Radiation risk to low fluences of α particles may be greater than we thought

Abstract

Based principally on the cancer incidence found in survivors of the atomic bombs dropped in Hiroshima and Nagasaki, the International Commission on Radiation Protection (ICRP) and the United States National Council on Radiation Protection and Measurements (NCRP) have recommended that estimates of cancer risk for low dose exposure be extrapolated from higher doses by using a linear, no-threshold model. This recommendation is based on the dogma that the DNA of the nucleus is the main target for radiationinduced genotoxicity and, as fewer cells are directly damaged, the deleterious effects of radiation proportionally decline. In this paper, we used a precision microbeam to target an exact fraction (either 100% or <20%) of the cells in a confluent population and irradiated their nuclei with exactly one ␣ particle each. We found that the frequencies of induced mutations and chromosomal changes in populations where some known fractions of nuclei were hit are consistent with non-hit cells contributing significantly to the response. In fact, irradiation of 10% of a confluent mammalian cell population with a single ␣ particle per cell results in a mutant yield similar to that observed when all of the cells in the population are irradiated. This effect was significantly eliminated in cells pretreated with a 1 mM dose of octanol, which inhibits gap junction-mediated intercellular communication, or in cells carrying a dominant negative connexin 43 vector. The data imply that the relevant target for radiation mutagenesis is larger than an individual cell and suggest a need to reconsider the validity of the linear extrapolation in making risk estimates for low dose, high linear-energy-transfer (LET) radiation exposure.

Genomic instability and bystander effects induced by high-LET radiation

“…Although these cells are immortalized Figure 8 Mutation frequency as a function of the number of aparticles per nucleus (data for the average number of particle traversals were calculated from cell population in which defined proportion of cells were exposed to a single a-particle). Due to the bystander effect, which is evident when only a proportion of the population is exposed, the risk at low doses is higher than predicted by a linear extrapolation from high doses (based on the data of Hei et al, 1997;Zhou et al, 2001) either spontaneously (MCF-10F human breast) or though viral transduction (BEP2D human bronchial), they are phenotypically normal, and do not express any transformed characteristics such as anchorage-independent growth and tumorigenicity in nude mice. After exposure to either 140 keV/mm a-particles or 1 GeV nucleon 56 Fe ions, transformed cells arise through a series of sequential stages including altered growth pattern, resistance to serum-induced terminal differentiation, agar-positive growth, tumorigenicity and metastasis ( Figure 9, Hei et al, 1994;Piao et al, 1999;Calaf and Hei, 2000).…”

“…A further series of experiments identified the importance of cell-cell communication via gap junctions as a mechanism of the bystander effect (Zhou et al, 2001). When A L cells were transfected with a dominantnegative connexin 43 vector (DN6), which eliminates gap-junction communication, the bystander effect essentially disappeared.…”

“…Thus, a simple linear extrapolation of radiation risk from intermediate (where they can be measured) to lower doses (where they must be inferred) would be of questionable validity, at least at high LET. This is illustrated in Figure 8, which combines the data of Zhou et al (2001) where only a proportion of cells are irradiated with a single particle (allowing the bystander effect to be manifest), together with a previous compilation of data by Hei et al (1997) where all cells were exposed to various numbers of particles from 1 to 4. Under these experimental conditions, it is evident that a linear extrapolation of risks from high to low doses (which average less than one particle per cell) would underestimate the risks at low doses.…”

Sharing signals: connecting lung epithelial cells with gap junction channels

“…Consistent with gap junctionmediated transmission of toxic substances in a more native system, cell death induced by gamma irradiation is cell density dependent and is abrogated by gap junction inhibitors (194). Even radiation levels on the order of one alpha particle per five cells can create cytotoxic substances transmitted through Cx43 gap junction channels (312).…”

A correlation of long term effects and radiation quality in the progeny of bystander cells after microbeam radiations: The experimental study of radiotherapy for cancer risk mitigation

“…However, there is a significant evidence suggesting that similar effects can also be seen in non-irradiated bystander cells, a phenomenon known as the non-targeted effects which include bystander effects, genomic instability and others [1][2][3][4][5][6][7][8][9]. Bystander effect refers to the phenomenon that the induction of biological effects in non-irradiated bystander cells whose nucleus has not been directly traversed by IR [10].…”