- •CONTENTS
- •Preface
- •Contributors
- •1 Introduction to Toxicology
- •1.1 Definition and Scope, Relationship to Other Sciences, and History
- •1.1.2 Relationship to Other Sciences
- •1.1.3 A Brief History of Toxicology
- •1.3 Sources of Toxic Compounds
- •1.3.1 Exposure Classes
- •1.3.2 Use Classes
- •1.4 Movement of Toxicants in the Environment
- •Suggested Reading
- •2.1 Introduction
- •2.2 Cell Culture Techniques
- •2.2.1 Suspension Cell Culture
- •2.2.2 Monolayer Cell Culture
- •2.2.3 Indicators of Toxicity in Cultured Cells
- •2.3 Molecular Techniques
- •2.3.1 Molecular Cloning
- •2.3.2 cDNA and Genomic Libraries
- •2.3.3 Northern and Southern Blot Analyses
- •2.3.4 Polymerase Chain Reaction (PCR)
- •2.3.5 Evaluation of Gene Expression, Regulation, and Function
- •2.4 Immunochemical Techniques
- •Suggested Reading
- •3.1 Introduction
- •3.2 General Policies Related to Analytical Laboratories
- •3.2.1 Standard Operating Procedures (SOPs)
- •3.2.2 QA/QC Manuals
- •3.2.3 Procedural Manuals
- •3.2.4 Analytical Methods Files
- •3.2.5 Laboratory Information Management System (LIMS)
- •3.3 Analytical Measurement System
- •3.3.1 Analytical Instrument Calibration
- •3.3.2 Quantitation Approaches and Techniques
- •3.4 Quality Assurance (QA) Procedures
- •3.5 Quality Control (QC) Procedures
- •3.6 Summary
- •Suggested Reading
- •4 Exposure Classes, Toxicants in Air, Water, Soil, Domestic and Occupational Settings
- •4.1 Air Pollutants
- •4.1.1 History
- •4.1.2 Types of Air Pollutants
- •4.1.3 Sources of Air Pollutants
- •4.1.4 Examples of Air Pollutants
- •4.1.5 Environmental Effects
- •4.2 Water and Soil Pollutants
- •4.2.1 Sources of Water and Soil Pollutants
- •4.2.2 Examples of Pollutants
- •4.3 Occupational Toxicants
- •4.3.1 Regulation of Exposure Levels
- •4.3.2 Routes of Exposure
- •4.3.3 Examples of Industrial Toxicants
- •Suggested Reading
- •5 Classes of Toxicants: Use Classes
- •5.1 Introduction
- •5.2 Metals
- •5.2.1 History
- •5.2.2 Common Toxic Mechanisms and Sites of Action
- •5.2.3 Lead
- •5.2.4 Mercury
- •5.2.5 Cadmium
- •5.2.6 Chromium
- •5.2.7 Arsenic
- •5.2.8 Treatment of Metal Poisoning
- •5.3 Agricultural Chemicals (Pesticides)
- •5.3.1 Introduction
- •5.3.3 Organochlorine Insecticides
- •5.3.4 Organophosphorus Insecticides
- •5.3.5 Carbamate Insecticides
- •5.3.6 Botanical Insecticides
- •5.3.7 Pyrethroid Insecticides
- •5.3.8 New Insecticide Classes
- •5.3.9 Herbicides
- •5.3.10 Fungicides
- •5.3.11 Rodenticides
- •5.3.12 Fumigants
- •5.3.13 Conclusions
- •5.4 Food Additives and Contaminants
- •5.5 Toxins
- •5.5.1 History
- •5.5.2 Microbial Toxins
- •5.5.3 Mycotoxins
- •5.5.4 Algal Toxins
- •5.5.5 Plant Toxins
- •5.5.6 Animal Toxins
- •5.6 Solvents
- •5.7 Therapeutic Drugs
- •5.8 Drugs of Abuse
- •5.9 Combustion Products
- •5.10 Cosmetics
- •Suggested Reading
- •6 Absorption and Distribution of Toxicants
- •6.1 Introduction
- •6.2 Cell Membranes
- •6.3 Mechanisms of Transport
- •6.3.1 Passive Diffusion
- •6.4 Physicochemical Properties Relevant to Diffusion
- •6.4.1 Ionization
- •6.5 Routes of Absorption
- •6.5.1 Extent of Absorption
- •6.5.2 Gastrointestinal Absorption
- •6.5.3 Dermal Absorption
- •6.5.4 Respiratory Penetration
- •6.6 Toxicant Distribution
- •6.6.1 Physicochemical Properties and Protein Binding
- •6.7 Toxicokinetics
- •Suggested Reading
- •7 Metabolism of Toxicants
- •7.1 Introduction
- •7.2 Phase I Reactions
- •7.2.4 Nonmicrosomal Oxidations
- •7.2.5 Cooxidation by Cyclooxygenases
- •7.2.6 Reduction Reactions
- •7.2.7 Hydrolysis
- •7.2.8 Epoxide Hydration
- •7.2.9 DDT Dehydrochlorinase
- •7.3 Phase II Reactions
- •7.3.1 Glucuronide Conjugation
- •7.3.2 Glucoside Conjugation
- •7.3.3 Sulfate Conjugation
- •7.3.4 Methyltransferases
- •7.3.7 Acylation
- •7.3.8 Phosphate Conjugation
- •Suggested Reading
- •8 Reactive Metabolites
- •8.1 Introduction
- •8.2 Activation Enzymes
- •8.3 Nature and Stability of Reactive Metabolites
- •8.4 Fate of Reactive Metabolites
- •8.4.1 Binding to Cellular Macromolecules
- •8.4.2 Lipid Peroxidation
- •8.4.3 Trapping and Removal: Role of Glutathione
- •8.5 Factors Affecting Toxicity of Reactive Metabolites
- •8.5.1 Levels of Activating Enzymes
- •8.5.2 Levels of Conjugating Enzymes
- •8.5.3 Levels of Cofactors or Conjugating Chemicals
- •8.6 Examples of Activating Reactions
- •8.6.1 Parathion
- •8.6.2 Vinyl Chloride
- •8.6.3 Methanol
- •8.6.5 Carbon Tetrachloride
- •8.6.8 Acetaminophen
- •8.6.9 Cycasin
- •8.7 Future Developments
- •Suggested Reading
- •9.1 Introduction
- •9.2 Nutritional Effects
- •9.2.1 Protein
- •9.2.2 Carbohydrates
- •9.2.3 Lipids
- •9.2.4 Micronutrients
- •9.2.5 Starvation and Dehydration
- •9.2.6 Nutritional Requirements in Xenobiotic Metabolism
- •9.3 Physiological Effects
- •9.3.1 Development
- •9.3.2 Gender Differences
- •9.3.3 Hormones
- •9.3.4 Pregnancy
- •9.3.5 Disease
- •9.3.6 Diurnal Rhythms
- •9.4 Comparative and Genetic Effects
- •9.4.1 Variations Among Taxonomic Groups
- •9.4.2 Selectivity
- •9.4.3 Genetic Differences
- •9.5 Chemical Effects
- •9.5.1 Inhibition
- •9.5.2 Induction
- •9.5.3 Biphasic Effects: Inhibition and Induction
- •9.6 Environmental Effects
- •9.7 General Summary and Conclusions
- •Suggested Reading
- •10 Elimination of Toxicants
- •10.1 Introduction
- •10.2 Transport
- •10.3 Renal Elimination
- •10.4 Hepatic Elimination
- •10.4.2 Active Transporters of the Bile Canaliculus
- •10.5 Respiratory Elimination
- •10.6 Conclusion
- •Suggested Reading
- •11 Acute Toxicity
- •11.1 Introduction
- •11.2 Acute Exposure and Effect
- •11.3 Dose-response Relationships
- •11.4 Nonconventional Dose-response Relationships
- •11.5 Mechanisms of Acute Toxicity
- •11.5.1 Narcosis
- •11.5.2 Acetylcholinesterase Inhibition
- •11.5.3 Ion Channel Modulators
- •11.5.4 Inhibitors of Cellular Respiration
- •Suggested Reading
- •12 Chemical Carcinogenesis
- •12.1 General Aspects of Cancer
- •12.2 Human Cancer
- •12.2.1 Causes, Incidence, and Mortality Rates of Human Cancer
- •12.2.2 Known Human Carcinogens
- •12.3 Classes of Agents Associated with Carcinogenesis
- •12.3.2 Epigenetic Agents
- •12.4 General Aspects of Chemical Carcinogenesis
- •12.5 Initiation-Promotion Model for Chemical Carcinogenesis
- •12.6 Metabolic Activation of Chemical Carcinogens and DNA Adduct Formation
- •12.7 Oncogenes
- •12.8 Tumor Suppressor Genes
- •12.8.1 Inactivation of Tumor Suppressor Genes
- •12.8.2 p53 Tumor Suppressor Gene
- •12.9 General Aspects of Mutagenicity
- •12.10 Usefulness and Limitations of Mutagenicity Assays for the Identification of Carcinogens
- •Suggested Reading
- •13 Teratogenesis
- •13.1 Introduction
- •13.2 Principles of Teratology
- •13.3 Mammalian Embryology Overview
- •13.4 Critical Periods
- •13.5 Historical Teratogens
- •13.5.1 Thalidomide
- •13.5.2 Accutane (Isotetrinoin)
- •13.5.3 Diethylstilbestrol (DES)
- •13.5.4 Alcohol
- •13.6 Testing Protocols
- •13.6.1 FDA Guidelines for Reproduction Studies for Safety Evaluation of Drugs for Human Use
- •13.6.3 Alternative Test Methods
- •13.7 Conclusions
- •Suggested Reading
- •14 Hepatotoxicity
- •14.1 Introduction
- •14.1.1 Liver Structure
- •14.1.2 Liver Function
- •14.2 Susceptibility of the Liver
- •14.3 Types of Liver Injury
- •14.3.1 Fatty Liver
- •14.3.2 Necrosis
- •14.3.3 Apoptosis
- •14.3.4 Cholestasis
- •14.3.5 Cirrhosis
- •14.3.6 Hepatitis
- •14.3.7 Oxidative Stress
- •14.3.8 Carcinogenesis
- •14.4 Mechanisms of Hepatotoxicity
- •14.5 Examples of Hepatotoxicants
- •14.5.1 Carbon Tetrachloride
- •14.5.2 Ethanol
- •14.5.3 Bromobenzene
- •14.5.4 Acetaminophen
- •14.6 Metabolic Activation of Hepatotoxicants
- •Suggested Reading
- •15 Nephrotoxicity
- •15.1 Introduction
- •15.1.1 Structure of the Renal System
- •15.1.2 Function of the Renal System
- •15.2 Susceptibility of the Renal System
- •15.3 Examples of Nephrotoxicants
- •15.3.1 Metals
- •15.3.2 Aminoglycosides
- •15.3.3 Amphotericin B
- •15.3.4 Chloroform
- •15.3.5 Hexachlorobutadiene
- •Suggested Reading
- •16 Toxicology of the Nervous System
- •16.1 Introduction
- •16.2 The Nervous system
- •16.2.1 The Neuron
- •16.2.2 Neurotransmitters and their Receptors
- •16.2.3 Glial Cells
- •16.3 Toxicant Effects on the Nervous System
- •16.3.1 Structural Effects of Toxicants on Neurons
- •16.3.2 Effects of Toxicants on Other Cells
- •16.4 Neurotoxicity Testing
- •16.4.1 In vivo Tests of Human Exposure
- •16.4.2 In vivo Tests of Animal Exposure
- •16.4.3 In vitro Neurochemical and Histopathological End Points
- •16.5 Summary
- •Suggested Reading
- •17 Endocrine System
- •17.1 Introduction
- •17.2 Endocrine System
- •17.2.1 Nuclear Receptors
- •17.3 Endocrine Disruption
- •17.3.1 Hormone Receptor Agonists
- •17.3.2 Hormone Receptor Antagonists
- •17.3.3 Organizational versus Activational Effects of Endocrine Toxicants
- •17.3.4 Inhibitors of Hormone Synthesis
- •17.3.5 Inducers of Hormone Clearance
- •17.3.6 Hormone Displacement from Binding Proteins
- •17.4 Incidents of Endocrine Toxicity
- •17.4.1 Organizational Toxicity
- •17.4.2 Activational Toxicity
- •17.4.3 Hypothyroidism
- •17.5 Conclusion
- •Suggested Reading
- •18 Respiratory Toxicity
- •18.1 Introduction
- •18.1.1 Anatomy
- •18.1.2 Cell Types
- •18.1.3 Function
- •18.2 Susceptibility of the Respiratory System
- •18.2.1 Nasal
- •18.2.2 Lung
- •18.3 Types of Toxic Response
- •18.3.1 Irritation
- •18.3.2 Cell Necrosis
- •18.3.3 Fibrosis
- •18.3.4 Emphysema
- •18.3.5 Allergic Responses
- •18.3.6 Cancer
- •18.3.7 Mediators of Toxic Responses
- •18.4 Examples of Lung Toxicants Requiring Activation
- •18.4.1 Introduction
- •18.4.2 Monocrotaline
- •18.4.3 Ipomeanol
- •18.4.4 Paraquat
- •18.5 Defense Mechanisms
- •Suggested Reading
- •19 Immunotoxicity
- •19.1 Introduction
- •19.2 The Immune System
- •19.3 Immune Suppression
- •19.4 Classification of Immune-Mediated Injury (Hypersensitivity)
- •19.5 Effects of Chemicals on Allergic Disease
- •19.5.1 Allergic Contact Dermatitis
- •19.5.2 Respiratory Allergens
- •19.5.3 Adjuvants
- •19.6 Emerging Issues: Food Allergies, Autoimmunity, and the Developing Immune System
- •Suggested Reading
- •20 Reproductive System
- •20.1 Introduction
- •20.2 Male Reproductive Physiology
- •20.3 Mechanisms and Targets of Male Reproductive Toxicants
- •20.3.1 General Mechanisms
- •20.3.2 Effects on Germ Cells
- •20.3.3 Effects on Spermatogenesis and Sperm Quality
- •20.3.4 Effects on Sexual Behavior
- •20.3.5 Effects on Endocrine Function
- •20.4 Female Reproductive Physiology
- •20.5 Mechanisms and Targets of Female Reproductive Toxicants
- •20.5.1 Tranquilizers, Narcotics, and Social Drugs
- •20.5.2 Endocrine Disruptors (EDs)
- •20.5.3 Effects on Germ Cells
- •20.5.4 Effects on the Ovaries and Uterus
- •20.5.5 Effects on Sexual Behavior
- •Suggested Reading
- •21 Toxicity Testing
- •21.1 Introduction
- •21.2 Experimental Administration of Toxicants
- •21.2.1 Introduction
- •21.2.2 Routes of Administration
- •21.3 Chemical and Physical Properties
- •21.4 Exposure and Environmental Fate
- •21.5 In vivo Tests
- •21.5.1 Acute and Subchronic Toxicity Tests
- •21.5.2 Chronic Tests
- •21.5.3 Reproductive Toxicity and Teratogenicity
- •21.5.4 Special Tests
- •21.6 In vitro and Other Short-Term Tests
- •21.6.1 Introduction
- •21.6.2 Prokaryote Mutagenicity
- •21.6.3 Eukaryote Mutagenicity
- •21.6.4 DNA Damage and Repair
- •21.6.5 Chromosome Aberrations
- •21.6.6 Mammalian Cell Transformation
- •21.6.7 General Considerations and Testing Sequences
- •21.7 Ecological Effects
- •21.7.1 Laboratory Tests
- •21.7.2 Simulated Field Tests
- •21.7.3 Field Tests
- •21.8 Risk Analysis
- •21.9 The Future of Toxicity Testing
- •Suggested Reading
- •22 Forensic and Clinical Toxicology
- •22.1 Introduction
- •22.2 Foundations of Forensic Toxicology
- •22.3 Courtroom Testimony
- •22.4.1 Documentation Practices
- •22.4.2 Considerations for Forensic Toxicological Analysis
- •22.4.3 Drug Concentrations and Distribution
- •22.5 Laboratory Analyses
- •22.5.1 Colorimetric Screening Tests
- •22.5.2 Thermal Desorption
- •22.5.6 Enzymatic Immunoassay
- •22.6 Analytical Schemes for Toxicant Detection
- •22.7 Clinical Toxicology
- •22.7.1 History Taking
- •22.7.2 Basic Operating Rules in the Treatment of Toxicosis
- •22.7.3 Approaches to Selected Toxicoses
- •Suggested Reading
- •23 Prevention of Toxicity
- •23.1 Introduction
- •23.2 Legislation and Regulation
- •23.2.1 Federal Government
- •23.2.2 State Governments
- •23.2.3 Legislation and Regulation in Other Countries
- •23.3 Prevention in Different Environments
- •23.3.1 Home
- •23.3.2 Workplace
- •23.3.3 Pollution of Air, Water, and Land
- •23.4 Education
- •Suggested Reading
- •24 Human Health Risk Assessment
- •24.1 Introduction
- •24.2 Risk Assessment Methods
- •24.2.2 Exposure Assessment
- •24.2.3 Dose Response and Risk Characterization
- •24.3 Noncancer Risk Assessment
- •24.3.1 Default Uncertainty and Modifying Factors
- •24.3.2 Derivation of Developmental Toxicant RfD
- •24.3.3 Determination of RfD and RfC of Naphthalene with the NOAEL Approach
- •24.3.4 Benchmark Dose Approach
- •24.3.5 Determination of BMD and BMDL for ETU
- •24.3.6 Quantifying Risk for Noncarcinogenic Effects: Hazard Quotient
- •24.3.7 Chemical Mixtures
- •24.4 Cancer Risk Assessment
- •24.5 PBPK Modeling
- •Suggested Reading
- •25 Analytical Methods in Toxicology
- •25.1 Introduction
- •25.2 Chemical and Physical Methods
- •25.2.1 Sampling
- •25.2.2 Experimental Studies
- •25.2.3 Forensic Studies
- •25.2.4 Sample Preparation
- •25.2.6 Spectroscopy
- •25.2.7 Other Analytical Methods
- •Suggested Reading
- •26 Basics of Environmental Toxicology
- •26.1 Introduction
- •26.2 Environmental Persistence
- •26.2.1 Abiotic Degradation
- •26.2.2 Biotic Degradation
- •26.2.3 Nondegradative Elimination Processes
- •26.3 Bioaccumulation
- •26.4 Toxicity
- •26.4.1 Acute Toxicity
- •26.4.2 Mechanisms of Acute Toxicity
- •26.4.3 Chronic Toxicity
- •26.4.5 Abiotic and Biotic Interactions
- •26.5 Conclusion
- •Suggested Reading
- •27.1 Introduction
- •27.2 Sources of Toxicants to the Environment
- •27.3 Transport Processes
- •27.3.1 Advection
- •27.3.2 Diffusion
- •27.4 Equilibrium Partitioning
- •27.5 Transformation Processes
- •27.5.1 Reversible Reactions
- •27.5.2 Irreversible Reactions
- •27.6 Environmental Fate Models
- •Suggested Reading
- •28 Environmental Risk Assessment
- •28.1 Introduction
- •28.2 Formulating the Problem
- •28.2.1 Selecting Assessment End Points
- •28.2.2 Developing Conceptual Models
- •28.2.3 Selecting Measures
- •28.3 Analyzing Exposure and Effects Information
- •28.3.1 Characterizing Exposure
- •28.3.2 Characterizing Ecological Effects
- •28.4 Characterizing Risk
- •28.4.1 Estimating Risk
- •28.4.2 Describing Risk
- •28.5 Managing Risk
- •Suggested Reading
- •29 Future Considerations for Environmental and Human Health
- •29.1 Introduction
- •29.2 Risk Management
- •29.3 Risk Assessment
- •29.4 Hazard and Exposure Assessment
- •29.5 In vivo Toxicity
- •29.6 In vitro Toxicity
- •29.7 Biochemical and Molecular Toxicology
- •29.8 Development of Selective Toxicants
- •Glossary
- •Index
ONCOGENES 245
methanesulfonate alkylate DNA to produce N-alkylated and O-alkylated purines and pyrimidines. Ionizing radiation and reactive oxygen species commonly oxidize guanine to produce 8-oxoguanine. Formation of DNA adducts may involve any of the bases, although the N -7 position of guanine is one the most nucleophilic sites in DNA. Of importance is how long the adduct is retained in the DNA. (+)-Benzo[a]pyrene-7,8- diol-9,10-epoxide-2 forms adducts mainly at guanine N -2, while aflatoxin B1 epoxide, another well-studied rodent and human carcinogen, binds preferentially to the N -7 position of guanine. For some carcinogens there is a strong correlation between the formation of very specific DNA-adducts and tumorigenicity. Quantitation and identification of specific carcinogen adducts may be useful as biomarkers of exposure. Importantly, the identification of specific DNA-adducts has allowed for the prediction of specific point mutations that would likely occur in the daughter cell provided that there was no repair of the DNA-adduct in the parent cell. As will be discussed in a later section, some of these expected mutations have been identified in specific oncogenes and tumor suppressor genes in chemically induced rodent tumors, providing support that the covalent carcinogen binding produced the observed mutation. In several cases, specific base pair changes in p53 tumor suppressor gene in human tumors are associated with a mutational spectrum that is consistent with exposure of the individual to a specific carcinogen. For example, the mutation spectra identified in p53 in human tumors thought to result from the exposure of the individual to ultraviolet radiation (UVR), aflatoxin, and benzo[a]pyrene (from cigarette smoke), are consistent with the observed specific mutational damage in p53 induced by these agents in experimental cellular systems.
12.7ONCOGENES
12.7.1Mutational Activation of Proto-oncogenes
Much evidence has accumulated for a role of covalent binding of reactive electrophilic carcinogens to DNA in chemical carcinogenesis. It is known that chemical mutagens and carcinogens can produce point mutations, frameshift mutations, strand breaks, and chromosome aberrations in mammalian cells. If the interaction of a chemical carcinogen with DNA leading to a permanent alteration in the DNA is a critical event in chemical carcinogenesis, then the identification of these altered genes and the function of their protein products is essential to our understanding of chemical carcinogenesis. While specific DNA-carcinogen adducts were isolated in the 1970s and 1980s, it was not until the early to mid-1980s that the identification of specific genes that were mutationally altered by chemical carcinogens became known. Certain normal cellular genes, termed proto-oncogenes, can be mutated by chemical carcinogens providing a selective growth advantage to the cell. The mutational activation of proto-oncogenes is strongly associated with tumor formation, carcinogenesis, and cell transformation. Proto-oncogenes are highly conserved in evolution and their expression is tightly regulated. Their protein products function in the control of normal cellular proliferation, differentiation, and apoptosis. However, when these genes are altered by a mutation, chromosome translocation, gene amplification, or promoter insertion, an abnormal protein product or an abnormal amount of product is produced. Under these circumstances these genes have the ability to transform cells in vitro, and they are termed oncogenes.
246 |
CHEMICAL CARCINOGENESIS |
|
Table 12.7 Oncogene Classification |
|
|
|
|
|
Families |
|
Genes |
|
|
|
Growth factors |
sis, hst-1, int-2, wnt-1 |
|
Growth factor receptor tyrosine kinases |
EGFR, fms, met/HGFR, ErbB2/neu/HER2, trk/NGFR |
|
Nonreceptor tyrosine kinases |
abl, src, fgr, fes, yes, lck |
|
Guanine nucleotide binding proteins |
H-ras, K-ras, N-ras, TC21, GA12 |
|
Serine/threonine kinases |
mos, raf, bcr, pim-1 |
|
DNA-binding proteins |
myc, fos, myb, jun, E2F1, ets, rel |
|
|
|
|
Over a 100 oncogenes have been identified with approximately 30 oncogenes having a major role in human cancer.
Most oncogene protein products appear to function in one way or another in cellular signal transduction pathways that are involved in regulating cell growth, differentiation or apoptosis. Signal transduction pathways are used by the cells to receive and process information to ultimately produce a biological cellular response. These pathways are the cellular circuitry conveying specific information from the outside of the cell to the nucleus. In the nucleus, specific genes are expressed, and their encoded proteins produce the evoked biological response. Oncogenes encode proteins that are components of this cellular circuitry (Table 12.7). If a component of the circuit is altered, then the entire cellular circuit of which the component is a part is altered. It is not difficult to imagine how an alteration in a pathway that regulates cellular growth, differentiation, or apoptosis could have very profound effects on cellular homeostasis. Indeed, this is the molecular basis of how oncogenes contribute to the cancer process.
12.7.2Ras Oncogene
Ras genes are frequently mutated in chemically induced animal tumors and are the most frequently detected mutated oncogenes in human tumors. Approximately 20–30% of all human tumors contain mutated ras. The Ras subfamily includes H-ras, K-ras, and N-ras, and all have been found to be mutationally activated in numerous types of tumors from a large variety of species including humans.
Activated ras oncogenes have been detected in a large number of animal tumors induced by diverse agents including physical agents, such as radiation, and a large number of chemical carcinogens. Some chemical carcinogens bind covalently to DNA, forming specific adducts which upon DNA replication yields characteristic alterations in the primary sequence of the Ha-ras proto-oncogene. The study of the ras oncogene as a target for chemical carcinogens has revealed a correlation between specific carcinogen-DNA adducts and specific activating mutations of ras in chemically induced tumors. For example, 7,12-dimethylbenz[a]anthracene, a polycyclic aromatic hydrocarbon carcinogen, is metabolically activated to a bay-region diol epoxide that binds preferentially to adenine residues in DNA. Skin tumors isolated from mice treated with DMBA contain an activated H-ras oncogene with an A to T transversion of the middle base in the 61st codon of H-ras. Therefore the identified mutation in ras is consistent with the expected mutation based on the DMBA-DNA adducts which have been identified. Likewise rat mammary carcinomas induced by nitrosomethylurea contain a G to A transition in the 12th codon of H-ras, and this mutation is consistent
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