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Among various altered fractionation regimens, hyperfractionated radiotherapy (HFRT) has been considered effective to raise survival rate(SR)as well as local control rate(LCR)in head and neck cancers. We reviewed our results of HFRT (117 cases) treated between 1995 and 2004 and compared with those of conventionally fractionated radiotherapy (CFRT; 80 cases) treated during the same period. By disease site, naso-/oro-/hypopharynx/larynx were 5/23/44/45 vs. 10/6/10/54. There were more advanced-stage cases in HFRT group (stage I/II/III/IV = 19/36/23/35 vs. 42/16/8/ 14). Median RT dose were 72 Gy vs. 66 Gy. In 71 cases, chemotherapy was added (HF/CF = 54/17). In stage III and IV cases, there was a borderline significant difference in LCR (at 5 years; 44.3% for HFRT group vs. 24.5% for CFRT group; p = 0.0502), and a tendency in SR(at 5 years; 50.7% for HFRT group vs. 16.7% for CFRT group; p = 0.1210). By disease site, LCR of HFRT group was higher in hypopharynx(p = 0.0005)and oropharynx(p = 0.0003), and SR of HFRT group was higher in hypopharynx(p = 0.0023). Acute toxicity was heavy but in most cases it was tolerable and there were no severe late toxicities. From our data, it was suggested that HFRT might be effective in certain kinds of head and neck cancers.

Plastic debris are important marine pollutants. Plastic debris consist of resin pellets and waste plastics. We are particularly interested in resin pellets. We made field survey of resin pellets at nearly 400 sites in 200 beaches in Japan and neighboring countries. The pellets were found at all most all Japan coasts we surveyed and at some beaches of Macao, Hong Kong, Xiamen, the north of Taipei, and Cheju Island in Korea. The number of pellets was more than 1000 pieces per m2 on the most abundant beach in Japan. Through further analysis using GC/ECD, endocrine disrupting chemicals, PCBs, DDTs, HCHs and Nonylphenol were detected in selected samples. Biota such as Bryozoa were observed on the surface of pellets washed up on the beaches in subtropical areas. Pellets has been suspected to affect wildlife and human health, but we have no report on affection to human.

The Chem-Bio Informatics division has developed the institute-wide computer network which is connected to the Internet via IMnet (Inter Ministry Network) sponsored by the Government. We call the network and associated information and computing infrastructure as NICI, the NIHS Information and Computing Infrastructure. The primary goal of NICI is to provide general communication environment such as e-mails, and the second goal is to provide WWW environment. Accomplishing these two goals the division is now challenging to develop information and computing environment that directly supports pharmaceutical and toxicological research. The prototype of this environment which consists of various chemical and biomolecular databases and computing tools has been developed under the name of MOBI-DICS. The concept and vision on how to extend the prototype to institute-wide infrastructure was discussed.

The criminal cases of poisonings caused by poisonous, deleterious or other hazardous chemicals in Japan were studied. The data (111 cases) were collected mainly from the newspaper database (Aug. 1984-Feb. 1999). More than half cases were caused by chemicals which are regulated by the "Poisonous and Deleterious Substance Control Law". Copy-cat poisonings occurred in succession in 1984-1985 and 1998. Many cases occurred at the laboratories of institutes and universities, and hospitals where there are various kinds of chemical reagents. The cases of chemical incidents such as those which occurred while transportation were also discussed.

From 1999 to 2000, NIHS Information and Computing Infrastructure (NICI) were newly renovated. The purposes of the renovation are (1) the improvement of the communication for business works in NIHS, (2) supporting for the research, (3) supporting for the administration work. The Internet connection speed was upgraded from 256 Kbps to 1.5 Mbps. The high quality network sever machines and database server machines were installed. The large-scale software systems were renewed their versions. Four experimental stations for medical plants at Hokkaido, Izu, Wakayama and Tanegashima connected to NIHS at Tokyo or Osaka branch by ISDN. We describe the providing information on NIHS home page, and how to utilize NICI for our research and official works.

Geographic Information System is becoming a very important tool for environmental health research. We have produced various digital maps for different scales for different purposes. The burst of E. Coli O-157, distribution of hazadarous chemicals in East Asia, and coastal resin pellets are some examples. It now becomes a problem how to archive these digital maps and how to retrieve these maps according to user's request. We have developed a computer system that can store various types of digital maps and can retrieve them from WWW client machines. The key concept of this archive system is to classify every digital maps according to their region of interest.

As cyber space exploding in a pace that nobody has ever imagined, it becomes very important to search cyber space efficiently and effectively. One solution to this problem is search engines. Already a lot of commercial search engines have been put on the market. However these search engines respond with such cumbersome results that domain specific experts can not tolerate. Using a dedicate hardware and a commercial software called OpenText, we have tried to develop several domain specific search engines. These engines are for our institute's Web contents, drugs, chemical safety, endocrine disruptors, and emergent response for chemical hazard. These engines have been on our Web site for testing.

We prepared a database on chemical regulations in Japan. The regulations consist of "The Law concerning the Examination and Regulation of Manufacture, etc., of Chemical Substances", "Poisonous and Deleterious Substances", Control Law", "Waterworks Law", "Law for the Control of Household Products containing Harmful Substances", and Pesticide Residues in Food Sanitation Law". We also set up a World Wide Web (WWW) homepage containing an explanation of the law as well as chemical names, CAS registry numbers, and standards. The WWW pages contain lists of chemicals and the retrieval page for the database.

We describe the development of NICI, which we extended during June 1996 to May 1998. The direct lines between our Experimental Stations for Medicinal Plants at Tsukuba and Tsukuba Node for Inter Ministry Network, and newly opened Pharmaceuticals and Medical Devices Evaluation Center at Minato-ku and NIHS at Setagaya-ku in Tokyo, were constructed. Although the main frame in NIHS at Setagaya is not different since May 1996, we provided many databases and useful information on Drugs, Foods and Chemicals, constructing the interface between World Wide Web and databases. Our Home Page was timely updated.

We reported a system for dissemination of the drug information and its related subjects through the Internet (Drug Info Guide) in Bull. Natl. Inst. Health Sci. 1996. Since then, further information were added in the system. These include the web site for ICH Guideline in Japanese and English, and Australasian Cochrane Centre mirror site. Furthermore, the titles and their abstracts which were reviewed by Cochrane groups in Cochrane Library were translated in Japanese, and these information together with the search guide for useful resource regarding the drug information were also presented on WWW.

We collected the data on accidents due to chemicals occurred in Japan, and prepared the database. We also set up the World Wide Web homepage containing the explanation on accidents due to chemicals and the retrieval page for the database. We designed the retrieval page so that users can search the data from keywords such as chemicals (e.g. chlorine gas, hydrogen sulfide, pesticides), places (e.g. home, factory, vehicles, tank), causes (e.g. reaction, leakage, exhaust gas) and others (e.g. cleaning, painting, transportation).

ge of the Japanese version of the International Chemical Safety Cards (ICSC). We prepared the Japanese text files of ICSC, converted them into HTML files and also prepared the dictionary database for the retrieval system, using programs which we developed. These programs shortened the time of work remarkably. 2D- and 3D-structures of chemicals were also incorporated in each ICSC page. Approximately 900 ICSCs in Japanese are provided at the moment on the homepage.

In recent years the Ministry of Health and Welfare (MHW) encountered large scale health hazards and medicare incidents that required flexible, intersectional, and dynamic responses. Both research institutions under the MHW and their researchers got involved in project teams which were organized in order to cope these hazards and incidents. However it might be more effective if some information infrastructure for hazard control is built as one component of the MHW hazard management system. In this paper the design concept and implementation for such information infrastructure were discussed. The infrastructure consists of computer networks and systems which are based on the Internet and the related technologies such as WWW.

The so called Geographical Information System (GIS) is one of the basic tools for wide range of public health applications. We had developed a general purpose GIS and applied it to represent geographical distribution of patients of the bacterium E. coli O-157 which bursted out in Japan last early summer particularly at Sakai City in Osaka Prefecture. The patient record have been supplied from the Food Safety Office of the Ministry of Health and Welfare. These records were handled by EXCEL. The basic geographical data was constructed from the map data provided by Japan Geographical Survey Institute, and ArcView 2 was used as the map system. The maps were converted to Graphics Interchange Format (GIF) files and put on our Web server.

We describe the information and computing infrastructure in National Institute of Health Sciences, which were constructed until May, 1996. The in house computer network and computing facilities for common usage in NIHS have been developed under the initiative of Division of Chem-Bio Informatics since 1989. The present LAN (Local Area Network) consists of coaxial cables and optic fibers which are connected by a LAN Switch. The LAN is connected to the Internet via IMnet, the inter ministry network back bone of the Science and Technology Agency. Various types of workstations and personal computers such as SUN WS, Silicon Graphics WS, IBM WS & PC, Macintosh, and NEC PC are connected to the LAN. This computing network environment which we named NICI (NIHS Information and Computing Infrastructure) not only provides network communications but also facilitates advanced computating systems for chemical safety research at NIHS as a COE.

An information system for chemical safety has been developed on the National Institute of Health Sciences (NIHS) Information and Computing Infrastructure. The system is based on client server systems on the local area network (LAN) connected to the Internet. A wide range of safety information for chemicals including foods, food additives, household goods, industrial chemicals and environmental pollutants were collected and put on the World Wide Web (WWW) server and the database management system, Sybase. In addition to original information contents, the System has links to many useful Web sites so that it functions as a global hub for chemical safety information.

We developed the system of the guide for the drug and the relevant information by using the database on the Internet. We set up a site of drug information (Drug Info Guide). This system enabled pharmaceutical and medical staff to easily access the latest drug information. Further, we attempted to promote the exchange of the information regarding the safety and the efficacy of drugs among them.

The development of information and computing infrastructure at NIHS (NICI), enabled us to provide a good environment for storing information that can be accessed by the Internet. Information can be stored either on WWW servers or on databases. All databases were developed on PC using database management systems such as 4th Dimension or Access, and were transferred to a UNIX machine with the database management system Sybase. A tool for accessing databases via the WWW (Web) was developed. This interface program used a freeware called Genera. Tools were also implemented for handling the so called VRML worlds.

A structure-based pharmaceutical database for drug interactions has been developed. This database is based on the ISIS/Desktop and the Microsoft Access relational database system for Windows. Data of Japanese accepted name, molecular formula, molecular weight, CAS registry number, therapeutic category index code, structural formula, Japan ethical drugs code, side effects information, drug interactions information were taken from "Japanese Accepted Names for Pharmaceuticals 1992", "Drugs in Japan Ethical Drugs 1993" and "Drug Intelligence Reinforce".

Calcitonin gene-related peptide (CGRP) and vasoactive intestinal polypeptide (VIP) are intrinsic vasodilatory substances contained in perivascular nerve fibers innervating large intracranial arteries. Effects of these substances on delayed cerebral vasospasm were examined using a rabbit model of experimental subarachnoid hemorrhage (SAH). Sixty-one anesthetized rabbits received intrathecal fresh arterial blood on day-1 and intrathecal administration of different doses of CGRP, VIP or distilled water on day-4. Prior to the treatment, caliber of the spastic basilar artery was 73.4 +/- 0.9% of pre-SAH values. Serial angiograms after treatment demonstrated that 10(-10)mol/kg of CGRP dilated the spastic artery to 117.1% of pre-SAH levels and that dilatory effect of CGRP continued up to 6 hours after treatment. VIP injection also brought arterial dilatation up to 114.9% of pre-SAH levels, although the duration of the effect was less than 3 hours. Intrathecal administration of CGRP or VIP showed no adverse effect on the systemic and neurological state of the animals. These results indicate that intrathecal CGRP and VIP have therapeutic potential in treating delayed cerebral vasospasm after subarachnoid hemorrhage. Further investigations are expected to extend the effect of CGRP and VIP.

Preparation of International Chemical Safety Cards (ICSC) is described. The main characteristics of the ICSC are the use of standard phrases, a compiler's guide and a program for their preparation by personal computer. Standard phrases harmonize expressions on ICSC and also facilitate translation into other languages. In our case more than 900 cards have been translated into Japanese and published. Recently, a new program to aid translation by personal computer has been developed.

The preparation of MSDS (material safety data sheets) began in Japan in April 1993 with the notice of three Ministries, the Ministry of Health and Welfare, the Ministry of International Trade and Industry and the Ministry of Labor. MSDS are designed to provide chemical information to protect human health and the environment from chemical hazards. Important points in describing hazard information in MSDS are explained as well as references which are useful for preparation of MSDS. Problems for further discussion are also pointed out.

Many carcinogens react with DNA and form critical DNA adducts, such as O6-alkylguanine (O6-AG), O4-alkylthymine (O4-AT), and 8-hydroxyguanine (8-OHG). This study provides a database that can be used for molecular dosimetry of these DNA adducts. A literature survey on DNA binding in vivo was done by the Dialog search from the MEDLINE database. We propose a Critical Covalent Binding Index (CCBI) for the assessment of in vivo DNA binding level (expressed as micro mol chemical bound per mol G or T/mmol chemical administered per kg body weight). The number of records and compounds in parenthesis of O6-AG, O4-AT, and 8-OHG were 245(13), 54(4), 79(15), respectively. Since the CCBI values for N-nitrosamine in target organ were higher than for non-target organ, they may provide a useful index for estimation of target organ site and carcinogenic potency. As a case example, CCBI values for O4-AT from animal data were applied for diethylnitrosamine human exposure estimation by diethylnitrosamine.

Acetonitrile is a high-polarity aprotic organic solvent used in DNA synthesizers, HPLC, and electrochemistry. In addition, it is used larger amounts at petrochemical companies and pharmaceutical firms. Preparation of an Environmental Health Criteria (EHC) monograph for acetonitrile was started in 1986, and its first draft except the environmental section was completed on June 21, 1991. The environmental section has been prepared by Dr. S. Dobson (ITE/UK). The first draft was circulated to EHC Contact Points for comment in March 1992.

The EHC is historically most important among the activities of IPCS which was inaugurated in 1980, and its first draft is being circulated to IPCS contact points throughout the world. Comments and suggestions in improvements to the first draft of the EHC monograph is essential to the sound development of this document. Our suggestions on such improvements are the basis of this report.

The preparation of a EHC monograph for anionic surfactants was started in 1980. The chemicals consist of linear alkylbenzene sulfonate (LAS), alkyl sulfate (AS) and alkyl alpha-olefin sulfonate (AOS). Although a preliminary draft appeared in 1985, further works were stopped for 5 years. For the development of the preliminary draft, up-dating the references was performed by using on-line JICST data base from 1981 to 1990. The number of literature on LAS was 486. On the other hand the number on AS was about 1/5 that of LAS. In the case of AOS, only 20 literatures were retrieved. The literatures on LAS were many in the research field of environmental science and very few in the toxicology field.

The first drafts of the EHC monographs in 1990 were summarized into Japanese. The chemicals consist of hexachlorocyclopentadiene, trichlorfon, fenitrothion, methylparathion, trichloroethane, platinum and selected platinum salts, di(2-ethylhexyl)phthalate, partially halogenated chlorofluorocarbons, methyl ethyl ketone, and propachlor.

We previously reported the newly developed quantitative measurement of the cerebral atrophy (pixel count method), and advocated the value CCR (CSF-cranial ratio) as the index of the volumetric measurement of the cerebral atrophy. As the pixel count method is somewhat troublesome, we tried to compare the various linear measurement methods with pixel count method by means of multivariant analysis, and reported a single formula to calculate CCR from the linear measurement methods. Now we studied 500 normal subjects using the pixel count method and examined the normal range of the cerebral atrophy during aging by means of the maximum likelihood method. The normal range was estimated as follows; 0.32 less than y less than 5.78 (t less than 48), 0.068 t--2.944 less than y less than 0.368 t--11.884 (t greater than 48). Using these formula and this newly reported normal range, we can easily predict whether the cerebral atrophy is pathological or not.