DOCSLIB.ORG

Special Thanks to Colleagues Dr. Gary Reisfield and Dr. Shannon Large

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Special Thanks to Colleagues Dr. Gary Reisfield and Dr. Shannon Large 3/17/2019 Direct biomarkers of alcohol consumption in professionals health programs Scott Teitelbaum, FAAP, DFASAM Pottash Professor in Psychiatry and Neuroscience Department of Psychiatry University of Florida Division Chief of Addiction Medicine Medical Director, Florida Recovery Center Special Thanks to Colleagues Dr. Gary Reisfield and Dr. Shannon Large Objectives • Name three direct biomarkers of alcohol consumption. • Describe the temporal windows of detection for alcohol and its direct biomarkers. • Identify the sources of clinical false positive and clinical false negative results in alcohol biomarker testing. • Identify the most commonly observed direct alcohol biomarker in participants and new evaluees in Florida’s professionals health programs. 1 3/17/2019 09/23/15 AlcoholUnchanged inmetabolism breath, urine, sweat ≤5% Ethanol ≥95% Alcohol dehydrogenase (ADH) Acetaldehyde Aldehyde dehydrogenase (ALDH) Acetate Adapted from: Karch S. Drug Abuse Handbook, 2007 BrAC monitoring 2 3/17/2019 BrAC and zero order kinetics .08 After 1 h .065 After 2 h .050 After 3 h .035 After 4 h .020 After 5 h .005 TAC Monit oring 3 3/17/2019 Unchanged in breath, urine, sweat ≤5% ≤0.1% Ethyl glucuronide (EtG) ≤0.1% Ethanol Ethyl sulfate ≥95% Alcohol dehydrogenase (EtS) (ADH) Acetaldehyde Aldehyde dehydrogenase (ALDH) Acetate Adapted from: Karch S. Drug Abuse Handbook, 2007 Urinary EtG/EtS limitations: 1 EtG EtS 1. Incidental exposures 1. Incidental exposures “Clinical false 2. UTI: E. coli * positive” 1. Dilution 1. Dilution “Clinical false 2. UTI: E. coli (with β-glucuronidase) negative” C. sordellii (with β-glucuronidase) 3. UGT 1A1 polymorphism (?) *In presence of alcohol (i.e., alcohol in urine or yeast (e.g., Candida albicans) + glucose) 4 3/17/2019 EtG/EtS limitations: 2 Alcohol dose group Low ( n=18) Medium ( n=18) High ( n=17) Target BAC (g/dL) 0.02 0.08 0.12 EtOH dose, mean (g) 26.3 57.8 78.8 Number of standard drinks 2 4 6 Peak BAC (g/dL) 0.03 0.09 0.14 89K 200K 11K ng/mL ng/mL ng/mL Alcohol dose group Low ( n=18) Medium ( n=18) High ( n=17) EtG , mean time (hrs) to final 22 ± 5 32 ± 10 37 ± 12 positive @ 100 ng/mL EtG , mean time (hrs) to final 12 ± 5 23 ± 3 26 ± 7 positive @ 500 ng/mL Jatlow PI, et al. Alcohol Clin Exp Res 2014;38:2056-2065 5 3/17/2019 Suggested EtS cut-off concentrations to detect any alcohol consumption [EtG] 4 Suggested EtG cut-off concentrations to detect any alcohol consumption • Anton (2014): • 100 ng/mL for clinical applications • 500 ng/mL for forensic applications • Jatlow (2014): 100 ng/mL or 200 ng/mL for clinical trials • Lowe (2015): 200 ng/mL for clinical and research purposes • McDonell (2015): • 100 ng/mL for clinical and research purposes • 200 ng/mL for when “minimizing false positive results is essential” • SAMHSA (2012): • 100 ng/mL for confirmation of total abstinence • 100-1,000 ng/mL indicates ethanol consumption or incidental exposures • >1,000 ng/mL confirms ethanol consumption Unchanged in breath, urine, sweat ≤5% ≤0.1% Ethyl glucuronide (EtG) ? ≤0.1% Phospholipase D (PLD) Phosphatidylethanol Ethanol (PEth) Ethyl sulfate ≥95% Alcohol dehydrogenase (EtS) (ADH) Acetaldehyde Aldehyde dehydrogenase (ALDH) Acetate Adapted from: Karch S. Drug Abuse Handbook, 2007 6 3/17/2019 Phosphatidylcholine choline water ethanol PLD choline choline ethanol Phosphatidic acid Phosphatidylethanol (PEth) Adapted from: Isaksson A, et al. Drug Testing and Analysis 2011; 3:195-200 PEth 16:0/18:1 Phosphatidyl ethanol 7 3/17/2019 Daily alcohol consumption n=44 Grams/day Drinks/day Women 16-16.5 1.15 Men 32-33 2.3 n=23 n=21 14 (<3.5-183) ng/mL <3.5 (<3.5-25) ng/mL 13 (<3.5-84) ng/mL 16 (5-120) ng/mL Kechagias S, et al. Alcohol and Alcoholism 2015;50:399-406 100 ng/mL 35 ng/mL 20 ng/mL Kechagias S, et al. Alcohol and Alcoholism 2015;50:399-406 8 3/17/2019 Piano MR, et al. Alcohol Alcohol 2015;50:519-525 Classification Definitions Abstainers (n=23) ≤1 drink in past month M: ≤3 drinks, ≤ 2x/week Moderate drinkers ( n=22) F: ≤2 drinks, ≤ 2x/week M: ≥ 5 drinks, ≥ 2x/week Binge drinkers* ( n=58) F: ≥ 4 drinks, ≥ 2x/week *Average number of past month binges: 7.2 ± 4 Average number of drinks per last binge: 8.3 ± 2 (range: 4-13) 4.1 drinks/week 16.5 drinks/week Piano MR, et al. Alcohol Alcohol 2015;50:519-525 9 3/17/2019 Our conclusions based on extant literature • PEth 20 theoretically offers perfect specificity for alcohol consumption • There are large inter-individual variations in PEth kinetics • PEth 20 can theoretically be detected for >4 weeks after last use • One cannot determine time/quantity of last drink from PEth concentration • Negative PEth 20 ≠ proof of alcohol abstinence • Negative PEth 20 is compatible with: • Alcohol abstinence • Daily low-risk (1-2 drinks/day) alcohol consumption • Positive PEth 20 disproves abstinence • Positive triple-digit PEth indicates heavy alcohol consumption The roles of phosphatidylethanol (PEth), ethyl glucuronide (EtG), and ethyl sulfate (EtS) in identifying alcohol consumption among participants in professionals’ health programs Reisfield G, University of Florida, Psychiatry Teitelbaum S, University of Florida, Psychiatry Morrison D, University of Florida, Psychiatry Large S, University of Florida, Psychiatry Jones J, United States Drug Testing Laboratories Inc 1,040 IMEs • uEtG, uEtS, PEth measured • ≥1 positive results 57 194 On contract New evaluations 10 3/17/2019 Percentage of IMEs with positive results at PEth 20 and/or different EtG/EtS cutoff concentrations On contract New evaluations Mdn: 58 ng/mL Mdn: 83 ng/mL Mdn: 688/47 ng/mL Mdn: 1,842/218 ng/mL Mdn: 3,567 ng/mL 153 40 Mdn: 1,384 ng/mL 120 26 58 4 Evaluees with a single positive biomarker Mdn: 51 ng/mL Mdn: 41 ng/mL 31 73 12% Oncontract 19 EtS100 Percentage of PEth 20 - and EtGEtG 500100/EtS/EtS1 25 -positive participants according to00 reason for referral n=57 100% Mdn: 51 ng/mL Mdn: 69 ng/mL 90% 81% 80% 70% 65% 58% 60% 50% Mdn: 310/40 ng/mL Mdn: 687/62 ng/mL 40% 26% 30% 27% 20% 10% 3% Oncontract 0% Alcohol-related referral (n=31) Non-alcohol-related referral (n=26) PEth EtG100/EtS25EtG500/EtS100 11 3/17/2019 Percentage of PEth 20 - and EtGEtG 500100/EtS/EtS1 25 -positive participants according to alcohol00 use disorder history 100% Mdn: 55 ng/mL Mdn: 122 ng/mL n=57 90% 86% Mdn: 310/40 ng/mL Mdn: 541/41 ng/mL 80% 76% 70% 60% 50% 43% 40% 30% 28% 20% 14% 11% 10% 0% Oncontract History of alcohol use disorder (n=36) No history of alcohol use disorder (n=21) PEth EtG100/EtS25EtG500/EtS100 Role of PEth in the IME PEth providing essential information 100% 90% 80% 70% 60% 50% 6 10% 40% 30% 20% 27 47% 10% 0% Oncontract PEth (+) PEth (-) IMEs with hair EtG 20 testing On contract New evaluations 16 50 31 6 15 1 12 3/17/2019 Conclusions 1. There is no single ideal biomarker for measuring alcohol abstinence 2. For detecting any recent alcohol use, PEth was the single most important biomarker, but… 3. For detecting any recent alcohol use, PEth combined with EtG/EtS had the greatest yield. 4. With regard to urinary biomarkers, traditional EtG 500 -only screening would have left most very recent alcohol consumption undetected. The greatest yield necessitates EtS testing. 5. Based on very limited evidence, hair EtG 20 offered the lowest yield for detecting alcohol consumption. 6. Best use of biomarkers requires history (days), history (weeks), history (months)! Additional talking points • Roles of PEth • In PHP • Early after +EtG • Random • In treatment • Early • Role of mobile BrAC monitoring tools 13.
Load more

Recommended publications
  • The 80-Hour Alcohol Test & More
    The 80-Hour Alcohol Test & More: Novel Biomarkers of Alcohol Exposure ACMT Alcohol Academy San Juan, PR March 14, 2013 Michael G. Holland, MD, FAACT, FACMT, FACOEM, FACEP Clinical Associate Professor, SUNY Upstate Medical University Consulting Medical Toxicologist Upstate New York Poison Center, Syracuse, NY Director of Occupational Medicine Center for Occupational Health of Glens Falls Hospital Glens Falls, NY 1 Disclosures Nothing to disclose 2 Alcohol Biomarkers Objective measures that are helpful as: 1. Outcome measures in studies 2. Screens for possible alcohol problems in individuals with unreliable drinking histories 3. Evidence of abstinence in individuals prohibited from drinking alcohol These tests are complimentary to self- report assessments 3 Categories of Alcohol Biomarkers Indirect Biomarkers Direct Biomarkers 4 Indirect Biomarkers Assesses alcohol effects on body systems Non-specific, insensitive AST, ALT, GGT, MCV – Things other than EtOH abuse causes elevations – Some abusers do not have elevations 5 Indirect Biomarkers Newest: CDL- Carbohydrate-deficient transferrin – Elevated after > 2 weeks of heavy EtOH abuse – Few other things cause elevations – Insensitive to bingeing 6 Direct Alcohol Biomarkers Analytes of alcohol or its metabolites – Measures alcohol directly in body matrices – Or alcohol adducts in body matrices Most common is BAC, BrAC 7 Direct Alcohol Biomarkers Alcohol Metabolites: – Most alcohol is oxidized by ADH and AlDH – A very small amount is broken down non- oxidatively, creating analytes that can be measured for a longer period than alcohol itself – Measured in the blood or urine. 8 Alcohol Metabolism Unchanged in breath, urine, sweat < 5% Ethyl < 1% < 1% Glucuronide Ethanol Ethyl Sulfate UDP- Sulfotransferase (EtG) glucuronosyl- (EtS) transferase ADH & > 95% AlDH Acetaldehyde and acetic acid 9 Direct Biomarkers Ethyl glucuronide (EtG), ethyl sulfate (EtS), and phosphatidyl ethanol (PEth).
    [Show full text]
  • Medical Consequences of Interactions Between Alcohol and Drugs
    Medical Consequences of Interactions between Alcohol and Drugs Jörn Schneede, M.D. 1 1 Effects of ethanol in general • Direct physico-chemical interactions with cell membranes – Direct cell injury • Dehydration • Precipitation of cytoplasm • Neurolysis (trigeminal neuralgia) – Integration in cell membranes: • PEth formation / fatty acid ethyl esters (FAEE) • Bacteriocidal / antifungal (dehydration, precipitation of proteins) • Interaction with a large number of receptors (GABA A, glycin, glutamate/NMDA, serotonin, acetylcholine, ion channels) • Enzyme induction (CYP 2E1, CYP1A2, CYP3A4, ALAT/ASAT, GGT) • Metabolic effects (formation of NADH during ADH-reaction; inhibition of gluconeogenesis and stimulation of liponeogenesis: AFLD) 2 2 1 Biological Markers in Clinical Diagnosis of Alcoholism • Ethyl glucuronide • Ethyl sulfate • Fatty acid ethyl esters (FAEE) • 5-hydroxy-tryptophol • CDT • PEth • GGT • MCV (>90) • AST/ALT 3 3 Peth/FAEE – non-oxidative metabolism 28 days! 4 4 2 Pharmacology Pharmacodynamics 5 5 Alcohol – mechanisms of action a lot of putative mechanisms! 6 6 3 Alcohol – mechanisms of action a lot of putative mechanisms! #2 7 7 Alcohol – mechanisms of action a lot of putative mechanisms! #3 8 8 4 Pharmacology Pharmacokinetics 9 9 Ethanol – key pharmacokinetic data • Vd: 37 l/70kg • First pass metabolism in liver – Extraction ratio 0.2 • Km at blood concentrations of 80 mg/L or 0.075‰ (rattfyllerigränsen går vid 0,2 ‰) • Zero order kinetics – no half life • Vmax elimination: 0.1 g/kg/h • Renal clearance 1 ml/min 10 10 5 ADH/ALDH/CYP-enzymes
    [Show full text]
  • ARK™ Ethyl Glucuronide Assay
    1 NAME ARK™ Ethyl Glucuronide Assay 2 INTENDED USE The ARK Ethyl Glucuronide Assay is intended for the qualitative and semiquantitative For Export Only – Not For Sale in USA determination of ethyl glucuronide in human urine at cutoff concentrations of 500 ng/mL and 1000 ng/mL. The assay provides a simple and rapid analytical screening procedure for detecting ethyl glucuronide in urine and is designated for professional use on automated ™ clinical chemistry analyzers. ARK Ethyl Glucuronide Assay The semiquantitative mode is for the purpose of (1) enabling laboratories to determine an This ARK Diagnostics, Inc. package insert for the ARK Ethyl Glucuronide Assay must be read appropriate dilution for the specimen for confirmation by a confirmatory method, or (2) prior to use. Package insert instructions must be followed accordingly. The assay provides permitting laboratories to establish quality control procedures. a simple and rapid analytical screening procedure for detecting ethyl glucuronide in urine. The ARK Ethyl Glucuronide Assay provides only a preliminary analytical result. A more specific Reliability of the assay results cannot be guaranteed if there are any deviations from the alternative chemical method must be used in order to obtain a confirmed positive analytical instructions in this package insert. result. Gas Chromatography/Mass Spectrometry (GC/MS) or Liquid Chromatography/tandem Mass Spectrometry (LC-MS/MS) is the preferred confirmatory method. Clinical consideration and professional judgment should be exercised with any drug test result, particularly when the preliminary test result is positive. CUSTOMER SERVICE C 3 SUMMARY AND EXPLANATION OF THE TEST ARK Diagnostics, Inc. Assessment of ethanol consumption is important for medical treatment of persons addicted 48089 Fremont Blvd Emergo Europe to alcohol.
    [Show full text]
  • Breath and Urine Alcohol Testing: Relationship to BAC and Use Patterns
    Breath and Urine Alcohol Testing: Relationship to BAC and Use Patterns ACMT ASM Huntington Beach, CA March 17, 2016 Michael G. Holland, MD, FAACT, FACMT, FACOEM, FACEP Associate Professor, SUNY Upstate Medical University & Consulting Medical Toxicologist, Upstate New York Poison Center, Syracuse, NY Occupational Medicine Director, Glens Falls Hospital Center for Occupational Health; Glens Falls, NY Senior Medical Toxicologist, Center for Toxicology and Environmental Health; North Little Rock, AR Disclosures No financial relationships to disclose I perform medical-legal consulting regarding drug and alcohol impairment My practice of Occupational Medicine uses BAT devices and I am a BAT trainer Alcohol Biomarkers Objective measures that are helpful as: 1. Outcome measures in studies 2. Screens for possible alcohol problems in individuals with unreliable drinking histories 3. Evidence of abstinence in individuals prohibited from drinking alcohol These tests are complimentary to self- report assessments Categories of Alcohol Biomarkers Indirect Biomarkers Direct Biomarkers Indirect Biomarkers Assesses alcohol effects on body systems Non-specific, insensitive AST, ALT, GGT, MCV – Things other than EtOH abuse cause elevations – Some abusers do not have elevations Indirect Biomarkers Newest: CDT- Carbohydrate-deficient transferrin – Elevated after > 2 weeks of heavy EtOH abuse (>5 drinks/day) – Few other things cause elevations – Insensitive to bingeing Direct Alcohol Biomarkers Analytes of alcohol or its metabolites – Measures alcohol directly in body matrices – Or alcohol adducts in body matrices Most common is BAC, BrAC Direct Alcohol Biomarkers Alcohol Metabolites: – Most alcohol is oxidized by ADH and AlDH – A very small amount is broken down non- oxidatively, creating analytes that can be measured for a longer period than alcohol itself – Analytes are measured in the blood or urine.
    [Show full text]
  • Biological Markers for Alcoholism
    UC San Diego UC San Diego Previously Published Works Title Consensus paper of the WFSBP task force on biological markers: biological markers for alcoholism. Permalink https://escholarship.org/uc/item/32r0d1jm Journal The world journal of biological psychiatry : the official journal of the World Federation of Societies of Biological Psychiatry, 14(8) ISSN 1562-2975 Authors Hashimoto, Eri Riederer, Peter Franz Hesselbrock, Victor M et al. Publication Date 2013-12-01 DOI 10.3109/15622975.2013.838302 Peer reviewed eScholarship.org Powered by the California Digital Library University of California The World Journal of Biological Psychiatry ISSN: 1562-2975 (Print) 1814-1412 (Online) Journal homepage: https://www.tandfonline.com/loi/iwbp20 Consensus paper of the WFSBP task force on biological markers: Biological markers for alcoholism Eri Hashimoto, Peter Franz Riederer, Victor M. Hesselbrock, Michie N. Hesselbrock, Karl Mann, Wataru Ukai, Hitoshi Sohma, Florence Thibaut, Marc A. Schuckit & Toshikazu Saito To cite this article: Eri Hashimoto, Peter Franz Riederer, Victor M. Hesselbrock, Michie N. Hesselbrock, Karl Mann, Wataru Ukai, Hitoshi Sohma, Florence Thibaut, Marc A. Schuckit & Toshikazu Saito (2013) Consensus paper of the WFSBP task force on biological markers: Biological markers for alcoholism, The World Journal of Biological Psychiatry, 14:8, 549-564, DOI: 10.3109/15622975.2013.838302 To link to this article: https://doi.org/10.3109/15622975.2013.838302 Published online: 18 Nov 2013. Submit your article to this journal Article views: 254 View related articles Citing articles: 14 View citing articles Full Terms & Conditions of access and use can be found at https://www.tandfonline.com/action/journalInformation?journalCode=iwbp20 The World Journal of Biological Psychiatry, 2013; 14: 549–564 CONSENSUS PAPER Consensus paper of the WFSBP task force on biological markers: Biological markers for alcoholism ERI HASHIMOTO 1 , PETER FRANZ RIEDERER 2 , VICTOR M.
    [Show full text]
  • Ethanol, Ethyl Glucuronide, and Ethyl Sulfate Kinetics After Multiple Ethanol Intakes
    1 Linköping University | Department of Physics, Chemistry and Biology Bachelor thesis, 16 hp | Bachelor of science in chemical engineering Spring term 2018 | LITH-IFM-G-EX--18/ 3504--SE – Ethanol, ethyl glucuronide, and ethyl sulfate kinetics after multiple ethanol intakes – A study of ethanol consumption to better determine the latest intake of alcohol in hip flask defence cases Rickard Lundberg Examiner, Johan Dahlén Supervisor, Robert Kronstrand Co-Supervisor, Gunnel Nilsson 2 Avdelning, institution Datum Division, Department Date 2018-05-30 Department of Physics, Chemistry and Biology Linköping University Språk Rapporttyp ISBN Language Report category Svenska/Swedish Licentiatavhandling ISRN: LITH-IFM-G-EX--18/3504--SE Engelska/English Examensarbete _____________________________________________________ C-uppsats ____________ D-uppsats Övrig rapport Serietitel och serienummer ISSN ________________ Title of series, numbering ___________________________ ___ ____________ _ URL för elektronisk version Titel Title Ethanol, ethyl glucuronide, and ethyl sulfate kinetics after multiple ethanol intakes Författare Author Rickard Lundberg Sammanfattning Abstract The hip-flask defence is a common claim in drunk drinking cases. In Sweden and Norway two different models are used to determine these cases. In Sweden one blood and two urine samples taken 60 minutes apart are used for analysis. In Norway two blood samples taken 30 minutes apart are used. Sweden focuses on the rise or fall of alcohol concentration in urine (UAC), and the ratio between UAC and blood alcohol concentrations (BAC). Norway focuses on the rise or fall of the alcohol metabolite ethyl glucuronide (EtG) and the ratio between BAC and EtG. The aim of this study was to test the models for multiple intakes and with different alcoholic beverages.
    [Show full text]
  • Porodnická Analgezie a Anestezie V České Republice Minulost
    Biological markers for abuse- and addiction Tomáš Zima Institute of Clinical Chemistry and Laboratory Diagnostic Charles University PraPraguegue, Czech ReRepublicpublic Denial is the feature of the alcoholism • Patient´s history. • Family • Psychologic examination • Laboratory markers of alcohol abuse. Conventional laboratory markers of alcohol abuse • GGT. • AST/ALT ratio. • mean erythrocytes corpuscular volume (MCV). sensitivity 27-52% specificity 85-90% Innovative markers of alcohol abuse • Sialic acid deficient protein: transferin, α-acidglycoprotein • Enzymatic systems: phosphatidylcholine hydroperoxide (PCOOH) • Direct ethanol metabolites - fatty acid ethyl ester - ethyl glucuronide - phosphatidyl ethanol -ethyl sulfate Carbohydrate-deficient transferrin - CDT • CDT – one of the most sensitive and specific laboratory markers of alcohol abuse. • Alcohol causes defficiency of sialic acid - measurement of this deffect is marker of alcohol abuse. • Half-time: 12 days cut-off value: 2.5% – 3% of CDT CDT – characteritics • Specificity 70-80% • False positivity 20-30% • Stability in serum 4C – week -20C 6 months – Serum separated - preferably during 4 hr • RIA, HPLC, turbidimetry • CDT – more specific then GGT • CAVE - genetic variation, congenital disoders of glycosilation • Disoders with transferin increase – pregnancy, oestrogen use, contraceptive use, iron deficiency anemia, anti-epileptic drug therapy – hepatic drug affects %CDT in cirrhotic patients active alcohol abuse, control patients with cirrhosis Box Plot %CDT Split By: etyl
    [Show full text]
  • Biomarkers of Heavy Drinking
    Biomarkers of Heavy Drinking John P. Allen, Ph.D., M.P.A.,* Pekka Sillanaukee, Ph.D.,† Nuria Strid, Ph.D.,‡ and Raye Z. Litten, Ph.D.§ *Scientific Consultant to the National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD †Tampere University Hospital, Research Unit and Tampere University, Medical School, Tampere, Finland ‡NS Associates, Stentorp, Sweden §Chief, Treatment Research Branch, Division of Clinical and Prevention Research, National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD In recent years significant advances have been markers for which fully automated test procedures made in biological assessment of heavy drinking. have yet to be developed. These advances include development of new labo­ Third, the expertise required to ensure valid ratory tests, formulation of algorithms to combine results from biomarkers is somewhat different from results on multiple measures, and more extensive that needed to obtain maximally valid self-report applications of biomarkers in alcoholism treat­ information, where rapport, assurance of confiden­ ment and research. tiality, motivation for honesty, current state of sobri­ Biomarkers differ from the psychometric ety, and testing conditions are important measures discussed in other chapters of this Guide considerations. The accuracy of biomarker informa­ in at least four major ways. Most importantly, they tion is rarely a function of sample collection, but do not rely on valid self-reporting, and, hence, are rather is closely related to sample handling, storage, not vulnerable to problems of inaccurate recall or and transmittal; quality assurance of laboratory reluctance of individuals to give candid reports of procedures for isolation of the biomarker; and their drinking behaviors or attitudes.
    [Show full text]
  • ENITRE Thesis Final CORRECTED 1
    TECHNISCHE UNIVERSITÄT MÜNCHEN Fachgebiet für Biowissenschaftliche Grundlagen in Kooperation mit der Gemeinsamen Forschungsstelle der Europäischen Kommission (DG JRC) in Ispra (Italien) Physiologically- based toxicokinetic and toxicodynamic modelling of single and repeated dose toxicity Monika Gajewska Vollständiger Abdruck der von der Fakultät Wissenschaftszentrum Weihenstephan für Ernährung, Landnutzung und Umwelt der Technishen Universität München zur Erlangung des akademischen Grades eines Doktors der Naturwissenschaften genehmigten Dissertation. Vorsitzender: Univ.-Prof. Dr. H.-W. Mewes Prüfer der Dissertation: 1. apl. Univ.-Prof. Dr. K.-W. Schramm 2. Univ.-Prof. Dr. H. Briesen Die Dissertation wurde am 28.10.2014 bei der Technischen Universität München eingereicht und durch die Fakultät Wissenschaftszentrum Weihenstephan für Ernährung, Landnutzung und Umwelt am 02.02.2015 angenommen. Abstract To analyse the effects of human exposure to selected chemicals, physiologically-based toxicokinetic (PBTK) and toxicodynamic (PBTD) models for the healthy adult Caucasian population were constructed and parameterised for the following nine case study compounds, which include industrial chemicals and substances found in consumer products and food: coumarin, estragole, hydroquinone, caffeine, ethanol, isopropanol, methyl iodide, styrene and nicotine. Literature quantitative structure-property relationships (QSPRs) for skin permeation, plasma protein binding and blood-to-air partition coefficient were collected and evaluated for these substances. A simple PBTK model structure was first refined in terms of the skin, gastrointestinal and respiratory tracts by introducing sub-compartments to give a better simulation of absorption profiles. Subsequently the PBTK model was applied for the purposes of interspecies (rat-to- human) and route-to-route extrapolations of experimental no-observed adverse effect level (NOAEL) doses, in vitro-to-in vivo correlations of skin permeation and liver clearance, and the prediction of metabolites in blood and urine.
    [Show full text]
  • URINE TESTING for ALCOHOL and ETHYL GLUCURONIDE Educational Commentary Is Provided Through Our Affili
    EDUCATIONAL COMMENTARY – URINE TESTING FOR ALCOHOL AND ETHYL GLUCURONIDE Educational commentary is provided through our affiliation with the American Society for Clinical Pathology (ASCP). To obtain FREE CME/CMLE credits, click on Earn CE Credits under Continuing Education on the left side of the screen. Learning Outcomes On completion of this exercise, the participant should be able to • recognize settings in which alcohol detection would be useful; • explain what ethyl glucuronide (EtG) is and how it relates to alcohol; • understand causes of false-positive or false-negative results in detection of alcohol in urine; • determine when testing for EtG would be more informative than testing for alcohol itself; and • know under what circumstances EtG is used as proof of alcohol use in legal proceedings. Introduction Alcohol, one of the most frequently abused substances, is also difficult to monitor, as it is metabolized quickly in the human body. Although consumption of alcohol is legal in most situations, alcohol can cause significant mental and physical impairment when consumed in excess. In the United States and other countries the consumption of alcohol is regulated by age, retail sale is regulated by time of day or seller type, and use is restricted in public spaces and in relation to operation of motor vehicles. Most employers prohibit employees from consuming alcohol during working hours and have disciplinary policies to deal with employees whose consumption of alcohol at any time affects their ability to perform job duties. Alcohol concentrations are most frequently tested in law-enforcement situations such as traffic stops or other situations that could be linked to the use of alcohol, in addiction recovery programs, and in pre- employment drug screening.
    [Show full text]
  • Fatty Acid Ethyl Esters (FAEE), a Biomarker of Alcohol Exposure: Hope for a Silent Epidemic of Fetal Alcohol Affected Children
    Fatty Acid Ethyl Esters (FAEE), A Biomarker of Alcohol Exposure: Hope for a Silent Epidemic of Fetal Alcohol Affected Children by Vivian Kulaga A thesis submitted in conformity with the requirements for the degree of Doctor of Philosophy Institute of Medical Science University of Toronto © Copyright by Vivian Kulaga 2009 Fatty Acid Ethyl Esters (FAEE), A Biomarker of Alcohol Exposure: Hope for a Silent Epidemic of Fetal Alcohol Affected Children Vivian Kulaga Doctor of Philosophy Institute of Medical Science University of Toronto 2009 Abstract One percent of children in North America may be affected by fetal alcohol spectrum disorder (FASD). FASD remains difficult to diagnose because confirmation of maternal alcohol use is a diagnostic criterion, and women consuming alcohol during pregnancy are reluctant to divulge this information for fear of stigmatization and losing custody of the child. Consequently, using a biomarker to assess alcohol exposure would provide a tremendous advantage. Recently, the measurement of fatty acid ethyl ester (FAEE) in hair has provided a powerful tool for assessing alcohol exposure. My thesis fills a translational gap of research between the development of the FAEE hair test and its application in the context of FASD. The guinea pig has been a critical model for FASD research, in which FAEE hair analysis has previously distinguished ethanol-exposed dams/offspring from controls. My first study, reports a positive dose-concentration relationship between alcohol exposure and hair FAEE, in the human, and the guinea pig. Humans also displayed over an order of magnitude higher FAEE incorporation per equivalent alcohol exporsure, suggesting that the test will be a sensitive clinical marker of fetal alcohol exposure.
    [Show full text]
  • Biomolecules and Biomarkers Used in Diagnosis of Alcohol Drinking and in Monitoring Therapeutic Interventions
    Biomolecules 2015, 5, 1339-1385; doi:10.3390/biom5031339 OPEN ACCESS biomolecules ISSN 2218-273X www.mdpi.com/journal/biomolecules/ Review Biomolecules and Biomarkers Used in Diagnosis of Alcohol Drinking and in Monitoring Therapeutic Interventions Radu M. Nanau 1 and Manuela G. Neuman 1,2,* 1 In Vitro Drug Safety and Biotechnology, University of Toronto, Toronto, ON M5G 0A3, Canada; E-Mail: [email protected] 2 Department of Pharmacology and Toxicology, Faculty of Medicine, University of Toronto, Toronto, ON M5G 0A3, Canada * Author to whom correspondence should be addressed; E-Mail: [email protected]; Tel.: +1-416-398-4880. Academic Editors: Natalia Osna and Kusum Kharbanda Received: 9 April 2015 / Accepted: 29 May 2015 / Published: 29 June 2015 Abstract: Background: The quantitative, measurable detection of drinking is important for the successful treatment of alcohol misuse in transplantation of patients with alcohol disorders, people living with human immunodeficiency virus that need to adhere to medication, and special occupational hazard offenders, many of whom continually deny drinking. Their initial misconduct usually leads to medical problems associated with drinking, impulsive social behavior, and drunk driving. The accurate identification of alcohol consumption via biochemical tests contributes significantly to the monitoring of drinking behavior. Methods: A systematic review of the current methods used to measure biomarkers of alcohol consumption was conducted using PubMed and Google Scholar databases (2010–2015). The names of the tests have been identified. The methods and publications that correlate between the social instruments and the biochemical tests were further investigated. There is a clear need for assays standardization to ensure the use of these biochemical tests as routine biomarkers.
    [Show full text]