toxicology1

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toxicology1
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  1. CELL DEFINITION
    • protoplasm: living matter of any plant or animal.
    • a single unit of protoplasm is called a cell.
    • plants, animals and humans consists of groups of interdependent cells.
    • these cells coordinate various functions.
    • cells serving same general function are called a tissue (bone, cartilage, muscles, nervous tissue, etc.)
  2. CELL ORGANIZATION
    • NUCLEUS
    • nucleoplasm or karyoplasm; carry on specific functions.
    • CYTOPLASM
    • organelles: metabolically active; carry on specific functions.
    • inclusions: metabolically inert, accumulate metabolic products (carbohydrates, proteins, lipids, crystals, pigments, secretory granules).
    • cytoskeleton: fibrillar components (microtubules, microfilaments, intermediate filaments, cytoplasmic matrix).
  3. TYPES OF CELLS
    • ANIMAL CELL
    • PLANT CELL
    • BACTERIA CELL
  4. PLASMA MEMBRANE (PM)
    • very thin, selectively permeable (more to lipids than to aqueous substances).
    • a lipid bilayer containing lipids, proteins and carbohydrates.
    • is permeable to water and small uncharged molecules such as O2 and CO2.
    • special transport systems such as active transport are available for charged particles such as Na+, K+, Cl-.
  5. PROTEINS OF PLASMA MEMBRANE
    • two kinds of proteins in the PM:
    • -integral: positioned according to their functions.
    • -transmembrane: across PM; studied by freeze fracture (-190°C under vacuum); PM cleaves at weak points.

    • transmembrane proteins of PM:
    • -transport nutrients (glucose, amino acids, etc)
    • -form channels for passive diffusions of ions.
    • -form pumps for Na+, K+, H+, and Ca++.
    • -form receptors for neurotransmitters/hormones.
    • function as carrier mediated endocytosis proteins.
  6. PLASMA MEMBRANE STRUCTURE
  7. THE NUCLEUS
    • largest organelle, centrally located, elliptical or spherical.
    • stains dark purple or blue with H&E.
    • irregular clumps in nucleoplasm called chromatin ---contains genetic material DNA and RNA.

  8. NUCLEAR ENVELOPE
    • double membrane with pores made of proteins.
    • peritubular cisternae continuous with ER space.
    • pores communicate between nucleus and cytoplasm.
    • envelope breaks during cell division and forms again after division.
  9. CHROMATIN
    • consists of ribonucleoproteins and histones.
    • - condensed: heterochromatin (stainable)
    • - dispersed: euchromatin (not stainable)
    • in dividing cells chromosomes become visible and are basophilic.
    • human somatic cells have 46 chromosomes (diploid or 2n)
    • germ cells have 23 chromosomes (haploid or n)
    • abnormal cells exhibit polyploidy.
  10. NUCLEOLUS
    • retractile, eccentric and basophilic.
    • forms nucleolus organizing region (NOR) and consists of various kinds of RNA.
  11. CYTOPLASM
    • site of metabolic activities and specialized functions.
    • contains: organelles, inclusions, cytosol, cytoskeleton.
  12. ORGANELLES
    • endomembrane system (endoplasmic reticulum, Golgi complex, endosomes, lysosomes, vacuoles).
    • mitochondria.
    • peroxisomes.
    • chloroplasts.
  13. INCLUSIONS
    • glycogen.
    • lipids.
    • pigments.
  14. CYTOSOL
    fluid containing electrolytes and colloids.
  15. CYTOSKELETON
    microtubules, microfilaments, intermediate filaments.
  16. ENDOMEMBRANES
    • organelles of endomembrane system are dynamic and integrated network.
    • materials (proteins) here are shuttled back and forth from one part of cell to the other.
    • distinct pathways:
    • biosynthetic or secretory
    • constitutive: destined for secretion.
    • regulated: secretion regulated upon stimulus.
    • endocytic.
  17. ENDOMEMBRANE SYSTEM
  18. ENDOMEMBRANES: STUDY APPROACHES
    • autoradiography: use of radioisotopes.
    • use of green fluorescent protein (GFP). the GFP from a jellyfish is physically attached to study the movement of proteins in a cell.
    • subcellular fractionation: cell free systems.
    • genetic mutants: a mutant is an organism or a cultured cell whose chromosomes contain 1 or more genes that encode abnormal proteins.
  19. ENDOMEMBRANE: SUBCELLULAR FRACTIONATION
    • involves homogenization or tissues.
    • this produces spherical vesicles from broken nuclei, mitochondria plasma membranes and endomembranes.
    • vesicles derived from endomembrane system form a collection of similar sized vesicles referred to as microsomes.
  20. ENDOPLASMIC RETICULUM (ER)
    • a system of membranes that enclose a space of lumen that is separated from surrounding cytosol.
    • the composition of luminal or cisternal space inside the ER is quite different from that of surrounding cytosolic space.
    • two types known: rough and smooth.
    • both types have important structural and functional differences.
  21. ER: ROUGH AND SMOOTH
  22. ROUGH ENDOPLASMIC RETICULUM
    • the RER has ribosomes bound to its cytosolic surface.
    • typically composed of a network of flattened sacs (cisternae).
    • the RER is continuous with the other membrane of the nuclear envelope which also bears ribosomes on its cytosolic surface.
    • the cells that secrete large amounts of proteins such as liver, pancreas or salivary glands, have extensive RER.
  23. RER: PROTEIN SYNTHESIS LOCATIONS
    • on ribosomes attached to RER:
    • proteins secreted form the cell.
    • integral membrane proteins.
    • soluble proteins residing inside endomembranes.
    • on free ribosomes:
    • proteins destined to remain in the cytosol.
    • peripheral plasma membrane proteins.
    • proteins to be incorporated into peroxisomes, mitochondria and chloroplasts.
  24. SMOOTH ENDOPLASMIC RETICULUM
    • membranous elements of SER are typically tubular.
    • form an interconnecting system or pipelines curving through the cytoplasm.
    • SER is extensively developed in cells of skeletal muscle, kidney tubules, and steroid producing endocrine cells.
    • when homogenized, the SER fragments into smooth-surfaced vesicles (called microsomes) and RER into rough-surfaced vesicles.
  25. SER: IS INVOLVED IN
    • synthesis of lipids including oils, phospholipids and steroids.
    • detoxication and bioactivation of a variety of organic compounds (microsomal enzymes).
    • carbohydrate metabolism: release of glucose-6-phosphate in liver cells.
    • as sarcoplasmic reticulum sequesters and releases Ca++ in muscle fibers.
  26. GOLGI COMPLEX
    • a network of tubules with double membranes.
    • site of concentration, modification, packaging and shipping of synthesized products.
    • consists of cisternae.
    • cis-face toward ER and trans-face toward PM.
    • transport accomplished by membrane vesicles.

  27. MITOCHONDRIA
    • power houses of cells, slender, rod like, double membranes.
    • inner membrane extensively folded forming cristae.
    • greater number in active cells generating ATP.
    • three principle reaction cycles--Krebs cycle, electron transport chain and β-oxidation of fatty acids.
    • are self duplicating, have their own DNA and ribosomes and hence called semiautonomous.
  28. LYSOSOMES
    • membrane bound dense bodies.
    • contain hydrolytic enzymes for intracellular digestion.
    • most active in leukocytes and phagocytes.
    • involved in endocytosis forming endosomes.
  29. PEROXISOMES
    • membrane bound.
    • generate H2O2 as a by-product or oxidative reactions.
    • enzymes: urate oxidase, D-amino oxidase, and catalase.
  30. CYTOSKELETON
    • microtubules (MT): hollow tubules, walls made of protofilaments (a polymer of tubulin), function --- maintenance of cell shape.
    • microfilaments (MF): examples G and F--actin forming actin filament, myosin, filamin (in PM), ankyrin and spectrin (red blood cells), dytsrophin (muscle cells). specialized in muscle cells---responsible for contractility of protoplasm.
    • intermediate filaments: diameter in between MT and MF; examples vimentin, desmin, keratin, neurofilaments and glial filaments.
    • cytoplasmic matrix: a central domain (endoplasm) and a peripheral domain (ectoplasm).
  31. CELL ACTIVITIES
    • cell division: mitosis and meiosis.
    • cell locomotion: ameboid movement of leukocytes; in cells in close contact; villi and microvilli are involved.
    • cell movement may be random or directional; directional movement is called chemotaxis.
    • movement within cells: organelles, vesicles, chromosomes move within the cell using motor molecules such as dyenin kinesin and myosin-1.
  32. CELL DEATH
    • necrosis: mechanical injury, toxins or anoxia.
    • apoptosis: active and programmed cell death---environment, developmental history or genome.
    • normal cell life span is from a few days to 80 years or more.
  33. WHAT IS A POISON?
    • any substance that causes injury or death.
    • Paracelsus: "All substances are poisons; there is none which is not a poison. The right dose differentiates a poison and a remedy."
    • no safe chemical.
    • by the same token there is NO chemical that CAN NOT be used safely.
  34. TOXICANTS/TOXINS/POISONS
    • toxicants: substances that produce adverse biological effects of any nature.
    • may be chemical or physical in nature.
    • effects may be of various types (acute, chronic, etc)
    • toxins: specific proteins produced by living organisms (mushroom toxin or tetanus toxin)
    • most exhibit immediate effects.
    • poisons: toxicants that cause immediate death or illness when experienced in very small amounts.
  35. WHAT IS TOXICOLOGY?
    • study of adverse effects of chemical agents on living organisms.
    • because of such a definition the word poison can be avoided.
    • most biochemical scientists such as physicians, pharmacologists, epidemiologists are all toxicologists. (except they are involved in both beneficial and adverse effects).
    • a toxicologist then has a primary focus on adverse effects of chemical agents.
  36. WHAT DO TOXICOLOGISTS DO?
    • assessment of acute and chronic exposure to chemical agents.
    • recognition, identification and quantitation of hazards from occupational exposure to chemical pollutants in air, water, food, drugs and environment.
    • development of agents selectively toxic to microorganisms (antibiotics), insects, weeds and fungi.
    • development of antidotes.
    • development of treatment regimens.
  37. TOXICOLOGY IS BOTH SCIENCE AND ART
    • science: involves observation and data collection.
    • art: allows prediction of hazards when there is no or little information available.
    • example: acrylonitrile is a carcinogen in animals (science) it has a potential to be so in humans (art).
  38. QUANTITATIVE AND QUALITATIVE ASPECTS OF TOXICITY
    • quantitative aspect: any substance can be toxic at some dose level and harmless at lower doses.
    • between these extremes there is a range of possible effects.
    • for example: vinyl chloride is a potent hepatotoxin at high doses and a carcinogen at low chronic doses. aspirin (acetyl salicylic acid) is a relatively safe drug; can cause ulcers on chronic exposure.
    • qualitative aspect: carbon tetrachloride is a potent hepatotoxicant in many species and relatively harmless in chicken.
  39. MECHANISM OF TOXIC ACTIONS
    • events leading to toxicity in vivo---uptake, distribution, metabolism, mode of action, excretion, etc.
    • biochemical toxicology: biochemical/molecular events, enzymes, reactive metabolites, interaction of xenobiotics, molecular biology, gene expression.
    • behavioral toxicology: CNS, PNS, endocrine system.
    • nutritional toxicology: effect of diet.
    • carcinogenic toxicology: events leading to cancer.
    • teratogenic toxicology: effect on development.
    • mutagenic toxicology: effect on genetic material.
    • organ toxicology: neuro-, hepato-, nephrotoxicity, etc.
  40. HOW ARE WE EXPOSED TO TOXICANTS?
    • exposure could be:
    • intentional, occupational, environment, or accidental.
    • acute: single exposure.
    • subacute: multiple exposures (one month or less).
    • chronic: multiple exposures (more than a month).
    • toxicity measurement: a complex task; depends on age, gender and diet, etc.
  41. ROUTE OF ENTRY AND TOXICITY
    • route of entry: ingestion (GI), inhalation (lungs), topical (skin), parenteral (subcutaneous, intradermal and intraperitoneal).
    • descending order of toxicity versus port of entry:
    • iv > inh > ip > sc > im > id > oral > topical
  42. STUDY OF TOXICANTS AND TOXICITY
    • analytical toxicology: identification and assay of toxicants.
    • toxicity testing: use of live animals in long and short term studies.
    • toxicologic pathology: changes in subcellular, cellular, tissue and organ morphology.
    • structure-activity study: chemical and physical property vs prediction of toxicity.
    • biomathematics and statistics: data analysis.
    • epidemiology: study of toxicity as it occurs in populations.
  43. APPLIED TOXICOLOGY
    • clinical toxicology: diagnosis and treatment of poisoning.
    • veterinary toxicology: diagnosis and treatment of poisoning in animals.
    • forensic toxicology: medico-legal aspects.
    • environmental toxicology: movement of toxicants in the environment.
    • industrial toxicology: dealing with work environment.
  44. CHEMICAL USES AND CLASSES
    • agricultural.
    • clinical.
    • drugs of abuse.
    • food additives.
    • industrial.
    • naturally occurring.
    • combustion products.
  45. AREAS OF TOXICOLOGY
    • DESCRIPTIVE
    • animal testing, effects in humans, insects, etc.
    • descriptive toxicologists are active in universities, research institutes and are supported by private (pharmaceutical and chemical companies), local state and federal agencies.

    • MECHANISTIC
    • mechanisms of toxic effects.
    • results are useful in developing tests for assessments.
    • needs knowledge of many other sciences.

    REGULATORY
  46. REGULATORY TOXICOLOGY
    • FDA (Food and Drug Administration)-- enforces laws according to Food, Drug and Cosmetics Act.
    • EPA (Environmental Protection Agency)-- regulates most other chemicals.
    • FIFRA-- Federal Insecticide, Fungicide, Rodenticide Act.
    • TSCA-- Toxic Substance Conservation Act.
    • RCRA-- Resource Conservation and Recovery Act.
    • SDWA-- Safe Walter Drinking Act.
    • OSHA (Occupational Safety and Health Administration)-- ensures protection of consumers from hazards of household products.
    • CSPS (Consumer product Safety Commission)-- ensures protection of consumers from hazards of household products.
    • DOT (Department of Transportation)-- ensures the materials transported across check points are safe.
  47. FATE OF A CHEMICAL AGENT AFTER EXPOSURE
  48. SPECTRUM OF TOXIC EFFECTS
    • therapeutic vs side effects: side effects could be desired or undesired.
    • local vs systemic effects: local means effect on site of exposure. example, ingestion of caustic substances or inhalation of irritable substances.
    • systemic requires absorption and then distribution to target sites. example, tetramethyl lead should reach CNS for its effects.
    • immediate vs delayed toxicity: rapid vs long term effect. example, vaginal/uterine cancer in utero in daughters of mothers who used DES (diethyl stilbestrol) to avoid miscarriages.
  49. SPECTRUM OF TOXIC EFFECTS
    • reversible vs irreversible toxicity: most effects in liver are reversible because of tissue regeneration. most CNS and carcinogenic effects are irreversible.
    • allergic reactions: hypersensitive to chemicals called allergens---exposure leads to release of antibodies, histamines, etc.
    • idiosyncratic reactions: genetically determined abnormal reactions. example, allergy to nitriles.
  50. CHEMICAL INTERACTIONS WHEN EXPOSED SIMULTANEOUSLY
    • additive effects: simple addition (2+3=5) combined effects is equal to sum of 2; example-- inhibition of acetylcholinesterase by organophosphates.
    • synergistic effects: combined effects is much more than sum (2+2=20); example--carbon tetrachloride+ethanol--both hepatotoxicants.
    • potentiation effects: one potentiates the effect of the other (0+2=10); example--isopropanol (a non-hepatoxicant)+carbon tetrachloride.
  51. CHEMICAL INTERACTIONS WHEN EXPOSED SIMULTANEOUSLY--ANTAGONISM
    • chemical here interfere with each other (4+6=8 or 4+4=0).
    • types of antagonism: functional, chemical or inactivation, dispositional, receptor.
  52. TYPES OF ANTAGONISM
    • functional antagonism: chemicals here produce opposite physiological effects.
    • barbiturates (convulsants) decrease BP and epinephrine (non-convulsants) increase BP.
    • chemical antagonism or inactivation: produce a less toxic substance.
    • chelation--dimercaprol (BAL) chelates metals such as Ar, Hg, Pb, etc.
    • dispositional antagonism: includes absorption, biotransformation, distribution and excretion of a chemical agent.
  53. DISPOSITIONAL ANTAGONISM
    • a metabolite of parent compound reaches the target site.
    • parathion
    • paraoxon
  54. RECEPTOR ANTAGONISM
    • two chemicals bind to same receptor and produce less effect.
    • receptor antagonists are often called blockers.
    • this antagonism has important clinical implications:
    • naloxone is used to treat depression by morphine.
    • oxygen is used to treat carbon monoxide poisoning.
    • atropine is use to treat organophophatepoisoning.
  55. CHEMICAL TOLERANCE
    • tolerance is a state of decreased responsiveness to toxic effect of chemicals.
    • dispositional tolerance: less amount of toxicant reaches target site. carbon tetrachloride (CCl4) produces tolerance b decreased formation of trichloromethyl radical CCl3.
    • decreased responsiveness of tissue: mechanism not completely understood.
  56. SELECTIVE TOXICITY
    • ability of a chemical to produce injury in one living form without harming the other form of life even if the two coexist in intimate contact.
    • living forms injured or killed are called uneconomic forms and living that are protected are called economic forms. example: parasites & hosts or two tissues in the same organism.
    • toxicologist predict effects in humans using results from animal models.
    • in agricultural situations crops are economic forms and pests (insects, weeds, fungi) are uneconomic.
    • in humans antibiotics are used for microorganisms that cause diseases.
  57. WHY SOME CHEMICALS ARE SELECTIVELY TOXIC?
    • chemicals may be equitoxic to both economic and uneconomic forms but preferentially accumulate in uneconomic form.
    • chemicals react fairly specifically with one form.
  58. ACCUMULATION IN UNECONOMIC FORM
    • differential distribution, biotransformation or excretion. example, effectiveness of 131I is due to its ability to reach thyroid gland alone.
    • surface area effects, mammals have larger surface area than insects--lesser quantity is required for insects.
  59. SPECIFIC REACTION IN ONE FORM
    • CYTOTOXICITY
    • plant have no nervous, cardiovascular or muscle systems but have photosynthetic property.
    • bacteria have cell walls and humans do not.
    • penicillin kills bacteria but relatively non-toxic to humans.

    • BIOCHEMICAL DIFFERENCE
    • bacteria do not absorb folic acid, instead they synthesize it from p-aminobenzoic acid.
    • mammals do not synthesize folic acid, instead they absorb it.
    • drug sulfonamide mimics p-aminobenzoic and no folic acid is formed in bacteria.
  60. DOSE RESPONSE RELATIONSHIPS
    • exposure and effects are closely related.
    • the relation is called dose-response (D-R) relationship.
    • the D-R is very important aspect of toxicology.
    • two important aspects of D-R are assumptions and calculations/evaluations.
  61. NOAEL vs LOAEL
    • NOAEL: highest data point at which there was not an observed toxic or adverse effect.
    • LOAEL: lowest data point at which there was an observed toxic or adverse effect.
  62. DOSE RESPONSE RELATIONSHIPS ASSUMPTIONS
    • response is due to chemical administration:
    • response observed only after chemical administration.
    • threshold dose with no effect.
    • NOAEL--no observed adverse effect level.

    • response is in fact related to dose:
    • there is a molecular receptor for the chemical.
    • concentration of chemical at target site is related to dose.

    • presence of a precise quantifiable method:
    • organophosphates (OP) vs inhibition of acetylcholinesterase (AChE).
    • indirect measures--changes in liver enzymes.
  63. CALCULATIONS AND EVALUATIONS
    • one way of expressing toxicity is LD50.
    • LD50 is the statistically derived single dose of a substance that is expected to cause death in 50% of exposed individuals.
    • LD50 cannot be effectively defined in terms of an S-shaped curve.
    • toxicologist have developed a PROBIT CURVE (a linear D-R relationship) for calculation of LD50.
    • in the PROBIT CURVE 50% mortality is equal to 5 Probit units.
  64. CALCULATIONS AND EVALUATIONS
    • significance of steep vs flat curves.
    • determination of LD50 is an essential aspect of toxicological studies.
    • LC50 and LD50 are influenced by species, gender, strain, age, etc, and also environmental factors such as temperature, prior exposure to other chemicals, crowding and diet.
    • these values can also be used for cancer, liver injury, etc.
    • other ways of describing toxicity include weight and surface area.
  65. CALCULATIONS AND EVALUATIONS
    • - types of D-R
    • effective dose (ED)--therapeutic.
    • toxic dose (TD)--liver injury.
    • lethal dose (LD)--mortality.

    • -therapeutic index (TI)
    • is the ration of LD50:ED50 TI=LD50/ED50
    • it represents relative safety of the chemical agent.
    • larger the ratio greater the safety; example, TI= 200/100.
    • TI is calculated from the median; does not say anything about slope of the curve
    • hence toxicologists look for a margin of safety (MS).
    • MS=LD1/ED99
  66. POTENCY VS EFFICACY
    • potency: capacity of a chemical to kill at a lower dose.
    • efficacy: kill at any dose.
  67. SYNTHETIC ORGANIC COMPOUNDS IN THE AIR
    • CO2 oxides N and S, hydrocarbons (HC), particulates.
    • sources:
    • transportation, industries, electric power generators, heating homes and buildings.
    • benzo[a]pyrene (B[a]P) from incomplete combustion of automobile exhausts.
    • pollution--a result of reaction between UV and HC such as acrolein, formaldehyde (HCHO).
  68. SYNTHETIC ORGANIC COMPOUNDS IN WATER AND FOOD
    • IN WATER
    • - chemicals from run off from urban areas, sewage, refineries, chemical plants, etc.
    • - agricultural chemicals such as HC, OP, carbamates (CA), chlorinated HC (DDT, chlordane, dieldrin), fertilizers, pesticides.
    • drinking water--low MW halogenated HC (chloroform, dichloromethane, CCl4) formed during water purification; also PCB, TCDD (tetrachlorodibenzop-dioxin).

    • IN FOOD
    • -bacterial toxins: exotoxin form Clostridium botulini.
    • -mycotoxins (aflatoxins) form Aspergillus falvus.
    • -plant alkaloids, animal toxins, PCBs, etc.
  69. WHERE DO TOXIC COMPOUNDS COME FROM?
    • FOOD ADDITIVES
    • preservatives: antibacterial, antifungal, anti oxidants.
    • the agents that change physical properties for processing, taste, color, etc.
    • examples--B-hydroxy toluene and anisole (BHT, BHA), ascorbic acid, etc.


    • WORKPLACE
    • Pb, Cu, Hg, Zn, Cd, Be, F, CO.
    • solvents--aliphatic HC (hexane), aromatic HC (benzene, toluene, xylene), halogenated HC (dichloromethane, vinyl chloride), alcohols (methanol), esters, etc.
  70. WHERE DO TOXIC COMPOUNDS COME FROM?
    • DRUGS OF ABUSE
    • CNS depressants: ethanol, secobarbital.
    • CNS stimulants: cocaine, metamphitamines, caffeine, nicotine, opioids, heroine, morphine.
    • hallucinogens: LSD (lysergic acid and diethylamide), PCP (phencyclidine), THC (tetrahydrocannabinol).

    • PESTICIDES
    • HC, OP, CA.
  71. WHERE DO TOXIC COMPOUNDS COME FROM?
    • MYCOTOXINS
    • Claviceps sp.--ergot alkaloid--affects NS and a vasoconstrictor.
    • Aspergillus sp.--aflatoxin--found in grains, peanuts--activated to be a carcinogen.
    • Fusarium sp.Tricothecenes--bactericidal and insecticidal--cause diarrhea, anorexia and ataxia.


    • MICROBIAL TOXINS
    • tetanus, botulinum, diphtheria toxins affect CNS.

    • PLANT TOXINS
    • sulfur compounds, lipids, phenols, alkaloids, glycosides.
    • also drugs of abuse--cocaine, caffeine, nicotine, heroine, morphine.
  72. ENVIRONMENT MOVEMENT OF TOXICANTS
    • chemicals rarely remain in the original form or in the location they are released from.
    • agricultural chemicals drift to run off water--susceptible to bacterial and fungal degradation.
    • some are detoxified and others are toxified (activated) or accumulate (DDT).
    • transfer between inanimate and animate phases.
    • bioaccumulation of lipophilic substances: DDT vs bald eagle. DDT production.
  73. DISPOSITION OF TOXICANTS
    • Barriers for absorption:
    • almost every known toxicant is now known to penetrate.
    • considerable known variations.
    • concentration of toxicants at the target site is important for toxicity.
    • concentration at target organ depends on its disposition.
    • the toxicity of a chemical agent is low if:
    • its rate of absorption is low.
    • it accumulates in organs other than the target.
    • it is biotransformed to a less toxic metabolite.
    • it is rapidly eliminated.
  74. INTRODUCTION
    toxicants must pass thru a number of barriers. (skin, lung, alimentary canal, etc).

    • once in blood stream, toxicant is available for distribution.
    • Hg, Pb --- CNS, kidney, hemopoietic organs.
    • benzene --- hemopoietic organs.
    • CCl4 --- liver damage.

    • toxicants are eliminated by the body by:
    • -biotransformation (liver).
    • -excretion (kidney, lungs, biliary).
    • -storage (fat).
  75. PLASMA MEMBRANES
    • thickness:
    • number of layers.
    • kinds of cells -- stratified epithelium in skin, simple in lungs, endothelium in blood vessels.

    • structure of plasma membranes (PM):
    • thickness 7nm.
    • lipid bilayer (phospholipids and cholesterol).
    • fatty acids in lipids are not rigid, hence called fluid mosaic model.
    • protein embedded in lipids, serve as transport proteins, channels, receptors, enzymes and form structures.
  76. SKIN LAYERS
  77. SKIN LAYERS
    • epidermis: surface layers that are keratinized.
    • dermis: dense fibro-elastic. connective tissue containing glands and hair.
    • hypodermis: loose connective tissue consisting largely of adipose tissue.
  78. TRANSPORT MECHANISMS
  79. PLASMA MEMBRANES: MECHANISMS OF ABSORPTION
    • passive diffusion.
    • specific transport.
    • active transport.
    • facilitated diffusion.
    • additional transport systems: phagocytosis and pinocytosis.
  80. PASSIVE DIFFUSION
    • most toxicants cross PM by simple diffusion.
    • small hydrophilic molecules diffuse thru aqueous channels.
    • large organic molecules diffuse thru hydrophobic domains. ethanol is lipid soluble and is hence easily absorbed thru stomach.
    • rate of transport depends on PC(partition coefficient) and concentration gradient across PM.
  81. FICK'S LAW
    • according to Fick's Law the rate of diffusion depends on:
    • concentration gradient across PM.
    • thickness of PM.
    • diffusion constant of toxicants.
    • molecular weight of toxicant.
    • surface area of PM.
  82. IONIZATION OF TOXICANTS
    • toxicants in a solution exist as ionized or unionized.
    • ionized or ionic ones are polar and unable to cross PM.
    • non-ionized or non-ionic are non-polar and rapidly cross PM.
    • their diffusion primarily depends on lipid solubility.
    • many toxicants are weak organic acids or bases.
    • the amount of weak organic acids or bases in solution depends on their dissociation constant K.
    • HA<--->H+ + A- affected by pH.
  83. LIPID BILAYER
  84. SIMPLE DIFFUSION: TCDD, DDT
    • channel mediated: tetrodotoxin.
    • carrier mediated:iron, 5-fluorouracil, paraquat, a-amantin calcium, lead.
    • active transport: penicillin (β-lactam antibiotics)
  85. PASSIVE DIFFUSION: PH, pKa AND HENDERSEN-HASSELBACH RELATIONSHIP
    • pH is the negative log of [H+].
    • pKa is the pH at which 50% of the acid is dissociated.
    • Hendersen-Hasselbach equation:
    • for weak acids

    • for weak bases

    • acids with low pKa are strong: acids with high pKa are weak.
    • bases with low pKa are weak: bases with high pKa are strong.
    • so pKa alone cannot say whether a compound is an acid or a base.
  86. INFLUENCE OF PARTITION COEFFICIENT ON ABSORPTION OF TOXICANTS
    • partition coefficient (PC) a solvent greatly influences penetration of toxicants across PM.
    • PC is related to the solubility of the toxicants in lipids.
    • PC = conc. of toxicant in lipids/conc. in water.
    • higher the PC higher the lipid solubility.
    • solvent commonly used for PC determination is octanol which best mimics phospholipids in PM.
    • other solvents include chloroform, ether and olive oil.
  87. MECHANISM OF ABSORPTION: SPECIAL TRANSPORT
    • active transport---ex. Na+ transport.
    • -against concentration gradient.
    • -saturation at high substrate concentration.
    • -a selective system; certain structural requirements.
    • -requires biochemical energy.
    • -essential for elimination of xenobiotics.

    • facilitated diffusion:
    • -carrier mediated.
    • -similar to active transport but no energy requirement and is not against concentration gradient.
    • -examples, glucose Gl to plasma and plasma to red blood cells.

    • additional transport systems:
    • -phagocytosis and pinocytosis: important for removal of particulate materials by macrophages.
  88. ACTIVE VS PASSIVE DIFFUSION
  89. ABSORPTION OF TOXICANTS
    • routes of absorption:
    • -absorption of toxicant by the gastrointestinal tract (GI).
    • -absorption of toxicants by the lungs.
    • -absorption of toxicants by the skin.
  90. ABSORPTION OF TOXICANTS BY THE GI
    • this is the transport from GI to blood---generally called absorption.
    • no special system for toxicants; toxicants are treated as any other molecules.
    • GI route is important for toxicologists because of ex. suicidal situations and children exposure.
    • GI is a tube within a tube system; chemicals still outside until absorbed.
    • examples, nitroglycerin--sublingual, rectal suppositories, most of the entry is oral.
  91. ABSORPTION OF TOXICANTS BY THE GI
    • GI absorption depends on the ionic species of the toxicant (ionized or unionized).
    • stomach pH is highly acidic and intestinal pH is near neutral.
    • using pKa values one can determine the possibility of absorption of toxicants.
    • mammalian GI also has specific transport systems for various substances.
    • two step absorption--Fe++ rapid absorption into mucosa and slow into blood.
    • active transport--very few substances.
    • facilitated diffusion--example dyes.
  92. INFLUENCE OF pH ON ABSORPTION OF A WEAK ACID (BENZOIC ACID, pKa ~ 4)
  93. INFLUENCE OF pH ABSORPTION OF A WEAK BASE (ANILINE, pKa ~ 5)
  94. FACTORS AFFECTING ABSORPTION BY THE GI
    • -resistance of toxicants to pH, enzymes, microflora.
    • snake venom is least toxic orally and fatal iv.
    • bacteria convert DDT to DDE.

    • -chelating agents.
    • ethylene diamine tetraacetic acid (EDTA) increases membrane permeability hence increasing absorption.

    • -GI motility.
    • higher the motility higher the absorption and vice versa.

    • -others.
    • one metal alters absorption of the other.
    • Cd↓Zn, Zn↓Cu, old age↓abs, starvation↑abs.
  95. ABSORPTION OF TOXICANTS BY THE LUNGS
    • GASES AND VAPORS
    • toxicants absorbed by lungs are usually gases and vapors (CO, NO2, SO2, etc.)
    • gases and vapors in the atmosphere are in direct equilibrium with blood.
    • if the gas is more soluble in blood it has high absorption rate---example: chloroform.

    • AEROSOLS AND PARTICLES
    • important characteristics of a toxicant under this is its size and water solubility.
    • particles 2-5 μm are deposited in the tracheo-bronchiolar region and later cleared by mucosa.
    • particles 1μm and smaller penetrate into the alveolar sacs.
    • overall removal of particles from alveoli is inefficient.
  96. WHAT HAPPENS TO ABSORPTION?
  97. ABSORPTION OF TOXICANTS BY THE SKIN
    • skin is a good barrier: certain chemical agents do enter such as the nerve gas sarin and CCl4.
    • the toxicants must pass thru several layers of packed keratinized epithelial cells.
    • major mechanism is diffusion called percutaneous absorption.
    • phase I (epithelium), II (dermis), III (blood and internal fluids).
    • certain chemical agents increase rate of penetration: dimethyl sulfoxide (DMSO) is believed to remove fat from skin and increase rate of absorption of chemicals
  98. DISTRIBUTION OF TOXICANTS
    • once in plasma after absorption or iv a toxicant is available for distribution.
    • distribution is very rapid and depends on: extent of blood supply to an organ, rate of diffusion or special transport, partition coefficient.
    • site of accumulation may not be site of action: which means the toxicant is inert until it reaches target.

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