Toxicokinetics process

Figure 10.1-6. Simplified model of a higher aquatic organism and of the toxicokinetic processes taking place.

The proportion of ionized and unionized forms of a chemical compound can be readily calculated according to the above equation. It can be easily seen that pK is also a pH value at which 50% of the compound exists in ionized form. The ionization of weak acids increases as the pH increases, whereas the ionization of weak bases increases when the pH decreases. As the proportion of an ionized chemical increases, the diffusion of the chemical through the biological membranes is greatly impaired, and this attenuates toxicokinetic processes. For example, the common drug acetosalicylic acid (aspirin), a weak acid, is readily absorbed from the stomach because most of its dose is in an unionized form at the acidic pH of the stomach. 

Physiologically based toxicokinetic models are nowadays used increasingly for toxicological risk assessment. These models are based on human physiology, and thus take into consideration the actual toxicokinetic processes more accurately than the one- or two-compartment models. In these models, all of the relevant information regarding absorption, distribution, biotransformarion, and elimination of a compound is utilized. The principles of physiologically based pharmaco/ toxicokinetic models are depicted in Fig. 5.41a and h. The... 

A systematic comparison of the available information on age-dependent maturation of metabolic and elimination processes as well as the toxicokinetics of chemicals in developing neonatal and young animals with that in infants and children can be found elsewhere (Gladtke, 1973 Stewart Hampton, 1987 Crom, 1994 Renwick, 1998 Clewell et al., 2002 Alcorn McNamara, 2003 Kearns et al., 2003 de Zwart et al., 2004 Ginsberg et al., 2004c). Table 2 summarizes the age dependency of toxicokinetic processes and determinants in children compared with adults. 

How do toxicokinetic processes relate across species and among different age groups and between sexes in humans ... 

With simple test objects, especially, QSAR relationships are fairly clear - for example with isolated enzymes, organelles or organs. But if substances are used in intact organisms such QSAR relationships are overlaid to a greater or lesser extent by toxicokinetic processes concerned primarily with absorption, distribution and breakdown. 

The complexity of toxicokinetic processes of solvents can be described in models, e.g., predicting exposure situations and distribution phenomena in the human body and quantifying these processes (e.g. dose-effect response relationships). This applies especially to Simula-... 

A very important issue - disregard of which is a big source of bad modeling studies - is the dear distinction of transport processes (toxicokinetics) and interactions with targets such as membranes, enzymes, or DNA (toxicodynamics). Figure 10.1-6 gives a rather simplified model of a fish to illustrate this distinction. 

The kinetic properties of chemical compounds include their absorption and distribution in the body, theit biotransformation to more soluble forms through metabolic processes in the liver and other metabolic organs, and the excretion of the metabolites in the urine, the bile, the exhaled air, and in the saliva. An important issue in toxicokinetics deals with the formation of reactive toxic intermediates during phase I metabolic reactions (see. Section 5.3.3). 

Absorption, distribution, biotransformation, and excretion of chemical compounds have been discussed as separate phenomena. In reality all these processes occur simultaneously, and are integrated processes, i.e., they all affect each other. In order to understand the movements of chemicals in the body, and for the delineation of the duration of action of a chemical m the organism, it is important to be able to quantify these toxicokinetic phases. For this purpose various models are used, of which the most widely utilized are the one-compartment, two-compartment, and various physiologically based pharmacokinetic models. These models resemble models used in ventilation engineering to characterize air exchange. 

The toxicity of chemicals to living organisms is determined by the operation of both toxicokinetic and toxicodynamic processes (Chapter 2). The evolution of defense mechanisms depends upon changes in toxicokinetics or toxicodynamics or both, which will reduce toxicity. Thus, at the toxicokinetic level, increased storage or metabolic detoxication will lead to reduced toxicity at the toxicodynamic level, changes in the site of action that reduce affinity with a toxin will lead to reduced toxicity. 

For convenience, the processes identified in Figure 2.1 can be separated into two distinct categories toxicokinetics and toxicodynamics. Toxicokinetics covers uptake, distribution, metabolism, and excretion processes that determine how much of the toxic form of the chemical (parent compound or active metabolite) will reach the site of action. Toxicodynamics is concerned with the interaction with the sites of action, leading to the expression of toxic effects. The interplay of the processes of toxicokinetics and toxicodynamics determines toxicity. The more the toxic form of the chemical that reaches the site of action, and the greater the sensitivity of the site of action to the chemical, the more toxic it will be. In the following text, toxicokinetics and toxicodynamics will be dealt with separately. 

Data from both in vivo and in vitro systems showed PbTx-3 to have an intermediate extraction ratio, indicating in vivo clearance of PbTx-3 was equally dependent upon liver blood flow and the activity of toxin-metabolizing enzymes. Studies on the effects of varying flow rates and metabolism on the total body clearance of PbTx-3 are planned. Finally, comparison of in vivo metabolism data to those derived from in vitro metabolism in isolated perfused livers and isolated hepatocytes suggested that in vitro systems accurately reflect in vivo metabolic processes and can be used to predict the toxicokinetic parameters of PbTx-3. 

Short-term non-invasive biomarkers for processes producing long-term lung damage-evaluation of the feasibility of candidate measurement systems. Toxicokinetic models have been developed to determine whether breath analysis of pentane and ethane can be used to estimate chronic lung damage from toxicants. 

In the 2002 review of the RfD and RfC processes (US-EPA 2002), the growing support for the use of CSAFs in place of DAFs was noted, and this will provide an incentive to fill existing data gaps. The US-EPA has not yet established a guidance for the use of chemical-specific data for deriving UFs, but the division of UFs into toxicodynamic and toxicokinetic components is in the RfC methodology (US-EPA 1994). It was pointed out that, for many substances, there are relatively few data available to serve as an adequate basis to replace defaults for interspecies differences and human variability with more informative CSAFs. Currently, relevant data for consideration are often restricted to the component of uncertainty related to interspecies differences in toxicokinetics. 

Walton et al. (2001a) examined data for compounds eliminated by the cytochrome P450 isoenzymes CYP1A2 in humans. Absorption, bioavailabihty, and route of excretion were generally similar between humans and the test species for each of the substances (caffeine, paraxanthine, theobromine, and theophylline). However, interspecies differences in the route of metabolism, and the enzymes involved in this process, were identified. The magnitude of difference in the internal dose, between species, showed that values for the mouse (10.6) and rat (5.4) exceeded the fourfold default factor for toxicokinetics, whereas the rabbit (2.6) and the dog (1.6) were below this value. 

In 1988, the US-EPA adopted the ADI approach with respect to the derivation of RfDs and RfCs with a 10-fold UF to account for interspecies extrapolation (US-EPA 1988, 1993), see Section 5.2.1.1. It was noted, in the 2002 review of the RfD and RfC processes (US-EPA 2002), that the interspecies UF is generally presumed to include both toxicokinetic and toxicodynamic aspects. 

Renwick and Lazarus (1998) analyzed the default UF for human variability based on the evaluation of an extensive database in relation to a subdivision of the 10-fold factor due to variability in toxicokinetics and toxicodynamics, as well as the adequacy of the 10-fold factor. Papers giving kinetic data were selected on the basis of the quality and/or size of the study, the interest of the results, and the physiological/metabolic process determining the kinetic parameter. Papers giving dynamic data were selected on the basis of the adequate separation of variability due to kinetics and dynamics. The data on kinetics and dynamics were tabulated, the coefficients of variation were averaged for different studies which measured a common endpoint, or for multiple doses which measured the same endpoint. 

It was noted in the 2002 review of the RfD and RfC processes (US-EPA 2002) that the most appropriate route of exposure is the route for which an evaluation is to be made. The toxicity of the chemical may differ with route of exposure because of differences in mechanism of action or toxicokinetics. Development of data to establish dosimetry for the purpose of route-to-route extrapolation is encouraged however, route-to-route extrapolation is inappropriate when based exclusively upon default assumptions regarding exposure and toxicokinetics. Even within the same route of exposure, responses may differ due to alterations in toxicokinetics, e.g., dietary or water exposure versus oral gavage. 

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