- •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
240 CHEMICAL CARCINOGENESIS
fat, and protein intake), excess alcohol, and late age of pregnancy are considered to function through a promotion mechanism. While smoking and UVR have initiating activity, both are also considered to have tumor-promoting activity. By definition, tumor promoters are not classified as carcinogens since they are considered inactive in the absence of initiated cells. However, an altered genotype or an initiated cell can arise from spontaneous mutations resulting from imperfect DNA replication/repair oxidative DNA damage, or can result from environmental carcinogens. Theoretically, in the presence of a tumor promoter these mutant cells would clonally expand to form a tumor. Therefore the nomenclature becomes somewhat a matter of semantics as to whether the tumor promoter should or should not be classified as a carcinogen. Certain hormones and immunosuppressive agents are classified as human carcinogens, although it is generally considered that these agents are not carcinogenic in the absence of initiated cells. Rather, like tumor promoters, they may only allow for the clonal expansion of cells with an altered genotype.
Some nongenotoxic/epigenetic agents have been shown to induce DNA damage in vivo, for example, some “nongenotoxic/epigenetic agents” can induce oxidative DNA damage in vivo through the direct or indirect production of reactive oxygen species. For example, certain estrogens may possess this ability and such a characteristic may contribute to their carcinogenicity. Thus, as we gain a better understanding of chemical carcinogenesis, we find that there is functional and mechanistic overlap and interaction between these two major categories of chemical carcinogens.
12.4GENERAL ASPECTS OF CHEMICAL CARCINOGENESIS
A great deal of evidence has accumulated in support of the somatic mutation theory of carcinogenesis, which simply states that mutations within somatic cells is necessary for neoplasia. As stated earlier, cancer development (carcinogenesis) involves the accumulation of mutations in multiple critical genes. These mutations can be the result of imperfect DNA replication/repair, oxidative DNA damage, and/or DNA damage caused by environmental carcinogens. Many chemical carcinogens can alter DNA through covalent interaction (DNA adducts) or direct and/or indirect oxidative DNA damage. Some chemical carcinogens are intrinsically reactive and can directly covalently bind to DNA, while others require metabolic via cytochromes P450 to produce reactive electrophilic intermediates capable of covalently binding to DNA (Figure 12.10). In the 1950s Elizabeth and James Miller observed that a diverse array of chemicals could produce cancer in rodents. In an attempt to explain this, they hypothesized that many carcinogens are metabolically activated to electrophilic metabolites that are capable of interacting with nucleophilic sites in DNA. The Millers termed this the electrophilic theory of chemical carcinogenesis. From this concept of metabolic activation, the important terms parent, proximate, and ultimate carcinogen were developed. A parent carcinogen is a compound that must be metabolized in order to have carcinogenic activity; a proximate carcinogen is an intermediate metabolite requiring further metabolism and resulting in the ultimate carcinogen, which is the actual metabolite that covalently binds to the DNA. The cell has many defense systems to detoxify the carcinogenic species, including cellular antioxidants and nucleophiles as well as a whole host of phase I and phase II enzymes. In addition reactive carcinogenic species may bind to noncritical sites in the cell, resulting in detoxification, or they can undergo spontaneous decomposition. If the carcinogenic species binds to DNA, the adducted DNA
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INITIATION-PROMOTION MODEL FOR CHEMICAL CARCINOGENESIS |
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Precarcinogen |
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Direct Acting Carcinogen |
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Ultimate Carcinogen |
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Noncritical Binding |
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Apoptosis |
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Repair |
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Promotion (clonal expansion: epigenetic process) |
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Malignant Tumor
Figure 12.10 General aspects of chemically induced carcinogenesis.
can be repaired and produce a normal cell. If there is error in the repair of the DNA or the DNA adduct is not repaired before the cell replicates, an error in the newly synthesized DNA could occur, and if so, a mutation would occur in the DNA of the daughter cell. If this change has occurred in a critical gene, for example, in a protooncogene or tumor suppressor gene, it would represent an important mutagenic event(s) in carcinogenesis.
The mutationally altered cell or “initiated cell” has an altered genotype and may remain dormant (not undergo clonal expansion) for the lifetime of the animal. However, additional mutations or “hits” in critical genes followed by clonal expansion could lead to tumor development as described earlier in this chapter. In addition to this mechanism, chemical carcinogenesis in experimental models can be divided into at least three stages: termed initiation, promotion, and progression (Figure 12.10); this model is thus often referred to as the initiation/promotion model of chemical carcinogenesis. As mentioned above, the “initiated cell” may remain dormant (not undergo clonal expansion) for the lifetime of the animal. However, if the animal is repeatedly exposed to a tumor promoter, it will provide a selective growth advantage to the “initiated cell,” which will clonally expand and eventually produce a benign tumor. This process is termed tumor promotion and is an epigenetic process favoring the growth of cells with an altered genotype. The development of a malignant tumor from a benign tumor encompasses a third step, termed progression and involves additional genetic changes.
12.5 INITIATION-PROMOTION MODEL FOR CHEMICAL CARCINOGENESIS
Experimentally, the initiation-promotion process has been demonstrated in several organs/tissues including skin, liver, lung, colon, mammary gland, prostate, and bladder
242 CHEMICAL CARCINOGENESIS
Group A X
No tumors
B X P P P P P P P
Tumors
C X P P P P P P P
Tumors
D P P P P P P P X
No tumors
E P P P P P P P
No tumors
F X P P P P P P P P
No tumors
Time
Figure 12.11 Initiation/promotion model. X = application of initiator, P = application of promoter.
as well as in variety of cells in culture. While tumor promoters have different mechanisms of action and many are organ specific, all have common operational features (Figure 12.11). These features include (1) following a subthreshold dose of initiating carcinogen, chronic treatment with a tumor promoter will produce many tumors; (2) initiation at a subthreshold dose alone will produce very few if any tumors;
(3) chronic treatment with a tumor promoter in the absence of initiation will produce very few if any tumors; (4) the order of treatment is critical as it must be first initiated and then promoted; (5) initiation produces an irreversible change; and (6) promotion is reversible in the early stages, for example, if an equal number of promoting doses are administered but the doses are spaced further apart in time, tumors would not develop or would be greatly diminished in number. Many tumor promoters are organ specific. For example, 12-O-tetradecanoylphorbol-13-acetate (TPA) also known as phorbol 12myristate 13-acetate (PMA) belongs to a family of compounds known as phorbol esters. Phorbol esters are isolated from croton oil (derived from the seeds of the croton plant) and are almost exclusively active in skin. Phenobarbital, DDT, chlordane, TCDD and peroxisome proliferators Wy 24,643, clofibrate, and nafenopin are hepatic tumor promoters. TCDD is also a promoter in lung and skin. Some bile acids are colonic tumor promoters, while various estrogens are tumor promoters in the mammary gland and liver. There are multiple mechanisms of tumor promotion, and this may explain the organ specific nature of the many promoters. Under conditions in which the chemical produces tumors without tumor promoter treatment, the chemical agent is often referred to as a complete carcinogen.
It is generally accepted that tumor promoters allow for the clonal expansion of initiated cells by interfering with signal transduction pathways that are involved in the regulation of cell growth, differentiation, and/or apoptosis (Table 12.6). While the precise mechanisms of tumor promotion are not completely understood at the molecular/biochemical level, current research is providing new and promising mechanistic insights into how tumor promoters allow for the selective growth of initiated cells.
METABOLIC ACTIVATION OF CHEMICAL CARCINOGENS AND DNA ADDUCT FORMATION |
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Table 12.6 Some General Mechanisms of Tumor Promotion
Selective proliferation of initiated cells
Increased responsiveness to and/or production of growth factors, hormones, and other active molecules
Decreased responsiveness to inhibitory growth signals Perturbation of intracellular signaling pathways
Altered differentiation
Inhibition of terminal differentiation of initiated cells
Acceleration of differentiation of uninitiated cells
Inhibition of apoptosis in initiated cells
Toxicity/compensatory hyperplasia
Resistance to toxicity by initiated cells
12.6 METABOLIC ACTIVATION OF CHEMICAL CARCINOGENS AND DNA ADDUCT FORMATION
Having described the general aspects of chemical carcinogenesis including the initia- tion-promotion model, we now examine some aspects of chemical carcinogenesis in more detail. Metabolic activation of chemical carcinogens by cytochromes P450 is well documented. The metabolism of benzo[a]pyrene has been extensively studied and at least 15 major phase I metabolites have been identified. Many of these metabolites are further metabolized by phase II enzymes to produce numerous different metabolites. Extensive research has elucidated which of these metabolites and pathways are important in the carcinogenic process. As shown in Figure 12.12, benzo[a]pyrene is metabolized by cytochrome P450 to benzo[a]pyrene-7,8 epoxide, which is then hydrated by epoxide hydrolase to form benzo[a]pyrene-7,8-diol. Benzo[a]pyrene-7,8-diol is considered the proximate carcinogen since it must be further metabolized by cytochrome P450 to form the ultimate carcinogen, the bay region diol epoxide, (+)-benzo[a]pyrene- 7,8-diol-9,10-epoxide-2. It is this reactive intermediate that binds covalently to DNA, forming DNA adducts. (+)-Benzo[a]pyrene-7,8-diol-9,10-epoxide-2 binds preferentially to deoxyguanine residues, forming N -2 adduct. (+)-Benzo[a]pyrene-7,8-diol- 9,10-epoxide-2 is highly mutagenic in eukaryotic and prokaryotic cells and carcinogenic in rodents. It is important to note that not only is the chemical configuration of the metabolites of many polycyclic aromatic hydrocarbons important for their carcinogenic activity, but so is their chemical conformation/stereospecificity (Figure 12.12). For example, four different stereoisomers of benzo[a]pyrene-7,8-diol-9,10 epoxide are formed. Each one only differs with respect to whether the epoxide or hydroxyl groups are above or below the plane of the flat benzo[a]pyrene molecule, but only one, (+)- benzo[a]pyrene-7,8-diol-9,10-epoxide-2, has significant carcinogenic potential. Many polycyclic aromatic hydrocarbons are metabolized to bay-region diol epoxides. The bay-region theory suggests that the bay-region diol epoxides are the ultimate carcinogenic metabolites of polycyclic aromatic hydrocarbons.
DNA can be altered by strand breakage, oxidative damage, large bulky adducts, and alkylation. Carcinogens such as N-methyl-N -nitro-N-nitrosoguanidine and methyl
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Figure 12.12 Benzo[a]pyrene metabolism to the ultimate carcinogenic species. Heavy arrows indicate major metabolic pathways, * represents ultimate carcinogenic species. (Adapted from A. H. Conney, Cancer Res. 42: 4875, 1982.)
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