Fundamental Toxicological Sciences

2023 - Vol. 10 No. 3

2023 - Vol. 10

Toxicomics Report
Effect of cadmium on expression of BIRC family genes in HeLa cells Vol.10, No.3, p.133-136
Jin-Yong Lee , Maki Tokumoto , Gi-Wook Hwang , Masahiko Satoh
Released: May 30, 2023
Abstract Full Text PDF[1M]

Cadmium (Cd) is an environmental pollutant with toxic effects in various tissues, including the kidney. In our previous study, Cd changed the expression of baculoviral inhibitor of apoptosis protein repeat-containing (BIRC) family genes in human proximal tubular cells. BIRC family genes inhibit apoptosis, and inducing the apoptosis pathway is an approach for anticancer therapeutics. In this study, the effect of Cd on expression of BIRC family genes was examined in HeLa human cervical cancer cells. Cd treatment affected cell viability, increased BIRC5 and BIRC6 mRNA levels, and decreased the BIRC8 mRNA level in HeLa cells. These results indicate that a low dose of Cd changes the expression of several genes in the BIRC family in HeLa cells. Changes in the mRNA levels of BIRC family genes by exposure to Cd may affect cancer chemotherapeutic agents targeting the apoptosis pathway.

K16ApoE inhibits the activity of acetylcholinesterase but is not the primary toxicological mechanism in mice Vol.10, No.3, p.125-131
Linlin Shao , Toby M. Michelena
Released: May 30, 2023
Abstract Full Text PDF[1M]

The blood-brain barrier restricts the administration of drugs for neurological diseases. K16ApoE is an effective drug delivery carrier to deliver drugs across the blood-brain barrier, but it contains acute and high toxicity. The toxicity mechanism of K16ApoE must be revealed for clinical uses. Previous studies hypothesized that the toxicity mechanism was acetylcholinesterase inhibition in the brain. However, these studies used improper buffers in the AChE assay, further leading to anomalous results. Meanwhile, previous studies have not investigated the effects of K16ApoE on all the AChE-containing tissues and organs throughout the body. The previous dose design was also too narrow. Herein, we designed a more comprehensive and rational dose interval for K16ApoE, observed and recorded the mouse responses after receiving K16ApoE, and collected the brain, diaphragm, and serum to investigate the systemic K16ApoE effects on AChE. We also incubated purified AChE with K16ApoE in vitro. It could reveal the direct effect of K16ApoE on AChE without the influence of absorption and metabolism in vivo. The in vitro results demonstrated that K16ApoE inhibits rhAChE activity as the dose increases. However, the in vivo results demonstrated that K16ApoE does not affect tissue AChE activity in female mice. Therefore, we confirmed the AChE inhibitory effect of K16ApoE, but contrary to our hypothesis, AChE inhibition is not the toxicological mechanism of K16ApoE. We also recorded toxicological responses after the mice received K16ApoE, which would promote further toxicological investigation on K16ApoE.

Original Article
A trial to predict skin irritancy of cosmetic products using cytotoxicity tests Vol.10, No.3, p.113-123
Minori Mezaki , Chika Manabe , Junichiro Nagumo , Tomohisa Yoshimura , Tohru Nagahama , Hiroshi Itagaki , Akiko Takaoka
Released: May 12, 2023
Abstract Full Text PDF[1M]

Alternatives to animal testing are being used to assess the safety of raw ingredients during the process of developing cosmetics. However, since cosmetic products are composed of a variety of raw ingredients, the safety of the product itself should also be tested. In this study we attempted to evaluate the skin irritation potential of skin lotions by modifying existing alternative test methods. To evaluate the skin irritation potential of commercial skin lotions in the form of an objective indicator, we calculated their Irritation Score (IS) based on the results of searches using keywords related to skin irritation in review statements posted on Japanese cosmetics and beauty websites. We then modified the reconstructed human epidermis (RhE) test method to evaluate irritation by commercial skin lotions. The results showed that exposure to skin lotions with higher ISs tended to result in lower cell viability, and that exposure to many of the lotions with lower ISs resulted in higher cell viability. Next, we tried using an in vitro short-term exposure (STE) test method to assess the skin irritation potential of skin lotions. By changing the test-substance exposure concentrations and exposure times in the STE test method, we were able to obtain results that correlated with those obtained by the modified RhE test method. In conclusion, both alternative methods were helpful for assessing the possibility of developing skin irritation of skin lotions. They may also be useful for screening formulations being developed and as means of evaluation before proceeding to human patch tests.

A survey of on the use of genotoxicity and carcinogenicity testing packages for ophthalmic drug development Vol.10, No.3, p.105-112
Haruna Tahara , Yu Haranosono
Released: May 12, 2023
Abstract Full Text PDF[726K]

For the non-clinical safety evaluation of pharmaceuticals for new drug applications (NDA), various toxicity studies must be conducted at each stage, from clinical trials to NDA. For topically applied drugs, the level of exposure at the administration site is high because the drug is administered directly to the administration site. However, because systemic exposure to ophthalmic drugs is generally lower than that of systemic drugs, systemic effects may not be adequately assessed. The bone marrow and liver are generally evaluated after systemic administration in in vivo genotoxicity tests, and local genotoxicity studies are conducted on a case-by-case basis. Therefore, we surveyed packages of genotoxicity and carcinogenicity tests for ophthalmic drugs approved in Japan from 2004 to 2021 to assist in the decision of test packages for the development of ophthalmic drugs. There were no major differences in genotoxicity test packages compared to systemic drugs; however, an unscheduled DNA synthesis test using the cornea after ocular instillation was conducted in some products as a test specific to ophthalmic drugs. In the development of ophthalmic drugs, if a positive result is found in an in vitro genotoxicity test, the safety margin between the positive concentration and the clinically applicable concentration (eye drop concentration) is required for safety assessment. If the safety margin cannot be ensured, additional tests may support safety assessment.

Original Article
Derivation of human health hazard assessment values of 1,2-dichloroethane under the Japan Chemical Substances Control Law Vol.10, No.3, p.91-103
Akira Kawashima , Kaoru Inoue , Kazuo Ushida , Kaoru Kai , Hiroshi Suzuki , Lucia Satiko Yoshida-Yamashita , Akihiko Hirose , Kenichi Masumura
Released: April 14, 2023
Abstract Full Text PDF[706K]

1,2-Dichloroethane, a priority assessment chemical substance under the Japan Chemical Substances Control Law (CSCL), required a detailed human health hazard assessment under Assessment II. We evaluated its general, reproductive, and developmental toxicities, genotoxicity, and carcinogenicity, based on the hazard information provided by domestic and international risk assessment organizations, and the hazard assessment values (HAVs) for oral and inhalation exposure were proposed. For oral exposure, a 78-week gavage carcinogenicity study (US NCI, 1978) with incidence data of hemangiosarcoma in male rats was selected as a significant toxicological endpoint and the lower confidence limit of benchmark dose (BMD) at 10% benchmark response (BMDL10) of 9.3 mg/kg/day was obtained as a point of departure (POD). A slope factor of 1.07 × 10−2 (mg/kg/day)−1 from which a carcinogenic 10−5 risk of 0.93 µg/kg/day was derived as an oral HAV. For inhalation exposure, a 104-week inhalation exposure carcinogenicity study (Nagano et al., 2006) with a BMDL10 of 11.5 ppm based on the incidence data of mammary gland tumors (adenocarcinoma + adenoma + fibroadenoma, combined) in female rats was obtained, and the human equivalent BMDL10 of 15.7 mg/m3 was calculated. Therefore, a unit risk of 6.40 × 10−6 (µg/m3)−1 from which a carcinogenic 10−5 risk of 1.6 µg/m3 (0.00039 ppm) was derived as an inhalation HAV.

Retraction: Quantitative morphometric analysis of vimentin filaments in Sertoli cells of rats after in utero DBP exposure
[Notice] The Original Article was published on May 13, 2017
Vol.10, No.3, p.1-1
Eisuke Kume , Yuya Okayama , Mituru Sugiyama , Hiroyuki Takahashi , Tomoko Muto , Michael F. Wempe , Hiroshi Ikegami , Shin Wakui
Released: June 06, 2023
Abstract Full Text PDF[588K]

Editor’s Announcement

Quantitative morphometric analysis of vimentin filaments in Sertoli cells of rats after in utero DBP exposure

Eisuke Kume, Yuya Okayama, Mituru Sugiyama, Hiroyuki Takahashi, Tomoko Muto, Michael F. Wempe, Hiroshi Ikegami, Shin Wakui

(Fundamental Toxicological Sciences, 4, 85-93, 2017)

I have retracted the above paper as Editor-in-Chief of Fundamental Toxicological Sciences since I have serious concerns about it, primarily due to inappropriate authorship on a non-negligible scale.

Since the possibility of inappropriate authorship in this paper was raised, I contacted the co-authors to confirm this point. I found out that several of them considered their listing as co-authors to be inappropriate. In addition, more than half of the co-authors agreed to the retraction of this paper.

These facts raise concerns about the paper. From the standpoint of maintaining the integrity of the research community, I felt that such a paper should be retracted at once.

Accordingly, I sent a summary of my concerns about this paper to the corresponding author, Dr. Shin Wakui. I also had an online interview with him to discuss this matter. I told Dr. Wakui that inappropriate authorship on a non-negligible scale is a serious problem that raises concerns about the paper.

I prepared a draft of this Editor’s Announcement and sent it to Dr. Wakui for review prior to revision and release. Although he did not agree to the retraction, I have decided to take this action from the standpoint of maintaining the integrity of the research community.

I coordinated my response to this issue with Dr. Toshiyuki Kaji, Editor-in-Chief of The Journal of Toxicological Sciences, a sister journal of Fundamental Toxicological Sciences.

Akira Naganuma, Ph.D.
Fundamental Toxicological Sciences