ÿWPCK Ÿ % øv¡y’׉v¡°·4sTëA—9zIÆ{~uTo|SÀ€ŠRâ\ÿ±½Ztì•Äý<ÑXwur [»GƒÆÝ¥pÔëìq•l¾‚…áFh+ƒ›$ª‡{¨†ŠK“”‚]³û<øñ¤\³;`¡G\µ—;ªwÀ)«£ß~{«”Û[ߪ ­$à~<ý+/}Žg‚sßã¿©èÏö]ÏJ x@ðPöFï1ÍöogÑWËÂ; ÕL¾ÿ•a6”™ùÈâ•ãAm¿•Ê~š_Æ`–“+ÏL¨Y>SͤiÍ<¢3YõþÊäŒ2¤3±@¼”–¸ÜÏf¹mVw×fçç„Ïþh³–¥¢E‹%’Ò&€ýR¡5PÁ|ï<7Í“´z¯§÷Çhø°úÀ=47t‹Öf[ ùˆç¼ÚvP1^ð8ž‚Ct*{¨£¯Ðìgl» Ì'aÛ_üýÖDå%gB¶EæE뼃³Š=fK#Ÿ}y©9&%`8„4d†ešä‰ÀÇ‘Ü‚Þ>ÎQ“¤7åȳZ àó÷"ƒßÀFû u¬¹nˆ‰|©SçÁó —PQ‚GÖYÐmûº{Šõ,Ó ®ñ{Ê£]ú:LÜR #!üUN %k 0(q^ ™w@¥4åù m  0 N!forÕ€GbÇÊ)Xó˜Okidata OL-810e,ü,,,,,ü0(ÈhH  Z6Times New Roman RegularX($¡¡Æ,V.á ‘¾’ƒ“U”¾•U–¾—ƒ˜U™¾šz/.3.wp¸·3|xš#ÿU‹ÿÀÀÀ(ÍO$——ÔÿÔòòóóÔÿÔhttp://www.pca.state.mn.us/waste/listedmetals.htmlhttp://www.health-science.com/index.htm?page=/fiber.htmlhttp://www.springboard4health.com/notebook/nutrients_fiber.htmlhttp://www.sis.nlm.nih.gov/ToxTutor/Tox2/a22.htmhttp://www.solae.com/NASAPP/solae/soy nutrition/nutrition basics/necessarynutrients/no nutrients.jspwww.iet.msu.edu/tox_for_public/riskasmt.htmÝ ƒ!ÝÝ  ÝÔ_ÔñŠñTopic:€Question€Set€1.€Question€1.€Questions€arising€from€the€historical€background€ofÏtoxicology.€Ì€€ÌSubject:€Question€Set€1.€Question€1.€Questions€arising€from€the€historical€background€ofÏtoxicology.€€€Posted:€Mar-04-02€at€4:05€PM€by€Kenneth€Campbell€€ÌÌò ò1.€€The€idea€of€causality€arose€during€the€middle€ages€and€Renaissance.€€This€builds€onÐ P   Ðcareful€observation€and€testing.€€How€might€this€give€rise€to€the€notions€of€occupationalÏhazards€or€the€Ô_ÔnonmysticalÔ_Ô€explanation€for€Ô_ÔoncogenesisÔ_Ô?ó óñŠñññÐ 0 € ÐñññŠññŠñññÌñññŠññŠññŽñ€ñŽñññÔÿÔñññŽñWhat€about€toxicity?€€As€a€toxin€can€have€a€lethal€or€a€Ô_ÔsublethalÔ_Ô€effect,€is€one€word€adequate€toÏdefine€it?€€It€would€seem€there€is€a€need€to€define€varying€types€and€levels€of€toxicity€or€toxicÏresponse.ÌÌLethality:€mortality,€death€(induced€reasonably€rapidly€as€an€obvious€consequence€of€exposure)ÌÌMorbidity:€a€decrease€in€functionality€that€may€ultimately€lead€to€a€decrease€in€Ô_ÔlifespanÔ_ÔÌÌReduced€reproductive€capacity:€decrease€in€reproductive€output€(this€has€a€genetic€carry-over€toÏthe€next€generation€because€there€is€a€resulting€change€in€the€potential€gene€pool)ÌÌDecrease€in€specific€functions€or€acuities€(sensory:€sight,€hearing,€taste,€smell,€touch;€specificÏmetabolic€functions€ð!ð€food€allergies;€appearance€ð!ð€hair€growth,€acne):€these€decrease€quality€ofÐ P  Ðlife€but€are€often€nonlethal,€do€not€decrease€Ô_ÔlifespanÔ_Ô€and€do€not€alter€the€geneÌÌReduced€Ô_ÔastheticsÔ_Ô€or€other€quality€of€life€issues:€these€are€often€issues€that€have€little€or€noÏmedical€impacts€except€at€the€psychological€or€emotional€levelsÌÌReduced€quality€of€the€environment:€this€may€impact€any€or€all€of€the€above€itemsÌÌNote€that€these€range€from€severe€immediate€impacts€on€the€individual,€through€prolonged€orÏdelayed€impacts€on€the€individual€or€the€species,€to€subtle€effects€that€may€only€alter€survival€orÏfunctions€of€individuals€or€species€via€alterations€of€behavior€or€mental€vitality.€€Evaluating€risksÏof€toxic€exposure€then€may€encompass€analysis€of€biological€risks€and€exposure€tests,€potentialÏmedical€or€economic€risks€of€exposure€to€or€lack€of€exposure€to€the€toxicant€of€interest,€andÏpossible€impacts€on€the€integrity€or€improvement€of€environmental€quality.€€The€overall€pictureÏmay€involve€a€variety€of€competing€interests€or€benefits€and€definitely€involves€a€cost/benefitÏanalysis.€€Even€at€the€individual€level€this€is€reflected€in€the€statements€that€exist€on€drug€andÏhousehold€chemical€packaging.€€For€medications€there€are€not€only€directions€for€proper€use,€butÏindications€of€possible€deleterious€side€effects.€€These€are€often€unrelated€to€the€drug€target€tissueÏof€interest,€e.g.,€antihistamines€not€only€decrease€swelling€in€nasal€mucus€membranes,€they€oftenÏsuppress€mental€alertness€and/or€increase€blood€pressure.€€The€detailed€analysis€of€positive€andÏnegative€drug€impacts€is€subsumed€in€the€science€of€pharmacology€but€has€obvious€overlap€andÏrelation€to€toxicology€both€in€its€tenets€and€methodologies€but€also€in€the€subjects€of€study€andÏthe€analyses€used€to€evaluate€study€results.ñŽñññÔÿÈÔñññŠñÐ ð-@), Ð.ÌPosted:€Feb-12-03€at€11:59€AM€by€Erin€Valentine€€€ÌÌ€€€1.€The€idea€of€studying€causality€through€careful€observation€and€testing€might€give€rise€to€theÏnotion€of€occupational€hazards€because€certain€occupations€expose€workers€to€unique€risks€ofÏexposure.€If€particular€subsets€of€workers€are€all€experiencing€a€similar€disease€or€condition,€theÏlogical€way€to€explain€the€symptoms€is€to€carefully€observe€the€working€conditions.€This€wouldÏentail€sampling€the€environment€in€search€of€the€causative€agent,€or€the€ð ðÔ_ÔtoxiconÔ_Ôðð.€PotentialÏcandidates€could€then€be€used€in€animal€or€in€vitro€tests€to€determine€response€to€various€doseÏlevels,€site€of€action€and€what€types€of€symptoms€are€observed€in€the€test€subjects.€They€couldÏalso€undergo€biochemical€analysis€to€determine€structure/activity€relationships.€The€informationÏgathered€could€then€be€used€to€determine€the€causative€agent€and€could€also€be€used€to€infer€otherÏpotential€hazards.€This€type€of€testing€could€then€also€be€used€to€test€other€potentially€hazardousÏworking€environments€before€workers€exhibit€symptoms.€This€would€allow€for€preventativeÏmeasures€to€be€taken€against€toxic€exposure.ÌÌIn€the€case€of€non-mystical€explanation€of€Ô_ÔoncogenesisÔ_Ô,€the€same€process€applies.€In€the€onset€ofÏunexplained€cancer,€one€can€carefully€observe€the€afflicted€individualððs€potential€exposure€to€aÏpotential€carcinogen.€Similar€tests€to€those€described€above€could€then€be€performed€to€identifyÏthe€culprit.ÌÌPosted:€Feb-12-03€at€3:38€PM€by€Lisa€McIntosh€€ÌÌThe€process€of€simple€observation€from€occupational€or€incidental€exposures€may€be€suitable€forÏÔ_ÔnoncarcinogenicÔ_Ô€effects€resulting€from€acute€exposures;€however,€for€chronic€adverse€effects€orÏÔ_ÔcarcinogenesisÔ_Ô,€it€is€not€as€easy€a€matter€as€to€pinpoint€the€potential€culprit.€€Liver€cancer,€orÏheart€disease,€for€example,€may€result€from€a€lifetime€of€cumulative€effects€of€numerousÏcausative€agents,€which€may€or€may€not€be€obvious€based€on€the€individual's€exposure.ÌÌPosted:€Feb-13-03€at€10:34€PM€by€Lisa€McIntosh€€ÌÌ"Watch€and€learn"€tactics.€In€the€past,€people€have€noted€adverse€effects€associated€with€exposureÏto€particular€substances.€Likewise,€it€was€noted€that€certain€occupations€had€correspondinglyÏhigher€incidences€of€diseases€(e.g.,€"Mad€Hatters"€syndrome,€resulting€from€mercury€toxicityÏ(Ô_ÔneurotoxicityÔ_Ô).€Mercury€was€commonly€used€by€hat€makersð8ð..).€As€for€Ô_ÔoncogenesisÔ_Ô,€the€sameÐ $à" Ðpremise€holds:€exposure€to€a€particular€substance€eventually€initiated€the€onset€of€cancer€(e.g.,Ïthe€elevated€incidence€of€lung€cancer€among€smokers).€One€problem€with€this€approach,Ïhowever,€is€that€a€particular€type€of€cancer€(or,€say,€a€nonspecific€Ô_ÔnoncancerÔ_Ô€effect)€may€correlateÏwith€a€substanceððs€use,€but€may€not€necessarily€be€directly€related€to€exposure.€SimpleÏobservation€does€not€take€into€account€confounding€factors€such€as€the€incidence€of€backgroundÏcancer€rates,€or€the€numerous€other€entities€in€our€lives€that€may€also€attribute€to€adverse€effectsÏ(e.g.,€diet,€acute€exposures,€etc.)ÌÌPosted:€Feb-15-03€at€11:30€AM€by€Ô_ÔDINAÔ_Ô€KATZ€€ÌÐ ð-@), ÐDuring€the€Renaissance,€the€idea€of€scientific€experiments€and€Ô_ÔreplicabilityÔ_Ô€arose.€It€becameÏunderstood€that€an€event€can€be€caused€by€something€non-immediate.€The€spread€of€literacy€andÏprinted€works€made€it€easier€for€scientists€and€others€to€share€observations€and€note€patterns,Ïsuch€as€the€high€occurrence€of€scrotal€cancer€in€chimney€sweepers.€Likewise€it€was€known€thatÏmining€and€covering€building€domes€with€gold€leaf€(I€believe€the€gold€was€in€a€mercury€solution)Ïwere€dangerous€occupations,€because€many€of€these€Ô_ÔprofesionalsÔ_Ô€died€relatively€quickly€ofÏsimilar€diseases,€such€as€lung€problems.€While€the€exact€mechanisms€of€lung€injury€were€notÏknown,€the€cause-effect€relationship€was€established.€Similarly,€while€initially€Ô_ÔoncogenesisÔ_Ô€wasÏattributed€to€mystical€causes,€the€observation€of€patterns€of€lifestyle€and€environment€amongÏvictims€contributed€to€the€uncovering€of€certain€cause-effect€relationships,€like€theÏabove-mentioned€scrotal€cancer€of€chimney€sweepers€and,€more€recently,€lung€cancer€andÏemphysema€among€heavy€smokers.ÌÌPosted:€Feb-15-03€at€2:59€PM€by€ERIC€FAULKNER€€ÌÌWhile€scientific€advancements€of€the€cause€and€effect€relationship€of€Ô_ÔtoxicantsÔ_Ô€on€the€humanÏsystem€did€occurred€during€the€Middle€Ages,€one€could€say€that€these€were€great€scientificÏalchemy€experiments€than€the€Ô_ÔprecusorsÔ_Ô€of€government€regulatory€bodies€like€OSHA,€EPA,€andÏthe€NIH.€€One€pioneer€of€the€Middle€Ages,€Catherine€de€Ô_ÔMediciÔ_Ô,€tested€toxic€concoctions€onÏmen.€€Now,€her€horrific€crimes€can€be€interpreted€to€modern€toxicology€terms€such€as€onset€ofÏaction,€specificity€of€action,€and€clinical€significant.€€The€fate€for€her€evil€ways€was€execution,Ïbut€one€could€argue€that€her€scientific€studies€are€exactly€what€occurs€during€Phase€I,€II,€and€IIIÏclinical€trials€of€new€chemical€entities€therapies.€€Overall€humans€have€tried€to€learn€from€thereÏmistakes€and€this€what€has€Ô_ÔinitatedÔ_Ô€Ô_ÔgovernmetalÔ_Ô€control€€Back€in€the€1900's€one€pharmaceuticalÏcompany€killed€108€children€with€their€cough€drop€medicine.€€They€had€used€ethylene€Ô_ÔgylcolÔ_ÔÏinstead€of€Ô_ÔproyleneÔ_Ô€glycol€in€their€formulation.€€Their€medicine€was€termed€the€Ô_ÔElixrÔ_Ô€of€deathÏand€hence€the€FDA€was€then€established€soon€afterwards.€ÌÌWith€regards€to€the€explanation€Ô_ÔoncgoneissÔ_Ô,€the€formation€of€tumors€can€be€Ô_ÔenviromentallyÔ_ÔÏÔ_ÔstimualedÔ_Ô€as€well€as€genetic€inherited.€€Indeed€OSHA€is€there€to€protect€workers€from€safety€andÏtoxic€hazards,€but€if€they€were€really€that€concerned€why€does€mining€still€exist.€€An€occupationÏwere€many€Ô_ÔmaliganciesÔ_Ô€have€been€well€document.€€Maybe€humans€have€not€really€Ô_ÔprogessedÔ_Ô€asÏmuch€as€we€have€thought.€€And€as€far€as€governmental€control,€the€pharmaceutical€company€thatÏmade€the€Elixir€of€death€is€still€in€business.€Ì€€€ÌPosted:€Feb-15-03€at€4:19€PM€by€ERIC€FAULKNERÌ€(Note:€The€spell€check€was€not€saved€from€the€original€response)ÌÌWhile€scientific€advancements€of€the€cause€and€effect€relationship€of€Ô_ÔtoxicantsÔ_Ô€on€the€humanÏsystem€did€occurred€during€the€Middle€Ages,€one€could€say€that€these€were€great€scientificÏalchemy€experiments€than€the€precursors€of€government€regulatory€bodies€like€OSHA,€EPA,€andÏthe€NIH.€€One€pioneer€of€the€Middle€Ages,€Catherine€de€Ô_ÔMediciÔ_Ô,€tested€toxic€concoctions€onÏmen.€€Now,€her€horrific€crimes€can€be€interpreted€to€modern€toxicology€terms€such€as€onset€ofÏaction,€specificity€of€action,€and€clinical€significant.€€The€fate€for€her€evil€ways€was€execution,Ïbut€one€could€argue€that€her€scientific€studies€are€exactly€what€occurs€during€Phase€I,€II,€and€IIIÐ ð-@), Ðclinical€trials€of€new€chemical€entities€therapies.€€Overall€humans€have€tried€to€learn€from€thereÏmistakes€and€this€what€has€initiated€governmental€control€€Back€in€the€1900's€one€pharmaceuticalÏcompany€killed€108€children€with€their€cough€drop€medicine.€€They€had€used€ethylene€glycolÏinstead€of€propylene€glycol€in€their€formulation.€€Their€medicine€was€termed€the€Elixir€of€deathÏand€hence€the€FDA€was€then€established€soon€afterwards.€ÌÌWith€regards€to€the€explanation€Ô_ÔoncogenesisÔ_Ô,€the€formation€of€tumors€can€be€environmentallyÏstimulated€as€well€as€genetic€inherited.€€Indeed€OSHA€is€there€to€protect€workers€from€safety€andÏtoxic€hazards,€but€if€they€were€really€that€concerned€why€does€mining€still€exist.€€An€occupationÏwere€many€malignancies€have€been€well€document.€€Maybe€humans€have€not€really€progressedÏas€much€as€we€have€thought.€€And€as€far€as€governmental€control,€the€pharmaceutical€companyÏthat€made€the€Elixir€of€death€is€still€in€business.€Ì€€€ÌPosted:€Feb-15-03€at€4:38€PM€by€Michael€George€€€ÌÌ€€€€€€€€€€€During€the€Middle€Ages€and€the€Renaissance,€the€beginnings€of€careful€observations€andÏtesting€began.€€Looking€at€the€cause€and€affects€of€a€toxicant/toxin€began.€€For€example,ÏCatherine€de€Ô_ÔMediciÔ_Ô€looked€at€toxic€effects€on€the€poor€by€noting€the€rapidity€of€the€toxicÏresponse€(onset€of€action),€the€effectiveness€of€the€compound€(potency),€the€degree€of€responseÏof€the€parts€of€the€body€(specificity,€site€of€action)€and€the€complaints€of€the€victims€(clinicalÏsigns€and€symptoms).€€As€cruel€as€these€experiments€were,€they€were€really€an€early€version€ofÏthe€Phase€I,€II,€and€III€testing.€€€During€the€Renaissance,€Ô_ÔParcellisÔ_Ô€was€the€first€to€look€at€aÏtoxicant€as€a€chemical€entity€rather€than€a€mixture€of€some€sort.€€His€3€concepts€were:ÌÌ1.)€€€€Experimentation€is€Essential€in€examination€of€responses€to€chemicals.ÌÌ2.)€€€€One€needs€to€make€a€distinction€between€therapeutic€and€toxic€properties€of€chemicals.ÌÌ3.)€€€€These€properties€above€are€sometimes€distinguishable€by€dose€but€not€always.ÌÌ4.)€€€€One€can€ascertain€a€degree€of€specificity€of€chemicals€and€their€therapeutic€or€toxic€sideÏaffects.ÌÌThis€can€really€be€seen€as€the€beginning€of€the€dose-response€relationship.€€Ô_ÔPercellisÔ_Ô€also€lookedÏat€the€etiology€of€diseases€associated€with€miners€and€how€to€treat/prevent€them.€€Also€theÏhazards€of€metal€working€began€with€the€works€of€Ô_ÔEllenborgÔ_Ô€warning€of€toxicity€of€mercury€andÏlead€in€goldsmith€work.€€All€these€lead€to€looking€at€the€occupational€hazards€of€Ô_ÔtoxicantsÔ_Ô€andÏlooking€at€Ô_ÔnonmysticalÔ_Ô€explanations€for€Ô_ÔoncogenesisÔ_Ô.€€€ÌPosted:€Feb-16-03€at€8:18€PM€by€Shaun€Ô_ÔMcAuliffeÔ_Ô€€ÌÌIf€one€considers€simple€hunter-gathering€an€occupation,€causality€€via€observation€and€testingÏlikely€developed€prior€to€the€middle€ages€and€Renaissance,€during€early€hunting€and€foragingÏexpeditions.€€Early€man€likely€encountered€poisonous€plant,€animal€and€insect€species.€€TribalÏleaders€likely€recorded€the€species€of€plant,€animal€and€insect€that€caused€a€toxic€response€in€aÏmember;€thus€establishing€early€causality.€Over€time€I€imagine€that€unexplained€and/orÐ ð-@), Ðmysterious€death€previously€attributed€to€mystical€causes€was€later€attributed€to€an€exposure€to€aÏnaturally€Ô_ÔoccuringÔ_Ô€toxin/species€delivering€said€toxin.€Once€studied€and€understood,€it€is€evidentÏfrom€early€manuscripts€that€early€man€was€able€to€apply€this€toxicological€knowledge€to€huntingÏand€warfare.ÌÌThis€early€study€was€later€refined€by€persons€like€Ô_ÔMaimonidesÔ_Ô€and€Hippocrates€who€furthered€theÏstudy€of€toxins€and€early€Ô_ÔtoxicantsÔ_Ô.€They€and€their€peers€authored€papers€on€poisoning€andÏantidotes.€Their€work€helped€to€define€how€most€poisons/toxins€of€the€time€manifestedÏthemselves€and€establish€the€notion€of€Ô_ÔbioavailabilityÔ_Ô.ÌÌAs€this€study€was€furthered,€individuals€like€Ô_ÔParacelsusÔ_Ô€and€Ô_ÔRamazziniÔ_Ô€documented€diseaseÏtrends€amongst€asbestos€workers,€miners€(radon,€dusts),€metallurgists,€printers,€potters,€weaversÏand€end€users€of€products€and/or€resources.€€Like€the€early€hunter-gatherers€and€their€peersÏfurthering€the€study€of€poisons€and€antidotes,€I€image€that€individuals€like€Ô_ÔEllenbogÔ_Ô,€Ô_ÔParacelsusÔ_Ô,Ïand€Ô_ÔRamazziniÔ_Ô€desired€to€further€establish€the€causal€relationships€between€occupation€andÏdisease.€€Once€established€and€like€€Ô_ÔMaimonidesÔ_Ô€and€Hippocrates,€Ô_ÔEllenbogÔ_Ô,€Ô_ÔParacelsusÔ_Ô,€andÏÔ_ÔRamazziniÔ_Ô€worked€to€develop€treatment€and€prevention€strategies.€ÌÌScientists€like€Percival€Pott€were€able€to€build€upon€the€foundation€that€Ô_ÔParacelsusÔ_Ô€andÏÔ_ÔRamazziniÔ_Ô€had€established.€€Armed€with€a€broader€depth€and€understanding€of€biological€andÏchemical€science,€scientists€like€Pott€were€able€to€establish€that€specific€occupational€exposuresÏled€to€the€development€of€organ€and/or€tissue€specific€disease€and/or€manifestations.ÌÌIn€summary,€it€is€clear€that€man's€pursuit€to€understand€causality€has€led€to€our€presentÏunderstanding€of€occupational€disease€and€Ô_ÔoncogenesisÔ_Ô.€€Perhaps€as€we€further€broaden€our€baseÏof€knowledge,€man€will€not€only€be€able€to€prevent€the€incidence€of€occupational€disease€but€alsoÏrepair€the€damage€that€an€accidental€exposure€has€caused.Ì€ÌPosted:€Feb-18-03€at€3:15€PM€by€Diana€€Ô_ÔEsshakiÔ_Ô€€ÌÌThe€idea€of€causality€seems€to€have€developed€around€the€introduction€of€theÏphysician-alchemist,€Ô_ÔParacelsusÔ_Ô.€He€promoted€the€idea€of€a€dose-response€relationship.€LookingÏat€the€relation€of€cause€(i.e.€"Ô_ÔtoxiconÔ_Ô"€exposure)€and€effect€(i.e.€disease,€death)€parallelsÏÔ_ÔParacelsusÔ_Ô'€studies€of€how€chemical€entities€can€elicit€various€responses€in€individuals-€both€neg.Ïand€positive.ÌÌThe€idea/doctrine€that€"all€things"€have€a€cause€definitely€give€rise€to€the€notions€of€occupationalÏhazards€and€Ô_ÔnonmysticalÔ_Ô€explanations€for€Ô_ÔoncogenesisÔ_Ô.€For€example,€exposure€to€mercury€andÏlead€(cause;€high€dose)leads€to€disease€(effect;€response).€Also,€in€the€field€of€oncology,€the€roleÏof€soot€in€scrotal€cancer€demonstrated€that€the€cause€of€disease€was€Ô_ÔnonmysticalÔ_Ô€(moving€awayÏfrom€antiquity€beliefs).€As€the€book€noted€(the€big€picture),€the€idea€of€causality€has€improvedÏmedical€practices,€given€a€greater€understanding€to€the€broader€fields€of€biology€and€chemistry,Ïdeveloped€the€beginnings€of€the€scientific€method€(Campbell),€and€aided€in€prevention€as€well.ÌÌPosted:€Feb-18-03€at€10:25€PM€by€Ô_ÔIvanaÔ_Ô€Ô_ÔDjureticÔ_Ô€€Ð ð-@), ЇI€would€just€point€out€again€the€Age€of€Ô_ÔEnlightmentÔ_Ô€and€the€Industrial€Revolution€as€majorÏbreakpoints€in€human€history€as€far€as€toxicology€is€concerned.€Throughout€most€of€the€history,Ïincluding€the€Middle€Ages,€concern€about€the€toxic€effects€of€chemicals€has€been€focused€onÏpoisons€which€act€quickly€and€result€in€death.€Socrates€ingested€hemlock€to€commit€Ô_ÔsucideÔ_Ô.ÏInfamous€Ô_ÔToffanaÔ_Ô€made€many€young€married€women€wealthy€widows€by€her€arsenic€Ô_ÔcontaingÔ_ÔÏcosmetics.€Since€exposure€to€these€chemicals€was€not€common€and€the€risks€were€well€knownÏthere€was€little€public€concern€about€these€poisons.ÌÌGradually€we€became€more€concerned€with€poisons,€especially€those€that€cause€adverse€effectsÏafter€long€periods€of€exposure.€Industrial€revolution€has€led€to€new€and€increased€uses€of€knownÏchemicals€and€the€synthesis€and€widespread€use€of€newly€developed€chemicals€which€has€startedÏa€greater€awareness€of€possible€adverse€health€effects€of€chemicals€other€than€lethality.€MoreÏrecently,€increase€in€the€average€human€life€span€due€to€cures€and€treatments€for€infectiousÏdiseases€has€made€chronic€non-infectious€diseases€more€common€and€opened€up€a€whole€newÏarea€of€research€for€toxicology.ÌÌPosted:€Feb-20-03€at€0:17€AM€by€Ô_ÔIvanaÔ_Ô€Ô_ÔDjureticÔ_Ô€€ÌÌReferenced€from:ÌÌÔ4‚Ý °ÔÝ‚ ÍOÝÔÿÔòòÝ  ÝÔ5  Ôwww.iet.msu.edu/tox_for_public/riskasmt.htmÔ6MÔÝ‚ ÍO)MƒÝóóÔÿÔÝ  ÝÔ7Ý PWMÔÐ pÀ ÐÌò òOldÐ P  ÐÌó óJoanne:Ð 0€ ÐFebruary€19,€2002ÌÌ1)€The€idea€of€Ô_ÔcasualityÔ_Ô€would€potentially€give€rise€to€the€notions€of€occupational€hazards€and/orÏthe€Ô_ÔnonmysticalÔ_Ô€explanations€for€Ô_ÔoncogenesisÔ_Ô€by€one's€observing€and€posing€a€plausible€causalÏrelationship€between€the€environment€(work€or€otherwise)€and€an€adverse€(cancer€promotingÏ..etc)€reaction€in€the€exposed€individual.€Instead€of€attributing€ailments€to€superstitious€beliefs,Ïthey€had€begun€to€establish€the€fundamental€beginnings€of€the€scientific€method.ÌÌAllison:ÌFebruary€19,2002Ì1.€Occupational€hazards€associated€with€metal€working€were€recognized€during€the€15th€century.ÏÔ_ÔParacelsusÔ_Ô€published€a€major€piece€of€work€addressing€the€etiology€of€miner's€disease,€along€withÏtreatment€and€prevention€strategies.ÌOccupational€diseases€and€Ô_ÔcausualityÔ_Ô€increased€during€the€Industrial€Revolution.€€TheÏrecognition€of€the€basis€behind€scrotal€cancer€among€chimney€sweeps€was€the€first€reportedÏexample€of€Ô_ÔpolyaromaticÔ_Ô€hydrocarbon€Ô_ÔcarcinogenityÔ_Ô.€€These€findings€led€to€improved€medicalÏpractices€and€prevention.€€Through€careful€observation,€diseases€that€were€Ô_ÔprevelantÔ_Ô€amongÌa€certain€group€of€workers€or€people€led€to€testing€and€experimenting€on€metals,€plants,€andÏminerals€that€they€might€be€exposed€to€or€using€in€their€daily€activity.€€This€led€to€theÏunderstanding€and€further€development€of€determination€of€how€workers€were€becoming€ill€andÐ ð-@), Ðthe€specific€cause€of€these€diseases.ÌÌÔ_ÔNeetuÔ_Ô:ÌFebruary€19,2002Ì1.€The€occupational€hazards€and€causalities€were€very€commonly€Ô_ÔoccuringÔ_Ô€in€olden€days.ÌPeople€were€perhaps,€exposed€to€many€chemicals€and€other€hazardous€material€in€their€workÌenvironment€due€to€ignorance€or€they€simply€did€not€have€any€other€choice.€They€had€to€work€inÌthe€environment€they€were€working€in€Ô_ÔbceauseÔ_Ô€there€were€not€many€jobs€and€because€they€hadÌto€Ô_ÔprovoideÔ_Ô€living€for€themselves€and€their€families.€After€the€industrial€revolution,€peopleÏstartedà  àbecoming€educated€and€taking€more€precautions,€which€made€the€working€environmentsÐ  p  Ðsafer.€€€With€the€advanced€type€of€technology,€and€medical€techniques,€conditions€are€muchÏbetter€now€than€they€were€during€industrial€revolution.€Learning,€understanding€and€takingÏprecautions€while€working,€Ô_ÔdefinatelyÔ_Ô€helped€prevent€occupational€hazards.ñŠññ‹ñÌñ‹ññ‹ñÌñ‹ññ‹ñÐ  Ð  ÐÔ_Ôñ‹ññŒññŠñÌñŠññŒññ‰ñTopic:€Question€Set€1.€Question€10.€€Risk€Strategies€&€Levels€of€Toxicity€€€ÌSubject:€Question€Set€1.€Question€10.€€Risk€Strategies€&€Levels€of€Toxicity€€€Posted:€Mar-04-02Ïat€4:04€PM€by€Kenneth€Campbell€€ÌÌò ò10.€What€distinctions€might€be€made€between€lethality,€morbidity,€reproductive€capacity,Ð pÀ Ðquality€of€life,€and€quality€of€environment€impacts€vis€a€vis€risk€assessment€strategies?ó óÐ ` ° ÐÌPosted:€Feb-12-03€at€12:11€PM€by€Erin€Valentine€€ÌÌ10.€€€€The€distinctions€between€these€categories€of€various€levels€of€risks€and€the€risk€assessmentÏstrategies€are€that€of€result€of€exposure€to€a€particular€toxic€substance.€Assessing€the€risk€of€aÏlethal€substance€would€include€animal€testing€and€determination€of€LD50€under€a€varying€set€ofÏconditions,€such€as€length€of€exposure,€site€of€exposure,€number€of€test€subjects,€etc.€AssessingÏthe€risk€of€a€morbid€agent€would€require€more€specific€testing.€The€observations€would€now€haveÏto€include€clinical€observation€of€symptoms€and€postmortem€examination€to€determine€the€site€ofÏaction€and€characterization€of€the€specific€effect€of€the€chemical.€These€observations€may€be€theÏoccurrence€of€tumors,€damage€to€particular€organs,€or€interruption€of€a€biological€function.€In€theÏcase€of€assessing€the€risk€to€reproductive€capacity,€the€tests€must€focus€specifically€on€theÏendocrine€and€reproductive€systems€of€the€organisms.€The€tests€to€determine€the€reproductiveÏtoxicity€of€an€agent€are€performed€on€rats€through€six€stages€described€by€the€InternationalÏCommission€on€Harmony,€from€premating€to€weaning€and€sexual€maturity€of€the€offspringÏ(Klaasen€2001).€Quality€of€life€risk€assessment€would€need€to€test€the€ability€of€the€agent€toÏaffect€a€condition€of€life€that€does€not€cause€death€or€disease€such€are€skin€and€eye€irritants.ÏQuality€of€environment€€impacts€risk€assessment€must€test€all€of€these€conditions€as€well€as€theÏeffect€of€the€agent€on€the€natural€habitat.€This€assessment€might€include€the€effect€of€an€airÏpollutant€on€the€human€population€(lethality,€morbidity,€reproductive€capacity,€quality€of€life)Ïand€on€the€wildlife€(LD50€of€certain€populations)€and€on€the€plant€life€(observation€of€decrease€inÏgrowth).ÌÌPosted:€Feb-14-03€at€9:58€PM€by€Lisa€McIntosh€€ÌÌOn€an€individual€basis,€the€first€three€terms€reflect€varying€degrees€of€toxicity:€lethality,Ïobviously,€is€the€most€severe;€morbidity€may€ultimately€decrease€lifespan;€reproductive€capacityÏin€and€of€itself€may€not€adversely€affect€an€individual,€although€could€negatively€impact€aÏpopulation€through€decreased€fecundity.ÌÌQuality€of€life€impacts€may€not€necessarily€result€in€harmful€effects€to€an€organism;€however,Ïthat€quality€is€degraded€from€optimal€conditions.€Nuisance€odors-€chemicals€present€atÏconcentrations€above€the€odor€recognition€threshold,€but€below€deleterious€levels-are€a€goodÏexample€of€this.€In€terms€of€risk€characterization€(in€Massachusetts,€anyway),€the€presence€ofÏnuisance€odors€indicates€a€condition€of€significant€risk€to€public€welfare€exists€(even€if€theÏcontaminants€may€not€present€a€risk€to€human€health).ÌÌQuality€of€the€environment,€be€it€on€a€localized€or€global€scale,€ultimately€determines€the€level€ofÏimpact.€Risk€assessment€is€a€tool€by€which€we€relate€the€quality€of€the€environment€to€publicÐ ð-@), Ðhealth€or€the€environment.€The€underlying€premise€is€that€there€is€an€"acceptable"€level€ofÐ ° Ðriskð"ðsuch€as€allowing€residual€contamination€to€remain€in€the€soil,€using€a€drug€for€therapeuticÐ  ð Ðeffects€despite€the€potential€for€side€effects,€or€using€household€cleaners€or€pesticides€that€may€beÏlethal€if€used€incorrectly.ÌÌPosted:€Feb-16-03€at€12:03€PM€by€ERIC€FAULKNER€€ÌÌRisk€assessment€can€be€classified€as€a€quantitative€estimate€of€the€potential€effects€on€humanÏhealth€and€the€environmental€significance€of€various€types€of€chemical€exposure€(Klassen).€€InÏidentifying€a€hazardous€agent,€tests€are€performed€to€determine€if€the€agent€will€cause€an€adverseÏeffect€through€structure€activity€analysis,€in€vitro€testing,€animal€bioassays,€and€epidemiologyÏstudies.€€Additional€testing€is€performed€to€determine€the€dose-response€relationship€and€theÏduration€of€exposure€to€the€hazardous€agent€in€question.€These€assessments€form€a€Venn€diagramÏthat€make€up€the€three€categories€of€toxicological€studies;€mechanistic,€regulatory,€andÏdescriptive.€€While€lethality,€morbidity,€reproductive€capacity,€quality€of€life,€and€quality€of€theÏenvironment€all€play€significant€roles€in€the€study€of€toxicology,€further€distinctions€can€be€madeÏby€the€following;€lethality€is€an€acute€test€first€performed€on€a€NCE€with€a€fixed€dose€on€a€smallÏpopulation€where€an€LD50€is€determined.€€Morbidity€can€be€considered€a€long€term€exposureÏstudy€where€a€population€is€subjective€to€an€agent€for€greater€than€3€months€where€alterations€onÏbiological€functions€are€addressed.€€Reproduction€takes€into€consideration€the€effects€of€theÏreproductive€system€and€the€potential€of€the€hazard€to€disrupt€embryonic€development.€€AndÏfurthermore,€quality€of€life€and€quality€of€the€environment€assess€the€effects€of€a€hazard€on€aÏlarge€population€and€in€nature€where€risk€managers€summarize€the€potential€risks.ÌSubject:€Re:Question€Set€1.€Question€10.€€Risk€Strategies€&€Levels€of€Toxicity€€€Posted:ÏFeb-17-03€at€1:29€AM€by€Michael€George€€€View€the€history€for€this€message€Reply€Edit€theÏmessage€Re:Question€Set€1.€Question€10.€Risk€Strategies€&€Levels€of€Toxicity€Delete€theÏmessage€Re:Question€Set€1.€Question€10.€Risk€Strategies€&€Levels€of€ToxicityÌLooking€at€individuals,€lethality€which€leads€to€death,€morbidity€which€leads€to€a€decrease€inÏlifespan,€and€reproductive€capacity€all€are€the€most€serious.€€The€last€one€could€end€up€affecting€aÏpopulation€as€a€whole€in€the€long€run.€€Quality€of€life€toxicity€issues€wont€necessary€affect€theÏorganism€in€harmful€ways,€but€may€cause€degradation€in€the€quality€of€life€for€the€organism.€€ForÏexample€a€annoying€smell€may€occur€in€the€organism€or€a€scar€which€may€be€unpleasant€butÏwonððt€probably€lead€to€death.€€But,€the€presence€of€an€odor€in€an€area€may€lead€to€fears€ofÏsomething€harmful€even€though€there€is€no€harmful€toxicant.€€Quality€of€environment€is€lookingÏat€the€safety€of€the€environment€as€a€whole.€€It€is€important€for€risk€assessments€because€it€allowsÏus€to€keep€the€public€informed€to€what€is€a€safe€level€of€risk€for€products€that€are€toxic€such€asÏhousehold€products.€€Also€in€what€are€side€effects€for€medicines.Ì€ÌPosted:€Feb-17-03€at€7:09€PM€by€DINA€KATZ€€ÌÌA€risk€assessment€is€an€expert's€opinion€of€the€likelihood€of€a€deleterious€effect.€Depending€onÏwhat€that€effect€might€be,€lethality(death),€morbidity(disease),€quality€of€life€(level€of€comfort€forÏthe€living€organism),€etc.,€the€assessment€will€differ€for€the€same€toxicant.€There€may€be€a€highÏrisk€of€reduction€in€the€quality€of€environment€(how€conducive€the€surroundings€are€to€life)€butÏnot€necessarily€lethality.€For€example,€an€oil€slick€is€a€high€risk€for€the€beach€by€your€house,€butÐ ð-@), Ðit€carries€a€very€low€risk€of€death€for€you€personally.€Similarly,€reproductive€capacity€ofÏpond-living€organisms€may€be€severely€reduced€by€a€toxicant€dumped€into€their€pond,€but€haveÏno€effect€on€their€own€quality€of€life.€Assessment€strategies€would€thus€have€to€be€tailored€toÏestimate€the€risk€to€a€specific€effect€(i.e.€if€it€is€necessary€to€carry€out€an€assessment€of€morbidityÏof€tadpoles€in€Lake€Erie,€one€should€probably€observe€behavior€and€collect€some€specimens€andÏinspect€their€tissues,€rather€than€spend€time€observing€a€reproductive€cycle€and€counting€young.)ÌÌPosted:€Feb-18-03€at€4:23€PM€by€Ivana€Djuretic€€ÌÌRisk€Ô_ÔassesmentÔ_Ô€strategies€require€the€following€components:ÌÌ-hazard€identification-an€evaluation€of€the€adverse€health€effects€the€agent€is€capable€of€causing:Ïdamage€to€liver,€nervous€system,€Ô_ÔcarcinogenesisÔ_ÔÌÌ-dose€response€assessment-includes€prediction€of€exposure€levels€at€which€risk€is€likely€to€beÏnegligible€or€nonexistentÌÌ-exposure€assessment€-€a€determination€of€how€much€of€an€agent€people€might€be€exposed€toÏunder€various€conditions€such€as€use€of€a€drug€or€a€consumer€product,€environmental€exposure€atÏa€hazardous€waste€site.ÌÌ-risk€characterization-€explicit€description€of€the€assumptions€and€uncertainties€that€go€into€theÏrisk€assessment,€and€the€overall€confidence€in€the€results€of€the€analysis.ÌÌIt€seems€like€risk€Ô_ÔassesmentÔ_Ô€strategies€will€only€characterize€lethality€of€a€substance€with€a€highÏdegree€of€certainty€(even€then€there€is€genetic€variability)€but€that€for€other€levels€of€toxicity€itÏwill€be€extremely€hard€to€predict€the€levels€of€risk.€Even€for€a€simpler€task€such€as€cancerÏassessment,€mathematical€models€are€needed€to€connect€the€results€of€experiments€with€a€limitedÏnumber€of€animals€to€large€scale€predictions€(more€than€1€additional€cancer€in€1€million€exposedÏpeople€is€unacceptable€risk,€but€you€cannot€test€1€million€animals).€So€morbidity,€reproductiveÏcapacity,€quality€of€life€and€environment€differ€from€lethality€in€the€certainty€of€risk€predicted€byÏrisk€Ô_ÔassesmentÔ_Ô€strategies.ÌÌI€will€use€this€question€to€comment€on€the€ambiguity€of€the€assigned€questions€(some,€not€all).€IÏfound€it€really€hard€to€formulate€an€answer€to€this€question€without€just€defining€what€lethality,Ïmorbidity€etc€is,€or€giving€the€type€of€tests€that€one€would€do€to€assess€lethality,€morbidity,€etc,Ïbut€that€doesn't€seem€to€be€what€the€question€asks.€Even€after€reading€Ch€4€and€doing€someÏadditional€research€I€couldn't€describe€in€one€simple€answer€how€risk€Ô_ÔassesmentÔ_Ô€strategies€wouldÏdistinguish€between€all€those€different€categories€of€toxicity.€The€answer€seems€to€be€the€entireÏof€toxicology.€Is€anybody€else€having€problems€with€the€nature€of€the€questions?€Maybe€we€areÏunable€to€start€threaded€discussions€because€people€are€interpreting€the€questions€in€differentÏways€and€its€hard€to€agree€or€disagree€with€someone€talking€about€an€entirely€different€thing€thanÏyourself.€Again€it€could€be€just€my€view,€but€I'm€almost€sure€that€having€more€specific€questionsÏwould€spark€a€discussion€less€vague.ÌÐ ð-@), ÐPosted:€Feb-20-03€at€10:29€PM€by€Diana€€Ô_ÔEsshakiÔ_Ô€€ÌÌThe€variety€of€adverse€effects€of€chemicals€on€humans€clearly€impacts€risk€assessment€strategies.ÏBioassays€and€LD50€aid€in€developing€these€strategies.€When€assessing€risk€of€toxins,€lethalityÏ(ability€to€cause€death),€morbidity€(ability€to€cause€disease),€reproductive€capacity,€quality€of€life,Ïand€quality€of€Ô_ÔenvronmentÔ_Ô€do€have€distinct€impacts€on€determining€risk.€In€this€case,€since€theÏquestion€is€quite€vague,€it€is€probably€more€helpful€to€look€at€an€example:€mold€spores.ÌÌ(Radiation€is€actually€a€more€clear€cut€example,€however,€I€am€assuming€that€we€aren'tÏconsidering€that€a€toxin.)ÌÌLethality:€Clearly€the€most€significant€factor€does€not€play€much€of€a€role€with€mold€sporeÏexposure.€Put€another€way,€when€assessing€risk,€this€"toxin"€does€not€cause€death.ÌÌMorbidity:€Exposure€to€mold€(Ô_Ôesp.indoorÔ_Ô€constant€exposure)€can€cause€a€wide€array€of€healthÏproblems.€Very€large€doses€of€mold€spores€(inhaling€or€ingesting)€can€result€in€poisoning€byÏÔ_ÔmycotoxinsÔ_Ô.€Exposure€can€cause€allergic€illnesses,€asthma,€and€infection€(lung€or€respiratoryÏtract).€In€this€case,€morbidity€has€a€very€high€and€quite€distinct€effect€on€risk€assessment.ÌÌReproductive€capacity:€Mold€spores€are€not€usually€a€health€risk€factor€on€Ô_ÔreproÔ_Ô.ÌÌQuality€of€life:€Mold€spores€indoors€can€not€only€cause€a€health€risk,€but€can€make€livingÏuncomfortable€by€adhering€to€ceilings,€etc.€in€the€home.ÌÌQuality€of€environment:€Varies€depending€on€indoors€vs.€outdoor€exposure-€indoor€causing€moreÏdirect€inhalation€and€infringing€on€safety€of€the€individuals€exposed.€ÌÌò òOldÐ P ÐÌó óAllison:Ð à0 ÐFebruary€20,€2002Ì10.€Risk€assessment€strategies€are€Ô_ÔdefinetlyÔ_Ô€impacted€by€differences€between€lethality,€morbidity,Ïreproducing€capacity,€and€quality€of€life€and€environment.€In€determination€of€the€risk€of€a€toxin,Ïacute€testing€would€be€performed€on€toxins€that€my€be€considered€lethal.€Morbidity€involves€aÏcompromise€of€function,€including,€disease€rates,€genetic€defects,€and€toxicant€effects,€all€ofÏwhich€may€not€be€lethal.€In€testing€whole€populations,€reproductive€capacity€and€morbidity€mayÏlead€to€Ô_ÔlethatlityÔ_Ô,€which€is€very€damaging€and€would€be€considered€in€those€risk€assessments.ÌHowever,€when€looking€at€individuals€rather€than€a€species€as€a€population,€morbidity€,ÏÔ_ÔreproducitveÔ_Ô€capacity,€as€well€as,€quality€of€life€and€environment€may€not€be€Ô_ÔextrememlyÔ_Ô€toxic€inÏthe€sense€that€one€can€still€survive.€Toxic€effects€exist€at€various€levels€and€when€assessing€riskÏof€a€toxin,€it€is€possible€that€they€will€not€induce€effects€that€generate€lethality€of€morbidity€butÏwill€alter€quality€of€life€and/or€environment.€In€these€cases,€the€strategy€about€how€assess€riskÏchanges€and€preventing€death€is€no€longer€a€goal,€but€instead€preserving€a€quality€of€life€andÌgeneral€well€being.ÌÐ ð-@), ÐJoanne:ÌFebruary€20,2002Ì10)€Lethality:€deathÌ€€€€Morbidity:€diseased€state,€decreased€life€spanÌ€€€€Reproductive€capacity:€ability€to€reproduce€€Ì€€€€Quality€of€Life:€Ô_ÔnonmedicalÔ_Ô€threats€that€compromise€one's€ability€to€enjoy€life€€€€Ì€€€€Quality€of€environment:€degree€of€safety,€Ô_ÔcomfortabilityÔ_Ô€and€security€in€surroundingsÌÌIn€terms€of€these€factors€with€respect€to€risk€assessment€strategies,€they€are€ordered€in€terms€ofÌimportance€with€the€greatest€stressor€on€lethality€and€in€descending€significance€thereafter.ÌÔ_ÔObviously,lethalityÔ_Ô€would€have€the€greatest€influence€on€risk€assessment.€Although€there€mayÏappear€to€be€an€element€of€subjectivity€(Ô_ÔieÔ_Ô€Ô_ÔreproducitveÔ_Ô€ability€vs€quality€ofÏenvironment..etc..etc),€overall€they€are€ranked€in€Ô_ÔaccordacneÔ_Ô€with€what€the€majority€ofÏindividuals€would€assess€in€terms€of€personal€importance.ÌÌÔ_ÔNeetuÔ_Ô:ÌFebruary€20,€2002Ì10.€Lethality€is€related€to€death,€morbidity€is€related€to€compromise€in€functionality.€InÏindividual€lethality,€it€is€not€necessary€that€it€means€inability€to€reproduce.€When€talking€aboutÏpopulation€lethality,€Ô_ÔthÔ_Ô€Ô_ÔemorbidityÔ_Ô€might€be€lethal.€The€toxins€might€change€Ô_Ôone;sÔ_Ô€quality€of€lifeÏor€living€standards€but€it€is€not€necessarily€lethal.€The€quality€of€environment€will€effect€eachÏindividual€differently.ÌÌÌÌÌÌÌÌÌÌÌÌÌÌÌÌÌÌÌÌÌÌÌÐ ð-@), Їñ‰ñDiscussions:Ô_Ô€Question€set€1.€Question€2.€Questions€arising€out€of€the€historical€background€ofÏtoxicology.ÌÌTopic:€Question€set€1.€Question€2.€Questions€arising€out€of€the€historical€background€ofÏtoxicology.€€ÌSubject:€Question€set€1.€Question€2.€Questions€arising€out€of€the€historical€background€ofÏtoxicology.€€€Posted:€Mar-04-02€at€3:43€PM€by€Kenneth€Campbell€€ÌÌò ò2.€What€information€already€discussed€is€Ô_ÔsubsummedÔ_Ô€in€the€notion€of€biochemical€kinetics?ó óÐ 0 € ÐÌPosted:€Feb-12-03€at€12:55€PM€by€Erin€Valentine€€€ÌÌ€€€1.€The€similarities€between€enzyme€kinetics€and€toxic€effects€are€apparent€when€comparingÏdose-response€curves€to€the€plot€of€the€Ô_ÔMichalisÔ_Ô-Menton€equation€also€called€the€rate€equation.ÏThe€concentration€of€substrate€on€the€X-axis€is€analogous€to€the€dose€and€the€velocity€of€theÏenzymatic€reaction€on€the€Y-axis€is€analogous€to€the€response€(efficacy).€The€median€lethal€doseÏ(LD50)€is€analogous€to€the€Km.,€the€substrate€concentration€at€which€the€reaction€velocity€isÏhalf-maximal,€ðð€Ô_ÔVmaxÔ_Ô.€A€small€Km€means€that€the€enzyme€achieves€maximal€catalyticÏefficiency€at€low€substrate€concentration.€A€small€LD50€means€that€50%€lethality€is€reached€at€aÏlow€dosage€of€the€toxicant.€This€also€applies€to€the€effective€dose€(ED)€and€toxic€dose€(TD).€TheÏmechanisms€that€facilitate€the€Ô_ÔtoxicantsÔ_Ô€delivery€to€its€target€site€could€potentially€influence€theÏLD50€or€ED50.€If€the€facilitators€decrease€the€dosage€needed€to€reach€the€half-mark,€they€wouldÏbe€akin€to€catalysts€of€an€enzymatic€reaction.€ÌÌPosted:€Feb-13-03€at€0:50€AM€by€Ô_ÔIvanaÔ_Ô€Ô_ÔDjureticÔ_Ô€€ÌÌÔ_ÔToxicantsÔ_Ô€affect€their€targets€(enzymes)€by€binding€to€them€in€the€same€ways€their€normalÏsubstrates€do:€Ô_ÔnoncovalentlyÔ_Ô€and€covalently.€Examples:€Ô_ÔTCDDÔ_Ô€binding€to€Ô_ÔarylÔ_Ô€hydrocarbonÏreceptor,€and€Ô_ÔacridineÔ_Ô€yellow€to€DNA€in€a€Ô_ÔnoncovalentÔ_Ô€manner;€metal€ions€and€free€radicals€areÏable€to€form€covalent€bonds€with€Ô_ÔbiomoleculesÔ_Ô.ÌÌJust€like€their€normal€substrates,€Ô_ÔtoxicantsÔ_Ô€can€stimulate€their€target€molecules€and€hence€causeÏtheir€dysfunction€by€activating€or€inhibiting€them€at€inappropriate€times.€Well€known€areÏmicrotubule€and€Ô_ÔactinÔ_Ô€impairing€drugs€such€as€Ô_ÔcolchicinÔ_Ô€and€Ô_ÔphalloidinÔ_Ô€or€morphine€whichÏactivates€opiate€receptors.ÌÌÔ_ÔToxicantsÔ_Ô€can€also€destroy€their€targets€upon€the€chemical€attack€by€means€of€cross€linking€andÏfragmentation.€Some€chemicals€are€just€big€enough€to€bind€to€the€cell€surface€proteins€inducingÏantibody€production€and€evoking€an€immune€response€(e.g.€drug€induced€lupus,€agranulocytosis,Ïand€hepatitis€like€syndrome).ÌÌPosted:€Feb-13-03€at€10:32€PM€by€Lisa€McIntoshÌÌChemical€absorption,€transformation,€elimination,€etc.€is€variable€not€only€among€substances,€butÏamong€individual€receptors€(as€in€a€human€receptor)€as€well€as€on€a€cellular€or€Ô_ÔsubcellularÔ_Ô€level.Ð ð-@), ÐIn€other€words,€toxicity€is€a€function€of€chemical€application,€uptake,€and€transfer€to€a€target,Ïeach€of€which€in€turn€are€dependent€on€the€organismððs€distinct€physiology€and€biochemistry.ÌÌPosted:€Feb-15-03€at€11:45€AM€by€Ô_ÔDINAÔ_Ô€KATZ€€ÌÌThe€dose-response€curves€of€toxic€substances€on€living€organisms€are€similar€in€shape€toÏvirtually€any€plot€of€some€effect€of€a€chemical€(in€varying€amounts)€on€a€living€organism,€such€asÏan€enzyme€and€its€product's€concentration€or€even€ingestion€of€glucose€and€Ô_ÔandÔ_Ô€its€level€in€theÏbloodstream.€This€is€because€the€general€mechanisms€of€any€substance's€function€are€similar:ÏThere€is€a€minimal€dosage€at€which€an€effect€is€found,€when€the€substance's€amount€is€sufficientÏto€trigger€a€reaction,€a€subsequent€somewhat€linear€relationship€between€dose€and€effect€(thoughÏthe€slope€will€differ),€and€a€later€reduction€in€the€rate€of€effect€increase.€This€last€may€be€due,Ïdepending€on€the€type€of€effect€observed,€to€a€saturation€of€receptors€for€the€chemical,€orÏpossibly€to€the€death€of€the€organism€and€shutdown€of€biological€processes€in€the€case€of€aÏhighly€toxic€substance.€€Ì€ÌPosted:€Feb-15-03€at€4:51€PM€by€ERIC€FAULKNER€€ÌÌBiochemical€kinetics€refers€to€the€rate€at€which€a€reaction€takes€place€(Ô_ÔPurichÔ_Ô€and€Ô_ÔAllsionÔ_Ô).€€€InÏmammalian€systems,€kinetic€mechanisms€play€a€vital€function€in€metabolic€pathways,€theÏmechanistic€action€of€enzymes,€and€the€processing€of€genetic€material.€€The€biochemical€kineticsÏcovered€in€class€was€focused€on€a€sigmoidal€curve.€€While€simple€in€structure,€this€shape€pertainsÏto€a€wide€variety€of€biological€and€chemical€systems;€titration€curves,€Ô_ÔisoelectricÔ_Ô€points€ofÏproteins,€and€curves€exhibited€by€regulatory€enzymes.€€This€sigmoidal€shape€also€exists€inÏtoxicology€and€is€seen€with€the€Ô_ÔquantalÔ_Ô-dose€response€relationship€curve.€€The€Ô_ÔquantalÔ_Ô€doseÏresponse€is€used€extensively€in€toxicology.€€First,€the€LD50€is€determined€where€50%€of€animalsÏtested€die€from€a€certain€dose.€€Second,€a€range€of€doses€are€used€in€a€larger€number€of€animals.€ÏFrom€this€a€sigmoidal€curve€can€be€obtained.€€As€with€all€biochemical€kinetics,€a€saturation€pointÏexists€where€a€stimulus€will€no€longer€result€in€an€effect.€€For€enzyme€kinetics,€only€so€manyÏactive€sites€exist€on€the€enzyme€for€the€substrate€to€bind.€€For€a€cumulative€mortality€curve,€onlyÏso€much€dose€can€be€given€before€death€occurs.ÌÌ€ÌÌ€that€regulate€€These€enzymes€are€called€regulatory€enzymes,€the€precursor€or€starting€point€at€theÏmetabolic€processÌÌPosted:€Feb-17-03€at€0:31€AM€by€Shaun€Ô_ÔMcAuliffeÔ_Ô€€ÌÌOur€discussion€of€biochemical€kinetics€touched€upon€the€following:ÌÌ€€€1.€the€rate€and/or€response€to€a€given€toxin€and/or€toxicant€could€be€graphically€depicted€as€aÏdose-response€curve;Ì€€€2.€the€dose-response€curve€is€most€often€sigmoidal;Ì€€€3.€curves€may€be€individual€or€Ô_ÔquantalÔ_Ô;Ð ð-@), Ѐ€€4.€the€basal,€middle€and€maximal€points€of€the€curve€may€correspond€to€a€wide€variety€ofÏendpoints;Ì€€€5.€cellular,€tissue,€organ,€individual€and€population€variability€may€be€attributed€to€dosage,Ïduration€and€frequency€of€dosage,€route€of€exposure,€chemical€and/or€physical€interaction,Ïgenetics,€environment€and€a€wide€variety€of€other€factorsÌ€€€6.€a€greater€level€of€confidence€exists€around€the€linear€portion€of€the€curve;Ì€€€7.€the€lack€of€confidence€at€the€asymptotic€portions€of€the€curve€is€due€to€factors€includingÏÔ_ÔhypersusceptibilityÔ_Ô,€the€inability€to€define€sub-threshold€Ô_ÔresponcesÔ_Ô,€and€resistance.ÌÌ€ÌÌÔ_Ôò òOldó óÔ_ÔÐ P  ÐÌSubject:€Ô_ÔRe:QuestionÔ_Ô€set€1.€Questions€arising€out€of€the€historical€background€of€toxicology.€€ÏPosted:€Mar-04-02€at€5:51€PM€by€Kenneth€Campbell€€€View€the€history€for€this€message€ReplyÏEdit€the€message€Ô_ÔRe:QuestionÔ_Ô€set€1.€Questions€arising€out€of€the€historical€background€ofÏtoxicology.€Delete€the€message€Ô_ÔRe:QuestionÔ_Ô€set€1.€Questions€arising€out€of€the€historicalÏbackground€of€toxicology.ÌJoanne:ÌFebruary€19,2002Ì2)€The€notion€of€Ô_ÔbiochemcialÔ_Ô€kinetics€was€encompassedÌin€our€discussion€of€dose-response€relationships€asÌwell€as€routes€of€entry€of€toxins/Ô_ÔtoxicantsÔ_Ô.€ForÌinstance€genetic€backgrounds€of€the€specimen€inÌquestion€(€recipient€of€toxin/toxicant)€will€have€anÌeffect€on€the€biochemical€result€depending€on€itsÌunderlying€genetic€makeup.€Such€variations€include:Ìsusceptibility€to€toxins/Ô_ÔtoxicantsÔ_Ô€as€well€as€theÌability€to€excrete/eliminate€toxins/Ô_ÔtoxicantsÔ_Ô€onceÌthey€infiltrate€through€the€biological€system.€TheÌparticular€route€of€entry€may€be€more€significantÌdependent€upon€the€genetic€background€of€theÌindividual€organism.ÌSubject:€Ô_ÔRe:QuestionÔ_Ô€set€1.€Questions€arising€out€of€the€historical€background€of€toxicology.€€ÏPosted:€Mar-04-02€at€5:58€PM€by€Kenneth€Campbell€€€View€the€history€for€this€message€ReplyÏEdit€the€message€Ô_ÔRe:QuestionÔ_Ô€set€1.€Questions€arising€out€of€the€historical€background€ofÏtoxicology.€Delete€the€message€Ô_ÔRe:QuestionÔ_Ô€set€1.€Questions€arising€out€of€the€historicalÏbackground€of€toxicology.ÌAllison:ÌFebruary€19,2002Ì2.€Dosage€and€form€of€delivery€and€the€aspect€of€Ô_ÔbioavailabilityÔ_Ô€areÌpartsÌof€biochemical€kinetics.€€Many€toxicant€problems€occur€when€naturallyÌÔ_ÔoccuringÔ_Ô€Ô_ÔtoxicantsÔ_Ô€are€concentrated€and€exposed€to€other€people.ÌExposureÐ ð-@), Ðat€low€levels€over€a€long€enough€time€for€the€Ô_ÔtoxicantsÔ_Ô€to€beÌdeactivatedÌeither€by€metabolism€or€adsorption€to€Ô_ÔsurgacesÔ_Ô€reduces€the€risk€of€aÌtoxicÌresponse.€€However,€if€the€same€total€dose€is€provided€over€a€shorterÌperiodÌof€time,€the€toxic€response€will€be€more€observable€due€to€theÌinactivationÌand€reduction€of€metabolic€and€adsorption€capacities.€€The€forms€ofÌdeliveryÌare€also€important€factors€in€biochemical€kinetics.€LipophilicÌmaterialsÌwill€not€be€adsorbed€on€hydrophobic€surfaces€like€charcoal€or€clayÌand€theÌtoxicant€will€be€unavailable€to€biological€systems,€unless€extreme€pHÌorÌmechanical€agitations€allow€the€toxicant€to€pass€through€theÌdigestiveÌsystem.€Dilution€of€lipophilic€materials€in€oils€will€lead€to€slowÌreleaseÌof€the€material.€€Ô_ÔBioaccumulationÔ_Ô€following€administration€is€alsoÌrelatedÌto€Ô_ÔbioavailabilityÔ_Ô€and€biochemical€kinetics.€Lipophilic€Ô_ÔtoxicantsÔ_ÔÌÔ_ÔaccumualteÔ_ÔÌand€partition€into€lipid€droplets€and€may€be€prevented€fromÌbiologicalÌbreakdown€and€against€biological€response€until€they€reach€highÌlevels€thatÌthe€adipose€cells€within€an€animal€cannot€accumulate€anymore€or€theÌÔ_ÔdegradativeÔ_Ô€systems€become€saturated€so€levels€of€the€toxicant€inÌÔ_ÔacqeousÔ_ÔÌcompartments€increase€and€evoke€toxic€responses.ÌSubject:€Ô_ÔRe:QuestionÔ_Ô€set€1.€Questions€arising€out€of€the€historical€background€of€toxicology.€€ÏPosted:€Mar-04-02€at€6:04€PM€by€Kenneth€Campbell€€€View€the€history€for€this€message€ReplyÏEdit€the€message€Ô_ÔRe:QuestionÔ_Ô€set€1.€Questions€arising€out€of€the€historical€background€ofÏtoxicology.€Delete€the€message€Ô_ÔRe:QuestionÔ_Ô€set€1.€Questions€arising€out€of€the€historicalÏbackground€of€toxicology.ÌÔ_ÔNeetuÔ_Ô:ÌFebruary€19,2002Ì2.€Ô_ÔBioavailabilityÔ_Ô€is€an€important€factor€when€talking€about€biochemical€kinetics.€The€amount€ofÌdose€absorbed€by€the€systemic€circulation€is€referred€to€as€Ô_ÔbioavailabiltyÔ_Ô.€The€concentration€ofÌthe€toxin€is€as€important€as€the€dose€of€the€toxin€when€dealing€with€toxins.€The€form€of€deliveryÌalso€plays€a€role€because€some€ways€are€better€than€others€to€make€sure€that€the€drug€entersÌthe€systemic€circulation.ÌÐ ð-@), ÐÔ_ÔÔ_Ô‡Discussions:€Question€set€1.€Question€6.€€Chronic€Toxicity€&€CarcinogenicityÌÌTopic:€Question€set€1.€Question€6.€€Chronic€Toxicity€&€Carcinogenicity€€ÌSubject:€Question€set€1.€Question€6.€€Chronic€Toxicity€&€Carcinogenicity€€€Posted:€Mar-04-02€atÏ3:59€PM€by€Kenneth€Campbell€€ÌÌò ò6.€Note€the€emphasis€of€chronic€toxicity€testing€and€mutagenesis€testing€on€Ô_ÔcarcinogenesisÔ_Ô.€Ð P   ÐIs€this€emphasis€currently€appropriate,€or€are€there€other€possible€chronic€outcomes€to€beÏconcerned€with?ó óÐ 0 € ÐÌPosted:€Feb-12-03€at€10:27€PM€by€Ô_ÔIvanaÔ_Ô€Ô_ÔDjureticÔ_Ô€€ÌÌCertainly,€as€scientific€methods€and€techniques€get€more€advanced€it€will€become€much€easierÏand€cost-effective€to€assess€various€other€effects€of€Ô_ÔtoxicantsÔ_Ô€beside€Ô_ÔcarcinogenesisÔ_Ô.€Why€is€thisÏimportant?€For€instance,€a€particular€signaling€protein€affected€by€a€toxicant€can€cause€anÏincrease€in€cellular€proliferation€(then€cancer)€but€this€protein€might€also€have€other€functionsÏeither€in€the€same€organ€or€in€different€organs.€Toxicant€might€also€affect€more€than€one€proteinÏwith€similar€binding€clefts€(e.g.€ATP€is€a€substrate€for€various€enzymes).€Activation€of€oneÏtyrosine€Ô_ÔkinaseÔ_Ô€receptor€by€a€toxicant€can€have€multiple€effects€via€diverging€signaling€cascades.ÏGenes€with€distinct€functions€could€be€affected€by€mutagenesis€(see€chapter€3€for€many€specificÏexamples).Continuous€displacement€of€homeostasis€can€therefore€lead€to€various€other€outcomesÏthat€might€not€be€readily€observed€under€Ô_ÔsubmaximalÔ_Ô€doses€but€require€further€investigation€(asÏmentioned€in€Session€2€notes:€"neural€degeneration,€arthritic€conditions,€vascular€rigidity,€loss€ofÏmuscle€mass,€loss€of€bone€mass,€decline€in€immune€function").€Animals€that€undergo€toxicityÏtesting€for€Ô_ÔcarcinogenesisÔ_Ô€should€be€used€for€further€microscopic€and€biochemical€examination.ÏAre€there€any€increases/decreases€in€protein€expression€in€experimental€group€compared€toÏcontrols,€any€changes€in€tissue/organ€architecture?€Do€animals€show€any€of€the€effects€mentionedÏabove?€Recent€advances€in€Ô_ÔproteomicsÔ_Ô€such€as€DNA,€mRNA,€and€protein€chips€will€allow€fasterÏanalysis.ÌÌPosted:€Feb-13-03€at€5:52€PM€by€Erin€Valentine€€ÌÌAlthough€it€remains€important€that€the€emphasis€of€chronic€toxicology€testing€is€onÏÔ_ÔcarcinogenesisÔ_Ô€and€mutagenesis,€other€possible€outcomes€are€similarly€significant.€One€suchÏexample€is€chronic€exposure€to€Ô_ÔmycotoxinsÔ_Ô.€Ô_ÔMycotoxinsÔ_Ô€are€secondary€products€of€Fungi€foundÏprimarily€in€food€or€animal€feed€due€mainly€to€poor€storage€environments.€€Due€to€theirÏlipophilic€nature,€these€toxins€are€generally€stored€in€fat€cells.€The€various€species€produce€aÏvariety€of€Ô_ÔmycotoxinsÔ_Ô€of€which€a€few€have€been€studied€extensively€for€toxicity€in€wide€rangesÏof€animal€species€(mainly€farm€and€laboratory€animals).€Symptoms€exhibited€by€mice€and€ratsÏchronically€exposed€to€Ô_ÔmycotoxinsÔ_Ô€included,€along€with€Ô_ÔcarcinogenesisÔ_Ô,€such€deleterious€effectsÏas€extensive€liver€damage,€gastric€ulcers,€and€thymic€depression.€It€has€been€shown€that€theÏÔ_ÔmycotoxinÔ_Ô,€aflatoxin,€is€Ô_ÔcytotoxicÔ_Ô€due€to€its€ability€to€induce€lipid€Ô_ÔperoxidationÔ_Ô€leading€toÏoxidative€damage€in€certain€cell€types.€Other€Ô_ÔmycotoxinsÔ_Ô€damage€cells€through€action€on€cellularÏrespiration€indicated€competitive€inhibition€of€Ô_ÔATPaseÔ_Ô€Ô_ÔsuccinateÔ_Ô€Ô_ÔdehydrogenaseÔ_Ô,€and€Ô_ÔcytochromeÔ_ÔÏC€Ô_ÔoxidaseÔ_Ô.€Some€examples€inhibit€protein€and€DNA€synthesis,€compromise€immunity,€and/orÐ ð-@), Ðdisrupt€the€endocrine€system€(above€issues€reviewed€in€Hussein€and€Ô_ÔBraselÔ_Ô€2001)€These€effectsÏcould€damage€any€number€of€essential€functions€for€survival.€The€reason€that€it€is€important€toÏseriously€consider€these€effects€alongside€Ô_ÔcarcinogeneisisÔ_Ô€and€mutagenesis€is€that€they€may€beÏjust€as€deadly.€€In€the€case€of€Ô_ÔmycotoxinsÔ_Ô,€chronic€exposure€to€humans€may€come€in€the€form€ofÏconsuming€milk€or€meat€from€intoxicated€farm€animals,€consuming€contaminated€food€directly,Ïand€inhaling€air€from€contaminated€buildings.€Lately,€the€issue€of€infected€buildings€hasÏrepeatedly€been€in€the€news,€and€the€report€often€includes€contamination€of€a€school€with€moldÏand€many€sick€children.ÌÌHussein,€HS€and€€Ô_ÔBraselÔ_Ô€JM,€Toxicity,€metabolism,€and€impact€of€Ô_ÔmycotoxinsÔ_Ô€on€humansÌand€animals.€Toxicology.€167€(2001)€101ð!ð134.Ð `  ÐÌPosted:€Feb-13-03€at€10:36€PM€by€Lisa€McIntosh€€ÌÌÔ_ÔCarcinogenesisÔ_Ô€is€certainly€emphasized€as€a€selective€endpoint€for€toxicity€testing,€althoughÏÔ_ÔnoncarcinogenicÔ_Ô€effects€that€may€potentially€impact€oneððs€life€are€by€no€means€considered€aÏweaker€endpoint.€Not€all€substances€are€carcinogenic;€therefore,€long-term,€low-dose€exposuresÏto€such€substances€obviously€should€be€evaluated€with€regard€to€Ô_ÔnoncarcinogenicÔ_Ô,€nonlethalÏeffects.€(Furthermore,€some€substances€shown€to€be€carcinogenic€in€laboratory€animals€have€notÏbeen€proven€to€cause€cancer€in€humans).ÌÌPosted:€Feb-15-03€at€11:14€AM€by€Ô_ÔHanaeÔ_Ô€Ô_ÔHiyoshiÔ_Ô€€ÌÌChronic€toxicity€test€usually€requires€at€least€1,000€animals€and€18€months€to€complete.€It€shouldÏhave€the€same€route€of€exposure€that€would€occur€in€humans€and€needs€a€close€watch€every€day.ÏI€think€the€current€emphasis€of€chronic€toxicity€testing€is€pretty€appropriate€to€check€onÏÔ_ÔcarcinogenesisÔ_Ô,€but€the€test€is€expensive€and€there€is€no€standard€measure€for€chronic€toxicity,Ïunlike€LD50€for€acute€toxicity.€Humans€are€generally€more€vulnerable€than€the€tested€animals,Ïand€different€species€have€different€way€of€responding€to€toxic€substances.€Today€the€estimationÏof€human€risk€is€still€one€of€the€difficult€problems,€since€quantitative€risk€analysis€is€especiallyÏdifficult€to€make€relationships€based€on€animal€data,€while€qualitative€risk€analysis€is€relativelyÏeasier€to€develop€by€finding€some€negative€toxic€effects€in€the€tested€animals€although€theÏapplicable€toxicity€use€level€is€quite€different€in€each€country.ÌÌPosted:€Feb-16-03€at€10:09€PM€by€Michael€George€€€ÌÌ€€€€€€€€€€€€Chronic€testing€looks€at€periods€from€6€months€ð!ð€two€years.€€These€tests€look€at€exposureÐ p&À!$ Ðover€most€of€the€animalððs€lifetime.€€These€tests€require€a€minimum€of€1000€animals.€€TheseÏanimals€have€to€free€of€any€tumors.€€These€studies€look€at€Ô_ÔMYDÔ_Ô€(maximum€tolerable€dose).€€ÏThese€tests€are€fairly€appropriate€but€can€be€costly€and€errors€do€occur.€€Humans€have€differentÏresponses€than€lab€animals€and€generally€are€more€vulnerable.€€Estimating€responses€to€Ô_ÔtoxicantsÔ_ÔÏin€humans€is€still€difficult€today€since€what€might€be€toxic€in€lab€animals€isnððt€necessarily€goingÏto€be€toxic€in€humans€and€vice€versa.€ÌÌPosted:€Feb-18-03€at€12:30€PM€by€Ô_ÔDINAÔ_Ô€KATZ€€Ð ð-@), ЇSince€cancer,€speaking€extremely€generally,€is€caused€by€(1)€a€mutation€of€some€sort€in€DNAÏwhich€then€causes€(2)€Ô_ÔuncontrolableÔ_Ô€mitotic€division€of€the€originally€affected€cell€or€tissue,€withÏthe€potential€to€(3)€Ô_ÔmetastaciseÔ_Ô,€there€are€several€routes€in€which€a€toxin€can€either€induce€orÏenhance€cancerous€development.€General€toxicity€testing€is.€of€course,€appropriate,€just€to€see€ifÏany€physiological€response€is€elicited,€and€mutagenesis€testing€checks€for€the€first€part€of€myÏdefinition.€However,€a€mutation€may€or€may€not€lead€to€cancer,€and€it€is,€in€my€opinion,€moreÏimportant€to€check€for€the€ability€of€a€toxin€or€toxicant€to€break€the€normal€regulation€of€a€cellÏcycle.€The€toxin/toxicant€may€not€be€Ô_ÔmutagenicÔ_Ô€itself,€but€may€cause€the€disruption€of€the€cellÏcycle,€possibly€in€addition€to€damage€done€by€some€other€agent€previously,€which€damaged€itÏand€yet€did€not€cause€the€cancer€cascade.€There€is€also€the€possibility€of€a€toxin/toxicantÏdamaging€cell-to-cell€connections€and€initiating€metastasis€of€the€cancerous€cells.ÌÌò òOldó óÐ ð@  ÐÌAllison:ÌFebruary€20,€2002Ì6.€Chronic€toxicity€tests€are€performed€to€assess€the€cumulative€toxicity€of€chemicals,€whichÏoften€include€a€consideration€of€the€carcinogenic€potential€of€chemicals€so€that€a€separate€studyÏthat€Ô_ÔsoleyÔ_Ô€addresses€Ô_ÔcarcinogenityÔ_Ô€does€not€have€to€be€performed.€€Chronic€toxicity€assays€areÏregulated€with€guidelines€that€require€that€both€benign€and€malignant€tumors€be€in€the€evaluation.€ÏWhile€this€type€of€testing€may€be€validated€with€discoveries€of€potential€cancer€causing€agents,Ïthere€are€some€problems.€€All€known€chemical€carcinogens€in€humans€have€been€found€to€beÏcarcinogenic€in€some€species€but€not€in€all€laboratory€animals.€However,€all€chemicals€that€areÌcarcinogenic€in€animals€are€carcinogenic€in€humans.€Species€variation€and€genetic€variationÏwithin€a€species€being€tested€may€account€for€some€Ô_ÔdiscripenciesÔ_Ô€when€chronic€testing€forÏcarcinogens€is€applied.€€Information€about€the€mechanism€of€action€of€the€carcinogen€mayÏindicate€that€a€positive€response€in€animals€is€not€relevant€to€humans€and€may€be€irrelevant€forÌhuman€risk€assessment.€In€this€case,€many€question€the€purpose€of€chronically€testing€animalsÏthat€may€not€provide€results€that€actually€relate€to€humans.Ì€€€Another€issue€with€chronic€toxicity€testing€is€that€they€are€used€mainly€for€carcinogenic€studiesÏwhen€the€possibility€of€other€toxic€effects€and€disease€may€occur.€These€other€effects€include,ÏÔ_ÔneurodegenerativeÔ_Ô€disorders,€problems€with€other€organs,€and€toxic€effects€to€the€digestive€andÌreproductive€systems.€€Also,€many€chronic€studies€expose€agents€in€one€or€two€forms€of€deliveryÏbut€do€not€test€the€effects€of€exposing€the€toxin€through€another€method€of€administration.€ThisÏmay€also€provide€results€that€differ€from€carcinogenic€effects€but€instead€lead€to€various€otherÏdiseases€and€malfunctions.ÌÌJoanne:ÌFebruary€20,€2002Ì6)€The€emphasis€on€chronic€toxicity€with€respect€to€Ô_ÔcarcinogenesisÔ_Ô€is€presumably€due€to€theÏmany€Ô_ÔoncogenicÔ_Ô€promoting€agents€in€the€environment€as€well€as€the€relatively€easiness€inÏmeasuring€them.€As€our€society€becomes€more€sophisticated€in€terms€of€understanding,Ìtechnology€and€preventative€strategies,€it€is€certain€that€the€range€of€chronic€toxicity€testing€willÌexpand.ÌÐ ð-@), ÐÔ_ÔNeetuÔ_Ô:ÌFebruary€20,€2002Ì6.€Chronic€toxicity€is€performed€to€find€out€the€possible€toxic€effect€s€of€a€certain€chemical.€It€isÌalso€done€to€check€if€the€drug€has€any€Ô_ÔcarciogenicÔ_Ô€potentials.€The€exposure€time€is€long€(moreÌthan€3€months)€for€chronic€toxicity;€Ô_ÔexcatlyÔ_Ô€how€long€depends€on€how€long€the€drug€will€be€usedÌfor€in€humans.€High€dose€is€required€for€mutagenesis€testing€and€chronic€testing€requires€theÌuse€of€a€drug€for€a€long€period€of€time.€These€two€factors€(high€dose€and€long€time€exposure)€canÌbe€deleterious€for€the€subjects.€Therefore,€in€order€to€perform€chronic€toxicity,€it€is€veryÏimportant€to€keep€maximal€tolerance€dose€(Ô_ÔMTDÔ_Ô)€concept€in€mind.€Ô_ÔMTDÔ_Ô€is€a€maximum€doseÏthat€can€be€used€in€testing€subjects€without€harming€them€before€they€go€through€the€restÏsuccessfully.€€Also,€it€is€important€to€use€Ô_ÔheatanimalsÔ_Ô€;€animals€whose€medical€history€has€beenÏclear€of€any€Ô_Ôtumors.ÌÌÌÌÌÌÌÌÌÌÌÌÌÌÌÌÌÌÌÌÌÌÌÌÌÌÌÌÌÌÌÌÔ_ÔÌÐ ð-@), ÐÔ_ÔÔ_Ô‡Discussions:€Question€Set€1.€Question€7.€€Toxin€Metabolism€ConsiderationsÌÌTopic:€Question€Set€1.€Question€7.€€Toxin€Metabolism€Considerations€€ÌSubject:€Question€Set€1.€Question€7.€€Toxin€Metabolism€Considerations€€€Posted:€Mar-04-02€atÏ4:00€PM€by€Kenneth€Campbell€€€ÌÌò ò7.€Emphasis€in€the€discussion€of€biochemical€and€physiological€means€of€toxin€metabolismÐ P   Ðand€clearance€is€on€the€adult€animal.€€Are€there€other€important€considerations€or€routes€toÏbe€considered€in€growing€offspring€or€during€the€reproductive€process?ó óÐ 0 € ÐÌPosted:€Feb-12-03€at€11:45€PM€by€Ivana€Djuretic€€ÌÌFor€a€developing€fetus€the€major€route€of€exposure€is€the€placenta.€Along€with€the€nutrients,Ïvarious€toxins€and€toxicants€that€enter€the€mother€via€standard€routes€move€across€this€barrierÏagainst€a€concentration€gradient.€Though€this€barrier€could€consist€of€multiple€layers,€theirÏnumber€is€not€of€great€importance€for€the€rate€of€diffusion€of€chemicals.€It€is€rather€the€solubilityÏof€toxicants€that€is€important€so€if€a€toxicant€was€able€to€rapidly€diffuse€across€other€bodyÏmembranes€it€will€do€so€across€the€placenta.€Luckily,€50-50€€equilibrium€is€not€alwaysÏestablished€between€the€mother€and€the€fetus€because€fetal€tissue€is€usually€less€developed€andÏless€able€to€concentrate€the€toxicant€(exception:€brain)ÌÌIn€addition€to€this,€developing€offspring€can€encounter€toxicants€postnatally€(through€lactation)Ïas€well€as€prior€to€conception€(through€seminal€fluid).€For€this€purpose€many€developmental€andÏreproductive€toxicity€tests€are€available.€Segment€I€tests€evaluate€the€effect€of€chemicals€onÏgeneral€fertility€and€reproductive€performance;€segment€II€tests€administer€chemicals€duringÏearly€pregnancy;€segment€III€tests€are€done€in€late€pregnancy€and€continue€into€lactation.ÌÌPosted:€Feb-13-03€at€6:35€PM€by€Erin€Valentine€€ÌÌIn€addition€to€the€placental€barrier,€another€important€route€to€consider€is€the€blood-testis€barrier.ÏThis€barrier€prevents€free€exchange€of€chemicals/drugs€between€the€blood€and€the€fluid€inside€theÏseminiferous€tubules.€The€barrier€is€composed€of€tightly€fit€epithelial€cells,€which€may€haveÏsections€with€leaky€junctions.€Lesser-developed€barriers€in€immature€testes€have€more€of€thisÏleakiness,€thus€leading€to€a€greater€chance€for€exposure.€If€a€toxin€does€pass€through€this€barrier,Ïseveral€mechanisms€for€metabolism€exist€in€the€testes.€These€include€mixed-function€oxidases,Ïepoxide-degrading€enzymes,€gonadal€cytochrome€P450€and€AHH€present€in€microsomes.€ThisÏmetabolism,€however,€can€have€adverse€effects€on€spermatogenesis€and/or€steriodogenesis.ÏMetabolites€of€toxicants€alter€testicular€structures€resulting€in€deleterious€effects€to€the€germÏcells.€Examples€of€this€include€the€oxidization€product€of€n-hexane,€2,5-HD,€which€alters€theÏmicrotubules€in€Sertoli€cells€ultimately€preventing€the€paracrine€support€for€the€germ€cells.€OtherÏtoxic€metabolites€cause€abnormal€sperm,€testicular€lesions,€decreased€sperm€mobility€andÏdamage€to€the€Sertoli€and€Leydig€cell€functions€(see€C&D€689-690).€All€of€these€factors€can€beÏdeleterious€to€the€possibility€of€reproduction.ÌÌPosted:€Feb-13-03€at€10:57€PM€by€Lisa€McIntosh€€Ð ð-@), ЇDifferences€in€a€childððs€behavior€and€physiology€are€major€factors€that€need€to€be€consideredÏwhen€addressing€toxicity.€Children€often€have€a€much€higher€exposure€potential€(toÏenvironmental€toxicants,€in€particular)€than€adults:€they€play€in€the€dirt€outside€or€on€the€carpet;Ïthey€consume€more€food€and€water€and€have€a€higher€inhalation€rate€per€body€weight;€they€orallyÏexplore€their€surroundings;€they€drink€breast€milk.€Likewise,€their€uptake,€metabolism,€andÏexcretion€mechanisms€vary€from€those€of€an€adult.€Because€of€their€enhanced€exposures,€childrenÏare€generally€more€susceptible€to€chemical€insult€than€adults.ÌÌPosted:€Feb-15-03€at€11:33€AM€by€Hanae€Hiyoshi€€ÌÌSome€routes€of€exposure€which€negatively€effects€on€reproductive€process€are€inhalation,Ïingestion€of€food€and€water€containing€toxin/toxicant,€and€skin.€As€an€example,€lead€can€beÏfound€in€many€kinds€of€food€or€in€leaded€paint.€Lead€is€a€tetratogen€that€can€cause€fetalÏmalformation,€a€mutagen€that€can€impair€fertility€and€affect€both€sperm€and€eggs.€ThroughÏinhalation€lead€is€almost€completely€absorbed€after€entering€lower€respiratory€tract,€and€it€affectsÏmajor€organs€in€the€body,€especially€childrenððs€nervous€system.€Its€absorption€rate€throughÏingestion€for€young€children€is€4€to€5€times€higher€than€for€adults,€causing€lead€poisoning€andÏpermanent€neurological,€cognitive€impairments.ÌÌResource:€Ô4‚ Ý ÔÝ‚ ÍOÝÔÿÔòòÝ  ÝÔ5  Ôhttp://www.pca.state.mn.us/waste/listedmetals.htmlÔ6TÔÝ‚ ÍOhƒÝóóÔÿÔÝ  ÝÔ7Ý –ÔÐ €Ð ÐÌPosted:€Feb-16-03€at€6:24€PM€by€Michael€George€€ÌÌIn€the€growing€offspring€or€developing€fetus,€a€number€of€considerations€need€to€be€made.€€TheÏgrowing€offspring€is€more€susceptible€to€toxicants€due€to€its€behavior€as€a€young,€i.e.€it€eatsÏmore,€plays€around€and€explores.€€Also,€their€methods€of€clearance,€metabolism,€detoxification,Ïand€excretion€are€not€as€developed€as€adults€along€with€their€immune€systems.€€DuringÏdevelopment,€the€fetus€absorbs€nutrients€from€the€mother€from€the€placenta,€so€whateverÏtoxicants€the€mother€may€be€able€to€clear,€the€fetus€may€not€be€able€to€and€absorbs€it.€€ExamplesÏof€this€can€include€leaded€paint,€where€in€small€amounts€to€adults€is€not€toxic€while€can€causeÏnumerous€developmental€problems€during€development.€Ì€ÌPosted:€Feb-18-03€at€7:10€PM€by€DINA€KATZ€€ÌÌFirst€of€all,€embryonic€and€fetal€development€in€mammals€makes€use€of€the€placenta,€which€isÏpermeable€to€many€toxins€and€toxicants€present€in€the€mother's€circulation,€as€well€as€viruses€andÏother€pathogens.€If€the€Ô_ÔpregancyÔ_Ô€happens€at€a€difficult€time€for€the€organism,€fat€reserves€may€beÏmobilized,€which€may€contain€a€significant€amount€of€toxic€substances€that€are€then€passed€to€theÏfetus.€Fetuses€and€newborns€often€have€underdeveloped€metabolic€pathways€for€clearing€toxinsÏand€Ô_ÔtoxicantsÔ_Ô€crossing€the€placental€barrier€or€passed€through€mother's€milk.€Once€infants€areÏweaned€at€least€partially,€any€other€food€is€also€a€consideration,€as€it€may€contain€substancesÏharmful€to€the€underdeveloped€systems,€which€might€go€unnoticed€in€adult€toxicity€testing.€TheÏsame€goes€for€other€routes€of€exposure:€anything€Ô_ÔinhalableÔ_Ô€or€in€dermal€contact€with€the€babyÏwhich€may€be€considered€safe€for€adults€may€not€be€safe€for€the€newborns.€In€addition,€onceÏchildren€are€mobile,€they€tend€to€ingest€and€come€in€contact€with€a€wider€variety€of€materials€notÐ ð-@), Ðintended€for€consumption€or€inhalation.ÌÌÔ_ÔTeratogenicÔ_Ô€effects€are€also€a€consideration.€When€a€toxicity€study€is€performed,€it€may€or€mayÏnot€be€done€on€pregnant€or€impregnating€animals;€if€it€is€not,€there€is€no€way€to€definitely€ruleÏout€possible€effects€on€the€reproductive€system€even€if€the€adult€test€subject€exhibits€no€adverseÏeffects€whatsoever.€It€is€also€possible€that€a€long-term€effect€exists,€as€a€result€of€a€slowÏmetabolic€pathway€to€the€ultimate€toxicant.€For€example,€a€rat€injected€with€a€potential€toxicantÏis€mated,€say,€three€days€after€the€injection,€and€the€offspring€exhibit€no€ill€effect.€However,€aÏmating€in€two€weeks€will€show€severe€Ô_ÔteratogenicÔ_Ô€effects€originally€attributable€to€the€injectedÏsubstance.ÌÔ_ÔÔ_ÔÌò òOldó óÐ P  ÐÌAllison:ÌFebruary€20,€2002Ì7.€Growing€offspring€and€embryos€developing€during€the€reproductive€process€are€moreÏsusceptible€to€the€effects€of€toxins€than€the€adult€animal.ÌBiochemical€and€physiological€means€of€toxin€metabolism€and€clearance€are€usually€focused€onÏthe€adult€animal€but€many€studies€have€been€performed€that€provide€data€on€the€vulnerability€ofÏgrowing€offspring€as€well€as€the€knowledge€that€most€chemicals€are€not€denied€entrance€into€aÏnumber€of€compartments€or€secretions€of€the€reproductive€tract.€This€includes€the€placenta€beingÏunable€to€restrict€and€prevent€most€chemicals€from€crossing€the€placenta.€Ô_ÔXenobioticÔ_Ô€and€certainÏdrugs€can€be€detected€in€uterine€secretions,€in€the€milk€of€lactating€mothers,€and€in€seminal€fluid.ÌThere€also€appear€to€be€no€specialized€barriers€to€prevent€chemicals€or€drugs€from€acting€on€theÏovary.Ì€€€Some€important€considerations€and€routes€of€delivery€to€be€looked€at€in€growing€offspring€andÏduring€the€reproductive€process€are€that€tissues€and€bones€have€not€fully€developed€and€thereforeÏdo€not€have€the€ability€to€withstand€toxins€as€in€adults€and€to€metabolize€and€secrete€to€eliminateÌthem€before€harmful€effects€can€take€place.€Growing€offspring€do€not€have€fully€developedÏdigestive€or€reproductive€systems€and€are€more€susceptible€due€to€protective€mechanisms€notÏbeing€intact€and€fully€developed.ÌÌJoanne:ÌFebruary€20,€2002Ì7)€YES!€Ô_ÔTeratogenesisÔ_Ô€(Ô_ÔieÔ_Ô€abnormal€development)€is€evidenced€by€mutations,€chromosomalÏbreaks,€altered€mitosis,€altered€nucleic€function,€Ô_ÔosmolarÔ_Ô€imbalance..etc..etc..€All€of€which€mayÏbe€triggered€by€toxic€agents€delivered€through€the€Ô_ÔconceptusÔ_Ô€at€the€cellular€level,€the€insult€mayÏoccur€through€a€direct€effect€on€the€embryo/fetus,€indirectly€through€toxicity€of€the€agent€to€theÏmother€and/or€the€placenta€or€through€a€combination€of€direct€and€indirect€routes€of€entry€(€C€&ÏD,€page€365).ÌÌAlso€-€a€developing€child€will€be€differentially€effected€as€a€young€child's€nervous€system€is€stillÌdeveloping€until€approximately€age€10.€For€instance,€Ô_ÔorganophosphateÔ_Ô€insecticides,€which€are€theÏcommonly€used€product€since€the€removal€of€Ô_ÔorganochlorinesÔ_Ô,€have€been€found€to€differentiallyÏeffect€adults€and€children.€Some€of€the€typical€cholinergic€signs€of€Ô_ÔbradycardiaÔ_Ô,€muscularÐ ð-@), ÐÔ_ÔfasiculationsÔ_Ô,€lacrimation€and€sweating€were€less€common€in€children€but€seizures,€lethargy€andÏcoma€were€most€prevalent€in€children.ÌBecause€the€toxic€agent€is€acting€on€two€different€systems€(Ô_ÔieÔ_Ô€developed€vs€undeveloped€NS,€aÏdifferent€result€would€be€expected).ÌÌÔ_ÔNeetuÔ_Ô:ÌFebruary€20,€2002Ì7.€It€is€Ô_ÔimporatntÔ_Ô€to€Ô_ÔundesrtandÔ_Ô€the€fetal€metabolic€pathways€Ô_ÔbecuaseÔ_Ô€offspring€can€be€exposedÌto€chemical€and€physical€agents€that€could€result€in€adverse€effect.€This€exposure€can€occur€atÌthe€time€of€conception,€during€pre€and€post€natal€development€(until€puberty€is€reached).€yes,Ìimportant€Ô_ÔconsiderstionsÔ_Ô€and€routes€should€be€considered€in€growing€children€Ô_ÔbecuaseÔ_Ô€theÌoffsprings€are€still€developing,€and€are€not€as€developed€as€adults,€and€therefore,€their€bodyÌworks€little€differently€than€that€of€adults.ÌÌÔ_ÔÌÌÌÌÌÌÌÌÌÌÌÌÌÌÌÌÌÌÌÌÌÌÌÌÌÌÌÌÌÔ_ÔÌÐ ð-@), ÐÔ_ÔÔ_ÔTopic:€Question€Set€1.€Question€10.€€Risk€Strategies€&€Levels€of€Toxicity€€€ÌSubject:€Question€Set€1.€Question€10.€€Risk€Strategies€&€Levels€of€Toxicity€€€Posted:€Mar-04-02Ïat€4:04€PM€by€Kenneth€Campbell€€ÌÌò ò10.€What€distinctions€might€be€made€between€lethality,€morbidity,€reproductive€capacity,Ð pÀ Ðquality€of€life,€and€quality€of€environment€impacts€vis€a€vis€risk€assessment€strategies?ó óÐ ` ° ÐÌPosted:€Feb-12-03€at€12:11€PM€by€Erin€Valentine€€ÌÌ10.€€€€The€distinctions€between€these€categories€of€various€levels€of€risks€and€the€risk€assessmentÏstrategies€are€that€of€result€of€exposure€to€a€particular€toxic€substance.€Assessing€the€risk€of€aÏlethal€substance€would€include€animal€testing€and€determination€of€LD50€under€a€varying€set€ofÏconditions,€such€as€length€of€exposure,€site€of€exposure,€number€of€test€subjects,€etc.€AssessingÏthe€risk€of€a€morbid€agent€would€require€more€specific€testing.€The€observations€would€now€haveÏto€include€clinical€observation€of€symptoms€and€postmortem€examination€to€determine€the€site€ofÏaction€and€characterization€of€the€specific€effect€of€the€chemical.€These€observations€may€be€theÏoccurrence€of€tumors,€damage€to€particular€organs,€or€interruption€of€a€biological€function.€In€theÏcase€of€assessing€the€risk€to€reproductive€capacity,€the€tests€must€focus€specifically€on€theÏendocrine€and€reproductive€systems€of€the€organisms.€The€tests€to€determine€the€reproductiveÏtoxicity€of€an€agent€are€performed€on€rats€through€six€stages€described€by€the€InternationalÏCommission€on€Harmony,€from€premating€to€weaning€and€sexual€maturity€of€the€offspringÏ(Klaasen€2001).€Quality€of€life€risk€assessment€would€need€to€test€the€ability€of€the€agent€toÏaffect€a€condition€of€life€that€does€not€cause€death€or€disease€such€are€skin€and€eye€irritants.ÏQuality€of€environment€€impacts€risk€assessment€must€test€all€of€these€conditions€as€well€as€theÏeffect€of€the€agent€on€the€natural€habitat.€This€assessment€might€include€the€effect€of€an€airÏpollutant€on€the€human€population€(lethality,€morbidity,€reproductive€capacity,€quality€of€life)Ïand€on€the€wildlife€(LD50€of€certain€populations)€and€on€the€plant€life€(observation€of€decrease€inÏgrowth).ÌÌPosted:€Feb-14-03€at€9:58€PM€by€Lisa€McIntosh€€ÌÌOn€an€individual€basis,€the€first€three€terms€reflect€varying€degrees€of€toxicity:€lethality,Ïobviously,€is€the€most€severe;€morbidity€may€ultimately€decrease€lifespan;€reproductive€capacityÏin€and€of€itself€may€not€adversely€affect€an€individual,€although€could€negatively€impact€aÏpopulation€through€decreased€fecundity.ÌÌQuality€of€life€impacts€may€not€necessarily€result€in€harmful€effects€to€an€organism;€however,Ïthat€quality€is€degraded€from€optimal€conditions.€Nuisance€odors-€chemicals€present€atÏconcentrations€above€the€odor€recognition€threshold,€but€below€deleterious€levels-are€a€goodÏexample€of€this.€In€terms€of€risk€characterization€(in€Massachusetts,€anyway),€the€presence€ofÏnuisance€odors€indicates€a€condition€of€significant€risk€to€public€welfare€exists€(even€if€theÏcontaminants€may€not€present€a€risk€to€human€health).ÌÌQuality€of€the€environment,€be€it€on€a€localized€or€global€scale,€ultimately€determines€the€level€ofÏimpact.€Risk€assessment€is€a€tool€by€which€we€relate€the€quality€of€the€environment€to€publicÐ ð-@), Ðhealth€or€the€environment.€The€underlying€premise€is€that€there€is€an€"acceptable"€level€ofÐ ° Ðriskð"ðsuch€as€allowing€residual€contamination€to€remain€in€the€soil,€using€a€drug€for€therapeuticÐ  ð Ðeffects€despite€the€potential€for€side€effects,€or€using€household€cleaners€or€pesticides€that€may€beÏlethal€if€used€incorrectly.ÌÌPosted:€Feb-16-03€at€12:03€PM€by€ERIC€FAULKNER€€ÌÌRisk€assessment€can€be€classified€as€a€quantitative€estimate€of€the€potential€effects€on€humanÏhealth€and€the€environmental€significance€of€various€types€of€chemical€exposure€(Klassen).€€InÏidentifying€a€hazardous€agent,€tests€are€performed€to€determine€if€the€agent€will€cause€an€adverseÏeffect€through€structure€activity€analysis,€in€vitro€testing,€animal€bioassays,€and€epidemiologyÏstudies.€€Additional€testing€is€performed€to€determine€the€dose-response€relationship€and€theÏduration€of€exposure€to€the€hazardous€agent€in€question.€These€assessments€form€a€Venn€diagramÏthat€make€up€the€three€categories€of€toxicological€studies;€mechanistic,€regulatory,€andÏdescriptive.€€While€lethality,€morbidity,€reproductive€capacity,€quality€of€life,€and€quality€of€theÏenvironment€all€play€significant€roles€in€the€study€of€toxicology,€further€distinctions€can€be€madeÏby€the€following;€lethality€is€an€acute€test€first€performed€on€a€NCE€with€a€fixed€dose€on€a€smallÏpopulation€where€an€LD50€is€determined.€€Morbidity€can€be€considered€a€long€term€exposureÏstudy€where€a€population€is€subjective€to€an€agent€for€greater€than€3€months€where€alterations€onÏbiological€functions€are€addressed.€€Reproduction€takes€into€consideration€the€effects€of€theÏreproductive€system€and€the€potential€of€the€hazard€to€disrupt€embryonic€development.€€AndÏfurthermore,€quality€of€life€and€quality€of€the€environment€assess€the€effects€of€a€hazard€on€aÏlarge€population€and€in€nature€where€risk€managers€summarize€the€potential€risks.ÌSubject:€Re:Question€Set€1.€Question€10.€€Risk€Strategies€&€Levels€of€Toxicity€€€Posted:ÏFeb-17-03€at€1:29€AM€by€Michael€George€€€View€the€history€for€this€message€Reply€Edit€theÏmessage€Re:Question€Set€1.€Question€10.€Risk€Strategies€&€Levels€of€Toxicity€Delete€theÏmessage€Re:Question€Set€1.€Question€10.€Risk€Strategies€&€Levels€of€ToxicityÌLooking€at€individuals,€lethality€which€leads€to€death,€morbidity€which€leads€to€a€decrease€inÏlifespan,€and€reproductive€capacity€all€are€the€most€serious.€€The€last€one€could€end€up€affecting€aÏpopulation€as€a€whole€in€the€long€run.€€Quality€of€life€toxicity€issues€wont€necessary€affect€theÏorganism€in€harmful€ways,€but€may€cause€degradation€in€the€quality€of€life€for€the€organism.€€ForÏexample€a€annoying€smell€may€occur€in€the€organism€or€a€scar€which€may€be€unpleasant€butÏwonððt€probably€lead€to€death.€€But,€the€presence€of€an€odor€in€an€area€may€lead€to€fears€ofÏsomething€harmful€even€though€there€is€no€harmful€toxicant.€€Quality€of€environment€is€lookingÏat€the€safety€of€the€environment€as€a€whole.€€It€is€important€for€risk€assessments€because€it€allowsÏus€to€keep€the€public€informed€to€what€is€a€safe€level€of€risk€for€products€that€are€toxic€such€asÏhousehold€products.€€Also€in€what€are€side€effects€for€medicines.Ì€ÌPosted:€Feb-17-03€at€7:09€PM€by€DINA€KATZ€€Ô_ÔÔ_ÔÌÌA€risk€assessment€is€an€expert's€opinion€of€the€likelihood€of€a€deleterious€effect.€Depending€onÏwhat€that€effect€might€be,€lethality(death),€morbidity(disease),€quality€of€life€(level€of€comfort€forÏthe€living€organism),€etc.,€the€assessment€will€differ€for€the€same€toxicant.€There€may€be€a€highÏrisk€of€reduction€in€the€quality€of€environment€(how€conducive€the€surroundings€are€to€life)€butÏnot€necessarily€lethality.€For€example,€an€oil€slick€is€a€high€risk€for€the€beach€by€your€house,€butÐ ð-@), Ðit€carries€a€very€low€risk€of€death€for€you€personally.€Similarly,€reproductive€capacity€ofÏpond-living€organisms€may€be€severely€reduced€by€a€toxicant€dumped€into€their€pond,€but€haveÏno€effect€on€their€own€quality€of€life.€Assessment€strategies€would€thus€have€to€be€tailored€toÏestimate€the€risk€to€a€specific€effect€(i.e.€if€it€is€necessary€to€carry€out€an€assessment€of€morbidityÏof€tadpoles€in€Lake€Erie,€one€should€probably€observe€behavior€and€collect€some€specimens€andÏinspect€their€tissues,€rather€than€spend€time€observing€a€reproductive€cycle€and€counting€young.)ÌÌPosted:€Feb-18-03€at€4:23€PM€by€Ivana€Djuretic€€ÌÌRisk€Ô_ÔassesmentÔ_Ô€strategies€require€the€following€components:ÌÌ-hazard€identification-an€evaluation€of€the€adverse€health€effects€the€agent€is€capable€of€causing:Ïdamage€to€liver,€nervous€system,€Ô_ÔcarcinogenesisÔ_ÔÌÌ-dose€response€assessment-includes€prediction€of€exposure€levels€at€which€risk€is€likely€to€beÏnegligible€or€nonexistentÌÌ-exposure€assessment€-€a€determination€of€how€much€of€an€agent€people€might€be€exposed€toÏunder€various€conditions€such€as€use€of€a€drug€or€a€consumer€product,€environmental€exposure€atÏa€hazardous€waste€site.ÌÌ-risk€characterization-€explicit€description€of€the€assumptions€and€uncertainties€that€go€into€theÏrisk€assessment,€and€the€overall€confidence€in€the€results€of€the€analysis.ÌÌIt€seems€like€risk€Ô_ÔassesmentÔ_Ô€strategies€will€only€characterize€lethality€of€a€substance€with€a€highÏdegree€of€certainty€(even€then€there€is€genetic€variability)€but€that€for€other€levels€of€toxicity€itÏwill€be€extremely€hard€to€predict€the€levels€of€risk.€Even€for€a€simpler€task€such€as€cancerÏassessment,€mathematical€models€are€needed€to€connect€the€results€of€experiments€with€a€limitedÏnumber€of€animals€to€large€scale€predictions€(more€than€1€additional€cancer€in€1€million€exposedÏpeople€is€unacceptable€risk,€but€you€cannot€test€1€million€animals).€So€morbidity,€reproductiveÏcapacity,€quality€of€life€and€environment€differ€from€lethality€in€the€certainty€of€risk€predicted€byÏrisk€Ô_ÔassesmentÔ_Ô€strategies.ÌÌI€will€use€this€question€to€comment€on€the€ambiguity€of€the€assigned€questions€(some,€not€all).€IÏfound€it€really€hard€to€formulate€an€answer€to€this€question€without€just€defining€what€lethality,Ïmorbidity€etc€is,€or€giving€the€type€of€tests€that€one€would€do€to€assess€lethality,€morbidity,€etc,Ïbut€that€doesn't€seem€to€be€what€the€question€asks.€Even€after€reading€Ch€4€and€doing€someÏadditional€research€I€couldn't€describe€in€one€simple€answer€how€risk€Ô_ÔassesmentÔ_Ô€strategies€wouldÏdistinguish€between€all€those€different€categories€of€toxicity.€The€answer€seems€to€be€the€entireÏof€toxicology.€Is€anybody€else€having€problems€with€the€nature€of€the€questions?€Maybe€we€areÏunable€to€start€threaded€discussions€because€people€are€interpreting€the€questions€in€differentÏways€and€its€hard€to€agree€or€disagree€with€someone€talking€about€an€entirely€different€thing€thanÏyourself.€Again€it€could€be€just€my€view,€but€I'm€almost€sure€that€having€more€specific€questionsÏwould€spark€a€discussion€less€vague.ÌÐ ð-@), ÐPosted:€Feb-20-03€at€10:29€PM€by€Diana€€Ô_ÔEsshakiÔ_Ô€€Ô_ÔÔ_ÔÌÌThe€variety€of€adverse€effects€of€chemicals€on€humans€clearly€impacts€risk€assessment€strategies.ÏBioassays€and€LD50€aid€in€developing€these€strategies.€When€assessing€risk€of€toxins,€lethalityÏ(ability€to€cause€death),€morbidity€(ability€to€cause€disease),€reproductive€capacity,€quality€of€life,Ïand€quality€of€Ô_ÔenvronmentÔ_Ô€do€have€distinct€impacts€on€determining€risk.€In€this€case,€since€theÏquestion€is€quite€vague,€it€is€probably€more€helpful€to€look€at€an€example:€mold€spores.ÌÌ(Radiation€is€actually€a€more€clear€cut€example,€however,€I€am€assuming€that€we€aren'tÏconsidering€that€a€toxin.)ÌÌLethality:€Clearly€the€most€significant€factor€does€not€play€much€of€a€role€with€mold€sporeÏexposure.€Put€another€way,€when€assessing€risk,€this€"toxin"€does€not€cause€death.ÌÌMorbidity:€Exposure€to€mold€(Ô_Ôesp.indoorÔ_Ô€constant€exposure)€can€cause€a€wide€array€of€healthÏproblems.€Very€large€doses€of€mold€spores€(inhaling€or€ingesting)€can€result€in€poisoning€byÏÔ_ÔmycotoxinsÔ_Ô.€Exposure€can€cause€allergic€illnesses,€asthma,€and€infection€(lung€or€respiratoryÏtract).€In€this€case,€morbidity€has€a€very€high€and€quite€distinct€effect€on€risk€assessment.ÌÌReproductive€capacity:€Mold€spores€are€not€usually€a€health€risk€factor€on€Ô_ÔreproÔ_Ô.ÌÌQuality€of€life:€Mold€spores€indoors€can€not€only€cause€a€health€risk,€but€can€make€livingÏuncomfortable€by€adhering€to€ceilings,€etc.€in€the€home.ÌÌQuality€of€environment:€Varies€depending€on€indoors€vs.€outdoor€exposure-€indoor€causing€moreÏdirect€inhalation€and€infringing€on€safety€of€the€individuals€exposed.€ÌÌò òOldÐ P ÐÌó óAllison:Ð à0 ÐFebruary€20,€2002Ì10.€Risk€assessment€strategies€are€Ô_ÔdefinetlyÔ_Ô€impacted€by€differences€between€lethality,€morbidity,Ïreproducing€capacity,€and€quality€of€life€and€environment.€In€determination€of€the€risk€of€a€toxin,Ïacute€testing€would€be€performed€on€toxins€that€my€be€considered€lethal.€Morbidity€involves€aÏcompromise€of€function,€including,€disease€rates,€genetic€defects,€and€toxicant€effects,€all€ofÏwhich€may€not€be€lethal.€In€testing€whole€populations,€reproductive€capacity€and€morbidity€mayÏlead€to€Ô_ÔlethatlityÔ_Ô,€which€is€very€damaging€and€would€be€considered€in€those€risk€assessments.ÌHowever,€when€looking€at€individuals€rather€than€a€species€as€a€population,€morbidity€,ÏÔ_ÔreproducitveÔ_Ô€capacity,€as€well€as,€quality€of€life€and€environment€may€not€be€Ô_ÔextrememlyÔ_Ô€toxic€inÏthe€sense€that€one€can€still€survive.€Toxic€effects€exist€at€various€levels€and€when€assessing€riskÏof€a€toxin,€it€is€possible€that€they€will€not€induce€effects€that€generate€lethality€of€morbidity€butÏwill€alter€quality€of€life€and/or€environment.€In€these€cases,€the€strategy€about€how€assess€riskÏchanges€and€preventing€death€is€no€longer€a€goal,€but€instead€preserving€a€quality€of€life€andÌgeneral€well€being.ÌÐ ð-@), ÐJoanne:ÌFebruary€20,2002Ì10)€Lethality:€deathÌ€€€€Morbidity:€diseased€state,€decreased€life€spanÌ€€€€Reproductive€capacity:€ability€to€reproduce€€Ì€€€€Quality€of€Life:€Ô_ÔnonmedicalÔ_Ô€threats€that€compromise€one's€ability€to€enjoy€life€€€€Ì€€€€Quality€of€environment:€degree€of€safety,€Ô_ÔcomfortabilityÔ_Ô€and€security€in€surroundingsÌÌIn€terms€of€these€factors€with€respect€to€risk€assessment€strategies,€they€are€ordered€in€terms€ofÌimportance€with€the€greatest€stressor€on€lethality€and€in€descending€significance€thereafter.ÌÔ_ÔObviously,lethalityÔ_Ô€would€have€the€greatest€influence€on€risk€assessment.€Although€there€mayÏappear€to€be€an€element€of€subjectivity€(Ô_ÔieÔ_Ô€Ô_ÔreproducitveÔ_Ô€ability€vs€quality€ofÏenvironment..etc..etc),€overall€they€are€ranked€in€Ô_ÔaccordacneÔ_Ô€with€what€the€majority€ofÏindividuals€would€assess€in€terms€of€personal€importance.ÌÌÔ_ÔNeetuÔ_Ô:ÌFebruary€20,€2002Ì10.€Lethality€is€related€to€death,€morbidity€is€related€to€compromise€in€functionality.€InÏindividual€lethality,€it€is€not€necessary€that€it€means€inability€to€reproduce.€When€talking€aboutÏpopulation€lethality,€Ô_ÔthÔ_Ô€Ô_ÔemorbidityÔ_Ô€might€be€lethal.€The€toxins€might€change€Ô_Ôone;sÔ_Ô€quality€of€lifeÏor€living€standards€but€it€is€not€necessarily€lethal.€The€quality€of€environment€will€effect€eachÏindividual€differently.ÌÌÌÌÌÌÌÌÌÌÌÌÌÌÌÌÌÌÌÌÌÌÌà  àÐ ð-@), ÐTopic:€Question€Set€2.€Question€6.€€Oral€Toxicity€Paradox€€Ì€ÌSubject:€Question€Set€2.€Question€6.€€Oral€Toxicity€Paradox€€€Posted:€Mar-04-02€at€6:54€PM€byÏKenneth€Campbell€€ÌÌò ò6.€Oral€toxicity€studies€have€defined€a€paradox€of€this€route€of€exposure.€€What€is€theÐ ` ° Ðparadox€and€how€might€it€be€explained?€€A€somewhat€similar€paradox€can€arise€if€dietaryÏinsoluble€fiber€is€high€and€exposure€is€again€oral.€€Why€might€this€occur?€€Are€either€ofÏthese€situations€of€possible€use€in€treating€acute€poisonings?€€In€chronic€intoxications?ó óÐ 0 € ÐññÌñññ‘ñÔÿÔñ‘ññ’ñ4.€€The€paradox€of€toxic€intake€by€the€oral€route:€that€lower€dose€concentrations€(and€largerÏvolumes)€can€sometimes€be€more€toxic€than€higher€dose€concentrations€[same€amount€of€toxicantÏin€either€case,€just€different€volumes].ÌÌNote€the€volume€sensitive€sphincter€separating€the€stomach€and€the€small€intestine€which€has€aÏvery€large€absorptive€layer.€€If€the€volume€of€the€dose€is€increased€this€may€lead€to€a€fasterÏemptying€of€the€stomach,€a€lesser€time€for€the€Ô_ÔHClÔ_Ô€in€the€stomach€to€potentially€inactivate€theÏdrug€or€toxicant,€and€more€rapid€exposure€of€the€intestinal€lining€to€a€toxicant€containingÏsolution.€€In€this€situation€even€a€lower€total€dose€of€compound€may€be€more€effective€than€aÏsmall€concentrated€dose.ÌÌIs€there€a€secondary€paradox?€€What€if€dietary€insoluble€fiber€is€present€in€the€stomach€at€theÏsame€time€as€the€dose?ÌÌWhat€is€insoluble€fiber?ÌÌIt€tends€to€be€macromolecular€and€will€include€polymers€that€are€nondigestible€for€the€species€inÏquestion,€e.g.€cellulose€(in€Ô_ÔnonherbivoresÔ_Ô),€Ô_ÔhemicelluloseÔ_Ô,€pectin,€silicates,€and€some€minerals.ÌÌAn€increase€in€insoluble€fiber€will€increase€the€transit€rate€through€the€gut,€i.e.,€it€will€decreaseÏthe€time€needed€to€transit€the€gut.€€This€effect€is€often€protective€as€it€reduces€time€of€exposure€toÏa€toxicant.€€The€effect€is€also€enhanced€by€the€presence€of€clean€insoluble€fiber€as€opposed€toÏpreviously€contaminated€fiber.€€This€is€because€clean€fiber€can€efficiently€adsorb€Ô_ÔtoxicantsÔ_Ô€fromÏsolution€and€effectively€sequester€them€from€absorption€by€the€intestinal€lining.ÌÌBut€contaminated€fiber€can€also€release€Ô_ÔtoxicantsÔ_Ô€for€absorption.€€So€there€is€an€equilibriumÏbetween€Ô_ÔtoxicantsÔ_Ô€free€in€solution€and€those€Ô_ÔparticulatesÔ_Ô€or€colloids,€including€insoluble€fiber,Ïwithin€the€digestive€tract.€€Insoluble€fiber€can€act€as€a€sink€or€source€for€Ô_ÔtoxicantsÔ_Ô€depending€onÏits€prior€exposure€to€toxicant.€ñ’ññ“ñÌÔ_Ôñ“ññ”ñÔÿÔñ”ñÔ_ÔÌPosted:€Feb-13-03€at€8:58€PM€by€Erin€Valentine€€ÌÌThe€paradox€of€oral€toxicity€studies€is€that€the€absorption€of€a€substance€depends€on€a€number€ofÏvariable€factors.€Organic€acids€and€bases€are€absorbed€in€the€section€of€the€GI€tract€where€theyÏexist€in€the€nonionized€form.€The€acidic€environment€of€the€stomach€versus€the€neutralÐ ð-@), Ðenvironment€of€the€intestine€can€markedly€affect€the€ability€of€a€toxin€to€be€absorbed.€DifferencesÏin€surface€area€of€the€stomach,€small€intestine€and€large€intestine€also€influence€Ô_ÔaborbancyÔ_Ô,€largerÏsurface€areas€generally€allowing€for€more€opportunity€for€absorption.€Another€factor€is€that€aÏnumber€of€Ô_ÔtoxicantsÔ_Ô€are€Ô_ÔbiotransformedÔ_Ô€in€the€GI€tract€into€substances€with€either€increased€orÏdecreased€toxicity.€The€time€a€toxic€agent€spends€in€the€GI€tract€can€also€influence€absorption,Ïthe€longer€time€spent,€the€more€opportunity.€Here€is€where€dietary€insoluble€fiber€can€come€intoÏplay.€If€the€level€of€insoluble€fiber€is€high,€then€movement€through€the€GI€tract€is€faster,€thusÏdecreasing€the€opportunity€of€a€toxin€to€be€absorbed.€These€situations€can€be€used€to€treat€acuteÏpoisonings€by€capitalizing€on€the€absorptive€properties€of€poison.€If€the€nature€of€the€poison€isÏknown,€administrating€ions€that€prevent€the€absorption€could€be€used€as€a€treatment.€AnotherÏtactic€may€be€to€administer€a€substance€that€would€decrease€the€solubility€of€the€substance.€If€theÏpoison€cannot€be€dissolved,€it€wonððt€be€absorbed.€The€property€of€dietary€insoluble€fiber€could€beÏused€to€flush€out€the€poison€from€the€GI€tract€by€essentially€pushing€it€through€before€it€could€beÏabsorbed€at€high€enough€concentrations€to€exhibit€a€toxic€effect.ÌÌPosted:€Feb-14-03€at€10:00€PM€by€Lisa€McIntosh€€ÌÌThe€paradox€is€that€the€oral€route€of€exposure€is€probably€the€most€common€route€(e.g.,Ïaccidental€or€intentional€ingestion),€and€intuitively€seems€like€it€would€be€the€most€direct€route€toÏtoxicity,€but€toxicity€generally€will€not€occur€through€oral€exposure€until€the€toxicant€is€absorbedÏinto€the€body€(with€the€exception€of€caustic€materials).€In€principle,€this€is€not€very€different€fromÏdermal€exposures-a€chemical€would€have€to€penetrate€the€skin€and€be€absorbed€into€theÏbloodstream€in€order€for€toxicity€to€result.€Thus€if€absorption€can€be€inhibited€within€theÏgastrointestinal€(Ô_Ôg.i.Ô_Ô)€tract,€toxicity€may€be€reduced€or€eliminated.€Numerous€factors€influence€aÏtoxicantððs€absorption€in€the€Ô_Ôg.i.Ô_Ô€tract:€pH,€surface€area,€active€and€passive€transport,€Ô_ÔpinocytosisÔ_Ô,Ïetc.ÌÌRegarding€insoluble€fiber,€ingestion€of€fiber€increases€the€rate€at€which€a€bolus€is€passed€throughÏthe€gut,€thereby€reducing€the€amount€of€time€available€for€exposure,€and€by€extension,€reducingÏabsorption.€Therefore,€if€a€toxicant€is€delivered€to€the€gut€coincidentally€with€another€substanceÏthat€either€increases€Ô_Ôg.i.Ô_Ô€elimination€rates€or€inhibits€absorption€of€that€toxicant,€toxicity€will€beÏreduced.€For€acute€poisonings,€this€would€be€(and€is)€an€effective€antidote.€For€chronicÏexposures,€it€may€be€also€be€beneficial,€as€in€the€case€of€insoluble€fiber.€One€problem€that€I€canÏforesee,€however,€is€that€chronic€administration€of€certain€substances€that€may€regulateÏabsorption€of€a€toxicant€may€also€decrease€absorption€of€beneficial€compounds€(Ô_ÔOlestraÔ_Ô,Ïanyone?).ÌÌPosted:€Feb-17-03€at€7:03€PM€by€Ô_ÔIvanaÔ_Ô€Ô_ÔDjureticÔ_Ô€€ÌÌI€am€not€sure€about€other€substances€that€regulate€absorption€but€in€the€case€of€dietary€fiberÏcontinuos€exposure€is€extremely€beneficial.€In€the€diets€of€many€third€world€cultures€betweenÏ150€and€175€grams€of€fiber€is€consumed€daily€(only€30€for€US).€Accordingly,€they€are€notÏplagued€with€most€of€the€"industrialized"€disorders€which€include€colon€and€breast€cancer,€heartÏdisease,€diabetes,€arthritis,€chronic€fatigue€syndrome,€weakened€immune€systems,€personalityÏdisorders,€and€all€of€the€hormone-based€female€disorders.€€Most€experts€now€agree€that€theseÐ ð-@), Ðnondigestible€carbohydrates€promote€not€only€Ô_ÔlaxationÔ_Ô,€but€blood€cholesterol€and€glucoseÏattenuation€as€well.€The€latter€two€functions€are€promoted€by€soluble€fiber.€Soluble€fiber€reducesÏcholesterol€by€reducing€its€absorption€in€the€intestine€and€by€Ô_ÔcomplexingÔ_Ô€with€bile€acids€(madeÏfrom€cholesterol€in€the€liver)€and€preventing€their€reabsorption€(so€that€liver€must€use€Ô_ÔadditionnalÔ_ÔÏcholesterol€for€making€more€bile€acids).€Soluble€fibers€also€help€normalize€blood€glucose€levelsÏby€slowing€the€rate€at€which€food€leaves€the€stomach€and€by€delaying€the€absorption€of€glucoseÏfollowing€a€meal.€They€also€increase€insulin€sensitivity.ÌÌInsoluble€fiber,€as€mentioned€before,€helps€maintain€bowel€regularity€by€increasing€the€bulk€ofÏthe€feces€and€decreasing€the€transit€time€of€fecal€matter€through€the€intestines.€Bowel€regularityÏis€associated€with€a€decreased€risk€for€colon€cancer€and€hemorrhoids.€Additionally,€fibers€haveÏbeen€shown€to€have€a€gentle€brooming€effect€on€the€inner€walls€of€the€intestines,€performingÏwhat€might€be€called€"daily€house€cleaning."€€They€have€a€binding€effect€on€toxins€in€the€colon,Ïas€well€as€harmful€estrogen€metabolites,€excess€dietary€fat€and€cholesterol,€so€they€are€able€toÏassist€in€the€rapid€excretion€of€these€materials,€thereby€blocking€their€re-absorption€into€theÏbloodstream.€Research€has€shown€that€heavy€metals,€such€as€lead€and€mercury,€are€excretedÏharmlessly€and€much€more€efficiently€when€pectin€(a€type€of€fiber)€is€included€in€the€diet.€AppleÏpectin,€rice€bran,€wheat€bran,€alfalfa€fiber€and€burdock€root€fiber,€along€with€other€sources€ofÏdietary€fiber,€have€been€shown€to€protect€the€body,€and€especially€the€gut,€against€the€toxicÏeffects€of€several€common€food€additives,€including€amaranth,€Ô_ÔTweenÔ_Ô€60,€sodium€cyclamate,ÏÔ_ÔtartrazineÔ_Ô,€and€Sunset€Yellow.€ÌÌTaken€all€of€the€above€into€account,€chronic€exposures€to€many€toxins/Ô_ÔtoxicantsÔ_Ô€CAN€be€treatedÏby€continuous,€moderate€intake€of€fiber.€Only€large€amounts€of€fiber€taken€continuously€wereÏfound€to€partially€block€the€digestion,€absorption€or€reabsorption€of€a€wide€variety€of€drugs€andÏfat€soluble€vitamins.€Taking€twice€as€much€fiber€as€is€recommended€(~50€grams€daily)€willÏimprove€rather€than€compromise€our€health.ÌÌPosted:€Feb-17-03€at€8:57€PM€by€Lisa€McIntosh€€ÌÌI€couldn't€agree€more€in€the€case€of€insoluble€fiber-but€I€was€suggesting,€rather,€that€perhapsÏother€substances€(not€noting€any€specifically)€that€may€inhibit€uptake€of€Ô_ÔtoxicantsÔ_Ô€into€the€gi€tractÏto€treat€Ô_ÔchonicÔ_Ô€exposures€may€possibly€have€a€negative€effect€on€absorption€of€essential€nutrients.€ÏI€gave€the€example€of€Ô_ÔOlestraÔ_Ô,€a€synthetic€fat€that€is€not€absorbed€(and€therefore€is€'calorie-free').ÏHowever,€it€was€noted€that€certain€nutrients€were€also€not€absorbed.€€In€the€long-term,€reducedÏabsorption€of€essential€nutrients€will€be€detrimental€to€an€organism's€health.ÌÌPosted:€Feb-19-03€at€11:59€PM€by€Ô_ÔIvanaÔ_Ô€Ô_ÔDjureticÔ_Ô€€ÌÌReferences€for€the€above€question€were:ÌÌÔ4‚ Ý °ÔÝ‚ ÍOÝÔÿÔòòÝ  ÝÔ5  Ôhttp://www.health-science.com/index.htm?page=/fiber.htmlÔ6î„ÔÝ‚ ÍO…ƒÝóóÔÿÔÝ  ÝÔ7Ý `0…ÔÐ  +p&) ÐandÌÔ4‚Ý °ÔÝ‚ ÍOÝÔÿÔòòÝ  ÝÔ5  Ôhttp://www.springboard4health.com/notebook/nutrients_fiber.htmlÔ6ä…ÔÝ‚ ÍOø…ƒÝóóÔÿÔÝ  ÝÔ7Ý ”&†ÔÐ -P(+ ÐÐ ð-@), ÐPosted:€Feb-15-03€at€8:06€PM€by€Ô_ÔHanaeÔ_Ô€Ô_ÔHiyoshiÔ_Ô€€ÌÌOral€toxicity€may€involve€Ô_ÔtransmucosalÔ_Ô€absorption€and€also€chemical€modification€in€theÏstomach€acid,€which€degrades€and€hydrolyze€the€compound€to€make€it€easily€degraded€orÏabsorbed.€The€paradox€is€that€the€body€of€animals,€including€humans,€does€not€really€resist€toxicÏmaterials€until€they€enter€into€the€bloodstream.€Most€of€animals€have€ð ðoral€toleranceððð"ðtheÐ ` ° Ðimmune€system€of€the€animals€does€not€recognize€potential€Ô_ÔimmunogensÔ_Ô€if€they€are€exposedÏorally€in€their€childhood.€Through€an€oral€route€those€organisms€invade€the€animalððs€intestinalÏtract€and€grow€inside€white€blood€cells€without€being€killed.ÌÌInsoluble€fiber,€such€as€cellulose,€Ô_ÔhomicelluloseÔ_Ô€and€Ô_ÔlegninÔ_Ô,€can€be€found€in€food€like€wheat€branÏand€is€useful€in€weight€control€because€it€gives€us€a€fullness€feeling.€It€is€not€broken€down€byÏdigestive€enzymes€and€could€be€useful€for€treating€acute€poisoning€because€it€slows€digestion,Ïreduces€metal€absorption,€and€speeds€up€bowel€elimination€processes.€Intoxication€occurs€whenÏwaste€in€the€bowel€is€trapped€for€a€longer€while,€causing€toxins€to€go€back€into€the€colon.€TheÏtoxins€then€eventually€go€into€the€bloodstream€through€the€blood€capillaries€along€the€bowel€wallÏand€harm€other€organs€and€cells.€Insoluble€fiber€can€help€foods€keep€moving€the€digestive€tract,Ïreducing€potential€carcinogens€in€the€colon.€Ì€€€ÌPosted:€Feb-17-03€at€7:17€PM€by€Ô_ÔIvanaÔ_Ô€Ô_ÔDjureticÔ_Ô€€ÌÌOther€answers€have€described€in€detail€the€paradox€of€the€oral€toxicity€and€pointed€at€intestine€asÏthe€main€site€for€entry€of€Ô_ÔxenobioticsÔ_Ô.€€Under€normal€conditions,€Ô_ÔxenobioticsÔ_Ô€are€poorly€absorbedÏwithin€the€mouth€and€esophagus,€due€mainly€to€the€very€short€time€that€a€substance€residesÏwithin€these€parts€of€the€GI€tract.€€There€are€some€exceptions€though.€Nicotine€readily€penetratesÏthe€mouth€mucosa€and€nitroglycerin€is€placed€under€the€tongue€for€immediate€absorption€andÏtreatment€of€heart€conditions.€€The€sublingual€mucosa€under€the€tongue€and€in€some€other€areasÏof€the€mouth€is€thin€and€highly€vascularized€so€that€some€substances€will€be€rapidly€absorbed.ÏVery€little€absorption€takes€place€in€the€colon€and€rectum.€€As€a€general€rule,€if€a€Ô_ÔxenobioticÔ_Ô€hasÏnot€been€absorbed€after€passing€through€the€stomach€or€small€intestine,€very€little€furtherÏabsorption€will€occur.€€However,€there€are€some€exceptions,€as€some€medicines€may€beÏadministered€as€rectal€suppositories€with€significant€absorption.€€An€example,€Ô_ÔAnusolÔ_Ô€is€used€forÏtreatment€of€local€inflammation€which€is€partially€absorbed€(about€25%).€Reference:ÏÔ4‚Ý °ÔÝ‚ ÍOÝÔÿÔòòÝ  ÝÔ5  Ôhttp://www.sis.nlm.nih.gov/ToxTutor/Tox2/a22.htmÔ6–’ÔÝ‚ ÍOª’ƒÝóóÔÿÔÝ  ÝÔ7Ý Ø’ÔÐ  #ð! ÐÌPosted:€Feb-18-03€at€9:56€PM€by€Ô_ÔDINAÔ_Ô€KATZ€€ÌÌA€paradox€in€the€po€route€of€exposure€lies€in€the€fact€that€a€chemical€passes€through€severalÏenvironments€(the€mouth,€esophagus,€stomach,€small,€then€large€intestine,€rectum),€most€ofÏwhich€are€lined€with€Ô_ÔmucosalÔ_Ô€layers€and€are€functionally€geared€to€eliminate€the€contents.€TheÏstomach€and€small€intestine€also€radically€change€the€pH€of€their€contents,€likely€Ô_ÔbiotransformingÔ_ÔÏthe€initial€toxicant.€Thus,€most€poisons€do€not€do€much€damage€in€the€alimentary€canal,€but€onlyÏonce€they€are€absorbed€from€there€into€the€bloodstream,€even€if€they€are€broad€cellularÏmechanism€Ô_ÔdisruptorsÔ_Ô€such€as€cyanide,€which€blocks€the€final€step€in€the€electron€transport€chainÏin€aerobic€respiration.€Insoluble€fiber€promotes€a€speedy€passage€through€the€intestines€and€has,Ð ð-@), Ðas€someone€mentioned,€a€"gentle€brushing€effect"€on€the€walls,€thereby€removing€Ô_ÔmucosalÔ_Ô€cellsÏthat€already€contain€the€poison€and€would€allow€it€to€diffuse€deeper€and€closer€to€theÏbloodstream.€Though€one€might€intuitively€think€that€fiber€"stops€up"€the€flow€as€it€does€in€aÏsink,€it€in€fact€promotes€elimination.€The€faster€the€flow,€the€less€material€will€get€absorbed€in€theÏalimentary€lining.ÌÌThis€idea€has€an€obvious€application€in€acute€poisoning€cases:€after€such€an€event,€a€good€quickÏtreatment€might€be€a€fast-acting€laxative,€such€as€syrup€of€ipecac.€Vomiting€may€or€may€not€be€aÏgood€idea;€although€elimination€from€the€body€might€be€faster,€the€ingested€contents€may€noÏlonger€be€in€the€stomach,€and€the€esophagus€does€not€have€much€lining,€so€it€may€be€damaged€byÏa€corrosive€poison€twice€(up€and€down).€Drinking€large€amounts€of€water€would€probably€not€beÏa€good€idea,€since€water€is€mostly€not€eliminated€through€the€bowels,€but€enters€circulation€andÏgoes€through€the€liver€and€kidneys€at€the€very€least.€I€don't€see€how€it€can€help€clear€the€GI€tract,Ïbut€I€could€be€wrong.€Anyone?ÌÌIn€chronic€(6€months€to€2€years)€intoxication€cases,€the€technique€is€not€likely€to€help.€I€supposeÏit's€possible€that€if€the€poison€is€extremely€slow€to€absorb,€intake€of€insoluble€fiber€would€helpÏclear€the€outer€Ô_ÔmucosalÔ_Ô€layers€where€much€of€the€toxicant€would€still€linger.€ÌÌò òOldÐ €Ð ÐÌó óAllison:Ð `° ÐFebruary€28,€2002Ì6.€One€of€the€main€sites€of€absorption€is€the€GI€tract.€Many€environmental€Ô_ÔtoxicantsÔ_Ô€enter€theÏfood€chain€and€are€absorbed€together€with€food€from€the€GI€tract.€Unless€a€noxious€agent€hasÏcaustic€or€irritating€properties,€poisons€in€the€GI€tract€usually€do€not€produce€systemic€injury€toÏan€individual€until€they€are€absorbed.€Absorptions€of€Ô_ÔtoxicantsÔ_Ô€can€take€place€along€the€entire€GIÏtract,€even€mouth€and€rectum.€There€are€factors€though€that€alter€the€GI€absorption€of€Ô_ÔtoxicantsÔ_ÔÏand€serve€as€a€paradox€in€these€studies.€The€mass€action€law,€surface€area,€and€blood€flow€rateÏhave€to€be€taken€into€consideration.€Some€studies€have€shown€that€oral€toxicity€of€someÏÔ_Ôchemicals€is€increased€by€diluting€the€dose.€This€can€be€explained€by€more€rapid€stomachÏemptying€induced€by€increased€dosage€volume,€which€in€turn€leads€to€more€rapid€absorption€inÏthe€duodenum€because€of€the€larger€surface€€area€there.€There€is€also€a€species-dependentÏabsorption€different€of€toxicants€due€to€the€gastrointestinal€flora.€It€dietary€insoluble€fiber€isÌhigh€and€exposure€to€a€toxicant€is€oral,€some€of€the€smae€problems€might€arise.€The€toxicant€mayÏnot€produce€any€deleterious€effets€until€once€it€has€absorbed€into€blood€at€the€time€of€elimination.ÏAcute€poisonings€might€be€treated€by€this€situation€if€the€insoluble€fiber€can€absorb€the€toxicantÏand€prevent€absorption€into€the€bloodstream€during€elimination.€Chronic€intoxications€might€beÏmore€difficult€to€treat€because€continuous€exposure€to€the€toxicant€will€ultimately€be€hazardousÏto€the€liver€and€be€unable€to€be€eliminated€before€deleterious€effects€take€place.ÌÌNeetu:ÌFebruary€28,€2002Ì6.€The€paradox€is€the€change€in€level€of€toxicantððs€absorption€into€the€blood€stream€and€theÌinterference€of€toxicant€with€other€minerals€(if€talking€about€insoluble€fibers).€The€toxins€thatÐ ð-@), Ðpass€through€the€GI€tract€(main€path€taken€when€dealing€with€oral€toxicity),€do€not€cause€anyÏtoxicity€until€they€are€absorbed€into€the€blood€stream,€which€might€take€some€time.€A€somewhatÏsimilar€paradox€can€arise€if€dietary€insoluble€fiber€is€high€and€exposure€is€oral.€Insoluble€dietaryÏfibers€include€cellulose,€hemi-cellulose€etc.€It€is€mostly€found€in€whole€grain€products€such€asÏwheat€bread€and€is€known€to€induce€bowel€movement.€Insoluble€fibers€speed€up€the€passage€ofÏfood€via€the€GI€tract,€promote€bowel€movement,€slow€down€the€breakdown€of€starch€and€delayÏthe€absorption€of€glucose.€Fiber€is€not€toxic;€it€can€however,€interfere€with€other€mineralÏabsorption,€if€the€intake€go€above€the€recommended€level€(20-35€g/day).€TOO€much€fiber€intakeÏcan€also€result€in€too€much€calories€intake€and€therefore,€can€cause€intestinal€discomfort€andÏexcess€gas€formation€Ì(Ô4‚Ý òÔÝ‚ ÍOÝÔÿÔòòÝ  ÝÔ5  Ôhttp://www.solae.com/NASAPP/solae/soy€nutrition/nutrition€basics/necessarynutrients/noÐ `  Ðnutrients.jspÔ6D¨ÔÝ‚ ÍOX¨ƒÝóóÔÿÔÝ  ÝÔ7Ý ˆ†¨Ô).€The€acute€poisoning€can€be€treated€because€the€exposure€of€the€toxicant€is€for€aÐ P  Ðshort€period€of€time€and€the€toxicant€might€not€be€absorbed€by€the€blood€stream€just€yet.€But€theÏchronic€poisoning€might€be€hard€to€treat€because€of€the€longer€exposure€time€and€the€toxicantÏwill€be€able€to€absorb€into€the€blood€stream€and€cause€deleterious€Ô_Ôeffects.ÌÌJoanne:ÌFebruary€28,€2002Ì6)€A€paradox€in€the€oral€route€of€exposure€is€that€of€€the€alimentary€canal.€It€is€the€route€thatÏserves€both€digestion€and€respirationð8ðthat€in€and€of€itself€is€a€blatant€paradox.€In€terms€ofÐ €Ð Ðtoxicity€however,€the€coupling€of€food€which€is€required€for€maintenance€and€sustenance€of€theÏorganism,€may€also€be€threatened€by€inadvertently€€Ô_ÔintakingÔ_Ô€toxins/Ô_ÔtoxicantsÔ_Ô€into€the€GI€tract.€ÏMany€environmental€Ô_ÔtoxicantsÔ_Ô€enter€the€food€chain€and€are€absorbed€with€food€from€the€GI€tractÏ(€C€&€D€page€111).€Although€the€GI€tract€is€within€the€body,€its€content€may€be€consideredÏð ðexteriorðð€to€the€body€thereby€not€typically€producing€injury€following€the€entrance€of€noxiousÏagents€until€they€are€actually€absorbed.€€Absorption€can€take€place€ð ðanywhereðð€along€the€GI€tractÏ(Ô_ÔieÔ_Ô€mouth€to€rectum)€depending€on€the€chemical€composition€of€the€€toxic€agent€in€question.ÌFor€example,€if€it€is€an€organic€acid/base,€it€is€usually€absorbed€by€simple€diffusion€at€the€pointÌwhere€it€manifests€its€most€nonionized€form.€An€additional€paradox€exists€when€thinking€aboutÌdigestion/respiration€as€routes€of€oral€entry.€For€the€absorption€of€toxic€gases€in€the€lungs€differsÏfrom€intestinal€and€Ô_ÔpercutaneousÔ_Ô€absorption€of€compounds€in€that€dissociation€of€acids€and€basesÏand€the€lipid€solubility€of€molecules€are€less€important€factors€in€pulmonary€absorption€becauseÏdiffusion€through€cell€membranes€is€not€the€rate€limiting€step€as€it€was€in€the€GI€tract€(€C€&€DÏ115).ÌÌDifferent€species€have€different€types€of€digestive€systems.€Some€are€more€capable/efficient€atÏbreaking€down€food€products€than€others.€Others€may€be€less€efficient€and€less€capable€ofÏbreaking€down€certain€food€products.€Those€with€efficient€systems€may€quickly€rid€themselves€ofÏa€food€product€while€others€may€store€these€products€in€their€less€than€optimal€systems.ÌÌWith€respect€to€question€#6€and€the€case€of€insoluble€fiber:ÌÌWith€the€increase€of€insoluble€Ô_Ôfiber,aÔ_Ô€decrease€in€gut€transit€time€would€be€expected€becauseÏfiber€is€able€to€bind€to€steroid€compounds€in€the€lumen€facilitating€their€excretion.€The€decreaseÏin€gut€transit€time€would€seem€to€lessen€Ô_ÔintenstinalÔ_Ô€absorption€of€compounds€in€the€gut.€SuchÐ ð-@), Ðreduced€absorption,€limits€the€availability€of€a€compound€to€travel€through€Ô_ÔenteroheptaicÔ_ÔÏcirculation€and€results€in€the€increase€of€the€original€compound€deposited€in€solid€waste€productsÏand€decreases€the€amount€in€urine€and€infiltrating€metabolites.€Because€less€of€the€Ô_ÔxenobioticÔ_ÔÏcompound€is€traveling€through€Ô_ÔenterohepaticÔ_Ô€circulation,€less€hepatic€filtering€may€contribute€toÌa€reduction€in€the€polarity€of€metabolites€excreted.€€By€tracking€such€Ô_ÔsteroidalÔ_Ô€components€mayÏprove€to€be€beneficial€markers€in€tracking€carcinogenic€properties.€Whether€acute€or€chronicÏdepends€on€the€individual€digestive€system€and€the€alteration€of€the€ingested€compound€inÏquestion.€For€instance€some€fibers€contain€estrogenic€or€anti-estrogenic€effects..Consumption€ofÏcertain€fiber€substances€may€reduce€the€risk€in€developing€certain€types€of€cancers€by€reducingÏthe€risk€of€tumor€growth€which€is€often€fostered€by€steroid€compounds.ÌÌÌÌÌÌÌÌÌÌÌÌÌÌÌÌÌÌÌÌÌTopic:€Question€Set€3.€Question€4.€€Time,€dose,€shielding.€Ì€€ÌSubject:€Question€Set€3.€Question€4.€€Time,€dose,€shielding.€€€Posted:€Mar-07-02€at€3:15€AM€byÏKenneth€Campbell€€ÌÌò ò4.€In€radiation€protection€there€are€three€cardinal€rules€for€minimizing€radiation€exposure:Ð €%Ð # ÐÌ€€€1.€€€€€minimize€time€of€exposure€to€the€sourceÌ€€€2.€€€€€maximize€distance€from€the€source€to€minimize€dose€deliveredÌ€€€3.€€€€€optimize€the€amount€and€type€of€shielding€used€to€minimize€dose€delivered.ÌÌCan€these€be€translated€into€considerations€in€toxicant€exposure?€€What€are€the€analogs€ofÏtime,€dose,€and€shielding€for€chemical€exposures?€€Are€there€any€differences€among€routesÏof€exposure€or€nature€of€toxicant€that€need€to€be€considered?€ó óñ•ñÐ -P(+ ÐÐ ð-@), ÐÔ_Ôñ•ññ–ñÔÿÔñ–ññ—ñSuch€questions€raise€the€points€of€health€concerns€during€radioisotope€use,€i.e.,€radiation€healthÏphysics€(RHP)€concerns.€€RHP€is€concerned€with€minimizing€the€exposure€of€subjects€to€theÏelectromagnetic€and€particulate€emissions€from€radiation€sources.€€Note€that€both€of€these€typesÏof€radiation€primarily€impact€targets€or€subjects€by€delivering€energy:€in€the€case€of€x-raysÏ(arising€from€electron€transitions€in€decaying€radioisotopes,€often€a€fall€from€a€high€energy€outerÏorbital€into€a€low€energy€inner€orbital€accompanied€by€the€release€of€a€corresponding€photon€ofÏhigh€energy€electromagnetic€radiation)€or€gamma€rays€(arising€from€transitions€within€theÏunstable€nucleus,€e.g.,€conversion€of€a€neutron€to€a€proton€and€a€beta€particle€(energetic€electron)Ïoften€with€the€loss€of€a€photon€of€high€energy€electromagnetic€radiation)€the€energy€delivered€isÏin€the€form€of€high€energy€photons€that€can€cause€chemical€bond€alterations€including€breakageÏand/or€molecular€motions€disruptive€of€normal€molecular€function€(e.g.,€in€biological€systems).€ÏParticulate€emissions€like€beta€particles,€positrons€(positively€charged€electrons),€alpha€particlesÏ(2€neutrons€+€2€protons),€or€neutrons€can€impart€kinetic€energy€to€target€molecules€causing€eitherÏmovement€or€bond€disruptions.€€If€particle€bombardment€is€intense€enough,€the€larger€particlesÏlike€alphas€or€neutrons,€especially,€can€also€cause€nuclear€alterations€that€can€generate€secondaryÏradioactive€atoms,€e.g.,€chlorine.€€Thus,€in€either€case€energy€is€being€imparted€to€the€target€andÏmay€result€in€alterations,€some€deleterious,€to€the€target.€€Particles,€however,€in€colliding€orÏglancing€off€the€electron€shells€of€the€atoms€of€the€target,€rapidly€lose€energy€and,€with€theÏexception€of€the€neutron,€do€not€penetrate€efficiently€within€a€target€medium.€€Neutrons€canÏpenetrate€because€they€lack€a€net€charge,€they€have€no€intrinsic€tendency€to€approach€or€beÏrepelled€by€the€electrons,€or€protons,€of€target€molecules,€they€are€unaffected€by€the€atomicÏmagnetic€fields€and€do€not€affect€those€particles€or€fields€unless€they€undergo€a€direct€collisionÏwith€a€nucleus€or€electron.€€(Photons€penetrate€better€than€charged€particles€but€have€an€intrinsicÏelectronic€and€magnetic€character€that€causes€them€to€interact€with€electrons€and€atomic€magneticÏfields;€when€the€allowed€energy€transition€levels€of€target€molecules€match€those€of€the€photonÏmoving€through€the€target€medium,€those€photons€are€efficiently€absorbed.)ÌÌRecapping€the€electromagnetic€spectrum:€long€wavelengths€mean€fewer€photons€per€unit€timeÏthrough€a€linear€distance,€lower€frequency,€lower€energy€(wavelength€is€inversely€proportional€toÏfrequency.€€Radiowaves€with€wavelengths€of€>um€(up€to€m€or€km)€occupy€the€long€end€of€theÏspectrum,€followed€by€microwaves€(um€lengths),€infrared€(IR,€heat,€~800€nm€-€a€few€um),€visibleÏ(300-800€nm),€ultraviolet€(UV,€10's-300€nm),€x-€and€gamma-rays€(angstrom€-€nm),€cosmic€rays,Ïand€intranuclear€forces€(atomic/subatomic€dimensions).ÌÌNote€that€since€radiation€is€propagated€from€the€source€in€all€directions€the€flux€of€that€radiationÏacross€any€plane€placed€near€the€source€will€be€inversely€proportional€to€the€square€of€theÏdistance€from€the€source€(distribution€in€two€dimensions,€not€just€one).€€Thus,€several€of€the€rulesÏof€RHP€have€to€do€with€maximizing€the€distance€or€effective€distance€from€the€source.€ÌÌThe€three€cardinal€rules€of€RHP€are:ÌÌ1.€Minimize€time€of€exposureÌÌ2.€Maximize€distance€from€sourceÌÔ_ÔÐ ð-@), Ð3.€Optimize€shielding€(protective€clothes,€gloves,€shields,€behaviors)ÌÌNote€that€3.€is€actually€a€variant€of€2.€in€that€it€addresses€"effective"€distance€from€the€source.€ÏThus,€if€a€radiation€absorbing€shield€is€interposed€between€the€source€and€the€subject,€we€areÏessentially€increasing€the€effective€distance€between€the€source€and€the€subject.€€Note€also€theÏindication€of€optimizing€shielding.€€Although€it€might€be€intuitive€to€use€a€high€density€shieldÏwhich€normally€corresponds€to€a€shield€made€of€a€material€of€high€atomic€number,€we€should€beÏaware€that€such€materials€provide€larger€atomic€targets€for€some€forms€of€radiation,€particularlyÏhighly€energetic€particles.€€When€such€highly€energetic€particles,€e.g.,€the€beta€particle€from€32PÏdecay,€encounter€large€atoms€(e.g.,€in€lead€or€leaded€glass€shields)€they€often€cause€electronÏorbital€alterations€that€result€in€the€production€of€secondary€particle€(Compton€electrons)€or€x-rayÏemission€(Ô_ÔBremstrallungÔ_Ô).€€As€the€electromagnetic€radiation€is€more€penetrating€than€mostÏparticles,€the€secondary€emissions€may€prove€more€damaging€than€the€primary€radiation.€€Thus,Ïin€such€cases,€low€to€moderate€sized€atomic€nuclei€are€used€to€build€composites€that€can€then€beÏused€as€effective€shielding,€e.g.,€high€density€plastic€(carbon/oxygen/hydrogen)€or€aluminum.€ÌÌNow€note€that€these€same€rules€for€limiting€radiation€exposure€have€close€or€exact€analogs€inÏrules€to€limit€chemical€or€toxicant€exposures:ÌÌ1.€Minimize€time€of€exposure.€€(This€limits€the€dose€and/or€the€time€for€the€toxicant€to€bind€to€itsÏtarget€molecules€or€to€act€on€its€target€molecules.)ÌÌ2.€Maximize€distance€from€source.€(This€minimizes€the€dose€or€encountered€concentration.)ÌÌ3.€Optimize€shielding.€€(This€limits€the€routes€of€exposure€and/or€optimizes€the€actions€ofÏendogenous€barriers,€e.g.,€the€immune€system€--€vaccines,€or€repair€processes.)€ÌÔ_Ôñ—ññšññ—ñClose€the€folder€Session€11.€Ô_ÔPharmacokineticsÔ_Ô.€Folderñ—ññ˜ñÌñ˜ññšññ˜ñÔ_ÔÔ_Ôñ˜ññšññ˜ñÌñ˜ññšññ™ñÔÿÔñ™ñÔ_ÔÔ_ÔñšñÌñšñÔ_ÔÌPosted:€Feb-12-03€at€12:12€PM€by€Erin€Valentine€€€ÌÌ4.€These€three€cardinal€rules€can€definitely€be€translated€into€considerations€in€toxicant€exposure.ÏThe€analog€of€time€in€chemical€exposure€is€the€duration€and€frequency€of€exposure.€This€includesÏthe€concepts€of€acute,€Ô_ÔsubchronicÔ_Ô€and€chronic€exposure.€The€analog€of€dose€is€the€applied€amountÏof€the€toxic€agent€(mg€agent/€kg€test€subject)€that€an€individual€is€exposed€to€or€more€specificallyÏthe€concentration€of€the€agent€at€the€target€site.€The€analogs€for€shielding€for€chemical€exposureÏinclude€mechanisms€for€preventing€absorption,€Ô_ÔpresystematicÔ_Ô€elimination€by€Ô_ÔbiotransformationÔ_Ô€atÏexposure€sites€(lungs,€stomach,€skin),€and€prevention€of€agentððs€function€through€inhibitoryÏbinding.€Shielding€could€also€come€in€the€form€of€protective€gear€specific€to€the€route€ofÏexposure€for€the€particular€toxicant.€The€nature€of€the€toxicant€needs€to€be€considered€if€the€effectÏof€the€toxicant€is€increased€by€certain€conditions.€If€the€delivery€of€the€toxicant€were€facilitatedÏwithin€the€system,€then€the€dosage€amounts€would€be€increased.€Also€if€the€toxicant€were€held€inÏan€inactive€state€after€exposure€until€particular€conditions€released€it,€then€the€timing€of€exposureÏwould€also€be€altered.ÌÌPosted:€Feb-13-03€at€6:53€PM€by€Ô_ÔIvanaÔ_Ô€Ô_ÔDjureticÔ_Ô€€ÌÐ ð-@), ÐDepending€on€the€route€of€exposure€biological€responses€to€a€toxicant€will€differ/its€toxicityÏchanges.€A€chemical€may€be€severely€toxic€by€inhalation€but€not€toxic€by€oral€or€dermalÏexposure.€Differences€in€toxicity€arise€due€to€several€factors:ÌÌ-Rate€of€absorption-€this€will€depend€on€the€nature€of€the€toxicant.€Main€sites€of€absorption€areÏGI€tract,€lungs,€and€skin.€Lungs€are€generally€more€penetrable€for€volatile€compounds€such€asÏgases,€vapors€and€aerosols.€Skin€is€impermeable€to€many€chemicals€but€not€to€nerve€gases,Ïcarbon€tetrachloride€etc.€GI€tract€absorbs€a€range€of€Ô_Ômolecules:lipophilicÔ_Ô€molecules€by€simpleÏÔ_ÔdifffusionÔ_Ô€and€hydrophilic€molecules€by€active€transport€or€by€passing€through€aqueous€pores€atÏthe€tight€junctions.€€ÌÌ-Availability€of€sites-€because€of€a€large€surface€area€(size€of€a€tennis€court€)€lungs€are€generallyÏthe€most€available€site€of€adsorption)ÌÌ-Presence€of€Ô_ÔdegradativeÔ_Ô€enzymes-liver€detoxifies€many€chemicals€so€LD50€for€a€given€toxicantÏdecreases€if€given€via€portal€circulation€(goes€to€liver)€than€via€inhalation€(systemic€circulation).ÏÔ_ÔDegradativeÔ_Ô€enzymes€are€also€present€in€stomach€and€intestine.€For€instance€snake€venom€isÏmuch€less€toxic€if€given€orally€rather€than€IV€because€it€is€broken€down€by€digestive€enzymes€inÏthe€GI€tract.ÌÌ-Extreme€conditions-€newborns€have€a€higher€pH€in€their€GI€tract€which€allows€for€conversion€ofÏnitrates€to€nitrites€and€leads€to€a€condition€called€Ô_ÔmethemoglobinemiaÔ_Ô€(defect€in€oxygenÏtransport)ÌÌ-Rate€of€transit€through€the€body-€the€slower€the€movements€of€the€GI€tract€the€more€absorption.Ð ð-@), ЇPosted:€Feb-13-03€at€10:40€PM€by€Lisa€McIntosh€€Ì‡In€terms€of€toxicant€exposure,€these€same€three€rules€likewise€hold:ÌÌ€€€€€€€€€1.€Minimize€the€time€of€exposure€to€the€source.€If€you€reduce€your€exposure€frequency€andÏduration,€you€reduce€your€risk€of€harm.Ì€€€€€€€€€2.€Maximize€the€distance€from€the€source€to€minimize€the€dose€delivered.€In€other€words,Ïavoid€exposure,€if€possible.€No€exposure€is€equivalent€to€no€toxicity.Ì€€€€€€€€€3.€Optimize€the€amount€and€type€of€shielding€used€to€minimize€dose€delivered.€We€canÏreduce€exposures€further€by€wearing€protective€equipment€(e.g.,€gloves,€respirators,€goggles)€orÏby€other€measures€such€as€washing€exposed€surfaces€following€contact.€ÌÌWhen€working€with€radioactive€materials,€dermal€penetration€of€rays€is€probably€one€of€theÏgreater€concerns;€however,€a€radioactive€compound,€as€with€any€compound,€can€enter€the€bodyÏthrough€various€routes€of€exposure-ingestion,€inhalation,€via€injection,€etc.ÌÌPosted:€Feb-15-03€at€4:14€PM€by€ERIC€FAULKNER€€ÌÌAs€ionizing€radiation€passes€through€a€substance€it€will€lose€energy,€due€to€the€fact€it€produces€anÏelectron€and€a€positively€charged€atom€residue.€€When€humans€are€exposed€to€radiation€forÏcertain€periods€of€time,€DNA€synthesis€becomes€disrupted€as€the€radiation€breaks€apart€theÏprecursors€of€DNA€replication€(Ô_ÔpurinesÔ_Ô€and€Ô_ÔpyrimidinesÔ_Ô€molecules).€€The€following€cardinalÏrules€for€minimizing€exposure€to€radiation€can€be€translated€into€considerations€to€toxic€exposureÏbecause€they€somewhat€pertain€to€an€individual€dose€response€curve€(1)€Deficiency€and€ToxicityÏwill€occurs€with€no€protection€from€the€radiation€source€and€(2)€Region€of€Homeostasis€willÏoccur€with€protection€form€the€radiation€source.€ÌÌThe€analogies€or€similarities€that€exist€would€be€time€is€to€the€frequency€of€exposure€to€radiation,Ïthe€dose€would€be€considered€the€intensity€(delivered€dose)€of€the€radiant€rays€from€the€distanceÏyou€stood€from€the€energy€source€(closer€you€are€the€greater€the€intensity),€and€shieldingÏexposures€would€be€the€protective€garments€worn€to€protect€the€skin€and€mucosa€from€absorptionÏand€distribution€to€the€target€site€(DNA).€€Differences€need€to€be€consider€among€the€nature€ofÏthe€toxicant€rather€than€the€routes€of€exposure.€€There€are€four€main€types€of€radiation,€due€to;Ïalpha€particles,€electrons,€gamma€rays,€and€X-rays€(Ô_ÔKlassenÔ_Ô).€€While€the€frequency€and€dose€ofÏradiation€given€to€take€pictures€of€teeth€and€broken€bones€is€suitable€to€patients€for€X-rays,€itÏwould€be€Ô_ÔdeterminantalÔ_Ô€to€patients€if€gamma€rays€were€used.€€ÌÌPosted:€Feb-16-03€at€3:37€PM€by€Ô_ÔDINAÔ_Ô€KATZ€€ÌÌThe€radiation€exposure€rules€can€definitely€be€translated€into€toxicant€exposure€rules.€ForÏchemical€exposure,€time€of€radiation€exposure€is€analogous€Ô_ÔtobÔ_Ô€the€amount€of€chemical€one€isÏbeing€exposed€to,€since€the€more€time€one€spends€exposed€to€radiation,€the€more€particles€haveÏthe€potential€to€hit€the€body.€The€dose€is€analogous€to€the€toxicity€of€the€chemical,€the€relativeÏspeed€and€amount€of€damage€done€at€target€sites,€or€possibly€route€of€exposure,€since€that€willÏcontrol€how€much€of€the€chemical€will€get€inside€the€body.€Shielding€can€be€compared€to€eitherÏthe€effectiveness€of€detoxification€processes€in€the€body€or€the€physical€barriers€preventing€theÏtoxicant€reaching€the€target€site.Ð ð-@), ЇSince€toxins€and€Ô_ÔtoxicantsÔ_Ô€are€so€different€from€each€other€in€their€mechanisms€of€toxicity,€anyÏof€the€three€above€variables€may€be€the€crucial€step€in€preventing€the€most€damage.€For€example,Ïfor€highly€toxic€materials€that€do€not€easily€detoxify€in€the€body,€'shielding'€takes€on€a€muchÏgreater€importance.€For€chemicals€of€relatively€low€toxicity,€limiting€the€'time'€or€concentrationÏfactor€may€prevent€major€damage.ÌÌPosted:€Feb-16-03€at€5:02€PM€by€Michael€George€€ÌÌYes,€these€can€be€translated€into€consideration€in€toxicant€exposure.ÌÌ1.)€€€€Minimize€time€of€exposure€to€the€source-if€you€can€reduce€the€amount€of€time€you€areÏexposed€to€a€toxicant€you€can€possibly€avoid€toxicant€effects€since€your€body€may€be€able€toÏeliminate€the€toxicant€in€small€doses.ÌÌ2.)€€€€Maximize€distance€from€source,€if€you€can€avoid€the€toxicant€than€no€toxic€effect€will€beÏproduced.ÌÌ3.)€€€€Optimize€the€amount€of€shielding€to€minimize€dose-using€goggles,€face€masks,€gloves,€etc.Ïcan€minimize€the€amount€of€toxicant€received.€ÌÌYes€there€are€differences€among€routes€of€exposure€or€the€nature€of€the€toxicant€that€need€to€beÏconsidered.€€In€radiation€there€are€basically€just€one€way€of€exposure,€via€x-ray€exposure€throughÏthe€skin.€€In€toxicant€exposure€there€are€a€number€of€different€routes€that€need€to€be€considered,ÏÔ_ÔieÔ_Ô.€Subcutaneous,€intravenous,€inhalation,€etc.€€Ô_ÔToxicantsÔ_Ô€can€be€a€Ô_ÔaÔ_Ô€number€of€different€formsÏalso,€Ô_ÔieÔ_Ô€solid,€powder,€liquid,€gas.€€ÌÌò òOldÐ ` ÐÌó óPosted:€Mar-11-02€at€12:07€PM€by€Ô_ÔallisonÔ_Ô€gold€€Ð ð@ ÐÌThe€three€cardinal€rules€for€minimizing€radiation€exposure€can€be€translated€in€toxicant€exposure.ÏMinimization€of€time€for€toxicant€exposure€reduces€the€time€available€to€act€on€the€toxicant'sÏtargets€and€Ô_ÔprimiaryÔ_Ô€molecules.€The€ability€of€the€toxicant€to€bind€and€act€on€targets€is€minimizedÏby€minimizing€time,€as€in€radiation€exposure€as€well.€Maximizing€distance€of€a€toxicant€relates€toÏdose/potency/concentration.€By€maximizing€distance€from€source€of€toxicant€theÏdose/potency/concentration€are€minimized.€Intensity€of€toxicant€is€inversely€proportional€to€theÏdistance€squared.€Ô_ÔToxicantsÔ_Ô€can€be€minimized€by€optimizing€Ô_ÔsheildingÔ_Ô.€This€includes€limiting€theÏroutes€of€exposure€available€to€the€toxicant.€Vaccines€may€also€act€as€an€internal€shield,€whichÏwill€optimize€endogenous€barriers€or€repair€processes€(Campbell,€Lecture€3/7/02).ÌÌPosted:€Mar-11-02€at€2:32€PM€by€Kenneth€Campbell€€ÌÌPlease€elaborate€on€your€last€comments.ÌÌPosted:€Mar-14-02€at€6:19€AM€by€Ô_ÔjoanneÔ_Ô€Ô_ÔvannahÔ_Ô€€Ð ð-@), ЇAnalogs€in€chemical€exposure:ÌÌ1)€(minimizing€time)€Decrease€in€time€allotted€for€binding€on€targets,€we€had€recently€discussedÏthe€GI€tract€and€how€toxic€effects€occur€only€after€they€are€absorbed,€by€limiting€the€time€factor,Ïone€decreases€the€degree€of€absorption,€thereby€lessening€the€toxicity€effect.ÌÌ2)(maximizing€distance)€Since€the€intensity€of€the€toxicant€is€inversely€proportional€to€theÏdistance€squared.€The€increase€in€distance€of€the€toxicant€from€its€target€cell€will€certainly€have€aÏcompromised€effect€in€terms€of€potency€and€concentration.ÌÌ3)(shielding)€This€may€be€accomplished€by€limiting€the€amount/dose,€limiting€the€exposureÏroutes,€dilution€may€be€helpful€in€some€cases€and€interaction€with€other€chemicals€may€decreaseÏthe€effect.ÌÌPosted:€Mar-11-02€at€12:10€PM€by€Ô_ÔallisonÔ_Ô€gold€€ÌÌ(Ô_Ôcon'tÔ_Ô)ÌÌThere€are€also€differences€among€route€of€exposure€or€nature€of€toxicant€that€need€to€beÏconsidered€in€minimizing€toxicant€exposure€because€limiting€access€to€one€route€of€exposure€thatÏis€known€to€be€a€risk€for€Ô_ÔtoxicantsÔ_Ô€may€make€another€route€of€exposure€more€accessible€to€theÏtoxicant€after€chronic€response.ÌÌPosted:€Mar-12-02€at€1:57€PM€by€Ô_ÔneetuÔ_Ô€Ô_ÔkainthÔ_Ô€€ÌÌ#4ÌÌyes,€these€rules€can€be€translated€into€considerations€in€toxicant€exposure.€Minimizing€timeÏmeans€Ô_ÔloweingÔ_Ô€the€time€Ô_ÔodÔ_Ô€toxicant€to€interact€with€its€target€molecule.€Dose/Potency/ÏConcentration€can€be€a€analog€of€dose€and€limiting€routes€of€exposures€via€vaccines;€optimizeÏendogenous€barrier€of€repair€processes€can€be€analog€of€shielding€for€chemical€exposure.€WellÏjust€like€with€any€other€toxicant;€you€want€to€choose€a€route€of€exposure€that€will€not€take€a€longÏtime€to€eliminate€that€toxicant.€You€also€want€to€choose€a€toxicant€that€can€be€easily€discarded€byÏthe€body.€Here,€we€are€talking€about€radiation,€therefore,€we€have€to€be€little€more€careful€than€ifÏwe€are€talking€about€some€kind€of€drug€because€radiation€can€cause€mutations€rapidly€andÏÔ_ÔthereoreÔ_Ô,€can€cause€developmental€defects.€Also,€depending€on€the€nature€of€the€toxicant,€youÏwant€to€choose€the€route€of€exposure€Ô_ÔtahtÔ_Ô€is€limited€and€will€easily€eliminate€the€toxicant.€ForÏexample,€if€the€toxicant€can€be€degraded€in€liver,€you€Ô_ÔwnatÔ_Ô€to€choose€the€route€of€exposure€that€isÏlimited€to€liver€only.Ì