Specific toxicity screening

Strictly speaking, an acute toxicity study is conducted to examine the effect of a single dose of a single compound. In designing specific toxicity screens, however, deviation from this principle is permissible if it increases screen sensitivity. For example, the sensitivity of mice to many indirect hepatotoxins will be enhanced by prior treatment with phenobarbital. Hence, the sensitivity of a hepatotoxicity screen will be enhanced if the mice are pretreated for three days with phenobarbital. 

Several vitro assays for detecting fermentation products with anthelmintic activity had been run without success, primarily because of the large number of toxic compounds which had to be eliminated. Finally, the decision was made to use an vivo assay in mice with the hope that the mice would screen out the non-specific toxic compounds. 

There are no formal criteria to identify structural alerts for toxicity in general, for a specific endpoint or for read-across to closely related substances. However, for substances where no data for one or more endpoints are available, the assessment at a screening level can be performed using data obtained from closely analogous substance(s) to indicate a potential for toxicity, e.g., if a closely related substance has a potential for inducing a specific toxic effect, the substance for which no data on this specific toxic effect are available may reasonably be expected to exhibit a similar potential for inducing this specific toxic effect. In the case of such knowledge, it should be considered whether these data are adequate for a hazard assessment. 

Thus, the development of new anthracycline antibiotics is of interest in which the therapeutical width is enhanced by decreasing toxicity and increasing specificity. Several screening methods are presently available in clinical tests. One is carried out by measurement of the survival rate of mice, induced with P 388 leukemia carcinoma [30, 32], Other methods are based on in-vitro tests either the 50% inhibitory concentration (IC50) of nucleosomal RNA synthesis is measured or the growth of tumor cell cultures like He La is observed [34],... 

A report by the National Academy of Sciences proposed that future toxicity screens not be organ-based as they are today, but that they instead focus on detecting specific mechanisms of toxicity.86 Thus, a suite of such assays may be used to determine what toxicity pathways are triggered by exposure to specific chemicals. Similar approaches may be applied to developmental toxicity tests. In this way, we need not know all the relevant developmental biology pathways... 

Application of the effect-directed analysis methodology has been reviewed. It consists of the search of toxic compounds present in complex samples, such as those stemming from the environment and industrial effluents, following the simplification operations shown in equation 4, where BA = biological assay, CA = chemical analysis and FR = fractionation. At present it is too expensive for screening applications however, it is amply justified for identification of specific toxicants near the source of emission, as was the case of mutagens in Table 2.D in river waters84. 

The in vitro screening methods have several advantages over in vivo testing such as the undisputable ethical benefits, a lower cost, and a shorter time to perform the study. Moreover, in vitro methods offer the possibility to identify and investigate specific toxicity mechanisms (such as oxidative stress, pathways involved in NM intracellular uptake, genotoxicity) in a relatively simple system, without the complexity and interferences of several factors present in vivo in a whole organism. 

Toxicity screening follows the conventional TLC development and analysis process, which has to be performed in advance to separate possible toxic substances on the HPTLC plate. The developed and dried plate is dipped into a suspension of bioluminescent bacteria. Vibrio fischeri, thereby exposing any separated bioactive compounds to the test orgartisms. The luminescent activity is reduced or stopped by substances toxic to the bacteria, which may also be toxic to humans. Healthy Vibrio fischeri, emit very weak tight of greenish color, which can not be detected with standard systems using daylight cameras. Thus, a specific bioluminescence detection system is required. 

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