Pulmonary delivery of d-methionine is associated with an increase in ALCAR and glutathione in cochlear fluids.

In animals, hearing loss resulting from cochlear mechanosensory cell damage can be mitigated by antioxidants such as d-methionine (d-met) and acetyl-l-carnitine (ALCAR). The systemic routes of administration of these compounds, that must of necessity transit trough the cochlear fluids, may affect the antioxidant levels in the cochlea and the resulting oto-protective effect. In this study, we analyzed the pharmacokinetics of [(14)C]d-met in the cochlea and four other tissues after intratracheal (IT), intranasal (IN), and oral by gavage (OG) administration and compared it to intravenous administration (IV). We then analyzed the effect of these four routes on the antioxidant content of the cochlear fluids after d-met or ALCAR administration, by liquid chromatography/mass spectrometry. Our results showed that the concentration of methionine and ALCAR in cochlear fluids significantly increased after their respective systemic administration. Interestingly, d-met administration also contributed to an increase of ALCAR. Our results also showed that the delivery routes differently affected the bioavailability of administered [(14)C]d-met as well as the concentrations of methionine, ALCAR and the ratio of oxidized to reduced glutathione. Overall, pulmonary delivery via IT administration achieved high concentrations of methionine, ALCAR, and oxidative-related metabolites in cochlear fluids, in some cases surpassing IV administration, while IN route appeared to be the least efficacious. To our knowledge, this is the first report of the direct measurements of antioxidant levels in cochlear fluids after their systemic administration. This report also demonstrates the validity of the pulmonary administration of antioxidants and highlights the different contributions of d-met and ALCAR allowing to further investigate their impact on oxidative stress in the cochlear microenvironment.

Exposures to drinking water chlorination by-products in a Russian city.

Exposures to water disinfection by-products (DBPs) via ingestion of drinking water, and dermal absorption and inhalation during showering/bathing were assessed in the city of Cherepovets, Russia, which uses heavy chlorination to disinfect organic-rich surface water. Concentrations of DBPs (mean +/- standard deviation) in tap water were the following: total trihalomethanes (THMs) 205 +/- 70 micrograms/l, five haloacetic acids (HAAs) 150 +/- 30 micrograms/l, and 3-chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone (mutagen X or MX) 160 +/- 50 ng/l. Concentrations of THMs and HAAs exceeded the corresponding US standards by a factor of 2.5, while MX concentrations were the highest ever reported. The mutagenic activity of tap water extracts in the Salmonella TA-100 assay was 14,900 net revertants/l. Concentrations of chloroform in breathing zone air in bathrooms during showering were 330 +/- 260 micrograms/m3, shower room air at an industrial plant 2,600 +/- 1,100 micrograms/m3, and bedrooms of local residents 2 +/- 2 micrograms/m3. The mean concentration of chloroform was 3.2 micrograms/m3 in exhaled air samples collected before showering and 110 micrograms/m3 after showering. Data on water ingestion and water use practices in the general population and for pregnant women were collected using questionnaires and diaries. Due to concerns over microbiological safety of water, average daily consumption of non-boiled tap water in pregnant women was only 0.01 l/day, while consumption of boiled tap water was 0.81 l/day. This resulted in low ingestion exposures to volatile THMs. Inhalation and dermal absorption determined total exposures to these compounds. HAAs and MX persist in boiled water and drinks resulting in high ingestion exposures. Several brands of inexpensive home water filters were tested for removal of these compounds. To demonstrate a method of exposure reduction in a sensitive subpopulation, the most efficient filters were given to a group of pregnant women. These women and a control group of pregnant women without filters maintained water ingestion diaries for two weeks. The use of home filters resulted in reduction of exposures to HAAs by a factor of three and a greater reduction in exposures to MX.