Gas-chromatography mass-spectrometry determination of phthalic acid in human urine as a biomarker of folpet exposure.

Agricultural workers are exposed to folpet, but biomonitoring data are limited. Phthalimide (PI), phthalamic acid (PAA), and phthalic acid (PA) are the ring metabolites of this fungicide according to animal studies, but they have not yet been measured in human urine as metabolites of folpet, only PA as a metabolite of phthalates. The objective of this study was thus to develop a reliable gas chromatography-tandem mass spectrometry (GC-MS) method to quantify the sum of PI, PAA, and PA ring-metabolites of folpet in human urine. Briefly, the method consisted of adding p-methylhippuric acid as an internal standard, performing an acid hydrolysis at 100 °C to convert ring-metabolites into PA, purifying samples by ethyl acetate extraction, and derivatizing with N,O-bis(trimethylsilyl)trifluoro acetamide prior to GC-MS analysis. The method had a detection limit of 60.2 nmol/L (10 ng/mL); it was found to be accurate (mean recovery, 97%), precise (inter- and intra-day percentage relative standard deviations <13%), and with a good linearity (R (2) > 0.98). Validation was conducted using unexposed peoples urine spiked at concentrations ranging from 4.0 to 16.1 μmol/L, along with urine samples of volunteers dosed with folpet, and of exposed workers. The method proved to be (1) suitable and accurate to determine the kinetic profile of PA equivalents in the urine of volunteers orally and dermally administered folpet and (2) relevant for the biomonitoring of exposure in workers

Toxicokinetics of captan and folpet biomarkers in orally exposed volunteers

The time courses of key biomarkers of exposure to captan and folpet was assessed in accessible biological matrices of orally exposed volunteers. Ten volunteers ingested 1 mg kg(-1) body weight of captan or folpet. Blood samples were withdrawn at fixed time periods over the 72 h following ingestion and complete urine voids were collected over 96 h post-dosing. The tetrahydrophthalimide (THPI) metabolite of captan along with the phthalimide (PI) and phthalic acid metabolites of folpet were then quantified in these samples. Plasma levels of THPI and PI increased progressively after ingestion, reaching peak values ~10 and 6 h post-dosing, respectively; subsequent elimination phase appeared monophasic with a mean elimination half-life (t(½) ) of 15.7 and 31.5 h, respectively. In urine, elimination rate time courses of PI and phthalic acid evolved in parallel, with respective t(½) of 27.3 and 27.6 h; relatively faster elimination was found for THPI, with mean t(½) of 11.7 h. However, phthalic acid was present in urine in 1000-fold higher amounts than PI. In the 96 h period post-treatment, on average 25% of folpet dose was excreted in urine as phthalic acid as compared with only 0.02% as PI. The corresponding value for THPI was 3.5%. Overall, THPI and PI appear as interesting biomarkers of recent exposure, with relatively short half-lives; their sensitivity to assess exposure in field studies should be further verified. Although not a metabolite specific to folpet, the concomitant use of phthalic acid as a major biomarker of exposure to folpet should also be considered. Copyright © 2011 John Wiley & Sons, Ltd

Études expérimentales sur la toxicocinétique du 1-hydroxypyrène

Thèse numérisée par la Direction des bibliothèques de l'Université de Montréal

L'inconstitutionnalité des pouvoirs du protonotaire spécial

The office of special prothonotary was created in 1975 by an amendment to the Code of Civil Procedure. The main purpose of the change was to ease the administration of justice before the courts. For this reason, the special prothonotary received many assignments which were reserved until then to a judge sitting in chambers and even to the court itself. Such transfer of duties and powers may conflict with section 96 of the BNA Act, which acts as a bar to prevent the withdrawal of judicial functions from a superior, county or district court. This paper deals with the interferences between various sections of the Code of Civil Procedure and section 96 of the BNA Act. The first part of the paper deals with the approach adopted by the courts. The true test, according to the case-law, is to determine the nature of the function involved. Since only judicial functions are protected by section 96, it is intravires the Legislature of Quebec to confer on a board or tribunal administrative or ministerial powers. If the transfer involves judicial functions, the courts will use the test adopted by the Privy Council in Labour Relations Board of Saskatchewan v. John East Iron Works and by Sir Lyman Duff in In re Adoption Act, and examine whether the transferee is analogous to a superior, district or county court. The courts will also have to apply the « 1867 statute books test » : was the particular function conferred to the prothonotary before 1867 ? If the results of each of the two tests are affirmative, then the function is one protected by section 96 of the BNA Act and its transfer is ultra vires the provincial Legislature. If the results are negative, the courts will examine if the provisions involved have the effect of vesting in the special prothonotary the powers of a superior court judge. If the courts conclude that it is so, then, the assignment is ultra vires the powers of the provincial Legislature. The second part deals with each of the assignments transferred to the special prothonotary. These are threefold in nature: 1. Actions by default to appear or by default to plead under article 195 C.C.P. ; 2. Jurisdiction under article 44.1(1) C.C.P. ; 3. Interlocutory or incidental proceedings, contested or not, but, if so, with the consent of the parties. The paper concludes that most of the provisions dealing with the duties and powers of the special prothonotary are unconstitutiona

A Biologically Based Dynamic Model for Predicting the Disposition of Methanol and Its Metabolites in Animals and Humans

A multicompartment biologically based dynamic model was developed to describe the time evolution of methanol and its metabolites in the whole body and in accessible biological matrices of rats, monkeys, and humans following different exposure scenarios. The dynamic of intercompartment exchanges was described mathematically by a mass balance differential equation system. The model's conceptual and functional representation was the same for rats, monkeys, and humans, but relevant published data specific to the species of interest served to determine the critical parameters of the kinetics. Simulations provided a close approximation to kinetic data available in the published literature. The average pulmonary absorption fraction of methanol was estimated to be 0.60 in rats, 0.69 in monkeys, and 0.58-0.82 in human volunteers. The corresponding average elimination half-life of absorbed methanol through metabolism to formaldehyde was estimated to be 1.3, 0.7-3.2, and 1.7 h. Saturation of methanol metabolism appeared to occur at a lower exposure in rats than in monkeys and humans. Also, the main species difference in the kinetics was attributed to a metabolism rate constant of whole body formaldehyde to formate estimated to be twice as high in rats as in monkeys. Inversely, in monkeys and in humans, a larger fraction of body burden of formaldehyde is rapidly transferred to a long-term component. The latter represents the formaldehyde that (directly or after oxidation to formate) binds to various endogenous molecules or is taken up by the tetrahydrofolic-acid-dependent one-carbon pathway to become the building block of synthetic pathways. This model can be used to quantitatively relate methanol or its metabolites in biological matrices to the absorbed dose and tissue burden at any point in time in rats, monkeys, and humans for different exposures, thus reducing uncertainties in the dose-response relationship, and animal-to-human and exposure scenario comparisons. The model, adapted to kinetic data in human volunteers exposed acutely to methanol vapors, predicts that 8-h inhalation exposures ranging from 500 to 2000 ppm, without physical activities, are needed to increase concentrations of blood formate and urinary formic acid above mean background values reported by various authors (4.9-10.3 and 6.3-13 mg/liter, respectively). This leaves blood and urinary methanol concentrations as the most sensitive biomarkers of absorbed methano

A Detailed Urinary Excretion Time Course Study of Captan and Folpet Biomarkers in Workers for the Estimation of Dose, Main Route-of-Entry and Most Appropriate Sampling and Analysis Strategies

Captan and folpet are two fungicides largely used in agriculture, but biomonitoring data are mostly limited to measurements of captan metabolite concentrations in spot urine samples of workers, which complicate interpretation of results in terms of internal dose estimation, daily variations according to tasks performed, and most plausible routes of exposure. This study aimed at performing repeated biological measurements of exposure to captan and folpet in field workers (i) to better assess internal dose along with main routes-of-entry according to tasks and (ii) to establish most appropriate sampling and analysis strategies. The detailed urinary excretion time courses of specific and non-specific biomarkers of exposure to captan and folpet were established in tree farmers (n = 2) and grape growers (n = 3) over a typical workweek (seven consecutive days), including spraying and harvest activities. The impact of the expression of urinary measurements [excretion rate values adjusted or not for creatinine or cumulative amounts over given time periods (8, 12, and 24 h)] was evaluated. Absorbed doses and main routes-of-entry were then estimated from the 24-h cumulative urinary amounts through the use of a kinetic model. The time courses showed that exposure levels were higher during spraying than harvest activities. Model simulations also suggest a limited absorption in the studied workers and an exposure mostly through the dermal route. It further pointed out the advantage of expressing biomarker values in terms of body weight-adjusted amounts in repeated 24-h urine collections as compared to concentrations or excretion rates in spot samples, without the necessity for creatinine correction

Liquid chromatography-tandem mass spectrometry (LC/APCI-MS/MS) methods for the quantification of captan and folpet phthalimide metabolites in human plasma and urine.

Captan and folpet are fungicides largely used in agriculture. They have similar chemical structures, except that folpet has an aromatic ring unlike captan. Their half-lives in blood are very short, given that they are readily broken down to tetrahydrophthalimide (THPI) and phthalimide (PI), respectively. Few authors measured these biomarkers in plasma or urine, and analysis was conducted either by gas chromatography coupled to mass spectrometry or liquid chromatography with UV detection. The objective of this study was thus to develop simple, sensitive and specific liquid chromatography-atmospheric pressure chemical ionization-tandem mass spectrometry (LC/APCI-MS/MS) methods to quantify both THPI and PI in human plasma and urine. Briefly, deuterated THPI was added as an internal standard and purification was performed by solid-phase extraction followed by LC/APCI-MS/MS analysis in negative ion mode for both compounds. Validation of the methods was conducted using spiked blank plasma and urine samples at concentrations ranging from 1 to 250 μg/L and 1 to 50 μg/L, respectively, along with samples of volunteers and workers exposed to captan or folpet. The methods showed a good linearity (R (2) > 0.99), recovery (on average 90% for THPI and 75% for PI), intra- and inter-day precision (RSD, <15%) and accuracy (<20%), and stability. The limit of detection was 0.58 μg/L in urine and 1.47 μg/L in plasma for THPI and 1.14 and 2.17 μg/L, respectively, for PI. The described methods proved to be accurate and suitable to determine the toxicokinetics of both metabolites in human plasma and urine

Chapitre 3. Un sanctuaire secret

L’étude pluridisciplinaire du site a montré que Pergouset représente un véritable archétype de ce que l’on doit nommer un sanctuaire secret, réservé à un ou deux officiants ou à quelques « initiés » seulement, bien différent des grands sanctuaires publics dont le type régional est la grotte du Pech‑Merle, justement baptisée « grotte‑temple » par A. Lemozi. Certains aspects de la technologie des tracés et surtout la répartition dynamique des thèmes soulignent l’homogénéité du dispositif pariétal de Pergouset et l’existence d’un véritable scénario se déroulant dans les profondeurs de la galerie. Le nombre des figurations de même que leur réalisme s’accroissent progressivement du fond vers le début du sanctuaire. Les trois vulves féminisent l’univers souterrain environnant. De façon spectaculaire les gravures animent la grotte ; elles paraissent surgir des reliefs rocheux. L’ensemble des observations réalisées au cours de ce long travail suggère que, pour les Magdaléniens, la cavité elle‑même semble avoir joué un rôle symbolique important en relation avec l’apparition de la vie dans le sein de la Terre, c’est‑à‑dire avec une mythologie de l’origine du monde.The multidisciplinary study of the site has shown that Pergouset represents a veritable archetype of what one can call a "secret sanctuary" reserved for one or two officiants or just a few " initiates ", and quite different from the great public sanctuaries whose regional type site is the cave of Pech‑Merle, aptly baptised a "Temple‑Cave" by A. Lemozi. Some aspects of the technology of the drawings, and especially the dynamic distribution of themes, underline the homogeneity of Pergouset’s parietal layout and the existence of a veritable scenario that unfolds in the depths of the gallery. The figures become more and more numerous and increasingly realistic from the back to the beginning of the sanctuary. The there vulvas feminise the surrounding subterranean universe. The engravings animate the cave in a spectacular fashion ; they seem to spring out of the rocky reliefs. All of the observations made in the course of this long investigation suggest that, for the Magdalenians, the cave itself seems to have played an important symbolic role in relation to the appearance of life in the bowels of the Earth, that is, to a mythology of the origin of the world.El estudio pluridisciplinar ha demostrado que Pergouset representa un verdadero arquetipo de lo que debe denominarse « santuario secreto », reservado a uno o dos oficiantes o a sólo algunos « iniciados », bien diferente de los grandes santuarios públicos, y cuyo ejemplo típico regional es él de Pech‑Merle con razón bautizado « gruta‑templo » por A. Lemozi. Algunos aspectos de la tecnología de los trazados lineales y, sobre todo la repartición dinámica de los temas, subrayan la homogeneidad del dispositivo parietal de Pergouset y la existencia de un verdadero escenario desarrollado en las profundidades de la galería: las figuraciones se van haciendo cada vez más numerosas y más realistas desde el fondo hasta el comienzo del santuario. Las tres vulvas feminizan el universo subterráneo circundante. Los grabados animan la gruta de una manera espectacular, pareciendo surgir de los relieves rocosos. Las observaciones realizadas durante este largo trabajo sugieren que la cueva misma jugaba un importante papel simbólico, relacionado con la aparición de la vida en el seno de la Tierra; es decir, con una mitología del origen del mundo

A modern nihilism

Presents the author's evolving views of the best current positions on certain core philosophical and psychological problems as they developed over time. These positions together suggest a skeptical or nihilist perspective modified by evolutionary psychology and contemporary philosophy that embraces our desire to live as best we can and the relative and psychological reality of values, free will and other phenomena while recognizing limitations on their foundations and our understanding. The below makes no claims to originality for most of the ideas expressed, drawing on a range of mostly unreferenced texts that will be familiar to philosophers and psychologists working in this area