Toxicity acute lethal

As discussed in the introduction to Section 2.1, there are a number of limitations in the human database for most health effects, the data are inadequate to assess the potential for humans having a particular effect. Because the human data are incomplete, hazard and risk must be extrapolated across species. A large number of adverse effects have been observed in animals, and most have been observed in every experimental animal species tested, if the appropriate dose is administered. This is illustrated in Table 2-8 for 8 major effects associated with CDD toxicity (acute lethality, hepatotoxicity, wasting syndrome, chloracne, immunotoxicity, reproductive toxicity, developmental toxicity, and cancer). With the exception of acute lethality in humans, positive responses have been observed in each tested species, when a response has been investigated. Despite the similarities in hazard response between different species, large species differences in sensitivity have been observed. Comparisons of species sensitivity demonstrate that no species is consistently sensitive or refractory for all effects and, for some effects,... 

This is a convenient way of expressing models for the prediction of LC50 values, and is easy to understand since a numerical increase in the response variable means an increase in toxicity (acute lethality in this case). Furthermore, it is apparent that the QSAR relates an increasing toxicity to an increasing partition coefficient. 

As a class of compounds, the two main toxicity concerns for nitriles are acute lethality and osteolathyrsm. A comprehensive review of the toxicity of nitriles, including detailed discussion of biochemical mechanisms of toxicity and stmcture-activity relationships, is available (12). Nitriles vary broadly in their abiUty to cause acute lethaUty and subde differences in stmcture can greatly affect toxic potency. The biochemical basis of their acute toxicity is related to their metaboHsm in the body. Following exposure and absorption, nitriles are metabolized by cytochrome p450 enzymes in the Hver. The metaboHsm involves initial hydrogen abstraction resulting in the formation of a carbon radical, followed by hydroxylation of the carbon radical. MetaboHsm at the carbon atom adjacent (alpha) to the cyano group would yield a cyanohydrin metaboHte, which decomposes readily in the body to produce cyanide. Hydroxylation at other carbon positions in the nitrile does not result in cyanide release. 

The propensity of nitriles to release cyanide subsequent to metaboHsm is the basis of their acute toxicity. Nitriles that form tertiary radicals at their alpha carbon atoms (eg, isobutyronitrile, 2-methylbutyronitrile) are substantially more acutely lethal than nitriles that form secondary radicals at their alpha carbons (eg, butyronitrile, propionitnle). Cyanohydrins are acutely toxic because they are unstable and release cyanide quickly. Alpha-aminonitriles are also acutely toxic, presumably by analogy with cyanohydrins. 

Considerable caution is necessary in making quantitative comparisons between different materials, even when considering the same toxic end point. This can be conveniendy illustrated using, as an example, death in response to a single exposure, ie, acute lethal toxicity. Studies to determine acute lethal toxicity by a particular route are usually conducted as described below. 

Although acute lethal toxicity has been used as an example, the principles discussed apply ia general to other forms of toxicity capable of being quantitated ia terms of dose—response relationships. 

An acute lethal dose (LC q) for vapor exposure to 1,1,2-trichloroethane in the rat is 2000 ppm for a 4-h exposure. The same lethal effect occurs at 18,000 ppm vapor during 3 h exposure to 1,1,1-trichloroethane. The oral LD q for 1,1,2-trichloroethane in rats is 0.1—0.2 g/kg, classifying it as moderately toxic (109). Liver and kidney damage occurs at even lower dosages. Skin adsorption is a possible route of overexposure. 

Parenteral lethality was determined by injecting rabbits of mixed sexes intraperitoneally with 31.6, 63, 126, 252, and 500 /xg/kg of 2,3,7,8-TCDD as a 0.01% corn oil suspension control rabbits were injected with corn oil. The rabbits were housed in individual holding cages and were observed for signs of toxicity for four weeks. The LDso s were calculated by the Weil modification of the Thompson method 14, 15) or by the Litchfield and Wilcoxon method (9). The acute lethality studies were terminated when it was evident that the survivors were not showing signs of toxicity. 

Marine toxins are not always acutely toxic. This may be particularly so for toxins which are used to deter competing occupants for living space since they often have comparatively slow actions on growth. With such toxins, the procedures for the evaluation of acutely lethal toxins cannot apply. However, interesting discoveries may be made by using the simplest of screen of alcoholic extracts for cytolytic actions as exemplified in Table I of Shier 109),... 

In a series of acute lethality studies on U.S. military fluids, single gavage doses (4,250 or 5,000 mg/kg) of one of several polyalphaolefin hydraulic fluids did not produce signs of neurological toxicity in rats within... 

No data were located regarding toxic effects in humans following oral exposure to polyalphaolefin hydraulic fluids. No deaths or body weight changes occurred in rats in a series of acute lethality studies with nine polyalphaolefin hydraulic fluids at doses ranging from 4,250 to 5,000 mg/kg. One of these fluids was also tested for neurotoxicity in chickens, and did not produce effects at 4,250 mg/kg. The available data have not identified a target organ or effect for these fluids. The data are inadequate for MRL derivation. No intermediate or chronic oral MRLs for polyalphaolefin hydraulic fluids were derived due to the lack of data. 

Acute lethality studies in animals exposed by inhalation, ingestion, or dermal contact to several mineral oil hydraulic fluids indicate that mineral oil fluids are not potent toxicants. Mineral oil hydraulic fluids produced no deaths in rats after 4-hour exposures to aerosol concentrations of 110-210 mg/m3 or gavage administration of single doses <5,000 mg/kg (Kinkead et al. 1987a, 1988). Rabbits, likewise, did not die after single 24-hour exposures to occluded dermal doses of several mineral oil hydraulic fluids <2,000 mg/kg (Kinkead et al. 1985, 1987a, 1988). 

Polyalphaolefin Hydraulic Fluids. Aside from the acute lethality of inhalation exposure to certain polyalphaolefin hydraulic fluids, little is known regarding the toxic effects produced by these materials. Additional animal studies to identify the possible toxic effects of exposure to these materials may provide information relevant to the investigation of methods for reducing the toxic effects. 

Mefenamic is a nonsteroidal anti-inflammatory drug used to treat pain, including menstrual pain. Hata et al. [11] treated that drug with P. sordida, and obtained a 90% reduction in mefenamic acid concentration (initial concentration 24 mg L ) after 6 days. The system produced four metabolites, identified as 3 -hydroxymethyl-mefenamic acid, 3 -hydroxymethyl-5-hydroxymefenamic acid, 3 -hydroxmethyl-6 -hydroxymefenamic acid, and 3 -carboxymefenamic acid. Moreover, the authors confirmed that the fungus almost completely removed the acute lethal toxicity of mefenamic towards the freshwater crustacean Thamnocephalus platyurus after 6 days of treatment, suggesting that the metabolites are less toxic than the parental compound. 

Acute-Duration Exposure. Information is available regarding the effects of acute-duration inhalation exposure of humans to acrylonitrile and the effects are characteristic of cyanide-type toxicity. Quantitative data are limited but are sufficient to derive an acute inhalation MRL. Further studies of humans exposed to low levels of acrylonitrile in the workplace would increase the confidence of the acute MRL. Studies in animals support and confirm these findings. No studies are available on the effects of acute-duration oral exposure in humans however, exposure to acrylonitrile reveals neurological disturbances characteristic of cyanide-type toxicity and lethal effects in rats and mice. Rats also develop birth defects. Animal data are sufficient to derive an acute oral MRL. Additional studies employing other species and various dose levels would be useful in confirming target tissues and determining thresholds for these effects. In humans, acrylonitrile causes irritation of the skin and eyes. No data are available on acute dermal exposures in animals. 

Dubitski (1911) (as cited in Flury and Zernik 1931) provided data on the acute lethality of arsine in cats, noting the following for 1-h exposures no observable signs of toxicity following exposure to 43-50 ppm, sick with recovery following exposure to 50-100 ppm, and death (12 10 h post-exposure) following exposure to 120-290 ppm. 

There are no definitive data regarding the metabolism of arsine. Based upon proposed mechanisms of action and the known interaction with RBCs and hemoglobin, metabolism per se may of limited importance relative to acute exposures to arsine. Delayed toxicity and lethality are observed in both humans and animals following acute exposure to arsine, and it is known that increased... 

Haun et al. (1970) also assessed the acute lethal toxicity of rats. Groups of 10 Sprague-Dawley rats were exposed to monomethylhydrazine (30, 60, 120, or 240 ppm) for 30, 60, 120, or 240 min. Similar to the results of Jacobson et al. (1955) the exposure-response curve was steep. The study authors calculated 30-, 60-, 120-, and 240-min LC50 values of427,244, 127, and 78 ppm, respectively. 

Acute lethality data for inhalation exposure to monomethylhydrazine are available for monkey, dog, rat, mouse, and hamster. Based upon the available data, hamsters appear to be the most resistant species, and the squirrel monkey and beagle dog are the most sensitive. The lethality of monomethylhydrazine appeared to follow a linear relationship for exposures up to 1 h. Most animal data focus on lethality as the toxicity endpoint with very limited exposure-response information available regarding nonlethal effects. The most significant effect reported in the acute exposure studies was the notable hemolytic response that was reversible upon cessation of exposure. However, the preponderance of the data suggest that there is little margin between exposures associated with nonlethal, reversible effects and those that result in death. 

Thain, J.E. 1984. Effects of mercury on the prosobranch mollusc Crepidula fornicata acute lethal toxicity and effects on growth and reproduction of chronic exposure. Mar. Environ. Res. 12 285-309. 

Waterborne solutions of zinc-cadmium mixtures were usually additive in toxicity to aquatic organisms, including freshwater fishes (Skidmore 1964) and amphipods (de March 1988), and to marine fishes (Eisler and Gardner 1973), copepods (Verriopoulos and Dimas 1988), and amphipods (Ahsanullah et al. 1988). However, mixtures of zinc and cadmium were less toxic than expected to Daphnia magna, as judged by acute lethality studies (Attar and Maly 1982). 

Alabaster, J.S., D.G. Shurben, and M.J. Mallett. 1983. The acute lethal toxicity of mixtures of cyanide and ammonia to smolts of salmon, Salmo salar L. at low concentrations of dissolved oxygen. Jour. Fish Biol. 22 215-222. 

An extensive literature search revealed no published data on famphur toxicity to aquatic animals. Unpublished studies of acute lethality were, however, conducted with the bluegill (Lepomis mac-rochirus) and rainbow trout (Oncorhynchus mykiss). In those studies, the range in LC50 values at 96 h was 18 to 21 mg/L in bluegills and 4.9 to 5.3 mg/L in rainbow trout. The no-observable-effect concentration at 96 h ranged from 14 to 18 mg/1 in bluegills and was 2.1 mg/L in rainbow trout (U.S. Environmental Protection Agency, OPPTS/OPP/EFED/EEB, personal communication, 30 June 1993). 

Oikari, A.O.J. 1987. Acute lethal toxicity of some reference chemicals to freshwater fishes of Scandinavia. Bull. Environ. Contam. Toxicol. 39 23-28. 

Ballantyne, B. 1983. The influence of exposure route and species on the acute lethal toxicity and tissue concentrations of cyanide. In Developments in the Science and Practice of Toxicology. Elsevier Science Publishers, New York, pp. 583- 586. 

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