Development and assessment of new risk assessment methods

Title of Research:
13_PT01-03-2

Development of a combined in vitro/in silico system to predict andevaluate the complex hepatotoxicity of chemical compounds.
Principal Investigator:
Kouichi Yoshinari (University of Shizuoka)
Collaborators:
Hiroyuki Kojima (Hokkaido Institute of Public Health)Summary of Research:
The aim of this study is to develop an in vitro/in silico system for toxicity evaluation andprediction, using the chemicals’ biological properties based on the in vitro reactivity toxenobiotic-responsive nuclear receptors in combination with the physicochemical properties
shown as chemical descriptors. Especially, we have developing an prediction system for rat
repeated dose toxicity (RDT) using a HESS database, which contains RDT test data of Chemical
Substances Control Law-related substances and is available from National Institute of Technologyand Evaluation, and a rat RDT test database of pesticides, which has been constructed by ourgroup. In this system, we are using a grouping (read-across) method based on hierarchicalclustering. In this research period, with HESS database compounds we have found that groupings
only with chemical descriptors show relatively high accordance with groupings with RDT test data
(Rand index: ~0.8). Meanwhile, some concerns and problems have been raised including theimportance of the selection of descriptors and toxicity findings and the insufficiency of in vitro
assay data. These points need to be solved and cleared in the next year. For the analysis withpesticides, the database construction and in vitro reporter assays of 4 nuclear receptors werecompleted. After calculation of descriptors, grouping analysis with these toxicity data, in vitro
assay data and descriptors will be performed in the next year.
Timeline:
March 2015 – February 2016
Topics:None
Publications:
Invited lecture
1. K. Yoshinari: Development of a combined in vitro/in silico system to predict and evaluate thecomplex hepatotoxicity of chemical compounds. in “What Will Work? Future Approaches andTechnologies for Assessing Chemical Safety”, 2015 ICCA-LRI & U.S. EPA Workshop. June,
2015. New Orleans, LA, USA.
2. K. Yoshinari: Role of nuclear receptors in chemical toxicity and its application to toxicity
prediction. 2015 LRI Annual Meeting, August, 2015. Tokyo.
3. K. Yoshinari: Development of an in vitro/in silico combined system for the toxicity prediction.
CBI Annual Meeting 2015. October, 2015. Tokyo.
4. K. Yoshinari: A new approach to the prediction of repeated dose toxicity. The 28th Annual
Meeting of the Japanese Society for Alternatives to Animal Experiments. December, 2015.
Yokohama.
5. K. Yoshinari: Role of xenobiotic-responsive nuclear receptors in hepatotoxicity. 13th Meetingof the Asia Pacific Federation of Pharmacologists. February, 2016. Bangkok, Thailand.
Oral/poster presentation
1. M. Masuda, K. Yoshinari: Toxicological characterization of hepatocyte hypertrophy using
public data of in vivo toxicity tests. The 135th Annual Meeting of the Pharmaceutical Societyof Japan. March, 2015. Kobe.
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Development and assessment of new risk assessment methods
K. Yoshinari, M. Masuda, A. Masuda, M. Sekimoto, K. Nemoto: Toxicological characterizationof hepatocyte hypertrophy using rat 2-year repeated dose toxicity/carcinogenicity tests. The
42nd Annual Meeting of the Japanese Society of Toxicology. June, 2015. Kanazawa.
A. Masuda, M. Masuda, M. Sekimoto, K. Nemoto, K. Yoshinari: Construction of the databaseof rat 90-day repeated dose toxicity tests and its application to toxicological characterizationof hepatocyte hypertrophy. The 42nd Annual Meeting of the Japanese Society of Toxicology.
June, 2015. Kanazawa.
K. Yoshinari, A. Masuda, M. Masuda: Construction of toxicity database of rat repeated dosetoxicity tests and its application to toxicological characterization of hepatocyte hypertrophy.
Forum 2015 Pharmaceutical Health Science & Environmental Toxicology. September, 2015.
Kobe.
A. Masuda, M. Masuda, K. Yoshinari: Toxicological characterization of hepatocyte
hypertrophy for the safety evaluation of food contaminants: Analysis using in vivo toxicity test
data of pesticides. The 1st Forum of Regulatory Sciences for Young Scientists. September,2015. Funabashi.
K. Yoshinari, H. Nakajima: In vitro and in silico analyses of the association of hepatocyte
hypertrophy with nuclear receptor activation and enzyme induction. 30th the JapaneseSociety for the Study of Xenobiotics Annual Meeting. November, 2015. Tokyo.

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