Toxicology Basics and Bioavailability

Irreversible Toxic Response

• CNS damage, carcinogenesis, mutagenesis, teratogenesis are examples of irreversible toxic responses

Factors Influencing Toxicity

• Factors influencing toxicity include dosage, route of exposure, age, sex, ability to be absorbed, metabolism (biotransformation), distribution within the body, excretion, and the presence of other chemicals

Bioavailability

• Bioavailability quantifies how much and how easily a compound can be absorbed
• An example of a method for testing the transmembrane movement potential is using the octanol-water partition coefficient (KOW), which refers to the ratio of the concentration of a chemical in octanol to its concentration in water
• A KOW of 10^2 to 10^3 indicates a good to ok chemical for absorption
• IV injection bypasses the absorption phase, making the substance 100% bioavailable

Phases of Toxicology

• The exposure phase involves understanding the time and frequency of exposure, as well as the route of administration
• The toxicokinetic phase describes what the body does to the toxin, including absorption, distribution, metabolism, and excretion
• The toxicodynamic phase describes what the toxin does to the body

Routes of Exposure

• Common routes of exposure include ingestion (GI tract), inhalation (lungs), dermal/topical (skin), and injection (IV, IM, IP, SC)
• The effectiveness of different routes of administration can be ranked as follows: IV > inhalation > IP > IM > SC > oral > topical

Types of Exposure

• Acute exposure involves a high dose over a short period of time
• Subchronic exposure involves repeated exposure for weeks to months
• Chronic exposure involves months to years to become recognizable

Toxicokinetics

• The absorption phase is crucial for the toxin to enter the body, except for IV administration
• Sites of absorption include the GI tract, skin, and lungs
• Factors governing transmembrane movement include lipid-water solubility, ionization of the molecule, functional groups, molecular size, and conformation

Distribution

• Distribution refers to how the toxin moves throughout the body
• Possible fates of the toxin include the site of action, storage, metabolism, and excretion
• Barriers to distribution include the blood-brain barrier, placental barrier, and mammary barrier
• Distribution occurs in the blood (fast moving) and lymph (slow moving immune system)
• Factors affecting distribution include tissue affinity, blood flow, protein binding, route of administration, and rate of metabolism
• Redistribution occurs through enterohepatic recirculation, where bile acids/salts are released into the GI tract and reabsorbed/reused

Metabolism

• Phase I metabolism converts functional groups of the toxin into more water-soluble forms
• Phase II metabolism involves conjugation reactions, which link molecules to the toxin or drug

Interaction of Toxins

• The presence of other chemicals can influence the toxicity of a toxin
• Types of interactions include additivity, synergism, antagonism, and potentiation

Dose-Response Curve

• Dose-response curves illustrate the relationship between the dose of a substance and the observed effect
• The NOAEL (No Observed Adverse Effect Level) is the highest dose at which no adverse effect is observed
• The LOAEL (Lowest Observed Adverse Effect Level) is the lowest dose at which an adverse effect is observed
• The LD50 (Lethal Dose 50) is the dose that causes death in 50% of the population
• The shape and slope of the dose-response curve can tell us about the toxicologic compound
• The steeper the slope, the more potent the toxin
• Two dose-response curves can be combined to compare the effective dose and toxic dose
• Potency refers to the range of doses over which a chemical results in increasing responses
• Maximal efficacy is the limit of the dose-response relationship

Therapeutic Index

• The therapeutic index is a measure of the safety of a drug, calculated as the LD50 divided by the ED50
• A larger ratio indicates greater safety
• The margin of safety (MOS) is a more conservative calculation, using the LD01 and ED99
• MOS is calculated as LD01/ED99x

Uncertainty Factors

• Uncertainty factors are used to provide additional safety in calculating human doses
• Factors are applied based on the type of study conducted in animals (chronic, prolonged ingestion, or short-term) with values of 100, 10, and 1000 respectively

Animal Testing

• Animal testing is required for pharmaceuticals and other chemicals
• The effects seen in animals can be extrapolated to humans
• Exposure to toxins at high doses in animals is a valid method for identifying hazards in humans

Neoplasia

• Tumor is a space-occupying lesion that may or may not be neoplastic
• A neoplasm is an independent growth of tissue with abnormal regulation of gene expression
• Metastases are secondary growths of cells from the primary neoplasm
• Cancer is a subset of malignant neoplastic lesions
• A carcinogen is an agent that causes or induces neoplasia
• Carcinoma is a malignant tumor arising in the epithelium
• Sarcoma is a malignant tumor arising in muscle or connective tissue

Carcinogens

• Carcinogens can include both synthetic compounds and other factors like hormonal imbalances, tobacco smoke, diesel exhaust, and dietary habits

Functional Groups

• Carcinogenic chemicals often contain nitrogen
• These groups interact well with DNA, leading to cancer and disruption

Ultimate Carcinogens

• Ultimate carcinogens are highly reactive metabolites involved in the carcinogenic process

This quiz covers fundamental concepts in toxicology, including irreversible toxic responses, factors influencing toxicity, and the importance of bioavailability. Explore how various factors such as dosage and route of exposure affect toxic responses and absorption. Test your knowledge on key definitions and principles related to toxic substances.