Toxicokinetics toxic expression

Lead toxicokinetics serves two critical roles in the delineation of lead toxicity. First, it provides the kinetic imderpinnings for expressions of lead intoxication in humans and other species. The rate of Pb entry into, and deposition within, tissues and cellular organelles is a prerequisite for toxic expressions with differing Pb exposiures. 

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. 

As discussed earlier, selectivity is the consequence of the interplay between toxicokinetic and toxicodynamic factors. Some examples are given in Table 2.8, which will now be briefly discussed (data from Walker and Oesch 1983, and Walker 1994a,b). These and other examples will be described in more detail under specific pollutants later in the text. In the table, comparisons are made between the median lethal doses or concentrations for different species or strains. Comparisons are made of data obtained in lethal toxicity tests where the same route of administration was used for species or strains that are compared. The degree of selectivity is expressed... 

As mentioned previously, the assessment of hazard and risk to humans from exposure to chemical substances is generally based on the extrapolation from data obtained in smdies with experimental animals. In the absence of comparative data in humans, a basic assumption for toxicological risk assessment is that effects observed in laboratory animals are relevant for humans, i.e., would also be expressed in humans. In assessing the risk to humans, an assessment factor is applied to take account of uncertainties in the differences in sensitivity to the test substance between the species, i.e., to account for interspecies variability (Section 5.3). If data are available from more than one species or strain, the hazard and risk assessment is generally based on the most susceptible of these except where data strongly indicate that a particular species is more similar to man than the others with respect to toxicokinetics and/or toxicodynamics. Two main aspects of toxicity, toxicokinetics and toxicodynamics, account for the namre and extent of differences between species in their sensitivity to xenobiotics this is addressed in detail in Chapter 5. 

Exposure should normally be understood as external exposure, which can be defined as the amount of substance ingested, the total amount in contact with the skin (which can be calculated from exposure estimates expressed as mg/cm or mg/cm ), or either the amount inhaled or the concentration of the substance in the atmosphere, as appropriate. In cases where a comparison needs to be made with systemic effects data (e.g., when inhalation or dermal toxicity values are lacking or when exposures due to more than one exposure route need to be combined) the total body burden has to be estimated. Since the assessment of the amount that is absorbed after ingestion, by inhalation or by the skin is usually done in the effects assessment (section on toxicokinetics), this calculation of the total body burden is often placed in the section on risk characterization. 

Common unspecific mode of action of all organic compounds has been taken up in quantitative structure-activity relationships (QSARs see Chapter 5) as the concept of baseline toxicity and in toxicokinetics as the body burden concept (see Chapter 2). Baseline toxicity refers to the idea that a minimum toxicity expectation may be formulated for any given organic compound based on considerations of a compound s partition properties between hydrophilic and lipophilic chemicals (e.g., between water and octanol). Commonly, this is expressed in terms of the octanol-water partition coefficient (K0,J of a chemical. The partition coefficient allows estimations of a local concentration or body burden for each individual chemical in the mixture. Assuming that this produces the same toxic effect (disturbances of cell membranes), it is then possible to anticipate joint narcotic action by adding together the respective local concentrations or body burdens for each individual mixture component. 

It is preferable that animal studies are conducted using appropriate routes of administration which relate to the potential route of human exposure. However, in practice, reproductive toxicity studies are commonly conducted using the oral route, and such studies will normally be suitable for evaluating the hazardous properties of the substance with respect to reproductive toxicity. However, if it can be conclusively demonstrated that the clearly identified mechanism or mode of action has no relevance for humans or when the toxicokinetic differences are so marked that it is certain that the hazardous property will not be expressed in humans then a substance which produces an adverse effect on reproduction in experimental animals should not be classified. 

It is difficult to establish uniform guidelines for pharmacokinetic studies for biotechnology-derived pharmaceuticals. Single and multiple dose pharmacokinetics, toxicokinetics, and tissue distribution studies in relevant species are useful however, routine studies that attempt to assess mass balance are not useful. Differences in pharmacokinetics among animal species may have a significant impact on the predictiveness of animal studies or on the assessment of dose response relationships in toxicity studies. Alterations in the pharmacokinetic profile due to immune-mediated clearance mechanisms may affect the kinetic profiles and the interpretation of the toxicity data. For some products there may also be inherent, significant delays in the expression of pharmacodynamic effects relative to the pharmacokinetic profile (e.g., cytokines) or there may be prolonged expression of pharmacodynamic effects relative to plasma levels. 

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