Toxicokinetics 2 Crispin Pierce, Ph.D. University of Washington (206)

Purposes of Toxicokinetics zTo quantify toxicant absorption, distribution, metabolism, and excretion (ADME). zTo provide an exposure framework for risk assessment.

The Value of Modeling zUnderstand biologic systems zDrive data collection zInterpolate zExtrapolate zPredict zReduce animal usage

? zModels are an abstraction of reality. To establish dose-risk relationships, we can choose anything between a completely theoretical model, and massive testing of humans to toxic chemicals. What are the hallmarks of a model/testing paradigm that you would mandate?

Four Modeling Approaches zHand-Waving zNon-Compartmental zCompartmental zPhysiologic

Hand Waving zThe same dose/kg gives the same blood concentration. zUse a 10-fold safety factor for test animal- human differences. zUse a 10-fold safety factor for interindividual differences. zUse a 1-10-fold modifying factor for additional uncertainties.

? zFor what kinds of substances, exposures, and test costs would the hand-waving approach be appropriate?

Non-Compartmental Models zEmpiric observation of volume, clearance, and half-life. zNo structural model of where the toxicant goes. AUC Time Blood (or plasma ) Concen tration CL = F·Dose/AUC

Compartmental Models zBody is viewed as distinct "compartments," which are interconnected by rate constants. zModeling is empiric, and compartments do not directly correspond to tissues. zComplete flexibility in fitting model parameters to observed data. Use of minimum number of compartments that adequately describe the data.

One Compartment Model zOne compartment model: xenobiotic distributes into a single, homogenous "vessel" (example: methanol).

? zHow would you define an adequate fit of your model to the data?

Two Compartment Model zTwo compartment model: xenobiotic distributes into a central, and then a peripheral compartment.

zRate of change of toxicant in central compartment = ka*Amount at absorption site - k12*Amount in Central Compartment + k21*Amount in Peripheral Compartment - k10*Amount in Central Compartment ka

zt 1/2,  = ln2/ , t 1/2,  = ln2/  zAUC = A/  + B/  zt 1/2, , t 1/2, , , and  are constant with dose. zA and B vary with dose. Time ln Conc i.v. dose A B slope = -  

? zHow would you test whether the kinetics of a chemical is better described by one or two compartments?

Physiologically-Based Kinetic (PBK) Modeling zAn attempt to simulate toxicant disposition in the body by using measured values: yTissue volumes and blood flows yToxicant-specific tissue partition coefficients and elimination rates

zBody is viewed as grouped tissue compartments which are interconnected by blood flows. zModeling is mechanistic, and compartments are defined by physiologic volumes and partition coefficients. zModel parameters are fit within physiologic bounds to observed data. Use of minimum number of compartments that adequately describe the data.

Lung Blood Q t Cven Q t = CO Cart Cva Q a =.09*CO Cvr Qr=.49 *CO Cvs Qs=.15 *CO Cvl Ql=.25 *CO Rapidly Perfused Tissues Slowly Perfused Tissues Adipose Tissues IV, dermal dose Oral Dose Liver Inhalation dose

Flow-Limited Delivery zFlow-limited delivery of xenobiotics to tissue groups: where: A t = Amount in tissue, Q t = Blood flow to tissue, C a = Arterial blood concentration, K p = Tissue/blood partition coefficient, V t = Tissue volume

Michaelis-Menten Metabolism V max = Maximum metabolic rate, K m = Michaelis constant (toxicant concentration at half-maximum metabolic rate)

? zWhich kind of model would you use to study identical dosing in a very homogeneous group (e.g., vaccinations in two year-olds)? zWhich kind of model would you use to study varied dosing in a heterogeneous group (e.g., genetically modified food in the general population)?

Uses of the PBK Model zUse across a wide range of doses - low to saturating. zInterspecies scaling, in particular with regards to risk. zDetermination of target tissue dose. zSimulating complex risk assessment conditions. zSearching for relevant interindividual differences.

Toxicant-Specific Considerations zMolecular weight, conformation, charge >>> Flow- or diffusion-limited delivery and filtration by kidney. zVapor pressure over blood >>> Elimination by exhalation. zMolecular weight, conformation, charge (lipophilicity) >>> Tissue distribution and accumulation.

Human Physiologic Considerations zGenetic polymorphism >>> Metabolic rates zSex and age differences >>> Blood flows and metabolic rates zWeight >>> Blood flows and tissue volumes zBody fat percentage >>> Adipose tissue volume zWorking conditions >>> Alveolar ventilation rate, cardiac output, blood flows zRoute of administration >>> First-pass effects

? zWhich PBK model parameters are likely known with greatest certainty? Which with least certainty? Which would you allow to vary within physiologic bounds to describe the data? zMight the PBK model be used to question the accuracy of data between studies?