Chairman

Dr. I. Bernard Weinstein, (1987-   )
Director, Columbia-Presbyterian Cancer Center
Frode Jensen Professor of Medicine
Columbia University
702 West 168th Street
New York, New York 10032

Chairman

Dr. Masaaki Terada (1992-   )
Director
National Cancer Center Research Institute
5-1-1 Tsukiji, Chuo-ku
Tokyo 104, Japan

Panel Members

Dr. Arthur Grollman (1990-   )
Professor and Chairman
Department of Pharmacological Sciences
State University of New York
Health Sciences Center
Stony Brook, New York 11794-8651

Dr. Frederica Perera (1992-1995, 1985-1992)
Program in Molecular Epidemiology
Division of Environmental Sciences
Columbia University School of Public Health
60 Haven Avenue, B-109
New York City, New York 10032

Dr. Gerald Wogan (1989-   )
Director
Division of Toxicology
Massachusetts Institute of Technology
77 Massachusetts Avenue
Building 16, Room 333
Cambridge, Massachusetts 02139

Dr. Taijiro Matsushima (1977-   )
Director
Japan Bioassay Laboratory
Japan Industrial Safety and Health Association
2445 Hirasawa, Hadano
Kanagawa 257, Japan

Dr. Masanao Miwa (1994-   )
Professor
Institute of Basic Medical Sciences
Tsukuba University
1-1-1 Tennodai, Tsukuba
Ibaraki 305, Japan

Dr. Shaw Watanabe (1992-   )
Chief
Epidemiology Division
National Cancer Center Research Institute
5-1-1 Tsukiji, Chuo-ku
Tokyo 104, Japan

Guidelines

Environmental Mutagenesis and Carcinogenesis Panels USJCMSP

Studies on the detection, prediction, interpretation, and mechanisms of the mutagenic and carcinogenic properties of environmental chemical, biological, and physical agents and their interrelationships

1. Development, refinement, validation, and application of laboratory assay systems for assessing mutagenicity and carcinogenicity including short-term, medium-term, and long-term assays
2. Systemic collection and evaluation of databases on mutagens and carcinogens
3. Molecular elucidation of the mechanism of mutagenesis and carcinogenesis including oncogene activation and suppressor gene inactivation
4. Investigation of factors that modify mutagenic and carcinogenic activity and experimental studies on multi-agent interactions including dose-time effects and repair processes.

Studies in Human Populations

Epidemiologic approaches to understanding and preventing environmental mutagenesis and carcinogenesis in human populations

1. Development, refinement, and validation of methods to determine exposure, molecular dosimetry (to DNA, RNA, protein, receptors, etc.) and early biologic effects of mutagens and carcinogens including somatic and germ cell mutations and disorders in signal transduction
2. Application of human monitoring methods to determine baseline frequencies of mutation or other monitored endpoints and to monitor high-risk groups such as chemotherapy patients, workers exposed to known or suspected mutagens and carcinogens, and individuals or families genetically predisposed to genetic damage and cancer
3. Development of better methods for monitoring the work place and the general environment for the presence and levels of mutagenic or carcinogenic agents
4. Expansion of epidemiologic and molecular epidemiologic resources to measure mutagenicity and carcinogenicity of agents in the human environment.

Multidisciplinary Approaches Combination of laboratory studies of agents, human hazards, and human exposure into a sound, scientifically based, risk analysis for mutagenicity and carcinogenicity.

Five-Year Summary

Broad Goals

Environmental agents to which humans are exposed from conception to death can have diverse and significant health effects. These Panels focus on two environmentally-induced diseases: cancer and heritable genetic diseases. According to the Panel's guidelines, which were revised in 1990, research activities have focused on both laboratory and epidemiological studies including interdisciplinary studies termed molecular or biochemical epidemiology. For both types of studies, the goal is to promote and exchange information that will lead to the prevention of diseases and application and transfer of this knowledge to populations throughout the world, particularly those in Asia, developing countries, and high-risk areas.

Progress/Accomplishments

During the past 5 years, the Environmental Mutagenesis and Carcinogenesis Panels have taken advantage of the explosion of new technologies and new knowledge to define basic cellular and molecular mechanisms involved in carcin-ogenesis and to examine the relationship between environmentally-induced genetic defects and cancer. For example, research over the last several years has led to the identification of more than a dozen genes responsible for predisposition to cancer. These include genes for susceptibility to breast, lung, colon, and bladder cancer. The isolation and identification of these genes will provide new insights into the influence of environmental agents and the expression of gene function (gene-environmental inter-actions). Other studies have provided new insights on the many steps involved in the expression of carcinogenesis and those that are required for the conversion of normal cells to malignant cells with metastatic and invasive capacities. Genomic instability, accompanied by the amplification (or deletion) of certain gene sequences, has been shown to play a key role in many forms of cancer. A given mutation in a cancer gene can serve as a specific "fingerprint" for cancer cells and their progeny. Identification of specific point mutations has enabled doctors to detect rare cancer cells in the sputum of patients with lung cancer, the stool of patients with colon cancer, and the urine of patients with bladder cancer. Another category of genes, the cyclins and cyclin-related, also may be critical targets during multistage carcinogenesis, as they play a central role in controlling cell cycle progression. Dominant acting mutations in these genes could interfere with DNA repair or perturb DNA and chromosome replication. Studies on the gene cyclin D1 have shown that it is often amplified and overexpressed in human esophageal tumors and in several other types of human cancer including human hepatocellular carcinomas.

New molecular biology approaches to assess the biological relevance of exposure to a variety of chemicals including polyaromatic hydro-carbons, polychlorinated biphenols (PCBs), and dioxins have been developed. All of these chemicals "turn on" specific genes, often in unique ways. Techniques have been developed to examine "fingerprints" of gene expression in circulating white blood cells. These "fingerprints" may indicate the degree of exposure to environmental pollutants. The availability of such markers can be incorporated into epidemiological studies to identify those individuals who are at high risk and guide the development of appropriate prevention/intervention strategies. The usefulness of biomarkers for exposure to carcinogens to assess the risk of cancer in humans has been demonstrated in studies on the relationship between aflatoxin biomarkers and liver cancers in Shanghai, Guangxi Province, China. These studies show that exposure to aflatoxins in contaminated foods, in the presence of hepatitis B virus infection, increases the risk of acquiring hepatocellular carcinoma by at least 60-fold.

Recent advances in transgenic and recombinant DNA technologies have provided novel animal models for conducting detailed studies on the relationship between mutagenesis and carcinogenesis. These models will enable one to evaluate more precisely the mutagenic and carcinogenic potential of environmental pollutants. Quantitative comparisons have demonstrated that the potencies of carcinogens in humans and rodents are often similar. Comparative studies on molecular carcinogenesis can be used to define the common biological basis for cancers, establish the etiology of various cancers, and improve the predictive value of rodent models for the detection of human carcinogens. Rodent models can be very useful in the elucidation of factors that might influence genetic susceptibility to cancer in humans.

Future Goals

Collaborative studies, the sharing of technologies, and the exchange of information between Japanese and U.S. scientists have advanced our understanding of the interactions between the environment and individual susceptibility to mutagenesis and cancer. The Environmental Muta-genesis and Carcinogenesis Panels Conferences and various additional collaborative activities continue to foster communication and collaboration among scientists in both countries. The Panels will continue to focus on the molecular mechanisms of mutagenesis and carcinogenesis, genetic susceptibility, and risk estimation of environmental carcinogens and mutagens.

Over the next 5 years, the Environmental Mutagenesis and Carcinogenesis Panels hope to identify collaborative activities that are particularly relevant to developing countries and high risk populations. A long-term goal is the application of the above knowledge to the prevention of cancer and other genetic diseases at an inter-national level.

Selected References

1. Grollman AP, Moriya, M. Mutagenesis by 8-oxoguanine: An enemy within. Trends Genet 1993; 9:246-9.
2. Groopman JD, Wogan GN, Roebuck BD, Kensler TW. Molecular biomarkers for aflatoxins and their application to human cancer prevention. Cancer Res 1994; 54:1907s-11s.
3. Perera F. Biomarkers and molecular epidemiology of occupationally related cancer. J Toxicol Environ Health 1993; 40:203-15.
4. Tennant RW, Rao GN, Russfield A, Seilkop S, Braun AG. Chemical effects in transgenic mice bearing oncogenes expressed in mammary tissue. Carcinogenesis 1993; 14:29-35.
5. Wei J, Zhang Y-J, Kahn S, Hollstein M, Santella R, Lu S-H, Harris C, Montesano R, Weinstein IB. Altered expression of the cyclin D1 and retinoblastoma genes in human esophageal cancer. Proc Natl Acad Sci; USA 1993; 90:9026-30.

1. Kyoizumi S, Umeki S, Akiyama M, Hirai Y, Kusunoko Y, Nakamura N, Endoh K, Konishi J, Sasaki MS, Mori T, Fujita S, Cologne JB. Frequency of mutant T lymphocytes defective in the expression of the T-cell antigen receptor gene among radiation-exposed people. Mutation Res 1992; 265:173-80.
2. Akiyama N, Tsuruta H, Sasaki H, Sakamoto H, Hamaguchi M, Ohmura Y, Sato M, Ueda R, Hirai H, Yazaki Y, Sugimura T, Terada M. Messenger RNA levels of five genes located at chromosome 11q13 in B-cell tumors with chromosome translocation t (11;14) (q13;32). Cancer Res 1994; 54:377-9.
3. Canzian F, Ushijima T, Serikawa T, Wakabayashi K, Sugimura T, Nagao M. Instability of microsatellites in rat colon tumors induced by heterocyclic amines. Cancer Res 1994; 54:6315-7.
4. Araki A, Noguchi T, Kato F, Matsushima T. Improved method for mutagenicity testing of gaseous compounds by using a gas sampling bag. Mutation Res 1994; 307:335-44.
5. Hasegawa R, Miyata E, Futakuti M, Hagiwara A, Nagao M, Sugimura T, Ito N. Synergistic enhancement of hepatic foci development by combined treatment rats with 10 heterocyclic amines at low doses. Carcinogenesis 1994; 15:1037-41.