China
Africa
Explore chapters and articles related to this topic
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.
Approaching a closer surrogate for the biologically effective dose with subcellular partitioning-based toxicokinetic models
Published in Critical Reviews in Environmental Science and Technology, 2023
T. T. Yen Le, Olivier Geffard, Alain Geffard, Willie J. G. M. Peijnenburg
Toxicokinetics and toxicodynamics are complementary components of toxicology. Toxicokinetics describe the effects that an organism exerts on a toxicant, while toxicodynamics show the effects that the toxicant exerts on the organism. The former addresses absorption, distribution, metabolism (biotransformation), and excretion of the toxicant, whilst the latter refers to the interactions between the toxicant and its target sites, which trigger toxicity (Escher & Fenner, 2011). Ideally, the toxicokinetic phase in TK-TD models provides estimates of the concentration of the toxicant at sites of toxic action. However, in most of the available models, toxic effects are related to the total internal concentration, excluding the significance of subcellular metal sequestration (Ashauer et al., 2013; Feng et al., 2018; Gao et al., 2015).
Development of a database on key characteristics of human carcinogens
Published in Journal of Toxicology and Environmental Health, Part B, 2019
Mustafa Al-Zoughool, Michael Bird, Jerry Rice, Robert A. Baan, Mélissa Billard, Nicholas Birkett, Daniel Krewski, Jan M Zielinski
Properly validated biomarkers corroborated in multiple studies might be utilized for cancer prognosis, and in defining strategies to reduce cancer-related morbidities and mortality (Ulrich and Ambrosone 2008). Genome-wide association investigations have been used to find genetic biomarkers associated with poor prognosis as in colorectal cancer (Bacolod and Barany 2011). Variation in cancer susceptibility is one of the toxicological endpoints considered in the current review, although it was not linked directly to any of the key characteristics of human carcinogens. Susceptibility is an important biomarker of a range of host factors mainly controlled by variations in genotype that affect the host response to carcinogenic agents. This endpoint potentially modulates each of the 10 key characteristics. It is an essential component of molecular epidemiological studies to understand inter-individual differences in susceptibility to chemically induced cancer. Low-penetrant but highly frequent gene-allele variations controlling toxicokinetics (cytochrome p450; Gold et al. 2009), and to a lesser extent toxicodynamics (estrogen receptor; Zheng et al. 2003), play an important role in population-attributable risk in chemical carcinogenesis. Variants in other genes contributing to cellular dysfunction such as RAS, TP53 or BRCA1 make even stronger contributions to individual susceptibility to cancer. Knowledge of individual genetic variations provides opportunities for more effective and individualized cancer therapy (Safgren et al. 2015).