Mono-n-hexyl phthalate: exposure estimation and assessment of health risks based on levels found in human urine samples.

Mono-n-hexyl phthalate (MnHexP) is a primary metabolite of di-n-hexyl phthalate (DnHexP) and other mixed side-chain phthalates that was recently detected in urine samples from adults and children in Germany. DnHexP is classified as toxic for reproduction category 1B in Annex VI of Regulation (EC) 1272/2008 and listed in Annex XIV of the European chemical legislation REACH; thereby, its use requires an authorisation. Health-based guidance values for DnHexP are lacking and a full-scale risk assessment has not been carried out under REACH. The detection of MnHexP in urine samples raises questions about the sources of exposure and concerns of consumer safety. Here, we propose the calculation of a provisional oral tolerable daily intake value (TDI) of 63 µg/kg body weight/day for DnHexP and compare it to intake levels corresponding to levels of MnHexP found in urine. The resulting mean intake levels correspond to less than 0.2% of the TDI, and maximum levels to less than 5%. The TDI was derived by means of an approximate probabilistic analysis using the credible interval from benchmark dose modelling of published ex vivo data on reduced foetal testosterone production in rats. Thus, for the dose associated to a 20% reduction in testosterone production, a lower and upper credible interval of 14.9 and 30.0 mg/kg bw/day, respectively, was used. This is considered a conservative approach, since apical developmental endpoints (e.g. changed anogenital distance) were only observed at higher doses. In addition, we modelled various scenarios of the exposure to the precursor substance DnHexP from different consumer products, taking measured contamination levels into account, and estimated systemic exposure doses. Of the modelled scenarios including the application of sunscreen (as a lotion or pump spray), the use of lip balm, and the wearing of plastic sandals, and considering conservative assumptions, the use of DnHexP-contaminated sunscreen was highlighted as a major contributing factor. A hypothetical calculation using conservative assumptions for the latter resulted in a margin of safety in relation to the lower credible interval of 3267 and 1007 for adults and young children, respectively. Most importantly, it was found that only a fraction of the TDI is reached in all studied exposure scenarios. Thus, with regard to the reported DnHexP exposure, a health risk can be considered very unlikely.

Small pouches, but high nicotine doses-nicotine delivery and acute effects after use of tobacco-free nicotine pouches.

Tobacco-free nicotine pouches are new nicotine products for oral consumption. They can contain very high nicotine amounts that have not been addressed with clinical studies yet. Thus, nicotine delivery, effects on craving, and side effects were assessed using pouches with up to 30 mg nicotine. In this single-center, five-arm, crossover study, 15 regular cigarette smokers consumed tobacco-free nicotine pouches from different brands with 6, 20, and 30 mg for 20 min. Comparators were nicotine-free pouches and tobacco cigarettes. At baseline and predefined time points over a study period of 240 min, plasma nicotine concentrations, effects on cigarette craving, and side effects were assessed. Cardiovascular parameters including arterial stiffness were measured using a MobilOGraph. Consumption of 30 mg nicotine pouches has led to a higher nicotine uptake compared with the cigarette (Cmax: 29.4 vs 15.2 ng/mL; AUC: 45.7 vs 22.1 ng/mL × h). Nicotine uptake in the acute phase was rapid during use of the 30 mg pouch and cigarette. Extraction rate of nicotine differed between pouches. Use of all products has reduced acute cigarette craving, even the nicotine-free pouch. During consumption of the cigarette and the pouches with 20 and 30 mg, heart rate increased about 27, 12, and 25 bpm, respectively. Parameters for arterial stiffness were elevated and all pouches have induced mouth irritations. The pouches with 30 mg nicotine had overall the strongest side effects and may induce addiction. As craving was also reduced by products with less nicotine, it is questionable whether such high nicotine contents should be allowed on the market. A limit of nicotine content is warranted. The nicotine release rate varies across products and needs to be known to estimate the nicotine delivery.

A targeted fluorescent nanosensor for ratiometric pH sensing at the cell surface.

The correlation between altered extracellular pH and various pathological conditions, including cancer, inflammation and metabolic disorders, is well known. Bulk pH measurements cannot report the extracellular pH value at the cell surface. However, there is a limited number of suitable tools for measuring the extracellular pH of cells with high spatial resolution, and none of them are commonly used in laboratories around the world. In this study, a versatile ratiometric nanosensor for the measurement of extracellular pH was developed. The nanosensor consists of biocompatible polystyrene nanoparticles loaded with the pH-inert reference dye Nile red and is surface functionalized with a pH-responsive fluorescein dye. Equipped with a targeting moiety, the nanosensor can adhere to cell membranes, allowing direct measurement of extracellular pH at the cell surface. The nanosensor exhibits a sensitive ratiometric pH response within the range of 5.5-9.0, with a calculated pKa of 7.47. This range optimally covers the extracellular pH (pHe) of most healthy cells and cells in which the pHe is abnormal, such as cancer cells. In combination with the nanosensors ability to target cell membranes, its high robustness, reversibility and its biocompatibility, the pHe nanosensor proves to be well suited for in-situ measurement of extracellular pH, even over extended time periods. This pH nanosensor has the potential to advance biomedical research by improving our understanding of cellular microenvironments, where extracellular pH plays an important role.

Polycyclic aromatic hydrocarbon skin permeation efficiency in vitro is lower through human than pigskin and decreases with lipophilicity.

Polycyclic aromatic hydrocarbons (PAH) are persistent environmental pollutants, which occasionally appear as contaminants in consumer products. Upon dermal contact, transfer of PAH into the stratum corneum (s.c.) and migration through the skin may occur, resulting in this class of highly toxic compounds to become bioavailable. In this study, dermal penetration through human and porcine skin of 24 PAH, comprising broad molar mass (M: 152-302 g/mol) and octanol-water partition coefficient (logP: 3.9-7.3) ranges, was evaluated via Franz diffusion cell in vitro assays. More lipophilic and potentially more toxic PAH had decreased permeation rates through the rather lipophilic s.c. into the more hydrophilic viable (epi-)dermis. Furthermore, human skin was less permeable than pigskin, a commonly used surrogate in skin penetration studies. In particular, the s.c. of human skin retains a greater share of PAH, an effect that is more pronounced for smaller PAH. Additionally, we compared the skin permeation kinetics of different PAH in pigskin. While small PAH (M < 230 g/mol, logP < 6) permeate the skin quickly and are detected in the receptor fluid after 2 h, large PAH (M > 252 g/mol, logP ≥ 6) do not fully permeate the skin up to 48 h. This indicates that highly lipophilic PAH do not become bioavailable as readily as their smaller congeners when transferred to the skin surface. Our data suggest that pigskin could be used as a surrogate for worst case scenario estimates of dermal PAH permeation through human skin.

Lessons learned in a decade: Medical-toxicological view of tattooing.

Tattooing has been part of the human culture for thousands of years, yet only in the past decades has it entered the mainstream of the society. With the rise in popularity, tattoos also gained attention among researchers, with the aim to better understand the health risks posed by their application. 'A medical-toxicological view of tattooing'-a work published in The Lancet almost a decade ago, resulted from the international collaboration of various experts in the field. Since then, much understanding has been achieved regarding adverse effects, treatment of complications, as well as their regulation for improving public health. Yet major knowledge gaps remain. This review article results from the Second International Conference on Tattoo Safety hosted by the German Federal Institute for Risk Assessment (BfR) and provides a glimpse from the medical-toxicological perspective, regulatory strategies and advances in the analysis of tattoo inks.

Less efficient skin penetration of the metal allergen Pd2+ compared to Ni2+ and Co2+ from patch test preparations.

BACKGROUND: Contrary to Ni2+- and Co2+-induced allergic contact dermatitis (ACD), reactions against Pd2+ are rare. However, Pd2+ activates a larger T cell fraction in vitro, suggesting an inefficient skin penetration. OBJECTIVES: This study compares Ni2+, Co2+ and Pd2+ skin penetration from commonly used diagnostic patch test preparations (PTPs) and aqueous metal salt solutions. METHODS: Using Franz diffusion cell assays, we applied the metals in PTPs (5% NiSO4, 1% CoCl2, 2% PdCl2 and 3% Na2PdCl4) and in solution to pigskin for 48 h, thereby mirroring the time frame of a patch test. The different compartments were analysed individually by inductively coupled plasma mass spectrometry. RESULTS: Metal ions were mainly retained in the upper stratum corneum layers. After application of PTPs, concentrations in the viable skin were lower for Pd2+ (1 and 7 µM) compared to Ni2+ and Co2+ (54 and 17 µM). CONCLUSIONS: Ni2+ and Co2+ penetrated the skin more efficiently than Pd2+ and thus may sensitize and elicit ACD more easily. This was observed for ions applied in petrolatum and aqueous solutions. We hypothesize that the differently charged metal complexes are responsible for the varying skin penetration behaviours.

A multi-technique approach for the quantification of 60 plasticizers and selected additives using GC- and LC-MS/MS and its application for beverages in the BfR MEAL study.

The development of multi-analyte methods is always challenging, especially when the target compounds derive from many different substance classes. We present an approach to analyze up to 60 additives - mainly plasticizer - including 28 phthalates and 32 further compounds such as sebacates, adipates, citrates, fatty acid amides, among others. Our multi-analyte multi-technique approach combines a single sample preparation step with one GC-MS/MS and two LC-MS/MS quantification methods. We demonstrate the applicability for beverages by a full validation in tomato juice matrix and determining the recoveries in apple juice, mulled wine, and spirits. The approach features good reproducibilities and high precisions with limits of quantification in the low µg·kg-1 food range, enabling the method to be applied for enforcement and especially for exposure investigations. In course of the BfR MEAL study, 16 pooled beverage samples were examined and - if at all - analytes were found only in very low concentrations.

Harmonization Risks and Rewards: Nano-QSAR for Agricultural Nanomaterials.

This comprehensive review explores the emerging landscape of Nano-QSAR (quantitative structure-activity relationship) for assessing the risk and potency of nanomaterials in agricultural settings. The paper begins with an introduction to Nano-QSAR, providing background and rationale, and explicitly states the hypotheses guiding the review. The study navigates through various dimensions of nanomaterial applications in agriculture, encompassing their diverse properties, types, and associated challenges. Delving into the principles of QSAR in nanotoxicology, this article elucidates its application in evaluating the safety of nanomaterials, while addressing the unique limitations posed by these materials. The narrative then transitions to the progression of Nano-QSAR in the context of agricultural nanomaterials, exemplified by insightful case studies that highlight both the strengths and the limitations inherent in this methodology. Emerging prospects and hurdles tied to Nano-QSAR in agriculture are rigorously examined, casting light on important pathways forward, existing constraints, and avenues for research enhancement. Culminating in a synthesis of key insights, the review underscores the significance of Nano-QSAR in shaping the future of nanoenabled agriculture. It provides strategic guidance to steer forthcoming research endeavors in this dynamic field.

Levels of nicotine and tobacco-specific nitrosamines in oral nicotine pouches.

BACKGROUND: Nicotine pouches without tobacco are new products that deliver nicotine into the body via the oral mucosa. There is a lack of independent research on the chemical composition and product characteristics of these products, contributing to uncertainties regarding product regulation. This study sought to address knowledge gaps by assessing levels of nicotine and screening for tobacco-specific nitrosamines (TSNAs) in a sample of these products. METHODS: Nicotine pouches (n=44) and nicotine-free pouches (n=2) from 20 different manufacturers were analysed regarding their contents of nicotine and TSNAs by gas chromatography with flame ionisation and liquid chromatography-tandem mass spectrometry, respectively. Product labelling and pH values of aqueous extracts were determined. RESULTS: Nicotine contents of products ranged from 1.79 to 47.5 mg/pouch; median product weight, pH, and proportion of free-base nicotine were 0.643 g, 8.8, and 86%, respectively. A clear labelling of the nicotine content was missing on 29 products and nicotine strength descriptions were ambiguous. TSNAs were detected in 26 products, with a maximum of 13 ng N-nitrosonornicotine/pouch. CONCLUSION: Although nicotine pouches may potentially be a reduced risk alternative for cigarette smokers or users of some other oral tobacco products, nicotine contents of some pouches were alarmingly high. Presence of carcinogenic TSNAs in the nicotine pouches is of serious concern. Better manufacturing processes and quality control standards should be implemented. Labels of nicotine strength on most products are misleading. A strict regulation regarding nicotine contents and its labelling would be advisable.