Sensitization rates species differences

Miltefosine, an alkylphosphocholine derivative, is a new antileishmanial drug and the first effective oral treatment of visceral leishmaniasis. However, there are concerns regarding teratogenicity, rapid emergence of resistance, and variable cure rates, possibly due to species differences in drug sensitivity. The mechanism of action of miltefosine is not known. 

ECETOC (2003) recommended that in the absence of any substance- or species-specific mechanism or PBPK modeling (Section 4.3.6), allometric seating based on metabolic rate (W° ) (caloric requirement approach. Section 5.3.2.3) is considered to provide an appropriate default for an assessment factor for interspecies differences with respect to systemic effects. Allometric scaling was stated as being a tool for estimating interspecies differences of internal exposure or body burden and to provide indirectly information on differences in sensitivity between species. Typical scaling factors for interspecies adjustment were noted as 7 for mouse, 4 for rat, and 2 for dog however. 

The National Research Council (NRC) published a report, Science and Judgment in Risk Assessment, that critiqued the current approaches to characterizing human cancer risks from exposure to chemicals. One issue raised in the report relates to the use of default options for assessing of cancer risks. These general guidelines can be used for risk assessment when specific information about a chemical is absent. Research on 1,3-butadiene indicates that two default options may no longer be tenable Humans are as sensitive as the most sensitive animal species and the rate of metabolism is a function of body surface area rather than inherent species differences in metabolic capacity. 

In the absence of definitive human data, risk assessment may have to depend on the results of cancer bioassays in laboratory animals, short-term tests, or other experimental methods. Hence the following issues must be addressed under such circumstances the ability of the test system to predict risks for man (quantitatively as well as qualitatively) the reproducibility of test results the influence of species differences in pharmacokinetics, metabolism, homeostasis, repair rates, life span, organ sensitivity, and baseline cancer rates extrapolation across dose and dose rates, and routes of exposure the significance of benign tumors fitting models to the data in order to characterize dose-incidence relationships and the significance of negative results. 

In vitro Metabolism. Numerous variables simultaneously modulate the in vivo metabolism of xenobiotics therefore their relative importance cannot be studied easily. This problem is alleviated to some extent by in vitro studies of the underlying enzymatic mechanisms responsible for qualitative and quantitative species differences. Quantitative differences may be related directly to the absolute amount of active enzyme present and the affinity and specificity of the enzyme toward the substrate in question. Because many other factors alter enzymatic rates in vitro, caution must be exercised in interpreting data in terms of species variation. In particular, enzymes are often sensitive to the experimental conditions used in their preparation. Because this sensitivity varies from one enzyme to another, their relative effectiveness for a particular reaction can be sometimes miscalculated. 

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. 

There are a number of factors which can contribute to herbicide selectivity, including soil placement, rates of absorption and subsequent translocation, localization (both within the plant and at the subcellular level), and transformation to products of modified phytotoxicity. In addition, the recent work on the elucidation of the modes of action of the aryloxyphenoxypropionate and cyclohexanedione groups of herbicides has highlighted the importance of species differences in sensitivity of the target site, in this case the enzyme acetyl-CoA carboxylase. The monocot and dicot enzymes studied to date show a remarkable difference in sensitivity to these herbicides which correlates very well with the high level of resistance among dicots. Biotypes of Chenopodium album and Amaranthus hybridus L. resistant to atrazine as a result of a mutation in the 32-kDa protein component of photosystem II would constitute a further example. 

Sensitivity The sensitivity for a one-point fixed-time integral method of analysis is improved by making measurements under conditions in which the concentration of the monitored species is larger rather than smaller. When the analyte s concentration, or the concentration of any other reactant, is monitored, measurements are best made early in the reaction before its concentration has substantially decreased. On the other hand, when a product is used to monitor the reaction, measurements are more appropriately made at longer times. For a two-point fixed-time integral method, sensitivity is improved by increasing the difference between times t and f2. As discussed earlier, the sensitivity of a rate method improves when using the initial rate. 

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