RXRS402 TOXICOLOGY

RXRS 402: Human Pharmacology: Challenge of Therapeutics in Society

General Overview of Toxicology

  • Instructor: Martine Culty

  • Department of Pharmacology and Pharmaceutical Sciences, USC

  • Term: Fall 2025

  • Focus: Understanding the principles of toxicology and its application in therapeutics.

Goals and Objectives

  • Aim: To provide a broad overview of toxicology.

  • Key Topics:

    • Basic Principles:

    • Dose-response

    • Toxicokinetics (TK) - Absorption, Distribution, Metabolism, Excretion, and Storage (ADME)

    • Toxicodynamics (TD)

    • Therapeutic Index (TI)

    • Risk vs. Hazard:

    • Understanding exposure factors.

    • Factors Affecting Susceptibility to Toxicants:

    • Example: Dietary supplements toxicity.

Toxicology vs Pharmacology

  • Etymology:

    • "Tox-" from Greek "τοξον" (bow, poisoned arrow)

    • "Pharma-" from Greek "pharmacon" (drug)

  • Concepts:

    • Toxins: Unwanted effects associated with therapeutic agents.

    • Adverse Effects in Pharmacology:

    • Also referred to as adverse drug events (ADE) or adverse drug reactions (ADR).

    • Defined as any unwanted or dangerous reaction to a drug.

What is Toxicology?

  • Definition:

    • Study of adverse effects of chemical, biological, or physical agents on living organisms.

  • Toxicant:

    • Chemical, physical, or biological agent that exerts harmful effects.

  • Xenobiotic:

    • Any substance foreign to a biological system.

Classification of Toxic Substances

  • Synthetic/Man-made:

    • Organic:

    • Examples: Hydrocarbons, solvents, plasticizers, industrial by-products.

    • Inorganic:

    • Examples: Acids, bases, pigments, metal oxides.

  • Natural Poisons:

    • Minerals:

    • Metals (e.g., mercury, lead), metalloids (e.g., arsenic, silicon), non-metallic (e.g., phosphorus).

    • Biological Toxins:

    • Plant (phytotoxin), Animal (zootoxin), Fungal (mycotoxin), Bacterial (microbial).

  • Use in Human Activities:

    • Drugs and excipients

    • Health care products, food additives

    • Pesticides, industrial and household chemicals, environmental pollutants.

Relevance of Toxicology in Society

  • Establishing exposure standards and informing the public on chemical exposure risks (EPA).

  • Optimizing drug use while minimizing adverse effects.

  • Regulatory actions, like the FDA's ban on Fen-Phen in 1997 due to increased health risks (myocardial infarction, valvular heart disease).

Historical Perspective on Toxicology

  • Development of toxicology from ancient texts on treatments and poisons.

  • Contributions of scientists like Paracelsus, the father of toxicology.

  • Recognition of toxicology as a distinct field during the mid-20th century.

Paracelsus' Contribution

  • Quote: "All substances are poisons; there is none which is not a poison; the right dose differentiates a poison from a remedy."

  • Established foundational concepts in toxicology and pharmacology.

  • His work highlighted occupational toxicology, focusing on miners’ exposure to toxins.

Case Study: Hydration Toxicity

  • Incident of dehydration-related death in a high school athlete due to excessive fluid intake.

    • Significant effects of over-hydration leading to brain swelling, potential seizures, coma, or death.

Regulatory Framework in Toxicology

  • Historical establishment of regulatory bodies (FDA, NIH, etc.) during the 1930s.

  • Recognition of toxicology's importance during World War II and post-war drug production increases.

Branches of Toxicology

  1. Clinical Toxicology: Hospital settings.

  2. Forensic Toxicology: Medical examinations.

  3. Environmental Toxicology: Government and academia focus.

  4. Biochemical and Molecular Toxicology: Industry and academic applications.

  5. Product Development Toxicology: Addressing safety in new products.

  6. Regulatory Toxicology: Ensuring compliance with government standards.

Environmental Toxicology and Pharmacology

  • Case: Pharmaceutical pollution of rivers examined in a study revealing environmental and health risks.

Emerging Trends in Toxicology (21st Century)

  • Toxicogenomics: Study of gene expression changes due to toxins.

  • Predictive Toxicology: In vitro and in silico risk assessment.

  • Transgenerational Toxicology: Effects of environmental exposure across generations.

Mechanisms of Toxicant Action

  • Analysis of toxicant interactions at molecular levels—using genomics and proteomics.

  • Identification of cellular mechanisms of toxicity and related biological pathways.

Developmental Toxicology

  • Focus on susceptibility at different developmental stages.

  • Human developmental timeline showing critical periods affected by teratogens.

Risk Assessment Framework

  • Risk Formula: Risk = Hazard x Exposure

    • Hazard: Potential source of damage.

    • Exposure: Contact state with the hazard.

Factors Influencing Toxic Response

  • Identify hazards, analyze risks, and design control measures for exposure.

  • The significance of exposure routes (oral, dermal, inhalation, injection).

Drug Toxicity Classifications

  • Acute toxicity: Short-term exposure.

  • Chronic toxicity: Long-term exposure.

Individual Susceptibility Factors

  • Genetic predispositions, gender differences, dietary habits, age effects, and health conditions.

Therapeutic vs. Lethal Doses

  • ED50: Effective dose for 50% efficacy.

  • TD50: Toxic dose for 50% adverse effect.

  • LD50: Lethal dose for 50% mortality.

  • Tolerable Daily Intake (TDI): Amount that can be ingested daily without harm.

Dose-Response Relationships

  • Shape of dose-response curves used to predict toxicity levels.

  • Points of interest: NOAEL (no observed adverse effect level), LOAEL (lowest observed adverse effect level).

Measures of Drug Safety

  • Therapeutic Index (TI): Ratio of TD50/ED50 indicating a drug's safety margin.

Case Studies of Drug Toxicity

  • Digoxin and Botox as examples of narrow therapeutic windows and toxicity considerations.

Dietary Supplements and Toxicity Concerns

  • Regulatory challenges and potential risks associated with dietary supplements.

  • Historical data showcasing adverse events from dietary supplements per year.

Summary of Risk vs. Benefits of Supplements

  • Lack of evidence for health benefits for most adults without deficiencies; acknowledgment of overdose risk.