Toxicity, species-selective

Tables 2.6 and 2.7 give examples of the modes of action of pollutants in animals and in plants/fungi, respectively. It is noteworthy that many of the chemicals represented are pesticides. Pesticides are designed to be toxic to target species. On the other hand, manufacturers seek to minimize toxicity to humans, beneficial organisms and, more generally, nontarget species. Selective toxicity is an important issue. Regardful of the potential risks associated with the release of bioactive compounds into the environment, regulatory authorities usually require evidence of the mode of toxic action before pesticides can be marketed. Other industrial chemicals are not subject to such strict regulatory requirements, and their mode of action is frequently unknown.

Note Since the enzyme is not found in mammals, inhibitors of this enzyme may be an effective means of controlling bacterial infection. Certainly, species-selective toxicity is an important consideration in the development of new antimicrobial agents. 

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. 

Chase WR, Nair MG, Putnam AR (1991) 2,2 -Oxo-l,l -azobenzene Selective toxicity of rye (Secale cereale L.) allelochemicals to weed and crop species II. J Chem Ecol 17(1) 9—19... 

Most commonly, bioassays for the evaluation of the acute toxic effects of pesticides are based on single aquatic species selected to be representative of a range of taxonomic and functional groups, i.e., bacteria, algae, invertebrates or fish [ 53,54]. Generally, toxicity evaluation using a single species is the alternative of choice rather than the use of multiple species, because extrapolation of effects to an ecosystem is more difficult and can often lead to incorrect conclusions. 

The selection of suitable single species and protocols is not a trivial task and may be dependent on various factors. Some of these include simplicity, low cost, or modest material and equipment demand. However, a higher sensitivity than other species to toxicants may be decisive in this choice in order to serve as warning systems. Table 1 shows the sensitivity in terms of effective concentration (EC50), which is the toxicity endpoint for the organisms (bacteria, crustaceans, algae, and fish) selected for the toxicity bioassays. These toxicity bioassays are usually classified according to the test species involved. 

The physiological similarity and phylogenetic proximity of nonhuman primates to humans are often cited as rationale for primate selection for safety studies especially when mechanisms of toxicity or pharmacologic action are expected to be closely related to potential physiological reactions in humans. Likewise, species selection is often based on the demonstration of pharmacologic activity of the test article. Many biopharmaceuticals do not exhibit their intended activity in nonprimate species, whereas small molecules may have activity across all species. 

When tested, the antibiotic compounds killed or inhibited the growth of two varieties of E. coli but had no effect on several other types of cells. These results show that in response to bacterial infection the ants elaborated an antibiotic that was selectively toxic to the pathogen. Their defense was tailored closely to their need. It is too soon to know more, but it seems that looking for new antibiotics in ants is a promising idea. Further research should establish whether ant antibiotics will lead to drugs for human use and also reveal whether other crowded species also synthesize antibiotics. 

Amidases can be found in all kinds of organisms, including insects and plants [24], The distinct activities of these enzymes in different organisms can be exploited for the development of selective insecticides and herbicides that exhibit minimal toxicity for mammals. Thus, the low toxicity in mammals of the malathion derivative dimethoate (4.44) can be attributed to a specific metabolic route that transforms this compound into the nontoxic acid (4.45) [25-27]. However, there are cases in which toxicity is not species-selective. Indeed, in the preparation of these organophosphates, some contaminants that are inhibitors of mammalian carboxylesterase/am-idase may be present [28]. Sometimes the compound itself, and not simply one of its impurities, is toxic. For example, an insecticide such as phos-phamidon (4.46) cannot be detoxified by deamination since it is an amidase inhibitor [24],... 

An issue of obvious importance in test species selection is the degree to which test results can be reliably applied to human beings. As we noted in the last chapter this is one of the principal problems in the evaluation of human risk, and we shall get back to it in the later chapters on risk assessment. For now, emphasis is on the selection of animal species and strains for their known reliability as experimental subjects. To put it in stark (but honest) terms - the animals are used as toxicity measuring devices. 

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. 

The development of new models for the prediction of chemical effects in the environment has improved. An Eulerian photochemical air quality model for the prediction of the atmospheric transport and chemical reactions of gas-phase toxic organic air pollutants has been published. The organic compounds were drawn from a list of 189 species selected for control as hazardous air pollutants in the Clean Air Act Amendments of 1990. The species considered include benzene, various alkylbenzenes, phenol, cresols, 1,3-butadiene, acrolein, formaldehyde, acetaldehyde, and perchloroethyl-ene, among others. The finding that photochemical production can be a major contributor to the total concentrations of some toxic organic species implies that control programs for those species must consider more than just direct emissions (Harley and Cass, 1994). This further corroborates the present weakness in many atmospheric models. 

It was the selective toxicity of the insecticide DDT that was destined to have a most profound effect on attitudes to chemical safety. DDT was a chemical that had first been synthesised decades before the Swiss chemist Muller discovered its potent insecticidal action in the late r930s. What was so remarkable about DDT was its selectivity. Even in extremely small doses, it was lethal to many species of insect yet it was remarkably non-toxic to humans even at quite high doses (Figure 6.3). The manufacture of DDT is... 

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. 

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. 

The mode of action of the sulfonamides as antagonists of 4-aminobenzoic acid (PAB) is well documented, as is the effect of physicochemical properties of the sulfonamide molecule, e.g. pK, on potency (B-81MI10802). Sulfonamides compete with PAB in the biosynthesis of folic acid (44), a vital precursor for several coenzymes found in all living cells. Mammalian cells cannot synthesize folic acid (44), and rely on its uptake as an essential vitamin. However, bacteria depend on its synthesis from pteridine precursors, hence the selective toxicity of sulfonamides for bacterial cells. Sulfonamides may compete with PAB at an enzyme site during the assembly of folic acid (44) or they may deplete the pteridine supply of the cell by forming covalently-bonded species such as (45) or they may replace PAB as an enzyme substrate to generate coupled products such as (46) which are useless to the cell. 

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