Ethers as Gasoline Additives Toxicokinetics and Acute Effects in Humans

Ethers or other oxygen-containing compounds are used as replacements for lead in gasoline and to ensure complete combustion. Methyl tertiary-butyl ether (MTBE) is already in use world-wide and ethyl tertiary-butyl ether (ETBE) may be used increasingly in the future. The aims of the present thesis were to study the uptake and disposition (toxicokinetics) of MTBE and ETBE in humans, to address the issue of biological monitoring and to measure acute effects (assessed by questionnaire, lung function, nasal and ocular measurements). Healthy male volunteers were experimentally exposed during 2 h to vaporized MTBE (5, 25 and 50 ppm, n=10) or ETBE (0, 5, 25 and 50 ppm, n=8) in a chamber (whole-body) and 13C-labeled MTBE (50 ppm, n=4) via a face-mask. The toxicokinetics of MTBE and ETBE in humans were quite similar, judging from breath, blood and urine profiles. However, the respiratory uptake of MTBE was higher (45% MTBE and 33% ETBE) and respiratory exhalation of unmetabolized MTBE was lower (38% MTBE and 47% ETBE) compared to ETBE. Linear kinetics was seen for the ethers and TBA up to 50 ppm. Low urinary excretion of unmetabolized ether (<0.1%) and of a metabolite, tertiary-butyl alcohol (TBA) (<1%), was seen. After 13C-labeled MTBE exposure two urinary metabolites, 2-methyl-1,2-propanediol and a-hydroxyisobutyric acid, were characterized by 13C-NMR. These metabolites were excreted in markedly higher amounts than TBA. A physiologically based toxicokinetic model was developed for ETBE using the determined partition coefficients and data from the chamber exposure. The model indicates that workload has a profound influence on internal dose. TBA excretion seemed to be less sensitive to fluctuations in exposure levels compared to the ether, especially in samples taken at the end of a workshift. Only a small accumulation of ether and TBA in the body was seen throughout a week of repeated exposure. MTBE vapor had very small or no effects up to 50 ppm. After ETBE exposure, elevated ratings of irritation in the throat and airways (50 ppm), and, in addition, minor pulmonary function impairments were seen (25 and 50 ppm ETBE, lung measures not performed for MTBE). This effect as such is not of clinical concern in healthy individuals. However, it cannot be excluded that other subjects may show more severe reactions. In conclusion, the toxicokinetic results as well as considering practical issues (i.e. sampling and analysis), implies that the concentration of TBA in urine is a good biological exposure marker for ether and gasoline vapor. However, further studies of other metabolites that are excreted in higher amounts in the urine (e.g., a-hydroxyisobutyric acid), may identify even more suitable candidates as biomarkers. The knowledge about the toxicokinetics and acute effects of MTBE and ETBE in humans presented in this thesis is relevant in e.g., risk assessments. Key words: acute effects, biological monitoring, ethyl tertiary-butyl ether, ETBE, man, methyl tertiary-butyl ether, MTBE, oxygenate, petrol, physiologically based toxicokinetic model, PBTK, PBPK, tertiary-butyl alcohol, TBA, toxicokinetics.Etrar eller andra ämnen som innehåller syre används i bensin för att ersätta bly och förbättra förbränningen. Metyl tertiär-butyl eter (MTBE) används globalt, men kan komma att ersättas av etyl tertiär-butyl eter (ETBE). Syftet med studien var att studera MTBE och ETBEs upptag och omsättning (toxikokinetik) hos människa, relatera till biologiska exponeringsmarkörer och mäta akuta effekter (frågeformulär, lungfunktion, näs- och ögonmätningar). Friska frivilliga män exponerades i 2 timmar under lätt arbete dels för förångad MTBE (5, 25 och 50 ppm) eller ETBE (0, 5, 25 och 50 ppm) i en kammare och dels för 13C-märkt MTBE (50 ppm) via en ansiktsmask. Blod-, utandnings- och urinprofiler av MTBE och ETBE hos människa visade på likartad toxikokinetik för båda ämnena. Dock var upptaget av MTBE högre (45% MTBE och 33% ETBE) och utandningen av ometaboliserad MTBE lägre (38% MTBE och 47% ETBE) än för ETBE. Etrar och TBA följde linjär kinetik upp till 50 ppm. Urinutsöndringen av eter (<0.1%) och av en metabolit, tertiär-butyl alkohol (TBA) (