RESUMO
The aim of the study was to assess non-occupational and occupational exposure to bisphenol compounds in Finland. The participants were 151 non-occupationally exposed volunteers and 15 potentially exposed employees of a sewage-pipe relining company and a floor-coating company. The following chemicals were measured in the urine samples: bisphenol A (BPA), bisphenol F (BPF), bisphenol A diglycidyl ether (BADGE), bisphenol F diglycidyl ether (BFDGE), and the metabolites of the latter two [bisphenol A (2,3-dihydroxypropyl) glycidyl ether (BADGE·H2O), bisphenol A bis(2,3-dihydroxypropyl) ether (BADGE·2â¯H2O), bisphenol A (3-chloro-2-hydroxypropyl) (2,3-dihydroxypropyl) ether (BADGE·HCl·H2O), bisphenol A (3-chloro-2-hydroxypropyl) glycidyl ether (BADGE·HCl), and bisphenol A bis(3-chloro-2-hydroxypropyl) ether (BADGE·2HCl) and bisphenol F bis(2,3-dihydroxypropyl) ether (BFDGE·2â¯H2O), and bisphenol F bis(3-chloro-2-hydroxypropyl) ether (BFDGE·2HCl)]. BADGE and BFDGE were also measured in breathing zone air samples and hand-wipe samples of the sewage-pipe relining and floor-coating workers. Non-occupational exposure to BPA has decreased in Finland. The BPF level of the non-occupationally exposed was higher than the respective levels reported in the recent literature. BPA and BPF concentrations in the workers' urine samples were in the same range as those in the corresponding concentrations of the non-occupationally exposed population. Higher concentrations of BADGE and BFDGE metabolites were found in some of the workers' urine samples. Elevated urine concentrations were also observed in the samples collected the next morning. Some of the urinary BADGE and BFDGE metabolite results correlated with the hand-wipe results. The results show that occupational exposure to BADGE and BFDGE may occur in sewage-pipe relining and floor-coating work. They also indicate that dermal contamination plays a role in total exposure. Although the measured urinary levels indicate that the absorption of these bisphenol compounds are unlikely to pose a systemic health risk, the risk of dermal sensitization remains.
Assuntos
Compostos Benzidrílicos , Compostos de Epóxi , Exposição Ocupacional , Fenóis , Humanos , Compostos Benzidrílicos/urina , Exposição Ocupacional/análise , Fenóis/urina , Finlândia , Adulto , Feminino , Masculino , Pessoa de Meia-Idade , Compostos de Epóxi/urina , Compostos de Epóxi/toxicidade , Exposição Ambiental , Adulto Jovem , Monitoramento Biológico , Monitoramento AmbientalRESUMO
The urinary mercapturic acids N-acetyl-S-(2-carbamoylethyl)-L-cysteine (AAMA) and N-acetyl-S-(2-carbamoyl-2-hydroxyethyl)-L-cysteine (GAMA) are short-term biomarkers of exposure from acrylamide and its metabolite glycidamide, respectively. The medium-term exposure to acrylamide and glycidamide is monitored by the adducts N-(2-carbamoylethyl)-Val (AA-Val) and N-(2-carbamoyl-2-hydroxyethyl)-Val (GA-Val) in hemoglobin (Hb), respectively. Three questions were addressed by application of these biomarkers in two diet studies including 36 omnivores, 36 vegans and 16 strict raw food eaters (abstaining from any warmed or heated food for at least four months): first, what is the internal acrylamide exposure following a vegan or a raw food diet in comparison to that in omnivores? Second, did the exposure change between 2017 and 2021? And third, what is the stability over time of AAMA/GAMA excretion compared to that of AA-Val/GA-Val levels in Hb between both time points? Median urinary AAMA excretion per day in non-smoking omnivores, vegans and raw food eaters were 62.4, 85.4 and 15.4 µg/day, respectively; the corresponding median AA-Val levels were 27.7, 39.7 and 13.3 pmol/g Hb, respectively. Median levels in strict raw food eaters were about 25% (AAMA excretion) and 48% (AA-Val) of those in omnivores. In comparison to 2017, AAMA and GAMA excretion levels were hardly altered in 2021, however, levels of AA-Val and GA-Val in 2021 slightly increased. There was a weak correlation between AAMA excretion levels determined four years apart (rS = 0.30), and a moderate correlation between levels of AA-Val (rS = 0.55) in this timeframe. Our data in strict raw food eaters confirm a significant endogenous formation to acrylamide in a size range, which is-based on the levels of AA-Val-distinctly higher than reported previously based on levels of urinary AAMA excretion. The relatively lower AAMA excretion in raw food eaters likely represents a lower extent of glutathione conjugation due to missing hepatic first-pass metabolism in case of endogenous formation of acrylamide, which leads to a higher systemic exposure.
Assuntos
Acetilcisteína , Acrilamida , Biomarcadores , Contaminação de Alimentos , Hemoglobinas , Temperatura Alta , Acrilamida/toxicidade , Acrilamida/urina , Humanos , Biomarcadores/urina , Hemoglobinas/metabolismo , Acetilcisteína/análogos & derivados , Acetilcisteína/urina , Masculino , Adulto , Feminino , Pessoa de Meia-Idade , Veganos , Dieta , Compostos de Epóxi/urina , Compostos de Epóxi/toxicidade , Exposição Dietética , Adulto JovemRESUMO
Despite the increasing popularity of e-cigarettes, their long-term health effects remain unknown. In animal models, exposure to e-cigarette has been reported to result in pulmonary and cardiovascular injury, and in humans, the acute use of e-cigarettes increases heart rate and blood pressure and induces endothelial dysfunction. In both animal models and humans, cardiovascular dysfunction associated with e-cigarettes has been linked to reactive aldehydes such as formaldehyde and acrolein generated in e-cigarette aerosols. These aldehydes are known products of heating and degradation of vegetable glycerin (VG) present in e-liquids. Here, we report that in mice, acute exposure to a mixture of propylene glycol:vegetable glycerin (PG:VG) or to e-cigarette-derived aerosols significantly increased the urinary excretion of acrolein and glycidol metabolitesâ3-hydroxypropylmercapturic acid (3HPMA) and 2,3-dihydroxypropylmercapturic acid (23HPMA)âas measured by UPLC-MS/MS. In humans, the use of e-cigarettes led to an increase in the urinary levels of 23HPMA but not 3HPMA. Acute exposure of mice to aerosols derived from PG:13C3-VG significantly increased the 13C3 enrichment of both urinary metabolites 13C3-3HPMA and 13C3-23HPMA. Our stable isotope tracing experiments provide further evidence that thermal decomposition of vegetable glycerin in the e-cigarette solvent leads to generation of acrolein and glycidol. This suggests that the adverse health effects of e-cigarettes may be attributable in part to these reactive compounds formed through the process of aerosolizing nicotine. Our findings also support the notion that 23HPMA, but not 3HPMA, may be a relatively specific biomarker of e-cigarette use.
Assuntos
Acroleína/química , Sistemas Eletrônicos de Liberação de Nicotina , Compostos de Epóxi/química , Aromatizantes/química , Propanóis/química , Acroleína/metabolismo , Acroleína/urina , Aerossóis/química , Animais , Biomarcadores , Cromatografia Líquida de Alta Pressão , Compostos de Epóxi/metabolismo , Compostos de Epóxi/urina , Aromatizantes/metabolismo , Masculino , Espectrometria de Massas , Camundongos , Camundongos Endogâmicos C57BL , Propanóis/metabolismo , Propanóis/urina , Solventes , VapingRESUMO
1,3-Butadiene (BD) is a known human carcinogen used in the synthetic polymer industry and also found in cigarette smoke, automobile exhaust and wood burning smoke. BD is metabolically activated by cytochrome P450 monooxygenases (CYP) 2E1 and 2A6 to 3,4-epoxy-1-butene (EB), which can be detoxified by GST-catalyzed glutathione conjugation or hydrolysis. We have previously observed ethnic differences in urinary levels of EB-mercapturic acids in white, Japanese American and Native Hawaiian smokers. In the present study, similar analyses were extended to urinary BD-DNA adducts. BD-induced N7-(1-hydroxy-3-buten-2-yl) guanine (EB-GII) adducts were quantified in urine samples obtained from smokers and non-smokers belonging to three racial/ethnic groups: white, Japanese American and Native Hawaiian. After adjusting for sex, age, nicotine equivalents, body mass index and batch, we found that Japanese American smokers excreted significantly higher amounts of urinary EB-GII than whites [1.45 (95% confidence interval: 1.12-1.87) versus 0.68 (95% confidence interval: 0.52-0.85) fmol/ml urine, P = 4 × 10-5]. Levels of urinary EB-GII in Native Hawaiian smokers were not different from those in whites [0.67 (95% confidence interval: 0.51-0.84) fmol/ml urine, P = 0.938]. There were no racial/ethnic differences in urinary EB-GII adduct levels in non-smokers. Racial/ethnic differences in urinary EB-GII adduct levels in smokers could not be explained by GSTT1 gene deletion or CYP2A6 enzymatic activity. Urinary EB-GII adduct levels in smokers were significantly associated with concentrations of BD metabolite dihyroxybutyl mercapturic acid. Overall, our results reveal that urinary EB-GII adducts in smokers differ across racial/ethnic groups. Future studies are required to understand genetic and epigenetic factors that may be responsible for these differences.
Assuntos
Butadienos/toxicidade , Citocromo P-450 CYP2A6/genética , Citocromo P-450 CYP2E1/genética , Adutos de DNA/efeitos dos fármacos , Acetilcisteína/urina , Adulto , Idoso , Asiático/genética , Carcinógenos/metabolismo , Carcinógenos/toxicidade , Adutos de DNA/genética , Adutos de DNA/urina , Compostos de Epóxi/efeitos adversos , Compostos de Epóxi/urina , Etnicidade/genética , Feminino , Glutationa Transferase/genética , Humanos , Masculino , Pessoa de Meia-Idade , Havaiano Nativo ou Outro Ilhéu do Pacífico/genética , Fumaça/efeitos adversos , Fumantes , Espectrometria de Massas por Ionização por Electrospray , Produtos do Tabaco/efeitos adversos , Emissões de Veículos/toxicidade , População Branca/genéticaRESUMO
The current study developed an ultrahigh-performance liquid chromatography tandem mass spectrometry method to simultaneously analyze cascade metabolites of acrylamide in urine of rats and humans, including acrylamide, glycidamide, N-acetyl-S-(2-carbamoylethyl)-l-cysteine (AAMA), N-acetyl-S-(2-carbamoylethyl)-l-cysteine-sulfoxide, N-acetyl-S-(2-carbamoyl-2-hydroxyethyl)-l-cysteine, and N-acetyl-S-(1-carbamoyl-2-hydroxyethyl)-l-cysteine. A tandem solid-phase extraction procedure was novelly used to purify all metabolites at once from human urine. The rapid analysis showed high sensitivity with LOD and LOQ ranges of 0.1-0.8 and 0.4-5.8 ng/mL, respectively, and achieved acceptable within-laboratory reproducibility (RSD < 12.0%) and spiking recovery (92.2%-117.3%) within 8 min per sample. Approximately 70.7 and 63.0% of ingested acrylamide were recovered during the toxicokinetics analysis from urine of male and female rats, respectively. For nonsmoking participants, the urinary levels of acrylamide and glycidamide were higher in men than women, whereas the urinary concentration of AAMA showed the opposite behavior. The current analysis provides methodological support of cascade metabolites of acrylamide for the dietary short-term internal exposure assessment of acrylamide.
Assuntos
Acrilamida/metabolismo , Exposição Dietética/efeitos adversos , Acrilamida/urina , Adulto , Animais , Biomarcadores/urina , Cromatografia Líquida de Alta Pressão , Compostos de Epóxi/urina , Feminino , Contaminação de Alimentos/análise , Humanos , Masculino , Ratos , Ratos Sprague-Dawley , Toxicocinética , Adulto JovemRESUMO
A new experimental model was designed to study the fate of globin adducts with styrene 7,8-oxide (SO), a metabolic intermediate of styrene and a model electrophilic compound. Rat erythrocytes were incubated with SO at 7 or 22 °C. Levels of specific amino acid adducts in globin were determined by LC/MS analysis of the globin hydrolysate, and erythrocytes with known adduct content were administered intravenously to recipient rats. The course of adduct elimination from the rat blood was measured over the following 50 days. In the erythrocytes incubated at 22 °C, a rapid decline in the adduct levels on the first day post-transfusion followed by a slow phase of elimination was observed. In contrast, the adduct elimination in erythrocytes incubated at 7 °C was nearly linear, copying elimination of intact erythrocytes. In the urine of recipient rats, regioisomeric SO adducts at cysteine, valine, lysine, and histidine in the form of amino acid adducts and/or their acetylated metabolites as well as SO-dipeptide adducts were identified by LC/MS supported by synthesized reference standards. S-(2-Hydroxy-1-phenylethyl)cysteine and S-(2-hydroxy-2-phenylethyl)cysteine, the most abundant globin adducts, were excreted predominantly in the form of the corresponding urinary mercapturic acids (HPEMAs). Massive elimination of HPEMAs via urine occurred within the first day from the erythrocytes incubated at both 7 and 22 °C. However, erythrocytes incubated at 7 °C also showed a slow second phase of elimination such that HPEMAs were detected in urine up to 50 days post-transfusion. These results indicate for the first time that globin adducts can be cleaved in vivo to modified amino acids and dipeptides. The cleavage products and/or their predictable metabolites are excreted in urine over the whole life span of erythrocytes. Some of the urinary adducts may represent a new type of noninvasive biomarker for exposure to adduct-forming chemicals.
Assuntos
Compostos de Epóxi/metabolismo , Compostos de Epóxi/urina , Globinas/metabolismo , Globinas/urina , Animais , Biomarcadores/metabolismo , Biomarcadores/urina , Cromatografia Líquida de Alta Pressão , Eritrócitos/efeitos dos fármacos , Eritrócitos/metabolismo , Hidrólise , Masculino , Ratos , Ratos Wistar , Espectrometria de Massas em Tandem , Xenobióticos/metabolismo , Xenobióticos/urinaRESUMO
BACKGROUND: Acrylamide (AA), a known neurotoxin, has been considered to be a probable human carcinogen. The discovery of AA in many common foods in 2002 has caused worldwide attention and led to numerous research efforts on the metabolism of AA. METHODS: By collecting research literatures related to metabolism of AA, the present review not only summarized the major metabolic pathways and enzymes of AA, but also compared the interindividual and the interspecies differences of AA metabolism among humans, rats and mice. Moreover, the application of the metabolites as biomarkers for the AA exposure assessment in human population was also discussed. RESULTS: The interindividual differences of AA metabolism may be attributed to the activity and/or genetic polymorphisms of metabolic enzymes in individuals with different gender, age, smoking and alcohol status. Moreover, the metabolism of AA in humans may be more prone to the phase II conjugation with glutathione (GSH) than the phase I conversion of AA to glycidamide (GA) when compared with rats and mice. Both the hemoglobin (Hb) adducts and urinary mercapturic acid (MA) metabolites have been successfully used as biomarkers for the risk assessment of AA and new metabolic biomarkers are being developed. CONCLUSION: The genotoxic risk from AA may be determined by the balance between the phase I P450 2E1 (CYP2E1)-dependent toxification pathway to form genotoxic GA and the phase II GSH-conjugated detoxification pathway to form MA metabolite. Understanding the metabolism of AA in the body is helpful for developing effective intervention strategies to mitigate its toxicity.
Assuntos
Acrilamida/metabolismo , Acrilamida/toxicidade , Carcinógenos/metabolismo , Carcinógenos/toxicidade , Citocromo P-450 CYP2E1/metabolismo , Dano ao DNA , Inocuidade dos Alimentos , Acetilcisteína/análise , Acetilcisteína/urina , Animais , Biomarcadores/sangue , Biomarcadores/metabolismo , Biomarcadores/urina , Citocromo P-450 CYP2E1/genética , Compostos de Epóxi/metabolismo , Compostos de Epóxi/urina , Glutationa/metabolismo , Glutationa Transferase/metabolismo , Hemoglobinas/metabolismo , Humanos , Camundongos , Ratos , Medição de Risco , Especificidade da EspécieRESUMO
Acrylamide is classified as a potential human carcinogen and neurotoxicant. Biological monitoring is a useful tool for monitoring worker exposure. However, other sources of exposure to acrylamide (including cigarette smoke and diet) also need to be considered. This study has performed repeat measurements of the urinary mercapturic acids of acrylamide (AAMA) and its metabolite glycidamide (GAMA) and determined globin adducts in 20 production-plant workers at a UK acrylamide production facility. The relationship between biomarker levels and environmental monitoring data (air levels and hand washes) was investigated. Good correlations were found between all of the biomarkers (r(2)=0.86-0.91) and moderate correlations were found between the biomarkers and air levels (r(2) = 0.56-0.65). Our data show that urinary AAMA is a reliable biomarker of acrylamide exposure. Occupational hygiene data showed that acrylamide exposure at the company was well within the current UK Workplace Exposure Limit. The 90th percentile of urinary AAMA in non-smoking production-plant workers (537 µmol/mol creatinine (n = 59 samples)) is proposed as a possible biological monitoring guidance value. This 90th percentile increased to 798 µmol/mol if smokers were included (n = 72 samples). These values would be expected following an airborne exposure of less than 0.07 mg/m(3), well below the current UK workplace exposure limit of 0.3mg/m(3). Comparison of biomarker levels in non-occupationally exposed individuals suggests regional variations (between UK and Germany), possibly due to differences in diet.
Assuntos
Acrilamida/urina , Monitoramento Ambiental/métodos , Exposição Ocupacional/normas , Acetilcisteína/urina , Biomarcadores/urina , Creatinina/urina , Compostos de Epóxi/urina , Desinfecção das Mãos , Humanos , Reino UnidoRESUMO
1,3-Butadiene (BD) is an important industrial and environmental carcinogen present in cigarette smoke, automobile exhaust, and urban air. The major urinary metabolites of BD in humans are 2-(N-acetyl-L-cystein-S-yl)-1-hydroxybut-3-ene/1-(N-acetyl-L-cystein-S-yl)-2-hydroxybut-3-ene (MHBMA), 4-(N-acetyl-L-cystein-S-yl)-1,2-dihydroxybutane (DHBMA), and 4-(N-acetyl-L-cystein-S-yl)-1,2,3-trihydroxybutyl mercapturic acid (THBMA), which are formed from the electrophilic metabolites of BD, 3,4-epoxy-1-butene (EB), hydroxymethyl vinyl ketone (HMVK), and 3,4-epoxy-1,2-diol (EBD), respectively. In the present work, a sensitive high-throughput HPLC-ESI(-)-MS/MS method was developed for simultaneous quantification of MHBMA and DHBMA in small volumes of human urine (200 µl). The method employs a 96 well Oasis HLB SPE enrichment step, followed by isotope dilution HPLC-ESI(-)-MS/MS analysis on a triple quadrupole mass spectrometer. The validated method was used to quantify MHBMA and DHBMA in urine of workers from a BD monomer and styrene-butadiene rubber production facility (40 controls and 32 occupationally exposed to BD). Urinary THBMA concentrations were also determined in the same samples. The concentrations of all three BD-mercapturic acids and the metabolic ratio (MHBMA/(MHBMA+DHBMA+THBMA)) were significantly higher in the occupationally exposed group as compared to controls and correlated with BD exposure, with each other, and with BD-hemoglobin biomarkers. This improved high throughput methodology for MHBMA and DHBMA will be useful for future epidemiological studies in smokers and occupationally exposed workers.
Assuntos
Acetilcisteína/química , Biomarcadores/química , Biomarcadores/urina , Butadienos/química , Butadienos/urina , Exposição Ocupacional/análise , Butadienos/toxicidade , Butanonas/química , Butanonas/urina , Carcinógenos/química , Cromatografia Líquida de Alta Pressão/métodos , Elastômeros/toxicidade , Compostos de Epóxi/química , Compostos de Epóxi/urina , Humanos , Estirenos/toxicidade , Espectrometria de Massas em Tandem/métodos , Urina/químicaRESUMO
OBJECTIVE: To determinate triptolide and wilforlide A in biological samples by liquid chromatography-tandem mass spectrometry (LC-MS/MS) method and to verify the method. METHODS: After 0.4 mL blood, urine or 0.4 g hepatic tissues with internal standard were extracted by ethyl acetate, they were separated on a Allure PFP Propyl (100 mm x 2.1 mm, 5 µm) with a mobile phase of methanol-20 mmol/L ammonium acetate using gradient elution. For mass spectrometric detection, electrospray ionization (ESIâº) in positive mode was elected and the data was collected using multiple-reaction monitoring (MRM). RESULTS: The linearity was good (r > 0.995 0) and the limit of detection was 2 ng/mL or 2 ng/g for triptolide and wilforlide A. The recovery was 61.08%-102.98%. The intra-day and inter-day precision was less than 12.58% for each biological sample, and the accuracy was 90.61%-105.80%. CONCLUSION: This method is simple, convenient and good selective, and could be applied to analysis of triptolide and wilforlide A in different biological samples. And the method may provide technical support for forensic medicine identification, clinical diagnosis and treatment of tripterygium wilfordii Hook. f. poisoning.
Assuntos
Cromatografia Líquida de Alta Pressão , Diterpenos/sangue , Diterpenos/urina , Ácido Oleanólico/análogos & derivados , Fenantrenos/sangue , Fenantrenos/urina , Espectrometria de Massas em Tandem , Compostos de Epóxi/sangue , Compostos de Epóxi/urina , Humanos , Ácido Oleanólico/sangue , Ácido Oleanólico/urina , Sensibilidade e EspecificidadeRESUMO
Benzo[a]pyrene (BaP), a potent polycyclic aromatic hydrocarbon carcinogen, is widely distributed in the human environment. All humans are exposed to BaP through the diet and contact with the general environment; cigarette smokers have higher exposure. An important pathway of BaP metabolism proceeds through formation of diol epoxides including the 'bay region diol epoxide' 7R,8S-dihydroxy-9S,10R-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene [BaP-(7R,8S)-diol-(9S,10R)-epoxide] and the 'reverse diol epoxide' 9S,10R-dihydroxy-7R,8S-epoxy-7,8,9,10-tetrahydrobenzo [a]pyrene [BaP-(9S,10R)-diol-(7R,8S)-epoxide]. The bay region diol epoxide is considered a major ultimate carcinogen of BaP based on studies in cell culture and laboratory animals, but the available data in humans are less convincing. The bay region diol epoxide and the reverse diol epoxide react with H2O to produce enantiomeric BaP-tetraols that are excreted in the urine. We used chiral stationary-phase high-performance liquid chromatography and gas chromatography-negative ion chemical ionisation-tandem mass spectrometry to quantify these enantiomeric BaP-tetraols in the urine of 25 smokers and 25 non-smokers. The results demonstrated that the BaP-tetraol enantiomer representing the carcinogenic bay region diol epoxide pathway accounted for 68±6% (range 56-81%) of total BaP-tetraol in smokers and 64±6% (range 46-78%) in non-smokers. Levels of the major BaP-tetraol enantiomer decreased by 75% in smokers who quit smoking. These data provide convincing evidence in support of the bay region diol epoxide mechanism of BaP carcinogenesis in humans.
Assuntos
Ativação Metabólica/fisiologia , Compostos de Epóxi/toxicidade , Compostos de Epóxi/urina , Pirenos/toxicidade , Pirenos/urina , Adulto , Benzo(a)pireno/toxicidade , Carcinógenos/química , Carcinógenos/toxicidade , Cromatografia Líquida de Alta Pressão , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fumar/efeitos adversos , Fumar/urinaRESUMO
Due to its cytotoxicity, genotoxicity, and adipogenicity observed in in vitro studies, bisphenol A diglycidyl ether (BADGE) may pose a health risk to humans. Quantifying BADGE exposure is an essential step to assess potential health risks associated with this ubiquitous compound widely used in certain plastic products. Due to the lack of endogenous sources for BADGE, bio-monitoring of BADGE and/or its hydrolytic metabolites (BADGE·H2O and BADGE·2H2O) can be a useful means to measure exposure. In this study, we developed a highly specific and sensitive method to measure BADGE, BADGE·H2O and BADGE·2H2O in plasma and urine, using a fast liquid-liquid extraction technique followed by a high-performance liquid chromatography and positive electrospray tandem mass spectrometry (LC-ESI-MS/MS) method. The method can quantify BADGE, BADGE·H2O and BADGE·2H2O with lower limits of quantification (LLOQ) of 0.05, 0.05 and 0.2 ng/ml, respectively. The percentage deviation of mean calculated concentrations from target concentrations was within 20%, variations across repeated analyses were within 15%, and mean extraction recovery was higher than 51.4% for all the three analytes in both plasma and urine matrices. The method has been applied to venous blood samples, cord blood samples, and urine samples collected from 9 to 14 adult volunteers. Results showed that concentrations of BADGE were lower than LLOQ in all of these samples except one urine sample. Low levels of BADGE·H2O from 0.108 to 0.222 ng/ml were observed in four venous blood samples and one urine sample (0.187 ng/ml). In contrast, concentrations of BADGE·2H2O were higher than LLOQ, varying from 0.660 to 303.593 ng/ml, in all the 10 venous blood samples and 1 cord blood sample (0.592 ng/ml) and two urine samples (0.200 and 0.306 ng/ml). The results suggest that bio-monitoring of blood and urine for BADGE exposure should focus on the hydrolysis derivatives of BADGE, mainly in the form of BADGE·2H2O.
Assuntos
Compostos Benzidrílicos/sangue , Compostos Benzidrílicos/urina , Cromatografia Líquida de Alta Pressão/métodos , Compostos de Epóxi/sangue , Compostos de Epóxi/urina , Espectrometria de Massas em Tandem/métodos , Compostos Benzidrílicos/química , Compostos Benzidrílicos/metabolismo , Compostos de Epóxi/química , Compostos de Epóxi/metabolismo , Sangue Fetal/química , Sangue Fetal/metabolismo , Humanos , Reprodutibilidade dos Testes , Sensibilidade e EspecificidadeRESUMO
AIM: To investigate the routes of elimination and excretion for triptolide recovered in rats. METHODS: After a single oral administration of [(3)H]triptolide (0.8 mg/kg, 100 µCi/kg) in Sprague Dawley rats, urine and fecal samples were collected for 168 h. To study biliary excretion, bile samples were collected for 24 h through bile duct cannulation. Radioactivity was measured using a liquid scintillation analyzer, and excretion pathway analysis was performed using an HPLC/on-line radioactivity detector. RESULTS: The total radioactivity recovered from the urine and feces of rats without bile duct ligation ranged from 86.6%-89.1%. Most of the radioactivity (68.6%-72.0%) was recovered in the feces within 72 h after oral administration, while the radioactivity recovered in the urine and bile was 17.1%-18.0% and 39.0%-39.4%, respectively. The HPLC/on-line radiochromatographic analysis revealed that most of the drug-related radioactivity was in the form of metabolites. In addition, significant gender differences in the quantity of these metabolites were found: monohydroxytriptolide sulfates were the major metabolites detected in the urine, feces, and bile of female rats, while only traces of these metabolites were found in male rats. CONCLUSION: Radiolabeled triptolide is mainly secreted in bile and eliminated in feces. The absorbed radioactivity is primarily eliminated in the form of metabolites, and significant gender differences are observed in the quantity of recovered metabolites, which are likely caused by the gender-specific expression of sulfotransferases.
Assuntos
Diterpenos/administração & dosagem , Diterpenos/farmacocinética , Fenantrenos/administração & dosagem , Fenantrenos/farmacocinética , Administração Oral , Animais , Bile/metabolismo , Biotransformação , Cromatografia Líquida de Alta Pressão , Diterpenos/urina , Compostos de Epóxi/administração & dosagem , Compostos de Epóxi/farmacocinética , Compostos de Epóxi/urina , Fezes/química , Feminino , Eliminação Hepatobiliar , Masculino , Fenantrenos/urina , Ratos Sprague-Dawley , Eliminação Renal , Contagem de Cintilação , Fatores Sexuais , TrítioRESUMO
Biomonitoring of human exposure to bisphenol A diglycidyl ethers (BADGEs; resin coating for food cans), p-hydroxybenzoic acid esters (parabens; preservatives), benzophenone-type UV filters (BP-UV filters; sunscreen agents), triclosan (TCS; antimicrobials), and triclocarban (TCC; antimicrobials) has been investigated in western European countries and North America. Nevertheless, little is known about the exposure of Greek populations to these environmental chemicals. In this study, 100 urine samples collected from Athens, Greece, were analyzed by liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) for the determination of total concentrations of five derivatives of BADGEs, six parabens and their metabolite (ethyl-protocatechuate), five derivatives of BP-UV filters, TCS, and TCC. Urinary concentrations of BADGEs, parabens, ethyl-protocatechuate, BP-UV filters, TCS and TCC (on a volume basis) ranged 0.3-20.9 (geometric mean: 0.9), 1.6-1010 (24.2), <2-71.0 (2.1), 0.5-1120 (4.4), <0.5-2580 (8.0) and <0.5-1.9 (0.6) ng/mL, respectively. All 19 target chemicals were found in urine, and the highest detection rates were observed for methyl paraben (100%), bisphenol A bis (2,3-dihydroxypropyl) ether (90%), ethyl paraben (87%), 2,4-dihydroxybenzophenone (78%), propyl paraben (72%), and TCS (71%). Estimated daily intakes (EDIurine), calculated on the basis of the measured urinary concentrations, ranged from 0.023 µg/kg bw/day for Σ5BADGEs to 31.4 µg/kg bw/day for Σ6Parabens.
Assuntos
Compostos Benzidrílicos/urina , Benzofenonas/urina , Carbanilidas/urina , Exposição Ambiental/análise , Poluentes Ambientais/urina , Compostos de Epóxi/urina , Parabenos/metabolismo , Triclosan/urina , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Exposição Ambiental/normas , Feminino , Grécia , Humanos , Masculino , Pessoa de Meia-Idade , Protetores Solares/metabolismo , Adulto JovemRESUMO
The purpose of the current study was to investigate the metabolite profile of [(3)H]triptolide in rats. The separation and characterisation techniques used to identify the major metabolites were high-performance liquid chromatography-online radiodetector, ultra-performance liquid chromatography-quadrupole time-of-flight mass spectrometry, and nuclear magnetic resonance. In all, 33 major metabolites were detected. The major components found in the rat plasma included the parent drug and its monohydroxy- and dihydroxy-metabolites. Reference standards for the monohydroxy-metabolites were obtained either by the incubation of the parent drug with rat liver microsomes or by microbial transformation with Cunninghamella blakesleana. The metabolites' structures were identified as 17-hydroxytriptolide, 16-hydroxytriptolide, tripdiolide, and 15-hydroxytriptolide. The major metabolites found in male rat urine included the monohydroxy-, dihydroxy-, and trihydroxy-metabolites. The major metabolites in female rat urine were the monohydroxy- and dihydroxy-metabolites, as well as sulphates of the monohydroxy-metabolites. A glutathione adduct, multiple hydroxy-metabolites, and a number of unidentified metabolites were detected in the bile and faeces of male rats. Sulphates of monohydroxy-metabolites were detected in the bile and faeces of female rats.
Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Diterpenos/análise , Diterpenos/metabolismo , Fenantrenos/análise , Fenantrenos/metabolismo , Animais , Bile/química , Diterpenos/química , Diterpenos/urina , Compostos de Epóxi/análise , Compostos de Epóxi/química , Compostos de Epóxi/metabolismo , Compostos de Epóxi/urina , Fezes/química , Feminino , Limite de Detecção , Masculino , Espectrometria de Massas , Metaboloma , Fenantrenos/química , Fenantrenos/urina , Ratos , Ratos Sprague-Dawley , Reprodutibilidade dos TestesRESUMO
Despite reports of the occurrence of bisphenol A diglycidyl ether (BADGE) and its derivatives in canned foods and consumer products, biomonitoring studies of human exposure to these compounds are lacking. In this study, 127 urine samples collected from the U.S. and China were analyzed for free and total (free plus conjugated) concentrations of BADGE and its three derivatives, bisphenol A (2,3-dihydroxypropyl) glycidyl ether [BADGE·H(2)O], bisphenol A (3-chloro-2-hydroxypropyl) (2,3-dihydroxypropyl) ether [BADGE·HCl·H(2)O], and bisphenol A bis (2,3-dihydroxypropyl) ether [BADGE·2H(2)O], using high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). BADGE and its three derivatives (collectively referred to as BADGEs) were found in 100% of the urine samples analyzed. Total urinary concentrations of BADGEs in the U.S. ranged from 1.24 to 9.03 ng/mL, with a GM concentration of 3 ng/mL. Concentrations of BADGEs in urine from adults (GM: 1.36 ng/mL) and children (1.02 ng/mL) in China were 3-fold lower than the concentrations found in the U.S. Both free and conjugated forms of BADGEs were present in urine, and the proportion of free form was inversely related to the total concentration of BADGEs. Among the four BADGEs measured in urine, BADGE·2H(2)O was the predominant compound, accounting for 45-60% of the total BADGEs concentration, followed by BADGE (17-24%). The distribution of the four BADGEs varied, depending on age, gender, and ethnicity of the adults and children. Daily intake (DI) and effective daily intake (DI(E)) of BADGEs were estimated based on urinary concentrations, and their respective values were 69.4 and 9.16 ng/kg-bw/day for the U.S. population and 28.4 and 5.69 ng/kg-bw/day for the Chinese population. The concentrations of BADGEs in U.S. urine were 3- to 4-fold higher than the corresponding concentrations of bisphenol A.
Assuntos
Compostos Benzidrílicos/urina , Monitoramento Ambiental , Compostos de Epóxi/urina , Mutagênicos/análise , Adulto , Compostos Benzidrílicos/análise , Criança , China , Cromatografia Líquida , Compostos de Epóxi/análise , Feminino , Alimentos em Conserva , Humanos , Masculino , Pessoa de Meia-Idade , Espectrometria de Massas em Tandem , Estados Unidos , Adulto JovemRESUMO
Triptolide, a major active constituent of Tripterygium wilfordii Hook F, has multiple pharmacological activities. In this work, a rapid, sensitive and specific liquid chromatography coupled to an ion trap mass spectrometer (MS) with electrospray ionization (ESI) interface has been developed for identification of triptolide and some of its metabolites in rat urine after oral administration of a single dose (0.6 mg/kg) of triptolide to healthy rats, as well as some metabolites in vitro after incubation with rat liver microsome (RLM) and rat intestinal flora, respectively. All samples were separated on a reversed-phase C18 column using a mobile phase of acetonitrile/water (70:30, v/v) and detected by an on-line MS(n) detector. Identification and structural elucidation of the selected metabolites were performed by comparing their full scan MS(n) spectra with those of the parent drug. In this paper we identified ten metabolites in rat urine, four metabolites in RLM incubation solution and one metabolite in rat intestinal flora incubation solution, after drug administration. The metabolic reactions of triptolide that we observed in vivo were hydrolysis reaction, hydroxylation reaction, and the conjugate reaction with sulfate, glucuronide and GSH, respectively. The in vitro metabolic reactions of triptolide observed were hydrolysis and hydroxylation reactions.
Assuntos
Cromatografia Líquida , Diterpenos/farmacocinética , Fenantrenos/farmacocinética , Espectrometria de Massas em Tandem , Acetonitrilas/química , Administração Oral , Animais , Bactérias/metabolismo , Biotransformação , Cromatografia de Fase Reversa , Diterpenos/administração & dosagem , Diterpenos/química , Diterpenos/urina , Compostos de Epóxi/administração & dosagem , Compostos de Epóxi/química , Compostos de Epóxi/farmacocinética , Compostos de Epóxi/urina , Feminino , Glucuronídeos/metabolismo , Glutationa/metabolismo , Hidrólise , Hidroxilação , Intestinos/microbiologia , Masculino , Microssomos Hepáticos/metabolismo , Estrutura Molecular , Fenantrenos/administração & dosagem , Fenantrenos/química , Fenantrenos/urina , Ratos , Ratos Wistar , Sensibilidade e Especificidade , Espectrometria de Massas por Ionização por Electrospray , Sulfatos/metabolismo , Água/químicaRESUMO
A convenient and reliable gas chromatographic method was developed for the simultaneous determination of six aromatic acid metabolites of styrene and styrene-oxide in rat urine; i.e., benzoic (BA), phenylacetic (PAA), mandelic (MA), phenylglyoxylic (PGA), hippuric (HA) and phenylaceturic (PAUA) acids. The method involves a one-pot esterification-extraction procedure, performed directly on urine without prior treatment. Analyses were performed on a RTX-1701 capillary column and the recovered isopropyl esters derivatives were detected by flame ionization detection. The analytical method was validated for selectivity, linearity, detection and quantification limits, recovery and intra-day and inter-day precisions. Calibration curves showed linearity in the range of 8-800 mg/L, except for HA and PAUA (40-800 mg/L). Limits of detection were between 0.2 (PPA) and 7.0 (PAUA) mg/L. The intra-day precisions determined at three concentrations levels were less than 5% for BA, PAA, MA and PGA and 9% for HA and PAUA, respectively. The corresponding mean inter-day precisions for these two groups were 8 and 16%, respectively. The method was successfully applied to quantitatively analyze styrene, styrene-oxide, ethylbenzene and toluene metabolites in urine samples from rats exposed by inhalation to these compounds at levels close to the occupational threshold limit values. Provided that this method can be transposed to human urine, it could have applications as part of biological monitoring for workers exposed to styrene or related compounds.
Assuntos
Ácidos Carbocíclicos/urina , Compostos de Epóxi/urina , Estireno/urina , Administração por Inalação , Animais , Ácido Benzoico/urina , Compostos de Epóxi/administração & dosagem , Compostos de Epóxi/farmacocinética , Ionização de Chama/métodos , Glioxilatos/urina , Hipuratos/urina , Exposição por Inalação , Limite de Detecção , Masculino , Ácidos Mandélicos/urina , Fenilacetatos/urina , Ratos , Ratos Endogâmicos F344 , Ratos Sprague-Dawley , Reprodutibilidade dos Testes , Estireno/administração & dosagem , Estireno/farmacocinética , Urinálise/métodosRESUMO
Acrylamide (AA) is formed during the heating of food and is classified as a genotoxic carcinogen. The margin of exposure (MOE), representing the distance between the bench mark dose associated with 10% tumor incidence in rats and the estimated average human exposure, is considered to be of concern. After ingestion, AA is converted by P450 into the genotoxic epoxide glycidamide (GA). GA forms DNA adducts, primarily at N7 of guanine (N7-GA-Gua). We performed a dose-response study with AA in female Sprague-Dawley (SD) rats. AA was given orally in a single dosage of 0.1-10 000 µg/kg bw. The formation of urinary mercapturic acids and of N7-GA-Gua DNA adducts in liver, kidney, and lung was measured 16 h after application. A mean of 37.0 ± 11.5% of a given AA dose was found as mercapturic acids (MAs) in urine. MA excretion in urine of untreated controls indicated some background exposure from endogenous AA. N7-GA-Gua adduct formation was not detectable in any organ tested at 0.1 µg AA/kg bw. At a dose of 1 µg/kg bw, adducts were found in kidney (around 1 adduct/10(8) nucleotides) and lung (below 1 adduct/10(8) nucleotides) but not in liver. At 10, respectively, 100 µg/kg bw, adducts were found in all three organs, at levels close to those found at 1 µg AA/kg, covering a range of about 1-2 adducts/10(8) nucleotides. As compared to DNA adduct levels from electrophilic genotoxic agents of various origin found in human tissues, N7-GA-Gua adduct levels within the dose range of 0.1-100 µg AA/kg bw were at the low end of this human background. We propose to take the background level of DNA lesions in humans more into consideration when doing risk assessment of food-borne genotoxic carcinogens.
Assuntos
Acrilamida/toxicidade , Carcinógenos/toxicidade , Adutos de DNA/metabolismo , Compostos de Epóxi/metabolismo , Guanina/metabolismo , Acrilamida/farmacocinética , Acrilamida/urina , Animais , Carcinógenos/farmacocinética , Dieta , Relação Dose-Resposta a Droga , Compostos de Epóxi/urina , Feminino , Humanos , Rim/efeitos dos fármacos , Rim/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Ratos , Ratos Sprague-DawleyRESUMO
The aim of this study was to evaluate biomarkers of acrylamide exposure, including hemoglobin adducts and urinary metabolites in acrylamide production workers. Biomarkers are integrated measures of the internal dose, and it is total acrylamide dose from all routes and sources that may present health risks. Workers from three companies were studied. Workers potentially exposed to acrylamide monomer wore personal breathing-zone air samplers. Air samples and surface-wipe samples were collected and analyzed for acrylamide. General-area air samples were collected in chemical processing units and control rooms. Hemoglobin adducts were isolated from ethylenediamine teraacetic acid (EDTA)-whole blood, and adducts of acrylamide and glycidamide, at the N-terminal valines of hemoglobin, were cleaved from the protein chain by use of a modified Edman reaction. Full work-shift, personal breathing zone, and general-area air samples were collected and analyzed for particulate and acrylamide monomer vapor. The highest general-area concentration of acrylamide vapor was 350 µg/cm(3) in monomer production. Personal breathing zone and general-area concentrations of acrylamide vapor were found to be highest in monomer production operations, and lower levels were in the polymer production operations. Adduct levels varied widely among workers, with the highest in workers in the monomer and polymer production areas. The acrylamide adduct range was 15-1884 pmol/g; glycidamide adducts ranged from 17.8 to 1376 p/mol/g. The highest acrylamide and glycidamide adduct levels were found among monomer production process operators. The primary urinary metabolite N-acetyl-S-(2-carbamoylethyl) cysteine (NACEC) ranged from the limit of detection to 15.4 µg/ml. Correlation of workplace exposure and sentinel health effects is needed to determine and control safe levels of exposure for regulatory standards.