Toxicology Flashcards
1
Q
What is toxicology?
A
- Study of the adverse effects of chemicals
2
Q
Discuss methods of exposure to Toxins?
A
- Deliberate exposure of specifically designed toxins.
- Deliberate over-exposure to natural toxin or drug.
- Environmental exposure to chemicals.
- Unexpected adverse effect to a drug
3
Q
Discuss unwanted effects of drugs.
A
- Side effects: relatively minor and reversible when treatment ceases or after a short while.
- Adverse effects: More serious and May be life threatening.
- Drug interactions: Unwanted effects that occur in presence of other drugs.
- Contraindications: Conditions that may precipitate an unwanted effect
4
Q
What are acute toxicity studies?
A
- Administration of a single dose or multiple doses can be tested.
- Monitoring for 14 days.
- Outcome is determined: adverse effects, death.
5
Q
What is subacute toxicology?
A
- Repeated dosing used (Usually 3 or 4 dose levels used).
- 14 days treatment.
- Histopathology and clinical chemistry
- Used to estimate dose for subchronic studies
6
Q
What is subchronic toxicology?
A
- Studies up to 90 days.
- Three doses used based on previous studies: low dose = non toxic, high doses = toxic but <10% fatal.
- Multiple endpoints: clinical chemistry, pathology, histopathology.
7
Q
What are Chronic toxicology studies?
A
- Studies of 3 mo to 2 yrs duration.
- Gross and microscopic studies are performed on all animals.
- Chronic studies often used to study carcinogenicity.
- Necessary to have control untreated animals.
8
Q
What are toxicology end points?
A
- Necessary to define what a toxic effect is: Death, organ damage, illness.
9
Q
What is LD50?
A
- Lethal dose.
- Acute toxicity study where death is endpoint.
- Examples: Sucrose: 29.7 g/kg (rat, oral), Botulinum toxin: 1 ng/kg (human, iv estimate).
10
Q
What is NOAEL?
A
- Defined as the highest dose tested that does not cause a statistically significant toxic response.
- Includes pharmacologic response.
- Not necessarily a risk-free dose.
11
Q
What are the problems with NOAEL?
A
- Must be a tested dose (DR curve is ignored).
- Depends on the number of animals used.
- Depends on assay used.
12
Q
What is LOAEL?
A
- Lowest Observed Adverse Effect Level.
- Lowest dose tested that generates a statistically significant toxic effect.
- Includes pharmacological response.
13
Q
What are the problems with LOAEL?
A
- Must be a tested dose (DR curve is ignored).
- Depends on the number of animals used.
- Depends on assay used.
14
Q
What is carcinogenesis?
A
- Carcinogenesis is the uncontrolled replication of tissue cells with a monoclonal character, implying origin from a single cell mutation.
15
Q
Describe the principles of carcinogenesis?
A
- Initiation: Mutation in key regulatory pathways
- Promotion: Expansion of the initiated cell through signal transduction pathways and inhibition of apoptosis.
- Progression: Conversion of an initiated cell to a malignant cell
- A complete carcinogen has all three activities
16
Q
What are non toxic carcinogenics?
A
- Drugs that are carcinogenic but are not mutagenic e.g. benzene, saccharin.
- May be due to promotion of spontaneous initiated tumours.
- May cause direct toxicity, cell damage and cell proliferation enhancing carcinogenesis.
17
Q
What is developmental toxicology?
A
- Adverse effects that may arise from pre-conception through to puberty due to exposure to a drug.
- Teratology: defects that occur between conception and birth.
- Reproductive toxicology: adverse effects of exposure to a drug on either the male of female reproductive systems
18
Q
What is genotoxicity?
A
- Determines if there is a potential to cause genetic damage
- Standard 3-test battery: test for gene mutations in bacteria, in vitro test for chromosomal damage in mammalian cells, in vivo test for chromosomal damage to rat haematopoietic cells.
19
Q
What are specific toxicology tests?
A
- Behavioural (neurotoxicity)
- Immunotoxicity
- Skin toxicity
20
Q
What is behavioural toxicity?
A
- Abuse potential: Reinforcing effects (self-administration), discriminative effects (drug discrimination), physical dependence (withdrawal).
- Functional observational battery: Behavioural tests, allow onset, progression, duration, reversibility of neurotoxicity to be determined.
- Studies of nature of neurotoxicity
21
Q
What is skin toxicity?
A
- Usually drug is administered intradermally (sometimes with Freund’s complete adjuvant).
- Subsequent challenge is with drug only.
- E.g. Draize and Guinea pig maximization test
22
Q
What is photo-toxicity?
A
- Drugs can make the skin hypersensitive to sunlight.
- May be immunological.
23
Q
What are immunological toxic reactions?
A
- When proteins are used as drugs they can be antigenic e.g. monoclonal antibodies leading to an immune reaction.
- Binding to proteins making them antigenic.
- Requires prior exposure and usually metabolism.
23
Q
What are immunological toxic reactions?
A
- When proteins are used as drugs they can be antigenic e.g. monoclonal antibodies leading to an immune reaction.
- Binding to proteins making them antigenic.
- E.g. penicillin.
- Requires prior exposure and usually metabolism.
24
What are the immune reaction types?
- Immediate reactions: Occur with 1 hour, usually IgE mediated (allergy), can cause anaphylaxis
- Delayed reactions: Occur after days of treatment, not IgE-dependent.
24
What are the immune reaction types?
- Immediate reactions: Occur with 1 hour, usually IgE mediated (allergy), can cause anaphylaxis
- Delayed reactions: Occur after days of treatment, not IgE-dependent.
25
What cause immune thrombocytopenia?
- Heparin-induced thrombocytopenia
- Heparin binds to PF4 on platelets
- Antibody binds to platelets
- Antibody-bound platelets are cleared
26
What is toxicogenetics?
- Gene polymorphisms can alter the response to a drug (pharmacogenetics).
- Can increase susceptibility to toxic effects.
27
What is idiosyncratic toxicity?
- Not dose-dependent
- Probably due to genetic polymorphisms: Often in metabolising enzymes.
- Can also be due to immune response.
- Difficult to predict.
