m4 part 1

• most affected by a toxic agent

  Target organ
• Events that signals intoxication, or damage within the target organ

  Critical effect
• Toxicity Measurements and End points

  • Animal tests for toxicity have been conducted prior to and in parallel with human clinical investigations as part of the non-clinical laboratory tests of pharmaceuticals.

  • Standardized animal toxicity tests have been highly effective in detecting toxicity that may occur in humans.
• They provide data on the relative toxicity likely to arise from a single or brief exposure, or sometimes multiple doses over a brief period of time

  Acute Toxicity
• These are employed to determine toxicity likely to arise from repeated exposures of several weeks to several months.

  Subchronic Toxicity
• This determine toxicity from exposure for a substantial portion

  of a subject's life. They are similar to the subchronic tests except that they extend over a longer period of time and involve larger groups of animals

  Chronic Toxicity
• These are similar to chronic toxicity tests. However, they extend over a longer period of time and require larger groups of animals in order to assess the potential for cancer

  Carcinogenicity
• This is intended to determine the effects of substances on gonadal function, conception, birth, and the growth and development of offspring. The oral route of administration is preferable.

  Reproductive Toxicity
• This testing detects the potential for substances to produce embryotoxicity and birth defects.

  Developmental Toxicity
• This determine the potential for an agent to cause irritation and inflammation of the skin.

  Dermal Toxicity
• This was at one time determined by applying a test substance for 1 second to the eyes of 6 test animals, usually rabbits. The eyes were then carefully examined for 72 hours, using a magnifying instrument to detect minor effects. An ocular reaction can occur on the cornea, conjunctiva, or iris. It may be simple irritation that is reversible and quickly disappears.


  Ocular Toxicity
• A battery of standardized neurotoxicity tests were developed to supplement the delayed neurotoxicity test in domestic chickens (hens). The hen assay determines delayed neurotoxicity resulting from exposure to anticholinergic substances, such as certain pesticides. The hens are protected from immediate neurological effects of the test substance and observed for 21 days for delayed neurotoxicity.


  Neurotoxicity
• This is determined using a wide range of test species including whole animals and plants (for example, rodents, insects, and corn), microorganisms, and mammalian cells. A large variety of tests have been developed to measure gene mutations, chromosome changes, and DNA activity


  Genetic Toxicity
• is a disease characterized by uncontrolled growth of altered cells and their ability to migrate from the original site and spread to different parts of the body

  Cancer
• are substances or mixtures which induce cancer or increase its incidence

  Carcinogens
• Group 1 - carcinogenic to humans

  • tobacco
  • alcoholic beverages
  • radiation (solar uv)
  • processed meat
• Group 2A - Probably carcinogenic to humans

  • Glphosphate
  • Anabolic steroids
  • HPV
  • Red meat
• Group 2B - Possibly carcinogenic to humans

  • Coffee
  • Gasoline
  • Magnetic field
• a permanent change in the amount or structure of the genetic material in a cell.

  mutation
• used for agents increasing the occurrence of mutations. Many mutagenic substances are also carcinogenic, but not all

  Mutagen
• agent: asbestos

  industrial process: construction, asbestos mining

  neoplasms: peritoneum bronchus
• agent: arsenic

  industrial process: mining and smelting

  neoplasms: skin, bronchus, liver
• agent: benzene

  industrial process: chemical manufacturing

  neoplasms: bone marrow
• agent: benzidine

  industrial process: dye and textile

  neoplasms: urinary bladder
• agent: polynuclear aromatic hydrocarbons

  industrial process: steel making, roofing, chimney cleaning

  neoplasms: skin, scrotum, bronchus
• agent: vinyl chloride monomer

  industrial process: chemical manufacturing

  neoplasms: liver
• agent: beryllium

  industrial process: aircraft manufacturing, electronics

  neoplasms: bronchus
• agent: cadmium

  industrial process: smelting

  neoplasms: bronchus
• agent: ethylene oxide

  industrial process: production of hospital supplies

  neoplasms: bone marrow
• agent: formaldehyde

  industrial process: plastic, textile, chemical

  neoplasms: nasal sinus, bronchus
• agent: polychlorinated biphenyls

  industrial process: electrical-equipment production and maintenance

  neoplasms: liver
• The Cardiovascular System and the Blood

  • Blood and Cardiovascular/Cardiac Toxicity results from xenobiotics acting directly on cells in circulating blood, bone marrow, and the heart.
• The Cardiovascular System and the Blood

  The effects of poisoning and overdose on the cardiovascular system are disturbances in:

  (a) chronotropy

  (b) inotropy

  (c) vascular tone.

  The pattern of the pulse, blood pressure, cardiac conduction and type of dysrhythmias may help identify the toxic agent. However, hypoxia, shock, hypothermia, and other superimposed complications may distort the typical pattern.
• The sympathetic response increases the automaticity, conduction velocity, and contractility of the heart, and lengthens the refractory period and produces constriction of most vascular beds.
• The parasympathetic response delays conduction velocity through the AV node (vagotonic block) and the ventricular tissue, diminishes contractility, shortens the refractory period, and generally produces vasodilation.
• There are two types of parasympathetic receptors: the nicotinic receptors, which may produce tachycardia and hypertension, and the muscarinic receptors, which produce bradycardia and hypotension
• may be produced by excess cholinergic activity, interference with release or depletion of the catecholamines, damage to the myocardium, or increased intracranial pressure.

  Bradycardia
• may be due to excess anticholinergic activity, stimulation of catecholamine release, inadequate venous return due to vasodilation, hypoxia, and direct injury to the myocardium, or increased metabolism.

  Tachycardia
• Dysrhythmias are caused by spontaneous depolarization (automaticity), abnormal impulse conduction (reentry), and “triggered” responses. They may be caused by:

  (a) direct or indirect sympathomimetic effects;

  (b) anticholinergic effects;

  (c) CNS-related regulation of peripheral autonomic activity; (d) direct effects on the myocardial membrane;

  (e) myocardial ischemia; or

  (f) secondary to hypotension, hypoxia, or disturbances in acid-base and electrolyte balance.
• Transient hypertension may be produced by substances acting indirectly to increase the release of NE from storage granules or by decreasing the re-uptake of norepinephrine.

  Vascular tone