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.)
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).
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 O 2 and CO special transport systems such as active transport are available for charged particles such as Na 2. +, 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). mitochondria. peroxisomes. chloroplasts.
glycogen. lipids. pigments.
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. endocytic.
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 H 2O 2 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
agricultural. clinical. drugs of abuse. food additives. industrial. naturally occurring. combustion products.
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.
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 (CCl 4) produces tolerance b decreased formation of trichloromethyl radical CCl 3. 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 u: parasites & hosts or two tissues in the same organism. neconomic forms and living that are protected are called economic forms. example 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
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.
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 LD 50. LD 50 is the statistically derived single dose of a substance that is expected to cause death in 50% of exposed individuals. LD 50 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 LD 50. in the PROBIT CURVE 50% mortality is equal to 5 Probit units.
CALCULATIONS AND EVALUATIONS
significance of steep vs flat curves. determination of LD 50 is an essential aspect of toxicological studies. LC 50 and LD 50 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 LD 50:ED 50 TI=LD 50/ED 50it 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=LD 1/ED 99
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
CO 2 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).
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, CCl 4) 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.
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.
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?
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.
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. CCl 4 --- liver damage.
toxicants are eliminated by the body by: -biotransformation (liver). -excretion (kidney, lungs, biliary). -storage (fat).
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.
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 +]. pK a is the pH at which 50% of the acid is dissociated. Hendersen-Hasselbach equation: for weak acids
for weak bases
acids with low pK: acids with high pK a are strong a are weak. bases with low pK: bases with high pK a are weak a are strong. so pK a 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 pK a 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, pK
a ~ 4)
INFLUENCE OF pH ABSORPTION OF A WEAK BASE (ANILINE, pK
a ~ 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.
-others. 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, NO 2, SO 2, 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 CCl 4. 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.