Toxicodynamics

Most of the organic pollutants described in the present text act at relatively low concentrations because they, or their active metabolites, have high affinity for their sites of action. If there is interaction with more than a critical proportion of active sites, disturbances will be caused to cellular processes, which will eventually be manifest as overt toxic symptoms in the animal or plant. Differences between species or strains in the affinity of a toxic molecule for the site of action are a common reason for selective toxicity. 

It should also be mentioned that some compounds of relatively low toxicity act as physical poisons, although such pollutants are seldom important in ecotoxicology. They have no known specific mode of action, but if they reach relatively high concentrations in cellular structures, for example, manbranes, they can disturb cellular processes. Examples include certain ethers and esters, and other simple organic compounds. 

The examples given in Tables 2.6 and 2.7 illustrate the wide range of different mechanisms by which pollutants cause toxic effects. The following account will focus on certain broad issues concerning mode of action. A more detailed description of individual examples will be given in later chapters devoted to particular types of pollutants. 

Broadly speaking, toxic interactions between chemicals and cellular sites of action are of two kinds  

The pollutant (xenobiotic) forms a stable covalent bond with its target. Examples include the phosphorylation of cholinesterases by the oxon forms of OPs, the formation of DNA adducts by the reactive epoxides of benzo[a] pyrene and other PAHs, and the binding of organomercury compounds to 

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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 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, ... 

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. 

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