An integrate-and-fire approach to Ca2+ signaling. Part I: Renewal model.

In computational neuroscience integrate-and-fire models capture the spike generation by a subthreshold dynamics supplemented by a simple fire-and-reset rule; they allow for a numerically efficient and analytically tractable description of stochastic single cell as well as network dynamics. Stochastic spiking is also a prominent feature of Ca2+ signaling which suggests to adopt the integrate-and-fire approach for this fundamental biophysical process. The model introduced here consists of two components describing 1) activity of clusters of inositol-trisphosphate receptor channels and 2) dynamics of the global Ca2+ concentrations in the cytosol. The cluster dynamics is given in terms of a cyclic Markov chain, capturing the puff, i.e., the punctuated release of Ca2+ from intracellular stores. The cytosolic Ca2+ concentration is described by an integrate-and-fire dynamics driven by the puff current. For the cyclic Markov chain we derive expressions for the statistics of the interpuff interval, the single-puff strength and the puff current assuming constant cytosolic Ca2+. The latter condition is often well approximated because cytosolic Ca2+ varies much slower than the cluster activity does. Furthermore, because the detailed two-component model is numerically expensive to simulate and difficult to treat analytically, we develop an analytical framework to approximate the driving puff current of the stochastic cytosolic Ca2+ dynamics by a temporally uncorrelated Gaussian noise. This approximation reduces our two-component system to an integrate-and-fire model with a nonlinear drift function and a multiplicative Gaussian white noise, a model that is known to generate a renewal spike train, i.e., a point process with statistically independent interspike intervals. The model allows for fast numerical simulations, permits to derive analytical expressions for the rate of Ca2+ spiking and the coefficient of variation of the interspike interval, and to approximate the interspike interval density and the spike train power spectrum. Comparison of these statistics to experimental data is discussed.

Drug-induced resistance evolution necessitates less aggressive treatment.

Increasing body of experimental evidence suggests that anticancer and antimicrobial therapies may themselves promote the acquisition of drug resistance by increasing mutability. The successful control of evolving populations requires that such biological costs of control are identified, quantified and included to the evolutionarily informed treatment protocol. Here we identify, characterise and exploit a trade-off between decreasing the target population size and generating a surplus of treatment-induced rescue mutations. We show that the probability of cure is maximized at an intermediate dosage, below the drug concentration yielding maximal population decay, suggesting that treatment outcomes may in some cases be substantially improved by less aggressive treatment strategies. We also provide a general analytical relationship that implicitly links growth rate, pharmacodynamics and dose-dependent mutation rate to an optimal control law. Our results highlight the important, but often neglected, role of fundamental eco-evolutionary costs of control. These costs can often lead to situations, where decreasing the cumulative drug dosage may be preferable even when the objective of the treatment is elimination, and not containment. Taken together, our results thus add to the ongoing criticism of the standard practice of administering aggressive, high-dose therapies and motivate further experimental and clinical investigation of the mutagenicity and other hidden collateral costs of therapies.

Enhanced brainstem phase-locking in low-level noise reveals stochastic resonance in the frequency-following response (FFR).

In nonlinear systems, the inclusion of low-level noise can paradoxically improve signal detection, a phenomenon known as stochastic resonance (SR). SR has been observed in human hearing whereby sensory thresholds (e.g., signal detection and discrimination) are enhanced in the presence of noise. Here, we asked whether subcortical auditory processing (neural phase locking) shows evidence of SR. We recorded brainstem frequency-following-responses (FFRs) in young, normal-hearing listeners to near-electrophysiological-threshold (40 dB SPL) complex tones composed of 10 iso-amplitude harmonics of 150 Hz fundamental frequency (F0) presented concurrent with low-level noise (+20 to -20 dB SNRs). Though variable and weak across ears, some listeners showed improvement in auditory detection thresholds with subthreshold noise confirming SR psychophysically. At the neural level, low-level FFRs were initially eradicated by noise (expected masking effect) but were surprisingly reinvigorated at select masker levels (local maximum near âˆ¼ 35 dB SPL). These data suggest brainstem phase-locking to near threshold periodic stimuli is enhanced in optimal levels of noise, the hallmark of SR. Our findings provide novel evidence for stochastic resonance in the human auditory brainstem and suggest that under some circumstances, noise can actually benefit both the behavioral and neural encoding of complex sounds.

Stochastic assembly process dominates bacterial succession during a long-term microbial enhanced oil recovery.

Microbial enhanced oil recovery (MEOR) has been successfully used in oil exploitation to increase oil production. However, the mechanisms of microbial interactions and community assembly related to oil production performance along MEOR process are poorly understood. Here, we investigated the microbiome of an oil reservoir for a period of 5 years under three phases of different treatments with the injection of a mixture of microbes, nutrients, and air at different intensity. During the MEOR process, amplification of functional genes revealed an increase of genes related to hydrocarbon degradation linked to methanogenesis, supported by stable isotope analysis for confirmation of the methanogenesis activity. Meanwhile, a lower contribution of the ubiquitous/common taxa, closer and more positive associations, and lower modularity were observed in bacterial co-occurrence networks, with the rare taxa being the keystone taxa. The null model analysis and structural equation modeling revealed that the contribution of stochastic processes affected by functional groups and co-occurrence patterns to bacterial community increased significantly with the increase of oil production. This provides new insight that stochastic assembly in bacterial community increased along with MEOR process, and it is worthwhile paying attention to the uncertain consequences caused by random evolution since the treatment effect of MEOR is closely related to the in-situ community in oil reservoir.

Simulated transient hearing loss improves auditory sensitivity.

Recently, it was proposed that a processing principle called adaptive stochastic resonance plays a major role in the auditory system, and serves to maintain optimal sensitivity even to highly variable sound pressure levels. As a side effect, in case of reduced auditory input, such as permanent hearing loss or frequency specific deprivation, this mechanism may eventually lead to the perception of phantom sounds like tinnitus or the Zwicker tone illusion. Using computational modeling, the biological plausibility of this processing principle was already demonstrated. Here, we provide experimental results that further support the stochastic resonance model of auditory perception. In particular, Mongolian gerbils were exposed to moderate intensity, non-damaging long-term notched noise, which mimics hearing loss for frequencies within the notch. Remarkably, the animals developed significantly increased sensitivity, i.e. improved hearing thresholds, for the frequency centered within the notch, but not for frequencies outside the notch. In addition, most animals treated with the new paradigm showed identical behavioral signs of phantom sound perception (tinnitus) as animals with acoustic trauma induced tinnitus. In contrast, animals treated with broadband noise as a control condition did not show any significant threshold change, nor behavioral signs of phantom sound perception.

Neuronal figure-ground responses in primate primary auditory cortex.

Figure-ground segregation, the brain's ability to group related features into stable perceptual entities, is crucial for auditory perception in noisy environments. The neuronal mechanisms for this process are poorly understood in the auditory system. Here, we report figure-ground modulation of multi-unit activity (MUA) in the primary and non-primary auditory cortex of rhesus macaques. Across both regions, MUA increases upon presentation of auditory figures, which consist of coherent chord sequences. We show increased activity even in the absence of any perceptual decision, suggesting that neural mechanisms for perceptual grouping are, to some extent, independent of behavioral demands. Furthermore, we demonstrate differences in figure encoding between more anterior and more posterior regions; perceptual saliency is represented in anterior cortical fields only. Our results suggest an encoding of auditory figures from the earliest cortical stages by a rate code.

The encoding of stochastic regularities is facilitated by action-effect predictions.

Our brains continuously build and update predictive models of the world, sources of prediction being drawn for example from sensory regularities and/or our own actions. Yet, recent results in the auditory system indicate that stochastic regularities may not be easily encoded when a rare medium pitch deviant is presented between frequent high and low pitch standard sounds in random order, as reflected in the lack of sensory prediction error event-related potentials [i.e., mismatch negativity (MMN)]. We wanted to test the implication of the predictive coding theory that predictions based on higher-order generative models-here, based on action intention, are fed top-down in the hierarchy to sensory levels. Participants produced random sequences of high and low pitch sounds by button presses in two conditions: In a "specific" condition, one button produced high and the other low pitch sounds; in an "unspecific" condition, both buttons randomly produced high or low-pitch sounds. Rare medium pitch deviants elicited larger MMN and N2 responses in the "specific" compared to the "unspecific" condition, despite equal sound probabilities. These results thus demonstrate that action-effect predictions can boost stochastic regularity-based predictions and engage higher-order deviance detection processes, extending previous notions on the role of action predictions at sensory levels.

Transcranial Random Noise Stimulation Acutely Lowers the Response Threshold of Human Motor Circuits.

Transcranial random noise stimulation (tRNS) over cortical areas has been shown to acutely improve performance in sensory detection tasks. One explanation for this behavioral effect is stochastic resonance (SR), a mechanism that explains how signal processing in nonlinear systems can benefit from added noise. While acute noise benefits of electrical RNS have been demonstrated at the behavioral level as well as in in vitro preparations of neural tissue, it is currently largely unknown whether similar effects can be shown at the neural population level using neurophysiological readouts of human cortex. Here, we hypothesized that acute tRNS will increase the responsiveness of primary motor cortex (M1) when probed with transcranial magnetic stimulation (TMS). Neural responsiveness was operationalized via the well-known concept of the resting motor threshold (RMT). We showed that tRNS acutely decreases RMT. This effect was small, but it was consistently replicated across four experiments including different cohorts (total N = 81, 46 females, 35 males), two tRNS electrode montages, and different control conditions. Our experiments provide critical neurophysiological evidence that tRNS can acutely generate noise benefits by enhancing the neural population response of human M1.SIGNIFICANCE STATEMENT A hallmark feature of stochastic resonance (SR) is that signal processing can benefit from added noise. This has mainly been demonstrated at the single-cell level in vitro where the neural response to weak input signals can be enhanced by simultaneously applying random noise. Our finding that transcranial random noise stimulation (tRNS) acutely increases the excitability of corticomotor circuits extends the principle of noise benefits to the neural population level in human cortex. Our finding is in line with the notion that tRNS might affect cortical processing via the SR phenomenon. It suggests that enhancing the response of cortical populations to an external stimulus might be one neurophysiological mechanism mediating performance improvements when tRNS is applied to sensory cortex during perception tasks.

Success of prophylactic antiviral therapy for SARS-CoV-2: Predicted critical efficacies and impact of different drug-specific mechanisms of action.

Repurposed drugs that are safe and immediately available constitute a first line of defense against new viral infections. Despite limited antiviral activity against SARS-CoV-2, several drugs are being tested as medication or as prophylaxis to prevent infection. Using a stochastic model of early phase infection, we evaluate the success of prophylactic treatment with different drug types to prevent viral infection. We find that there exists a critical efficacy that a treatment must reach in order to block viral establishment. Treatment by a combination of drugs reduces the critical efficacy, most effectively by the combination of a drug blocking viral entry into cells and a drug increasing viral clearance. Below the critical efficacy, the risk of infection can nonetheless be reduced. Drugs blocking viral entry into cells or enhancing viral clearance reduce the risk of infection more than drugs that reduce viral production in infected cells. The larger the initial inoculum of infectious virus, the less likely is prevention of an infection. In our model, we find that as long as the viral inoculum is smaller than 10 infectious virus particles, viral infection can be prevented almost certainly with drugs of 90% efficacy (or more). Even when a viral infection cannot be prevented, antivirals delay the time to detectable viral loads. The largest delay of viral infection is achieved by drugs reducing viral production in infected cells. A delay of virus infection flattens the within-host viral dynamic curve, possibly reducing transmission and symptom severity. Thus, antiviral prophylaxis, even with reduced efficacy, could be efficiently used to prevent or alleviate infection in people at high risk.

Balanced stochastic versus deterministic assembly processes benefit diverse yet uneven ecosystem functions in representative agroecosystems.

Ecological assembly processes, by influencing community composition, determine ecosystem functions of microbiomes. However, debate remains on how stochastic versus deterministic assembly processes influence ecosystem functions such as carbon and nutrient cycling. Towards a better understanding, we investigated three types of agroecosystems (the upland, paddy, and flooded) that represent a gradient of stochastic versus deterministic assembly processes. Carbon and nutrient cycling multifunctionality, characterized by nine enzymes associated with soil carbon, nitrogen, phosphorous and sulfur cycling, was evaluated and then associated with microbial assembly processes and co-occurrence patterns of vital ecological groups. Our results suggest that strong deterministic processes favour microorganisms with convergent functions (as in the upland agroecosystem), while stochasticity-dominated processes lead to divergent functions (as in the flooded agroecosystem). To benefit agroecosystems services, we speculate that it is critical for a system to maintain balance between its stochastic and deterministic assembly processes (as in the paddy agroecosystem). By doing so, the system can preserve a diverse array of functional traits and also allow for particular traits to flourish. To further confirm this speculation, it is necessary to develop a systematic knowledge beyond merely characterizing general patterns towards the associations among community assembly, composition, and ecosystem functions.

Prospective STAR-Guided Ablation in Persistent Atrial Fibrillation Using Sequential Mapping With Multipolar Catheters.

BACKGROUND: A novel stochastic trajectory analysis of ranked signals (STAR) mapping approach to guide atrial fibrillation (AF) ablation using basket catheters recently showed high rates of AF termination and subsequent freedom from AF. METHODS: This study aimed to determine whether STAR mapping using sequential recordings from conventional pulmonary vein mapping catheters could achieve similar results. Patients with persistent AF<2 years were included. Following pulmonary vein isolation AF drivers (AFDs) were identified on sequential STAR maps created with PentaRay, IntellaMap Orion, or Advisor HD Grid catheters. Patients had a minimum of 10 multipolar recordings of 30 seconds each. These were processed in real-time and AFDs were targeted with ablation. An ablation response was defined as AF termination or cycle length slowing ≥30 ms. RESULTS: Thirty patients were included (62.4±7.8 years old, AF duration 14.1±4.3 months) of which 3 had AF terminated on pulmonary vein isolation, leaving 27 patients that underwent STAR-guided AFD ablation. Eighty-three potential AFDs were identified (3.1±1.1 per patient) of which 70 were targeted with ablation (2.6±1.2 per patient). An ablation response was seen at 54 AFDs (77.1% of AFDs; 21 AF termination and 33 cycle length slowing) and occurred in all 27 patients. No complications occurred. At 17.3±10.1 months, 22 out of 27 (81.5%) patients undergoing STAR-guided ablation were free from AF/atrial tachycardia off antiarrhythmic drugs. CONCLUSIONS: STAR-guided AFD ablation through sequential mapping with a multipolar catheter effectively achieved an ablation response in all patients. AF terminated in a majority of patients, with a high freedom from AF/atrial tachycardia off antiarrhythmic drugs at long-term follow-up. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02950844.

The impact of community-wide, mass drug administration on aggregation of soil-transmitted helminth infection in human host populations.

BACKGROUND: Soil-transmitted helminths (STH) are intestinal parasites estimated to infect over 1.5 billion people. Current treatment programmes are aimed at morbidity control through school-based deworming programmes (targeting school-aged children, SAC) and treating women of reproductive age (WRA), as these two groups are believed to record the highest morbidity. More recently, however, the potential for interrupting transmission by treating entire communities has been receiving greater emphasis and the feasibility of such programmes are now under investigation in randomised clinical trials through the Bill & Melinda Gates Foundation funded DeWorm3 studies. Helminth parasites are known to be highly aggregated within human populations, with a small minority of individuals harbouring most worms. Empirical evidence from the TUMIKIA project in Kenya suggests that aggregation may increase significantly after anthelminthic treatment. METHODS: A stochastic, age-structured, individual-based simulation model of parasite transmission is employed to better understand the factors that might induce this pattern. A simple probabilistic model based on compounded negative binomial distributions caused by age-dependencies in both treatment coverage and exposure to infection is also employed to further this understanding. RESULTS: Both approaches confirm helminth aggregation is likely to increase post-mass drug administration as measured by a decrease in the value of the negative binomial aggregation parameter, k. Simple analytical models of distribution compounding describe the observed patterns well. CONCLUSIONS: The helminth aggregation that was observed in the field was replicated with our stochastic individual-based model. Further work is required to generalise the probabilistic model to take account of the respective sensitivities of different diagnostics on the presence or absence of infection.

Inconsistent effects of stochastic resonance on human auditory processing.

It has been demonstrated that, while otherwise detrimental, noise can improve sensory perception under optimal conditions. The mechanism underlying this improvement is stochastic resonance. An inverted U-shaped relationship between noise level and task performance is considered as the signature of stochastic resonance. Previous studies have proposed the existence of stochastic resonance also in the human auditory system. However, the reported beneficial effects of noise are small, based on a small sample, and do not confirm the proposed inverted U-shaped function. Here, we investigated in two separate studies whether stochastic resonance may be present in the human auditory system by applying noise of different levels, either acoustically or electrically via transcranial random noise stimulation, while participants had to detect acoustic stimuli adjusted to their individual hearing threshold. We find no evidence for behaviorally relevant effects of stochastic resonance. Although detection rate for near-threshold acoustic stimuli appears to vary in an inverted U-shaped manner for some subjects, it varies in a U-shaped manner or in other manners for other subjects. Our results show that subjects do not benefit from noise, irrespective of its modality. In conclusion, our results question the existence of stochastic resonance in the human auditory system.

Ecological and Evolutionary Stochasticity Shape Natural Selection.

The distribution of biodiversity depends on the combined and interactive effects of ecological and evolutionary processes. The joint contribution of these processes has focused almost exclusively on deterministic effects, even though mechanisms that increase the importance of random ecological processes are expected to also increase the importance of random evolutionary processes. Here we manipulate the sizes of old field fragments to generate correlated sampling effects for a focal population (a gall maker) and its enemy community. Traits and communities were more variable in smaller patches. However, because of the preference of some enemies for some trait values (gall sizes), random variation in population mean trait values exacerbated differences in community composition. The random distribution of traits and interactions created predictable but highly variable patterns of natural selection. Our study highlights how stochastic processes can affect ecological and evolutionary processes structuring the strength and direction of selection locally and at larger scales.

Drivers in AF colocate to sites of electrogram organization and rapidity: Potential synergy between spectral analysis and STAR mapping approaches in prioritizing drivers for ablation.

INTRODUCTION: Stochastic trajectory analysis of ranked signals (STAR) mapping has recently been used to ablate persistent atrial fibrillation (AF) with high rates of AF termination and long-term freedom from AF in small, single-arm studies. We hypothesized that rapidity and organization markers would correlate with early sites of activation (ESA). METHODS: Patients undergoing persistent AF ablation as part of the STAR mapping study were included. Five-minute unipolar basket recordings used to create STAR maps were used to determine the minimum-cycle length (Min-CL) and CL variability (CLV) at each electrode to identify the site of the fastest Min-CL and lowest CLV across the left atrium (LA). The location of ESA targeted with ablation was compared with these sites. Dominant frequency was assessed at ESA and compared with that of neighboring electrodes to assess for regional gradients. RESULTS: Thirty-two patients were included with 83 ESA ablated, with an ablation response at 73 sites (24 AF termination and 49 CL slowing ≥30 ms). Out of these, 54 (74.0%) and 56 (76.7%) colocated to sites of fastest Min-CL and lowest CLV, respectively. Regional CL and frequency gradients were demonstrable at majority of ESA. ESA colocating to sites of fastest Min-CL and lowest CLV were more likely to terminate AF with ablation (odds ratio, 34 and 29, respectively, P = .02). These showed a moderate sensitivity (74.0% Min-CL and 75.3% CLV) and specificity (66.7% Min-CL and 76.9% CLV) in predicting ESA with an ablation response. CONCLUSIONS: ESA correlate with rapidity and organization markers. Further work is needed to clarify any role for spectral analysis in prioritizing driver ablation.

A model of the cost of delaying treatment of Hashimotos thyroiditis: thyroid cancer initiation and growth.

Hashimoto's thyroiditis (HT) is an autoimmune disorder that drives the function of thyroid gland to the sequential clinical states:euthyroidism (normal condition), subclinical hypothyroidism (asymptomatic period) and overt hypothyroidism (symptomatic period). In this disease, serum thyroidstimulating hormone (TSH) levels increase monotonically, stimulating the thyroid follicular cells chronically and initiating benign (non-cancerous) thyroid nodules at various sites of the thyroid gland. This process can also encourage growth of papillary thyroid microcarcinoma. Due to prolonged TSH stimulation, thyroid nodules may grow and become clinically relevant without the administration of treatment by thyroid hormone replacement. Papillary thyroid cancer (80% of thyroid cancer) whose incidence is increasing worldwide, is associated with Hashimoto's thyroiditis. A stochastic model is developed here to produce the statistical distribution of thyroid nodule sizes and growth by taking serum TSH value as the continuous input to the model using TSH values from the output of the patientspecific deterministic model developed for the clinical progression of Hashimoto's thyroiditis.

Mechanistically derived Toxicant-mediated predator-prey model under Stoichiometric constraints.

Studies in ecological stoichiometry highlight that grazer dynamics are affected by insufficient food nutrient content (low phosphorus (P)/carbon (C) ratio) as well as excess food nutrient content (high P:C). Contaminant stressors affect all levels of the biological hierarchy, from cells to organs to organisms to populations to entire ecosystems. Eco-toxicological modeling under the framework of ecological stoichiometry predicts the risk of bio-accumulation of a toxicant under stoichiometric constraints. In this paper, we developed and analyzed a Lotka-Volterra type predator- prey model which explicitly tracks the environmental toxicant as well as the toxicant in the populations under stoichiometric constraints. Analytic, numerical, slow-fast steady state and bifurcation theory are employed to predict the risk of toxicant bio-accumulation under varying food conditions. In some cases, our model predicts different population dynamics, including wide amplitude limit cycles where producer densities exhibit very low values and may be in danger of stochastic extinction.

STAR mapping method to identify driving sites in persistent atrial fibrillation: Application through sequential mapping.

INTRODUCTION: The optimal way to map localized drivers in persistent atrial fibrillation (AF) remains unclear. The objective of the study was to apply a novel vector mapping approach called Stochastic Trajectory Analysis of Ranked signals (STAR) in AF. METHODS AND RESULTS: Patients having persistent AF ablation were included. Early sites of activation (ESA) identified on global STAR maps created with basket catheters were used to guide AF ablation post-pulmonary vein isolation (PVI). All patients also had sequential STAR maps created with ≥10 PentaRay recordings of 30 seconds. These were validated offline in their ability to identify the ESA targeted with a study-defined ablation response (AF termination or cycle length [CL] slowing of ≥30 ms). Thirty-two patients were included in whom 92 ESA were identified on the global STAR maps, with 73 of 83 targeted sites demonstrating an ablation response (24 AF termination and 49 CL slowing). Sixty-one out of 73 (83.6%) ESA were also identified on the sequential STAR maps. These showed greater consistency (P < .001), were seen pre- and post-PVI (P < .001) and were more likely to be associated with AF termination on ablation (P = .007). The sensitivity and specificity of sequential mapping for the detection of ESA with an ablation response was 84.9% (95% confidence interval [CI] = 74.6-92.2) and 90.0% (95% CI = 55.5-99.8), respectively. During a follow-up of 19.4 ± 3.7 months, 28 (80%) patients were free from AF/atrial tachycardia. CONCLUSIONS: STAR mapping consistently identified ESA in all patients and the ablation response was compatible with ESA being driver sites. Mechanistically important ESA were successfully identified using sequential recordings.

Phylogeny of Paullinia L. (Paullinieae: Sapindaceae), a diverse genus of lianas with dynamic fruit evolution.

Paullinia L. is a genus of c. 220 mostly Neotropical forest-dwelling lianas that display a wide diversity of fruit morphologies. Paullinia resembles other members of the Paullinieae tribe in being a climber with stipulate compound leaves and paired inflorescence tendrils. However, it is distinct in having capsular fruits with woody, coriaceous, or crustaceous pericarps. While consistent in this basic plan, the pericarps of Paullinia fruits are otherwise highly variable-in some species they are winged, whereas in others they are without wings or covered with spines. With the exception of the water-dispersed indehiscent spiny fruits of some members of Paullinia sect. Castanella, all species are dehiscent, opening their capsules while they are still attached to the branch, to reveal arillate animal-dispersed seeds. Here we present a molecular phylogeny of Paullinia derived from 11 molecular markers, including nine newly-developed single-copy nuclear markers amplified by microfluidics PCR. This is the first broadly sampled molecular phylogeny for the genus. Paullinia is supported as monophyletic and is sister to Cardiospermum L., which together are sister to Serjania Mill + Urvillea Kunth. We apply this novel phylogenetic hypothesis to test previous infrageneric classifications and to infer that unwinged fruits represent the ancestral condition, from which there were repeated evolutionary transitions and reversals. However, because the seeds of both winged and unwinged fruits are dispersed by animals, we conclude that the repeated transitions in fruit morphology may relate to visual display strategies to attract animal dispersers, and do not represent transitions to wind dispersal.

A quantitative comparison of the chemo- and radiotoxicity of uranium at different enrichment grades.

OBJECTIVE: The radiotoxic effects of uranium are often in the focus of the public fears but the chemical toxic effects of uranium are reported to surpass radiation effects. As there is no uranium isotope that is not radioactive, it is not possible to study chemical effects fully independently from radiation effects. In order to quantitate and compare radio- and chemotoxicity, we determined the median lethal doses of uranium due to its chemical toxicity and calculated the absorbed radiological doses resulting from the ingestion or inhalation of corresponding amounts depending on the isotopic enrichment grade. Committed effective doses over 50 years are related to the stochastic health effects like cancer occurrence and can be converted to a loss of statistical life time (mean loss 0.4 day / mSv). The equivalent doses absorbed within a short time frame permits conclusion on the induction of deterministic effects (e.g. acute radiation sickness). METHOD: Simulations were based on the biokinetic models of the International Commission for Radioprotection and performed using Integrated Modules for Bioassay Analysis software. Results were compared with the doses given by the calculator of the WISE uranium project. The fractions of the total doses absorbed within different time periods were derived from the respective areas under the activity-time curves in the whole body. RESULTS: The distribution of the total dose on the organs and tissues depends on the invasion pathway and the solubility of the compound. In the case of inhalation, the absorption of the total dose is more protracted than after ingestion. The incorporation of depleted or natural uranium in lethal amounts due to nephrotoxicity does not lead to deterministic radiation effects and is associated with committed effective doses reaching at most about 200 mSv (proposed possible threshold for therapeutic interventions after accidental radionuclide incorporation). The inhalation of low enriched uranium leads to higher effective doses up to 690 mSv, but they are still insufficient to cause acute deterministic effects. Even highly enriched uranium seems not to induce radiation nephropathy, but deterministic effects on the hematopoetic system cannot be excluded in particularly sensitive patients. But the equivalent doses to the lungs associated with the inhalation of poorly soluble compounds of highly enriched uranium are in a range that may induce radiation pneumonitis. CONCLUSION: Our findings give clear evidence that for depleted and natural uranium chemical toxicity is much more marked than radiotoxicity. However, this conclusion must not be drawn for enriched and in particular highly enriched compounds that besides stochastic effects may even cause deterministic radiation effects.