Poisons, People and the Environment
Poisons, People and the Environment TOX 201
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Human Health Risk Assessment In sum UMVFHSiTV A I Ioucology Definitions Risk Probabiiity of an adverse outcome Risk Assessment Characterization of potenhai adverse heaiih effecE resuiung from egtposure to hazardous agenEsituations Risk Managemen Poiicv acuons seiected to conimi hazards Risk Communication Making HSK process comprehensibie to omers Risk Perce t39on Behaviorai response to HSK A t V r Risk Assessment Process mm Hazard Identification dverse effects of agent or activity is determined a Endpoints mortaity reproductive or developmental organ toxicity cancer etc a Derived from variety ofspecies human or animal m 5quot Hazard Identification Methods a structure Activity Relationships SAR aFuncuonai groups con gurauon stabiiity In Vitro and shortterm tes eBacterrai mutagen assavs to dermai parnung Studies a Animal Bioassays eRoute speci c hoie organism Epidemiological stu ies epossrpie evidence ofhuman exposure m nunn Risk Assessment Process m n Exposure Assessment Characterize the exposure setting a Physical environmen Potentially exposed populations Identify exposure pathways ource and mechanism of chemical release a Fate amp trans ort of chemicals Identify points of potential contact with con minated media a Identify exposure routes at contact points Quantitatively stimate exposure m Exposure Routes Determined by environmental media and activities at exposure points Three basic routes Ingest on ground or surtate wata e lnEldmtai ingestion Dfmll or sediment e ingestion uffuud Inhalation ecaseaus vapur aaasal gr partltulate pnase tnemitals Dermal Contact ground or surtate wata esail or sediment r Quantify Exposure and Dose Ingestion of Soil or Food EPCZxIRxCFxFIxEFxED igs B D Intake dose attnemital through ingestion Dfsnll mgkgrday nemital concentration in sail or fund mgkg v a tram Untamlnated murte unitless uenty dasyear ears aw my WElg AT Averaglng time days Exposure Factors How much dirt does an average person eat About 100 mgday Exposure Factors Handbook Where ar p located over tim and w e they doIn 7 Consolidated Human Actle Database CHAD eNatianal Expus e Researtn Laboratory NERL Exposure Factors Example Ingestion of Soil or Food EPQ Site specific measured value IR 200 mgd child age 16 100 mgd age gt6 ears FI Chemical and pathway specific assumed 1 EF 365 daysyr can be sitepathway specific ED 70 yrs lifetime 30 yrs 90th nnile of residence time BW 70 Kg adult 16 Kg child AT noncancer EDX365 dyr Cancer 70 yearsx365 yr Ivl vl Risk Assessment Process n Toxicity Assessment DoseResponse Assessment Molecular Interaction Cellular Interaction Toxic i1esponse Toxicity Assessment Threshold NOAEL LOAEL Low Dose Extrapolation ZEI Toxicity Assessment NonCarcinogenic Toxicity Factors Reference Dose RfD u Ingestion Dermal route a RfD NOAEL or LOAELUFsMFs Reference Concentration RfC u Inhalation route a RfC NOAEL or LOAELUFsMFs RfD and RfC Derivation Uncertainty Factor UF of 10 is used a when LOAEL used instead of NOAEL a when subchronic study for chronic RfD a for extrapolation from animals to humans a for protection of sensitive subpopulations Modification Factor MF of 1 to 10 used a for database uncertainties a when alternate exposure route considered m amtiquot Toxicity Assessment Carcinogenic Factors Cancer Slope Factor CSF a Risk er mgk Xday of exposure or mgligxday a Used to estimate excess cancer risk from exposure to contaminants in foodwater Unit Risk Factor B De minims risk 1E6 per unit concentration commonly in mgm39 a Used to estimate excess cancer risk from exposure to contaminants in air Risk Assessment Process Hazard Identification Exposure Toxicity Assessment Assessment Risk Characterization Risk Characterization NonCancer Effects Expressed as a Hazard Quotient HQ not a HQ probability RfD Cumulative hazard expressed as Hazard HI ZHQ Index HI Goal HI s 1 Risk Characterization Cancer Risk is a unitless probability a 1 in a 1000000 Risk Dosei x CSF Dose a Chronic daily intake dose averaged over lifetime of 70 years Cumulative Risk 2Riskchem Risk Characterization Characterize potential for adverse effects to occur a Estimate noncancer hazard quotients a Estimate cancer ris Combine riskshazards across exposure Quantify riskshazards from multiple chemicals Assess and present uncertainty in risk estimates ml mam Current Research Efforts Probabilistic eg Monte Carlo vs deterministic ie point estimates Harmonization of cancer and non cancer risk assessment Integration of human and ecological risk assessment Probabilistic Risk Assessment Recall the exposure equations a I sure do not weigh 70 kg m Ty ically every variable is represented by a porPnt estimate eg 95 UCL for EPC a PRA replaces any or every point estimate with a distribution where sufficient data exist a Exposure eqouation is then solved many times eg 1000 person simulation a The result is a distribution of exposuredose for a population rather than a point estimate Exposure Model Structure Input Algorithms Output Databases r J 1 rent an quot r r FOOd Res dues Calculate lndlvldual ReclpeFOOd Draw EwosureDose Pro le 1 quotr r Exposure Factor Dismbutions WW Target Organ Toxicity Endocr ne System In sum umvrasmr A I Ioucology Endocrine System Assemotage of organs grands that orooooe onemroat messengers normones that regotate vartous ooorw funcuons M H r Dmmslasts e veDvudutnve system enemY pvuoottron m etabuhsm Pnysrotoorret pm gressron 4212 oevetupment omwth one motorotron Organs Hypnthalamus Prmrtery Thyrmd and Parathyrmd Aormet coneos Testrs or Ovanes Endocrine Physiology Neuro Endocrine Signaling Cascades STIMULI sphvsiotogicat or environmenta ETECTION BY THE BRAIN sutttmatew one hvpothamamus quotsunnymane NEUROVENDOCRINE GLAND nemafndamwellarmane ENDOCRINE GLAND Endarnlrellarmane TARGET ORGAN 5 AdrenprvmmWPr Endocrine System Hormones and Regulated lfrocesses Example Testustevune Hormone Ern u Anoruoens w t t mntnon hbd Estrooens noEstroorot GlUEDEDYUEDMS tornsot Adrenots rnyroro Thvvmane r setono norot enstrts ro Ovanes testes Sexua orrreren on re ThYde atone Fetot man one u Regulated Prntess Testes sorenots Sexua orrrerent ow sex sexua oone oevetupment omen EDHSUM Dtmn Steroid Nuclear Receptor Action Slemtd Harmer m s a cell Surhte Membrane Slqnzl smooth m aural n Endocrine Disruption Endocrine Disruption Principally involves binding to hormone Hormone receptor agonists receptor a Chemical that binds to and activates a u Agonistic receptor a Antagonist u Estrogen receptor is very susceptible u Hormone level modulators 1 7 DE A v u are y 5 23 Endocrine Disruption Hormone receptor antagonists u Inhibits receptor activity by preventing Inhibit r5 f h rm ne SyntheSiS receptor binding of endogenous hormone CYP19 testosterone 9 17 estradiol inhibited u Inducers of hormone clearance u Estrogen receptor antagonists Glucuronosyl transferase T4 elimination Increased Pharmaceuticals TomOXIfen following PCB exposure Environmental contaminants PCBs Hormone displacement from binding proteins a Cause defeminization Serum protein competitive binding PCB metabolites displace T4 binding Endocrine Disruption Hormone level modulators nialn Target Organ Toxicity Reproductive System Reproductive Toxicity Any adverse effect on any aspect of male or female sexual structure function and lactation including effects on the reproductive potential and viability of the offspring General Mechanism a Endocrine Disrupting Chemicals EDCs A 7 Synthetic and naturally occurring compounds that can adversely f f gtshe normal hormonal homeostasis and functions In Androgenic act like an androgen Estrogenic act like estrogen Antiandrogenic suppress androgen Antiestrogenic suppress estrogen Reproductive System Physiology Males gonads mmquot a Secretion of sex hormones testes secrete mostly testosterone dihyd39otestosterone a little estrogens a R oduction of germ cells Spermatogenesis production of spermatozoa from spermatogonia Reproductive System Physiology Males Sertoli Cells a Assist in sperrnatogenesis a Secrete various hormones Leydig Cells a Testosterone synthesis Reproductive System Physiology Males Hypothalamicpituitarygonadal axis Hypothalamus Anterior Htuitary h Testosterone Toxic Mechanisms for Male Reproductive System Mimic endogenous compounds n eg hormones and act as agonists or antagonists Cytotoxicity a Direct or activated to toxic chemicals Enzyme Inhibition n Indirect effects by altering key enzymes I h39b39 B n I Iquot Estradb39 involved in steroid synthe5is m 6 uni Chemical Specific Examples of Male Reproductive Toxicants Effects to Male Systems Lead pb Effects on endocrine function Gk A quot quot n Cimetidine Ta amet 39 39 393quot a used In pottery plumbmg palm Used for o eatge39itofpepnculcers EU UK Note early use as spermicide Cornpeies Wig dihydroteztosierone for amen ne a Effects include rzcieg tggisin etesnsan aoceSory Decreased fertility Leads in low Spam count gynecomasna Low sperm counis motility increased abnormal sperm a Mechanism induce ch39omaijd and ch39omosom n Oral contraceptives occlpaijonal xposure Leads to gynecomas oa n Ketoconazole un al Inhibits testosterone biosyndwesis by inhibiting steroidogenic enzymes in Leydig cells Irmami 2 i3 Reproductive System Phy logy Females Gonads tam Secretion of sex hormones eovaries secrete varylng rn 0 es ogens rnainlv estragioi and progesterone Reduction of germ cells Dogenesis production or mum and 3 polar bodies Reproductive System Physiology Females Hypothalamicpituitarygonadal agtltis HPG Hypothalamus l7pstradiul Progesterone m cmquot Reproductive System Phy 39ology Females mm Reproductive System Physiology Females Differences in circulating hormone concentrations at difl erent stages of the cycle mm iei min Reprod uctive System Physiology Females Ovarian cycles a Estrus period whe e male coincides with high levels of circulating esh39o en ilLirnans primates cycle at rnonlhlv intervals others must undergo induced ovulation estirnuiated or mating e g cam n the female is most receptive frodents polyestrus a uccessi nor estrus cycles ream seasonallv sprlng eaer raii polveslrous eoogs rnonestrcs Most mammals ovulate spontaneously while sueu Female Reproductive Toxica nts EDCs In humans esh39ogenic compounds n alter natural hormone c le n are associated with breast cancer induction a war unctim as promoters or inducers of carcinogenesis p e a Sorne persistent Organic PollutanE pops eaairtniarnetea biphm ls Pcas e DDT e trichlereethene cempeund a Serurn levels or DDE a DDT metabolite and or PCBs have been found to be Currelated with incidence bereast cancer a Net cerrelated with incidence bereast cancer as Other Toxic Targets for Female Reproductive System I h h 39d u Amenorrhea abnormal hormone Wmquot 5P anquot e levels leading to destruction of ova Mechanism iii a Gonadal dysfunction through It LL Mm im w destruction of primordial follicles v Radiation and alkylating agents cyclophosphamide vincristine busulfan ntmn a n ovarian effects mng u Premature menopause and sexual a quotin g fquot dysfunction quot7quot I win Toxic Targets for Female Systems Uterine Effects u Dela ed implantation fetal deve opment and parturition giving birth Mechanism u inhibited uterine decidual induction Tamoxifen and clomiphene antiestrogens WWW CH 00 mm a suppress endometrial decidualization 7m 0 Hydroxyflutamide antiandrogen O O O 70 clomiphene tamoxifen antrastrugemc antrastrugemc funmam Target Organ Toxicity Developmental Toxicology NC STATE UNIVFHSlW 5 Ao I oncology Developmental Toxicology Any morphologicalfunctional alteration caused by chemicalphysical insult that interferes with a Normal growth a Homeostasis a Development a Differentiation u Behavior Teratology a Study of the etiology of abnormal development and birth defects u Teratogens xenobiotics and other factors which cause malformations m 1 Inhaler Developmental Physiology Mammalian embryonic development Zygote l Morula l Blastocyst Inner Cell Mass ICM differentiates all cell types gives rise to the embryo Trophoblast eventually forms chorion 11mm Developmental Physiology ICM Gastrulation Ectoderm Mesoderm Endoderm Epidermis et al Muscle Urogenital Epithelium Nervous System Cardiovascular etc Respiratory GI etc Inu c w 1 Developmental Physiology Major fetal outcomes depend on stage of pregnancy affected Stage of Exposure 0ntonmes Preimplantation Embryonic lethality Implanlation in time of organogene5ls Fetal to Neonatal Morphological defecls Functional disorders g rowth retardation carcinogenesis Developmental Physiology Critical exposure periods for organogenesis in the human GENlTALlA lLlMBl l M l HEART Implant I BRAIN gt O 10 20 30 4O 50 60 70 cm Day quotmum Developmental Toxicology Chemical Teratogens Thalidomide n A sedativehypnotic drug used 3 in Europe from 1957 1961 a Critical time period of as aroun gestation days GD 3550 a Common effecls include 7 Amelia or absence of limbs r Phocomelia or severe shormning of limbs 39339 Developmental Physiology Critical exposure periods throughout development span a Organogenesis origination of organs a Hisotogenesis formation of tissues from undifferentiated cells 395 lmFuricuomal Mamranonrr u impimi 395 g l r r r r quotHlsmgenesls 7777777 quotl a In lrrrOrgariogerleslsmrl aim Feel l m Embryonic Feral 5 Developmental Toxicology Chemical Teratogens Deithylstilbestrol DES u A synthetic estrogen used from 19401970 for pregnancy maintenance a Effects were not seen in offspring until they reached puberty Females vaginal neoplasia tumors vaginal n adenosis cervical erosw Maes Hypotrophic testes poor semen volume and qua ity Developmental Toxicology Chemical Teratogens Fetal Alcohol Syndrome FAS a Ethyl alcohol ingestion by mothers a First trimester is the most susceptible period a Common effects include growd1 relardau39on craniofacial anomalies all 39 Target Organ Toxicity Lung NC STATE UNIVFRSITV onicology Respiratory System Phys39 logy Conducting airways n Delivery n tructural support a Defense 7 mucociliary escalator Alveoi a Gas exchange a urfactant production Defense Decreasmg diameter Increasing surface area 7 macrophages ii i l Respiratory System Physiology Nasal and Oral a mouth nose Conducting Airways n trachea bronchi Gas Exchange Region n alveoli run on Inhalation Exposure Directly inhaled toxicants ases s ozone N02 502 CO Vapors fumes and aerosols r chlorine gas cadmium oxide Particulates r grains benzopyrenes metals fibers n Mixtures 7 cl arette smoke diesel exhaust PM25 Indirect exposure systemic route a Paraquat s Ingestion dermal uptake Repiratory Toxicology Dosimetry Gas Deposition a Water solubility is important 7 more soluble less penetration s so2 very soluble deposits in nose 7 Ozone less soluble deposits in alveoli Particle Deposition a Physical features quotw s Size and geometry n Airflow mu 7 Velocity and patterns Defense Mechanisms Against Toxicants Clearance n Nasal 39 Wiping blowing swallowing n Tracheobronchial x Mucociiary escalator t a Lower respiratory tract macrophagemediated Metabolism n CYPs and FMOs Detogtltication or activation Engulfed particles Responses of Lung to Injury Acute Airway Reacti ity Conuacuon ofsrnoodn muscle ln response to lrrltal lB Pulmonary Edema Thlckel39led alveolarrcaplllary barrler Cell Necrosis Acldlc or alkallne agenB alter membrane perrneablllty lead to cell death Cell Holif t era ion Type l cells replaced by transformed Type n cells Acute Airway Injury Aluulus Alvnblm Qlwlua Alumina Chronic Response Pulmonary Fibrosis Increase amount of collagen fb in alveolar interstitium Cause Flbroblast prollrerauo In reased collagen syndnesrs or deposmc Decreased collagen degradatlon Pulmonary Fibrosis Asbestosis Agent Asbestos bers Factors 5 Mann nages phagntytlze partltes scleared macmpn esatturmlateln alveulllh lncornplaely lngestedlun noes o Me lamr rerele ed that attract lrnrnunocells Dr stlmulate Dllagen prnduttlun Macrophages Obstructive Lung Disease Obstructive Lung Disease Asthma Emphysema I Characterized by shortness j of breath I Characterized by permanent enlargement of air spaces a Range of severity Hovoked by various agents 39 Agent I Agents 339 n Tobacco smoke I Mechanism n Elastases break down lung elastin n Toxicants accelerate process increased production of elastases inhibition of calantiprotzease Antigens r pollens dander Fumes dusts gases I Mechanism Bronchiole constriction due a lack 0 control ofairway smooth muscle shortening Lung Cancer Lung Cancer Agents N I Tumors typically a orma Tobacco smoke gt Human develop in bronchi n Asbestos Lung n Metallic dusts n Radon gas l l I Mechanism m carcinogens Reactive oxygen species Target Organ Toxicity Nervous System m sum unwrale I onioology Nervous System Physiolog Cenh39al Nervous System urn n vauh l Brai Spinal Cord Peripheral Newous System Nerves mat navel to and from spinal cord Nervous System Physiology Nerve Cells axon rons Speclallzed cells to recewe and lIanSmlt lnformallon Electrlcal slgnals Chemlcal slgnals 5 Nervous System Physiology Inte neuronal Communication Neumtvansmlttev Preswaphc neuron vesltles Svnapse Posmvnapm neuron mun Hum Nervous System Physiology Interneuronal Communication Neumtransmmer packaged rn vesmles r 39 Reteutuv run hannel released mm the synaptl le blnds m retepturs an pus ynytl membrane sawn Nervous System Physiology Intraneuronal Communication When menbrane putmtlal changes mare run lwawnels Dpen sumqr Nervous System Phy logy Nervous System Phy logy Intra neuronal Communication The End of the Message Tnts pmtess Dnttnues Mmmntne Oxtdaxe m a attn dawn the gain 9 kelwzmhmxlenxe Neumttmntttet 0 eesyewn Vomit otnet ten hannets Meneetntne eyteese types A e a eytetze dnpamtne Asety tenettnestetese teaves azety lthnhne quot2 WEE neteptnepnnne m M em ewe Nervous System Physiology Additional Features Myelin Speeds Transmission Glial Cells of the Nervous System Myein sheaths To protect and enhance pmdueed by Dhgudendmcytes ms and ECHme eHs PNS 39 PNS Schwann cells 7 Ce 1 tnyettn segment 7 E eitrtcat tnsutetet I CNS Glia ottgodendtocytes Myehnate ch neumns s 1 02 pmjemuns that Wrap amqu tneny neumns Atd tn eycn regenerattnn tn DWer yetteetetes Nudes Bf Ranv te The smart pntmttal ts 2 te Jump tram nude te nude Addi ional Features Addi ional Features Glial Cells of the Nervous System The BloodBrain Barrier CNS Glia 39 Microglial cells T ghtmmms rPhagocytosts tn tine CNS b etween 7 endethettet eHs WW2 immune funcu ons endrfeet ASSN d Passive hansport 7 tom esupportan trntt Ly yd Sotubtttt dtmston D V N D t tak 0 ular Stze euro anyquot e p e Active hansport and rel ease actotnotecutes Em wanwnes Organtc canons E 9 t 99 3 MDRP m m Neuronal Toxicity Neurotogtlticity n Adverse change in either the structure or 39 newous system following exposure to a xenobiotic Types n Neuronopathy Axonopathy Myelinopa n Neurotransmission toxicity snyc nine Muscimo Tetrodomxin Black widow toxin 1 Nicotine Botulinum mxin Sites of Neurotransmission Toxicity Botulinum toxin Black widow toxin Ecstasy Cocaine Tetrodomxin Sax imxin strycnnine Nicotine Organophoqohates m Neurotransmission Toxicity Acetylcholinesterase a primary mechanism for removal of acetylcholine from the neuromuscular junction Choline Mar 0 binding site RS 0H Acu39ve steratic CHa ioline ACh Acetylcholinesterase AChe 5mm Neurotransmission Toxicity Organophosphates x CZHSOk a P PestICIdes no cszog a Nerve agents used Basic OP ure Para for chemical warfare OPs bind to AChe like ACh does Neurotransmission Toxicity Acetylcholinesterase AChe breaks down acetylcholine ACh to choline and acetate waysOE nuka Neurotransmission Toxicity Organophosphate leaving group Y is hydrolyzed remainder is dif cult to remove Slow hydrolysis Rsulis in greatly reduced AChe activity in the CNS and PNS Neurotransmission Toxicity AChe is inhibited by OPs Excessive acetylcholine in neuromuscular junction ACh receptors get over stimulated All Achdependent processes are intensi ed aivation Lacrimation Qrination Qefecation SLUD quotIdum Antidotes to GP toxicity Acetylcholinesterase reactivators a Protopam pralidoxime chloride or 2PAM pyridine adogtlty methiodate Q4 a Act by dephosphorylating the inactivated cholinesterase a Will not work if enzyme is quotagedquot m nunum Antidotes to iOP toxicity Ach receptor antagonists a Atropine a Blocks Ach from binding Ach Ach to receptors on the Au neuromuscularjunction Classes of Poisons Natural Substances Natural Poisons Summary Classic Chemicals Animal I Bacteria u Insect I I D A h Fung39 Dthc 39 Algae 39 D Diatoms u Amphibians Iroxicology u Dinoflagellates D Rept39les Plant uml IInhahvv Classic Natural Poisons Arsenic Poisoning I Arsenic Exposure u Ingestion a Main chemical forms Inorganic A503 A505 AsH3 Organic dimethylarsenate u Sources and Uses Smeting activities Pb Cu Dietary food and water Distribution a Rapid distribution through body 39 Reaction time a Following acute exposure Pesticides isiy mrptoms appear within iz Ceramics enamels paints I Elimination So u Urinary t12 10hr m I mMm Mechanisms of General Arsenic Toxicity Toxicity Arsenic Biotransformation u Methylation MMA DMA Mechanism u Trivalent AsIII more toxic u Binds to SH groups of proteins a Inhibits mitochondrial respiration Effects and Symptoms u Acute severe GI distress 9death a Chronic gangrene in extremities skin cancer Mechanisms of General Toxicity Inhibition of Respiration by Compounds of Arsenic ill ui ll l ilm HiMIx39 l ll I i lNH Illll Infamous Arsenic Poisoner Mary Ann Cotton 1832 1873 a 1520 possible murders 1St husband William Mowbry 8 of her 9 c il ren 2 d husband George Ward 1 of 3d husband James Robinson s childre before marriage 2 after along with her remaining child Her mother 4 husband Frederick Cotton his sister 3 h d en oftheirc I r Her lover Guiahquot Classic Natural Poisons Cyanide a Main chemical forms HCN salts NaCN KCN prussic 3 acid CN in aqueous solution methyl isocyanate cyanogens u Sources and Uses Bacteria fungi algae Cassava roots lima beans Fruit pits cherries apricots peaches almon s Cyanide Poisoning Exposure u Ingestion Dietary water and food for salts u Inhalation Hydrogen cyanide gas a Dermal Distribution a Rapid Reaction time a On the order of minutes for acute exposures fink kn Cyanide TOXICIty 7 Mechanism a Interrupts electron transport chain in mitochondria thus cellular respiration ceases Effects n Acute vomiting convulsions shortness of breath unconsciousnss death a Chronic difficulty walking dimness of vision eafness Gum Infamous Cyanide Poisonings Rasputin a Mad39 monk con dant to Russian royal family Romanovs during 1900s a Poisoned with cakes and wine laced with cyanide a Shot in chest once in back once in forehead eventually drowned Tylenol a Chicago IL 1982 n 7 random people poisoned n Spurned tamper resistant packaging no more capsules39 um Classic Natural Poisons Strychnine u Sources 5tryc7705 I7UX yamca dog button plant seeds Strychnine Poisoning Exposure a Ingestion Bitter crystalline powder a Inhalation dust a Dermal eye Distribution a Rapid from GI Reaction time a 1560 minutes cm Gumn Strychnine Toxicity Mechanism u Neurotoxicant that increases levels of excitatory transmitters Effect u Muscle spasms fierce convulsions death by asphyxiation Infamous Strychnine Poisoner Dr Thomas Neil Cream 1850 1892 u Suspected of a few murders in Chicago convicted of one poisoning 39 a While in England poisoned at least 4 prostitutes u Had a strange habit of providing a little too much information to authorities Bacterial Toxins Organism u Staphylococcus aureus Toxin u Staphylococcal enterotoxin B Exposure u Ingestion of contaminated food a Most common cause of food poisoning in the US Effects u Nausea vomiting retching Bacterial Toxins Organism V a Costrdum botuI39num Toxin a Type A botulinus toxin V L a One of the most poisonous substances 39 LDSO 15 ngKg L Exposure a Foodborne contaminated canned u Effects and Toxici a Difficulty breathing swallowing asphyxiation a Inhibits acetylcholine release at peripheral nerve endings Fungal Toxins Organism u Cavceps purpurea Toxin u Ergotamine Exposure v Rye mold Ingestion of contaminated bread Effects and Toxicity u Hallucinations convulsions gangrene of the extremities u Vasoconstriction neurotransmitter blocker Fungal Toxins Organism u Amant39a muscan39a Fly agaric Toxin u Ibotenic acid and muscimol Exposure u Ingestion Effects and Toxicity u Drowsiness hyperactivity hallucinations possible nausea H EranI u Nerve impulse stimulant 0 T N 0 2 7 HZNH2 m v mIaIwr Fungal Toxins Organism u AspergYus spp eg A faIus Toxin u AflatoxinBl Exposure u Ingestion of badly molded corn peanuts u Inhaled contaminated particles containing toxin Effects and Toxicity u Liver cancer Algal Toxins Diatoms Organism u Pseudonitzschia spp eg P j austrais u Domoic Acid Exposure u Ingestion of contaminated shellfish mussels Effects and Toxicity mtent effects GI distress Toxin H u Agrgesm shellfish p0sonng mogul IL Fungal Toxins Organism u Amanta phalodes death ca p Toxin u amanitins Exposure u Ingestion Effects and Toxicity 1 f u Latent effects severe abdominal 39 pain vomiting 9 irreversible 1 x kidney liver cardiac damage 9 A quot death quot u Inhibits mRNA synthesis 1 mm flum Algal Toxins Dinoflagellates Organism u Alexandn39um tamarense Toxin u Saxitoxins Exposure u Ingestion of contaminated shellfish mussels clams scallops u Paralytic shellfish poisoning PSP Effects and Toxicity u Numbness weakness paralysis a Block Na channels in nerve cells Algal Toxins Dinoflagellates FL Red Tide and Fish Kill Organism n Karena breII39s quot Toxin n brevetoxins Exposure n Ingestion of contaminated shellfish FL Gulf of Mexico a Neurotoxic shellfish poisoning NSP Effects and Toxicity n Headaches diarrhea muscle pain difficulty breathing blurred vision a Interfere with Na channels in nerve cells M39 Plant Toxms Plant Toxms Early InsectICIdes Early InsectICIdes Organism Organism u Pyrethrum a type of Chrysanthemum n Nicotana spp tobacco I Toxin 39 Toxin u Pyrethrin D Nicotine Exposure Exposure u Inhalation n Inhalation smoking tobacco products I A n Ingestion H30 CH3 CH n Ingestion chew D HSCgt ni EH 07W 393 Hsc Effects and Toxicity H Effects and Toxicity N N n Hyperexcitability nausea vomitingf 3 0 n Extensive salivation nausea vomiting W respiratory failure Pyrethrinl convulsions respiratory failure a Interupt normal neuron function u Acts like neurotransmitter Nicotine rm Fm Poisonous Plants Poisonous Plants Organism Organism n Conum macuatum hemlock Afro93 b930390 a Deadly Nightshade Toxm Toxin coniine n Atropine I Exposure Exposure n Ingestion n Dermal CHBK Effects and Toxicity n Weakening muscles Effects and Toxicity 39 T a Dry mouth hallucmations amnesra O respiratory failure coma O H u Blocks muscarinic receptors 1 itemquot Im39 KITquot Poisonous Plants 0r anism Mam commone Castor bean Toxin Ricin aggiu nin Exposure n Effecls and Toxicity abdominai pain vomillrig diarrnea dehydration deatn Innibit protein Sy theSiS Notable Ricin Poisoning Georgi Markov 1929 1978 n Bulgarian novelistplaywright 397quot n Emigrated to UK worked as BBC broadcast journalist n Poisoned by dart from a highly developed secretory glands and mechanisms for toxin delivery 0 Insect Toxins Animal Toxms Bees 39 39 Organism I Poisonous ammals fsmyifya scalyaid n tissues contain toxins but no mechanism geiergimzed honeybee i Net for delivery oxin Venomous animals ADamWei meim Exposure Sim Effecls and Toxicity iocai in ammatory response a death Arachnid Toxins Spiders Organism Latrodedus macfa biack Widow Toxin Aiphariairotomn Exposure Bite Exposure Bite Effecls and Toxicity I I Muscie cramps abdominai pain 39 EMS and TOXICItY weakne si chest pain reSDiratorv 39 ssue degradation myieiin sneatn dir iCUi degradation erythrocyte iniS Sumuiate neurotransmitter reiease A r x mau outquot im Arachnid Toxins S Organism Luxus ryes redusa brown reciuse Toxin Hyaiuronidase Sphingornyeiinase Arachnid Toxins Scorpions Flsh Toxms Organism Organism u Centmrodes eXYicauda bark u Sphaerodes spp Puffer or scorpion Blow fishes Toxin Toxin u Several proteins a Tetrodotoxin Exposure Exposure u Tail sting u Fugu poisoning Effects Toxicity Effects and Toxicity u Numbness hypersalivation u Hy otension respiratory hypertension respiratory distress fai ure death death a Disrupt nerve impulses u Disrupt nerve impulses Ii m E Amphibian Toxrns Cane Toad Organism Organism u Bqus man39nus u Phylobates tembYls poison dart frogs u Found in warm climates CentralSouth Am I Toxin u Introduced to Australia in 19305 to combat u Batrachotoxin cane beetle Exposure Toxin I I I u Dermal contact with secretions BthOtznln 539OH DMT amp cardloaCthe Effects and Toxicity I EXSES J39I u Hypotension respiratory failure death a Disrupt nerve impulses Effects and Toxicity u Hallucinations 9 death u Inhalation smoked a Not by Ingestion licking Iliulnulwy Reptilian Toxins Organism u Crotaus spp eg C adamanteus eastern diamondback Toxin a Multiple adamalysin Exposure a bite Effects and Toxicity u Excessive thirst vomiting paralysis hypotension kidney failure death a Alteration of blood vessel resistances changes in blood cells and coagulation Target Organ Toxi Blood Hematotoxicity Blood PhySIology Connective Tissue Distributes nuh39ienls to cells wastes to excretor or ans Several Cell types Origi ate frorn stern ceiis found in bone marrow A We onncology Differenhahon coniroiied bv means or hmuiaung factors m m C0 Poisoning Statistics CDC Hematotoxi ity Anemia Carbon Monoxide eAiters oxygen carrving capacity or nernogiobin due to preferentiai binding of co eteads to iow biood pressure rainung dizziness neadacne nausea dean m as Hematotoxicity Cytotoxic Hypoxia Cells cannot utilize 02 during metabolism and energy production a Agenls envdrogen cvanide ch Hvdrogen sui de H25 act as innibirors or eiectron transport a cvoc renew ase compiex eCan iead to dearn rm Hematotoxicity Blood Disorders dyscrasias Abnormal cellular composition e g t 00 manv ofone cell type Thmnbutympenie little m nu thmmbutyfes iaeiee leads in external m internal mum lass Lmkemie a W normal White blood cells and me many leukemia b last tells Chlordan e Pmtympenia a reduction in all cell types Target Organ Toxicity in suit UNWFRSWV 1 oxieolog Liver Structu re WM mm m le mu rage Glucose l5 towered m en En mes lesme melems li yJJDprmens vawd First pass metabolis vein to he ver a high concenh39ations of xenobioticmetabo enzymes P450 FMO etc ilnvolved in detoxicauon or acnvauon Increased halflife of xenobiotic Enterohepatic circulation may increase hepatotoxicity Liver Toxicity Susceptib ity Largest organ after the skin in the body m h39act are h39ansported Iizing Suppression or blockage bile flow me imazole mepazine mestanol sulfanilamide amimptline estadiol 5 retenllon of bile of mum mam such Liver Toxicity Cirrhosis A progressive disease resulting normal alcohol from e combination of diffuse fibrosis and nodules of regenerating liver cells n Characterized t deposition of Hepatitis B collagen fibers ResulB 39n Restriction of blood flow a Changes in normal metabolic processes a Changes in detoxication process a Liver failure Caused y Excessive alcohol consumption Hepatitis B roughout the liver Liver Toxicity Hepatitis Inflammation of the liver Viral HepatI Is A B nonA nonB CytomegBalovims CM Q eastein arrvirus EB j ellow fever virus erpes simplex or Zoster virus Coxsackie virus Rubella virus Chemical Eroniazid Methoxyfluorane alothane Isoniazld Papaverine Zoxazolamine Imipramine Phenyl butazone1ndomethacin 6 Mercaptopurine Cholchicine Methy o EnVIronmental Agents Causmg Liver Injury Home Poisons a rat poisons cleaning solutions medicines paint lead Air Pollution U I 39 39 39 a he m Rural toxic substances pesticides and herbicides fungal spores on grains fertilizers Industrial toxicity solvents metals chemicals Food additives w oil red dye saccharine cyclamates nitrates Drugs antibiotis anesthetics analgesics stimulanls depressants hormones chemotherapeutic agenls ethyl alcohol m nkkn Target Organ Toxicity Kidney Renal Toxicity NC STATE UNlVFRSITV A I onicology Kidney Physiology Blood vessels interwine with urine collecting tubes Each kidney contains about 1 mi lion nephrons Functions a Elimination of waste roducB Nepnrun mm mm u m Imam l Regulation of homeostasis a Hormone synthesis mm nknu Kidney Toxicity Susceptibility High renal blood flow Concentration of tubular fluid and chemicals Biotransformation of toxic metabolites u eg CYP metabolism generating reactive products Kidney TOXICIty Glomerular Filh39ation Nepmonc syndrome Presmte afpmeem m the we due in damage en Mar 2 9 bad haam Nepmmc syndrome Fresmte afpmcem and mm m the u n2 assumatad mm m ammauan Aitered permeabmty Anubmnts pummymn nr2 25 gentamymn daneaaes KIdney Toxicity Tubular Reabsorption Gweosuna and ammoacwdurwa e mmbman nfgiumse Dr armrmamd reabmrptmn a g ajmmm bad Tubular Secretion Acute mbuiar necrosis HEavy meme anomaucs argam suivmts Kidney Toxicity Obsh39uctlve Uropaihles Urme ow prevented Eih iene giymi aimum waste accurmiaunn m pmwmai mbuie History of Toxicology Antiquity NC STATE UNIVFRSlTV Goxicoiogy Word Origins Toxin derived from a Texan Greek for bow and arrow B TeXken related to poison dipped Poison derives from pal to drink and becoming potare in Latin potion a Venomous nature derived from wen to win and led to venusvenerate throu h love potions called ven39nl Antiquity Prehistoric Man Knowledge of poisonous plants and animals Hunting war 9 asassination if 39 s s First Mention 3100 3000 BC Menes a Egyptian pharoah of the 1St dynasty United upper and lower Egypt founded Memphis as capital building of dams founding of many new cults and temp es a Cultivated and studied effects of poisonous and medicinal plants First Written Record 2700 BC actuall ublished in 1600 Ala y p l Shen Nung early emperor of China a ung n is39ao ching 39 gilDivine Hus ndman39s Maten39a E edica r r conmined 55 of poisonous and medicinal plane and dru s Included EffecE and antidotes r Eg iodine opium canna is mercury Ancient Egypt 1500 BC Egypt Ebers papyrus Mentions plant animal and mineral poisons Describes effects of lead copper antimony hemlock and opium a Modes of administration Antiquity The Vedas Antiquity 900 BC Hindu Scriptures Aiharva Veda efrst indian text deaiing Winn medicine 600 BC Homer Odysseus obtains poison ror o noon orpoisoningr his arr Ws 460355 BC Hippoc t 5 introduced priheipies or eiihieai or use rowcoiogyreia e o in warrare e g arrows wiih bioavaiiabiiity or tOXiCai iB duce castor bean poison 0am to not p i 39 poisoned neB and nook tn piease nu ne iii I prescribe traps a deadiy drug nor owe advice which may cause his death an oaki m AntIquIty Blble I 400 BC Deuterono Antiquity Theophrastus 370286 Wi the venom of re uies iidin in the dust p g g poisonous are meir grapes and bitter their ciusters Born in Eresus on one isiano or 39 Lesbos dent of I e Book of for one arrows orihe Aimignty pierce me and rhy spirit drinks meir poison The poison or asps he shaii drink in ihe viper39s rangs shaii siay hi rhquot Most reievant Work is De Him75 PantsUm Included numerous references to poisonous planis A nth u Ity 469399 BC Socrates EXKutiDHsuitide death bey neminck 1977130 ESC Nicander oet physician to Auaius Biihynia lexiphal Antiquity 385322 BC Demosthens a Great Greek i m e oesnioes Duisuns in oeneioi anaivses or w spetifit Duisuns and tuies a JAi speech is Vain and empty uniess it be accompanied by rare 7 destiibes FDiSDi iDUS anim 2 5 he effetts uf heii Duisuns and DiuDer remedies e First acoon a Suicide by poisoned pen retarded iefeiente tn the use ufieethes eieiiii Mel5H emneon ammo e 6930 BC Cleopatra a Suicide by poisonous snake Antiquity 13283 BC King Mithridates VI of Pontus Poison paranoia rAttempted sulclde by polson but felled at attempt st Poison Law Circa 82 BC Dictator Lucius Cornelius Sulla Lex ComeIa a Growing conspiracy to kill men for profit Hovisions for both the poisoner and the provider of from Anazarlaus suuthrtentral Turkey Greek surgeon Wlth the Roman a Complled medlcmal neros later translated mto Laun as 05 Mate75 Me Classl cauon standard of ant ammal and mmera pl Re the authorlty m medlcmal pl ans for over 1500 years 3 g 2 m 1 rmy persons H ito s of the poison m rm m Mu Dioscorides Dioscorides Therapeutics 4090 AD Arwn mamam A urn or Cuckooert Ancient physicians called this plant the Drakontaia Mikre or small dragon quot because central stalk resemb es a serpent According to Dioscorides its shape revealed its purpose as an antidote for snakebite Rub mg one s hands wlth Arurn root was supposed to make one unblteabler g Apsynthion Bathyprikon Arbemisia absWiwn Wormwood Recommended for GI disorders e y for jaundice and a 39 a popular a 3 u g 3 a mo 53 g cm u mx 5395 25 o 5 m v Q n E 2 u to repel moths and mice Dioscorides Therapeutics Dioscorides Therapeutics Physallis Pi sai39s alreeigr39 Physalis or flIintercher Chinese lanterns Dioscorides prescribed stem as asedative and its berris a diuretics Mixed vyith honey Physalis vvas said to Improve eYesight With Wine it supposed y cured toothache Nero I 3768 AD a Mother Agrippina consults with skilled poisoner Locusta to poison ror Claudius such that her son from a previous marriage Nero seize power a Cleverly poisoned stepbrother Brittanicus a Used slavs as food tasters to differentiate poisonous mushrooms rom edi e ones Galen I 129199 AD Claudius Galen of Pergamum I Greek physician philosopher I Believed therapeutics should be in the hands of physicians rather than herbalists I Galena a remedy or antidote for poison Middle Ages 9801037 Avicenna Ibn Sina a Persian Physician Philosopher Scientist n Wrote 450 books The Canons of Medicine a At an early age turned to medicine and then determined treatments fort e 5ic rm GIed n Middle Ages Early Renaissance I 11351204 Moses ben Maimon Poisons and Their Antidots 1198 e eatmel39lt of Dolsmlngs from ll39lsects snakes and mad dogs a Wrote on the subject of bioavailability enotlng mllk butter cream could delay ll39ltestll39lal absorptlol39l of Scbstances I 12005 Alchemists Fermented product to yield 60 ethanol beverage m Middle Ages Early Renaissance I 16005 Toffana Naples Italy a Acqua Toffana39 e Marketed cosmetlcs corltall39lll39rg arsenlc I 16005 Hieronyma Spara Rome Aquetta di Perugia39 r Drgal39llzed female soclety of polsorlel39s young mamed Women of wealm ramllles 7 malan arsenlc used ler and 12 others nanged olners publicly lDDed Scientific Principles and Toxicological Concepts NC STATE UNIVFRSlTY A I 1 onlcology Scientific Method 101 I Observations made phenomena described questions asked II Scientific hypotheses are formulated a tentative explanations to phenomena III Predictions are made using hypothesis IV Experiments conducted to test validity V Conclusions are drawn You Use it More Than You Think For example your car won t start a The engine does not turn observation a my car won t start because the battery is deadquot hypothesis a You check the lights to see if they were left on experimental test a You check the voltage across the battery terminal experimental test Depending on the outcome you may draw a conclusion the battery is dead or formulate a new hypothesis the battery is not dead um Gunuquot Scientific Method Welltested and accepted patterns in the data become Scientific Laws conduct Exyperirnevnls and Collect Dala Observe Phenomena Make new Predictions Welltested and accepted y ecome Scientific Theories cm nunum Misuse of Scientific Method Biased Interpretation a Scientist may have preferred outcome to experimental 9 No tests conducted a Due to common sense and logic IgnoreDiscount nonsensical data a May get more eltplaining than data that support hypo esrs Quantitative estimate of systematic errors a Doubleedged swor can miss science due to errors or interpret errors as science Hypothesis Formulation Types of Hypotheses u NonDirectional u Directional u Null Hypotheses Research Question a Will students who take this class have better knowledge of chemicals in their environment than those who do not min nk m Hypothesis Formulation NonDirectional a At re end of re class there will be a difference in re kno Wedge of chemicals in re39r en VI39ronment of grade 3 who took ris class compared WI39 r rose ero o no N u H a At re end of re class there will be no difference in re kno Wedge of chemicals in re39r en VI39ronment of stutdens who took ris class compared to rose who do no Directional a At re end of re class aftdens who took ris class will ave more now dge ofclreml39cas 39n re39r en VI39ronment compared Wi r rose who do not awn Scientific Research Identify a problem Derive a hypothesis Critically review prior research Develop methods a Collect data Statistically analyze data Interpret results Draw conclusions Gurum Scienti 39c Experiments and Data Analysis Single Variable Analysis n Isolate and study the effect ofa single faclnr by crating two study e experimenial group die variable m be studied is altered in a known way e g concenuation a conuol group identical m experimenml i I r e c gr exceptin almred Multivariable Analysis n Usuall in environmental smdis t is dif cult to control for all variables hosen variable is not Example Scientific Experiment Nonnative species Observation u Nonnative Atlantic mudsnails invade and capture territory from native Pacific mudsnails Hypothesis u Atlantic snails directly outcompete Pacific snails in richer mudflats leaving Pacific snails to poorer highland marsh areas Scientific Experiment Nonnative species CONTROL Gui Scientific Experiment Nonnative species EXPERIMENTAL Scientific Experiment Nonna ve species ResulB n Atlantic snails twice as likely to be in richer feeding areas than Paci c snails Conclusion n Hypothesis not disproven Robert Koch 18431910 e Kochs Postulates V Condluons that must be saus ed before lt carl be a cepted dnat a blologlcal agerlt causes e ganrsm nus 72 rigamt bm an merEdmst andgmwn m pure tumre m we labsam e r am we we tumre are mom5151th a EusfaptlbE has 079mmquot rz mus case we Liliaasa e The mam brgmrsm muszbe ferryStet from we messed organ5m and gm wn m pure cums Must ask questions about What modl cauorls rleeded for appllcauorl to chemlcalrexposurerdlsease corlurluurn BLOOD STREAM n BODY TISSUES and ORGAFS limination Toxicologx The Science of Poisons Study of the harmful effects of chemlcals arld other pnysrcal pnenomena on blologlcal systems cause dlsrupuorls of blologlcal systems resulurlg rn togtltlc effects plred to bodn natural and syndneuc cnemcals equally W by P otecurlg numans and odner organrsms rrom negauye fee of toxica B Provlde knowledge for the safer use of chemlcals arld radlauon Any substance typrcally at low doses that causes a narmrul effect wnen admrnrstered to a lryrng organrsm Toxicant Any cnemrcal of natural or syndneuc orlglrl capable of causlrlg an adyerse effect on an organrsm oxin Toxlcarlt produced by a lryrng organrsm Xenobiotic Any cnemrcal lrlteracurlg wrdnrn an organrsm tnat does not occur rn normal metabolrc padnways of dnatorganrsm Toxicological Pr nciples Toxi ty State of belng polsonous adyerse effecB produced by porsons or toxrcane Acute Toxici Sudden onset of symptoms dnat last for a snort perrod of u Usuallyreverslble Chronic Toxicity ms are of long and corltlrluous durauorl Usuallylrreverslble i it Toxicological Principles Local Toxicity a Symptoms occur at the site of exposure Systemic Toxicity a Adverse effects occur at sites far removed from site of exposure Toxicity Example Carbon Tetrachloride Exposure Acute Local Toxicity high 9 eyethroat irritation 9 no symptoms 0 Acute Systemic Toxicity high 9 following absorption transport to brain depresses CNS 0 9 no symptoms Chronic Systemic Toxicity high Tyears 9 kidney liver damage CNS depression death Toxicological Principles Timing Immediate Toxicity n Symptoms occur immediately following exposure Delayed Toxicity n Symptoms occur long after exposure Exposure n Acute shortterm a Chronic longterm Principles Dell tuxitity Classification of Toxicants dassi ca on categories Pl39wsical state Gas Liqud solid or DLst Use Pesn ode Solvent Food Addm ve anemicai Structure Aronauc Amines Aiipnatcs Glycol General Acton Air Pol LENS c on c Poisons lndLstIial Tox cane Effect carcinogens Mutagens Teratogers Target or an Neurotoxt cants Hepatomxcane Nephrotox cane Mechanism of Acton innbitors Anmgonise Agonsts Labeling Requrenent Oxdzer Aod Egt gtlosive General or Use uass Plastics organic anemicais Heavy Metals ma 5 How to Determine Toxicity Use well defined end effects following exposure to a substance in the form of a Toxicity Tests Select an organism Select endeffect response Establish test duration Establish test dosing regimen wa tquot 1 Selection of Test Model In Viva in life n Use of whole live animals plants bacteria r fungi Typically not humans or endangered species due mora and ethical concerns In Vita in glass n Use cultured cells isolated ceuar organe es In 3957ica in 21St century computational n Use computer models based on animalhuman physiology 2 Selection of Response Should be easily observable measurable and quantifiable a Death u Biological products presence or bsence a Cell morphology structure a Tumors u Altered Behavior eg sleeping pattern a Growth and development m Gun m 3 Duration of the Test Depends on a Type of test performed Irritant seconds Reproductive years a Test model employed Lifetime of organism with regard to type of test m nialn 4 Dose Selection Can depend on size of organism in vivo or test medium volume in iitro organism Weight g 25 Mouse 100 2 5 Rat 250 100 25 Guinea pg 500 100 50 Rabbit 1500 100 150 Cat 2500 100 250 Monkey 5000 100 500 Do 10000 100 1000 Human 75000 100 7500 rulinde 4 Dose Selection Testing needs to be performed over the range of doses that contains the desired response and threshold response Toxicity Rating Chart Probable Lethal Oral Intake for Humans Toxicity Rating or class Dosage mglkg Volume I gpllrllgledone In a legarlthmlc l Practicallynontoxlc gt15000 gtlouan 301 0 1 10 10 100 k 2 Slightlytoxlc 500045000 pintrquan 39 39 d mg g 3 Moderatelytoxlc 50075000 Duncerplnt 39 Det m ln Pm Prlor eXPeFence 4 yenTm 507500 easpmpn or Similarity With other chemicals 5 Extremelytoxlc 575D 7er r as non EDI fluted n Em I39venu DoseResponse Terminology LDSO median et a dose a Quantity of chemical estimated to be fatal to 50 of organisms under stated conditions of the test Threshold dose a Dose below which no effect or response is observed NOEL no observed effect level 39 e of a chemical that causes no 0 ervable adverse effect in the test organism LOEL lowest observed effect leve Lowest dose level of a chemical that causes an observable adverse effect in the test organism Tox ty Rating Chart m Wm m g A h3xol Sam um l m mm mm mn Gum m I nIItvn General Factors Affecting Tox39 39ty Toxmlty vs Hazard Species tgforpuon dlsmbuuonblobansformauon ellmnauon storage 39 Hazardous nature Of a Chem39cal l erences Gen er determined by AgeB O Tmst mm Mame a Inherent danger of substance due to Metabollcdevelopmental dlfferences harmful properties Nutritional Status lmpalred cellular funcuon 8399quot mms39verless39 tox39c39ty Disease State a The ease at Wthh contact WIth an I in teffectlnteracuon Wll toxlcant organism can be established Hormoneenzyme uctuations Gullahquot m nm Safe or Hazardous Factors Affecting Metabolism and Toxicity 39uc STATE UNIVERSITY onicoio i NutritionaliEffects Protein a Low protein diets generally decrease monooxygenase activity in rat microsomes Carbohydrates a High carbohydrate diets have a similar effects as low protein diets W VIA IO ll Lipids 39 quot u Deficiencies in linoleic acid or other unsaturated fats reduce CYP and related activities in the rat orMm Overview of Physiological Factors Nutritional Effects Physiological Effects a Development a Gender u Hormonal status a Pregnancy a Disease u Diurnal rhythm Species Variations Polymorphic Variants Age or Developmental Variable Activity Levels a Low in the fetus and neonates develops rapidly after birth a Highest activity in young adults a Decreases in old age metabolism and clearance rates decline Presence of Enzymes u Clusters of metabolizing enzymes appear during critical periods of life such as birth weaning and puberty quotwkhr Nutritional Effects Micronutrients D Vitamin deficiencies generally reduce monooxygenase activity Ascorbic acid decreased p450 and activity Vitamins A and E decreased ctivity Thiamine increased activity Nutrients Requirements u Vitamins Bcomplex u Essential amino acids 7 u Inorganic nutrients I 45quot Iron copper 39 a 39 P w39 nkmy Gender Differences Major gender differences apparent in rodents not as prevalent among humans Species Toxicant Susceptibility Rat EPN warfarin strychnine F gt M Rat Aldrin lead epinephrine M gt F Cat Dinitrophenol F gt M Rabbit Benzene F gt M Mouse Folic acid F gt M Dog Digitoxin M gt F Differential activation of 2AAF in male and female mice quotis 513 mum imiw WWW mm i sulfuvansfevase amin in 39393939 quotV male ms is much highei 39 Gender Differences Gender Differences CYP development in male amp female rats 39 sexuaI39Y dimorphic t 100 Male P4505 arise by E 9 neonatal imprinting Female in male g Growth hormone gg 5 pulsatile production g and testosterone in gg male lead to E isoforms such as 47 0 5 io is 20 25 30 35 40 45 50 CYP2C11 AdUlMa e Adultfemale m AGE DAYS mm mm CYPZCM Y Gender Differences Pregnancy In general xenobiotic metabolizing enzymes decrease during pregnancy u Catechol Omethyltransferase u Monoamine ogtltidase u Glucuronide conjugation a Liver CYP activity Exception u FMOZ in rabbit lung increases in pregnancy mul Gumn Disease Acute or Chronic Hepatitis a decreased ability to metabolize substance Kidney Disease a renal impairment a reduced eliminationincreased toxicant half life Diurnal Rhythms CYP levels and susceptibility to toxicants fluctuate in rodents in response to light cycle or other diurnal activities Gunluv Acarici des Nematocides Insecl Odes RodenlJcides s Differences sticide selectivity depends upon species differences a In Mammals HerbicidesFungicides Nblluscicides Species Differences Natural P ons Naturally occurring poisons known to have interspecies differences In toxicity Nicotine e insecticide that kills many insects at low doses however dEiary rule in same species Belladonna Many rabbit eatBelladunna eeyes Wii Dut eny eeyese enece yiniie other mammals are easily pnimned Cyanide anal 39 As a defense mecdnensm millipedes 4 1 can seciece cyeni e HCN m nkuquot Carb Species Differences Target Organs Speci c organ toxicity di erencs tenachl 39 cHepatotomcant in seyeiai species not chicken Dinitrophenol cCataiacmin enE rod D ceggshell thinning in falcons and mallard ducks not found in gallinaceous species such as pheasants quail grouse and turkey Species Differences An ne Hydroxylation Aniline hydroxylation in females of various species l H nee memo ii iii Species Differences Phenol Metabolism Typically four metabolic producB Species Differences Phenol Metabolism Metabolic conversion of phenol in vivo Snecles mnl thnl I Fig inn n n Rhesusmnnkey 65 n a 87 i3 Human M n Rel 68 n squinei monkey in n Guineapig i7 n abbii as a 5m Genetic Polymorphism A monogenetic trait that exists in the population in at least two genotypes one or more variant alleles and is stably inherited a Within coding region reillt in differences in function u Outside coding region 7 protein is not expressed Llnimndzl Disliihulinn Log Mamuhc Rae Bimndd Disliihulinn nan Lug Nelabohc Rate quotalsva Polymorphisms Metabolic capability Extensive metabolizers EM versus poor metabolizers PM Debrisoquine PM a White 610 a Black 5 a Asian lt1 o Concentration 39U E Time hours m mumn Polymorphisms CYP2A6 Smokers adjust cigarette consumption levels to maintain brain nicotine lev els 7080 of nicotine is metabolized by CYP2A6 Among smokers very few individuals with defective CYP2A6 alleles a Those with defective alleles smoke signi cantly fewer Cigarettes Inhibition of CYP2A6 may be useful therapy for smoking cessation Chemical Interactions A nontoxic compound is metabolized to a potent toxicant u in the presence of an inhibitor there is a reduction in toxicity u in the presence of an inducer is more toxic inhibitor NT 96 T l inducer NT gt T f Second Example of Chemical Interaction A toxicant is metabolically detoxified u the presence of an inhibitor of the detoxifying enzyme results in an increase in toxicity n In the presence of an inducer of the detoxifying enzyme the toxicity is reduced irhibilor T 96gt T f T NT undoIvquot Inhibition De ned as a restraining a holding back Here refers to a reduction in the rate of an enzyme reaction a Can cause an increase or decrease in toxicity u Inhibition is reversible or irreversible Inhibition CYP Inhibitors he Inhibition Effects on metabolism u Disulfiram Antabuse effects on ethanol metabolism acetaldehyde accumulation o 1 H30 OH H30 H i i H30 OH Disu lfiram Ethanol Acetaldelnyde Aceuc aod Emu rum Synergism and Potentiation Synergism a one of the compounds has little or no intrinsic toxicity when administered alone a 0 2 10 Potentiation a both compounds have appreciable toxicity but when administered together have a greater toxicity a 2 2 10 MWWA Hmlmbenzoirlazde LAST RperorM butoxlde 1 NW 5 525A w N I Allwsopropyaoeemlde Metyrapome Synergism and Potentiation Toxicity of two chemicals is greater than would be expected from the combined toxicities of the chemicals administered alone n Holds true when administered either simultaneously or sequentially m hdeHn Synergism Use of an insecticide synergist to determine mechanism of resistance Test Strain LD50 NSySy RS Cyper Susceptible 10 Cyper PB Susceptible 06 17 Cyper Resistant 1613 160 Cyper PB Resistant 83 194 14 m mIvr Potentiation Asbestos workers a 5fold higher incidence of lung cancer than general public Smokers a 10fold higher incidence Asbestos workers who smoke a 50fold higher incidence of cancer m 7 Antagonism The toxicity of two compounds is less than would be expected from a consideration of the toxicities of the two compounds when given alone n holds true when administered either simultaneously or sequentially Antagonism Examples Hexobarbital a sleeping time is reduced from 11 hours to 17 minutes by rior treatment of rals with phenobarbi Benzoapyrene carcino enici is reduced b henobarbital treatmegnt ty y p Organophosphates opine locks muscarinic acetylcholine receptors preventing organophosphate toxicity v kd n m anquot Examples of Substrates Induc n Inh39 39tors and Inducers of P4505 Process of increasing mas the amount ofan enzyme following 739 39 hm 2 exposure to an inducing l 6 mm mmumm WW mm L agent 7 mm um gamma mm swam quotmm Increase in transcription f T quotE T 23 33 s39mmquot 5 andor translation of the 39 W mew mm myquot quotmum amp HEW mm se in the mm degradation of the mm m a Simplified Scheme for Gene Expresswn Animals Classes of Poisons Pharmaceuticals Drugs NC STATE UNlVFRSlTV I onicology Benzodiazepines a Valium Effects a Sedation muscle relaxation Mechanism and Toxicity a Depresses neuronal activity a Drowsiness ataxia insomnia following discontinuation a OD associated with coma confusion Safer not associated with serious addiction and other side effects lam nkbu Therapeutic Drugs Depressants Barbiturates a Barbital and Phenobarbital Effects a Sedation reduce heart rate and blood pressure Mechanism and Toxicity a Depresses neuronal activity a Overdose may lead to anesthesia coma and even death respiratory and CV depression Potential to cause tolerance and dependence mill Therapeutic Drugs Antidepressants Tricyclic Antidepressants m a Doxepin clomipramine Effects a Sedation Mechanism and Toxicity neurotransmitters Norepinephrine and serotonin is r a Dizziness tiredness blurred 7 vision urinary retention a OD confusion convulsions vomiting coma z A x l J o q a Blocks reuptake of D3 r k1 Mechanism Barbiturates and Benzodiazepines Amygdala a Part of the limbic system a Involved with emotion particularly regarding fear GABAA receptor complex a Binding of inhibito neurotransmitter molecule BA S ammaAminobutyric acid a ows Cl into the neuron making it less likely o ire n Benzodiazepines bind to GABAner Ic sites and block the am 9 ala39s Processing of fearin ucing in ormation or stimuli Therapeutic Drugs Antidepressants Selective Serotonin Reuptake Inhibitors SSRI a Zoloft Sertraline a Prozac Fluoxetine Treatment a Depression OCD panic N er r disord Effects and Toxicity a Occasional anxiety agitation impulsivity mania a Some drug interactions Therapeutic Drugs Ant39depressants Mechanism of Action a Block serotonin reuptake transporter Therapeut39c Drugs Stimulants Amphetamines amphetaminedextroarnphetarnine OW fec s CNS stirnuianmr Euphoria aierthess sense a Amumulation of ofexcitatiori or exhiiaration Paranoia depression possioiusuicide rnav u serotonin at synapse roiiow after Withdrawa Mechanism and Toxicity Jo Increased reiease and decreased reuptake of D catechoiamines norepinephrine and dopamine Tachvcardia hvpertenson seizures shock mm mm an Drugs of Abuse Herom Herom Heroin diacetv39rmrphine AbsorptimDismbuti n Eggvgmfrom Rawdiv dgmburedro brain inineaiainend Nemoussysiem o idgintaiiusunthesized to cure morphine Effects a ic ion Rush Warm ushing of Cutviith drugs sugar starch a 5m heawfee mgsm 39 U59 extremities no pain gt30 rnos vbut has grown With v ungerpergong Mechanism of action Exposure Metaboiizedto rnorphine j Iniection IV or IM opioid iii Shirred ieCeDtOiS Inhaied smoke x 39 um uhvn um Heroin Drugs of Abuse Cocaine Acute Toxici Source 739 Nausea vomihrig severe itching Cocaine hvd ochioride Cardiac runction and breathing siows Extracted tromErythoXVon Coca death 7 5 ant H Chronic Toxicity f CutWith starch taicurn sugar other It thsicai addictionWithdrawi S W m 9 Scarre coiiap d i Use Infections tissue and iung 1 5M USV steadv Liver kidnev iseas Exposure HBV i t Vi t1 Typicaiiysnirred Hegnan wo Inhaed or srnoked Heroin crosses the i 7 crack puri ed through aikaiiriizirig With baking mda and extrattirig With sniverit in ected acerita e BabiES burn to add t mothers WiH be miladdicted to heoin as weii and Drugs of Abuse Cocaine AbsorptionDistribution a Rapid particularly when smoked Effects u Euphoria and excitement u Typically results in physical and psychological dependency Cocaine Toxicity Mechanism of Action u Acts on ventral tegmental area VTA of brain a Blocks dopamine reuptake Cocaine Toxicity Acute toxicity WH a Constricted blood vessels CFO CA WI N Equot a Increased heart rateblood pressure m mm 017 mu M avior hyper ermia elzures cardiac arrest respiratory failure and death Chronic toxicity a Addictiontolerance a heart attacks respiratory failure strokes seizures a Es chotic and a gressive e S Methamphetamine Methamphetamine speed crank Exposure a Ingestion a Inhaled smoke Use a WesUSW 9 MidW and S US Effects a Euphoria increased physical activit AbsorptionDistribution a Rapid depePdent on route es sec 9 minu wkquot Methamphetamine Mechanism of Action u Stimulates release of dopamine Mstnsmunalzmlna mummies n slams or excess dopamine Methamphetamine Acute Toxicity u Damage to nerve terminals in dopamine containing regions of the brain a Hyperthermia u Convulsions Chronic Toxicity u Addiction psychosesparanoia hallucinations a stroke m nkkw Ecstasy His 1970s enha Exposure 805 us psvchiamsm nced communi can on 1985 us DEA banned drug 4meihyIenedloxymeihamphetamine MD MA I39Y Deveioped in Germanv 1900s to Swihe ize pnarmaceuucais used as tooi for 39Wiih pauene E Peaked 10M admitted users at ieast once Ingesuon oftabiet 0r capsuie aJQ JgJJ WOJ Ecstasy Absorpuon and DiSiIibutiO Rapi interferes Wii dey meiabuiism nfit and niherdrugs I Mechanism of Achon Increases nadmh39ansmitter reiease sernmmn dnpamine nnrepinephrine Serumer piays iargemie in mead sieep pain reguiatiun EffectS Mentai stimu SUD emutmnai aasea Warmth errpaihy mwards nihers N mus sweating biurredvisinn OD39HigH hp panic attacks seizures hypemamia e kidney faiiure I Toxici Damage ta semtemn Dniaimng nadmns Memury inpairmmt am m an em Drugs of Abuse CannabinOIds Marijuana Marijuana 5797Tetrahydr0cannabin0i From the Camerassa THC famiiv 0f pianm main agent aidneugntnere are PEt grass reefer weed ab summers u Use Most commoniv used High iipuphiiimty Rapidiy isurbai in iungs set iiiicitdrug EfV be fquotZ SW 5151 39 Exp sure Pa mtand active m iabgiite 9 Innaiaimn ofsmoke 0 c n2 1te 35 ng u n food or MetaboiismEiiminauon iiquid escooHsdgsTHc Feces 25 and unne NI3 am sew am amquot MarIJuana Efrem Eupnuna veiax Manamsm DfActiDn Ads un tannamnmd veteDtuvs e undnauy rm endudenuus tannaunmds Stimuiatesveieaseufduua Azute Tnxitity inneased heart rate biuud Dress Shuvtrtevm mem c mntee e Apatnv at ur interest mutw mine inn a cnmmt mudh bini ithiliS unawndms emDhYsema immunesystem muduiatmsmustiy suDDiEssiuH ease dvisku tantev Maiessdetveasedsuevmat uenusis s evm mutiiitY and deneased p uve 0w iuss iuss er tudmtwe funttiun iasma testes evune slim intrusDettiun sieepiness Anuety pant deiusiuns Medical Marijuana Orai 0r inhaiatiun Reseavth suDDuvts eifed distinttiun between vuutes impiitanun i5 uthev themitaisltannabmums MAY be waived Pain r ii Sume evidente uf effitatv nanuw therapeuti margin huwevev Neumiugitai am Mavemnt Disurdas e 9 Ms epiiepw Parkinsnns Vew iimited ii i number ur studies and effitaEY Nausea and Vumiting antimtits ta eeunerenemednaapy Smukmu effedwE uthev mai annabinuinds egtd512 a dmnamnai Giaum Smukmu iuwevs intiautuiai pressure 10v pvevents dam ade 0 Huh neyve methamsm unimuwn Appetite stimuiati n Fund eniuyment and eatnd frequenEV intveased sue Hallucinogens and Dissociative Drugs HallucinogensDrugs that distort perception of reality a LSD Lysergic Acid Diethylamide most ommon Dissociatives Promote feelings of detachment from environment a PCP phencyc 39dine Deveoped for general anesthetic new Hallucinogens LSD Exposure Ingestion AbsorptionDistribution 3090 minutes Effects a Last upwards to 12 hours a Dramatic effecis on senses Hallucinogen Mechanism of Action Serotonin receptor agonist m Acts to disruptlnteractlon i of nerve cells With serotonin eNoi oa armed therefan perceptan unbalanced m a Toxicity 1 1 i i Perslstentpsvchoas quot l 39 a Bad h lps flashbacks Dissociative Drugs PCP Emosure Smgked Wim pm ingestan gftilet I Mechanism of AclJOrl Disruprrunorioning ngMDA Nememylorasariace retwmr complexes a rres lratan than es kipolnhey deEnege mnvi lgns Emma death Inhalants httpwwwnidanihgov Sources Glue cleaners nail polisn removers nair sprav paints Mechanism 0 Action thought to dissolve rnvelln sheath surrounding neurons resulong in cell death Toxicity Acute effecE ecardiaz armymmias depresslgn delirium resplramry railure Chronic effecE adama e to Viral organs EACH nean lungs rain llver and kldneys Sahel II Absorption and Distribution of Poisons In sum unwrasmr I oxicolo y XENOBIOTIC E BODY TISSUES and ORGANSZ Toxicity lt Metabolism gt Storage Elimination Lecture Oyerview Exposure Physiology review a Portals of Entr Membranes Influential characteristics of chemicals Solubility lipid and water Ionization Chemical transport Routespecific absorption Distribution of chemical Exposure Occurs when a substance comes in contact with a biologic membrane containing an inherent potential to be absorbed n Ifa substance is something that cannot be absorbed does exposure matter m m u Physiology Portals of Entry Physiology Membrane barriers Routes of xenobiotic entry To enter the body a chemical must a Integumentaiy system pass through biological membranes Dermal cutaneous skin absorption a Each may vaiy in thickness but are similar a Rspiratoiy system in structure aa Mayer qu hlrucldilzl lur mldulx Milanan n Gastrointestinal system quotmmquot m m 39 u 39quot Ingestion ora mm mm mum mm mm mquot man mum man whit m 39 a In m MIN 11th Biological Membrane Structure I m we General Factors Affecting Transport Molecular size and shape Solubility in membrane environment a Lipid solubility of the substance Charge a Degree of ionization Selective Permeability of Cell Membrane Due to the structure of cell membranes ie the lipid bilayer 4 ewe endolheglarge peer rwerer some New re wheeH e cl ca p s we hydrogen gangrenourem Influential Characteristics of he 39 als Partitioning Partitioning 39 Dlshlbuuon of a solute between two lmmsclble solvene at equlllbnum Partition Coef icien Measure of De ends Ol lll o hlllcl or hydprophoblcl p D W ngher coef clent more permeable e g DDT mum PCBS KCLCW e e 9 KW or octanol Water partmon reemrrem OctanolWater Partition Coef cient ow As an example if octanolwater system used for chemical X and you measure a c0 6000 ugL a CW 20 rigL Then a KOW600020300 n Log KW 48 Influential Characteristics of Chemicals Water Solub 39ty W Water solubility a Polar groups OH NH2 CO0R Less ermeable n Increased ionization rLesspermea le Lipophilic vs NonLipophilic Substances Lipophilic Ipidlowhg compounds u Well absorbed u Widely distributed a Tend to persist in the body for longer periods of time n More pronounced first pass effect ateration of chemical before entrance into systemic circulation Influential Characteristics of Chemicals Ionization Based on partitioning theory a Only non ionized nonpolar chemicals penetrate membrane At equilibrium concentration of the nonionized species is equal 1 1 on both sides n Ionized substances cannot I penetrate membrane by simple diffusion EDI wJwln m Gnu hquot Chemical Transport 1 Passive Diffusion Features that favor diffusion No external energy is expended 39 Chemica39 Properties a Low molecular weight At eqUIIIbrIum net transfer IS zero a Lipid solubility As determined by chemical structure nonpolar molecules o I ed state Membrane Properties a Large surface area a Thin membrane High concentration gradient nm rr nln m Gunhquot Chemical Transport Chemical Transport 2 Carrier Mediated Transport Carrier Mediated May involve energy use active against 39 FaCi39iFated Ta ctra on radiant concentration gradient or not facilitated a NO energy consumption SE a h 7379 Important for substances lacking sufficient lipid a xjs39l sdpggcrf ismbrane Proteins 5quot Fugmam solubility Carriermay be specificforthe u 39 chemlcal Active transport Transport against concentration E 39 Iquot gradient I mumm Requires energy consumption 3939 Assisted by integral membrane proteins Carrier mw be highly speci c for the chemical m Gun nu l Routes of Absorption Chemical Absorption 1 Dermal Process by which a chemical 39 SBIleglcal funcmns f substance crosses epithelial cell physical Barrier membrane at one of the portals of S a lmwm um entry a Thermoregulation hair sweat glands a Mechanical support ooagen water a Neurosensory reception a Immunological response keratinocytes Langerhans oells a Metabolic capability cm w iu mm Routes of Absorption Dermal Structure Dermal Structure Brick amp Mortar Model 39 3 Layers 397 Proteinrich Intracellular Epidermls toxicant quotmagmas LIIP s 5ramm carneum 39 WWW germWW J J J l E u Dermis Highy vascularized j l l l Gands sweat oil Foiies i C C C l E D Hypodermis A intercellular Conneitive and adipose B iranscellular tissue fammrage Crimmwhr J C C C 1 D via sweat dycis mam quotuhInn mar uni an Dermal Absorption Routes of Absorption Differences in Penetration Respiratory Rate of penetration andabsorption quot Respiration involves movement and differs by egtltc ange of air a Body site e Scrotum gt Forehead gt Mia gt Scaip gt Back Abdomen gt Pairn and Diantar foot surface a Specis r Rodenm gtgt dogs cam ruminanm gtgt DigS Pumonary Alveolar WWW Most vulnerable system a Direct contact with media a Rich capillary exchange Reasons n Differencs in anatom e Skin thickness varies from about 107600 pm 7 iipio composition a Differencs in ph siology 7 biood ow and distribution of biood vesseis Togtlticant absorption depends on n Respiratio rate Chemical properties gases or particulates Inhalation Absorption Inhalation Absorption Gases and Vapors Chemicals on Particulates Absorption takes place in f Particle Deposition the alveolar region D Size dependent location 4 will quotquotquotquot a Equilibration is nearly i 523 201332 3 i I I r r Tracheobronchial instantaneous I P p I I 4 mm Dependent on bloodgas amce gestlon g j 9 partitioning I 71 n Mucocilliary escalator EA AWL 5 u Absorption rate is dependent is a Particle Phagocytosis jut UPOI39l if 7 transfer of particles to A 39h Blood flow through lungs lymph bhy lung mquot Rate and depth of respiration macrOp ages immensi Routes of Absorption Gastrointestinal Tract VIIII and MicrOVIIII 39 System quot C39Udes Provide increased surface area for a mouth esophagus stomach small and large intestines rectum anus liver absorption pancreas Many factors affect GI absorption u Concentration gradient exists a Lipid solubility of the xenobiotic nonpolaruncharged molecules absorb 7quot g faster 39 a pH of the GI tract a Surface area of GI mucosa vii and microvilli structure rezmri ti 1m Administration Differences IV Topical Dermal and Oral Distribution of Toxicants I SelemeCtin absorption in dogs I Zis tcoigfatci or osition so as to be properly apportionedP over or throughout an area llle 7 u refers here to the movementtransport of the toxicant from site of absorption Occurs when an absorbed toxicant enters the 733035 mglltg iv M mmw u Lymphatic system 0 mameg Capillaries nodes tissues tonsils spleen thymus 24 mykgmpical lymphocytes WBCs Drains excess fluid from tissues 24 mgfkg Oral u Circulatory system Heart vessels blood RBCs WBCs platelets plasma Transports nutrientswaste tofrom organstissuescells g Concentration nghrlL 200 400 600 800 1000 Time hours 1mm Factors In uencing Distribution Portal of entryorgan system specific considerations tract toxicant could enter circulatory system via portal vein but sport to liver to be metabolized then to heartlungs Toxicant could enter lymphatic system drain into venous blood su py then to the heart without being biotrans ormed n Respiratory tract Enters via alveoli pulmonary circulation to heart then distributed to tissues Enters lymphatic system as small particles Sk39 In Enter peripheral blood supply m Physiological Factors Affecting Distribution Ratio of blood flow to tissue mass perfusion n Well perfused tissue will more rapidly take up toxicant High ratio organs 7 Brain kidney heart endocrine orgms liver 9 ns Low ratio or a 7 Muscle skin fat bone Percent of total cardiac output a Greater percent likely to receive more toxicant MassVolume a Larger tissue mass provides more toxicant binding sites m Puman quotmmn Physiological Factors Affectl ng DI strl butlo n 39 Blood Flow PerfLsion Rate Organ Body Volume cardiac output ml mi n ml mi nml tissue Lungs 2 100 5000 10 Kldnew 1 22 1100 4 d Grand 0 03 1 50 2 4 Adrenal Glands 0 03 0 2 25 1 2 leer 2 3 27 1 350 0 a Heart 0 4 4 200 0 s Bram 2 14 700 0 5 5U eerl 0 3 1 5 77 0 4 Fat 20 4 200 0 03 Mmde 43 15 750 0 025 m 5mm Physiological Factors Affecting Distribution Structural Barriers to Toxicant Slow rather than actually prevent distribution a Bloodbrain barrier Astrocyte foot processes form tight junctions that separate capillary endothelium from brain neurons u Placental barrier Protecls fetus from some toxicanls due to slowing of absorption from maternal circulation Other Factors In uencing Distribution Presence of vascular or lymphatic componenls e g lrldlrlg to protelrls albumln Abundance of metabolic enzymes Dlsrupt equlllbnum oonoencranon wrlh respectto stored togtltlcarlt Properties of the toxicant Llpld solu lllty Relative amoune or nonmlzed and unbound togtltlcarft Concentration gradient Depends on apparent volume ordsmpunon yo 7 Were a substance ls to be dlstllbum sum as the blood plasma lrlfelsnnal fluld lrmacdlulal uld 7 smaller D Wlll Vlad lows Qladlem large hlglil uladlmt Specific tissue affinities Af nlty of to hl gtltlcarltfor a speo c ussue e c arneedllpumrlrtthemrtels PCEs DDT at r adlDosenssue e Twatvcllnesr me e Amrnugymsldes r kldrEv Emu fads i Mutagenesis and Carcinogenesis no sunwwrnsm 3 RNA rR NA lR NA T 2 I l 39 nxicolo i Mutagenesis 7 No Mutation Mutation Permanent alteration of the genetic information DNA of the cell Types ipomt base subsnmuon and framesnlft mutauons Chromosome aberrahons Mutagens a Chemical and hysical agenis capable of producing mu tIons iradlauon chemomerapeuuc agenm many carcmogens m an Navmalvmiem BasePair Substitution Emma One nucleotide base replaces another Can result in mutant protein Base Deletion Leading to a Frame Shift Mutation Muiani mun Summary of Mutation Effects None a Multiple codons for several amino acids Missense a Different amino acids Nonsense n Abbreviated proteins due to stop codon Chromosome Aberrations Large scale mutations affecting the structure and the number of chromosomes deletions duplications Conditions termed a Aneuploidy egaln or loss of one cnrornosornes Polyploid rAddluonal sets or cnrornosornes m 3 mm 3 Mutagen Assays CarcmogeneSIs Ams Test Carcinogenesis Process mrougn wnlcn cancer develops quot SEW5 Field of chemical carcinogenesis involves Developmentuullzauol39l of expenrnenral systems almed Spec al zed m that rt at determll39lll39lg wnedner a substance l a potel39lual nurnan lS unable to ca C mge e smdy of rnecnanlsrns mrougn wnlcn cnernlcal meme 5mm carclnogens lnduce cancer 7 l r d on nlsudlne Cancer Not a slngle dlsease but a large group ofdlseases cnaracrenzed by uncontrolled growdn of an abnormal cell to produce a populanon of cells mar nave ac ulred me ablllty to mullpr and ll39lvade surroundlng an dlstal39lt ussues quotnoquot CarcinogeneSIs A Mult Stage Process AgeRelated ColonRectum Cancer Incidence And Mortality Rates in UiL41998 Cancer Mutauonsresul f t rorn lrnperrecr DNA repllcatlonrwalr Dxldatlve DNA damage andor DNA damage cased b mvlronmmial caclnogens Overview of the Cancer Process Dnngene Alteration oi Genes mmm S vvrtssnr A n quulatmq Avnvtnsls Gene Ina n res n Altaed mm oi Neg v2 Growth quu amry m Innal Exvanslnn Additional Snmatlt Eu mungquot Malignant n envlasm loss oi mm Cancer Cancer is a type of neoplasm u an abnormal mass of tissue ihe growih of which exceeds and is uncoordinated wiih normal tissue growih and persisis alter ihe cessation of ihe stimuli ihat prov e it wwrmxmmmmmimmmmw nm mm M u WWW mm Cancer Cases by Sites and Gender 2006 Nbquot anui 7 3 12mm 5195 3 memm m m m M m 1 Uunawbladdev All Wash 1 Cancer Deaths by Gender 2006 Lunvaianchus es and Nbquot Wm M WWW 3 291m 2115 7 m cmwm m Biusi mm m m amalgam Vanciex a a Vancius Wm M at am mmnmwm m m Lememia MW cm Nahum Emmi H mm mum cm cm mummy WW 2 Mulhplemyelama Uimawbladdei cm 2 BumM WV 3 m Niamevsiks All aihei snes m m mmmww Mk Mortality Rates 1930 Sites in Males Age Adjusted Mortality Rates 1930 2001 for Selected Sites in Females Tobacco Use and Consequences Causes of Cancer Cancer susceptibility is determined by mplex interac ions etween a e environment and an individuals genetic u It is estimated that 3580 ofall cancers re en VI39ronmenbaIrind uced includes all aspecls of our lifestyle such as diet smo ing exposure to na ra and medical radiation occupation cultural and sexual behavior and exposure to substances in the air water and soil mm quotas Causes of Cancer Japanese Immigrants Assume Cancer Incidence of California Caucasians it Mm um mt m strum Sui iir Wm iiimmm Emilynu Hmr Dmlh m pm cum lCuNyuvd mi km rN minimu mm International Agency for Research on Cancer IARC List of Known Human Carcinogens Classes of Agents Associated with Carcinogenesis DNA damaging agenls genotoxic Mutagenic in in VlU O mutagenicity assays Produce permanent alterauons in geneuc material Epigenetic agenls nongenotoxic NOT utagenic in in VlU O rrutagel39ilcltyassays Do NOT produce permanent alterauons in the genetic material Alter tne efresslol i or represson of certain enes uce perturbations in signal trans ucuon pamw ays tnat in uence cellular evens related to prollferauol i dlfferel39mauol39i or a o tosis ariv contrl ute to clonal expanslol i ofcells containing altered geneuchmaterlal to form tumors but in me absence of suc DNA alterauons these epigeneuc agens m n u on 3 0 effect on mmor forma DNA Damaging Agents Epigenetic Agents Directracting carcinogens gt ormones lnmnsicaHyreactwe Dmpuunds du nut Cunjugated e mgens and dieihylstilbsteml 735 me mam m cavaimw 3 39 lmrrunosuppresswe Xenobioucs lndirectacung carcinogens 39 WWW and Ev 0wquot 39 Sohd state agen Require meiabuh activatmn by Emmy enzymes in farm the ultimate amnngem PM wwans and asbsms 7 species that Manny binds a DNA Tu o oters r 39 39 pr 2 Orteh39adeannylphnmulrl rieiate WA 39 gt permist pmhferamrs TCDD and phennbarbiial W rudmt Nudes in humans i V 7 Diet extess almhul and late age Dr 7 Radiauon and Reacuve Oxygen Species ROS DNA damage can accur man Dr indirectly Inorganic agens g arsmit hmmium and nickel a39e piednanty ave mnsideied m mnmun hiuuqh e unshared DNA damging m aimuugn a pmmuuun methamsm de nitive mchamsm is argey unknown 7 Ciqaietbz 5m ukmq and UVR have initiating ava bum ave alsu mnsideied u have m M W manning adith General Aspects of Chemical Benzoapyrene Metabolism to Carcmogene5is Ultimate Carcmogenic SpeCIes Wm n UlUMEIE sitinuuen quot39 ammoquot amp mm m Malignant Tumui Tumor Promotion Cmv A 39 9 mm M 39 0 h l r Manama TOX201 Poisons People and the Environment NC STATE UNrVERSITV Goxicolo y TIIEIIE llllE ll IIIIBEII 0F Ellillllllls II TIIIS llllll lll llllanv oiwllicll are svrmrmcrrr All at which are DEADLY My First Experience Honey could you please pass the POISON I Saccharin n Arti cial sweetener discovered in 1879 a Canadian study Bladder tumors in male rats fed HIGH doses n FDA proposed ban in 1977 withdrew in 1991 n NIEHS NTP formally removed from cancer threat list in 2000 m1 Guidon The Great Apple Scare of 1989 I Alar Daminozide a Used to prevent pre harvest rotting u The most potent cancer causing agent in our food supplY 60 MinutesEd Bradley Phil Donahue Meryl Streep Daminozide u Removed from markets following public pressure Cult Suicides by Poison I Ghana on Nov 18 1978 I Rancho Santa Fe I J m Janesof the Peoples California on Apr 7 1997 Temple I MarshalAppewh te of 39 Gate 913 people died by suicide Heaven 5 cyanide laced punch or 39 people ingested by murder gunshot phenobarbitol laced applesauce or pudding and washed down with vodka Cult Homicides by Poison Tokyo Japan in March 20 1995 Shaka Asahara of the Supreme Truth Sect Sarin gas released in subway 11 died with 5500 injured Political Poisonings Too many cooks spoil the broth Ukraine Winter 2004 Viktor Yuschenko presidential candidate poisoned with dioxin 39 quot Political Poisonings II Be Careful Who You Dine With Alexander Litvinenko 43 n Believed he had been poisoned on Nov 1 2006 while investigating the October slaying of a Russian joumalist Anna l Politkovskaya n Ultimately died due to m radioactive element Polonium210 Em awn Industrial Incidental Release Organic Mercury Hg l1 l u Minamata Japan u 19321968 chemical company dumped Hg chemicals in Bay a 19505 severe nervous system dysfunction a Diet was fish from Bay Industrial Accidental Release Bhopal India in Dec 3 1984 Pesticide plant released highly toxic gas methyl Isocyanate Casualties n 2000J3eople killed Imme lately a 600000 injured 6000 died since u Scores ofanimal deaths Industrial Accidental Release Part II Local Apex NC Oct 56 2006 EQ Industrial Services a Hazardous waste handling facility Chlorine Gas Several hospitalized Thousands evacuated Oil Spills Prince William Sound Alaska March 24 1989 Exxon Valdez 11 million gal of crude oil Killed about 50000 250000 birds sh an other wildlife rs Poisoned Playgrounds Chromated Copper Arsenate CCA on Wood Decks and Playsets WOOCI IS TOXIC for a Excessive risk of cancer ZOO AHII I IBIS from arsenic V a Bleaching creates hexavalent chromium another potent carcinogen Voluntary removal in Dec a 2003 If Arsenic Treated Pesticides Substances designed to KILL something Since designed and labeled as such is it apparent that there is no safe exposure level Occupational Exposures Mecuric Nitrate HgNO3 and Mad Hatter Disease n In the mid 18005 chemical used to shape wool felt hats u Exposed individuals exhibited psychotic symptoms including hallucmatlons Pesticides Gone Astray DDT a Common use insecticide 19405705 Peregrine Falcons near extinction in Eastern a Reproductive success damaged by eggshell thinning Banned in US in 1972 Reality or Scare Mad Cow Disease l Anthrax Ricin Genetically Modified 39 g Foods E Teeth Whiteners quot39 Shampoo Children s Motrin Children s Toys 25 Castleberry s quot Fact or Fiction Perceptions of Chemicals Everything physical in our world is a chemical Synthetic chemicals are unnatural therefore they are dangerous Organic or allnatural substances are always better quotI M Independent Thinking Manmade Toxic Persistent Toxic Complexity Toxic L m in mm Communication Pathways 39 0 What does toxicology mean to you Look for Balance