HumanEPIDataWhere the Question of Health Risk is RaisedResponseLog DosePaustenbach (1995)AnimalDataGeneral Approaches To Risk Assessment• Qualitative approach using scientific judgment• Quantitative approach using safety factors• Quantitative approach using mathematical models• Quantitative approach using linear extrapolationWhat Drives Most Types of Environmental Health Risk Assessment?• There are many types of risk assessment – Cancer– Developmental toxicity– NeurotoxicityCancer Risk Assessment• Population risks for environmental carcinogens are usually set at one additional cancer per 100,000 or 1,000,000 individuals• Occupational risks are frequently much higher, with one additional cancer per 1,000 workers being not uncommonHazard Identification• A qualitative risk assessment• Does an agent have the potential to increase the incidence of cancer under any conditionsDose-Response Assessment• The relationship between dose and response (cancer incidence)• Two sets of data are usually available– Data in the observable range– Extrapolation to responses below the observable rangeExposure Assessment• EPA uses the cumulative dose received over a lifetime• This is expressed as the average daily exposure• Occupational exposures are usually based on exposure during the work weekRisk Characterization• Provides an overall conclusion and confidence of risk for the risk manager• Gives the assumptions made• Explains the uncertainties• Outlines the data gapsIssues Related to Uncertainty in Risk Assessment• High to low dose extrapolation• Species to species extrapolation• Mechanism of carcinogenesis• Interindividual differences• Chemicals that are carcinogenic in animals are expected to be carcinogenic in humans• Humans are assumed to be as sensitive as the most sensitive animal• The dose-response is assumed to be linearMajor Default Assumptions in Cancer Risk AssessmentEmerging Issues in Biologically-based Risk Assessment• Incorporation of PBPK models• Use of molecular dosimetry as a surrogate of exposure• Role of cell proliferation• Mode of action information• Life stage differences in susceptibilityPotential of Molecular Dosimetry in Risk Assessment• High to low dose extrapolation– Saturation of metabolic activation– Saturation of detoxication– Saturation of DNA repair• Route to route differences• Species to species differencesHow is Causality Determined?Bradford Hill Criteriafor Cancer Causation• Consistency• Strength• Specificity• Temporality• Coherence• Dose Response• Biological Plausibility• Experimental Support• AnalogyIPCS/EPA Framework for Evaluating Mechanistic Data• Introduction• Postulated mode of action• Key events• Dose-response relationship• Temporal association• Strength, consistency and specificity of association with key events• Biological plausibility and coherence• Other modes of action• Assessment of mode of action• Uncertainties, inconsistencies and data gapsChemical Exposure (air, water, food, etc.)Internal ExposureMetabolic ActivationMacromolecular BindingDetoxicationDNA RNA ProteinBiologically Effective DoseEfficiency of MispairingCell ProliferationXXInitiationkkkkkk123465(Biomarker)cabIncreasing External ExposureIncreasing Adduct ConcentrationSublinearSupralinearSOURCES OF MUTATIONSENDOGENOUS DNA DAMAGE EXOGENOUS DNA DAMAGEDepurinationDNA REPAIRMUTATIONLifeStylesEnvironmentalAgentsFreeRadicalsPolymeraseErrorsCELL REPLICATIONInitiatingEventCell Proliferation(clonal expansion)ProgressionCell ProliferationCell ProliferationMalignancySecond Mutating EventThird Mutating EventDDSSSSIIIIMμ1μ2β2First EventSecond EventA Moolgavkar Representation of Multistage CarcinogenesisRole of Increased Cell Proliferation in Carcinogenesis• Decreases time available for DNA repair• Converts repairable DNA damage intononrepairable mutations• Necessary for chromosomal aberrations, insertions, deletions and gene amplification• Clonally expands existing cell populations8-oxo-G, FapyGuaLipid PeroxidationLipid PeroxideMDA, 4-HNEAP SitesDNA Base ModificationDNA Base adductROSSugarDamageDNA Base adductM1G, edG, edAOxidative Stress Induced-DNA DamageGlycosylasehOGG1GlycosylaseMPGBase PropenalNon-smoker Lymphocytes0.001.002.003.004.005.006.007.008.009.00123456789108OHdG/dG (10e-6)Pentachlorophenol Used as a Pesticide and Wood Preservatives Introduction to Humans: Air, Food and Drinking water Mutagen, Rodent CarcinogenOHClClClClClOHClClOHClClOClClOClClOClClOHClClO2O2-H2O2OHInduced Oxidative StressCalf Thymus DNA Exposed to TCHQCalf Thymus DNA Exposed to TCHQ010203040500.1 1 10 100 1000TCHQ (uM)8OHdG/dG (10e-6)Aldehydic DNA lesions (ADL) in HeLa cells exposed to H2O2(0.06-20 mM) for 15 min05101520250 5 10 15 20H2O2 (mM)ADL/1,000,000 ntd010203040500.01 0.1 1 10 100H2O2 (mM)Increased ADLs/H2O2 concentrationEfficiency of Low Doses of H2O2DNA Alkylation7%2%7%14%ENUDEN0.4%0.1%7%70%MNUDMN--0.3%85%MMSO2 Alkyl ThymineO4 Alkyl ThymineO6 AkylGuanineN7AlkylGuanineN-7-MethylguanineO -Methylguanine10000 1000 100 10 1 0.1 0.01 0.001 0.001 0.01 0.1 1 10 10040302010 032106DMN (mg/kg)Alkylations/10 guaninesAlkylations/10 guanines66AB0.00E+002.00E-064.00E-066.00E-068.00E-061.00E-051.20E-050 1020304050607080Duration of DEN exposure, daysMolar ratio in DNAO4-EtdThdO6-EtdGuo020 40 60 80 100020406080100020406080100Dose (ppm DEN) ET (pM)/dT (μM)0 5 10 15 20051015051015O2-ET O4-ETMolecular Dosimetry of DENVinyl Chloride• Vinyl chloride is a known human and animal carcinogen that induces hepatic angiosarcomas• Carcinogenic response is associated with high exposure (>50 ppm)• To date, 178 VC workers have developed hepatic angiosarcomas. All of them started work prior to lowering the occupational exposure 1 ppm• Vinyl chloride is present in many Superfund sites and some public drinking water in ppb amountsVinyl Chloride MetabolismClOClClOP-450Epoxide HydrolaseHOOClOHAlcohol dehydrogenaseGlutathioneDetoxicationDNA AdductsExposure-Response for Vinyl Chloride Metabolism and Carcinogenicity05000100000 1000 2000 3000 4000VC Exposure (ppm)ν (μg / 6 hr)(Gehring et al, 1978)0.00.10.20 2000 4000 6000VC Exposure (ppm)ASL Incidence(Maltoni et al, 1981)Formation of [13C2]-DNA Adducts by Vinyl ChlorideCH2ClOClNNHNNNOOHdRibNNNNdRibNNNNdRibONHNH2NNNHOdRibONHNNNNOdRibCYP450 2E1vinyl chloridechloroethylene
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