Yoichi Konishi

Effects of phenyl N-tert-butyl nitrone and its derivatives on the early phase of hepatocarcinogenesis in rats fed a choline-deficient, L-amino acid-defined diet

The present study examined the effects of various derivatives of a radical trapping agent, phenyl N‐tert‐butyl nitrone, on the early phase of hepatocarcinogenesis in male Wistar rats fed a cholinedeficient, L‐amino acid‐defined diet for 16 weeks. The derivatives used were 4‐hydroxyphenyl (a physiologically major metabolite), 3‐hydroxyphenyl, 2‐hydroxyphenyl and 2‐sulfoxyphenyl N‐tert‐butyl nitrone, and their effects were studied in a comparison with those of the parent compound, phenyl N‐tert‐butyl nitrone. The sizes of putatively preneoplastic, glutathione S‐transferase placental form‐positive lesions and the levels of extra‐nuclear oxidative injury of hepatocytes, using the formation of 2‐thiobarbituric acid‐reacting substances as a parameter, were decreased by all doses (0.009%, 0.045% and 0.090% in diet) of 4‐hydroxyphenyl N‐tert‐butyl nitrone and only by the highest dose of 3‐hydroxyphenyl N‐tert‐butyl nitrone and phenyl N‐tert‐butyl nitrone. While 4‐hydroxyphenyl N‐tert‐butyl nitrone, 3‐hydroxyphenyl N‐tert‐butyl nitrone and phenyl N‐tert‐butyl nitrone all enhanced and inhibited hepatocellular apoptosis in preneoplastic lesions and their surrounding tissue, respectively, only 4‐hydroxyphenyl N‐tert‐butyl nitrone additionally inhibited hepatocyte proliferation both in preneoplastic lesions and their surrounding tissue. 2‐Hydroxyphenyl or 2‐sulfoxyphenyl N‐tert‐butyl nitrone did not exert any of the above effects. These results suggest that the selective induction of apoptosis in preneoplastic hepatocyte populations plays a crucial role in the inhibition of hepatocarcinogenesis derived by phenyl N‐tert‐butyl nitrone and its effective derivatives. Further, the metabolic conversion to 4‐hydroxyphenyl N‐tert‐butyl nitrone may also be important for the inhibitory effects of phenyl N‐tert‐butyl nitrone on hepatocarcinogenesis. (Cancer Sci 2003; 94: 26–31)

Regulatory Forum Opinion Piece* Supporting the Need for International Harmonization of Safety Assessments for Food Flavoring Substances

The advancement of technology and the growth of international commerce underscore the need for global harmonization of regulatory safety requirements and their assessment pertaining to consumer products such as drugs, medical devices, and food. This need is particularly relevant when safety requirements involve time-intensive and costly animal safety studies. Here we present the current regulatory requirements in Europe, the United States, and Japan for flavoring substances (FSs) used in foods and point out significant differences relevant to the international standardization for safety assessments that in our opinion need to be addressed and overcome. The safety assessments that are carried out for FSs in various countries are influenced by divergent definitions of FS, by the information required and available for regulatory submission, and by different regulatory procedures, including the use of decision tree approaches. The European Food Safety Authority (EFSA), the Expert Panel of the U.S. Flavor and Extract Manufacturers Association (FEMA), and the Joint Food and Agriculture Organization (FAO)/World Health Organization (WHO) Expert Committee on Food Additives (JECFA) are making efforts to improve and harmonize the safety assessment of FSs. The application of in silico methods such as quantitative structure–activity relationships and read-across strategies relying on expert input are useful as a first-step screening of the assessment. Application of the Threshold of Toxicological Concern (TTC) approach permits conclusions that are compatible with the risk assessment approaches currently used by international advisory committees. The Japanese Regulatory Authority, on the other hand, does not yet consider in silico methods but still requires in vivo and in vitro genotoxicity test data as well as repeat-dose 90-day toxicity data in at least one species, to be submitted as the first step in the safety assessment of FSs. With this article, we echo requests that have been made for xenobiotics by the pharmaceutical industry worldwide, extending them to food-related products, especially FSs. We encourage regulatory agencies to adopt globally harmonized safety assessment procedures, regulatory guidelines, and review practices for FSs to foster global trade and to reduce costs and laboratory animal use.

Multi-step lung carcinogenesis model induced by oral administration of N-nitrosobis(2-hydroxypropyl)amine in rats.

N-Nitrosobis(2-hydroxypropyl)amine (BHP) was first synthesized by Krüger et al. (1974), and has been shown to primarily induce pancreatic duct adenocarcinomas by a subcutaneous injection in Syrian hamsters. By contrast, the carcinogenic effect of BHP has been indicated at the different target organs in rats, namely the lung. When rats are received by an oral administration of BHP in drinking water for 25 weeks, a high incidence of lung carcinomas are induced, which include adenocarcinomas, squamous cell carcinomas and combined squamous cell and adenocarcinomas. So many similarities are observed in terms of not only histological appearances but also gene alterations between human and BHP-induced rat lung cancers. Moreover, the step by step development of lung lesions, from preneoplastic lesions to cancers in rat lung carcinogenesis by BHP offers a good model to investigate the mechanisms underlying the pathogenesis of lung cancers. Because data for genetic and epigenetic alterations have indeed been accumulated during the BHP-induced rat lung carcinogenesis, we will introduce them in this review and hence demonstrate that this lung carcinogenesis model provides a useful opportunity for the research on the pathogenesis of lung cancers of both humans and rats.

Foundation and Progress of Japanese Society of Toxicologic Pathology

The Japanese Society of Toxicologic Pathology (JSTP) has a differing conceptual framework from the Japanese Society of Pathology (JSP) and Japanese Society of Toxicology (JST) and was founded in 1985 by the leadership of late Dr. Yasukazu Nishiyama with the cooperation of several founding members and the support of JSP. The aim of the JSTP is to improve the human and animal health using an interdisciplinary scientific approach based on pathology and toxicology. In its development as a professional society, the JSTP has established society rules and activities. The JSTP has grown in terms of membership and financial aspects and is now recognized not only domestically but also internationally as a well-organized scientific society. To maintain the high professional standard and visibility of JSTP, we here provide the historical background of the society as a basis for current members to contribute to the continued improvement of our scientific organization.