Laboratory rats sensitivity levels

The use of a rat study for developing an RfD for GA is complicated by the fact that rodents have a much lower RBC-AChE activity level compared to humans (Ellin, 1981). By itself, this could cause rats to be relatively more sensitive than humans to anticholinesterase compounds however, the lower RBC-AChE activity may be offset by the presence of ahesterases in the blood of rats. Aliesterases, which are not found in human blood plasma, are known to bind to and, therefore, reduce the toxicity of GB, and a similar mechanism may operate in the case of GA. Other species differences, such as in the rates of aging of the GA-ChE complex, in the rates of synthesis of plasma-ChE in the liver, and in the levels of AChE in the nervous system (see Ivanov et al., 1993) may also result in difference between species in sensitivity to GA. Data are insufficient to more fuUy evaluate these possibihties. There is httle human acute toxicity data that can be compared with the available rat data however, acute toxicity data for primates in general (see Table 2) suggests that humans are likely to be more sensitive than rats. Therefore, for the purpose of this assessment, the standard EPA method will be followed which assumes that humans can be as much as ten times more sensitive to a chemical than laboratory animals. 

An uncertainty factor of 10 is used for animal-to-human extrapolation because there is ample evidence that humans are more sensitive to GB than laboratory rodents. In humans, the single dose oral RBC-AChE 50 (dose required to lower red blood cell cholinesterase by 50%) is 0.01 mg/kg (Grob and Harvey, 1958), and an average daily dose of 0.034 mg/kg for three days resulted in moderate signs of toxicity. In comparison, rats receiving 0.3 mg GB Type Il/kg/day for 90 days exhibited decreases in blood cholinesterase levels but no signs of toxicity (Bucci and Parker, 1992). 

For laboratories interested in measuring concentrations of GHB at or below endogenous levels, a GC-MS method with negative ionization has been described for the measiuement of GHB in rat brain (Ehrhardt et al., 1988). It involves a complicated liquid-liquid extraction with subsequent derivatization of GHB with MTBSTEA. This method is very sensitive, with the capability of detecting as little as 2pg of GHB. The calibration curve showed linearity from 0 to 64 ng of GHB. Another method, described by Shima et al. (2005),... 

The first component we will discuss is the assessment of actual hazard, usually done with laboratory animal tests. Depending on the regulatory agency involved, studies are done in the most sensitive animal species using the most discriminating test available. Such safety studies are usually conducted in at least two rodent species, and any evidence of toxicity determined. The strains of mice and rats used are sometimes dependent on the type of chemical to be tested. In reality a number of sequential studies are conducted to determine the acute toxic dose and to define a profile of the disease induced. For some compounds or endpoints, such as birth defects, other animal species may be used, such as dogs, monkeys, or rabbits. Longer studies are then conducted to determine so-called subchronic effects and help select the doses used for chronic studies. The aim of these experiments is to determine the no observed adverse effect level, the NOAEL. 

Signs of famphur toxicosis in cattle include ataxia, muscular fasciculations, general weakness, lacrimation, salivation, and diarrhea. In comparison with European breeds of cattle (Bos taurus), the Brahman (Bos indicus) and European X Brahman hybrids are more sensitive to famphur, and Brahman bulls are more sensitive than cows. At a comparatively low famphur dose of 16.6 mg/kg BW, both B. taurus and B. indicus are tolerant of intramuscular injectable famphur however, B. indicus is more sensitive and bulls sometimes died when treatment levels exceeded 33.3 mg/kg BW. In addition to cattle, famphur-induced mortality in other species of mammals was documented. Single exposures of famphur in mg/kg BW killed rabbits (Oryctolagus sp.) at 2730.0 in dermal exposure mice (Mus sp.) at 27.0 in oral dose or 11.6 by intraperitoneal injection domestic sheep (Ovis aires) at 400.0 in oral dose and laboratory white rats (Rattus sp.) at 400.0 dermal exposure or >28.0 in oral dose. Mice receiving fatal or near-fatal intraperitoneal injections of famphur or famoxon began to convulse 10-20 min postinjection death came within 45 min post-injection, usually from respiratory failure. Mice remaining alive at 60 min post-injection usually recovered. 

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