Antonia M. Calafat

Exposure of the U.S. Population to Bisphenol A and 4-tertiary-Octylphenol: 2003–2004

Background Bisphenol A (BPA) and 4-tertiary-octylphenol (tOP) are industrial chemicals used in the manufacture of polycarbonate plastics and epoxy resins (BPA) and nonionic surfactants (tOP). These products are in widespread use in the United States. Objectives We aimed to assess exposure to BPA and tOP in the U.S. general population. Methods We measured the total (free plus conjugated) urinary concentrations of BPA and tOP in 2,517 participants ≥ 6 years of age in the 2003–2004 National Health and Nutrition Examination Survey using automated solid-phase extraction coupled to isotope dilution–high-performance liquid chromatography–tandem mass spectrometry. Results BPA and tOP were detected in 92.6% and 57.4% of the persons, respectively. Least square geometric mean (LSGM) concentrations of BPA were significantly lower in Mexican Americans than in non-Hispanic blacks (p = 0.006) and non-Hispanic whites (p = 0.007); LSGM concentrations for non-Hispanic blacks and non-Hispanic whites were not statistically different (p = 0.21). Females had statistically higher BPA LSGM concentrations than males (p = 0.043). Children had higher concentrations than adolescents (p < 0.001), who in turn had higher concentrations than adults (p = 0.003). LSGM concentrations were lowest for participants in the high household income category (>

Urinary Concentrations of Bisphenol A and 4-Nonylphenol in a Human Reference Population

45,000/year). Conclusions Urine concentrations of total BPA differed by race/ethnicity, age, sex, and household income. These first U.S. population representative concentration data for urinary BPA and tOP should help guide public health research priorities, including studies of exposure pathways, potential health effects, and risk assessment.

Polyfluoroalkyl Chemicals in the U.S. Population: Data from the National Health and Nutrition Examination Survey (NHANES) 2003–2004 and Comparisons with NHANES 1999–2000

Bisphenol A (BPA) is used to manufacture polycarbonate plastic and epoxy resins, which are used in baby bottles, as protective coatings on food containers, and for composites and sealants in dentistry. 4-Nonylphenol (NP) is used to make nonylphenol ethoxylates, nonionic surfactants applied as emulsifying, wetting, dispersing, or stabilizing agents in industrial, agricultural, and domestic consumer products. The potential for human exposure to BPA and NP is high because of their widespread use. We measured BPA and NP in archived urine samples from a reference population of 394 adults in the United States using isotope-dilution gas chromatography/mass spectrometry. The concentration ranges of BPA and NP were similar to those observed in other human populations. BPA was detected in 95% of the samples examined at concentrations ≥0.1 μg/L urine; the geometric mean and median concentrations were 1.33 μg/L (1.36 μg/g creatinine) and 1.28 μg/L (1.32 μg/g creatinine), respectively; the 95th percentile concentration was 5.18 μg/L (7.95 μg/g creatinine). NP was detected in 51% of the samples examined ≥0.1 μg/L. The median and 95th percentile concentrations were < 0.1 μg/L and 1.57 μg/L (1.39 μg/g creatinine), respectively. The frequent detection of BPA suggests widespread exposure to this compound in residents of the United States. The lower frequency of detection of NP than of BPA could be explained by a lower exposure of humans to NP, by different pharmacokinetic factors (i.e., absorption, distribution, metabolism, elimination), by the fact that 4-n-nonylphenol—the measured NP isomer—represents a small percentage of the NP used in commercial mixtures, or a combination of all of the above. Additional research is needed to determine the best urinary biomarker(s) to assess exposure to NP. Despite the sample population’s nonrepresentativeness of the U.S. population (although sample weights were used to improve the extent to which the results represent the U.S. population) and relatively small size, this study provides the first reference range of human internal dose levels of BPA and NP in a demographically diverse human population.

Cord Serum Concentrations of Perfluorooctane Sulfonate (PFOS) and Perfluorooctanoate (PFOA) in Relation to Weight and Size at Birth

Background Polyfluoroalkyl chemicals (PFCs) have been used since the 1950s in numerous commercial applications. Exposure of the general U.S. population to PFCs is widespread. Since 2002, the manufacturing practices for PFCs in the United States have changed considerably. Objectives We aimed to assess exposure to perfluorooctane sulfonic acid (PFOS), perfluorooctanoic acid (PFOA), perfluorohexane sulfonic acid (PFHxS), perfluorononanoic acid (PFNA), and eight other PFCs in a representative 2003–2004 sample of the general U.S. population ≥ 12 years of age and to determine whether serum concentrations have changed since the 1999–2000 National Health and Nutrition Examination Survey (NHANES). Methods By using automated solid-phase extraction coupled to isotope dilution–high-performance liquid chromatography–tandem mass spectrometry, we analyzed 2,094 serum samples collected from NHANES 2003–2004 participants. Results We detected PFOS, PFOA, PFHxS, and PFNA in > 98% of the samples. Concentrations differed by race/ethnicity and sex. Geometric mean concentrations were significantly lower (approximately 32% for PFOS, 25% for PFOA, 10% for PFHxS) and higher (100%, PFNA) than the concentrations reported in NHANES 1999–2000 (p < 0.001). Conclusions In the general U.S. population in 2003–2004, PFOS, PFOA, PFHxS, and PFNA serum concentrations were measurable in each demographic population group studied. Geometric mean concentrations of PFOS, PFOA, and PFHxS in 2003–2004 were lower than in 1999–2000. The apparent reductions in concentrations of PFOS, PFOA, and PFHxS most likely are related to discontinuation in 2002 of industrial production by electrochemical fluorination of PFOS and related perfluorooctanesulfonyl fluoride compounds.

Prenatal Phenol and Phthalate Exposures and Birth Outcomes

Background Recent studies have reported developmental toxicity among rodents dosed with perfluorooctane sulfonate (PFOS) and perfluorooctanoate (PFOA). Objectives We examined the relationship between concentrations of PFOS and PFOA in cord serum (surrogates for in utero exposures) and gestational age, birth weight, and birth size in humans. Methods We conducted a hospital-based cross-sectional epidemiologic study of singleton deliveries in Baltimore, Maryland. Cord serum samples (n = 293) were analyzed for PFOS and PFOA by online solid-phase extraction, coupled with reversed-phase high-performance liquid chromatography–isotope dilution tandem mass spectrometry. Maternal characteristics and anthropometric measures were obtained from medical charts. Results After adjusting for potential confounders, both PFOS and PFOA were negatively associated with birth weight [per ln-unit: β = −69 g, 95% confidence interval (CI), −149 to 10 for PFOS; β = −104 g, 95% CI, −213 to 5 for PFOA], ponderal index (per ln-unit: β = −0.074 g/cm3 × 100, 95% CI, −0.123 to −0.025 for PFOS; β = −0.070 g/cm3 × 100, 95% CI, −0.138 to −0.001 for PFOA), and head circumference (per ln-unit: β = −0.32 cm, 95% CI, −0.56 to −0.07 for PFOS; β = −0.41 cm, 95% CI, −0.76 to −0.07 for PFOA). No associations were observed between either PFOS or PFOA concentrations and newborn length or gestational age. All associations were independent of cord serum lipid concentrations. Conclusions Despite relatively low cord serum concentrations, we observed small negative associations between both PFOS and PFOA concentrations and birth weight and size. Future studies should attempt to replicate these findings in other populations.

Trends in exposure to polyfluoroalkyl chemicals in the U.S. Population: 1999-2008.

BACKGROUND Many phthalates and phenols are hormonally active and are suspected to alter the course of development. OBJECTIVE We investigated prenatal exposures to phthalate and phenol metabolites and their associations with body size measures of the infants at birth. METHODS We measured 5 phenol and 10 phthalate urinary metabolites in a multiethnic cohort of 404 women in New York City during their third trimester of pregnancy and recorded size of infants at birth. RESULTS Median urinary concentrations were > 10 microg/L for 2 of 5 phenols and 6 of 10 phthalate monoester metabolites. Concentrations of low-molecular-weight phthalate monoesters (low-MWP) were approximately 5-fold greater than those of high-molecular-weight metabolites. Low-MWP metabolites had a positive association with gestational age [0.97 day gestational age per ln-biomarker; 95% confidence interval (CI), 0.07-1.9 days, multivariate adjusted] and with head circumference. Higher prenatal exposures to 2,5-dichlorophenol (2,5-DCP) predicted lower birth weight in boys (-210 g average birth weight difference between the third tertile and first tertile of 2,5-DCP; 95% CI, 71-348 g). Higher maternal benzophenone-3 (BP3) concentrations were associated with a similar decrease in birth weight among girls but with greater birth weight in boys. CONCLUSIONS We observed a range of phthalate and phenol exposures during pregnancy in our population, but few were associated with birth size. The association of 2,5-DCP and BP3 with reduced or increased birth weight could be important in very early or small-size births. In addition, positive associations of urinary metabolites with some outcomes may be attributable partly to unresolved confounding with maternal anthropometric factors.

Impact of Early-Life Bisphenol A Exposure on Behavior and Executive Function in Children

Since 2002, practices in manufacturing polyfluoroalkyl chemicals (PFCs) in the United States have changed. Previous results from the National Health and Nutrition Examination Survey (NHANES) documented a significant decrease in serum concentrations of some PFCs during 1999-2004. To further assess concentration trends of perfluorooctane sulfonate (PFOS), perfluorooctanoate (PFOA), perfluorohexane sulfonate (PFHxS), and perfluorononanoate (PFNA), we analyzed 7876 serum samples collected from a representative sample of the general U.S. population ≥12 years of age during NHANES 1999-2008. We detected PFOS, PFOA, PFNA, and PFHxS in more than 95% of participants. Concentrations differed by sex regardless of age and we observed some differences by race/ethnicity. Since 1999-2000, PFOS concentrations showed a significant downward trend, because of discontinuing industrial production of PFOS, but PFNA concentrations showed a significant upward trend. PFOA concentrations during 1999-2000 were significantly higher than during any other time period examined, but PFOA concentrations have remained essentially unchanged during 2003-2008. PFHxS concentrations showed a downward trend from 1999 to 2006, but concentrations increased during 2007-2008. Additional research is needed to identify the environmental sources contributing to human exposure to PFCs. Nonetheless, these NHANES data suggest that sociodemographic factors may influence exposure and also provide unique information on temporal trends of exposure.

Prenatal Bisphenol A Exposure and Early Childhood Behavior

OBJECTIVES: To estimate the impact of gestational and childhood bisphenol A (BPA) exposures on behavior and executive function at 3 years of age and to determine whether child gender modified those associations. METHODS: We used a prospective birth cohort of 244 mothers and their 3-year-old children from the greater Cincinnati, Ohio, area. We characterized gestational and childhood BPA exposures by using the mean BPA concentrations in maternal (16 and 26 weeks of gestation and birth) and child (1, 2, and 3 years of age) urine samples, respectively. Behavior and executive function were measured by using the Behavior Assessment System for Children 2 (BASC-2) and the Behavior Rating Inventory of Executive Function-Preschool (BRIEF-P). RESULTS: BPA was detected in >97% of the gestational (median: 2.0 μg/L) and childhood (median: 4.1 μg/L) urine samples. With adjustment for confounders, each 10-fold increase in gestational BPA concentrations was associated with more anxious and depressed behavior on the BASC-2 and poorer emotional control and inhibition on the BRIEF-P. The magnitude of the gestational BPA associations differed according to child gender; BASC-2 and BRIEF-P scores increased 9 to 12 points among girls, but changes were null or negative among boys. Associations between childhood BPA exposure and neurobehavior were largely null and not modified by child gender. CONCLUSIONS: In this study, gestational BPA exposure affected behavioral and emotional regulation domains at 3 years of age, especially among girls. Clinicians may advise concerned patients to reduce their exposure to certain consumer products, but the benefits of such reductions are unclear.

Altered Semen Quality in Relation to Urinary Concentrations of Phthalate Monoester and Oxidative Metabolites

Background Prenatal exposure to bisphenol A (BPA) increases offspring aggression and diminishes differences in sexually dimorphic behaviors in rodents. Objective We examined the association between prenatal BPA exposure and behavior in 2-year-old children. Methods We used data from 249 mothers and their children in Cincinnati, Ohio (USA). Maternal urine was collected around 16 and 26 weeks of gestation and at birth. BPA concentrations were quantified using high-performance liquid chromatography–isotope-dilution tandem mass spectrometry. Child behavior was assessed at 2 years of age using the second edition of the Behavioral Assessment System for Children (BASC-2). The association between prenatal BPA concentrations and BASC-2 scores was analyzed using linear regression. Results Median BPA concentrations were 1.8 (16 weeks), 1.7 (26 weeks), and 1.3 (birth) ng/mL. Mean (± SD) BASC-2 externalizing and internalizing scores were 47.6 ± 7.8 and 44.8 ± 7.0, respectively. After adjustment for confounders, log10-transformed mean prenatal BPA concentrations were associated with externalizing scores, but only among females [β = 6.0; 95% confidence interval (CI), 0.1–12.0]. Compared with 26-week and birth concentrations, BPA concentrations collected around 16 weeks were more strongly associated with externalizing scores among all children (β = 2.9; 95% CI, 0.2–5.7), and this association was stronger in females than in males. Among all children, measurements collected at ≤ 16 weeks showed a stronger association (β = 5.1; 95% CI, 1.5–8.6) with externalizing scores than did measurements taken at 17–21 weeks (β = 0.6; 95% CI, −2.9 to 4.1). Conclusions These results suggest that prenatal BPA exposure may be associated with externalizing behaviors in 2-year-old children, especially among female children.

Urinary Concentrations of Triclosan in the U.S. Population: 2003–2004

Background: Phthalates are multifunctional chemicals used in a variety of consumer, medical, and personal care products. Previously, we reported dose–response associations of decreased semen quality with urinary concentrations of monobutyl phthalate (MBP) and monobenzyl (MBzP) phthalate, which are metabolites of dibutyl phthalate and butylbenzyl phthalate, respectively. The present study extends our work in a larger sample of men and includes measurements of di(2-ethylhexyl) phthalate (DEHP) oxidative metabolites. Methods: Between January 2000 and May 2004, we recruited 463 male partners of subfertile couples who presented for semen analysis to the Massachusetts General Hospital. Semen parameters were dichotomized based on World Health Organization reference values for sperm concentration (<20 million/mL) and motility (<50% motile) and the Tygerberg Kruger Strict criteria for morphology (<4% normal). The comparison group was men with all 3 semen parameters above the reference values. In a single spot urine sample from each man, phthalate metabolites were measured using solid-phase extraction coupled to high-performance liquid chromatography isotope-dilution tandem mass spectrometry. Results: There were dose–response relationships of MBP with low sperm concentration (odds ratio per quartile adjusted for age, abstinence time, and smoking status = 1.00, 3.1, 2.5, 3.3; P for trend = 0.04) and motility (1.0, 1.5, 1.5, 1.8; P for trend = 0.04). There was suggestive evidence of an association between the highest MBzP quartile and low sperm concentration (1.00, 1.1, 1.1, 1.9; P for trend = 0.13). There were no relationships of monoethyl phthalate, monomethyl phthalate, and the DEHP metabolites with these semen parameters. Conclusion: The present study confirms previous results on the relationship of altered semen quality with exposure to MBP at general population levels. We did not find associations between semen parameters and 3 DEHP metabolites.