Behavior of xenobiotics

Garten, C. T., Trabalka, J. R. (1983) Evaluation of models for predicting terrestrial food chain behavior of xenobiotics. Environ. Sci. Technol. 17, 590-595. 

In summary, the kinetic parameters described previously are used to describe the behavior of xenobiotics in the body following exposure via several routes the extent of distribution within the body, the amount available for action and elimination, the... 

Whereas compartmental models are abstract mathematical representations of an animal or a human body, in the form of a certain number of boxes, PBPK models describe the behavior of xenobiotics on the basis of the actual anatomy, physiology, and biochemistry of human beings and animals. Being realistically modeled on how the body functions, PBPK models take into consideration the complex relationships that exist between critical biological and physicochemical determinants such as blood flow, ventilation rates, metabolic rate constants, tissue solubilities, and binding to proteins (e.g., albumin and glycoproteins) or other macromolecules (e.g., DNA and hemoglobin). 

Thus, the behavior of xenobiotics may be characterized as "What the compound does to the body" and "What the body does to the compound". In pharmacology one speaks of "pharmacodynamic effects" to indicate what a drug does to the body, and "pharmacokinetic effects" to indicate what the body does to the drug. 

Airborne toxicants can be simplified to two general types of compounds, namely gases and aerosols. Compounds such as gases, solvents, and vapors are subject to gas laws and are carried easily to alveolar air. Much of our understanding of xenobiotic behavior is with anesthetics. Compounds such as aerosols, particulates, and fumes are not subject to gas laws because they are in particulate form. 

Multiple forms of GST have been demonstrated in the liver of many mammalian species multiple forms also occur in insects. Most GSTs are soluble dimeric proteins with molecular weights ranging between 45,000 and 50,000 daltons. All forms appear to be nonspecific with respect to the reaction types described, although the kinetic constants for particular substrates vary from one form to another. They are usually named from their chromatographic behavior. At least two are membrane-bound glutathione transferases, one of which is involved in metabolism of xenobiotics and is designated... 

The presence of acidic functional groups, mostly carboxyl and phenolic OH groups, in the molecular structure of soil HS renders them major players in the acid-base buffering capacity of soils and in the fate, bioavailability, and physico-chemical behavior of macro- and micronutrients, toxic metal ions, and several xenobiotic organic compounds in soil (Ritchie and Perdue, 2003 Senesi and Loffredo, 2005). Consequently, the effects of amendment on the acid-base properties of soil HAs and FAs is a subject of considerable interest. 

As demonstrated below, nonlinear model analysis can be used to predict the dependence of the oscillatory behavior of glycolysis on e.g. exposure of the cell to a xenobiotic. Experimentally, the oscillatory behavior is monitored via NADH fluo-... 

Some neurons are more sensitive than others to the effects of a variety of toxicants that is, they display a selective vulnerability to neurotoxicants. For example, mitochondrial respiratory complex inhibitors such as cyanide and 3-nitropropionic acid are toxic to all cell types yet within the CNS, neurons in the basal ganglia (a group of regions that collectively control motor behavior) appear to be particularly sensitive to these agents. In most cases, selective vulnerability to neurotoxicants arises because of a unique combination of factors that predispose a cell type or region to particular insults. These factors may include the presence of certain ion channels, receptors or uptake sites, the activity level of xenobiotic metabolizing or antioxidant enzymes, the expression profile of neurotrophic factors or their receptors, and so on. Three CNS sites highly vulnerable to neurotoxicant effects are described separately below. 

For the purposes of this chapter, reproductive toxicity will refer to any manifestations of xenobiotic exposure, including endocrine disruption (see discussion below), reflecting adverse effects on any of the physiological processes and associated behaviors and/or anatomical structures involved in animal reproduction or development (Figure 36.1). This is a fairly broad definition which encompasses developmental toxicity, as well as any toxic... 

When using such models, it is assumed that the disposition of a chemical is governed by first-order processes. This means that the rate of disappearance of a xenobiotic from the body, as a result of excretion and/or biotransformation, is proportional to the amount of the xenobiotic in the body at that time. In other words, the quantity of a xenobiotic that leaves the body is large when the amount of xenobiotic in the body is large (e.g., immediately after exposure), whereas this quantity is small when the amount in the body is small (e.g., several hours after exposure). Most xenobiotics exhibit this type of behavior, provided that the several biological mechanisms responsible for disposition are not saturated, i.e., not overwhelmed by large concentrations of xenobiotics (see section Dose-Dependent Kinetics). 

Once formulated, a PBPK model can be used to simulate the kinetic behavior of a xenobiotic (e.g., amount metabolized, blood or tissue concentrations, and percentage of dose excreted) in animals or humans. An important step in the development of PBPK model is its validation. Validation is usually based on the visual or statistical comparison of model predictions with experimental observations in humans or animals. 

Toxicokinetic (TK) behavior of most chemicals is determined to a large extent by metabolism (xenobiotic-metabolizing enzymes). If metabolic processes were to be measured in in vitro cellular systems, it is of utmost importance to ensure that they are actually functional or at least incorporated in one way or another and at levels similar to those in vivo. 

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