Toxicology

Introduction to ToxicologyIntroduction to Toxicology

Children's Health and the EnvironmentChildren's Health and the Environment

CHEST Training Package for the Health SectorCHEST Training Package for the Health Sector

TRAINING FOR THE HEALTH SECTORTRAINING FOR THE HEALTH SECTOR

Toxicology

Definition ToxicologyDefinition Toxicology

Definition of toxicologyDefinition of toxicology is  is  "the study of the "the study of the adverse effects of chemicals or physical adverse effects of chemicals or physical agents on living organismsagents on living organisms

Toxicology

Philippus Theophrastus Aureolus Bombastus von Hohenheim

PARACELSUS(Einsiedeln, Zürich, 1493 -

Salzburg, 1541)

All substances are poisons; it is the dose that makes the poison

Toxicology

Toxicology TerminologyToxicology Terminology

Toxicology

Toxic agent or substanceToxic agent or substance

Toxic agent Toxic agent is anything that can produce is anything that can produce an adverse biological effect.  It may be an adverse biological effect.  It may be chemical, physical, or biological in form.  chemical, physical, or biological in form.  Toxic agents may be:Toxic agents may be:chemical chemical (such as cyanide)(such as cyanide), , physical physical (such as radiation)(such as radiation) and and biological biological (such as snake venom)(such as snake venom)..

Toxic substance Toxic substance is simply a material which is simply a material which has toxic properties.has toxic properties.

Toxicology

Systematic or organ toxinsSystematic or organ toxins

A A systemic toxin systemic toxin is one that affects the is one that affects the entire body or many organs rather than a entire body or many organs rather than a specific sitespecific site

A A organ toxin organ toxin is one that affects only is one that affects only specific tissues or organsspecific tissues or organs

Toxicology

Factors determining adverse effectsFactors determining adverse effects

intrinsic toxicity dose exposure conditions response of host

Toxicology

Intrinsic toxicityIntrinsic toxicity

Chemical propertiesChemical properties

molecular structure & functional groupsmolecular structure & functional groups

solubility - insolubilitysolubility - insolubility

volatilityvolatility

stability (light, water, acids, enzymes, …)stability (light, water, acids, enzymes, …)

reactivityreactivity

Physical propertiesPhysical properties

gas (density, …)gas (density, …)

liquid (vapour pressure, …)liquid (vapour pressure, …)

solid (crystal structure, size, shape, …)solid (crystal structure, size, shape, …)

Toxicology

MisunderstandingsMisunderstandings

Natural compounds Natural compounds safe compounds safe compounds Synthetic agents Synthetic agents toxic agents toxic agents

Pure substancePure substance

pure substance + impuritiespure substance + impurities

pure substance in (complex) mixturepure substance in (complex) mixture

Toxicology

Factors determining adverse effectsFactors determining adverse effects

intrinsic toxicity dose exposure conditions response of host

Toxicology

DoseDose

The dose isThe dose is the amount of a substance the amount of a substance administered at one timeadministered at one time

Toxicology

DoseDose

Types of dosesTypes of doses, e.g., exposure dose, , e.g., exposure dose, absorbed dose, administered dose and absorbed dose, administered dose and total dosetotal dose

Toxicology

Dose unitsDose units

Toxicology

Dose-response relationshipDose-response relationship

““The dose-response relationship is the The dose-response relationship is the most fundamental and pervasive most fundamental and pervasive concept in toxicology”concept in toxicology”

Toxicology

Dose-effect relationshipDose-effect relationship

                              

                                                                                                                                                                                                      

              

Toxicology

Dose-response curveDose-response curve

                              

                                                                                                                                                                                                      

              

Toxicology

Dose-response curveDose-response curve

                              

                                                                                                                                                                                                      

              

Toxicology

Dose estimatesDose estimates

Toxicology

Effective doseEffective dose

Toxicology

Toxic doseToxic dose

Toxicology

Toxicology

NOAEL and LOAELNOAEL and LOAEL

Toxicology

Dose-response relationshipDose-response relationship

Our knowledge of the effects of chemicals Our knowledge of the effects of chemicals stems mainly fromstems mainly from

clinical and occupational toxicologyclinical and occupational toxicology relatively high doses, limited number of agents

epidemiologyepidemiology complex exposures, rarely “causal” associations

animal experimentsanimal experiments high doses, single chemicals, statistical limitations, healthy

animals, species differences

Toxicology

Exposure and responseExposure and response

Patterns of exposurePatterns of exposure

acute or high dose

chronic low dose

Patterns of responsePatterns of response

clinically manifest

subtle and/or long-term cancer reproductive effects neurodegenerative

disease immunologic susceptibility …

epidemiology

Toxicology

Statistical limitationsStatistical limitations

Assuming no background tumors

Occurrence of adverse effect in 0.01% of the population (1,000/10,000,000) requirestesting in at least 30,000 animals !

Toxicology

Extrapolation from animal dataExtrapolation from animal data

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Toxicology

Factors determining adverse effectsFactors determining adverse effects

intrinsic toxicity dose exposure conditions response of host

Toxicology

Exposure conditionsExposure conditions

routes of exposureroutes of exposure frequency & duration of exposurefrequency & duration of exposure mixed exposuresmixed exposures environmental circumstancesenvironmental circumstances

Toxicology

Routes of exposureRoutes of exposure

OralOral InhalationInhalation DermalDermal ParenteralParenteral

Toxicology

Oral exposureOral exposure

drugsdrugs therapeutic non-therapeutic

water & soil pollutantswater & soil pollutants contamination of food & drinks hand-mouth behaviour children (not pica!)

occupational agents occupational agents hand hygiene

Toxicology

InhalationInhalation

smokingsmoking indoor air pollutionindoor air pollution

domestic occupational schools hobby & sports

outdoor air pollutionoutdoor air pollution urban, industry & vehicle traffic natural sources

Toxicology

Dermal exposureDermal exposure

occupational agentsoccupational agents solvents pesticides

cosmeticscosmetics

some water pollutantssome water pollutants

Toxicology

Factors determining adverse effectsFactors determining adverse effects

intrinsic toxicity dose exposure conditions response of host

Toxicology

Toxic effectsToxic effects

A target organ is an organ that is damaged A target organ is an organ that is damaged by the xenobiotic or its metabolite. There by the xenobiotic or its metabolite. There may be more than one target for toxicity for may be more than one target for toxicity for a particular substance. a particular substance.

For example, the targets for alcohol are the For example, the targets for alcohol are the central nervous system and the liver.central nervous system and the liver.

Toxicology

Toxic effectsToxic effects

Cellular, biochemical, or macromolecular changesCellular, biochemical, or macromolecular changes

cell replacement, such as fibrosis damage to an enzyme system disruption of protein synthesis production of reactive chemicals in cells DNA damage

Toxicology

Factors Influencing Toxic EffectsFactors Influencing Toxic Effects

form and innate chemical activityform and innate chemical activity dosage, especially dose-time dosage, especially dose-time

relationshiprelationship exposure routeexposure route speciesspecies ageage sexsex

Toxicology

Factors Influencing Toxic EffectsFactors Influencing Toxic Effects

ability to be absorbedability to be absorbed

metabolismmetabolism

distribution within the bodydistribution within the body

excretionexcretion

presence of other chemicalspresence of other chemicals

Toxicology

Systemic Toxic Effects Acute ToxicityAcute Toxicity

Subchronic ToxicitySubchronic Toxicity

Chronic ToxicityChronic Toxicity

Toxicology

Systemic Toxic Effects (continued)

Developmental ToxicityDevelopmental Toxicity

Toxicology

Systemic Toxic Effects (continued)(continued)

Genetic Toxicity Genetic Toxicity (somatic cells)(somatic cells)

Toxicology

Systemic Toxic Effects ((continued)continued)

CarcinogenicityCarcinogenicity Multistage process Initiation Promotion

Benign tumors

Malignant tumors

Toxicology

Organ specific toxic effectsOrgan specific toxic effects

Blood/Cardiovascular ToxicityBlood/Cardiovascular Toxicity

Dermal/Ocular ToxicityDermal/Ocular Toxicity

Genetic Toxicity Genetic Toxicity (germ cells)(germ cells)

Toxicology

Organ specific toxic effectsOrgan specific toxic effects

HepatotoxicityHepatotoxicity

Toxicology

Organ specific toxic effectsOrgan specific toxic effects

ImmunotoxicityImmunotoxicity

NephrotoxicityNephrotoxicity

NeurotoxicityNeurotoxicity

Toxicology

Organ specific toxic effectsOrgan specific toxic effects

Reproductive ToxicityReproductive Toxicity

Respiratory ToxicityRespiratory Toxicity

Toxicology

Frequency & durationFrequency & duration

Acute toxicity (single dose or < 24h)Acute toxicity (single dose or < 24h) may lead to immediate (“acute”) effects may lead to delayed or persistent (“chronic”)

effects

Chronic toxicity (repeated doses)Chronic toxicity (repeated doses) may lead to sudden (“acute”) effects results from accumulation of toxic agent or from

cumulative effects may lead to delayed or persistent (“chronic”)

effects

Toxicology

Mixed exposuresMixed exposures

Additive effects Additive effects (1+1 = 2)(1+1 = 2)

Synergistic effectsSynergistic effects toxicokinetic interactions (1+ 0 = 2)

e.g. improved dermal penetration by solvents toxicodynamic interactions (1+1 = 3)

e.g. smoking + air pollutants

Antagonistic effects Antagonistic effects (1+1 = 1)(1+1 = 1)

Toxicology

Response of hostResponse of host

DetoxificationDetoxification

BioactivationBioactivation