Factors Influencing Drug Toxicity

What are the major routes for toxicant entry?

1. Gastrointestinal tract (ingestion) 2. Lungs (inhalation) 3. Skin (topical) - other eg. parenteral

What are the 2 broad classes of deviation from sigmoidal dose-response relationships?

1. Idiosyncratic responses 2. Hypersensitivity responses

What are the 4 main factors that influence drug toxicity?

1. Magnitude of exposure (ie. the dose) 2. Route and site of exposure 3. Duration and frequency of exposure 4. The latency of the toxic response - how quickly or slowly the toxicity appears after exposure to a chemical

are chemicals more toxic via and oral route or a parenteral route (i.v.)?

Many chemicals are more toxic via parenteral route (i.v.) - less toxic by the oral route

Explain the basics of the dose-response curve - include what the graph establishes, what NOAEL is, and what steepness represents

Number responding (%) vs. log10 dosage - The steeper the slope, the quicker the toxicity is observed - Helps identify people who will show toxicity at low doses - establishes causality (ie. that the chemical has in fact caused toxicity) - suggests threshold dose where an effect occurs - no adverse effect level = NOAEL - shows rate at which the injury builds up (the slope represents this)

What is the effect of "dose fractionation"?

Subdividing or fractionating doses of toxicants usually reduces the toxic effect - ie. 10 grams of a chemical is more toxic in a single dose than if administered over 10 days note: carcinogens and mutagens may be exceptions

Explain idiosyncratic responses to toxicity

There are due to unusual traits of the exposed individual: - genetic traits for abnormal response - genetic traits for abnormal metabolism

Define "Dose"

Total amount of material to which an individual is exposed

Define "dosage"

defines the amount of material in relation to a characteristic of recipient (eg.body weight)

When is Acute exposure evident?

exposure for less than 24 hrs

When is Subacute exposure evident?

exposure for less than 30 days

When is Subchronic exposure evident?

exposure over 1- 3 months

When is Chronic exposure evident?

exposure over more than 3 months

explain hypersensitivity responses to toxicity

usually involve immune/allergic response: - occur at low incidence rate (they are rare) - involve prior exposure = priming of the immune system

Explain the biological variability that is observed with dose-response relationships?

within a population, most individuals respond similarly to any given dose of toxicant - however, subsets of individuals will display either heightened susceptibility or resistance --> resistant individuals have a mild response, susceptible individuals can have severe response - distribution of responses is typically bell shaped

What does the latency of a toxic response refer to? give examples

refers to when the toxicity is evident - toxicity can occur either soon after exposure, or after a delay Eg. diethylstilbestrol (DES) - used to prevent miscarriages - vaginal/uterine tumours in female offspring - due to in utero exposure Eg. Tri-o-cresylphosphate (TOCP) - plasticizer used in varnishes, lubricants etc. - has anticholinesterase activity - produces a dealyed neuropathy syndrome - muscle eakness, unsteady gait, ataxia, leg paralysis

What kind of graph is the dose-response relationship for toxic substances?

resembles a sigmoidal D-R curve of pharmacology - Sigmoidal curve (S-shaped