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Treatments and Challenges
Published in Franklyn De Silva, Jane Alcorn, The Elusive Road Towards Effective Cancer Prevention and Treatment, 2023
Franklyn De Silva, Jane Alcorn
Studies evaluating the nutritkinetics (or pharmacokinetics (PK), the study of what the body does to the xenobiotic) [1357, 1358] and nutridynamics (or pharmacodynamics (PD), the study of what the xenobiotic does to the body) [1359] have provided critical understanding of the putative role of natural products in cancer treatment and prevention. As an area of study, nutrikinetics can additionally address the compositional complexity of dietary ingredients, types of diets, interindividual variation, metabolic profiling, interactions between the host metabolome and the microbiome as well as absorption, distribution, metabolism, and excretion of dietary items within the organism [1359] . When a xenobiotic results in toxicity, toxicokinetics is a term used to describe the processes by which the compound reaches a target tissue, while the subsequent responses that take place in the tissue once the toxic xenobiotic reaches an effective dose is called toxicodynamics [1360]. Understanding and describing the relationship between a natural product compound's pharmacophore (i.e., the three-dimensional, steric and electronic features that are required to guarantee an optimal supramolecular interaction with a biological target to display a response(s) [1361]) and its intended target(s) and/or off-targets with their cumulative dynamic effects on cells, tissues, organs, and an entire organism as well as the rate and extent of its absorption, distribution, and elimination is central to understanding the overall ability of a natural product to exert positive pharmacological outcomes in cancer.
Neurotoxicology
Published in Philip B. Gorelick, Fernando D. Testai, Graeme J. Hankey, Joanna M. Wardlaw, Hankey's Clinical Neurology, 2020
Sean D. McCann, Trevonne M. Thompson
Care of the patient with neurotoxicity should be approached from the framework used in the general care of the poisoned patient. Medical toxicology is rooted in a principle originally articulated by the 16th-century Swiss physician Paracelsus: “All things are poison, and nothing is without poison; the dosage alone makes it, so a thing is not a poison.” Substances considered benign or therapeutic may become toxic at high doses as is seen with water intoxication, which can present with severe hyponatremia, seizures, and hemolysis. At toxic doses, substances may have pharmacologic, pharmacodynamic, and pharmacokinetic properties that are different from those seen at physiologic or therapeutic concentrations. Thus, we refer to their toxicologic, toxicodynamic, and toxicokinetic properties in order to distinguish from the effects observed under normal or therapeutic conditions. Several aspects of care unique to the poisoned patient should be considered in the assessment and treatment of these individuals.
Hazard Characterization and Dose–Response Assessment
Published in Ted W. Simon, Environmental Risk Assessment, 2019
Toxicodynamics is the consideration of how a xenobiotic chemical interacts with tissues, cells, or biomolecules as part of the toxic response. Once a chemical distributes to the target tissue via ADME processes, it interacts with cells of that tissue to produce effects. For example, the binding of a DNA-reactive chemical to nucleic acid would be a toxicodynamic process. The initial biochemical event has been referred to as the molecular initiating event.199 This toxicodynamic event will certainly be a key event in the mode of action. Some risk analysts consider the MIE as too strong a term when insufficient evidence is available to link this presumably first biochemical event to downstream KEs; hence, the term initial molecular event may be more apt.
What can we learn from epidemiological studies on chronic boron exposure?
Published in Critical Reviews in Toxicology, 2023
Yalçın Duydu, Nurşen Başaran, Hermann M. Bolt
Both inter-species and inter-individual differences are subdivided into toxicokinetic and toxicodynamic aspects. In the case of boron, the default UF for inter-species differences of 10 (2.5toxicodynamic × 4toxicokinetic) is appropriate. However, toxicokinetic data are available to modify the default inter-individual uncertainty for boron. The glomerular filtration rate (GFR) in pregnant women is 144 ± 32 mL/min (Dourson et al. 1998). Accordingly, the human variability in GFR (the critical physiological process in boron clearance) during pregnancy is 1.8 (144/(144 – (2 × 32)). The default inter-individual uncertainty can be modified using this variability calculated for the GFR in pregnancy. The default inter-individual uncertainty is 10 (3.2toxicodynamic × 3.2toxicokinetic). When we modify this default inter-individual uncertainty, the resulting UF of boron is 6 (3.2 × 1.8 = 5.76 rounded up to 6). Accordingly, the composite UF of boron is 60 ((2.5animal-toxicodynamic × 4animal-toxicokinetic) × (3.2human-toxicodynamic × 1.8human-toxicokinetic)). This is the widely accepted chemical-specific adjustment factor for boric acid (Duydu et al. 2016).
Interactive effect of carbendazim and imidacloprid on buffalo bone marrow derived mesenchymal stem cells: oxidative stress, cytotoxicity and genotoxicity
Published in Drug and Chemical Toxicology, 2023
Harpreet Singh, Milindmitra Kashinath Lonare, Manjinder Sharma, Rahul Udehiya, Saloni Singla, Simrat Pal Saini, Vinod Kumar Dumka
A mixture can be defined as a combination of two or more environmental agents (Groten et al.2001, Sexton and Hattis 2007). The generated and co-incidental mixtures created in the environment are countless and their impact on human health is largely unknown. Interactions may take place in the toxicokinetic phase and/or in the toxicodynamic phase, which may be weaker (antagonistic) or stronger (potentiated or synergistic). The data of generalized and biochemical findings of the present study revealed that the mixture comprising of a fungicide and an insecticide affected the activity of the concerned enzymes, where lower combinations showed antagonism while high-dose combinations showed potentiation. The combination of IMI and CBZ treatment showed a less prominent effect on the parameters studied as compared to the sum of their individual effects, indicating that the predominant antagonistic effect was in a similar pattern as that of earlier reports on pesticides studies (Krishnan et al.1994, Mansour et al.2001). Agent-to-agent interactions, toxicokinetic and toxicodynamic interactions (Viau 2002, Mumtaz et al.2007, Sexton and Hattis 2007) have been described by a mathematical model to predict the type of toxicity of mixtures. Moreover, toxicity is not always simple to predict for mixtures because interaction may be influenced by the dose and the dose ratio, common cellular targets or metabolic pathways (Rashatwar and Matsumura 1985, Spurgeon et al. 2010).
Evaluation of genotoxicity induced by herbicide pendimethalin in fresh water fish Clarias batrachus (linn.) and possible role of oxidative stress in induced DNA damage
Published in Drug and Chemical Toxicology, 2022
Priyanka Gupta, Sushant Kumar Verma
Determination of median lethal concentration (LC50) can be considered as most useful criterion of toxicity. The 96 h- LC50 value of pendimethalin for C. batrachus was determined as 3.55 mg/L which is similar to those obtained by Ahmad et al. (2000) in Nile tilapia (3.55 mg/L). However it was found to be 0.19 mg/L in bluegill sunfish and 0.138 mg/L in rainbow trout (USEPA 1996). These observed differences in obtained values of LC50 for different species were may be due to age, size and health (Abdul Farah et al. 2004) or physico-chemical parameters of water (Eaton and Gilbert 2008). LC50 of different toxicants may also differ with different species because of differences in toxicokinetics as well as toxicodynamics between the species (Rubach et al. 2011). Toxicokinetics include ability of a species to regulate the uptake of toxicant, detoxify it and finally eliminate it whereas toxicodynamics include interaction of the toxicant with enzymes and ability to repair damage. Concentration and formulation of chemicals are also important factors which can be considered during determination of median lethal concentration of a toxicant (Young and Woodside 2001).