Tissue Dosimetry Research Articles

Novel dosimetric study of the sp2 to sp3 hybridisation ratio in free–standing carbon nanotubes buckypaper

Over the past several years a great deal of research has focused on the adaptation of carbon nanotubes (CNTs) for a wide range of applications, including as gas detectors, in energy storage, for various photonics purposes, also as radiation sensors. In previous studies by this group, investigating thermoluminescent (TL) properties, the sensitivity of CNTs towards ionising radiations has been observed using beta radiation at dose levels from fractions of a Gy and more. Strain and impurity defects in CNTs give rise to substantial TL yields, the extent to which electron trapping centres exist varying inversely with the quality of CNT, from super-pure to pure to raw. In present study the contribution to TL of beta particle irradiated CNTs has been investigated with respect to changes in the lattice atomic orbitals, pointing to the possibility of a new radiation dosimetry method. The surface-sensitive method, one highly suited to the thin (few tens of µm thick) CNT samples produced in the form of free-standing buckypaper, is based on use of the X-Ray Photoelectron Spectroscopy (XPS) technique, evaluating sp2 to sp3 hybridisation. The CNT samples have been examined subsequent to irradiation using a relatively large activity 90Sr/90Y radionuclide source (Eβ = 0.546 MeV/2.28 MeV), delivering doses in the range 0.2–6 Gy, in all three qualities sp2 to sp3 hybridisation being observed to increase with dose deposition. Considerable advantage is seen in making use of such thin CNTs in dosimetry, rendering them particularly suitable for beta particle soft tissue dosimetry.

A Method for Using a Radiophotoluminescence Glass Dosimeter in Accurate Tissue Dosimetry

In the field of radiation dosimetry, a radiophotoluminescence glass dosimeter (RPLGD) has become one of widely used dosimeters owing to its better properties compared to other conventionally used dosimeters. However, it is questionable if its absorbed dose can represent dose received by water or body tissue because the RPLGD has significantly different physical and radiological properties from those of water, which is commonly accepted as standard material in clinical dosimetry. In the present paper, the feasibility of using the RPLGD in tissue dosimetry was investigated by means of Monte-Carlo simulations, which were validated with experimental data obtained under well-defined conditions. As a result, it was quantitatively demonstrated that RPLGD dose and water dose generally do not agree each other, while such differences can be compensated by employing a correction factor. In this study, we present a method combining experimental and computational dosimetry techniques that could reduce uncertainty in dosimetry.

PERFORMANCE OF THE VARSKIN 5 (v5.3) ELECTRON DOSIMETRY MODEL.

A new electron skin dosimetry model was developed for the VARSKIN 5 tissue dosimetry code. This model employs energy deposition kernels that provides for improved accuracy of energy deposition at the end of electron tracks. The Monte Carlo code EGSnrc was utilized to develop these energy deposition kernels such that scaling of electron energy loss is dependent on effective atomic number and density of the source material, electron range and conservation of energy. This work contrasts VARSKIN's electron dosimetry model to several existing deterministic and Monte Carlo dosimetry tools to determine the efficacy of these improvements. Comparison results are given for a wide range of scenarios that extend beyond the typical use of VARSKIN, including mono-energetic electrons and a homogenous water medium. For planar and point sources in contact with the skin, VARSKIN produces results equated to other dosimetry methods within 10%. However, it appears that VARSKIN is unable to account accurately for electron energy loss with the introduction of a cover material or an air gap. The comparisons herein confirm that VARSKIN provides accurate electron dose calculations for skin-contamination scenarios.

Developing integrated PBPK/PD coupled mechanistic pathway model (miRNA-BDNF): An approach towards system toxicology

Integration of a dynamic signal transduction pathway into the tissue dosimetry model is a major advancement in the area of computational toxicology. This paper illustrates the ways to incorporate the use of existing system biological model in the field of toxicology via its coupling to the Physiological based Pharmacokinetics and Pharmacodynamics (PBPK/PD) model. This expansion framework of integrated PBPK/PD coupled mechanistic system pathway model can be called as system toxicology that describes the kinetics of both – the chemicals and – biomolecules, help us to understand the dynamic and steady-state behaviors of molecular pathways under perturbed condition. The objective of this article is to illustrate a system toxicology based approach by developing an integrated PBPK/PD coupled miRNA-BDNF pathway model and to demonstrate its application by taking a case study of the PFOS mediated neurotoxicity. System dynamic involves miRNA-mediated BDNF regulation, which plays an important role in the control of neuronal cell proliferation, differentiation, and survivability.

Percent depth doses and X-ray beam characterizations of a fluoroscopic system incorporating copper filtration.

In this investigation, we sought to characterize X-ray beam qualities and quantitate percent depth dose (PDD) curves for fluoroscopic X-ray beams incorporating added copper (Cu) filtration, such as those commonly used in fluoroscopically guided interventions (FGI). The intended application of this research is for dosimetry in soft tissue from FGI procedures using these data. All measurements in this study were acquired on a Siemens (Erlangen, Germany) Artis zeego fluoroscope. X-ray beam characteristics of first half-value layer (HVL), second HVL, homogeneity coefficients (HCs), backscatter factors (BSFs) and kVp accuracy and precision were determined to characterize the X-ray beams used for the PDD measurements. A scanning water tank was used to measure PDD curves for 60, 80, 100, and 120 kVp X-ray beams with Cu filtration thicknesses of 0.0, 0.1, 0.3, 0.6, and 0.9 mm at 11 cm, 22 cm, and 42 cm nominal fields of view, in water depths of 0 to 150 mm. X-ray beam characteristics of first HVLs and HCs differed from previous published research of fluoroscopic X-ray beam qualities without Cu filtration. PDDs for 60, 80, 100, and 120 kVp with 0 mm of Cu filtration were comparable to previous published research, accounting for differences in fluoroscopes, geometric orientation, type of ionization chamber, X-ray beam quality, and the water tank used for data collection. PDDs and X-ray beam characteristics for beam qualities with Cu filtration are presented, which have not been previously reported. The data sets of X-ray beam characteristics and PDDs presented in this study can be used to estimate organ or soft tissue doses at depth involving similar beam qualities or to compare with mathematical models.

Numerical prediction of tissue dosimetry in respiratory tract using computer simulated person integrated with physiologically based pharmacokinetic–computational fluid dynamics hybrid analysis

Indoor environmental quality, e.g. air quality and thermal environments, has a potential impact on residents in indoors. Development of a computer simulated person (CSP) for indoor computational fluid dynamics (CFD) simulation can contribute to the improvement of design and prediction method regarding the interaction between indoor air/thermal environmental factors and human responses. In this study, a CSP integrated with a virtual airway was developed and used to estimate inhalation exposure in an indoor environment. The virtual airway is a numerical respiratory tract model for CFD simulation that reproduces detailed geometry from the nasal/oral cavity to the bronchial tubes by way of the trachea. Physiologically based pharmacokinetic (PBPK)-CFD hybrid analysis is also integrated into the CSP. Through the coupled simulation of PBPK-CFD-CSP analysis, inhalation exposure under steady state conditions where formaldehyde was emitted from floor material was analysed and respiratory tissue doses and their distributions of inhaled contaminants are discussed quantitatively.

Lower limits of detection in using carbon nanotubes as thermoluminescent dosimeters of beta radiation

World-wide, on-going intensive research is being seen in adaptation of carbon nanotubes (CNTs) for a wide variety of applications, particular interest herein being in the thermoluminescent (TL) properties of CNTs and their sensitivity towards energetic radiations. Using beta radiation delivering dose levels of a few Gy it has been observed in previous study that strain and impurity defects in CNTs give rise to significant TL yields, providing an initial measure of the extent to which electron trapping centres exist in various qualities of CNT, from super-pure to raw. This in turn points to the possibility that there may be considerable advantage in using such media for radiation dosimetry applications, including for in vivo dosimetry. CNTs also have an effective atomic number similar to that of adipose tissue, making them suitable for soft tissue dosimetry. In present investigations various single-wall carbon nanotubes (SWCNT) samples in the form of buckypaper have been irradiated to doses in the range 35–1.3Gy, use being made of a 90Sr beta source, the response of the CNTs buckypaper with dose showing a trend towards linearity. It is shown for present production methodology for buckypaper samples that the raw SWCNT buckypaper offer the greatest sensitivity, detecting doses down to some few tens of mGy.

Detailed prospective peer review in a community radiation oncology clinic

PurposeIn 2012, we instituted detailed prospective peer review of new cases. We present the outcomes of peer review on patient management and time required for peer review. Methods and materialsPeer review rounds were held 3 to 4 days weekly and required 2 physicians to review pertinent information from the electronic medical record and treatment planning system. Eight aspects were reviewed for each case: 1) workup and staging; 2) treatment intent and prescription; 3) position, immobilization, and simulation; 4) motion assessment and management; 5) target contours; 6) normal tissue contours; 7) target dosimetry; and 8) normal tissue dosimetry. Cases were marked as, “Meets standard of care,” “Variation,” or “Major deviation.” Changes in treatment plan were noted. As our process evolved, we recorded the time spent reviewing each case. ResultsFrom 2012 to 2014, we collected peer review data on 442 of 465 (95%) radiation therapy patients treated in our hospital-based clinic. Overall, 91 (20.6%) of the cases were marked as having a variation, and 3 (0.7%) as major deviation. Forty-two (9.5%) of the cases were altered after peer review. An overall peer review score of “Variation” or “Major deviation” was highly associated with a change in treatment plan (P < .01). Changes in target contours were recommended in 10% of cases. Gastrointestinal cases were significantly associated with a change in treatment plan after peer review. Indicators on position, immobilization, simulation, target contours, target dosimetry, motion management, normal tissue contours, and normal tissue dosimetry were significantly associated with a change in treatment plan. The mean time spent on each case was 7 minutes. ConclusionsProspective peer review is feasible in a community radiation oncology practice. Our process led to changes in 9.5% of cases. Peer review should focus on technical factors such as target contours and dosimetry. Peer review required 7 minutes per case.

Delayed luminescence of erythrosine in biological tissue and photodynamic therapy dosimetry

The features of delayed fluorescence (DF) and phosphorescence in erythrosine stained healthy and cancer-diseased mammary gland tissues of BYRB-line mice were investigated in vitro.Thermoactivated delayed fluorescence (TDF), triplet-triplet annihilation (TTA) and originated from singlet-triplet annihilation (STA) delayed fluorescence are investigated as competing channels of radiative relaxation of the triplet states of erythrosine. The dominant role of diffusive-mobile molecular oxygen in deactivation of triplet-excited long-live states of the dye molecules in cells is determined.The previously not described phenomenon of light quenching of DF under pulsed laser irradiation (light quenching of DF, LQDF) in stained tissue was revealed.LQDF is increased if the energy of excited pulses is rise and their sequence period is decreased. The DF depletion disappears if time interval between pulses in the series is >5s. This phenomenon is due two process competition: fast consumption of singlet oxygen by oxidation of cell organelles right after laser pulse excitation and slow diffusive recovery of oxygen concentration in the pause between the pulses.Statistically valid distinction between DF characterization as well as LQDF erythrosine extent in healthy and pathological tissues was established.The use of this phenomenon will greatly simplify the determination of radiation “dose” in photodynamic therapy (PDT) directly during the treatment session.

A Comparative Evaluation of Normal Tissue Doses for Patients Receiving Radiation Therapy for Hodgkin Lymphoma on the Childhood Cancer Survivor Study and Recent Children's Oncology Group Trials

Survivors of pediatric Hodgkin lymphoma (HL) are recognized to have an increased risk of delayed adverse health outcomes related to radiation therapy (RT). However, the necessary latency required to observe these late effects means that the estimated risks apply to outdated treatments. We sought to compare the normal tissue dose received by children treated for HL and enrolled in the Childhood Cancer Survivor Study (CCSS) (diagnosed 1970-1986) with that of patients treated in recent Children's Oncology Group (COG) trials (enrolled 2002-2012). RT planning data were obtained for 50 HL survivors randomly sampled from the CCSS cohort and applied to computed tomography planning data sets to reconstruct the normal tissue dosimetry. For comparison, the normal tissue dosimetry data were obtained for all 191 patients with full computed tomography-based volumetric RT planning on COG protocols AHOD0031 and AHOD0831. For early-stage patients, the mean female breast dose in the COG patients was on average 83.5% lower than that for CCSS patients, with an absolute reduction of 15.5Gy. For advanced-stage patients, the mean breast dose was decreased on average by 70% (11.6 Gy average absolute dose reduction). The mean heart dose decreased on average by 22.9Gy (68.6%) and 17.6Gy (56.8%) for early- and advanced-stage patients, respectively. All dose comparisons for breast, heart, lung, and thyroid were significantly lower for patients in the COG trials than for the CCSS participants. Reductions in the prescribed dose were a major contributor to these dose reductions. These are the first data quantifying the significant reduction in the normal tissue dose using actual, rather than hypothetical, treatment plans for children with HL. These findings provide useful information when counseling families regarding the risks of contemporary RT.

MRI Morphologic Alterations After Liver-SBRT: Assessment of Correlation With Dose Based on Deformable Matching

CT-morphologic alterations after SBRT are described in the literature and they can be correlated to histopathologic alterations. In this work we analyzed the correlation of MRI-morphologic alterations with radiation doses to assess the potential for MR-based in-vivo dosimetry in healthy liver tissue. MRI data of 22 patients with liver metastases before and after 7±3 weeks after image guided SBRT in computer-controlled deep inspiratory breath hold (DIBH) were analyzed retrospectively. T1- and T2-weighted MRI sequences were matched to the planning CT with the corresponding dose distribution with a commercially available deformable registration algorithm. Isodose lines were directly correlated to the radiologic changes. Absolute doses were converted to BED2 with an α/β-value of 2 and 3 for healthy liver tissue and 10 for tumor tissue (BED2=Dx (d+α/β)/(2+α/β)). Nominal prescription dose was 48.9±14.7Gy (median 60Gy) in single doses of 14.1±6.7Gy (median 12Gy). BED2 was 93.9±26.8Gy (median 110Gy) for the PTV (α/β10). Central necrosis was observed within the isodose lines of nominally 48.8±14.7Gy (median 60Gy), BED2 (α/β10) 93.9±26.7Gy (median 110Gy). A surrounding contrast medium accumulation was observed within the isodose lines of nominal 47.4±14.9Gy (median 58.5Gy), BED2 (α/β10) 91.8±27.4Gy (median 105.8Gy). Outside the high-dose volume, in the region of radiation beam entrance, characteristic sharply defined radiological changes were observed which could be directly correlated to the isodose lines: T1 hypo- or hyperintensity occurred starting at isodose lines of nominally 22.2±6.8Gy (median 24Gy), BED2(α/β2) 43.4±7.8Gy (median 42Gy), BED2 (α/β3) 39.3±6.8Gy (median 37.6Gy). T2-hyper/or hypointensity was observed within isodose lines of nominally 22.4±6.7Gy (median 24Gy), BED2 (α/β2) 43.1±11.6Gy (median 41.5Gy), BED2 (α/β3) 39.6±9.8Gy (median 38,7Gy). No high grade toxicity or changes in liver laboratory values were observed. (1) A sharply defined pattern of radiological changes indicates a precise dose application in repetitive breath hold during hypofractionated SBRT. (2) Characteristic radiogenic changes occur in the first post-SBRT MRI. Within the high-dose region of the PTV, tumor necrosis and peripheral contrast medium accumulation can be observed. Beam entrance doses of 37-42Gy (BED2) induce MRI morphologic changes which can be correlated to isodose lines. These changes have not resulted in clinical or biochemical toxicity in the studied cohort. Based on deformable matching, these data allow a direct spatial and dosimetric correlation and quantification of SBRT-induced changes in healthy liver tissue.

Testis dosimetry in individual patients by combining a small-scale dosimetry model and pharmacokinetic modeling-application of 111In-Ibritumomab Tiuxetan (Zevalin®)

A heterogeneous distribution of radionuclides emitting low-energy electrons in the testicles may result in a significant difference between an absorbed dose to the radiosensitive spermatogonia and the mean absorbed dose to the whole testis. This study focused on absorbed dose distribution in patients at a finer scale than normally available in clinical dosimetry, which was accomplished by combining a small-scale dosimetry model with patient pharmacokinetic data. The activity in the testes was measured and blood sampling was performed for patients that underwent pre-therapy imaging with 111In-Zevalin®. Using compartment modeling, testicular activity was separated into two components: vascular and extravascular. The uncertainty of absorbed dose due to geometry variations between testicles was explored by an assumed activity micro-distribution and by varying the radius of the interstitial tubule. Results showed that the absorbed dose to germ cells might be strongly dependent on the location of the radioactive source, and may exceed the absorbed dose to the whole testis by as much as a factor of two. Small-scale dosimetry combined with compartmental analysis of clinical data proved useful for gauging tissue dosimetry and interpreting how intrinsic geometric variation influences the absorbed dose.

Computational modeling of nanoscale and microscale particle deposition, retention and dosimetry in the mouse respiratory tract

Comparing effects of inhaled particles across rodent test systems and between rodent test systems and humans is a key obstacle to the interpretation of common toxicological test systems for human risk assessment. These comparisons, correlation with effects and prediction of effects, are best conducted using measures of tissue dose in the respiratory tract. Differences in lung geometry, physiology and the characteristics of ventilation can give rise to differences in the regional deposition of particles in the lung in these species. Differences in regional lung tissue doses cannot currently be measured experimentally. Regional lung tissue dosimetry can however be predicted using models developed for rats, monkeys, and humans. A computational model of particle respiratory tract deposition and clearance was developed for BALB/c and B6C3F1 mice, creating a cross-species suite of available models for particle dosimetry in the lung. Airflow and particle transport equations were solved throughout the respiratory tract of these mice strains to obtain temporal and spatial concentration of inhaled particles from which deposition fractions were determined. Particle inhalability (Inhalable fraction, IF) and upper respiratory tract (URT) deposition were directly related to particle diffusive and inertial properties. Measurements of the retained mass at several post-exposure times following exposure to iron oxide nanoparticles, micro- and nanoscale C60 fullerene, and nanoscale silver particles were used to calibrate and verify model predictions of total lung dose. Interstrain (mice) and interspecies (mouse, rat and human) differences in particle inhalability, fractional deposition and tissue dosimetry are described for ultrafine, fine and coarse particles.

INTEGRA: Investigating the Exposure Continuum from Global Scale Contamination to Tissue Dose

INTEGRA: Investigating the Exposure Continuum from Global Scale Contamination to Tissue DoseAbstract Number:2590 Dimosthenis Sarigiannis*, Spyridon Karakitsios, Alberto Gotti, George Loizou, John Cherrie, Roel Smolders, Katleen De Brouwere, Karen Galea, Kate Jones, Evangelos Handakas, Krystalia Papadaki, and Anne Sleeuwenhoek Dimosthenis Sarigiannis* Aristotle University of Thessaloniki, Department of Chemical Engineering, Environmental Engineering Laboratory, Greece, E-mail Address: [email protected] Search for more papers by this author , Spyridon Karakitsios Aristotle University of Thessaloniki, Department of Chemical Engineering, Environmental Engineering Laboratory, Greece, E-mail Address: [email protected] Search for more papers by this author , Alberto Gotti Aristotle University of Thessaloniki, Department of Chemical Engineering, Environmental Engineering Laboratory, Greece, E-mail Address: [email protected] Search for more papers by this author , George Loizou Health and Safety Laboratory, Computational Toxicology Team, United Kingdom, E-mail Address: [email protected] Search for more papers by this author , John Cherrie Insitute of Occupational Medicine, United Kingdom, E-mail Address: [email protected] Search for more papers by this author , Roel Smolders Vlaamse Instelling Voor Technologisch Onderzoek (VITO), Belgium, E-mail Address: [email protected] Search for more papers by this author , Katleen De Brouwere Vlaamse Instelling Voor Technologisch Onderzoek (VITO), Belgium, E-mail Address: [email protected] Search for more papers by this author , Karen Galea Insitute of Occupational Medicine, United Kingdom, E-mail Address: [email protected] Search for more papers by this author , Kate Jones Health and Safety Laboratory, Computational Toxicology Team, United Kingdom, E-mail Address: [email protected] Search for more papers by this author , Evangelos Handakas Aristotle University of Thessaloniki, Department of Chemical Engineering, Environmental Engineering Laboratory, Greece, E-mail Address: [email protected] Search for more papers by this author , Krystalia Papadaki Aristotle University of Thessaloniki, Department of Chemical Engineering, Environmental Engineering Laboratory, Greece, E-mail Address: [email protected] Search for more papers by this author , and Anne Sleeuwenhoek Insitute of Occupational Medicine, United Kingdom, E-mail Address: [email protected] Search for more papers by this author AbstractThe objective of the INTEGRA project is to bring together all information necessary for assessing the source-to-dose exposure continuum over the entire life cycle of substances covering an extensive chemical space through the use of QSARs. The major outcome of INTEGRA is a comprehensive computational platform that integrates multimedia environmental and micro-environmental fate, (external) exposure and internal dose within a dynamic framework in time. The platform allows multimedia interactions across different spatial scales, taking into account environmental releases and related processes at global, regional and local scale, up to the level of personal microenvironment. Coupling seamlessly exposure models with refined computational tools for internal dosimetry transforms exposure/risk assessment of environmental chemicals since it allows risk characterization to be based on internal dosimetry metrics. In this way high throughput system data such as the ones generated by Tox21 in vitro testing can be used to support exposure based risk assessment. This opens the way towards a higher level of assessment that incorporates refined exposure (tissue dosimetry) and toxicity testing (Biological Pathway Altering Dose – BPAD) associated to environmental contamination at different scales. The applicability of INTEGRA was tested on bisphenol-A. Tier 1 assessment (environmental releases based on production volumes, worst case exposure estimates and Tolerable Daily Intake of 50µg/kg_bw/d) indicated that specific exposure scenarios (i.e. bottle fed neonates and premature infants hosted in intensive care units) are close to the legislative thresholds. The refined exposure assessment incorporating probabilistic analysis, actual environmental release data, detailed consumer exposure modelling and the use of BPAD as an internal exposure risk characterization metric, resulted in increased margins of safety compared to conventional exposure/risk characterization.

Comparative iron oxide nanoparticle cellular dosimetry and response in mice by the inhalation and liquid cell culture exposure routes

BackgroundToxicity testing the rapidly growing number of nanomaterials requires large scale use of in vitro systems under the presumption that these systems are sufficiently predictive or descriptive of responses in in vivo systems for effective use in hazard ranking. We hypothesized that improved relationships between in vitro and in vivo models of experimental toxicology for nanomaterials would result from placing response data in vitro and in vivo on the same dose scale, the amount of material associated with cells.MethodsBalb/c mice were exposed nose-only to an aerosol (68.6 nm CMD, 19.9 mg/m3, 4 hours) generated from of 12.8 nm superparamagnetic iron oxide particles (SPIO). Target cell doses were calculated, histological evaluations conducted, and biomarkers of response were identified by global transcriptomics. Representative murine epithelial and macrophage cell types were exposed in vitro to the same material in liquid suspension for four hours and levels of nanoparticle regulated cytokine transcripts identified in vivo were quantified as a function of measured nanoparticle cellular dose.ResultsTarget tissue doses of 0.009-0.4 μg SPIO/cm2 in lung led to an inflammatory response in the alveolar region characterized by interstitial inflammation and macrophage infiltration. In vitro, higher target tissue doses of ~1.2-4 μg SPIO/ cm2 of cells were required to induce transcriptional regulation of markers of inflammation, CXCL2 & CCL3, in C10 lung epithelial cells. Estimated in vivo macrophage SPIO nanoparticle doses ranged from 1-100 pg/cell, and induction of inflammatory markers was observed in vitro in macrophages at doses of 8-35 pg/cell.ConclusionsApplication of target tissue dosimetry revealed good correspondence between target cell doses triggering inflammatory processes in vitro and in vivo in the alveolar macrophage population, but not in the epithelial cells of the alveolar region. These findings demonstrate the potential for target tissue dosimetry to enable the more quantitative comparison of in vitro and in vivo systems and advance their use for hazard assessment and extrapolation to humans. The mildly inflammogentic cellular doses experienced by mice were similar to those calculated for humans exposed to the same material at the existing permissible exposure limit of 10 mg/m3 iron oxide (as Fe).Electronic supplementary materialThe online version of this article (doi:10.1186/s12989-014-0046-4) contains supplementary material, which is available to authorized users.

Use of novel inhalation kinetic studies to refine physiologically-based pharmacokinetic models for ethanol in non-pregnant and pregnant rats

Ethanol (EtOH) exposure induces a variety of concentration-dependent neurological and developmental effects in the rat. Physiologically-based pharmacokinetic (PBPK) models have been used to predict the inhalation exposure concentrations necessary to produce blood EtOH concentrations (BEC) in the range associated with these effects. Previous laboratory reports often lacked sufficient detail to adequately simulate reported exposure scenarios associated with BECs in this range, or lacked data on the time-course of EtOH in target tissues (e.g. brain, liver, eye, fetus). To address these data gaps, inhalation studies were performed at 5000, 10 000, and 21 000 ppm (6 h/d) in non-pregnant female Long-Evans (LE) rats and at 21 000 ppm (6.33 h/d) for 12 d of gestation in pregnant LE rats to evaluate our previously published PBPK models at toxicologically-relevant blood and tissue concentrations. Additionally, nose-only and whole-body plethysmography studies were conducted to refine model descriptions of respiration and uptake within the respiratory tract. The resulting time-course and plethysmography data from these in vivo studies were compared to simulations from our previously published models, after which the models were recalibrated to improve descriptions of tissue dosimetry by accounting for dose-dependencies in pharmacokinetic behavior. Simulations using the recalibrated models reproduced these data from non-pregnant, pregnant, and fetal rats to within a factor of 2 or better across datasets, resulting in a suite of model structures suitable for simulation of a broad range of EtOH exposure scenarios.

Three-dimensional dosimetry of the full and empty bladder in high dose rate vaginal cuff brachytherapy.

The objectives of the study were to assess the bladder doses during vaginal cuff brachytherapy and to examine the effect of bladder filling on normal tissue dosimetry by means of computed tomography. A total number of 45 women were enrolled in a prospective clinical trial. Patients were treated with the application of a single-line source vaginal cylinder. All the patients were asked to consume 400 mL of water 40 minutes before computed tomography scans were taken. For each patient, 2 treatment plans were performed-one with full bladder and the other one when the bladder was emptied. A dose-volume histogram and the equivalent of 2-Gy dose for full and empty bladder were calculated. Doses to the bowels in 2 states of the bladder were estimated. Thirty-five patients received a lower dose to the empty bladder than to the filled organ. The average dose difference was 0.5 Gy. Ten patients received a lower dose to the full bladder than to the empty one. However, in this case, the difference amounted only to 0.2 Gy on average. Dose parameters (the maximal dose received by 0.1 cm of tissue and the maximal dose received by 2 cm of tissue) were lower in the empty state, but the volumetric parameters (the percent of bladder volume receiving ≥50% of the prescribed dose and the percent of bladder volume receiving ≥80% of the prescribed dose) were higher in the empty state of the bladder. Doses to the bowels seemed to be higher in the empty bladder. However, none of the doses exceeded the limitations. The results have shown that in most cases, the dose to the empty bladder is lower than when the bladder is full. Simultaneously, the doses to the bowels increase proportionally in the empty state of the bladder comparing to the full organ. Protection of the bowels, which are more radiosensitive, suggests treating the patients in the full state of the bladder. Early and late bowel toxicity should be investigated to establish clear standards of treatment.

The Relevance of Dosimetry in Animal Models of Cochlear Irradiation

To compare dose measurements of three different irradiation setups for an animal model of unilateral cochlear irradiation using radiochromic films positioned at the cochlear plane. A method of dosimetry is proposed. Radiation field simulation was performed to locate the cochlear plane for irradiation experiments using CT scan images. Fifteen film pieces were irradiated at the cochlear plane with 3 different irradiation field sizes. A 12-mm diameter field (n = 5), 5.7 mm diameter field (n = 5), and a 6.5 × 7.2 mm field (n = 5). After obtaining an ideal irradiation field size, 15 film pieces were used to compare dosimetry between tissue substitute materials (PVC n = 5 and PVC + Teflon, 5 each) and real tissue (frozen animal, n = 5). Auditory brainstem responses at 3 frequencies (8, 16, 20, and 25 kHz) were performed on 7 guinea pigs after a cycle of fractionated unilateral irradiation. Dosimetry in real tissue demonstrated an asymmetric dose distribution at the cochlear plane and ultimately a lower dose deposition (30%) when compared with tissue substitute materials. Auditory brainstem responses of ears subjected to radiotherapy demonstrated progressive hearing loss in long-term assessment. Asymmetric dose deposition at the cochlear plane highlights the need of comprehensive real tissue dosimetry in animal studies of cochlear irradiation. To avoid misleading discrepancies in dose-deposition between different studies using the same animal model, appropriate planning and confirmatory dosimetry systems are highly desirable.

Crystallographic Analysis and Mimicking of Estradiol Binding: Interpretation and Speculation

In their recent article, Gosavi et al. (2013) presented the results of a crystallographic analysis of the binding of tetrabromobisphenol A (TBBPA) and 3-hydroxy-2,2´,4,4´-tetrabromodiphenyl ether (3-OH-BDE-47) to estrogen sulfotransferase (SULT1E1). The authors demonstrated that the tested molecules fit into the same binding pocket as estradiol. However, although the study’s methodology and interpretation of the crystallographic analysis provide insight into how binding might occur in isolated and in vitro systems, they did not provide evidence that the tested molecules would initiate any biological activity with the relevant estrogen receptors (ERs) or proteins in a human body. For example, the ability of TBBPA to interact with the ER and estrogen-related receptors has been evaluated in recombinant yeast strains, mammalian cell–based assays, and tests developed by the Organisation for Economic Co-operation and Development (Lee et al. 2012; Nakagawa et al. 2007; Ogunbayo et al. 2007, 2008; Reistad et al. 2005, 2007; Strack et al. 2007). Those studies found that TBBPA either did not interact with ERs or that it acted as a weak ER agonist/antagonist with a potency orders of magnitude below that of natural ER ligands. In addition, the data presented by Gosavi et al. (2013) did not include the use of controls to validate the methods. The use of both positive controls (such as diethylstilbestrol and ethinyl estradiol) and a negative control (such as testosterone) would provide validation of the analysis and allow for the quantification and comparison of the two test substances in relation to the binding potentials of the controls. The authors also speculated about the possible additivity of the various brominated flame retardants and their metabolites and suggested that low-dose exposure to multiple low-affinity binding compounds may result in endocrine disruption. However, none of the data presented directly addressed this point. It is highly complex, not well understood, and speculative to extrapolate data on inhibition of enzymes such as SULT1E1 in in vitro assay systems to endocrine-system modulation of selective gene expression, receptor binding, and activation and the production of adverse effects that would characterize endocrine disruption in vivo by additivity of different chemicals competing on the same receptors. Only through a more complete understanding of target tissue dosimetry, potency of interaction of the chemical of interest with the macromolecule of interest (e.g., SULT1E1), and subsequent events can one address the likelihood of in vivo additivity.

Modeling in vitro cellular responses to silver nanoparticles.

Engineered nanoparticles (NPs) have been widely demonstrated to induce toxic effects to various cell types. In vitro cell exposure systems have high potential for reliable, high throughput screening of nanoparticle toxicity, allowing focusing on particular pathways while excluding unwanted effects due to other cells or tissue dosimetry. The work presented here involves a detailed biologically based computational model of cellular interactions with NPs; it utilizes measurements performed in human cell culture systems in vitro, to develop a mechanistic mathematical model that can support analysis and prediction of in vivo effects of NPs. The model considers basic cellular mechanisms including proliferation, apoptosis, and production of cytokines in response to NPs. This new model is implemented for macrophages and parameterized using in vitro measurements of changes in cellular viability and mRNA levels of cytokines: TNF, IL-1b, IL-6, IL-8, and IL-10. The model includes in vitro cellular dosimetry due to nanoparticle transport and transformation. Furthermore, the model developed here optimizes the essential cellular parameters based on in vitro measurements, and provides a “stepping stone” for the development of more advanced in vivo models that will incorporate additional cellular and NP interactions.