toxicity studies.

Answer 2

Acute toxicology studies SINGLE DOSE
- Detect overdose
Chronic toxicology studies REPEAT DOSES
- Detects long term effects

Question 3

Describe the methods and rationale for reproductive studies across multiple generations.

Answer 3

Reproductive studies

• Aim to detect the potential for teratogenicity and harm to the foetus
• Combination of studies should allow exposure of mature adults and all stages of development from conception to sexual maturity
• Measure penetration of blood/uterus barrier (placental transfer)
• Transfer into milk
• Examine effects on F0 and F1 generation

Question 4

Explain the measurement principles for in vitro genotoxicity and in vivo carcinogenicity studies.

Answer 4

In vitro genotoxicity: Ames Test
- tests for bacterial mutation of genome/chromosome

In vivo carcinogenicity: Micronucleus
- Micronucleus assay (looks for chromosomal aberration)

Question 5

What are Anti-sense Oligonucleotide therapies?

Answer 5

• ASO’s are nucleic acid oligomers complementary to a gene’s mRNA (mRNA sequence is called the “sense” sequence)
• They bind mRNA and inhibit its action in various ways
• Potential targets include genetic disorders, cancers, and infectious diseases

Question 6

Describe some of the new challenges faced by regulators by the development of oligonucleotide therapeutics.

Answer 6

Potential toxicities of ASOs:
o Exaggerated pharmacological effects
o Off-target hybridisation effects
o Sequence-related non-hybridisation effects