The Acute Toxic Properties

The classification as very toxic, toxic, or harmful is based on the median lethal dose (LD50, see Section 2.3). Most often the LD50 value (oral, rat) is used for the classification, because oral investigations are most often carried out to determine the acute toxicity. In contrast to the oral toxicity, the dermal and inhalative toxici-ties are much more important for the workplace assessment, the oral toxicity being of little relevance to the workplace. Howevei the oral, dermal, and inhalative toxicities do not usually differ significantly. 

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It is natural to consider one or another of these trans-species dose prescriptions for scaling dose-response relationships in carcinogenesis. But in any chronic effect, such as carcinogenesis, another parameter enters namely, time. Whereas the LDjo describes the acutely toxic properties of a chemical, the relevant dose for carcinogenesis is usually accumulated over a long time. One must consider, therefore, the relationship between daily dose, total lifetime dose, and body weight. The difference in life spans between man and mouse—70 years versus 2 years—amounts to a factor 35. Most analyses, however, consider that it is the daily dose that is more relevant, and that the shorter lifetime of the mouse represents the effects of its higher metabolic rate. The difference between these various interspecies dose conversion schemes is illustrated in Thble 8.1. 

The acute toxic properties of all the organochlorine pesticides in humans are qualitatively similar. These agents interfere with inactivation of the sodium channel in excitable membranes and cause rapid repetitive firing in most neurons. Calcium ion transport is inhibited. These events affect repolarization and enhance the excitability of neurons. The major effect is central nervous system stimulation. With DDT, tremor may be the first manifestation, possibly continuing to convulsions, whereas with the other compounds convulsions often appear as the first sign of intoxication. There is no specific treatment for the acute intoxicated state, and management is symptomatic. 

Stubblefield WA, McKee RH, Kapp RW Jr, et al. 1989. An evaluation of the acute toxic properties of liquids derived from oil sands. J AppI Toxicol 9 59-65. 

The different properties are subdivided into different categories. The acute toxic properties are divided into 5 categories. 

Stmctural alerts may provide useful information for assessment of the acute toxicity of certain substances. One example is that for highly water-soluble salts of substances with well-characterized toxic properties, the systemic toxicity can be expected to be similar. Another example is the group of organophosphoms insecticides for which the acute toxicity is due to their anticholinesterase action. 

Brown VKH, Muir C, Thorpe J The acute toxicity and skin irritant properties of 1,2,4-trichlorohenzene. Occup Med 12 209-212, 1969... 

The acute toxicity is high by all routes of exposure. The effects are similar to other soluble compounds of barium (see Barium). The oral and subcutaneous lethal doses in dogs are as follows (R. N. Lewis (Sr.). 1996. Sax s Dangerous Properties of Industrial Materials, 9th ed., New York Van Nostrand Reinhold.)... 

Brown, V.K.H., Ferrlgan, L.W., and Stevenson, D.E. The acute toxicity and skin Irritant properties of tropllidene (cyclo-hepta-l,3,5-trlene). Ann. Occup. Hyg. 10 123-126, 1967. 

Inorganic acids have similar acute toxic properties corrosive action on the skin, the respiratory tract, and especially the eyes where corneal damage may occur. Severe exposures may cause blindness, pulmonary edema, and even death. The onset of symptoms may be delayed for several hours after exposure. Prolonged exposures to low concentrations produce chronic effects such as tooth erosion, chronic bronchitis, and photosensitization of the skin (J >2, ). 

The guiding principle for all workers should be to treat all chemicals as potentially harmful. The following discussion (pp. 46-48) centres on compounds with acute toxic properties which are likely in organic laboratories those which give rise to particularly severe chronic effects are noted on pp. 48-51. Substances marked C are also known to be carcinogenic, but the discussion of their availability or control is noted. 

Benzene is widely used for its solvent properties and as an intermediate in the synthesis of other chemicals. The 1999-2000 recommended threshold limit values are given in Table 57-1. The acute toxic effect of benzene is depression of the central nervous system. Exposure to 7500 ppm for 30 minutes can be fatal. Exposure to concentrations larger than 3000 ppm may cause euphoria, nausea, locomotor problems, and coma vertigo, drowsiness, headache, and nausea may occur at concentrations ranging from 250 to 500 ppm. No specific treatment exists for the acute toxic effect of benzene. 

Polychlorinated diphenyl ethers (PCDE) are common impurities in chlorophenol formulations, which were earlier used as fungicides, slimicides, and as wood preservatives. PCDEs are structurally and by physical properties similar to polychlorinated biphenyls (PCB). They have low water solubility and are lipophilic. PCDEs are quite resistant to degradation and are persistent in the environment. In the aquatic environment, PCDEs bioaccumulate. These compounds are found in sediment, mussel, fish, bird, and seal. PCDEs show biomagnification potential, since levels of PCDEs increase in species at higher trophic levels. PCDEs are also detected in human tissue. Despite the persistence and bio accumulation, the significance of PCDEs as environmental contaminants is uncertain. The acute toxicity and Ah-receptor-me-diated (aryl hydrocarbon) activity of PCDEs is low compared to those of polychlorinated di-benzo-p-dioxins (PCDD) and dibenzofurans (PCDF). Due to structural similarity to thyroid hormone, PCDEs could bind to thyroid hormone receptor and alter thyroid function. Furthermore, PCDEs might be metabolized to toxic metabolites. In the environment, it is possible that photolysis converts PCDEs to toxic PCDDs and PCDFs. 

An informative paper by Di Toro et al. (1991), on predicting the acute toxicity of Cd and Ni in sediments by assessing the acid volatile suflide (AVS), illustrates that the sediment properties that determine the concentration (activity) of the sediment in the interstitial water determine the fraction of the metal that is bioavailable and potentially toxic. The study of Di Toro et al. is based on measurements of acute toxicity to benthic organisms (amphipodes, oligo-chaetes, and snails). It is shown that this toxicity is essentially related to the free metal ions in solubility equilibrium with the solid metal sulfides present. 

Data which can be determined by observations of the properties of a compound and which can be used to characterize the compound, will be called observables. It is highly probable that several of the observables of a molecule are related to the chemical behaviour of that molecule when it undergoes a given chemical reaction. It is also probable that some observables are not at all related to the phenomena involved in the reaction under study, e.g. it is not to be expected that the acute toxicity of a compound towards guinea-pigs will have any strong relation to the rate of the reaction in a nucleophilic displacement. This example shows an important principle ... 

Organophosphates. The acute toxicity of organophosphate pesticides is basically derived from the anticholinesterase property of these chemicals. This property, which results in accumulation of acetylcholine at synapses and myoneural junctions, is responsible for both the insecticidal activity and mammalian toxicity. Early symptoms of organophosphate poisoning in humans include, among others, miosis (pinpoint pupils) and blurred vision, and a response known as the SLUD (salivation, lacrimation, urination, and diarrhea) syndrome all of these are the result of muscarinic effects (12-15). Clinical manifestations of more severe poisoning involve predominantly nicotinic and central effects which include convulsions, paralysis, depressed respiration and cardiovascular functions, and coma (12-15). Death is usually due to respiratory failure, accompanied by cardio-vascular failure (13). 

The toxicity of compounds has often been related to the polarizability of compounds. This descriptor is related to the intermolecular interactions in biological environments and can be ascribed both to the drug-receptor interactions as well as to the properties determining the bioavailability of a compound [112], Thus it was shown that even the CNDO/2 calculated molecular polarizability (a) can be successfully correlated with the acute toxicity in a series of 20 nitriles [113] ... 

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