Sawant, S. G., Zheng, W., Hopkins, K. M., Randers-Pehrson, G., Lieberman, H. B. and Hall, E. J. The Radiation-Induced Bystander Effect for Clonogenic Survival. Radiat. Res. 157, 361–364 (2002).

It has long been accepted that the radiation-induced heritable effects in mammalian cells are the result of direct DNA damage. Recent evidence, however, suggests that when a cell population is exposed to a low dose of α particles, biological effects occur in a larger proportion of cells than are estimated to have been traversed by α particles. Experiments involving the Columbia University microbeam, which allows a known fraction of cells to be traversed by a defined number of α particles, have demonstrated a bystander effect for clonogenic survival and oncogenic transformation in C3H 10T½ cells. When 1 to 16 α particles were passed through the nuclei of 10% of a C3H 10T½ cell population, more cells were unable to form colonies than were actually traversed by α particles. Both hit and non-hit cells contributed to the outcome of the experiments. The present work was undertaken to assess the bystander effect of radiation in only non-hit cells. For this purpose, Chinese hamster V79 cells transfected with hygromycin- or neomycin-resistance genes were used. V79 cells stably transfected with a hygromycin resistance gene and stained with a nuclear dye were irradiated with the charged-particle microbeam in the presence of neomycin-resistant cells. The biological effect was studied in the neomycin-resistant V79 cells after selective removal of the hit cells with geneticin treatment.

Lyng, F. M., Seymour, C. B. and Mothersill, C. Initiation of Apoptosis in Cells Exposed to Medium from the Progeny of Irradiated Cells: A Possible Mechanism for Bystander-Induced Genomic Instability? Radiat. Res. 157, 365–370 (2002).

Genomic instability and bystander effects have recently been linked experimentally both in vivo and in vitro. The aim of the present study was to determine if medium from irradiated cells several passages distant from the original exposure could initiate apoptosis in unirradiated cells. Human keratinocytes (from the HPV-G cell line) were irradiated with 0.5 Gy or 5 Gy γ rays. Medium was harvested at each passage up to the 7th passage (approximately 35 population doublings) postirradiation and transferred to unirradiated keratinocytes. Intracellular calcium levels, mitochondrial membrane potential, and the level of reactive oxygen species were all monitored for 24 h after medium transfer. Rapid calcium fluxes (within 30 s), loss of mitochondrial membrane potential, and increases in reactive oxygen species (from 6 h after medium transfer) were observed in the recipient cells. There was no significant difference between medium conditioned by cells irradiated with 0.5 or 5 Gy. The effect of medium from progeny was the same as the initial effect reported previously and did not diminish with increasing passage number. The data suggest that initiating events in the cascade that leads to apoptosis are induced in unirradiated cells by a signal produced by irradiated cells and that this signal can still be produced by the progeny of irradiated cells for several generations.

Lee, Y-J., Park, G-H., Cho, H-N., Cho, C-K., Park, Y-M., Lee, S-J. and Lee, Y-S. Induction of Adaptive Response by Low-Dose Radiation in RIF Cells Transfected with Hspb1 (Hsp25) or Inducible Hspa (Hsp70). Radiat. Res. 157, 371–377 (2002).

An adaptive response results in a reduced effect of a high challenging dose of a stressor after a smaller, inducing dose has been applied a few hours earlier. Radiation-induced fibrosarcoma (RIF) cells did not show an adaptive response, i.e. a reduced effect from a high challenging dose (2 Gy) of a radiation after a priming dose (1 cGy) had been applied 4 or 7 h earlier, but cells of a thermoresistant clone (TR) derived from RIF cells did. Since the expression of inducible Hspa (also known as Hsp70) and Hspb1 (also known as Hsp25) was different in these two cell lines, the role of inducible Hspa and Hspb1 in the adaptive response was examined. When RIF cells were transfected with inducible Hspa or Hspb1, both radioresistance measured by clonogenic assays and a reduction of apoptosis were detected. The adaptive response was also acquired by these two cell lines. The inducible Hspa transfectant showed a more pronounced adaptive response than the Hspb1 transfectant. Based on these results, it appears that inducible Hspa and Hspb1 are at least partly responsible for the induction of the adaptive response in these cells. Moreover, when inducible Hspa or Hspb1 was transfected into RIF cells, co-regulation of the two genes was detected. Heat-shock factor (Hsf) was found to be at least partially responsible for the induction of the adaptive response in these cells.

Mohanty, S. K., Rapp, A., Monajembashi, S., Gupta, P. K. and Greulich, K. O. Comet Assay Measurements of DNA Damage in Cells by Laser Microbeams and Trapping Beams with Wavelengths Spanning a Range of 308 nm to 1064 nm. Radiat. Res. 157, 378–385 (2002).

DNA damage induced in NC37 lymphoblasts by optical tweezers with a continuous-wave Ti:sapphire laser and a continuous-wave Nd:YAG laser (60–240 mW; 10–50 TJ/m²; 30–120 s irradiation) was studied with the comet assay, a single-cell technique used to detect DNA fragmentation in genomes. Over the wavelength range of 750–1064 nm, the amount of damage in DNA peaks at around 760 nm, with the fraction of DNA damage within the range of 750–780 nm being a factor of two larger than the fraction of DNA damage within the range of 800–1064 nm. The variation in DNA damage was not significant over the range of 800–1064 nm. When the logarithm of damage thresholds measured in the present work, as well as values reported previously in the UV range, was plotted as a function of wavelength, a dramatic wavelength dependence became apparent. The damage threshold values can be fitted on two straight lines, one for continuous-wave sources and the other for pulsed sources, irrespective of the type of source used (e.g. classical lamp or laser). The damage threshold around 760 nm falls on the line extrapolated from values for UV-radiation-induced damage, while the data for 800–1064 nm fall on a line that has a different slope. The change in the slope between 320 and 340 nm observed earlier is consistent with a well-known change in DNA-damaging mechanisms. The change observed around 780 nm is therefore suggestive of a further change in the mechanism(s). The data from this work together with our previous measurements provide, to the best of our knowledge, the most comprehensive view available of the DNA damage produced by microfocused light.

Kuwahara, Y., Shimada, A., Mitani, H. and Shima, A. A Critical Stage in Spermatogenesis for Radiation-Induced Cell Death in the Medaka Fish, Oryzias latipes. Radiat. Res. 157, 386–392 (2002).

To ensure the high-fidelity transmission by reproductive cells of genetic information from generation to generation, cells have evolved surveillance systems to eliminate genomic lesions by inducing cell suicide and/or DNA repair. In this report, γ-ray-induced cell death was investigated using the medaka fish, Oryzias latipes, because of the ease with which the differentiation stages of its spermatogenic cells can be identified. After 4.75 Gy γ irradiation, the maximum rate of death of spermatogonial stem cells was observed at 18 h, and that of differentiating spermatogonia was at 12 h, followed by a peak in the extent of DNA fragmentation detected by the TUNEL assay. Dose–response curves for the death rate showed an obvious increase in the death rate for early-differentiating spermatogonia even after 0.11 Gy irradiation, whereas there were no such increases for spermatogonial stem cells and late-differentiating spermatogonia. In the male germ cells of this fish, the stage during spermatogenesis most sensitive to radiation-induced cell death is in early-differentiating spermatogonia, the immediate descendants of the stem cells. These spermatogonia may have a rigorous surveillance system for genomic lesions induced in spermatogonial stem cells.

Moulder, J. E., Fish, B. L., Regner, K. R. and Cohen, E. P. Angiotensin II Blockade Reduces Radiation-Induced Proliferation in Experimental Radiation Nephropathy. Radiat. Res. 157, 393–401 (2002).

Total-body irradiation or renal irradiation is followed by a well-defined sequence of changes in renal function leading eventually to renal failure. Previous studies in a rat model have shown that inhibition of angiotensin-converting enzyme or blockade of angiotensin II receptors can prevent the structural and functional changes that occur after renal irradiation, and that these interventions are particularly important between 3 and 10 weeks after irradiation. We have now shown that in the same rat model, total-body irradiation induces proliferation of renal tubular cells (i.e., an increase in the number of cells staining positive for proliferating cell nuclear antigen) within 5 weeks after irradiation. Treatment with an angiotensin II receptor blocker delays this radiation-induced tubular proliferation and decreases its magnitude. Renal radiation also induces proliferation of glomerular cells, but the relative increase in glomerular proliferation is not as great as that seen in renal tubular cells, and the increase is not delayed or decreased by treatment with an angiotensin II receptor blocker. We hypothesize that angiotensin II receptor blockers exert their beneficial effect in radiation nephropathy by delaying the proliferation (and hence the eventual mitotic death) of renal tubular cells that have been genetically crippled by radiation.

Moison, R. M. W. and Beijersbergen van Henegouwen, G. M. J. Topical Antioxidant Vitamins C and E Prevent UVB-Radiation-Induced Peroxidation of Eicosapentaenoic Acid in Pig Skin. Radiat. Res. 157, 402–409 (2002).

Eicosapentaenoic acid protects against UV-radiation-induced immunosuppression and photocarcinogenesis, but it is also prone to oxidative degradation, which may reduce or abolish its beneficial effects. The protective effect of topically applied vitamin E, vitamin C, or both against UVB-radiation-induced lipid peroxidation in the presence of eicosapentaenoic acid was investigated using an ex vivo pig skin model. Changes in the bioavailability of both antioxidants induced by UV radiation were studied in different skin compartments. The UVB-radiation dose used (25 kJ/m²) was similar to that required to induce immunosuppression in BALB/c mice. Exposure of pig skin with an epidermal eicosapentaenoic acid content of 1.0 ± 0.3 mol% to UVB radiation resulted in an 85% increase of epidermal lipid peroxidation (P < 0.005). Topical application of vitamin E or vitamin C 60 min prior to UVB irradiation resulted in a major increase in both antioxidants in the stratum corneum and viable epidermis (P < 0.05). Vitamin E and vitamin C completely protected against UVB-radiation-induced lipid peroxidation (P < 0.005), but compared to vitamin E, a 500-fold higher vitamin C dose was needed. UVB irradiation induced a vitamin E consumption of up to 100% in the stratum corneum and viable epidermis, and a vitamin C consumption of only 21% in the stratum corneum. Simultaneously applied vitamin E and vitamin C also completely protected against UVB-radiation-induced lipid peroxidation (P < 0.05), and lower antioxidant doses were needed compared to vitamin E or vitamin C alone. In the presence of vitamin C, epidermal vitamin E was more stable upon UVB irradiation (P < 0.05), suggesting interaction between vitamin E and vitamin C. In conclusion, topically applied vitamin E and/or vitamin C efficiently protect against UVB-radiation-induced lipid peroxidation in the presence of eicosapentaenoic acid. The beneficial biological effects of eicosapentaenoic acid may therefore be improved if vitamin E and/or vitamin C are present in sufficient amounts. The ex vivo pig skin model provides a useful tool for assessing short-term biochemical effects related to UVB radiation, without the use of living experimental animals.

Shore, R. E., Moseson, M., Xue, X., Tse, Y., Harley, N. and Pasternack, B. S. Skin Cancer after X-Ray Treatment for Scalp Ringworm. Radiat. Res. 157, 410–418 (2002).

Some 2,224 children given X-ray therapy for tinea capitis (ringworm of the scalp) have been followed for up to 50 years to determine cancer incidence, along with a control group of 1,380 tinea capitis patients given only topical medications. The study found a relative risk (RR) of 3.6 (95% confidence interval, 2.3–5.9) for basal cell skin cancer (BCC) of the head and neck among irradiated Caucasians (124 irradiated cases and 21 control cases), in response to a scalp dose of about 4.8 Gy. No melanomas of the head and neck have been seen, and only a few squamous cell carcinomas. About 40% of irradiated cases have had multiple BCCs, for a total of 328 BCCs. Although 25% of both the irradiated and control groups are African-American, only 3 skin cancers have been seen among them, all in the irradiated group, indicating the importance of susceptibility to UV radiation as a cofactor. Light complexion, severe sunburning and North European ancestry were predictive of BCC risk in the irradiated group, but chronic sun exposure was not. Children irradiated at young ages had the highest BCC risk. The RR for BCC risk is approximately constant with time since exposure, suggesting that risk will probably last for a lifetime.

Nyberg, U., Nilsson, B., Travis, L. B., Holm, L-E. and Hall, P. Cancer Incidence among Swedish Patients Exposed to Radioactive Thorotrast: A Forty-Year Follow-up Survey. Radiat. Res. 157, 419–425 (2002).

Thorotrast is an α-particle-emitting radiological contrast medium that caused chronic exposure to internal α-particle radiation when it was administered systemically. Cancer incidence in 432 Swedish patients exposed to Thorotrast was evaluated by computerized linkage of the cohort with the Swedish Cancer Register. Standardized incidence ratios (SIRs) were calculated as the ratio of observed cases in the cohort to expected cases in the general population. A total of 170 cancers occurring in 152 individuals were reported, whereas only 57 cases were expected. The SIR was significantly increased for cancer at all sites (3.0), with the largest excesses noted for primary liver and gallbladder cancer (SIR = 39.2). Other significantly elevated risks were observed for liver cancer not specified as primary, small intestine cancer, stomach cancer, leukemia, kidney cancer, CNS tumors, and pancreatic cancer. Among women, there was a significantly increased risk for lung cancer, based on a small number. Our results show that cumulative radiation exposure is directly related to carcinogenesis in the liver and gallbladder, which is consistent with earlier findings. In addition, there may be a relationship between radiation exposure and the development of other solid tumors.

Rosemann, M., Lintrop, M., Favor, J. and Atkinson, M. J. Bone Tumorigenesis Induced by Alpha-Particle Radiation: Mapping of Genetic Loci Influencing Predisposition in Mice. Radiat. Res. 157, 426–434 (2002).

The present study was carried out to determine the extent to which genetic factors modify the incidence of radiation-induced bone tumorigenesis in mice, and to map putative susceptibility genes. We conducted a genome-wide linkage analysis in a cohort of 47 interstrain backcrossed mice. After the mice were injected with the bone-seeking α-particle-emitting radionuclide ²²⁷Th, 21 of the mice developed osteosarcomas. Two loci, one on chromosome 7 close to D7Mit145 and a second on chromosome 14 (D14Mit125), exhibited suggestive linkage to osteosarcoma predisposition, with LOD scores of 1.37 and 1.05, respectively. The LOD score increased considerably when interaction between these two loci was taken into account (LOD = 3.48). Nine of 12 mice inheriting a susceptibility allele at both loci developed osteosarcomas after ²²⁷Th injection, compared to only four osteosarcomas in 18 animals that did not inherit either of the susceptibility alleles. Variance component analysis revealed that these genetic factors determine approximately one-fifth of the total incidence of osteosarcomas. This study demonstrates the presence of a genetic component that modulates predisposition to radiation-induced osteosarcoma.

Nikjoo, H., Khvostunov, I. K. and Cucinotta, F. A. The Response of Tissue-Equivalent Proportional Counters to Heavy Ions. Radiat. Res. 157, 435–445 (2002).

The paper presents a theoretical model for the response of a tissue-equivalent proportional counter (TEPC) irradiated with charged particles. Heavy ions and iron ions in particular constitute a significant part of radiation in space. TEPCs are used for all space shuttle and International Space Station (ISS) missions to estimate the dose and radiation quality (in terms of lineal energy) inside spacecraft. The response of the tissue-equivalent proportional counters shows distortions at the wall/cavity interface. In this paper, we present microdosimetric investigation using Monte Carlo track structure calculations to simulate the response of a TEPC to charged particles of various LET (1 MeV protons, 2.4 MeV α particles, 46 MeV/nucleon ²⁰Ne, 55 MeV/nucleon ²⁰Ne, 45 MeV/nucleon ⁴⁰Ar, and 1.05 GeV/nucleon ⁵⁶Fe). Data are presented for energy lost and energy absorbed in the counter cavity and wall. The model calculations are in good agreement with the results of Rademacher et al. (Radiat. Res. 149, 387–389, 1998), including the study of the interface between the wall and the sensitive region of the counter. It is shown that the anomalous response observed at large event sizes in the experiment is due to an enhanced entry of secondary electrons from the wall into the gas cavity.

Coelho, D., Fischer, B., Holl, V., Jung, G. M., Denis, J. M., Dufour, P., Bergerat, J. P., Gueulette, J. and Bischoff, P. L. Involvement of TP53 in Apoptosis Induced in Human Lymphoblastoid Cells by Fast Neutrons. Radiat. Res. 157, 446–452 (2002).

We investigated the involvement of TP53 in apoptosis induced by fast neutrons in cells of three human B-lymphoblast cell lines derived from the same donor and differing in TP53 status: TK6 (wild-type TP53), WTK1 (mutant TP53) and NH32 (knockout TP53). Cells were exposed to X rays or to fast neutrons at doses ranging from 0.5 to 8 Gy. Apoptosis was determined by measurements of the sub-G₀ /G₁-phase DNA content and by the externalization of phosphatidylserine. Fast neutrons induced extensive apoptosis in TK6 cells, as shown by the formation of hypodiploid particles, the externalization of phosphatidylserine, and the activation of caspases. In contrast, cell death was triggered at a significantly lower rate in cells lacking functional TP53. However, TP53-independent cell death also expressed the morphological and biochemical hallmarks of apoptosis. Proliferation tests and clonogenic assays showed that fast neutrons can nevertheless kill WTK1 and NH32 cells efficiently. The absence of functional TP53 only delays radiation-induced cell death, which is also mediated by caspases. These results indicate that fast-neutron irradiation activates two pathways to apoptosis and that the greater relative biological effectiveness of fast neutrons reflects mainly an increase in clonogenic cell death.

Schmid, E., Regulla, D., Guldbakke, S., Schlegel, D. and Roos, M. Relative Biological Effectiveness of 144 keV Neutrons in Producing Dicentric Chromosomes in Human Lymphocytes Compared with ⁶⁰Co Gamma Rays under Head-to-Head Conditions. Radiat. Res. 157, 453–460 (2002).

The RBE for neutrons was assessed in a head-to-head experiment in which cultures of lymphocytes from the same male donor were irradiated simultaneously with 144 keV neutrons and with ⁶⁰Co γ rays as the reference radiation and evaluated using matched time, culture conditions, and the end point of chromosomal aberrations to avoid potential confounding factors that would influence the outcome of the experiment. In addition, the irradiation time was held constant at 2 h for the high-dose groups for both radiation types, which resulted in rather low dose rates. For the induction of dicentric chromosomes, the exposure to the 144 keV neutrons was found to be almost equally as effective (yield coefficient α_dic = 0.786 ± 0.066 dicentrics per cell per gray) as that found previously for irradiation with monoenergetic neutrons at 565 keV (α_dic = 0.813 ± 0.052 dicentrics per cell per gray) under comparable exposure and culture conditions (Radiat. Res. 154, 307–312, 2000). However, the values of the maximum low-dose RBE (RBE_m) relative to ⁶⁰Co γ rays that were determined in the present and previous studies show an insignificant but conspicuous difference: 57.0 ± 18.8 and 76.0 ± 29.5, respectively. This difference is mainly due to the difference in the α_dic value of the ⁶⁰Co γ rays, the reference radiation, which was 0.0138 ± 0.0044 Gy⁻¹ in the present study and 0.0107 ± 0.0041 Gy⁻¹ in the previous study. In the present experiment, irradiations with 144 keV neutrons and ⁶⁰Co γ rays were both performed at 21°C, while in the earlier experiment irradiations with 565 keV neutrons were performed at 21°C and the corresponding reference irradiation with γ rays was performed at 37°C. However, the temperature difference between 21°C and 37°C has a minor influence on the yield of chromosomal alterations and hence RBE values. The large cubic PMMA phantom that was used for the γ irradiations in the present study results in a larger dose contribution from Compton-scattered photons compared to the mini-phantom used in the earlier experiments. The contribution of these scattered photons may explain the large value of α_dic for γ irradiation in the present study. These results indicate that the yield coefficient α_dic for 144 keV neutrons is similar to the one for 565 keV neutrons, and that modification of the α_dic value of the low-LET reference radiation, due to changes in the experimental conditions, can influence the RBE_m. Consequently, α_dic values cannot be shared between cytogenetic laboratories for the purpose of assessment of RBM_m without verification of the comparability of the experimental conditions.

Duran, A., Barquinero, J. F., Caballín, M. R., Ribas, M., Puig, P., Egozcue, J. and Barrios, L. Suitability of FISH Painting Techniques for the Detection of Partial-Body Irradiations for Biological Dosimetry. Radiat. Res. 157, 461–468 (2002).

Peripheral blood was irradiated with 2, 3, 4 or 5 Gy of X rays and was mixed with nonirradiated blood at five different dilutions to simulate partial-body irradiations. Analysis by FISH was performed using whole-chromosome painting probes for chromosomes 1, 4 and 11 in combination with a pancentromeric probe. Chromosome aberrations affecting the painted fraction were classified according to the PAINT nomenclature; other unstable aberrations affecting the unpainted material were also recorded. To evaluate the suitability of painting for dose assessment in partial-body irradiations, the ability of the u test and a proposed s test to detect the expected overdispersion and the similarity between the real doses and the doses estimated using Dolphin's approach were considered. For short-term biodosimetry, compared with solid-stained dicentric analyses, the suitability of FISH painting techniques for the detection of partial-body exposures is reduced, because of the decrease in the frequency of aberrations detected by FISH and in the number of cells with two or more aberrations. For reconstruction of past doses, when only complete apparently simple translocations in cells free of unstable aberrations were considered, the detection of the overdispersion and the accuracy of dose estimations were dramatically reduced. In a partial-body exposure, as the original dose increased, the whole-body dose estimated a long time after irradiation would tend to be lower, and the difference from the original dose would tend to be greater.

Edwards, A., Maznik, N., Moquet, J., Hone, P., Vinnikov, V., Lloyd, D. and Cox, R. Choosing Metaphases for Biological Dosimetry by Fluorescence In Situ Hybridization (FISH). Radiat. Res. 157, 469–471 (2002).

Data are presented for a subset of lymphocytes characterized by FISH as missing painted chromosomal material. These lymphocytes occur in both control and irradiated subjects. These cells have a much greater frequency of one-way translocations than cells in which all of the painted chromosomal material is present. Their presence contributes to interindividual variability in control translocation yields. These cells do not appear to be more prevalent in persons exposed to high radiation doses. It is suggested that their exclusion when selecting cells for analysis may improve the sensitivity of FISH as a biological dosimeter at low doses. Mechanisms for the production of these one-way translocations in vivo are also discussed, with a proposal that their variable frequency in individuals may be consistent with exposure to chemical clastogens.

Vral, A., Thierens, H., Baeyens, A. and De Ridder, L. The Micronucleus and G₂-Phase Assays for Human Blood Lymphocytes as Biomarkers of Individual Sensitivity to Ionizing Radiation: Limitations Imposed by Intraindividual Variability. Radiat. Res. 157, 472–477 (2002).

As part of a program to assess the applicability of the micronucleus (MN) and G₂-phase assays as biomarkers of cancer susceptibility, we investigated the inter- and intraindividual variations of these end points. For the MN assay, unstimulated blood cultures from 14 healthy donors were exposed in vitro to 3.5 Gy ⁶⁰Co γ rays; for the G₂-phase assay, PHA-stimulated cell cultures were irradiated with a dose of 0.4 Gy ⁶⁰Co γ rays in the G₂ phase of the cell cycle. Two of the 14 volunteers were assayed 9 times over a period of 1 year. The repeat experiments revealed that the intraindividual variability was not significantly different from the interindividual variability for both the G₂-phase and MN assays. Since the intraindividual variability determines the reproducibility of the assay, our results highlight the limitations of these end points in detecting reproducible differences in radiation sensitivity between individuals within a normal population. For example, one donor of the population was identified as being radiosensitive (based on the 90th percentile criterion) but turned out to be normal when the assay was repeated twice. We conclude that the determination of individual radiosensitivity with these two cytogenetic assays is unreliable when based on one blood sample.

Daino, K., Ichimura, S. and Nenoi, M. Early Induction of CDKN1A (p21) and GADD45 mRNA by a Low Dose of Ionizing Radiation is due to Their Dose-Dependent Post-transcriptional Regulation. Radiat. Res. 157, 478–482 (2002).

Previous studies have shown that induction of some genes by low-dose radiation has a different dependence on the time after irradiation than induction by high doses. To examine the mechanisms underlying this phenomenon, we investigated the changes in the time course of the rates of transcription of genes in cells of the human myeloblastic leukemia cell line ML-1 by a nuclear run-on assay. It is possible that the more rapid induction of the mRNA of the CDKN1A and GADD45 genes after exposure to 50 cGy of X rays than after 20 Gy is due to a lower level of stabilization of the mRNA of these genes after 50 cGy. In addition, our results show that 50 cGy of X rays increases the transcription rates of the CDKN1A and GADD45 genes, with a maximum induction at 0.5 to 1 h after irradiation, much earlier than the maximum accumulation of stabilized TP53 protein. We suggest the involvement of BRCA1 protein in the early induction of transcription of these two genes.

Sigurdson, A. J., Stovall, M., Kleinerman, R. A., Maor, M. H., Taylor, M. E., Boice, J. D., Jr. and Ron, E. Feasibility of Assessing the Carcinogenicity of Neutrons among Neutron Therapy Patients. Radiat. Res. 157, 483–489 (2002).

Nuclear workers, oil well loggers, astronauts, air flight crews, and frequent fliers can be exposed to low doses of neutrons, but the long-term human health consequences of neutron exposure are unknown. While few of these exposed populations are suitable for studying the effects of neutron exposure, patients treated with neutron-beam therapy might be a source of information. To assess the feasibility of conducting a multi-center international study of the late effects of neutron therapy, we surveyed 23 cancer centers that had used neutron beam therapy. For the 17 responding institutions, only 25% of the patients treated with neutrons (2,855 of 11,191) were alive more than 2 years after treatment. In a two-center U.S. pilot study of 484 neutron-treated cancer patients, we assessed the feasibility of obtaining radiotherapy records, cancer incidence and other follow-up data, and of estimating patient organ doses. Patients were treated with 42 MeV neutrons between 1972 and 1989. Applying a clinical equivalence factor of 3.2 for neutrons, total average organ doses outside the treatment beam ranged from 0.14 to 0.29 Gy for thyroid, 0.40 to 2.50 Gy for breast, 0.63 to 2.35 Gy for kidney, and 1.12 to 1.76 Gy for active bone marrow depending upon the primary cancer treatment site. We successfully traced 97% of the patients, but we found that patient survival was poor and that chemotherapy was not confirmable in a quarter of the patients. Based on our findings from the international survey and the feasibility study, we conclude that a large investigation could detect a fivefold or higher leukemia risk, but would be inadequate to evaluate the risk of solid cancers with long latent periods and therefore would likely not be informative with respect to neutron-related cancer risk in humans.