Title of Research:
22-6-02

Development of an objective read-across method based on
statistical and mathematical sciences for evaluation of
repeated-dose toxicity
Principal Investigator:
Kouichi Yoshinari (School of Pharmaceutical Sciences, University of Shizuoka)
52-1 Yada, Suruga-ku, Shizuoka 422-8526 Japan. E-mail: yoshinari@u-shizuoka-ken.ac.jp
Collaborators:
Jun-ichi Takeshita (Research Institute of Science for Safety, National Institute of Advanced
Industrial Science and Technology (AIST))
Tomomichi Suzuki (Department of Industrial Administration, Tokyo University of Science)
Summary of Research:
Repeated-dose toxicity (RDT) test is important for chemical safety evaluation. Currently, it is highly
recommended to develop alternatives to rat RDT tests, but it remains very difficult to develop sucha method largely due to the diversity and complexity of the toxicity. The aim of this project is todevelop an objective read-across method, in which the toxicity of an untested substance ispredicted from the toxicity information of similar substances (called “source substances”), usingchemical information and in vitro assays as an alternative to rat RDT tests. In this year, weselected test substances from HESS and REACH databases and set 8 group endpoints (6hepatotoxicity- and 2 hematotoxicity-related) as targets. Studies were conducted on criteria for
judging the presence or absence of toxicity of test substances from source substances, molecular
descriptors to be used for similarity assessment, and methods for selecting source substances.
Results obtained indicate that the criteria for judging the toxicity of test substances should beadjusted based on the positive rate of the group endpoints, source substances differ depending on
the type of inter-substance distances used, the descriptors should be selected by an appropriate
method, and the accuracy of toxicity prediction is improved by appropriately selecting descriptors.
Timeline:
March 1, 2022 - February 28, 2023
Topics:Publication #1 (Yu Harakawa) received Presentation Award for Students at the 35th annual
meeting of the Japanese Society for Alternatives to Animal Experiments.
Publications:
1. Y Harakawa, N Omura, J Takeshita, R Shizu, T Hosaka, Y Kanno, K Yoshinari. Developmentof a read-across method for evaluating repeated-dose toxicity using molecular descriptors:
Examination of methods of selecting molecular descriptors for better prediction. The 35thannual meeting of the Japanese Society for Alternatives to Animal Experiments. Shizuoka,Japan, 2022.11.18-20.
2. K Yoshinari. Evaluation of developmental neurotoxicity of chemical substances by aread-across method using chemical structure information. The 35th annual meeting of theJapanese Society for Alternatives to Animal Experiments. Shizuoka, Japan, 2022.11.18-20.
3. K Yoshinari. Safety assessment of chemical compounds by in vitro and in silico methods:
challenges and future prospects. ILSI Japan symposium: Alternatives to animal experimentsin the food science area -current situation, trends and initiatives for the future. Online,2023.2.3.
4. Y Harakawa, N Omura, R Shizu, T Hosaka, J Takeshita, K. Yoshinari. Examination of theselection method of molecular descriptors for the evaluation of repeated-dose toxicity using aread-across approach. The Society of Toxicology 62nd Annual Meeting and ToxExpo.
Nashville, TN, USA. 2023.3.19-23.