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.

Table of Contents:
Sessions I - VI.- Cytochrome P-450 Oxidations and the Generation of Biologically Reactive Intermediates.- Formation of Reactive Intermediates by Phase II Enzymes: Glutathione-Dependent Bioactivation Reactions.- Role of the Well-Known Basic and Recently Discovered Acidic Glutathione S-Transf erases in the Control of Genotoxic Metabolites.- Bioactivation of Xenobiotics by Flavin-Containing Monooxygenases.- Formation of Biological Reactive Intermediates By Peroxidases: Halide Mediated Acetaminophen Oxidation and Cytotoxicity.- Peroxyl Free Radicals: Biological Reactive Intermediates Produced During Lipid Oxidation.- Biological Significance of Active Oxygen Species: In Vitro Studies on Singlet Oxygen-Induced DNA Damage and on the Singlet Oxygen Quenching Ability of Carotenoids, Tocopherols and Thiols.- Physiological and Toxicological Roles of Hydroperoxides.- Overview: Theoretical Aspects of Isotope Effects on the Pattern of Metabolites Formed by Cytochrome P-450.- S-Thiolation of Protein Sulfhydryls.- Cytochrome P-450 as a Target of Biological Reactive Intermediates.- Hapten Carrier Conjugates Associated with Halothane Hepatitis.- Metabolism of Drugs by Activated Leukocytes: Implications for Drug-Induced Lupus and Other Drug Hypersensitivity Reactions.- Formation of Reactive Metabolites and Appearance of Anti-Organelle Antibodies in Man.- Formation of a Protein-Acetaldehyde Adduct in Liver During Chronic Alcohol Exposure.- Dose-Response Relationships in Chemical Carcinogenesis: From DNA Adducts to Tumor Incidence.- The Single Cell Gel (SCG) Assay: An Electrophoretic Technique for the Detection of DNA Damage in Individual Cells.- Monitoring Human Exposure to Environmental Carcinogens.- Comparing the Frequency and Spectra of Mutations Induced When an SV40-Based Shuttle Vector Containing Covalently Bound Residues of Structurally-Related Carcinogens Replicates in Human Cells.- Molecular Targets of Chemical Mutagens.- Mutagenic Consequences of the Alteration of DNA by Chemicals and Radiation.- Gene Specific Damage and Repair After Treatment of Cells with UV and Chemotherapeutical Agents.- Proto-Oncogene Activation in Rodent and Human Tumors.- Short Communications.- Toxicity of 3-Methyleneoxindole, A Proposed Reactive Intermediate in the Metabolism of 3-Methylindole.- The Role of Cytochrome P450IIE1 in Bioactivation of Acetaminophen in Diabetic and Acetone-Treated Mice.- Arylamine-Induced Hemolytic Anemia: Electron Spin Resonance Spectrometry Studies.- Selective Alterations in the Profiles of Newly Synthesized Proteins by Acetaminophen (APAP) and Its Dimethylated Analogues: Relationship to Oxidative Stress.- Benzene Metabolism by Two Purified, Reconstituted Rat Hepatic Mixed Function Oxidase Systems.- Stereochemical Induction of Cytochrome P450IVA1 (P452) and Peroxisome Proliferation in Male Rat.- Cyanide Liberation and Oxidative Stress by Organothiocyanates, Organonitriles and Nitroprusside in Isolated Hepatocytes.- Mixed Function Oxidase Enzyme Responses to In Vivo and In Vitro Chromate Treatment.- Fatty Acid ?-Oxidation-Dependent Bioactivation of 5,6-Dichloro-4-Thia-5-Hexenoate and Analogs in Isolated Rat Hepatocytes.- Role of the Acetone Inducible P-450IIE1 in the Deethylation of Diethylnitrosamine In Hamster.- Stereochemistry of the Microsomal Glutathione S-Transferase-Catalyzed Addition of Glutathione to Chlorotrifluoroethene in Isolated Rat Hepatocytes.- The Pathophysiological Significance of Reactive Oxygen Formation in Rat Liver.- Oxidative Stress During Hypoxia in Isolated-Perfused Rat Heart.- Alteration of Growth Rate and Fibronectin by Imbalances in Superoxide Dismutase and Glutathione Peroxidase Activity.- The Antidotal Activity of the Thiol Drug Diethyldithiocarbamate Against N-Acetyl-p-Benzoquinone Imine in Isolated Hepatocytes.- Two Classes of Azo Dye Reductase Activity Associated with Rat Liver Microsomal Cytochrome P-450.- Expression of a cDNA Encoding Rat Liver DT-Diaphorase in Escherichia Coli.- Suicidal Inactivation of Cytochrome P-450 by Halothane and Carbon Tetrachloride.- Structure-Activity Relationships of Acrylate Esters: Reactivity Towards Glutathione and Hydrolysis by Carboxylesterase In Vitro.- Glutathione Conjugates of Hydralazine Formed in Theperoxidase/Hydrogen Peroxide/Glutathione System.- Contribution of 3,4-Dichlorophenylhydroxylamine in Propanil-Induced Hemolytic Anemia.- A Reduction in Mixed Function Oxidases and in Tumor Promoting Effects of Ethanol in a NDEA-Initiated Hepatocarcinogenesis Model.- Selective Inducers of the Coh-Locus Enhance the Metabolisms of Cou marin- and of Quinoline-Derivatives But Not That of Naphthalenes.- Primaquine-Induced Oxidative Stress in Isolated Hepatocytes as a Result of Reductive Activation.- Nitroprusside: A Potpourri of Biologically Reactive Intermediates.- Denitrosation of N-Nitrosodimethylamine in the Rat In Vivo.- Effect of Phenol and Catechol on the Kinetics of Human Myeloperoxidase-Dependent Hydroquinone Metabolism.- Activation of 1-Hydroxymethylpyrene to an Electrophilic and Mutagenic Metabolite by Rat Hepatic Sulfotransferase Activity.- Bioactivation of 2,6-Di-Tert-Butyl-4-Methyl Phenol (BHT) and Hydroxylated Analogues to Toxic Quinoid Metabolites.- Further Evidence for the Role of Myeloperoxidase in the Activation of Benzo[A]Pyrene-7,8-Dihydrodiol by Polymorpho-Nuclear Leukocytesm.- Quinones and Their Glutathione Conjugates as Irreversible Inhibitors of Glutathione S-Transferases.- Cytochrome P450 IA2 Activity in Man Measured by Caffeine Metabolism: Effect of Smoking, Broccoli, and Exercise.- Tissue Difference in Expression of Cytochrome P-450 Between Liver and Lung of Syrian Golden Hamsters Treated with 3-Methylcholanthrene.- Session VII - XII.- Role of Calcium in Toxic and Programmed Cell Death.- Molecular Mechanisms of ?-Diketone Neuropathy.- Microtubule Assembly Is Altered Following Covalent Modification by the n-Hexane Metabolite 2,5-Hexanedione.- The Role of Hepatic Metabolites of Benzene in Bone Marrow Peroxidase-Mediated Myelo- and Genotoxicity.- Glutathione Conjugation as a Mechanism of Targeting Latent Quinones to the Kidney.- Hepatic Bioactivation of 4-Vinylcyclohexene to Ovotoxic Epoxides.- Testicular Metabolism and Toxicity of Halogenated Propanes.- Lung Vascular Injury from Monocrotaline Pyrrole, a Putative Hepatic Metabolite.- Reactive Oxygen Species in the Progression of CCl4-Induced Liver Injury.- Parenchymal and Nonparenchymal Cell Interactions in Hepatotoxicity.- Signal Paths and Regulation of Superoxide, Eicosanoid, and Cytokine Formation in Macrophages of Rat Liver.- Reactive Metabolites from N-Nitrosamines.- Bisfuranoid Mycotoxins: Their Genotoxicity and Carcinogenicity.- Covalent Bonding of Bay-Region Diol Epoxides to Nucleic Acids.- Electrophilic Sulfuric Acid Ester Metabolites of Hydroxy-Methyl Aromatic Hydrocarbons as Precursors of Hepatic Benzylic DNA Adducts In Vivo.- Heterocyclic Amines: New Mutagens and Carcinogenes in Cooked Foods.- Acetaminophen and Protein Thiol Modification.- Formation and Reactivity of a Quinone Methide in Biological Systems.- Mechanisms for Pyrrolizidine Alkaloid Activation and Detoxification.- Sulfur Conjugates as Putative Pneumotoxic Metabolites of the Pyrrolizidine Alkaloid, Monocrotaline.- The Metabolism of Benzene to Muconic Acid, A Potential Biological Marker of Benzene Exposure.- Lessons on the Second Cancers Resulting from Cancer Chemotherapy.- Genetic Polymorphism of Drug Metabolism in Humans.- Human Health Risk Assessment and Biological Reactive Intermediates: Hemoglobin Binding.- Quantitating the Production of Biological Reactive Intermediates in Target Tissues: Example, Dichloromethane.- Trapping of Reactive Intermediates by Incorporation of 14C-Sodium Cyanide During Microsomal Oxidation.- Multiple Bioactivation of Chloroform: A Comparison Between Man and Experimental Animals.- Short Communications.- CCl4-Induced Cytochrome P-450 Loss and Lipid Peroxidation in Rat Liver Slices.- Alteration of Benzo(A)Pyrene-DNA Adduct Formation by Rats Exposed to Simple Mixtures.- Comparison of the Toxicity of Naphthalene and Naphthalene-1,2-Dihydrodiol (DIOL).- Selective Binding of Acetaminophen (APAP) to Liver Proteins in Mice and Men.- Post-Treatment Protection with Piperonyl Butoxide Against Acetaminophen Hepatotoxicity is Associated with Changes in Selective But Not Total Covalent Binding.- Covalent Binding of a Halothane Metabolite and Neoantigen Production in Guinea Pig Liver Slices.- Extensive Alteration of Genomic DNA and Rise in Nuclear Ca2+In Vivo Early After Hepatotoxic Acetaminophen Overdose in Mice.- The Possible Role of Glutathione on the Hepatotoxic Effect of Papaverine Hydrochloride In Vitro.- In Vivo and In Vitro Evidence for In Situ Activation and Selective Covalent Binding of Acetaminophen (APAP) in Mouse Kidney.- Metabolism of Dichlorobenzenes in Organ Cultured Liver Slices.- Inhibition of Protein Synthesis and Secretion by Volatile Anesthetics in Guinea Pig Liver Slices.- Dichlorobenzene Hepatotoxicity Strain Differences and Structure Activity Relationships.- The Use of 19F NMR in the Study of Protein Alkylation by Fluorinated Reactive Intermediates.- S-Ethylthiotrifluoroacetate Enhancement of the Immune Response to Halothane in the Guinea Pig.- Bone Marrow DNA Adducts and Bone Marrow Cellularity Following Treatment with Benzene Metabolites In Vivo.- The Role of ?-Glutamyl Transpeptidase in Hydroquinone-Glutathione Conjugate Mediated Nephrotoxicity.- Cytochrome P450IIE1 Metabolism of Pyridines: Evidence for Production of a Reactive Intermediate Which Exhibits Redox-Cycling Activity and Causes DNA Damage.- Morphological Cell Transformation and DNA Adduction by Benz(J)Aceanthrylene and Its Presumptive Reactive Metabolites in C3H10T1/2CL8 Cells.- Covalent Binding of Oxidative Biotransformation Reactive Intermediates to Protein Influences Halothane-Associated Hepatotoxicity in Guinea Pigs.- The Nephrotoxicity of 2,5-Dichloro-3-(Glutathion-S-YL)-1,4-Benzo-Quinone. and 2,5,6-Trichloro-3-(Glutathion-S-YL)-1,4-Benzoquinone Is Potentiated by Ascorbic Acid and AT-125.- Generation of Free Radicals Results in Increased Rates of Protein Degradation in Human Erythrocytes.- Free Radicals Generated in Ethanol Metabolism May Be Responsible for Tumor Promoting Effects of Ethanol.- Composition of Hepatic Lipids After Ethanol, Cod Liver Oil and Vitamin E Feeding in Rats.- Dietary Polyunsaturated Fatty Acid Promote Peroxidation and Its Possible Role in the Promotion of Cancer.- Chiral Epoxides, Their Enantioselective Reactivity Towards Nucleic Acids, and a First Outline of a Quantum Chemical Structure-Reactivity Calculation.- Comparison of 8-Hydroxydeoxyguanosine and 5-Hydroxy-Methyluracil as Products of Oxidative DNA Damage.- Modulation of Aortic Smooth Muscle Cell Prolifertion by Dinitrotoluene.- Reactive Potential of Diethylstilbestrol Reactive Metabolites Towards Cellular Nuclear Proteins: Implications for Estrogen-Induced Carcinogenesis.- Biochemical and Morphologic Response of Nasal Epithelia to Hyperoxia.- Membrane Stabilization as a Fundamental Event in the Mechanism of Chemoprotection Against Chemical Intoxication.- Biochemical Effects and Toxicity of Mitoxantrone in Cultured Heart Cells.- Evidence for the Induction of an Oxidative Stress in Rat Hepatic Mitochondria by 2,3,7,8-Tetrachlorodibenzo-P-Dioxin (TCDD).- Antioxidation Potential of Indole Compounds - Structure Activity Studies.- Measurement of Styrene-Oxide Cysteine Adducts in Hemoglobin by Selective Catalytic Reduction.- Studies on Biochemical Determinants of Quinone-Induced Toxicity in Primary Murine Bone Marrow Stromal Cells.- Selective Alteration of Cytokeratin Intermediate Filament by Cyclosporine A Is a Lethal Toxicity in PTK2 Cell Cultures.- Rat Hepatic DNA Damage Induced by 1,2,3-Trichloropropane.- Oxidation of Reduced Porphyrins by the Mitochondrial Electron Transport Chain: Stimulation by Iron and Potential Role of Reactive Oxygen Species.- Future Research Needs for the Application of Mechanistic Data to Risk Assessment.- Contributors.