Fundamental Toxicological Sciences

2016 - Vol. 3 No. 5

2016 - Vol. 3

Combined effect of circadian dysfunction and cadmium on immune suppression Vol.3, No.5, p.237-242
Katsumi Ohtani , Atsushige Ashimori , Yukie Yanagiba , Hiroki Yoshioka , Tatsuya Hasegawa , Gi-Wook Hwang , Masayuki Ikeda , Nobuhiko Miura
Released: October 04, 2016
Abstract Full Text PDF[344K]

Most living beings including human beings have endogenous 24-hr rhythms, called circadian rhythms. The most important factor to alter the circadian rhythms is light. Therefore, this biological rhythms can easily disrupt by exposure to light at night (LAN). In modern society, rotating shift work with night work (night shift work) is essential working arrangement and induces circadian disruption to workers by LAN exposure. Epidemiologic studies indicate that a long-term biological rhythm disruption induced by a long-term LAN exposure causes many serious health disorders including immune dysfunction. Cd also dysregulates the immune system. Main exposure source of Cd is tobacco smoking and food intake in living environment. Further, in work places with handling Cd, occupational environment also be an exposure source with high concentration of Cd. In this report, we paid attention to and examined the combined effect of Cd and LAN on immune system. Mice were kept under the light/dark shift condition and/or injected CdCl2 (0.33 or 1.0 mg/kg) twice a week for 4 weeks followed by sacrificing 7 days after the last injection. The mitogen activity induced by phytohemagglutinin was markedly reduced by shift condition; further, this reduced mitogen activity was completely inhibited by additional Cd treatment. This result indicates a possibility of enhancement of immune dysfunction by Cd and LAN combination. Our result suggests that Cd exposure when being the circadian disruption had potential for more inhibition of immune function.

Hepatoprotective effect of kampo formula “Juzen-taiho-to” on bromobenzene-induced toxicity in mice Vol.3, No.5, p.233-236
Hiroki Yoshioka , Shiori Fukaya , Nobuhiko Miura , Akito Nagatsu , Tsunemasa Nonogaki
Released: September 10, 2016
Abstract Full Text PDF[278K]

Acute liver disease may develop due to various causes and occur by different mechanisms. Carbon tetrachloride (CCl4), a well-known hepatic toxicant, was selected as a model of alkylating agents that do not induce glutathione depletion. Our previous study indicated CCl4-induced hepatotoxicity was decreased by pretreatment with the Japanese herbal medicine “Juzen-taiho-to” (JTX), suggesting that prophylaxis with JTX protects mice from CCl4-induced acute hepatic toxicity. In contrast, bromobenzene (BB) is a known glutathione-depleting agent. Although BB-induced hepatotoxicity also promotes lipid peroxidation, the mechanism of hepatic injury is different from that of CCl4. Hence, in this study, we investigated whether pretreatment with JTX ameliorated BB-induced hepatotoxicity. Mice injected with BB showed increased plasma levels of hepatic injury markers (alanine aminotransferase and aspartate aminotransferase) in addition to hepatic lipid peroxidation. Pretreatment with JTX decreased BB-induced plasma levels of hepatic injury markers. BB-induced hepatotoxicity is mainly caused by oxidative stress. JTX pretreatment also decreased BB-induced lipid peroxidation. Our results suggest that JTX has the potential to protect against BB-induced hepatotoxicity and modulate oxidative stress.

Ocular instillation toxicity study: current status and points to consider on study design and evaluation Vol.3, No.5, p.217-232
Masaaki Kurata , Ikuyo Atsumi , Yoshinori Yamagiwa , Hideyuki Sakaki
Released: August 18, 2016
Abstract Full Text PDF[285K]

Ocular instillation toxicity studies (OITSs) are one of general toxicity studies. Yet, OITSs have a unique characteristic that the test article is directly administered as eye drops to the target organ. Compared with general toxicity studies aiming systemic exposure, the study design of OITSs is somewhat distinctive in selecting test species, dosing formulation, administration volume/frequency and ocular examinations. After the administration of eye drops, the exposure level is high in the ocular surface, whereas the bioavailability in the eye balls, especially in the posterior segment, is low. In contrast to the general toxicity studies aiming systemic exposure, the absolute systemic exposure level in OITSs is generally low, while the systemic bioavailability is relatively high. These pharmacokinetic features determine the profiles of local and systemic toxicities in OITSs. Systemic toxicities are more often found in animals of relatively small body size, and are in most cases related with pharmacological actions. Current progress in ophthalmologic imaging technologies enables advanced safety evaluation using imaging biomarkers. Bioanalysis detecting drug levels present in blood in trace amount leads to a detailed safety assessment of systemic toxicity and yields accurate safety margins. Recognizing the peculiar characteristics of OITSs, toxicologists need to propose an appropriate study design and strategy of safety evaluation. Further discussion may be awaited on rationales for testing both sexes, and for conducting separated toxicity studies to evaluate systemic toxicity. This mini-review provides insight regarding current status and points to consider of OITSs.

Original Article
In vitro and in vivo toxicological assessments of Antrodia cinnamomea health food product (Leader Antrodia cinnamomea Capsule) Vol.3, No.5, p.205-216
Yu-Hsing Lin , K.J. Senthil Kumar , M. Gokila Vani , Jiunn-Wang Liao , Chin-Chung Lin , Jong-Tar Kuo , Sheng-Yang Wang
Released: August 02, 2016
Abstract Full Text PDF[234K]

A unique medicinal mushroom Antrodia cinnamomea has been used for centuries to treat various human diseases. Recent studies revealed its potent pharmacological effects including anti-cancer, anti-inflammation, anti-oxidant, anti-diabetic, neuroprotection and hepatoprotection. The present study was aimed to investigate the toxicological effects of A. cinnamomea health food product “Leader Antrodia cinnamomea Capsule (LACC)” by measuring its genotoxic, oral toxic and teratotoxic effects in vitro and in vivo. Result of Ames test with 5 strains of Salmonella typhimurium shows no sign of increase in the numbers of revertant colonies upon exposure to LACC. Treatment of Chinese Hamster Ovary cells (CHO-K1) with LACC did not affect increase in the frequency of chromosomal aberration in vitro. In addition, treatment with LACC did not affect the proportions of immature to total erythrocytes and the number of micronuclei in the immature erythrocytes of ICR mice. Moreover, acute oral toxicity (14-days single-dose) or prolonged oral toxicity (28- and 90-days repeated oral dose) tests with rats showed that there were no observable adverse effects were found. Furthermore, teratological studies with LACC (500-2500 mg/kg/day) for 20 days, shows no observable segment II reproductive and developmental toxic evidences in pregnant SD rats and their fetus. These toxicological assessments strongly support the safety efficacy of LACC for human consumption.

Original Article
Acute toxicity of phorate oxon by oral gavage in the Sprague-Dawley rat Vol.3, No.5, p.195-204
Thomas H. Snider , Kevin G. McGarry , Michael C. Babin , David A. Jett , Gennady E. Platoff Jr. , David T. Yeung
Released: July 22, 2016
Abstract Full Text PDF[4M]

The oral toxicity of phorate oxon (PHO), with emphasis on gender- and age-related effects, was characterized in the Sprague-Dawley rat. The oral LD50 (95% fiducial limits) for PHO in corn oil was 0.88 (0.79, 1.04) mg/kg in males and 0.55 (0.46, 0.63) mg/kg in females with a probit slope of 15. Females had higher baseline blood cholinesterase titers, but males were significantly more tolerant. Younger rats generally had lower absolute cholinesterase blood titers. However as PHO challenges increased, baseline-normalized cholinesterase inhibition was independent of age and gender. Butyrylcholinesterase (BChE) and especially acetylcholinesterase (AChE) in brains of younger females were affected more than that in either males or older females. In summary, while female rats, especially older females, had higher titers relative to males, female rats were more susceptible in terms of absolute cholinesterase inhibition and 24‑hr lethality data, but the differences were not observed when titers were normalized to baseline levels.