Ultimate toxicant

Endpoint/Concentration/Rationale 5 ppm for 1 h considered as a no-observed-effect level (NOEL) for decreased hematocrit levels. A NOEL was used because of an extremely steep dose-response curve and the fact that the ultimate toxic effect, renal failure, is delayed for several days. 

A large number of studies have investigated the metabolism of benzene per se or in relation to toxification and, particularly, myelotoxicity. Most evidence shows that benzene oxide (10.1, Fig. 10.8) is not the ultimate toxic species, as was initially believed. Indeed, phenol and quinone metabolites of benzene are more active in forming adducts with macromolecular nucleophiles and eliciting cellular toxicity. For example, the efficacy of benzene metabolites (see Fig. 10.8) to inhibit DNA synthesis in a mouse lymphoma cell line decreased in the order benzoquinone (10.17) > hydroquinone (10.16)... 

There are many different mechanisms underlying toxicity, leading to the different types of responses. However, most toxicity is due to the interaction between the ultimate toxicant and a target molecule. The ultimate toxicant may be a reactive metabolite, a stable metabolite, or the parent compound. The molecule could be part of a structure, the cell membrane, for example, or an individual macromolecule such as an enzyme. 

If the reactivity of the molecule toward the ultimate toxicant is low, no interaction may ensue. Thus, if the ultimate toxicant is an electrophile but the macromolecule has no suitable nucleophilic groups, which are accessible, reaction is unlikely. 

The function of the target molecule may be critical or mncritical. Thus, if the target molecule is an enzyme, this could be involved in a crucial metabolic pathway, such as mitochondrial oxidative phosphorylation. In this case, an adverse interaction with the ultimate toxicant is likely to lead to cell dysfunction and possibly death (e.g., as with cyanide or salicylate). Chemicals such as methimazole and resorcinol, which are activated to free radical intermediates by thyroperoxidase, cause destruction of the enzyme. This then disturbs thyroid hormone synthesis and thyroid function with pathological consequences such as thyroid tumors. 

Most toxicity is due to the interaction between the ultimate toxicant and a target molecule via covalent bonding non-covalent bonding, hydrogen abstraction, electron transfer, or an enzyme reaction. 

Thus the metabolic reduction of chromium(VI) may represent bioactivation and/or detoxification. If a bioactivation process, intracellular reduction of chromium(VI) would lead to the ultimate toxic species. Conversely, if chromium(VI) is the toxic agent, effects would be elicited only if the amount of chromium(VI) entering target cells saturates the reducing mechanisms. 

The fungicidal properties of dithiocarbamates, like thiram, are probably associated with their ability to chelate with essential trace metals such as copper and zinc. Additionally, the 1 1 metal chelates are themselves fungicidal with the ability to penetrate lipid barriers in the fungal cell, and are probably the ultimate toxicants in these fungicides.3 Alkyl esters of dithiocarbamic acids are readily prepared by treatment of sodium dithiocarbamate (4) with the appropriate alkyl halide (Scheme 20). 

Captan (72), an example of the N-trichloromethanesulfenyl fungicides, is a useful protective foliar fungicide and seed dressing. It is prepared from butadiene and maleic anhydride (see Chapter 9, p. 151). The fungicidal activity arises from interaction with cellular thiols to give thiophosgene, which is probably the ultimate toxicant (Scheme 15). 

Fluoroacetate is rapidly absorbed by the gastrointestinal tract but not well absorbed dermally. Fluoroacetate is converted to the ultimate toxicant, fluorocitrate. Fluoroacetate is distributed to lipid-rich organs, such as the liver, brain, and kidneys. Fluoroacetate is primarily eliminated through urine. Up to 50% of the fluoroacetate is excreted unchanged in the urine by 72 h following administration. The kinetic half-life for sodium fluoroacetate is species dependent. Reported half-lives in rabbits, goats, and sheep are 1.1, 4-7, and 13.3 h, respectively. 

Vinyl acetate is rapidly metabolized in the body to acetaldehyde. In vitro studies have revealed similar toxic effects in cell cultures incubated in the presence of either vinyl acetate or acetaldehyde. These results suggest that the acetaldehyde is the ultimate toxic metabolite of vinyl acetate. 

Characteristics such as whether a pollutant is solid, liquid, or gas whether it is soluble in water or lipid and whether it is organic or inorganic, ionized or nonionized, etc., can affect the ultimate toxicity of the pollutant. For example, since membranes are more permeable to a nonionized than an ionized substance, a nonionized substance will generally have a higher toxicity than an ionized substance. 

Figure 1 The common solvents n-hexane and methyl n-butyl methane are converted by co-1 hydroxy lation and oxidation to the ultimate toxicant, 2,5-hexanedione (2,5-HD). 2,5-HD reacts with lysyl e-amines of proteins (black rectangle) to form pyrrolylated proteins, which undergo intra- and intermolecular cross-linking reactions, including dimer formation.

The nature and severity of the toxicity that may result from mercury exposure are functions of the magnitude and duration of exposure, the route of exposure, and the form of the mercury or mercury compound to which exposure occurs. Since the ultimate toxic species for all mercury compounds is thought to be the mercuric ion, the kinetics of the parent compound are the primary determinant of the severity of parent compound toxicity. It is differences in the delivery to target sites that result in the spectrum of effects. Thus, mercury, in both inorganic and organic forms, can be toxic to humans and other animals. 

Concentrations of individual chemicals in a mixture are not necessarily predictive of the ultimate toxic effects (Chapter 2). 

The toxic effects of lipophilic hydrophilic mixtures are not necessarily predictive of the ultimate toxic mechanism. Such mixtures induce the toxic effects by absorbing and transporting greater quantities of toxic chemicals to their ultimate sites of action. I2,3 ... 

Other reactions must be mentioned beside the major reactions described above. These reactions may be responsible for the transformation of a toxic metabolite into the ultimate toxicant. Rearrangements and cyclizations are examples of reactions involved in these processes. In the case of the solvent hexane (Figure 33.19), the toxic metabolite, 2, 5-hexanedione, is formed by four successive oxidations of the molecule. The condensation of the -dicetone with the lysyl amino group of a neurofilament protein is followed by a Paal-Knorr cyclization reaction. This is the initial process that explains the hexane-induced neurotoxicity." A further auto-oxidation of the A-pyrrolyl derivatives leads to the cross-linking of the axonal intermediate filament proteins and the subsequent occurrence of peripheral neurotoxicity." ... 

Bromobenzene is also nephrotoxic, possibly due to the production of a reactive metabolite and covalent binding to protein. It has been suggested that the reactive metabolite is formed in the liver and then transported to the kidney. 2-Bromophenol and 2-bromohydroquinone are both nephrotoxic. It seems that the ultimate toxic metabolite is a diglutathionyl conjugate formed from 2-bromohydroquinone (figure 7,14) as this will cause the same lesions in the kidney as bromobenzene, 2-bromophenol and 2-bromohydroquinone when administered to animals. 

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