exploring carcinogen risk analysis through benzene

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Exploring Carcinogen Risk Analysis Through Benzene. Image from Matthew J. Dowd Department of Medicinal Chemistry Virginia Commonwealth University. Objective. Use benzene as a case for exploring Toxicology Epidemiology Uncertainty Regulatory Science. Toolbox Building. - PowerPoint PPT Presentation

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  • Exploring Carcinogen Risk Analysis Through BenzeneImage from Matthew J. DowdDepartment of Medicinal ChemistryVirginia Commonwealth University

  • ObjectiveUse benzene as a case for exploringToxicologyEpidemiologyUncertainty Regulatory Science

  • Toolbox BuildingLikelihood MaximizationCurve fittingBootstrappingZ-ScoresRelative RiskDose-Response extrapolation

  • Overview of benzeneFairly common hydrocarbonManufacturingPetroleum productsStrongly suspected human carcinogenAnimal assaysMany epidemiological studiesLeukemia as important endpoint

  • Benzene structureImage from Matthew J. DowdDepartment of Medicinal ChemistryVirginia Commonwealth University

  • Benzene Data in Should We Risk It?Toxicological Data, p. 175 et seq.Epidemiological Data p 211 216But many other data setsOther toxicological data (rare)Chinese workersTurkish workers

  • Toxicology Data SetCrump and Allen 1984

    Number of miceMice with tumorsMouse dose500050414502027503759

  • What are risks from benzene?Risk as potency times exposureHow do we determine potency?Extrapolate from animal data?Extrapolate from epidemiological data?How wrong will we be?What are real exposures?What are effects at these levels?

  • ToxicologyParacelsus the dose makes the poisonRegulatory assumptions!This is not Dr. Gerstenbergers Toxicology!

  • ReadingSWRI Chapter 5US EPA Proposed guidelines (US EPA 1996)Cox 1996

  • General ideaApplied dosesGreater specificity about exposure than epidemiologyObserved effectsArtificial control of exposure

  • Physiologically Based PharmacokineticsPBPKInvestigate flows of materials through bodiesSystem dynamics modelsMore on these in exposure lecture

  • StudiesAnimalsRarely humansPartsCelltissue

  • EffectsChronic cancer fatalityincreasing interest in other issueslead and intelligence in children.AcuteReversible Irreversible

  • Crump and Allen Benzene data setAnimals at various concentrationsFour data pointsDesigner mice

  • Relevance to HumansHow to get from high level, lifetime studies of animalstoanticipated low dose effects in humans?

  • Questions about benzeneIs benzene a mouse carcinogen?Is benzene a human carcinogen?If so, how potent?

  • Crump and Allen data set (Crump and Allen 1984)Note: the actual doses are not stated correctly here. See notes for more informationBenzene data set I

    Number of Test mice

    Number of Mice with tumors

    Mouse Test Dose (mg/kg/d)

    (Oral gavage)

    50

    0

    0

    50

    4

    25

    50

    20

    50

    50

    37

    100

  • Crump and Allen data set.Benzene data set II

  • Uncertainty PervadesOften understatedCreates (or at least prolongs) conflictThink as we go! (Part of Homework PS 2)

  • Animal Test IssuesInterspecific comparisonStatistical uncertaintyHeterogeneityExtrapolationDose Metric

  • Interspecific comparisonMouse-humanMetabolism as a function of body weightDosehuman = sf Dosemousesf = (BWhuman/BWmouse)1-bb is empirically derived as 0.75aa. See SWRI page 177.

  • Interspecific comparisonLifetime of human = lifetime mouse?Mice age 30 days per human dayTotal mouse lifetime is much shorterAnalogous organs or processes?Do mice have cancer points we do not?Do we have cancer points mice do not?a. See SWRI page 177.

  • 1. Hallenbeck, 19932. Finley et al., 1994Interspecific comparison

    Species

    Sex

    Std. Adult BW (kg1,2)

    Human

    Male

    78.7

    Female

    65.4

    Both

    71.0

    Rat

    Male

    0.5

    Female

    0.35

    Mouse

    Male

    0.03

    Female

    0.025

  • sf = (BWhuman/BWmouse)1-bsf = (70/0.03)0.25 = 7.0Dosehuman = 7.0 DosemouseInterspecific comparison

    Number of Test mice

    Number of Mice with tumors

    Mouse Test Dose (mg/kg/day)

    (Oral gavage)

    Equivalent human dose (mg/kg/day)

    50

    0

    0

    50

    4

    25

    50

    20

    50

    50

    37

    100

  • Crump and Allen data set, converted to humansInterspecific comparison

    Number of Test mice

    Number of Mice with tumors

    Mouse Test Dose (mg/kg/day)

    (Oral gavage)

    Equivalent human dose (mg/kg/day)

    50

    0

    0

    0

    50

    4

    25

    175

    50

    20

    50

    350

    50

    37

    100

    700

  • Animal Test IssuesInterspecies comparisonStatistical uncertaintyHeterogeneityExtrapolationDose Metric

  • Binomial Distribution50 genetically identical micebinomial distribution?Can use this to generate likelihood function to compare the likelihood that any given probability is

  • Likelihood MaximizationMore appropriate than Least Squares when you know something about likelihoodsBootstrapping method neededWe will work through likelihood maximization

  • Can calculate standard deviation using the binomial Recall that two standard deviations to either side represents a 95% confidence interval, and...Statistical Uncertainty

  • Crump and Allen data set, applied to humansP(cancer)00.20.4Human Dose (mg/kg/day)01753505257001.00.80.6Statistical Uncertainty

  • Animal Test IssuesInterspecies comparisonStatistical uncertaintyHeterogeneityExtrapolationDose Metric

  • HeterogeneityEpidemiology and toxicologyGenetically identical mice compared to diverse humansPredictable versus unpredictable susceptibility Male and female differences (observed cancer rates are different)

  • HeterogeneityGenetic diversity among humansEarly insights into cancer mechanism: subpopulation born with one of two steps competedVariability as a function of age

  • Animal Test IssuesInterspecies comparisonStatistical uncertaintyHeterogeneityExtrapolationDose Metric

  • ExtrapolationTheoretical or Mechanistic models: one-hit two-hittwo-stageEmpirical Cox data-driven, model free curve fitting EPA Proposed Guidelines

  • Extrapolation ConcernsOverestimationTautological effectsThresholdsHormesis, or Vitamin effectUnderestimationSaturationSynergistic effectsSusceptibilityOmission

  • After EPA (1996)

  • Crump and Allen data set, applied to humansP(cancer)00.20.4Human Dose (mg/kg/day)01753505257001.00.80.6Statistical Uncertainty

  • P(cancer)00.20.4Human Dose (mg/kg/day)01753505257001.00.80.6LED(10) =100 mgb/kg/day

  • If LED(10) = 100 mg/kg/day, then

    LED(10-6) = 100 10-6 / 0.1 = 1 10-4 mg/kg/day

    Extrapolation

  • Animal Test IssuesInterspecies comparisonStatistical uncertaintyHeterogeneityExtrapolationDose Metric

  • Dose MetricAssumption: exposure is irrelevant to effectArea under the curve/expected value.Lifetime dose leads to average daily dose.Particularly problematic if there are threshold effects or extreme effects

  • Risk to Humans?Lifetime cancer risk40 hours per week50 weeks per year30 yearsAverage 10 ppm(v) exposure?

  • Calculate Risk10ml benzene/liter air0.313 ml/mg20m3 air / day1000 liters/ m370kg person

  • Cancer RiskLifetime Cancer Probability is a function of Dose and PotencyAssume cumulative doseUse Daily Dose per kg body weight, averaged over lifetimePotency usually given as q*Additional risk per unit dose

  • Cancer Risk: Exposure Term

  • Computed Exposure Terms

  • Computed Exposure Terms

  • Cancer Risk

  • Regulatory Science IssuesNeither a simple question nor a mindless approach(although often stated this way)Human health conservative versusHeavy hand of conservative assumptions?May be overestimatesMay be underestimates

  • Regulatory ToxicologyReal risk is a reified riskALL estimates, including central tendencies, are probably wrongMore science does not guarantee less risk less uncertainty

  • Likelihood MaximizationA curve fitting technique

  • Binomial Distribution50 genetically identical micebinomial distribution?Can use this to generate likelihood function for a predicted outcome given an observed outcome

  • Likelihood MaximizationMore appropriate than Least Squares when you know something about likelihoodsBootstrapping method needed

  • Can calculate standard deviation using the binomial Recall that two standard deviations to either side represents a 95% confidence interval, and...Statistical Uncertainty

  • Crump and Allen data set, applied to humansP(cancer)00.20.4Human Dose (mg/kg/day)01002003004001.00.80.6Statistical Uncertainty

  • Counting RulesWhat is the likelihood of getting 13 heads on 50 flips of a fair coin?We know the EXPECTED valueExpected value is 25 heads

  • Binomial DevelopedP(13|50) =

    0.000315P(25|50) = 0.112P(37|50) = 0.000315

    P(24|50) = 0.108P(50|50) = 8.88 E-16P(20|50) = 0.0412

    Can use function in excel

  • Chart1

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