RESUMO
BACKGROUND: Epidemiological studies have reported associations of anti-androgenic phthalate metabolite concentrations with later onset of male puberty, but few have assessed associations with progression. OBJECTIVES: We examined the association of prepubertal urinary phthalate metabolite concentrations with trajectories of pubertal progression among Russian boys. METHODS: At enrollment (ages 8-9 years), medical history, dietary, and demographic information were collected. At entry and annually to age 19 years, physical examinations including testicular volume (TV) were performed and spot urines collected. Each boy's prepubertal urine samples were pooled, and 15 phthalate metabolites were quantified by isotope dilution LC-MS/MS at Moscow State University. Metabolites of anti-androgenic parent phthalates were included: butylbenzyl (BBzP), di-n-butyl (DnBP), diisobutyl (DiBP), di(2-ethylhexyl) (DEHP) and diisononyl (DiNP) phthalates. We calculated the molar sums of DEHP, DiNP, and all AAP metabolites. We used group-based trajectory models (GBTMs) to identify subgroups of boys who followed similar pubertal trajectories from ages 8-19 years based on annual TV. We used multinomial and ordinal regression models to evaluate whether prepubertal log-transformed phthalate metabolite concentrations were associated with slower or faster pubertal progression trajectories, adjusting for covariates. RESULTS: 304 boys contributed a total of 752 prepubertal urine samples (median 2, range: 1-6) for creation of individual pools. The median length of follow-up was 10.0 years; 79% of boys were followed beyond age 15. We identified three pubertal progression groups: slower (34%), moderate (43%), and faster (23%) progression. A standard deviation increase in urinary log-monobenzyl phthalate (MBzP) concentrations was associated with higher adjusted odds of being in the slow versus faster pubertal progression trajectory (aOR 1.47, 95% CI 1.06-2.04). None of the other phthalate metabolites were associated with pubertal progression. CONCLUSIONS: On average, boys with higher concentrations of prepubertal urinary MBzP had a slower tempo of pubertal progression, perhaps attributable to the disruption of androgen-dependent biological pathways.
Assuntos
Dietilexilftalato , Poluentes Ambientais , Ácidos Ftálicos , Humanos , Masculino , Adulto Jovem , Adulto , Adolescente , Poluentes Ambientais/metabolismo , Cromatografia Líquida , Espectrometria de Massas em Tandem , Ácidos Ftálicos/urina , Antagonistas de Androgênios , Exposição Ambiental/análiseRESUMO
The worldwide plasticizer markets are facing constant substitution processes. Many classic ortho-phthalate plasticizers like di(2-ethylhexyl) phthalate (DEHP) are phased out, due to their proven toxicity to reproduction. Assumedly less critical, less regulated plasticizers such as di(2-ethylhexyl) terephthalate (DEHTP) are increasingly applied in consumer near products like toys, food contact materials, and medical devices. With the increasing use of DEHTP, increasing exposures of the general population have to be expected likewise. Human biomonitoring is a well-established tool to determine population exposures. In the present study we investigate the time trend of exposure to DEHTP using 24-hour urine samples of the German Environmental Specimen Bank (ESB) collected from 1999 to 2017. In these samples (60 per odd-numbered year, 600 samples in total) collected from young German adults (20-29â¯years, equal gender distribution) we determined four specific urinary metabolites as biomarkers of DEHTP exposure. From 1999 to 2009, the main specific urinary metabolite 5cx-MEPTP was quantifiable in <10% of the samples. Thereafter, detection rates and levels constantly increased, in line with rapidly increasing DEHTP consumption volumes. In 2017, all samples had 5cx-MEPTP levels above the limit of quantification (LOQ) with a median concentration of 3.35⯵g/L (95th percentile: 12.8⯵g/L). The other metabolites were detected less frequently and at lower levels but correlated well with 5cx-MEPTP robustly confirming the increasing DEHTP exposure. All 5cx-MEPTP concentrations were well below the German health based guidance value (HBM-I) of 2800⯵g/L for adults. Likewise, the median calculated daily intake, based on 5cx-MEPTP measured in 2017, was 0.74⯵g/kgâ¯bw∗d (95th percentile: 3.86⯵g/kgâ¯bw∗d), still well below the tolerable daily intake (TDI) of 1000⯵g/kgâ¯bw∗d. Based on current toxicological knowledge we can hence conclude that for the population investigated, DEHTP exposure gives no reason for immediate concern. However, the steep ongoing increase of DEHTP exposure warrants further close monitoring in the future, preferably also in sub-populations with known higher exposures to plasticizers, especially children.
Assuntos
Poluentes Ambientais/urina , Ácidos Ftálicos/urina , Plastificantes/análise , Adulto , Monitoramento Biológico , Biomarcadores/urina , Feminino , Alemanha , Humanos , Masculino , Adulto JovemRESUMO
OBJECTIVE: To examine prenatal APAP exposure in relation to language development in offspring at 30 months of age. METHOD: A population-based pregnancy cohort study including 754 women who enrolled in the Swedish Environmental Longitudinal, Mother and child, Asthma and allergy (SELMA) study in pregnancy week 8-13. Two exposure measures were used: (1) maternally reported number of APAP tablets taken between conception and enrollment; (2) APAP urinary concentration at enrollment. Language development at 30 months was assessed by nurse's evaluation and parental questionnaire, including the number of words the child used (<25, 25-50 and >50). Main study outcome; parental report of use of fewer than 50 words, termed language delay (LD). RESULTS: 59.2% of women enrolled in weeks 8-13 reported taking APAP between conception and enrollment. APAP was measurable in all urine samples and urinary APAP was correlated with the number of APAP taken during pregnancy (P<0.01). Language delay was more prevalent in boys (12.6%) than girls (4.1%) (8.5% in total). Both the number of APAP tablets and urinary APAP concentration were associated with greater LD in girls but not in boys. The adjusted odds ratio (OR) for LD among girls whose mothers reported >6 vs. 0 APAP tablets was 5.92 (95% confidence interval (CI) 1.10-31.94). The OR for LD in girls whose mothers' urinary APAP was in the highest compared to the lowest quartile was 10.34 (95% CI 1.37-77.86). While it cannot be ruled out, our available data do not support confounding by indication. CONCLUSIONS: Given the prevalence of prenatal APAP use and the importance of language development, these findings, if replicated, would suggest that pregnant women should limit their use of this analgesic during pregnancy.
Assuntos
Acetaminofen , Transtornos do Desenvolvimento da Linguagem , Efeitos Tardios da Exposição Pré-Natal , Acetaminofen/sangue , Acetaminofen/uso terapêutico , Adulto , Pré-Escolar , Estudos de Coortes , Correlação de Dados , Feminino , Humanos , Transtornos do Desenvolvimento da Linguagem/diagnóstico , Transtornos do Desenvolvimento da Linguagem/epidemiologia , Transtornos do Desenvolvimento da Linguagem/etiologia , Estudos Longitudinais , Masculino , Razão de Chances , Gravidez , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Efeitos Tardios da Exposição Pré-Natal/diagnóstico , Efeitos Tardios da Exposição Pré-Natal/prevenção & controle , Efeitos Tardios da Exposição Pré-Natal/psicologia , Prevalência , Fatores de Risco , Fatores Sexuais , Inquéritos e Questionários , Suécia/epidemiologiaRESUMO
This study aims to elucidate in greater detail the dermal uptake of nicotine from air or from nicotine-exposed clothes, which was demonstrated recently in a preliminary study. Six non-smoking participants were exposed to gaseous nicotine (between 236 and 304 µg/m3 ) over 5 hours while breathing clean air through a hood. Four of the participants wore only shorts and 2 wore a set of clean clothes. One week later, 2 of the bare-skinned participants were again exposed in the chamber, but they showered immediately after exposure instead of the following morning. The 2 participants who wore clean clothes on week 1 were now exposed wearing a set of clothes that had been exposed to nicotine. All urine was collected for 84 hours after exposure and analyzed for nicotine and its metabolites, cotinine and 3OH-cotinine. All participants except those wearing fresh clothes excreted substantial amounts of biomarkers, comparable to levels expected from inhalation intake. Uptake for 1 participant wearing exposed clothes exceeded estimated intake via inhalation by >50%. Biomarker excretion continued during the entire urine collection period, indicating that nicotine accumulates in the skin and is released over several days. Absorbed nicotine was significantly lower after showering in 1 subject but not the other. Differences in the normalized uptakes and in the excretion patterns were observed among the participants. The observed cotinine half-lives suggest that non-smokers exposed to airborne nicotine may receive a substantial fraction through the dermal pathway. Washing skin and clothes exposed to nicotine may meaningfully decrease exposure.
Assuntos
Poluição do Ar em Ambientes Fechados/análise , Vestuário , Exposição Ambiental/análise , Nicotina/análise , Poluição por Fumaça de Tabaco/análise , Idoso , Monitoramento Ambiental/métodos , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , Nicotina/farmacocinética , Pele/metabolismo , Absorção CutâneaRESUMO
In this preliminary study, we have investigated whether dermal uptake of nicotine directly from air or indirectly from clothing can be a meaningful exposure pathway. Two participants wearing only shorts and a third participant wearing clean cotton clothes were exposed to environmental tobacco smoke (ETS), generated by mechanically "smoking" cigarettes, for three hours in a chamber while breathing clean air from head-enveloping hoods. The average nicotine concentration (420 µg/m3 ) was comparable to the highest levels reported for smoking sections of pubs. Urine samples were collected immediately before exposure and 60 hour post-exposure for bare-skinned participants. For the clothed participant, post-exposure urine samples were collected for 24 hour. This participant then entered the chamber for another three-hour exposure wearing a hood and clothes, including a shirt that had been exposed for five days to elevated nicotine levels. The urine samples were analyzed for nicotine and two metabolites-cotinine and 3OH-cotinine. Peak urinary cotinine and 3OH-cotinine concentrations for the bare-skinned participants were comparable to levels measured among non-smokers in hospitality environments before smoking bans. The amount of dermally absorbed nicotine for each bare-skinned participant was conservatively estimated at 570 µg, but may have been larger. For the participant wearing clean clothes, uptake was ~20 µg, and while wearing a shirt previously exposed to nicotine, uptake was ~80 µg. This study demonstrates meaningful dermal uptake of nicotine directly from air or from nicotine-exposed clothes. The findings are especially relevant for children in homes with smoking or vaping.
Assuntos
Poluição do Ar/análise , Vestuário , Exposição Ambiental/análise , Nicotina/análise , Poluição por Fumaça de Tabaco/análise , Cotinina/urina , Feminino , Humanos , Masculino , Nicotina/farmacocinética , Nicotina/urina , Pele/metabolismo , Absorção CutâneaRESUMO
Plasticizers have been widely used for decades as additives in diverse applications, including consumer and building products, toys, cables, and floorings. Due to toxicological concerns and restrictions of different dialkyl ortho-phthalates, other plasticizers have been increasingly used in recent years. Therefore, di-isononyl cyclohexane-1,2-dicarboxylate (DINCH), di(2-ethylhexyl) terephthalate (DEHT), di(2-ethylhexyl) adipate (DEHA), acetyl tri-n-butyl citrate (ATBC), and trioctyl trimellitate (TOTM) plasticizer levels in indoor air and dust samples from 63 daycare centers in Germany were measured. Moreover, the urine samples of 208 children who attend 27 of these facilities were analyzed for the presence of four DINCH metabolites. DINCH, DEHT, and DEHA were present in indoor air with median values of 108 ng/m(3), 20 ng/m(3), and 34 ng/m(3), respectively. Median values of 302 mg/kg for DINCH, 49 mg/kg for DEHA, 40 mg/kg for DEHT, and 24 mg/kg ATBC were found in dust. In the urine samples, the three secondary metabolites of DINCH were observed with median values (95th percentiles) of 1.7 µg/l (10.0 µg/l) for OH-MINCH, 1.5 µg/l (8.0 µg/l) for oxo-MINCH, and 1.1 µg/l (6.1 µg/l) for cx-MINCH. Overall, these metabolite levels are orders of magnitude lower than the current HBM I values set by the German Human Biomonitoring Commission. Using general exposure assumptions, the intake resulting from dust ingestion and inhalation is low for children. The total daily DINCH intake calculated from biomonitoring data was 0.5 µg/kg b.w. using median values and 9.8 µg/kg b.w. as the maximum value. At present, non-phthalate plasticizers, especially DINCH, can be found in considerable amounts in dust samples from daycare centers and as DINCH metabolites in the urine of children. In relation to previous studies, the concentrations of DINCH in dust and urine have an increasing time trend. Compared with tolerable daily intake values, the total daily intake of DINCH reached only 1% of its maximum value to date; however, due to its increased use, higher exposure of DINCH is expected in the future.
Assuntos
Poluição do Ar em Ambientes Fechados/análise , Creches , Ácidos Cicloexanocarboxílicos/metabolismo , Ácidos Dicarboxílicos/metabolismo , Poeira/análise , Exposição Ambiental/análise , Poluentes Ambientais/urina , Plastificantes/metabolismo , Criança , Pré-Escolar , Monitoramento Ambiental , Alemanha , Humanos , Ácidos Ftálicos , Instituições AcadêmicasRESUMO
Bis-(2-propylheptyl)-phthalate (DPHP) has been introduced as a substitute for other high molecular weight phthalates primarily used in high temperature applications (e.g. cable wires, roofing membranes). The aim of this study was to investigate how the increased usage of DPHP is reflected in urine samples collected over the last 14 years and to evaluate the current extent of exposure. We analyzed 300 urine samples (24h voids) from the German Environmental Specimen Bank collected in the years 1999, 2003, 2006, 2009 and 2012, 60 samples per year, from 30 male and 30 female volunteers (age: 20-30 years) for three specific, secondary oxidized DPHP metabolites (with hydroxy, oxo and carboxy modifications of the alkyl side chain). We determined DPHP metabolites with a previously developed GC-HRMS method, enabling us to unambiguously distinguish DPHP metabolites from co-eluting, structurally isomeric di-iso-decyl phthalate (DIDP) metabolites. All samples were blinded before analysis. We detected no DPHP metabolites in urine samples from the years 1999, 2003 and 2006. Thereafter, detection rates increased from 3.3% in 2009 to 21.7% in 2012. Mono-oxo-propylheptylphthalate (oxo-MPHP) was the most abundant metabolite, with concentrations between Assuntos
Exposição Ambiental/análise
, Poluentes Ambientais/urina
, Ácidos Ftálicos/urina
, Adulto
, Métodos Analíticos de Preparação de Amostras/métodos
, Bancos de Espécimes Biológicos
, Monitoramento Ambiental/métodos
, Feminino
, Alemanha
, Humanos
, Masculino
, Adulto Jovem
RESUMO
In 2004 the European Commission and Member States initiated activities towards a harmonized approach for Human Biomonitoring surveys throughout Europe. The main objective was to sustain environmental health policy by building a coherent and sustainable framework and by increasing the comparability of data across countries. A pilot study to test common guidelines for setting up surveys was considered a key step in this process. Through a bottom-up approach that included all stakeholders, a joint study protocol was elaborated. From September 2011 till February 2012, 17 European countries collected data from 1844 mother-child pairs in the frame of DEMOnstration of a study to COordinate and Perform Human Biomonitoring on a European Scale (DEMOCOPHES).(1) Mercury in hair and urinary cadmium and cotinine were selected as biomarkers of exposure covered by sufficient analytical experience. Phthalate metabolites and Bisphenol A in urine were added to take into account increasing public and political awareness for emerging types of contaminants and to test less advanced markers/markers covered by less analytical experience. Extensive efforts towards chemo-analytical comparability were included. The pilot study showed that common approaches can be found in a context of considerable differences with respect to experience and expertize, socio-cultural background, economic situation and national priorities. It also evidenced that comparable Human Biomonitoring results can be obtained in such context. A European network was built, exchanging information, expertize and experiences, and providing training on all aspects of a survey. A key challenge was finding the right balance between a rigid structure allowing maximal comparability and a flexible approach increasing feasibility and capacity building. Next steps in European harmonization in Human Biomonitoring surveys include the establishment of a joint process for prioritization of substances to cover and biomarkers to develop, linking biomonitoring surveys with health examination surveys and with research, and coping with the diverse implementations of EU regulations and international guidelines with respect to ethics and privacy.
Assuntos
Saúde Ambiental/métodos , Monitoramento Ambiental/métodos , Cooperação Internacional , Desenvolvimento de Programas , Biomarcadores/análise , Interpretação Estatística de Dados , Exposição Ambiental/análise , Europa (Continente) , Estudos de Viabilidade , Humanos , Projetos PilotoRESUMO
Susceptibility to environmental stressors has been described for fetal and early childhood development. However, the possible susceptibility of the prepubertal period, characterized by the orchestration of the organism towards sexual maturation and adulthood has been poorly investigated and exposure data are scarce. In the current study levels of cadmium (Cd), cotinine and creatinine in urine were analyzed in a subsample 216 children from 12 European countries within the DEMOCOPHES project. The children were divided into six age-sex groups: boys (6-8 years, 9-10 years and 11 years old), and girls (6-7 years, 8-9 years, 10-11 years). The number of subjects per group was between 23 and 53. The cut off values were set at 0.1 µg/L for Cd, and 0.8 µg/L for cotinine defined according to the highest limit of quantification. The levels of Cd and cotinine were adjusted for creatinine level. In the total subsample group, the median level of Cd was 0.180 µg/L (range 0.10-0.69 µg/L), and for cotinine the median wet weight value was 1.50 µg/L (range 0.80-39.91 µg/L). There was no significant difference in creatinine and cotinine levels between genders and age groups. There was a significant correlation between levels of cadmium and creatinine in all children of both genders. This shows that even at such low levels the possible effect of cadmium on kidney function was present and measurable. An increase in Cd levels was evident with age. Cadmium levels were significantly different between 6-7 year old girls, 11 year old boys and 10-11 year old girls. As there was a balanced distribution in the number of subjects from countries included in the study, bias due to data clustering was not probable. The impact of low Cd levels on kidney function and gender differences in Cd levels needs further investigation.
Assuntos
Envelhecimento/urina , Cádmio/urina , Cotinina/urina , Monitoramento Ambiental/métodos , Caracteres Sexuais , Biomarcadores/urina , Criança , Creatinina/urina , Europa (Continente) , Feminino , Humanos , Masculino , Puberdade/urinaRESUMO
In 2011 and 2012, the COPHES/DEMOCOPHES twin projects performed the first ever harmonized human biomonitoring survey in 17 European countries. In more than 1800 mother-child pairs, individual lifestyle data were collected and cadmium, cotinine and certain phthalate metabolites were measured in urine. Total mercury was determined in hair samples. While the main goal of the COPHES/DEMOCOPHES twin projects was to develop and test harmonized protocols and procedures, the goal of the current paper is to investigate whether the observed differences in biomarker values among the countries implementing DEMOCOPHES can be interpreted using information from external databases on environmental quality and lifestyle. In general, 13 countries having implemented DEMOCOPHES provided high-quality data from external sources that were relevant for interpretation purposes. However, some data were not available for reporting or were not in line with predefined specifications. Therefore, only part of the external information could be included in the statistical analyses. Nonetheless, there was a highly significant correlation between national levels of fish consumption and mercury in hair, the strength of antismoking legislation was significantly related to urinary cotinine levels, and we were able to show indications that also urinary cadmium levels were associated with environmental quality and food quality. These results again show the potential of biomonitoring data to provide added value for (the evaluation of) evidence-informed policy making.
Assuntos
Biomarcadores/análise , Exposição Ambiental/análise , Exposição Ambiental/estatística & dados numéricos , Poluentes Ambientais/análise , Adulto , Biomarcadores/urina , Cádmio/análise , Cádmio/urina , Criança , Cotinina/urina , Interpretação Estatística de Dados , Monitoramento Ambiental/métodos , Monitoramento Ambiental/estatística & dados numéricos , Poluentes Ambientais/urina , Europa (Continente) , Feminino , Regulamentação Governamental , Cabelo/química , Humanos , Mercúrio/análise , Mercúrio/urina , População Rural/estatística & dados numéricos , Alimentos Marinhos/estatística & dados numéricos , Fumar/legislação & jurisprudência , Fumar/urina , Inquéritos e Questionários/normas , População Urbana/estatística & dados numéricosRESUMO
N-Ethyl-2-pyrrolidone (NEP) is an industrial solvent that has been increasingly used to substitute N-methyl-2-pyrrolidone. NEP is under scrutiny in scientific and regulatory committees because of developmental toxic and teratogenic effects in rodents. The two postulated NEP metabolites 5-hydroxy-N-ethyl-2-pyrrolidone (5-HNEP) and 2-hydroxy-N-ethylsuccinimide (2-HESI) have recently been detected in urine samples from the general population. Thus, the toxicokinetic characterization of these biomarkers of NEP exposure in humans is of relevance both in the occupational as well as the environmental field. We orally dosed 20.9 mg NEP to three male volunteers. These volunteers collected all their urine samples over a period of 4 days post dose. In these samples we identified and quantified the above postulated NEP metabolites 5-HNEP and 2-HESI and determined their urinary elimination kinetics and their metabolic conversion factors. After 4 days we recovered 50.7 % of the dose as these two metabolites in urine, 29.1 % as 5-HNEP and 21.6 % as 2-HESI. The largest share of 5-HNEP was excreted within 24 h post dose, while the major share of 2-HESI was excreted on day 2 post dose. We estimated an elimination half-time for 5-HNEP of approx. 7 h and for 2-HESI of approx. 22-27 h. While the elimination of 5-HNEP was basically finished 72 h post dose, significant amounts of 2-HESI were still eliminated after 96 h. Both biomarkers can now be used in human biomonitoring studies to extrapolate from urinary measurements to the NEP dose taken up and thus to evaluate the risk caused by exposure to this chemical.
RESUMO
In urine specimens that were collected from pregnant women in a large cohort, 24% contained more than 10 ng/ml of total bisphenol A (BPA), suggesting external contamination. Therefore, we conducted an investigation of the source(s) of extraneous BPA in the specimens. We found that under the conditions used to collect urine specimens in the epidemiologic study, contamination with BPA occurred, and by two separate mechanisms.
Assuntos
Compostos Benzidrílicos/urina , Fenóis/urina , Manejo de Espécimes , Adulto , Feminino , Humanos , GravidezRESUMO
Human biomonitoring studies measuring bisphenol A (BPA) in urine have shown widespread exposure in the general population. Diet is thought to be a major route of exposure. We studied urinary BPA patterns in five individuals over a 48-h period of fasting (bottled water only). Personal activity patterns were recorded with a diary to investigate non-dietary routes of exposure. All urine void events during the fast were collected, as well as events before and after the fast. The pattern of BPA concentrations was similar for all participants: they rose near the beginning of the fast (after the pre-fast meal), declined over the next 24h, fluctuated at lower levels during the second day, and then rose after the post-fast meal. Concentrations (~2 µg/g creatine) and calculated BPA intakes (~0.03 µg/kg-day) in these individuals during the first 24h were consistent with general population exposures. For the second 24h, concentrations and intakes declined by about two-thirds. One of the individuals had an extraordinary pre-fast exposure event with concentrations rising as high as 98 µg/g creatine but declining to <5 µg/g creatine by day 2. Given patterns found in day 1 and the subsequent decline to lower levels in day 2, we hypothesize that BPA exposures in these individuals were diet-driven. No events in the diary (use of personal care products, e.g.) appear associated with exposures. On day 2, non-dietary sources may still be present, such as from dust. Another hypothesis is that small reservoirs of BPA from past exposures are released from storage (lipid reservoirs, e.g.) and excreted.
Assuntos
Compostos Benzidrílicos/metabolismo , Dieta/estatística & dados numéricos , Exposição Ambiental/análise , Poluentes Ambientais/metabolismo , Fenóis/metabolismo , Adulto , Compostos Benzidrílicos/urina , Carga Corporal (Radioterapia) , Exposição Ambiental/estatística & dados numéricos , Poluentes Ambientais/urina , Jejum , Feminino , Contaminação de Alimentos/estatística & dados numéricos , Humanos , Masculino , Fenóis/urinaRESUMO
An individual (male, 36 years, 87 kg) ingested two separate doses of di-n-butyl phthalate (DnBP) and diisobutyl phthalate (DiBP) at a rate of ~60 µg/kg. Key monoester and oxidized metabolites were identified and quantified in urine continuously collected until 48 h post-dose. For both DnBP and DiBP, the majority of the dose was excreted in the first 24 h (92.2 % of DnBP, 90.3 % of DiBP), while only <1 % of the dose was excreted in urine on day 2. In each case, the simple monoesters were the major metabolites (MnBP, 84 %; MiBP, 71 %). For DnBP, ~8 % was excreted as various side chain oxidized metabolites. For DiBP, approximately 20 % was excreted mainly as the oxidized side chain metabolite 2OH-MiBP, indicating that the extent of oxidative modification is around 2.5 times higher for DiBP than for DnBP. All DnBP and DiBP metabolites reached peak concentrations between 2 and 4 h post-exposure, followed by a monotonic decline. For DnBP metabolites, the elimination halftime of MnBP was 2.6 h; longer elimination halftimes were estimated for the oxidized metabolites (2.9-6.9 h). For DiBP metabolites, MiBP had the shortest halftime (3.9 h), and the oxidized metabolites had somewhat longer halftimes (4.1 and 4.2 h). Together with the simple monoesters, secondary oxidized metabolites are additional and valuable biomarkers of phthalate exposure. This study provides basic human metabolism and toxicokinetic data for two phthalates that have to be considered human reproductive toxicants and that have been shown to be omnipresent in humans.
Assuntos
Dibutilftalato/análogos & derivados , Dibutilftalato/metabolismo , Plastificantes/metabolismo , Adulto , Creatinina/sangue , Dibutilftalato/farmacocinética , Monitoramento Ambiental , Meia-Vida , Humanos , Indicadores e Reagentes , Masculino , Oxirredução , Plastificantes/farmacocinéticaRESUMO
Di(2-ethylhexyl)phthalate (DEHP) is a reproductive and developmental toxicant in animals and a suspected endocrine modulator in humans. There is widespread exposure to DEHP in the general population. Patients can be additionally exposed through DEHP-containing medical devices. Toxicokinetic and metabolic knowledge on DEHP in humans is vital not only for the toxicological evaluation of DEHP but also for exposure assessments based on human biomonitoring data. Secondary oxidized DEHP metabolites like mono-(2-ethyl-5-hydroxyhexyl)phthalate (5OH-MEHP), mono-(2-ethyl-5-oxohexyl)phthalate (5oxo-MEHP), mono-(2-ethyl-5-carboxypentyl)phthalate (5cx-MEPP) and mono-[2-(carboxymethyl)hexyl]phthalate (2cx-MMHP) are most valuable biomarkers of DEHP exposure. They represent the major share of DEHP metabolites excreted in urine (about 70% for these four oxidized metabolites vs. about 6% for MEHP); they are immune to external contamination and possibly the ultimate developmental toxicants. Long half-times of elimination make 5cx-MEPP and 2cx-MMHP excellent parameters to measure the time-weighted body burden to DEHP. 5OH-MEHP and 5oxo-MEHP more reflect the short-term exposure. We calculated the daily DEHP intake for the general population (n = 85) and for children (n = 254). Children were significantly higher exposed to DEHP than adults. Exposures at the 95th percentile (21 and 25 microg/kg/day, respectively) scooped out limit values like the Reference Dose (RfD, 20 microg/kg/day) and the Tolerable Daily Intake (TDI, 20-48 microg/kg/day) to a considerable degree. Up to 20-fold oversteppings for some children give cause for concern. We also detected significant DEHP exposures for voluntary platelet donors (n = 12, 38 microg/kg/apheresis, dual-needle technique). Premature neonates (n = 45) were exposed to DEHP up to 100 times above the limit values depending on the intensity of medical care (median: 42 microg/kg/day; 95th percentile: 1,780 microg/kg/day).
Assuntos
Doadores de Sangue , Dietilexilftalato/metabolismo , Dietilexilftalato/toxicidade , Exposição Ambiental , Plastificantes/análise , Biomarcadores/análise , Remoção de Componentes Sanguíneos/efeitos adversos , Carga Corporal (Radioterapia) , Dietilexilftalato/urina , Monitoramento Ambiental , Meia-Vida , Humanos , Recém-Nascido , Plastificantes/metabolismo , Valores de ReferênciaRESUMO
We have developed and validated a new, reliable and very sensitive method for the determination of the urinary metabolites of the most common pyrethroids in one analytical run. After acidic hydrolysis for the cleavage of conjugates, the analytes cis-3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropane-1-carboxylic acid (cis-Cl(2)CA), trans-3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropane-1-carboxylic acid (trans-Cl(2)CA), cis-3-(2,2-dibromovinyl)-2,2-dimethylcyclopropane-1-carboxylic acid (Br(2)CA), 4-fluoro-3-phenoxybenzoic acid (F-PBA) and 3-phenoxybenzoic acid (3-PBA) were extracted from the matrix with a liquid-liquid extraction procedure using n-hexane under acidic conditions. For further clean-up, NaOH was added to the organic phase and the carboxylic acids were re-extracted into the aqueous phase. After acidification and extraction into n-hexane again, the metabolites were then derivatised to volatile esters using N-tert.-butyldimethylsilyl-N-methyltrifluoroacetamid (MTBSTFA). Separation and detection were carried out using capillary gas chromatography with mass-selective detection (GC-MS). 2-Phenoxybenzoic acid (2-PBA) served as internal standard for the quantification of the pyrethroid metabolites. The limit of detection for all analytes was 0.05 microg/l urine. The RSD of the within-series imprecision was between 2.0 and 5.4% at a spiked concentration of 0.4 microg/l and the relative recovery was between 79.3 and 93.4%, depending on the analyte. This method was used for the analysis of urine samples of 46 persons from the general population without known exposure to pyrethroids. The metabolites cis-Cl(2)CA, trans-Cl(2)CA and 3-PBA could be found in 52, 72 and 70% of all samples with median values of 0.06, 0.11 and 0.16 microg/l, respectively. Br(2)CA and F-PBA could also be detected in 13 and 4% of the urine samples.
Assuntos
Medicina Ambiental , Cromatografia Gasosa-Espectrometria de Massas/métodos , Inseticidas/urina , Piretrinas/urina , Adolescente , Adulto , Calibragem , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Padrões de Referência , Reprodutibilidade dos Testes , Sensibilidade e EspecificidadeRESUMO
We have developed a new method for the quantitative trace determination of 3,5,6-trichloro-2-pyridinol (TCPyr). TCPyr is a urinary metabolite specific to the organophosphorus pesticides chlorpyrifos and chlorpyrifos-methyl. After hydrolysis and separation of TCPyr from the urinary matrix using semi-automated steam distillation and solid-phase extraction on a new polystyrol-divinylbenzene copolymer (Isolute 101) the analyte was converted into its tert-butyldimethylsilyl derivative by N-tert-butyldimethylsilyl-N-methyltrifluoroacetamide (MTBSTFA). Separation and quantitative analysis were carried out by capillary gas chromatography and mass selective detection in selected ion monitoring mode. 2,6-Dibromophenol (DBP) was used as the internal standard. The detection limit was 0.05 microg/l; the limit of quantification was 0.1 microg/l urine. The relative standard deviation of the within-series imprecision was 4.2% at a concentration of 3.5 microg/l. The relative recovery was 104%. The new method was used to analyse the urine samples of 12 persons from the general population without known exposure to the above-mentioned pesticides. TCPyr concentrations between 0.27 and 6.6 microg/l urine were detected in all urine samples. This indicates that there is a baseline excretion of TCPyr in the general population. Four urine samples collected from workers who had applied chlorpyrifos were also analysed. In these samples TCPyr was found in concentrations from 4.7 to 7.9 microg/l.
Assuntos
Cromatografia Gasosa-Espectrometria de Massas/métodos , Inseticidas/urina , Compostos Organofosforados , Piridonas/urina , Calibragem , Exposição Ambiental , Humanos , Exposição Ocupacional , Padrões de Referência , Reprodutibilidade dos Testes , Sensibilidade e EspecificidadeRESUMO
In this study we determined the concentrations of 3,5,6-trichloro-2-pyridinol (TCPyr) in urine samples from the general population. TCPyr is a specific metabolite of the organophosphorus pesticides chlorpyrifos and chlorpyrifos-methyl. By the introduction of a new sensitive analytical method a limit of quantification (LOQ) of 0.1 microgram per litre urine could be achieved, a tenfold improvement of recent methods. Extraction of TCPyr from the urine and the clean up process were carried out by automatic steam distillation. Separation and quantitative analysis were performed using capillary gas chromatography and mass selective detection in selected ion monitoring mode. The excretion of TCPyr was studied by analysing spontaneous urine samples from 5 women and 45 men between the ages of 22 and 57 (median: 40 years) living in Mecklenburg-Vorpommern (Germany) who were not occupationally exposed to organophosporus pesticides. TCPyr was detected in all specimens and the concentrations were quantified. The median excretion was 1.4 micrograms/l (range: 0.12 to 124.8 micrograms/l), the 95th percentile 11.3 micrograms/l. Under the worst case assumption that all TCPyr measured in urine originated from the intake of intact pesticides and not (less toxic) breakdown products, a TCPyr concentration of 1.4 micrograms/l urine corresponds to a daily intake of approximately 2.5 micrograms chlorpyrifos/chlorpyrifos-methyl. The intake at the 95th percentile would be about 23 micrograms chlorpyrifos/chlorpyrifos-methyl per day. According to FAO/WHO the acceptable daily intake (ADI) is 10 micrograms per kg bodyweight and day for both chlorpyrifos and chlorpyrifos-methyl.
Assuntos
Clorpirifos/análogos & derivados , Clorpirifos/análise , Exposição Ambiental , Herbicidas/urina , Inseticidas/análise , Piridonas/urina , Adulto , Clorpirifos/metabolismo , Clorpirifos/farmacocinética , Feminino , Humanos , Inseticidas/metabolismo , Inseticidas/farmacocinética , Masculino , Pessoa de Meia-Idade , Saúde Pública , Valores de Referência , Sensibilidade e Especificidade , UrináliseRESUMO
In UMR-106 osteosarcoma cells we found that PTH activated both the cAMP/protein kinase A and the Ca(2+)-dependent phosphoinositide/protein kinase C (PKC) pathways, but prostaglandin E2 (PGE2) activated only the cAMP pathway. Activation of PKC by the phorbol ester PMA had no effect on cAMP production but enhanced PTH-stimulated cAMP production by 50% or more; the effect on PGE2-induced cAMP was negligible. Inhibition of the alpha-subunit of the inhibitory guanine nucleotide binding protein (Gi) by pertussis toxin pretreatment also enhanced PTH-mediated cAMP production but had no effect on PGE2-induced cAMP production. These results suggest that although PTH-mediated adenylate cyclase activity is regulated via both the stimulatory (Gs) and inhibitory (Gi) guanine nucleotide binding proteins, only Gs regulates PGE2-mediated adenylate cyclase activity in UMR-106 cells. Costimulation with pertussis toxin and PMA did not increase PTH-stimulated cAMP production above that obtained with PMA alone. This implies a similar target of action for pertussis toxin and PMA, that is, the alpha-subunit of Gi. The alpha-subunit of Gi was found to be a substrate for in vitro PKC phosphorylation of membrane fractions from UMR-106 cells, seen as a +/- 40 kD band on SDS-PAGE. Stimulation of in situ 32P-labeled cells with either PMA or PTH also enhanced incorporation of 32P into the 40 kD band. Using the peptide antisera AS/7 and EC/2, we showed that pertussis toxin-labeled subunits of both Gi1 alpha/Gi2 alpha and Gi3 alpha could be immunoprecipitated, respectively, but immunoprecipitation of membrane proteins after in situ phosphorylation and stimulation with PMA precipitated only Gi2 alpha.(ABSTRACT TRUNCATED AT 250 WORDS)