RESUMO
[This corrects the article DOI: 10.3389/fchem.2023.1212744.].
RESUMO
Leachable investigations are routinely undertaken across a range of sectors (e.g., pharmaceuticals, medical devices, etc.) to determine whether chemicals from a container closure system transfer into a product under normal conditions of use. For Electronic Nicotine Delivery Systems (ENDS) the container closure system includes all materials in contact with the e-liquid that is aerosolized and subsequently inhaled by the user. Currently, there is no guidance for conducting leachable studies for ENDS products, however, there are relevant guidance documents for orally inhaled drug products that can be applied to an ENDS container closure system. We present a case study of the analytical investigation of two leachable compounds identified in simulated leachable studies using aged JUULpods filled with unflavored e-liquid (PG/VG/nicotine/benzoic acid). Both compounds had limited toxicological information and were considered data deficient. A qualitative analysis of the aerosol collected from aged commercial JUULpods (Virginia Tobacco and Menthol), using a similar analytical method (LC-MS/MS) used in the simulated leachable studies, showed no trace or detectable levels of either leachable compound. Therefore, this qualitative analysis did not provide semi-quantitative values for the data-deficient leachable compounds necessary to support toxicological risk assessment. Further, no commercial authentic standards or reasonable synthetic route were available due to the molecular size and structural complexity of the compounds. Instead, method limits were established using an alternative approach to standard ICH guidelines. The experimentally determined method limit of quantitation, using spiked samples of simulated leachable e-liquid, provided conservative semi-quantitative values for each data deficient leachable compound in the aerosol that enabled a transfer efficiency from e-liquid to aerosol to be estimated. The transfer efficiency of each leachable compound was experimentally determined to be less than 2% based on the limit of quantitation, which then could be used to define a relevant exposure limit for the toxicological risk assessment. This work details a novel analytical approach for determining the transfer efficiency of data deficient leachable compounds from ENDS container closure systems into the ENDS aerosol to support toxicological health risk assessments.
RESUMO
Contiene: introducción, toxicología ambiental, evaluación de riesgos ambientales, restauración ambiental y prevención de la contaminación.
Assuntos
Toxicologia , Saúde Ambiental , Riscos Ocupacionais , Saúde Ocupacional , Poluição Ambiental , Riscos AmbientaisRESUMO
The mechanism of arsine (AsH3) toxicity is not completely understood, but hemoglobin (Hb) has long been recognized as a necessary component of the overall mechanism of AsH3-induced hemolysis. In this study, the role of Hb in AsH3-induced hemolysis was investigated. The purpose was to determine whether exposure to AsH3 altered the structure of the heme or globin constituents of Hb. Arsine was incubated with isolated, human oxyhemoglobin (oxyHb) and carboxyhemoglobin (carboxyHb), and the release of heme and formation of AsH3-induced hemoglobin modifications were examined. Arsine increased the amount of heme released from oxyHb by 18%. When carboxyHb was incubated with AsH3, there was no change in heme release, suggesting that the sixth ligand position on the heme iron may be critical in the interaction with AsH3. Arsine-Hb interactions were studied by mass spectral analysis of heme, alpha-chain globin, and beta-chain globin. Arsine had no significant effect on the alpha- or beta-chain LCMS spectra in oxyHb and carboxyHb, but in oxyHb, arsine consistently increased the frequency of methyl acetate ion fragment (.CH2OOH, m/z = 59) loss from heme in the matrix-assisted laser desorption/ionization-mass spectrometry (MALDI-MS) spectra. The formation of Hb-protein crosslinks was investigated by Western blotting using an anti-Hb antibody in isolated membranes from AsH3-treated erythrocytes, but no Hb-membrane adducts were found. These results suggest that the interaction between AsH3 and hemoglobin result in an increase in heme release which may contribute to the hemolytic mechanism of AsH3.
