Species differences selective toxicity

There are many different examples of species differences in the toxicity of foreign compounds, some of which are commercially useful to man, as in the case of pesticides and antibiotic drugs where there is exploitation of selective toxicity. Species differences in toxicity are often related to differences in the metabolism and disposition of a compound, and an understanding of such differences is extremely important in the safety evaluation of compounds in relation to the extrapolation of toxicity from animals to man and hence risk assessment. 

Toxicity is the outcome of interaction between a chemical and a living organism. The toxicity of any chemical depends on its own properties and on the operation of certain physiological and biochemical processes within the animal or plant that is exposed to it. These processes are the subject of the present chapter. They can operate in different ways and at different rates in different species—the main reasons for the selective toxicity of chemicals between species. On the same grounds, chemicals show selective toxicity (henceforward simply selectivity ) between groups of organisms (e.g., animals versus plants and invertebrates versus vertebrates) and also between sexes, strains, and age groups of the same species. 

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. 

Selective toxicity (selectivity) Difference in toxicity of a chemical toward different species, strains, sexes, age groups, etc. 

For the derivation of the PNEC several approaches have been proposed. Generally these can be categorised into three distinct assessments a conservative, a distributional, and a mixture toxicity approach. In conservative approaches, usually the most (realistic) sensitive endpoint such as LC50 or the known no observed effect concentration (NOEC) is taken and divided by an uncertainty factor (10-100). The selected uncertainty factor value depends on the type of endpoint and the number of available data, and is applied to account for laboratory to field extrapolations, species differences in sensitivities, and similar uncertainties. In distributional approaches, a series of, or all available, literature data are taken and a selected cut-off value is applied to the distribution of these data. The cut-off value may be, e.g., the concentration value that will protect 95% of the species (tested). In general, again an uncertainty factor (usually of 10) is then applied to take into account species differences. In the mixture toxicity approach, a similar mode of action is assumed for the assessment of the combined (additive) effect of the mixture. All relevant mixture components are scaled relative to the most potent one. This results in relative potencies for each component. The total effect of the mixture is then evaluated by... 

Although all tetracyclines have a similar mechanism of action, they have different chemical structures and are produced by different species of Streptomyces. In addition, structural analogues of these compounds have been synthesized to improve pharmacokinetic properties and antimicrobial activity. While several biological processes in the bacterial cells are modified by the tetracyclines, their primary mode of action is inhibition of protein synthesis. Tetracyclines bind to the SOS ribosome and thereby prevent the binding of aminoacyl transfer RNA (tRNA) to the A site (acceptor site) on the 50S ri-bosomal unit. The tetracyclines affect both eukaryotic and prokaryotic cells but are selectively toxic for bacteria, because they readily penetrate microbial membranes and accumulate in the cytoplasm through an energy-dependent tetracycline transport system that is absent from mammalian cells. 

Recall in our discussion of routes of biotransformation we considered species differences using malathion as an example. Insects convert this compound to its toxic oxidation product more quickly than they detoxify it by hydrolysis. Humans do the conversions in the opposite priority. However, the insects which might be different from the general population and perform detoxification reactions at a faster rate would survive pesticide application and their "resistant" genes would be selectively passed on to the next generations. 

Hydrolytic reactions. There are numerous different esterases responsible for the hydrolysis of esters and amides, and they occur in most species. However, the activity may vary considerably between species. For example, the insecticide malathion owes its selective toxicity to this difference. In mammals, the major route of metabolism is hydrolysis to the dicarboxylic acid, whereas in insects it is oxidation to malaoxon (Fig. 5.12). Malaoxon is a very potent cholinesterase inhibitor, and its insecticidal action is probably due to this property. The hydrolysis product has a low mammalian toxicity (see chap. 7). 

The onset of symptoms depends on the particular organophosphorus compound, but is usually relatively rapid, occurring within a few minutes to a few hours, and the symptoms may last for several days. This depends on the metabolism and distribution of the particular compound and factors such as lipophilicity. Some of the organophosphorus insecticides such as malathion, for example (chap. 5, Fig. 12), are metabolized in mammals mainly by hydrolysis to polar metabolites, which are readily excreted, whereas in the insect, oxidative metabolism occurs, which produces the cholinesterase inhibitor. Metabolic differences between the target and nontarget species are exploited to maximize the selective toxicity. Consequently, malathion has a low toxicity to mammals such as the rat in which the LD50 is about 10 g kg-1. 

In the mid-1960s we showed firstly that the natural tolerance of houseflies to cyclodienes resulted mainly from oxidative detoxication (33 55) and secondly that another enzyme system, epoxide hydrase, converted certain dieldrin analogues into the corresponding trans-diols, (56,57) Interspecific differences in ability to attack enzymatically the unchlorinated ring systems of various analogues, either oxidatively and/or hydratively (if appropriate) can confer selective toxicity between insect species and also between insects and mammals (58) ... 

Selective toxicity refers to differences in toxicity between two species simultaneously exposed. See Figure 9.26, where rats show a higher response than mice to a certain dose. This is the basis for the effectiveness of pesticides and drugs. For example, an insecticide is lethal to insects but relatively nontoxic to animals in the same vein, antibiotics are selectively toxic to microorganisms while virtually non-toxic to humans. 

When tests are performed on terrestrial animals, it is common to apply single (measured) doses orally, topically (i.e., applied to the skin or cuticle), or by injection into tissues or body fluids. There can be very large differences among groups of organisms and among species in their susceptibility to the toxic action of chemicals. The selective toxicity ratio (SER) is expressed in terms of the median lethal dose, and is important for the differentiation between beneficial organisms and pests ... 

Pest control with insecticides is based on the probability that species differ greatly in susceptibility to toxicants and that it is possible to show selective toxicity among species, i.e., controlling one without harming others in the same environment. Evidence has shown that this probability is high, even though its basis is not always understood (Terriere, 1982). In this chapter we will compare the xenobiotic metabolizing enzyme activity of various species to learn how much this may contribute to toxicity differences. 

With the preceding discussion as background, it would be easy to understand how the selective toxicity of insecticide occurs, showing that some species are more susceptible to the toxicants than others. In fact, we would not be able to develop selective insecticides if it were not for the species differences that have evolved. Metabolism is not the only mechanism for selectivity, however. Ecological selectivity, which involves particular behavioral characteristics of the target pest, is also important, e.g., the use of insecticide bait against some species, or systemic insecticides against others. 

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