RESENHAS REVIEWS
Endocrine disruptors and environmental impact in Japan
Introduction
Various chemical substances are used in business, industries, agriculture and our daily life. It is an important subject to prevent hazards to our health and living environment resulted from environmental contamination by toxic substances. In Japan, we have experienced the contamination caused by harmful chemical substances, such as methylmercury cadmium, PCB in the wastewater from chemical plants. The atmospheric pollution by dioxin, which are formed unintentionally as byproducts from waste incineration and diesel exhaust, also affects the people in the area. Recent investigations suggests that a number of man-made chemicals ranging from plastics products to pesticides may interact with the endocrine system of humans and wildlife populations. Many of them are known by their high toxic levels in animal studies, but not scientifically determined the low level toxic effects in the environment on humans and ecological systems.
Research projects
Many relating projects were recently started in government institutes, universities and industries. So serious is the problem that it could well threaten the very survival of mankind itself. Japanese Environmental Agency completed and presented the Strategic Program on Environmental Endocrine Disruptors '98 (SPEED '98) to the public in May 1998. Based on these programs, studies were started throughout Japan to determine the extent of environmental pollution and its effects on wild life. Other Japanese governments, such as Ministry of Health and Welfare (MHW), Ministry of Agriculture, Forestry and Fisheries (MAFF), Ministry of Construction (MOC), and local governments also started studies on this subject. Relating reports are provided via World Wide Web (WWW) (Table 1).
MHW started work on this issue in 1996 and engaged in research on the High Throughput Pre Screening Methods (HTPS), on mechanisms relating to human health and test methods, and on exposure of foods and containers etc. to fetuses and adults. Examples of references are:
Exposure to endocrine disrupting chemicals: Ema et al. (1999a, 1999b, 2000), Hirose et al. (1999), Ikeda et al. (1999), Nagao et al. (1999a, 1999b, 2000a, 2000b), Ohta et al. (2000), Shirai et al. (1999), Tamura et al. (1999).
Test methods: Akimoto et al. (2000), Minegishi et al. (1997, 1998), Nagasaki et al. (1999a, 1999b), Nakagomi et al. (1999a, 1999b), Ohkura et al. (1999a, 1999b), Ohno et al. (1999), Suzuki et al. (1999a, 1999b).
Rough outlines of these works were shown in Table 2.
The Advisory Committee on Health Influence of Endocrine Disrupting Chemicals was established in April of 1998, in order to examine problems of endocrine disrupting chemicals. An interim report was published in November of the same year and provided via WWW (Table 1).
The Japan Society of Endocrine Disruptor Research, comprised of scientists and engineers from various different fields, was established in June 1998 to shed light on the scientific aspects of the problem. The background of the member scientists is spreading in a wide variety including medical, biological, fisheries, environmental sciences and engineering as well. The International Symposiums on Environmental Endocrine Disruptors were held at Kyoto in December 1998 and in Kobe in December 1999. The main topics in the symposiums and related meetings were: (a) Screening Methods and Cellular Mechanisms; (b) Testing and Hormone Responses; (c) Mechanism of Action; (d) Fish Testing; (e) The Effect of Endocrine Disruptors (ED) on Humans; (f) The Effect of EDs on Wildlife; (g) Dose-response; (h) Potential Effects on Human Health; (i) Basic Biology; (j) Pesticide; (k) Activities in Japan.
Rough outlines of these works were shown in Table 2.
Database
One of the best ways to provide information widely is the use of Internet, especially WWW. Although English is necessary for international information exchange, Japanese is easier for domestic people. In the Home Page of National Institute of Health Sciences (NIHS), the information on Drugs, Food, Chemicals and Environment are represented. Recently, Endocrine Disruptor Information Guide for Researchers was included in the Topics of NIHS Home Page (Table 1). Although it is not yet completed, the Search Engine: (Web search for Endocrine Disruptors) and Lists of Paradigmatic Chemicals were available.
In NIHS, we have been developing related databases, such as Endocrine Disruptor Structure Database (EDSD) (Nakano et al., 1998), Binding Affinity Database for Endocrine Disruptor (BADB) (Kaminuma et al., 2000) and Receptor Database (RDB) (Nakata et al., 1999). In EDSD, chemical names, CAS registry numbers, synonyms, physicochemical properties and two-dimensional and three-dimensional structural data of 149 substances were included. With appropriate viewing software, users can generate three-dimensional images of chemicals. In BADB, experimental data for interaction of exogenous chemicals and bio-molecules were stored. At present, 742 Competition Binding Experimental results and 376 Enzyme Induction Experimental results were included in BADB. Figure 1 shows the relative binding affinity between human estrogen receptor a/b and ligands, which were picked up from BADB.
RDB included various receptor information, for instance structural information (amino acid sequences, secondary structure prediction, three dimensional structure image), functional information (DNA binding sites, ligand binding sites, etc.), genetic information (DNA sequences, gene information), the cell signaling networks information and transcription information. At present (June 2000), RDB contains 1,576 receptor proteins. The three-dimensional structure information was included in 121 receptor proteins. The DNA binding site and ligand binding site information were included in 206 and 130 receptor proteins, respectively. The data for transmembrane region was included in 1,070 receptor proteins. Recent versions of RDB included both information of EDSD and BADB, and much more. Using the table Steroid Hormone Receptor and Possible Endocrine Disruptor in the top page of RDB <http:// impact.nihs.go.jp/RDB.html>, users can refer to a steroid hormone receptor and possible endocrine disrupters (Figure 2).
Global Information Network on Chemicals
In June 1992, the United Nations Conference on Environment and Development Collection (UNCED) was held in Rio de Janeiro, Brazil. Chapter 19 of Agenda 21 of UNCED (UN, 1992) calls on communities "to promote intensified exchanges of information on chemical safety, use and emissions among all involved parties". It recommends that governments and relevant international organizations with the co-operation of industry should strengthen national institutions responsible for information exchange on toxic chemicals and strengthen international institutions and networks responsible for information exchange on toxic chemicals. Within the frame of the Inter-Organization Program for the Sound Management of Chemicals (IOMC), World Health Organization (WHO), International Labour Organization (ILO), United Nations Environmental Programs (UNEP) and Organization for Economic Cooperation and Development (OECD), with the support of the NIHS Japan initiated a project to establish a Global Information Network on Chemicals (GINC). The aim of GINC project is to provide networking arrangements for linking and better access by various users to existing international databases and documents on chemicals, as well as databases and chemical information systems available, or to be developed in each country.
Since the Internet has been launched and the WWW has become popular, the idea spread widely. GINC Home Page <http://www.nihs.go.jp/GINC/ index.html> was designed for the navigation to a wide range of WWW pages and databases in order to find useful information related to chemical safety: regulations, chemical names and synonyms, physico-chemical properties, toxicological data, protection for workers, environmental exposures, assessments and regulations. The United Nations organizations, the OECD, Environmental Protection Agency (EPA, United States), National Institute of Environmental Health Science (NIEHS, United States), and other Center of Excellences (COEs) have provided this information.
For the first GINC meeting at Tokyo 1994, only Korea and Japan were represented from Asia. Since then, attendance from China, Indonesia, Korea, Philippine, Singapore, Sri Lanka, Thailand and Vietnam gathered with the members from International Program on Chemical Safety/WHO (IPCS/WHO), International Register of Potentially Toxic Chemicals (IRPTC/UNEP), International Occupational Safety and Health Information Centre (CIS/ILO), OECD, EPA, NIEHS and Japan in GINC Asia Meeting. The corresponding organizations opened their Web Page for information exchange. These Home Pages and the GINC Asia page <http://www.nihs.go.jp/GINC/collabo.html> were connected reciprocally.
Discussion
EPA formed the Endocrine Disruptor Screening and Testing Committee (EDSTAC) in 1996, and provided the reports EDSTAC via WWW. Under the legislation, some 80,000 existing chemicals and new chemicals were undergoing various screens and/or tests for their potential estrogenicity, as well as other hormonal activities. The integrated computational approach was reported to set priorities for these chemicals for experimental screening and testing (Tong et al., 1999). The OECD endocrine disruptor activity was initiated in 1996. The focus of the activity was to provide information on national and regional activities concerning endocrine disruptors, develop appropriate Test Guidelines and harmonize risk assessment approaches (Huet, 1999).
In the International Symposium on Environmental Endocrine Disruptors at Kobe 1999, many speakers from Denmark, Finland, Germany, Italy, Japan, Netherlands, OECD, Sweden, United Kingdom and United Station reported their works, and had heated discussion with the participants (Table 2). We expect these activities will lead to solutions for the endocrine disruptor problems.
Kotoko Nakata
Division of Chem-Bio Informatics, National Institute of Health Sciences, Tokyo, Japan.
nakata@nihs.go.jp
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