Index. Topic 1 Introduction to Toxicology - Disciplines of toxicology - Water intoxication

Transcription

1 Index Tpic 1 Intrductin t Txiclgy - Disciplines f txiclgy - Water intxicatin Tpic 2 Chemicals and Effects - Data n txic substances - Site f txic actin Types f txic effects Irritatin Allergic Reactin Specific Organ Effects Cancer Reprductive Effects Time curse f txic effects - Measurement f txicity Animal testing (in viv) Nn-animal testing (in vitr) - Txicity and risk phases Tpic 3 ADME - Absrptin Passive Diffusin Facilitated Diffusin Active Transprt Other Prcesses Cupled Transprt Pincytsis Phagcytsis Gastrintestinal tract absrptin Respiratry absrptin Skin absrptin - Distributin Rates f absrptin, bitransfrmatin and excretin Bld flw Partitin cefficient - Metablism and bitransfrmatin Epxides Free radicals - Excretin - Accumulatin Tpic 4 Txickinetics - Kinetics Linear kinetics (zer rder) First rder kinetics - Multiple cmpartment mdels - Graphical estimatin f the eliminatin half-life

2 Tpic 5 Fundamental Mlecular Interactins in Txiclgy - Slvent/slute interactins - Osmtic effects - ph changes: acids and bases Mineral substances Organic substances - Oxidatin prcesses - Chemical binding - Key cncepts Nn-cvalent binding Hydrgen bnding Van der Waal's frces Inic attractin Crdinate bnding Txic ligands Txic metals Cvalent bnding Electrphilic agents Chemicals nt requiring biactivatin: epxides Chemicals requiring biactivatin Tpic 6 Bichemical Interactins in Txiclgy - Carbhydrates - Lipids Perxidatin Malndialdehyde Chemicals capable f causing free radical initiated damage - Prteins and related mlecules Enzymes Txic ligands Reversible and irreversible binding Types f txic effects n enzymes Txic metals Receptrs n the surface f cells Transprt prteins Haemglbin Carbxyhaemglbin Methaemglbin Cytchrme C Cyanide pisning Antidte - Nucleic acids Prtein pisns that attack nucleic acids Enzymatic pisns Plant/bacterial pisns: ricin - Summary

3 Tpic 7 Mutagenesis and Carcingenesis - Mutatins DNA repair mechanisms - Gentxic carcingenesis Benign tumurs Malignant tumurs Initiatin Prmtin Prgressin Malignant cnversin - Epigenetic carcingenesis - Dse-respnse relatinships Linear relatinship Sigmidal (curved) relatinship - Carcingenic agents Inrganic substances Asbests Metals Organic subtances Plycyclic armatic hydrcarbns (PAHs) Alkylating agents Armatic amines 2-napthylamine Benzene IARC classificatins Tpic 8 Chemicals and the Immune System - The immune system Innate Immunity Surface and mechanical barriers Chemical agents Phagcytsis Neutrphils Macrphages The cmplement system Adaptive (Acquired) Immunity: Antibdies Types f immunglbulin Humral immunity Plasma cells Memry cells Cell-mediated immunity Types f T cells Cyttxic T cells Helper T cells Memry T cells Regulatry T cells (previusly knwn as suppressr T cells) Natural Killer T Cells (NKT Gamma Delta T cells (γδ T cells) Immune tlerance - The immune system in the defence against txins Txids: Tetanus and Diphtheria immunity Antitxins and antivenins: Venm immunity - Hypersensitivity Type I hypersensitivity reactins IgE Antibdies Hives (Urticaria) Brnchial asthma Anaphylactic shck Type IV hypersensitivity reactins: cell-mediated delayed-type hypersensitivity T lymphcytes and lymphkines Haptens - Immunsuppressin Anti-cancer drugs Anthrax txin - Chemically induced autimmunity

4 Tpic 9 Target Organ Txiclgy - Respiratry txicity Structure f the respiratry system Nse and airways Muccilliary esclatry Alvelar macrphages Assessing lung and airways functin Diseases affecting the airways r lungs Lung cancer Pneumcnisis Asthma Fibrsis Asbestsis Silicsis Cal miners' pneumcnisis - Hepattxicity (liver) - Nephrtxicity (kidneys) Txic metals Halgenated hydrcarbns - Dermal (skin) txicity Irritant cntact dermatitis Allergic cntact dermatitis Eczema Skin cancer Case study 1: envirnmental cancer (histrical) - Optical (eyes) txicity Systemic agents Lcal acting agents Acids Alkalis Organic Slvents Lachrymatrs - Neurtxicity Transmissin f an actin ptential Synapses Neurtxic effects CNS depressin (narcsis) Hypxia Simple asphyxia Chemical asphyxia Disrupted nerve transmissin DDT Lead Picrtxin Musciml Military Nerve Agents Myelin damage Lead Trialkyl-tin Thallium Neurnal damage neurpathy N-hexane Carbn disulfide Acrylamide Organ-mercury cmpunds - Reprductive Txicity Effect n males Effect n females - Carditxicity (bld) Interference with xygen transprt Haemlysis Attacking the bne marrw Affecting the heart itself

5 Tpic 1 Intrductin t Txiclgy - Txiclgy is the study f the harmful effects f chemicals n living rganisms - The main aim f txiclgy is t assess the txicity f chemicals s that they may be used in apprpriate and safe ways - All chemicals, whether natural r synthetic, are ptentially txic if the dse is sufficient - All substances can be harmful if t much is cnsumed including salt (ptentially fatal electrlyte disturbance) and xygen (xidative and free radical damage affecting the nervus system, lungs and eyes) - Just abut everything is ptentially txic if the dse is sufficient; even water - Txiclgy can be cnsidered t be a branch f pharmaclgy which deals with the rigin, nature, chemistry and adverse effects f chemical substances Many different prfessinal grups may be invlved in dealing with txic chemicals including chemists, envirnmental scientists, fd scientists, frensic scientists, clinical scientists and regulatrs. Depending n their prfessinal rles, they may take very different appraches t dealing with txic chemicals and their effects Disciplines f Txiclgy There are 5 disciplines f txiclgy (1) Descriptive Txiclgy: Txicity testing f drugs and chemicals (2) Mechanistic Txiclgy: Scientific investigatin f hw particular chemicals cause their txic effects at the bichemical and system level (3) Regulatry Txiclgy: Assessment f therapeutic and cnsumer chemicals by regulatry bdies (4) Clinical Txiclgy: Cnducted in supprt f medical investigatins r prcedures Clinical txiclgy is abut identifying the cause f pisning s that a suitable treatment can be applied (5) Frensic Txiclgy: The investigatin f txic events in legal investigatins It is abut finding evidence that culd supprt r refute a pssible cause f pisning in supprt f a criminal investigatin Water Intxicatin - The patient may have symptms f cnfusin, disrientatin, nausea, vmiting, changes in mental state, psychtic symptms - Water intxicatin prvkes disturbances in electrlyte balance, resulting in a rapid decrease in serum sdium cncentratin and eventual death

6 Tpic 2 Chemicals and Effects Intrductin - All chemicals are ptentially txic, depending n their dse - Sme chemicals are much mre txic than thers which means that the dse required t cause harm is much less - Fr instance it requires several hundred grams f pure alchl (ethanl) t kill an average human, but less than a milligram f ricin is fatal - Whenever we are dealing with the ptential txic effects f a substance there are certain key pieces f infrmatin that are required in rder t assess the risk, including, hw it gets int a persn r animal, what txic effects it has, hw lng they take t ccur and what dse is required t cause thse effects - In this tpic we will examine hw we can btain txicity data and learn abut the main types f txic effects, their time curse, and measures f txicity Data n Txic Substances - Only 8,000 (0.16%) f the 5 millin chemicals knwn have actually been tested - The three mst imprtant txic chemical summaries have been written in the fllwing fur surces RTECS: Registry f Txic Effects f Chemical Substances CHEMINFO MSDS: Material Safety Data Sheets Clinical Txiclgy Infrmatin Services

7 RTECS - Summary f infrmatin f several thusand chemicals is available n databases such as RTECS - RTECS is a cmpendium f data extracted frm the pen scientific literature - Six types f txicity data are included in the file (1) Primary irritatin (2) Mutagenic effects (3) Reprductive effects (4) Tumrigenic effects (5) Acute txicity (6) Other multiple dse txicity - Specific numeric values such as LD50, LC50, TDL and TCL are nted as well as species studied and rute f administratin used - A typical RTECS entry fr a single substances cntains many lines f infrmatin in a table, each ne f which cntains a very brief summary f a research finding CHEMINFO - CHEMINFO cntains infrmatin n abut 1300 chemicals used in industry - CHEMINFO cntains much mre infrmatin then RTECS, but it des nt cntain references t all the surces f infrmatin that are summarised in the database MSDS - MSDS are prvided by manufacturers and suppliers f chemicals - Cmpanies that imprt, manufacture r distribute and industrial substances in Australia are legally bliged t prvide infrmatin in the frm f MSDS t users - MSDS cntain infrmatin n txicity f the substance and ther hazards including fire and explsin, crrsin and chemical reactivity - Like CHEMINFO, MSDS need nt cntain the references t the infrmatin that they cntain Clinical Txiclgy Infrmatin Services - Mst cuntries have natinal r state pisns infrmatin services that are fr the use f hspitals, physicians and emergency medical services - These services prvide infrmatin n the emergency treatment f pisning, diagnsis, assays and antidtes

8 Site f Txic Actin The txic actin f chemical substances may be dependent n the site f cntact - A txic substance may be able t exert bth lcal and systemic txic effects frm the same dse Lcal Txicity - Sme chemicals are lcally-acting and exert their txic effect at the pint f interactin - Thse that ccur at the site f first cntact, such as crrsive burns n the skin, and may arise frm cntact with crrsive substances such as acids r alkalis Systemic Txicity - Other chemicals may shw their effects at anther part r parts f the bdy i.e. absrptin and distributin f the chemical frm the pint f entry, t a distant site at which the deleterius effect ccurs - Such effects are frequently predminantly evident in ne r tw rgans, knwn as the target rgans r target systems fr that chemical - Imprtant target areas fr systemic txicity include Central nervus system (CNS) Peripheral nervus system (PNS) Cardivascular system (CVS) Bld and bld frming tissues Liver Kidneys

9 Types f Txic Effects - Mechanisms invlving txic chemicals are cmplex - The bichemical changes that result frm small dses might g unbserved and invlve n pathlgical r histlgical changes - Hwever it is pssible t measure sme bilgical changes such as the cncentratins f carbxy-haemglbin and acetylchline esterase - When the dse f a txic substance is high enugh clinical changes ccur and these might be bserved as varius types f txic effects - Imprtant examples f txic effects are (1) Irritatin (2) Allergic Reactin (3) Specific Organ Effects (4) Cancer (5) Reprductive Effects (1) Irritatins - Irritatin f the skin r mucus membranes is a cmmn lcal txic effect f industrial chemicals - While irritatin a the pint f cntact is the mst likely utcme, systemic distributin f chemicals ingested r inhaled can cause reversible irritatin f bth the skin and eyes (2) Allergic Reactin (Hypersensitivity) - Hypersensitivity is the adverse respnse resulting frm prir sensitizatin t the chemical r t a similarly structured ne - Hypersensitivity is typified by the first expsure t the chemical having little adverse effect while later expsures, even t much lwer dses, cause significant and rapid respnses (3) Specific Organ Effects - All rgan systems can be the target f txic chemicals - In industrial txiclgy the lungs, skin and eyes are frequent sites f cntact, while the liver, kidney, nervus and respiratry systems are frequently sites f damage (4) Cancer - A number f substances are capable f causing cancer in humans/animals - Carcingenesis is generally a slw multi-stage prcess, and can take years in the case f humans fllwing expsure (5) Reprductive Effects - Mst reprductive studies have fcused n the teratgenic effects (birth defects) t the fetus frm chemical expsure t the mther prir t and during pregnancy - Of equal imprtance are the effects n bth male and female fertility and genetic damage t sperm and va

10 Time Curse f Txic Effects Acute (Shrt-Term) Txicity - Acute txicity relates t the effect f a single dse r multiple dses ver a shrt perid such as 24 hurs - The acute txic effects may be either lcal r systemic and generally they ccur shrtly after expsure, althugh in sme cases clinical signs may be delayed - Example: Cyanide Chrnic Txicity - Sme txic chemicals may cause adverse effects nly after prlnged r repeated expsures - Example: Tbacc Delayed (Latent) Txic Effects - Sme chemicals may cause changes which have lng latency perids until their effects becme evident - Fr example mutagenic effects may ccur in nly ne cell and hence will remain indiscernible until that cell has undergne multiple divisins - Example: Cancer Reversible/Irreversible Effects - The effect f a chemical may be reversible r irreversible Reversible Effects: Thse which cause a temprary change in the functin f the rgan r system, hwever the functin returns t nrmal fllwing the remval f the chemical Irreversible Effects: Thse which result in a permanent change in the bilgical system and these d nt return t nrmal n the remval f the chemical

11 Measurement f Txicity - The txicity f a chemical can nly be accurately assessed thrugh testing in a bilgical system - It may be pssible t make an educated deductin abut the txic effects f a substances by cnsidering its mlecular structure - It is als pssible t btain sme infrmatin by testing the substance in cells in culture/animals/humans Animal Testing (in viv) - Mst measurements f txicity are carried ut n experimental animals such as rats, rabbits r mice - A range f dses are used and the test substance may be administered in a number f ways such as by an ral gavage, intravenus injectin, implantatin, skin applicatin r inhalatin - The fllwing are all measures that can be derived frm experimentatin f the acute r shrtterm effects f chemicals n test grups f animals (NOTE: The first three measures are measures f the acute txic effects f the chemical, while the later tw are measures f the effects f an immediate r sustained dse f the chemical r drug) LD50: Dse causing death f 50% f the test grup in a shrt-time perid Mst cmmn Des nt tell anything abut the effects f lwer dses that result in chrnic txicity LDLO: Least dse at which death f any f the test grup ccurs LC50: Cncentratin (e.g. in air r water) causing the death f 50% f the test grup ver the whle test duratin LCLO: Least cncentratin (e.g. in air r water( at which death f any f the test grup ccurs) ED50: Effective dse at which the required (therapeutic) effect ccurs in 50% f the test grup ED90: Effective dse at which the required (therapeutic) effect ccurs in 90% f the test grup NOTE: Nne f these measures give any infrmatin abut the chrnic effects, delayed effects, r the effects f lw dses f the chemical in questin - The mst cmmnly used measure f txicity is the median acute lethal dse (LD50); this tells us the acute dse that culd cause death, but it des nt tell us anything abut the effects f lwer dses that result in chrnic txicity Nn-Animal Testing (in vitr) - Nn-animal txicity testing systems are being used with increasing frequency t study the ptentially harmful effects f chemicals - Cnt nt very imprtant

12 Txicity and Risk Phases - In Australia, the NOHSC has published three fficial phrases fr use in MSDS based n the acute ral LD50 in rats