Dose metrics PBPK model

Monte Carlo simulation, an iterative technique which derives a range of risk estimates, was incorporated into a trichloroethylene risk assessment using the PBPK model developed by Fisher and Allen (1993). The results of this study (Cronin et al. 1995), which used the kinetics of TCA production and trichloroethylene elimination as the dose metrics relevant to carcinogenic risk, indicated that concentrations of 0.09-1.0 pg/L (men) and 0.29-5.3 pg/L (women) in drinking water correspond to a cancer risk in humans of 1 in 1 million. For inhalation exposure, a similar risk was obtained from intermittent exposure to 0.07-13.3 ppb (men) and 0.16-6.3 ppb (women), or continuous exposure to 0.01-2.6 ppb (men) and 0.03-6.3 ppb (women) (Cronin et al. 1995). 

Traditional, default approaches for toxicological risk assessment are not based on specific understanding of modes of action and tissue dose metrics (e.g., tissue concentrations, body burdens, AUCs). In recent years, PBPK/PBTK modeling has found frequent application in risk assessments where PBPK models serve as important adjuncts to studies on modes of action of xenobiotics. 

PBPK models rely on a series of simultaneous differential equations that simulate chemical delivery to tissues via the arterial circulation and removal via the venous circulation. The models are run in time steps such that the entire course of chemical disposition can be presented for calculation of the area-under-the-curve (AUC) dose, often a key metric for chronic risk assessment. The physiologic parameters can be adapted for different species, sexes, age groups, and genetic variants to facilitate extrapolation from one type of receptor to another. 

When it comes to mixtures, an important development is the use of the internal dose as a dose metric, particularly in human assessments. The internal dose is either measured directly or modeled using PBPK models, for example, as a blood or a target tissue concentration. Application of an internal dose metric makes it possible to account for 1) interindividual variability in toxicokinetics, 2) temporal variations in exposure patterns, and 3) interactions between substances during absorption, metabolism, and transport. In ecological risk assessment, internal doses are sometimes measured but rarely modeled with PBPK models. The awareness is growing that the internal dose is a useful metric but the use in formal risk assessment procedures is still limited, for separate compounds as well as for mixtures. 

As shown previously, PBPK models allow the conversion of potential dose or exposure concentration to tissue dose, which can then be used for risk characterization purposes. The choice of an internal dose metric is based principally on an understanding of the mode of action of the chemical species of concern. The internal dose metric (sometimes called the biologically effective dose) is often used in place of the applied dose in quantitative dose-response assessments, in order to reduce the uncertainty inherent in using the applied dose to derive risk values. 

Sixth, and finally, the adequacy of model structure as well as parameter values should be evaluated based on comparison of mode predictions with experimental data that had not been used for calibration purpose. This process essentially evaluates whether the PBPK model is capable of providing reliable predictions of the various dose metrics of potential use in a cancer risk assessement. The model should not only reprodnce consistently the shape of the pharmacokinetic time-course curve (i.e., including bnmps and valleys) and not jnst provide satisfactory fit only to a portion of the cnrve. Evaluation or validation of PBPK models should be regarded... 

By facilitating the simulation of the dose metrics for use in cancer dose-response analysis, the PBPK models address the uncertainty associated with interspecies, route-to-route, and high-dose to low-dose extrapolations (Andersen et al. 1993 Andersen and Krishnan 1994 Clewell et al. 2002a Clewell and Andersen 1987 Melnick and Kohn 2000). Since the first demonstration of the application of PBPK models in cancer risk assessment by Andersen and co-workers in 1987, there have been substantial efforts to evaluate the appropriate dose metrics and cancer risk associated with a number of other volatile organic chemicals using the PBPK modeling approach (Table 21.3). These risk assessments have been based on the PBPK model simulations of a variety of dose metrics that reflect the current state... 

TABLE 21.3. Examples of PBPK Models Developed for Assessing Dose Metrics and Cancer Risks... 

Back-calculation of the potential dose or exposure concentration associated with the dose metric for a predetermined (i.e., acceptable) risk level (e.g., 1 X 10 ) or threshold level, using the human PBPK model, based on the assumption of equivalent tissue responses for equivalent dose metrics regardless of the species (Andersen et al. 1987 Krishnan and Andersen 1991b). 

The PBPK-based route-to-route extrapolation in cancer risk assessment frequently begins with the determination of a slope factor, associated with the response data for one exposure route, on the basis of the appropriate dose metrics (Dt), e.g., 2 X 10 pCT milligram metabofized per day per g of tissue. Then, the PBPK model, parametrized for other exposure route(s) of interest, is used to deter-nune the exposure dose that genrates the same Dt—that is, that corresponding to a predetermined risk level (e.g., 1 x 10 ) (Clewell et al. 2001). When linear extrapolation is appropriate, the following equation is used ... 

Obtaining predictions of dose metrics for each mixture component in humans, based on information on exposure condition defined as input to the mixture PBPK model... 

Establishment of a tissue dose metric-based slope factor ( iissue) using the animal PBPK model for each of the mixture constituents... 

Computation of the dose metric for each mixture constituent (Dussue) associated with human exposure conditions using mixture PBPK models... 

TABLE 21.5. Improvement of Cancer Dose-Response Assessment for Dichloromethane Using PBPK Models to Compute Relevant Dose Metrics... 

The assessment of liver cancer risks associated with human exposure to trichloroethylene (TCE) was initially conducted by Fisher and Allen (1993) using a PBPK-modeling approach. The use of the amount of TCE metabolized per day as dose metric used in the linearized multistage model led to lOppb in air and 7 ag/L in water as acceptable concentrations—that is, environmental levels corresponding to a population cancer risk of 1 in 10 (Fisher and Allen 1993). Corresponding values based on circulating levels of the metabolite, trichloroacetic acid, were 10 times and twice lower than those based on the amount of TCE metabolized per unit time, whereas the acceptable TCE concentration in air as defined by the EPA at the time was 90 times lower. A number of authors subsequently investigated the dose metrics and cancer risks associated with TCE [e.g., Bois (2000), CleweU and Andersen... 

This was a great step forward for risk assessment. First, a reasonable dose metric was chosen for which there was evidence of a close mechanistic relationship with the potential adverse outcome. Second, because of this understanding and the knowledge of the metabolism and pharmacokinetics, a PBPK model was constructed. This model enabled a quantification of the dose metric in different species and for different dosing and exposure regimens and routes. Thus interspecies and interdose extrapolations could be done more rationally and with less uncertainty. Third, because of the first two developments the risk assessment was based on mode of action hence the relevance of dose, exposure levels, and test species relevance was better understood and considered. As a result, the cancer potency for DCM was changed by close to an order of magnitude from the previous value. 

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