Toxicokinetics is the study of the absorption, distribution, metabolism, and excretion (ADME) of toxic parent compounds and their metabolites. It helps predict the concentration of toxin at the site of injury and resulting damage.

Acute toxicity: Result of single, large exposure; effects visible within minutes to hours (sometimes delayed).

Chronic toxicity: Effect of prolonged exposure; may manifest after years.

Absorption:

Primary sites: Gastrointestinal tract, respiratory tract, skin.

• Ingested: Food contaminants, therapeutics, lead.
• Inhaled: Air pollutants (cigarette smoke, exhaust, ozone), occupational exposures (benzene, asbestos), chemical warfare agents.
• Dermal: Relatively impermeable; caustic liquids or organic compounds (glycol ethers, insecticides) can diffuse through, especially after prolonged contact.

Distribution:

Rapid via circulation; vessel-rich organs (brain, liver, kidney) exposed faster. Tissue concentration determined by affinity. Plasma proteins bind toxins, retarding distribution. Lipophilic molecules diffuse directly; water-soluble use channels/pumps/receptors. Blood-brain barrier excludes polar molecules.

Elimination:

Primarily renal and hepatic excretion. Respiratory system eliminates gases/volatiles. Storage in fat/bone (e.g., lead in bone for decades, DDE in fat) prolongs presence. Inhaled particulates phagocytosed by macrophages may never be eliminated.

Xenobiotics modified by Phase I (oxidation via cytochrome P450) and Phase II (conjugation) reactions to increase hydrophilicity for excretion.

Three possible changes:

1. Detoxication: Rendered less toxic.
2. Conversion to another toxic species.
3. Toxication: Relatively inert xenobiotic converted to toxic species (e.g., benzene → benzene oxide → phenolic compounds → aplastic anemia).

Side effects of some therapeutics occur via toxication (e.g., acetaminophen → NAPQI → hepatic necrosis if glutathione depleted). Balance of toxication/detoxication determines ultimate toxicity.

At molecular level, compounds can:

1. Interfere physically with lipids, nucleic acids, proteins.
2. Form reactive species that damage biological macromolecules.
3. Generate inflammatory/immune responses.
4. Stimulate/inhibit vital processes (oxygen delivery, energy generation, ion sequestration, neurotransmission, gene expression, cellular replication).

Cell damage may be repaired; if not, apoptosis or necrosis occurs. Prolonged exposure → organ dysfunction, fibrosis, carcinogenesis, teratogenesis. Toxins often act via multiple mechanisms (e.g., reactive species → adducts → inflammation).

i) Nonspecific Macromolecular Damage:

Strong acids/alkalis, oxidants/reductants, detergents damage tissue by hydrolyzing, oxidizing, reducing, or denaturing macromolecules. Affect exposed systems (skin, eyes, respiratory, digestive). Hydrofluoric acid (HF) penetrates deeply, destroys bone matrix, releases calcium → cardiac arrhythmias.

ii) Reactive Oxidative Species (ROS):

Nucleophiles, electrophiles, free radicals react with biological macromolecules. Often metabolites of inert compounds. Example: CCl4 → trichloromethyl radical → lipid peroxidation → hepatotoxicity/renal toxicity/cancer.

iii) Inflammatory and Immuno-mediated Mechanisms:

Immune response removes damaged cells but can be pathologic. Two main mechanisms: Hypersensitivity responses (allergy) and autoimmune reactions.

1. Type I (Immediate, Allergy): IgE-mediated; mast cell degranulation → histamine/leukotrienes → bronchoconstriction, vasodilation, inflammation. Examples: Platinum salts (rhinitis, asthma), insect stings (anaphylaxis).
2. Type II (Antibody-dependent cytotoxic): Toxin binds cells (e.g., RBCs); IgG triggers lysis via complement/cytotoxic T cells/phagocytosis. Examples: Penicillin, quinidine, di-isocyanates, acid anhydrides.
3. Type III (Immune complex-mediated): Antigen-antibody complexes deposit in tissues (kidneys, joints, lung) → activate leukocytes/complement → inflammation. Example: Serum sickness from antivenoms, farmer’s lung from hay dust/mold spores.
4. Type IV (Delayed-type): T cell-mediated; presents as contact dermatitis. Example: Urushiol (poison ivy) acts as hapten; pentadecacatechol modifies intracellular proteins → presented by MHC I → CD8 T cell response.

Autoimmunity: Immune system attacks own cells. Examples: Methyldopa (hemolytic anemia vs. Rh), hydralazine/isoniazid/procainamide (lupus-like), halothane (autoimmune hepatitis), mercury (glomerular nephritis), silica (scleroderma).

Toxins interfere with metabolic pathways/critical receptors: neurotransmission, cardiac rhythm, oxygen delivery, ATP generation, calcium homeostasis.

Acetylcholinesterase inhibitors: Organophosphates (tabun, sarin, soman, VX) and carbamates (pesticides: parathion, malathion, carbaryl). Organophosphates form irreversible serine-phosphate bonds; "aging" increases toxicity. Selective toxicity: more toxic to arthropods than humans.

Receptor-mediated: Dioxin (TCDD) binds aryl hydrocarbon receptor (AhR) → activates CYP1A gene transcription. Affinity varies among species.

Oxygen delivery inhibitors: Carbon monoxide binds hemoglobin, reduces O2 capacity, increases affinity preventing unloading. Methemoglobin formers (TNT, amyl nitrate, primaquine) oxidize heme iron → tissue hypoxia.

Energy production inhibitors: Cyanide binds cytochrome c oxidase → inhibits electron transport chain → ATP depletion.

Cells repair damaged macromolecules:

• Proteins: oxidized thiols reduced; denatured proteins refolded by chaperones; degraded by proteases.
• Lipids: reduced/hydrolyzed and replaced.
• DNA: excision repair, direct repair of alkylation, recombination repair.

Cell death:

• Apoptosis: Programmed, ordered cell death; cell shrinkage, chromatin condensation, apoptotic bodies; minimal inflammation.
• Necrosis: Uncontrolled cell death; enzymatic digestion, protein denaturation, membrane disruption; cell swelling; attracts inflammation, damages nearby cells.

Apoptosis preferable; necrosis causes more tissue dysfunction. Cancer cells may evade apoptosis.

Pattern depends on regenerative capacity.

Liver:

• Hepatic necrosis (centrilobular – acetaminophen, CCl4)
• Hepatitis (inflammatory – halothane-induced autoimmune)
• Cholestasis (bile accumulation – organic arsenic, oral contraceptives, anabolic steroids)
• Regeneration possible; chronic toxicity → cirrhosis (ethanol).

Lungs:

• Emphysema: destruction of gas-exchange membranes by elastase (cigarette smoke inflammation).
• Fibrosis: abnormal collagen deposition (asbestos, silica, ammonia, chlorine, ozone).

CNS: Neurons cannot regenerate; blood-brain barrier excludes many toxins. Non-polar toxins cross. Peripheral neurotoxins affect Schwann cells (regenerative). Examples: Methyl mercury (encephalopathy), MPTP (Parkinsonism), formic acid from methanol (retinal/optic nerve damage).

Kidney: Susceptible due to concentration of xenobiotics. Mechanisms: altered hemodynamics, tubular damage/obstruction, glomerular nephropathy, interstitial nephritis. Loss of nephrons → compensatory changes → glomerular sclerosis → progressive renal failure.

Carcinogenesis: transformation of normal cell to neoplastic cell + clonal expansion. Involves multiple genetic changes over years. Stages: initiation (genetic damage), promotion (epigenetic changes encouraging growth), progression.

Initiators: Damage DNA, interfere replication/repair. Often reactive species (pre-carcinogens activated by Phase I). Example: Benzo[a]pyrene → dihydroxy epoxide → DNA breaks.

Gene mutations:

• Proto-oncogenes: encourage cell cycle; mutations cause constitutive activation.
• Tumor suppressor genes: inhibit cell cycle; mutations inactivate (e.g., p53).

Promoters: Encourage growth/prevent apoptosis (e.g., exogenous hormones, phenobarbital). Chronic tissue damage/regeneration (e.g., ethanol → cirrhosis → hepatocellular cancer) also promotes.

Teratogenesis: creation of birth defects. Teratogen: substance inducing defects.

Six Principles:

1. Susceptibility depends on genotype-environment interaction.
2. Susceptibility varies with developmental stage.
3. Agents act via specific mechanisms on developing cells/tissues.
4. Access depends on nature of agent.
5. Manifestations: death, malformation, growth retardation, functional deficit.
6. Frequency/severity increase with dose (threshold pattern).

Developmental stages: Pre-embryonic, embryonic (organogenesis: 3rd–8th week – most sensitive), fetal. Teratogens most potent during organogenesis.

Mechanisms: Alter DNA/chromosomes, affect energy/precursors, interfere cell cycle/proliferation/differentiation/apoptosis/cell interactions.

Maternal-fetal factors: Maternal toxicokinetics, metabolism, clearance, placental transfer determine fetal exposure. Low-level exposure follows threshold dose-response.