Much of organic chemistry is based on the ability of suitably structured chemicals to bind together through the formation of covalent bonds. Biochemistry is replete with exam ples of enzymatically catalyzed reactions in which normal body constituents can be linked through covalent bonds during the process of intermediary metabolism. The finding that xenobiotic chemicals that enter the body from the environment, are metabolized to highly reactive species, and then covalently react with cellular macromolecules to induce toxic and carcinogenic effects was an observation that spawned the research featured in the Fifth International Symposium on Biological Reactive Intermediates (BRI V). The group of investigators that became fascinated with this process and its signifi cance in terms of human health began their discussions in Turku, Finland (J 975), and continued them at Guildford, England (1980), College Park, Maryland (1985), Tucson, Arizona (1990), and Munich, Germany (1995). Among the results were a series of reports listed below, as well as the book for which this serves as the Preface. • Jollow, DJ., Kocsis, J.J., Snyder, R. and Vainio, H. (eds), Biological Reactive Intermediates: Formation, Toxicity and Inactivation, Plenum Press, NY, 1975. • Snyder, R., Park, D.V., Kocsis, J.J., Jollow, D.V., Gibson, G.G. and Witmer, C.M. (eds), Biological Reactive Intermediates II: Chemical Mechanisms and Biological Effects, Plenum Press, N.Y., 1982.

This volume presents a discussion of the biological effects produced following the metabolism of xenobiotic chemicals to chemically reactive metabolites, i.e., toxic and carcinogenic effects, which have been the basis of all five earlier volumes in this series. In particular, this volume devotes sections to structure-activity relationships, recent advances in the understanding of the chemistry of reactive metabolites, and the generation and activity of reactive oxygen species with special emphasis on nitric oxide. There are also segments on DNA damage by reactive metabolites and DNA repair, tissue specific responses to BRIs, and human health effects of BRIs. The papers that comprise this volume were submitted by world class scientists who were in attendance at The Symposium on Biological Reactive Intermediates VI at the Université René Descartes, July 16-20, 2000.

This volume contains the proceedings of the third in a series of conferences entitled, The International Symposium on Biological Reactive Intermediates. The first was held at the University of Turku in Finland, in 1975, the second at the University of Surrey in the United Kingdom, in 1980 and the most recent at the University of Maryland in the United States, in 1985. The significance of these conferences has been emphasized by the rapid growth of mechanistic toxicology over the last decade. These conferences were initially stimulated by the attempt to uncover the significance behind the observations that the toxicity of carcinogenic responses produced by many chemicals was associated with the observation that their metabolism led to the formation of chemcially reactive electrophiles which covalently bound to nucleophilic sites in cells such as proteins, nucleic acid or fats. Recently, newer concepts have arisen which have necessitated the expansion of subjects covered by the conference. For example, the application of newer knowledge of the role of active oxygen species in reactive metabolite formation, the concept of suicide substrates, examination of the function of glutathione in cells, application of immunological techniques and molecular biological probes to the solution of toxicological problems all had an impact on the study of the biological reactive intermediates.

The finding that chemicals can be metabolically activated to yield reactive chemical species capable of covalently binding to cellular macromolecules and the concept that these reactions could initiate toxicological and carcinogenic events stimulated a meeting by a small group of toxicologists at the University of Turku, in Finland, in 1975 (Jollow et al. , 1977). The growing interest in this field of research led to subsequent symposia at the University of Surrey, in England in 1980 (Snyder et al. , 1982), and the University of Maryland in the U. S. A. in 1985 (Kocsis et al. , 1986). The Fourth International Symposium on Biological Reactive Intermediates was hosted by the Center for Toxicology at the University of Arizona and convened in Tucson, Arizona, January 14-17, 1990. Over 300 people attended. There were 60 platform presentations by invited speakers, and 96 volunteer communications in the form of posters were offered. These meetings have grown from a small group of scientists working in closely related areas to a major international series of symposia which convene every five years to review, and place in context, the latest advances in our understanding of the formation, fate and consequences of biological reactive intermediates. The Organizing Committee: Allan H. Conney, Robert Snyder (Co-chairman), and Charlotte M. Witmer (Rutgers University, Piscataway, NJ), David J. Jollow Co chairman) (Medical University, South Carolina, Charleston, SC), 1. Glenn Sipes (Co chairman) (University of Arizona, Tucson, AZ), James J. Kocsis and George F.

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A wonderfully successful NATO Advanced Study Institute on "Sulfur-Centered Reactive Intermediates in Chemistry and Biology" was held 18-30 June, 1989, at the Hotel Villa del Mare in Maratea, Italy. Despite the beautiful setting with mountains behind us and over looking the clear blue Mediterranean Sea under a cloudless sky (and with a private beach available), the lectures were extremely well attended. While some credit can go to the seriousness of the students, more must go to the calibre of speakers and the high quality of C. Chatgilialoglu, and Co-Director, Professor K. -D. their presentations. The Director, Dr. Asmus, are to be congratulated for putting together such an outstanding scientific program. Dr. Chatgilialoglu is also to be commended for arranging an equally stimulating social pro gram which included bus, train and boat trips to many local sites of interest. It was particularly fitting that a meeting on the chemistry and biochemistry of sulfur should be held in Italy since Italian chemists have made major contributions to our under standing of the organic chemistry of sulfur, including the chemistry of its reactive inter mediates. The early Italian interest in sulfur chemistry arose from the fact that Italy, or more specifically, Sicily, was a major world producer of sulfur prior to the development and exploitation of the Frasch process in Texas and Louisiana.