Public health assessment : Railroad Avenue groundwater contamination, West Des Moines, Polk County, Iowa EPA facility ID: IA0001610963 (2004)

The Railroad Avenue groundwater contamination site (the site) is in West Des Moines, Polk County, Iowa. Located on approximately 120 acres. The site comprises mixed residential, industrial and commercial properties. Underneath the site, chlorinated volatile organic compounds (VOCs) have contaminatcd the shallow (i.e., 30-50 feet deep) groundwater. These compounds have compromised several shallow wells within the West Des Moines water works system. A contamination source, however, has not yet been identified. In 1993, routine water analysis by the City of West Des Moines identified 1, 2 cis-dichlorocthylcne (1, 2 cis-DCE) at a concentration of 1.2 μg/L (micrograms) per liter of water) in the water supply. Subsequently. several shallow municipal wells were found to be contaminated by VOCs, including 1. 2 cis-DCE, trichloroethylene (TCE), tetrachloroethylene (PCE) and benzene. Five of these wells have been taken out of service. Because of the impact on the West Des Moines water supply, the U.S. Environmental Protection Agency (USEPA) has assigned the site to the National Priorities List. Surface water und sediment at the site have not been impacted by the VOCs. Testing for VOCs in surface soils has not revealed any significant VOC contamination. Subsurface soils -- generally 8 feet or greater in depth -- are contaminated with VOCs, but at levels which should not present a health hazard. The past, present, and future health hazard category chosen for this site is no apparent public health hazard. This category is used when exposure to toxins might be occurring or might have occurrcd in the past, but at levels below any known health hazard. Analysis of available environmental data has not revealed that residental or commercial water customers are or have been exposed to VOCs at concentrations that might cause any adverse health effects.

Timing and intensity of precommercial thinning and their effects on the first commercial thinning in Scots pine stands

Abstract

Etude des niveaux de concentration d'hydrocarbures aromatiques polycycliques (HAPs) dans la poussière de bois et des marqueurs biologiques d'effets génotoxiques chez les travailleurs du bois

L'exposition aux poussières de bois est associé à un risque accru d'adénocarcinomes des fosses nasales et des sinus paranasaux (SNC, 'Sinonasal cancer') chez les travailleurs du bois. Les poussières de bois sont ainsi reconnues comme cancérogènes avérés pour l'homme par le Centre international de Recherche sur le Cancer (CIRC). Toutefois, l'agent causal spécifique et le mécanisme sous-jacent relatifs au cancer lié aux poussières de bois demeurent inconnus. Une possible explication est une co-exposition aux poussières de bois et aux Hydrocarbures Aromatiques Polycycliques (HAP), ces derniers étant potentiellement cancérogènes. Dans les faits, les travailleurs du bois sont non seulement exposés aux poussières de bois naturel, mais également à celles générées lors d'opérations effectuées à l'aide de machines (ponceuses, scies électriques, etc.) sur des finitions de bois (bois traités) ou sur des bois composites, tels que le mélaminé et les panneaux de fibres à densité moyenne (MDF, 'Medium Density Fiberboard'). Des HAP peuvent en effet être générés par la chaleur produite par l'utilisation de ces machines sur la surface du bois. Les principaux objectifs de cette thèse sont les suivants: (1) quantifier HAP qui sont présents dans les poussières générées lors de diverses opérations courantes effectuées sur différents bois (2) quantifier l'exposition individuelle aux poussières de bois et aux HAP chez les travailleurs, et (3) évaluer les effets génotoxiques (dommages au niveau de l'ADN et des chromosomes) due à l'exposition aux poussières de bois et aux HAP. Cette thèse est composée par une étude en laboratoire (objectif 1) et par une étude de terrain (objectifs 2 et 3). Pour l'étude en laboratoire, nous avons collecté des poussières de différents type de bois (sapin, MDF, hêtre, sipo, chêne, bois mélaminé) générées au cours de différentes opérations (comme le ponçage et le sciage), et ceci dans une chambre expérimentale et dans des conditions contrôlées. Ensuite, pour l'étude de terrain, nous avons suivi, dans le cadre de leur activité professionnelle, 31 travailleurs de sexe masculin (travailleurs du bois et ébenistes) exposés aux poussières de bois pendant deux jours de travail consécutifs. Nous avons également recruté, comme groupe de contrôle, 19 travailleurs non exposés. Pour effectuer une biosurveillance, nous avons collecté des échantillons de sang et des échantillons de cellules nasales et buccales pour chacun des participants. Ces derniers ont également rempli un questionnaire comprenant des données démographiques, ainsi que sur leur style de vie et sur leur exposition professionnelle. Pour les travailleurs du bois, un échantillonnage individuel de poussière a été effectué sur chaque sujet à l'aide d'une cassette fermée, puis nous avons évalué leur exposition à la poussière de bois et aux HAP, respectivement par mesure gravimétrique et par Chromatographie en phase gazeuse combinée à la spectrométrie de masse. L'évaluation des dommages induits à l'ADN et aux chromosomes (génotoxicité) a été, elle, effectuée à l'aide du test des micronoyaux (MN) sur les cellules nasales et buccales et à l'aide du test des comètes sur les échantillons de sang. Nos résultats montrent dans la poussière de la totalité des 6 types de bois étudiés la présence de HAP (dont certains sont cancérogènes). Des différences notoires dans les concentrations ont été néanmoins constatées en fonction du matériau étudié : les concentrations allant de 0,24 ppm pour la poussière de MDF à 7.95 ppm pour le mélaminé. Nos résultats montrent également que les travailleurs ont été exposés individuellement à de faibles concentrations de HAP (de 37,5 à 119,8 ng m-3) durant les opérations de travail du bois, alors que les concentrations de poussières inhalables étaient relativement élevés (moyenne géométrique de 2,8 mg m-3). En ce qui concerne la génotoxicité, les travailleurs exposés à la poussière de bois présentent une fréquence significativement plus élevée en MN dans les cellules nasales et buccales que les travailleurs du groupe témoin : un odds ratio de 3.1 a été obtenu pour les cellules nasales (IC 95% : de 1.8 à 5.1) et un odds ratio de 1,8 pour les cellules buccales (IC 95% : de 1.3 à 2.4). En outre, le test des comètes a montré que les travailleurs qui ont déclaré être exposés aux poussières de MDF et/ou de mélaminé avaient des dommages à l'ADN significativement plus élevés que les deux travailleurs exposés à la poussière de bois naturel (sapin, épicéa, hêtre, chêne) et que les travailleurs du groupe témoin (p <.01). Enfin, la fréquence des MN dans les cellules nasales et buccales augmentent avec les années d'exposition aux poussières de bois. Par contre, il n'y a pas de relation dose-réponse concernant la génotoxicité due à l'exposition journalière à la poussière et aux HAP. Cette étude montre qu'une exposition aux HAP eu bien lieu lors des opérations de travail du bois. Les travailleurs exposés aux poussières de bois, et donc aux HAP, courent un risque plus élevé (génotoxicité) par rapport au groupe témoin. Étant donné que certains des HAP détectés sont reconnus potentiellement cancérogènes, il est envisageable que les HAP générés au cours du travail sur les matériaux de bois sont un des agents responsables de la génotoxicité de la poussière de bois et du risque élevé de SNC observé chez les travailleurs du secteur. Etant donné la corrélation entre augmentation de la fréquence des MN, le test des micronoyaux dans les cellules nasales et buccales constitue sans conteste un futur outil pour la biosurveillance et pour la détection précoce du risque de SNC chez les travailleurs. - Exposures to wood dust have been associated with an elevated risk of adenocarcinomas of the Dasal cavity and the paranasal sinuses (sinonasal cancer or SNC) among wood workers. Wood dust is recognized as a human carcinogen by the International Agency for Research on Cancer. However, the specific cancer causative agent(s) and the mechanism(s) behind wood dust related carcinogenesis remains unknown. One possible explanation is a co-exposure to wood dust and polycyclic aromatic hydrocarbons (PAH), the latter being carcinogenic. In addition, wood workers are not only exposed to natural wood but also to wood finishes and composite woods such as wood melamine and medium density fiber (MDF) boards during the manipulation with power tools. The heat produced by the use of power tools can cause the generation of PAH from wood materials. The main objectives of the present thesis are to: (1) quantify possible PAH concentrations in wood dust generated during various common woodworking operations using different wood materials; (2) quantify personal wood dust concentrations and PAH exposures among wood workers; and (3) assess genotoxic effects (i.e., DNA and chromosomal damage) of wood dust and PAH exposure in wood workers. This thesis is composed by a laboratory study (objective 1) and a field study (objectives 2 and 3). In the laboratory study we collected wood dust from different wood materials (fir, MDF, beech, mahagany, oak, and wood melamine) generated during different wood operations (e.g., sanding and sawing) in an experimental chamber under controlled conditions. In the following field study, we monitored 31 male wood workers (furniture and construction workers) exposed to wood dust during their professional activity for two consecutive work shifts. Additionally, we recruited 19 non exposed workers as a control group. We collected from each participant blood samples, and nasal and buccal cell samples. They answered a questionnaire including demographic and life-style data and occupational exposure (current and past). Personal wood dust samples were collected using a closed-face cassette. We used gravimetrie analysis to determine the personal wood dust concentrations and capillary gas chromatography - mass spectrometry analysis to determine PAH concentrations. Genotoxicity was assessed with the micronucleus (MN) assay for nasal and buccal cells and with the comet assay for blood samples. Our results show that PAH (some of them carcinogenic) were present in dust from all six wood materials tested, yet at different concentrations depending on the material. The highest concentration was found in dust from wood melamine (7.95 ppm) and the lowest in MDF (0.24 ppm). Our results also show that workers were individually exposed to low concentrations of PAHs (37.5-119.8 ng m"3) during wood working operations, whereas the concentrations of inhalable dust were relatively high (geometric mean 2.8 mg m"3). Concerning the genotoxicity, wood workers had a significantly higher MN frequency in nasal and buccal cells than the workers in the control group (odds ratio for nasal cells 3.1 (95%CI 1.8-5.1) and buccal cells 1.8 (95%CI 1.3-2.4)). Furthermore, the comet assay showed that workers who reported to be exposed to dust from wooden boards (MDF and wood melamine) had significantly higher DNA damage than both the workers exposed to natural woods (fir, spruce, beech, oak) and the workers in the control group (p < 0.01). Finally, MN frequency in nasal and buccal cells increased with increasing years of exposure to wood dust. However, there was no genotoxic dose-response relationship with the per present day wood dust and PAH exposure. This study shows that PAH exposure occurred during wood working operations. Workers exposed to wood dust, and thus to PAH, had a higher risk for genotoxicity compared to the control group. Since some of the detected PAH are potentially carcinogenic, PAH generated from operations on wood materials may be one of the causative agents for the observed increased genotoxicity in wood workers. Since increased genotoxicity is manifested in an increased MN frequency, the MN assay in nasal and buccal cells may become a relevant biomonitoring tool in the future for early detection of SNC risk.

Major mite allergen Der f 1 concentration is reduced in buildings with improved energy performance.

BACKGROUND: Environmental conditions play a crucial role in mite growth, and optimal environmental control is key in the prevention of airway inflammation in chronic allergic rhinoconjunctivitis or asthma. OBJECTIVE: To evaluate the relationship between building energy performance and indoor mite allergen concentration in a cross-sectional study. METHODS: Major allergen concentration (Der f 1, Der p 1, mite group 2, Fel d 1 and Bla g 2) was determined by quantitative dot blot analysis from mattress and carpet dust samples in five buildings designed for low energy use (LEB) and in six control buildings (CB). Inhabitants had received 4 weeks prior to mite measurement a personal validated questionnaire related to the perceived state of health and comfort of living. RESULTS: Cumulative mite allergen concentration (with Der f 1 as the major contributor) was significantly lower in LEB as compared with CB both in mattresses and in carpets. In contrast, the two categories of buildings did not differ in Bla g 2 and Fel d 1 concentration, in the amount of dust and airborne mould collected. Whereas temperature was higher in LEB, relative humidity was significantly lower than in CB. Perceived overall comfort was better in LEB. CONCLUSIONS: Major mite allergen Der f 1 preferentially accumulates in buildings not specifically designed for low energy use, reaching levels at risk for sensitization. We hypothesize that controlled mechanical ventilation present in all audited LEB may favour lower air humidity and hence lower mite growth and allergen concentration, while preserving optimal perceived comfort.

Warranties used as a mean to promote commercial FOSS

From a business standpoint, this paper describes the point of view on the question of warranties of a FOSS editor doing business in a risk-averse market segment. It is based on 15-years experience of AdaCore in the safety-critical embedded industry. However, it is not only the point of view of a provider, as it also aims at demonstrating that the interests of providers and users are aligned in this area. From a legal point of view, the enforceability of these warranties will be partly covered, as well as the articulation between the license and the warranties on one hand, and the articulation between the license and the other contracts that can be created in a business relationship on the other hand.

Concentration of Airborne Staphylococcus aureus (MRSA and MSSA), Total Bacteria, and Endotoxins in Pig Farms.

Pigs are very often colonized by Staphylococcus aureus and transmission of such pig-associated S. aureus to humans can cause serious medical, hygiene, and economic problems. The transmission route of zoonotic pathogens colonizing farm animals to humans is not well established and bioaerosols could play an important role. The aim of this study was to assess the potential occupational risk of working with S. aureus-colonized pigs in Switzerland. We estimated the airborne contamination by S. aureus in 37 pig farms (20 nursery and 17 fattening units; 25 in summer, 12 in winter). Quantification of total airborne bacterial DNA, airborne Staphylococcus sp. DNA, fungi, and airborne endotoxins was also performed. In this experiment, the presence of cultivable airborne methicillin-resistant S. aureus (MRSA) CC398 in a pig farm in Switzerland was reported for the first time. Airborne methicillin-sensitive S. aureus (MSSA) was found in ~30% of farms. The average airborne concentration of DNA copy number of total bacteria and Staphylococcus sp. measured by quantitative polymerase chain reaction was very high, respectively reaching values of 75 (± 28) × 10(7) and 35 (± 9.8) × 10(5) copy numbers m(-3) in summer and 96 (± 19) × 10(8) and 40 (± 12) × 10(6) copy numbers m(-3) in winter. Total mean airborne concentrations of endotoxins (1298 units of endotoxin m(-3)) and fungi (5707 colony-forming units m(-3)) exceeded the Swiss recommended values and were higher in winter than in summer. In conclusion, Swiss pig farmers will have to tackle a new emerging occupational risk, which could also have a strong impact on public health. The need to inform pig farmers about biological occupational risks is therefore crucial.

Synthetic calibrators for the analysis of total metanephrines in urine: revisiting the conditions of hydrolysis.

BACKGROUND: The quantification of total (free+sulfated) metanephrines in urine is recommended to diagnose pheochromocytoma. Urinary metanephrines include metanephrine itself, normetanephrine and methoxytyramine, mainly in the form of sulfate conjugates (60-80%). Their determination requires the hydrolysis of the sulfate ester moiety to allow electrochemical oxidation of the phenolic group. Commercially available urine calibrators and controls contain essentially free, unhydrolysable metanephrines which are not representative of native urines. The lack of appropriate calibrators may lead to uncertainty regarding the completion of the hydrolysis of sulfated metanephrines, resulting in incorrect quantification. METHODS: We used chemically synthesized sulfated metanephrines to establish whether the procedure most frequently recommended for commercial kits (pH 1.0 for 30 min over a boiling water bath) ensures their complete hydrolysis. RESULTS: We found that sulfated metanephrines differ in their optimum pH to obtain complete hydrolysis. Highest yields and minimal variance were established for incubation at pH 0.7-0.9 during 20 min. CONCLUSION: Urinary pH should be carefully controlled to ensure an efficient and reproducible hydrolysis of sulfated metanephrines. Synthetic sulfated metanephrines represent the optimal material for calibrators and proficiency testing to improve inter-laboratory accuracy.

Genetic control of iron concentration in Mesoamerican and Andean common bean seeds

The objective of this work was to evaluate the main differences in the genetic control of the iron concentration in Mesoamerican and Andean common bean seeds, in early generations, and to select recombinants with a high iron concentration in the seeds. F1, F1 reciprocal, F2, F2 reciprocal, and backcross (BC11 and BC12) generations were produced by crosses between Mesoamerican (CNFP 10104 x CHC 01-175) and Andean (Cal 96 x Hooter) inbred lines. The expression of significant maternal effect was observed for the Mesoamerican gene pool. Iron concentration was higher in the seed coat of Mesoamerican common bean seeds (54.61 to 67.92%) and in the embryo of Andean common bean seeds (69.40 to 73.44%). High broad-sense heritability was obtained for iron concentration in Mesoamerican and Andean common bean seeds. Gains with the selection of higher magnitude, from 20.39 to 24.58%, are expected in Mesoamerican common bean seeds. Iron concentration in common bean seeds showed a continuous distribution in F2, which is characteristic of quantitative inheritance in Mesoamerican and Andean common bean seeds. Recombinants with high iron concentration in seeds can be selected in both Mesoamerican and Andean common bean hybrids.

Eräiden paperinvalmistuksessa käytettävien vahadispersioiden stabiilisuuden hallinta

Diplomityön tavoitteena oli selvittää millainen laaduntarkastus AKD-dispersioille tulisi suorittaa kuormien vastaanotossa ja tulisiko dispersioiden laatu tarkastaa uudelleen ennen annostelua. Tätä varten seurattiin toimituserien laadun tasaisuutta ja tarkasteltiin varastointiolosuhteiden vaikutusta dispersioiden säilyvyyteen. Lisäksi kartoitettiin dispersioiden käsittelyssä ja kartonginvalmistusprosessissa esiintyvien riskitekijöiden vaikutuksia kaupallisten dispersioiden stabiilisuuteen. Kirjallisuusosassa perehdyttiin kolloidisiin dispersioihin sekä niiden stabiilisuuteen vaikuttaviin tekijöihin. AKD-dispersiot valmistetaan emulgointitekniikoiden avulla, joten dispergointimenetelmien ohella käsiteltiin myös emulsioiden valmistamista. Lisäksi luotiin katsaus dispersioteknologian tärkeimpiin analyysimenetelmiin. Alkyyliketeenidimeerin osalta käsiteltiin emulgoinnin lisäksi vahan ja muiden lisäaineiden vaikutuksia dispersioiden stabiilisuuteen ja myös niiden merkitystä dispersioiden formuloinnissa. AKD-liimauksen osalta esiin tuotiin AKD:n tärkeimmät reaktiomekanismit, sillä ne liittyvät osittain myös dispersioiden stabiilisuuteen. Lopuksi luotiin lyhyt katsaus AKD-dispersioiden stabiilisuutta käsittelevään tutkimukseen, jota on toistaiseksi julkaistu varsin niukasti. Kokeellisessaosassa tarkastelun kohteeksi valittiin neljä kaupallista alkyyliketeenidimeerinvesidispersiota, joiden koostumus ja ominaisuudet selvitettiin perusteellisesti. Tarkoituksena oli auttaa ymmärtämään dispersioiden stabiilisuudessa mahdollisesti esiintyviä eroja. Laajamittainen dispersioiden karakterisointi näyttää olevan tarpeen ainakin otettaessa uutta AKD-laatua käyttöön, sillä dispersioiden koostumus ja ominaisuudet voivat vaihdella merkittävästi. AKD-dispersioiden laadussa esiintyi vaihtelua eri toimituserien välillä. Suurimmat vaihtelut havaittiin dispersioiden varaustiloissa ja partikkelikokojakaumissa. Laadun epätasaisuuden vuoksi vastaanottotarkastuksen merkitys korostuu. Vastaanottotarkastuksessa syytä olisi kiinnittää dispersion kuiva-ainepitoisuuden ohella sen viskositeettiin, varaustilaan, tehoainepitoisuuteen sekä rakenteeseen. Rakenteen tarkastelussa optinen mikroskooppi voi rutiininomaisessa seurannassa korvata partikkelikokojakauman määrittämisen. Varastointilämpötilan vaikutus dispersioidenlaatuun on merkittävä. Dispersiot säilyvät parhaiten viileässä, joten jos varastosäiliöissä ei ole jäähdytystä, on dispersioiden laadun tarkastus tarpeen myös ennen annostelua. Jotta dispersion kunnosta saadaan luotettava arvio, on viskositeetin määrittämiseen yhdistettävä vähintään rakenteen tarkastelu optisella mikroskoopilla. Mekaaninen rasitus voi dominoivasta stabilointimekanismistariippuen aiheuttaa dispersiossa hienoaineen muodostumista tai partikkelien flokkaantumista. Stabilointimekanismi vaikuttaa niin ikään partikkelien käyttäytymiseen korkeissa lämpötiloissa. Dispersioiden stabiilisuuden todettiin heikkenevän pH:n kohotessa emäksiselle alueelle. Elektrolyyttikonsentraatio vaikuttaa partikkelien mikroelektroforeettiseen ioniliikkuvuuteen merkittävästi. Kartonkikoneen märkäosan kemikaaleista anionisen retentioaineen (BMA) todettiin vuorovaikuttavan kationisten AKD-partikkelien kanssa selvimmin. Mikroelektroforeettisen ioniliikkuvuuden mittaaminen kiertovedessä todettiin tärkeäksi, sillä se kuvaa dispersion käyttäytymistä sen käyttöympäristössä.

Laimentimen merkitys metallien neste-nesteuutossa

Työssä tutkittiin korkean leimahduspisteen laimentimien vaikutusta uuton tehokkuuteen ja turvallisuuteen. Kirjallisuusosa sisältää katsauksen uuttolaitoksilla tapahtuneista suuronnettomuuksista, staattisen sähkön aiheuttamista vaaroista uuttolaitoksilla ja kaupallisesti saatavista laimentimista. Lisäksi kirjallisuusosassa tarkastellaan hiilivetyjen molekyylirakenteen vaikutusta niiden leimahduspisteeseen, haihtuvuuteen, viskositeettiin ja liuotinominaisuuksiin. Kokeellisessa osassa tutkittiin uuton tehokkuutta kuvaavia ominaisuuksia, joita olivat sekoituksen pisarakoko, faasien selkeytymisnopeus,uuton ja takaisinuuton kinetiikka, orgaanisen faasin viskositeetti ja tiheys. Uuttoliuosten turvallisuusominaisuuksia tutkittiin mittaamalla synteettisten uuttoliuosten ja laimentimien leimahduspisteitä sekä sähköisesti varattujen laimentimien relaksaatioaikoja. Korkean leimahduspisteen laimentimena käytettiin Orfom SX 11-laimenninta. Vertailukohteena käytettiin Shellsol D70- ja Escaid 100- laimentimia. Malliuuttona käytettiin kuparin uuttoa hydroksioksiimireagensilla happamasta sulfaattiliuoksesta. Kokeissa havaittiin, että korkean leimahduspisteen laimentimen viskositeetti oli huomattavasti suurempi kuin Shellsol D70- laimentimella. Korkea viskositeetti hidasti faasien selkeytymistä uutossa, mutta sillä ei ollut vaikutusta uuton kinetiikkaan tai sekoituksen aiheuttamaan pisarakokoon. Uuttoliuoksen reagenssipitoisuudella havaittiin olevan vaikutusta uuttoliuoksen leimahduspisteeseen, mutta uuttoliuoksen latausasteella ei havaittu olevan vaikutusta. Sähköisesti varattujen laimentimien varauksien relaksaatioajoissa oli hieman eroja, mutta relaksaatioajat olivat kaikilla laimentimilla liian pitkiä staattisen sähkön aiheuttaman vaaran poistamiseksi.

Ochratoxin A at nanomolar concentration perturbs the homeostasis of neural stem cells in highly differentiated but not in immature three-dimensional brain cell cultures.

Ochratoxin A (OTA), a fungal contaminant of basic food commodities, is known to be highly cytotoxic, but the pathways underlying adverse effects at subcytotoxic concentrations remain to be elucidated. Recent reports indicate that OTA affects cell cycle regulation. Therefore, 3D brain cell cultures were used to study OTA effects on mitotically active neural stem/progenitor cells, comparing highly differentiated cultures with their immature counterparts. Changes in the rate of DNA synthesis were related to early changes in the mRNA expression of neural stem/progenitor cell markers. OTA at 10nM, a concentration below the cytotoxic level, was ineffective in immature cultures, whereas in mature cultures it significantly decreased the rate of DNA synthesis together with the mRNA expression of key transcriptional regulators such as Sox2, Mash1, Hes5, and Gli1; the cell cycle activator cyclin D2; the phenotypic markers nestin, doublecortin, and PDGFRα. These effects were largely prevented by Sonic hedgehog (Shh) peptide (500ngml(-1)) administration, indicating that OTA impaired the Shh pathway and the Sox2 regulatory transcription factor critical for stem cell self-renewal. Similar adverse effects of OTA in vivo might perturb the regulation of stem cell proliferation in the adult brain and in other organs exhibiting homeostatic and/or regenerative cell proliferation.

Feasibility of Therapeutic Drug Monitoring (TDM) for Imatinib: Preliminary considerations on the dosage adjustment approach for CML patients enrolled in the Imatinib Concentration Monitoring (I-COME) study

Background: As imatinib pharmacokinetics are highly variable, plasma levels differ largely between patients under the same dosage. Retrospective studies in chronic myeloid leukemia (CML) patients showed significant correlations between low levels and suboptimal response, and between high levels and poor tolerability. Monitoring of plasma levels is thus increasingly advised, targeting trough concentrations of 1000 μg/L and above. Objectives: Our study was launched to assess the clinical usefulness of systematic imatinib TDM in CML patients. The present preliminary evaluation questions the appropriateness of dosage adjustment following plasma level measurement to reach the recommended trough level, while allowing an interval of 4-24 h after last drug intake for blood sampling. Methods: Initial blood samples from the first 9 patients in the intervention arm were obtained 4-25 h after last dose. Trough levels in 7 patients were predicted to be significantly away from the target (6 <750 μg/L, and 1 >1500 μg/L with poor tolerance), based on a Bayesian approach using a population pharmacokinetic model. Individual dosage adjustments were taken up in 5 patients, who had a control measurement 1-4 weeks after dosage change. Predicted trough levels were confronted to anterior model-based extrapolations. Results: Before dosage adjustment, observed concentrations extrapolated at trough ranged from 359 to 1832 μg/L (median 710; mean 804, CV 53%) in the 9 patients. After dosage adjustment they were expected to target between 720 and 1090 μg/L (median 878; mean 872, CV 13%). Observed levels of the 5 recheck measurements extrapolated at trough actually ranged from 710 to 1069 μg/L (median 1015; mean 950, CV 16%) and had absolute differences of 21 to 241 μg/L to the model-based predictions (median 175; mean 157, CV 52%). Differences between observed and predicted trough levels were larger when intervals between last drug intake and sampling were very short (~4 h). Conclusion: These preliminary results suggest that TDM of imatinib using a Bayesian interpretation is able to bring trough levels closer to 1000 μg/L (with CV decreasing from 53% to 16%). While this may simplify blood collection in daily practice, as samples do not have to be drawn exactly at trough, the largest possible interval to last drug intake yet remains preferable. This encourages the evaluation of the clinical benefit of a routine TDM intervention in CML patients, which the randomized Swiss I-COME study aims to.

Improvement of the thermal performance of commercial freezers using phase change materials (PCM)

The aim of this work is to improve the thermal performance of commercial freezers using phase change materials (PCM) and the prove the importance of the correct PCM selection (melting temperature) for each application. To do this a vertical freezer with and without macro encapsulation PCM are used to assess the benefits of using PCM in minimizing temperature fluctuations and to maintain at the lowest possible temperature the freezer under heat of losses.

Selective catalytic reduction of nitrogen oxides with ammonia in forced unsteady state reactors - Case based reasoning and mathematical model simulation reasoning

The application of forced unsteady-state reactors in case of selective catalytic reduction of nitrogen oxides (NOx) with ammonia (NH3) is sustained by the fact that favorable temperature and composition distributions which cannot be achieved in any steady-state regime can be obtained by means of unsteady-state operations. In a normal way of operation the low exothermicity of the selective catalytic reduction (SCR) reaction (usually carried out in the range of 280-350°C) is not enough to maintain by itself the chemical reaction. A normal mode of operation usually requires supply of supplementary heat increasing in this way the overall process operation cost. Through forced unsteady-state operation, the main advantage that can be obtained when exothermic reactions take place is the possibility of trapping, beside the ammonia, the moving heat wave inside the catalytic bed. The unsteady state-operation enables the exploitation of the thermal storage capacity of the catalyticbed. The catalytic bed acts as a regenerative heat exchanger allowing auto-thermal behaviour when the adiabatic temperature rise is low. Finding the optimum reactor configuration, employing the most suitable operation model and identifying the reactor behavior are highly important steps in order to configure a proper device for industrial applications. The Reverse Flow Reactor (RFR) - a forced unsteady state reactor - corresponds to the above mentioned characteristics and may be employed as an efficient device for the treatment of dilute pollutant mixtures. As a main disadvantage, beside its advantages, the RFR presents the 'wash out' phenomena. This phenomenon represents emissions of unconverted reactants at every switch of the flow direction. As a consequence our attention was focused on finding an alternative reactor configuration for RFR which is not affected by the incontrollable emissions of unconverted reactants. In this respect the Reactor Network (RN) was investigated. Its configuration consists of several reactors connected in a closed sequence, simulating a moving bed by changing the reactants feeding position. In the RN the flow direction is maintained in the same way ensuring uniformcatalyst exploitation and in the same time the 'wash out' phenomena is annulated. The simulated moving bed (SMB) can operate in transient mode giving practically constant exit concentration and high conversion levels. The main advantage of the reactor network operation is emphasizedby the possibility to obtain auto-thermal behavior with nearly uniformcatalyst utilization. However, the reactor network presents only a small range of switching times which allow to reach and to maintain an ignited state. Even so a proper study of the complex behavior of the RN may give the necessary information to overcome all the difficulties that can appear in the RN operation. The unsteady-state reactors complexity arises from the fact that these reactor types are characterized by short contact times and complex interaction between heat and mass transportphenomena. Such complex interactions can give rise to a remarkable complex dynamic behavior characterized by a set of spatial-temporal patterns, chaotic changes in concentration and traveling waves of heat or chemical reactivity. The main efforts of the current research studies concern the improvement of contact modalities between reactants, the possibility of thermal wave storage inside the reactor and the improvement of the kinetic activity of the catalyst used. Paying attention to the above mentioned aspects is important when higher activity even at low feeding temperatures and low emissions of unconverted reactants are the main operation concerns. Also, the prediction of the reactor pseudo or steady-state performance (regarding the conversion, selectivity and thermal behavior) and the dynamicreactor response during exploitation are important aspects in finding the optimal control strategy for the forced unsteady state catalytic tubular reactors. The design of an adapted reactor requires knowledge about the influence of its operating conditions on the overall process performance and a precise evaluation of the operating parameters rage for which a sustained dynamic behavior is obtained. An apriori estimation of the system parameters result in diminution of the computational efforts. Usually the convergence of unsteady state reactor systems requires integration over hundreds of cycles depending on the initial guess of the parameter values. The investigation of various operation models and thermal transfer strategies give reliable means to obtain recuperative and regenerative devices which are capable to maintain an auto-thermal behavior in case of low exothermic reactions. In the present research work a gradual analysis of the SCR of NOx with ammonia process in forced unsteady-state reactors was realized. The investigation covers the presentationof the general problematic related to the effect of noxious emissions in the environment, the analysis of the suitable catalysts types for the process, the mathematical analysis approach for modeling and finding the system solutions and the experimental investigation of the device found to be more suitable for the present process. In order to gain information about the forced unsteady state reactor design, operation, important system parameters and their values, mathematical description, mathematicalmethod for solving systems of partial differential equations and other specific aspects, in a fast and easy way, and a case based reasoning (CBR) approach has been used. This approach, using the experience of past similarproblems and their adapted solutions, may provide a method for gaining informations and solutions for new problems related to the forced unsteady state reactors technology. As a consequence a CBR system was implemented and a corresponding tool was developed. Further on, grooving up the hypothesis of isothermal operation, the investigation by means of numerical simulation of the feasibility of the SCR of NOx with ammonia in the RFRand in the RN with variable feeding position was realized. The hypothesis of non-isothermal operation was taken into account because in our opinion ifa commercial catalyst is considered, is not possible to modify the chemical activity and its adsorptive capacity to improve the operation butis possible to change the operation regime. In order to identify the most suitable device for the unsteady state reduction of NOx with ammonia, considering the perspective of recuperative and regenerative devices, a comparative analysis of the above mentioned two devices performance was realized. The assumption of isothermal conditions in the beginningof the forced unsteadystate investigation allowed the simplification of the analysis enabling to focus on the impact of the conditions and mode of operation on the dynamic features caused by the trapping of one reactant in the reactor, without considering the impact of thermal effect on overall reactor performance. The non-isothermal system approach has been investigated in order to point out the important influence of the thermal effect on overall reactor performance, studying the possibility of RFR and RN utilization as recuperative and regenerative devices and the possibility of achieving a sustained auto-thermal behavior in case of lowexothermic reaction of SCR of NOx with ammonia and low temperature gasfeeding. Beside the influence of the thermal effect, the influence of the principal operating parameters, as switching time, inlet flow rate and initial catalyst temperature have been stressed. This analysis is important not only because it allows a comparison between the two devices and optimisation of the operation, but also the switching time is the main operating parameter. An appropriate choice of this parameter enables the fulfilment of the process constraints. The level of the conversions achieved, the more uniform temperature profiles, the uniformity ofcatalyst exploitation and the much simpler mode of operation imposed the RN as a much more suitable device for SCR of NOx with ammonia, in usual operation and also in the perspective of control strategy implementation. Theoretical simplified models have also been proposed in order to describe the forced unsteady state reactors performance and to estimate their internal temperature and concentration profiles. The general idea was to extend the study of catalytic reactor dynamics taking into account the perspectives that haven't been analyzed yet. The experimental investigation ofRN revealed a good agreement between the data obtained by model simulation and the ones obtained experimentally.