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Experimental Lung Carcinogenesis by Intratracheal Instillation
Published in Joan Gil, Models of Lung Disease, 2020
Although data directly comparing the lung carcinogenicity of inhaled and instilled substances are limited, a definite tendency can be noticed. Substances listed in this chapter as carcinogenic to the lung after IT instillation did not always show lung carcinogenicity after inhalation, whereas substances that were carcinogenic to the lung after inhalation always showed lung carcinogenicity after IT instillation. Moreover, only strong carcinogens, such as radionuclides, were able to induce lung tumors after both IT instillation and inhalation in three species—hamsters, rats, and mice—although hamsters and mice developed low incidences of lung tumors after inhalation. Other substances reviewed in this article showed lung carcinogenicity only in rats after both IT instillation and inhalation. In hamsters, some substances, such as B(a)P or arsein, showed lung carcinogenicity after IT instillation but not after inhalation. Lung carcinogenicity of substances administered by IT instillation or inhalation in rats and hamsters is listed in Table 1.
Quick Methods: Structure-Activity Relationships and Short-Term Bioassay
Published in Samuel C. Morris, Cancer Risk Assessment, 2020
Craig and Enslein (1981) note, for example, that a potent carcinogen such as aflatoxin B1 can clearly be termed “carcinogenic,” but it is difficult to make such a positive and conclusive assignment for weaker carcinogens. Available data from animal experiments leaves much to be desired for structural activity comparisons. The cost and time involved in animal testing limits the amount of data available. Data limitations result in all the data being used for model development, leaving none for validation (see Chap. 15). The number of animals that can practically be included in such experiments limits the reliability of the results. Differences among species create confusion; a compound may cause tumors in one species but not another or cause tumors in different tissues in different species. At least with current knowledge, SAR is oversensitive. There are structural characteristics which are common to most organic chemical carcinogens (Table 10-1). Presence of one of these characteristics in a compound is suggestive of carcinogenicity, but each characteristic also appears in noncarcinogens. So the suggestion is merely tentative and must be confirmed by bioassay (Ashby, 1985). SAR can prove a useful prescreening method, however, for identifying and setting priorities for the more expensive and lengthy bioassays.
Nonclinical Safety Evaluation of Drugs
Published in Pritam S. Sahota, James A. Popp, Jerry F. Hardisty, Chirukandath Gopinath, Page R. Bouchard, Toxicologic Pathology, 2018
Thomas M. Monticello, Jeanine L. Bussiere
In those cases in which the biopharmaceutical product is biologically active and nonimmunogenic in the rodent model, and where other ancillary studies have not provided sufficient information to allow an assessment of carcinogenic potential, additional experimentation is warranted, which should be hypothesis driven and could include a variety of experimental approaches. Alternatives to evaluating carcinogenicity are continually being explored. Ultimately, it is important that the nonclinical carcinogenic data obtained provide useful guidance in product labeling (Vahle et al. 2010).
Biomedical application of chondroitin sulfate with nanoparticles in drug delivery systems: systematic review
Published in Journal of Drug Targeting, 2021
Abebe Feyissa Amhare, Jian Lei, Huan Deng, Yizhen Lv, Jing Han, Lei Zhang
Cytotoxicity is referring to the quality of being toxic to cells. If cells are treated with the cytotoxic compound, it may lose membrane integrity and even rapidly die (undergo necrosis) due to cell lysis. The cells can stop actively growing and decrease in cell viability [62]. The cytotoxicity test is one of the biological evaluations by using cells in vitro to observe cell growth and morphological changes by developed drugs [63–65]. It has a series of advantages along with the preferred and mandatory items [64]. Cytotoxicity testing is important in ensuring safety ranging from environmental exposures to medical devices [66]. The previous study reported that cytotoxic drugs can kill cancer cells but they can also damage normal cells which are considered as the side effects of most chemotherapy drugs [67]. So, precautions are recommended specifically to avoid carcinogenicity and mutagenicity.
Systematic review of the potential respiratory carcinogenicity of metallic nickel in humans
Published in Critical Reviews in Toxicology, 2020
Robyn L. Prueitt, Wenchao Li, Yu-Chi Chang, Paolo Boffetta, Julie E. Goodman
Our analysis of the in vitro mechanistic evidence for metallic nickel carcinogenicity highlights the importance of a systematic evaluation of the literature for mechanistic evidence that considers the quality and RoB, as well as the relevance of each study, and is integrated with the human and experimental animal evidence to support a causal conclusion. Simply noting that a substance can induce certain changes in cells that are consistent with mechanistic pathways associated with carcinogenesis or tumor progression does not provide strong evidence of carcinogenicity. An example of this is IARC's "key characteristics of carcinogens" approach to evaluating mechanistic evidence for carcinogenicity (Smith et al. 2016; Guyton et al. 2018). This approach involves a set of 10 characteristics that are common to known human carcinogens. If a study of a substance has a positive finding for one of these characteristics, one may conclude that it supports some level of evidence for that characteristic. Although metallic nickel has been shown to have some of the 10 characteristics in certain (mostly in vitro) studies (e.g. some types of genotoxicity, induction of oxidative stress), it is not apparent until one evaluates the quality and relevance of these studies, and how they inform what is known from the human and experimental animal evidence (and vice versa), that these positive results do not support metallic nickel as a human carcinogen (Goodman and Lynch 2017).
Biological detoxification of ochratoxin A in plants and plant products
Published in Toxin Reviews, 2019
Mahmoud Sheikh-Zeinoddin, Mohammadreza Khalesi
OTA is considered in the category of carcinogens “group 2B”. The mechanism of its carcinogenicity is not related to DNA reactivity but mostly associated with its role in genome instability via upsetting the cell division, causing undesirable changes in chromosome segregation, accordingly forming the tumor cells (Rached et al. 2006, Adler et al. 2009). The transformation of OTA to OTα is a recognized detoxification way, as OTα is almost a thousand-fold less toxic than OTA to brain cells (Bruinink et al. 1998). The half-life elimination of OTα in the body is approximately 10 times shorter than OTA (Li et al. 1997) and possesses no effect as an immune-suppressor in mice (Abrunhosa et al. 2006). Therefore, OTα is considered as a nontoxic ochratoxin (Abrunhosa and Venâncio 2007). Nevertheless, the isocoumarin moiety of OTA may interfere the metabolisms of proteins and ATP (Xiao et al. 1996).