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Pharmacokinetic Modeling of Environmental Chemicals Part 2: Applications. Harvey J. Clewell, Ph.D. Director, Center for Human Health Assessment The Hamner Institutes for Health Sciences Research Triangle Park, North Carolina. TODAY’S TOPICS.

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Pharmacokinetic modeling of environmental chemicals part 2 applications l.jpg

Pharmacokinetic Modeling of Environmental ChemicalsPart 2: Applications

Harvey J. Clewell, Ph.D.

Director, Center for Human Health Assessment

The Hamner Institutes for Health Sciences

Research Triangle Park, North Carolina


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TODAY’S TOPICS

  • Application of PBPK Models in Risk Assessments Based on Animal Studies

    • - vinyl chloride

    • - trichloroethylene

  • Application of PBPK Models to Understand the Health Implications of Human Biomonitoring Data

  • - methylmercury

  • - perfluorooctanoic acid


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    Part 1: RISK ASSESSMENT

    “The characterization of the potential adverse effects of human exposures to environmental hazards.”

    - National Academy of Sciences, 1983


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    Risk Assessment Questions

    • Qualitative: Is the chemical potentially harmful under ANY conditions?

    • Quantitative: At what human exposure concentration does the RISK become SIGNIFICANT?


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    The Dose is Important

    “All substances are poisons; there is none which is not a poison. The right dose differentiates a poison and a remedy.”

    –- Paracelsus, 1493-1541

    “Dancing with proper limitations is a salutary exercise, but when violent and long continued in a crowded room it is extremely pernicious, and has hurried many young people to the grave.”

    --A. Murray, M.D., 1826


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    ??

    Risk

    Dose

    Dose Response Assessment

    ??

    Agent

    Dose

    Exposure Assessment

    Four Components of Risk Assessment(National Academy of Sciences, 1983)

    ??

    Agent

    Effect

    Hazard Identification

    Risk

    Characterization


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    Key Definitions In Contemporary Human Health Risk Assessment

    Default – A generic, conservative (safe-sided) approach, for use when chemical-specific information is lacking

    Mode of Action - in a broad sense, the critical sequence of events involved in the production of a toxic effect by a chemical

    Dosimetry – Estimation of the tissue exposure to the form of the chemical (e.g., a reactive metabolite) that is most directly related to the toxic effect


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    Steps in a Toxic Mode of Action

    Exposure

    absorption, distribution, metabolism, excretion

    Tissue Dose

    local metabolism, binding

    Molecular Interactions

    reactivity, DNA adducts, receptor activation

    Early Cellular Effects

    cytotoxicity, DNA mutation,

    increased cell division

    Toxic Responses

    toxicity, cancer


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    Mode of Action Considerations

    • Parent Chemical(ethylene oxide)

    • vs. Stable Metabolite (trichloroacetic acid from trichloroethylene)

    • or Reactive Metabolite (methylene chloride)

    • Physical effect(acute neurotoxicity of solvents)

    • vs. Reactivity (formaldehyde)

    • or Receptor Binding (dioxin)

    • Direct Genotoxicity(mutations from vinyl chloride adducts)

    • vs. Indirect (oxidative stress)

    • or Nongenotoxic (arsenic inhibition of DNA repair)


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    Role of PBPK Modeling in Risk Assessments for Chemicals

    • Define the relationship between external concentration or dose and an internal measure of (biologically effective) exposure:

    • in experimental animals

    • in subjects from human studies

    • in the population of concern


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    Application of Pharmacokinetics in Risk Assessment

    • Underlying Assumption: Tissue Dose Equivalence

    • Effects occur as a result of tissue exposure to the toxic form of the chemical.

    • Equivalent effects will be observed at equal tissue exposure/dose in experimental animals and humans.

    • Appropriate measure of tissue dose depends critically on the mode of action for the effect of the chemical.


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    Steps for Incorporating PBPK Modeling in Human Health Risk Assessment

    • Identify toxic effects in animals or human populations

    • Evaluate available data on mode(s) of action, metabolism,

      for compound and related chemicals

    • Describe potential mode(s) of action

    • Propose relationship between response and tissue dose

    • Develop/adapt an appropriate PBPK model

    • Estimate tissue dose during toxic exposures with model

    • Estimate risk in humans based on assumption of similar tissue response for equivalent target tissue dose


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    Applications of PBPK Modeling in Human Risk Assessment by Regulatory Agencies

    • Methylene Chloride (EPA, OSHA, ATSDR, Health Canada)

    • 2-Butoxy Ethanol (EPA, Health Canada)

    • Vinyl Chloride (EPA)

    • Chloroform (Health Canada)

    • Dioxin (EPA)

    • Trichloroethylene (EPA)

    • Perchloroethylene (EPA)

    • Isopropanol (EPA)


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    Considering Pharmacokinetic and Mechanistic Information in Cancer Risk Assessment

    Examples:

    Easy: Vinyl Chloride

    Hard: Trichloroethylene


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    Considering Pharmacokinetic and Mechanistic Information in Cancer Risk Assessment

    Example 1: Vinyl Chloride

    • Used to produce plastics; formed in groundwater from

    • bacterial degradation of other contaminants

    • Cross-species correspondence of a rare tumor type: liver angiosarcoma in mouse, rat, and human (workers).

    • Carcinogenic at doses with no evidence of toxicity

    • DNA-reactive, mutagenic

    • Likely to be carcinogenic even at low doses


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    Metabolism of Vinyl Chloride Cancer Risk Assessment

    Dose metric:

    concentration of

    chloroethylene epoxide


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    PBPK Model for Vinyl Chloride Cancer Risk Assessment

    (Clewell et al. 2001)

    Dose metric:

    production rate of

    reactive metabolite

    per gram liver


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    Rats -- Pharmacokinetics Cancer Risk Assessment


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    Rats -- Metabolism Cancer Risk Assessment


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    Human -- Subject A Cancer Risk Assessment


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    Human -- Subject B Cancer Risk Assessment


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    Comparison of Cancer Risk Estimates for Vinyl Chloride Cancer Risk Assessment

    Basis

    Old EPA -- Animal

    PBPK -- Animal

    PBPK -- Human (Epidemiology)

    Inhalation(1 ug/m3)

    84.0 x 10-6

    1.1 x 10-6

    0.2 - 1.7 x 10-6

    Drinking Water(1 ug/L)

    54.0 x 10-6

    0.7 x 10-6


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    Considering Pharmacokinetic and Mechanistic Information in Cancer Risk Assessment

    Example 2: Trichloroethylene

    • Popular solvent for degreasing ;

    • replaced by perchloroethylene for dry cleaning

    • Lung and liver tumors in mice but not rats;

    • kidney tumors in rats but not mice

    • Equivocal human evidence (contradictory studies)

    • Tumors generally associated with toxicity

    • Little evidence of direct interaction with DNA

    • Unlikely to be carcinogenic at low doses


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    PBPK Model for TCE Cancer Risk Assessment(Clewell and Andersen, 2004)

    CI

    QP

    CX

    CV

    CA

    Alveolar Air

    Alveolar Blood

    QC

    QC

    QTB

    CVTB

    Tracheo-Bronchial Tissue

    VMTB, KMTB

    Lung Toxicity

    CVF

    QF

    Fat Tissue

    CVR

    QR

    Rapidly Perfused Tissue

    CVS

    QS

    Slowly Perfused Tissue

    KTSD

    KTD

    Gut Lumen

    Stomach Lumen

    PDose

    KAD

    KAS

    QG

    Gut Tissue

    CVG

    QL

    CVL

    Liver Tissue

    Kidney Toxicity

    Liver Effects

    KF

    VM, KM


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    Comparison of Linear Cancer Risk Estimates (per million) for Vinyl Chloride and TCE

    Basis

    Vinyl Chloride:

    Old EPA

    PBPK -- Animal

    PBPK -- Human

    TCE:

    Old EPA

    PBPK -- Animal

    Inhalation(1 ug/m3)

    84.0

    1.1

    0.2 - 1.7

    1.3

    3.5

    Drinking Water(1 ug/L)

    54

    0.7

    0.32

    1.2

    So… low-dose risk estimates using PBPK modeling would seem to

    suggest that TCE is a more potent carcinogen than vinyl chloride!

    (What’s wrong with this picture?)


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    PBPK modeling can only go so far… Vinyl Chloride and TCE

    Also need an understanding of the toxic mechanism to interpret low-dose risks


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    Part 2: Use of PBPK Modeling to Interpret Vinyl Chloride and TCE

    Human Biomonitoring Data

    • Issue:

      • Detection of chemicals in human blood (“chemical trespass”)

      • Uncertain relationship to doses in animal toxicity studies

    • Goal:

      • Reconstruct exposures

      • Compare to regulatory guidelines (MCL, RfD, etc)

    • Tools:

      • Pharmacokinetic (PBPK) models

      • Monte Carlo analysis of exposure variability and sampling uncertainty

    • Products:

      • Margins of safety

      • Objective interpretation of biomonitoring data


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    Relationship of Human Biomonitoring Data to Animal Toxicity Data

    Margin of safety

    Chemical concentrations in human blood from biomonitoring studies

    Chemical concentrations in animal blood in toxicity studies

    Reverse dosimetry

    Forward dosimetry

    Pharmacokinetic

    Modeling

    Pharmacokinetic

    modeling

    Human exposures

    (Chemical concentrations in environment)

    Animal exposures

    (Administered doses in

    toxicity studies)

    Traditional risk assessment


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    Reconstructing Exposure with a PBPK Model: Data

    An Example with Methylmercury

    • Accidental poisoning episode

      • Iraq – 1972

        • Seed grain, treated with methylmercury fungicide, inadvertently used to prepare bread

        • Exposures continued over 1- to 3-month period

        • Symptoms (late walking, late talking, neurological performance) observed in children of asymptomatic mothers exposed during pregnancy


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    PBPK Model for Gestational Exposure to Methylmercury Data

    Clewell et al. 1999,

    Shipp et al. 2000


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    Effect of Changes in Fetal and Maternal Data

    Physiology on Dosimetry

    Non-human primates exposed to a constant

    daily dose of methylmercury during gestation


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    Exposure Reconstruction With a PBPK Model Data

    Iraqi woman exposed during pregnancy

    to grain contaminated with methylmercury

    Estimated exposure:

    42 ug/kg/day

    EPA Reference Dose:

    0.1 ug/kg/day


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    Exposure Reconstruction for perfluoro-octanoic acid Data

    • Perfluoro-octanoic acid (PFOA) is used in the production of

      “non-stick” surface coatings; it is also a by-product of the

      production of water- and grease-repellent finshes

    • PFOA is highly persistent compound that has been found

      in human blood and in the environment, raising public concerns

      regarding the possible effects of exposure

    • In this study, a pharmacokinetic model of PFOA was used to

      estimate exposures in a population exposed to high

      concentrations of PFOA in drinking water and in a group of

      workers exposed to PFOA in the workplace



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    Predicted time course of PFOA in plasma pharmacokinetic model for PFOA

    at different exposure levels

    ng/kg/day:

    150

    90*

    46

    Occupational exposure

    Serum PFOA Concentration (ng/mL)

    Environmental exposure

    Blood levels in general population: 5 ng/mL)

    *Estimated safe exposure based on effects in animal studies


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    Different fractional volume of fat between male and female effects dioxin concentration

    Transplacental exposure to dioxin in maternal blood

    Dilution of infant dioxin concentration by rapid growth

    Application of PBPK Modeling to Predict the Effect

    Of Age-Dependent PK on Dioxin Blood Levels

    (Clewell et al., 2004)

    Predicted blood levels assuming a constant daily exposure throughout life


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    Summary: Use of PBPK Modeling in Risk Assessments for Environmental Chemicals

    • Pharmacokinetics can be used to improve the accuracy of extrapolations across species, and to estimate exposures associated with human biomonitoring results

    • BUT:

    • Mechanistic data is essential for the selection of the appropriate dose metric to use in pharmacokinetic modeling as well as for the selection of the appropriate approach for characterizing the dose-response below the range of experimental observation of toxic effects


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    Physiological Pharmacokinetic Modeling Applications Environmental Chemicals

    References

    Andersen, M.E., Clewell, H.J. III, Gargas, M.I., Smith, F.A., and Reitz, R.H. (1987). Physiologically-based pharmacokinetics and the risk assessment process for methylene chloride. Toxicol. Appl. Pharmacol. 87, 185

    Clewell, H.J., III and Andersen, M.E. 2004. Applying mode-of-action and pharmacokinetic considerations in contemporary cancer risk assessments: An example with trichloroethylene. Crit Rev Toxicol 34(5):385-445.

    Clewell, H.J., Gearhart, J.M., Gentry, P.R., Covington, T.R., VanLandingham, C.B., Crump, K.S., and Shipp, A.M. 1999. Evaluation of the uncertainty in an oral Reference Dose for methylmercury due to interindividual variability in pharmacokinetics. Risk Anal 19:547-558.

    Clewell, H.J., Gentry, P.R., Covington, T.R., Sarangapani, R., and Teeguarden, J.G. 2004. Evaluation of the potential impact of age- and gender-specific pharmacokinetic differences on tissue dosimetry. Toxicol. Sci. 79:381-393.

    Clewell, H.J., Gentry, P.R., Gearhart, J.M., Allen, B.C., Andersen, M.E., 2001. Comparison of cancer risk estimates for vinyl chloride using animal and human data with a PBPK model. Sci. Total Environ. 274 (1-3), 37–66.

    Shipp, A.M., Gentry, P.R., Lawrence, G., VanLandingham, C., Covington, C., Clewell, H.J., Gribben, K., and Crump, K. 2000. Determination of a site-specific reference dose for methylmercury for fish-eating populations. Toxicol Indust Health 16(9-10):335-438.

    Tan, Y.-M., Liao, Kai H., Conolly, R.B., Blount, B.C., Mason, A.M., and Clewell, H.J. 2006. Use of a physiologically based pharmacokinetic model to identify exposures consistent with human biomonitoring data for chloroform. J. Toxicol. Environ. Health, Part A, 69:1727-1756.


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