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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

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

slide2
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
slide3
Part 1: RISK ASSESSMENT

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

- National Academy of Sciences, 1983

slide4
Risk Assessment Questions
  • Qualitative: Is the chemical potentially harmful under ANY conditions?
  • Quantitative: At what human exposure concentration does the RISK become SIGNIFICANT?
slide5
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

slide6
??

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

slide7
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

slide8
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

slide9
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)
slide10
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
slide11
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.
slide12
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
slide13
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)
slide14
Considering Pharmacokinetic and Mechanistic Information in Cancer Risk Assessment

Examples:

Easy: Vinyl Chloride

Hard: Trichloroethylene

slide15
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
slide16
Metabolism of Vinyl Chloride

Dose metric:

concentration of

chloroethylene epoxide

slide17
PBPK Model for Vinyl Chloride

(Clewell et al. 2001)

Dose metric:

production rate of

reactive metabolite

per gram liver

slide23
Comparison of Cancer Risk Estimates for Vinyl Chloride

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

slide24
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
slide25
PBPK Model for TCE(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

slide26
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?)

slide27
PBPK modeling can only go so far…

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

slide28
Part 2: Use of PBPK Modeling to Interpret

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
relationship of human biomonitoring data to animal toxicity data
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

slide30
Reconstructing Exposure with a PBPK Model:

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
slide31
PBPK Model for Gestational Exposure to Methylmercury

Clewell et al. 1999,

Shipp et al. 2000

slide32
Effect of Changes in Fetal and Maternal

Physiology on Dosimetry

Non-human primates exposed to a constant

daily dose of methylmercury during gestation

slide33
Exposure Reconstruction With a PBPK Model

Iraqi woman exposed during pregnancy

to grain contaminated with methylmercury

Estimated exposure:

42 ug/kg/day

EPA Reference Dose:

0.1 ug/kg/day

slide34
Exposure Reconstruction for perfluoro-octanoic acid
  • 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

slide36
Predicted time course of PFOA in plasma

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

slide37
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

slide38
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
slide39
Physiological Pharmacokinetic Modeling Applications

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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