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Diisobutyl ketone (DIBK) and diisobutyl carbinol (DIBC) are important organic solvents widely used as industrial intermediates. It was hypothesized that DIBC and DIBK have common metabolic pathways and metabolites, and as such, toxicological data on DIBK could be used to characterize the hazards of DIBC. To confirm or refute this hypothesis a comparative metabolism and pharmacokinetics assessment of DIBK and DIBC was conducted. Dosing was via single oral gavage dosing in male SD rats, followed by blood collection, metabolite identification, major biomarker quantitation, and pharmacokinetics analysis. Overall, the major metabolites of both DIBC and DIBK in blood were their corresponding monohydroxylated metabolites (DIBC alcohol and DIBK alcohol) with the site of hydroxylation at the σ and σ-1 positions, respectively. Quantitative analysis of DIBC, DIBK, DIBC-alcohol, and DIBK-alcohol in blood samples collected from 5 min to 120 h after single dosing indicated the following: (1) DIBC and DIBK are both well absorbed following oral gavage with substantial evidence of enterohepatic recirculation of DIBK, DIBC, DIBK-alcohol, and DIBC-alcohol; (2) DIBK and DIBC are interconverted metabolically in rats; (3) DIBC and DIBK have similar bioavailability after oral administration; (4) higher systemic exposure was found for DIBK-alcohol than DIBC-alcohol, implying that DIBC-alcohol may be more easily conjugated and eliminated in bile. In summary, the metabolic similarities and the difference in systemic exposure to metabolites between these substances observed in the current study support the hypothesis that DIBC might have a lower potential toxicity than that of DIBK. The current study results support that toxicological data on DIBK could be used to characterize the hazards of DIBC [ABSTRACT FROM AUTHOR]

N -alkyl-2-pyrrolidones are important organic solvents for varnishes in industry. This study investigates exposure to N -ethyl-2-pyrrolidone (NEP) in varnishing of hard plastic components in an automobile plant. Two specific biomarkers of exposure, 5-hydroxy- N -ethyl-2-pyrrolidone (5-HNEP) and 2-hydroxy- N -ethylsuccinimide (2-HESI), were analyzed in urine samples of 14 workers. For this purpose, pre-shift, post-shift and next day pre-shift urine samples were collected midweek. Twelve workers performed regular work tasks (loading, wiping and packing), whereas two workers performed special work tasks including cleaning the sprayer system with organic solvents containing N -alkyl-2-pyrrolidones. Spot urine samples of nine non-exposed persons of the same plant served as controls. Median post-shift urinary levels of workers with regular work tasks (5-HNEP: 0.15 mg/L; 2-HESI: 0.19 mg/L) were ∼5-fold higher compared to the controls (0.03 mg/L each). Continuously increasing metabolite levels, from pre-shift via post-shift to pre-shift samples of the following day, were observed in particular for the two workers with the special working tasks. Maximum levels were 31.01 mg/L (5-HNEP) and 8.45 mg/L (2-HESI). No clear trend was evident for workers with regular working tasks. In summary, we were able to show that workers can be exposed to NEP during varnishing tasks in the automobile industry. [ABSTRACT FROM AUTHOR]

Abstract: 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; 12m3), aging volunteers (n =10; >58 years) were exposed to propylene glycol monomethyl ether (PGME, CAS no. 107-98-2) at 50ppm for 6h. 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. [Copyright &y& Elsevier]

Abstract: The aim of the study was to quantify the variability on biological indicators of exposure between men and women for three well known solvents: methyl ethyl ketone, 1-methoxy-2-propanol and 1,1,1-trichloroethane. Another purpose was to explore the effect of selected CYP2E1 polymorphisms on the toxicokinetic profile. Controlled human exposures were carried out in a 12m3 exposure chamber for each solvent separately, during 6h and at half of the threshold limit value. The human volunteers groups were composed of ten young men and fifteen young women, including ten women using hormonal contraceptive. An analysis of variance mainly showed an effect on the urinary levels of several biomarkers of exposure among women due to the use of hormonal contraceptive, with an increase of more than 50% in metabolites concentrations and a decrease of up to 50% in unchanged substances concentrations, suggesting an increase in their metabolism rate. The results also showed a difference due to the genotype CYP2E1*6, when exposed to methyl ethyl ketone, with a tendency to increase CYP2E1 activity when volunteers were carriers of the mutant allele. Our study suggests that not only physiological differences between men and women but also differences due to sex hormones levels can have an impact on urinary concentrations of several biomarkers of exposure. The observed variability due to sex among biological exposure indices can lead to misinterpretation of biomonitoring results. This aspect should have its place in the approaches for setting limits of occupational exposure. [Copyright &y& Elsevier]

Abstract: Organic solvents are still essential in many industrial applications. To improve safety and health in the working environment lower occupational thresholds limits have been established and less toxic substitutes were introduced. N-Methyl-2-pyrrolidone (NMP) is a versatile solvent that is used as a substitute for dichloromethane in paint strippers. Due to conflicting results, there is a debate whether NMP causes irritations of the upper airways/eyes or not. In a human experimental study we examined the chemosensory effects of NMP under controlled conditions. Fifteen healthy males were investigated in a cross-over study. NMP vapor concentrations were 10, 40 and 80mg/m3 for 2×4h with an exposure-free lunch break of 30min. To maximize chemosensory effects a peak exposure scenario (25mg/m3 baseline, 160mg/m3 peaks 4×15min, time-weighted average: 72mg/m3) was tested. The four different conditions were conducted with and without moderate physical workload. Chemosensory effects were measured physiologically by anterior rhinomanometry, eye blink rate and breathing frequency. Subjectively, ratings of acute health symptoms and intensity of olfactory and trigeminal sensations were collected repeatedly throughout the exposures. All physiological variables were unaffected by the different NMP concentrations and even the peak exposures were non-effective on these measures. Olfactory mediated health symptoms increased dose-dependently. For these symptoms a strong adaptation was observable, especially during the first 4h of the exposures. Other acute symptoms were not significantly affected. Comparable to the symptoms, only olfactory sensations increased dose-dependently. Trigeminal sensations (e.g. eye and nose irritations) were evaluated as being barely detectable during the different exposures, only during 160mg/m3 exposure peak weak and transient eye irritation were reported. The results clearly suggest that NMP concentrations of up to 160mg/m3 caused no adverse sensory irritation or undue annoyance. [Copyright &y& Elsevier]

Percutaneous absorption of m-xylene (XYL) was determined in volunteers exposed to 29.4 μg cm-3 XYL vapour on the forearm and hand for 20, 45, 120 and 180 min. The internal exposure was assessed by measuring the concentration of XYL in exhaled air. The systemic kinetics were determined using a reference exposure by inhalation. The dermal permeation rate and the cumulative absorption of XYL as a function of time were calculated using mathematical deconvolution. From these relationships, the average flux into the skin throughout the exposure (Jskin, average) and the maximal flux into the blood (Jblood, max) were derived. Both fluxes were dependent on the duration of exposure, approaching each other at longer exposure durations. The values of Jskin, average, adjusted to a concentration of 1 μg cm-3, were 0.091 μg cm-2 h-1 during 20-min exposure falling to 0.072, 0.066 and 0.061 μg cm-2 h-1 for 45, 120 and 180 min, respectively. The values of Jblood, max showed an opposite trend, gradually increasing from 0.034 μg cm-2 h-1 at an exposure duration of 20 min to 0.042, 0.059 and 0.063 μg cm-2 h-1 for 45, 120 and 180 min of exposure durations, respectively. [Copyright &y& Elsevier]