Introduction To Toxicology The Dose-response And Basic Concepts.
INTRODUCTION TO TOXICOLOGYTHE DOSE-RESPONSE AND BASICCONCEPTS.MARINA GOUMENOUChemist - ToxicologistBSc, MSc, PhD, ERTEUROPEAN FOOD SAFETY AUTHORITY
DISCLAIMERThis presentation contains the view of the author, and does notrepresent an official view of European Food Safety Authority2Dr. Marina, Goumenou, Scope and ethical principles of toxicology and 3R, EUROTOX Course of Basic Toxicology, Zagreb, Croatioa, 4/4/2016
PRESENTATION OVERVIEW1 Basic terms2 Fields of Toxicology3 The dose and the dose – response4 The Risk Assessment5 Toxicity TestingIntroduction to Toxicology, the Dose-Response and Basic Concepts, EUROTOX Course of Basic Toxicology, Dr. Marina Goumenou4/4/2016
WHAT IS TOXICOLOGY?“The science of poisons”“The study of how natural or man-made poisons causeundesirable effects in living organisms”“The study of the adverse effect of chemical or physicalagents on living organisms”Introduction to Toxicology, the Dose-Response and Basic Concepts, EUROTOX Course of Basic Toxicology, Dr. Marina Goumenou4/4/2016
WHAT IS ADVERSITY?“A change in the morphology, physiology, growth,development, reproduction or lifespan of an organism, systemor (sub)population that results in an impairment of functionalcapacity, an impairment in the capacity to compensate foradditional stress or an increase in susceptibility to otherinfluences” (IPCS/WHO, 2009)Adverse effects may occur in many forms, ranging from immediate death to subtle changes not realized until months or yearslater. They may occur at various levels within the body, such as an organ, a type of cell, or a specific biochemical. Knowledge ofhow toxic agents damage the body has progressed along with medical knowledge. It is now known that various observablechanges in anatomy or body functions actually result from previously unrecognized changes in specific biochemicals in the bodyIntroduction to Toxicology, the Dose-Response and Basic Concepts, EUROTOX Course of Basic Toxicology, Dr. Marina Goumenou4/4/2016
PARACELSUS ( 1500AD)"All substances are poisons; there is nonewhich is not a poison. The right dosedifferentiates a poison and a remedy“ Specific chemicals were actually responsible for the toxicityof a plant or animal poison. The body's response to those chemicals depended on thedose received. Small doses of a substance might be harmless or beneficialwhereas larger doses could be toxic.Introduction to Toxicology, the Dose-Response and Basic Concepts, EUROTOX Course of Basic Toxicology, Dr. Marina Goumenou4/4/2016
THE DOSE MAKESTHE POISONIntroduction to Toxicology, the Dose-Response and Basic Concepts, EUROTOX Course of Basic Toxicology, Dr. Marina Goumenou4/4/2016
TOXICANT, TOXIN, OR POISON?A toxic agent is anything thatcan produce an adversebiological effect. It may bechemical, physical, orbiological in form. Forexample, toxic agents may bechemical (such as cyanide),physical (such as radiation)and biological (such as snakevenom).Introduction to Toxicology, the Dose-Response and Basic Concepts, EUROTOX Course of Basic Toxicology, Dr. Marina Goumenou4/4/2016
HOW DOES TOXICITY DEVELOP?The toxicity pathway concept as proposedby the National Academies. The horizontalline depicts a biological process, orsignaling pathway, that generates anormal biologic function from an input.When a xenobiotic chemical is introduced(vertical arrows descending toward thepathway), interaction of the chemical withsome molecular target perturbs thepathway and leads to early cellularchanges. At low levels of exposure (lowinternal dose), homeostatic mechanismsgenerate adaptive responses thatmaintain or restore the function of thepathway. At high doses, these adaptiveresponses are overcome, leading to cellinjury and, eventually, to morbidity andmortality. Adapted from NRC (2007).Introduction to Toxicology, the Dose-Response and Basic Concepts, EUROTOX Course of Basic Toxicology, Dr. Marina Goumenou4/4/2016
WHAT IS A “SENSITIVE SUB-POPULATION?” A sensitive sub-population describesthose persons who are more at risk fromillness due to exposure to hazardoussubstances than the average, healthyperson. These persons usually include thevery young, the chronically ill, and thevery old. It may also include pregnantwomen and women of childbearing age.Depending on the type of contaminant,other factors (e.g., age, weight, lifestyle,sex) could be used to describe thepopulation.Introduction to Toxicology, the Dose-Response and Basic Concepts, EUROTOX Course of Basic Toxicology, Dr. Marina Goumenou4/4/2016
FIELDS OF TOXICOLOGY (1) How various plants, animals, and humans are affected by exposure to toxic substances. Study of chemicals that contaminate food, water, soil, or the atmosphere.Environmental Toxic substances that enter bodies of waters such as lakes, streams, rivers, and oceans.Toxicology Study of health effects from exposure to chemicals in the workplace.Occupational High exposure in specific chemicals (e.g. operator exposure)ToxicologyIntroduction to Toxicology, the Dose-Response and Basic Concepts, EUROTOX Course of Basic Toxicology, Dr. Marina Goumenou4/4/2016
FIELDS OF TOXICOLOGY (2)RegulatoryToxicology Gathers and evaluates existing toxicological information to establish concentration-basedstandards of “safe” exposure. The standard is the level of a chemical that a person can be exposed to without anyharmful health effects.FoodToxicology Safe and edible supply of food to the consumer. determine the acceptable daily intake levelfor those substances. Additives and processing aids, pesticides, heavy metals, contaminants, novel foods Food allergies.Introduction to Toxicology, the Dose-Response and Basic Concepts, EUROTOX Course of Basic Toxicology, Dr. Marina Goumenou4/4/2016
FIELDS OF TOXICOLOGY (3)ClinicalToxicology Diseases and illnesses associated with short term or long termexposure to toxic chemicals. Poisonings The science of toxicity testing for safety evaluation and regulatoryrequirementsDescriptiveToxicology Information from animal experimentation.Introduction to Toxicology, the Dose-Response and Basic Concepts, EUROTOX Course of Basic Toxicology, Dr. Marina Goumenou4/4/2016
FIELDS OF TOXICOLOGY (4)ForensicToxicologyAnalyticalToxicology Establish cause and effect relationships between exposure to adrug or chemical and the toxic or lethal effects that result from thatexposure. Analytical toxicology identifies the toxicant through analysis ofbody fluids, stomach content, excrement, or skin.Introduction to Toxicology, the Dose-Response and Basic Concepts, EUROTOX Course of Basic Toxicology, Dr. Marina Goumenou4/4/2016
FIELDS OF TOXICOLOGY (5)MechanisticToxicologyMixturesToxicology Study of the molecular, bio-molecular and cellular basisof toxic effects Study of mixtures toxicity and interactions of thecomponents. Specific requirements in Risk AssessmentIntroduction to Toxicology, the Dose-Response and Basic Concepts, EUROTOX Course of Basic Toxicology, Dr. Marina Goumenou4/4/2016
WHAT IS A DOSE IN TOXICOLOGY? The actual amount of achemical that enters the body.BUT . Acute (short) exposure: a veryshort period of time, usually 24hours Chronic (long-term) exposure:long periods of time such asweeks, months, or years.Introduction to Toxicology, the Dose-Response and Basic Concepts, EUROTOX Course of Basic Toxicology, Dr. Marina Goumenou4/4/2016
WHAT IS THE DOSE-RESPONSE RELATIONSHIP?Dose-response relationship is a relationship between exposure and healtheffect, that can be established by measuring the response relative to anincreasing dose.The dose-response curve is the mathematical curve that expresses thisrelationship.The dose-response relationship is based on observed data fromexperimental animal, human clinical, or cell studiesIntroduction to Toxicology, the Dose-Response and Basic Concepts, EUROTOX Course of Basic Toxicology, Dr. Marina Goumenou4/4/2016
HOW A DRC LOOKS LIKE?Usual assumption:Monotonic DRCs!However there are NonMonotonic DRCs!Introduction to Toxicology, the Dose-Response and Basic Concepts, EUROTOX Course of Basic Toxicology, Dr. Marina Goumenou4/4/2016
HOW A DRC LOOKS LIKE?Introduction to Toxicology, the Dose-Response and Basic Concepts, EUROTOX Course of Basic Toxicology, Dr. Marina Goumenou4/4/2016
WHAT A DRC SERVES? Establishes causality that thechemical has in fact inducedthe observed effects Establishes the lowest dosewhere an induced effectoccurs Determines the rate at whichinjury builds up - the slope forthe dose response.Introduction to Toxicology, the Dose-Response and Basic Concepts, EUROTOX Course of Basic Toxicology, Dr. Marina Goumenou4/4/2016
WHAT IS THE THRESHOLD DOSE?ResponseThe dose below which(adverse) effect is notseenActual dataApproximate sensitivity limitDoseNo thresholdThresholdIntroduction to Toxicology, the Dose-Response and Basic Concepts, EUROTOX Course of Basic Toxicology, Dr. Marina Goumenou No observed adverseeffect level (NOAEL), orthe no observed effectlevel (NOEL). No all effects have athreshold!!!Genotoxicity4/4/2016
WHAT A DRC SERVES?A threshold for toxic effects occurs at the point where the body's ability to detoxify a xenobioticor repair toxic injury has been exceeded. For most organs there is a reserve capacity so that lossof some organ function does not cause decreased performance. For example, the developmentof cirrhosis in the liver may not result in a clinical effect until over 50% of the liver has beenreplaced by fibrous tissue.Knowledge of the shape and slope of the dose-response curve is extremely important inpredicting the toxicity of a substance at specific dose levels. Major differences among toxicantsmay exist not only in the point at which the threshold is reached but also in the percent ofpopulation responding per unit change in dose (i.e., the slope). As illustrated above, Toxicant Ahas a higher threshold but a steeper slope than Toxicant B.Introduction to Toxicology, the Dose-Response and Basic Concepts, EUROTOX Course of Basic Toxicology, Dr. Marina Goumenou4/4/2016
WHAT IS THE THRESHOLD DOSE?A, B, C, D: Options for low-dose extrapolation(below observed response level)E: Point of departure (POD)F: No observed adverse effect level (NOAEL)G: Lowest observed adverse effect level (LOAEL)H, I: Mid and high dose responseT: Threshold doseED10 (EC10)ED50 (EC50)etc.Introduction to Toxicology, the Dose-Response and Basic Concepts, EUROTOX Course of Basic Toxicology, Dr. Marina Goumenou4/4/2016
What is the Benchmark Dose (BMD)?The dose that corresponds to aspecific change in an adverseresponse compared to the responsein unexposed subjects, and the lower95% confidence limit is termed thebenchmark dose level (BMDL).BMD10 10% increase versus controlBMDL10 lower one-sided 95%confidence interval for BMD10Introduction to Toxicology, the Dose-Response and Basic Concepts, EUROTOX Course of Basic Toxicology, Dr. Marina Goumenou4/4/2016
What is Hormesis?Introduction to Toxicology, the Dose-Response and Basic Concepts, EUROTOX Course of Basic Toxicology, Dr. Marina Goumenou4/4/2016
NO THRESHOLD EFFECTS?Implying one molecule may causeadversityRadiation, genotoxicans and maybeendocrine disruptorsExamples of divergence of opinion onwhether to assess as threshold or nothreshold carcinogen:naphthalene,formaldehyde, ethylbenzene4/4/2016Introduction to Toxicology, the Dose-Response and Basic Concepts, EUROTOX Course of Basic Toxicology, Dr. Marina Goumenou
Hazard identification In silico- QSAR, structure alerts, selective binding to specific receptors In vitro- prokaryotic/eukaryotic, cell/organ culture In vivo- Single dose toxicity (also skin and eye irritation)- Repeat dose toxicity (oral, dermal etc)- Genotoxicity (in vitro, in vivo)- Carcinogenicity (rodent lifetime assay)- Reproduction (fertility, developmental tox)- Other; sensitization, immunotoxicity, neurotoxicityIntroduction to Toxicology, the Dose-Response and Basic Concepts, EUROTOX Course of Basic Toxicology, Dr. Marina Goumenou4/4/2016
DEFINITION OF RISK ASSESSMENT Many definitions!!!! But keep in mind:Risk Assessment is a scientific/ mathematicaldiscipline which is a substantive, changingand controversial fieldIntroduction to Toxicology, the Dose-Response and Basic Concepts, EUROTOX Course of Basic Toxicology, Dr. Marina Goumenou4/4/2016
Risk Management:Putting theelements togetherIntroduction to Toxicology, the Dose-Response and Basic Concepts, EUROTOX Course of Basic Toxicology, Dr. Marina Goumenou4/4/2016
TERMINOLOGY OF RISK files/scientific output/files/main documents/2664.pdfIntroduction to Toxicology, the Dose-Response and Basic Concepts, EUROTOX Course of Basic Toxicology, Dr. Marina Goumenou4/4/2016
TERMINOLOGY OF RISK ASSESSMENTRisk assessment approaches of CAC, OIE and IPPC organisations cover in principle the same mainquestions: What can cause an adverse effect? How can it cause an adverse effect? What is the probability of an adverse effect occurring (i.e. what is the risk)? What are the consequences? What are the prerequisites for an adverse effect to indeed occur? CAC: Codex Alimentarius Commission of the FAO/WHO OIE: The World Organisation for Animal Health (Office International des Epizooties) IPPC: The relevant international and regional organisations operating within the framework of the International PlantProtection ConventionIntroduction to Toxicology, the Dose-Response and Basic Concepts, EUROTOX Course of Basic Toxicology, Dr. Marina Goumenou4/4/2016
RISK ASSESSMENT - CACA scientifically based process consisting of the following steps:(i) hazard identification,(ii) hazard characterization,(iii) exposure assessment, and(iv) risk characterization. (CAC, 2011)Qualitative Risk Assessment:A risk assessment based on data which, while forming an inadequate basis for numericalrisk estimations, nonetheless, when conditioned by prior expert knowledge andidentification of attendant uncertainties permits risk ranking or separation intodescriptive categories of risk. (FAO/WHO, 2008)Quantitative Risk Assessment: A risk assessment that provides numerical expressions ofrisk and indication of the attendant uncertainties (FAO/WHO, 2008)Introduction to Toxicology, the Dose-Response and Basic Concepts, EUROTOX Course of Basic Toxicology, Dr. Marina Goumenou4/4/2016
RISK ASSESSMENT - OIE & IPPCOIEEvaluation of the likelihood and the biological and economic consequences ofentry, establishment and spread of a hazard within the territory of an importingcountry (OIE, 2011)IPPCPest risk assessment (for quarantine pests): Evaluation of the probability of theintroduction and spread of a pest and the magnitude of the associated potentialeconomic consequences (IPPC, 2011b)Pest risk assessment (for regulated non quarantine pests): Evaluation of theprobability that a pest in plants for planting affects the intended use of thoseplants with an economically unacceptable impact (see (IPPC, 2011b)Introduction to Toxicology, the Dose-Response and Basic Concepts, EUROTOX Course of Basic Toxicology, Dr. Marina Goumenou4/4/2016
RISK ASSESSMENT: TWO ROADSQualitative virtually the same thing as“hazard evaluation” step of“Quantitative” RiskAssessment is the material harmful tohumans under anycircumstancesQuantitative A formal process withfour steps Ends with amathematicalestimation of actualrisk, usually quantifiedas deaths per 1,000,000per year or less. Codified by agencies,especially for cancerIntroduction to Toxicology, the Dose-Response and Basic Concepts, EUROTOX Course of Basic Toxicology, Dr. Marina Goumenou4/4/2016
“HAZARD EVALUATION” IS THE EQUIVALENTOF QUALITATIVE RISK ASSESSMENT.(in many instances the three further steps are not taken)Examples: EPA, IARC Cancer MonographsIntroduction to Toxicology, the Dose-Response and Basic Concepts, EUROTOX Course of Basic Toxicology, Dr. Marina Goumenou4/4/2016
TYPES OF STUDIES AVAILABLE FOR HAZARD EVALUATION BEST: Human Evidence (Epidemiology) Next best: Whole animal studies (toxicology; animals exposed to knowndose and allowed to live to times of sacrifice or natural death) Other: In-vitro studies (studies on cells in culture) Structure-function relationship study and similar Identification of active compounds in metabolismIntroduction to Toxicology, the Dose-Response and Basic Concepts, EUROTOX Course of Basic Toxicology, Dr. Marina Goumenou4/4/2016
EXPOSURE ASSESSMENT Who will be exposed?From what source(s)?How much of the chemical do people inhale/ ingest ?In what period of time?To what exactly?Do exist interactions (e.g. smoking)Introduction to Toxicology, the Dose-Response and Basic Concepts, EUROTOX Course of Basic Toxicology, Dr. Marina Goumenou4/4/2016
EXPOSURE ASSESSMENT Do exist adequate data for exposure assessment? Select the type of assessment based on the availabledata Screening Deterministic Probabilistic Model the exposure if possible How many do we want to include? E.g. 95%?Introduction to Toxicology, the Dose-Response and Basic Concepts, EUROTOX Course of Basic Toxicology, Dr. Marina Goumenou4/4/2016
RISK CHARACTERIZATION3 main ways:1) derivation of a health-based guidance value, such as an ADI, TDI oracute reference dose (ARfD);2) estimation of the margin of exposure (MOE) between a defined pointon the dose–response curve and the level of human exposure; and3) quantification of the magnitude of the risk at specified levels ofhuman 44065/8/WHO EHC 240 8 eng Chapter5.pdfIntroduction to Toxicology, the Dose-Response and Basic Concepts, EUROTOX Course of Basic Toxicology, Dr. Marina Goumenou4/4/2016
RISK CHARACTERIZATIONCalculation of the health-based guidance value (HBGV) can be described asfollows:HBGV POD / Ufswhere POD is a point of departure synonymously with Reference Point, RP(e.g. NOAEL) and UF is the uncertainty factor, a term often usedsynonymously with safety factor.Introduction to Toxicology, the Dose-Response and Basic Concepts, EUROTOX Course of Basic Toxicology, Dr. Marina 4065/8/WHO EHC 240 8 eng Chapter5.pdf4/4/2016
RISK CHARACTERIZATIONIndication of the margin between recommended or actual intakes and the RP Reference points (RPs) in toxicology studies used to calculate a safe level for human intake:NOAEL or BMD Description of the scientific uncertainties associated with the RP estimates Indication of the degree of scientific confidence that can be placed in these estimates where RP cannot be established an indication should be given on the highest level of intakewhere there is reasonable confidence in data on the absence of adverse effects Health-based guidance value (e.g. TDI) NOAEL / UF UF Uncertainty Factor (interspecies X intraspecies X other elements)Introduction to Toxicology, the Dose-Response and Basic Concepts, EUROTOX Course of Basic Toxicology, Dr. Marina Goumenou4/4/2016
RISK ASSESSMENT VS RISK MANAGEMENTIntroduction to Toxicology, the Dose-Response and Basic Concepts, EUROTOX Course of Basic Toxicology, Dr. Marina Goumenou4/4/2016
BASIC BIBLIOGRAPHY! Casarett and Doull's Toxicology (C. Klaassen, M. Amdur, and J.Doull, eds.) Principles and Methods of Toxicology (A. W. Hayes, ed.) Basic Environmental Toxicology (L. Cockerham and B. Shane, eds.) Industrial Toxicology (P. Williams and J. Burson, eds.)Introduction to Toxicology, the Dose-Response and Basic Concepts, EUROTOX Course of Basic Toxicology, Dr. Marina Goumenou4/4/2016
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CONCEPTS. MARINA GOUMENOU Chemist - Toxicologist BSc, MSc, PhD, ERT EUROPEAN FOOD SAFETY AUTHORITY . represent an official view of European Food Safety Authority Dr. Marina, Goumenou, Scope and ethical principles of toxicology and 3R, EUROTOX Course of Basic Toxicology, Zagreb, Croatioa, 4/4/2016 . Introduction to Toxicology, the Dose .
May 02, 2018 · D. Program Evaluation ͟The organization has provided a description of the framework for how each program will be evaluated. The framework should include all the elements below: ͟The evaluation methods are cost-effective for the organization ͟Quantitative and qualitative data is being collected (at Basics tier, data collection must have begun)
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A Small Dose of Toxicology A book chapter of A Small Dose of Toxicology - The Health Effects of Common Chemicals By Steven G. Gilbert, PhD, DABT Institute of Neurotoxicology & Neurological Disorders (INND) Seattle, WA 98115 E-mail: sgilbert@innd.org Supporting web sites web: www.asmalldoseof.org - "A Small Dose of Toxicology"
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