Concepts in Toxicology
Course Introduction

  • Instructor: Dr. Laura Basirico

  • Course Code: ENVS 1126

  • Semester: Fall 2025

Biotransformation

  • Definition: The process by which substances interact with enzymes in the bloodstream to undergo changes for elimination.

  • Key Functions: Organisms eliminate various chemicals from environmental/dietary entry.

  • Main Excretory Organ: Kidneys efficiently eliminate polar molecules.

  • Polar vs Non-Polar Compounds: Non-polar compounds persist longer until transformed into more polar/water-soluble metabolites.

  • Reaction Phases: Non-polar, non-volatile toxicants undergo a two-phase biochemical reaction.

Phase I and Phase II Reactions

  • Biotransformation Overview: A living organism chemically alters foreign chemicals (xenobiotics) to detoxify them, transforming lipophilic compounds into more hydrophilic metabolites for elimination. This enzymatically driven process can sometimes yield more toxic forms.

Phase I Reactions

  • Mechanism: Introduces a polar group onto a lipophilic toxicant, increasing water solubility and reactivity.

    • Catalyzing Enzyme: Cytochrome P-450 monooxygenase enzyme system (heme-containing, abundant in liver's smooth endoplasmic reticulum).

  • Reactions Included: Oxidation, Reduction, Hydrolysis, resulting in small increases in hydrophilicity.

Example of Phase I Reaction

  • Chloroprene Epoxide Formation: Transformation of chloroprene into a reactive benzene epoxide via cytochrome P-450, causing toxicity (e.g., bone marrow damage, leukemia, acute CNS poisoning at higher concentrations).

Phase II Reactions

  • Mechanism: Enzymatically catalyzed conjugation (attachment of an endogenous molecule) to a polar functional group on the toxic compound, further increasing water solubility and aiding elimination.

    • Products of Phase I reactions often serve as reactants.

    • Metabolites are usually less toxic than the parent compound.

  • Energy Requirement: Requires ATP.

  • Conditions: Occurs with reactive functional groups (-OH, -COOH, -X), mainly involving cytochrome P-450 II enzymes.

Functional Groups in Phase II Reactions

  • Types: Carboxyl (-COOH), Hydroxyl (-OH), Halogen (F, Cl, Br, I), Amino (-NH_2).

  • Properties of Conjugation Products: Higher polarity leads to greater water solubility for easier elimination.

Toxicant Metabolism

  1. Detoxification: Conversion of harmful chemicals into less toxic, excretable forms.

  2. Bioactivation: Conversion of xenobiotics into more reactive or toxic forms (e.g., Aflatoxin B1 forming a DNA-binding toxic compound).

  3. Key Organs in Metabolism:

    • Liver: Rich in biotransformation enzymes, quickly transforms absorbed substances.

    • Kidneys: Filter and remove water-soluble toxicants/metabolites for excretion in urine.

    • Bioaccumulation: Substances with low elimination rates can accumulate over time.

Kinetic Phase of Toxicant Metabolism

  • Different Outcomes: Toxicants can be detoxified, remain unchanged, or be further metabolized/excreted.

  • Protoxicant: Metabolically converted to a toxic form, interacting with biological systems.

Results of Exposure

  • Toxic Effects Categorization: Systemic toxicity varies by site, including:

    1. Mutagenesis

    2. Teratogenesis

    3. Carcinogenesis

    4. Effects on Immune and Reproductive Systems

Mutagenesis

  • Definition: Mutagens alter DNA and gene expression, causing inheritable traits (genotoxicity).

  • Types of Mutations: Gene mutation (base sequence change), chromosome aberrations, aneuploidy/polyploidy (chromosome number changes).

  • Health Implications: Can cause cancer and birth defects, often via DNA alkylation.

Teratogenesis

  • Definition: Teratogens are chemicals causing birth defects.

  • Mechanisms: Mutating germ cells or damaging embryonic/fetal cells (e.g., Thalidomide).

  • Biochemical Mechanisms: Inhibiting enzymes, depriving essential substrates, interfering with energy supply, altering placental membrane permeability.

  • Vulnerabilities: Fetal P-450 system and organ systems are immature, making them highly vulnerable.

Carcinogenesis

  • Definition: Uncontrolled cellular replication and abnormal growth, a complex, multi-stage process leading to cancer.

  • Carcinogenic Agents: Chemical (PAHs), biological (viruses), ionizing radiation (X-rays), and genetic factors.

  • Unique Properties: Persistent, cumulative biological effects; effects from divided doses; distinct genetic mechanisms.

Historical Context in Carcinogenesis Research

  • Significant Observations: Early links between exposures and cancer (e.g., Sir Percival Pott and chimney sweeps in 1775; tobacco, radium, asbestos, 2-naphthylamine in dye workers).

Examples of Major Carcinogens

  • Naturally Occurring: Griseofulvin, Safrole, N-methyl-N-formylhydrazine (require bioactivation).

  • Synthetic: Benzo(a)pyrene, Vinyl chloride (require bioactivation).

  • Primary Carcinogens: Do not require bioactivation.

Immune System Response

  • Protection Against: Xenobiotics, infectious agents, and neoplastic cells.

  • Effects of Toxicants: Immunosuppression (reduced response) or hypersensitivity (overactive response) from agents like beryllium, chromium, nickel, and pesticides.

Endocrine Disruption

  • Affected Groups: Aquatic organisms are particularly vulnerable.

  • Endocrine Regulation: Controls metabolism and reproductive functions.

  • Effects: Reproductive dysfunctions, abnormal steroid/hormonal levels, altered sex characteristics.

  • Examples: Synthetic/natural hormones acting as endocrine disruptors, including 17α-ethinylestradiol, PCBs, and phthalates.