Exercise Day 3-13 A PBPK Model for Methyl Mercury Interpretation of biomonitoring data using physiologically based pharmacokinetic modeling Center for Human Health Assessment September 25-29, 29, 2006
Objectives Use a PBPK model for methyl mercury (MeHg( MeHg) ) to estimate an Iraqi woman s s exposure (through consumption of contaminated bread during pregnancy) based on the concentrations of MeHg in her blood after she was admitted to the hospital. Use the PBPK model with the estimated ingestion rate to simulate: Hg concentrations in her hair; and MeHg concentration in the infant s s blood at birth. Use the model simulations to determine The peak fetal blood concentration; and The average fetal brain concentration during the third trimester.
What is the story? Seed grain, treated with methyl mercury fungicide, inadvertently used to prepare bread in Iraq in 1972 Exposures continued over 1-1 to 3-month 3 period before symptoms were recognized parasthesia (tingling in the extremities) cerebral palsy (muscle control disorders) Symptoms observed in children of asymptomatic mothers exposed during pregnancy late walking late talking impaired neurological test performance
What is the story? One Iraqi woman, who was pregnant at the time of the poisoning episode, was admitted to the hospital with symptoms of mercury poisoning about halfway through her pregnancy The hospital collected blood samples from the mother during her hospital stay, as well as from the infant after it was born They also collected samples of her hair Hair grows at about 1cm/month, so hair segments from the follicle to the end can be used to reconstruct exposure over a long period
What is the story? We can estimate the duration of this woman s s exposure to MeHg by the date when the contaminated grain was distributed and the date when she was admitted to the hospital Since the exposure was from eating bread, we can assume that the daily ingestion rate is relatively constant The parameters in the PBPK model have all been determined separately Physiological data on maternal changes during pregnancy and fetal growth Controlled human exposures (fish ingestion) Data from the Iraqi population (half-life) life) What we want to do is estimate the woman s s daily dose rate, for comparison with the EPA Reference dose of 0.1 ug/kg/day
MeHg PBPK model structure PBPK M odel for M ehg Exposure D iv Red Blood Cells k rbc k v Plasm a Q c Kidney Q k k u Urine Fetal Compartment Richly Perfused Q r Fat Q f Placenta Q pl Slow ly Perfused k h Q s k fe Fetal Plasma Q fe Hair k l k rbcf Brain Blood Q br Fetal RBC's Brain k br Fetal Brain Q fbr Placenta k fe Q pl Fetal Body Q fb Fetus Liver Q l Inorganic M ercury k i k b Gut Q g Q g k r Intestine k o D oral k d k f Inorganic M ercury k f Feces
Running the PBPK model for MeHg to reconstruct an exposure Open the PBPK model (file/open/mehgpbpk.mmd MeHgPBPK.mmd) Examine the model code {Dosing controls} ; Scaling of doses Oralstart = Dtime*24 Oralstop = (Dtime+Dmax)*24 OralLength = Dmax*24 IVstart=1 IVLength=STOPTIME ; time to start oral dosing (h) ; time to stop oral dosing (h) Do= IF (Time>=Oralstart) AND (TIME<=Oralstop) THEN Doi*BWF*FracInc ; total dose changed with body weight ELSE 0.0
The PBPK model includes maternal physiology changes during pregnancy VRBC = IF (Time<=TPreg) AND (TIME>=BTIME) THEN VRBCC*BW ELSE BW*(VRBCC+(0.0075*EXP(-6.53026*(EXP(-0.000590*TScale*GD))))) VF = IF (Time<=TPreg) AND (TIME>=BTIME) THEN VFC*BW ELSE BW*(VFC+(0.09*EXP(-12.90995862*(EXP(-0.000797*TScale*GD)))))
Estimate the ingestion rate Run the model Change the daily ingestion rate (Doi( Doi) ) in the Parameter Window to achieve the best fit to the measured MeHg concentration in blood. 1.8 1.6 1.4 Doi =?? mg/kg/day 1.2 CB, #PaminCB 1 0.8 0.6 0.4 0.2 Doi = 0.005 mg/kg/day 0 1e+4 1.286e+4 1.571e+4 1.857e+4 TIME 2.143e+4 2.429e+4 2.714e+4 3e+4
Hg in hair After you fit the blood data, toggle the Page button at the top of the Graph Window to Page 2 2 to show the data and simulations of Hg in hair for the same individual.
MeHg in infant s s blood Now toggle the Page button at the top of the Graph Window to Page 3 3 to show the data and simulations of MeHg in the blood of the infant when it is born.
What was the peak MeHg concentration in the fetal blood during gestation? Use the Readout function to determine the highest MeHg concentration in the fetal blood How does this compare with the Benchmark Dose for the neurological effects of MeHg (0.0058 mg/l)
What was the average fetal brain MeHg concentration during the third trimester Toggle the Page button at the top of the Graph Window to Page 4 4 to show the simulations of MeHg in fetal brain. Assuming that the third trimester is between the 200 th (16800 h) and 270 th (18480) day of a pregnancy, use the Table function to estimate the average fetal brain MeHg conc during this period. Table Function
So what s s the point? In this case, we were able use information on the nature of the exposure to make it possible to reconstruct the daily dose-rate from the resulting blood concentrations knowledge of when the exposure started and stopped assuming a constant dose-rate for ingestion of MeHg contaminated grain in bread The estimated exposure could be compared directly with the EPA Reference Dose, which is in units of daily dose- rate The physiological structure of the PBPK model allowed us to simultaneously estimate the fetal exposure that would result from the estimated maternal exposure Peak fetal blood concentration for comparison with the NOAEL Target tissue dose: average brain concentration during the window of greatest susceptibility (the third trimester)