TOX4000.docx - Principles of Toxicology What is Toxicology...

Principles of Toxicology
What is Toxicology?
 Study of adverse effects of chemical or physical agents (ex: radiation) on living organisms
What is Medical Toxicology?
 Must consider whether drug is safe or effective --> Determining if and at what doses it is safe
Why study Medical Toxicology?
 Mechanistic Tox
o Determining how the agent causes that effect
 Regulatory Tox
o Government agencies that determine whether product is safe & effective
 Descriptive Tox
o Giving an agent, and seeing what effect is (Cause and effect)
 Risk assessment
o Develop new drug --> seen effect and safety in other species --> seen toxicity at high doses
o Until you give pill to human, can’t know 100% if it’s safe in humans (differences in species)
o Want to do everything you can to minimize the risk
o Virtually impossible to say 0% risk until you perform clinical trials
Does an agent cause a toxicological response?
 Causation vs Correlation
1. Strength of association - Relationship between independent and dependent variables
2. Consistency of findings
3. Biological gradient - Dose response
4. Temporal sequence
i. Cause before effect --> Exposure before incidence of disease
5. Biological and theoretical plausibility - Mechanism of action
6. Coherence w/ established knowledge - No competing hypothesis
7. Specificity of association - Cause is tightly linked w/ outcome
Characteristics of Exposure

Dose-Response Relationship
 Examples? Essential nutrients Water Ethanol
 Too much of anything can be toxic
Ultimate Toxicological Dose- Response: LD50
 Lethal dose (effective in 50% of people)
 Causes death in 50% of population

What determines whether something is a toxicant or not?
 Depends on dose
 Therapeutic index
o Window between an effective dose & toxic dose
o Wider T.I. = greater safety
o TI = TD50/ED50
 10-fold diff in concentrations
 Lower the number, the
 Dose and dose rate
o Consider exposure
o Accumulation and frequency of exposure
 Acute
 Subchronic
 Chronic
o Single dose
 Rate of elimination
 Concentration of 2 is toxic
 Fast rate of elimination means not in window of toxicity for long
o Repeated doses
 A --> very slow metabolism/elimination
 B --> additive, not all eliminated in a day, same amount eliminated
 C --> eliminated at the end of the day
Descriptive animal toxicology testing
 Assumptions
o Biological response in animals is representative of humans
o Exposure to high doses necessary + valid
o Results from new genomics technology still requires verification
 Large screening, still have to validate that gene
 Acute testing
o High dose
o Goals
 Provide estimate of intrinsic toxicity of the substance (LD50)
 Provide info on target organs & other clinical manifestations
 Identify species diff and susceptible species
 Establish reversibility of toxic response

 Provide info that will guide dose selection for longer-term studies
 Chronic administration
o 6 months to 2 years in rodents, 1 year in other species
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