Toxicology Note PDF

Exam Revi restonse ODose Cures Differenceb w individualandpopulation curve Individual dose response or graded characterized by continuous scale ofadoses that lead to an increase bothcompare in the magnitude of speci...

Exam Revi restonse ODose Cures Differenceb w individualandpopulation curve Individual dose response or graded characterized by continuous scale ofadoses that lead to an increase bothcompare in the magnitude of specific response doses and populationdoseresponse orquantal all or none i esponses at anygivendose andindividualis classified as a responder or nonresponder normal distribution gaussian Threshold aneffect orpointonthedoseresponsecurve LDso lethaldose of asolid in 50 not a measure ofhazard LOAEL RETENEEE Hypersensitive or hypersusceptible verysusceptible show up on left sideorof curve resistent show up on rightside of curve Hyposensitive Thresholddose minimal effectivedoseED of anychemicalthat evokes an all or none responsedose at whichtoxicityis first observed Slopesofdoseresponse curve flat curvedemonstrates that alarge changeindose is requiredbefore asignificantchangein response will beobserved a steep curve indicates a relatively small change indosewill cause alargechangeinresponse Canhave same EDso withdifferentslopes Dose response cure for essential nutrientsmay be monotonic Multipleinfectionpoints exist alongthe curve that change theshape Curves are variable and can resemble biphasic Valley U shaped or J shaped or an entire hill for an inverted U shaped essentialnutrients neededfor homeostasis Lowdosesleadtodeficiencyhighdosesleadtotoxicity Dose response cure for carcinogens shape of curve varies dependingon themechanism oftoxicity genotoxic carcinogens directlymodify anddamageDNA havebeenassumedtoincreasethe risk of cancereven atthelowestpossibledose linear nonthreshold extrapolation isused ContributionsfromParacelsus Ramazzini andPotts Paracelsus thedose makesthe poison first sound articulation of dose response curve Anything can be a poison Father of toxicology Published on theminer'ssickness andotherdiseasesof miners acknowledgesdiseases specificto this occupation Ramazzini Father ofOccupational Medicine Published Discourse in the Diseases ofWorkers Outlined wide of occupations and diseases range Askedpatients whattrade are you Potts recognized role of soot in scrotal cancer among chimney sweeps of this time First record of PAHcarcinogenicity First occupational link to cancer What is a chemical allergy Immunologically mediated adversereactionto achemical resulting from aprevious exposure to that chemical or astructurally similar one Termhypersensitivity is mostoften usedto describethis response for agiven individual reactions can bedoserelated Dose response cures don'tapply Mechanism mostchemicals are not largeenoughtobe recognizedbytheimmunesystem as aforeignsubstance combines w proteintoformantigen hapten hapten protein complex is capableof eliciting formation of antibodies 1 2 weeks upon subsequentexposuretheantigen is recognized by the antibody leadingto anallergicreaction vanes from mild to fatal Once sensitization hasoccurred reactions can happenin response toverylowdoses Typesof EpidemiologyStudies Cohort Prospective Exposedus nonexposed rate Incidence Case control Retrospective Diseased vs non diseased Relativeodds Cross sectional Either exposure or disease Either prospective orretrospective Prevalence Can'testablishcausality Free radicals and antioxidants molecule or molecularfragment that contains one 0 more unpairedelectrons in its out orbital Formedby accepting or losing an electronor fissionof acovalent bond Also naturallyoccurringendogenoussources Superoxide anion radical 02 isstartingcompoundin 2 toxication pathways Metals arenotoriousfor changing valence states in the body Can initiate apoptosis in cells oralso causenecrosis Critical to immunesystemfunction toomaryaredetrimental Antioxidant an counteract or neutralize damagingeffects can donate an elector wo becoming a radical Toxicology an art and science Science observationaland datagatheringphase Art utilization ofthe data to predictoutcomesof exposure in human and animal populations Acute 24hrs singleorrepeatedexposuresw i 24hrs subacute month Chronics 3 months Subcheonic 1 3months Acuters chronic studies Acute performedon rodents and aim todetermine LDso w i 4days Subacute repeated dose performedtoobtain info on toxicity of a chemical after repeatedadministration and as an aid to establishdosesfor sub chronic studies Sub chronic 90 days Breeks is most common length can establish NOAEL and COAEL Chronic 6 months to 2 yrs maximum tolerabledose MTB is usually given Systemic vs Local Effects Local occur at site offirstcontactb w biologicalsystem and toxicant ivery littlechemical is absorbed intoblood stresseston ofcaustics inhalation of irritants Systemic requiresabsorption and distributionof atoxicant from its entry point to a distant site at whichdeleterious effects are produced Mostsubstancesexcepthighlyreactivematerials producesystemiceffects RoutesofExposure inOccupationalSettings Inhalation Skin exposure CombinedEffectsof Chemicals Additive combinedeffect is equalto the sum of the effectsof each agentgiven 2 3 5 Most commoneffect Synergistic combinedeffect is muchgreaterthan the sum of the effects of eachagentgiven 2 2 20 Ex carbon tet andethanol liverdamage  Potentiation one substancedoesnot have a toxic effect on a certain organ orsystem but when addedto another chemical that chemical is much more toxic 3 75 8 pool increasehepatotoxicityofcarbonto Antagonism twochemicals when giventogetherinterfere w each others actions or one interferes with the action of after 8 4 4 0 Basis ofmany antidotes Factorsthat GovernDepositionofParticlesGases in RespiratorySystem Differsfrom GI absorption dissociationof acids base and lipid solubility are lessimportant Gases vapors mucosa of nose covered byextremely important film glycoprotein Water soluble reactive gasesreact with cell surface components in glycoprotein Nose nasal passages act as a scrubber which protect thelungs Non water soluble non reactive reachlower gases areas of lungin similarconcentration that wasinhaled Blood gaspartitioncoefficient solubility ratio describes solubility ofinhaled chemical concentrationinbloodconcent in gasphasebefore or at saturation at equilibrium Lowsolubility ratio rate oftransferdepends on bloodflowthroughlungs perfusionlimited Highsolubility ratio rate oftransfer isprimarily afunction of rate anddepth ofrespiration Aerosols Particles size andsolubilityof chemical is important surface Site of depositionofaerosolsdependlargely on the site of theparticles arp.fimpdheae Particles 5rem coarse particles deposited in nasopharyngeal region may be dissoledin  I P mx ab d bl 4 or trapped in nasal cilia and eventuallyswallowed Particles 2 Sym fineparticles depositedin traches bronchiolorregion clearedthrough mucociliary escalator Small enoughto escape impactionmechanisms Particles slum penetrate to areolar sacs of thelungs Generally removal of particlesfromareoli is relatively insufficient Some particles may remain indefinitely Biotransformation Purpose w o it ahighlypermeablexenobioticexcreted in urine or bile wouldbe reabsorbed in thekidney or intestine rather than eliminated in wine of feces Usually decreaselipidsolubility of a compound and increases water solubility May also be calledmetabolism Enzymaticprocess of chemical modification that of a xenobiotic changes the physiochemicalproperties fromthosethat favor absorption anddistributionto those that favorelimination Differencesb w phase I andPhase Biotransformation Phase I facilitates elimination ofxenobioticsby TPSA and 109 elimination Favors octonal water partition blumonww coefficient Relativelymodestchangesthat result in soluble decreased membranepermeability Favors elimination anddecreaseslikelihoodof Typicallycloser excretedmetabolitesbeingabsorbed toparentchemical May undergophaseII after Catalizedbyenzymesystemsthat can bedivided into categoriesbasedonreactiontheycatalyze Hydrolists reduction oxidation additionof OH NHz SH COOH  Phase II facilitateseliminationbyadding an ionizable group usually acid negativelycharged w pHof7 large TPSA large logP Relativelylargechanges that resultin decrased membrane permeability Typically mediatedoutusingsomekindoftransporter after biotransformation I metabolitewith Conjugationof a xenobiotic or phaseacid acid gluconicacid sulfonic twitterionglutathioneor aminoacids glycinetaurine glutamine Acetylation methylation Eliminatedviabileor urine leadstodecreasedlipophilicity Deraddeftigartfient Xenobiotictransformation enzymes arewidelydistributed throughoutbody typically think ofthem asbeingassociated w theliver CYP is a common enzyme Biotransformationisgenerallypositive sometimes canincrease toxicity toxication Principles that GovernAbsorptionand Excretion Lipophilic hydrophobic generally 79 5 1 small hydrophilic moleculespermeatemembranesthrough pores parcellehler Shidlson aqueous moleculesdiffuseacrosslipiddomaintranscellular Hydrophobicsoluble lipid compounds In general as lipophicity increasespartition coefficient also increases and so doesspeedof movement throughthe membrane NegativelogP more water solublethan lipidsoluble Larger thelogP thelargerthe amountofthatcomponentinthe lipedfraction  If something is nonionized itis mostlikelylipidsoluble In general nonionizedformof weakorganicacids and bases is to some extentlipedsoluble resultingindiffusionacross the lipeddomain of the membrane With the exceptionof very small ionized moleculesthat can pass throughmembranepores only non ionizedformsofmostelectrolytes are able to cross membranes Ionized forms are generallytolarge to passthroughaqueous pores and areinsufficientlylipophilicto betransferredby passiediffusion pka describesstrengthofcicide andbases acids pka pH log 1 1 5 bases plan pH lyhf.fmEas largernonionizedfractorfavorsabsorption Asdiameterof molecules increase rate of movement acrossmembranedecreases Smaller moleculesgenerally morewatersoluble Brain capillarieshaveverylowaqueousporosity b c of lack of fenestrae In GI particleabsorptionincreases w decreasingparticlediameter Primarymechanism forexcretionofxenobiotics Judney Secondary feces bileexcretion must firstbe biotransformed to watersolublecompound Tertiary lungs exhaledgases Featuresof Mammalian CellMembrane Consist ofphospholipid bi layer 59989 Outside morepolar and hydrophilic 688888 Interior lipophilicfattyand tails  Form some permeats ban in contros movementofsubstancesin andoutockholesterol Hasselectivepermeability givesstructure Integralproteins receptorstransporters Ion channels Lipid soluble can diffusethroughlipididget Water solublecan't morethroughlipidlayer InitiatingFactors for Apoptosis andNecrosis Damaged cells eliminated byapoptosis ornecrosis Apoptosis internaltriggers suicide Inherent self destructsequencebuiltintocells Normallyinhibited bytrophicgrowthfactors e g NOF External triggers murder Destructuresequenceorderedby other What w we're concerned from Embbybsatuktye.bg tumornecrosis oxicologystandpoint Releaseofcytochromes is 1ststep Damageto DNAappearsto be central event fering apoptosis in injuredcells Necrosis lack of oxygen Na K pump Initiated bydamage Role of P53 in Apoptosis Cancer Tumor suppressor transcriptionfactor DNA damagecellcyclecheckpoint halts cellcycle until DNArepaired When severedamage occurs inducesgenesPUNANOXA which inhibit BCL 2 Concerts alwaysbattlingapoptosis Cancercells usually havesuppressedP53mutatedor underexpressed Terms Concepts Presystemicelimination.in ihtSsdestributiontotoryet site toxicentiseliminatedpriorto reachingsystemiccirculation Not unusual for chemicals absorbedfrom GI If liver istargetorganmayincrease toxicity  Toxication biotransformationtoharmfulproducts whenbiotransformationincreasestoxicity Detoxication biotransformationswhicheliminatetheultimate toxicant orpreventits formation Necrosis disorderly messy celldeath causes inflammation due to cell membranebursting ends w debrisis inextracellular environment disruption inATPsynthesiswhich power source for walkpump w o this cellsburst passive celldeath Apoptosis orderlyplannedcell death active cell death shrinks and breaks intomembraneboundfragments apoptic bodies that are phagocytosed deadcells are removed w o inflammation deletionof cells w DNA damagepreventstheir malignanttransformation cancer Homeostasis steady state Phase I andPhaseII biotransformations seeabove Toxin producedbybiologicalsystems plants animals fungi bacteria Toxicant producedby or are aby productof anthropogenic human made activities Octanol waterpartitioncoefficient waytoexpresslipid solubility largernumber more lipidsoluble xenobiotic chemical substanceforeignto an organism assil Simplediffusion passive requiresnoenergyfrom cell does punspot not involve participation of anymembraneproteins Fick's law concentrationgradienthigh to low is afactor Blood gaspartitioncoefficient solubilityratio concentration in blood concentration in gasphasebefore or at saturation at Quik Horsesw low ratio rate oftransferdependson bloodflow throughhangs Gase w high ratio rate of transferisprimarily functionof rate and depth of respiration special Active transport chemicals are movedacrosselectrochemical transport or concentration gradients selectivefor certain structural featuresofchemicals andhaspotentialforcompetitneinhibition b w compoundsthat aretransportedby same transporter requires expenditureof ATP Facilitated diffusion carrier mediated transport that exhibits propertiesof activetransportexceptthat thesubstrate is no movedagainst an electrochemical orconcentration gradient and thetransportprocessdoes notrequirethe inputof energymetabolicpoisonsdo notinterfere thistransport w Fibrosis abnormal collagendeposition 2most common types are hepatic fibrosis andpulmonaryfibrosis overshoot of repair process Topologicalpolarsurface area involvedin phase I and II biotransformation estimatestotal surface area of a molecule contributed by polar atoms like oxygen andnitrogeniprovides indication of lipidsolubility Typesoftolerance state of decreasedresponsiveness to a toxic effectof a chemical resultingfroma priorexposureto that chemical or tostructurallyrelatedchemical Dispositionaltolerance amountofchemical reaching site of actiondecreases over time leading toreducedresponsiveness of the tissue tostimulation e g phenobarbital Chemicalcellulartolerance may result in loweravailabilit ofreceptors and or mediatorsabuse like e.g drugsof morphine