Toxicant Absorption and Exposure Routes

Absorption of Toxicants

• Toxicants enter the body through absorption, where ingested and inhaled materials cross cellular barriers.
• Absorption is essential for a substance to affect internal organs, beyond local effects like irritation.
• Absorption rates are vary with specific chemicals and the route of exposure.
• For skin, oral, or respiratory exposure, only a fraction of the external dose is absorbed.
• Injected or implanted substances have an exposure dose equal to the absorbed dose.

Factors Affecting Xenobiotic Absorption

• Route of exposure
• Concentration at the contact site
• Chemical and physical properties of the substance

Primary Exposure Routes for Xenobiotics

• Gastrointestinal (GI) Tract: Key for environmental contaminants from food and water, and a major pathway for pharmaceuticals.
• Respiratory Tract: Significant for airborne environmental and occupational contaminants; used for some pharmaceuticals like inhalers.
• Skin: Important for environmental and occupational exposures; common route for consumer and pharmaceutical products.

Other Exposure Routes

• Injections: Primarily for pharmaceuticals.
• Implants: Used for slow, time-release of pharmaceuticals like hormones and medical devices.
• Conjunctival Instillations (eye drops): Treats ocular conditions, with potential for systemic toxicity.
• Suppositories: Used for drugs poorly absorbed orally or for local therapy, administered rectally or vaginally.

Role of Cell Membranes in Absorption

• Xenobiotics must cross cell membranes to enter, move within, and exit the body.
• Cell membranes act as barriers against foreign substances.
• Xenobiotics need to penetrate cell membranes, which requires crossing multiple membranes to move between body areas.
• Substances must cross a cell membrane to enter a cell, pass through it, and then exit across another membrane.
• Reaching the site for toxic effects often involves navigating several membrane barriers.

Movement Across Cell Membranes

• Toxicants cross membrane barriers either with relative ease or with difficulty.
• Two general methods are used: passive transfer and specialized transport mechanisms.

Passive Transfer

• Passive transfer is simple diffusion or osmotic filtration that doesn't require cellular energy.

Specialized Transport Mechanisms

• Facilitated diffusion
• Active transport
• Endocytosis (phagocytosis and pinocytosis)

Passive Transfer Factors

• Concentration gradients
• Ability to move through membrane pores or lipophilic interior

Factors Affecting Passive Transfer

• Lipid solubility
• Molecular size
• Degree of ionization

Lipid Solubility

• High lipid solubility = easy diffusion through the phospholipid membrane.

Molecular Size

• Small water-soluble molecules = passage through aqueous pores.

Pore Size

• Aqueous pores size = ~4 Angstroms
• Capillaries and kidney glomeruli pores = ~40 Angstroms, allowing molecules up to 50,000 molecular weight to pass.
• High ionization interferes with lipid solubility, hindering passage through the lipid membrane.

Facilitated Diffusion

• Facilitated diffusion is similar to simple diffusion because it requires no energy and follows a concentration gradient.
• This process uses special transport proteins to move molecules across the cell membrane, facilitating and accelerating the movement across the membrane.

Active Transport

• Active transport is used when substances are unable to move with diffusion, dissolve in the lipid layer, and are too large to pass through aqueous channels.
• Active transport can move substances against the concentration gradient, from low to high concentrations.
• This process requires cellular energy, specifically adenosine triphosphate (ATP).
• IT is important for transport of xenobiotics and maintaining electrolyte and nutrient balance.

Endocytosis (Phagocytosis and Pinocytosis)

• Endocytosis: a process where cells engulf large molecules and particles.
• During endocytosis, the cell surrounds the substance with a section of its cell wall, engulfing it.
• Two main forms of endocytosis include phagocytosis and pinocytosis.

Phagocytosis

• Phagocytosis, or cell eating, involves engulfing large particles suspended in the extracellular fluid.
• Phagocytosis destroys or transports particles in cells.
• This process is particularly important for lung phagocytes and certain liver and spleen cells.

Pinocytosis

• Pinocytosis, or cell drinking, is similar to phagocytosis bur it involves engulfing liquids or very small particles in the extracellular fluid.

Gastrointestinal Tract

• Foreign substances must pass through the gastrointestinal mucosa.
• Substances must be absorbed via the gastrointestinal tract to exert toxic effects.
• Absorption can occur along the gastrointestinal tract, but varies based on site.
• absorption depends on the type of cells, the duration the substance remains and the pH.

Mouth and Esophagus

• Because substance resides for a short time in this region, xenobiotics are poorly absorbed in the mouth and esophagus.
• Rapid absorption can occur in some areas of the mouth because the sublingual mucosa are thin, vasularized.

Stomach

• The stomach's acidity contributes to the absorption of weak organic acids in a nonionized, lipid-soluble form.
• Acidic conditions help chemically break down some substances.
• Food in the stomach can affect absorption.

Intestine

• The most absorption of chemicals occurs in the intestines, small intestine.
• It has a large surface area for diffusion across cell membranes.
• weak bases and acids exist in nonionized form, favoring absorption by passive diffusion.
• Facilitated and active transport facilitate the absorption of essential nutrients like glucose, amino acids, and calcium, as well as toxins

Colon and Rectum

• Little absorption occurs due to xenobiotic absorption in the stomach or small intestine.
• Some medications are absorbed via rectal suppositories.

Respiratory Tract

• Absorption can occur anywhere along the respiratory tract.
• Absorption depends on xenobiotic physical form and solubility.

Respiratory Tract Regions

• Nasopharyngeal region
• Tracheobronchial region
• Pulmonary region

Mucociliary Membrane

• The mucociliary membrane covers most of the bronchi, bronchioles, and nose.
• It contains it pushes cells and inhaled particles or microorganisms out by swallowing or by the mouth..

Pulmonary Region

• The pulmonary region is the most important absorption site and includes bronchioles, alveolar sacs.
• Lungs have a very large surface area, 50 times that of the skin.
• Alveoli consist of a single layer that separates inhaled air from the bloodstream.
• Gases/particles are absorbed more efficiently vs gastrointestinal tract.
• Water-soluble gases/aerosols cross the alveolar membrane via passive diffusion.

Physical Form Impact

• Absorption depends on the physical form and solubility of the agent.
• If a gas or vapor has high solubility in the blood, it is absorbed rapidly in the lungs via passive diffusion.
• Absorption through the alveolar membrane is by passive diffusion, following the concentration gradient.
• Blood-soluble gases/vapors can be exhaled if blood is quickly saturated.
• Insoluble gases/vapors can be absorbed by the lungs before exhalation and equilibrium in the blood is more quickly reached.

Airborne Particles

• Absorption differs from gases or vapors, regardless of solubility.
• Large particles (>5 µM) are deposited in the nasopharyngeal region with minimal absorption.
• Particles 2-5 μM penetrate the tracheobronchial region.
• Very small particles (1 µM) penetrate the alveolar sacs where they can deposit and be absorbed.

Differences in Absorption Among Regions of the Respiratory Tract

• Nasopharyngeal Region: Limited absorption due to thick mucosa and rapid movement of gases and particles.
• Tracheobronchial Region: Soluble gases can enter the blood stream quickly; particles are moved to the mouth and swallowed.
• Pulmonary Region: Efficient absorption in the alveoli, substances are absorbed into systemic circulation.

Entry of Toxicants via Skin

• Skin contamination can allow toxicants to enter the body.
• Industrial solvents cause systemic toxicity by penetrating the skin.

Skin Layers

• Epidermis
• Dermis
• Subcutaneous tissue

Epidermis and Stratum Corneum

• Stratum corneum regulates skin contaminant penetration.
• Keratin, is chemically resistant and impenetrable, protects cell walls.
• Agents must pass through layers resistant to chemicals to enter blood vessels, 100 µM from the surface.

Thickness

• Stratum corneum varies with thicker palms and soles (400-600 μΜ) versus thinner on arms, back, and legs (8-15 µM).
• The stratum corneum of the axillary(underarm) and inguinal (groin) regions are the thinnest and inversely relates to the epidermis's thickness.

Damage

• Damage can enhance the penetration of xenobiotic, e.g., abrasions, scratches, or cuts.
• Acids, alkalis, and corrosives can injure the stratum corneum and dermal absorption with skin burns and dermatitis.

Passive Diffusion

• Toxicants move across the stratum corneum by passive diffusion.
• Polar and nonpolar toxicants diffuse differently.
• Polar compounds diffuse through the hydrated keratinized layer's outer surface.
• Nonpolar compounds dissolve and diffuse through the lipid material between the keratin filaments.

Water

• Water plays a important role in dermal absorption, the stratum corneum is usually hydrated, this is 10x more effective, increased hydration increases ability of polarcompound to enter the epidermis.

Species

• Skin penetration varies by species, influencing safety testing species.
• Chemical penetration is different among animals versus humans.

Dermis and Subcutaneous Tissue

• Substances enter these lower layers, less resistant and permeable to diffusion.
• Large numbers of venous and lymphatic capillaries in the dermis allow toxicants to enter the circulatory system.

Other Exposure Routes

• Intradermal injections: Minimal tissue reaction, slow absorption.
• Subcutaneous injection: Rapid absorption due to vascular tissue.
• Intramuscular route: Injection into muscle tissue; absorption is similar to subcutaneous.
• Intravenous/Intra-arterial routes: Direct injection into blood vessels for immediate action.
• Parenteral injections: Direct to body cavities, minimal blood vessels = slow absorption.