ANS National
 Meetings/
 Sessions

November 1995

James E. Trosko

(Michigan State Univ)

1. Can Low-Level Radiation Cause Cancer?

"Cancer is not 'caused' by only one thing

                "Health in a multi-cellular organism is maintained by homeostatic processes. Disruption of these homeostatic controls at the molecular, biochemical, cellular, and organ systems levels can be brought about by irreversible changes in the genetic material (mutagenesis), cell death (cytotoxicity), or reversible changes in the expression of genes at the transcriptional, translational, or posttranslational levels (epigenesis). While radiation is known to induce DNA damage/mutations, cell, death and epigenetic changes, in addition to cancers that are found in radiation-exposed animals, experimentally, and in humans, epidemiologically, the question is, At low-level exposure, what is the risk that cancers are 'caused' by the radiation?

"CANCER IS A MULTI-STEP, MULTI-MECHANISM PROCESS

                "Our understanding of experimental in vitro and in vive studies, as well as epidemiological data, suggests that carcinogenesis is the result of many endogenous and exogenous factors interacting during a multi-step, multi-mechanism process.^l No single factor causes cancer.²

                "Carcinogenesis a multi-step, multi-mechanism process involving the irreversible conversion of a stem cell to a terminal-differentiation-resistant cell (initiation), followed by the clonal expansion of this cell (promotion) and by the acquisition of other genetic and epigenetic alterations leading to malignancy (progression) (Fig. 1)

                "The initiation and progression steps seem to be facilitated by mutagenesis, whereas promotion has been associated with agents that cause mitogenesis (e.g., cell killing, growth regulators, chemical mitogens). Regardless of the actual mechanisms that could lead to cancer, cancer cells are phenotypically characterized as being non-contact inhibited, blocked in their ability to terminally differentiate and having no growth control. In effect, cancer is a problem of homeostatic control within and between cells. Cancer is more than a cell problem, it is a cell-society problem.

                "A hypothesis had been advanced that cancer cells are the result of some dysfunction in gap junction intercellular communication (GJIC). Cell-to-cell communication, mediated by extracellular factors (growth regulators, hormones, neurotransmitters, etc.), which trigger intracellular signals (e.g., Cell, pH, phosphorylation changes), could modulate (up or down) GJIC (Fig. 2).

                "This integrated hypothesis postulates that chemical promoters, oncogenes coding for growth factors, receptors or transmembrane signaling elements, and transcription factors can isolate an initiated cell from the suppressing influence of surrounding normal cells by downregulating the transfer of ions and small molecules through gap junctions. Tumor-suppressor genes would be predicted to upregulate GJIC or to prevent the downregulation of GJIC by oncogenes.

                "Ionizing radiation, as an efficient clastogen and inducer of deletion mutations, might be affecting any of the steps (e.g., deleting regulator genes controlling oncogenes, rearranging oncogenes to have altered expression, causing cell death to promote surviving stem cells initiated by other agents, and deleting tumor-suppressor genes). The stem cell pool at the time of acute ionizing radiation, the number of initiated cells in the body, and the amount of cell killing by a given dose of ionizing radiation would all contribute to the carcinogenic risk.

                "It will be difficult to estimate the frequency of gene or chromosomal mutations in the few stem cells that give rise to cancer. If ionizing radiation leaves a unique fingerprint in the kind of DNA lesions/mutations found in the tumors of exposed organisms (molecular epidemiology), there might be some estimate to ionizing radiation's contributory role in carcinogenesis. Even more difficult will be the estimation of ionizing radiation's role in inducing cell death (particularly in the induction of apoptosis or in the induction of altered gene expression) because both of these end points are induced by many natural and other exogenous non-radiation factors. At low-level exposure, detecting biomarkers for ionizing radiation's effects on signal transduction, an epigenetic effect, will be difficult to assess.³"

1. J.E.TROSKO, "Radiation-induced Carcinogenesis: Paradigm Considerations, "Biological Effects of Low Level Exposures: Dose-Response Relationships, p. 205,E. J. CALABRESE, Ed., CRC Press, Boca Raton, Florida (1994).

2. J.E.TROSKO, "Does Radiation Cause Cancer?" RERF Update 4, 3 (1992).

3. J.E.TROSKO, "Epigenetic Biomarker: Potentials and Limitations," Biomarkers and Occupational Health, p. 264, M. MENDELSON, J.P. JEETERS, M.J. NORMANDY, Eds., Joseph Henry Press, Washington. D.C. (1995).