Loewe additive

According to Placket and Hewlett, there are two types of combined action without interaction (Table 10.1) simple similar action (dose addition, Loewe additivity) and simple dissimilar action. This latter type contains two concepts effect or response additivity and Bliss independence. The independence criterion seems not to be widely used in toxicology (Groten et al. 2001). 

Simple Similar Action (Dose Addition, Loewe Additivity)... 

Methods are required that allow more reliable calculations of additive mixture effects from information about the responses of an organism to individual mixture components. For this purpose, 2 concepts have emerged concentration addition (often also called dose addition or Loewe additivity ) and independent action (also referred to as response addition or Bliss additivity ) (Greco et al. 1992). These concepts are based on 2 entirely different ideas about how the joint action of chemicals can be perceived. See Chapter 4 for a more detailed elaboration of these concepts here only a brief description is given. 

At a cellular level, the purported sorafenib editors should be assayed using the renal cancer cell line RCC-786-O and NRVMs (neonatal rat ventricular monocytes). In RCCs, the sorafenib/WBZ 4 combination yields agonistic synergy, marked by an increased inhibition of cell proliferation when compared to sorafenib-alone levels at equivalent bulk concentrations (Fig. 12.5a) The dose-dependent inhibition is greater than the Loewe-additive values [20, 21] (Fig. 12.5b). By contrast, the sorafenib-induced recruitment of the pro-apoptotic pathway in cardiomyocytes should be impaired by the downstream interference of WBZ 4 through JNK inhibition (Fig. 12.3a). Consequently, cytosolic release of... 

There are numerous ways to approach studies on chemical mixtures, and part of the challenge that remains in insecticide and repellent research is selecting the appropriate model for the analysis of the combined effects especially when information on the mode(s) of action are sometimes limiting. The more simplified and qualitative approach of Berenbaum and Laska offers options including variations of Loewe additivity and tests for significance (Figure 15.1). 

Response equal to prediction Loewe additivity Bliss independence Inertism Inertism... 

G. H. Loew, A. T. Pudzianowski, A. Czerwinski, J. E. Ferrell Jr., Mechanistic Studies of Addition of Nucleophiles to Arene Oxides and Diol Epoxides Candidate Ultimate Carcinogens , Int. J. Quantum Chem. 1980, 7, 223 - 244. 

The concept of concentration addition (CA) looks at mixture effects of chemicals in terms of a dilution principle. It assumes that 1 chemical can be replaced totally or in part by an equal fraction of an equi-effective concentration of another (hence the term similar action ), without diminishing the overall combined effect (Loewe and Muischneck 1926). If the assumption of CA holds true, these fractions of equi-effective concentrations, which are also called toxic units, sum up to a value of 1—thus the name dose or concentration addition. CA implies that every chemical in any concentration contributes to the overall toxicity of a mixture. Whether the individual doses are also effective alone does not matter. Thus, combination effects should also result from chemicals at or below effect thresholds, provided sufficiently large numbers of components sum up to a sufficiently high total effect dose. 

The membrane dipole potential ( d) can be measured using voltage-sensitive fluorescent probes. The use of di-8-ANEPPS for this purpose was first suggested by Loew and co-workers, who noted that the addition of 6-ketocholestanol, known to increase Wd, and phloretin, known to decrease fl d, to di-8-ANEPPS-bound man-branes caused a blue and a red shift, respectively, in the fluorescence excitation spectrum of the dye [13]. 

Toxicity tests were conducted according to the standard procedures (ASTM 1980) and have been described in detail previously (Broderius and Kahl 1985). Briefly, juvenile fathead minnows (Pimephales promelas) were placed in continuous-flow diluters having five treatment concentrations and a control for each test. Mortalities were recorded daily, and the estimated median lethal concentration (LC50) was determined after 96 hours. Binary mixtures of chemicals were tested at ratios of 5 0, 4 1,2 1,1 1,1 2,1 4, and 0 5. The 96-hr LC50 of these binary mixtures were used to construct isoboles (Loewe 1953, 1928) of joint toxic action. The procedures used to analyze results by concentration or response addition models are according to those proposed by Finney (1971) and Anderson and Weber (1975). 

Only estimates of the numbers of compounds tested as chemosterilants can be offered. Since 1955, when insect sterility acquired a certain economic potential, close to 10,000 compounds have been screened in various USDA laboratories, primarily in house flies, screwworms, Mexican fruit flies Anastrepha ludens Loew), and boll weevils Anthonomus grandis Bohe-man). Some 600 of these compounds had more or less pronounced streiliz-ing effects, and many were further tested in over 100 species of insects and other organisms. Possibly thousands of additional compounds were screened in other laboratories here and abroad, but an exact count of the active and inactive compounds has not been made. By the end of 1972, more than 1000 insect chemosterilants were described in the scientific literature. This number is more than twice that listed in a survey published by Borkovec (1966). 

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