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.

Mitochondrial dysfunction in human pathologies

“…those that modify the structure of microtubules). However, the relevance of carcinogens whose main action is the increased production of ROS, is becoming evident (234,235). ROS can mutate DNA both directly and indirectly.…”

Mesenchymal Stem Cells: An Innovative Approach in Pharmacokinetics

“…This involves the transfer of a low molecular weight fluorescent dye (<1000Da) between contiguous cells [41]. It is thought that chronic disruption of GJIC may release some factors that favor clonal expansion and ultimately tumor formation [42]. Reduced expression of GJs following treatment with nongenotoxic carcinogens appears to affect specific target organ [43,44].…”

Oxidative-Dependent Integration of Signal Transduction with Intercellular Gap Junctional Communication in the Control of Gene Expression

“…These pathways, either directly or indirectly, are widely involved in many of the cells redox responses (1). Cancer is a disease that involves aberrant communication between and within cells (22,99), and MAPK pathways are key signaling networks involved in the regulation of normal cell proliferation, survival, and differentiation (22,79), thus redox regulation of MAPK pathways is one significant and probable link of oxidative stress and cancer. Numerous articles have been published that clearly link oxidative stress with hyperproliferation of cells within a tissue and has been clearly a focus of cancer research, thus understanding the mechanism of redox regulation of mitogenic signaling pathways such as MAPKs will offer more specific strategies of preventions and cures.…”

“…However, pathological causes of many chronic diseases, particularly cancer, have also been linked with noncytotoxic nongenotoxic events, and the role of ROS and antioxidants in human diseases must also address epigenetic events (10,15,29,76,99).…”

“…Yet, many chronic diseases affiliated with oxidative stress, such as cancer and cardiovascular diseases, are not always a consequence of tissue necrosis, DNA damage, and genetic instability and mutations, or protein damage, but rather to altered gene expression through epigenetic mechanisms (98,99,104). Organic peroxides, for example, act as tumor promoters and not as initiators (34,53,73,86), indicating that these oxidants are not mutagens, but rather epigenetic effectors.…”