Dataset Information

Cumulative exposure to phthalates from phthalate-containing drug products: a Danish population-wide study.

ABSTRACT:

Aims

Up to 50-fold higher levels of urinary phthalate metabolites have been observed in users of phthalate-containing drug products compared with non-users. This is of concern, as phthalates are suspected endocrine disrupters and have been associated with cancer development. This study aims to quantify annual cumulated phthalate exposure from drug products among users of phthalate-containing oral medications in Denmark throughout the period of 2004-2016.

Methods

We conducted a Danish nationwide cohort study using The Danish National Prescription Registry and an internal database held by The Danish Medicines Agency. These databases hold information on drug products; date of dispensing, and the type and quantity of excipients in drugs with Danish marketing permission. We present the number of users over time and their distribution of exposure to enteric phthalate polymers and ortho-phthalates.

Results

The annual number of individuals exposed to phthalate-containing products declined during 2004-2016. The total number of individuals exposed to dibutyl phthalate declined from 21?499 in 2004 to 5400 in 2016. However, among those exposed, the median dibutyl phthalate exposure remained above European regulatory limit of exposure ranging between 380-1710 mg/year throughout the study period. Lithium-products constituted the majority of dibutyl phthalate exposure. Diethyl phthalate exposure, mainly caused by erythromycin, theophylline and diclofenac products, did not exceed the EMA regulatory limit.

Conclusion

While the number of individuals exposed to phthalates from oral medications during 2004-2016 declined, the use of phthalate-containing drugs is still considerable.

SUBMITTER: Ennis ZN

PROVIDER: S-EPMC6046487 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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Publications

Cumulative exposure to phthalates from phthalate-containing drug products: a Danish population-wide study.

Ennis Zandra Nymand ZN Broe Anne A Pottegård Anton A Ahern Thomas P TP Hallas Jesper J Damkier Per P

British journal of clinical pharmacology 20180603 8

<h4>Aims</h4>Up to 50-fold higher levels of urinary phthalate metabolites have been observed in users of phthalate-containing drug products compared with non-users. This is of concern, as phthalates are suspected endocrine disrupters and have been associated with cancer development. This study aims to quantify annual cumulated phthalate exposure from drug products among users of phthalate-containing oral medications in Denmark throughout the period of 2004-2016.<h4>Methods</h4>We conducted a Dan ...[more]

PMID: 29688578

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Project description:BACKGROUND:Anti-androgenic phthalates are reproductive toxicants that may have additive effects on male development. Diet is the primary exposure source for most phthalates, which contaminate the food supply through food contact materials and industrialized production. OBJECTIVE:To compare dietary sources of cumulative phthalates exposure between "food at home" (e.g. food consumed from a grocery store) and "food away from home" (e.g. food consumed from fast food/restaurants and cafeterias) in the U.S. general population. METHODS:We estimated cumulative phthalates exposure by calculating daily intake from metabolite concentrations in urinary spot samples for 10,253 participants (?6?years old) using National Health and Nutrition Examination Survey (NHANES, 2005-2014) data. We constructed a biologically relevant metric of phthalates daily intake (?androgen-disruptor, ?g/kg/day) by converting phthalates into anti-androgen equivalent terms prior to their summation. Particular foods and the percent of total energy intake (TEI) consumed from multiple dining out sources were ascertained from 24-h recall surveys. Associations with ?androgen-disruptor levels were estimated for children, adolescents, and adults using multivariable linear regression. RESULTS:We observed a consistent positive association between dining out and ?androgen-disruptor levels across the study population (p-trend <0.0001). Among adolescents, high consumers of foods outside the home had 55% (95% CI: 35%, 78%) higher ?androgen-disruptor levels compared to those who only consumed food at home. The contribution of specific dining out sources to ?androgen-disruptor levels varied by age group. For example, cafeteria food was associated with 15% (95% CI: 4.0%, 28%) and 64% (95% CI: 40%, 92%) higher ?androgen-disruptor levels in children and adults, respectively. Particular foods, especially sandwiches (i.e. cheeseburgers), were associated with increased ?androgen-disruptor levels only if they were purchased away from home (p?<?0.01). CONCLUSION:Dining out may be an important source of biologically relevant cumulative phthalates exposure among the U.S. POPULATION:Future studies should evaluate modifiable production practices that remove phthalates from the food supply in addition to the efficacy of interventions that promote eating fresh foods prepared at home.

Project description:Importance:Although phthalate exposure during pregnancy has been associated with preterm birth, the association of preconception exposure in either parent with preterm birth constitutes a knowledge gap. Objective:To examine the association of paternal and maternal preconception urinary concentrations of biomarkers of phthalates and phthalate substitutes with singleton preterm birth. Design, Setting, and Participants:This study, conducted at an academic fertility center in Boston, Massachusetts, included a prospective preconception cohort of subfertile couples comprising 419 mothers and 229 fathers and their 420 live-born singleton offspring born between January 1, 2005, and December 31, 2018. Statistical analysis was performed from August 1 to October 31, 2019. Exposures:Urinary concentrations of metabolites of phthalates and phthalate substitutes obtained before conception. Main Outcomes and Measures:Gestational age was abstracted from delivery records and validated using the American College of Obstetricians and Gynecologists guidelines for births after medically assisted reproduction. The risk ratio (RR) of preterm birth (live birth before 37 completed weeks' gestation) was estimated in association with urinary concentrations of 11 individual phthalate metabolites, the molar sum of 4 di-(2-ethylhexyl) phthalate (ΣDEHP) metabolites, and 2 metabolites of 1,2-cyclohexane dicarboxylic acid diisononyl ester (DINCH, a nonphthalate plasticizer substitute) using modified Poisson regression models adjusted for covariates. Results:The mean (SD) age of the 419 mothers was 34.7 (4.0) years, the mean (SD) age of the 229 fathers was 36.0 (4.5) years, and the mean (SD) gestational age of the 420 singleton children (217 boys) was 39.3 (1.7) weeks, with 34 (8%) born preterm. In adjusted models, maternal preconception ΣDEHP concentrations (RR, 1.50; 95% CI, 1.09-2.06; P = .01) and cyclohexane-1,2-dicarboxylic acid monohydroxy isononyl ester (MHiNCH, a metabolite of DINCH) concentrations (RR, 1.70; 95% CI, 0.89-3.24; P = .11) were associated with an increased risk of preterm birth. After additional adjustment for prenatal ΣDEHP or MHiNCH concentrations, the association of maternal preconception exposure to ΣDEHP and preterm birth remained robust (RR, 1.69; 95% CI, 1.17-2.44; P = .006), while the association of maternal preconception exposure to MHiNCH and preterm birth was attenuated (RR, 1.17; 95% CI, 0.49-2.81; P = .72). The remaining urinary metabolites examined in either parent showed no association with preterm birth. Conclusions and Relevance:In this prospective cohort of subfertile couples, maternal preconception exposure to ΣDEHP metabolites was associated with an increased risk of preterm birth. The results suggest that female exposure to select phthalate plasticizers during the preconception period may be a potential risk factor for adverse pregnancy outcomes, which may need to be considered in preconception care strategies.

Project description:BackgroundPhthalates and their replacements have been implicated as developmental toxicants. Young children may be exposed to phthalates/replacements when using skin care products (SCPs).ObjectivesOur objective is to assess the associations between use of SCPs and children's urinary phthalate/replacement metabolite concentrations.MethodsChildren (4-8 years old) from the Environmental Influences on Child Health Outcomes-Fetal Growth Study (ECHO-FGS) cohort provided spot urine samples from 2017 to 2019, and mothers were queried about children's SCP use in the past 24 h (n=906). Concentrations of 16 urinary phthalate/replacement metabolites were determined by liquid chromatography-tandem mass spectrometry (n=630). We used linear regression to estimate the child's use of different SCPs as individual predictors of urinary phthalate/replacement metabolites, adjusted for urinary specific gravity, age, sex assigned at birth, body mass index, and self-reported race/ethnic identity, as well as maternal education, and season of specimen collection. We created self-organizing maps (SOM) to group children into "exposure profiles" that reflect discovered patterns of use for multiple SCPs.ResultsChildren had lotions applied (43.0%) frequently, but "2-in-1" hair-care products (7.5%), sunscreens (5.9%), and oils (4.3%) infrequently. Use of lotions was associated with 1.17-fold [95% confidence interval (CI): 1.00, 1.34] greater mono-benzyl phthalate and oils with 2.86-fold (95% CI: 1.89, 4.31) greater monoethyl phthalate (MEP), 1.43-fold (95% CI: 1.09, 1.90) greater monobutyl phthalate (MBP), and 1.40-fold (95% CI: 1.22, 1.61) greater low-molecular-weight phthalates (LMW). Use of 2-in-1 haircare products was associated with 0.84-fold (95% CI: 0.72, 0.97) and 0.78-fold (95% CI: 0.62, 0.98) lesser mono(3-carboxypropyl) phthalate (MCPP) and MBP, respectively. Child's race/ethnic identity modified the associations of lotions with LMW, oils with MEP and LMW, sunscreen with MCPP, ointments with MEP, and hair conditioner with MCPP. SOM identified four distinct SCP-use exposure scenarios (i.e., profiles) within our population that predicted 1.09-fold (95% CI: 1.03, 1.15) greater mono-carboxy isononyl phthalate, 1.31-fold (95% CI: 0.98, 1.77) greater mono-2-ethyl-5-hydroxyhexyl terephthalate, 1.13-fold (95% CI: 0.99, 1.29) greater monoethylhexyl phthalate, and 1.04-fold (95% CI: 1.00, 1.09) greater diethylhexyl phthalate.DiscussionWe found that reported SCP use was associated with urinary phthalate/replacement metabolites in young children. These results may inform policymakers, clinicians, and parents to help limit children's exposure to developmental toxicants. https://doi.org/10.1289/EHP13937.

Project description:BackgroundPhthalates and their potential replacements, including non-phthalate plasticizers, are ubiquitous in home environments due to their presence in building materials, plastics, and personal care products. As a result, exposure to these compounds is universal. However, the primary pathways of exposure and understanding which products in the home are associated most strongly with particular exposures are unclear.ObjectivesWe sought to investigate the relationships between phthalates and non-phthalate plasticizers in paired samples of house dust, hand wipes, and their corresponding metabolites in children's urine samples (n = 180). In addition, we compared product use or presence of materials in the household against all compounds to investigate the relationship between product use or presence and exposure.MethodsChildren aged 3-6 years provided hand wipe and urine samples. Questionnaires were completed by mothers or legal guardians to capture product use and housing characteristics, and house dust samples were collected from the main living area during home visits.ResultsPhthalates and non-phthalate replacements were detected frequently in the environmental matrices. All urine samples had at least 13 of 19 phthalate or non-phthalate replacement metabolites present. Hand wipe mass and dust concentrations of diisobutyl phthalate, benzyl butyl phthalate (BBP), bis(2-ethylhexyl) phthalate, and di-isononyl phthalate were significantly associated with their corresponding urinary metabolites (rs = 0.18-0.56, p < 0.05). Bis(2-ethylhexyl) terephthalate (DEHTP) in dust was also significantly and positively correlated with its urinary metabolites (rs = 0.33, p < 0.001). Vinyl flooring was most significantly and positively associated with particular phthalate exposures (indicated by concentrations in environmental matrices and urinary biomarkers). In particular, children who lived in homes with 100% vinyl flooring had urinary concentrations of monobenzyl phthalate, a BBP metabolite, that were 15 times higher than those of children who lived in homes with no vinyl flooring (p < 0.0001). Levels of BBP in hand wipes and dust were 3.5 and 4.5 times higher, respectively, in those homes with 100% vinyl flooring (p < 0.0001 for both).ConclusionsThis paper summarizes one of the most comprehensive phthalate and non-phthalate plasticizer investigation of potential residential exposure sources conducted in North America to date. The data presented herein provide evidence that dermal contact and hand-to-mouth behaviors are important sources of exposure to phthalates and non-phthalate plasticizers. In addition, the percentage of vinyl flooring is an important consideration when examining residential exposures to these compounds.

Project description:BackgroundSchool-aged children living near plastics-producing factories may have higher risk of exposure to phthalates released during the manufacturing processes.ObjectivesWe aimed to investigate the urinary concentrations of phthalate metabolites in school-aged children living near a petrochemical complex and estimate the cumulative risk of phthalate exposure.MethodsWe used a well-established cohort (Taiwan Petrochemical Complex Cohort for Children, TPE3C) of school-aged children (6-13 years old) living near polyvinyl chloride (PVC) and vinyl chloride monomer (VCM) factories in central Taiwan from October 2013 to September 2014. A total of 257 children were included from five elementary schools: Syu-Cuo Branch (n = 58, school A, ~0.9 km), Feng-An (n = 40, school B, ~2.7 km), Ciao-Tou (n = 58, school C, ~5.5 km), Mai-Liao (n = 37, school D, ~6.9 km), and Lung-Feng (n = 57, school E, ~8.6 km). We analyzed 11 metabolites of seven phthalates (including di-2-ethylhexyl phthalate (DEHP) and di-n-butyl phthalate (DnBP)) in urine. Daily intakes (DIs) were compared with acceptable intake levels to calculate the hazard quotient (HQ) for individual phthalates, and the cumulative risk for each child was assessed using a hazard index (HI), which was the sum of the the individual HQs.ResultsThe geometric mean and proportion of participants with HIs exceeding one for hepatic (HIhep) and reproductive (HIrep) effects were 0.33 (13.2%) and 0.24 (7.8%), respectively. The major contributors to phthalate exposure risk were DEHP, di-iso-butyl phthalate (DiBP) and DnBP in all children. Moreover, we observed a U shaped distribution of DEHP exposure by school distance from the PVC and VCM factories (school A: 7.48 μg/kg/day and school E: 80.44 μg/kg/day). This may be due to emissions (closest) and and being located downwind of PVC scrap incineration (farthest).ConclusionsOur findings suggest that children living near a petrochemical complex were at a greater risk of phthalate exposure than normal school-aged children and that phthalate exposure was mainly attributed to DEHP, DiBP and DnBP. In addition, inhalation may have been a risk factor for people living near to PVC and VCM factories.

Dataset Information

Cumulative exposure to phthalates from phthalate-containing drug products: a Danish population-wide study.

Aims

Methods

Results

Conclusion

Publications

Cumulative exposure to phthalates from phthalate-containing drug products: a Danish population-wide study.

Similar Datasets

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