Toxicodynamic effect

The term toxicodynamics means the process of interaction of chemical substances with target sites and the subsequent reactions leading to adverse effects. The toxicodynamic effect is driven by the concentration at the effect site(s) directly or indirectly and may be reversed or modified by several factors such as repair mechanisms for DNA damage and compensatory cell proliferation (EC 2003). 

In cases of acute thallium intoxication in humans, similar distributions were observed (Weinig and Walz 1971, Arnold 1986), with specific thallium depot compartments being kidney and muscle. However, no correlation was found between the tissue distribution and particular sensitivity to the toxicodynamic effects of thallium (Forth and Henning 1979). Brain areas densely populated with neurons have been found to accumulate thallium more readily than other brain regions thallium is also accumulated in the testes, and this may lead to reduced sperm motility (Manzo and Sab-bioni 1988). 

Klawitter J, Haschke M, Kahle C, Dingmann C, Leibfritz D, Christians U. Toxicodynamic effects of ciclosporin are reflected by metabolite profiles in the urine of healthy individuals after a single dose. Br J Clin Pharmacol 2010 70(2) 241-51. 

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. 

The threshold for a specific effect may vary considerably for different exposure routes and for different species because of differences in the toxicokinetics for different species and exposure routes, and possibly also because of differences in the toxicodynamics. The NOAEL and LOAEL derived for a given smdy will therefore in general depend on the experimental smdy design, i.e., species, sex, age, strain, and developmental status of animals number of animals per exposure level selection of exposure levels the spacing between the exposure levels duration of exposure and sensitivity of methods used to measure the responses. Thus, the sensitivity of a particular smdy may... 

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. 

The concept that infants and children may be a sensitive subgroup relates to their relative immaturity compared to adults. Children, as well as the unborn child, have in some cases appeared to be uniquely vulnerable to toxic effects of chemicals because periods of rapid growth and development render them more susceptible to some specific toxic effects when compared to adults. In addition to such toxicodynamic factors, differences in toxicokinetics may contribute to an increased susceptibility during these periods. It should be noted, however, that during the developmental and maturational periods the susceptibility to exposure to xenobiotics in children may be higher, equal, or even lower than in adults. Except for a few specific substances, not very much is known about whether and why the response to a substance may differ between age groups. It should also be borne in mind that, in terms of risk assessment, children are not simply small adults, but rather a unique population (Nielsen et al. 2001). 

Generally, it appears that effects of xenobiotics on organs or endpoints may be similar in children and adults, e.g., liver necrosis observed in adults will also be observed in children. As regards toxicodynamics, age-dependent differences are primarily related to the specific and unique effects that substances may have on the development of the embryo, fetus, and child in that the physiological development of the nervous, immune, and endocrine/reproductive systems continues until adolescence (12 to 18 years). Furthermore, receptors and other molecular targets for various xenobiotics are continuously developing during the embryonic, fetal, and infant periods. This may cause age-dependent differences in the outcome of receptor-xenobiotic interactions and even result in opposite effects of xenobiotics in infants and adults. The available data are insufficient to evaluate... 

Interactions may take place in the toxicokinetic phase and/or in the toxicodynamic phase. The interactions may result in either a weaker (antagonistic) or stronger (potentiated, synergistic) combined effect than would be expected from knowledge about the toxicity and mode of action of each individual compound. 

PBTK models can potentially be extended to include the toxicodynamic phase (PBTK/TD model) if a direct relationship exists between the concentration of the active metabolite (or parent compound) and the toxic effect (Yang et al. 1995). 

Occurrence of complex dissimilar actions is thought to be rare at low exposure (ADI) levels but it should always be considered whether a plausible hypothesis exists for effect interactions of two or more compounds. Interactions can occur both in the toxicodynamic phase (e.g., endocrine disrup-tors) and in the toxicokinetic phase (e.g., interference with transport, metabolism (activation, deactivation), distribution, and elimination of another compound). 

As an example, Hsieh et al. identified toxicodynamic biomarkers in monkey semm that demonstrated a quantitative relationship with drug exposure (Cr iax, AUC) and related pathological events [148], The biomarkers were used for a more precise calculation of the no observed adverse effect level (NOAEL). The safety of three different dosing schedules was predicted using pharmacokinetic pharmacodynamic (PKPD) modeling and biomarker analysis. 

Environmental toxicity considerations for choice of solvents include the degree of absorption reported in the literature, exploration of toxic mechanisms, and the use of Stmcture-Activity Relationships (SAR). The relative seriousness of the toxic effect depends upon the extent of exposure to the substance, its bioavailability, and the importance of the physiologic process that the substance has disrupted (DeVito, 1996a). Over this information must be laid the physical parameters of the solvent s use (i.e., amount, state, reaction environment, etc). This requires a basic understanding of the processes involved in chemical toxicokinetics and toxicodynamics. 

Absorption, Distribution, Metabolism, and Excretion. There is an obvious data need to determine the pharmacokinetic and toxicokinetic behavior of HDl in both humans and laboratory animals. Determination of blood levels of inhaled, ingested and dermally absorbed HDl would be difficult, given the very short half-life in biological matrices (Berode et al. 1991) and the rate at which HDl binds to proteins in the blood. Although some information is known about the metabolism of HDl in humans inhaling a known quantity of HDl (Brorson et al. 1990), the rate at which absorption occurs, where the majority of the metabolism of HDl occurs (in the water in the mucous layer of the bronchi as opposed to the blood or the kidney), and the distribution patterns and toxic effects of the metabolite (if any) are not well described. Information in these areas of toxicokinetics and toxicodynamics could also be useful in developing a PBPK/PD model for HDl. Research should focus on the respiratory and dermal routes of exposure. 

Pharmacodynamics The study of the way in which xenobiotics exert their effects on living organisms. Synonym toxicodynamics. 

The term toxicokinetics denotes the absorption, distribution, excretion, and metabolism of toxins, toxic doses of therapeutic agents, and their metabolites. The term toxicodynamics is used to denote the injurious effects of these substances on vital functions. Although many similarities exist between the pharmacokinetics and toxicokinetics of most substances, there are also important differences. The same caution applies to pharmacodynamics and toxicodynamics. 

Toxicodynamics study of the effects of toxic substances on biological systems (e.g., interaction with receptors). 

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