The Effects of
Low Level Ionizing Radiation Exposure on
Living Tissue, Cells, Chromosomes and DNA
(Return to: TOP; Table of Contents; Author Index)
Summary:
Every living thing
on this planet is exposed to low-level ionizing radiation (LLIR) from both
natural and man-made sources. Natural uranium, radium and radon and their
radioactive decay products are present in low concentrations throughout our
air, water and earth. Since the advent of the nuclear age, and particularly as
a result of atmospheric nuclear testing from 1945 through 1972, many
biologically active radioactive isotopes have been produced and have been
dispersed around the world. Nuclear accidents such as those at
Unlike ultraviolet
radiation from the sun and other sources of low-energy electromagnetic
radiation which must actually strike a molecule to do damage, ionizing
radiation creates a path of disrupted molecules in its wake. Alpha and beta
particles, emitted as ionizing radiation from radioactive sources, are
electrically charged. It is this electrical charge that rips electrons out of
neighboring molecules when the charged particle passes nearby. This “force at a
distance” effect is similar to moving a magnet above a pile of iron filings.
X-rays and the more energetic gamma rays, though not charged, are also ionizing
radiation through what is known as the Compton effect. When one of these
high-energy photons strikes a molecule, it causes one of the molecule’s own
electrons to fly off from the molecule as a high-energy beta particle,
destroying the molecule in the process. Furthermore, along with the released
electron, a new gamma or X-ray having a somewhat lower energy than the
original, is also given off, allowing the process to repeat several more times.
Thus a single sufficiently energetic gamma ray can be responsible for the
release of many ionizing beta particles.
The Bystander Effect and Low Dose Effects in Radiation Induced Cytotoxicity
The following articles show that radiation damage can induce signals in cells that are sent to neighboring cells that have not received direct radiation. This “bystander effect” can result in far more cellular damage than expected for the number of cells that are directly hit by alpha and beta particles. This information has been neglected in most arguments that suggest that internalized depleted uranium would not have sufficient radiation effects to produce a significant increase in cancers. These papers discuss the implications of this effect for radon gas exposure, but it would also apply to ionizing particles emitted by any radioactive element, including uranium or plutonium. It has been argued “If DNA damage were to occur in bystander cells in vivo, and these cells survived such damage, these results would impact significantly on the assessment of cancer risk initiated by low fluence exposures to alpha radiation.” [Azzam et al., PNAS, 98, 478, 2001, see below] .
Details:
Batchelor (1), in 1980, demonstrated that when enriched uranium (with higher concentration of fissionable U-235 than depleted uranium) was introduced into rat lungs by injection or inhalation, and the rat subjected to neutron bombardment (thus initiating nuclear fission of the U-235), squamous cell carcinomas developed at the site containing enriched uranium. Injected depleted uranium oxide did not show this effect, and adenocarcinomas were observed in rats subjected to enriched uranium oxide exposure even without neutron bombardment, clearly demonstrating that alpha particle radiation from uranium oxides in pulmonary tissue is carcinogenic.
Sister chromatid exchange (SCE) is generally believed to lead to increased genetic mutations in daughter cells. Nagasawa (2) observed SCE in hamster ovary cells in 1992 after low-dose alpha particle irradiation and found that 30% of the cells were affected even though only 1% of the cells had been directly exposed.
In 1996, Chen (3) reported developing a computer simulation to predict radiation-induced chromosome abberations. Using FISH (fluorescent in-situ hybridization) to visualize a wide variety of chromosome aberrations, Chen (11) compared the results obtained from a computer simulation and found a good correlation.
Brenner (4) reports in 1996 that chromatid exchanges observed in Hiroshima A-bomb blast victims points to neutrons, rather than gamma radiation as previously thought, as being the dominant exposure vector. This in turn calls to question previous conclusions on which dose and exposure risk data have been based.
RC Miller (5), of Columbia U, found that oncogenic transformation in cells from direct exposure to radon gas (which emits alpha particles with a variety of energies) was comparable to that produced from exposure to a spectrum of energy-tuned alpha particles from an accelerator, lending credence to the use of laboratory methodology for determining exposure limits for radon gas.
Sachs (6) calculates that irradiation therapy to kill cancer cells must take into account the growth rate of the cancer cells between treatments and concludes that concentrating irradiation dosage earlier in the program is best. Sachs also calculates the proximity effects (7) that give rise to chromosome aberrations when a damaged DNA molecule attempts to repair itself after being exposed to ionizing radiation and further reported (9) that comparing the ratio of intraarm vs. interarm chromatid exchanges might provide a means of deducing extent of initial radiation exposure. He concludes (10) that at low radiation dosage, the linear quadratic model is the best predictor of resulting molecular damage. Brenner (8) also defended the use of the linear quadratic model as appropriate in clinical radiation oncology and later reported (13) that this model and others commonly used in radiation therapy for time-dose relationships produce similar results.
Hei (12) reported that single alpha particle exposure to a cell resulted in less than 20% mortality but a high mutagenicity (110 cells out of 100,000 survivors), with both figures being dose dependent. Miller (15) reported oncogenic transforming potential to cells traversed by single alpha particles and multiple alpha particles and found risks to be much lower than anticipated for single particle exposure. One conclusion from this study was that extrapolating radon risk from population studies of uranium miners to risks associated with domestic radon exposure might tend to overestimate domestic risk.
Sachs (14) reported in 1998 on the observed clustering of DNA double strand breaks (DSB) along a chromosome and on creating a model relating the extent of clustering to the intensity of radiation dose. Johnson (16) reported that DNA cleavage from radiation exposure was non-random, with certain chromosomes as well as certain specific regions within chromosomes experiencing greater likelihood of damage. However, Cornforth (30) reported in 2002 that his experiments pointed to essentially random damage within the irradiated chromosomes.
Brenner (24) showed that chromosome damage can serve as a reliable biomarker for previous exposure to radiation. Hande (31), using a new technique to detect chromosome damage, found that blood cells of plutonium workers showed a long-lasting signature of previous radiation exposure, even among workers whose exposure had ended many years before.
Lehnert (28f) reported on the influence of reactive oxygen species initiated within cells by ionizing radiation and/or chemical exposure and the possible beneficial and detrimental effects resulting from such exposure.
Smith (20) studied low radiation doses to determine if they might be more effective in destroying tumor cells than higher doses, but found no significant deviation from the linear quadratic model even for the low radiation dose experiments. RC Miller (21), (22) showed that low energy neutron irradiation of cells result in oncogenic transformations.
Nagasawa (19) observed the bystander effect at low radiation doses on Chinese hamster ovarian cells. Sawant (25), Brenner (26), 28a, (29), (32), Azzam (27), Iyer (22m), (28m) , Zhou (23), (28), (33), Mitchell (35), (36) and Ponnaiya (37) reported on their detailed studies of bystander effects. Goldberg (29m) published a review in 2002 detailing studies on the bystander effect.
Brenner (34) published a review in 2003 on risks associated with low energy radiation exposure and proposed that the minimum exposure level demonstrated to date that results in cancer formation is 10-50 msev for acute exposure and 50-100 msev for protracted exposure and suggested that the linear no-threshold model is appropriate for extrapolating dose/risk relationships to extremely small dose levels.
(Return to: TOP; Table of Contents; Author Index)
1. The
carcinogenic effect of localized fission fragment irradiation of rat lung,
by AL Batchelor, et al.. Int J Radiat
Biol Relat Stud Phys Chem Med. Vol. 37(3), Mar. 1980 (pp. 249-66).
In a preliminary
investigation of 'hot particle' carcinogenesis uranium oxide particles were
introduced into the lungs of rats either by intubation of a liquid suspension
of the particles or by inhalation of an aerosol. Subsequently the animals were
briefly exposed to slow neutrons in a nuclear reactor, resulting in localized
irradiation of the lung by fission fragments emitted from 235U atoms in the
oxide particles. The uranium used in the intubation experiments was either
enriched or depleted in 235U. Squamous cell carcinomas developed at the site of
deposition of the enriched uranium oxide in many cases but no lung tumours
occurred in the rats with the depleted uranium oxide, in which the lung tissue
was exposed to very few fission fragments. Only enriched uranium oxide was used
in the inhalation experiments. Pulmonary squamous cell carcinomas occurred
after the fission fragment irradiation but were fewer than in the intubation
experiments. Adenocarcinomas of the lung were seen in rats exposed to uranium
oxide without subsequent irradiation by neutrons in the reactor and in rats
irradiated with neutrons but not previously exposed to uranium oxide. It is
concluded that (i) fission fragments were possibly implicated in the genesis of
the squamous cell carcinomas, which only developed in those animals exposed to
enriched uranium oxide and neutrons and (ii) the adenocarcinomas in the rats
inhaling enriched uranium oxide only were likely to have been caused by
protracted irradiation of the lung with alpha-rays emitted from the enriched
uranium.
[Batchelor198003IJRBv37n3p249]. ( PMID: 6966271 [PubMed - indexed for MEDLINE])
2. Induction of sister chromatid exchanges by extremely low doses of alpha-particles, by H. Nagasawa, et al., Cancer Research Vol. 52, 1992 (pp. 6394-6396).
Chinese hamster
ovary cells grown in culture were irradiated with low doses of alpha-particles (31 mrads) during G1
((pre-DNA synthesis) phase. Found that 30% of cells had increased
frequency of sister chromatid exchange (SCE), even though less than 1% of cells
would have been traversed by an alpha-particle. Although the significance
of SCE isn’t clear, it is generally recognized that SCE can lead to increased
genetic mutations in daughter cells. Authors suggest that intercellular
communication may be responsible for this phenomenon.
[Nagasawa1992xxCRv52nxp6394].
3. Proximity effects for chromosome aberrations measured by FISH, by AM Chen, et al., Department of
Mathematics,
A
[Chen199604IJRBv69n4p411]. (PMID: 8627123 [PubMed -
indexed for MEDLINE]).
4. Direct biological evidence for a significant neutron dose to survivors of the Hiroshima atomic bomb, by Brenner DJ, Center for Radiological Research, Columbia University, New York 10032, USA. Radiat Res. Vol. 145(4), Apr. 1996 (pp. 501-7).
Erratum in: Radiat Res. Vol. 145(5), May 1996 (pp.
653). Comment in: Radiat Res.
Vol. 147(4), Apr. 1997 (pp. 506-510).
In the past few years much physical evidence has
accumulated that the A-bomb survivors at
[Brenner199604RRv145n4p501] (PMID: 8600511 [PubMed - indexed for MEDLINE]).
5. The biological effectiveness of radon-progeny alpha particles. V. Comparison of oncogenic transformation by accelerator-produced monoenergetic alpha particles and by polyenergetic alpha particles from radon progeny, by RC Miller, et al., Center for Radiological Research, Columbia University, New York, New York 10032, USA. Radiat Res. Vol. 146(1), Jul. 1996 (pp. 75-80).
Generation of estimates of risk caused by exposure to radon in the
home, either from miner data or from A-bomb data, requires several scaling
factors such as for dose, dose rate and radiation quality, and possible
synergisms. Such scaling factors are best developed from laboratory-based
studies. Two possible sources of alpha particles for such studies are (1) a
polyenergetic spectrum, generated directly by radon and its progeny, or (2) a
series of monoenergetic alpha particles. We compare here the results of
oncogenic transformation from studies using both systems. At the Columbia
University Radiological Research Accelerator Facility (RARAF), C3H 10T1/2 cells
were irradiated with alpha particles of various energies, with defined LETs
from 70 to 200 keV/mum. At Pacific Northwest Laboratory, cells from the same
stock were exposed to alpha particles from radon gas and its progeny, which
were in equilibrium with the culture medium. There was good agreement between
the results of oncogenic transformation experiments using the two different
exposure systems. Apart from the experimental transformation frequencies
themselves, such a comparison requires (1) reliable dosimetry at both
facilities and (2) estimated LET distributions for the polyenergetic
alpha-particle irradiator. Thus this good agreement gives some confirmation to
the technique which is used to fold together oncogenic transformation rates
from monoenergetic alpha particles to yield a predicted rate for a spectrum of
alpha particles.
[Miller199607RRv146n1p75].
(PMID: 8677301 [PubMed - indexed for MEDLINE]).
6. Dose timing in
tumor radiotherapy: considerations of cell number stochasticity, by RK Sachs , et al., Department of Mathematics,
A typical tumor radiotherapy regimen using external
beam X rays consists of doses on weekdays for 4-7 weeks. During the final
weeks, the tumor may contain only a few cells capable of regenerating the tumor
and may be growing exponentially between doses. Stochastic fluctuations of the
cell number can influence the optimal time pattern of dose delivery. If the
total dose is fixed, a deterministic model of exponential tumor growth,
neglecting stochastic effects, predicts that the way the radiation dose is
spread out in time does not affect the average number of tumor cells at the
end. However, we here show, within the framework of a birth-death model, that
when stochastics are taken into account, the earlier the dose is given
(consistent with other constraints imposed by quite different considerations),
the better. The proof uses a transformation that simplifies the characteristic
equation of the partial differential equation governing the probability
generating function for a birth-death process with time-dependent rates. The
theorem that earlier is better holds for any statistical distribution of cell
number from patient to patient at the start of the exponential growth phase and
for virtually any cell-killing model. Numerical results indicate the stochastic
effects, although not dominant, are not negligible.
[Sachs199612MBv138n2p131] (PMID: 8987356 [PubMed - indexed for MEDLINE]).
7. Review: proximity effects in the production of chromosome aberrations by
ionizing radiation, by RK Sachs,
et al., Department of Mathematics,
After ionizing radiation has induced double-strand DNA breaks (dsb), misrejoining produces chromosome aberrations. Aberration yields are influenced by "proximity' effects, i.e., by the dependence of misrejoining probabilities on initial dsb separations. We survey proximity effects, emphasizing implications for chromosome aberration-formation mechanisms, for chromatin geometry, and for dose-response relations. Evidence for proximity effects comes from observed biases for centric rings and against three-way interchanges, relative to dicentrics or translocations. Other evidence comes from the way aberration yields depend on radiation dose and quality, tightly bunched ionizations being relatively effective. We concludes (1) that misrejoining probabilities decrease as the distance between dsb at the time of their formation increases, and almost all misrejoining occurs among dsb initially separated by < 1/3 of a cell nucleus diameter; (2) that chromosomes occupy (irregular) territories during the G0/G1 phase of the cell cycle, having dimensions also roughly 1/3 of a cell nucleus diameter, (3) that proximity effects have the potential to probe how much different chromosomes intertwine on move relative to each other: and (4) that incorporation of proximity effects into the classic random breakage-and-reunion model allows quantitative interrelation of yields for many different aberration types and of data obtained with various FISH painting methods or whole-genome scoring.
[Sachs199701IJRBv71n1p1]
8 The use of the linear-quadratic model in clinical radiation oncology can be defended on the basis of empirical evidence and theoretical argument, by DJ Brenner, et al., Columbia University, Center for Radiological Research, New York, New York 10032, USA. djb3@columbia.edu. Med Phys. Vol. 24(8), Aug. 1997 (pp. 1245-1248).
Comment in: Med Phys. Vol. 24(8), Aug. 1997 (pp. 1329).
[Brenner199708MPv24n8p1245]. (PMID: 9284247 [PubMed - indexed for
MEDLINE]).
9. Intra-arm and interarm chromosome intrachanges: tools for probing the geometry and dynamics of chromatin, by RK Sachs, et al., Department of Mathematics, University of California, Berkeley 94720, USA. Radiat Res. Vol. 148(4), Oct. 1997 (pp. 330-40.)
Many chromosome-type, exchange-type chromosomal aberrations produced by radiation are intrachanges, i.e. involve only one chromosome. It is assumed such intrachanges are formed by illegitimate reunion of two double-strand breaks (DSBs) on the chromosome. The yield of intra-arm intrachanges (acentric rings or paracentric inversions) relative to that of interarm intrachanges (centric rings or pericentric inversions) is larger than would occur if production and illegitimate reunion of DSBs were spatially random. The excess of intra-arm intrachanges is presumably due to proximity effects for illegitimate reunions, i.e. enhancement of the intrachange probability when two DSBs are formed close to one another. Radiation track structure may also play a role. Using a polymer description for "large-scale" chromatin geometry (>2 Mb), and using two alternate (rapid or slow motion) models for the way that DSBs move after they are produced, theoretical estimates are given for size distributions of intrachanges at low or high linear energy transfer (LET). The ratio of intra-arm to interarm intrachanges is derived from the size distribution and compared with data from the literature on centric rings, inversions, interstitial deletions and excess acentric fragments. Proximity effects enhance yields of intra-arm relative to interarm intrachanges at least severalfold and perhaps as much as 10-fold compared to expectations based on spatial randomness. We argue that further measurements of intra-arm and interarm intrachanges would be informative about large-scale chromatin structure and chromosome motion. Because inversions are more frequent than estimates of randomness would indicate, and are transmissible to daughter cells, their size distribution could also help characterize past exposure to high-LET radiation.
[Sachs199710RRv148n4p330] (PMID: 9339949 [PubMed - indexed for MEDLINE]).
10. The link between low-LET dose-response relations and the underlying kinetics of damage production/repair/misrepair, by RK Sachs, et al., Department of Mathematics, University of California, Berkeley 94720, USA. Int J Radiat Biol. Vol. 72(4), Oct. 1997 (pp. 351-74).
PURPOSE: To review current opinion on the production and temporal evolution of low-LET radiobiological damage. METHODS: Standard cell survival models which model repair/misrepair kinetics in order to quantify dose-response relations and dose-protraction effects are reviewed and interrelated. Extensions of the models to endpoints other than cell survival, to multiple or compound damage processing pathways, and to stochastic intercellular damage fluctuations are surveyed. Various molecular mechanisms are considered, including double strand breaks restitution and binary misrepair. CONCLUSIONS: (1) Linking dose-response curves to the underlying damage production/processing kinetics allows mechanistic biological interpretations of observed curve parameters. (2) Various damage processing pathways, with different kinetics, occur. (3) Almost every current kinetic model, whether based on binary misrepair or saturable repair, leads at low or intermediate doses to the LQ (linear-quadratic) formalism, including the standard (generalized Lea-Catcheside) dependence on dose protraction. (4) Two-track (beta) lethal damage is largely due to dicentric chromosome aberrations, but one-track (alpha) lethal damage is largely caused by other mechanisms such as point mutations in a vital gene, small deletions, residual chromosome breaks, induced apoptosis, etc. (5) A major payoff for 50 years of radiobiological modelling is identifying molecular mechanisms which underly the broadly applicable LQ formalism.
[Sachs199710IJRBv72n4p351] PMID: 9343102 [PubMed - indexed for MEDLINE]).
11. Computer simulation of data on chromosome aberrations produced by X rays or alpha particles and detected by fluorescence in situ hybridization, by AM Chen, et al., Department of Mathematics, University of California, Berkeley 94720, USA. Radiat Res. Vol. 148(5 Suppl), Nov. 1997 (pp. S93-101).
With fluorescence in situ hybridization (FISH), many
different categories of chromosome aberrations can be recognized-dicentrics,
translocations, rings and various complex aberrations such as insertions or
three-way interchanges. Relative frequencies for the various aberration
categories indicate mechanisms of radiation-induced damage and reflect
radiation quality. Data obtained with FISH support a proximity version of the
classic random breakage-and-reunion model for the formation of aberrations. A
[Chen199711RRv148n5SupppS93] (PMID: 9355862 [PubMed - indexed for MEDLINE]).
12. Mutagenic effects of a single and an exact number of alpha-particles in mammalian cells, by T.K. Hei, et al., Proceedings of the National Academy of Sciences Vol. 94, 1997 (pp. 3765-3770).
Using hamster-human hybrid cells in culture, showed that single
alpha-particle traversal was only slightly cytotoxic (>80% survival) but
highly mutagenic (110 mutants/100,000 survivors). Cytotoxicity and mutant
induction were both dose dependent.
[Hei1997xxPNASv94nxp3765].
13. The linear-quadratic model and most other common radiobiological models result in similar predictions of time-dose relationships, by DJ Brenner, et al., Center for Radiological Research, Columbia University, New York, New York 10032, USA. Radiat Res. Vol. 150(1), Jul. 1998 (pp. 83-91).
One of the fundamental tools in radiation biology is a formalism describing time-dose relationships. For example, there is a need for reliable predictions of radiotherapeutic isoeffect doses when the temporal exposure pattern is changed. The most commonly used tool is now the linear-quadratic (LQ) formalism, which describes fractionation and dose-protraction effects through a particular functional form, the generalized Lea-Catcheside time factor, G. We investigate the relationship of the LQ formalism to those describing other commonly discussed radiobiological models in terms of their predicted time-dose relationships. We show that a broad range of radiobiological models are described by formalisms in which a perturbation calculation produces the standard LQ relationship for dose fractionation/protraction, including the same generalized time factor, G. This approximate equivalence holds not only for the formalisms describing binary misrepair models, which are conceptually similar to LQ, but also for formalisms describing models embodying a very different explanation for time-dose effects, namely saturation of repair capacity. In terms of applications to radiotherapy, we show that a typical saturable repair formalism predicts practically the same dependences for protraction effects as does the LQ formalism, at clinically relevant doses per fraction. For low-dose-rate exposure, the same equivalence between predictions holds for early-responding end points such as tumor control, but less so for late-responding end points. Overall, use of the LQ formalism to predict dose-time relationships is a notably robust procedure, depending less than previously thought on knowledge of detailed biophysical mechanisms, since various conceptually different biophysical models lead, in a reasonable approximation, to the LQ relationship including the standard form of the generalized time factor, G.
[Brenner199807RRv150n1p83] (PMID: 9650605 [PubMed - indexed for MEDLINE]).
14. A formalism for analysing large-scale clustering of radiation-induced
breaks along chromosomes, by RK
Sachs, et al., Department of Mathematics,
PURPOSE: To model intrachromosomal clustering of DSB (DNA double strand breaks) induced by ionizing radiation. That DSB are located non-randomly along chromosomes after high LET irradiation, with clustering even at extremely large scales, has been confirmed by recent pulsed field gel electrophoresis data for size distributions of DNA fragments. We therefore extend the standard random-breakage model for DNA fragment-size distributions to a more general 'clustered-breakage' formalism, which can take correlations of DSB locations along a chromosome into account. METHODS: The new formalism is based mainly on a one-track probability distribution, describing the DNA fragment-size pattern due to a single primary high-energy particle, a pattern determined by track structure and chromatin geometry. Multi-track fragment-size distributions are derived mathematically from the one-track distribution, so that dose response relations are obtained. RESULTS: The clustered-breakage formalism is applicable to any chromosomal geometry and any radiation track structure. It facilitates extrapolations of high-dose data to the much lower doses of interest for most applications. When applied to recently published data for irradiation of mammalian cells with ions of LET approximately 100 keV microm(-1) it indicates a pattern of Mbp-scale DSB clusters, each containing a number of DSB and corresponding to a very large-scale, multiply-damaged chromatin site. Although DSB are bunched, DSB clusters are scattered almost at random throughout the genome. Estimates of DSB yield are markedly increased by resolving such clusters into individual DSB. The dose response relation for fragments of a given size becomes non-linear when clusters from different tracks interlace or adjoin, as can occur for high doses and large sizes. CONCLUSIONS: DSB clustering along chromosomes, which influences important radiobiological endpoints, is described quantitatively by the clustered-breakage formalism.
[Sachs199808IJRBv74n2p185] (PMID: 9712548 [PubMed - indexed for MEDLINE]).
15. The oncogenic
transforming potential of the passage of single alpha particles through
mammalian cell nuclei, by RC Miller, et al., Center for Radiological
Research,
Domestic, low-level exposure to radon gas is considered a major environmental
lung-cancer hazard involving DNA damage to bronchial cells by alpha particles
from radon progeny. At domestic exposure levels, the relevant bronchial cells
are very rarely traversed by more than one alpha particle, whereas at higher
radon levels-at which epidemiological studies in uranium miners allow
lung-cancer risks to be quantified with reasonable precision-these bronchial
cells are frequently exposed to multiple alpha-particle traversals. Measuring
the oncogenic transforming effects of exactly one alpha particle without the
confounding effects of multiple traversals has hitherto been unfeasible,
resulting in uncertainty in extrapolations of risk from high to domestic radon
levels. A technique to assess the effects of single alpha particles uses a
charged-particle microbeam, which irradiates individual cells or cell nuclei
with predefined exact numbers of particles. Although previously too slow to
assess the relevant small oncogenic risks, recent improvements in throughput
now permit microbeam irradiation of large cell numbers, allowing the first
oncogenic risk measurements for the traversal of exactly one alpha particle
through a cell nucleus. Given positive controls to ensure that the dosimetry
and biological controls were comparable, the measured oncogenicity from exactly
one alpha particle was significantly lower than for a Poisson-distributed mean
of one alpha particle, implying that cells traversed by multiple alpha
particles contribute most of the risk. If this result applies generally,
extrapolation from high-level radon risks (involving cellular traversal by
multiple alpha particles) may overestimate low-level (involving only single
alpha particles) radon risks.
[Miller199901PNASv96n1p19]. (PMID: 9874764 [PubMed - indexed for
MEDLINE]).
16. Radiation-induced breakpoint misrejoining in human chromosomes: random or
non-random? by KL Johnson, et
al., Center for Radiological Research,
PURPOSE: To investigate whether radiation-induced misrejoining of chromosome breakpoints is randomly or non-randomly distributed throughout the human genome. MATERIALS AND METHODS: Data were combined from as many published cytogenetic studies as possible. The percentage of radiation-induced breaks per megabase (Mb) of DNA between all human chromosomes was calculated, and the observed and expected numbers of breakpoints based on DNA content between and within chromosomes were compared. RESULTS: A DNA-proportional distribution of breakpoints in 14 autosomes and a statistically significant deviation from proportionality in the other eight autosomes and the sex chromosomes was found. Regression analysis showed no significant change in breakpoint frequency per Mb of DNA relative to autosome size. Analysis between chromosome arms showed a non-random distribution of induced breakpoints within certain autosomes, particularly the acrocentrics. In cases of non-random distributions, a prevalence of events was found at heterochromatic regions and/or telomeres, and a clustering of breakpoints was found near the centromeres of many chromosomes. CONCLUSIONS: There is an approximately linear proportionality between autosomal DNA content and observed breakpoint number, suggesting that subsets of autosomes can be used to estimate accurately the overall genomic frequency of misrejoined breakpoints contingent upon a carefully selected subset. However, this conclusion may not apply to the sex chromosomes. The results also support the influence of chromatin organization and/or preferential DNA repair/misrejoining on the distribution of induced breakpoints. However, these effects are not sufficient at a global level to dismiss the value of cytogenetic analysis using a genome subset for biodosimetry.
[Johnson199902IJRBv75n2p131] (PMID: 10072174 [PubMed - indexed for MEDLINE]).
17. Does fractionation decrease the risk of breast cancer
induced by low-LET radiation? by DJ Brenner, Center for Radiological
Research,
Comments
in: Radiat Res. Vol. 151(2), Feb. 1999 (pp. 123-124). Radiat Res.
Vol. 152(1), Jul. 1999 (pp. 104-105). Radiat Res. Vol. 152(5), Nov.
1999 (pp. 567).
Whether fractionation decreases the risk of breast cancer induced by
low-LET radiation is a question of some importance. Analyses of the data for TB
cohorts who were exposed to multiple fluoroscopies show an apparently similar
breast cancer risk compared with those for the acutely exposed A-bomb
survivors. However, the fluoroscopy cohorts were subjected to very much
lower-energy photons (60-80 kVp) compared with the A-bomb survivors; the
increased RBE associated with the low photon energies to which these
fluoroscopy cohorts were exposed suggests that, in comparison to the risk
estimates for the A-bomb survivors, the risk estimates from the X-ray
fluoroscopy cohorts are increased because of the lower-energy X rays and
decreased by a similar amount due to fractionation, resulting in an overall
apparent equality of risk. Thus the results from the most powerful
epidemiological data sets available for assessing breast cancer risks after
fractionated exposure to low-LET radiation (the fluoroscopy cohorts) are quite
consistent with a lower radiation risk for a fractionated exposure in
comparison to an acute exposure. In general, for any cancer site, estimates of
the dose-rate effectiveness factor (DDREF) generated by comparing the results
for A-bomb survivors with those for the TB fluoroscopy cohorts should probably
be roughly doubled from their apparent values because of the increased RBE of
the fluoroscopy X rays.
[Brenner199902RRv151n2p225]. (PMID: 9952308 [PubMed - indexed for
MEDLINE]).
18. Chromosome
aberrations of clonal origin in irradiated and unexposed individuals:
assessment and implications, by KL Johnson, et al., Center for
Radiological Research,
Chromosome painting has proven useful for the detection of chromosomal
rearrangements, although the presence of cells containing clonal aberrations
can have an effect on the outcome of cytogenetic analyses (e.g. aberration
frequency and chromosomal distribution studies). Cells with clonal chromosomal
changes have been found in studies of both radiation-exposed
[Johnson199907RRv152n1p1]. (PMID: 10381835 [PubMed - indexed for
MEDLINE]).
19. Unexpected sensitivity to the induction of mutations by very low doses of alpha-particle radiation: evidence for a bystander effect, by H. Nagasawa, et al., Radiation Research Vol. 152, 1999 (pp. 552-557).
Found a linear dose response for radiation induced mutations in Chinese
hamster ovary cells in culture in the dose range of 5 cGy to 1.2 Gy (>20
fold range), but the response was not linear below 5 cGy, instead it was much
higher than expected from extrapolation of the linear data. There was a
nearly 5 fold increase in mutations over expected response at lowest doses
studied. This supports the bystander effect, i.e., mutations arising in
nonirradiated cells through signals from neighboring cells exposed to
radiation.
[Nagasawa1999xxRRv152nxp552].
20. Investigation of hypersensitivity to fractionated low-dose radiation
exposure, by LG Smith, et al., Department
of Radiation Oncology,
PURPOSE: Hypersensitivity to cell killing of exponentially growing
cells exposed to X-rays and gamma rays has been reported for doses below about
0.5 Gy. The reported results have been interpreted to suggest that a dose of
0.5 Gy or less is not sufficient to trigger an inducible repair mechanism. The
purpose of this study was to examine this suggested hypersensitivity after
multiple low doses (0.3 Gy) of gamma rays where a) the effect would be expected
to be significantly magnified, and b) the effect might be of clinical
relevance. METHODS AND MATERIALS: C3H 10T1/2 mouse embryo cells were grown to
confluence in culture vessels. While in plateau phase of growth, cells were
exposed to 6 Gy of gamma rays, delivered in either 6 Gy, 3 Gy, 2 Gy, 1 Gy, or
0.3 Gy well-separated fractions. Corresponding experiments were performed with
V-79 and C3H 10T1/2 cells in exponential growth. Cells were replated at low
density and assayed for clonogenicity. RESULTS: The results of this study were
not inconsistent with some hypersensitivity at low doses, in that 20 fractions
each of 0.3 Gy produced a slightly lower (though nonsignificant) surviving
fraction compared with the same dose given in 2-Gy fractions. However, the
results of the 20 x 0.3 Gy exposures also agreed well with the standard
linear-quadratic (LQ) model predictions based on high dose per fraction (1-6
Gy) data. In addition, effects of cellular redistribution were seen which were
explained quantitatively with an extended version of the LQ model. CONCLUSIONS:
These experiments were specifically designed to magnify and probe possible
clinical implications of proposed "low-dose hypersensitivity"
effects, in which significant deviations at low doses from the LQ model have
been suggested. In fact, the results at low doses per fraction were consistent
with LQ predictions based on higher dose per fraction data. This finding is in
agreement with the well-documented utility of the LQ approach in estimating
isoeffect doses for alternative fractionation schemes, and for brachytherapy.
[Smith199908IJROBPv45n1p187]. (PMID: 10477023 [PubMed - indexed for
MEDLINE]).
21. Neutron-energy-dependent
cell survival and oncogenic transformation, by RC Miller, et al., Center
for Radiological Research,
Both cell lethality
and neoplastic transformation were assessed for C3H10T1/2 cells exposed to
neutrons with energies from 0.040 to 13.7 MeV. Monoenergetic neutrons with
energies from 0.23 to 13.7 MeV and two neutron energy spectra with average
energies of 0.040 and 0.070 MeV were produced with a Van de Graaff accelerator
at the Radiological Research Accelerator Facility (RARAF) in the Center for
Radiological Research of Columbia University. For determination of relative
biological effectiveness (RBE), cells were exposed to 250 kVp X rays. With
exposures to 250 kVp X rays, both cell survival and radiation-induced oncogenic
transformation were curvilinear. Irradiation of cells with neutrons at all
energies resulted in linear responses as a function of dose for both biological
endpoints. Results indicate a complex relationship between RBEm and neutron
energy. For both survival and transformation, RBEm was greatest for cells
exposed to 0.35 MeV neutrons. RBEm was significantly less at energies above or
below 0.35 MeV. These results are consistent with microdosimetric expectation.
These results are also compatible with current assessments of neutron radiation
weighting factors for radiation protection purposes. Based on calculations of
dose-averaged LET, 0.35 MeV neutrons have the greatest LET and therefore would
be expected to be more biologically effective than neutrons of greater or
lesser energies.
[Miller199912JRRv40nsuppp53].
(PMID: 10804994 [PubMed - indexed for MEDLINE]).
22. Oncogenic
transformation in C3H10T1/2 cells by low-energy neutrons, by RC Miller,
et al., Center for Radiological Research,
PURPOSE: Occupational
exposure to neutrons typically includes significant doses of low-energy
neutrons, with energies below 100 keV. In addition, the normal-tissue dose from
boron neutron capture therapy will largely be from low-energy neutrons. Microdosimetric
theory predicts decreasing biological effectiveness for neutrons with energies
below about 350 keV compared with that for higher-energy neutrons; based on
such considerations, and limited biological data, the current radiation
weighting factor (quality factor) for neutrons with energies from 10 keV to 100
keV is less than that for higher-energy neutrons. By contrast, some reports
have suggested that the biological effectiveness of low-energy neutrons is
similar to that of fast neutrons. The purpose of the current work is to assess
the relative biological effectiveness of low-energy neutrons for an endpoint of
relevance to carcinogenesis: in vitro oncogenic transformation. METHODS:
Oncogenic transformation induction frequencies were determined for C3H10T1/2
cells exposed to two low-energy neutron beams, respectively, with dose-averaged
energies of 40 and 70 keV, and the results were compared with those for
higher-energy neutrons and X-rays. RESULTS: These results for oncogenic
transformation provide evidence for a significant decrease in biological
effectiveness for 40 keV neutrons compared with 350 keV neutrons. The 70 keV
neutrons were intermediate in effectiveness between the 70 and 350 keV beams.
CONCLUSIONS: A decrease in biological effectiveness for low-energy neutrons is
in agreement with most (but not all) earlier biological studies, as well as
microdosimetric considerations. The results for oncogenic transformation were
consistent with the currently recommended decreased values for low-energy neutron
radiation weighting factors compared with fast neutrons.
[Miller200003IJRBv76n3p327]
(PMID: 10757312 [PubMed - indexed for MEDLINE])
22m. Factors underlying the cell growth-related bystander responses to alpha particles, by R Iyer, et al., Bioscience Division, Los Alamos National Laboratory, New Mexico 87545, USA. Cancer Res. Vol. 60(5), Mar. 2000 (pp. 1290-1298).
Increases in cell proliferation are widely viewed as being of importance in carcinogenesis. We report that exposure of normal human lung fibroblasts to a low dose of alpha particles like those emitted by radon/radon progeny stimulates their proliferation in vitro, and this response also occurs when unirradiated cells are treated with supernatants from alpha-irradiated cells. We attribute the promitogenic response to superoxide dismutase- and catalase-inhibitable a particle-induced increases in the concentrations of transforming growth factor beta1 (TGF-beta1) in cell supernatants. TGF-beta1 at concentrations commensurate with those in the supernatants capably induces increases in intracellular reactive oxygen species (ROS) in unirradiated cells. Furthermore, the addition of supernatants from alpha-irradiated cells to unirradiated cells decreases cellular levels of TP53 and CDKN1A and increases CDC2 and proliferating cell nuclear antigen in the latter. Like the increased intracellular ROS bystander effect, this "decreased TP53/CDKN1A response" can be mimicked in otherwise untreated cells by the addition of low concentrations of TGF-beta1. Our results indicate that alpha particle-associated increases in cell growth correlate with intracellular increases in ROS along with decreases in TP53 and CDKN1A, and that these cellular responses are mechanistically coupled. As well, the proliferating cell nuclear antigen and CDC2 increases that occur along with the decreased TP53/CDKN1A bystander effect also would expectedly favor enhanced cell growth. Such processes may account for cell hyperplastic responses in the conducting airways of the lower respiratory track that occur after inhalation exposure to radon/ radon progeny, as well as, perhaps, other ROS-associated environmental stresses.
[Iyer200003CRv60nfp1290].
23. Induction of a bystander mutagenic effect of alpha particles in mammalian cells, by H. Zhou, et al., Proc. Natl. Acad. Sci. Vol. 97, 2000 (pp. 2099-2104).
Showed that genetic mutations were about 3 fold higher than expected if
one assumes no bystander effect. Also showed that the types of mutations
induced were different from those occurring spontaneously (without
radiation). Radical scavengers had no effect on mutagenicity. These
results further support intercellular communication inducing the bystander
effect.
[Zhou2000xxPNASv97nxp2099].
24. Biomarkers specific to densely-ionising (high LET) radiations, by DJ Brenner, et al., Center for Radiological Research, Columbia University 630 West 168th Street, New York, NY 10032, USA. djb3@columbia.edu : Radiat Prot Dosimetry Vol. 97(1), 2001 (pp. 69-73).
There have been several suggestions of biomarkers that are specific to
high LET radiation. Such a biomarker could significantly increase the power of
epidemiological studies of individuals exposed to densely-ionising radiations
such as alpha particles (e.g. radon, plutonium workers, individuals exposed to
depleted uranium) or neutrons (e.g. radiation workers, airline personnel. We
discuss here a potentially powerful high LET biomarker (the H value) which is
the ratio of induced inter-chromosomal aberrations to intra-arm aberrations.
Both theoretical and experimental studies have suggested that this ratio should
differ by a factor of about three between high LET radiation and any other
likely clastogen, and will yield more discrimination than the previously
suggested F value (ratio of inter-chromosomal aberrations to intra-chromosomal
inter-arm aberrations). Evidence of the long-term stability of such chromosomal
biomarkers has also been generated. Because these stable intra-arm anld
inter-chromosomal aberrations are (1) frequent and (2) measurable at long times
after exposure, this H value appears to be a practical biomarker of high LET
exposure, and several in vitro studies have confirmed the approach for unstable
aberrations. The approach is currently being tested in a population of Russian
radiation workers exposed several decades ago to high- or low LET radiation.
[Brenner2001xxRPDv97n1p69]. ( PMID: 11763360 [PubMed - indexed for
MEDLINE]).
25. The bystander effect in radiation oncogenesis: I. Transformation in C3H 10T1/2 cells in vitro can be initiated in the unirradiated neighbors of irradiated cells, by SG Sawant, et al., Center for Radiological Research, Columbia University, New York, New York 10032, USA. Radiat Res. Vol.155(3), Mar. 2001 (pp. 397-401).
It has long been accepted that radiation-induced genetic effects require that DNA be hit and damaged directly by the radiation. Recently, evidence has accumulated that in cell populations exposed to low doses of alpha particles, biological effects occur in a larger proportion of cells than are estimated to have been traversed by alpha particles. The end points observed include chromosome aberrations, mutations and gene expression. The development of a fast single-cell microbeam now makes it possible to expose a precisely known proportion of cells in a population to exactly defined numbers of alpha particles, and to assay for oncogenic transformation. The single-cell microbeam delivered no, one, two, four or eight alpha particles through the nuclei of all or just 10% of C3H 10T1/2 cells. We show that (a) more cells can be inactivated than were actually traversed by alpha particles and (b) when 10% of the cells on a dish are exposed to alpha particles, the resulting frequency of induced transformation is not less than that observed when every cell on the dish is exposed to the same number of alpha particles. These observations constitute evidence suggesting a bystander effect, i.e., that unirradiated cells are responding to damage induced in irradiated cells. This bystander effect in a biological system of relevance to carcinogenesis could have significant implications for risk estimation for low-dose radiation.
[Sawant200103RRv155n3p397] (PMID: 11182789 [PubMed - indexed for MEDLINE]).
26. The bystander
effect in radiation oncogenesis: II. A quantitative model, by DJ
Brenner, et al.,Center for Radiological Research,
There is strong evidence that biological response to ionizing radiation has a contribution from unirradiated "bystander" cells that respond to signals emitted by irradiated cells. We discuss here an approach incorporating a radiobiological bystander response, superimposed on a direct response due to direct energy deposition in cell nuclei. A quantitative model based on this approach is described for alpha-particle-induced in vitro oncogenic transformation. The model postulates that the oncogenic bystander response is a binary "all or nothing" phenomenon in a small sensitive subpopulation of cells, and that cells from this sensitive subpopulation are also very sensitive to direct hits from alpha particles, generally resulting in a directly hit sensitive cell being inactivated. The model is applied to recent data on in vitro oncogenic transformation produced by broad-beam or microbeam alpha-particle irradiation. Two parameters are used in analyzing the data for transformation frequency. The analysis suggests that, at least for alpha-particle-induced oncogenic transformation, bystander effects are important only at small doses-here below about 0.2 Gy. At still lower doses, bystander effects may dominate the overall response, possibly leading to an underestimation of low-dose risks extrapolated from intermediate doses, where direct effects dominate.
[Brenner200103RRv155n3p402] (PMID: 11182790 [PubMed - indexed for MEDLINE]).
27. Direct evidence for the participation of gap junction-mediated intercellular communication in transmission of damage signals from alpha-particle irradiated to nonirradiated cells, by EI Azzam, et al., Proc. Natl. Acad. Scis. Vol. 98, 2001 (pp. 473-478).
Using genetically engineered cells with compromised gap junctions,
showed that the bystander effect is mediated by gap junctions, i.e.,
nonirradiated cells respond to radiation induced damage in neighboring
cells. They found increased expression/activation of specific biochemical
markers that are induced by stress which also correlated with induction of DNA
damage, seen in the increased number of micronuclei in cells arising from DNA
double-strand breaks.
[Azzam2001xxPNASv98nxp473].
28. Radiation Risk to low fluences of alpha-particles may be greater than we thought, by H. Zhou, et al., Proc. Natl. Acad. Sci. Vol. 98, 2001 (pp. 14410-14415).
It was shown in this paper that when 10% of cells in a confluent
population were hit with a single alpha-particle the result was similar to that
observed when all cells are irradiated. It was found that the bystander
effect could be eliminated by treating the cell culture with octanol, a
chemical that blocks intercellular communication through gap junctions (direct
communication channels between contiguous cells).
[Zhou2001xxPNASv98nxp14410].
28a. The potential impact of bystander effects on radiation
risks in a Mars mission, by Brenner DJ, et al., Radiat Res. Vol. 156
(5pt2), Nov. 2001 (pp. 612-617).
[Brenner200111RRv156n5pt2p612]
(PMID: 11604082 [PubMed - indexed for MEDLINE]).
28f. Exposure to low-level chemicals and ionizing
radiation: reactive oxygen species and cellular pathways, by BE Lehnert, et al., Bioscience
Division,
[Lehnert200202HETv21n2p65].
28m Low dose, low-LET ionizing radiation-induced radioadaptation and
associated early responses in unirradiated cells, by R Iyer, et al., Bioscience
Division, MS 888,
Numerous investigators have reported that irradiation of cells with a low dose of ionizing radiation (IR) can induce a condition of enhanced radioresistance, i.e. a radioadaptive response. In this report, we investigated the hypothesis that a radioadaptive bystander effect may be induced in unirradiated cells by a transmissible factor(s) present in the supernatants of cells exposed to low dose gamma-rays. Normal human lung fibroblasts (HFL-1) were irradiated with a 1 cGy dose of gamma-rays and their supernatants were transferred to unirradiated HFL-1 as a bystander cell model. Compared with the directly irradiated cells, such treatment resulted in increased clonogenic survival following subsequent gamma-irradiation with 2 and 4 Gy. This radioadaptive bystander effect was found to be preceded by early decreases in cellular levels of TP53 protein, increase in intracellular ROS, and increase in the redox and DNA repair protein AP-endonuclease (APE). The demonstration that radioadaptation can occur in unirradiated cells via a fluid-phase, transferable factor(s) adds to the complexity of the current understanding of mechanisms by which radioadaptive responses can be induced by low dose, low-LET IR.
[Iyer200206MRv503n1to2p1].
29. Do low dose-rate bystander effects influence domestic radon risks?, by Brenner DJ, et al.,Center for Radiological Research, Columbia University, 630 West 168th Street, New York, NY 10032, USA. djb3@columbia.edu. Int J Radiat Biol. Vol. 78(7), Jul. 2002 (pp. 593-604).
PURPOSE: Radon risks derive from exposure of bronchio-epithelial cells to high-linear energy transfer (LET) alpha-particles. alpha-particle exposure can result in bystander effects, where irradiated cells emit signals resulting in damage to nearby unirradiated bystander cells. This can result in non-linear dose-response relations, and inverse dose-rate effects. Domestic radon risk estimates are currently extrapolated from miner data, which are at both higher doses and higher dose-rates, so bystander effects on unhit cells could play a large role in the extrapolation of risks from mines to homes. Therefore, we extend an earlier quantitative mechanistic model of bystander effects to include protracted exposure, with the aim of quantifying the significance of the bystander effect for very prolonged exposures. MATERIALS AND METHODS: A model of high-LET bystander effects, originally developed to analyse oncogenic transformation in vitro, is extended to low dose-rates. The model considers radiation response as a superposition of bystander and linear direct e It attributes bystander effects to a small subpopulation of hypersensitive cells, with the bystander contribution dominating the direct contribution at very low acute doses but saturating as the dose increases. Inverse dose-rate effects are attributed to the replenishment of the hypersensitive subpopulation during prolonged irradiation. RESULTS: The model was fitted to dose- and dose-rate-dependent radon-exposed miner data, suggesting that one directly hit target bronchio-epithelial cell can send bystander signals to about 50 neighbouring target cells. The model suggests that a naive linear extrapolation of radon miner data to low doses, without accounting for dose-rate, would result in an underestimation of domestic radon risks by about a factor of 4, a value comparable with the empirical estimate applied in the recent BEIR-VI report on radon risk estimation. CONCLUSIONS: Bystander effects represent a plausible quantitative and mechanistic explanation of inverse dose-rate effects by high-LET radiation, resulting in non-linear dose-response relations and a complex interplay between the effects of dose and exposure time. The model presented provides a potential mechanistic underpinning for the empirical exposure-time correction factors applied in the recent BEIR-VI for domestic radon risk estimation.
[Brenner200207IJRBv78n7p593] (PMID: 12079538 [PubMed - indexed for MEDLINE]).
29m. Radiation-induced effects in unirradiated cells: a
review and implications in cancer, by Z Goldberg, et al., Department of
Radiation Oncology,
[Goldberg200208IJOv21n2p337].
30. Chromosomes
are predominantly located randomly with respect to each other in interphase
human cells, by MN Cornforth, et al., Department of Radiation Oncology,
To test
quantitatively whether there are systematic chromosome-chromosome associations
within human interphase nuclei, interchanges between all possible heterologous
pairs of chromosomes were measured with 24-color whole-chromosome painting
(multiplex FISH), after damage to interphase lymphocytes by sparsely ionizing
radiation in vitro. An excess of interchanges for a specific chromosome pair
would indicate spatial proximity between the chromosomes comprising that pair.
The experimental design was such that quite small deviations from randomness
(extra pairwise interchanges within a group of chromosomes) would be
detectable. The only statistically significant chromosome cluster was a group
of five chromosomes previously observed to be preferentially located near the
center of the nucleus. However, quantitatively, the overall deviation from
randomness within the whole genome was small. Thus, whereas some chromosome-chromosome
associations are clearly present, at the whole-chromosomal level, the
predominant overall pattern appears to be spatially random.
[Cornforth200210JCBv159n2p237]
(PMID: 12403811 [PubMed - indexed for MEDLINE]).
31. Past exposure to densely ionizing radiation leaves a
unique permanent signature in the genome, by MP Hande, et al., Center for Radiological Research,
Speculation has long surrounded the question of whether past exposure to ionizing radiation leaves a unique permanent signature in the genome. Intrachromosomal rearrangements or deletions are produced much more efficiently by densely ionizing radiation than by chemical mutagens, x-rays, or endogenous aging processes. Until recently, such stable intrachromosomal aberrations have been very hard to detect, but a new chromosome band painting technique has made their detection practical. We report the detection and quantification of stable intrachromosomal aberrations in lymphocytes of healthy former nuclear-weapons workers who were exposed to plutonium many years ago. Even many years after occupational exposure, more than half the blood cells of the healthy plutonium workers contain large (>6 Mb) intrachromosomal rearrangements. The yield of these aberrations was highly correlated with plutonium dose to the bone marrow. The control groups contained very few such intrachromosomal aberrations. Quantification of this large-scale chromosomal damage in human populations exposed many years earlier will lead to new insights into the mechanisms and risks of cytogenetic damage.
[Hande200306AJHGv72n5p1162] (PMID: 12679897 [PubMed - indexed for MEDLINE]).
32. Domestic radon risks may be dominated by bystander effects--but the risks are unlikely to be greater than we thought, by Brenner DJ, et al., Center for Radiological Research, Columbia University, 630 West 168th Street, New York, NY 10032, USA. djb3@columbia.edu. Health Phys. Vol. 85(1), Jul. 2003 (pp. 103-8).
Radon risks derive from exposure of bronchio-epithelial cells to alpha particles. Alpha-particle exposure can result in bystander effects when irradiated cells emit signals resulting in damage to nearby unirradiated bystander cells. Bystander effects can cause downwardly-curving dose-response relations and inverse dose-rate effects. We have extended a quantitative mechanistic model of bystander effects to include protracted exposure, with inverse dose-rate effects attributed to replenishment, during exposure, of a subpopulation of cells which are hypersensitive to bystander signals. In this approach, bystander effects and the inverse dose-rate effect are manifestations of the same basic phenomenon. The model was fitted to dose- and dose-rate dependent radon-exposed miner data; the results suggest that one directly-hit target cell can send bystander signals to about 50 neighboring cells and that, in the case of domestic radon exposures, the risk could be dominated by bystander effects. The analysis concludes that a naive linear extrapolation of radon miner data to low doses, without accounting for dose rate/bystander effects, would result in an underestimation of domestic radon risks by about a factor of approximately 4. However, recent domestic radon risk estimates (BEIR VI) have already applied a phenomenological correction factor of approximately 4 for inverse dose-rate effects, and have thus already implicitly taken into account corrections which we here suggest are due to bystander effects. Thus current domestic radon risk estimates are unlikely to be underestimates as a result of bystander effects.
[Brenner20037HPv85n1p103]
33. Interaction between radiation-induced adaptive response and bystander mutagenesis in mammalian cells, by Zhou H, et al., Center for Radiological Research, College of Physicians and Surgeons, Columbia University, New York, New York 10032, USA. hz63@columbia.edu. Radiat Res. Vol. 160(5), Nov. 2003 (pp. 512-6).
Two conflicting phenomena, the bystander effect and
the adaptive response, are important in determining biological responses at low
doses of radiation and have the potential to have an impact on the shape of the
dose-response relationship. Using the
[Zhou200311RRv160n5p512] (PMID: 14565832 [PubMed - indexed for MEDLINE])
34. Cancer
risks attributable to low doses of ionizing radiation: assessing what we really
know, by DJ Brenner, et al., Center for Radiological Research,
High doses of ionizing radiation clearly produce deleterious consequences in humans, including, but not exclusively, cancer induction. At very low radiation doses the situation is much less clear, but the risks of low-dose radiation are of societal importance in relation to issues as varied as screening tests for cancer, the future of nuclear power, occupational radiation exposure, frequent-flyer risks, manned space exploration, and radiological terrorism. We review the difficulties involved in quantifying the risks of low-dose radiation and address two specific questions. First, what is the lowest dose of x- or gamma-radiation for which good evidence exists of increased cancer risks in humans? The epidemiological data suggest that it is approximately 10-50 mSv for an acute exposure and approximately 50-100 mSv for a protracted exposure. Second, what is the most appropriate way to extrapolate such cancer risk estimates to still lower doses? Given that it is supported by experimentally grounded, quantifiable, biophysical arguments, a linear extrapolation of cancer risks from intermediate to very low doses currently appears to be the most appropriate methodology. This linearity assumption is not necessarily the most conservative approach, and it is likely that it will result in an underestimate of some radiation-induced cancer risks and an overestimate of others.
[Brenner200311PNASv100n24p13761] PMID: 14610281 [PubMed - in process])
35. The bystander response in C3H 10T1/2 cells: the influence
of cell-to-cell contact, Mitchell SA, et al., Radiat Res. Vol. 161
(4), Apr. 2004 (pp. 397-401).
[Mitchell200404RRv161n4p397]
(PMID: 15038773 [PubMed - indexed for MEDLINE]).
36. Bystander effect and adaptive response in C3H 10T(1/2)
cells, by Mitchell SA, et al., Int J Radiat Biol. Vol. 80 (7),
July 2004 (pp. 465-472).
[Mitchell200407IJRBv80n7p465]
(PMID: 15360084 [PubMed - indexed for MEDLINE]).
37. Biological responses in known bystander cells relative to
known microbeam-irradiated cells, by Ponnaiya B, et al., Radiat Res. Vol.
162 (4), Oct. 2004 (pp. 426-432).
[Ponnaiya200410RRv162n4p426] (PMID: 15447040 [PubMed -
indexed for MEDLINE]).
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