Toxicity toxicodynamics

Scientists then determine the appropriate uncertainty (or safety) factors to apply to the no-observed-adverse-effect level (NOAEL) or lowest-observed-adverse-effect level (LOAEL) for the critical effect, based on considerations of the available toxicity, toxicodynamic, and toxicokinetic data. Uncertainty factors (UFs) used in the estimation of safe doses are necessary reductions to account for the lack of data and inherent uncertainty in these extrapolations. Other areas of uncertainty include extrapolations of subchronic-to-chronic exposure, LOAEL to NOAEL, and use of an incomplete database. The major assumptions underlying each of these UFs are described in Table 1. 

Ricaurte GA, McCann UD, Szabo Z, et al Toxicodynamics and long-term toxicity of the recreational drug 3,4-methylenedioxy-methamphetamine (MDMA, Ecstasy ). Toxicol Lett 112-113 143-146, 2000 Robinson TN, Killen JD, Taylor CB, et al Perspectives on adolescent substance use a defined population study. JAMA 258 2072-2076, 1987 Rubinstein JS Abuse of antiparkinson drugs feigning of extrapyramidal symptoms to obtain trihexyphenidyl. JAMA 239 2365, 1978 Rumack BH (ed) LSD, in Poisindex, Vol 54. Denver, CO, Micromedex, 1987 Rusyniak DE, Banks ML, Mills EM, et al Dantrolene use in 3,4-methylenedioxymethamphetamine ( ecstasy )-medicated hyperthermia (letter). Anesthesiology 10 263, 2004... 

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. 

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... 

Toxicodynamics Relating to the toxic action of chemicals on living organisms. 

There are several points along the pathway to hazard that can be influenced through molecular design that are described in more detail later in this chapter. The magnitude and duration of a toxic event can be minimized through influencing the toxicodynamic and toxicokinetic phases associated with the manifestation of toxicity. 

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). 

The interindividual variability reflects differences in toxicokinetics as well as in toxicodynamics. With respect to toxicokinetic factors, interindividual differences in the metabolism of chemicals are generally considered as the most significant explanatory factor. Hardly any knowledge is available with respect to the factors that influence toxicodynamics. Thus, it is necessary to take such variation into account when extrapolating animal toxicity data to the human simation. 

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). 

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. 

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. 

In the commercial chemical industry, any biological activity of chemicals is undesirable and should be avoided. Thus, what we seek is a set of Lipinski-like guidelines for compounds that are biologically inactive. One way to achieve lack of activity is to ensure that the chemical is not bioavailable. If achieving this and retaining the desired chemical function is not feasible, one can also aim to reduce distribution, reduce bioactivation (or increase deactivation), accelerate excretion, and/or eliminate any potential toxicodynamic interactions responsible for specific toxicity. These aims are illustrated in Figure 13.4. 

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