Phthalate Diesters and Their Metabolites, Biomarkers of Exposure
Phthalate Diesters and Their Metabolites, Biomarkers of Exposure
Background: Phthalates may pose a risk for perinatal developmental effects. An important question relates to the choice of suitable biological matrices for assessing exposure during this period.
Objectives: This study was designed to measure the concentrations of phthalate diesters or their metabolites in breast milk, blood or serum, and urine and to evaluate their suitability for assessing perinatal exposure to phthalates.
Methods: In 2001, 2-3 weeks after delivery, 42 Swedish primipara provided breast milk, blood, and urine samples at home. Special care was taken to minimize contamination with phthalates (e.g., use of a special breast milk pump, heat treatment of glassware and needles, addition of phosphoric acid).
Results: Phthalate diesters and metabolites in milk and blood or serum, if detected, were present at concentrations close to the limit of detection. By contrast, most phthalate metabolites were detectable in urine at concentrations comparable to those from the general population in the United States and in Germany. No correlations existed between urine concentrations and those found in milk or blood/serum for single phthalate metabolites. Our data are at odds with a previous study documenting frequent detection and comparatively high concentrations of phthalate metabolites in Finnish and Danish mothers' milk.
Conclusions: Concentrations of phthalate metabolites in urine are more informative than those in milk or serum. Furthermore, collection of milk or blood may be associated with discomfort and potential technical problems such as contamination (unless oxidative metabolites are measured). Although urine is a suitable matrix for health-related phthalate monitoring, urinary concentrations in nursing mothers cannot be used to estimate exposure to phthalates through milk ingestion by breast-fed infants.
Phthalates are used in large quantities as softeners in many plastic products, paint, glue, putty, pharmaceutical products and cosmetics (Agency for Toxic Substances and Disease Registry 2001, 2002; Schettler 2006). About 5,000-6,000 tons of phthalates, including di(2-ethylhexyl) phthalate (DEHP), are used per year in Sweden. Typically, phthalates are not chemically bound to the product matrix and may thus migrate and permit extensive exposure. People may be exposed in the work environment, via food from plastic containers and via inhalation of dust in domestic environments (Wormuth et al. 2006). Dermal exposure via clothes and cosmetics may also occur. Small population groups may be exposed via medical equipment -- for example, to DEHP migrating from plastic tubing used for treatment of premature infants (Calafat et al. 2004a; Weuve et al. 2006).
Numerous studies have reported reproductive effects, including reduced sperm production and shortened anogenital distance (AGD) in laboratory animals, and concern exists that phthalates may induce antiandrogenic and/or proestrogenic effects in humans (Andrade et al. 2006; Borch et al. 2006; Fabjan et al. 2006; Gray et al. 2006; Hauser 2006; Hauser et al. 2006; Pflieger-Bruss et al. 2004). Developmental defects in male rat pups, similar to those seen in humans in a syndrome termed testicular dysgenesis syndrome (TDS), have been documented after dosing pregnant dams with di-n-butyl phthalate (DBP), DEHP, or butyl benzyl phthalate (BBzP) (Sharpe 2005). Signaling pathways affected by phthalates are currently under intense study (Ge et al. 2007; Hallmark et al. 2007; Howdeshell et al. 2007; Lahousse et al. 2006; Liu et al. 2005; Mahood et al. 2006; Sharpe 2006).
Phthalate diesters are metabolized, and most studies of human exposure report concentrations of phthalate metabolites in urine. In the body, hydrolytic monoester metabolites can undergo phase 1 (e.g., oxidation) and phase 2 (e.g., glucuronidation) metabolism (Koch et al. 2003b). In biological samples, such as blood or serum, milk, or other complex biological samples, contaminating phthalate diesters may be hydrolyzed by esterases to their respective hydrolytic monoesters during sampling, storage, and analysis (Kato et al. 2004). However, oxidized monoester metabolites cannot easily be ascribed to contamination (Koch et al. 2003b, 2004, 2005, 2006b).
2,500 individuals participating in the National Health and Nutrition Examination Survey (NHANES) [Centers for Disease Control and Prevention (CDC) 2005; Silva et al. 2004a]. In general, higher concentrations of urinary metabolites were found in women than in men. This pattern was also seen in a German study (Koch et al. 2003b), and other studies show ethnic differences (CDC 2005; Silva et al. 2004a).
The toxicologic profile of phthalates and perhaps a higher prevalence of exposure among women suggest that pregnant women, fetuses, and newborns could be highly sensitive risk groups. In the present study, performed in 2001 at the request of the Swedish Environmental Protection Agency, we measured several common phthalates and their metabolites in human milk, blood or serum, and urine. The main objectives of this study were to evaluate whether multimatrix biomonitoring of phthalates in women of childbearing ages is feasible, and to identify the most suitable biological matrix for health-related environmental monitoring of risk groups in the general population.
Background: Phthalates may pose a risk for perinatal developmental effects. An important question relates to the choice of suitable biological matrices for assessing exposure during this period.
Objectives: This study was designed to measure the concentrations of phthalate diesters or their metabolites in breast milk, blood or serum, and urine and to evaluate their suitability for assessing perinatal exposure to phthalates.
Methods: In 2001, 2-3 weeks after delivery, 42 Swedish primipara provided breast milk, blood, and urine samples at home. Special care was taken to minimize contamination with phthalates (e.g., use of a special breast milk pump, heat treatment of glassware and needles, addition of phosphoric acid).
Results: Phthalate diesters and metabolites in milk and blood or serum, if detected, were present at concentrations close to the limit of detection. By contrast, most phthalate metabolites were detectable in urine at concentrations comparable to those from the general population in the United States and in Germany. No correlations existed between urine concentrations and those found in milk or blood/serum for single phthalate metabolites. Our data are at odds with a previous study documenting frequent detection and comparatively high concentrations of phthalate metabolites in Finnish and Danish mothers' milk.
Conclusions: Concentrations of phthalate metabolites in urine are more informative than those in milk or serum. Furthermore, collection of milk or blood may be associated with discomfort and potential technical problems such as contamination (unless oxidative metabolites are measured). Although urine is a suitable matrix for health-related phthalate monitoring, urinary concentrations in nursing mothers cannot be used to estimate exposure to phthalates through milk ingestion by breast-fed infants.
Phthalates are used in large quantities as softeners in many plastic products, paint, glue, putty, pharmaceutical products and cosmetics (Agency for Toxic Substances and Disease Registry 2001, 2002; Schettler 2006). About 5,000-6,000 tons of phthalates, including di(2-ethylhexyl) phthalate (DEHP), are used per year in Sweden. Typically, phthalates are not chemically bound to the product matrix and may thus migrate and permit extensive exposure. People may be exposed in the work environment, via food from plastic containers and via inhalation of dust in domestic environments (Wormuth et al. 2006). Dermal exposure via clothes and cosmetics may also occur. Small population groups may be exposed via medical equipment -- for example, to DEHP migrating from plastic tubing used for treatment of premature infants (Calafat et al. 2004a; Weuve et al. 2006).
Numerous studies have reported reproductive effects, including reduced sperm production and shortened anogenital distance (AGD) in laboratory animals, and concern exists that phthalates may induce antiandrogenic and/or proestrogenic effects in humans (Andrade et al. 2006; Borch et al. 2006; Fabjan et al. 2006; Gray et al. 2006; Hauser 2006; Hauser et al. 2006; Pflieger-Bruss et al. 2004). Developmental defects in male rat pups, similar to those seen in humans in a syndrome termed testicular dysgenesis syndrome (TDS), have been documented after dosing pregnant dams with di-n-butyl phthalate (DBP), DEHP, or butyl benzyl phthalate (BBzP) (Sharpe 2005). Signaling pathways affected by phthalates are currently under intense study (Ge et al. 2007; Hallmark et al. 2007; Howdeshell et al. 2007; Lahousse et al. 2006; Liu et al. 2005; Mahood et al. 2006; Sharpe 2006).
Phthalate diesters are metabolized, and most studies of human exposure report concentrations of phthalate metabolites in urine. In the body, hydrolytic monoester metabolites can undergo phase 1 (e.g., oxidation) and phase 2 (e.g., glucuronidation) metabolism (Koch et al. 2003b). In biological samples, such as blood or serum, milk, or other complex biological samples, contaminating phthalate diesters may be hydrolyzed by esterases to their respective hydrolytic monoesters during sampling, storage, and analysis (Kato et al. 2004). However, oxidized monoester metabolites cannot easily be ascribed to contamination (Koch et al. 2003b, 2004, 2005, 2006b).
2,500 individuals participating in the National Health and Nutrition Examination Survey (NHANES) [Centers for Disease Control and Prevention (CDC) 2005; Silva et al. 2004a]. In general, higher concentrations of urinary metabolites were found in women than in men. This pattern was also seen in a German study (Koch et al. 2003b), and other studies show ethnic differences (CDC 2005; Silva et al. 2004a).
The toxicologic profile of phthalates and perhaps a higher prevalence of exposure among women suggest that pregnant women, fetuses, and newborns could be highly sensitive risk groups. In the present study, performed in 2001 at the request of the Swedish Environmental Protection Agency, we measured several common phthalates and their metabolites in human milk, blood or serum, and urine. The main objectives of this study were to evaluate whether multimatrix biomonitoring of phthalates in women of childbearing ages is feasible, and to identify the most suitable biological matrix for health-related environmental monitoring of risk groups in the general population.
