Lethality test, compound

Vogel, E., Blijleven, W.G.H., Kortselius, M.J.H. and Zijlstra, J.A. (1981) Mutagenic activity of 17 coded compounds in the sex-linked recessive lethal test in Drosophila melanogaster, in Progress in Mutation Research, Volume 1 Evaluation of Short-Term Tests Carcinogens (eds F.J. de Serres and J. Ashby), Elsevier, Amsterdam. 

Valencia, R. Houtchens, K. (1981) Mutagenic activity of 10 coded compounds in the Drosophila sex-linked recessive lethal test. In de Serres, F.J. Ashby, J., eds, Evaluation of Short-Term Tests for Carcinogens. Report of the International Collaborative Program (Progress in Mutation Research, Vol. 1), Amsterdam. Elsevier, pp. 651-659... 

Polybrominated diphenyl ethers from the Indonesian marine sponge Dysidea herbacea are active against the Gram-positive bacteria Bacillus subtilis (MIC 0.20 pg/ml) and the phytopathogenic fungus Cladosporium cucumerinum. Compounds 90 and 91 are also active in the brine shrimp lethality test (LC50 0.96 and 0.94 pg/ml) [81]. 

An advantage of this sort of test is that it is much easier and more rapid than dominant-lethal tests, chromosomal-aberration studies, and specific-locus mutation experiments. Because the test is done in vivo, activation of the test chemical is possible in the germ cells themselves or in other organs that might then release the active compound to the circulatory system and thereby cause an interaction with the germ cells. For most of the chemicals looked at, the measurement of DNA repair in mouse germ cells appears to be a considerably more sensitive biologic end point than measurement of dominant lethals or translocations. 

Fluorocarbon greases (Krytox) originally required a chlorinated fluorocarbon for removal. In the last few years, it was found that an industrial solvent (such as BH-38 from Spartan Chemical Co. ) can remove Krytox. Tests that this author has conducted seem to show a film of some kind remains on the joint, so it is unknown exactly how safe it is to heat a joint or stopcock that has been cleaned with this technique. Do not use heat to remove Krytox because heating (> 260°C) will produce fumes (lethal fluorine compounds, such as HF) that are highly toxic. For more information on cleaning these greases, see Sec. 3.3.3. 

In the early days, when the role of histamine in allergy had been accepted, much discussion took place on the question of whether or not histamine reacts on an own receptor. In fact, this question was important, because it underlined whether or not it made sense to search for antihistamines. At the time, specific pharmacological models were not available, but one pioneer in the field was Staub, who defined an antihistaminic index (AHI). This was the number of LD5() doses blocked by 5 mg of the compound under investigation. In a model (which for ethical reasons would be completely unacceptable today), the test compound was dosed at 5 mg to mice (i.v.) and subsequently histamine was injected at one, two, three, etc., times the i.v. LD50 dose [5] ultimately, the parameter measured was lethality. 

With each of the anesthetics, four series of experiments are performed to determine the righting reflex, purposeful movement response, heart rate response, and lethal effect. The concentrations of the test compounds and the standard are spaced equally between the above-mentioned doses. 

Male albino rats receive either morphine or saline i.p. twice daily. The starting dose of morphine is 20 mg/kg followed by 40 mg/kg increments daily until by day 11 the level is 420 mg/kg. Maintenance at 400 mg/kg is continued through day 20. The test compound is similarly administered to groups of 10 rats each. The daily increments have to be adjusted to a maximum level that is not lethal for the duration of the experiment. 

The final system used In the evaluatln of BZ was the dominant-lethal assay (1). The only effect observed in these studies was a decrease In the fertility of the males at the highest dose tested. Such an effect Is Indicative only of the toxic effects of the test compound. 

Molar concentrations or dosages provide a more accurate assessment of the toxicity of a particular compound. This relationship will be explored further in our discussion of quantitative structure-activity relationships. Another weakness of the LC50, EC50, and IC50 is that they reflect the environmental concentration of the toxicant over the specified time of the test. Compounds that move into tissues slowly may have a lower toxicity in a 96-h test simply because the concentrations in the tissue have not reached toxic levels within the specified testing time. L. McCarty has written extensively on this topic and suggests that a lethal body burden or some other measurement be used to reflect tissue concentrations. 

Dominant Lethal Test. Dominant lethal mutation is a genetic event that kills the individual which carries it. The damage, which notably consists of chromosomal-type mutations, is detected as preimplantation loss of non-viable blastocysts and as early embryonic death.14 Fetal wastage above the spontaneous background rate is attributed to dominant lethal mutations since only the males are treated with the test compound females can be treated also, although this test is more difficult to interpret. This test has been well evaluated by several investigators.15-21... 

Thcfrojj embryo teratogenesis assay (FETAX) is a similar ex vivo test based on a Xenopus laevis model. Fertilized eggs in the mid- to late-blastula stage are exposed to test compounds and scored for lethality, growth retardation, and malformations. An interlaboratory validation study with 12 compounds [13], including a metabolic activation system, provided repeatable data, and a recent publication from a pharma industry reported very positive results testing over 400 chemicals with 81 % predictivity and a minimal proportion of false-positive compounds [14]. 

Amoebtasis - Little new has appeared in this area during the past two years. Several reviews, essentially clinical, have been published. Efforts continue primarily with other nitroimidazoles to achieve superiority to metronidazole. Tinidazole (lO) is receiving substantial favorable attention. Novel bls-anadines of 2,6-diaminoanthraquinone related to 11 have shown activity comparable to the activity of metronidazole against E. histolytica cecal infections tfi rats and hepatic infections, in hamsters. The compounds were nonmutagenic in the Ames and dominant lethal tests. 

Compound No. Serial Dilution Assay Zone of inhibition Fungicidal Activity against Brine Shrimp Lethality Test... 

Of the 19 pesticides grouped in Table II, all were negative in five Phase I bioassays and the Phase 2 bioassays performed. These compounds included insecticides (I), fungicides (F), and herbicides (H). Malath ion, parathion, pentachloronitrobenzene (PCNB), and phorate were also negative for heritable chromosomal effects in the mouse dominant lethal test. The six compounds grouped in Table III that were positive in three or more bioassays were acephate, captan, demeton, folpet, monocrotophos, and trichlorfon. Positive results were seen for demeton in all in vitro tests in Phase 1 and Phase 2. Folpet and captan were positive in all Phase 1 and all Phase 2 in vitro assays except the test for unscheduled DNA synthesis in WI-38 cells. Trichlorfon was positive in all Phase 1 and Phase 2 in vitro tests, with the exclusion of relative toxicity tests with E coli and subtiI is. 

In Phase 2 tests for unscheduled DNA synthesis In WI-38 cells, a positive response with disulfoton was found. When examined In Phase 1 microbial tests, this compound had not been detected. Positive responses were also Induced by bromacll and simazine In the Drosophila sex-1 Inked recessive lethal test In Phase 2. As these results may represent false negatives for the Phase 1 tests, they are a matter for concern. Under ordinary circumstances, these three pesticides would not have been evaluated In Phase 2. Further testing will explore the possibility of false negatives and if there is additional evidence, it may be necessary to modify the present Phase 1 test battery. 

The Compound 48/80 Lethality Test. Control data and the protection obtained after oxatomide administration have fully been... 

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