The Carcinogenic Effects of Polycyclic Aromatic Hydrocarbons

The following sections are included:

• Preface

• In Memoriam: Anthony Dipple (1940–1999)

• List of Contributors

• Contents

The association of human cancer with the exposure to polycyclic aromatic hydrocarbons (PAHs) dates back to Percivall Pott's observation of chimney sweeps' cancer in 1775.¹ Pott (1714–1788), who was surgeon to St. Bartholomew's Hospital in London, described the occurrence of scrotal cancer in chimney sweeps, and traced it to the contamination of the skin by soot. The interest of this observation lay in the first proof of the environmental origin of one particular form of cancer. About 100 years later, Volkmann and Bell confirmed the early observation made by Pott by describing several cases of scrotal skin tumors among workers in the German and Scottish paraffin industry, respectively.^2,3 In 1907, the following definition was included into the Workmen's Compensation Act of Great Britain: "scrotal epithelioma occurring in chimney sweeps and epitheliomatous cancer or ulceration of the skin occurring in the handling or use of pitch, tar or tarry compounds".⁴ With this addendum it has been officially acknowledged for the first time that cancer of any cutaneous site could be caused by pitch, tar or tarry compounds. A few years later, bitumen, mineral oil and paraffin were also included into the Compensation Act. All of these regulations resulted from the knowledge that was gained in the second half of the nineteenth and the beginning of the twentieth century, when the skin carcinogenicity of soot, tar and related PAH-containing mixtures was confirmed under various work place conditions.⁴ Until then, physicians collected the unforeseen outcome of an undesigned and undesirable grand-scale 'natural experiment' based on the rise of industrialization. The imperative next step was that of systematic inquiry and reproduction of the diseases at will. After many failures to reproduce the human outcome in laboratory animals, success was finally achieved by Yamagiwa and Ichikawa in 1915. Their report on the production of malignant epithelial tumors by repetitive application of coal tar to the ear skin of rabbits^5,6 marked the transition into the modern era of PAH-related experimental cancer research. Shortly thereafter, painting of the back of mice was introduced as a method of biological testing of carcinogenic tars,⁷ and subsequently ethereal extracts of soot were confirmed to be carcinogenic in this mouse model.⁸…

The following sections are included:

• Introduction

• Structure-Activity Relationships

• Enzymatic Activation
  • Monooxygenation and Dihydrodiol Epoxide Pathway
  • Stereochemistry of Activation
  • One-Electron Oxidation
  • Formation of Quinones
  • 'Bioalkylation' and Benzyfic Ester Pathway

• Detoxification

• Summary and Perspectives

• Acknowledgment

• References

The following sections are included:

• Introduction

• Studies at Work Places/Occupational Exposure to PAHs

• Non-Occupational Exposure to PAHs

• Metabolism and Excretion of PAHs

• Biomonitoring of PAHs and Their Metabolites
  • Principal Considerations
  • 1-Hydroxypyrene and Its Glucuronide
  • Enzyme Polymorphisms and Excretion Levels of 1-Hydroxypyrene
  • Phenanthrene Metabolites
  • Benzo[a]pyrene Metabolites

• Summary

• Conclusions

• Acknowledgment

• References

The following sections are included:

• Introduction

• Methods of Detection

• Occupational Exposure to PAHs
  • Iron and Steel Production
  • Aluminum Production
  • Coke Ovens and Graphite Electrode Manufacture
  • Other Occupational Exposures

• Environmental Exposure to PAHs

• Coal Tar Therapy

• Diet

• Discussion and Summary

• Acknowledgment

• References

The following sections are included:

• Introduction

• Evolution of Research on PAHs

• Chemistry and Biological Effects

• Significance of Stable versus Unstable PAH-DNA Adducts

• Mutagenicity of PAH-DNA Adducts
  • Site-Specific Mutagenicity of PAH-DNA Adducts
    • Effects of host cell co-factors, DNA sequence context, and stereochemistry of DNA adducts
    • Effects of leading versus lagging strands of DNA
    • Effects of structural bioactivity and DNA reparability: fjord-region versus bay-region-containing PAHs
  • Translesional Synthesis

• Cancer Epidemiology and PAH-DNA Adducts
  • Mapping of PAH-DNA Adducts
  • Additional Evidence for the Etiological Relevance of PAHs in Human Carcinogenesis: The Exemplary Case of p53 Mutations in Lung Cancer

• Concluding Remarks

• Acknowledgment

• References

The following sections are included:

• Introduction

• Nucleotide Excision Repair
  • Mammalian DNA Nucleotide Excision Repair
  • Subunits of the Human NER Machinery
  • Transcription-Coupled DNA Repair
  • Global NER Deficiency and Cancer

• Repair of PAH-DNA Adducts
  • The In Vitro Oligonucleotide Excision Reaction
  • Base Pair Conformation-Dependent Excision of B[a]PDE-dG Adducts
  • Unrepaired Fjord-Region PAH-DNA Adducts in Ras Codon 61 Mutational Hotspots
  • Bipartite Recognition of PAH-DNA Adducts
  • Modulation of Human NER Activity by 5-Methyicytosines
  • Antagonistic Interaction of NER Factors between Substrate and Decoy DNA Adducts
  • Mechanism of PAH Adduct Recognition by the Human NER Machinery

• Conclusion

• Acknowledgment

• References

The following sections are included:

• Introduction

• Cancer-Related Genetic and Epigenetic Alterations induced by PAHs
  • Ras Activation
  • Effects on p53
  • Effects on Mitogen-Activated Protein Kinases
  • Disruption of BRCA1 Expression
  • Inhibition of Intercellular Communication

• Atherosclerosis-Related Alterations Induced by PAHs

• Apoptosis-Related Alterations Induced by PAHs

• Summary

• Acknowledgment

• References

The following sections are included:

• Introduction

• Bacterial Systems
  • In Vitro Mutagenicity Tests Using Bacterial Target Cells
  • Other Endpoints of Genotoxicity in Bacterial Target Cells
  • Host-Mediated Assays Using Microbial Target Cells

• Mammalian Systems
  • Mutations in Mammalian Cells in Culture
  • Other Endpoints of Genotoxicity Using Mammalian Ceils in Culture
  • Genotoxicity in Mammalian Cells In Vivo

• Characterization of DNA Sequence Changes Induced by PAHs

• Summary

• Acknowledgment

• References

The following sections are included:

• Introduction

• Environmental Genotoxic Agents

• PAHs as Representative Examples of Environmental Mammary Carcinogens
  • Levels and Carcinogenic Potency of PAHs
  • Metabolic Activation of PAHs and Potential Biomarkers

• NO₂-PAHs as Representative Examples of Environmental Mammary Carcinogens
  • Levels and Carcinogenic Potency of NO₂-PAHs
  • Metabolic Activation of NO₂-PAHs and Potential Biomarkers

• Summary and Future Recommendations

• Acknowledgment

• References

The following sections are included:

• Introduction

• Cytochrome P450-Dependent Monooxygenases
  • CYP1A1
  • CYP1B1
  • CYP2C9

• Epoxide Hydrolase

• Glutathione S-Transferases

• NAD(P)H:Quinone Oxidoreductase

• Myeloperoxidase

• Combined Genotype Effects

• Concluding Remarks

• References

The following sections are included:

• Exposure and Risk

• Incorporation and Biotransformation

• Monitoring Human Exposure

• Molecular Epidemiology: Individual's Susceptibility?

• Molecular Mechanisms of DNA Damage

• Reprise

• Acknowledgment

• References

The following sections are included:

• List of Abbreviations

• Index