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Early Methods Applied To Drug Combination Studies
Published in Marshall N. Brunden, Thomas J. Vidmar, Joseph W. McKean, Drug Interaction and Lethality Analysis, 2019
Marshall N. Brunden, Thomas J. Vidmar, Joseph W. McKean
The earliest contributions from the statistical field appear in the late 1930s. Bliss2 was one of the forerunners in the area of insecticide combination analysis. He proposed three types of actions that chemicals follow when used in combination where the dependent variable is dichotomous. The first he termed independent joint action. When chemicals are used in combination and follow this action, they are said to have different modes of toxic action and act independently of one another. This form of action may be stated in terms of the proportion of test insects that die in an experiment:
Computational Modeling to Predict Human Toxicity
Published in Brian J. Lukey, James A. Romano, Salem Harry, Chemical Warfare Agents, 2019
Janet Moser, Douglas. R. Sommerville, George. R. Famini
As defined by the U.S. Society of Toxicology (Society of Toxicology, 2005; Wexler et al., 2014):Toxicity is the adverse end product of a series of events that is initiated by exposure to chemical, physical, or biological agents. Toxicity can manifest itself in a wide array of forms, from mild biochemical malfunctions to serious organ damage and death. These events, any of which may be reversible or irreversible, include absorption, transport, metabolism to more or less toxic metabolites, excretion, interaction with cellular macromolecules, and other modes of toxic action.
Caenorhabditis elegans as a tool for environmental risk assessment: emerging and promising applications for a “nobelized worm”
Published in Critical Reviews in Toxicology, 2019
L. Queirós, J. L. Pereira, F. J. M. Gonçalves, M. Pacheco, M. Aschner, P. Pereira
Table 1 depicts a summary with the strengths and limitations of C. elegans as an experimental model organism in biomedical research, as well as an appraisal of the features that can concomitantly be valuable for understanding the worm as a model in ERA. The promotion of this nematode species as a laboratory model in medical fields stems from several internal and external attributes that have been making the research with this species particularly fruitful. The knowledge of its complete genome sequence bearing conserved gene sequences, and the peculiar sharing of signaling pathways and cellular machinery for DNA replication and repair between C. elegans and humans (Table 1) are worth noting in this context. These are key attributes for the investigation of the modes of toxic action and disease pathways, which are frequently similar between humans and this invertebrate model (Cole et al. 2004; Kaletta and Hengartner 2006; Leung et al. 2008; Destefani et al. 2017). The available mutant and transgenic C. elegans strains (Table 1) are also very useful to mechanistically clarify modes of action, oxidative stress pathways, DNA damage patterns, and neurodegeneration (Corsi et al. 2015; Hunt 2016). As an organism with metabolically active digestive, reproductive, endocrine, sensory, and neuromuscular systems (Table 1), C. elegans responds as a functional multicellular and multisystems unit in the toxicity assays. Furthermore, the logistics involved in culturing and testing with C. elegans is relatively easy to handle, which mostly derives from the species biological and physiological characteristics (Table 1). The nematode has a life cycle that extends only for 3.5 days when incubated at 20 °C (Figure S1). The organisms of this species are mostly self-fertilizing hermaphrodites, meaning that only one animal is needed to populate an entire plate. Only 0.1–0.2 % of the population produced by self-fertilization are males as consequence of the rare meiotic non-disjunction of the X chromosome, with most of the tests being carried out with hermaphrodites even though tests with males can also be done depending on the research hypothesis. As integrated in ERA, tests with hermaphrodites would, thus, be the most straightforward option following, with the advantage of supporting comparison to previous data, but sex-specific effects can also be tested particularly at higher ERA tiers where population and community studies are typically considered for a better and more direct insight on ecological responses (see Figure 1). C. elegans can be cultured within a large interval of temperature, ranging from 12 to 25 °C, meaning that its growth rate can be controlled by manipulating the temperature within this range. In vivo toxicity assays with the organism can be performed within a short time period and using simple equipment. Moreover, they are cheaper and faster than the tests available with rodent models (Hunt 2016). All mentioned features are also valuable in the environmental sciences field, specifically regarding integration in ERA approaches.