Modeling How the Human Body Handles Drugs and Toxicants

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Modeling How the Human Body Handles Drugs and
Toxicants

• Crispin Pierce, Ph.D.
• UWEC Faculty / Academic Staff Forum
• 27 October 2004

http//www.uwec.edu/piercech/model.ppt
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UWEC Student-Faculty Research
Mia Jewell, Laura Schrage, Julie Friedhoff,
Alison Deneen, and Ashley LaCasse
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Crispin Pierce, Mia Jewell, and Karen Bartosh Not
pictured Erin Moritz, Chris Judkins-Helpsmeet,
and Kristin Hardy
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Acknowledgements

• Michael Morgan and Russell Dills, University of
  Washington, Seattle
• UWEC Office of Research and Sponsored Programs
• NIOSH SERCA Grant 5 K01 OH00164
• Superfund Basic Research program, NIEHS ES 04696
• NIH/ NIBIB Grant 2 P41 EB001975

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We Are Exposed to 1,000s of Chemicals Every Day
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Voluntary exposure

• Eating and drinking

http//www.runslinux.net/belanaomi/Friends.htm
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• Smoking

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• Filling up our gas tank

http//www.quantico.usmc-mccs.org/business/retail-
services.htm
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• Use of chemicals (e.g., pesticides, drugs)

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Exposure at the Workplace
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Ambient (Environmental) Exposure
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How Do We Predict the Effects of These Chemicals?

• Empirical Observations
• Exposure to air pollution reduces lung function
  in children.
• I take two aspirin to relieve pain.
• Regular dosing with folic acid during the first
  trimester of pregnancy lowers risk of fetal
  health risks.
• Chronic consumption of fatty meats raises risks
  of cardiovascular disease and cancer.

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Dose-Response Relationships

• We use animal dosing experiments and results from
  epidemiological studies to make observations
  about dose-response relationships.

http//homepage.psy.utexas.edu/HomePage/class/Psy3
08/salinas/Psychopharmacology/Psychopharm.html
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All Substances Are Poisons at the Wrong Dose
http//homepage.psy.utexas.edu/HomePage/class/Psy3
08/salinas/Psychopharmacology/Psychopharm.html
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Can We Open Up This Black Box?
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Yes, We Can Examine the Changing Chemical
Concentration in Blood
From these data, we can estimate the rates of
absorption and excretion.
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Half-Life is a Valuable Descriptor
http//www.geo.arizona.edu/palynology/geos462/10ra
diometric.html
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We Can Also Create Models for How the Body
Eliminates Chemicals

• The Georgia Center for Continuing Education

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Why Would We Want to Understand How the Body
Handles the Chemical?

• To answer the following questions
• Why are some chemicals more toxic to test animals
  than humans, and vice versa?
• Are cancer risks that we measure at very high
  doses in animal studies linear down to the low
  exposures that we receive?
• Can we make drugs more effective and less toxic?
• Can we develop new antidotes to poisons?

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• To figure out why different people react
  differently to the same dose of the same
  substance.

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Student Project 1 Toxicokinetics of Toluene

• Toxicokinetics toxicon (poison) kinetic
  (movement) movement of poisons throughout the
  body.
• Toluene is the most widely-used industrial
  solvent.
• An understanding of how the body handles toluene,
  a less toxic substance, can help us understand
  the much higher risks from similar substances
  such as benzene, which causes cancer.

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• Goal To see if anthropometric characteristics,
  including body weight, body fat percentage,
  height and age are predictive of how the body
  handles toluene.

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• Methods Seven males inhaled 50 ppm of 13C- and
  2H-toluene over a two hour period. Blood,
  breath, and urine samples were collected for up
  to 100 hr post-exposure and were analyzed for
  parent and metabolite concentrations. This
  portion of the study took place at the University
  of Washington and was approved by the Human
  Subjects Division.

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• An Excel macro developed by Russell Dills was
  used to fit three lines through the data points
  a lagrange method, a log-trapezoidal method, and
  a linear method. The best visual method between
  each pair of points was used.

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• This macro determined the kinetic parameters of
  k-elimination, terminal half-life, area under the
  curve (AUC), clearance (Cl), mean residence time
  for the central compartment (MRTC), and volume of
  distribution at a steady state (Vdss).

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• Multiple regressions were used to determine which
  anthropometric characteristic were predictors of
  clearance, terminal half life, Vdss(the volume
  into which toluene distributes), MRTC (the
  average time a chemical spends in the body),
  maximum peak height/dose, and AUC/dose (how
  quickly the body gets rid of toluene).

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What About the Mechanism of How the Body Handles
Chemicals?
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Student Project 2 Examining MTBE Risk
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What Are MTBE and ETBE?

• Fuel additives that increase O2 in gasoline
• 1990 Clean Air Act Amendments
• Reduce carbon monoxide ozone components in air
  pollution
• 30 of U.S. gasoline is oxygenated
• 87 of oxygenated gas contains MTBE

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Problems With MTBE

• Associated with complaints of headaches, nausea,
  disorientation
• Ubiquitous in urban areas
• Unpleasant odor and taste
• Leaks into drinking water
• Contaminated ground water in all 50 states
• Possible human carcinogen

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Methods of Exposure

• Contaminated Water
• Drinking
• Showering
• Inhalation
• At the gas pump
• While driving
• Work environments

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Previous Experiment

• 10 Healthy Caucasian volunteers 5 women, 5 men.
• Target inhaled concentrations of 2.5 ppm
  2H12-MTBE and 2.5 ppm ETBE.
• Two hours of exposure with alternating periods of
  30 min 50W exercise and 15 min rest.

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• Model representing MTBE path through the body

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Experimental Goals

• Statistical testing of MTBE, ETBE, and TBA models
• Risk assessment based on cancer- AUC

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Statistical Testing

• Monte Carlo
• Used PopKinetics software to create a 95
  confidence interval around the mean predicted
  line

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Compare the differences between the yellow data
points and the mean model prediction (black line)
to the differences between the upper or lower
confidence interval (gold or yellow line) and the
mean prediction (black line).
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Monte Carlo 0.06718 gt Model Fits
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Risk Determination

• Used lowest literature standards for MTBE
• Inhalation
• Drinking water
• Calculated a dose based on above values
• Ran models with calculated dose as input
• Determined overall risk
• Used SAAMs AUC

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MTBE Regulations
EPA Standard ACGIH 8-Hour TWA TLV New Jersey and New York Wisconsin California
2040 ppb drinking water 40 ppm in air 10 ppb drinking water 60 ppb drinking water 13 ppb (primary) 5 ppb (secondary) drinking water
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Assumptions Used

• 70 kg body weight and 25 adipose content
• Alveolar ventilation and cardiac output rates
  were set as low and constant
• Drinking water experiment
• Drink 2 L of water per day (10 ppb MTBE)
• 70-year lifetime
• Inhalation experiment
• 40 year working lifetime (40 ppm)

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Area Under the Curve
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Results Single-day AUCs

• Typical daily exposure
• Drinking water 9.17e-3 umol-hr/L
• Inhalation (Gas pump) 1.36e-1 umol-hr/L
• 15 times higher risk from gas pump exposure

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Results Lifetime AUCs

• Based on standards
• Drinking water 2.44e2 umol-hr/L
• Inhalation (Work exposure) 2.18e6 umol-hr/L
• 9,000 times higher risk from work exposure.

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Conclusions

• Empirical and mechanistic approaches can be used
  to understand how the body handles chemicals
• Anthropometric characteristics affect how
  different people handle a chemical.
• Models can be used to predict risk of toxicity
  from different kinds of chemical exposures.

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