Fetal exposure to phthalates – a pilot study

The fetus is considered to be the most sensitive stage of life to the potential developmental and reproductive toxicity of the phthalates. But, data on human fetal exposure to phthalates is still scarce. In this pilot study we collected 11 pairs of amniotic fluid (AF) and corresponding maternal urine (MU) samples during Caesarean section and analysed them for several phthalate metabolites by LC-MS/MS. In all AF samples, metabolites of di-n-butyl phthalate (DnBP), diisobutyl phthalate (DiBP), butylbenzyl phthalate (BBzP), di(2-ethylhexyl) phthalate (DEHP) were detectable. For the first time, we were able to detect also oxidative phthalate metabolites in AF, with two carboxy metabolites of DEHP showing the highest abundance. In the MU samples, the concentrations of the phthalate metabolites were generally much higher than in the AF samples. There was a statistically significant linear correlation for the DiBP monoester (MiBP) (r=0.93; p<0.001) in the AF and MU samples. We also found a significant correlation for the DEHP monoester (MEHP) (r=0.91; p<0.001), although there was a most likely external contamination with MEHP in the MU samples. Our results suggest that several phthalates or their metabolites, respectively, reach the human fetus, which might be able to affect fetal health. Further research is needed to elucidate fetal metabolism of phthalates and to evaluate the in utero phthalate exposure and the potential effects on fetal reproductive development. Due to the continuous turn over of AF, urinary levels may be most appropriate for assessing both maternal and fetal phthalate exposure.     

Levels of seven urinary phthalate metabolites in a human reference population

Using a novel and highly selective technique, we measured monoester metabolites of seven commonly used phthalates in urine samples from a reference population of 289 adult humans. This analytical approach allowed us to directly measure the individual phthalate metabolites responsible for the animal reproductive and developmental toxicity while avoiding contamination from the ubiquitous parent compounds. The monoesters with the highest urinary levels found were monoethyl phthalate (95th percentile, 3,750 ppb, 2,610 microg/g creatinine), monobutyl phthalate (95th percentile, 294 ppb, 162 microg/g creatinine), and monobenzyl phthalate (95th percentile, 137 ppb, 92 microg/g creatinine), reflecting exposure to diethyl phthalate, dibutyl phthalate, and benzyl butyl phthalate. Women of reproductive age (20-40 years) were found to have significantly higher levels of monobutyl phthalate, a reproductive and developmental toxicant in rodents, than other age/gender groups (p < 0.005). Current scientific and regulatory attention on phthalates has focused almost exclusively on health risks from exposure to only two phthalates, di-(2-ethylhexyl) phthalate and di-isononyl phthalate. Our findings strongly suggest that health-risk assessments for phthalate exposure in humans should include diethyl, dibutyl, and benzyl butyl phthalates.     

Phthalate metabolites in urine samples from Danish children and correlations with phthalates in dust samples from their homes and daycare centers

Around the world humans use products that contain phthalates, and human exposure to certain of these phthalates has been associated with various adverse health effects. The aim of the present study has been to determine the concentrations of the metabolites of diethyl phthalate (DEP), di(n-butyl) phthalate (DnBP), di(iso-butyl) phthalate (DiBP), butyl benzyl phthalate (BBzP) and di(2-ethylhexyl) phthalate (DEHP) in urine samples from 441 Danish children (3–6 years old). These children were subjects in the Danish Indoor Environment and Children's Health study. As part of each child's medical examination, a sample from his or her first morning urination was collected. These samples were subsequently analyzed for metabolites of the targeted phthalates. The measured concentrations of each metabolite were approximately log-normally distributed, and the metabolite concentrations significantly correlated with one another. Additionally, the mass fractions of DEP, DnBP, DiBP and BBzP in dust collected from the children's bedrooms and daycare centers significantly correlated with the concentrations of these phthalates’ metabolites (monoethyl phthalate (MEP), mono-n-butyl phthalate (MnBP), mono-isobutyl phthalate (MiBP) and monobenzyl phthalate (MBzP), respectively) in the children's urine. Such correlations indicate that indoor exposures meaningfully contributed to the Danish children's intake of DEP, DnBP, DiBP and BBzP. This was not the case for DEHP. The urine concentrations of the phthalate metabolites measured in the present study were remarkably similar to those measured in urine samples from children living in countries distributed over four continents. These similarities reflect the globalization of children's exposure to phthalate containing products.     

Phthalate Excretion Pattern and Testicular Function: A Study of 881 Healthy Danish Men

Background: In animals, some phthalates impair male reproductive development and function. Epidemiological studies have reported inconsistent evidence of associations between phthalates and markers of human testicular function.Objectives: We aimed to provide estimates of the effects of phthalate exposure on reproductive hormone levels and semen quality in healthy men.Methods: A total of 881 men gave urine, serum, and semen samples. Serum levels of testosterone, estradiol (E₂), sex hormone-binding globulin (SHBG), luteinizing hormone (LH), follicle-stimulating hormone (FSH), and inhibin-B; semen quality; and urinary concentrations of 14 phthalate metabolites, including metabolites of di(2-ethylhexyl) phthalate (DEHP) and diisononyl phthalate (DiNP), were assessed. The proportions of DEHP and DiNP excreted as their respective primary metabolites [mono(2-ethylhexyl) phthalate (MEHP) and mono-isononyl phthalate (MiNP)] were calculated and expressed as percentages (%MEHP and %MiNP, respectively).Results: The free androgen index was 15% lower [95% confidence interval (CI): –23, –8%] for men in the highest %MiNP quartile compared to the lowest quartile (p < 0.001) after adjusting for confounders, and 9% lower (95% CI: –16, –1%) in the highest %MEHP quartile (p = 0.02). %MEHP and %MiNP were negatively associated with the ratio of testosterone/LH and testosterone/FSH. %MEHP was negatively associated with total testosterone, free testosterone, and ratio of testosterone/E₂. %MiNP was positively associated with SHBG. There was little evidence of associations between urinary phthalate metabolites or sums of phthalates with reproductive hormones or semen qualityConclusion: Our data suggest that both testosterone production and pituitary–hypothalamic feedback may be compromised in individuals excreting a high proportion of primary metabolites of long-chained phthalates relative to the proportion of secondary metabolites.     

Relationship between urinary phthalate and bisphenol A concentrations and serum thyroid measures in U.S. adults and adolescents from the National Health and Nutrition Examination Survey (NHANES) 2007-2008

Background: Limited animal, in vitro, and human studies have reported that exposure to phthalates or bisphenol A (BPA) may affect thyroid signaling.Objective: We explored the cross-sectional relationship between urinary concentrations of metabolites of di(2-ethylhexyl) phthalate (DEHP), dibutyl phthalate (DBP), and BPA with a panel of serum thyroid measures among a representative sample of U.S. adults and adolescents.Methods: We analyzed data on urinary biomarkers of exposure to phthalates and BPA, serum thyroid measures, and important covariates from 1,346 adults (ages ≥ 20 years) and 329 adolescents (ages 12–19 years) from the National Health and Nutrition Examination Survey (NHANES) 2007–2008 using multivariable linear regression.Results: Among adults, we observed significant inverse relationships between urinary DEHP metabolites and total thyroxine (T₄), free T₄, total triiodothyronine (T₃), and thyroglobulin, and positive relationships with thyroid-stimulating hormone (TSH). The strongest and most consistent relationships involved total T₄, where adjusted regression coefficients for quintiles of oxidative DEHP metabolites displayed monotonic dose-dependent decreases in total T₄ (p-value for trend < 0.0001). Suggestive inverse relationships between urinary BPA and total T₄ and TSH were also observed. Conversely, among adolescents, we observed significant positive relationships between DEHP metabolites and total T₃. Mono(3-carboxypropyl) phthalate, a secondary metabolite of both DBP and di-n-octyl phthalate, was associated with several thyroid measures in both age groups, whereas other DBP metabolites were not associated with thyroid measures.Conclusions: These results support previous reports of associations between phthalates—and possibly BPA—and altered thyroid hormones. More detailed studies are needed to determine the temporal relationships and potential clinical and public health implications of these associations.     

Variability and predictors of urinary phthalate metabolites in Spanish pregnant women

Developmental exposure to phthalates may be associated with adverse health outcomes but information on the variability and predictors of urinary phthalate metabolite concentrations during pregnancy is limited. We evaluated in Spanish pregnant women (n = 391) the reproducibility of urinary phthalate metabolite concentrations and predictors of exposure. We measured mono-(4-methyl-7-hydroxyoctyl) phthalate (7-OHMMeOP), mono-(2-ethylhexyl) phthalate (MEHP), mono-(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP), mono-(2-ethyl-5-oxohexyl) phthalate (MEOHP), mono-(2-ethyl-5-carboxypentyl) phthalate (MECPP), mono-(2-carboxyhexyl) phthalate (MCMHP), mono-benzyl phthalate (MBzP), mono-ethyl phthalate (MEP), mono-iso-butyl phthalate (MiBP) and mono-n-butyl phthalate (MnBP) in two spot urine samples collected in the first and third pregnancy trimesters. Questionnaires on predictors and food-frequency questionnaires were administered in the first and/or third pregnancy trimesters. Using creatinine-adjusted phthalate metabolite concentrations (log₁₀-trasformed) we calculated intraclass correlation coefficients (ICCs). Linear mixed and regression models assessed the associations between predictors and phthalate metabolites. The ICCs ranged from 0.24 to 0.07 and were higher for MBzP, MEP, MiBP, and lower for MEOHP and MEHHP. Overweight, lower education and social class, and less frequent consumption of organic food were associated with higher levels of some phthalate metabolites. The use of household cleaning products (bleach, ammonia, glass cleaners, oven cleaning sprays and degreasing products) at least once per week during pregnancy was associated with 10–44% higher urinary phthalate metabolites. Bottled-water consumption, consumption of food groups usually stored in plastic containers or cans, use of plastic containers for heating food and cosmetic use were not associated with increased concentrations of phthalate metabolites. This large study with repeated phthalate measurements suggests that, in this Spanish setting, sociodemographic and lifestyle factors and household cleaning product use are better predictors of phthalate exposure levels in pregnant women than average water and food consumption and use of plastic containers and cosmetics.     

Integrating biomonitoring exposure data into the risk assessment process: phthalates [diethyl phthalate and di(2-ethylhexyl) phthalate] as a case study

The probability of nonoccupational exposure to phthalates is high given their use in a vast range of consumables, including personal care products (e.g., perfumes, lotions, cosmetics), paints, industrial plastics, and certain medical devices and pharmaceuticals. Phthalates are of high interest because of their potential for human exposure and because animal toxicity studies suggest that some phthalates affect male reproductive development apparently via inhibition of androgen biosynthesis. In humans, phthalates are rapidly metabolized to their monoesters, which can be further transformed to oxidative products, conjugated, and eliminated. Phthalate metabolites have been used as biomarkers of exposure. Using urinary phthalate metabolite concentrations allows accurate assessments of human exposure because these concentrations represent an integrative measure of exposure to phthalates from multiple sources and routes. However, the health significance of this exposure is unknown. To link biomarker measurements to exposure, internal dose, or health outcome, additional information (e.g., toxicokinetics, inter- and intraindividual differences) is needed. We present a case study using diethyl phthalate and di(2-ethylhexyl) phthalate as examples to illustrate scientific approaches and their limitations, identify data gaps, and outline research needs for using biomonitoring data in the context of human health risk assessment, with an emphasis on exposure and dose. Although the vast and growing literature on phthalates research could not be covered comprehensively in this article, we made every attempt to include the most relevant publications as of the end of 2005.     

Toxicoanthropology: Phthalate exposure in relation to market access in a remote forager-horticulturalist population

Phthalates are a class of plasticizing chemicals produced in high volume and widely found in consumer products. Evidence suggests that phthalates may have non-monotonic effects on reproductive hormone activity. With exposure to phthalates virtually ubiquitous among industrialized populations, identifying unexposed and/or minimally exposed human populations is essential for understanding the effects of low level exposures. Our primary objective was to quantify urinary phthalate metabolite concentrations in the Tsimane’, a remote population of Bolivian forager-horticulturalists. Our secondary objectives were to determine if phthalate metabolite concentrations vary in relation to access to market goods; and to explore relationships between phthalate and reproductive hormone metabolite concentrations. Given that phthalate exposure is of particular concern during fetal development, we focused on reproductive age women in the current analyses. Phthalate metabolites were assayed in urine samples from 59 naturally cycling, reproductive age Tsimane’ women. Market access was assessed as: (1) distance from residence to the largest nearby town (San Borja, Bolivia) and (2) Spanish fluency. Urinary reproductive hormone metabolite concentrations were quantified using enzyme immunoassays. We fit linear models to examine: (1) predictors of phthalate exposure; and (2) relationships between urinary phthalate and reproductive hormone metabolite concentrations. Eight phthalate metabolites were detectable in at least 75% of samples. Median concentrations were up to an order of magnitude lower than industrialized populations. Proximity to San Borja and Spanish fluency were strong predictors of exposure. In exploratory analyses, the sum of the di-2-ethylhexyl phthalate metabolites (∑DEHP) and Mono-isobutyl phthalate (MiBP) were significantly associated with altered concentrations of urinary reproductive hormone metabolites. Remote, subsistence populations, like the Tsimane’, offer a unique window into the health effects of endocrine active compounds because: (1) exposures are low and likely to be first generation; (2) a natural fertility lifestyle allows for exploration of reproductive effects; and (3) ever-increasing globalization will result in increasing exposure in the next decade.     

Temporal variability of urinary phthalate metabolite levels in men of reproductive age

Phthalates are a family of multifunctional chemicals widely used in personal care and other consumer products. The ubiquitous use of phthalates results in human exposure through multiple sources and routes, including dietary ingestion, dermal absorption, inhalation, and parenteral exposure from medical devices containing phthalates. We explored the temporal variability over 3 months in urinary phthalate metabolite levels among 11 men who collected up to nine urine samples each during this time period. Eight phthalate metabolites were measured by solid-phase extraction-high-performance liquid chromatography-tandem mass spectrometry. Statistical analyses were performed to determine the between- and within-subject variance apportionment, and the sensitivity and specificity of a single urine sample to classify a subject's 3-month average exposure. Five of the eight phthalates were frequently detected. Monoethyl phthalate (MEP) was detected in 100% of samples; monobutyl phthalate, monobenzyl phthalate, mono-2-ethylhexyl phthalate (MEHP), and monomethyl phthalate were detected in > 90% of samples. Although we found both substantial day-to-day and month-to-month variability in each individual's urinary phthalate metabolite levels, a single urine sample was moderately predictive of each subject's exposure over 3 months. The sensitivities ranged from 0.56 to 0.74. Both the degree of between- and within-subject variance and the predictive ability of a single urine sample differed among phthalate metabolites. In particular, a single urine sample was most predictive for MEP and least predictive for MEHP. These results suggest that the most efficient exposure assessment strategy for a particular study may depend on the phthalates of interest.     

Exposure to phthalates in 5-6 years old primary school starters in Germany--a human biomonitoring study and a cumulative risk assessment

We determined the internal exposure of 111 German primary school starters by analyzing urinary metabolites of six phthalates: butyl benzyl phthalate (BBzP), di-iso-butyl phthalate (DiBP), di-n-butyl phthalate (DnBP), di (2-ethylhexyl) phthalate (DEHP), di-iso-nonyl phthalate (DiNP) and di-iso-decylphthalate (DiDP). From the urinary metabolite levels, we calculated daily intakes and related these values to Tolerable Daily Intake (TDI) values. By introducing the concept of a relative cumulative Tolerable Daily Intake (TDI(cum)) value, we tried to account for the cumulative exposure to several of the above-mentioned phthalates. The TDI(cum) was derived as follows: the daily intake (DI) calculated from the metabolite level was divided by the TDI for each phthalate; this ratio was multiplied by 100% indicating the TDI percentage for which the DI accounted. Finally the % TDIs of the different phthalates were totalled to get the TDI(cum). A TDI(cum) above 100% is a potential cause for concern. We confirmed the ubiquitous exposure of the children to all phthalates investigated. Exposures were within range of levels previously reported for GerES, albeit slightly lower. Regarding daily intakes, two children exceeded the TDI for DnBP, whereas one child closely approached the TDI for DEHP. 24% of the children exceeded the TDI(cum) for the three most critical phthalates: DEHP, DnBP and DiBP. Furthermore, 54% of the children had total exposures that used up more than 50% the TDI(cum). Therefore, the overall exposure to a number of phthalates, and the knowledge that these phthalates (and other anti-androgens) act in a dose-additive manner, urgently warrants a cumulative risk assessment approach.     

Phthalate exposure in pregnant women and newborns – The urinary metabolite excretion pattern differs distinctly

Some phthalates are endocrine disruptors and reproductive and developmental toxicants. Data on newborn phthalate exposure and elimination characteristics are scarce. We determined 21 urinary phthalate metabolites (indicating exposure to 11 parent phthalates) in two study approaches: in the first approach we collected the urine of 20 healthy newborns at days 2–5 post partum together with 47 urine samples of 7 women during pregnancy. In the second fine tuned approach we collected first urine samples of 9 healthy newborns together with their mother's urine shortly before birth. To ensure full and contamination free collection of the newborns first urines we used special adhesive urine bags for children. All urine samples revealed ubiquitous exposures to phthalates comparable to other populations. Metabolite levels in the newborns first day urine samples were generally lower than in all other samples. However, the newborns urines (both first and day 2–5 urines) showed a metabolite pattern distinctly different from the maternal and general population samples: in the newborns urines the carboxy-metabolites of the long chain phthalates (DEHP, DiNP, DiDP) were the by far dominant metabolites with a relative share in the metabolite spectrum up to 6 times higher than in maternal urine. Oppositely, for the short chain phthalates (DBP, DiBP) oxidized metabolites seemed to be less favored than the simple monoesters in the newborns urines. The skewed metabolite distribution in the newborns urine warrants further investigation in terms of early phthalate metabolism, the quantity of internal phthalate exposure of the fetus/newborn and its possible health effects.     

Urinary excretion of phthalate metabolites in 129 healthy Danish children and adolescents: estimation of daily phthalate intake

Background

Phthalates are a group of chemicals with widespread use in the industrial production of numerous consumer products. They are suspected to be involved in male reproductive health problems and have also been associated with several other health problems in children including obesity and asthma.

Objectives

To study the urinary excretion of phthalate metabolites in Danish children recruited from the general population, and to estimate the daily intake of phthalates in this segment of the population.

Method

One 24 h urine sample and to consecutive first morning urine samples were collected from 129 healthy Danish children and adolescents (range 6–21 yrs). The concentrations of 11 phthalate metabolites of 5 different phthalate diesters were analyzed by liquid chromatography–tandem mass spectrometry.

Results

The analyzed metabolites were detectable in almost all 24 h urine samples. The median concentrations of monoethyl phthalate (MEP), monobenzyl phthalate (MBzP) and the sums of the two monobutyl phthalate isoforms (∑MBP(i+n)), metabolites of di-(2-ethylhexyl) phthalate (∑DEHPm) and of di-iso-nonyl phthalate (∑DiNPm) were 29, 17, 111, 107 and 31 ng/mL, respectively. The youngest children were generally more exposed to phthalates than older children and adolescents (except diethyl phthalate (DEP)). Boys were more exposed than girls. The median estimated daily intake of phthalate diesters was: 4.29 (dibutyl phthalate isoforms (DBP(i+n))), 4.04 (DEHP), 1.70 (DiNP), 1.09 (DEP) and 0.62 (butylbenzyl phthalate (BBzP)), all calculated as μg/kg body weight/24 h. Between 40% and 48% of the absolute amount of phthalate metabolites excreted over 24 h were excreted in first morning urine voids.

Conclusion

Danish children are exposed simultaneously to multiple phthalates. The highest exposure levels were found for DBP(i+n) and DEHP, which in animal models are the known most potent anti-androgenic phthalates. The combined exposure to the two isoforms of DBP, which have similar endocrine-disrupting potencies in animal models, exceeded the TDI for di-n-butyl phthalate (DnBP) in several of the younger children.     

Identifying sources of phthalate exposure with human biomonitoring: Results of a 48 h fasting study with urine collection and personal activity patterns

Human biomonitoring studies measuring phthalate metabolites in urine have shown widespread exposure to phthalates in the general population. Diet is thought to be a principle route of exposure to many phthalates. Therefore, we studied urinary phthalate metabolite patterns over a period of strict fasting and additionally recorded personal activity patterns with a diary to investigate non-dietary routes of exposure. Five individuals (3 female, 2 male, 27–47 years of age) fasted on glass-bottled water only over a 48-h period. All urine void events were captured in full, and measured for metabolites of the high molecular weight (HMW) di-(2-ethylhexyl) phthalate (DEHP), di-isononyl phthalate (DINP) and di-isodecyl phthalate (DiDP), and the low molecular weight (LMW) di-n-butyl phthalate (DnBP), di-iso-butyl phthalate (DiBP), butylbenzyl phthalate (BBzP), dimethyl phthalate (DMP), and diethyl phthalate (DEP). In all, 21 metabolites were measured in a total of 118 urine events, including events before and after the fasting period. At the onset of the study all phthalate metabolite concentrations were consistent with levels found in previous general population studies. Metabolites of the HMW phthalates (DEHP, DiNP and DiDP) showed a rapid decline to levels 5–10 times lower than initial levels within 24 h of the fast and remained low thereafter. After food consumption resumed, levels rose again. By contrast, metabolites of the LMW phthalates including DMP, DEP, BBzP, DnBP and DiBP showed a cyclical pattern of rising and declining concentrations suggestive of ongoing non-food exposures. Furthermore, metabolites of most of the LMW phthalates (BBzP, DnBP and DiBP) tracked each other remarkably well, suggesting concurrent exposures. Diary entries could not help explain exposure sources for these phthalates, with one exception: rises in MEP concentrations around males’ showers suggest personal care products as a major source of DEP. Exposure to HMW phthalates in this cohort appears to be driven by dietary intake, while non-dietary routes such as use of personal care products and ubiquitous sources including dust and indoor air appear to explain exposure to LMW phthalates.     

Trends of the internal phthalate exposure of young adults in Germany--follow-up of a retrospective human biomonitoring study

The exposure of the general population to phthalates is of increasing public health concern. Variations in the internal exposure of the population are likely, because the amounts, distribution and application characters of the phthalate use change over time. Estimating the chronological sequences of the phthalate exposure, we performed a retrospective human biomonitoring study by investigating the metabolites of the five most prominent phthalates in urine. Therefore, 24 h-urine samples from the German Environmental Specimen Bank (ESB) collected from 240 subjects (predominantly students, age range 19–29 years, 120 females, 120 males) in the years 2002, 2004, 2006 and 2008 (60 individuals each), were analysed for the concentrations of mono-n-butyl phthalate (MnBP) as metabolite of di-n-butyl phthalate (DnBP), mono-iso-butyl phthalate (MiBP) as metabolite of di-iso-butyl phthalate (DiBP), mono-benzyl phthalate (MBzP) as metabolite of butylbenzyl phthalate (BBzP), mono-(2-ethylhexyl) phthalate (MEHP), 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-MMHxP) as metabolites of di(2-ethylhexyl) phthalate (DEHP), monohydroxylated (OH-MiNP), monooxidated (oxo-MiNP) and monocarboxylated (cx-MiNP) mono-iso-nonylphthalates as metabolites of di-iso-nonyl phthalates (DiNP). Based on the urinary metabolite excretion, together with results of a previous study, which covered the years 1988–2003, we investigated the chronological sequences of the phthalate exposure over two decades. In more than 98% of the urine samples metabolites of all five phthalates were detectable indicating a ubiquitous exposure of people living in Germany to all five phthalates throughout the period investigated. The medians in samples from the different years investigated are 65.4 (2002), 38.5 (2004), 29.3 (2006) and 19.6 μg/l (2008) for MnBP, 31.4 (2002), 25.4 (2004), 31.8 (2006) and 25.5 μg/l (2008) for MiBP, 7.8 (2002), 6.3 (2004), 3.6 (2006) and 3.8 μg/l (2008) for MBzP, 7.0 (2002), 5.6 (2004), 4.1 (2006) and 3.3 μg/l (2008) for MEHP, 19.6 (2002), 16.2 (2004), 13.2 (2006) and 9.6 μg/l (2008) for 5OH-MEHP, 13.9 (2002), 11.8 (2004), 8.3 (2006) and 6.4 μg/l (2008) for 5oxo-MEHP, 18.7 (2002), 16.5 (2004), 13.8 (2006) and 10.2 μg/l (2008) for 5cx-MEPP, 7.2 (2002), 6.5 (2004), 5.1 (2006) and 4.6 μg/l (2008) for 2cx-MMHxP, 3.3 (2002), 2.8 (2004), 3.5 (2006) and 3.6 μg/l (2008) for OH-MiNP, 2.1 (2002), 2.1 (2004), 2.2 (2006) and 2.3 μg/l (2008) for oxo-MiNP and 4.1 (2002), 3.2 (2004), 4.1 (2006) and 3.6 μg/l (2008) for cx-MiNP. The investigation of the time series 1988–2008 indicates a decrease of the internal exposure to DnBP by the factor of 7–8 and to DEHP and BzBP by the factor of 2–3. In contrast, an increase of the internal exposure by the factor of 4 was observed for DiNP over the study period. The exposure to DiBP was found to be stable. In summary, we found decreases of the internal human exposure for legally restricted phthalates whereas the exposure to their substitutes increased. Future investigations should verify these trends. This is of increasing importance since the European Commission decided to require ban or authorization from 1.1.2015 for DEHP, DnBP, DiBP and BzBP according to REACh Annex XIV.     

Urinary levels of seven phthalate metabolites in the U.S. population from the National Health and Nutrition Examination Survey (NHANES) 1999-2000

We measured the urinary monoester metabolites of seven commonly used phthalates in approximately 2,540 samples collected from participants of the National Health and Nutrition Examination Survey (NHANES), 1999-2000, who were greater than or equal to 6 years of age. We found detectable levels of metabolites monoethyl phthalate (MEP), monobutyl phthalate (MBP), monobenzyl phthalate (MBzP), and mono-(2-ethylhexyl) phthalate (MEHP) in > 75% of the samples, suggesting widespread exposure in the United States to diethyl phthalate, dibutyl phthalate or diisobutylphthalate, benzylbutyl phthalate, and di-(2-ethylhexyl) phthalate, respectively. We infrequently detected monoisononyl phthalate, mono-cyclohexyl phthalate, and mono-n-octyl phthalate, suggesting that human exposures to di-isononyl phthalate, dioctylphthalate, and dicyclohexyl phthalate, respectively, are lower than those listed above, or the pathways, routes of exposure, or pharmacokinetic factors such as absorption, distribution, metabolism, and elimination are different. Non-Hispanic blacks had significantly higher concentrations of MEP than did Mexican Americans and non-Hispanic whites. Compared with adolescents and adults, children had significantly higher levels of MBP, MBzP, and MEHP but had significantly lower concentrations of MEP. Females had significantly higher concentrations of MEP and MBzP than did males, but similar MEHP levels. Of particular interest, females of all ages had significantly higher concentrations of the reproductive toxicant MBP than did males of all ages; however, women of reproductive age (i.e., 20-39 years of age) had concentrations similar to adolescent girls and women 40 years of age. These population data on exposure to phthalates will serve an important role in public health by helping to set research priorities and by establishing a nationally representative baseline of exposure with which population levels can be compared.     

Comparisons of urinary phthalate metabolites and daily phthalate intakes among Japanese families

We measured urinary phthalate metabolites, including di-n-butyl phthalate (DnBP), di-isobutyl phthalate, benzyl butyl phthalate (BBzP), and di(2-ethylhexyl) phthalate (DEHP), from 178 school-aged children and their 284 family members using gas chromatography-mass spectrometry, and we calculated daily phthalate intakes. The highest median levels of phthalate metabolites were for mono-isobutyl phthalate in all participants except schoolchildren, where the highest levels were for mono-(2-ethyl-5-oxohexyl) phthalate (MEOHP). Comparing the schoolchildren with their parents, the schoolchildren had significantly higher urinary metabolites for MEOHP, mono-(2-ethyl-5-carboxypentyl) phthalate, and ΣDEHP. Regarding daily intakes, the schoolchildren had significantly higher daily intakes of DnBP, BBzP, and ΣDEHP. All phthalate metabolite and sums of metabolite levels in the schoolchildren were positively correlated with their mothers’ levels, except for MEHP, whereas fathers were less correlated with their children. The DEHP intake in this study was higher than that of most other studies. Moreover, 10% of the children and 3% of the adults exceeded the Reference Dose (RfD) value (20 μg/kg/day) of the U.S. Environmental Protection Agency, which indicates that it is important to focus on children's DEHP exposure because the children exceeded the RfD more than adults among the same families who shared similar exposure sources. Our results will contribute to considerations of the regulations for some phthalates and the actual phthalate exposure levels in the Japanese population.     

Assessing human exposure to phthalates using monoesters and their oxidized metabolites as biomarkers

Phthalates are a group of industrial chemicals with many commercial uses, such as solvents, additives, and plasticizers. For example, di-(2-ethylhexyl) phthalate (DEHP) is added in varying amounts to certain plastics, such as polyvinyl chloride, to increase their flexibility. In humans, phthalates are metabolized to their respective monoesters, conjugated, and eliminated. However, despite the high production and use of DEHP, we have recently found that the urinary levels of the DEHP metabolite mono-(2-ethylhexyl) phthalate (MEHP) in 2,541 persons in the United States were lower than we anticipated, especially when compared with urinary metabolite levels of other commonly used phthalates. This finding raised questions about the sensitivity of this biomarker for assessing DEHP exposure. We explored the utility of two other DEHP metabolites, mono-(2-ethyl-5-oxohexyl) phthalate (MEOHP) and mono-(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP), as additional DEHP biomarkers. These metabolites are formed by oxidative metabolism of MEHP. In urine from 62 people, both the range and the mean urinary levels of MEOHP and MEHHP were on average 4-fold higher than those of MEHP; the mean of the individual ratios of MEHHP/MEOHP, MEHHP/MEHP, and MEOHP/MEHP were 1.4, 8.2, and 5.9, respectively. These data suggest that MEOHP and MEHHP are more sensitive biomarkers of exposure to DEHP than is MEHP. These findings also suggest a predominant human metabolic route for DEHP hydrolysis to MEHP followed by oxidation of MEHP; they also imply that a similar mechanism may be relevant for other high-molecular-weight phthalates, such as di-n-octyl, di-isononyl, and di-isodecyl phthalates.     

Obesity or diet? Levels and determinants of phthalate body burden – A case study on Portuguese children

In this study we analyzed one of the most comprehensive sets of 21 urinary phthalate metabolites representing exposure to 11 parent phthalates (DEP, DMP, DiBP, DnBP, BBzP, DEHP, DiNP, DiDP, DCHP, DnPeP, DnOP) in first morning urine samples of 112 Portuguese children (4–18 years) sampled in 2014/15. The study population consisted of two groups: group 1 with normal weight/underweight children (N?=?43) following their regular diet and group 2 with obese/overweight children (N?=?69) following a healthy diet (with nutritional counselling). Most of the metabolites were above the limits quantification (81–100%) except for MCHP, MnPEP and MnOP. Metabolite levels were generally comparable to other recent child and general populations sampled worldwide, confirming the steady decline in exposures to most phthalates. Compared to Portuguese children sampled in 2011/2012, median urinary metabolite levels decreased by approximately 50% for DEHP, DnBP, DiBP and BBzP. Risk assessments for individual phthalates and the sum of the anti-androgenic phthalates did not indicate to attributable health risks, also at the upper percentiles of exposure. In the healthy diet group the median concentration of the DEHP metabolites was significant lower, while all phthalate metabolites except MEP tended to be lower compared to the regular diet group. Multiple log-linear regression analyses revealed significantly lower daily intakes (DIs) for all phthalates in the healthy diet group compared to the regular diet group (geometric mean ratios (gMR) between 0.510–0.618; p?≤?0.05), except for DEP (gMR: 0.811; p?=?0.273). The same analyses with the continuous variable body mass index instead of the diet groups also showed effects on the DIs (gMRs between 0.926–0.951; p?≤?0.05), however much smaller than the effects of the diet. The results indicate that obese children following a healthy diet composed of fresh and less packaged/processed food can considerably reduce their intake for most phthalates and can have lower phthalate intakes than regular weight/regular diet children.     

Urinary Phthalate Metabolites in Relation to Preterm Birth in Mexico City

Background

Rates of preterm birth have been rising over the past several decades. Factors contributing to this trend remain largely unclear, and exposure to environmental contaminants may play a role.

Objective

We investigated the relationship between phthalate exposure and preterm birth.

Methods

Within a large Mexican birth cohort study, we compared third-trimester urinary phthalate metabolite concentrations in 30 women who delivered preterm (< 37 weeks of gestation) with those of 30 controls (≥ 37 weeks of gestation).

Results

Concentrations of most of the metabolites were similar to those reported among U.S. females, although in the present study mono-n-butyl phthalate (MBP) concentrations were higher and monobenzyl phthalate (MBzP) concentrations lower. In a crude comparison before correcting for urinary dilution, geometric mean urinary concentrations were higher for the phthalate metabolites MBP, MBzP, mono(3-carboxylpropyl) phthalate, and four metabolites of di(2-ethyl-hexyl) phthalate among women who subsequently delivered preterm. These differences remained, but were somewhat lessened, after correction by specific gravity or creatinine. In multivariate logistic regression analysis adjusted for potential confounders, elevated odds of having phthalate metabolite concentrations above the median level were found.

Conclusions

We found that phthalate exposure is prevalent among this group of pregnant women in Mexico and that some phthalates may be associated with preterm birth.     

Exposure assessment of phthalates in French pregnant women: Results of the ELFE pilot study

The ubiquitous use of phthalate esters in plastics, building material, medical devices, personal care products and food packaging materials results in a widespread exposure of general population. This study reports measurement of urinary concentration of phthalate metabolites in France and provides a first assessment of the exposure of French pregnant women to this chemical class. For the majority of the phthalate metabolites, concentrations measured in urine were similar to those reported in previous studies except for two phthalates that were characterized by high concentrations of metabolites if compared to previous European and American studies: DiNP (Di-iso-nonylphthalate) and DEHP (Di(2-ethylhexyl)phthalate). In a second part of the study, a pharmacokinetic model was used in order to gain understanding on exposure to DEHP. A high concentration of the primary metabolite of DEHP, MEHP (Mono(2-ethylhexyl)phthalate), was thus identified probably because of a very recent exposure to perfusion materials at the hospital. Pharmacokinetics modelling highlighted that gathering data on the time gap between exposure and biomonitoring is an essential information requirement for reconstructing the dose of non persistent pollutants. Information about exposure pathway is also crucial for conducting effective reverse dosimetry.