Mechanisms of Toxicity

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Mechanisms of Toxicity
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Stages in Development of Toxicity

• Delivery of toxicant from the site of exposure to
  the target tissue/site
• Reaction of the toxicant with the target molecule
• Cellular dysfunction and resulting toxicity
• Repair or dysrepair

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Delivery of Toxicant to Target Site

• Four primary factors affecting delivery
• Absorption
• Distribution
• Excretion
• Biotransformation

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Absorption

• Transfer of the toxicant/chemical from the site
  of exposure into the systemic circulation
• Lipid solubility
• First pass elimination

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Distribution

• Movement of toxicants from the bloodstream into
  the ECF and/or tissues
• Facilitation
• Porosity of capillary endothelium
• Transport across membranes
• Inhibition
• Binding to plasma proteins
• Tight junctions
• Storage/intracellular binding proteins

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Excretion

• Removal of xenobiotics from blood to the external
  environment
• Major organs
• Kidney and liver
• Highly hydrophilic chemicals removed efficiently
• Reabsorption
• Lipophilic

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Biotransformation

• Metabolism or detoxication of chemicals into
  forms that are easily excreted
• Hydrophilic
• Toxication or Metabolic activation
• Metabolism results in a harmful product
• Common reactive metabolites
• Electrophiles
• Free radicals
• Nucleophiles
• Redox-active reactants

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Reaction of Toxicant with Target

• Toxicant reacts with endogenous compounds
• Nucleic acids
• Proteins
• Membranes
• Types of Reactions
• Noncovalent binding
• Covalent binding
• Hydrogen abstraction
• Electron transfer

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Effects on Target Molecules

• Dysfunction of target molecules
• Activate or inhibit target molecules
• Mimic endogenous ligands
• Block receptors, ion channels or enzymes
• Alter structure of proteins
• Interfere with transcription/translation of DNA
• Destruction of target molecules
• Adduct formation
• Cross-linking and fragmentation
• Alteration of the microenvironment

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Cellular Dysfunction

• Gene expression
• Transcription
• Interaction with promotor gene, transcription
  factors (TFs)
• Signal transduction
• Activation of TFs via intracellular signaling
  networks
• Promote mitosis and tumor formation

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Cellular Dysfunction

• Ongoing cellular activity
• Electrically excitable cells
• Alteration of neurotransmitter levels
• Alteration of receptor-ligand interactions
• Alter signal transduction
• Voltage gated Na channels
• Inhibition of transporter molecules

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Cell Death

• Necrosis
• Degenerative process leading to cell death
• Usually localized to specific tissue or organ
• Cellular changes
• Karyolysis
• Nuclear disintegration
• Mitochondria swell
• More granules
• Cytoplasmic changes

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Cell Death

• Apoptosis
• Programmed cell death
• Cell shrinkage
• Nuclear fragmentation
• Not associated with inflammation

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Mechanisms of Cell Death

• Depletion of ATP
• Interference with the delivery of H to ETC
• Inhibition of electron transfer along ETC
• Interference with oxygen delivery
• Inhibition of ATP synthase
• Sustained rise in intracellular Ca
• Influx into cytoplasm
• Inhibition of Ca export

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Mechanisms of Cell Death

• Excess intracellular calcium
• Inhibits ATPase in oxidative phosphorylation
• Dysfunction of microfilaments
• Generation of reactive oxygen and nitrogen
  species (ROS, RNS)
• Mitochondrial permeability transition
• ? mitochondrial inner-membrane permeability
• Stops ATP synthesis

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Cell Repair

• Repair of proteins and lipids
• DNA repair
• Excision repair
• Apoptosis
• Proliferation
• ONLY cells capable of dividing!

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Dysrepair

• Rate of injury exceeds rate of repair!
• Necrosis
• Fibrosis
• Carcinogenesis
• Failure of DNA repair
• Failure of apoptosis