Term
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Definition
– Absorption
– Distribution
– Biotransformation
– Excretion
( fundamental factor that contributes to potential toxicity) |
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Term
| toxicity is dependent on..? |
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Definition
| the conc. at the site of action |
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Term
| Conc. at the site of action |
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Definition
• usually proportional to “internal dose” at the site of action
• target tissue, cell or molecule
depends on absorption, distribution and excretion
• (biotransformation)
• determine the potential for adverse events occurring |
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Term
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Definition
separate higher organisms from environmental toxicants:
– skin
– lungs
– alimentary canal: mouth to anus
– exclude caustic or corrosive agents that act topically
• acid, base, salt & oxidizer |
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Term
| Factors affecting disposition of xenobiotic/toxicant: |
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Definition
insufficient conc. at the target site:
• poor absorption or low rate of absorption
• poor distribution
• rapid biotransformation to less toxic form
• rapid excretion (elimination)
– “the dose make the poison” |
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Term
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Definition
| transfer of a toxicant from exposure site into systemic circulation |
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Term
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Definition
| entry of a toxicant into internal body fluid (blood stream); translocates throughout the fluid compartments of the body |
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Term
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Definition
| removal of absorbed toxicant from systemic circulation though excretion, metabolism and storage |
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Term
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Definition
removal of systemic toxicant through excretory processes
– renal (kidneys), fecal (GI tract), pulmonary (volatile substances) |
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Term
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Definition
stratified epithelium of skin/mouth
– simple squamous epithelia of lung/kidney glomeruli/ blood vessels/capillaries (endothelial)
– cuboidal epithelia of kidney tubules
– simple columnar epithelia (cilia) of GI tract |
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Term
|
Definition
phospholipid bilayer
– phospholipid (variants)
– glycolipid (lipids with carbohydrates)
– cholesterol
– proteins
semifluid
• unsaturated fatty acids abundance
• facilitate active and passive transport
• differentially permeable
Proteins inserted/embedded |
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Term
|
Definition
amphiphilic (7–9 nm thick)
• hydrophilic polar heads: outer/inner surface (has phosphate group and glycerol)
• hydrophobic trails: inward – hydrophobic inner space (kinks due to cis double bond) |
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Term
|
Definition
– transverse the entire lipid bilayer
– receptors
– aqueous pores
– ion channels
– transporters |
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Term
|
Definition
(passive transport)
– many toxicants
– no energy expenditure
– Fick’s Law: down the conc. gradient
– transcellular diffusion
– paracellular diffusion |
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Term
|
Definition
• crosses lipid domain
• cross apical and basal membrane
– and basolateral
• small lipophilic/hydrophobic molecul |
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Term
|
Definition
• “aqueous pores”
• between cells – intercellular space
• small hydrophilic molecules
• < 600 Da (600 g/mol)
• smaller: rapid diffusion (ethanol) |
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Term
| Rate of diffusion pertaining to large organic molecules |
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Definition
correlates with lipophilicity
– pertains to large organic molecules
– lipid solubility
– degrees of lipophilicit |
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Term
| Partition Coefficient (P) |
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Definition
– represents the lipophilic/hydrophilic nature of compound
– function of Gibbs energy of transfer from water to octanol
– thermodynamic tendency of neutral compounds to partition preferential between 2 media |
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Term
|
Definition
– determined by octanol/water partition coefficient P
– ratio of compound in organic and aqueous phases under equilibrium conditions
P = [X]org / [X]aq
– expresses as Log P
– Physiochemical parameter to assess potential membrane permeability |
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Term
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Definition
Lead acetate Log P = - 0.63
negative: low lipid solubility (some amino acids) |
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Term
|
Definition
TCDD Log P = 7.05
positive: high lipid solubility |
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Term
|
Definition
Pharmacology (drug design)
Toxicology
Bioconcentration
Soil/sediment accumulation (sorption) |
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Term
| Weak Organic Acids and Bases |
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Definition
– ionize in water (Arrhenius’ theory)
– Acid ionize -> H+
– Base ionize -> OH-
– Ionized forms: Low lipid solubility
– slow permeation through the lipid domain of PM
– low MW: aqueous pores (slow/insufficient)
– nonionized forms: some lipid solubility, lipid domain PM |
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Term
|
Definition
pH at which 50% ionized à pKa and pKb
pH = - Log [H+]
pKa = - Log Ka smaller pKa = stronger the acid
Ka = [A-][H3O+]/[AH][H2O]
pKa + pKb = 14
Kw = [H3O+][OH-] = 1.0×10−14 M2 at 25ºC |
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Term
| Henderson-Hasselbalch Equations |
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Definition
– derive pH as a function of pKa in biological system
pH = pKa + Log [ionized]/[nonionized]
pH = pKa - Log [nonionized]/[ionized]
extend of ionization
acid: pKa – pH = log [nonionized]/[ionized]
base: pKa – pH = log [ionized]/[nonionized]
degree of ionization depends on its pka & ph of soln |
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Term
| Degree of Ionization of Benzoic acid and Aniline |
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Definition
• Benzoic acid:
– readily translocates through PM from an acidic env.
• Aniline:
– readily translocates through PM from a basic env. |
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Term
| Passive diffusion requires certain conditions |
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Definition
– concentration gradient
– lipid soluble toxicant
– toxicant must be in nonionized form |
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Term
|
Definition
(simple diffusion)
– bulk movement of water across membrane pores
• channels
• aqueous pores (fenestrate endothelium)
• aquaporins
– small solutes pass though pores with water
– passage though pores = filtrations
– osmotic pressure (force) |
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Term
|
Definition
• primary site of filtration
• aqueous pores = 70 nm
• passage of small molecules (~ 60 kDa) |
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Term
|
Definition
– large compounds
– xenobiotics, amino acids, nucleic acids
• restricted from diffusion/filtration/aqueous pores
• specialized transport systems
• membrane-associated transporters
• facilitate chemical disposition
• often against conc. gradient
• influx and efflux transporters
• 500 genes involving specialized PM transporters |
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Term
|
Definition
(special transport)
– carrier-mediated transport system
– movement down a conc. or electrochemical gradient
– no energy expenditure
– high conc. may saturate transporters
– exclude metabolic poisons (active transport) |
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Term
| ex. for facilitated diffusion |
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Definition
nutrients
• glucose
– from GI tract across basolateral PM of intestinal epithelium
– from plasma into red blood cells
– from blood into CNS |
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Term
|
Definition
(special transport)
• Carrier-mediated transport system
• ~ 5% of all human genes are transport-related
• influx and efflux of xenobiotics
• many are bidirectional
• Two main categories / two major super families
Active transport
– energy-dependent transport
– ATP-binding cassett (ABC) transporters
– largely efflux
Facilitated transport
– Solute carriers (SLCs)
– largely influx |
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Term
|
Definition
(special transport)
• movement across PM against conc. and electrochemical gradients
• requires expenditure of energy
• selective for certain structural features
• subjected to competitive inhibition by chemical antagonist (congeners = biochemical variant)
• competition with other chemicals using the same transporter
• subjected to saturation at high substrate conc.
• may be inhibited by metabolic poisons
• metabolic inhibitors can block the transport process |
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Term
| first identified active transport protein ex. |
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Definition
Phosphoglycoprotein
– overexpressed in tumor cells that showed resistance to anticancer drug
– Multidrug Resistance (MDR) to the cell
– coined: P-glycoprotein (P-gp or MDR1)
– gene name MDR1
– transporter functions as an efflux pump
– exudes cytotoxic drugs out of the tumor cell
– protect cell from drug-mediated destruction |
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Term
|
Definition
(aka ABCB1)
– first member of large super family of transport proteins known as
Ø ATP-binding cassette (ABC) transporters |
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Term
| ATP-binding cassette (ABC) transporters |
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Definition
7 subfamilies of ABC transported (A–G)
• involve 49 human genes
– first large family of xenobiotic transporters
– requires binding and hydrolysis of ATP to function
– two structural domains (repeated)
• Hydrophobic membrane spanning lipid domain (MSD)
• Hydrophilic intracellular nucleotide binding domain (NBD) -> ATP binding and hydrolysis site |
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Term
|
Definition
are vital to maintaining homeostasis of endogenous substrates
– Absorption and elimination of many xenobiotics
• GI tract absorption
• Bile/urine elimination
– Maintain barrier functions
• BBB
• Maternal-fetal barrier |
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Term
|
Definition
egulates cholesterol in cell
• mediate its efflux from liver |
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Term
|
Definition
transport phospholipid substrates
• Phosphatidylethanolamines (PE) are a class of phospholipids found in biological membranes |
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Term
|
Definition
(C subfamily):
– aka multiresistant drug protein (MRD) family
• multidrug resistant-associated protein
– five domains |
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Term
|
Definition
(MRD1):
• isolated from multidrug resistant cells
• excrete chemicals from cells |
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Term
|
Definition
important in efflux of xenobiotic metabolites
• conjugated to UDP-glucoronic acid or glutathione |
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Term
|
Definition
(G subfamily):
– Breast cancer resistance protein BCRP
• isolated from breast cancer cell lines
• also expressed in normal tissue
• efflux of endogenous and xenobiotic sulfate conjugates
• expressed in stem cells
• protection from xenobiotics |
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Term
|
Definition
(SLCs superfamily)
– facilitated transporters
– 43 SLC gene families
– ~ 300 genes
– Disposition of endogenous compounds
• glucose, neurotransmitter, nucleotides, peptides, essential metals
– xenobiotic disposition: organic anions/cations
– Expressed in body’s epithelium |
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Term
|
Definition
– Organic Anion Transporting Polypeptide ATP
– Organic Anion Transporters OATs
– Organic Cation Transporters OCTs
– Peptide transporters PEPTs
– Multidrug and Toxin Extrusion MATE |
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Term
Organic Anion Transporting Peptides
(substrate) |
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Definition
– OATPs major groups in this family
– substrate: large hydrophobic organic anions
– amphipathic
– MW >350 DA
– bile acids
– conjugated to steroids, hormones, peptides, mushroom toxins, drugs (antibiotics/cancer drugs) |
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Term
| OATPs (largely influx pumps) |
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Definition
allow bidirectional movement of solutes
– important in hepatic uptake of xenobiotics
– liver anion uptake
– expressed: intestines, brain, liver, kidneys, testes |
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Term
|
Definition
transport of organic anions, cations, and neutral compounds (Na+ independent)
– anion exchange mechanism
– cellular influx of organic compound is coupled with efflux of HCO3-, glutathione/conjugates
– affected by pH (pH increase/increase activity)
12 domains |
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Term
| Organic anion transporter (substrate) |
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Definition
| substrates: smaller, more hydrophilic organic anions |
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Term
|
Definition
– anion exchange mechanism:
– sodium-independent
– important role in renal uptake of anions
– generally facilitated diffusion
– transport substrate against electrochemical gradient
– exchange for intracellular dicarboxylates
transport organic anions, predominately in kidney |
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Term
|
Definition
| kidneys, skeletal muscles, brain, placenta |
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Term
| OATs (organic-carboxylate exchangers) |
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Definition
• α-ketoglutartae
• gradient maintained by Na+/K+ ATPase
• antiviral/anticancer drugs
– associated with drug-drug interactions |
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Term
| Organic-cation transporter |
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Definition
– substrate: organic cations
– important role in liver uptake of xenobiotics (also kidneys)
– novel OCTs (OCTNs) transport exogenous cations and endogenous compounds
– generally facilitated diffusion
– transport against electrochemical gradient of the transported cation
– tissue: liver-specific, weak expression in heart skeletal muscles, kidneys, brain, placenta
• broad range of organic cations
• affinity for substrate do depend on ionization
• endogenous/exogenous substrates, drugs, neurotransmitters, antiviral drugs |
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Term
| Peptide transporters PEPTs |
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Definition
– di and tri- peptide transport
– various drugs and toxicants
(SLCs) |
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Term
| Multidrug and Toxin Extrusion MATE transporters |
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Definition
– cation efflux pumps
– liver and kidneys
(SLCs) |
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Term
| Xenobiotic Transporters: Additional transport processes |
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Definition
• Phagocytosis
• Pinocytosis (receptor mediated)
• Lungs: alveoli (nanoparticles)
• Blood: reticuloendothelial system of liver and spleen |
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Term
|
Definition
• Cross body membranes and enters bloodstream
• Main sites:
– GI tract,
– lungs and
– skin |
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Term
|
Definition
– most important
– environmental toxins enter with food
– absorption à entire GI: mouth-anus
– sublingually / rectal suppositories
– chemical and physical properties of toxicants
– Gastric juices pH 2 / Small intestine pH 6
most substances is absorbed by diffusion
• lipid-soluble substances more effective
• simple diffusion
• weak organic acids/bases nonionized forms (neutral)
• lipid-soluble form |
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Term
|
Definition
mass action law, surface area, blood flow rate
– absorption is a dynamic process: blood removes toxicant once it’s absorbed
• keeps conc. low
• small intestine: villi/microvilli à increase surface area 600-fold à facilitate absorption |
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Term
| GI tract (transport system) |
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Definition
Carrier-mediated transport systems
• nutrients/electrolytes
• iron: rapidly absorbed my GI mucosa cells by transport protein
• divalent metal transporter 1 or DMT1
• protein-iron complex (ferritin) stores iron à iron is only released once blood iron conc. drops à continued absorption to replenish stored iron
Specialized Transporters for Nutrients
• xenobiotics compete/interact
– Special Xenobiotic Transporters
• SLC transporters/carriers |
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Term
|
Definition
– Absorption of particles and particulate matter
• particle size
• inversely related to absorption
– increase in size (diameter)/decrease in absorption
– oral exposure of metallic mercury less toxic
• pinocytosis ( > 20 um)
• nanoparticles
• lipid-solubility and ionization is less important |
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Term
| GI tract Other factors that influence absorption |
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Definition
• pH
• presence of food and digestive enzymes
• bile acids
• gut microflora (bacteria)
• GI tract permeability and motility |
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Term
| GI tract (chemical resistance/lack of resistance) |
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Definition
| hydrolysis by stomach acids, biotransformation by enzymes, modified by microflora à new compound with altered toxicity compared to original |
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Term
|
Definition
• influence absorption and toxicity
• Clostridium and Eubacterium species
• reduction of nitroaromatic compounds (nitrobenzene to aromatic amine)
• nitroreductases
• produce toxic carcinogenic aromatic amines |
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Term
|
Definition
increase lipid solubility of metals (lead)
• absorption of the metal complex |
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Term
GI tract
– Systemic circulation is determined by: |
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Definition
• Absorption and biotransformation by GI tract
• Extraction of xenobiotics by liver into bile
• Transporters affect influx and efflux |
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Term
|
Definition
| (first-pass effect) = removal before entrance into systemic circulation |
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Term
| Chemical with a high first-pass effect |
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Definition
have lower absorption
• rapid elimination |
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Term
|
Definition
Inhalation exposure, Respiratory absorption
• Airborne contaminants
• The lungs are an important entry point for toxic gases, solvents, aerosols, and particulates. |
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Term
| Why are lungs so absorbent? |
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Definition
Pulmonary tissue is highly vascularized and has a large surface area (approximately 100 m2 in adults) for toxicant absorption.
Toxicant |
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Term
| Toxicant absorption from the respiratory system |
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Definition
| nasopharyngeal-> tracheobronchial-> alveolar-> lymph (can enter the blood from any of these organs) |
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Term
| Examples of inhalation exposure and symptoms |
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Definition
Occupational Hazards
CO poisoning (acute exposure)
• CDC: Flu-like: headache, dizziness, weakness, upset stomach, vomiting, chest pain, and confusion.
• reversible and irreversible (neurological)
• lethal: pass out and die
• fetal hypoxia
• everyone is at risk
Silicosis: silica dust (chronic exposure)
• CDC: pneumoconiosis: swelling in the lungs (restrictive lung disease) and chest lymph nodes
• pulmonary nodules
• irreversible
• other adverse effects: lung cancer, pulmonary tuberculosis, and airways diseases |
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Term
| Major groups of inhaled toxicants |
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Definition
– gases: carbon monoxide, nitrogen dioxide, sulfur dioxide
– Vapors of volatile and volatilizable liquids: benzene and CCl4
• volatile organic compounds: VOC
– Aerosols and particles |
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Term
|
Definition
Vapor: a gas of substance that can exist as a solid or a liquid at atmospheric pressure and ambient temp.
– liq. -> gas/vapor -> evaporation
– solid -> gas -> sublimation |
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Term
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Definition
| pressure excreted by vapors above its liquid (closed system) |
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Term
|
Definition
| high tendency to evaporate |
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Term
| high vapor pressure at RT |
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Definition
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Term
| absorption of toxicant through inhalation |
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Definition
| largely lungs (surface area) |
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Term
|
Definition
trap water-soluble vapors
react with cellular components |
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Term
|
Definition
lung protection (scrubber)
nasal adverse effect
formaldehyde: nasal turbinates-tumors in rats |
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Term
| Factors of inhalation exposure |
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Definition
ionized molecules: very low volatility -> low conc. in normal ambient air
short distance of diffusion: pneumocytes type I are a thin layer/gas exchange
Rapid removal from lungs by blood (surface area and extensive capillaries) |
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Term
|
Definition
§ diffusion from alveolar space into capillaries
§ gas dissolve in blood
§ physical process: dissolving |
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Term
| Process of diffusion of inhaled gas |
|
Definition
Result is that the gas partition between media
lung<->blood<->tissue
(lung<->blood: absorptive phase)
(blood<->tissue: distribution phase)
Inhaled gas continuous to dissolve in blood until there is an equilibrium between gas in blood and gas in alveolar space
§ At equilibrium ratio is constant
[gas]blood/ [gas]alveolar space
§ This solubility ratio = blood-to-gas partition coef.
Lung |
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Term
| [gas]blood/ [gas]alveolar space |
|
Definition
lung<->blood
gas-blood-partition coefficient
§ unique value for each gas
§ Ratio is constant and varies according to
§ Henry’s law
Lung |
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Term
|
Definition
amount of gas dissolved in liquid is proportional to the partial vapor pressure of the gas at any conc. before or at saturation
Ptotal = Pgas1 + Pgas2 +…+ Pgasn
§ pressure gradient
§ higher inhaled conc. -> higher partial pressure -> higher blood conc.
§ ratio remains constant unless saturation occurs
[gas]blood/ [gas]alveolar space |
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Term
| At equilibrium (for inhalation) |
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Definition
| rate of transfer for alveolar space to blood = rate of removal by blood from alveolar space |
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Term
| blood-to-gas partition coefficient examples |
|
Definition
Chloroform (CHCl3) = 20 (large value)
§ very soluble in blood
§ requires large amount of gas to dissolve in blood before partial pressure in blood is increases and gas exist blood and enter other tissue cell membranes
Ethylene (CH2CH2) = 0.14 (very low)
à blood is quickly saturated
§ requires small amount of gas to dissolve in blood before partial pressure in blood is increases and gas exist blood and enter other tissue (brain)
§ a smaller percentage of ethylene is removed from alveolar space into blood |
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Term
| Rate of absorption in lungs depends on... |
|
Definition
depends on toxicant’s solubility ratio at equilibrium
[gas]blood/ [gas]alveolar space
§ The more soluble the toxin is in blood, the more will dissolve by the time equilibrium is reached |
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Term
|
Definition
(blood/gas) > 1
à rapid transfer during single respiratory cycle à little remain in alveolar space before next inhalation |
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Term
|
Definition
(blood/gas) < 1
à quick saturation à slow transfer à high conc. remain in alveolar space |
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Term
| Increased respiratory rate |
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Definition
| increase uptake of compounds with low solubility – gets removed from site of equilibrium |
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Term
| the ionization potential (weak organic acids/ bases) and lipid solubility for respiratory are... |
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Definition
| less important of respiratory absorption compared to intestinal and percutaneous absorption |
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Term
| Gases with high solubility |
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Definition
ventilation-limited
§ rate and depth of respiration determines the extend of distribution |
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Term
| Gases with low solubility |
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Definition
perfusion limited
§ here the rate of blood flow is the primary factor for distribution |
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Term
| way lungs limit systemic circulation |
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Definition
| Lungs can be site of biotransformation and or elimination |
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