Urinary Metabolite Concentrations Research Articles

Erratum: Maternal Peripartum Serum DDT/E and Urinary Pyrethroid Metabolite Concentrations and Child Infections at 2 Years in the VHEMBE Birth Cohort.

Erratum: Maternal Peripartum Serum DDT/E and Urinary Pyrethroid Metabolite Concentrations and Child Infections at 2 Years in the VHEMBE Birth Cohort.

Non-linear model analysis of the relationship between cholinesterase activity in rats exposed to 2, 2-dichlorovinyl dimethylphosphate (dichlorvos) and its metabolite concentrations in urine

Urinary dialkylphosphates (DAPs) are measured to assess exposure to organophosphorus pesticides (OPs), but they are common metabolites of OPs and not specific indices for individual agents. Biomonitoring (BM) of urinary DAPs has been widely adopted as an assessment of individual exposure in general environments, however, guidance values for DAPs based on health effects have yet to be established. The present study aimed to clarify the relationship between the amount of urinary dimethylphosphate (DMP), a metabolite of dichlorvos (DDVP), and the inhibition of cholinesterase (ChE) activity in rats exposed to DDVP. The relationship was analyzed using a nonlinear model analysis, and the excretion level of urinary DMP equivalent to ChE 20 % inhibition (EL20) and the lower limit of the 95 % confidence interval of EL20 (ELL20) were estimated. EL20 and ELL20 (mg/24 h urine) of brain, erythrocyte, and plasma ChE activities after 10-day administration of DDVP were 0.21 and 0.15, 0.11 and 0.06, and 0.23 and 0.09, respectively. Extrapolating ELL20 of the brain ChE to humans, the range of 24 h urinary DMP concentration according to the 20 % inhibition of cholinesterase activity was estimated to be 20.5–30.8 mg/l. In conclusion, the amount of urinary DMP as ELL20 for DDVP exposure was identified and could probably be used as a novel index for the assessment of risk from OP exposure. Further studies are needed to clarify the ELL20 s derived from OPs other than DDVP, for informing efforts to establish guidance values of urinary OP metabolites that should prevent neurotoxicity.

Urinarni metaboliti kao indikatori izloženosti ljudi hemijskim karcinogenima

Population exposure to environmental chemical carcinogens is a growing public health problem. Carcinogenic chemicals may be classified into two groups: genotoxic and non-genotoxic. A genotoxic chemical has a potential to induce the development of cancer, either in direct interaction with DNA or with cell structures, which are responsible for the maintenance of genome integrity. A non-genotoxic chemical has a potential to induce cancer indirectly by entering the processes of cancer etiopathogenesis. Previous research studies indicate that inorganic arsenic compounds may be associated with various malign diseases (lung cancer, urinary bladder cancer, skin, kidney, liver and prostate cancer). Inorganic arsenic is mainly present in meat, dairy products and grains, while organic arsenic (arsenobetaine) is present in seafood, fruit and vegetables. Benzene metabolites are associated with different types of leukemias and lymphomas, benzidine with bladder cancer, nickel with lung cancer, chromium compounds with lung cancer, nose and nasal sinus cancer. The greatest occupational exposure to benzene is in industry (leather, electronic device, shoes, sports equipment), while people may come into contact with benzidine through consumer goods (leather products, clothes, toys). The highest concentrations of nickel were measured in the beans, walnuts and grains. Cadmium and cadmium compounds cause lung cancer, and influence the occurrence of renal and prostate cancer. The risk of hepatocellular carcinoma is significantly increased in respondents with high concentrations of urinary metabolites of aflatoxin (aflatoxin N7-gvanine adducts). Lindane isomers are present in dairy products, meat, fish, poultry, garden fruit, oils and lipids, leaf and root vegetables and sugar, and they cause non-Hodgkin lymphoma. There is a positive correlation between the consumption of Aristolochia plants and the occurrence of urothelial carcinoma. There are no screening examinations for the identification of persons who are at great risk of developing malign disease in the next 10 or 20 years. As for the prevention of malign diseases, it is necessary to put an accent on finding the adequate methods for determining the concentrations of urinary metabolites for toxic chemical carcinogens and define their risk values.

Policiklični aromatični ugljovodonici, njihovi urinarni metaboliti i zdravlje

The World Health Organization (WHO) stated as one of its conclusions that air pollution is a leading environmental health risk. Polycyclic aromatic hydrocarbons (PAHs) are well-known carcinogens (above five hundred compounds) that cause lung and skin cancer, especially in occupationally exposed workers. By significantly reducing emissions from modern combustion plants, traffic control, and strict smoking bans in public places, PAHs exposure can be reduced. PAH exposure ought to be better investigated, especially in the field of mass biomonitoring of the urinary concentrations of their major metabolites. Such biomonitoring ought to integrate exposures to chemical carcinogens from different sources (air, water, food, consumer products, professional procedures, etc.), as well as exposure to chemical noxae through the respiratory tract by (inhalation), digestive tract (ingestion), or through the skin. Analysis of the concentration of main PAHs metabolites in urine must be done with highly sophisticated equipment for a valid database to be obtained. The data thus obtained are necessary for risk assessment and health policymaking in order to reduce exposure to chemical carcinogens.

Plasma and urine metabolomic analyses in aortic valve stenosis reveal shared and biofluid-specific changes in metabolite levels.

Aortic valve stenosis (AVS) is a prevalent condition among the elderly population that eventually requires aortic valve replacement. The lack of reliable biomarkers for AVS poses a challenge for its early diagnosis and the application of preventive measures. Untargeted gas chromatography mass spectrometry (GC-MS) metabolomics was applied in 46 AVS cases and 46 controls to identify plasma and urine metabolites underlying AVS risk. Multivariate data analyses were performed on pre-processed data (e.g. spectral peak alignment), in order to detect changes in metabolite levels in AVS patients and to evaluate their performance in group separation and sensitivity of AVS prediction, followed by regression analyses to test for their association with AVS. Through untargeted analysis of 190 urine and 130 plasma features that could be detected and quantified in the GC-MS spectra, we identified contrasting levels of 22 urine and 21 plasma features between AVS patients and control subjects. Following metabolite assignment, we observed significant changes in the concentration of known metabolites in urine (n = 14) and plasma (n = 15) that distinguish the metabolomic profiles of AVS patients from healthy controls. Associations with AVS were replicated in both plasma and urine for about half of these metabolites. Among these, 2-Oxovaleric acid, elaidic acid, myristic acid, palmitic acid, estrone, myo-inositol showed contrasting trends of regulation in the two biofluids. Only trans-Aconitic acid and 2,4-Di-tert-butylphenol showed consistent patterns of regulation in both plasma and urine. These results illustrate the power of metabolomics in identifying potential disease-associated biomarkers and provide a foundation for further studies towards early diagnostic applications in severe heart conditions that may prevent surgery in the elderly.

The Relationship between Dietary Polyphenol Intakes and Urinary Polyphenol Concentrations in Adults Prescribed a High Vegetable and Fruit Diet.

Urinary polyphenol metabolites are potential biomarkers of dietary polyphenol intake. The current study aims to evaluate associations between total diet, vegetable and fruit polyphenol intakes with urinary polyphenol metabolite concentrations in a sample of adults prescribed a diet rich in vegetables and fruit. Thirty-four participants completed a 10-week pre-post study. Participants were asked to consume Australian recommended daily vegetable and fruit serves and attend measurement sessions at baseline and at weeks 2 and 10. Two 24-h diet recalls were collected at each time-point and polyphenol intakes were calculated using the Phenol-Explorer database. Spot urine samples, collected at each time-point, were analyzed for 15 polyphenol metabolites using liquid chromatography-mass spectroscopy. Spearman’s correlation analyzes assessed the strength of relationships between urinary and dietary polyphenols. Linear mixed models were used to investigate relationships between polyphenol excretion and intake. Total urinary polyphenols were significantly correlated with total polyphenol intakes at week 10 (rs = 0.47) and fruit polyphenols at week 2 (rs = 0.38). Hippuric acid was significantly correlated with vegetable polyphenols at baseline (rs = 0.39). Relationships were identified between individual polyphenol metabolites and vegetable and fruit polyphenols. Linear mixed model analyzes identified that for every 1 mg increase in polyphenol intakes, urinary polyphenol excretion increased by 16.3 nmol/g creatinine. Although the majority of relationships were not sufficiently strong or consistent at different time-points, promising relationships were observed between total urinary polyphenols and total polyphenol intakes, and hippuric acid and vegetable polyphenols.

Longitudinal exposure to pyrethroids 3-PBA, trans-TCC & 2,4 D herbicides in rural schoolchildren, Maule, Chile.

Background: Several studies show that early exposure to pesticides and during the preschool and school stage affects the development and health of children. In Maule, a series of studies have shown the exposure of organophosphate pesticides(OP), however, there are no studies assessing exposure to pyrethroids and herbicide 2,4 D. Objetive: To evaluate exposure to pyrethroids 3-phenoxybenzoic acid 3-PBA, trans-2,2-(dichloro)-2-dimethylvinylcyclopropane carboxylic acid trans-DCCA(Trans-TCC) and 2,4 D herbicides in schoolchildren. Method: Longitudinal study, 48 schoolchildren from 5 to 13 years old from two rural schools in the Maule. Specific metabolites of pyrethroids 3-PBA, Trans-TCC and 2.4 D in the urine of the school children were evaluated. The data were correlated with an earlier study that evaluated the exposure of OP metabolites. Two samples were taken in September and 2 samples in November, a total of 384 urine samples were obtained during 2016 and 2017. Data analysis: descriptive, U Mann Whitney for repeated measurements, Spearman and GEE. Results: The 100% of schoolchildren have more than two pesticide metabolites in their urine in both years, with the 3-PBA metabolite being the most frequent. 3-PBA in November 2017 increases its presence in urine compared to 2016(from 0.69 μg/L in 2016 to 1.90μg/L in 2017). In 2016, the specific metabolites of 3-PBA correlate with TCC, 2,4 D, chlorpyrifos, diazinon, paration. In 2017, 3-PBA was correlated with 2,4 D and TCC. Importantly, the concentrations of 3-PBA pesticide metabolites in urine found in Chilean children was higher than studies in the USA where there is an association of exposure from prenatal stage to these metabolites with difficulties in emotional control and attention. Conclusions: Promote the monitoring, training and active epidemiological surveillance of agricultural communities. The increased use of pyrethroids is worrying. Promote the intervention of school communities, involving government agencies and agricultural companies, considering preventing to the population.

Phthalate Exposure and Respiratory Diseases Among Adults and Children: the US NHANES 2007-2016

Background/Aim: Phthalates are used as plasticizers in many consumer products. Although they have associations with multiple adverse health outcomes, studies on phthalate exposure and respiratory outcomes are limited. The objective of our study was to examine the association between phthalate exposure and respiratory diseases in the US population. Methods: Using data from the National Health and Nutrition Examination Survey (NHANES) 2007-2016, we analyzed the data on twelve urinary metabolites and current respiratory diseases (asthma, bronchitis, and emphysema) among adults (≥ 20 years of age) and children and adolescents (6-19 years of age). The logistic regression was conducted to estimate the odds ratios (ORs) per one log10 unit increase in the concentration of urinary phthalate metabolites, and age, gender, race, waist/height ratio, urinary creatinine, serum cotinine level, and poverty index ratio were included in the model for adjustment. Analyses were conducted separately on children and adults to investigate the difference by age. Results: In adults, mono-benzyl phthalate (MBzP) was positively associated with asthma and chronic bronchitis (OR 1.34; 95% CI 1.11-1.61 and OR 1.39; 95% CI 1.02-1.91). Mono-(3-carboxypropyl) phthalate and mono-(carboxynonyl) phthalate also showed the significant associations with chronic bronchitis (OR 1.38; 95% CI 1.04-1.84 and OR 1.44; 95% 1.03-2.02). Although there was a trend with elevated risk between low-molecular-weight phthalates and emphysema, it was not significant (OR 1.26; 95% CI 0.98-1.62 for mono-ethyl phthalate, and OR 1.28; 95% CI 0.80-2.04 for mono-isobutyl phthalate). In children and adolescents, no evidence of associations between phthalates and asthma was found. Conclusion: Our cross-sectional study advocates for the positive associations of high-molecular -weight phthalate metabolites with respiratory diseases among adults. However, in children, the evidence of such association was absent, for which further analysis and research are recommended.

Arsenic metabolism association with body mass index is mediated by physical activity in Mexican women

Background/Aim: A positive association of body mass index (BMI) with inorganic arsenic (iAs) metabolism parameters (percentage dimethylarsinic acid [%DMA] and second methylation index [SMI]) was reported in epidemiological studies, suggesting that obesity improves iAs detoxification. However, BMI is a rough indicator of obesity, which is the product of the balance between calorie intake and physical activity. Physical activity consumes methyl groups that are necessary to metabolize iAs. Therefore, our objective was to evaluate whether physical activity modifies the relationship between BMI and iAs metabolism.Methods: We performed a cross-sectional secondary analysis of 800 healthy women, 20 years and over, that participated as population controls in a previous study on breast cancer in northern Mexico. Participants were interviewed about physical activity during their lifetime, and their weight and size were obtained. Concentrations of urinary arsenic metabolites were determined by high performance liquid chromatography coupled with mass spectrometry.Results: In the study population, total arsenic ranged from 0.71 to 303.29 µg/L, BMI from 14.60 to 57.81 kg/m2, and the lifetime average physical activity from 0 to 13.14 h/week. BMI was significantly and positively associated with %DMA and SMI. These associations remained after stratifying for physical activity. A significant antagonistic interaction (p=0.003) emerged only between physical activity and SMI on BMI: BMI association with SMI differed between women with higher (β= 0.004 95% CI: 0.001, 0.007) and lower physical activity (β= 0.011, 95% CI: 0.007, 0.015).Conclusion: Our findings do not support a direct relationship between BMI and iAs metabolism. Physical activity appears to play an important role in iAs detoxification in obese women. This finding warrant further research.

Exposure to pyrethroid insecticides among pregnant women and their child in Rio de Janeiro City - Results from a birth cohort (PIPA Project)

Background/aims: Pyrethroid insecticides are largely used in Brazil, one of the world's largest consumers of pesticides. We investigated the exposure of pregnant women and their child at the time of birth and 3rd month of life to pyrethroids and its association with sociodemographic variables, self-reported diseases, and childbirth outcomes in the City of Rio de Janeiro. Few studies investigate levels of pyrethroid in neonates.Methods: We performed a cross-sectional analysis of data from Rio birth cohort (PIPA study). Pregnant women at 3rd trimester who received antenatal care at the Federal University of Rio de Janeiro’s Maternity School. Mother’s sociodemographic, daily habits, existing disease and some birth outcomes about child was collected. Mother's (n=138), newborn's (n=29) and 3-month old child's (n=46) urine samples was analyzed for detection of pyrethroid metabolites 3-PBA and 4-FPBA using liquid chromatography coupled to mass spectrometry. We did a descriptive analysis of the excretion profile of pyrethroids from mothers and their children.Results: From all samples, 70% of woman, 28% of newborns, 30% of 3 months old children showed urinary concentrations of pyrethroid metabolites. Pyrethroid metabolites geometric mean (GM) was 0,78 ng mg-1 for mothers, 0,16 ng mg-1 for newborns and 0,89 ng mg-1 at 3rd month old. Mother’s pyrethroid levels doesn’t seem to have relationship with child’s pyrethroid levels at follow up. Pregnant women with diabetes excreted higher levels of pyrethroids in the urine (p<0,01); newborns small for gestational age (SGA) excreted higher levels of pyrethroids in the urine (p=0,01); similarly, cephalic perimeter and Apgar was associated with pyrethroid exposure in 3rd month old babies (p=0,02; p=0,02).Conclusions: Newborns (28%) presented pyrethroids metabolites in urine even at birth. Pyrethroid exposure appears to be related with diabetes in mothers, withsize for gestational age in newborns and with cephalic perimeter and Apgar in 3 months old child.

Gestational exposure to organophosphate esters (OPEs) and maternal blood pressure during pregnancy: The HOME Study

Background: After the phase-out of polybrominated diphenyl ethers, exposure to organophosphate esters (OPEs), which are potential endocrine disruptors, is ubiquitous. No study has examined the associations between gestational exposure to OPEs and blood pressure and the risk of pregnancy-induced hypertensive diseases.Methods: We used data from 333 women who had liveborn singletons without congenital abnormalities in the Health Outcomes and Measures of the Environment (HOME) Study, a prospective birth cohort. We quantified maternal urinary OPE metabolites at 16 weeks of gestation. Outcomes included the highest maternal blood pressure measurement at ≥20 weeks of gestation and pregnancy-induced hypertensive diseases (gestational hypertension, preeclampsia, and eclampsia) from medical chart review. We used linear regression and modified Poisson regression with covariate adjustment to estimate the associations of exposure with blood pressure and the risk of pregnancy-induced hypertensive diseases, respectively.Results: Diphenyl phosphate (DPHP) had the highest geometric mean urinary concentrations (1.65 µg/g creatinine), followed by bis(1,3-dichloro-2-propyl) phosphate (BDCIPP; 0.76 µg/g creatinine), bis(2-chloroethyl) phosphate (BCEP; 0.70 µg/g creatinine), and dibutyl phosphate (DBUP; 0.25 µg/g creatinine). There were 29 (8.7%) women diagnosed with pregnancy-induced hypertensive diseases. Average systolic and diastolic blood pressure, measured at an average of 31 weeks gestation (range: 20-41), were 117±13 and 72±9 mmHg, respectively. None of the urinary OPE metabolites were significantly associated with the highest maternal blood pressure at ≥20 weeks of gestation, nor were they strongly associated with an increased risk of pregnancy-induced hypertensive diseases. The relative risk (RR; 95% confidence interval) of pregnancy-induced hypertensive diseases by a 10-fold increase in exposure was 1.31 (0.66, 2.59) for DPHP, 1.36 (0.51, 3.67) for BDCIPP, 0.63 (0.16, 2.39) for BCEP and 2.13 (0.78, 5.77) for DBUP.Conclusion: This study suggests no associations between maternal urinary OPE metabolite concentrations and blood pressure or an increased risk of pregnancy-induced hypertensive diseases during pregnancy.

Prenatal polycyclic aromatic hydrocarbon (PAH) exposure and early childhood asthma in a diverse US pregnancy cohort

Background/AimExposure to polycyclic aromatic hydrocarbons (PAH) may increase risk of pediatric asthma. Effects of prenatal PAH exposure, specifically, are hypothesized but understudied. The ECHO PATHWAYS Consortium investigated these relationships in a large, diverse prospective cohort study.MethodsWe included 919 mother-child dyads from the CANDLE Study, a longitudinal pregnancy cohort set in Shelby County, TN. PAH metabolites were measured in second trimester urine and adjusted for specific gravity. Seven metabolites detected in >80% of women were included in analysis. When children were 4-6 years old, mothers completed the International Study on Allergies and Asthma in Childhood survey. Poisson regression with robust standard errors was used to estimate relative risk of current wheeze, current asthma, and ever asthma associated with each metabolite in separate models, adjusted for maternal age, race, education and other asthma risk factors. Effect modification by child sex and maternal asthma was assessed using interaction models. We did not adjust for multiple comparisons.ResultsParticipants were 66% Black, 44% White; 58% with high school education or less. On average, urinary PAH metabolite concentrations were higher than in other US cohorts. Mean (SD) child age at assessment was 4.3 (0.4) years. Prevalence of reported current wheeze and asthma and ever asthma was 19.4%, 16.1%, and 14.6%, respectively. In multivariable models, we observed no evidence that any metabolite was associated with any outcome. No differences by child sex were observed. Maternal asthma modified associations between 1/9-hydroxyphenanthrene and current asthma (RRmaternal asthma = 0.88; 95%CI: 0.78, 0.99 versus RRwithout maternal asthma = 1.09; 95%CI: 0.97, 1.23 per two-fold increase in exposure; pinteraction=0.012).ConclusionsResults of our analysis, the largest cohort study of prenatal PAH and childhood airway outcomes conducted to date, did not support the hypothesis that prenatal PAHs increases risk of early childhood asthma.

Pesticide Urinary Metabolite Concentration and Asthma Morbidity in Socially Disadvantaged Children

Background: Little is known about urinary pesticide (UP) concentration in socially disadvantaged children. These children may be at greater exposure risk because low income is associated with more household pest exposure. Urinary pesticide concentration and its association with asthma morbidity was measured in 161 children with asthma (7-12 years) residing in subsidized housing in three U.S. cities (Boston, Cincinnati, New Orleans).Methods: Morning void and convenience spot samples were collected at three time points over one year. Urine samples were analyzed for seven pesticide metabolites; 3 organophosphates (OPs): TCPY, IMPY, PNP; 3 pyrethroids (PYR): 4-F-3-PBA, 3-PBA, trans-DCCA; and 1 herbicide: 2,4-D. Total PYR was calculated as the sum of 4-F-3PBA, 3-PBA, and trans-DCCA and total OP as the sum of TCPY, IMPY, and PNP. Outcomes were forced expiratory volume in one second (FEV1), and respiratory inflammation measured as fractional exhaled nitric oxide (FeNO).Results: A total of eight hundred and ten urine samples were collected. The proportion with detectable metabolites ranged from 35% (trans-DCCA) to 97% (TCPY and PNP). Geomeans of each pesticide were higher in this cohort compared to a national sample (NHANES 2009-2010) of children 6-11 years. In models adjusting for socio-demographic factors, a 1 µg/mL increase in TCPy, IMPY, trans-DCCA, 2,4-D, total OPs and PNP was associated with a reduction in FEV1 (-0.004 to -0.158) although no model reached statistical significance (p<0.05). An increase in TCPY, total OPs, and 4-F-3-PBA, resulted in a non-statistically significant increase in FeNO (0.0004 to 0.0675) .Conclusion: Results demonstrate these low-income children with asthma residing in subsidized housing are exposed to higher concentrations of pesticides compared to a general population sample. Additionally, the evidence suggests negative respiratory outcomes with increasing levels of UPs. Reducing exposure to pesticides is important to mitigate the potential negative health effects for vulnerable populations.

Exposure to organophosphate ester flame retardants and plasticizers during pregnancy: Thyroid endocrine disruption and mediation role of oxidative stress

Organophosphate esters (OPEs) are widely used as flame retardants and plasticizers in consumer and industrial products. Human exposure to OPEs raises concerns due to their endocrine disruptive potentials. Till now, the effects of OPEs on thyroid hormones (THs) and the mediating role of oxidative stress in pregnant women have not been studied. In this study, prenatal urinary concentrations of OPE metabolites (mOPEs), levels of free triiodothyronine (FT3), free thyroxine (FT4), thyroid-stimulating hormone (TSH), and oxidative stress levels of 8-hydroxy-2-deoxy guanosine (8-OHdG) and malondialdehyde (MDA) were measured in pregnant women (n = 360) from a coastal urbanized region and moderate socioeconomic status. Neonatal TSH in heel blood was also measured in newborns (n = 309). Dibutyl phosphate (DBP) and diphenyl phosphate (DPHP) were extensively detected with a median creatinine-adjusted level of 0.19 μg/g and 0.66 μg/g, respectively, and the median of ∑mOPEs was 1.82 μg/g. DBP and DPHP were included in the analysis. The concentrations of DBP and DPHP were positively associated with either maternal or neonatal TSH levels, while not for maternal FT3 and FT4 levels. Positive associations for maternal and neonatal TSH were particularly observed in girls as stratified by newborn sex suggesting a sex-selective difference. Furthermore, 8-OHdG, the biomarker of DNA damage, was found to be a major mediator (>60%) for the association between neonatal TSH and DPHP, suggesting that DNA damage is involved in fetal thyroid function disruption. On the other hand, MDA showed a partially suppressing effect (<40%) for the associations between mOPEs and neonatal TSH, which needs further clarification. For maternal TSH, both 8-OHdG and MDA showed moderate mediating effects while the direct effects of mOPEs on maternal TSH also contributed. These results suggest thyroid disrupting effects of OPE exposure on mothers and fetuses during pregnancy and the potential influence mediated by the oxidative stresses of DNA damage and lipid peroxidation.

Paternal mixtures of urinary concentrations of phthalate metabolites, bisphenol A and parabens in relation to pregnancy outcomes among couples attending a fertility center

BackgroundFew epidemiologic studies have evaluated the impact of paternal environmental exposures, particularly as mixtures, on couples’ pregnancy outcomes. ObjectiveWe investigated whether mixtures of paternal urinary bisphenol A (BPA), paraben, and phthalates were associated with pregnancy outcomes among couples attending a fertility center. MethodsWe included 210 couples undergoing 300 in vitro fertilization (IVF) between 2004 and 2017 in this prospective analysis. We quantified paternal urinary biomarker concentrations in one sample per cycle using isotope-dilution tandem mass spectrometry. We used principal component analysis (PCA) to identify correlations of biomarker concentrations and multivariable Cox proportional hazards models for discrete survival time to estimate the hazard ratios (HRs) and 95% CIs for the associations between PCA-derived factor scores and probability of failing to achieve a live birth. Interactions were also included in the models to examine strength of associations over three vulnerable periods [embryo transfer to implantation, implantation to clinical pregnancy, and clinical pregnancy to live birth]. Models were adjusted for paternal and maternal ages and body mass indexes, urinary dilution (specific gravity) and year of collection, infertility diagnosis, and other PCA factor scores. Sensitivity analyses with further adjustment for maternal PCA factor scores were performed. ResultsWe identified three factors, representing di-2-ethylhexyl phthalate (DEHP) metabolites, BPA and non-DEHP metabolites, and parabens, accounting for 56%, 15% and 10%, respectively, of the total variance explained. An interquartile range (25th and 75th percentiles) increase in the DEHP-related factor score was associated with elevated probability of failing prior to live birth (HR = 1.41, 95% CI: 1.08, 1.81) and the association was stronger between implantation and clinical pregnancy as well as between clinical pregnancy and live birth compared to before implantation. The overall HRs of failure for the BPA/non-DEHP-related and paraben-related factor scores were HR = 1.24 (95% CI: 0.97, 1.59) and HR = 0.99 (95% CI: 0.80, 1.24). We found similar HRs when additionally adjusting for maternal PCA factor scores. ConclusionPaternal mixtures of urinary concentrations of DEHP metabolites were related to higher infertility treatment failure.

Concentration and Variability of Urinary Phthalate Metabolites, Bisphenol A, Triclosan, and Parabens in Korean Mother–Infant Pairs

Concentrations of toxic chemicals in mothers highly correlate with those in their children; moreover, the levels are higher in children than in mothers. Non-persistent chemicals with a short half-life including phthalate metabolites, bisphenol A (BPA), triclosan (TCS), and parabens are metabolized and excreted through urine. Therefore, we assessed the urine concentrations of phthalate metabolites, BPA, TCS, and parabens; correlated the concentrations with exposure levels; and assessed the within-individual variability of these chemicals in mothers and their infants. We collected 225 and 71 samples from 45 mothers and 36 infants, respectively. For the variability analysis, 189 and 42 samples were collected from nine mothers and their infants, respectively. The median concentrations of phthalate metabolites in the mothers and infants were 0.53–26.2 and 0.81–61.8 μg/L, respectively, and those of BPA, TCS, and parabens were 0.24–76.3 and 2.06–12.5 μg/L, respectively. The concentrations of monoethyl phthalate (MEP), mono-N-butyl phthalate (MnBP), mono-isobutyl phthalate (MiBP), and BPA in the mothers were positively correlated with those in infants (0.45, 0.62, and 0.89, respectively; p &lt; 0.05), whereas toxic chemical concentrations in infants were higher than those in the mothers. With respect to the within-individual intraclass correlation coefficient (ICC), the first morning void (FMV) of the mothers had high ICCs for all chemicals (range: 0.72–0.99), except for BPA, monobenzyl phthalate (MBzP), and monocarboxyoctyl phthalate (MCOP). The ICC values of most chemicals were moderate to high (range: 0.34–0.99) in the first morning void. However, there were different patterns of ICCs in the infants. These findings indicate the importance of mother–infant pair studies and the necessity of research in infants, as they have different exposure sources and pathways from adults.

Estimating human exposure to pyrethroids’ mixtures from biomonitoring data using physiologically based pharmacokinetic modeling

Human biomonitoring data provide evidence to exposure of environmental chemicals. Physiologically based pharmacokinetic (PBPK) modelling together with an adequate exposure scenario allows to transpose measured concentrations of chemicals or their metabolites into exposure levels, as daily intakes. In France, high levels of urinary pyrethroids metabolites have been measured in populations. Our work aims at estimating the exposure of the French ENNS cohort to mixtures of four pyrethroids (deltamethrin, permethrin, cypermethrin, and cyfluthrin) from the urinary concentrations of five pyrethroids' metabolites commonly measured in biomonitoring studies. We developed a modelling approach based on a global toxicokinetic model that accounts for the cumulative exposure to pyrethroids as some of the metabolites can be shared by several parent compounds and for human inter-individual variability in metabolism. The median of the individual daily intakes was estimated to 8.1 ng/kg bw/day for permethrin, 17.7 ng/kg bw/day for cypermethrin, 20.4 ng/kg bw/day for cyfluthrin and 34.3 ng/kg bw/day for deltamethrin leading to similar weights for the pair permethrin and cypermethrin (36%), cyfluthrin (31%) and deltamethrin (33%) to the cumulative exposure. Accounting for human variability enabled to explain some of the variations in the metabolites' levels within the cohort. The cumulative exposure was then weighted by their toxicities towards three neurotoxic effects to calculate margins of exposure (MOE). Low MOE values were always associated with high measured concentrations of metabolites in urine and the lowest MOEs were observed for the autonomic division. No risks associated with reconstructed mixtures of pyrethroids were expected for the ENNS cohort. Our approach is an asset to analyse the biomarkers of exposure to pyrethroids simultaneously and could be easily adapted to any local or national specificities in pyrethroids’ exposure or populations.

Between- and within-individual variability of urinary phthalate and alternative plasticizer metabolites in spot, morning void and 24-h pooled urine samples

Due to international regulations, commonly used phthalates such as di(2-ethylhexyl) phthalate (DEHP) are being replaced by other phthalates, such as di-isononyl phthalate (DINP), and di-isodecyl phthalate (DIDP) and by alternative plasticizers (APs) with similar chemical characteristics, like di(isononyl)cyclohexane-1,2-dicarboxylate (DINCH), di(2-ethylhexyl) terephthalate (DEHTP), or di-(2-ethylhexyl) adipate (DEHA). Urinary concentrations of metabolites are frequently used in the exposure assessment of non-persistent chemicals and for biomonitoring purposes, the intra- and inter-day variability of the metabolites should be known. However, the short-term variability of AP and several phthalate biomarkers has not been investigated yet. In this study, we collected all spot samples from 10 healthy adults for 5 consecutive days and 24h pooled urine on one additional day to investigate the short-term variability of 22 biomarkers of phthalates and APs. Metabolites of DEP, DEHP, DiBP, DnBP, DBzP, DINP and DIDP were found in high detection frequencies, while metabolites of most APs were found in approximately 50% of the samples. The short-term reproducibility of metabolites with diet as primary source (DEHP, DINP, DIDP) was poor (intraclass correlation coefficient – ICC < 0.4), whereas biomarkers of DEP, DnBP, DiBP and BBzP showed good consistency, most likely due to more continuous sources resulting in less between-day variance. ICC values of AP metabolites were similar to those of DEHP, but more studies are required to confirm these findings. Overall, reproducibility improved considerably when values were corrected for urinary dilution and when only morning voids samples were considered. Levels in morning voids samples were consistent for 5 days and comparable to 24-h pooled urine for all metabolites except for OH-MEHTP, sum DINP and sum DIDP, which supports the use of morning voids in human biomonitoring studies.

Urinary Resveratrol Metabolites Output: Differential Associations with Cardiometabolic Markers and Liver Enzymes in House-Dwelling Subjects Featuring Metabolic Syndrome.

Metabolic syndrome (MetS) components are strongly associated with increased risk of non-alcoholic fatty liver disease (NAFLD) development. Several studies have supported that resveratrol is associated with anti-inflammatory and antioxidant effects on health status. The main objective of this study was to assess the putative associations between some urinary resveratrol phase II metabolites, cardiometabolic, and liver markers in individuals diagnosed with MetS. In this cross-sectional study, 266 participants from PREDIMED Plus study (PREvención con DIeta MEDiterránea) were divided into tertiles of total urinary resveratrol phase II metabolites (sum of five resveratrol conjugation metabolites). Urinary resveratrol metabolites were analyzed by ultra- performance liquid chromatography coupled to triple quadrupole mass spectrometry (UPLC-Q-q-Q MS), followed by micro-solid phase extraction (µ-SPE) method. Liver function markers were assessed using serum levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), and gamma-glutamyl transferase (GGT). Moreover, lipid profile was measured by triglycerides, very-low-density lipoprotein cholesterol (VLDL-c), and total cholesterol/high-density lipoprotein ratio (total cholesterol/HDL). Linear regression adjusted models showed that participants with higher total urine resveratrol concentrations exhibited improved lipid and liver markers compared to the lowest tertile. For lipid determinations: log triglycerides (βT3 = −0.15, 95% CI; −0.28, −0.02, p-trend = 0.030), VLDL-c, (βT3 = −4.21, 95% CI; −7.97, −0.46, p-trend = 0.039), total cholesterol/HDL ratio Moreover, (βT3 = −0.35, 95% CI; −0.66, −0.03, p-trend = 0.241). For liver enzymes: log AST (βT3 = −0.12, 95% CI; −0.22, −0.02, p-trend = 0.011, and log GGT (βT3 = −0.24, 95% CI; −0.42, −0.06, p-trend = 0.002). However, there is no difference found on glucose variables between groups. To investigate the risk of elevated serum liver markers, flexible regression models indicated that total urine resveratrol metabolites were associated with a lower risk of higher ALT (169.2 to 1314.3 nmol/g creatinine), AST (599.9 to 893.8 nmol/g creatinine), and GGT levels (169.2 to 893.8 nmol/g creatinine). These results suggested that higher urinary concentrations of some resveratrol metabolites might be associated with better lipid profile and hepatic serum enzymes. Moreover, urinary resveratrol excreted showed a reduced odds ratio for higher liver enzymes, which are linked to NAFLD.

Exploring the Association between Urine Caffeine Metabolites and Urine Flow Rate: A Cross-Sectional Study.

Examination of urine excretion of caffeine metabolites has been a simple but common way to determine the metabolism and effect of caffeine, but the relationship between urinary metabolites and urine flow rate is less discussed. To explore the association between urinary caffeine metabolite levels and urine flow rate, 1571 participants from the National Health and Nutrition Examination Survey (NHANES) 2011–2012 were enrolled in this study. We examined the association between urinary caffeine metabolites and urine flow rate with linear regression models. Separate models were constructed for males and females and for participants aged <60 and ≥60 years old. A positive association was found between concentrations of several urinary caffeine metabolites and urine flow rate. Three main metabolites, namely, paraxanthine, theobromine, and caffeine, showed significance across all subgroups. The number of caffeine metabolites that revealed flow-dependency was greater in males than in females and was also greater in the young than in the elderly. Nevertheless, the general weakness of NHANES data, a cross-sectional study, is that the collection is made at one single time point rather than a long-term study. In summary, urinary concentrations of several caffeine metabolites showed a positive relationship with the urine flow rate. The trend is more noticeable in males and in young subgroups.