Toxicity screening

The second method for mixture analysis is the use of specialized software together with spectral databases. We have developed a mixture analysis program AMIX for one- and multidimensional spectra. The most important present applications are the field of combinatorial chemistry and toxicity screening of medical preparations in the pharmaceutical industry. An important medical application is screening of newborn infants for inborn metabolic errors. 

The brine shrimp (Anemia salina) has been evaluated as an alternative to the mouse bioassay for use in cyanobacterial toxicity screening assays." " " As in the... 

Monomethyltin Rat MMTC 8 weeks at 0, 30, 150, and 750 mg/kg diet = 0, 1.5, 7.5, and 37.5 mg/kg body weight Fertility, developmental toxicity, and maternal toxicity (screening) NOAEL = 7.5 Appel Waalkens-Berendsen (2004a)... 

Persoone, G.G., Janssen, C., and De Coen, W. (2000). New Microbiotests for Routine Toxicity Screening and Biomonitoring. New York Kluwer. 

Screening Techniques for Detecting Toxicity. Simple toxicity screening techniques are necessary to identify toxic species and to monitor the efficacy of isolation and purification procedures used to purify toxins. Atterwill and Steele 108) have recently comprehensively reviewed in vitro methods for toxicology and so much of the following is in the nature of a general overview. 

McCarron s paper (this volume) describes the behaviors of 1,000 adults admitted to an inpatient service with acute symptoms of PCP intoxication. She states that some of the patients have appropriate behavior while many have mute and staring episodes, bizarre facial grimacing, localized dystonic reactions, rigidity, tremors, coarse jerky movements, and nystagmus. Thus, there is similarity between the acutely intoxicated adult s behavior and that of the newborn with a positive urine toxic screen for PCP. 

Toxicity screen (e.g., HERG or equivalent especially for CNS approaches)... 

Combined repeated dose toxicity study with the reproduction/developmental toxicity screening test OECD... 

Quan, Y. S., Hattori, K., Lundborg, E., Fujita, T., Murakami, M., Muranishi, S., Yamamoto, A., Effectiveness and toxicity screening of various absorption enhancers using Caco-2 cell monolayers, Biol. Pharm. Bull. 1998, 21, 615-620. 

Murthy MS Induction of gene conversion in diploid yeast by chemicals Correlation with mutagenic action and its relevance in geno-toxicity screening. Mutat Res 1979 64 1-17. 

W. Purcell, Approaches to High-Throughput Toxicity Screening, Taylor Francis, London, 2000. 

Developmental toxicity screening study (OECD 421) Developmental toxicity study (OECD 414)... 

To Provide Mechanistic Insight. For example, if an agent is negative in a wide range of genetic toxicity screens, but still produces tumors in animals, then one could hypothesize that an epigenetic mechanism was involved. 

Fowler and his colleagues (1979) have described a rat toxicity screen (illustrated in Figure 5.17) that is more extensive and detailed than the one shown in Figure 5.16. It includes two rounds of dosing. In the first round, up to 12 rats are (singly)... 

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. 

There are a number of test systems that use cultured mammalian cells, from both established and primary lines, that now have a large database of tested chemicals in the literature, are relatively rapid, and are feasible to use for genetic toxicity screening. These are discussed in the next section. 

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. 

Lochry, E.A. (1987). Concurrent use of behavioral/functional testing in existing reproductive and developmental toxicity screens Practical consideration. J. Am. Coll. Toxicol. 6 433-439. 

Seidenberg JM, Anderson DG, Becker RA. 1986. Validation of an in vivo developmental toxicity screen in the mouse. Teratogenesis Carcinog Mutagen 6(5) 361-374. 

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