Roger W. Howell

Managing Radiation Use in Medical Imaging: A Multifaceted Challenge

This special report aims to inform the medical community about the many challenges involved in managing radiation exposure in a way that maximizes the benefit-risk ratio. The report discusses the state of current knowledge and key questions in regard to sources of medical imaging radiation exposure, radiation risk estimation, dose reduction strategies, and regulatory options.

Radiation spectra for Auger‐electron emitting radionuclides: Report No. 2 of AAPM Nuclear Medicine Task Group No. 6

Radiation spectra for radionuclides currently provided by the MIRD Committee and ICRP do not include the very low-energy N- and O-shell Auger electrons. These electrons, emitted in large numbers by radionuclides decaying by electron capture and/or internal conversion, are important for determining the absorbed dose in microscopic volumes. Accordingly, the present AAPM Report employs Monte Carlo computational methods to obtain a self-consistent set of complete radiation spectra for a variety of radionuclides including 55Fe, 67Ga, 99mTc, 111In, 113mIn, 115mIn, 123I, 125I, 193mPt, 195mPt, 201Tl, and 203Pb. Although the conventional spectra provided by MIRD and ICRP are adequate for most dosimetry calculations, the Auger electron spectra provided in this report are recommended for calculating the dose to target volumes < 1 microns in diameter.

Free radical-initiated and gap junction-mediated bystander effect due to nonuniform distribution of incorporated radioactivity in a three-dimensional tissue culture model

Abstract Bishayee, A., Hill, H. Z., Stein, D., Rao, D. V. and Howell, R. W. Free Radical-Initiated and Gap Junction-Mediated Bystander Effect due to Nonuniform Distribution of Incorporated Radioactivity in a Three-Dimensional Tissue Culture Model. To investigate the biological effects of nonuniform distribution of radioactivity in mammalian cells, we have developed a novel three-dimensional tissue culture model. Chinese hamster V79 cells were labeled with tritiated thymidine and mixed with unlabeled cells, and multicellular clusters (∼1.6 mm in diameter) were formed by gentle centrifugation. The short-range β particles emitted by 3H impart only self-irradiation of labeled cells without significant cross-irradiation of unlabeled bystander cells. The clusters were assembled in the absence or presence of 10% dimethyl sulfoxide (DMSO) and/or 100 μM lindane. DMSO is a hydroxyl radical scavenger, whereas lindane is an inhibitor of gap junctional intercellular communication. The clusters were maintained at 10.5°C for 72 h to allow 3H decays to accumulate and then dismantled, and the cells were plated for colony formation. When 100% of the cells were labeled, the surviving fraction was exponentially dependent on the mean level of radioactivity per labeled cell. A two-component exponential response was observed when either 50 or 10% of the cells were labeled. Though both DMSO and lindane significantly protected the unlabeled or bystander cells when 50 or 10% of the cells were labeled, the effect of lindane was greater than that of DMSO. In both cases, the combined treatment (DMSO + lindane) elicited maximum protection of the bystander cells. These results suggest that the bystander effects caused by nonuniform distributions of radioactivity are affected by the fraction of cells that are labeled. Furthermore, at least a part of these bystander effects are initiated by free radicals and are likely to be mediated by gap junctional intercellular communication.

Macroscopic dosimetry for radioimmunotherapy: nonuniform activity distributions in solid tumors

In the context of radioimmunotherapy of cancer, there is a need for continued improvement of dosimetry of radionuclides localized in tumors. Current methods assume uniform distribution of radionuclides in the tumor despite experimental evidence indicating nonuniormity. We have developed a model in which nonuniform distribution of radioactivity in the tumor is taken into account. Spherically symmetric radionuclide distributions, depending linearly and exponentially on the radial position, are considered. Dose rate profiles in the tumor are calculated for potentially useful beta-emitting radionuclides, including 32P, 67Cu, 90Y, 111Ag, 131I, and 188Re, and for 193mPt, an emitter of conversion electrons and low-energy Auger electrons. For the radionuclide distributions investigated, high-energy beta emitters, such as 90Y, are most effective in treating large tumors (diameter, d greater than approximately 1 cm), whereas for small tumors (d approximately 1 mm), medium energy beta emitters such as 67Cu are better suited. Very small tumors (d less than 1 mm), and micrometastases are best handled with low-energy electron emitters such as 193mPt.

Evidence for pronounced bystander effects caused by nonuniform distributions of radioactivity using a novel three-dimensional tissue culture model.

A new in vitro multicellular cluster model has been developed to assess the impact of nonuniform distributions of radioactivity on the biological response of mammalian cells, and the relative importance of bystander effects compared to conventional radiation effects. Chinese hamster V79 cells are labeled with tritiated thymidine

Dosimetry of Auger-electron-emitting radionuclides: report no. 3 of AAPM Nuclear Medicine Task Group No. 6.

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Adaptive Responses to Low-Dose/Low-Dose-Rate γ Rays in Normal Human Fibroblasts: The Role of Growth Architecture and Oxidative Metabolism

, mixed with unlabeled V79 cells, and centrifuged gently to form multicellular clusters about 1.6 mm in diameter. The short range of the3 H β particles effectively allows only self-irradiation of labeled cells and no cross-irradiation of unlabeled cells. The percentage of labeled cells is controlled precisely by varying the number of labeled cells mixed with unlabeled cells prior to assembling the cluster. The clusters are assembled in the absence or presence of 100 μM lindane, a chemical that is known to inhibit formation of gap junctions. After the clusters are maintained at 10.5°C for 72 h, the cells are dispersed and plated for...

The question of relative biological effectiveness and quality factor for auger emitters incorporated into proliferating mammalian cells.

The biological effects of Auger-electron-emitting radionuclides can be as severe as those of alpha particles of high linear energy transfer. A great deal of effort has been expended in exploring the biological effects of Auger electron emitters. Much of this effort has been devoted to improving theoretical and experimental techniques required to calculate absorbed doses and correlate them with the observed biological effects. Given that the main purpose of dosimetry is to obtain a physical descriptor with which to correlate radiation toxicity, then nowhere is this challenge greater than when biological specimens are subject to Auger electron cascades. The dense shower of short-range Auger electrons released by radionuclides, which decay by electron capture or internal conversion, results in biological damage that is highly dependent on the location of the decay site within the cell. In this report, different approaches to Auger electron dosimetry are described and compared. Methods to calculate the absorbed dose from Auger electron emitters at the DNA, cellular, multicellular, and organ levels are described as they relate to the biological effects. The concept of a radiation weighting factor for Auger electrons to be used in the calculation of equivalent dose is reviewed. The importance of subcellular distribution of Auger emitters in determining the biological effects of these radionuclides is emphasized and incorporated into the equivalent dose formalism. The Task Group recommends that a preliminary radiation weighting factor of 10 be used for deterministic effects of Auger electrons, and a value of 20 for stochastic effects.

Induction of Sperm Head Abnormalities by Incorporated Radionuclides: Dependence on Subcellular Distribution, Type of Radiation, Dose Rate, and Presence of Radioprotectors

Abstract de Toledo, S. M., Asaad, N., Venkatachalam, P., Li, L., Howell, R. W., Spitz, D. R. and Azzam, E. I. Adaptive Responses to Low-Dose/Low-Dose-Rate γ Rays in Normal Human Fibroblasts: The Role of Growth Architecture and Oxidative Metabolism. Radiat. Res. 166, 849–857 (2006). To investigate low-dose/low-dose-rate effects of low-linear energy transfer (LET) ionizing radiation, we used γ-irradiated cells adapted to grow in a three-dimensional architecture that mimics cell growth in vivo. We determined the cellular, molecular and biochemical changes in these cells. Quiescent normal human fibroblasts were irradiated with single acute or chronic doses (1–10 cGy) of 137Cs γ rays. Whereas exposure to an acute dose of 10 cGy increased micronucleus formation, protraction of the dose over 48 h reduced micronucleus frequency to a level similar to or lower than what occurs spontaneously. The protracted treatment also up-regulated the cellular content of the antioxidant glutathione. These changes correlated with modulation of phospho-TP53 (serine 15), a stress marker that was regulated by doses as low as 1 cGy. The DNA damage that occurred after exposure to an acute dose of 10 cGy was protected against in two ways: (1) up-regulation of cellular antioxidant enzyme activity by ectopic overexpression of MnSOD, catalase or glutathione peroxidase, and (2) inhibition of superoxide anion generation by flavin-containing oxidases. These results support a significant role for oxidative metabolism in mediating low-dose radiation effects and demonstrate that cell culture in three dimensions is ideal to investigate radiation-induced adaptive responses. Expression of connexin 43, a constitutive protein of gap junctions, and the G1 checkpoint were more sensitive to regulation by γ rays in cells maintained in a three-dimensional than in a two-dimensional configuration.

Cell proximity is a prerequisite for the proliferative response of bystander cells co-cultured with cells irradiated with γ-rays

The problem of determining RBE values for Auger emitters incorporated into proliferating mammalian cells is examined. In general, the reference radiation plays a key role in obtaining experimental RBE values. Using survival of cultured Chinese hamster V79 cells as the experimental model, new data are provided regarding selection of a reference radiation for internal Auger emitters. These data show that gamma rays delivered acutely (137Cs) are more than twice as lethal as gamma rays delivered chronically with an exponentially decreasing dose rate (99mTc). The results confirm that the reference radiation should be delivered chronically in a manner consistent with the extended exposure received by the cells in the case of incorporated radionuclides. Through a direct comparison of the radiotoxicity of Auger emitters and alpha emitters, the high RBE values reported for DNA-bound Auger emitters are confirmed. These studies reveal that the DNA binding compound [125I]iododeoxyuridine (125IdU) is about 1.6 times more effective in killing V79 cells than 5.3 MeV alpha particles from intracellularly localized 210Po-citrate. In addition, toxicity studies with the radiochemicals 125IdU and [125]-iododeoxycytidine (125IdC) establish the equivalence of the radiosensitivity of thymine and cytosine base sites in the DNA. In view of these results, and information already available, the question of establishing quality factors for Auger emitters is considered. Finally, a method for calculation of the dose equivalent for internal Auger emitters is advanced.