Selective toxicity tests

Corrective Action Application In Massachusetts, a municipal wastewater treatment plant receives a number of wastestreams containing heavy metals from local industries. When tested, the dewatered sludge failed the EP toxicity test. In order to permit landfill disposal of the sludge, solidification processes were examined. A soluble, silicate-based system, developed by Chemfix, was ultimately selected which produced a product whose leachate passed the EP toxicity test (Sullivan, 1984). 

As discussed earlier, selectivity is the consequence of the interplay between toxicokinetic and toxicodynamic factors. Some examples are given in Table 2.8, which will now be briefly discussed (data from Walker and Oesch 1983, and Walker 1994a,b). These and other examples will be described in more detail under specific pollutants later in the text. In the table, comparisons are made between the median lethal doses or concentrations for different species or strains. Comparisons are made of data obtained in lethal toxicity tests where the same route of administration was used for species or strains that are compared. The degree of selectivity is expressed... 

Such sentinel workflow uses a prediction to select compounds for a more expensive screen that can confirm predicted hazards (liabilities, such as toxicity). It is, provably, the best workflow in contexts where a low prevalence of the hazard is anticipated, and where there is a backstop means further downstream (e.g., preclinical toxicity testing) for detecting hazards before humans are exposed. This workflow then allows the compounds predicted as safe to bypass the expensive hazards screen, without unacceptable risk, and can add significant value in terms of external screening costs or avoiding use of what may be a bottleneck resource. 

Borthwick, P.W. and G.E. Walsh. 1981. Initial Toxicological Assessment of Ambush, Bolero, Bux, Dursban, Fentrifanil, Larvin, and Pydrin Static Acute Toxicity Tests with Selected Estuarine Algae, Invertebrates, and Fish. U.S. Environ. Protection Agen. Rep. 600/4-81-076. 20 pp. 

While changes in cell phenotypes have proved useful in some settings to characterize the immunotoxicity of xenobiotics,1 phenotypic analysis alone is often not a sensitive indicator of low dose immunotoxicity for many agents that alter immune function. Xenobiotics that exert selective toxicity on lymphoid and myeloid cells may be discovered through immunophenotypic analysis. However, most agents produce immunotoxicity at doses much lower than those required to produce cytotoxicity or interfere with primary lymphoid organ differentiation. Some of the most potent immunosuppressive chemicals that have been tested, such as cyclosporine A, do not alter immunophenotype at doses that are immunosuppressive. On the other hand, when phenotyping is linked to assessment of functional parameters of the cells, immunotoxic effects are more likely to be identified. 

Toxicology and environmental health studies often lack a firm foundation of baseline data, and the NASGLP is a perfect starting point for a baseline data survey. During the field component of the survey, the crews collected two composite samples. One represented the top 5 cm of the soil directly below the litter layer (which will include a lot of the airborne components if they are present), and a second came from the 0-30-cm interval, independent of which soil horizon this may represent. Within this interval (the active layer), most of the interactions between biota and the non-living soil components take place, and thus is the important interval for this type if study. Environment Canada s Biological Methods Division selected one of the northern New Brunswick sites to collect a bulk sample in an attempt to create reference sites across Canada for standardized toxicity test methods. 

Another possible use of in vitro developmental toxicity tests would be to select the least developmentally toxic backup from among a group of structurally related compounds with similar pharmacological activity [use (2) in the list above], for example, when a lead compound causes malformations in vivo and is also positive in a screen that is related to the type of malformation induced. However, even for this limited role for a developmental toxicity screen, it would probably also be desirable to have a measure of the comparative matemotoxicity of the various agents and/or information on the pharmacokinetics and distribution of the agents in vivo. 

Study Type. Metabolic and pharmacokinetic data from a rodent species and a nonrodent species (usually the dog) used for repeat dose safety assessments (14 days, 28 days, 90 days or six months) are recommended. If a dose dependency is observed in metabolic and pharmacokinetic or toxicity studies with one species, the same range of doses should be used in metabolic and pharmacokinetic studies with other species. If human metabolism and pharmacokinetic data also are available, this information should be used to help select test species for the full range of toxicity tests, and may help to justify using data from a particular species as a human surrogate in safety assessment and risk assessment. 

Most microalgal toxicity tests procedures recommend the use of initial cellular concentrations of 104 cells mL 1. This cellular concentration should be selected because it is the minimum cellular concentration that can be measured in haematocytometers (Neubauer chambers). Furthermore, natural cellular concentrations in non-polluted conditions (in marine environments) are often below the concentration mentioned. The importance of cellular density at the beginning of the test has been demonstrated for certain toxicants [43]. The lower the cellular concentration, the higher the sensitivity of the test, at least for certain types of xenobiotics, such as heavy metals. 

When tested, the antibiotic compounds killed or inhibited the growth of two varieties of E. coli but had no effect on several other types of cells. These results show that in response to bacterial infection the ants elaborated an antibiotic that was selectively toxic to the pathogen. Their defense was tailored closely to their need. It is too soon to know more, but it seems that looking for new antibiotics in ants is a promising idea. Further research should establish whether ant antibiotics will lead to drugs for human use and also reveal whether other crowded species also synthesize antibiotics. 

Illudins M 112 and S 113 are sesquiterpenes produced by Omphalotus illu-dens, the jack-o -lantern mushroom [149]. These compounds demonstrated in vitro selective toxicity for a wide range of tumor cells compared to normal cells, but poor therapeutic indices were found when tested in vivo [150]. The spiro-cyclopropane and a, -unsaturated ketone moities present in the illudin skeleton constitute a bis-electrophile that is responsible for the DNA damage (vide supra Sect. 2.6) [150,151]. Illudin derivatives with greatly improved therapeutic indices have been prepared first of all dehydroilludin M 114 has shown better... 

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