Clinical Toxicology

Clinical Toxicology: Scope & Key Definitions

• Concerned with diseases caused by, or uniquely associated with, toxic substances present in clinical or environmental settings.
• Toxin – toxic substance produced by biological systems (plants, animals, fungi, bacteria) that is poisonous to other organisms.
• Toxigenicity – genetically determined ability of an organism to produce toxins.
• Toxinosis – disease caused by a toxin.
  • Toxemia – toxin disseminated through the blood (e.g., tetanus, diphtheria).
  • Intoxication – disease following ingestion of a pre-formed toxin (e.g., botulism).
• Target-based toxin names: neurotoxins, enterotoxins, hemotoxins, nephrotoxins.

Virulence Factors & Pathogenic Mechanisms

• Virulence factors = microbial adaptations allowing invasion, survival, and damage in the host.
  • Major categories: extracellular enzymes (exoenzymes), toxins, antiphagocytic factors.

Extracellular (Exo) Enzymes and Their Actions

• General roles: break down host tissues, dissolve defensive barriers, enable deeper invasion.
• Key examples:
  • Mucinase – digests protective mucus (Entamoeba → amebic dysentery).
  • Keratinase – digests keratin of skin/hair (ringworm fungi).
  • Collagenase – attacks collagen in connective tissue (Clostridium spp., some parasitic worms).
  • Hyaluronidase – digests hyaluronic acid "cement" between animal cells (staphylococci, clostridia, streptococci, pneumococci).
  • Coagulase – clots plasma, walling off organisms (pathogenic staphylococci).
  • Bacterial kinases (streptokinase, staphylokinase) – dissolve fibrin clots; therapeutic streptokinase marketed as “streptase” for thrombi/emboli.

Toxins: Types, Targets & Comparative Properties

• A toxin is a specific poisonous chemical product of microbes, plants, or animals.

Enterotoxins

• Target intestinal mucosa → watery diarrhea, fluid loss.
• Produced by enterotoxigenic Escherichia coli & Staphylococcus aureus.

Exotoxins vs. Endotoxins (comparative highlights)

• Release:
  • Exotoxin – actively secreted by live cells.
  • Endotoxin – released only on cell lysis; integral \text{LPS} of Gram-(–) outer membrane.
• Chemical nature:
  • Exotoxin – polypeptide/protein; heat-labile; can be converted to toxoid for vaccines.
  • Endotoxin – lipopolysaccharide; heat-stable; cannot form toxoid.
• Potency & effects:
  • Exotoxin – toxic in minute amounts; specific cellular targets; e.g., botulin, tetanospasmin, diphtheria, erythrogenic toxin, hemolysins.
  • Endotoxin – toxic only in high doses; systemic effects (fever, inflammation, hemorrhage, shock); Gram-negative bacteremia may lead to fatal endotoxic shock.
• Immune response: exotoxins elicit strong antitoxin (antibody) formation; endotoxins do not.
• Fever: endotoxins typically induce fever; exotoxins usually do not.

Hemolysins

• Sub-class of exotoxins that lyse red blood cells → release hemoglobin; may also damage other host cell membranes.

Host-Defense Interaction

• Phagocytosis: engulfment & destruction of foreign material.
  • Neutrophils – handle small particles/microbes.
  • Macrophages – larger cells resident or wandering; fuse phagosome with lysosome → digestion.
• Antiphagocytic factors: virulence factors that help microbes evade or kill phagocytes.
  • Leukocidins produced by Streptococcus & Staphylococcus species directly destroy white blood cells.

Environmentally Associated Non-Infectious / Non-Communicable Diseases

• Chemical categories implicated:
  • Halogenated & other organics: PCBs, DDT, mirex, endrin, PBBs, vinyl chloride, CFCs.
  • Heavy metals: Pb, Hg, Cd, Ba, Ni, V, Se, etc.
  • Non-metallic/metalloid inorganics: arsenic, asbestos.
  • Biological contaminants: aflatoxins, veterinary/human drugs, food additives, hormones.

Lead (Pb)

• Cumulative poison depositing in bone, blood, tissues; minimal excretion in children.
• Clinical manifestations: mental retardation, blindness, chronic kidney disease, fatigue, anemia, gastroenteritis, muscular paralysis, behavioral changes, hypertension, birth defects.
• Common sources: paints; leaded fuels/transport; pigments; PVC cladding; glassmaking lead oxide; printing & tanning chemicals; lead-glazed pottery/ceramics.
  • FDA ceramic leachate limits: 0.5 ppm (storage bowls), 7.0 ppm (dishes), 5.0 ppm (small bowls).
• Regulatory guidelines (drinking water):
  • WHO & Philippines (PNSDW) = 0.010\, \text{mg L}^{-1}; US EPA & DAO 34 (Class AA) = 0.05\, \text{mg L}^{-1}.
• Pediatric health concern (USA):
  • Acutely elevated blood lead level (BLL) ≥ 70\,\mu\text{g/dL} → coma, death.
  • High-risk children screened every 3!–!6 months: initial erythrocyte protoporphyrin (EP) test, repeat EP, then blood lead (BL) if EP ≥ 35\,\mu\text{g/dL}.
  • Children ≤ 6 yrs: BL ≥ 25\,\mu\text{g/dL} with EP ≥ 35\,\mu\text{g/dL} → medical follow-up.
  • BL 10!–!15\,\mu\text{g/dL} already concerning; WHO action level 20\,\mu\text{g/dL}.

Mercury (Hg) & Minamata Disease

• Exists as elemental \text{Hg(0)}, inorganic \text{Hg^{2+}}, organic forms (e.g., methylmercury).
• Past/Current uses: syphilis treatment, agricultural fungicide, dental amalgams.
• Environmental release: industrial effluent → sediment deposition → bioaccumulation in fish.
• Minamata, Japan (1932–1968): Chisso Corp. discharged ≈ 27 tons of mercury compounds into Minamata Bay.
  • Population consuming fish developed severe methylmercury poisoning (“cat dancing disease”).
  • Syndrome now called Minamata Disease: sensory disturbance, ataxia, constricted visual fields, hearing & speech impairment, fetal neurologic damage.

Chromium (Cr)

• Natural crustal element; valence states: \text{Cr(0)}, \text{Cr(III)}, \text{Cr(VI)}.
  • \text{Cr(III)} – essential trace nutrient.
  • \text{Cr(VI)} – strong oxidizer; human carcinogen (lung cancer) per WHO & EPA.
• Public awareness: groundwater contamination case vs. PG&E, dramatized in movie “Erin Brockovich.”

Arsenic (As)

• Crystalline metalloid, ubiquitous in soil & water; commercially used in pesticides, wood preservatives, manufacturing.
• Chronic low-level exposure → melanosis (generalized skin darkening) & multiple cancers (skin, lung, bladder, etc.).

Asbestos

• Six naturally occurring silicate minerals; most common:
  • Chrysotile (white, serpentine, curly fibers) – historically most used.
  • Amosite (brown); Crocidolite (blue, straight/stiff fibers, most hazardous).
  • Others: actinolite, tremolite, anthophyllite.
• Fiber size: 0.1!–!10\,\mu\text{m} → invisible to naked eye.
• Health hazards (latency 10!–!35 yrs):
  1. Asbestosis – diffuse interstitial pulmonary fibrosis (non-malignant scar tissue).
  2. Bronchogenic carcinoma – primary lung cancer.
  3. Mesothelioma – malignancy of pleural or peritoneal lining.
  4. Cancers of stomach, colon, rectum.
     • Crocidolite retains longer in lung, but chrysotile also capable of inducing mesothelioma & lung neoplasms.

Organ-Specific Toxic Agents (Selected Examples)

• Blood: benzene, aniline.
• Kidneys: lead, mercury, chromium.
• Heart: carbon monoxide, toluene.
• Brain: arsenic, manganese, acetaldehyde.
• Eyes: cresol, acrolein.
• Skin: benzyl chloride, butyl alcohol, phenol, nickel.
• Lungs: asbestos, chromium, hydrogen sulfide, mica, nitrogen dioxide.
• Liver: chloroform, carbon tetrachloride, toluene, trichloroethylene.

These notes integrate clinical, microbiological, and environmental dimensions of toxicology, highlighting mechanisms of toxicity, regulatory guidelines, landmark poisoning events, and organ-specific hazards to provide a comprehensive study reference.