Toxicity- delivery of toxicant to its target that may
trigger perturbations and initiate repair mechanisms
STEP 1- DELIVERY: FROM SITE OF EXPOSURE TO THE
TARGET
Toxication (metabolic activation)- biotransformation to
harmful products

Detoxications- biotransformation that eliminate or
prevent the formation of the ultimate toxicant

Intensity of toxic effect depends on the
concentration and persistence of ultimate toxicant
Concentration of ultimate toxicant depends on the
relative effectiveness of processes
Apoptosis- programmed cell death

Elevation of intracellular Ca2+ can result in:
1. Depletion of energy reserve
2. Dysfunction of microfilaments
3. Activation of hydrolytic enzymes
4. Generation of ROS and RNS
STAGES OF IN THE DEVELOPMENT OF TOXICITY
ABSORPTION VS PRESYSTEMIC ELIMINATION
 Absorption- transfer of chemical from site of
exposure to the systemic circulation
 Factors that affect absorption:
Concentration
Surface area of exposure
Characteristics of epithelial layer
Lipid solubility
 Presystemic Elimination (FIRST PASS
ELIMINATION)
 GI mucosa and Liver may eliminate a
significant fraction of toxicant.
 Reduces the toxic effects of chemicals
but may contribute to the injuring the
digestive mucosa
DISTIBUTION TO AND AWAY FROM THE TARGET

Toxicants exit the blood, enter the extracellular
space, and reach their site of action.
 Mechanisms Facilitating Distribution to a Target
 Porosity of the Capillary Endothelium
-favors the accumulation of chemicals in the
liver and kidneys (50 to 150nm in diameter)
-permits the passage of even protein-bound
xenobiotics



Specialized transport across the plasma
membrane
-specialized ion channels and membrane
transporters: Na+, K+ ATPase, Voltage-gated
Ca2+ channels
Accumulation in Cell Organelles
-lysosomal accumulation by pH trapping
-mitochondrial accumulation by electrophoresis
Reversible Intracellular Binding
 Mechanisms opposing Distribution to a target
 Binding to plasma protein
 Specialized barriers
 Distribution to Storage sites
 Association with intracellular binding proteins
 Export from cells
EXCRETION VS REABSORPTION
 EXCRETION
- Removal of xenobiotics from blood and
their return to the external environment
- A physical mechanism
- Route and speed of excretion depends
physicochemical properties of the toxicant
- Elimination of biotransformation-resistant
chemicals
 Excretion from mammary gland
 Excretion in bile
 Excretion into the intestinal lumen
from blood
- Volatile, non-reactive toxicants diffuse from
pulmonary capillaries in the alveoli and are
exhaled
 REABSORPTION
- Toxicants delivered into the renal tubules
may diffuse back across the tubular cells
into the peritubular capillaries
- Toxicants delivered to the GI tract by biliary,
gastric, and intestinal excretion and
secretion by salivary glands and exocrine
pancreas
TOXICATION VS DETOXICATION
 TOXICATION (metabolic activation)
-biotransformation to harmful products
-increased reactivity may be due to conversion
into:
 electrophiles
 free radicals
 nucleophiles
 redox-active reactants
- Most reactive metabolites are electron
deficient molecules and molecular
fragments such as electrophiles and neutral
or cationic free radicals
 DETOXICATION
 Detoxication of toxicants with no
functional groups
 Detoxication of nucleophiles
 Detoxication of electrophiles
 Detoxication of free radicals
 Detoxication of protein toxins
STEP 2: REACTION OF THE ULTIMATE TOXICANT WITH
THE TARGET MOLECULE
 ATTRIBUTES OF TARGET MOLECULE
 Ultimate toxicant must:
- reacts with the target and adversely affects its
function
-reaches an effective concentration at target
site
-alters the target in a way that is
mechanistically related to the observed toxicity
 TYPES OF REACTIONS
 Non-covalent binding
 Covalent binding
 Hydrogen abstraction
 Electron transfer
 Enzymatic reactions
 EFFECTS OF TOXICANTS ON TARGET
MOLECULES
 Dysfunction of target molecules
 Destruction of target molecules
 Neoantigen formation
 TOXICITY NOT INITIATED BY REACTION WITH
TARGET MOLECULES
-some xenobiotics alter biological environment
leading to a toxic response
1. Chemicals that alter H+ ion concentrations in
aqueous biophase
2. Solvents and detergents that
physicochemically alter the lipid phase of the cell
membranes and destroy transmembrane solute
gradients
3. xenobiotics that cause harm merely by
occupying a site or space
STEP 3: CELLULAR DYSFUNCTION AND RESULTANT
TOXICITIES
-alteration of the regulatory or maintenance function of
the cell
STEP 4: REPAIR OR DYSREPAIR
 MOLECULAR REPAIR
 Repair of proteins
 Repair of lipids
 Repair of DNA
- Direct repair
- Excision repair
- Recombinational repair (postreplication)
 CELLULAR REPAIR
-a strategy in peripheral neurons
 TISSUE REPAIR
 APOPTOSIS
- Active deletion of damaged cells
 PROLIFERATION
- Regeneration of tissue
- Replacement of loss cells by mitosis
- Replacement of the extracellular matrix
 SIDE REACTIONS TO TISSUE INJURY
-INFLAMMATION
-ALTERED PROTEIN SYNTHESIS: ACUTE-PHASE
PROTEINS
-GENERALIZED REACTIONS
 MECHANISMS OF ADAPTATION may be due to:
1. Diminished delivery of the toxicant to the
target
2. Decreased size of the toxicant
3. Increased capacity of organism to repair
itself
4. Strengthened mechanisms to compensate
the toxicant-inflicted dysfunction
 TOXICITY RESULTING FROM DYSREPAIR
 Tissue necrosis disables the repair
mechanism, including:
-repair of damaged molecules
-elimination of the damaged cells by
apoptosis
-replacement of lost cells by cell division
 Fibrosis
-excessive deposition of an extracellular
matrix of abnormal composition
 Carcinogenesis involves inappropriate
function of repair mechanism, including:
1. Failure of DNA repair
2. Failure of apoptosis
3. Failure to terminate cell proliferation