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In December 2020, high soil concentrations of polychlorinated dibenzo-p-dioxins (PCDDs) and dibenzofurans (PCDFs) were discovered across large parts of Lausanne, Switzerland. Concentrations reached up to 640 ng TEQ WHO-2005 /kg dry weight. The most likely source was a former municipal waste incinerator. A three-step, multidisciplinary approach to human health risk assessment was conducted to determine the potential population exposure to PCDD/Fs and identify appropriate preventive measures. First, exposure scenarios were developed based on contaminated land uses. Second, the toxicological risks of different scenarios were evaluated using a toxicokinetic model estimating increases in blood serum PCDD/F concentrations over background concentrations from the general population's food consumption. Third, a detailed geostatistical mapping of PCDD/F soil contamination was performed. Stochastic simulations with an external drift and an anisotropic model of the variogram were generated to incorporate the effects of distance from emission source, topography, and main wind directions on the spatial distribution of PCDD/Fs in topsoil. Three main scenarios were assessed: i) direct ingestion of soil by children in playgrounds; ii) consumption of vegetables from private gardens by children and adults; and iii) consumption of food from livestock and poultry raised on contaminated soil. The worst exposure scenario involved the consumption of eggs from private hen houses, resulting in PCDD/F concentrations in serum an order of magnitude higher than might normally be expected. No relevant increases in serum concentrations were calculated for direct soil ingestion and vegetable consumption, except for cucurbitaceous vegetables. Combining mapping and exposure scenario assessment resulted in targeted protective measures for land users, especially concerning food consumption. The results also raised concerns about the potential unsafe consumption of products derived from animals raised on land with PCDD/F concentrations only moderately over environmental background levels.

Tolylfluanid (TF) is a sensitizing biocide used in antifouling products and wood preservatives. Paint application is associated with skin exposure; however, the importance of this exposure route is uncertain as TF skin permeation rates are lacking in the peer-reviewed scientific literature. TF is a lipophilic powder that hydrolyses rapidly in contact with water to dimethylamino sulfotoluidid (DMST). DMST is also a TF metabolite. We characterized TF and DMST skin permeation using an ex vivo flow-through diffusion system with viable and frozen human skin. TF permeated as DMST with a low permeation rate (0.18 ± 0.05 μg/cm 2 /h) and a moderate time lag (7.1 ± 1.4 h) in viable human skin. Applying DMST gave a 3.5-fold lower permeation rate (0.05 ± 0.01 μg/cm 2 /h) compared to TF under a similar experimental setting. We simulated paint activities in an exposure chamber to understand a possible skin exposure from airborne TF concentrations. Although, paint can deposit onto the skin during work activities, TF permeation when paint was applied to human skin ex vivo was very low (as TF: 0.004 ± 0.005 μg/cm 2 /h, and as DMST: 0.02 ± 0.001 μg/cm 2 /h). Our results show that TF can permeate skin, and consequently, can contribute to sensitization, which support previous reports on sensitization in TF exposed workers.

210Po is a radioactive component of conventional cigarette tobacco smoke and is a recognized carcinogen. Despite the expanding market of heated tobacco products, no data are available on the activity of 210Po in the smoke of IQOS Heets® cigarette. We determined the 210Po activity in the mainstream smoke of thirteen cigarette brands available on the Swiss market using a smoking machine and compared the results to the 210Po activity measured in the mainstream smoke of the IQOS® system. In addition, we measured the 210Po and 210Pb loss on heating after uniform heating from 50 to 600°C for several cigarette brands and the Heets® cigarettes. 13.6 ± 4.1% of 210Po activity was found in the mainstream smoke in conventional cigarette smoking (7% for 210Pb). This dropped to 1.8 ± 0.3% in the mainstream smoke of IQOS Heets®. Conversely, when the tobacco was heated uniformly at 330°C, a loss of 210Po of more than 80% was observed for all type of cigarettes. Apparently, IQOS® significantly reduced the 210Po and 210Pb activities in the mainstream smoke. However, our results show that only 15% of the Heets® tobacco reaches 330°C with IQOS®. While IQOS® reduces the 210Po and 210Pb activities in the mainstream smoke compared to conventional cigarettes, it only heats a marginal fraction of the tobacco present in the Heets® cigarette. Because smoking is an addiction (mostly due to nicotine), IQOS® could possibly deliver an unsatisfactory dose of nicotine to a Heets® cigarette smoker, as most of the tobacco is left unaltered.

Skin exposures are common during cleaning activities, and may contribute to the overall body burden. Cleaning products may contain irritants such as monoethanolamine (MEA) and diethanol amine (DEA). The significance of the skin exposure route is unknown, as no estimates for MEA skin permeation are available. We used in vitro flow-through diffusion cells with excised fresh human skin to measure skin permeation, and assessed skin damage with histological methods. MEA(aq) by itself (2%) or as a constituent in cleaning products (0.25% working solution) did not permeate after 1 h or 24 h of exposure. MEA(aq) (10%) did not permeate skin after 1 h but after 24 h with a delay (Tlag; 7 h) and a moderate permeation rate (J; 26.6 μg/cm2/h). MEA permeation rate was 20-fold greater (544 μg/cm2/h) and ¼ of the time lag (1.5 h) when applied as undiluted cleaning product (13% MEA) compared to 10% MEA(aq). DEA in cleaning products did not permeate skin after 24 h. MEA and DEA produced skin irritations at low concentrations (1% MEA) and severe skin irritations when tested as a constituent in cleaning products. Absorption increased from 0 to 3% after 24 h to 14–29% after 88 h of MEA exposure, and is likely explained by the increased damage of the skin barrier. Limitations of this study are the low number of skin donors (N = 5) available. Our results demonstrate that topically applied MEA permeates across human skin relatively slowly and not below 5% while relatively extensively as a constituent of a commercial cleaning product.

International audience; Despite the richness of data collected on pesticide concentrations in ambient air in France, knowledge on this topic remains partial and heterogeneous in the absence of specific regulations. The population exposure remains thus difficult to estimate; therefore it was necessary to define modalities for implementing national monitoring of pesticides in ambient air in metropolitan France and in the overseas territories. The objective of this work was to identify which active substances (a.s.) have to be monitored in priority. As part of a collective expertise, a group of multidisciplinary experts has developed a method to rank active substances authorised as plant protection products, biocides and antiparasitic agents, which were available on the French market in 2015. A 3-steps approach has been developed. The first step consisted of a theoretical approach based on a hierarchy of substances according to four criteria: (a) national uses, (b) emission potential to the air, (c) persistence in the air, and (d) chronic toxicity. The three first criteria give information on their potential to be present in the atmosphere, and the fourth criterion allows to consider their potential of hazard. The second step was an observational approach based on existing database on pesticide air measurements in France. In the third step, both approaches were combined using decision trees to select priority pesticides. Among the 1316 a.s. first identified from the EU Pesticides database, 90 were selected, among which 43 required metrological and/or analytical development. The experts recommended confirming the relevance of performing a longer term monitoring of these a. s. after a one-year exploratory campaign. The proposed method is reproduceable, transparent, easy to update (e.g. in the light of a change in product authorization), and can be adapted to other agricultural and geographical conditions, and objectives (e.g. monitoring of the ecotoxicological effects of pesticides).

Skin exposure to cleaning products in the general and occupational population are a public health concern. Among the most frequently identified amphiphilic organic solvents in cleaning products are propylene glycol monomethyl ether (PGME) and propylene glycol n-butyl ether (PGBE). Internal dose from skin exposure may be efficiently evaluated using in vitro flow-through diffusion cells with excised human skin. Our aim in this study was two-fold; 1) characterize the permeation rates (J), time lag (Tlag), and permeation coefficients (Kp) of PGME and PGBE in human ex-vivo skin permeation assays, and 2) determine a possible mixture effect on skin permeation characteristics when applied together. Our results showed a short Tlag for PGME and was reduced further depending on the amount of PGBE in the mixture (Tlag was reduced from 2 h to 1–1.7 h) for fresh skin. PGBE Tlag slightly increased when mixed with 50 % or more PGME. Permeation rate decreased to half for both PGME and PGBE in mixture at any concentration. This substantial permeation was greater with previously frozen skin. This mixture effect could favor permeation of other compounds through human skin.

Skin exposures to chemicals may lead, through percutaneous permeation, to a significant increase in systemic circulation. Skin is the primary route of entry during some occupational activities, especially in agriculture. To reduce skin exposures, the use of personal protective equipment (PPE) is recommended. PPE efficiency is characterized as the time until products permeate through material (lag time, Tlag). Both skin and PPE permeations are assessed using similar in vitro methods; the diffusion cell system. Flow-through diffusion cells were used in this study to assess the permeation of two herbicides, bentazon and isoproturon, as well as four related commercial formulations (Basagran(®), Basamais(®), Arelon(®) and Matara(®)). Permeation was measured through fresh excised human skin, protective clothing suits (suits) (Microchem(®) 3000, AgriSafe Pro(®), Proshield(®) and Microgard(®) 2000 Plus Green), and a combination of skin and suits. Both herbicides, tested by itself or as an active ingredient in formulations, permeated readily through human skin and tested suits (Tlag

Bisphenol A (BPA) in vitro skin permeation studies have shown inconsistent results, which could be due to experimental conditions. We studied the impact of in vitro parameters on BPA skin permeation using flow-through diffusion cells with ex-vivo human skin (12 donors, 3-12 replicates). We varied skin status (viable or frozen skin) and thickness (200, 400, 800 μm), BPA concentrations (18, 250 mg/l) and vehicle volumes (10, 100 and 1000 μl/cm 2 ). These conditions led to a wide range of BPA absorption (2%-24% after 24 h exposure), peak permeation rates (J = 0.02-1.31 μg/cm 2 /h), and permeability coefficients (K p = 1.6-5.2 × 10 -3 cm/h). This is the first time steady state conditions were reached for BPA aqueous solutions in vitro (1000 μl/cm 2 applied at concentration 250 mg/l). A reduction of the skin thickness from 800 and 400 μm to 200 μm led to a 3-fold increase of J (P < 0.05). A reduction of the vehicle volume from 1000 to 100 led to a 2-fold decrease in J (P > 0.05). Previously frozen skin led to a 3-fold increase in J compared to viable skin (P < 0.001). We found that results from published studies were consistent when adjusting J according to experimental parameters. We propose appropriate J values for different exposure scenarios to calculate BPA internal exposures for use in risk assessment.

In this study, silver/copper (Ag/Cu)-coated catheters were investigated for their efficacy in preventing methicillin-resistant Staphylococcus aureus (MRSA) infection in vitro and in vivo . Ag and Cu were sputtered (67/33% atomic ratio) on polyurethane catheters by direct-current magnetron sputtering. In vitro , Ag/Cu-coated and uncoated catheters were immersed in phosphate-buffered saline (PBS) or rat plasma and exposed to MRSA ATCC 43300 at 10 4 to 10 8 CFU/ml. In vivo , Ag/Cu-coated and uncoated catheters were placed in the jugular vein of rats. Directly after, MRSA (10 7 CFU/ml) was inoculated in the tail vein. Catheters were removed 48 h later and cultured. In vitro , Ag/Cu-coated catheters preincubated in PBS and exposed to 10 4 to 10 7 CFU/ml prevented the adherence of MRSA (0 to 12% colonization) compared to uncoated catheters (50 to 100% colonization; P < 0.005) and Ag/Cu-coated catheters retained their activity (0 to 20% colonization) when preincubated in rat plasma, whereas colonization of uncoated catheters increased (83 to 100%; P < 0.005). Ag/Cu-coating protection diminished with 10 8 CFU/ml in both PBS and plasma (50 to 100% colonization). In vivo , Ag/Cu-coated catheters reduced the incidence of catheter infection compared to uncoated catheters (57% versus 79%, respectively; P = 0.16) and bacteremia (31% versus 68%, respectively; P < 0.05). Scanning electron microscopy of explanted catheters suggests that the suboptimal activity of Ag/Cu catheters in vivo was due to the formation of a dense fibrin sheath over their surface. Ag/Cu-coated catheters thus may be able to prevent MRSA infections. Their activity might be improved by limiting plasma protein adsorption on their surfaces.

At the 8th conference of Occupational and Environmental Exposure of the Skin to Chemicals (OEESC) (16–18 September 2019) in Dublin, Ireland, several researchers performing skin permeation assays convened to discuss in vitro skin permeability experiments. We, along with other colleagues, all of us hands-on skin permeation researchers, present here the results from our discussions on the available OECD guidelines. The discussions were especially focused on three OECD skin absorption documents, including a recent revision of one: i) OECD Guidance Document 28 (GD28) for the conduct of skin absorption studies (OECD, 2004), ii) Test Guideline 428 (TGD428) for measuring skin absorption of chemical in vitro (OECD, 2004), and iii) OECD Guidance Notes 156 (GN156) on dermal absorption issued in 2011 (OECD, 2011). GN156 (OECD, 2019) is currently under review but not finalized. A mutual concern was that these guidance documents do not comprehensively address methodological issues or the performance of the test, which might be partially due to the years needed to finalize and update OECD documents with new skin research evidence. Here, we summarize the numerous factors that can influence skin permeation and its measurement, and where guidance on several of these are omitted and often not discussed in published articles. We propose several improvements of these guidelines, which would contribute in harmonizing future in vitro skin permeation experiments.

Road construction workers are simultaneously exposed to two carcinogens; solar ultraviolet (UV-S) radiation and polycyclic aromatic hydrocarbons (PAHs) in bitumen emissions. The combined exposure may lead to photogenotoxicity and enhanced PAH skin permeation rates. Skin permeation rates (J) for selected PAHs in a mixture (PAH-mix) or in bitumen fume condensate (BFC) with and without UV-S co-exposures were measured with in vitro flow-through diffusion cells mounted with human viable skin and results compared. Possible biomarkers were explored. Js were greater with UV-S for naphthalene, anthracene, and pyrene in BFC (0.08-0.1 ng/cm javax.xml.bind.JAXBElement@5490394f /h) compared to without (0.02-0.26 ng/cm javax.xml.bind.JAXBElement@2ff08242 /h). This was true for anthracene, pyrene, and chrysene in the PAH-mix. Naphthalene and benzo(a)pyrene (BaP) in the PAH-mix had greater Js without (0.97-13.01 ng/cm javax.xml.bind.JAXBElement@4d9aaf01 /h) compared to with UV-S (0.40-6.35 ng/cm javax.xml.bind.JAXBElement@6fa62fdf /h). Time until permeation (T javax.xml.bind.JAXBElement@3a293925 ) in the PAH-mix were generally shorter compared to the BFC, and they ranged from 1 to 13 h. The vehicle matrix could potentially be the reason for this discrepancy as BFC contains additional not identified substances. Qualitative interpretation of p53 suggested a dose-response with UV-S, and somewhat with the co-exposures. MMP1, p65 and cKIT were not exploitable. Although not statistically different, PAHs permeate human viable skin faster with simultaneous exposures to UV.

The emergence of electronic cigarettes (e-cigs) has given cannabis smokers a new method of inhaling cannabinoids. E-cigs differ from traditional marijuana cigarettes in several respects. First, it is assumed that vaporizing cannabinoids at lower temperatures is safer because it produces smaller amounts of toxic substances than the hot combustion of a marijuana cigarette. Recreational cannabis users can discretely “vape” deodorized cannabis extracts with minimal annoyance to the people around them and less chance of detection. There are nevertheless several drawbacks worth mentioning: although manufacturing commercial (or homemade) cannabinoid-enriched electronic liquids (e-liquids) requires lengthy, complex processing, some are readily on the Internet despite their lack of quality control, expiry date, and conditions of preservation and, above all, any toxicological and clinical assessment. Besides these safety problems, the regulatory situation surrounding e-liquids is often unclear. More simply ground cannabis flowering heads or concentrated, oily THC extracts (such as butane honey oil or BHO) can be vaped in specially designed, pen-sized marijuana vaporizers. Analysis of a commercial e-liquid rich in cannabidiol showed that it contained a smaller dose of active ingredient than advertised; testing our laboratory-made, purified BHO, however, confirmed that it could be vaped in an e-cig to deliver a psychoactive dose of THC. The health consequences specific to vaping these cannabis preparations remain largely unknown and speculative due to the absence of comprehensive, robust scientific studies. The most significant health concerns involve the vaping of cannabinoids by children and teenagers. E-cigs could provide an alternative gateway to cannabis use for young people. Furthermore, vaping cannabinoids could lead to environmental and passive contamination.

Methylchloroisothiazolinone (MCI) and methylisothiazolinone (MI) are biocides used in many types of products such as cosmetics, paints, and cleaning agents. Skin contact is often encountered when using these products. Although MCI and MI are strong allergens and cause skin irritation, no scientific skin permeation study has been reported except for some unpublished data. Therefore, this study assessed the permeation of MCI and MI both separately and as a mixture through freshly dermatomed human skin (800 µm) in a flow-through diffusion cell system. Different concentrations of aqueous standards (1.5/1, 70/50, 150/35, and 750/175 µg/mL of MCI/MI) and various commercial products were assessed after 15-20 h of exposure. In parallel, the dose-dependent irritant effects of MCI/MI and MI were estimated by histology following 6- or 24-h exposure. Overall results show that MI in formulations or in aqueous standard solutions quickly permeated the skin with time lags less than 15 min while MCI was much slower (>3.5 h). MCI in formulations had permeation rates up to five times greater than that for MI in the same product, and in two tested creams were not found to permeate skin. Some signs of irritation were observed by histology; especially at the highest MCI/MI concentrations (750/250 µg/mL) in aqueous solutions. This confirms that MCI reacts readily with skin and may induce local irritation. The MCI and MI permeations are also greatly influenced by the topical vehicle. It is, therefore, more relevant to test exposures to formulations than aqueous standard solutions.

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 5 2) and grape growers (n 5 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 corrections.

Passive exposure to cannabis smoke may induce effects on behavior and psychomotor skills, and have legal consequences, including the risk of being falsely considered as a cannabis user. This can become a concern, especially in occupational contexts or when driving vehicles. In order to enable a differentiation between a passive and an active exposure to cannabis and to limit the likeliness to be detected positive following passive exposure, this review identified specific biomarkers of passive exposure in urine, blood, oral fluid, hair, and sebum. Out of 958 papers identified on passive exposure to cannabis, 21 were selected. Although positive tests had been observed in all matrices following extremely high passive exposure, some distinctive features were observed in each matrix compared to cannabis active use. More specifically, in everyday life conditions, 11-nor-delta-9-THC-carboxylic acid (THC-COOH) urinary level should be detected below the positivity threshold used to confirm active smoking of cannabis, especially after normalization to creatinine level. Measuring delta-9-tetrahydrocannabinol (THC) and THC-COOH in blood is an appropriate alternative for appraising passive exposure as low and very low concentrations of THC and THC-COOH, respectively, should be measured. In hair, oral fluid (OF) and sweat/sebum emulsion, no THCCOOH should be detected. Its presence in hair argues for regular cannabis consumption and in OF or sweat for recent consumption. The experts should recommend to persons who have to demonstrate abstinence from cannabis to avoid heavily smoky and unventilated environments.

Therapeutic cannabis administration is increasingly used in Western countries due to its positive role in several pathologies. Dronabinol or tetrahydrocannabinol (THC) pills, ethanolic cannabis tinctures, oromucosal sprays or table vaporizing devices are available but other cannabinoids forms can be used. Inspired by the illegal practice of dabbing of butane hashish oil (BHO), cannabinoids from cannabis were extracted with butane gas and the resulting concentrate (BHO) was atomized with specific vaporizing devices. The efficiency of “cannavaping,” defined as the “vaping” of liquid refills for e-cigarettes enriched with cannabinoids, including BHO, was studied as an alternative route of administration for therapeutic cannabinoids. The results showed that illegal cannavaping would be subjected to marginal development due to the poor solubility of BHO in commercial liquid refills (especially those with high glycerin content). This prevents the manufacture of liquid refills with high BHO concentrations adopted by most recreational users of cannabis to feel the psychoactive effects more rapidly and extensively. Conversely, “therapeutic cannavaping” could be an efficient route for cannabinoids administration because less concentrated cannabinoids-enriched liquid refills are required. However, the electronic device marketed for therapeutic cannavaping should be carefully designed to minimize potential overheating and contaminant generation.

Aging adults represent the fastest growing population segment in many countries. Physiological and metabolic changes in the aging process may alter how aging adults biologically respond to pollutants. In a controlled human toxicokinetic study (exposure chamber; 12 m 3 ), aging volunteers ( n = 10; >58 years) were exposed to propylene glycol monomethyl ether (PGME, CAS no. 107-98-2) at 50 ppm for 6 h. The dose-dependent renal excretion of oxidative metabolites, conjugated and free PGME could potentially be altered by age. Aims (1) Compare PGME toxicokinetic profiles between aging and young volunteers (20–25 years) and gender; (2) test the predictive power of a compartmental toxicokinetic (TK) model developed for aging persons against urinary PGME concentrations found in this study. Methods Urine samples were collected before, during, and after the exposure. Urinary PGME was quantified by capillary GC/FID. Results Differences in urinary PGME profiles were not noted between genders but between age groups. Metabolic parameters had to be changed to fit the age adjusted TK model to the experimental results, implying a slower enzymatic pathway in the aging volunteers. For an appropriate exposure assessment, urinary total PGME should be quantified. Conclusion Age is a factor that should be considered when biological limit values are developed.

A human in vivo toxicokinetic model was built to allow a better understanding of the toxicokinetics of folpet fungicide and its key ring biomarkers of exposure: phthalimide (PI), phthalamic acid (PAA) and phthalic acid (PA). Both PI and the sum of ring metabolites, expressed as PA equivalents (PAeq), may be used as biomarkers of exposure. The conceptual representation of the model was based on the analysis of the time course of these biomarkers in volunteers orally and dermally exposed to folpet. In the model, compartments were also used to represent the body burden of folpet and experimentally relevant PI, PAA and PA ring metabolites in blood and in key tissues as well as in excreta, hence urinary and feces. The time evolution of these biomarkers in each compartment of the model was then mathematically described by a system of coupled differential equations. The mathematical parameters of the model were then determined from best fits to the time courses of PI and PAeq in blood and urine of five volunteers administered orally 1 mg kg(-1) and dermally 10 mg kg(-1) of folpet. In the case of oral administration, the mean elimination half-life of PI from blood (through feces, urine or metabolism) was found to be 39.9 h as compared with 28.0 h for PAeq. In the case of a dermal application, mean elimination half-life of PI and PAeq was estimated to be 34.3 and 29.3 h, respectively. The average final fractions of administered dose recovered in urine as PI over the 0-96 h period were 0.030 and 0.002%, for oral and dermal exposure, respectively. Corresponding values for PAeq were 24.5 and 1.83%, respectively. Finally, the average clearance rate of PI from blood calculated from the oral and dermal data was 0.09 ± 0.03 and 0.13 ± 0.05 ml h(-1) while the volume of distribution was 4.30 ± 1.12 and 6.05 ± 2.22 l, respectively. It was not possible to obtain the corresponding values from PAeq data owing to the lack of blood time course data.

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.

Biological monitoring of occupational exposure is characterized by important variability, due both to variability in the environment and to biological differences between workers. A quantitative description and understanding of this variability is important for a dependable application of biological monitoring. This work describes this variability,using a toxicokinetic model, for a large range of chemicals for which reference biological reference values exist. A toxicokinetic compartmental model describing both the parent compound and its metabolites was used. For each chemical, compartments were given physiological meaning. Models were elaborated based on physiological, physicochemical, and biochemical data when available, and on half-lives and central compartment concentrations when not available. Fourteen chemicals were studied (arsenic, cadmium, carbon monoxide, chromium, cobalt, ethylbenzene, ethyleneglycol monomethylether, fluorides, lead, mercury, methyl isobutyl ketone, penthachlorophenol, phenol, and toluene), representing 20 biological indicators. Occupational exposures were simulated using Monte Carlo techniques with realistic distributions of both individual physiological parameters and exposure conditions. Resulting biological indicator levels were then analyzed to identify the contribution of environmental and biological variability to total variability. Comparison of predicted biological indicator levels with biological exposure limits showed a high correlation with the model for 19 out of 20 indicators. Variability associated with changes in exposure levels (GSD of 1.5 and 2.0) is shown to be mainly influenced by the kinetics of the biological indicator. Thus, with regard to variability, we can conclude that, for the 14 chemicals modeled, biological monitoring would be preferable to air monitoring. For short half-lives (less than 7 hr), this is very similar to the environmental variability. However, for longer half-lives, estimated variability decreased. [Supplementary materials are available for this article. Go to the publisher's online edition of Journal of Occupational and Environmental Hygiene for the following free supplemental resource: tables detailing the CBTK models for all 14 chemicals and the symbol nomenclature that was used.] [Authors]

Introduction L’utilisation de cannabis therapeutique est en augmentation dans les pays occidentaux, notamment grâce a son efficacite pour traiter plusieurs pathologies (sclerose en plaque, vomissements en chimiotherapie…). Toutefois, seuls sont disponibles des pilules de dronabinol (THC synthetique), des teintures alcooliques, des sprays oraux ou des vaporisateurs medicaux, presentant des inconvenients de concentration, contamination ou efficacite selon les formes galeniques [1] . Inspiree de la pratique illegale du « dabbing » (consommation fumee de condensats de cannabinoides extraits par butane [Butane Hashish Oil: BHO]), l’efficacite du « cannavaping », defini comme le vapotage d’e-liquides enrichis avec des cannabinoides (THC-A et THC), BHO inclus, a ete etudie comme une alternative a l’administration de cannabis therapeutique. Methodes Cette evaluation a considere la facilite de fabrication d’e-liquides enrichis en THC (et leur usage a but recreatif), la possibilite de generer des aerosols enrichis en THC sans pyrolyse et la formation de contaminants potentiellement toxiques, soit des composes organiques volatils (COVs) et des composes carbonyles, echantillonnes a l’aide de cartouches specifiques et analyses par CL-SM/SM, CL-UV et CG/SM. Le BHO a ete prepare en suivant des protocoles disponibles sur Internet a partir de cannabis medical (Bedrocan BV, The Netherlands), puis dilue a 3, 5 et 10 % dans des e-liquides commerciaux. Une machine a vapoter a ete concue et mise en place specifiquement pour realiser ces echantillonnages a partir d’e-dispositifs commerciaux (e-cigarette iTaste VV type, voltage variable de 3,5 a 5 V, clearomizers CE4+, 1,6 mL, 4 meches). Resultats Les resultats ont montre que le « cannavaping » illegal serait sujet a un developpement marginal a cause de la faible solubilite du BHO dans des e-liquides commerciaux (surtout ceux contenant beaucoup de glycerine), restreignant ainsi la fabrication d’e-liquides a hauts taux de BHO, adoptes par la plupart des consommateurs pour ressentir les effets psychoactifs plus rapidement. Des inhalations d’environ 100 bouffees de 70 mL (BHO dilue a 10 % dans l’e-liquide) etaient necessaires pour atteindre une dose de THC equivalente a celle mesuree dans un joint de 800 mg (cannabis/tabac : 50:50). En revanche, le « cannavaping » therapeutique pourrait etre une alternative efficace pour l’administration de cannabinoides, car des e-liquides de concentrations moindres en cannabinoides sont requis. Cependant, les e-dispositifs pour le « cannavaping » therapeutique doivent etre soigneusement concus pour minimiser une potentielle surchauffe et generation de contaminants (composes carbonyles, COV…). De meme, les acteurs de sante publique devront considerer l’utilisation d’autres stupefiants (amphetamines, cocaine, drogues de synthese…) qui pourraient etre consommes via les nouveaux developpements autour de l’e-cigarette, comme c’est le cas actuellement.

Studies assessing skin irritation to chemicals have traditionally used laboratory animals; however, such methods are questionable regarding their relevance for humans. New in vitro methods have been validated, such as the reconstructed human epidermis (RHE) model (Episkin®, Epiderm®). The comparison (accuracy) with in vivo results such as the 4-h human patch test (HPT) is 76% at best (Epiderm®). There is a need to develop an in vitro method that better simulates the anatomo-pathological changes encountered in vivo.To develop an in vitro method to determine skin irritation using human viable skin through histopathology, and compare the results of 4 tested substances to the main in vitro methods and in vivo animal method (Draize test).Human skin removed during surgery was dermatomed and mounted on an in vitro flow-through diffusion cell system. Ten chemicals with known non-irritant (heptylbutyrate, hexylsalicylate, butylmethacrylate, isoproturon, bentazon, DEHP and methylisothiazolinone (MI)) and irritant properties (folpet, 1-bromohexane and methylchloroisothiazolinone (MCI/MI)), a negative control (sodiumchloride) and a positive control (sodiumlaurylsulphate) were applied. The skin was exposed at least for 4h. Histopathology was performed to investigate irritation signs (spongiosis, necrosis, vacuolization).We obtained 100% accuracy with the HPT model; 75% with the RHE models and 50% with the Draize test for 4 tested substances. The coefficients of variation (CV) between our three test batches were0.1, showing good reproducibility. Furthermore, we reported objectively histopathological irritation signs (irritation scale): strong (folpet), significant (1-bromohexane), slight (MCI/MI at 750/250ppm) and none (isoproturon, bentazon, DEHP and MI).This new in vitro test method presented effective results for the tested chemicals. It should be further validated using a greater number of substances; and tested in different laboratories in order to suitably evaluate reproducibility.

Phthalates are suspected to be endocrine disruptors. Di(2-ethylhexyl) phthalate (DEHP) is assumed to have low dermal absorption; however, previous in vitro skin permeation studies have shown large permeation differences. Our aims were to determine DEHP permeation parameters and assess extent of skin DEHP metabolism among workers highly exposed to these lipophilic, low volatile substances. Surgically removed skin from patients undergoing abdominoplasty was immediately dermatomed (800 μm) and mounted on flow-through diffusion cells (1.77 cm(2)) operating at 32°C with cell culture media (aqueous solution) as the reservoir liquid. The cells were dosed either with neat DEHP or emulsified in aqueous solution (166 μg/ml). Samples were analysed by HPLC-MS/MS. DEHP permeated human viable skin only as the metabolite MEHP (100%) after 8h of exposure. Human skin was able to further oxidize MEHP to 5-oxo-MEHP. Neat DEHP applied to the skin hardly permeated skin while the aqueous solution readily permeated skin measured in both cases as concentration of MEHP in the receptor liquid. DEHP pass through human skin, detected as MEHP only when emulsified in aqueous solution, and to a far lesser degree when applied neat to the skin. Using results from older in vitro skin permeation studies with non-viable skin may underestimate skin exposures. Our results are in overall agreement with newer phthalate skin permeation studies.

A human in vivo toxicokinetic model was built to allow a better understanding of the toxicokinetics of folpet fungicide and its key ring biomarkers of exposure: phthalimide (PI), phthalamic acid (PAA) and phthalic acid (PA). Both PI and the sum of ring metabolites, expressed as PA equivalents (PAeq), may be used as biomarkers of exposure. The conceptual representation of the model was based on the analysis of the time course of these biomarkers in volunteers orally and dermally exposed to folpet. In the model, compartments were also used to represent the body burden of folpet and experimentally relevant PI, PAA and PA ring metabolites in blood and in key tissues as well as in excreta, hence urinary and feces. The time evolution of these biomarkers in each compartment of the model was then mathematically described by a system of coupled differential equations. The mathematical parameters of the model were then determined from best fits to the time courses of PI and PAeq in blood and urine of five volunteers administered orally 1 mg kg(-1) and dermally 10 mg kg(-1) of folpet. In the case of oral administration, the mean elimination half-life of PI from blood (through feces, urine or metabolism) was found to be 39.9 h as compared with 28.0 h for PAeq. In the case of a dermal application, mean elimination half-life of PI and PAeq was estimated to be 34.3 and 29.3 h, respectively. The average final fractions of administered dose recovered in urine as PI over the 0-96 h period were 0.030 and 0.002%, for oral and dermal exposure, respectively. Corresponding values for PAeq were 24.5 and 1.83%, respectively. Finally, the average clearance rate of PI from blood calculated from the oral and dermal data was 0.09 ± 0.03 and 0.13 ± 0.05 ml h(-1) while the volume of distribution was 4.30 ± 1.12 and 6.05 ± 2.22 l, respectively. It was not possible to obtain the corresponding values from PAeq data owing to the lack of blood time course data.

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 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.

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

Oxidative stress can contribute to the development of diseases, and may originate from exposures to toxicants commonly found in air pollution and cigarette smoke such as polycyclic aromatic hydrocarbons (PAHs) and volatile organic compounds (VOCs). Yet, associations between these exposures and oxidative stress biomarkers are poorly characterized. We report here novel associations between 14 exposure biomarkers of PAHs and VOCs, and two oxidative stress biomarkers; 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) and 8-isoprostaglandin F 2α (8-isoprostane) in urine obtained from smokers participating in an ongoing clinical study (ESTxENDS, NCT03589989). We also assessed associations between six biomarkers of tobacco smoke exposure (metabolites of nicotine and tobacco-specific nitrosamines (TSNAs)) and both oxidative stress biomarkers. We then quantified the relative importance of each family of the 20 exposure biomarkers on oxidative stress. Participating smokers (153 men and 117 women, median age 44 years) had on average smoked 25 [2-62] years and smoked about 17 [5-40] cigarettes per day at the time of the study. Multiple linear regression results showed an association between 8-oxodG concentrations and the following metabolites in decreasing relative importance: PAHs (beta coefficient β = 0.105, p-value 2 = 0.15) > VOCs (β = 0.028, p < 0.001, partial R 2 = 0.09) > nicotine (β = 0.226, p < 0.001, partial R 2 = 0.08); and between 8-isoprostane concentrations and metabolites of PAHs (β = 0.117, p < 0.001, partial R 2 = 0.14) > VOCs (β = 0.040, p < 0.001, partial R 2 = 0.14) > TSNAs (β = 0.202, p = 0.003, partial R 2 = 0.09) > nicotine (β = 0.266, p < 0.001, partial R 2 = 0.08). Behavioral factors known to contribute to oxidative stress, including sleep quality, physical activity, and alcohol consumption, did not play a significant role. Exposures to PAHs and VOCs among smokers were significantly associated with oxidative stress.