Helmut Greim is a toxicologist and former chair of the Institute of Toxicology and Environmental Hygiene at the Technical University of Munich, Germany. His research experience is drug metabolism, toxicokinetics, mechanisms of carcinogenic agents, in vitro test systems. He has been member or chair of numerous national and international scientific committees. In 1996 he received the Arnold Lehman Award of SOT and in 2001 the Herbert Stockinger Award of the American Conference of Governmental Industrial Hygienists. At present he chairs the Scientific Committee on Health and Environmental Risks of the DG SANCO, Brussels, is member of the Scientific Committee on Occupational Exposure Limits of DG EMPLOYMENT, Luxembourg and member of the Risk Assessment Committee of the European Chemicals Agency in Helsinki, Finland. Dr. Albertini is currently Research Professor of Pathology at the University of Vermont (USA). He retired from the Department of Medicine at that University in 2000 and is now an Emeritus Professor of Medicine. He received the M.D. degree in 1963 and a Ph.D. in Medical Genetics in 1972, both from the University of Wisconsin, Madison (USA). Dr. Albertini joined the Department of Medicine at the University of Vermont that same year, becoming full Professor in 1979. He was clinically active in the areas of oncology, hematology and AIDS for many years and served as Director of the Vermont Cancer Center from 1993 to 1995. Dr. Albertini’s fundamental research has been and remains in the area of mutagenesis and the relationship of somatic mutations to cancer. In the past, Dr. Albertini served as President of the Environmental Mutagen Society and as editor-in-chief of Environmental and Molecular Mutagenesis.

The Cellular Response to the Genotoxic Insult

The Question of Threshold for Genotoxic Carcinogens

By Helmut Greim, Richard J. Albertini

The Royal Society of Chemistry

Copyright © 2012 The Royal Society of Chemistry
All rights reserved.
ISBN: 978-1-84973-177-5

Contents

Introduction and Conclusion: The Rationale for Thresholds for Genotoxic Carcinogens Helmut Greim and Richard J. Albertini,
1. Threshold Effects Observed in Experimental Studies,
2. Metabolic Inactivation of Genotoxic Reactants,
3. DNA Repair,
4. Apoptosis,
5. Epigenetic Mechanisms,
Subject Index,

CHAPTER 1

Mechanisms Responsible for the Chromosome and Gene Mutations Driving Carcinogenesis: Implications for Dose-Response Characteristics of Mutagenic Carcinogens

R. JULIAN PRESTON

National Health and Environmental Effects Research Laboratory, US Environmental Protection Agency, Research Triangle Park, NC 27711, USA

Email: preston.julian@epa.gov

1.1.1 Introduction

Over the past few years the development of sophisticated techniques for sequencing genomes and for establishing gene expression profiles, for example, has led to a much more detailed characterization of tumors at the molecular level. What is apparent is that the carcinogenic process is complex and involves a range of interacting genotypic and phenotypic alterations to drive a normal cell to a transformed one and ultimately to a tumor. In addition, the role of environmental agents in initiating or accelerating this process is becoming better understood. However, putting all of these types of information together to predict the likelihood of an exposure scenario inducing tumors above the background level is really a daunting task. This is necessary if it is going to be possible to characterize tumor dose-response curves in a qualitative and quantitative manner. The aim of this chapter is to consider the form of tumor dose-response curves for mutagenic chemicals and to determine whether or not there is the potential for non-linearity or perhaps a threshold response.

1.1.2 Genetic Alterations and Cancer

It is well-recognized that all cancers contain somatic mutations. In fact, it has been shown that a metastatic tumor contains in excess of 10 000 genetic alterations, both gene and chromosomal. However, it has been determined that a subset of these alterations can be considered to be driver mutations because they confer a selective growth advantage and thus are integral to cancer development. The non-driver genetic alterations are termed ‘passengers’ because they are a product of the cancer process that confers genomic instability on cells.

Recent studies have shed some light on the drivers for specific tumors and for cancers overall. Pleasance et al. sequenced the genomes of a malignant melanoma and a lymphoblastoid cell line from one individual and thereby developed a catalogue of the somatic mutations from an individual cancer. Although the specific drivers could not be identified from a single cancer, the method could be applied to a large number of similar cancer types to identify the drivers. However, it was possible to identify mutations that were consistent with exposure to ultraviolet (UV) light — a known risk factor for melanoma.

Using a similar ultra high throughput sequencing approach, Greenman et al. re-sequenced 210 cancer cell genomes and concluded, based on computational analysis, that there were driver mutations in about 120 genes, with the remainder (of the order of a thousand) being passengers. Based on this st