Introduction
Frank A. Barile in Barile’s Clinical Toxicology, 2019
The classic definition of toxicology has traditionally been understood as the study of xenobiotics, or simply as the science of poisons—that is, the interaction of exogenous agents with mammalian physiological compartments. For purposes of organizing the nomenclature, chemicals, compounds, or drugs are often referred to as agents. And since such agents have the ability to induce undesirable effects, they are usually referred to as toxins. Yet, most agents were justifiably initially used for benevolent purposes. The desire to seek remedies eventually led to the discoveries that therapeutic drugs also did harm. Thus, this text uses terms such as agent, chemical, drug, or toxin interchangeably, depending on the application. Consequently, toxicology involves internal and external physiological exposure to toxins and their interactions with the body’s compartments. With time, the nomenclature has evolved to include many chemically unrelated classes of agents. What transforms a chemical into a toxin depends more on the length of time of exposure (duration), the dose (or concentration) of the chemical, and the route of exposure as well as the chemical structure, product formulation, or intended use of the material. As a result, almost any chemical has the potential for toxicity and thus, falls under the broad definition of toxicology.
Nonclinical Safety Evaluation of Drugs
Pritam S. Sahota, James A. Popp, Jerry F. Hardisty, Chirukandath Gopinath, Page R. Bouchard in Toxicologic Pathology, 2018
In the 1920s, J.W. Trevan proposed an experiment in mice to determine the dose of a chemical that would cause a 50% death rate, termed the median lethal dose (LD50). Pharmacologists branching into toxicology subsequently proposed acute testing in several species, on the basis of observations regarding species differences in responsiveness to both the pharmacologic and acute toxic effects of chemicals. When the guidelines for repeat-dose toxicity experiments were developed in the early 1940s, the concept of using more than one species was automatically included. In response to demands from the US FDA and other national and international regulatory bodies in the 1960s, the protocols for toxicology testing became highly formalized with requirements to conduct all studies in a rodent and non-rodent species (Zbinden 1993). Because of advances in animal toxicology study designs and endpoints, the LD50 approach is no longer utilized because we no longer need to depend on crude estimates of achieving lethality.
Introduction to Toxicology
David Woolley, Adam Woolley in Practical Toxicology, 2017
Toxicology is a very broad discipline, requiring broad expertise in a number of areas, including chemistry, pharmacology, physiology, biochemistry, anatomy, and numerous others. Definitions of toxicology tend to emphasize the role of exogenous substances or xenobiotics (literally foreign chemicals), while implicitly ignoring the contribution to toxic effect that can be seen with endogenous substances. The overproduction of endorphins in athletes and resulting runners’ high is an example of this; the storage of various proteins in Alzheimer’s disease is another. While many drug development candidates are clearly nonendogenous (xenobiotic), it may be prudent to consider unnaturally high concentrations of an endogenous substance in an unusual location to be xenobiotic too. It should also be considered that toxicity of a substance varies from subject to subject and a toxic reaction can occur from exposure to a normally nonnoxious substance, such as peanuts.
Hazards of current concentration-setting practices in environmental toxicology studies
Published in Critical Reviews in Toxicology, 2023
Jeffrey C. Wolf, Helmut E. Segner
It is somewhat ironic that much of scientific progress relies on imitation, for without it, we would needlessly reinvent the wheel (as opposed to creating a better wheel), with all the associated costs in time and resources that would entail. Periodically, however, it is important to reassess the established methodologies we imitate, to ensure that the wheel that we design is not based on flawed structural principles. The origin of the median lethal dose (LD50) is credited to a paper by J. W. Trevan in 1927, in which the author described a method for determining the relative toxicity of therapeutic substances that were not readily available as pure chemicals (Trevan 1927; Rowan 1983). Well-recognized in the toxicology field, this venerable approach involves the short-term (e.g. 96-h) exposure of a group of experimental animals to varying quantities of a test substance to determine the dose at which 50% of the subjects die. Fast forward to the twenty-first century, and the LD50 or LC50 (median lethal concentration, which is used more commonly in aquatic toxicology where exposures often occur via ambient water), has become the de facto launch pad for investigating the toxic effects of myriad chemicals in myriad animal species (not to mention a kick starter for the careers of myriad graduate students). In fact, according to one recent survey, the fish acute toxicity test (OECD 2019) is by far the most commonly employed regulatory guideline assay conducted in vertebrates (Burden et al. 2017).
Toxicity dose descriptors from animal inhalation studies of 13 nanomaterials and their bulk and ionic counterparts and variation with primary particle characteristics
Published in Nanotoxicology, 2023
Niels Hadrup, Nicklas Sahlgren, Nicklas R. Jacobsen, Anne T. Saber, Karin S. Hougaard, Ulla Vogel, Keld A. Jensen
We gathered data from animal inhalation studies available in the scientific literature for 13 groups of nanomaterials sorted by primary element (Ag, C, Ce, Co, Cu, Fe, Ni, Si, Ti, and Zn). We also collected data on their bulk and ionic counterparts. We selected the following endpoints of toxicity: (1) pulmonary inflammation in terms of neutrophil numbers in bronchoalveolar lavage (BAL) fluid at the end of the experiment (or up to 24 hours later); and (2) genotoxicity and carcinogenicity at any time point after exposure. We selected inhalation as an important route of exposure because we consider the airways the most critical organ of exposure in particle toxicology, especially in the occupational setting. The specific endpoints of inflammation and genotoxicity/carcinogenicity were selected because they are important toxicological endpoints for setting occupational exposure limits (OELs). An example of the importance of these endpoints is from Sweden where Effects on the respiratory system (other than irritation of upper passages) was the second-most assigned critical effect in the period from 1979 to 1994. Irritation of eyes and mucous membranes was the most assigned critical effect, while cancer was the third most assigned critical effect (Hansson 1997). These assessments were made by scientists that evaluated the available scientific and medical information on substances for setting national OEL’s.
Development of reliable quantitative structure–toxicity relationship models for toxicity prediction of benzene derivatives using semiempirical descriptors
Published in Toxicology Mechanisms and Methods, 2023
Ayushi Singh, Sunil Kumar, Archana Kapoor, Parvin Kumar, Ashwani Kumar
Toxicokinetic studies are required to link the dose or chemical concentration to the chemical’s mode of action and its different metabolites. Toxicology investigations in vivo and in vitro are used to determine the toxicity of chemical substances (Jain et al. 2018). Animal-based preclinical safety investigations are time-consuming and expensive. There exists a tremendous call for alternative toxicology methods, such as in silico techniques to predict toxicity in order to reduce the use of animals. Soft predictive toxicology (a study involving the prediction of toxicity using in silico methods) is expected to reduce resource waste, regulatory review load, animal use, eliminate the need for interspecies uncertainty factors, improve accuracy, sensitivity, and specificity, and forecast harmful effects that are not observable in animals (Kapetanovic 2008). The European Union’s chemical evaluation policy (REACH: Registration, Evaluation, and Authorization of Chemicals) has been a strong supporter of alternative in silico methods of predicting chemical toxicity in order to reduce animal testing and save time as well as resources (Simon-Hettich et al. 2006).
Related Knowledge Centers
- Adverse Effect
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- Toxicant
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- Evidence-Based Toxicology