title: The emperor wears no clothes in the field of carcinogen risk assessment: ignored concepts in cancer risk assessment.
abstract: The following is a position paper challenging the paradigm that 'carcinogen = mutagen', and that the current rodent bioassay to predict risks to human cancers is relevant and useful. Specifically, we review current observations concerning carcinogenesis that might lead to another approach for assessing the identification of human carcinogenic hazards and the risk assessment that chemicals might pose. We give a brief review of the multistage and multimechanism process of cancer in a tissue that involves not only genotoxic but also epigenetic events, and the importance of stem and progenitor cells in the development of cancer. We focus on the often ignored 'epigenetic' effects of carcinogens and the role of cell communication systems in epigenetically altering gene expression that leads to an imbalance of cell proliferation, differentiation and apoptosis in a tissue that can contribute to the cancer process. To draw attention to the fact that the current paradigm and policy to test toxic chemicals is often misleading and incorrect, we discuss how oxidative stress, in spite of the DNA damaging data, most probably contributes to cancer at the epigenetic level. Additionally, we briefly review how this mutagenic concept has greatly diverted attention away from doing research on the lower molecular weight, non-genotoxic, polycyclic aromatic hydrocarbons (PAHs), and how these low molecular weight PAHs are etiologically more relevant to the disease potential of environmental mixtures such as cigarette smoke.
authors.affiliation: National Food Safety Toxicology Center, Department of Pediatrics and Human Development, Michigan State University, East Lansing, MI 48824, USA. james.trosko@ht.msu.edu
authors.forename: James E
authors.initials: JE
authors.lastname: Trosko
authors.forename: Brad L
authors.initials: BL
authors.lastname: Upham
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015197:Carcinogenicity Tests; D002273:Carcinogens / Q000633:toxicity*; D002450:Cell Communication / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D044127:Epigenesis, Genetic; D006801:Humans; D008954:Models, Biological; D009153:Mutagens / Q000633:toxicity; D009369:Neoplasms / Q000139:chemically induced* / Q000235:genetics; D014411:Neoplastic Stem Cells / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects; D011084:Polycyclic Aromatic Hydrocarbons / Q000633:toxicity; D018570:Risk Assessment; D018874:Spheroids, Cellular
chemical_list: D002273:Carcinogens; D009153:Mutagens; D011084:Polycyclic Aromatic Hydrocarbons