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Review of the Human Health Toxicology and Ecotoxicology of 1,4-Dioxane
Published in Thomas K.G. Mohr, William H. DiGuiseppi, Janet K. Anderson, James W. Hatton, Jeremy Bishop, Barrie Selcoe, William B. Kappleman, Environmental Investigation and Remediation, 2020
Janet K. Anderson, William B. Kappleman
The available human data for 1,4-dioxane are limited to studies primarily on the health risks following inhalation exposure in occupational exposure settings and volunteer studies. There are no oral 1,4-dioxane exposure studies in humans. There have been two case reports of acute occupational poisonings with 1,4-dioxane, showing that exposure to high concentrations resulted in liver, kidney, and central nervous system toxicity (Barber, 1934; Johnstone, 1959). Barber (1934) described a small number of deaths that occurred among factory workers exposed to high (unspecified) concentrations of 1,4-dioxane via inhalation, and possibly dermal exposures. Post-mortem analyses revealed extensive lesions (hemorrhagic nephritis) in the kidneys, which was attributable as the cause of death, and centrilobular necrosis of the liver. Johnstone (1959) discussed one fatality following a worker exposed for 1 week to 208–650 ppm 1,4-dioxane, with a mean air concentration of 470 ppm. Post-mortem evaluation showed significant histopathological changes in the liver (centrilobular necrosis), kidney (hemorrhagic necrosis), and brain (perivascular widening with small foci of demyelination in the cortex and basal nuclei). Acute inhalation studies in human volunteers show that acute exposure (a few minutes) to concentrations of 1,4-dioxane >200 – 5,500 ppm results in irritation of the eyes, nose, and throat, as well as vertigo (Yant et al., 1930; Wirth and Klimmer, 1936; Silverman et al., 1946; Young et al., 1977). Two studies reported no symptoms after exposure to 1,000–2,000 ppm 1,4-dioxane vapors for 3–5 min (Fairley et al., 1934) or to 20 ppm 1,4-dioxane for 2 hours (Ernstgård et al., 2006).
Clinical Toxicology of Copper
Published in Debasis Bagchi, Manashi Bagchi, Metal Toxicology Handbook, 2020
Sonal Sekhar Miraj, Mahadev Rao
In animals, the daily maximum tolerable dose is around 250,000 mcg Cu/kg (Haywood and Loughran 1985). The dose of Cu exceeding this causes severe hepatic centrilobular necrosis. Both species of animal and type of Cu compounds determine toxicity with Cu. Sheep, dogs, and cats are the most sensitive species compared to rodents, pigs, and poultry (Ishmael et al. 1971; Andrews et al. 1990). On the other hand, compared with rats, mice exhibit more resistance toward cupric sulfate toxicity (Hebert et al. 1993). Moreover, dogs have higher susceptible to Cu overload than humans because of variations in the metabolism of Cu (Twedt et al. 1979).
Evaluation of the carcinogenicity of carbon tetrachloride
Published in Journal of Toxicology and Environmental Health, Part B, 2023
Samuel M. Cohen, Christopher Bevan, Bhaskar Gollapudi, James E. Klaunig
While CYP2E1 is the primary enzyme associated with CCl4 bioactivation, CYP3A was reported to be involved in its metabolism under high-dose conditions (Raucy, Kraner, and Lasker 1993). The linkage between metabolism of CCl4 by CYP2E1 and resulting liver toxicity was examined using inducers and inhibitors of CYP450. Sipes, Krishna, and Gillette (1977) found that CCl4 metabolism was inducible by phenobarbital or ethanol. Studies with general CYP450 inhibitors such as SKF-525A inhibited the metabolism of CCl4 and also prevented liver damage (Letteron et al. 1990). Similarly, Wong, Chan, and Lee (1998) using CYP2E1 null mice examined the role of CYP2E1 in CCl4-induced liver toxicity. Using wild-type mice, Wong, Chan, and Lee (1998) demonstrated that CCl4 induced a significant rise in serum ALT and AST along with centrilobular necrosis in the liver 24 hr following an i.p. dose of 1 ml/kg CCl4. In contrast, the same CCl4 treatment to CYP2E1 null mice exerted no marked effect on liver enzymes or histopathology. Several investigators reported that liver cell lines that over-express CYP450 enzymes contain elevated levels of CCl4-induced cytotoxicity (Dai and Cederbaum 1995; Takahashi et al. 2002).
Capecitabine-loaded anti-cancer nanocomposite hydrogel drug delivery systems: in vitro and in vivo efficacy against the 4T1 murine breast cancer cells
Published in Journal of Biomaterials Science, Polymer Edition, 2020
Nastaran Taleblou, Mohammad Sirousazar, Zuhair Muhammad Hassan, Sahar Ghaffari Khaligh
In the selected animal of group N (Figure 9(e,f)), focal necrosis in hepatocyte nearby centrilobular zone with mild diffuse fatty degeneration was observed. Mammillary adenocarcinoma was also found. Focal centrilobular necrosis was distinguished by red cytoplasm and pyknotic nuclei. The grade of metastatic adenocarcinoma cells is +1. Furthermore, interstitial pneumonia with hyperemia and a few focal metastatic adenocarcinoma cells around the bronchial veins were observed in the lung. Based on the histopathological images, it can be deduced the prepared NHDDSs can control the metastasis better than the pure CAP with lower toxic effects on the normal cells. In general, the histopathological observations confirmed the superior anti-cancer efficacy of the prepared NHDDSs on cancer cells of the animal models as compared with the pure CAP.
Hesperetin upregulates Fas/FasL expression and potentiates the antitumor effect of 5-fluorouracil in rat model of hepatocellular carcinoma
Published in Egyptian Journal of Basic and Applied Sciences, 2020
Merna G. Aboismaiel, Mohamed El-Mesery, Amro El-Karef, Mamdouh M. El-Shishtawy
Success of HCC induction by TAA at the selected dose was proved by marked elevation of AFP level and the increased number and size of tumor nodules appearing in histopathological examination of liver tissue. TAA was largely demonstrated as a powerful hepatic toxin causing centrilobular necrosis accompanied by increased serum levels of ALT, AST and bilirubin [28]. Its chronic application results in cirrhosis and development of HCC in animals under experiment [29]. TAA is converted to TAA sulfoxide, which is again metabolized to produce a more reactive S, S-dioxide metabolite that can attack lipids and proteins. These reactive metabolites and free radicals produced during TAA oxidation are involved in alteration of cell permeability and inhibition of mitochondrial activity followed by cell death [30].