Fundamental Toxicological Sciences

2019 - Vol. 6 No. 4

2019 - Vol. 6

Original Article
Validation of the statistical parameters and model selection criteria of the benchmark dose methods for the evaluation of various endpoints in repeated-dose toxicity studies Vol.6, No.4, p.125-136
Mariko Matsumoto , Mutsuko Hirata-Koizumi , Tomoko Kawamura , Sawako Sakuratani , Atsushi Ono , Akihiko Hirose
Released: May 17, 2019
Abstract Full Text PDF[7M]

The benchmark dose (BMD) approach is one of the important techniques in dose-response assessment for the risk assessment of chemicals and adapted by various international organizations. We investigated the appropriateness of the statistical parameters and model selection criteria for BMD lower bound (BMDL) estimation by BMD software (BMDS) (developed by the US Environmental Protection Agency) and PROAST (developed by the National Institute for Public Health and the Environment of the Netherlands). Publicly available repeated-dose toxicity study data (226 dichotomous datasets and 151 continuous datasets) were used for the investigation. Our findings were applied to establish BMD technical guidance for BMDS for the evaluation of various endpoints in repeated-dose toxicity studies. Under the Japan Chemical Substance Control Law (CSCL), the DRA-BMDS guidance (i.e., Division of Risk Assessment-BMDS guidance) is used for the evaluation of a “Priority Assessment Chemical Substance.” Namely, selecting of an extra risk of 10% (dichotomous data) or a level change of 1SD (continuous data) as a default benchmark response. Running all the models without or with parameter constraints. Selecting the model that calculated the lowest BMDL but excluding the one that estimated a BMD/BMDL ratio ≥ 10 or lowest dose/BMDL ratio ≥ 10. We believe that the DRA-BMDS guidance can assist risk assessors in the selection of the BMD model.

Toxicomics Report
Gene expression profiles of immortalized S1, S2, and S3 cells derived from each segment of mouse kidney proximal tubules Vol.6, No.4, p.117-123
Hitomi Fujishiro , Seiichiro Himeno
Released: May 14, 2019
Abstract Full Text PDF[746K]

Kidney proximal tubules are composed of S1, S2, and S3 segments having different properties of excretion and substance reabsorption. Since renal toxicants such as cadmium and cisplatin cause segment-specific toxicity, it is important to examine the segment-specific transport and detoxification systems of renal toxicants. Here, we investigated the gene expression profiles of immortalized S1, S2, and S3 cells derived from each segment of mouse kidney proximal tubules. Microarray analyses showed distinct expression of various genes in each cell line. We compared the expression levels of selected genes related to the transport and detoxification of renal toxicants. Some genes showed segment-specific expression patterns similar to those observed in in vivo studies. The gene expression profiles of each cell line shown in this study will provide a foundation for the future utilization of immortalized S1, S2, and S3 cells for toxicity screenings as well as for the elucidation of renal toxicity mechanisms.