Neutron, proton, and photonuclear cross-sections for radiation therapy and radiation protection

I review recent work at Los Alamos undertaken to evaluate neutron, proton, and photonuclear cross-sections up to 150 MeV (to 250 MeV for protons), based on experimental data and nuclear model calculations. These data are represented in the ENDF format and can be used in computer codes to simulate radiation transport. They permit calculations of absorbed dose in the body from therapy beams, and through use of kerma coefficients allow absorbed dose to be estimated for a given neutron energy distribution. In radiation protection, these data can be used to determine shielding requirements in accelerator environments and to calculate neutron, proton, gamma-ray, and radionuclide production. Illustrative comparisons of the evaluated cross-section and kerma coefficient data with measurements are given.     

The action of osmolytes on the destructive effect of ionizing radiation,hyperthermia, microwave radiation,and ultrasound

New data on the influence of osmolytes (NaCl, glycerol) on the destructive effect of ionizing radiation, hyperthermia, microwave radiation and ultrasound were obtained from experiments with bacterial cells. The pattern of manifestation of the osmolyte protective effect is presented. It was found that the protective effect of osmolytes from damaging factors (antagonistic interaction) can be detected only within a certain range of agent “doses.” Inside this range, there is an optimum providing the maximum protection. It was shown that, to provide the highest antagonistic effect with increased intensity of one of the agents, a corresponding change in the intensity of the other agent involved in the interaction is required. It is concluded that, in addition to DNA damage, membrane injury and osmotic homeostasis system may be considered as critical targets in cell destruction after the combined action of various environmental factors.     

Adenoviral gene therapy, radiation, and prostate cancer

Viral gene therapy has exceptional potential as a specifically tailored cancer treatment. However, enthusiasm for cancer gene therapy has varied over the years, partly owing to safety concerns after the death of a young volunteer in a clinical trial for a genetic disease. Since this singular tragedy, results from numerous clinical trials over the past 10 years have restored the excellent safety profile of adenoviral vectors. These vectors have been extensively studied in phase I and II trials as intraprostatically administered agents for patients with locally recurrent and high-risk local prostate cancer. Promising therapeutic responses have been reported in several studies with both oncolytic and suicide gene therapy strategies. The additional benefit of combining gene therapy with radiation therapy has also been realized; replicating adenoviruses inhibit DNA repair pathways, resulting in a synergistic sensitization to radiation. Other, nonreplicating suicide gene therapy strategies are also significantly enhanced with radiation. Combined radiation/gene therapy is currently being studied in phase I and II clinical trials and will likely be the first adenoviral gene therapy mechanism to become available to urologists in the clinic. Systemic gene therapy for metastatic disease is also a major goal of the field, and clinical trials are currently under way for hormone-resistant metastatic prostate cancer. Second- and third-generation "re-targeted" viral vectors, currently being developed in the laboratory, are likely to further improve these systemic trials.     

Ultraviolet radiation,ozone depletion,and marine photosynthesis

Concerns about stratospheric ozone depletion have stimulated interest in the effects of UVB radiation (280–320 nm) on marine phytoplankton. Research has shown that phytoplankton photosynthesis can be severely inhibited by surface irradiance and that much of the effect is due to UV radiation. Quantitative generalization of these results requires a biological weighting function (BWF) to quantify UV exposure appropriately. Different methods have been employed to infer the general shape of the BWF for photoinhibition in natural phytoplankton, and recently, detailed BWFs have been determined for phytoplankton cultures and natural samples. Results show that although UVB photons are more damaging than UVA (320–400 nm), the greater fluxes of UVA in the ocean cause more UV inhibition. Models can be used to analyze the sensitivity of water column productivity to UVB and ozone depletion. Assumptions about linearity and time-dependence strongly influence the extrapolation of results. Laboratory measurements suggest that UV inhibition can reach a steady-state consistent with a balance between damage and recovery processes, leading to a non-linear relationship between weighted fluence rate and inhibition. More testing for natural phytoplankton is required, however. The relationship between photoinhibition of photosynthesis and decreases in growth rate is poorly understood, so long-term effects of ozone depletion are hard to predict. However, the wide variety of sensitivities between species suggests that some changes in species composition are likely. Predicted effects of ozone depletion on marine photosynthesis cannot be equated to changes in carbon flux between the atmosphere and ocean. Nonetheless, properly designed studies on the effects of UVB can help identify which physiological and ecological processes are most likely to dominate the responses of marine ecosystems to ozone depletion.Abbreviations BWF biological weighting function - BWF/P-I photosynthesis versus photosynthetically available irradiance as influenced by biologically-weighted UV - Chl chlorophyll a - DOM dissolved organic matter - E _PAR irradiance in energy units (PAR) - E _s saturation parameter for PAR in the BWF/P-I model - E _inh ^* biologically-weighted dimensionless fluence rate for photoinhibition of photosynthesis by UV and PAR - biological weighting coefficient - % MathType!MTEF!2!1!+-% feaafiart1ev1aaatCvAUfeBSjuyZL2yd9gzLbvyNv2CaerbuLwBLn% hiov2DGi1BTfMBaeXatLxBI9gBaerbd9wDYLwzYbItLDharqqtubsr% 4rNCHbGeaGqiVu0Je9sqqrpepC0xbbL8F4rqqrFfpeea0xe9Lq-Jc9% vqaqpepm0xbba9pwe9Q8fs0-yqaqpepae9pg0FirpepeKkFr0xfr-x% fr-xb9adbaqaaeGaciGaaiaabeqaamaabaabaaGcbaGafqyTduMbae% baaaa!37AC!\[\bar \varepsilon \]_PAR biological weighting coefficient for damage to photosynthesis by E _PAR - k() diffuse attenuation coefficient for wavelength - MAAs mycosporine-like amino acids - PAR photosynthetically available radiation - P ^B rate of photosynthesis normalized to Chl - P _s ^B maximum attainable rate of photosynthesis in the absence of photoinhibition - UVA ultraviolet A (320–400 nm) - UVB ultraviolet B (280–320 nm)     

Na,K-ATPase: radiation inactivation studies

Na,K-ATPase from duck salt gland and ox brain in the membrane-bound or solubilized form was studied by the radiation inactivation technique using ATP, CTP, GTP or p-NPP as substrates. The values of radiation inactivation size (RIS) were compared with the target size (TS) for the alpha-subunit of the enzyme obtained by an independent method as well as with analytical centrifugation data obtained for C12E8-solubilized enzyme. It was concluded that during ATP (CTP) hydrolysis the enzyme operates as an oligomeric structure; the complex formation requires the presence of K+ and adenosine triphosphate binding to the sites with a low affinity for the nucleotide. Specially designed experiments revealed that the degree of enzyme oligomerization increases with an increase in the microviscosity of the membrane lipid environment.     

Hybridization, transgressive segregation, genetic covariation, and adaptive radiation

Analysis of adaptive radiation has had a central role in the development of evolutionary theory, but it is not clear why some groups radiate and others do not. Two recent papers by Albertson and colleagues on the genetic architecture of East African cichlid fishes implicate hybridization, transgressive segregation and genetic covariation in the early stages of adaptive radiation. Transgressive segregation and genetic covariation might be key innovations in genetic architecture that favor adaptive radiation.     

Flagellin treatment protects against chemicals, bacteria, viruses, and radiation

Sudden exposure of human populations to chemicals, pathogens, or radiation has the potential to result in substantial morbidity. A potential means of rapidly protecting such populations might be to activate innate host defense pathways, which can provide broad protection against a variety of insults. However, innate immune activators can, by themselves, result in severe inflammatory pathology, which in large part is driven by hemopoietic-derived cytokines such as TNF-alpha. We reasoned that, because it preferentially activates epithelial cells, the TLR5 agonist flagellin might not induce severe inflammatory pathology and yet be an ideal agent to provide such non-specific protection, particularly at the mucosal surfaces that serve as a front line of host defense. In accordance, we observed that systemic treatment of mice with purified flagellin did not induce the serologic, histopathologic, and clinical hallmarks of inflammation that are induced by LPS but yet protected mice against chemicals, pathogens, and ionizing radiation. Flagellin-elicited radioprotection required TLR5, the TLR signaling adaptor MyD88, and was effective if given between 2 h before to 4 h after exposure to irradiation. Flagellin-elicited radioprotection was, in part, mediated via effects on cells in bone marrow but yet rescued mortality without a pronounced rescue of radiation-induced anemia or leukopenia. Thus, systemic administration of flagellin may be a relatively safe means of providing temporary non-specific protection against a variety of challenges.     

Resolving an ancient, rapid radiation in Saxifragales

Despite the prior use of approximately 9000 bp, deep-level relationships within the angiosperm clade, Saxifragales remain enigmatic, due to an ancient, rapid radiation (89.5 to 110 Ma based on the fossil record). To resolve these deep relationships, we constructed several new data sets: (1) 16 genes representing the three genomic compartments within plant cells (2 nuclear, 10 plastid, 4 mitochondrial; aligned, analyzed length = 21,460 bp) for 28 taxa; (2) the entire plastid inverted repeat (IR; 26,625 bp) for 17 taxa; (3) "total evidence" (50,845 bp) for both 17 and 28 taxa (the latter missing the IR). Bayesian and ML methods yielded identical topologies across partitions with most clades receiving high posterior probability (pp = 1.0) and bootstrap (95% to 100%) values, suggesting that with sufficient data, rapid radiations can be resolved. In contrast, parsimony analyses of different partitions yielded conflicting topologies, particularly with respect to the placement of Paeoniaceae, a clade characterized by a long branch. In agreement with published simulations, the addition of characters increased bootstrap support for the putatively erroneous placement of Paeoniaceae. Although having far fewer parsimony-informative sites, slowly evolving plastid genes provided higher resolution and support for deep-level relationships than rapidly evolving plastid genes, yielding a topology close to the Bayesian and ML total evidence tree. The plastid IR region may be an ideal source of slowly evolving genes for resolution of deep-level angiosperm divergences that date to 90 My or more. Rapidly evolving genes provided support for tip relationships not recovered with slowly evolving genes, indicating some complementarity. Age estimates using penalized likelihood with and without age constraints for the 28-taxon, total evidence data set are comparable to fossil dates, whereas estimates based on the 17-taxon data are much older than implied by the fossil record. Hence, sufficient taxon density, and not simply numerous base pairs, is important in reliably estimating ages. Age estimates indicate that the early diversification of Saxifragales occurred rapidly, over a time span as short as 6 million years. Between 25,000 and 50,000 bp were needed to resolve this radiation with high support values. Extrapolating from Saxifragales, a similar number of base pairs may be needed to resolve the many other deep-level radiations of comparable age in angiosperms.     

Failla memorial lecture. Risk, research, and radiation protection

Radiation protection concerns the risk of stochastic late effects, especially cancer, and limits on radiation exposure both occupationally and for the public tend to be based on these risks. The risks are determined, mainly by expert committees, from the steadily growing information on exposed human populations, especially the survivors of the atomic bombs dropped in Japan in 1945. Risks of cancer estimated up to the early 1980s were in the range 1 to 5 X 10(-2)/Sv, but recent revisions in the dosimetry of the Japanese survivors and additional cycles of epidemiological information suggest values now probably at the high end of this range. These are likely to require an increase in the values used for radiation protection. A major problem with risk estimation is that data are available only for substantial doses and must be extrapolated down to the low-dose region of interest in radiation protection. Thus the shape of the dose-response curve is important, and here we must turn to laboratory research. Of importance are studies involving (1) dose rate, which affects the response to low-LET radiation and often to high-LET radiation as well; (2) radiation quality, since the shapes of the dose-response curves for high- and low-LET radiation differ and thus the RBE, the ratio between them, varies, reaching a maximum value RBEM at low doses; and (3) modifiers of the carcinogenic response, which either enhance or reduce the effect of a given dose. Radiation protection depends both on risk information, and especially also on comparisons with other occupational and public risks, and on research, not only for extrapolations of risk to low doses but also in areas where human information is lacking such as in the effects of radiation quality and in modifications of response.     

Ultraviolet radiation,resistance to infectious diseases,and vaccination responses

Exposure to ultraviolet (UV) radiation, as in sunlight, can modulate immune responses in animals and humans. This immunomodulation can lead to positive health effects especially with respect to certain autoimmune diseases and allergies. However, UV-induced immunomodulation has also been shown to be deleterious. Experimental animal studies have revealed that UV exposure can impair resistance to many infectious agents, such as bacteria, parasites, viruses, and fungi. Importantly, these effects are not restricted to skin-associated infections, but also concern systemic infections. The real consequences of UV-induced immunomodulation on resistance to infectious diseases are not known for humans. Risk estimations have been performed through extrapolation of animal data, obtained from infection models, to the human situation. This estimation indicated that UV doses relevant to outdoor exposure can impair the human immune system sufficiently to have effects on resistance to infections. To further quantify and validate this risk estimation, data, e.g., from human volunteer studies, are necessary. Infection models in humans are not allowed for ethical reasons. However, vaccination against an infectious disease evokes a similar immune response as the pathogen and thereby provides an opportunity to measure the effect of UV radiation on the immune system and an estimate of the possible consequences of altered resistance to infectious agents. Effects of controlled UVB exposure on immune responses after hepatitis B vaccination have been established in mice and human volunteers. In mice, cellular and Th1-associated humoral immune responses to hepatitis B were significantly impaired, whereas in human volunteers no significant effect of UVB on these responses could be found. Preliminary data indicate that cytokine polymorphisms might be, at least in part, responsible for interindividual differences in immune responses and in susceptibility to UVB-induced immunomodulation. In addition, adaptation to UV exposure needs to be considered as a possible explanation for the difference between mice and humans that was observed in the hepatitis B vaccination model.     

Altitude, radiation, and mortality from cancer and heart disease

The variation in background radiation levels is an important source of information for estimating human risks associated with low-level exposure to ionizing radiation. Several studies conducted in the United States, correlating mortality rates for cancer with estimated background radiation levels, found an unexpected inverse relationship. Such results have been interpreted as suggesting that low levels of ionizing radiation may actually confer some benefit. An environmental factor strongly correlated with background radiation is altitude. Since there are important physiological adaptations associated with breathing thinner air, such changes may themselves influence risk. We therefore fit models that simultaneously incorporated altitude and background radiation as predictors of mortality. The negative correlations with background radiation seen for mortality from arteriosclerotic heart disease and cancers of the lung, the intestine, and the breast disappeared or became positive once altitude was included in the models. By contrast, the significant negative correlations with altitude persisted with adjustment for radiation. Interpretation of these results is problematic, but recent evidence implicating reactive forms of oxygen in carcinogenesis and atherosclerosis may be relevant. We conclude that the cancer correlational studies carried out in the United States using vital statistics data do not in themselves demonstrate a lack of carcinogenic effect of low radiation levels, and that reduced oxygen pressure of inspired air may be protective against certain causes of death.