Damien Barbeau

Relevance of Urinary 3-Hydroxybenzo(a)pyrene and 1-Hydroxypyrene to Assess Exposure to Carcinogenic Polycyclic Aromatic Hydrocarbon Mixtures in Metallurgy Workers

OBJECTIVESnIn metallurgy, workers are exposed to mixtures of polycyclic aromatic hydrocarbons (PAHs) in which some compounds are carcinogenic. Biomonitoring of PAH exposure has been performed by measuring urinary 1-hydroxypyrene (1-OHP), a metabolite of pyrene which is not carcinogenic. This study investigated the use of 3-hydroxybenzo(a)pyrene (3-OHBaP), a metabolite of benzo(a)pyrene (BaP) which is the main carcinogenic component in PAHs, to improve carcinogen exposure assessment.nnnMETHODSnWe included 129 metallurgy workers routinely exposed to PAHs during working hours. Urinary samples were collected at three sampling times at the beginning and at the end of the working week for 1-OHP and 3-OHBaP analyses.nnnRESULTSnWorkers in anode production showed greater exposure to both biomarkers than those in cathode or silicon production, with respectively, 71, 40, and 30% of 3-OHBaP concentrations exceeding the value of 0.4 nmol mol(-1) creatinine. No difference was observed between the 3-OHBaP levels found at the end of the penultimate workday shift and those at the beginning of the last workday shift. Within these plants, the 1-OHP/3-OHBaP ratios varied greatly according to the workers activity and emission sources. Using linear regression between these two metabolites, the 1-OHP level corresponding to the guidance value for 3-OHBaP ranged from 0.7 to 2.4 µmol mol(-1) creatinine, depending on the industrial sector.nnnCONCLUSIONSnThis study emphasizes the interest of monitoring urinary 3-OHBaP at the end of the last workday shift when working week exposure is relatively steady, and the irrelevance of a single guideline value for 1-OHP when assessing occupational health risk.

Occupational exposure to polycyclic aromatic hydrocarbons: relations between atmospheric mixtures, urinary metabolites and sampling times

AbstractPurposenOccupational exposure to polycyclic aromatic hydrocarbons (PAHs) can be assessed by either air monitoring or biomonitoring using urinary 1-hydroxypyrene (1-OHP) or 3-hydroxybenzo(a)pyrene (3-OHBaP). The aim of this study was to understand the links between atmospheric PAHs and urinary metabolites, in order to improve the biomonitoring strategy for assessing carcinogenic risk.MethodsPersonal air sampling for pyrene and BaP measurements, and urines for 1-OHP and 3-OHBaP analyses of seven workers from electrode production plant were collected every day of the working week.ResultsHigh variability of atmospheric levels between activities and between days was observed, especially for gaseous pyrene. No correlation was found between urinary metabolites: 1-OHP maximum levels occurred for “electrode extrusion” activity; those of 3-OHBaP occurred for “raw materials dispatcher.” Sixty percentage of 3-OHBaP maximum levels were observed in urines collected at the beginning of shift the last workday. Those of 1-OHP occurred at different sampling times, depending on the gaseous pyrene levels (not stopped by P3 respirators). Dermal absorption of PAHs was confirmed by significant effect of particulate pyrene on 1-OHP in the samples collected the morning of the following day (pxa0<xa00.02, nxa0=xa025).ConclusionsLack of correlation between metabolites concentrations emphasizes the non-relevance of 1-OHP, from a non-carcinogenic gaseous and particulate compound, and the great interest of 3-OHBaP, from carcinogenic BaP. Its slower urinary elimination prevents the risk of exposure underestimation, and urinary analysis should be performed at the beginning of shift the end of working week, especially in case of high exposure variability.

Use of physiologically-based pharmacokinetic modeling to simulate the profiles of 3-hydroxybenzo(a)pyrene in workers exposed to polycyclic aromatic hydrocarbons.

Biomathematical modeling has become an important tool to assess xenobiotic exposure in humans. In the present study, we have used a human physiologically-based pharmacokinetic (PBPK) model and an simple compartmental toxicokinetic model of benzo(a)pyrene (BaP) kinetics and its 3-hydroxybenzo(a)pyrene (3-OHBaP) metabolite to reproduce the time-course of this biomarker of exposure in the urine of industrially exposed workers and in turn predict the most plausible exposure scenarios. The models were constructed from in vivo experimental data in rats and then extrapolated from animals to humans after assessing and adjusting the most sensitive model parameters as well as species specific physiological parameters. Repeated urinary voids from workers exposed to polycyclic aromatic hydrocarbons (PAHs) have been collected over the course of a typical workweek and during subsequent days off work; urinary concentrations of 3-OHBaP were then determined. Based on the information obtained for each worker (BaP air concentration, daily shift hours, tasks, protective equipment), the time courses of 3-OHBaP in the urine of the different workers have been simulated using the PBPK and toxicokinetic models, considering the various possible exposure routes, oral, dermal and inhalation. Both models were equally able to closely reproduce the observed time course of 3-OHBaP in the urine of workers and predicted similar exposure scenarios. Simulations of various scenarios suggest that the workers under study were exposed mainly by the dermal route. Comparison of measured air concentration levels of BaP with simulated values needed to obtain a good approximation of observed time course further pointed out that inhalation was not the main route of exposure for most of the studied workers. Both kinetic models appear as a useful tool to interpret biomonitoring data of PAH exposure on the basis of 3-OHBaP levels.

A realistic human skin model to study benzo[a]pyrene cutaneous absorption in order to determine the most relevant biomarker for carcinogenic exposure

Polycyclic aromatic hydrocarbons (PAH) are ubiquitous pollutants, among which benzo[a]pyrene (B[a]P) is the only compound classified carcinogenic to humans. Besides pulmonary uptake, skin is the major route of PAH absorption during occupational exposure. Health risk due to PAH exposure is commonly assessed among workers using biomonitoring. A realistic human ex vivo skin model was developed to explore B[a]P diffusion and metabolism to determine the most relevant biomarker following dermal exposure. Three realistic doses (0.88, 8.85 and 22.11xa0nmol/cm2) were topically applied for 8, 24, and 48xa0h. B[a]P and its metabolites were quantified by liquid chromatography coupled with fluorimetric detection. The impact of time, applied dose, and donor age were estimated using a linear mixed-effects model. B[a]P vastly penetrated the skin within 8xa0h. The major metabolites were 3-hydroxybenzo[a]pyrene (3-OHB[a]P) and 7,8,9,10-tetrahydroxy-7,8,9,10-tetrahydrobenzo[a]pyrene (B[a]P-tetrol). This latter predominantly derives from the most carcinogenic metabolite of B[a]P, benzo[a]pyrene-7,8-diol-9,10-epoxide (BPDE), as well as benzo[a]pyrene-9,10-diol-7,8-epoxide (reverse-BPDE). Benzo[a]pyrene-trans-7,8-dihydrodiol (B[a]P-7,8-diol) was a minor metabolite, and benzo[a]pyrene-trans-4,5-dihydrodiol (B[a]P-4,5-diol) was never quantified. Unmetabolized B[a]P bioavailability was limited following dermal exposure since less than 3% of the applied dose could be measured in the culture medium. B[a]P was continuously absorbed and metabolized by human skin over 48xa0h. B[a]P-tetrol production became saturated as the applied dose increased, while no effect was measured on the other metabolic pathways. Age had a slight positive effect on B[a]P absorption and metabolism. This work supports the relevance of B[a]P-tetrol to assess occupational exposure and carcinogenic risk after cutaneous absorption of B[a]P.

Geographic dimensions of a health network dedicated to occupational and work related diseases

BackgroundAlthough introduced nearly 40xa0years ago, Geographic Information Systems (GISs) have never been used to study Occupational Health information regarding the different types, scale or sources of data. The geographic distribution of occupational diseases and underlying work activities were always analyzed independently. Our aim was to consider the French Network of Occupational Disease (OD) clinics, namely the “French National OD Surveillance and Prevention Network” (rnv3p) as a spatial object in order to describe its catchment.MethodsWe mapped rnv3p observations at the workplace level. We initially analyzed rnv3p capture with reference to its own data, then to the underlying workforce (INSEE “Employment Areas”), and finally compared its capture of one emblematic occupational disease (mesothelioma) to an external dataset provided by a surveillance system thought to be exhaustive (PNSM).ResultsWhile the whole country is covered by the network, the density of observations decreases with increase in the distance from the 31 OD clinics (located within the main French cities). Taking into account the underlying workforce, we show that the probability to capture and investigation of OD (assessed by rates of OD per 10,000 workers) also presents large discrepancies between OD clinics. This capture rate might also show differences according to the disease, as exemplified by mesothelioma.ConclusionThe geographic approach to this network, enhanced by the possibilities provided by the GIS tool, allow a better understanding of the coverage of this network at a national level, as well as the visualization of capture rates for all OD clinics. Highlighting geographic and thematic shading zones bring new perspectives to the analysis of occupational health data, and should improve occupational health vigilance and surveillance.

Surveillance biologique de l’exposition aux hydrocarbures aromatiques polycycliques (HAP) lors de l’application d’enrobés bitumineux

Introduction Les bitumes issus du raffinage du petrole sont utilises pour l’application d’enrobes routiers. De nombreux HAP sont emis a partir des liants bitumineux, incluant des composes gazeux et particulaires (dont certains cancerogenes). Du fait de modifications recentes des conditions d’application des bitumes (enrobes tiedes, aspiration des fumees), une nouvelle evaluation de l’exposition professionnelle aux HAP a ete conduite. Materiels/methodes Une surveillance des expositions a ete realisee par des metrologies atmospheriques individuelles (prelevements et analyses de 17xa0HAP) en complement d’une surveillance biologique basee sur le recueil de 2xa0echantillons urinaires en debut et fin de poste, avec analyse des metabolites du pyrene (1-OHP), benzo(a)pyrene (3-OHBaP), naphtalene (1- et 2-naphtols), fluorene (1- 2- 3- 9-fluorenols) et phenanthrene (1- 2- 3- 4- 9-phenanthrols). L’etude a ete conduite sur 10xa0chantiers/36xa0travailleurs, dont 9xa0conducteurs de finisseur, 9xa0regleurs, 14xa0operateurs râteau et 4xa0autres postes. Les analyses ont ete realisees par HPLC-fluorescence et GC-spectrometrie de masse au Laboratoire de toxicologie professionnelle et environnementale du CHU de Grenoble. Resultats Les concentrations urinaires de 1-OHP sont faibles, tres influencees par tabagisme (moyennes geometriques MG de 0,05xa0et 0,10xa0μmol/mol de creatinine en fin de journee chez les non-fumeurs et fumeurs), et dans leur majorite largement inferieures aux valeurs recommandees en milieu professionnel (1xa0μmol/mol). Les niveaux de 3-OHBaP sont extremement faibles, souvent indetectables avec un maximum de 0,17xa0nmol/mol de creatinine (niveaux recommandesxa0 Conclusions Lors de l’application d’enrobes bitumineux, les expositions sont faibles pour les HAP gazeux et tres faibles pour les particulaires (notamment BaP), avec une coherence entre la surveillance biologique et la metrologie atmospherique. L’utilisation de bitumes tiedes et le faible pourcentage de liants bitumineux permettent de diminuer encore les expositions aux HAP ce qui va dans le sens des recommandations ANSES (2013). L’efficacite des systemes d’aspiration des fumees est en cours d’evaluation.

Surveillance de l’exposition des populations aux agents chimiques cancérogènes en milieux professionnel et environnemental : exemple des hydrocarbures aromatiques polycycliques

Alors que la survenue de cancers represente l’heritage du passe, la surveillance temporelle et spatiale de l’exposition des populations a des agents cancerogenes permet actuellement de definir les groupes de sujets ou d’activites a risques afin de mettre en place au sein de ces groupes des mesures de prevention primaire pour eviter la survenue de maladie. L’estimation des expositions individuelles, combinant modelisation et mesures d’ambiance enregistrees par les reseaux de la qualite de l’air, est tres utilisee notamment dans le cadre d’etudes d’impact environnemental. Le mesurage des expositions individuelles commence a etre utilise en milieu environnemental du fait de sa precision et c’est la seule methode reglementaire en milieu professionnel pour evaluer l’exposition des travailleurs. Si la metrologie atmospherique des polluants est une approche indispensable pour identifier les sources et les pics d’emission, la surveillance biologique de l’exposition est la methode qui permet le mieux d’estimer le risque sanitaire des populations car elle prend en compte toutes les sources et voies d’exposition, les moyens de protection et les facteurs individuels. Depuis plus de 10 ans, nous avons mis en place une base de donnees d’exposition atmospherique et biologique aux HAP en milieu professionnel en collectant pour chaque sujet les facteurs determinants des niveaux d’exposition (quantite et composition des produits, procedes d’emission, activites de travail, protection, tabagisme). Du fait de l’exposition des populations a des melanges d’HAP gazeux et particulaires de composition et de niveaux varies, nous avons developpe plusieurs types de biomarqueurs utilisables tant en milieu professionnel pour estimer les expositions cancerogenes qu’en environnement general pour evaluer l’impregnation des populations.