Toxicokinetics

Toxicokinetics describes the journey of a toxicant within a living system. The process includes four fundamental steps absorption, distribution, metabolism, and excretion. Simplistically, toxicokinetics may be thought of as what the body does to a chemical. This is contrasted by the term toxicodynamics, which may be thought of as what the chemical does to the body. The amount of toxicant in the blood over 

Gastrointestinal Tract. The gastrointestinal (GI) tract is a complex system comprised of several diverse environments including the acidic stomach and alkaline intestines. Substances that are taken into the body through the mouth follow this 

Dermal Route. Substances that are able to penetrate the skin may follow the dermal absorption path. The skin, or epidermis, is a relatively difficult barrier to penetrate. It has many layers of cells, is comparatively dry, and provides only limited access to blood vessels. The outer layer of the skin, the stratum comeum, is packed with the protein keratin that makes it especially difficult to penetrate. 

Other Routes. The GI tract, respiratory tract, and epidermis are the most important absorption paths of most toxicants, but other routes do exist, especially in 

Distribution is the step of toxicokinetics in which a toxicant moves from the site of absorption throughout the body. The toxicant may pass cell barriers, enter the circulation system, or enter the lymphatic system. The distribution mechanism can have profound effects on the action of a toxicant. A substance absorbed through the GI tract will be transported through the portal system to the liver. Compounds absorbed through the lungs, skin, or intravenous injection, however, will immediately enter systemic circulation. These two routes are metabolically distinct, as demonstrated in the next section. 

Data on the toxicokinetics of a substance can be very useful in the interpretation of toxicological findings, and may replace the use of some default extrapolation factors used in route-to-route (Section 5.5) or interspecies extrapolations (Section 5.3). In addition, interindividual differences in sensitivity to toxicants may be identified on the basis of toxicokinetic data, thereby making it possible to make the risk assessment more comprehensive by including sensitive subpopulations (Section 5.4). In conjunction with information on the relationship between concentration-dose at the target site and the toxic effect, toxicokinetic information may be an important tool for extrapolation from high to low dose effects. 

The term toxicokinetics is used to describe the time-dependent fate of a substance within the body. This includes absorption, distribution, metabolism, and/or excretion. (EC 2003). The term, often abbreviated ADME, has essentially the same meaning as pharmacokinetics, but the latter term should be restricted only to pharmaceuticals. 

Absorption relates to how, how much, and how fast a substance enters the body. 

Distribution relates to the reversible transfer of a substance between various parts of the organism, i.e., body fluids or tissues. 

Metabolism (biotransformation) relates to the enzymatic or nonenzymatic transformation of a substance into a stmcturally different chemical (metabolite). 

One key word defined in this chapter is toxicokinetics. Toxicokinetics can be defined as how a chemical acts in the body. This concept is discussed first, followed by a discussion of factors that affect toxicity within and across species. Since we saw in the last chapter that the majority of toxic effects are measured in species other than humans, and sometimes at the level of the individual cell, these concepts are key to understanding how toxic effects can be extrapolated to the typical human. Finally, this chapter discusses how a toxic effect is selected for use in quantifying the toxicity of a chemical to humans. 

This area of toxicology is divided into the following four components  

This area of toxicology is also described as the disposition of a chemical. Absorption is defined as passage of a chemical across a membrane into the body. Until a chemical is absorbed, toxic effects are only rarely observed, and then only at 

For absorption from the lungs to occur, a chemical must pass from the alveoli into the bloodstream. The alveoli are extremely thin structures each is just one cell thick. 

The lining of our alveoli is moist oxygen exchange could not otherwise occur. Therefore, some areas on the alveoli produce a surfactant, which is a fatty substance that lines the alveolar surface and keeps the thin structures from collapsing. Because this surfactant is primarily composed of fatty chemicals, fat-soluble (or lipid-soluble) chemicals will pass through the layer and into the cells more readily than water-soluble ones. 

From a toxicological point of view, the critical issue is how much of the toxic form of the chemical reaches the site of action. This will be determined by the interplay of the processes of uptake, distribution, metabolism, storage, and excretion. These processes will now be discussed in a little more detail. 

Assuming at equilibrium that unbound concentration in tissue and plasma are equal, then we let the ratio of fu/fUT replace CTW/C and determine the volume of distribution as follows  

It is possible to predict what happens to Vd when fu or fur changes as a result of physiological or disease processes in the body that change plasma and/or tissue protein concentrations. For example, Vd can increase with increased unbound toxicant in plasma or with a decrease in unbound toxicant tissue concentrations. The preceding equation explains why because of both plasma and tissue binding, some Vd values rarely correspond to a real volume such as plasma volume, extracellular space, or total body water. Finally interspecies differences in Vd values can be due to differences in body composition of body fat and protein, organ size, and blood flow as alluded to earlier in this section. The reader should also be aware that in addition to Vd, there are volumes of distribution that can be obtained from pharmacokinetic analysis of a given data set. These include the volume of distribution at steady state (Vd]SS), volume of the central compartment (Vc), and the volume of distribution that is operative over the elimination phase (Vd ea). The reader is advised to consult other relevant texts for a more detailed description of these parameters and when it is appropriate to use these parameters. 

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. 

Immediately on entering the body, a chemical begins changing location, concentration, or chemical identity. It may be transported independently by several components of the circulatory system, absorbed by various tissues, or stored the chemical may effect an action, be detoxified, or be activated the parent compound or its metabo-lite(s) may react with body constituents, be stored, or be eliminated—to name some of the more important actions. Each of these processes may be described by rate constants similar to those described earlier in our discussion of first-order rate processes that are associated with toxicant absorption, distribution, and elimination and occur 

It should be noted, however, that as the toxicant is being absorbed and distributed throughout the body, it is being simultaneously eliminated by various metabolism and/or excretion mechanisms, as will be discussed in more detail in the following chapters. However, one should mention here that an important pharmacokinetic parameter known as clearance Cl) can be used to quantitatively assess elimination of a toxicant. Clearance is defined as the rate of toxicant excreted relative to its plasma concentration, Cp  

There are very limited quantitative toxicokinetic data on L. Although there are no published estimates of the diffusion rates of L through the skin, observations from acute toxicity studies indicate that it penetrates rapidly. Studies of the kinetics of elimination of arsenic after subcutaneous injection of L in rabbits show that it is eliminated with a half life of 55-75 hours. The primary metabolite of L is 2-chlorovinyl-arsenous acid, which is formed by hydrolysis. This metabolite, like the parent compound, is able to bind to sulphydryl containing proteins. It is this property that is believed to be responsible for the toxicological effects of L, although no primary biochemical lesion has been identified. In rabbits the apparent volume of distribution 

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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. 

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

FIGURE 5.31 Subdivision of the 100-fold uncertainty factor showing the relationship between the use of uncertainty factors (above the dashed line) and proposed subdivisions based on toxicokinetics and toxicodynamics. Actual data should be used to replace the default values if available, ... 

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. 

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 simplest toxicokinetic analysis involves measurement of the plasma concentrations of a chemical at several time points after the administration of... 

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... 

S1 C(R1) Dose Selection for Carcinogenicity Studies of Pharmaceuticals Limit Dose S2A Guidance on Specific Aspects of Regulatory Genotoxicity Tests for Pharmaceuticals S2B Genotoxicity A Standard Battery for Genotoxicity Testing of Pharmaceuticals Toxicokinetics and Pharmacokinetics... 

S3A Note for Guidance on Toxicokinetics The Assessment of Systemic Exposure in Toxicity Studies... 

Pharmacokinetics concerns the fate of a dmg in the body at the approximate therapeutic dose range, while toxicokinetics assesses behaviour at the higher dose levels associated with toxic effects. The fate of a dmg is dictated by the rates of ... 

You L, Muralidhara S, Dallas CE Comparisons between operant response and 1,1,1-trichloroethane toxicokinetics in mouse blood and brain. Toxicology 93 151—... 

These experts collectively have knowledge of methyl parathion s physical and chemical properties, toxicokinetics, key health end points, mechanisms of action, human and animal exposure, and quantification of risk to humans. All reviewers were selected in conformity with the conditions for peer review specified in Section 104(I)(13) of the Comprehensive Environmental Response, Compensation, and Liability Act, as amended. 

The primary purpose of this chapter is to provide public health officials, physicians, toxicologists, and other interested individuals and groups with an overall perspective on the toxicology of methyl parathion. It contains descriptions and evaluations of toxicological studies and epidemiological investigations and provides conclusions, where possible, on the relevance of toxicity and toxicokinetic data to public health. 

Fazekas 1971) exposed by various routes. Because of a lack of toxicokinetic data, it cannot be assumed that the end points of methyl parathion toxicity would be quantitatively similar across all routes of exposure. The acute effects of dermal exposures to methyl parathion are not well characterized in humans or animals. Therefore, additional dermal studies are needed. 

Absorption, Distribution, Metabolism, and Excretion. Evidence of absorption comes from the occurrence of toxic effects following exposure to methyl parathion by all three routes (Fazekas 1971 Miyamoto et al. 1963b Nemec et al. 1968 Skiimer and Kilgore 1982b). These data indicate that the compound is absorbed by both humans and animals. No information is available to assess the relative rates and extent of absorption following inhalation and dermal exposure in humans or inhalation in animals. A dermal study in rats indicates that methyl parathion is rapidly absorbed through the skin (Abu-Qare et al. 2000). Additional data further indicate that methyl parathion is absorbed extensively and rapidly in humans and animals via oral and dermal routes of exposure (Braeckman et al. 1983 Flollingworth et al. 1967 Ware et al. 1973). However, additional toxicokinetic studies are needed to elucidate or further examine the efficiency and kinetics of absorption by all three exposure routes. 

Practically all toxicokinetic properties reported are based on the results from acute exposure studies. Generally, no information was available regarding intermediate or chronic exposure to methyl parathion. Because methyl parathion is an enzyme inhibitor, the kinetics of metabolism during chronic exposure could differ from those seen during acute exposure. Similarly, excretion kinetics may differ with time. Thus, additional studies on the distribution, metabolism, and excretion of methyl parathion and its toxic metabolite, methyl paraoxon, during intermediate and chronic exposure are needed to assess the potential for toxicity following longer-duration exposures. 

A study of the dermal toxicokinetics of methyl parathion in female rats, sponsored by ATSDR, is being conducted at the University of Mississippi Medical Center. The principal investigator is Dr. Ing K. Ho, Department of Pharmacology and Toxicology, 500 North State Street, Jackson, Mississippi 39216-4505. 

Braeckman RA, Audenaert P, Willems JL, et al. 1983. Toxicokinetics of methyl parathion and parathion in the dog after intravenous and oral administration. Arch Toxicol 54 71-82. 

Toxicokinetic—The study of the absorption, distribution and elimination of toxic compounds in the living organism. 

This chapter provides a health effects summary based on evaluations of existing toxicologic, epidemiologic, and toxicokinetic information. This summary is designed to present interpretive, weight-of-evidence discussions for human health end points by addressing the following questions. 

The carcinogenic potential of the profiled substance is qualitatively evaluated, when appropriate, using existing toxicokinetic, genotoxic, and carcinogenic data. ATSDR does not currently assess cancer potency or perform cancer risk assessments. Minimal risk levels (MRLs) for noncancer end points (if derived) and the end points from which they were derived are indicated and discussed. 

Species The test species, whether animal or human, are identified in this column. Chapter 2, "Relevance to Public Health," covers the relevance of animal data to human toxicity and Section 3.4, "Toxicokinetics," contains any available information on comparative toxicokinetics. Although NOAELs and LOAELs are species specific, the levels are extrapolated to equivalent human doses to derive an MRL. 

In rats, exposed males and females appear to have different sensitivities to the lethal effects of endosulfan exposure. Summary data submitted by Hoechst (1990) showed that female LDjg values ranged between 10 and 23 mg/kg, whereas male LDjo values ranged between 40 and 125 mg/kg. Thus, female rats appear to be 4-5 times more sensitive to the lethal effects of technical-grade endosulfan than male rats. This difference may be related to differences in the toxicokinetics of endosulfan in male and female rats (see also Section 2.3). Insufficient data were available to determine whether differences in sensitivity to lethal effects exist between males and females of species other than the rat. 

The data in animals are insufficient to derive an acute inhalation MRL because serious effects were observed at the lowest dose tested (Hoechst 1983a). No acute oral MRL was derived for the same reason. The available toxicokinetic data are not adequate to predict the behavior of endosulfan across routes of exposure. However, the limited toxicity information available does indicate that similar effects are observed (i.e., death, neurotoxicity) in both animals and humans across all routes of exposure, but the concentrations that cause these effects may not be predictable for all routes. Most of the acute effects of endosulfan have been well characterized following exposure via the inhalation, oral, and dermal routes in experimental animals, and additional information on the acute effects of endosulfan does not appear necessary. However, further well conducted developmental studies may clarify whether this chemical causes adverse developmental effects. 

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