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- 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.)
- nucleoplasm or karyoplasm; carry on specific functions.
- 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).
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-.
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.
PLASMA MEMBRANE STRUCTURE
- 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.
- 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.
- 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.
- retractile, eccentric and basophilic.
- forms nucleolus organizing region (NOR) and consists of various kinds of RNA.
- site of metabolic activities and specialized functions.
- contains: organelles, inclusions, cytosol, cytoskeleton.
- endomembrane system (endoplasmic reticulum, Golgi complex, endosomes, lysosomes, vacuoles).
fluid containing electrolytes and colloids.
microtubules, microfilaments, intermediate filaments.
- 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.
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.
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.
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.
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.
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.
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.
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.
- 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.
- 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.
- membrane bound dense bodies.
- contain hydrolytic enzymes for intracellular digestion.
- most active in leukocytes and phagocytes.
- involved in endocytosis forming endosomes.
- membrane bound.
- generate H2O2 as a by-product or oxidative reactions.
- enzymes: urate oxidase, D-amino oxidase, and catalase.
- 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).
- 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.
- 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.
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.
- 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.
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.
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.
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).
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.
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.
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.
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
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.
- 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.
CHEMICAL USES AND CLASSES
- drugs of abuse.
- food additives.
- naturally occurring.
- combustion products.
AREAS OF TOXICOLOGY
- 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.
- mechanisms of toxic effects.
- results are useful in developing tests for assessments.
- needs knowledge of many other sciences.
- 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.
FATE OF A CHEMICAL AGENT AFTER EXPOSURE
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.
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.
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.
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.
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.
- 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.
- 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.
- 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.
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.
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.
SPECIFIC REACTION IN ONE FORM
- 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.
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.
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.
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.
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.
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.
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/ED50it 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).
POTENCY VS EFFICACY
- potency: capacity of a chemical to kill at a lower dose.
- efficacy: kill at any dose.
SYNTHETIC ORGANIC COMPOUNDS IN THE AIR
- CO2 oxides N and S, hydrocarbons (HC), particulates.
- 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).
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.
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.
- 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.
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).
WHERE DO TOXIC COMPOUNDS COME FROM?
- 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.
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.
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.
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).
- 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.
- 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.
PLASMA MEMBRANES: MECHANISMS OF ABSORPTION
- passive diffusion.
- specific transport.
- active transport.
- facilitated diffusion.
- additional transport systems: phagocytosis and pinocytosis.
- 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.
- 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.
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.
SIMPLE DIFFUSION: TCDD, DDT
- channel mediated: tetrodotoxin.
- carrier mediated:iron, 5-fluorouracil, paraquat, a-amantin calcium, lead.
- active transport: penicillin (β-lactam antibiotics)
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.
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.
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.
ACTIVE VS PASSIVE DIFFUSION
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.
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.
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.
INFLUENCE OF pH ON ABSORPTION OF A WEAK ACID (BENZOIC ACID, pKa ~ 4)
INFLUENCE OF pH ABSORPTION OF A WEAK BASE (ANILINE, pKa ~ 5)
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.
- one metal alters absorption of the other.
- Cd↓Zn, Zn↓Cu, old age↓abs, starvation↑abs.
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.
WHAT HAPPENS TO ABSORPTION?
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
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.