Validity of the 1984 Interim Guidelines on Airborne Ultrasound and Gaps in the Current Knowledge.

ABSTRACT: Airborne ultrasound is used for various purposes both in industrial and public settings, as well as being produced as a by-product by a range of sources. The International Radiation Protection Association (IRPA) published interim guidelines on limiting human exposure to airborne ultrasound in 1984, based on the limited scientific evidence that was available at that time. In order to investigate whether research since 1984 requires the development of revised exposure guidelines we considered (a) within the context of ultrasound exposure the relevance to health of the biological endpoints/mechanisms listed in the IRPA guidelines, (b) the validity of the exposure limits, and (c) whether there are biological endpoints/mechanisms not covered in the guidelines. The analysis of the available evidence showed that the biological endpoints that form the basis of the guidelines are relevant to health and the guidelines provide limits of exposure based on the evidence that was available at the time. However, the IRPA limits and their associated dosimetry were based on limited evidence, which may not be considered as scientifically substantiated. Further, there is no substantiated evidence of biological endpoints/mechanisms not covered by the IRPA guidelines. These two observations could mean that IRPA's limits are too low or too high. Research since the IRPA guidelines has made some improvements in the knowledge base, but there are still significant data gaps that need to be resolved before a formal revision of the guidelines can be made by ICNIRP, including research needs related to health outcomes and improved dosimetry. This statement makes a number of recommendations for future research on airborne ultrasound.

ICNIRP Statement on Short Wavelength Light Exposure from Indoor Artificial Sources and Human Health.

ABSTRACT: Concerns have been raised about the possibility of effects from exposure to short wavelength light (SWL), defined here as 380-550 nm, on human health. The spectral sensitivity of the human circadian timing system peaks at around 480 nm, much shorter than the peak sensitivity of daytime vision (i.e., 555 nm). Some experimental studies have demonstrated effects on the circadian timing system and on sleep from SWL exposure, especially when SWL exposure occurs in the evening or at night. The International Commission on Non-Ionizing Radiation Protection (ICNIRP) has identified a lack of consensus among public health officials regarding whether SWL from artificial sources disrupts circadian rhythm, and if so, whether SWL-disrupted circadian rhythm is associated with adverse health outcomes. Systematic reviews of studies designed to examine the effects of SWL on sleep and human health have shown conflicting results. There are many variables that can affect the outcome of these experimental studies. One of the main problems in earlier studies was the use of photometric quantities as a surrogate for SWL exposure. Additionally, the measurement of ambient light may not be an accurate measure of the amount of light impinging on the intrinsically photosensitive retinal ganglion cells, which are now known to play a major role in the human circadian timing system. Furthermore, epidemiological studies of long-term effects of chronic SWL exposure per se on human health are lacking. ICNIRP recommends that an analysis of data gaps be performed to delineate the types of studies needed, the parameters that should be addressed, and the methodology that should be applied in future studies so that a decision about the need for exposure guidelines can be made. In the meantime, ICNIRP supports some recommendations for how the quality of future studies might be improved.

Effects of Environmental and Electric Perturbations on the pKa of Thioredoxin Cysteine 35: A Computational Study.

Here we present a theoretical-computational study dealing with the evaluation of the pKa of the Cysteine residues in Thioredoxin (TRX) and in its complex with the Thioredoxin-interacting protein (TXNIP). The free energy differences between the anionic and neutral form of the Cysteine 32 and 35 have been evaluated by means of the Perturbed Matrix Method with classical perturbations due to both the environment and an exogenous electric field as provided by Molecular Dynamics (MD) simulations. The evaluation of the free energies allowed us to show that the effect of the perturbing terms is to lower the pKa of Cysteine 32 and Cysteine 35 with respect to the free amino-acid. On the other hand, in the complex TRX-TXNIP, our data show an enhanced stabilization of the neutral reduced form of Cys 35. These results suggest that external electric stimuli higher than 0.02 V/nm can modulate the Cysteine pKa, which can be connected to the tight regulation of the TRX acting as an antioxidant agent.

A rationale for non-linear responses to strong electric fields in molecular dynamics simulations.

Many approaches for calculation of the field-dependent electric properties of water solutions rely on the Onsager and Kirkwood theories of polar dielectrics. Such basic theories implicitly consider the electric field intensity to fulfill the so-called 'weak field conditions', i.e. to produce a linear response in the system. In this work we made use of molecular dynamics simulations to investigate possible non-linear effects induced by high intensity electric fields, specifically continuous wave bursts with nanosecond duration, comparing them with the ones predicted by the theory. We found that field intensities above 0.15 V nm-1 produce remarkable nonlinear responses in the whole 100 MHz-100 GHz frequency window considered, with the onset of higher order polarization signals, which are the clear fingerprint of harmonic distorsions. That non-linear response turned out to depend on the considered frequency. We finally show that MD outcomes are consistent with a modelization based on an extended formulation of the Langevin function including a frequency-dependent parameter.

Human Fibroblasts In Vitro Exposed to 2.45 GHz Continuous and Pulsed Wave Signals: Evaluation of Biological Effects with a Multimethodological Approach.

The increasing exposure to radiofrequency electromagnetic fields (RF-EMF), especially from wireless communication devices, raises questions about their possible adverse health effects. So far, several in vitro studies evaluating RF-EMF genotoxic and cytotoxic non-thermal effects have reported contradictory results that could be mainly due to inadequate experimental design and lack of well-characterized exposure systems and conditions. Moreover, a topic poorly investigated is related to signal modulation induced by electromagnetic fields. The aim of this study was to perform an analysis of the potential non-thermal biological effects induced by 2.45 GHz exposures through a characterized exposure system and a multimethodological approach. Human fibroblasts were exposed to continuous (CW) and pulsed (PW) signals for 2 h in a wire patch cell-based exposure system at the specific absorption rate (SAR) of 0.7 W/kg. The evaluation of the potential biological effects was carried out through a multimethodological approach, including classical biological markers (genotoxic, cell cycle, and ultrastructural) and the evaluation of gene expression profile through the powerful high-throughput next generation sequencing (NGS) RNA sequencing (RNA-seq) approach. Our results suggest that 2.45 GHz radiofrequency fields did not induce significant biological effects at a cellular or molecular level for the evaluated exposure parameters and conditions.

Restoring the encoding properties of a stochastic neuron model by an exogenous noise.

Here we evaluate the possibility of improving the encoding properties of an impaired neuronal system by superimposing an exogenous noise to an external electric stimulation signal. The approach is based on the use of mathematical neuron models consisting of stochastic HH-like circuit, where the impairment of the endogenous presynaptic inputs is described as a subthreshold injected current and the exogenous stimulation signal is a sinusoidal voltage perturbation across the membrane. Our results indicate that a correlated Gaussian noise, added to the sinusoidal signal can significantly increase the encoding properties of the impaired system, through the Stochastic Resonance (SR) phenomenon. These results suggest that an exogenous noise, suitably tailored, could improve the efficacy of those stimulation techniques used in neuronal systems, where the presynaptic sensory neurons are impaired and have to be artificially bypassed.

The CNP signal is able to silence a supra threshold neuronal model.

Several experimental results published in the literature showed that weak pulsed magnetic fields affected the response of the central nervous system. However, the specific biological mechanisms that regulate the observed behaviors are still unclear and further scientific investigation is required. In this work we performed simulations on a neuronal network model exposed to a specific pulsed magnetic field signal that seems to be very effective in modulating the brain activity: the Complex Neuroelectromagnetic Pulse (CNP). Results show that CNP can silence the neurons of a feed-forward network for signal intensities that depend on the strength of the bias current, the endogenous noise level and the specific waveforms of the pulses. Therefore, it is conceivable that a neuronal network model responds to the CNP signal with an inhibition of its activity. Further studies on more realistic neuronal networks are needed to clarify if such an inhibitory effect on neuronal tissue may be the basis of the induced analgesia seen in humans and the antinociceptive effects seen in animals when exposed to the CNP.

Water response to intense electric fields: A molecular dynamics study.

This paper investigated polarization properties of water molecules in close proximity to an ionic charge in the presence of external electric fields by using an approach based on simulations at the atomic level. We chose sodium and chloride ions in water as examples of dilute ionic solutions and used molecular dynamics simulations to systematically investigate the influence of an external static electric field on structural, dipolar, and polarization properties of water near charged ions. Results showed that a threshold electric field higher than 10(8) V/m is needed to affect water polarization and increase mean dipole moment of water molecules close to the ion. A similar threshold holds for water permittivity profiles, although a field 10× higher is needed to ensure that water permittivity is almost constant independently of the position close to the ion. Electric fields of such intensities can greatly enhance polarizability of water in hydration shells around ions.

Numerical characterization of intraoperative and chronic electrodes in deep brain stimulation.

An intraoperative electrode (microelectrode) is used in the deep brain stimulation (DBS) technique to pinpoint the brain target and to choose the best parameters for the electrical stimulus. However, when the intraoperative electrode is replaced with the chronic one (macroelectrode), the observed effects do not always coincide with predictions. To investigate the causes of such discrepancies, a 3D model of the basal ganglia has been considered and realistic models of both intraoperative and chronic electrodes have been developed and numerically solved. Results of simulations of the electric potential (V) and the activating function (AF) along neuronal fibers show that the different geometries and sizes of the two electrodes do not change the distributions and polarities of these functions, but rather the amplitudes. This effect is similar to the one produced by the presence of different tissue layers (edema or glial tissue) in the peri-electrode space. Conversely, an inaccurate positioning of the chronic electrode with respect to the intraoperative one (electric centers not coincident) may induce a completely different electric stimulation in some groups of fibers.

A complete model for the evaluation of the magnetic stimulation of peripheral nerves.

In this paper, a numerical procedure for the analysis of peripheral nerve excitation through magnetic stimulation is presented and used to investigate the physical parameters influencing stimulation. The finite difference technique is used to evaluate the electric field distribution induced inside an arm by the current flowing through a coil, and a nonlinear cable model is used to describe the response of the nerve fiber to the induced electric field. The comparison among several forearm structures has evidenced that the heterogeneous non dispersive forearm model is a good reference condition. With this model, the lowest charging voltage on the stimulator capacitance, able to produce the nerve stimulation, is achieved when the coil is shifted, with respect to the nerve, of a quantity slightly lower than the coil radius but it is also possible to excite the nerve fiber by applying a shift equal to zero. The charging voltage increases when the coil radius is increased and when a three-dimensional coil geometry is considered. Moreover, this voltage is strongly dependent on the nerve position inside the forearm and on the kind of tissue surrounding the nerve.

Controlled release from magnetoliposomes aqueous suspensions exposed to a low intensity magnetic field.

Recently, the use of liposomes loaded with magnetic nanoparticles (magnetoliposomes, (MLs)) has been intensely growing as a new drug delivery system. With the use of alternating magnetic fields, it is possible to remotely control the delivery of a drug or any other macromolecule loaded inside the MLs. In this experiment, the release of a fluorescent dye from MLs is achieved through an alternating magnetic field of 20 kHz and amplitude below 100 A/m, and without a macroscopic temperature increase.

Stochastic resonance induced by exogenous noise in a model of a neuronal network.

This study investigates the possibility of using exogenous noise to restore the processing performances of neuronal systems where the endogenous noise is reduced due to the ageing or to degenerative diseases. This idea is based on the assumption, supported by theoretical studies, that the endogenous noise has a positive role in neuronal signal detection and that its reduction impairs the system function. Results, obtained on a two-layers feedforward network, show the onset of the Stochastic Resonance (SR) behavior, as long as the exogenous noise is properly tailored and filtered. The amount of noise to be furnished from the outside to optimize the system performance depends on the residual level of endogenous noise, indicating that both kinds of noise cooperate to the signal detection. These results support potentially new bioengineering applications where exogenous noise is furnished to enhance signal detectability.

Microdosimetric study for nanosecond pulsed electric fields on a cell circuit model with nucleus.

Recently, scientific interest in electric pulses, always more intense and shorter and able to induce biological effects on both plasma and nuclear membranes, has greatly increased. Hence, microdosimetric models that include internal organelles like the nucleus have assumed increasing importance. In this work, a circuit model of the cell including the nucleus is proposed, which accounts for the dielectric dispersion of all cell compartments. The setup of the dielectric model of the nucleus is of fundamental importance in determining the transmembrane potential (TMP) induced on the nuclear membrane; here, this is demonstrated by comparing results for three different sets of nuclear dielectric properties present in the literature. The results have been compared, even including or disregarding the dielectric dispersion of the nucleus. The main differences have been found when using pulses shorter than 10 ns. This is due to the fact that the high spectral components of the shortest pulses are differently taken into account by the nuclear membrane transfer functions computed with and without nuclear dielectric dispersion. The shortest pulses are also the most effective in porating the intracellular structures, as confirmed by the time courses of the TMP calculated across the plasma and nuclear membranes. We show how dispersive nucleus models are unavoidable when dealing with pulses shorter than 10 ns because of the large spectral contents arriving above 100 MHz, i.e., over the typical relaxation frequencies of the dipolar mechanism of the molecules constituting the nuclear membrane and the subcellular cell compartments.

Effect of high exogenous electric pulses on protein conformation: myoglobin as a case study.

Protein folding and unfolding under the effect of exogenous perturbations remains a topic of great interest, further enhanced by recent technological developments in the field of signal generation that allow the use of intense ultrashort electric pulses to directly interact at microscopic level with biological matter. In this paper, we show results from molecular dynamics (MD) simulations of a single myoglobin molecule in water exposed to pulsed and static electric fields, ranging from 10(8) to 10(9) V/m, compared to data with unexposed conditions. We have found that the highest intensity (10(9) V/m) produced a fast transition (occurring within a few hundreds of picoseconds) between folded and unfolded states, as inferred by secondary structures and geometrical analysis. Fields of 10(8) V/m, on the contrary, produced no significant denaturation, although a relevant effect on the protein dipolar behavior was detected.

Systematic review of wireless phone use and brain cancer and other head tumors.

We conducted a systematic review of scientific studies to evaluate whether the use of wireless phones is linked to an increased incidence of the brain cancer glioma or other tumors of the head (meningioma, acoustic neuroma, and parotid gland), originating in the areas of the head that most absorb radiofrequency (RF) energy from wireless phones. Epidemiology and in vivo studies were evaluated according to an agreed protocol; quality criteria were used to evaluate the studies for narrative synthesis but not for meta-analyses or pooling of results. The epidemiology study results were heterogeneous, with sparse data on long-term use (≥ 10 years). Meta-analyses of the epidemiology studies showed no statistically significant increase in risk (defined as P < 0.05) for adult brain cancer or other head tumors from wireless phone use. Analyses of the in vivo oncogenicity, tumor promotion, and genotoxicity studies also showed no statistically significant relationship between exposure to RF fields and genotoxic damage to brain cells, or the incidence of brain cancers or other tumors of the head. Assessment of the review results using the Hill criteria did not support a causal relationship between wireless phone use and the incidence of adult cancers in the areas of the head that most absorb RF energy from the use of wireless phones. There are insufficient data to make any determinations about longer-term use (≥ 10 years).

Modeling of chemical reactions in micelle: water-mediated keto-enol interconversion as a case study.

The effect of a zwitterionic micelle environment on the efficiency of the keto-enol interconversion of 2-phenylacetylthiophene has been investigated by means of a joint application of experimental and theoretical/computational approaches. Results have revealed a reduction of the reaction rate constant if compared with bulk water essentially because of the different solvation conditions experienced by the reactant species, including water molecules, in the micelle environment. The slight inhibiting effect due to the application of a static electric field has also been theoretically investigated and presented.

Microdosimetry for nanosecond pulsed electric field applications: a parametric study for a single cell.

A microdosimetric study of nanosecond pulsed electric fields, including dielectric dispersivity of cell compartments, is proposed in our paper. A quasi-static solution based on the Laplace equation was adapted to wideband signals and used to address the problem of electric field estimation at cellular level. The electric solution was coupled with an asymptotic electroporation model able to predict membrane pore density. An initial result of our paper is the relevance of the dielectric dispersivity, providing evidence that both the transmembrane potential and the pore density are strongly influenced by the choice of modeling used. We note the crucial role played by the dielectric properties of the membrane that can greatly impact on the poration of the cell. This can partly explain the selective action reported on cancerous cells in mixed populations, if one considers that tumor cells may present different dielectric responses. Moreover, these kinds of studies can be useful to determine the appropriate setting of nsPEF generators as well as for the design and optimization of new-generation devices.

Quantitative assessment of dielectric parameters for membrane lipid bi-layers from RF permittivity measurements.

In this article, we propose and validate theoretical and experimental methods to quantitatively assess the Debye dielectric model of membrane lipid bi-layers. This consists of two steps: permittivity measurements of biological solutions (liposomes), and estimation of the model parameters by inverse application of the Effective Medium Theory. The measurements are conducted in the frequency domain between 100 MHz and 2 GHz using a modified coaxial connector, at the temperatures of 27 and 30 degrees C. Estimations have been performed using a three-layered model based on the Maxwell-Wagner formulation. Debye parameters (mean value +/- standard error) found from fitting experimental data are: epsilon(s) = 11.69 +/- 0.09, epsilon(infinity) = 4.00 +/- 0.07, f(relax) = 179.85 +/- 6.20 MHz and epsilon(s) = (1.1 +/- 0.1) x 10(-7) S/m. This model can be used in microdosimetric studies aiming to precisely determine the E-field distribution in a biological target down to the single cell level. In this context the use of an accurate membrane dielectric model, valid through a wide frequency range, is particularly appropriate.

Modeling electromagnetic fields detectability in a HH-like neuronal system: stochastic resonance and window behavior.

Noise has already been shown to play a constructive role in neuronal processing and reliability, according to stochastic resonance (SR). Here another issue is addressed, concerning noise role in the detectability of an exogenous signal, here representing an electromagnetic (EM) field. A Hodgkin-Huxley like neuronal model describing a myelinated nerve fiber is proposed and validated, excited with a suprathreshold stimulation. EM field is introduced as an additive voltage input and its detectability in neuronal response is evaluated in terms of the output signal-to-noise ratio. Noise intensities maximizing spiking activity coherence with the exogenous EM signal are clearly shown, indicating a stochastic resonant behavior, strictly connected to the model frequency sensitivity. In this study SR exhibits a window of occurrence in the values of field frequency and intensity, which is a kind of effect long reported in bioelectromagnetic experimental studies. The spatial distribution of the modeled structure also allows to investigate possible effects on action potentials saltatory propagation, which results to be reliable and robust over the presence of an exogenous EM field and biological noise. The proposed approach can be seen as assessing biophysical bases of medical applications funded on electric and magnetic stimulation where the role of noise as a cooperative factor has recently gained growing attention.