TOXICOLOGY | PRELIM | TOPIC 2

Topic Outline • Other Absorption Routes:

➤ Absorp(on o Nasal passages
➤ Distribu(on o Eye surface
➤ Metabolism o Injection (intravenous, intramuscular) - usually for medications.
➤ Biotransforma(on
- the route of exposure significantly influences how much of a chemical is absorbed
➤ Elimina(on
and its potential for toxicity.
Toxicodynamics and Toxicokine4cs
rate of absorption is
- concentration of the chemical at the absorbing surface
Toxicodynamics
- rate of exposure and the dissolution of the chemical
- describes the harmful ac(ons a chemical exerts on specific body components,
- Area of the exposed site
organs or cell func(ons
- “what the toxicant does to the body”. -

Lipid solubility
Toxicokine4cs
- lipid-soluble chemicals are absorbed more readily than water- soluble
- denotes the fate of foreign chemicals within the body
substances.
- “what the body does to the toxicant”.

• ↑ conc = ↑absorption
• ↑ surface area = ↑ absorption
• ↑ exposure & readily dissolve = ↑absorption
• lipid soluble > water soluble

Four basic processes govern the concentra(on of toxicants in vulnerable (ssues:

• Absorp4on: How a toxicant penetrates cell barriers to enter (ssues.
• Distribu4on: How a toxicant is dispersed to par(cular organs and (ssue
compartments.
• Metabolism: How a toxicant undergoes chemical transforma(on (typically in the
liver).
• Excre4on: How a toxicant (parent compound or metabolites) is eliminated (urine,
feces, or both).

These processes dictate the 'toxicokine(c fate' of a xenobio(c.

The behavior of a xenobio(c during these processes is influenced by its:

• Physico-chemical proper(es (mass, charge, water/lipid solubility).

- Hundreds of xenobio(c-handling proteins (enzyme catalysts and membrane

transporters) control the disposi(on of ingested chemicals.

- Toxicant interac(ons are possible: One chemical might alter the ability of these
proteins to metabolize or export another xenobio(c.

- The intensity of a toxic effect depends primarily on the concentra4on and

persistence of the ul(mate toxicant at its site of ac(on.

- The ul4mate toxicant is the chemical species that reacts with the endogenous
target molecule (e.g., receptor, enzyme, DNA, microfilamental protein, lipid) or
cri(cally alters the biological (micro) environment, ini(a(ng structural and/or
func(onal altera(ons that result is toxicity.

ABSORPTION

Absorption: The process by which chemicals cross biological membranes and enter the
bloodstream.

Primary Routes of Absorption:

• Inhalation (Lungs):
o Most important for volatile chemicals, gases, and small airborne
particles.
o Lungs lack strong barriers against inhaled substances.
o Significant concern for occupational exposures.
o the fastest route

• Dermal (Skin):
o Stratum corneum provides some protection, but many chemicals can
penetrate.
o Important for occupational exposures (e.g., spray painters, agricultural
workers).
o Also relevant for topical application of cosmetics and lotions.

• Oral (Ingestion):
o Chemicals enter through contaminated food, water, or hand-to-mouth
contact.
o Absorption mainly occurs in the upper gastrointestinal tract (small
intestine).
TOXICOLOGY | PRELIM | TOPIC 2
Attributes of Absorbed Chemicals Accumulation in Body Tissues
- Some molecules bind strongly to specific tissue components (e.g., muscle),
SIZE causing accumulation.
- strongly influences its absorption upon initial contact with the body
- Fat-soluble chemicals accumulate in fatty tissues, increasing their time in the
• Molecular Size Limit: body and enabling long-term detection (e.g., THC, steroids).
o above 500-600 Daltons (Da) are generally poorly absorbed.
o upper limit for absorption from most tissue sites. - These pollutants (pesticides, PCBs) accumulate in fat, making health risk
• Transcellular Permeability (Well-Absorbed Chemicals): assessment difficult. Fat mobilization can cause acute toxicity.
o below 500-600 Da, with appropriate properties, can pass through cell
membranes. - Metals and inorganic substances (lead, fluorine, strontium) accumulate in bone,
o primary absorption mechanism for easily absorbed chemicals. with slow release due to bone turnover.
• Paracellular Permeability (Small, Water-Soluble Molecules):
o Very small, water-soluble molecules (around 150 Da or less) can pass - High levels can cause fractures and deformities.
between cells.
o They use water-filled intercellular spaces as a pathway. - Slow release can lead to long-term exposure of other organs (e.g., lead in the
o Important for absorption of metal ions and small organic molecules (like CNS).
alcohol).
- Bone turnover rates influence susceptibility to toxicity (e.g., lead).

SOLUBILITY METABOLISM (BIOTRANSFORMATION)

- Fat-soluble chemicals accumulate in tissues, potentially becoming toxic.
Lipid Solubility is Key: Chemicals must dissolve in hydrophobic (water-fearing) solvents
- The body uses enzymes to modify and eliminate foreign substances
to cross cell membranes, which are made of a lipid bilayer.
(xenobiotics).
Lipophilicity (Fat-Loving): Lipophilic chemicals readily penetrate lipid-rich cell
- liver is the main site of xenobiotic metabolism.
membranes.

Hydrophilicity (Water-Loving): Hydrophilic chemicals struggle to cross cell membranes

Xenobiotic-metabolizing enzymes have:
due to their poor solubility in lipids. They often have N or O groups that bond strongly
• Broad Specificity: Metabolize many different chemicals.
with water.
• Flexible Active Sites: Accommodate diverse, large substrates.
- Works with the immune system; targets small molecules.
Most Chemicals are a Mix: Most toxicants have both lipophilic and hydrophilic properties, - Metabolism usually makes chemicals more water-soluble for excretion.
allowing them to interact with both watery and fatty environments in the body, - Some chemicals (DDT, PCBs) resist metabolism, leading to long tissue residence.
influencing their movement and toxicity.
Two-Phase Model (Old):
• Phase 1: Transformation (e.g., oxidation).
• Phase 2: Conjugation for elimination.
CHARGE

Neutrality for Diffusion: Only uncharged molecules can passively cross cell membranes.

pH and Ionization: A molecule's charge (ionization) changes with pH. The GI tract has a
wide pH range (acidic stomach to basic intestines).

pKa Predicts Ionization: pKa determines how readily a molecule ionizes at a given pH.

• Strong Acids (low pKa): Nonionized (neutral) in the acidic stomach.

• Organic Bases: Nonionized in the neutral/basic small intestine.

Duodenum Absorption: The duodenum is the main absorption site despite varying
ionization states due to its large surface area and blood supply.

Sufficient Nonionized Form: Enough uncharged molecules are present in the duodenum
for absorption, even if the environment favors the charged form.

DISTRIBUTION

- Once within the bloodstream, absorbed chemicals enter the second stage of the
toxicokinetic process –
- After penetrating the biological barriers that interface with the external
environment, chemicals encounter many additional membrane barriers as they
penetrate deeper and deeper into body tissues

Glucuronidation
- most commonly utilized pathway of conjugative transformation in humans
involves glucuronidation reactions, facilitated by a family of enzymes known as
Blood-Borne Chemicals
glucuronosyltransferases
- Chemicals distribute differently; some accumulate in specific tissues (fat, muscle,
liver), others stay mainly in the blood.
EXCRETION
- Chemicals in the bloodstream often bind to proteins (albumin, glycoproteins), - Metabolizing lipophilic xenobiotics is a first step, but ultimately, the body needs
affecting their availability to tissues. to remove both the metabolites and any remaining unmetabolized parent
compound.
- This final stage of ADME is crucial for eliminating chemical substances from the
- Water-soluble chemicals tend to remain in the bloodstream and can concentrate
body.
in kidneys, potentially causing damage.
Primary Routes: The kidneys and liver are the main organs of excretion.
- Fat-soluble chemicals readily penetrate tissues and are found in low Minor Routes: Other routes exist for certain chemicals:
concentrations in the blood. • Lungs (volatile substances like alcohol)
• Breast milk (basic drugs like some antidepressants)
• Sweat (some metals like nickel)

Urine and Feces: These are the ultimate destinations for most foreign chemicals.
TOXICOLOGY | PRELIM | TOPIC 2
Bile or Urine

Early Research (1975): A study in rats found that molecular weight is a key factor:
• <350 g/mol: Primarily excreted in urine.
• 450-850 g/mol: Primarily excreted in bile. Blocking the bile duct leads to toxic
accumulation.
• 350-450 g/mol: Excreted in both urine and bile.

Later Findings: Chemical properties also matter:

• Small, hydrophilic (water-loving) molecules: Primarily urine.
• Large, amphipathic (having both hydrophilic and lipophilic parts) organic
compounds: Primarily bile.

Mechanism Clarification: The mechanisms behind these different excretion routes were
once unclear but are now better understood thanks to research on xenobiotic
transporters.

Renal Excretion
- elimination of small, water-soluble substances including conjugates formed
during xenobiotic biotransformation is performed by the nephrons in each adult
kidney.
- Nephron is susceptible to chemical damage; limited replacement capacity.
- Blood constantly filtered by nephrons (every 4-5 minutes).

Three Excretion Processes:

• Glomerular Filtration: Filters most xenobiotics (except large proteins);
limited by protein binding.
• Active Transport: Proximal tubules actively transport chemicals from blood
to filtrate (cation and anion transporters).
• Passive Reabsorption: Lipophilic, uncharged chemicals can be reabsorbed
from filtrate back into blood.

Biliary Excretion
- While the kidneys handle many xenobiotics, the liver's ability to excrete
chemicals via bile is crucial for removing large, lipophilic molecules and
conjugated metabolites (especially those derived from bulky molecules).

- molecular pumps or transporters in the liver cell membranes (specifically the

canalicular membranes) facilitate the excretion of chemicals into the bile.

- substances excreted into the bile are returned to the gut and, along with any
unabsorbed molecules (from oral ingestion), are eliminated in feces.

- foreign chemicals across biological barriers emphasized physicochemical

properties such as size, lipophilicity and ionization as determinants of the
effectiveness with which substances penetrate body tissues