Origins toxicity

Some biomarker responses provide evidence only of exposure and do not give any reliable measure of toxic effect. Other biomarkers, however, provide a measure of toxic effects, and these will be referred to as mechanistic biomarkers. Ideally, biomarker assays of this latter type monitor the primary interaction between a chemical and its site of action. However, other biomarkers operating down stream from the original toxic lesion also provide a measure of toxic action (see Figure 14.3 in Chapter 14), as, for instance, in the case of changes in the transmission of action potential... 

Finally, toxicity (defined in terms of a standard extraction procedure followed by chemical analysis for specific substances) is a characteristic of all chemicals, whether petroleum or nonpetroleum in origin. Toxic wastes are harmful or fatal when ingested or absorbed, and when such wastes are disposed of on land, the chemicals may drain (leach) from the waste and pollute groundwater. Leaching of such chemicals from contaminated soil may be particularly evident when the area is exposed to acid rain. The acidic nature of the water may impart mobility to the waste by changing the chemical character of the waste or the character of the minerals to which the waste species are adsorbed. 

There seems to be no doubt that patients who take levodopa are more likely to have a fracture (1). The most hkely explanation is simply that they are more mobile and thus more likely to fall than before treatment was begun, but it should be borne in mind that benserazide caused skeletal changes in rats in the original toxicity studies. 

Figure 35. Naphthenic acid concentrations and toxicity (Microtox 1C20) for (a) waters collected along the Athabasca River (from about 100 km upstream of Fort McMurray to the delta of Lake Athabasca), and (b) various waters at Syncrude s Mildred Lake Site. With time, the original toxicity and naphthenic acid levels in the fresh process waters (PW, SP) show a steady decrease when removed from fresh input of tailings (SS, 1, 3, and 5 years). Levels in the Athabasca River represent natural surface waters.

Saxitoxin is a very stable compound under strongly acidic conditions. Only upon heating in 7.5 N HCl at 100° for several hours is the carbamate moiety hydrolyzed to afford decarbamoylsaxitoxin (26) which retains about 70% of the original toxicity 43). On the other hand, saxitoxin decomposes rapidly at basic pH s, although in the absence of oxygen it is stable enough to withstand NMR measurements 40). 

Triaryl phosphates are produced from the corresponding phenols (usually mixtures) by reaction with phosphoms oxychloride, usually in the presence of a catalyst (94—96). They are subsequently distilled and usually washed with aqueous bases to the desired level of purity. Tricresyl phosphate was originally made from petroleum-derived or coal-tar-derived cresyflc acids, ie, cresols, variously admixed with phenol and xylenols. Discovery of the toxicity of the ortho-cresyl isomers led manufacturers to select cresols having very Httle ortho-isomer. 

Seafood Toxins. Vktually scores of fish and shellfish species have been reported to have toxic manifestations. Most of these toxicities have been shown to be microbiological ki origin. There are a few, however, that are natural components of seafoods. 

I. Hirono, Toxicants of Plant Origin, CRC Press, Boca Raton, Fla., 1989. 

Phosphoric Acid and Phosphorothioic Acid Anhydrides. The aUphatic organophosphoms esters originally developed by Schrader (27) are extremely toxic to mammals and are largely of historic interest. Tetraethyl pyrophosphate [107-49-3] (40) (bp 104—110°C at 10.7 Pa, d 1.185, vp 6.1 mPa at 30°C) is miscible with water and hydrolyzes very rapidly with a half-life of 6.8 h at 25°C. The rat LD qS ate 1.1 (oral) and 2.4 (dermal) mg/kg. 

In this type of activation, which occurs in both animal and plant tissues, the original insecticide is relatively stable and can be translocated through plant tissues without destmctive hydrolysis until the oxidation has occurred, which then makes the insecticide both highly toxic and relatively unstable so that it rapidly is hydroly2ed to nontoxic products. 

Hexa.cya.no Complexes. Ferrocyanide [13408-63 ] (hexakiscyanoferrate-(4—)), (Fe(CN) ) , is formed by reaction of iron(II) salts with excess aqueous cyanide. The reaction results in the release of 360 kJ/mol (86 kcal/mol) of heat. The thermodynamic stabiUty of the anion accounts for the success of the original method of synthesis, fusing nitrogenous animal residues (blood, horn, hides, etc) with iron and potassium carbonate. Chemical or electrolytic oxidation of the complex ion affords ferricyanide [13408-62-3] (hexakiscyanoferrate(3—)), [Fe(CN)g] , which has a formation constant that is larger by a factor of 10. However, hexakiscyanoferrate(3—) caimot be prepared by direct reaction of iron(III) and cyanide because significant amounts of iron(III) hydroxide also form. Hexacyanoferrate(4—) is quite inert and is nontoxic. In contrast, hexacyanoferrate(3—) is toxic because it is more labile and cyanide dissociates readily. Both complexes Hberate HCN upon addition of acids. 

The typical acid catalysts used for novolak resins are sulfuric acid, sulfonic acid, oxaUc acid, or occasionally phosphoric acid. Hydrochloric acid, although once widely used, has been abandoned because of the possible formation of toxic chloromethyl ether by-products. The type of acid catalyst used and reaction conditions affect resin stmcture and properties. For example, oxaUc acid, used for resins chosen for electrical appHcations, decomposes into volatile by-products at elevated processing temperatures. OxaUc acid-cataly2ed novolaks contain small amounts (1—2% of the original formaldehyde) of ben2odioxanes formed by the cycli2ation and dehydration of the ben2yl alcohol hemiformal intermediates. 

Eor virtually all radiopharmaceuticals, the primary safety consideration is that of radiation dosimetry. Chemical toxicity, although it must be considered, generally is a function of the nonradio active components of the injectate. These are often unreacted precursors of the intended radioactive product, present in excess to faciUtate the final labeling reaction, or intended product labeled with the daughter of the original radioactive label. 

Besides being slower, anaerobic treatment is more difficult to manage and can generate by-products that are more mobile or toxic than the original compound, for example, the daughter products of TCE, ie, dichloroethenes and vinyl chloride. It requires a longer acclimation period which means slower startup times in the field. The microbial processes are less well understood, and hence, ate less controlled than for aerobic systems. 

Lldoc ine. Lidocaine hydrochloride, an anilide, was originally introduced as a local anesthetic in 1943 and found to be a potent antiarrhythmic in 1960. The compound is a reverse amide of procainamide. Lidocaine is generally considered to be the dmg of choice in the treatment of ventricular arrhythmias and those originating from digitalis glycoside toxicity (1,2,15—17). 

Phenytoin. Phenytoin sodium is sodium diphenylhydantoin [630-93-3] which is stmcturally related to the barbiturates. It was originally introduced as an anticonvulsant (18) (see Hypnotics, sedatives, and anticonvulsants) and later found to have antiarrhythmic properties (19), although not approved by the PDA for any arrhythmic indications. Phenytoin is effective in the treatment of ventricular arrhythmias associated with acute MI and with digitalis toxicity (20). It is not very effective in treatment of supraventricular arrhythmias (20). 

Properties. Some physical properties of nerve agents are given in Table 2. The G-agents, miscible in both polar and nonpolar solvents, hydrolyze slowly in water at neutral or slightly acid pH and more rapidly under strong acid or alkaline conditions. The hydrolysis products are considerably less toxic than the original agent. 

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