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PubMed1981

A compartmental model for the uptake of chlorphentermine in isolated perfused rat lung.

Equilibrium binding studies in vitro have established that chlorphentermine (CP) can be accumulated in rat lung by both binding and partitioning. Kinetic analysis of CP uptake in the isolated organ assuming an exponential process also suggests two separate mechanisms, one being saturable binding or transport, and the other, non-saturable partitioning. The present study was concerned with an alternative compartmental representation of the uptake process, and the validity of conclusions based on an exponential model. A three compartment model was finally selected which explain ed the observed uptake over a wide range of CP perfusate concentrations (2.5 x 10(-7) - 2.5 x 10(-5) mol/L) to within experimental error; it consisted of a binding and partitioning compartment in addition to one associated with the vascular bed. At low perfusate concentrations (2.5 x 10(-7) mol/L) uptake was essentially due to binding, while at higher perfusate concentrations (2.5 x 10(-5) mol/L) most uptake was due to partitioning. The total number of kinetically estimated binding sites (0.109 mumol/g) was less than that found by equilibrium dialysis for lung homogenates in vitro (8.3 mumol/g), suggesting an accessibility limitation for binding sites in the isolated preparation receiving a brief (10 min) perfusion. The data also indicate that there are probably two classes of binding sites or regional concentration of CP in the lung. It is proposed that interpretation of exponential model parameters may be problematical.

Animals↗

PubMed2007

Membrane thickness design of implantable bio-MEMS sensors for the in-situ monitoring of blood flow.

This paper presents some ideas for the membrane thickness design of of implantable bio-micro-electro-mechanical systems (bio-MEMS) for the in situ monitoring of blood flow. The objective is to develop a smart wireless sensing unit for non-invasive early stenosis detection in heart bypass grafts. The design includes considerations of nonlinear material models, multiscale blood flows, and appropriate analyical models for data interpretation, as well as preliminary studies of the pressure and flow sensing concepts. The paper also examines the use of surface coatings for the design on biocompatibility and non-adhesion of blood platelets and constituents. The implications of the results are discussed for in vivo deployment of such sensor systems.

Animals↗

PubMed2003

Tenofovir resistance and resensitization.

Human immunodeficiency viruses in 321 samples from tenofovir-naïve patients were retrospectively evaluated for resistance to this nucleotide analogue. All virus strains with insertions between amino acids 67 and 70 of the reverse transcriptase (n = 6) were highly resistant. Virus strains with the Q151M mutation were divided into susceptible (n = 12) and highly resistant (n = 8) viruses. This difference was due to the absence or presence of the K65R mutation, which was confirmed by site-directed mutagenesis. Viral clones with various combinations of the mutations M41L, K70R, L210W, and T215F or T215Y were analyzed for cross-resistance induced by thymidine analogue mutations (TAMs). The levels of increased resistance induced by single, double, and triple mutations at the indicated positions could be ranked as follows: for mutants with single mutations, mutations at positions 41 > 215 > 70; for mutants with double mutations, mutations at positions 41 and 215 > 70 and 215 = 210 and 215 > 41 and 70; for mutants with triple mutations, mutations at positions 41, 210, and 215 > 41, 70, and 215. Viral clones with M184V or M184I exhibited slightly increased susceptibilities to tenofovir (0.7-fold). Almost all clones with TAM-induced resistance were resensitized when M184V was present (P < 0.001). Among the viruses in the clinical samples, the rate of tenofovir resistance significantly increased with the number of TAMs both in the samples with 184M and in those with 184V (P = 0.005 and P = 0.003, respectively). A resensitizing effect of M184V was confirmed for all samples exhibiting at least one TAM (P = 0.03). However, accumulation of at least two TAMs resulted in more than 2.0-fold reduced susceptibility to tenofovir, irrespective of the presence of M184V. Decision tree building, a classical machine learning technique, was used to generate models for the interpretation of mutations with respect to tenofovir resistance. The application of previously proposed cutoffs for a reduced response to therapy and treatment failure demonstrated the central roles of positions 215 and 65 for 1.5- and 4.0-fold reduced susceptibilities, respectively. Thus, clinically relevant resistance may be conferred by the accumulation of TAMs, and the resensitizing effect of M184V should be considered only minor.

Adenine↗

PubMed2002

Experimental assessment and modelling of nitrate utilisation for primary sludge.

Electron acceptor utilisation potential of filtered primary sludge under anoxic conditions was experimentally investigated. Major kinetic and stoichiometric parameters were assessed by means of model evaluation of nitrate profile obtained in batch reactors. ASM1, modified for endogenous decay, and ASM3 were used for model simulation. Both models provided consistent interpretation of experimental data. ASM1 yielded mu(H) and Y(HD) values of 6.1 d(-1) and 0.64 g cell COD(g COD)(-1) respectively for heterotrophic anoxic growth. The corresponding storage mechanism associated with ASM3 could be characterised by a k(STO) of 13 g COD (g COD d)(-1) and a Y(STO) of 0.78 g COD(g COD)(-1). The high k(STO) value suggests re-evaluation of the concept of readily biodegradable substrate as defined in ASM3 and tested in the study.

Biodegradation, Environmental↗

PubMedDate not supplied

Elastic properties of the composite outer hair cell wall.

We propose a mathematical model for analyses of the elastic properties of the wall of the outer hair cell (OHC) in the inner ear. The model reflects the properties of the major components of the OHC wall: the subsurface cisternae, the cortical lattice, the plasma membrane, and the radial pillars. The wall is treated as a composite consisting of three elastic cylindrical shells. Two inner shells, isotropic and orthotropic/ are adjacent to each other, and the outermost isotropic shell is connected to the combined inner shell by elastic springs. We derive Flugge-type equations for the composite wall and apply the model to the interpretation of the experiments with axial loading and with inflation of the OHC. We derive expressions for the axial stiffness and the wall strains measured in these experiments in terms of the elastic properties of the wall components. We also consider a conceivable experiment with torsion of the OHC and obtain relations between the torque (the axial reaction) and the angle of torsion. These solutions provide necessary information for the future determination of the OHC elastic properties.

Biomechanical Phenomena↗

PubMed2005

High pressure reveals that the stability of interdimeric contacts in the R- and T-state of HbA is influenced by allosteric effectors: Insights from computational simulations.

The molecular details of the mechanism of action of allosteric effectors on hemoglobin oxygen affinity are not clearly understood. The global allostery model proposed by Yonetani et al. suggests that the binding of allosteric effectors can take place both in the R and T states and that they influence oxygen affinity through inducing global tertiary changes in the subunits. Recently published high pressure studies yielded dissociation constants at atmospheric pressure that showed a stabilizing effect of heterotropic allosteric effectors on the dimer interface in the R state, and a more pronounced destabilizing effect in a T state model. In the present work, we report on computational modeling used to interpret the high pressure experimental data. We show structural changes in the hemoglobin interdimeric interfaces, indicative of a global tertiary structural change induced by the binding of allosteric effectors. We also show that the number of water molecules bound at the interface is significantly influenced by binding effectors in the T state in accordance with the experimental data. Our results suggest that the binding of effectors at definite sites leads to tertiary changes that propagate to the interfaces and results in overall structural re-organizations.

Allosteric Regulation↗

PubMed1986

Dynamic variations of the brain cell microenvironment in relation to neuronal hyperactivity.

Neuronal hyperactivity has been shown to cause transient changes in ionic concentrations as well as in the volume of the extracellular space (ECS). During enhanced neuronal activity in the sensorimotor cortex of the cat, increases in the extracellular K+ concentration to a ceiling value of 10 mM have been observed concomitant with decreases in the Na+ concentration of similar magnitude. Simultaneously, the Cl- concentration rose steadily during the enhanced neuronal activity, and the extracellular space decreased by about 30%. A mathematical model allowed the interpretation of these concentration and volume changes as results of K+ release by active neurons in exchange for Na+, removal of K+ from the ECS by spatial glial buffering and movements of KCl into glial cells, as well as cell swelling due to metabolically induced transient increases in cellular osmolarity. Similar mechanisms have also been found to operate in gliotic scar tissue, where glial cells appeared to function the same way as in normal cortex, in rat hippocampal slices, and in preparations studied by other investigators.

Animals↗

PubMed2006

Deformity of the femoral head following vascular infarct in piglets.

BACKGROUND: In Legg-Calvé-Perthes disease (LCPD), 4 major patterns (coxa plana, coxa magna, coxa vara, subluxation) of the femoral head are commonly observed. However, direct observation of pathological specimens is rarely possible. An animal model of LCPD may clarify the pathogenesis of femoral head deformity. ANIMALS AND METHODS: In 26 piglets, we interrupted the vascular supply to the capital femoral epiphysis by cutting the ligamentum teres and ligating the femoral neck containing the epiphyseal artery. 6-7 piglets in each experimental group were killed at early (2 and 4 weeks: P2 and P4), intermediate (12 weeks: P12), and late (20 weeks: P20) periods. We examined the extracted femoral heads macroscopically and radiographically. RESULTS: The mean decrease in epiphyseal height was 1.5 mm, 4.1 mm, 5.0 mm, and 7.5 mm in P2, P4, P12 and P20, respectively (rs = 0.76, p = 0.002). The mean increase of diameter was 4.1 mm, 6.9 mm, and 6.8 mm in P4, P12 and P20, respectively. Decrease of the articulotrochanteric distance was mild in P2 and P4, and severe in P12 and P20. Subluxation of the femoral head was observed only in P12 and P20 piglets. INTERPRETATION: The piglet model of LCPD was useful in the early stage of devascularization for investigation of the developmental pattern of femoral head deformity. However, when the piglets had grown to 20 weeks old or more--that is, to full skeletal maturity--the femoral head and acetabulum showed severe deformities that were most likely caused by heavy body weight.

Acetabulum↗

PubMed1986

Simulation of biomolecular diffusion and complex formation.

Diffusion is a phenomenon of very widespread importance in molecular biophysics. Diffusion can determine the rates and character of the assembly of multisubunit structures, the binding of ligands to receptors, and the internal motions of molecules and assemblies that involve solvent surface displacements. Current computer simulation techniques provide much more detailed descriptions of diffusional processes than have been available in the past. Models can be constructed to include such realistic features as structural subunits at the submolecular level (domains, monomers, or atoms); detailed electrostatic charge distributions and corresponding solvent-screened inter- and intramolecular interactions; and hydrodynamic interactions. The trajectories can be analyzed either to provide direct information on biomolecular function (e.g., the bimolecular rate constant for formation of an electron-transfer complex between two proteins), or to provide or test models for the interpretation of experimental data (e.g., the time dependence of fluorescence depolarization for segments of DNA). Here, we first review the theory of diffusional simulations, with special emphasis on new techniques such as those for obtaining transport properties of flexible assemblies and rate constants of diffusion-controlled reactions. Then we survey a variety of recent applications, including studies of large-scale motion in DNA segments and substrate "steering" in enzyme-substrate binding. We conclude with a discussion of current work (e.g., formation of protein complexes) and possible areas for future work.

Biopolymers↗

PubMed2005

Statistical determinants of dendritic morphology in hippocampal pyramidal neurons: A hidden Markov model.

Dendritic structure is traditionally characterized by distributions and interrelations of morphometric parameters, such as Sholl-like plots of the number of branches versus dendritic path distance. However, how much of a given morphology is effectively captured by any statistical description is generally unknown. In this work, we assemble a small number of standard geometrical parameters measured from experimental data in a simple stochastic algorithm to describe the dendrograms of hippocampal pyramidal cells. The model, consistent with the hidden Markov framework, is feedforward, local, and causal. It relies on two "hidden" local variables: the expected number of terminal tips in a given subtree, and the current path distance from the soma. The algorithm generates dendrograms that statistically reproduce all morphological essentials of dendrites observed in real neurons, including the distributions of branching and termination points, branch lengths, membrane area, topological asymmetry, and (assuming passive membrane parameters within physiological range) electrotonic characteristics. Thus, this algorithm and the small number of its morphometric parameters constitute a remarkably complete description of the dendrograms of hippocampal pyramidal cells. Specifically, it is found that CA3 and CA1 basal dendrites and CA3 apical dendrites can each be described as homogeneous morphological classes. In contrast, the accurate generation of CA1 apical dendrites necessitates the separate sampling of two types of branches, main and oblique, suggesting their derivations from different developmental mechanisms (terminal and interstitial growth, respectively). We further offer a plausible biophysical interpretation of the model hidden variables, relating them to microtubules and other intracellular resources.

Algorithms↗

PubMed2005

A model of executive functions in very old community dwellers: evidence from The Sydney Older Persons Study.

Executive functions (EF) are generally described as showing greater sensitivity to ageing compared to other cognitive domains. Numerous pitfalls exist in the measurement of EF due to loose definitions and lack of agreement on these concepts and uncertainty about the constructs being measured. To this date, the validity of EF constructs has not been examined in the old-old population. Performance of 122 randomly selected community dwellers aged between 81 and 97 years on nine EF tasks (seven of which commonly used in clinical practice) was examined. Factor analytic procedures using structural equation modelling (SEM) failed to satisfactorily explain the data according to four a priori models, the first two models reflecting two major constructs commonly found in current models of EF ("set" and "switch"), the last two reflecting task requirements. The best measure for each task was extracted using statistically driven analyses and further SEM revealed an orthogonal two-factor model which provided a good fit of the data, explaining between 8% and 25% of the total variance. This model can be interpreted in terms of reactive and spontaneous flexibility as proposed by Eslinger and Grattan (1993), with the first factor reflecting internally driven strategies and the second environment dependent strategies. Furthermore, these findings also suggest that: (a) unique tasks of EF may not be applicable to all age groups due to individual experience and changes in strategies; and (b) current clinical instruments may be inadequate to measure very specific aspects of the complex construct of EF.

Aged↗

PubMed2006

Bsoft: image processing and molecular modeling for electron microscopy.

Bsoft is a software package written for image processing of electron micrographs, interpretation of reconstructions, molecular modeling, and general image processing. The code is modularized to allow for rapid testing and deployment of new processing algorithms, while also providing sufficient infrastructure to deal with many file formats and parametric data. The design is deliberately open to allow interchange of information with other image and molecular processing software through a standard parameter file (currently a text-based encoding of parameters in the STAR format) and its support of multiple image and molecular formats. It also allows shell scripting of processes and allows subtasks to be distributed across multiple computers for concurrent processing. Bsoft has undergone many modifications and advancements since its initial release [Heymann, J.B., 2001. Bsoft: image and molecular processing in electron microscopy. J. Struct. Biol. 133, 156-169]. Much of the emphasis is on single particle analysis and tomography, and sufficient functionality is available in the package to support most needed operations for these techniques. The key graphical user interface is the program bshow, which displays an image and is used for many interactive purposes such as fitting the contrast transfer function or picking particles. Bsoft also offers various tools to manipulate atomic structures and to refine the fit of a known molecular structure to a density in a reconstruction.

Algorithms↗

PubMed1998

A microdosimetric-kinetic theory of the dependence of the RBE for cell death on LET.

Experiments with cultured mammalian cells exposed to ionizing radiation of varying LET are examined in the context of a microdosimetric-kinetic (MK) model of radiation induced mammalian. cell killing similar to the site model of the theory of dual radiation action. The experimentally measured RBE, in the limit of zero dose, increases linearly with LET for LET less than a value that lies in the range of about 40-90 keV per micron. It is shown that the tendency of the RBE to increase linearly with LET can be explained as a result of the random variation of specific energy among microscopic sized domains (sites), into which the nucleus may be partitioned, and the effect of this variation on the formation of lethal lesions by pairwise combination of repairable primary lesions in DNA. the microscopic subunits corresponding to a site have diameter in the range of 0.56-0.75 microns. The linearity of RBE with increasing LET implies that value of the quadratic parameter of the linear-quadratic survival relation (beta) is constant, at least for LET low enough to be in the linear range, and this in turn implies the production of primary DNA lesion, likely double strand breaks, does not increase with LET. the experiments, interpreted with MK model, also imply that the repairability and potential for lethality of the primary DNA lesion does not change with variation of LET within the linear range. The failure of RBE to maintain its linear increase for higher values of LET, and the resulting RBE maximum at about 100 keV per micron, are likely primarily due to the departure of the distribution of lethal lesions among cells from the Poisson distribution. Some implications concerning the use of radiation to treat cancer are noted.

Animals↗

PubMed2005

Delayed disease progression after allogeneic cell vaccination in hormone-resistant prostate cancer and correlation with immunologic variables.

PURPOSE: There are a significant number of patients with asymptomatic hormone-resistant prostate cancer who have increasing prostate-specific antigen (PSA) levels but little or no evaluable disease. The immunogenicity and minimal toxicity associated with cell-based vaccine therapy makes this approach attractive for these patients. EXPERIMENTAL DESIGN: We have evaluated a vaccine comprising monthly intradermal injection of three irradiated allogeneic prostate cell lines (8 x 10(6) cells each) over 1 year. The first two doses were supplemented with bacille Calmette-Guérin as vaccine adjuvant. Twenty-eight hormone-resistant prostate cancer patients were enrolled. Patients were assessed clinically and PSA levels were measured monthly. Radiologic scans (X-ray, computed tomography, and bone scan) were taken at baseline and at intervals throughout the treatment period. Comprehensive monthly immunologic monitoring was undertaken including proliferation studies, activation markers, cytokine protein expression, and gene copy number. This longitudinal data was analyzed through predictive modeling using artificial neural network feed-forward/back-propagation algorithms with multilayer perceptron architecture. RESULTS: Eleven of the 26 patients showed statistically significant, prolonged decreases in their PSA velocity (PSAV). None experienced any significant toxicity. Median time to disease progression was 58 weeks, compared with recent studies of other agents and historical control values of around 28 weeks. PSAV-responding patients showed a titratable T(H)1 cytokine release profile in response to restimulation with a vaccine lysate, while nonresponders showed a mixed T(H)1 and T(H)2 response. Furthermore, immunologic profile correlated with PSAV response by artificial neural network analysis. We found predictive power not only in expression of cytokines after maximal stimulation with phorbol 12-myristate 13-acetate, but also the method of analysis (qPCR measurement of IFN-gamma > qPCR measurement tumor necrosis factor-alpha > protein expression of IFN-gamma > protein expression of interleukin 2). CONCLUSIONS: Whole cell allogeneic vaccination in hormone-resistant prostate cancer is nontoxic and improves the natural history of the disease. Longitudinal changes in immunologic function in vaccinated patients may be better interpreted through predictive modeling using tools such as the artificial neural network rather than periodic "snapshot" readouts.

Aged↗

PubMed2005

UHMWPE wear debris upregulates mononuclear cell proinflammatory gene expression in a novel murine model of intramedullary particle disease.

BACKGROUND: We examined the effects of ultra-high molecular weight polyethylene (UHMWPE) particles on mononuclear cell proinflammatory gene expression in a novel murine model. We hypothesized that mononuclear cell gene transcription of tumor necrosis factor-alpha (TNF-alpha), interleukin-1 beta (IL-1beta), interleukin-6 (IL-6) and macrophage chemoattractant protein-1 (MCP-1) would be upregulated by the addition of polyethylene particles in this murine intramedullary rod model. MATERIAL AND METHODS: The model involved a stainless steel Kirschner wire inserted retrograde with a line-to-line fit in bilateral femora of C57bl/6 mice. Additionally, the right femora were injected with 3 x 10(9) UHMWPE particles. Mononuclear marrow cells were isolated by bone marrow aspiration and Ficoll-Paque centrifugation at 2, 4 and 10 weeks post-surgery. Total RNA was isolated and real-time RT-PCR was performed to quantify gene expression. Histological specimens of explanted femora were also analyzed to track the changes in periprosthetic tissue. RESULTS: UHMWPE particles stimulated gene transcription in mononuclear cells when examined at 2, 4 and 10 weeks post-surgery, compared to the rod-only group. Relative levels of IL-1beta and MCP-1 mRNA increased in a linear fashion over the 10-week time-course. IL-6 mRNA showed increased expression which peaked at 4 weeks. TNF-alpha mRNA expression was variable and reached a minimum at 4 weeks. The addition of UHMWPE particles stimulated ingress of macrophages and multinuclear cells of macrophage origin to the bone-implant interface. INTERPRETATION: In this model, a single bolus of UHMWPE particles had a long-term effect on gene transcription in mononuclear cells which perpetuated a chronic inflammatory state. This murine model of intramedullary particle-induced inflammation simulates periprosthetic events associated with implant wear in humans, and may contribute to a more mechanistic understanding of wear-debris associated prosthesis failure.

Animals↗

PubMed1993

Statistical model for fetal death, fetal weight, and malformation in developmental toxicity studies.

The purpose of this paper is to present a statistical model for analyzing the joint effects of exposure on fetal death, fetal weight, and malformation in a developmental toxicity study. In addition to allowing for the usual litter effect, the model allows for correlations between different outcomes measured on the same fetus. Fitting the model requires first focusing on non-live outcomes by modeling the probability of fetal death or resorption as a function of dose. Then outcomes among live fetuses are modeled using a two-stage regression approach. The first stage models fetal weight as a function of dose and the second stage models fetal malformation as a function of dose, as well as residuals from the weight model. The regression coefficients from the malformation model have intuitive interpretations in terms of correlations between littermates and between different outcomes measured within the same fetus. Not only does the approach provide a useful way to investigate the relationship between adverse fetal outcomes, it also yields a natural framework for conducting quantitative risk assessment. A procedure is proposed for quantifying overall risk by incorporating the three outcomes in order to estimate safe dose levels and corresponding lower confidence limits. The method is illustrated using data from an experiment in mice conducted through the National Toxicology Program.

Abnormalities, Drug-Induced↗

PubMed2006

Simple stochastic fingerprints towards mathematical modeling in biology and medicine 2. Unifying Markov model for drugs side effects.

Most of present mathematical models for biological activity consider just the molecular structure. In the present article we pretend extending the use of Markov chain models to define novel molecular descriptors, which consider in addition other parameters like target site or biological effect. Specifically, this mathematical model takes into consideration not only the molecular structure but the specific biological system the drug affects too. Herein, a general Markov model is developed that describes 19 different drugs side effects grouped in eight affected biological systems for 178 drugs, being 270 cases finally. The data was processed by linear discriminant analysis (LDA) classifying drugs according to their specific side effects, forward stepwise was fixed as strategy for variables selection. The average percentage of good classification and number of compounds used in the training/predicting sets were 100/95.8% for endocrine manifestations, (18 out of 18)/(13 out of 14); 90.5/92.3% for gastrointestinal manifestations, (38 out of 42)/(30 out of 32); 88.5/86.5% for systemic phenomena, (23 out of 26)/(17 out of 20); 81.8/77.3% for neurological manifestations, (27 out of 33)/(19 out of 25); 81.6/86.2% for dermal manifestations, (31 out of 38)/(25 out of 29); 78.4/85.1% for cardiovascular manifestation, (29 out of 37)/(24 out of 28); 77.1/75.7% for breathing manifestations, (27 out of 35)/(20 out of 26) and 75.6/75% for psychiatric manifestations, (31 out of 41)/(23 out of 31). Additionally a back-projection analysis (BPA) was carried out for two ulcerogenic drugs to prove in structural terms the physical interpretation of the models obtained. This article develops a mathematical model that encompasses a large number of drugs side effects grouped in specifics biological systems using stochastic absolute probabilities of interaction ((A)pi(k)(j)) by the first time.

Drug-Related Side Effects and Adverse Reactions↗

PubMed2002

International issues on human health effects of exposure to chemical mixtures.

In this article, we highlight new developments and recent studies concerning adverse human health effects related to chemical mixtures. One group of activities comprises the development of a new computer program for analyzing mixture studies and a mathematical model as a basis for combination rules that predict the toxicity of mixtures. Other new activities in the area of experimental studies are the application of gene expression technologies in mixture research, and pattern recognition as a tool in safety evaluation of complex mixtures. A "bottom-up" approach for chemosensory detection of mixtures has recently been presented. Other topics include a method for the safety evaluation of natural flavoring complexes, and an evaluation of the possible health effects of the simultaneous intake of food additives. Examples of issues related to mixtures of airborne chemicals are potential interaction of fine particles and gaseous pollutants in ambient air, nasal cancer associated with inhaled chemical mixtures, and the recommendation of a limit value for volatile organic compounds. Topics of a more strategic nature include studies concerning the public health effects of large airports, and the development of criteria for a harmonized classification of chemical mixtures. This overview illustrates that strategies to tackle the safety evaluation of combined exposures and complex mixtures as well as models facilitating the interpretation of findings in the context of risk assessment of mixtures have become increasingly important. It is true that exposure of humans to chemical mixtures is the rule rather than the exception, and therefore health risk assessments should focus on mixtures and not on single chemicals. It is also true, however, that humans have learned to cope with exposure to huge numbers of chemicals simultaneously (food, water, air, soil, and consumer products). Therefore, in view of limited resources for toxicological research, the focus in toxicology should be on priority mixtures--priority being determined by (estimated) health risk (= toxicity and exposure).

Air Pollutants↗