Exposure PBPK modeling

PBPK models improve the pharmacokinetic extrapolations used in risk assessments that identify the maximal (i.e., the safe) levels for human exposure to chemical substances (Andersen and Krishnan 1994). PBPK models provide a scientifically sound means to predict the target tissue dose of chemicals in humans who are exposed to environmental levels (for example, levels that might occur at hazardous waste sites) based on the results of studies where doses were higher or were administered in different species. Figure 3-4 shows a conceptualized representation of a PBPK model. 

Levels of Significant Exposure to Trichloroethylene - Inhalation 2-2 Levels of Significant Exposure to Trichloroethylene - Oral 2-3 Parameters Used in Two Human PBPK Models 2-4 Genotoxicity of Trichloroethylene/n Vivo... 

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). 

This study, like that of Fisher and Allen (1993), incorporated a linear multistage model. However, the mechanism of trichloroethylene carcinogenicity appears to be non-genotoxic, and a non-linear model (as opposed to the linearized multistage model) has been proposed for use along with PBPK modeling for cancer risk assessment. The use of this non-linear model has resulted in a 100-fold increase in the virtually safe lifetime exposure estimates (Clewell et al. 1995). 

While these models simulate the transfer of lead between many of the same physiological compartments, they use different methodologies to quantify lead exposure as well as the kinetics of lead transfer among the compartments. As described earlier, in contrast to PBPK models, classical pharmacokinetic models are calibrated to experimental data using transfer coefficients that may not have any physiological correlates. Examples of lead models that use PBPK and classical pharmacokinetic approaches are discussed in the following section, with a focus on the basis for model parameters, including age-specific blood flow rates and volumes for multiple body compartments, kinetic rate constants, tissue dosimetry,... 

FUN tool is a new integrated software based on a multimedia model, physiologically based pharmacokinetic (PBPK) models and associated databases. The tool is a dynamic integrated model and is capable of assessing the human exposure to chemical substances via multiple exposure pathways and the potential health risks (Fig. 9) [70]. 2-FUN tool has been developed in the framework of the European project called 2-FUN (Full-chain and UNcertainty Approaches for Assessing Health Risks in FUture ENvironmental Scenarios www.2-fun.org). 

Its capability to conduct full-chain risk assessment on a common system, which allows for linking the simulation of chemical fate in the environmental media, multiple pathways of exposure and the detailed analysis for multiple effects in different target tissues in human body (by PBPK models). 

However, as a general observation, this study demonstrated the feasibility of the integrated modeling approach to couple an environmental multimedia and a PBPK models, considering multi-exposure pathways, and thus the potential applicability of the 2-FUN tool for health risk assessment. The global sensitivity analysis effectively discovered which input parameters and exposure pathways were the key drivers of Pb concentrations in the arterial blood of adults and children. This information allows us to focus on predominant input parameters and exposure pathways, and then to improve more efficiently the performance of the modeling tool for the risk assessment. 

Both /nmv-permethrin and bioresmethrin were effectively cleaved by rat serum CES on the other hand, deltamethrin, esfenvalerate, a-cypermethrin, and cis-permethrin were slowly hydrolyzed. These results suggest that PBPK models of some pyrethroids may require the parameter of esterase activity to calculate the concentrations in the intestinal tract, liver, and serum if it is shown that the compounds in the model are appreciably hydrolyzed within these tissues. Such data for human and animal tissues will help to improve the accuracy of extrapolation between species (e.g., rats to humans) and thus enable better predictions of tissue and blood concentrations in humans following exposure to pyrethroids [30]. 

Levels of Significant Exposure to -Hexane—Inhalation 2-2 Levels of Significant Exposure to -Hexane—Oral 2-3 Levels of Significant Exposure to -Hexane—Dermal 2-4 Parameters Used in the Perbellini PBPK Model for -Hexane 2-5 Parameters Used in the Fisher PBPK Model for -Hexane 2-6 In Vivo Genotoxicity of -Hexane... 

The Perbellini PBPK model for -hexane is the only validated model for this chemical identified in the literature. The Fisher model was intended for risk assessment to predict which of 19 volatile organic chemicals may be present in milk at a high enough level after workplace exposure to raise health concerns for a nursing infant. 

If the neurotoxicity of /7-hexane was potentiated in this study by co-exposure to acetone, the level of n-hexane alone required to produce these effects would be higher than 58 ppm and the MRL level would be higher. Results from simulations with a PBPK model that accurately predicted /7-hexane blood and 2,5-hexanedione urine levels (Perbellini et al. 1986, 1990a) indicate that at concentrations of 50 ppm, the rate-limiting factor in /7-hexane metabolism is delivery to the liver, not metabolic activity. This suggests that at this concentration (and at the MRL concentration of 0.6 ppm), induction of P-450 enzymes in the liver by acetone or other chemicals would not affect the rate at which 2,5-hexanedione was produced. 

There is no experimental evidence available to assess whether the toxicokinetics of -hexane differ between children and adults. Experiments in the rat model comparing kinetic parameters in weanling and mature animals after exposure to -hexane would be useful. These experiments should be designed to determine the concentration-time dependence (area under the curve) for blood levels of the neurotoxic /7-hcxane metabolite 2,5-hexanedione. w-Hcxanc and its metabolites cross the placenta in the rat (Bus et al. 1979) however, no preferential distribution to the fetus was observed. -Hexane has been detected, but not quantified, in human breast milk (Pellizzari et al. 1982), and a milk/blood partition coefficient of 2.10 has been determined experimentally in humans (Fisher et al. 1997). However, no pharmacokinetic experiments are available to confirm that -hexane or its metabolites are actually transferred to breast milk. Based on studies in humans, it appears unlikely that significant amounts of -hexane would be stored in human tissues at likely levels of exposure, so it is unlikely that maternal stores would be released upon pregnancy or lactation. A PBPK model is available for the transfer of M-hcxanc from milk to a nursing infant (Fisher et al. 1997) the model predicted that -hcxane intake by a nursing infant whose mother was exposed to 50 ppm at work would be well below the EPA advisory level for a 10-kg infant. However, this model cannot be validated without data on -hexane content in milk under known exposure conditions. 

The PBPK model development for a chemical is preceded by the definition of the problem, which in toxicology may often be related to the apparent complex nature of toxicity. Examples of such apparent complex toxic responses include nonlinearity in dose-response, sex and species differences in tissue response, differential response of tissues to chemical exposure, qualitatively and/or quantitatively difference responses for the same cumulative dose administered by different routes and scenarios, and so on. In these instances, PBPK modeling studies can be utilized to evaluate the pharmacokinetic basis of the apparent complex nature of toxicity induced by the chemical. One of the values of PBPK modeling, in fact, is that accurate description of target tissue dose often resolves behavior that appears complex at the administered dose level. 

The principal application of PBPK models is in the prediction of the target tissue dose of the toxic parent chemical or its reactive metabolite. Use of the target tissue dose of the toxic moiety of a chemical in risk assessment calculations provides a better basis of relating to the observed toxic effects than the external or exposure concentration of the parent chemical. Because PBPK models facilitate the prediction of target tissue dose for various exposure scenarios, routes, doses, and species, they can help reduce the uncertainty associated with the conventional extrapolation approaches. Direct application of modeling includes... 

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