EURADOS STRATEGIC RESEARCH AGENDA 2020: VISION FOR THE DOSIMETRY OF IONISING RADIATION.

Since 2012, the European Radiation Dosimetry Group (EURADOS) has developed its Strategic Research Agenda (SRA), which contributes to the identification of future research needs in radiation dosimetry in Europe. Continued scientific developments in this field necessitate regular updates and, consequently, this paper summarises the latest revision of the SRA, with input regarding the state of the art and vision for the future contributed by EURADOS Working Groups and through a stakeholder workshop. Five visions define key issues in dosimetry research that are considered important over at least the next decade. They include scientific objectives and developments in (i) updated fundamental dose concepts and quantities, (ii) improved radiation risk estimates deduced from epidemiological cohorts, (iii) efficient dose assessment for radiological emergencies, (iv) integrated personalised dosimetry in medical applications and (v) improved radiation protection of workers and the public. This SRA will be used as a guideline for future activities of EURADOS Working Groups but can also be used as guidance for research in radiation dosimetry by the wider community. It will also be used as input for a general European research roadmap for radiation protection, following similar previous contributions to the European Joint Programme for the Integration of Radiation Protection Research, under the Horizon 2020 programme (CONCERT). The full version of the SRA is available as a EURADOS report (www.eurados.org).

Characterization of passive dosimeters in proton pencil beam scanning - A EURADOS intercomparison for mailed dosimetry audits in proton therapy centres.

The lack of mailed dosimetry audits of proton therapy centres in Europe has encouraged researchers of EURADOS Working Group 9 (WG9) to compare response of several existing passive detector systems in therapeutic pencil beam scanning. Alanine Electron Paramagnetic Resonance dosimetry systems from 3 different institutes (ISS, Italy; UH, Belgium and IFJ PAN, Poland), natLiF:Mg, Ti (MTS-N) and natLiF:Mg, Cu, P (MCP-N) thermoluminescent dosimeters (TLDs), GD-352M radiophotoluminescent glass dosimeters (RPLGDs) and Al2O3:C optically stimulated dosimeters (OSLDs) were evaluate. Dosimeter repeatability, batch reproducibility and response in therapeutic Pencil Beam Scanning were verified for implementation as mail auditing system. Alanine detectors demonstrated the lowest linear energy transfer (LET) dependence with an agreement between measured and treatment planning system (TPS) dose below 1%. The OSLDs measured on average a 6.3% lower dose compared to TPS calculation, with no significant difference between varying modulations and ranges. Both GD-352M and MCP-N measured a lower dose than the TPS and luminescent response was dependent on the LET of the therapeutic proton beam. Thermoluminescent response of MTS-N was also found to be dependent on the LET and a higher dose than TPS was measured with the most pronounced increase of 11%. As alanine detectors are characterized by the lowest energy dependence for different parameters of therapeutic pencil beam scanning they are suitable candidates for mail auditing in proton therapy. The response of luminescence detector systems have shown promises even though more careful calibration and corrections are needed for its implementation as part of a mailed dosimetry audit system.

Dose distribution of secondary radiation in a water phantom for a proton pencil beam-EURADOS WG9 intercomparison exercise.

Systematic 3D mapping of out-of-field doses induced by a therapeutic proton pencil scanning beam in a 300 × 300 × 600 mm3 water phantom was performed using a set of thermoluminescence detectors (TLDs): MTS-7 (7LiF:Mg,Ti), MTS-6 (6LiF:Mg,Ti), MTS-N (natLiF:Mg,Ti) and TLD-700 (7LiF:Mg,Ti), radiophotoluminescent (RPL) detectors GD-352M and GD-302M, and polyallyldiglycol carbonate (PADC)-based (C12H18O7) track-etched detectors. Neutron and gamma-ray doses, as well as linear energy transfer distributions, were experimentally determined at 200 points within the phantom. In parallel, the Geant4 Monte Carlo code was applied to calculate neutron and gamma radiation spectra at the position of each detector. For the cubic proton target volume of 100 × 100 × 100 mm3 (spread out Bragg peak with a modulation of 100 mm) the scattered photon doses along the main axis of the phantom perpendicular to the primary beam were approximately 0.5 mGy Gy-1 at a distance of 100 mm and 0.02 mGy Gy-1 at 300 mm from the center of the target. For the neutrons, the corresponding values of dose equivalent were found to be ~0.7 and ~0.06 mSv Gy-1, respectively. The measured neutron doses were comparable with the out-of-field neutron doses from a similar experiment with 20 MV x-rays, whereas photon doses for the scanning proton beam were up to three orders of magnitude lower.

COMPARISON OF RESPONSE OF PASSIVE DOSIMETRY SYSTEMS IN SCANNING PROTON RADIOTHERAPY-A STUDY USING PAEDIATRIC ANTHROPOMORPHIC PHANTOMS.

Proton beam therapy has advantages in comparison to conventional photon radiotherapy due to the physical properties of proton beams (e.g. sharp distal fall off, adjustable range and modulation). In proton therapy, there is the possibility of sparing healthy tissue close to the target volume. This is especially important when tumours are located next to critical organs and while treating cancer in paediatric patients. On the other hand, the interactions of protons with matter result in the production of secondary radiation, mostly neutrons and gamma radiation, which deposit their energy at a distance from the target. The aim of this study was to compare the response of different passive dosimetry systems in mixed radiation field induced by proton pencil beam inside anthropomorphic phantoms representing 5 and 10 years old children. Doses were measured in different organs with thermoluminescent (MTS-7, MTS-6 and MCP-N), radiophotoluminescent (GD-352 M and GD-302M), bubble and poly-allyl-diglycol carbonate (PADC) track detectors. Results show that RPL detectors are the less sensitive for neutrons than LiF TLDs and can be applied for in-phantom dosimetry of gamma component. Neutron doses determined using track detectors, bubble detectors and pairs of MTS-7/MTS-6 are consistent within the uncertainty range. This is the first study dealing with measurements on child anthropomorphic phantoms irradiated by a pencil scanning beam technique.

Measurement of stray radiation within a scanning proton therapy facility: EURADOS WG9 intercomparison exercise of active dosimetry systems.

PURPOSE: To characterize stray radiation around the target volume in scanning proton therapy and study the performance of active neutron monitors. METHODS: Working Group 9 of the European Radiation Dosimetry Group (EURADOS WG9-Radiation protection in medicine) carried out a large measurement campaign at the Trento Centro di Protonterapia (Trento, Italy) in order to determine the neutron spectra near the patient using two extended-range Bonner sphere spectrometry (BSS) systems. In addition, the work focused on acknowledging the performance of different commercial active dosimetry systems when measuring neutron ambient dose equivalents, H(∗)(10), at several positions inside (8 positions) and outside (3 positions) the treatment room. Detectors included three TEPCs--tissue equivalent proportional counters (Hawk type from Far West Technology, Inc.) and six rem-counters (WENDI-II, LB 6411, RadEye™ NL, a regular and an extended-range NM2B). Meanwhile, the photon component of stray radiation was deduced from the low-lineal energy transfer part of TEPC spectra or measured using a Thermo Scientific™ FH-40G survey meter. Experiments involved a water tank phantom (60 × 30 × 30 cm(3)) representing the patient that was uniformly irradiated using a 3 mm spot diameter proton pencil beam with 10 cm modulation width, 19.95 cm distal beam range, and 10 × 10 cm(2) field size. RESULTS: Neutron spectrometry around the target volume showed two main components at the thermal and fast energy ranges. The study also revealed the large dependence of the energy distribution of neutrons, and consequently of out-of-field doses, on the primary beam direction (directional emission of intranuclear cascade neutrons) and energy (spectral composition of secondary neutrons). In addition, neutron mapping within the facility was conducted and showed the highest H(∗)(10) value of ∼ 51 µSv Gy(-1); this was measured at 1.15 m along the beam axis. H(∗)(10) values significantly decreased with distance and angular position with respect to beam axis falling below 2 nSv Gy(-1) at the entrance of the maze, at the door outside the room and below detection limit in the gantry control room, and at an adjacent room (<0.1 nSv Gy(-1)). Finally, the agreement on H(∗)(10) values between all detectors showed a direct dependence on neutron spectra at the measurement position. While conventional rem-counters (LB 6411, RadEye™ NL, NM2-458) underestimated the H(∗)(10) by up to a factor of 4, Hawk TEPCs and the WENDI-II range-extended detector were found to have good performance (within 20%) even at the highest neutron fluence and energy range. Meanwhile, secondary photon dose equivalents were found to be up to five times lower than neutrons; remaining nonetheless of concern to the patient. CONCLUSIONS: Extended-range BSS, TEPCs, and the WENDI-II enable accurate measurements of stray neutrons while other rem-counters are not appropriate considering the high-energy range of neutrons involved in proton therapy.

Highly polarized light from stable ordered magnetic fields in GRB 120308A.

After the initial burst of γ-rays that defines a γ-ray burst (GRB), expanding ejecta collide with the circumburst medium and begin to decelerate at the onset of the afterglow, during which a forward shock travels outwards and a reverse shock propagates backwards into the oncoming collimated flow, or 'jet'. Light from the reverse shock should be highly polarized if the jet's magnetic field is globally ordered and advected from the central engine, with a position angle that is predicted to remain stable in magnetized baryonic jet models or vary randomly with time if the field is produced locally by plasma or magnetohydrodynamic instabilities. Degrees of linear polarization of P ≈ 10 per cent in the optical band have previously been detected in the early afterglow, but the lack of temporal measurements prevented definitive tests of competing jet models. Hours to days after the γ-ray burst, polarization levels are low (P < 4 per cent), when emission from the shocked ambient medium dominates. Here we report the detection of P =28(+4)(-4) per cent in the immediate afterglow of Swift γ-ray burst GRB 120308A, four minutes after its discovery in the γ-ray band, decreasing to P = 16(+5)(-4) per cent over the subsequent ten minutes. The polarization position angle remains stable, changing by no more than 15 degrees over this time, with a possible trend suggesting gradual rotation and ruling out plasma or magnetohydrodynamic instabilities. Instead, the polarization properties show that GRBs contain magnetized baryonic jets with large-scale uniform fields that can survive long after the initial explosion.

A headache presenting in the emergency room, a clinical manifestation of an unfortunate diagnosis (grade III left frontal anaplastic ependymoma with 1p deletion).

An 18-year-old girl presented with a headache and behavioural changes. She was found to have a frontal mass. Neuroimaging revealed an intra-axial mass, located at the left frontal cortical/subcortical region approximately 6×7, 5×7, 5 cm (TxApxL), having a heterogeneous density with cysts and calcification. She had total gross excision of the neoplasm. Histopathological examination revealed an anaplastic ependymoma. Fluorescence in situ hybridisation, a molecular cytogenetic test, reported deletion of 1p without deletion of 19q. The patient had a good postoperative improvement.

Quantitative determination of regional contributions to fine and coarse particle mass in urban receptor sites.

In this study, we demonstrate that regression analysis of trajectories residence time estimates the contributions of geographical sectors to fine and coarse particle mass in urban receptor sites. We applied the methodology to coarse and fine particles in Amsterdam, Athens, Birmingham and Helsinki. The sectors with the highest contributions on PM2.5 and PM10-2.5 for Amsterdam and Birmingham were Central/Eastern Europe and the Atlantic Ocean/North Sea, respectively. For Athens, the four sectors within 500 km accounted for the largest fraction of PM2.5. The Mediterranean Sea and North Africa added more than half of PM10-2.5 in Athens. For Helsinki, more than 50% of PM2.5 and PM10-2.5 were from sources outside Finland. This approach may be applied to assess the impact of transport on particle mass levels, identify the spatial patterns of particle sources and generate valuable data to design national and transnational efficient emission control strategies.

Association between exhaled breath condensate nitrate + nitrite levels with ambient coarse particle exposure in subjects with airways disease.

OBJECTIVES: Studies of individual inflammatory responses to exposure to air pollution are few but are important in defining the most sensitive markers in better understanding pathophysiological pathways in the lung. The goal of this study was to assess whether exposure to airborne particles is associated with oxidative stress in an epidemiological setting. METHODS: The authors assessed exposure to particulate matter air pollution in four European cities in relation to levels of nitrite plus nitrate (NOx) in exhaled breath condensate (EBC) measurements in 133 subjects with asthma or chronic obstructive pulmonary disease using an EBC capture method developed for field use. In each subject, three measurements were collected. Exposure measurements included particles smaller than 10 µm (PM(10)), smaller than 2.5 µm (PM(2.5)) and particle number counts at a central site, outdoors near the subject's home and indoors. RESULTS: There were positive and significant relationships between EBC NOx and coarse particles at the central sampling sites (increase of 20.4% (95% CI 6.1% to 36.6%) per 10 µg/m(3) increase of coarse particles of the previous day) but not between EBC NOx and other particle measures. Associations tended to be stronger in subjects not taking steroid medication. CONCLUSIONS: An association was found between exposure to ambient coarse particles at central sites and EBC NOx, a marker of oxidative stress. The lack of association between PM measures more indicative of personal exposures (particularly indoor exposure) means interpretation should be cautious. However, EBC NOx may prove to be a marker of PM-induced oxidative stress in epidemiological studies.

Outdoor air pollution is associated with disease severity in alpha1-antitrypsin deficiency.

The aim of this study was to determine whether long-term air pollution exposure is associated with clinical phenotype in alpha(1)-antitrypsin deficiency. In total, 304 PiZZ subjects underwent full lung function testing and quantitative high-resolution computed tomography to identify the presence and severity of the disease. Mean annual air pollutant data for 2006 was matched to the location of patients' houses and used in regression models to identify phenotypic associations with pollution, controlling for covariates. Relative trends in pollution levels were assessed to validate use of a single year's data to indicate long-term exposure. Pollutant levels correlated significantly with one another, with higher levels of primary particles, SO(2) and NO(2) being associated with lower ozone levels. Regression models showed that estimated higher exposure to ozone was associated with worse gas transfer and more severe emphysema. Regression parameters suggested that significance from other pollutants was due to collinearity with ozone. The 2006 pollutant levels showed linear relationships with cumulative years, thus validating the model. Higher exposures to ozone may be associated with worse respiratory status in alpha(1)-antitrypsin deficiency, identifying a group susceptible to ambient air pollution.

Doses to organs and tissues from concomitant imaging in radiotherapy: a suggested framework for clinical justification.

The increasing use of imaging for localization and verification in radiotherapy has raised issues concerning the justifiable doses to critical organs and tissues from concomitant exposures, particularly when extensive image-guided radiotherapy is indicated. Doses at positions remote from the target volume include components from high-energy leakage and scatter, as well as from concomitant imaging. In this paper, simulated prostate, breast and larynx treatments are used to compare doses from both high-energy and concomitant exposures as a function of distance from the target volume. It is suggested that the fraction, R, of the total dose at any point within the patient that is attributable to concomitant exposures may be a useful aid in their justification. R is small within the target volume and at large distances from it. However, there is a critical region immediately adjacent to the planning target volume where the dose from concomitant imaging combines with leakage and scatter to give values of R that approach 0.5 in the examples given here. This is noteworthy because the regions just outside the target volume will receive total doses in the order of 1 Gy, where commensurately high risk factors may not be substantially reduced because of cell kill. Other studies have identified these regions as sites of second cancers. The justification of an imaging regimen might therefore usefully take into account the maximum value of R encountered from the combination of imaging and radiotherapy for particular treatment sites.

Doses to critical organs following radiotherapy and concomitant imaging of the larynx and breast.

The development of conformal radiotherapy carries with it the implication of an increased number of imaging procedures at various stages throughout the overall treatment, principally for verification at some, or all, of the treatment fractions. This raises the issue of the balance between the benefit of these additional imaging exposures and the associated risk of radiocarcinogenesis arising from them. As such, it is necessary to appreciate the doses to critical organs for which individual carcinogenic risks have been estimated. In this study, doses to these organs have been measured with lithium fluoride thermoluminescence dosimetry loaded in anthropomorphic phantoms and subjected to realistic radiotherapy treatments of the larynx and breast, including concomitant CT and electronic portal imaging exposures associated with localization and verification of these treatments. Even for large numbers of concomitant images of either modality, arising from imaging at every fraction, the leakage and scatter from the radiotherapy itself is shown to dominate the overall organ dose, with imaging procedures generally contributing 5-20% of the total organ dose.

Organ doses from prostate radiotherapy and associated concomitant exposures.

In addition to the therapeutic exposure, a course of radiotherapy will involve the additional (concomitant) irradiation of the patient using CT, simulator or portal imaging systems, for localization of the target volume and subsequent verification of treatment delivery. The number of concomitant exposures is likely to increase as the developing technical capabilities for conformal, image-guided radiotherapy make target and critical organ definition an increasingly important aspect of radiotherapy. Estimation of doses and risks to critical organs in the body from all sources is thus necessary to provide the basis for adequate justification of the exposures as required by ICRP. In this paper, doses to selected organs and tissues for which ICRP have identified fatal cancer probabilities have been measured using a realistic anthropomorphic phantom loaded with thermoluminescent dosemeters and irradiated using a treatment protocol for radical radiotherapy of the prostate. Independently, doses to the same organs and tissues have been measured from concomitant CT and portal imaging exposures given for localization and verification purposes. Although negligible in comparison with the target dose, realistic numbers of concomitant exposures give a small but significant contribution to the total dose to most organs and tissues outside the target volume. Generally, this is in the range 5-10% of the total organ dose, but can be as high as 20% for bone surfaces. These data may be used to estimate concomitant doses from any combination of CT and portal imaging and may help in the justification process, especially when additional verification exposures may be required during treatment.

Local and regional air pollution in Ireland during an intensive aerosol measurement campaign.

An intensive two month measurement campaign has been performed during a two year study of major component composition of urban PM10 and PM2.5 in Ireland (J. Yin, A. G. Allen, R. M. Harrison, S. G. Jennings, E. Wright, M. Fitzpatrick, T. Healy, E. Barry, D. Ceburnis and D. McCusker, Atmos. Res., 2005, 78(3-4), 149-165). Measurements included size-segregated mass, soluble ions, elemental carbon (EC) distributions, fine and coarse fraction organic carbon (OC) and major gases along with standard meteorological measurements. The study revealed that urban emissions in Ireland had mainly a local character and therefore were confined within a limited area of 20-30 km radius, without significantly affecting regional air quality. Gaseous measurements have shown that urban emissions in Ireland had clear, but fairly limited influence on the regional air quality due to favorable mixing conditions at higher wind speeds, in particular from the western sector. Size-segregated mass and chemical measurements revealed a clear demarcation size between accumulation and coarse modes at about 0.8 microm which was constant at all sites. Carbonaceous compounds at the urban site accounted for up to 90% of the particle mass in a size range of 0.066-0.61 microm. Nss SO4(2-) concentrations in PM2.5 were only slightly higher at the urban site compared to the rural or coastal sites, while NO3- and NH4+ concentrations were similar at the urban and coastal sites, but were a factor of 2 to 3 higher than at the rural site. OC was highly variable between the sites and revealed clear seasonal differences. Natural or biogenic OC component accounted for <10% in winter and up to 30% in summer of the PM2.5 OC at urban sites. A contribution of biogenic OC component to PM2.5 OC mass at rural site was dominant.

Effect of inhaled sulphur dioxide and carbon particles on heart rate variability and markers of inflammation and coagulation in human subjects.

OBJECTIVE: To measure the inflammatory and autonomic responses of healthy humans and patients with coronary artery disease to controlled concentrations of two specific components of vehicle derived air pollution, carbon particles and sulphur dioxide (SO2). METHODS: Placebo controlled, double blind, random order human challenge study examining the effects of carbon particles (50 microg/m3) and SO2 (200 parts per billion (ppb)) on heart rate variability (HRV) and circulating markers of inflammation and coagulation in healthy volunteers and patients with stable angina. RESULTS: In healthy volunteers, markers of cardiac vagal control did not fall in response to particle exposure but, compared with the response to air, increased transiently immediately after exposure (root mean square of successive RR interval differences (RMSSD) 15 (5) ms with carbon particles and 4 (3) ms) with air, p < 0.05). SO2 exposure resulted in no immediate change but a significant reduction in HRV markers of cardiac vagal control at four hours (RMSSD -2 (3.6) ms with air, -7 (2.7) ms with SO2, p < 0.05). No such changes were seen in patients with stable angina. Neither pollutant caused any change in markers of inflammation or coagulation at zero, four, or 24 hours. CONCLUSION: In healthy volunteers, short term exposure to pure carbon particles does not cause adverse effects on HRV or a systemic inflammatory response. The adverse effects of vehicle derived particulates are likely to be caused by more reactive species found on the particle surface. SO2 exposure does, however, reduce cardiac vagal control, a response that would be expected to increase susceptibility to ventricular arrhythmia.

Measurement and modelling of air pollution and atmospheric chemistry in the U.K. West Midlands conurbation: overview of the PUMA Consortium project.

The PUMA (Pollution of the Urban Midlands Atmosphere) Consortium project involved intensive measurement campaigns in the Summer of 1999 and Winter of 1999/2000, respectively, in which a wide variety of air pollutants were measured in the UK West Midlands conurbation including detailed speciation of VOCs and major component analysis of aerosol. Measurements of the OH and HO2 free radicals by the FAGE technique demonstrated that winter concentrations of OH were approximately half of those measured during the summer despite a factor of 15 reduction in production through the photolysis of ozone. Detailed box modelling of the fast reaction chemistry revealed the decomposition of Criegee intermediates formed from ozone-alkene reactions to be responsible for the majority of the formation of hydroxyl in both the summer and winter campaigns, in contrast to earlier rural measurements in which ozone photolysis was predominant. The main sinks for hydroxyl are reactions with NO2, alkenes and oxygenates. Concentrations of the more stable hydrocarbons were found to be relatively invariant across the conurbation, but the impacts of photochemistry were evident through analyses of formaldehyde which showed the majority to be photochemical in origin as opposed to emitted from road traffic. Measurements on the upwind and downwind boundaries of the conurbation revealed substantial enhancements in NOx as a result of emissions within the conurbation, especially during westerly winds which carried relatively clean air. Using calcium as a tracer for crustal particles, it proved possible to reconstruct aerosol mass from the major chemical components with a fairly high degree of success. The organic to elemental carbon ratios showed a far greater influence of photochemistry in summer than winter, presumably resulting mainly from the greater availability of biogenic precursors during the summer campaign. Two urban airshed models were developed and applied to the conurbation, one Eulerian, the other Lagrangian. Both were able to give a good simulation of concentrations of both primary and secondary pollutants at urban background locations.

Addendum to the IPEMB code of practice for the determination of absorbed dose for x-rays below 300 kV generating potential (0.035 mm Al-4 mm Cu HVL).

This addendum to the code of practice for the determination of absorbed dose for x-rays below 300 kV has recently been approved by the IPEM and introduces three main changes: (i) Due to a lack of available data the original code recommended a value of unity for k(ch) in the very-low-energy range (0.035-1.0 mm Al HVL). A single table of k(ch) values, ranging from 1.01 to 1.07, applicable to both designated chamber types is now presented. (ii) For medium-energy x-rays (0.5-4 mm Cu HVL) methods are given to determine the absorbed dose to water either at 2 cm depth or at the surface of a phantom depending on clinical needs. Determination of the dose at the phantom surface is derived from an in-air measurement and by extending the low-energy range up to 4 mm Cu HVL. Relevant backscatter factors and ratios of mass energy absorption coefficients are given in the addendum. (iii) Relative dosimetry: although not normally forming part of a dosimetry code of practice a brief review of the current literature on this topic has been added as an appendix. This encompasses advice on techniques for measuring depth doses, applicator factors for small field sizes, dose fall off with increasing SSD and choice of appropriate phantom materials and ionization chambers.

Ovarian senescence in the rhesus monkey (Macaca mulatta).

BACKGROUND: A decline in fertility is evident in human females past their middle thirties. This 'reproductive senescence', marked by a sharp decline in pregnancy rates, may be attributed to reductions in numbers of available oocytes and their quality. Because Old World primates exhibit ovarian morphology and physiological control and timing of menstrual cycles closely resembling those of humans, the current study investigated the rhesus macaque as a potential model for human reproductive senescence. METHODS: Ovaries collected from females aged 1-25 years and divided into five age groups were analysed histologically. RESULTS: General ovarian morphology demonstrated significant changes as the females approached menopause. The proportions of primordial and primary follicles all demonstrated significant differences across age groups (primordial: 77.1, 79.9, 69.7, 62.9, 55.1%; primary: 21.5, 18.8, 28.5, 35.2, 43.1% for age groups 1 to 5 respectively; P<0.0001 for both). Samples from females approaching or undergoing the menopausal transition (aged 20-25 years) demonstrated evidence of ovarian senescence, having scattered and atretic follicles, low numbers of primordial follicles and reduced stromal tissue. CONCLUSION: This study supports the value of the rhesus monkey as a model for reproductive ageing because its ovary undergoes follicular reservoir depletion similar to that seen in humans.