Evaluation of dosimetric variance in whole breast forward-planned intensity-modulated radiotherapy based on 4DCT and 3DCT

This study was performed to explore and compare the dosimetric variance caused by respiratory movement in the breast during forward-planned IMRT after breast-conserving surgery. A total of 17 enrolled patients underwent the 3DCT simulation scans followed by 4DCT simulation scans during free breathing. The treatment planning constructed using the 3DCT images was copied and applied to the end expiration (EE) and end inspiration (EI) scans and the dose distributions were calculated separately. CTV volume variance amplitude was very small (11.93 ± 28.64 cm³), and the percentage change of CTV volumes receiving 50 Gy and 55 Gy between different scans were all less than 0.8%. There was no statistically significant difference between EI and EE scans (Z =–0.26, P = 0.795). However, significant differences were found when comparing the D_mean at 3DCT planning with the EI and EE planning (P = 0.010 and 0.019, respectively). The homogeneity index at EI, EE and 3D plannings were 0.139, 0.141 and 0.127, respectively, and significant differences existed between 3D and EI, and between 3D and EE (P = 0.001 and 0.006, respectively). The conformal index (CI) increased significantly in 3D treatment planning (0.74 ± 0.07) compared with the EI and EE phase plannings (P = 0.005 and 0.005, respectively). The V₃₀, V₄₀, V₅₀ and D_mean of the ipsilateral lung for EE phase planning were significantly lower than for EI (P = 0.001–0.042). There were no significant differences in all the DVH parameters for the heart among these plannings (P = 0.128–0.866). The breast deformation during respiration can be disregarded in whole breast IMRT. 3D treatment planning is sufficient for whole breast forward-planned IMRT on the basis of our DVH analysis, but 4D treatment planning, breath-hold, or respiratory gate may ensure precise delivery of radiation dose.     

VMAT–SBRT planning based on an average intensity projection for lung tumors located in close proximity to the diaphragm: a phantom and clinical validity study

The aim of the this study was to validate the use of an average intensity projection (AIP) for volumetric-modulated arc therapy for stereotactic body radiation therapy (VMAT–SBRT) planning for a moving lung tumor located near the diaphragm. VMAT–SBRT plans were created using AIPs reconstructed from 10 phases of 4DCT images that were acquired with a target phantom moving with amplitudes of 5, 10, 20 and 30 mm. To generate a 4D dose distribution, the static dose for each phase was recalculated and the doses were accumulated by using the phantom position known for each phase. For 10 patients with lung tumors, a deformable registration was used to generate 4D dose distributions. Doses to the target volume obtained from the AIP plan and the 4D plan were compared, as were the doses obtained from each plan to the organs at risk (OARs). In both phantom and clinical study, dose discrepancies for all parameters of the dose volume (D_min, D₉₉, D_max, D₁ and D_mean) to the target were <3%. The discrepancies of D_max for spinal cord, esophagus and heart were <1 Gy, and the discrepancy of V20 for lung tissue was <1%. However, for OARs with large respiratory motion, the discrepancy of the D_max was as much as 9.6 Gy for liver and 5.7 Gy for stomach. Thus, AIP is clinically acceptable as a planning CT image for predicting 4D dose, but doses to the OARs with large respiratory motion were underestimated with the AIP approach.     

Dosimetric study of a respiratory gating technique based on four-dimensional computed tomography in non-small-cell lung cancer

This study sought to compare the differences in target volumes and dose distributions to the targets and organs at risk (OARs) between a four-dimensional computed tomography (4DCT)-based respiratory-gated intensity-modulated radiation therapy (IMRT) plan (Plan_EOE) and a three-dimensional CT (3DCT)-based IMRT plan (Plan_3D) in patients with non-small-cell lung cancer (NSCLC). For 17 patients with Stages I–III NSCLC, both 4DCT data and conventional 3DCT data were obtained. The Plan_3D and Plan_EOE were designed based on 3DCT data and 4DCT data, respectively. The displacements of the gross tumor volume (GTV) centroid were 0.13 ± 0.09 cm, 0.15 ± 0.1 cm, and 0.27 ± 0.27 cm in the right–left, anterior–posterior, and superior–inferior directions, respectively. The volume of the GTV_EOE was 3.05 ± 5.17 cm³ larger than that of the GTV_3D. The volume of the PTV_3D was 72.82 ± 48.65 cm³ larger than that of the PTV_EOE. There was no significant difference between the PTV_3D and PTV_EOE for V55.8, V60, V66 and the homogeneity index. The PTV_3D had a lower target conformity index than the PTV_EOE (P = 0.036). Plan_EOE had a significantly lower lung V10, V20, V30, V40 and mean lung dose (MLD) than Plan_3D. For the heart, Plan_EOE had a significantly lower V₃₀ and mean dose. In conclusion, 4DCT is an appropriate method for assessing the displacement of the GTV centroid in three dimensions. Plan_EOE has smaller PTVs and a decreased dose and volume for the normal lung and heart, as compared with Plan_3D.     

Inverse planning for combination of intracavitary and interstitial brachytherapy for locally advanced cervical cancer

The main purpose of this study was to compare three different treatment plans for locally advanced cervical cancer: (i) the inverse-planning simulated annealing (IPSA) plan for combination brachytherapy (BT) of interstitial and intracavitary brachytherapy, (ii) manual optimization based on the Manchester system for combination-BT, and (iii) the conventional Manchester system using only tandem and ovoids. This was a retrospective study of 25 consecutive implants. The high-risk clinical target volume (HR-CTV) and organs at risk were defined according to the GEC-ESTRO Working Group definitions. A dose of 6 Gy was prescribed. The uniform cost function for dose constraints was applied to all IPSA-generated plans. The coverage of the HR-CTV by IPSA for combination-BT was equivalent to that of manual optimization, and was better than that of the Manchester system using only tandem and ovoids. The mean V₁₀₀ achieved by IPSA for combination-BT, manual optimization and Manchester was 96 ± 3.7%, 95 ± 5.5% and 80 ± 13.4%, respectively. The mean D₁₀₀ was 483 ± 80, 487 ± 97 and 335 ± 119 cGy, respectively. The mean D₉₀ was 677 ± 61, 681 ± 88 and 513 ± 150 cGy, respectively. IPSA resulted in significant reductions of the doses to the rectum (IPSA D_2cm³: 408 ± 71 cGy vs manual optimization D_2cm³: 485 ± 105 cGy; P = 0.03) and the bladder (IPSA D_2cm³: 452 ± 60 cGy vs manual optimization D_2cm³: 583 ± 113 cGy; P < 0.0001). In conclusion, combination-BT achieved better tumor coverage, and plans using IPSA provided significant sparing of normal tissues without compromising CTV coverage.     

Vitamin D Serum Levels in Subjects Tested for SARS-CoV-2: What Are the Differences among Acute,Healed, and Negative COVID-19 Patients? A Multicenter Real-Practice Study

Vitamin D might play a role in counteracting COVID-19, albeit strong evidence is still lacking in the literature. The present multicenter real-practice study aimed to evaluate the differences of 25(OH)D₃ serum levels in adults tested for SARS-CoV-2 (acute COVID-19 patients, subjects healed from COVID-19, and non-infected ones) recruited over a 6-month period (March–September 2021). In a sample of 117 subjects, a statistically significant difference was found, with acute COVID-19 patients demonstrating the lowest levels of serum 25(OH)D₃ (9.63 ± 8.70 ng/mL), significantly lower than values reported by no-COVID-19 patients (15.96 ± 5.99 ng/mL, p = 0.0091) and healed COVID-19 patients (11.52 ± 4.90 ng/mL, p > 0.05). Male gender across the three groups displayed unfluctuating 25(OH)D₃ levels, hinting at an inability to ensure adequate levels of the active vitamin D3 form (1α,25(OH)2D3). As a secondary endpoint, we assessed the correlation between serum 25(OH)D₃ levels and pro-inflammatory cytokine interleukin-6 (IL-6) in patients with extremely low serum 25(OH)D₃ levels (<1 ng/mL) and in a subset supplemented with 1α,25(OH)₂D₃. Although patients with severe hypovitaminosis-D showed no significant increase in IL-6 levels, acute COVID-19 patients manifested high circulating IL-6 at admission (females = 127.64 ± 22.24 pg/mL, males = 139.28 ± 48.95 ng/mL) which dropped drastically after the administration of 1α,25(OH)₂D₃ (1.84 ± 0.77 pg/mL and 2.65 ± 0.92 ng/mL, respectively). Taken together, these findings suggest that an administration of 1α,25(OH)₂D₃ might be helpful for treating male patients with an acute COVID-19 infection. Further studies on rapid correction of vitamin D deficiency with fast acting metabolites are warranted in COVID-19 patients.     

Rectal dose-sparing effect with bioabsorbable spacer placement in carbon ion radiotherapy for sacral chordoma: dosimetric comparison of a simulation study

It is difficult to treat patients with an inoperable sarcoma adjacent to the gastrointestinal (GI) tract using carbon ion radiotherapy (C-ion RT), owing to the possible development of serious GI toxicities. In such cases, spacer placement may be useful in physically separating the tumor and the GI tract. We aimed to evaluate the usefulness of spacer placement by conducting a simulation study of dosimetric comparison in a patient with sacral chordoma adjacent to the rectum treated with C-ion RT. The sacral chordoma was located in the third to fourth sacral spinal segments, in extensive contact with and compressing the rectum. Conventional C-ion RT was not indicated because the rectal dose would exceed the tolerance dose. Because we chose spacer placement surgery to physically separate the tumor and the rectum before C-ion RT, bioabsorbable spacer sheets were inserted by open surgery. After spacer placement, 67.2 Gy [relative biological effectiveness (RBE)] of C-ion RT was administered. The thickness of the spacer was stable at 13–14 mm during C-ion RT. Comparing the dose–volume histogram (DVH) parameters, D_max for the rectum was reduced from 67 Gy (RBE) in the no spacer plan (simulation plan) to 45 Gy (RBE) in the spacer placement plan (actual plan) when a prescribed dose was administered to the tumor. Spacer placement was advantageous for irradiating the tumor and the rectum, demonstrated using the DVH parameter analysis.     

Comparative study on the inhibitory effects of antioxidant vitamins and radon on carbon tetrachloride-induced hepatopathy

We have previously reported that radon inhalation activates anti-oxidative functions and inhibits carbon tetrachloride (CCl₄)-induced hepatopathy. It has also been reported that antioxidant vitamins can inhibit CCl₄-induced hepatopathy. In the current study, we examined the comparative efficacy of treatment with radon, ascorbic acid and α-tocopherol on CCl₄-induced hepatopathy. Mice were subjected to intraperitoneal injection of CCl₄ after inhaling approximately 1000 or 2000 Bq/m³ radon for 24 h, or immediately after intraperitoneal injection of ascorbic acid (100, 300, or 500 mg/kg bodyweight) or α-tocopherol (100, 300, or 500 mg/kg bodyweight). We estimated the inhibitory effects on CCl₄-induced hepatopathy based on hepatic function-associated parameters, oxidative damage-associated parameters and histological changes. The results revealed that the therapeutic effects of radon inhalation were almost equivalent to treatment with ascorbic acid at a dose of 500 mg/kg or α-tocopherol at a dose of 300 mg/kg. The activities of superoxide dismutase, catalase, and glutathione peroxidase in the liver were significantly higher in mice exposed to radon than in mice treated with CCl₄ alone. These findings suggest that radon inhalation has an anti-oxidative effect against CCl₄-induced hepatopathy similar to the anti-oxidative effects of ascorbic acid or α-tocopherol due to the induction of anti-oxidative functions.     

Usefulness of double dose contrast-enhanced magnetic resonance imaging for clear delineation of gross tumor volume in stereotactic radiotherapy treatment planning of metastatic brain tumors: a dose comparison study

The purpose of this study was to compare the size and clearness of gross tumor volumes (GTVs) of metastatic brain tumors on T1-weighted magnetic resonance images between a single dose contrast administration protocol and a double dose contrast administration protocol to determine the optimum dose of contrast-enhancement for clear delineation of GTV in stereotactic radiotherapy (SRT). A total of 28 small metastatic brain tumors were evaluated in 13 patients by intra-individual comparison of GTV measurements using single dose and double dose contrast-enhanced thin-slice (1-mm) magnetic resonance imaging (MRI). All patients had confirmed histological types of primary tumors and had undergone hypo-fractionated SRT for metastatic brain tumors. The mean tumor diameter with single dose and double dose contrast-enhancement was 12.0 ± 1.1 mm and 13.2 ± 1.1 mm respectively (P < 0.001). The mean incremental ratio (MIR) obtained by comparing mean tumor diameters was 11.2 ± 0.02 %. The mean volume of GTV-1 (single dose contrast-enhancement) and GTV-2 (double dose contrast-enhancement) was 1.38 ± 0.41 ml and 1.59 ± 0.45 ml respectively (P < 0.01). The MIR by comparing mean tumor volumes was 32.3 ± 0.4 %. The MIR of GTV-1 with < 1ml volume and GTV-1 with > 1ml volume was 41.8 ± 0.05 % and 12.4 ± 0.03 % respectively (P < 0.001). We conclude that double dose contrast-enhanced thin-slice MRI is a more useful technique than single dose contrast-enhanced thin-slice MRI, especially for clear delineation of GTVs of small metastatic brain tumors in treatment planning of highly precise SRT.     

Dose rate in the highest irradiation area of the rectum correlates with late rectal complications in patients treated with high-dose-rate computed tomography-based image-guided brachytherapy for cervical cancer

The purpose of this study was to evaluate the effect of dose rate to the rectum on late rectal complications in patients treated with computed tomography (CT)-based image-guided brachytherapy (IGBT) for cervical cancer. The subjects were 142 patients with cervical cancer who underwent Ir-192 high-dose-rate (HDR)-IGBT between March 2012 and January 2018. The dose rate to the rectum was calculated using in-house software. The minimum, mean and maximum effective dose rate (EDR) was calculated for voxels of the rectal volume covered by cumulative doses >D_0.1cc, >D_2cc, and > D_5cc. The average EDR of three to four brachytherapy sessions was calculated (EDR for patients; EDR_p). The total dose of the rectum was calculated as the biologically equivalent dose in 2-Gy fractions (EQD₂). The associations between EDR_p for D_0.1cc, D_2cc, and D_5cc and the respective rectal EQD₂ values with late rectal complications were then analyzed. The median follow-up period was 40 months. Patients with rectal complications of ≥Grade 1 received a significantly higher mean EDR_p for D_0.1cc–5cc and had a greater EQD₂ for D_0.1cc–5cc. Multivariate analysis was performed using the mean EDR_p for D_2cc, EQD₂ for D_2cc, heavy smoking and BMI. Of these four variables, mean EDR_p for D_2cc (HR = 3.38, p = 0.004) and EQD₂ for D_2cc (HR = 2.59, p = 0.045) emerged as independent predictors for late rectal complications. In conclusion, mean EDR_p and EQD₂ were associated with late rectal complications in patients treated with HDR CT-based IGBT for cervical cancer.     

Proton beam irradiation stimulates migration and invasion of human U87 malignant glioma cells

Migration and invasion of malignant glioma play a major role in tumor progression and can be increased by low doses of gamma or X-ray irradiation, especially when the migrated tumor cells are located at a distance from the main tumor mass or postoperative cavity and are irradiated in fractions. We studied the influence of proton beam irradiation on migration and invasion of human U87 malignant glioma (U87MG) cells. Irradiation at 4 and 8 Gy increased cell migration by 9.8% (±4, P = 0.032) and 11.6% (±6.6, P = 0.031) and invasion by 45.1% (±16.5, P = 0.04) and 40.5% (±12.7, P = 0.041), respectively. After irradiation at 2 and 16 Gy, cell motility did not differ from that at 0 Gy. We determined that an increase in proton beam irradiation dose to over 16 Gy might provide tumor growth control, although additional specific treatment might be necessary to prevent the potentially increased motility of glioma cells during proton beam therapy.     

Estimation of relative biological effectiveness for boron neutron capture therapy using the PHITS code coupled with a microdosimetric kinetic model

The absorbed doses deposited by boron neutron capture therapy (BNCT) can be categorized into four components: α and ⁷Li particles from the ¹⁰B(n, α)⁷Li reaction, 0.54-MeV protons from the ¹⁴N(n, p)¹⁴C reaction, the recoiled protons from the ¹H(n, n) ¹H reaction, and photons from the neutron beam and ¹H(n, γ)²H reaction. For evaluating the irradiation effect in tumors and the surrounding normal tissues in BNCT, it is of great importance to estimate the relative biological effectiveness (RBE) for each dose component in the same framework. We have, therefore, established a new method for estimating the RBE of all BNCT dose components on the basis of the microdosimetric kinetic model. This method employs the probability density of lineal energy, y, in a subcellular structure as the index for expressing RBE, which can be calculated using the microdosimetric function implemented in the particle transport simulation code (PHITS). The accuracy of this method was tested by comparing the calculated RBE values with corresponding measured data in a water phantom irradiated with an epithermal neutron beam. The calculation technique developed in this study will be useful for biological dose estimation in treatment planning for BNCT.     

Inter-Day Reliability of Resting Metabolic Rate and Maximal Fat Oxidation during Exercise in Healthy Men Using the Ergostik Gas Analyzer

The attainment of high inter-day reliability is crucial to determine changes in resting metabolic rate (RMR), respiratory exchange ratio (RER), maximal fat oxidation during exercise (MFO) and the intensity that elicits MFO (Fatmax) after an intervention. This study aimed to analyze the inter-day reliability of RMR, RER, MFO and Fatmax in healthy adults using the Ergostik gas analyzer. Fourteen healthy men (age: 24.4 ± 5.0 years, maximum oxygen uptake (VO₂max): 47.5 ± 11.9 mL/kg/min) participated in a repeated-measures study. The study consisted of two identical experimental trials (Day 1 and Day 2) in which the participants underwent an indirect calorimetry assessment at resting and during an incremental exercise test. Stoichiometric equations were used to calculate energy expenditure and substrate oxidation rates. There were no significant differences when comparing RMR (1999.3 ± 273.9 vs. 1955.7 ± 362.6 kcal/day, p = 0.389), RER (0.87 ± 0.05 vs. 0.89 ± 0.05, p = 0.143), MFO (0.32 ± 0.20 vs. 0.31 ± 0.20 g/min, p = 0.776) and Fatmax (45.0 ± 8.6 vs. 46.4 ± 8.4% VO₂max, p = 0.435) values in Day 1 vs. Day 2. The inter-day coefficient of variation for RMR, RER, MFO and Fatmax were 4.85 ± 5.48%, 3.22 ± 3.14%, 7.78 ± 5.51%, and 6.51 ± 8.04%, respectively. In summary, the current results show a good inter-day reliability when RMR, RER, MFO and Fatmax are determined in healthy men using the Ergostik gas analyzer.     

Long-term outcomes of patients with unresectable benign meningioma treated with proton beam therapy

This study aimed to evaluate the long-term efficacy of proton beam therapy (PBT) for unresectable benign meningiomas at the University of Tsukuba, Japan. From 1986–1998, 10 patients were treated at the Particle Radiation Medical Science Center (PRMSC) with a relative biological effectiveness (RBE) value of 1.0 using an accelerator built for physics experiments. The total dose was compensated with an X-ray in three patients. Following that, from 2002–2017, 17 patients were treated with a RBE value of 1.1 at the Proton Medical Research Center (PMRC) which was built for medical use. At the PRMSC, the total dose ranged from 50.4–66 Gy (median: 54 Gy). During the follow-up, which lasted between 3.8 and 31.6 years (median: 25.1 years), the 5-, 10-, 15-, 20- and 30-year local control rates were 100%, and the 5-, 10-, 15-, 20- and 30-year survival rates were 90, 80, 70, 70 and 36%, respectively. One patient died of brainstem radiation necrosis 5.1 years after PBT. At PMRC, the total dose ranged from 45.0–61.2 GyE, with a median of 50.4 GyE. During the follow-up, which lasted between 3 and 17 years with a median of 10.5 years, the 5-, 10- and 15-year local control rates were 94.1%, and the 5-, 10- and 15-year survival rates were 100, 100 and 88.9%, respectively. Neither malignant transformation nor secondary malignancy was observed, indicating that fractionated PBT may be effective and safely control benign unresectable meningioma even for the lifelong period of time.     

Radiobiological model-based bio-anatomical quality assurance in intensity-modulated radiation therapy for prostate cancer

A bio-anatomical quality assurance (QA) method employing tumor control probability (TCP) and normal tissue complication probability (NTCP) is described that can integrate radiobiological effects into intensity-modulated radiation therapy (IMRT). We evaluated the variations in the radiobiological effects caused by random errors (r-errors) and systematic errors (s-errors) by evaluating TCP and NTCP in two groups: patients with an intact prostate (G_intact) and those who have undergone prostatectomy (G_tectomy). The r-errors were generated using an isocenter shift of ±1 mm to simulate a misaligned patient set-up. The s-errors were generated using individual leaves that were displaced inwardly and outwardly by 1 mm on multileaf collimator field files. Subvolume-based TCP and NTCP were visualized on computed tomography (CT) images to determine the radiobiological effects on the principal structures. The bio-anatomical QA using the TCP and NTCP maps differentiated the critical radiobiological effects on specific volumes, particularly at the anterior rectal walls and planning target volumes. The s-errors showed a TCP variation of –40–25% in G_tectomy and –30–10% in G_intact, while the r-errors were less than 1.5% in both groups. The r-errors for the rectum and bladder showed higher NTCP variations at ±20% and ±10%, respectively, and the s-errors were greater than ±65% for both. This bio-anatomical method, as a patient-specific IMRT QA, can provide distinct indications of clinically significant radiobiological effects beyond the minimization of probable physical dose errors in phantoms.     

Ventilatory function in workers exposed to low levels of toluene diisocyanate: a six-month follow-up

Peters, John M., Murphy, Raymond L. H., and Ferris, Benjamin, G., Jr. (1969).Brit. J. industr. Med.,26, 115-120. Ventilatory function in workers exposed to low levels of toluene diisocyanate: a six-month follow-up. Thirty-four workers exposed to toluene diisocyanate during production of polyurethane foam were examined with a respiratory questionnaire and tests of ventilatory capacity. The tests of pulmonary function were conducted on Monday morning and afternoon and on Tuesday morning and afternoon. Twenty-eight of these 34 workers had been examined with the same tests six months earlier. On Monday a mean change in the one-second forced expiratory volume (F.E.V._1·0) of –0·16 l. occurred that did not return to the baseline value (Monday a.m.) on Tuesday morning. A statistically significant decrease in all the measurements of ventilatory capacity except the forced vital capacity occurred over the six months in the 28 workers. The F.E.V._1·0 fell an average of 0·14 l. and flow rates at 75%, 50%, 25%, and 10% of vital capacity also decreased significantly. There was a highly significant correlation coefficient (r = 0·72) between one-day changes in F.E.V._1·0 (measured six months earlier) and six-month changes in F.E.V._1·0. Workers with respiratory symptoms (cough and/or phlegm) demonstrated greater falls in F.E.V._1·0 than did asymptomatic workers.

All air concentrations of toluene diisocyanate measured during this study were below the threshold limit value (0·02 p.p.m.).

     

An Estimate of the Global Burden of Anthropogenic Ozone and Fine Particulate Matter on Premature Human Mortality Using Atmospheric Modeling

Background

Ground-level concentrations of ozone (O₃) and fine particulate matter [≤ 2.5 μm in aerodynamic diameter (PM_2.5)] have increased since preindustrial times in urban and rural regions and are associated with cardiovascular and respiratory mortality.

Objectives

We estimated the global burden of mortality due to O₃ and PM_2.5 from anthropogenic emissions using global atmospheric chemical transport model simulations of preindustrial and present-day (2000) concentrations to derive exposure estimates.

Methods

Attributable mortalities were estimated using health impact functions based on long-term relative risk estimates for O₃ and PM_2.5 from the epidemiology literature. Using simulated concentrations rather than previous methods based on measurements allows the inclusion of rural areas where measurements are often unavailable and avoids making assumptions for background air pollution.

Results

Anthropogenic O₃ was associated with an estimated 0.7 ± 0.3 million respiratory mortalities (6.3 ± 3.0 million years of life lost) annually. Anthropogenic PM_2.5 was associated with 3.5 ± 0.9 million cardiopulmonary and 220,000 ± 80,000 lung cancer mortalities (30 ± 7.6 million years of life lost) annually. Mortality estimates were reduced approximately 30% when we assumed low-concentration thresholds of 33.3 ppb for O₃ and 5.8 μg/m³ for PM_2.5. These estimates were sensitive to concentration thresholds and concentration–mortality relationships, often by > 50%.

Conclusions

Anthropogenic O₃ and PM_2.5 contribute substantially to global premature mortality. PM_2.5 mortality estimates are about 50% higher than previous measurement-based estimates based on common assumptions, mainly because of methodologic differences. Specifically, we included rural populations, suggesting higher estimates; however, the coarse resolution of the global atmospheric model may underestimate urban PM_2.5 exposures.