Part twi

• Toxicokinetics


  The study of "how a substance gets into the body and what happens to it in the body"
• Pharmacokinetics


  The study of the kinetics (movement) of chemicals, originally conducted with pharmaceuticals
• Pharmacokinetics


  Generally deals with doses in a therapeutic range
• Toxicokinetics


  The study of systemic exposure during toxicological experiments
• The primary purpose of toxicokinetic studies is to determine the rate, extent and duration of systemic exposure of the test animal species to the test compound at the different dose levels employed during toxicity studies and to provide data for direct comparison with human exposure to the test compound
• Four processes involved in toxicokinetics

  • Absorption
  • Distribution
  • Biotransformation
  • Excretion
• Factors determining the severity of toxicity

  • Duration and concentration of a substance at the portal of entry
  • Rate and amount of the substance that can be absorbed
  • Distribution in the body and concentration of the substance at specific body sites
  • Efficiency of biotransformation and nature of the metabolites
  • Ability of the substance or its metabolites to pass through cell membranes and come into contact with specific cell components
  • Amount and duration of storage of the substance (or its metabolites) in body tissues
  • Rate and sites of excretion of the substance
  • Age and health status of the person exposed
• Absorption, distribution, biotransformation, and elimination are inter-related processes
• Transporters


  Transmembrane proteins that play an important role in the processes of absorption, distribution, metabolism, and elimination (ADME)
• Adverse reactions in the liver to a xenobiotic such as a drug could be caused by genetic or disease-induced variations of transporter expression or drug-drug interactions at the level of these transporters
• Changes in transporter expression and/or function could enhance the accumulation of toxicants and make the kidneys more susceptible to injury, for example, when xenobiotic uptake by carrier proteins is increased or the efflux of toxicants and their metabolites is reduced
• Nephrotoxic chemicals


  • Environmental contaminants such as some hydrocarbon solvents, some heavy metals, and the fungal toxin ochratoxin
  • Some antibiotics
  • Some antiviral drugs
  • Some chemotherapeutic drugs
• A mode of action (MoA) describes a functional or anatomical change, at the cellular level, resulting from exposure to a substance, while a mechanism of action (MOA) describes changes at the molecular level
• Toxicodynamics


  Describes the dynamic interactions of a toxicant with a biological target and its biological effects
• Toxicokinetics


  Describes how a toxicant enters the body and reaches a target tissue
• Toxicodynamics


  Describes what happens to the target tissue once the toxicant reaches an effective dose
• Biological target/site of action

  Binding proteins, lipids, ion channels, DNA, or a variety of other receptors that interact with the toxicant and produce structural or functional alterations
• Dose-response relationship


  NOEL: No Observed Effect Level, NOAEL: No Observed Adverse Effect Level, LOAEL: Lowest Observed Adverse Effect Level
• Types of toxicity based on affected parts

  • Local toxicity
  • Systemic toxicity
• Target organs of toxicity

  • Central nervous system
  • Blood circulation system
  • Liver
  • Kidneys
  • Lungs
  • Skin
  • Muscle and bones
  • Male and female reproductive systems
• Mechanisms of action of toxicants

  • Specific action of toxicant: Receptor mediated events, Enzyme mediated events
  • Non-specific action of toxicants: Physical toxicants, Chemical toxicants
• Receptor mediated events


  The actions at the specific receptors for neurotransmitters, hormones, and drugs either as agonists or as antagonists are responsible for numerous toxic responses
• Neurotoxins acting within and outside the central nervous system

  • strychnine
  • morphine
  • atropine
• Enzyme mediated events


  Toxicants interact directly with specific enzymes which catalyze some important physiologic processes to produce their toxic effects
• The severity and duration of poisoning can be influenced by the strength of toxicant-enzyme interaction
• Toxicants that produce their toxicity through enzyme inhibition

  • Organophosphorus and carbamate insecticides (inhibition of cholinesterases)
  • HCN (inhibition of cytochrome oxides)
  • Lead (inhibition of membrane bound Na+-K+ ATPase, δ-aminolevulinic acid synthetase and ferrochelate)
• Physical toxicants


  Toxicants that act by their physical deposition in body tissues, and organs like lungs
• Physical toxicants


  • Industrial and heavy metals dust
  • Silicon
  • Asbestos
• Direct chemical injury


  Direct chemical injury to tissues either causes protoplasmic precipitation or alters the membrane dependent homeostatic control of cell functions
• Compounds that cause direct chemical injury

  • Acids
  • Bases
  • Phenols
  • Aldehydes
  • Alcohols
  • Petroleum distillates
  • Some salts of heavy metals
• Necrosis of epithelial cells

  Systemic toxins can cause epithelial necrosis mainly by producing ischaemia (reduced blood flow) resulting in damage to metabolically active cells
• Toxicants that cause necrosis of epithelial cells

  • Carbon monoxide
  • Cyanide
  • Nitrite
• Uncoupling of oxidative phosphorylation


  The release of energy in the electron transport chain becomes uncoupled from the formation of ATP, resulting in no phosphorylation of ADP to ATP. The energy is dissipated as heat rather than stored in high energy phosphate bonds.
• Toxicants that uncouple oxidative phosphorylation

  • Dinitrophenol
  • Chlorophenol fungicides
  • Arsenates
• Inhibition of oxidative phosphorylation

  This results in limited oxygen uptake with lower ATP formation, leading to fatigue and weakness but no fever
• Inhibition of nucleic acid and protein synthesis


  Toxicants that injure DNA or bind to ribosomes during transcription or translocation
• Toxicants that inhibit nucleic acid and protein synthesis

  • Aflatoxins
  • Organomercurials
  • Trichloro carbons
• Interference with fat metabolism

  Toxins that affect the rough endoplasmic reticulum resulting in reduced synthesis of lipid acceptor proteins or reduced incorporation of phospholipids and triglycerides into transport lipoproteins, leading to fat accumulation in the cell
• Toxicants that interfere with fat metabolism

  • Carbon tetrachloride
  • Ethionine
  • Yellow phosphorus
  • Puromycin
• Injury to blood, vascular and respiratory system

  Toxicants can cause hypoplasia or aplasia of cellular components of blood, coagulopathy, lysis of erythrocytes, inactivation of haemoglobin, and interference with oxygen exchange in pulmonary alveoli or cellular utilization of oxygen