Physiologically based pharmacokinetic exposure route

Once a chemical is in systemic circulation, the next concern is how rapidly it is cleared from the body. Under the assumption of steady-state exposure, the clearance rate drives the steady-state concentration in the blood and other tissues, which in turn will help determine what types of specific molecular activity can be expected. Chemicals are processed through the liver, where a variety of biotransformation reactions occur, for instance, making the chemical more water soluble or tagging it for active transport. The chemical can then be actively or passively partitioned for excretion based largely on the physicochemical properties of the parent compound and the resulting metabolites. Whole animal pharmacokinetic studies can be carried out to determine partitioning, metabolic fate, and routes and extent of excretion, but these studies are extremely laborious and expensive, and are often difficult to extrapolate to humans. To complement these studies, and in some cases to replace them, physiologically based pharmacokinetic (PBPK) models can be constructed [32, 33]. These are typically compartment-based models that are parameterized for particular... 

The explanation of the pharmacokinetics or toxicokinetics involved in absorption, distribution, and elimination processes is a highly specialized branch of toxicology, and is beyond the scope of this chapter. However, here we introduce a few basic concepts that are related to the several transport rate processes that we described earlier in this chapter. Toxicokinetics is an extension of pharmacokinetics in that these studies are conducted at higher doses than pharmacokinetic studies and the principles of pharmacokinetics are applied to xenobiotics. In addition these studies are essential to provide information on the fate of the xenobiotic following exposure by a define route. This information is essential if one is to adequately interpret the dose-response relationship in the risk assessment process. In recent years these toxicokinetic data from laboratory animals have started to be utilized in physiologically based pharmacokinetic (PBPK) models to help extrapolations to low-dose exposures in humans. The ultimate aim in all of these analyses is to provide an estimate of tissue concentrations at the target site associated with the toxicity. 

Physiologically based pharmacokinetic (PBPK) models are used to estimate the dose of toxic metabolites reaching target tissues. Model outputs provide internal dose estimates for specific life stages and differences between sexes, species, dose routes, and exposure patterns. These models provide a tool for understanding the... 

Sweeney, R.E., Langenberg, J.P., Maxwell, D.M. (2006). A physiologically based pharmacokinetic (PB/PK) model for multiple exposure routes of soman in multiple species. Arch. Toxicol. 80 719-31. 

Hazard identification is the step in the risk assessment that qualitatively characterizes the inherent toxicity of a chemical. Scientific data are evaluated to establish a possible causal relationship between the occurrence of adverse health effects and chemical exposure. This step includes characterization of acute, subchronic, and chronic effects the potential for local versus systemic effects the influence of the route of exposure the relevance, to humans, of effects seen in animals an evaluation of the biological importance of the observed effects the likelihood of the effects occurring under certain conditions and the potential implications for public health. This step should be based on a thorough review of all the data that may provide information that is relevant to evaluating the potential chemical hazard. This may include data describing the effects on a variety of test animals, in vitro studies that characterize mechanisms of toxicity, metabolism, physiologically based pharmacokinetic studies, structure-activity relationships, short-term human studies, and epidemiological studies. Animal studies may focus on particular types of effects and may include reproductive toxicity studies,... 

Present-day risk assessment methodologies have an increasing emphasis on physiologically based pharmacokinetics (PBPK) or toxicokinetic models and mode of action (MOA). Snch models have been developed to predict exposure levels in target tissues for a large number of agents. PBPK models are especially useful in the risk assessment context because they allow data to be extrapolated across species, dose levels, and routes of exposure. 

Both of these approaches allow for assessment of systemic absorption by not conducting complete mass balance studies (e.g., expired air to catch absorbed compound metabolized to COj or HjO expired end products). In vivo dermal absorption studies not taking into account other routes of excretion must be interpreted with caution. One extension of this mass balance excretory analysis is to assess dermal absorption by only monitoring the primary excretory route for the compound studied. Dermal bioavailability has been assessed in exhaled breath using real-time ion trap mass spectrometry to track the uptake and ehmination of compounds (e.g., trichloroethylene) from dermal exposure in humans and rats (Poet et al., 2000). A physiologically based pharmacokinetic model can be used to estimate the total bioavailability of compoimds. The same approach was extended to determine the dermal uptake of volatile chemicals imder non-steady-state conditions using real-time breath analysis in rats, monkeys, and humans (Thrall et al., 2000). 

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