SAR modelling of complex phenomena: probing methodological limitations

The increased acceptance of the use of structure-activity relationship (SAR) approaches to toxicity modelling has necessitated an evaluation of the limitations of the methodology. In this study, the limit of the capacity of the MULTICASE SAR program to model complex biological and toxicological phenomena was assessed. It was estimated that, provided the data set consists of at least 300 chemicals, divided equally between active and inactive compounds, the program is capable of handling phenomena that are even more "complex" than those modelled up to now (for example, allergic contact dermatitis, Salmonella mutagenicity, biodegradability, inhibition of tubulin polymerisation). However, within the data sets currently used to generate SAR models, there are limits to the complexity that can be handled. This may be the situation with regard to the modelling of systemic toxicity (for example, the LD50).     

Analysis of the effect of mobile phone base station antenna loading on localized SAR and its consequences for measurements

In this work, the effect of antenna element loading on the localized specific absorption rate (SAR) has been analyzed for base station antennas. The analysis was conducted in order to determine whether localized SAR measurements of large multi-element base station antennas can be conducted using standardized procedures and commercially available equipment. More specifically, it was investigated if the antenna shifting measurement procedure, specified in the European base station exposure assessment standard EN 50383, will produce accurate localized SAR results for base station antennas larger than the specified measurement phantom. The obtained results show that SAR accuracy is affected by the presence of lossy material within distances of one wavelength from the tested antennas as a consequence of coupling and redistribution of transmitted power among the antenna elements. It was also found that the existing standardized phantom is not optimal for SAR measurements of large base station antennas. A new methodology is instead proposed based on a larger, box-shaped, whole-body phantom.     

SAR measurement due to mobile phone exposure in a simulated biological media

The specific absorption rate (SAR) measurements are carried out for compliance testing of personal 3G Mobile phone. The accuracy of this experimental setup has been checked by comparing the SAR in 10?gm of simulated tissue and an arbitrary shaped box. This has been carried out using a 3G mobile Phone at 1718.5?MHz, in a medium simulating brain and muscle phantom. The SAR measurement system consists of a stepper motor to move a monopole E-field probe in two dimensions inside an arbitrary shaped box. The phantom is filled with appropriate frequency-specific fluids with measured electrical properties (dielectric constant and conductivity). That is close to the average for gray and white matters of the brain at the frequencies of interest (1718.5?MHz). Induced fields are measured using a specially designed monopole probe in its close vicinity. The probe is immersed in the phantom material. The measured data for induced fields are used to compute SAR values at various locations with respect to the mobile phone location. It is concluded that these SAR values are position dependent and well below the safety criteria prescribed for human exposure.     

SAR measurement due to mobile phone exposure in a simulated biological media

The specific absorption rate (SAR) measurements are carried out for compliance testing of personal 3G Mobile phone. The accuracy of this experimental setup has been checked by comparing the SAR in 10 gm of simulated tissue and an arbitrary shaped box. This has been carried out using a 3G mobile Phone at 1718.5 MHz, in a medium simulating brain and muscle phantom. The SAR measurement system consists of a stepper motor to move a monopole E-field probe in two dimensions inside an arbitrary shaped box. The phantom is filled with appropriate frequency-specific fluids with measured electrical properties (dielectric constant and conductivity). That is close to the average for gray and white matters of the brain at the frequencies of interest (1718.5 MHz). Induced fields are measured using a specially designed monopole probe in its close vicinity. The probe is immersed in the phantom material. The measured data for induced fields are used to compute SAR values at various locations with respect to the mobile phone location. It is concluded that these SAR values are position dependent and well below the safety criteria prescribed for human exposure.     

Frequency dependence of heating of human skin exposed to millimeter waves

In this paper we studied experimentally the frequency dependence of heating of human skin exposed to millimeter waves. Theoretical modeling of obtained data was performed using the hybrid bio-heat equation. It was found that the skin heating and SAR increased with increasing the exposure frequency. The frequency dependence of heating was entirely resulted from that of reflection from the skin. Unlike temperature, the frequency dependence of the SAR was due to the increased absorption of millimeter wave energy within the thin surface layer of the skin.     

Frequency dependence of heating of human skin exposed to millimeter waves

In this paper we studied experimentally the frequency dependence of heating of human skin exposed to millimeter waves. Theoretical modeling of obtained data was performed using the hybrid bio-heat equation. It was found that the skin heating and SAR increased with increasing the exposure frequency. The frequency dependence of heating was entirely resulted from that of reflection from the skin. Unlike temperature, the frequency dependence of the SAR was due to the increased absorption of millimeter wave energy within the thin surface layer of the skin.     

Electromagnetic heating of tissue-equivalent phantoms with thin,insulating partitions

The electromagnetic power absorption in tissue-equivalent phantoms that are used for evaluation of diathermy and hyperthermia applicators is analyzed for the purpose of determining the effect of an insulating partition that is frequently used to facilitate separation of the phantom for thermographic analysis of heating distributions. An analysis that is based on the plane wave spectrum decomposition of the electromagnetic field is applied to a simplified model of the medium. The simplified model is valid whenever the insulating partition does not significantly alter the fields in the medium. The curves that are presented indicate that thin partitions do not significantly alter the power absorption for most situations of therapeutic interest. Data on the effects of partition thickness and electrical parameters are presented for microwave and radiofrequencies of interest for diathermy and hyperthermia.     

Detailing Radio Frequency Heating Induced by Coronary Stents: A 7.0 Tesla Magnetic Resonance Study

The sensitivity gain of ultrahigh field Magnetic Resonance (UHF-MR) holds the promise to enhance spatial and temporal resolution. Such improvements could be beneficial for cardiovascular MR. However, intracoronary stents used for treatment of coronary artery disease are currently considered to be contra-indications for UHF-MR. The antenna effect induced by a stent together with RF wavelength shortening could increase local radiofrequency (RF) power deposition at 7.0 T and bears the potential to induce local heating, which might cause tissue damage. Realizing these constraints, this work examines RF heating effects of stents using electro-magnetic field (EMF) simulations and phantoms with properties that mimic myocardium. For this purpose, RF power deposition that exceeds the clinical limits was induced by a dedicated birdcage coil. Fiber optic probes and MR thermometry were applied for temperature monitoring using agarose phantoms containing copper tubes or coronary stents. The results demonstrate an agreement between RF heating induced temperature changes derived from EMF simulations versus MR thermometry. The birdcage coil tailored for RF heating was capable of irradiating power exceeding the specific-absorption rate (SAR) limits defined by the IEC guidelines by a factor of three. This setup afforded RF induced temperature changes up to +27 K in a reference phantom. The maximum extra temperature increase, induced by a copper tube or a coronary stent was less than 3 K. The coronary stents examined showed an RF heating behavior similar to a copper tube. Our results suggest that, if IEC guidelines for local/global SAR are followed, the extra RF heating induced in myocardial tissue by stents may not be significant versus the baseline heating induced by the energy deposited by a tailored cardiac transmit RF coil at 7.0 T, and may be smaller if not insignificant than the extra RF heating observed under the circumstances used in this study.     

Detecting condylar contact loss using single-plane fluoroscopy: A comparison with in vivo force data and in vitro bi-plane data

Knee contact mechanics play an important role in knee implant failure and wear mechanics. Femoral condylar contact loss in total knee arthroplasty has been reported in some studies and it is considered to potentially induce excessive wear of the polyethylene insert.Measuring in vivo forces applied to the tibial plateau with an instrumented prosthesis is a possible approach to assess contact loss in vivo, but this approach is not very practical. Alternatively, single-plane fluoroscopy and pose estimation can be used to derive the relative pose of the femoral component with respect to the tibial plateau and estimate the distance from the medial and lateral parts of the femoral component towards the insert. Two measures are reported in the literature: lift-off is commonly defined as the difference in distance between the medial and lateral condyles of the femoral component with respect to the tibial plateau; separation is determined by the closest distance of each condyle towards the polyethylene insert instead of the tibia plateau.In this validation study, lift-off and separation as measured with single-plane fluoroscopy are compared to in vivo contact forces measured with an instrumented knee implant. In a phantom study, lift-off and separation were compared to measurements with a high quality bi-plane measurement.The results of the in vivo contact-force experiment demonstrate a large discrepancy between single-plane fluoroscopy and the in vivo force data: single-plane fluoroscopy measured up to 5.1 mm of lift-off or separation, whereas the force data never showed actual loss of contact. The phantom study demonstrated that the single-plane setup could introduce an overestimation of 0.22 mm±±0.36 mm. Correcting the out-of-plane position resulted in an underestimation of medial separation by −0.20 mm±±0.29 mm.In conclusion, there is a discrepancy between the in vivo force data and single-plane fluoroscopic measurements. Therefore contact loss may not always be determined reliably by single plane fluoroscopy analysis.     

Design and Evaluation of a Hybrid Radiofrequency Applicator for Magnetic Resonance Imaging and RF Induced Hyperthermia: Electromagnetic Field Simulations up to 14.0 Tesla and Proof-of-Concept at 7.0 Tesla

This work demonstrates the feasibility of a hybrid radiofrequency (RF) applicator that supports magnetic resonance (MR) imaging and MR controlled targeted RF heating at ultrahigh magnetic fields (B₀≥7.0T). For this purpose a virtual and an experimental configuration of an 8-channel transmit/receive (TX/RX) hybrid RF applicator was designed. For TX/RX bow tie antenna electric dipoles were employed. Electromagnetic field simulations (EMF) were performed to study RF heating versus RF wavelength (frequency range: 64 MHz (1.5T) to 600 MHz (14.0T)). The experimental version of the applicator was implemented at B₀ = 7.0T. The applicators feasibility for targeted RF heating was evaluated in EMF simulations and in phantom studies. Temperature co-simulations were conducted in phantoms and in a human voxel model. Our results demonstrate that higher frequencies afford a reduction in the size of specific absorption rate (SAR) hotspots. At 7T (298 MHz) the hybrid applicator yielded a 50% iso-contour SAR (iso-SAR-50%) hotspot with a diameter of 43 mm. At 600 MHz an iso-SAR-50% hotspot of 26 mm in diameter was observed. RF power deposition per RF input power was found to increase with B₀ which makes targeted RF heating more efficient at higher frequencies. The applicator was capable of generating deep-seated temperature hotspots in phantoms. The feasibility of 2D steering of a SAR/temperature hotspot to a target location was demonstrated by the induction of a focal temperature increase (ΔT = 8.1 K) in an off-center region of the phantom. Temperature simulations in the human brain performed at 298 MHz showed a maximum temperature increase to 48.6C for a deep-seated hotspot in the brain with a size of (19×23×32)mm³ iso-temperature-90%. The hybrid applicator provided imaging capabilities that facilitate high spatial resolution brain MRI. To conclude, this study outlines the technical underpinnings and demonstrates the basic feasibility of an 8-channel hybrid TX/RX applicator that supports MR imaging, MR thermometry and targeted RF heating in one device.     

A numerical and experimental comparison of human head phantoms for compliance testing of mobile telephone equipment

A new human head phantom has been proposed by CENELEC/IEEE, based on a large scale anthropometric survey. This phantom is compared to a homogeneous Generic Head Phantom and three high resolution anatomical head models with respect to specific absorption rate (SAR) assessment. The head phantoms are exposed to the radiation of a generic mobile phone (GMP) with different antenna types and a commercial mobile phone. The phones are placed in the standardized testing positions and operate at 900 and 1800 MHz. The average peak SAR is evaluated using both experimental (DASY3 near field scanner) and numerical (FDTD simulations) techniques. The numerical and experimental results compare well and confirm that the applied SAR assessment methods constitute a conservative approach.     

Behavior of fresh vs. aged chemicals in soil

Existing data indicate that chemicals freshly added to soils are more amenable to losses, including biodegradation, than chemicals that have been in contact with soils for extended periods of time. This review presents the results of studies that indicate that increased soil‐chemical contact time increased the resistance of chemicals to desorption, volatilization, biodegradation, and extraction. Thus, results from studies conducted on chemicals freshly added to soils should not be used to predict the behavior of chemicals that have been in contact with soils for extended periods of time. In addition, a measure of the total chemical concentration present in a soil does not adequately indicate the availability of the chemicals for biodegradation or release, and does not indicate the potential for the chemical to be transported to and have an adverse effect on a human or ecological receptor.     

Structural determinants of developmental toxicity in hamsters.

A CASE/MULTICASE structure activity relationship (SAR) model of developmental toxicity of chemicals in hamsters (HaDT) was developed. The model exhibited a predictive performance of 74%. The model's overall predictivity and informational content were similar to those of an SAR model of mutagenicity in Salmonella. However, unlike the Salmonella mutagenicity model, the HaDT model did not identify overtly chemically reactive moieties as associated with activity. Moreover, examination of the number and nature of significant structural determinants suggested that developmental toxicity in hamsters was not the result of a unique mechanism or attack on a specific molecular target. The analysis also indicated that the availability of experimental data on additional chemicals would improve the performance of the SAR model.     

Antagonistic interaction between systemic acquired resistance and the abscisic acid-mediated abiotic stress response in Arabidopsis

Systemic acquired resistance (SAR) is a potent innate immunity system in plants that is effective against a broad range of pathogens. SAR development in dicotyledonous plants, such as tobacco (Nicotiana tabacum) and Arabidopsis thaliana, is mediated by salicylic acid (SA). Here, using two types of SAR-inducing chemicals, 1,2-benzisothiazol-3(2H)-one1,1-dioxide and benzo(1,2,3)thiadiazole-7-carbothioic acid S-methyl ester, which act upstream and downstream of SA in the SAR signaling pathway, respectively, we show that treatment with abscisic acid (ABA) suppresses the induction of SAR in Arabidopsis. In an analysis using several mutants in combination with these chemicals, treatment with ABA suppressed SAR induction by inhibiting the pathway both upstream and downstream of SA, independently of the jasmonic acid/ethylene-mediated signaling pathway. Suppression of SAR induction by the NaCl-activated environmental stress response proved to be ABA dependent. Conversely, the activation of SAR suppressed the expression of ABA biosynthesis-related and ABA-responsive genes, in which the NPR1 protein or signaling downstream of NPR1 appears to contribute. Therefore, our data have revealed that antagonistic crosstalk occurs at multiple steps between the SA-mediated signaling of SAR induction and the ABA-mediated signaling of environmental stress responses.     

Evaluation of microwave hyperthermia applicators.

Hyperthermia has been used in conjunction with radiation and chemotherapy for cancer treatment. When using electromagnetic heating, applicators are critical components in contact with or in proximity to patients and can be the determining factor for effective and safe treatment. Tissue absorption of electromagnetic energy is determined by many factors. Three cases are shown to illustrate the complexity of microwave heating: 1) The BSD MA-151 applicator has good center heating on a muscle-only phantom as shown in the operation manual. When fat slabs of 0.25, 0.5, 1, and 2 cm thick were added, two hot spots near the periphery of the applicator were evident on all fat surfaces, exposed at 631 MHz. At 915 MHz, the heating was elongated on the surface of the models with 0.25- and 2-cm fat, and two hot spots were observed on the 0.5- and 1-cm fat surfaces. 2) Heating patterns of the Clini-Therm applicators on a muscle-only phantom, as indicated in the operations guide, are elliptical with their major axes perpendicular to the electric field. However, when a bolus is used, the elliptical pattern is parallel to the E field. 3) Heating patterns in cylindrical structures were studied with inhomogeneous models of limbs. Arm and thigh models consisting of fat, bone, and muscle material were heated with Clini-Therm L, M, and MS applicators at 915 MHz. In addition to the geometric effect, the results indicated that placing the applicators with E field parallel to the long axis of cylindrical structures can minimize required power, produce less heating of fats and reduce stray radiation. In conclusion, to apply penetrating microwave or other RF fields for tissue heating, one must simulate the clinical exposure conditions as closely as possible to obtain useful heating patterns.     

SAR modeling of genotoxic phenomena: the effect of supplementation with physiological chemicals

Structure-activity relationship (SAR) modeling of toxicological phenomena is optimal when the ratio of toxicants to non-toxicants included in the model is unity. Frequently, however, the experimental data available are enriched with toxicants, this appears to be especially true for genotoxicity data sets. It is demonstrated herein, using a Salmonella mutagenicity data set, that when there is a paucity of non-toxicants, the learning set may be augmented with physiological chemicals on the assumption that they are non-genotoxic.     

The properties of human body phantoms used in calculations of electromagnetic fields exposure by wireless communication handsets or hand-operated industrial devices

According to international guidelines, the assessment of biophysical effects of exposure to electromagnetic fields (EMF) generated by hand-operated sources needs the evaluation of induced electric field (E _in) or specific energy absorption rate (SAR) caused by EMF inside a worker's body and is usually done by the numerical simulations with different protocols applied to these two exposure cases. The crucial element of these simulations is the numerical phantom of the human body. Procedures of E _in and SAR evaluation due to compliance analysis with exposure limits have been defined in Institute of Electrical and Electronics Engineers standards and International Commission on Non-Ionizing Radiation Protection guidelines, but a detailed specification of human body phantoms has not been described. An analysis of the properties of over 30 human body numerical phantoms was performed which has been used in recently published investigations related to the assessment of EMF exposure by various sources. The differences in applicability of these phantoms in the evaluation of E _in and SAR while operating industrial devices and SAR while using mobile communication handsets are discussed. The whole human body numerical phantom dimensions, posture, spatial resolution and electric contact with the ground constitute the key parameters in modeling the exposure related to industrial devices, while modeling the exposure from mobile communication handsets, which needs only to represent the exposed part of the human body nearest to the handset, mainly depends on spatial resolution of the phantom. The specification and standardization of these parameters of numerical human body phantoms are key requirements to achieve comparable and reliable results from numerical simulations carried out for compliance analysis against exposure limits or within the exposure assessment in EMF-related epidemiological studies.     

Evaluation of a rule base for identifying contact allergens by using a regulatory database: Comparison of data on chemicals notified in the European Union with "structural alerts" used in the DEREK expert system

To assess the suitability of the use of structural alerts to identify the skin-sensitising properties of chemicals, the 40 originally published structural alerts for the prediction of skin-sensitisation properties used by the DEREK system (which now contains 59 structural alerts), have been evaluated against a database developed in the German Federal Institute for Health Protection of Consumers and Veterinary Medicine (BgVV), which contains data submitted under the procedure for notifying new chemicals within the European Union. The evaluation of the 40 structural alerts used in DEREK revealed that eight of the 40 structural alerts for the prediction of skin-sensitising potential could be used without any further refinement. Ten structural alerts may need further specifications or refinements in order avoid false-positive predictions - proposals for refinement are discussed. Not enough substances were found within the BgVV database (containing data for more than 1000 substances) to evaluate ten of the DEREK substructures; hence, for these structural alerts, a judgement on their suitability for prediction of skin-sensitisation properties in expert systems is not possible. For 12 structural alerts, no comparative result could be obtained, because these rules did not "fire" for any of the examined chemicals. As a general result of the evaluation process, the approach of using structural alerts for the prediction of skin-sensitising properties of chemicals proved to be reliable. Proposals are given for a refinement of the structural alerts for prediction of contact allergy used in the DEREK system. In addition, advice and several preconditions are given, that apply when trying to teach a computer system to use structural alerts to predict toxicological properties.     

SAR modeling of genotoxic phenomena: the consequence on predictive performance of deviation from a unity ratio of genotoxicants/non-genotoxicants

SAR approaches to the study of genotoxic phenomena are finding increased applications. However, the data being modeled are frequently not considered optimal due to the small size of the dataset and an uneven distribution of genotoxicants and non-genotoxicants in the dataset. The effects of such imbalances on the performance of one SAR approach were investigated with respect to the modeling of the induction of unscheduled DNA synthesis in rat hepotocytes and of sister chromatid exchanges and chromosomal aberrations in cultural CHO cells. The analyses indicate that if genotoxicants exceed non-genotoxicants, the performance of the SAR model can be improved if the dataset is supplemented with physiological chemicals which are assumed to be non-genotoxicants. On the other hand, if non-genotoxicants exceed genotoxicants, it was found that the predictive performance of the resulting SAR model is not improved by removal of genotoxicants from the dataset to achieve a ratio of genotoxicants/genotoxicants of unity. Overall, the present analyses did not result in the development of SAR models of greatly increased predictivity. Conceivably, for the particular datasets and SAR paradigm the limit of predictivity has been reached. The possibility of investigating the use of a "battery" of SAR paradigms should be considered.     

Outdoor measurement of SAR in a full-sized human model exposed to 29.9 MHz in the near field

Localized and averaged specific absorption rates (SARs) were obtained in a full-size muscle-equivalent human model exposed to near-field 29.9 MHz irradiation at an outdoor facility. The model was positioned erect on a metallic groundplane 1.22 m (4 ft) from the base of a 10.8-m (35 ft) whip antenna with an input power of 1.0 kW. For whole-body SAR, a mean value of 0.83 W/kg was determined using two gradient-layer calorimeters in a twin-well configuration. The localized SARs at 12 body locations were measured using nonperturbing temperature probes and were highest in the ankle region. We conclude that averaged SAR measurements in a full-size phantom are feasible using a twin-calorimeter approach; measurements in the field are practical when human-size (183 x 61 x 46 cm) calorimeters are used.