PCOL3011: Toxicology

Overview of Course
The basic science of poisons

- Clinical
o Poisoning, TDM (therapeutic drug monitoring)
- Non-clinical
o LD_50 signs of toxicity in animals, allometric scaling
- Environmental
- Epidemiological
o Identification of risk factors and the use of the Hill criteria

What do toxicologists do?

Learn facts

Interpret data

Solve problems

Estimate risks!!

Risks from what?

- Adverse drug reactions

- Drugs in development
- Chemical products in the household
- Environmental hazards
Content Areas

1. Xenobiotic Metabolism
Toxicokinetics, drug-drug interactions, pharmacogenomics, bioactivation of
toxicants
2. Epidemiology and statistics
Interpreting data, calculating thresholds, OR, RR, standardization of death rates,
estimating risks
Types of study, how we know
3. Target organ toxicology
Why toxicants affect some tissues differently
Lung, Brain and kidney
4. Toxinology
Snake and spider toxins
Alpha and beta neurotoxins
Myotoxins, Haemotoxins, etc.
Other venoms
Cone shell toxins
5. The biology of cancer
How cancer works
Initiation and promotion, progression
Complete carcinogens do all three
How do toxicants cause cancer?

Lecture One: What is toxicology?

Lecture Outline
1. What is a toxicant?
2. What factors determine toxicant induced damage to the body?
3. How does a toxicant cause damage in the body?
4. The 5 basic themes of the course
5. Administrative details of the course

Learning Objectives
1. Explain what is meant by a toxicant
2. Outline the factors that determine toxicant induced damage in the body
3. Describe the different processes by which a toxicant can cause damage in the body

Lecture Notes

Toxin vs. Toxicant

- Toxicant: any agent that is capable of producing deleterious effects in the body (or
organism)
o E.g. Carcinogens, lead, etc.
- Toxin: a natural product e.g. from plant or animal
o E.g. Coniine from Hemlock or Amatoxins from Death cap and destroying angel
Factors that determine toxicitiy

Dose

The most important determinant of toxicity

- The dose makes the poison

- LD_50 can be used for toxicity comparisons

Dose Response

- Can be single, sub-chronic, chronic

- Dose determines concentration at the target organ or receptor site
- Concentration determines extent of toxic effect

Dose Response Curves

- Dose response relationship can be graphed

- Y-Axis is response in pharmacology
- Y-axis often % mortality in toxicology
- Both can be treated mathematically in the same way
- Taking the log of the X-axis (dose) produces a sigmoidal dose-response curve
-
- LD_50 instead of EC_50

LD_50 as measure of toxicity

- Distribution of responses (mortality frequency) is normal shape on log-X axis

- Cumulative presentation becomes sigmoid
- Inflection point shows LD_50 value on X axis (mg/kg)
- Each probit unit is one SD such that scale shows 2SD each side of LD_50

Exposure

Route of exposure

- Toxic effect may not occur with all routes of exposure

- Routes in descending order of effectiveness for toxicity:
o Inhalation > intraperitoneal > subcutaneous > intramuscular > intradermal > oral >
dermal

Toxicokinetics

- How a substance gets into the body and what happens to it in the body.
- ADME
o Absorption
o Distribution
o Metabolism
o Elimination

Timing of exposure

- Toxicity sometimes only appears after prolonged exposure

- Carcinogenicity testing requires prolonged exposure to the potential agent
- Exposure can be classified by duration:
o Acute (e.g. <24 hours)
o Subacute (e.g. < 1 month)
o Subchronic (1 3 months)
o Chronic (> 3 months)