Pilot study of urinary biomarkers of phytoestrogens, phthalates, and phenols in girls.BACKGROUND: Hormonally active environmental agents have been measured among U.S. children using exposure biomarkers in urine. However, little is known about their variation by race, age, sex, and geography, and no data exist for newly developed biomarkers. OBJECTIVE: Our goal was to characterize relevant, prevalent exposures for a study of female pubertal development. METHODS: In a pilot study among 90 girls from New York City New York City: see New York, city. New York City City (pop., 2000: 8,008,278), southeastern New York, at the mouth of the Hudson River. The largest city in the U.S. , New York New York, state, United States New York, Middle Atlantic state of the United States. It is bordered by Vermont, Massachusetts, Connecticut, and the Atlantic Ocean (E), New Jersey and Pennsylvania (S), Lakes Erie and Ontario and the Canadian province of , Cincinnati, Ohio “Cincinnati” redirects here. For other uses, see Cincinnati (disambiguation). Cincinnati is a city in the U.S. state of Ohio and the county seat of Hamilton County. , and northern California Northern California, sometimes referred to as NorCal, is the northern portion of the U.S. state of California. The region contains the San Francisco Bay Area, the state capital, Sacramento; as well as the substantial natural beauty of the redwood forests, the northern , we measured 25 urinary analytes representing 22 separate agents from three chemical families: phytoestrogens Phytoestrogens Compounds found in plants that can mimic the effects of estrogen in the body. Mentioned in: Premenstrual Syndrome phytoestrogens, n.pl plant-derived estrogen analogs. , phthalates Phthalates, or phthalate esters, are a group of chemical compounds that are mainly used as plasticizers (substances added to plastics to increase their flexibility). They are chiefly used to turn polyvinyl chloride from a hard plastic into a flexible plastic. , and phenols phenols (fēˑ·n  lz),n. . Exposures occur chiefly from the diet and from household or personal care products. RESULTS: Participants represented four racial/ethnic groups (Asian, black, Hispanic, white), with mean age of 7.77 years. Most analytes were detectable in > 94% of samples. The highest median concentrations for individual analytes in each family were for enterolactone (298 [micro]g/L), monoethylphthalate (MEP MEP maximum expiratory pressure. MEP, n muscle energy procedure; diagnostic and therapeutic technique. Pulsed muscle energy techniques (MET) and integrated neuromuscular inhibition technique (INIT) are two examples. ; 83.2 [micro]g/L), and benzophenone-3 (BP3; 14.7 [micro]g/L). Few or no data have been reported previously for four metabolites Metabolites Substances produced by metabolism or by a metabolic process. Mentioned in: Interactions : mono(2-ethyl-5-carboxypentyl) phthalate Phthal´ate n. 1. (Chem.) A salt of phthalic acid. , triclosan, bisphenol A Bisphenol A is a chemical compound containing two phenol functional groups. It belongs to the phenol class of aromatic organic compounds. It is widely prepared and sold and various important polymers/plastics are made from it. (BPA BPA British Paediatric Association. ), and BP3; these were detected in 67-100% of samples with medians of 1.8-53.2 [micro]g/L. After multivariate adjustment, two analytes, enterolactone and BPA, were higher among girls with body mass index < 85th reference percentile than those at or above the 85th percentile. Three phthalate metabolites differed by race/ethnicity [MEP, mono(2-ethylhexyl) phthalate, and mono-3-carboxypropylphthalate]. CONCLUSIONS: A wide spectrum of hormonally active exposure biomarkers were detectable and variable among young girls, with high maximal concentrations (> 1,000 [micro]g/L) found for several analytes. They varied by characteristics that may be relevant to development. KEY WORDS: biomarkers, children, exposure, phenols, phthalates, phytoestrogen phytoestrogen /phy·to·es·tro·gen/ (-es´tro-jen) any of a group of weakly estrogenic, nonsteroidal compounds widely occurring in plants. phy·to·es·tro·gen n. , urine. Environ Health Perspect 115:116-121 (2007). doi:10.1289/ehp.9488 available via http://dx.doi.org/ [Online 19 October 2006] ********** Effects of hormonally active environmental agents on early child development have been of concern, as knowledge has become available about their biological activity and about widespread exposure. For agents that are short-lived in the body (i.e., rapidly metabolized and/or eliminated), assessment of exposure biomarkers in urine is usually preferred for several reasons: The metabolites are readily detectable in urine, urine is easy to collect, and urine generally has higher concentrations of polar metabolites than other biologic media. Although exposures to many of these agents have been characterized in children [Centers for Disease Control and Prevention Centers for Disease Control and Prevention (CDC), agency of the U.S. Public Health Service since 1973, with headquarters in Atlanta; it was established in 1946 as the Communicable Disease Center. (CDC See Control Data, century date change and Back Orifice. CDC - Control Data Corporation ) 2005], little is known about variation of these exposure biomarkers by race, age, body mass index (BMI BMI body mass index. BMI abbr. body mass index Body mass index (BMI) A measurement that has replaced weight as the preferred determinant of obesity. ), and sex. The Breast Cancer and the Environment Research Centers (BCERC) are a consortium established by the National Institute of Environmental Health Sciences The National Institute of Environmental Health Sciences (NIEHS) is one of 27 Institutes and Centers of the National Institutes of Health (NIH),which is a component of the Department of Health and Human Services (DHHS). The Director of the NIEHS is Dr. David A. Schwartz. and the National Cancer Institute to elucidate influences of environmental factors on early pubertal development in girls, and thereby possible future risk for breast cancer and other chronic diseases among women. For this purpose, the study design employs biomarkers to assess a variety of environmental exposures. The highest-priority urinary exposure biomarkers identified by the BCERC consortium are phytoestrogens, phthalate acids, and phenols. Agents in these groups were selected because they possess hormonal activity that may be agonistic agonistic /ag·o·nis·tic/ (ag?o-nis´tik) pertaining to a struggle or competition; as an agonistic muscle, counteracted by an antagonistic muscle. or antagonistic (Fenton 2006; Rajapakse et al. 2002; Sohoni and Sumpter 1998); they have been detected at sufficiently high concentrations to constitute a potential risk (CDC 2005); and they were known or expected to have adequate interindividual variability to serve as exposure markers. Exposures to these chemicals occur chiefly through the diet and use of household or personal care products (Table 1) (Calafat et al. 2005; CDC 2005; Duty et al. 2005). The CDC has previously reported concentrations in child participants in the National Health and Nutrition Examination Survey (NHANES NHANES National Health and Nutrition Examination Survey (US CDC) ) for some biomarkers (CDC 2005). However, no data are available in children for certain phenols, including bisphenol A (BPA), a chemical with hormonal activity relevant to pubertal development (vom Saal and Hughes 2005). In addition, prevalence and variability of these exposure biomarkers have not been described among young girls, and it is not known how these exposures may vary by race, geographic location, or age. In this report we provide initial information on levels of biomarkers for three chemical families of primary interest--phytoestrogens, phthalates, and phenols--and on their distribution by demographic factors among a subsample sub·sam·ple n. A sample drawn from a larger sample. tr.v. sub·sam·pled, sub·sam·pling, sub·sam·ples To take a subsample from (a larger sample). of the BCERC study population. Methods Participants in this pilot study were among the first children enrolled at three BCERC centers. We are recruiting approximately 1,200 girls 6-8 years of age into a longitudinal study longitudinal study a chronological study in epidemiology which attempts to establish a relationship between an antecedent cause and a subsequent effect. See also cohort study. , with the aim of following pubertal development from its earliest stages through menarche menarche /me·nar·che/ (me-nahr´ke) establishment or beginning of the menstrual function.menar´cheal me·nar·che n. The first menstrual period, usually during puberty. . Eligibility includes age 6-8 years, female sex, and no underlying endocrine medical conditions See carpal tunnel syndrome, computer vision syndrome, dry eyes and deep vein thrombosis. . All sites obtained informed consent from parent or guardian and child assent, approved by each institution's institutional review board. Study designs and methods were standardized for most but not all components, because each center retained some unique scientific aims, and their recruitment began at different dates. Mount Sinai School of Medicine
Mount Sinai School of Medicine is a medical school found in the borough of Manhattan in New York City. (MSSM MSSM Mount Sinai School of Medicine MSSM Minimal Supersymmetric Standard Model MSSM Maine School of Science and Mathematics MSSM Master of Science In Systems Management MSSM Minimal Sypersymmetric Standard Model MSSM Modified Step-Segment Method ) is recruiting black and Latina girls from clinics, schools, and community centers in East Harlem in New York City; the sample population from the University of Cincinnati/Cincinnati Children's Hospital A children's hospital is a hospital which offers its services exclusively to children. The number of children's hospitals proliferated in the 20th century, as pediatric medical and surgical specialties separated from internal medicine and adult surgical specialties. (Cincinnati) is recruited from and examined at schools or through a breast cancer registry A cancer registry is a systematic collection of data about cancer and tumor diseases. The data is collected by Cancer Registrars. Cancer Registrars capture a complete summary of patient history, diagnosis, treatment, and status for every cancer patient in the United States, and ; the Kaiser Permanente Kaiser Permanente is an integrated managed care organization, based in Oakland, California, founded in 1945 by industrialist Henry J. Kaiser and physician Sidney R. Garfield. Northern California (Kaiser) study group is recruited from the Kaiser health maintenance organization (HMO HMO health maintenance organization. HMO n. A corporation that is financed by insurance premiums and has member physicians and professional staff who provide curative and preventive medicine within certain financial, ) membership in the San Francisco Bay area “Bay Area” redirects here. For other uses, see Bay Area (disambiguation). The San Francisco Bay Area, colloquially known as the Bay Area or The Bay . At all sites, a baseline questionnaire was completed by the girl's parent or guardian (usually the mother) that included a detailed medical history, product use and exposures, exercise, diet, and demographic variables. Self-reported race/ethnicity included white, black, American Indian American Indian or Native American or Amerindian or indigenous American Any member of the various aboriginal peoples of the Western Hemisphere, with the exception of the Eskimos (Inuit) and the Aleuts. , Pacific Islander Pacific Islander n. 1. A native or inhabitant of any of the Polynesian, Micronesian, or Melanesian islands of Oceania. 2. A person of Polynesian, Micronesian, or Melanesian descent. See Usage Note at Asian. , or Asian, as well as Hispanic ethnicity. There were 10 Hispanics of Mexican origin at MSSM who did not report a race but who were identified by interviewers as Native Americans by ascertaining child and parental birthplace and native language (Mexican Indians). For the purposes of this report, race/ethnicity was classified as black (including black Hispanic), non-black Hispanic, non-Hispanic white, or non-Hispanic Asian. Height and weight were measured using calibrated cal·i·brate tr.v. cal·i·brat·ed, cal·i·brat·ing, cal·i·brates 1. To check, adjust, or determine by comparison with a standard (the graduations of a quantitative measuring instrument): scales and stadiometers by interviewers who had been trained and certified uniformly across all three sites. BMI was calculated as weight/height-squared (kilograms per square meter Noun 1. square meter - a centare is 1/100th of an are centare, square metre area unit, square measure - a system of units used to measure areas ) and then classified as < 85th national percentile, age- and sex-specific, or [greater than or equal to] 85th percentile (Himes and Dietz 1994), using CDC growth charts (CDC 2000). In this CDC data set, the 85th percentile BMI cut points for girls in the first month of 6, 7, and 8 years of age are 17.100, 17.626, and 18.317 kg/[m.sup.2], respectively. Urine specimens were collected at the time of the baseline examination baseline examination Clinical practice A physical exam which is part of an initial Pt-physician contact, and designed to assess a Pt's eligibility for enrollment in a clinical trial and produce requisite baseline data. or in a 6-month follow-up visit (Cincinnati). MSSM and Kaiser collected spot specimens at baseline, and Cincinnati collected early morning voids. Each center submitted 30 urine samples to CDC for determining the concentrations of phthalate metabolites, phenols, phytoestrogens, and creatinine creatinine /cre·at·i·nine/ (kre-at´i-nin) an anhydride of creatine, the end product of phosphocreatine metabolism; measurements of its rate of urinary excretion are used as diagnostic indicators of kidney function and muscle mass. (to normalize normalize to convert a set of data by, for example, converting them to logarithms or reciprocals so that their previous non-normal distribution is converted to a normal one. for urine dilution). Samples from MSSM and Cincinnati were selected randomly from the samples donated before December 2005 with at least 40 mL of urine. Kaiser sent the first 30 samples collected with sufficient volume. The study size was limited by budgetary constraints and by the need to conduct the pilot study at an early stage of recruitment. Laboratory techniques Laboratory techniques are the sum of procedures used on natural sciences such as chemistry, biology, physics in order to conduct an experiment, all of them follow scientific method; while some of them involves the use of complex laboratory equipment from laboratory glassware to used by CDC for measuring the selected exposure biomarkers in urine have been published. Briefly, metabolites are deconjugated enzymatically, because these agents are excreted almost entirely as conjugated conjugated adj. Conjugate. estrogens, conjugated Warning - Hazardous drug! C.E.S. metabolites. Matrix removal and analyte enrichment are accomplished by solid phase extraction Solid-phase extraction (SPE) is a separation process that is used to extract compounds (called analytes) from a mixture of impurities. Analytical laboratories use solid phase extraction to concentrate and purify samples for analysis. , and instrumental analysis is done with high performance liquid chromatography--tandem mass spectrometry mass spectrometry or mass spectroscopy Analytic technique by which chemical substances are identified by sorting gaseous ions by mass using electric and magnetic fields. using isotope dilution quantification (Kato et al. 2005; Kuklenyik et al. 2004; Rybak et al. 2006; Ye et al. 2005a). The laboratory is certified according to according to prep. 1. As stated or indicated by; on the authority of: according to historians. 2. In keeping with: according to instructions. 3. the Clinical Laboratories Improvement Act, and procedures incorporate quality control (QC) measures to ensure accuracy and precision of results, including annual proficiency testing compliance (Norrgran et al. 2006). A laboratory batch must meet quality control criteria, including acceptable blanks, or the batch is entirely reanalyzed. Results are blank-corrected. Enterodiol data for two girls were not available because these results did not fulfill the quality assurance/quality control requirements. Creatinine was measured using an enzymatic reaction on a Roche Hitachi 912 chemistry analyzer (Roche Hitachi, Basel Switzerland). We performed statistical analyses using SAS (1) (SAS Institute Inc., Cary, NC, www.sas.com) A software company that specializes in data warehousing and decision support software based on the SAS System. Founded in 1976, SAS is one of the world's largest privately held software companies. See SAS System. (version 9.1.3 for PC; SAS Institute SAS Institute Inc., headquartered in Cary, North Carolina, USA, has been a major producer of software since it was founded in 1976 by Anthony Barr, James Goodnight, John Sall and Jane Helwig. Inc., Cary, NC). Because of the unequal distribution of characteristics among sites, we first used nonparametric methods to examine variation of exposure biomarker concentrations in relation to study characteristics. For analytes detected in > 60% of samples, we then performed multivariate analyses adjusting for age, race/ethnicity, site, BMI, and season of sample collection using the general linear model (GLM GLM Global Language Monitor GLM Global Marine (stock symbol) GLM Graduated Length Method (ski instruction) GLM Good Looking Mom (used in pediatric practices) GLM God Loves Me ) procedure, which accommodates unbalanced designs. For age, we computed Spearman spear·man n. A man, especially a soldier, armed with a spear. correlations with each biomarker. Using the Kruskal-Wallis test of rank sums (NPAR NPAR Nuclear Plant Aging Research (program) NPAR Navy Precision Approach Radar NPAR Number Port Activation Request NPAR National Patient Antibody Registry 1WAY procedure with Wilcoxon option), we compared medians of the creatinine-corrected concentrations (micrograms per gram creatinine) by race/ethnicity, site, BMI, and season (coded as Summer = June, July, August vs. other seasons; use of several products listed in Table 1 was considered likely to vary by season). For exposure biomarkers whose medians exhibited differences with respect to these characteristics [see Supplemental Materials, Table 1 (http://www.ehponline.org/docs/2006/9488/suppl.pdf)], we then examined whether the multivariate geometric means were significantly different across characteristic levels using the LSMEANS option of the GLM procedure. Four Asians were retained in the multivariate analyses, with racial/ethnic differences reported only for blacks, Hispanics, and whites but not Asians. In parametric analyses, we used log-transformed values of the urinary metabolite metabolite, organic compound that is a starting material in, an intermediate in, or an end product of metabolism. Starting materials are substances, usually small and of simple structure, absorbed by the organism as food. concentrations to normalize the distribution and we substituted the value LOD/[square root of]2 for results below the limit of detection (LOD Lod (lōd), city (1994 pop. 51,200), central Israel. It is also known as Lydda. Its manufactures include paper products, chemicals, oil products, electronic equipment, processed food, and cigarettes. ) following the CDC practice (Wolff et al. 2005). Results Participants represented four racial/ethnic groups (Asian, black, Hispanic, white) and three geographic locations (New York City, Cincinnati metropolitan area, and the San Francisco Bay area of California; Table 2). Mean age was 7.77 years at date of sample collection (range, 6.4-9.2). Samples collected at Kaiser were almost all from 7-year-old girls (29 of 30); there were two 6-year-old girls from Cincinnati and nine from MSSM. Race/ethnicity varied by site, with Kaiser and Cincinnati girls mainly white (> 60%) or black, and with no whites at MSSM. All four Asians were from Kaiser, and most Hispanics (18 of 22) were from MSSM. Compared with national data (CDC 2000), 32% of girls were [greater than or equal to] 85th percentile of BMI, and the distributions of BMI within sites were similar. Samples from Kaiser were all collected in summer; no samples from Cincinnati and nine from MSSM were collected in summer. Eighteen of the 25 analytes were detected in at least 94% of the samples (Table 3). Phytoestrogens as a group had the highest concentrations (e.g., median 298 [micro]g/L for enterolactone), and all six phytoestrogens were detected in > 98% of samples. Phthalate metabolites were intermediate in concentration, with 9 of the 10 biomarkers detected in > 94% of samples. Phenols had the lowest concentrations and were least detected (only 3 of the 9 were detected in > 94% of samples). Seventeen exposure biomarkers had medians > 10 [micro]g/L (10 ppb ppb abbr. parts per billion ), and six had medians > 50 [micro]g/L. Four phytoestrogens, four phthalates, and two phenols had maximum values > 1,000 [micro]g/L (1 ppm). The ranges for 10 of 25 exposure biomarkers encompassed at least 3 orders of magnitude (e.g., 1-1,000 [micro]g/L). The highest individual biomarker measurement was for benzophenone-3 (BP3; 26,700 [micro]g/L). To verify that the very high BP3 urinary measurements reflected absorbed dose ab·sorbed dose n. The quantity of radiation energy, expressed in rads, that is administered or absorbed per unit mass of target. absorbed dose rather than surface contamination during sample collection, storage, or analysis, we measured free (i.e., unbound unbound said of electrolytes, e.g. iron and calcium, and other substances which are circulating in the bloodstream and are not bound to plasma proteins so that they are available immediately for metabolic processes. See also calcium, iron. ) BP3 in the nine samples having concentrations >1,000 [micro]g/L. The concentrations of unbound BP3 were minimal, < 1-20 [micro]g/L (data not shown), consistent with excretion of absorbed BP3 as conjugated species (Ye et al. 2005b). Multivariate adjusted concentrations of creatinine-corrected exposure biomarkers (geometric means) are presented in Table 4 according to race/ethnicity, geographic site, BMI, and season of collection; included are the 20 analytes that were detected in at least 60% of samples. Differences in the medians (unadjusted) by characteristics are shown in the Supplemental Material, Table 1 (http://www.ehponline.org/docs/2006/9488/suppl.pdf). Compared with the unadjusted values, there were fewer significant associations in the multivariate models for race (5 vs. 8), site (3 vs. 9), and season (1 vs. 6). Enterolactone and BPA differed significantly with regard to BMI (< 85th percentile vs. [greater than or equal to] 85th percentile). The adjusted geometric means of three phthalate metabolites varied by race/ethnicity, with whites having lower concentrations of mono(2-ethylhexyl) phthalate (MEHP MEHP Monoethylhexylphthalate ) and monoethyl phthalate (MEP) but higher mono(3-carboxypropyl) phthalate (MCPP mCPP meta-chlorophenylpiperazine (serotonin agonist) MCPP Mackinac Center for Public Policy MCPP Marine Corps Planning Process MCPP Microsoft Communication Protocol Program MCPP 2-(2-Methyl-4-Chlorophenoxy) ). Among the phenols, 2,5-dichlorophenol (25DCP DCP - definitional constraint programming ) was higher in blacks than whites, and BP3 was higher in whites. O-Desmethylangolensin (O-DMA), 25DCP, and 2,4-dichlorophenol (24DCP) differed across the three study sites. BP3 was higher in samples collected in summer. Patterns by race and season for MEHP, MEP, MCPP, 25DCP, and 24DCP remained the same if the geometric means were adjusted for age, race, BMI, and season but not for site. When the correlation between age as a continuous variable and each analyte was examined, it was significantly associated only with equol (micrograms equol/grams creatinine; [r.sub.S]-0.26, p = 0.013). In the multivariate model for equol [ln, micrograms per gram creatinine], the beta for age (years) was -0.44 (p = 0.029, adjusted for race/ethnicity, geographic site, BMI, and season of collection). The strongest correlations between individual biomarkers within a family were seen among those arising from the same parent compound (e.g., [r.sub.S] = 0.79-0.99 among four di(2-ethylhexyl) phthalate [DEHP DEHP Di(2-ethylhexyl)phthalate DEHP Diethylhexylphthalate DEHP Diethyl Hydrogen Phosphite DEHP Dual Encoding Hierarchical Pipelining ] metabolites: mono(2-ethyl-5-carboxypentyl) phthalate [MECPP], mono(2-ethyl-5-hydroxyhexyl) phthalate [MEHHP], (2-ethyl-5-oxohexyl) phthalate [MEOHP], and MEHP; data not shown). We computed correlations between creatinine and the urinary exposure biomarkers to examine the appropriateness of creatinine-corrections for dilution. The lowest correlations were seen for BP3 ([r.sub.S] = -0.03, p = 0.758) and O-DMA ([r.sub.S] = 0.24, p = 0.022); correlations of creatinine with other biomarkers were fairly strong ([r.sub.S] > 0.3, p < 0.01; data not shown). Associations of phthalate metabolites with creatinine were stronger ([r.sub.S] = 0.50-0.72) than for phytoestrogens ([r.sub.S] = 0.33-0.52, not including O-DMA) and phenols ([r.sub.S] = 0.42-0.54 for triclosan, 25DCP, BPA, and 24DCP). Because BP3 was not related to urinary creatinine, it may be inappropriate to correct for dilution using creatinine (Hauser et al. 2004; Miller et al. 2004). When we examined BP3 in relation to the characteristics in Table 4 using the concentration as micrograms per liter (uncorrected for creatinine), we obtained almost identical results. The range of creatinine was 7.6-255 mg/dL with 9 samples < 20 mg/dL, which could potentially influence the data in Tables 3 and 4 by overinflating the creatinine-corrected values. We examined the distribution of values for the nine low-creatinine samples in those exposure biomarkers that varied significantly by the factors in Table 4; they were fairly evenly distributed in terms of concentrations, and excluding them from the multivariate adjusted models did not alter the differences seen in the exposure biomarkers with regard to characteristics described above. In addition, in models where biomarkers were not creatinine-corrected (micrograms per liter), we observed results similar to those in Table 4, except that two associations were not significant (BPA with BMI, p = 0.11; and 24DCP by site, p = 0.13). Discussion This pilot study of peripubertal girls examined urinary biomarkers of exposures among three chemical families that possess known or likely hormonal activity. Biomarkers from these families appear to be ubiquitous, have wide variability, and show relatively high urinary concentrations in 6- to 9-year-old girls, suggesting that they are suitable for study of exposure--outcome associations related to puberty. Among the 25 exposure biomarkers measured in this study, we had initially identified eight compounds as high priority for the epidemiologic study epidemiologic study A study that compares 2 groups of people who are alike except for one factor, such as exposure to a chemical or the presence of a health effect; the investigators try to determine if any factor is associated with the health effect , based on criteria of having prevalent, high exposure levels, toxicologic relevance, and exposure biomarker reliability. These included three phytoestrogens (enterolactone, daidzein, genistein), three phthalate metabolites (mono-n-butyl phthalate [MBP (Manchester Bus Powered) A synchronous transmission standard used in industrial networks. It provides 31.25 Kbps over a two-wire connection that delivers power in the bus and intrinsic safety. ], monobenzyl phthalate [MBzP], MEP), and two phenols (BPA, nonylphenol). Seven of these biomarkers were detected in at least 94% of samples, and the ranges of concentrations were wide, from the LOD (< 1) to > 26,000 [micro]g/L (minimum-maximum). Nonylphenol was not determined because CDC as yet has no optimal biomarker for this compound (Calafat et al. 2005). Levels of phytoestrogen and phthalate metabolites in this study were similar to those reported in the NHANES 2001-2002 children (CDC 2005), although enterodiol appeared to be higher and MBzP and monomethyl phthalate (MMP MMP Matrix Metalloproteinase (enzymes related to tissue healing/remodeling and cancer cell metastasis) MMP Mixed Member Proportional (New Zealand electoral system) MMP Multi-man Publishing ) lower in our study population. MECPP and MEP had the highest levels of the 10 phthalate metabolites measured. MECPP, a DEHP metabolite, has not been previously reported in NHANES nor in school-age children. The relationship of equol with age could be of interest, but it was the only analyte related to age. This association could also be attributable to population characteristics that can be explored in the future, such as diet. Two biomarkers (enterolactone and BPA) varied by BMI, and three phthalates differed by race. Relationships of phthalates with race/ethnicity were quite similar to those reported for all ages in the NHANES 2001-2002--for example, MEP and MEHP were highest in blacks and MCPP highest in whites (CDC 2005) (the CDC report does not provide race-specific data for children). One biomarker varied by season (BP3) and three by site (O-DMA, 25DCP, 24DCP), differences that may reflect diverse exposures; alternatively, these observations may be attributed to the unequal distribution of characteristics by site, a notion supported by the finding that both BP3 and 25DCP also differed by race. Differences by race and BMI may also be attributed to other confounding confounding when the effects of two, or more, processes on results cannot be separated, the results are said to be confounded, a cause of bias in disease studies. confounding factor factors, including socioeconomic status socioeconomic status, n the position of an individual on a socio-economic scale that measures such factors as education, income, type of occupation, place of residence, and in some populations, ethnicity and religion. (SES), that were not available for consideration. SES may affect body size, dietary habits, and product use, for example. Among the four DEHP metabolites measured, MEHP differed significantly by race after multivariate adjustment, whereas the trends for the three oxidative metabolites of DEHP were similar but not statistically significant (Table 4). It is possible that we did not detect significant racial/ethnic trends for the three DEHP oxidative metabolites because of limited sample size. It is also possible for MEHP to arise from sample contamination or hydrolysis hydrolysis (hīdrŏl`ĭsĭs), chemical reaction of a compound with water, usually resulting in the formation of one or more new compounds. , whereas the oxidative metabolites must be endogenous; however, this is unlikely to explain racial/ethnic variability. Alternatively, although overall exposures to DEHP may have been fairly uniform, recent ambient exposures to DEHP may have varied by race/ethnicity in this population. In another study, racial/ethnic differences in MEP levels were attributed to greater use of cologne by blacks and Hispanics (Duty et al. 2005). If recent exposures were responsible for the racial/ethnic differences in our data, a possibility would be that MEHP as the first metabolite formed might differ by race/ethnicity, reflecting mainly the most recent exposures. Another possible explanation is that there may be racial/ethnic variability in the primary but not the secondary DEHP metabolic routes. MEHP is the initial metabolite of DEHP, and it can undergo further oxidation through separate pathways, producing MECPP by one route and MEHHP and MEOHP by another. Racial/ethnic differences in the secondary pathways could be smaller than for MEHP formation. In addition, the oxidative metabolites have longer half-lives [10-15 hr vs. 5 hr for MEHP (Koch et al. 2006)], possibly constituting a more integrated measure of long-term exposures that vary less by race/ethnicity. The high correlations observed among four DEHP metabolites signify a common source of exposure from the parent compound (Silva et al. 2006). The proportion of MECPP (> 50% of the total of four metabolites reported here) is consistent with previous research suggesting that infants have a much higher proportion of MECPP (66%) than adults (32%) (Silva et al. 2006). Among other phthalate metabolites, MCPP and MEP, which differed significantly by race but in different directions, were not highly correlated with each other ([r.sub.S] = 0.33), supporting different product origins and environmental exposures for these agents. The relationships of the urinary exposure biomarkers to creatinine levels are of interest. One site collected early-morning (but not first-morning) voids, which may reflect different accumulated exposures than daytime spot samples that creatinine correction cannot resolve entirely. However, collection time is not likely to bias our exposure measures, because the adjusted means differed by site for only three analytes in two chemical families, and specific exposures are as likely to explain these findings as collection time. As recognized by others, care must be taken in normalizing urinary analytes for dilution because the excretory ex·cre·to·ry adj. Of, relating to, or used in excretion. excretory pertaining to excretion. excretory behavior see elimination behavior. mechanisms are not the same for creatinine and certain chemicals (Hauser et al. 2004; Miller et al. 2004). This possibility is evident in our study where the correlations between creatinine and endocrine disruptor Endocrine disruptors are exogenous substances that act like hormones in the endocrine system and disrupt the physiologic function of endogenous hormones. Studies have linked endocrine disruptors to adverse biological effects in animals, giving rise to concerns that low-level biomarkers varied, from zero (BP3) to 0.72 (mono-isobutyl phthalate [MiBP]), suggesting that excretion or metabolic capacity may affect these associations, possibly related to the amount of bound (e.g., glucuronidated) versus unbound metabolites. However, in agreement with previous research (Ye et al. 2005b), our data show that even at very high concentrations, BP3 is excreted mostly conjugated in urine; in contrast, MEP is mostly unconjugated (Silva et al. 2003). Unlike creatinine, glucuronide conjugates are actively excreted by tubular secretion, which may explain in part the low correlation of BP3 with creatinine as well as the wide range of correlations between creatinine and these biomarkers (see Hauser et al. 2004 and references therein). An alternative to correcting for urinary concentration is urinary specific gravity specific gravity, ratio of the weight of a given volume of a substance to the weight of an equal volume of some reference substance, or, equivalently, the ratio of the masses of equal volumes of the two substances. (Hauser et al. 2004; Miller et al. 2004), but this measurement was not performed on our samples. The differences in exposure biomarkers by race/ethnicity and BMI are potentially relevant to pubertal development which is known to be associated with these characteristics (Herman-Giddens et al. 1997). Furthermore, the associations of enterolactone and BPA with BMI and of phthalate metabolites with race are notable because these biomarkers did not vary by other factors in our data. Although the differences we observed are suggestive only, because the sample size is small and unbalanced with regard to some characteristics, we used a conservative approach, considering only a limited number of a priori a priori In epistemology, knowledge that is independent of all particular experiences, as opposed to a posteriori (or empirical) knowledge, which derives from experience. comparisons. Furthermore, the findings for phthalate metabolites were consistent with earlier reports. In general, concentrations of the 25 urinary exposure biomarkers we measured are far higher than those of more widely studied environmental agents such as 1, 1'-dichloro-2, 2'-bis(4-chlorophenyl)ethylene (DDE (Dynamic Data Exchange) A message protocol in Windows that allows application programs to request and exchange data between them automatically. DDE - Dynamic Data Exchange ) and elemental lead (CDC 2005). In addition, some of these agents have relatively potent hormonal activity. In yeast assays, for example, BPA and butylbenzyl phthalate (the parent compound of MBzP) have greater antiandrogenic and estrogenic activity than DDE (Sohoni and Sumpter 1998). However, the proportional biological effects of these exposures in humans are not known. Several exposure biomarkers reported here have not previously been measured in children nor in different parts of the United States United States, officially United States of America, republic (2005 est. pop. 295,734,000), 3,539,227 sq mi (9,166,598 sq km), North America. The United States is the world's third largest country in population and the fourth largest country in area. . On the basis of this pilot study, we are considering the potential relevance to child development of additional exposures that were not originally planned for study, and we are exploring alternatives to creatinine correction. If we identify any of these biomarkers as either protective or detrimental in terms of child maturation, the levels of these chemicals in the body may be modifiable because they are derived from the diet or ambient environment or from personal product use. Additional studies are under way to identify sources of these agents in our population and to assess the temporal variation of urinary metabolites among children. REFERENCES Calafat AM, Kuklenyik Z, Reidy JA, Caudill SP, Ekong J, Needham LL. 2005. Urinary concentrations of bisphenol A and 4-nonylphenol in human reference population. Environ Health Perspect 113:391-395. CDC. 2000. CDC Growth Charts: United States. Atlanta, GA:Centers for Disease Control and Prevention. Available: http://www.cdc.gov/growthcharts/ [accessed 25 September 2006]. CDC. 2005. National Report on Human Exposure to Environmental Chemicals. Atlanta, GA:Centers for Disease Control and Prevention. Available: http://www.cdc.gov/exposurereport/ [accessed 25 September 2006]. Duty SM, Ackerman RM, Calafat AM, Hauser R. 2005 Personal care product use predicts urinary concentrations of some phthalate monoesters. Environ Health Perspect 113:1530-1535. Fenton SE. 2006. Endocrine-disrupting compounds and mammary gland mammary gland, organ of the female mammal that produces and secretes milk for the nourishment of the young. A mammal may have from 1 to 11 pairs of mammary glands, depending on the species. Generally, those mammals that bear larger litters have more glands. development: early exposure and later life consequences. Endocrinology 147:S18-S24. Hauser R, Meeker JD, Park S, Silva MJ, Calafat AM. 2004. Temporal variability or urinary phthalate metabolite levels in men of reproductive age. Environ Health Perspect 112:1734-1740. Herman-Giddens ME, Slora EJ, Wasserman RC, Bourdony CJ, Bhapkar MV, Koch GG, et al. 1997. Secondary sexual characteristics Noun 1. secondary sexual characteristic - the genetically determined sex characteristics that are not functionally necessary for reproduction (pitch of the voice and body hair and musculature) secondary sex character, secondary sex characteristic and menses menses /men·ses/ (men´sez) the monthly flow of blood from the female genital tract. men·ses n. in young girls seen in office practice: a study from the Pediatric Research Pediatric Research is one of the most respected peer-reviewed medical journals within the field of pediatrics in the world. It is the official publication of the American Pediatric Society, the European Society for Paediatric Research, and the Society for Pediatric in Office Settings network. Pediatrics 99:505-512. Himes JH, Dietz WH. 1994. Guidelines for overweight in adolescent preventive services: recommendations from an expert committee. The Expert Committee on Clinical Guidelines for Overweight in Adolescent Preventive Services. Am J Clin Nutr 59:307-316 Kato K, Silva MJ, Needham LL, Calafat AM. 2005. Determination of 16 phthalate metabolites in urine using automated sample preparation and on-line preconcentration/high-performance liquid chromatography/tandem mass spectrometry. Anal Chem 77:2985-2291. Koch HM, Preuss R, Angerer J. 2006. Di (2-ethylhexyl)phthalate (DEHP): human metabolism and internal exposure--an update and latest results. Int J Androl. 1:155-165. Kuklenyik Z, Ye X, Reich JA, Needham LL, Calafat AM. 2004. Automated online and off-line solid-phase extraction methods for measuring isoflavones isoflavones (īˑ·sō·flāˈ·vōnz), n.pl phytoestrogenic compounds found in various plants, including red clover and soy. and lignans in urine. J Chromatogr Sci 42:495-500. Miller RC, Brindle brindle a pattern of coat pigmentation in which darker hairs form bands on a lighter background. A common coat color in Great Danes and Boston terriers. E, Holman DJ, Shofer J, Klein NA, Soules MR, et al. 2004. Comparison of specific gravity and creatinine for normalizing urinary reproductive hormone concentrations. Clin Chem 50:924-932. Norrgran J, Bravo R, Bishop AM, Restrepo P, Whitehead RD, Needham LL, Barr DB. 2006. Quantification of six herbicide herbicide (hr`bəsīd'), chemical compound that kills plants or inhibits their normal growth. A herbicide in a particular formulation and application can be described as selective or nonselective. metabolites in human urine Urine is liquid waste product of the body secreted by the kidneys by a process of filtration from blood and excreted through the urethra. This waste is eventually expelled from the body in a process known as urination. . J Chromatogr B Analyt Technol Biomed Life Sci 830:185-195. Rajapakse N, Silva E, Kortenkamp A. 2002. Combining xenoestrogens at levels below individual no-observed-effect concentrations dramatically enhances steroid hormone steroid hormone n. See steroid. action. Environ Health Perspect 110:917-921. Rybak ME, Parker DL, Pfeiffer CM. 2006. Determination of Urinary Phytoestrogens by HPLC-MS/MS: A Comparison of Atmospheric Pressure Chemical Ionization Atmospheric pressure chemical ionization (APCI) is an ionization method used in mass spectrometry. It is a form of chemical ionization which takes place at atmospheric pressure. (APCI APCI Atmospheric Pressure Chemical Ionization APCI Air Products & Chemicals, Inc. APCI Association of Professional Color Imagers APCI Advisory Panel on Country Information (UK) APCI Applied Personal Computing, Inc. ) and Electrospray Ionization Electrospray ionization (ESI) is a technique used in mass spectrometry to produce ions. It is especially useful in producing ions from macromolecules because it overcomes the propensity of these molecules to fragment when ionized. (ESI (Edge Side Includes) A markup language for Web pages that enables elements of a Web page to be dynamically assembled in servers distributed throughout the Internet. ). Presented at 54th ASMS ASMS American Society for Mass Spectrometry ASMS Association of Salaried Medical Specialists ASMS Advanced Satellite Mobile Systems ASMS Alabama School of Mathematics and Science ASMS American Society for Mohs Surgery ASMS Arkansas School for Math and Science Conference on Mass Spectrometry, 28 May-1 June 2006, Seattle, Washington  This page is protected from moves until disputes have been resolved on the .The reason for its protection is listed on the protection policy page. . Available: http://www.asms.org/Desktopmodules/inmergeabstractsearch/programprintview.aspx?sess=TP16 [accessed 27 November 2006]. Silva MJ, Barr DB, Reidy JA, Kato K, Malek NA, Hodge CC, et al. 2003. Glucuronidation patterns of common urinary and serum monoester mon·o·es·ter n. An ester having only one ester group. phthalate metabolites. Arch Toxicol 77:561-567. Silva MJ, Reidy JA, Preau JL, Samandar E, Needham LL, Calafat AM. 2006. Measurement of eight urinary metabolites of di (2-ethylhexyl) phthalate as biomarkers for human exposure assessment. Biomarkers 11:1-13. Sohoni P, Sumpter JP. 1998. Several environmental oestrogens are also anti-androgens. J Endocrinol 158:327-339. vom Saal FS, Hughes C. 2005. An extensive new literature concerning low-dose effects of bisphenol A shows the need for a new risk assessment. Environ Health Perspect 113:926-933. Wolff MS, Teitelbaum SL, Lioy PJ, Santella RM, Wang RY, Jones RL, et al. 2005. Exposures among pregnant women near the World Trade Center site on 11 September 2001. Environ Health Perspect 113:739-748. Ye X, Kuklenyik Z, Needham LL, Calafat AM. 2005a. Automated on-line column-switching HPLC-MS/< S method with peak focusing for the determination of nine environmental phenols in urine. Anal Chem 77:5407-5413. Ye X, Kuklenyik Z, Needham LL, Calafat AM. 2005b. Quantification of urinary conjugates of bisphenol A, 2, 5-dichlorophenol, and 2-hydroxy-4-methoxybenzophenone in humans by online solid phase extraction-high performance liquid chromatography-tandem mass spectrometry. Anal Bioanal Chem 383:638-644. Mary S. Wolff, (1) Susan L. Teitelbaum, (1) Gayle Windham, (2) Susan M. Pinney, (3) Julie A. Britton, (1) Carol Chelimo, (1) James Godbold, (1) Frank Biro, (4) Lawrence H. Kushi, (5) Christine M. Pfeiffer, (6) and Antonia M. Calafat (6) (1) Mount Sinai School of Medicine, Division of Environmental Health Sciences, Department of Community and Preventive Medicine preventive medicine, branch of medicine dealing with the prevention of disease and the maintenance of good health practices. Until recently preventive medicine was largely the domain of the U.S. , New York, New York, USA; (2) Division of Environmental and Occupational Disease Control, California Department of Health Services Department of Health Services may refer to:
Oakland (IPA: /ˈoʊklənd/), founded in 1852, is the eighth-largest city in the U.S. , USA; (3) Department of Environmental Health, University of Cincinnati The University of Cincinnati is a coeducational public research university in Cincinnati, Ohio. Ranked as one of America’s top 25 public research universities and in the top 50 of all American research universities,[2] College of Medicine, Cincinnati, Ohio, USA; (4) Division of Adolescent Medicine adolescent medicine n. The branch of medicine concerned with the treatment of youth between 13 and 21 years of age. Also called ephebiatrics, hebiatrics. , Cincinnati Children's Hospital Medical Center Cincinnati Children's Hospital Medical Center is a hospital in Cincinnati, Ohio. In June of 1883, a meeting of women from parish communities around Cincinnati established a mission to create a Diocesan Hospital for Children. , Ohio, USA; (5) Division of Research, Kaiser Permanente, Oakland, California, USA; (6) Division of Laboratory Sciences, National Center for Environmental Health, Centers for Disease Control and Prevention, Atlanta, Georgia, USA Address correspondence to M.S. Wolff, Department of Community and Preventive Medicine, Division of Environmental Health Sciences, Mount Sinai School of Medicine, One Gustave L. Levy Place, Box 1057, New York, NY 10029 USA. Telephone: (212) 241-6183. Fax: (212) 996-0407. E-mail: mary.wolff@mssm.edu Supplemental Material is available online at http://www.ehponline.org/docs/2006/9488/suppl.pdf We thank the study investigators and staff at the three medical centers involved in this research including S. Peter, A. Mejia, A. Richiez, J. Guiterrez, R. Osborne, M. Galvez, and B. Brenner (Mount Sinai); C. Dahl, C. Baker, S. Myatt, K. Ford, B. Bornschein, and L. Yaghjyan (Cincinnati); R. Hiatt, L. Greenspan, B. Sternfeld, C. Ashley, C. Bonnell, A. Beeck, C. Chan, D. Davis, E. Landaverde, S. Burleson, and M. Trotter (Kaiser Permanente). We are grateful to M. Silva, E. Samandar, and J. Preau for phthalate measurements; X. Ye and A. Bishop for phenols measurements; J. Reidy for phthalate and phenols quality control/quality assurance analysis; and M. Rybak and D. Parker for phytoestrogens measurements. We gratefully acknowledge G.W. Collman [National Institute of Environmental Health Sciences (NIEHS NIEHS National Institute of Environmental Health Sciences (NIH, DHHS) )], L.L. Needham [Centers for Disease Control and Prevention (CDC)], L. Reinlib (NIEHS), and D.G. Winn [National Cancer Institute (NCI See Liberate. )] for arranging the interagency collaboration that supported analysis of these samples. This study was conducted within the Breast Cancer and the Environment Research Centers, a network of centers including the Fox Chase Cancer Center The Fox Chase Cancer Center is a medical research facility and hospital located in the northeast section of Philadelphia, Pennsylvania, United States. The Center is an independent, non-profit institution which specializes in the treatment and prevention of cancer. , Michigan State University Michigan State University, at East Lansing; land-grant and state supported; coeducational; chartered 1855. It opened in 1857 as Michigan Agricultural College, the first state agricultural college. , the University of Cincinnati, and the University of California The University of California has a combined student body of more than 191,000 students, over 1,340,000 living alumni, and a combined systemwide and campus endowment of just over $7.3 billion (8th largest in the United States). San Francisco San Francisco (săn frănsĭs`kō), city (1990 pop. 723,959), coextensive with San Francisco co., W Calif., on the tip of a peninsula between the Pacific Ocean and San Francisco Bay, which are connected by the strait known as the Golden Comprehensive Cancer Center and supported by grants ES/CA12770, 012771, 012800, 012801 from the NIEHS and the NCI, NIH "Not invented here." See digispeak. NIH - The United States National Institutes of Health. , DHHS DHHS Department of Health & Human Services (US government) DHHS Dana Hills High School (Dana Point, California) DHHS Deaf and Hard of Hearing Services DHHS Deaf and Hard of Hearing Services . We acknowledge support from the NIEHS (ES009584 and ES012645), U.S. Environmental Protection Agency Environmental Protection Agency (EPA), independent agency of the U.S. government, with headquarters in Washington, D.C. It was established in 1970 to reduce and control air and water pollution, noise pollution, and radiation and to ensure the safe handling and (R827039 and RD831711), Agency for Toxic Substances and Disease Registry The United States Agency for Toxic Substances and Disease Registry, (ATSDR) is an agency for the U.S. Department of Health and Human Services that is directed by a congressional mandate to perform specific functions concerning the effect on public health of hazardous (ATU (ADSL Transceiver Unit) A device that provides ADSL modulation of the telephone line. The device at the telco side is the ATU-C (Central), which is a line card plugged into the DSLAM. 300014), NCI (CA93447), and National Center for Research Resources The National Center for Research Resources or NCRR, is a United States government agency. NCRR provides funding to laboratory scientists and researchers for facilities and tools in the goal of curing and treating diseases. (NCRR NCRR National Center for Research Resources NCRR North Carolina Railroad NCRR Nikkei for Civil Rights & Redress NCRR Network Cost Reduction Ratio NCRR Non Conformance Release Report ) (MO1-RR-00071). The contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIEHS, NCI, NCRR, NIH, or CDC. The authors declare they have no competing financial interests. Received 6 July 2006; accepted 19 October 2006.
Table 1. Biomarkers, their parent compounds, and examples of their
environmental soures.
Main parent compound
Chemical class and examples Abbreviation (if applicable)
Phytoestrogens
Isoflavones (genistein, daidzein)
Lignans (enterolactone)
Phthalate metabolites
Mono(2-ethylhexyl) phthalate MEHP Di(2-ethylhexyl)
phthalate (DEHP)
Mono(3-carboxypropyl) phthalate MCPP Di-n-octyl phthalate
Monobenzyl phthalate MBzP Butylbenzyl phthalate
Monoethyl phthalate MEP Diethyl phthalate
(DEP)
Monomethyl phthalate MMP Dimethyl phthalate
(DMP)
Mono-n-butyl phthalate, MBP, MiBP Dibutyl phthalate
mono-isobutyl phthalate (DBP), diisobutyl
phthalate (DiBP)
Phenols
Bisphenol A BPA
Benzophenone-3 BP3
(2-hydroxy-4-
methoxy-benzophenone)
Triclosan [5-chloro-2- TRCS
(2,4-dichlorophenoxy)phenol]
2,4-Dichlorophenol and 24DCP, Phenoxy- and other
trichlorophenols 245TCP, derivatives
246TCP
2,5-Dichlorophenol 25DCP 4-dichlorobenzene
ortho-Phenylphenol o-PP
4-tert-Octylphenol 4-t-OP
Chemical class and examples Exposure sources
Phytoestrogens Dietary intake
Isoflavones (genistein, daidzein) Soy products, including processed
meats, meat substitutes,
breads, and protein food bars
Lignans (enterolactone) Flax, seeds, grains
Phthalate metabolites Industrial and personal product
additives
Mono(2-ethylhexyl) phthalate Soft plastic including tubing,
especially polyvinyl chloride
(PVC; e.g., sometimes present
in clear food wrap)
Mono(3-carboxypropyl) phthalate Soft plastic
Monobenzyl phthalate Vinyl flooring, adhesives
Monoethyl phthalate Shampoo, scents, soap, lotion,
cosmetice
Monomethyl phthalate Insect repellant, plastic
Mono-n-butyl phthalate, Adhesives, caulk, cosmetics
mono-isobutyl phthalate
Phenols Commercial and personal products
and additives
Bisphenol A Polycarbonate containers and
coatings (cans, cups), dental
sealant
Benzophenone-3 Sunscreen
(2-hydroxy-4-
methoxy-benzophenone)
Triclosan [5-chloro-2- Microbicide in cleaning fluids
(2,4-dichlorophenoxy)phenol]
2,4-Dichlorophenol and Herbicides
trichlorophenols
2,5-Dichlorophenol Mothballs
Ortho-Phenylphenol Fungicide
4-tert-Octylphenol Detergent surfactant
Table 2. Characteristics of the study population, BCERC pilot study,
2004-2005.
No. per site
Characteristic No. (%) MSSM Cincinnati Kaiser
Age at sample
collection (years) (a)
6.0-6.9 11 (12.2) 9 2 0
7.0-7.9 57 (63.3) 9 19 29
[greater than or equal to] 8.0 22 (24.4) 12 9 1
Race/ethnicity
Asian 4 (4.4) 0 0 4
Black 26 (28.9) 12 9 5
Hispanic 22 (24.4) 18 1 3
White 38 (42.2) 0 20 18
Site
Cincinnati 30 (33.3)
MSSM 30 (33.3)
Kaiser 30 (33.3)
BMI for age (b)
< 85th percentile 61 (67.8) 21 19 21
[greater than or equal to] 85th 29 (32.2) 9 11 9
percentile
Collection time (c)
June-August 39 (43.3) 9 0 30
Other months 51 (56.7) 21 30 0
(a) Some samples were collected at a visit 6 months after the baseline
visit. (b) Available: http://www.cdc.gov/growthcharts/ (CDC 2000).
(c) October 2004 to September 2005.
Table 3. Distribution of BCERC phytoestrogen, phthalate, and phenol and
biomarkers for all sites combined, 2004-2005.
Range
LOD Percent ([micro]g/L)
Analyte No. No. > LOD ([micro]g/L) > LOD Low High
Phytoestrogens
Enterolactone 90 90 0.3 100.0 4.6 6730.0
Daidzein 90 90 0.3 100.0 2.4 9690.0
Enterodiol 88 88 0.3 100.0 1.0 548.0
Genistein 90 90 0.3 100.0 1.2 5360.0
Equol 90 89 0.3 98.9 0.2 485.0
O-DMA 90 89 0.2 98.9 0.1 3210.0
Phthalates
MECPP (b) 90 90 0.25 100.0 5.9 2260.0
MEHHP (b) 90 90 0.32 100.0 1.4 1699.0
MEOHP (b) 90 90 0.45 100.0 1.3 1070.0
MEHP (b) 90 85 0.90 94.4 0.6 110.0
MEP 90 90 0.40 100.0 5.3 2580.0
MBP 90 88 0.40 97.8 0.3 363.0
MBZP 90 89 0.11 98.9 0.1 191.0
MIBP 90 87 0.26 96.7 0.2 144.0
MCPP 90 90 0.16 100.0 0.4 76.9
MMP 90 18 1.00 20.0 < LOD 15.6
Phenols
BP3 90 86 0.34 95.6 < 0.2 26700.0
Triclosan 90 61 2.27 67.8 < 1.6 956.0
25DCP 90 88 0.12 97.8 < 0.1 3120.0
BPA 90 85 0.36 94.4 < 0.3 54.3
24DCP 90 70 0.17 77.8 < 0.1 92.7
246TCP 90 22 0.50 24.4 < LOD 6.1
245TCP 90 21 0.10 23.3 < LOD 1.2
4-t-OP 90 5 0.17 5.6 < LOD 0.4
o-PP 90 3 0.10 3.3 < LOD 2.5
Creatinine 90 7.6 254.8
(mg/dL)
Median Geometric mean Geometric mean
Analyte ([micro]g/L) [GSD ([micro]g/C)] [GSD ([micro]g/gC)]
Phytoestrogens
Enterolactone 298.0 269.0 (4.1) 420.0 (3.7)
Daidzein 98.0 112.0 (5.7) 175.0 (5.2)
Enterodiol 63.7 54.8 (3.3) 86.5 (2.8)
Genistei 50.1 60.4 (5.4) 94.3 (4.7)
Equol 10.5 10.9 (4.1) 17.0 (3.5)
O-DMA 5.7 5.7 (9.3) 8.9 (8.6)
Phthalates
MECPP (b) 53.2 50.3 (3.1) 78.5 (2.5)
MEHHP (b) 25.9 28.0 (3.4) 43.5 (2.7)
MEOHP (b) 17.8 18.8 (3.3) 29.3 (2.6)
MEHP (b) 3.2 3.3 (3.0) 5.2 (2.7)
MEP 83.2 75.7 (3.9) 118.0 (3.1)
MBP 37.4 28.2 (3.4) 44.1 (2.4)
MBZP 22.2 18.4 (4.0) 28.7 (2.8)
MIBP 7.7 7.1 (3.6) 11.1 (2.5)
MCPP 6.3 6.1 (2.9) 9.5 (2.1)
MMP < LOD < LOD < LOD
Phenols
BP3 14.7 19.7 (14.6) 30.8 (15.5)
Triclosan 7.2 10.9 (6.5) 17.1 (5.5)
25DCP 7.1 9.0 (11.9) 14.0 (9.9)
BPA 1.8 2.0 (3.2) 3.0 (3.0)
24DCP 0.9 0.9 (5.3) 1.4 (4.3)
246TCP < LOD < LOD < LOD
245TCP < LOD < LOD < LOD
4-t-OP < LOD < LOD < LOD
o-PP < LOD < LOD < LOD
Creatinine 76.2
(mg/dL)
NHANES 50th
Analyte percentile (a) ([micro]g/L]
Phytoestrogens
Enterolactone 329.0
Daidzein 72.7
Enterodiol 35.4
Genistein 31.5
Equol 13.6
O-DMA 5.7
Phthalates
MECPP (b)
MEHHP (b) 32.9
MEOHP (b) 22.6
MEHP (b) 4.4
MEP 71.9
MBP 32.4
MBZP 37.0
MIBP 4.4
MCPP 6.6
MMP 1.8
Phenols
BP3 82.3
Triclosan 12.5
25DCP 3.1
BPA 2.4
24DCP 0.6
246TCP 0.3
245TCP 0.1
4-t-OP 0.5
o-PP 0.4
Creatinine
(mg/dL)
Abbreviations: GSD, geometric standard deviation; [micro]g/gC, the
urinary concentration ([micro]g/L) corrected for creatinine (g/L).
(a) NHANES 50th percentile values for phthalates and phytoestrogens for
6- to 11-year-old children obtained from the Third National Report on
Human Exposure to Environmental Chemicals (CDC 2005); 50th-percentile
values for phenols obtained from Ye et al. (2005a). (b) Derived from
DEHP.
Table 4. Geometric means ([micro]g/g creatinine) of phytoestrogen,
phthalate, and phenol biomarkers (those [greater than or equal to] 60%
LOD) adjusted for age, race, site, BMI, and season, 2004-2005.
Race/ethnicity Site
Asian Black Hispanic White Cincinnati
Total (n = 90) (n = 4) (n = 26) (n = 22) (n = 38) (n = 30)
Phytoestrogens
Enterolactone 174.0 414.0 388.0 287.0 292.0
Daidzein 53.4 166.0 188.0 205.0 154.0
Enterodiol 157.0 58.5 81.5 97.1 113.0
Genistein 52.2 83.7 96.8 111.0 81.8
Equol 12.1 10.7 20.2 17.9 17.9
O-DMA 0.9 12.0 6.6 7.5 7.1
Phthalates
MECPP (a) 119.0 80.7 98.1 69.2 91.5
MEHHP (a) 58.2 55.0 43.3 42.0 48.3
MEOHP (a) 37.3 33.8 29.0 29.0 31.6
MEHP (a) 8.3 7.9 4.5 4.3* 5.9
MEP 66.1 194.0 231.0 73.5* 161.0
MBP 48.2 39.0 50.9 44.4 46.7
MBZP 8.0 24.2 33.2 35.7 24.9
MiBP 15.3 10.1 11.3 11.8 10.4
MCPP 5.5 6.5 9.6 12.0* 9.3
Phenols
BP3 42.2 21.7 14.9 92.7* 14.5
Triclosan 6.7 22.0 16.3 14.3 21.2
25DCP 16.2 28.5 15.6 8.8* 6.7
BPA 2.7 3.1 3.4 2.3 3.2
24DCP 1.5 1.7 1.3 1.2 0.9
Site BMI for age
MSSM Kaiser < 85th reference percentile
Total (n = 90) (n = 30) (n = 30) (n = 61)
Phytoestrogens
Enterolactone 185.0 495.0 513.0
Daidzein 69.8 234.0 115.0
Enterodiol 65.4 107.0 107.0
Genistein 56.3 123.0 68.4
Equol 20.1 8.9 16.7
O-DMA 1.6 10.1* 6.7
Phthalates
MECPP (a) 111.0 71.5 86.6
MEHHP (a) 64.8 37.8 43.0
MEOHP (a) 41.5 25.2 28.8
MEHP (a) 7.2 5.0 5.5
MEP 100.0 111.0 102.0
MBP 49.7 40.3 43.3
MBZP 22.3 18.9 20.4
MiBP 14.6 11.3 10.8
MCPP 7.8 7.2 8.8
Phenols
BP3 25.6 101.0 26.9
Triclosan 14.8 8.0 15.8
25DCP 85.0 7.1* 12.3
BPA 2.6 2.8 3.7
24DCP 3.4 0.9* 1.3
BMI for age Season of sample
[greater than or equal to] 85th collection
reference percentile Summer Other season
Total (n = 90) (n = 29) (n = 39) (n = 51)
Phytoestrogens
Enterolactone 174.0* 236.0 378.0
Daidzein 161.0 97.1 190.0
Enterodiol 79.9 99.9 85.4
Genistein 100.0 55.5 123.0
Equol 12.9 10.7 20.2
O-DMA 3.5 3.5 6.8
Phthalates
MECPP (a) 93.4 100.0 80.9
MEHHP (a) 56.1 53.0 45.5
MEOHP (a) 35.8 33.6 30.6
MEHP (a) 6.5 6.4 5.6
MEP 144.0 140.0 105.0
MBP 47.6 42.1 48.9
MBZP 23.5 21.1 22.7
MiBP 13.3 10.2 14.1
MCPP 7.3 8.5 7.6
Phenols
BP3 41.8 83.8 13.4*
Triclosan 11.7 13.3 13.9
25DCP 20.6 10.9 23.0
BPA 2.2* 2.9 2.8
24DCP 1.6 1.1 1.8
(a) All derived from DEHP. *p-Value < 0.05 for one or more LSMEANS tests
between characteristic levels (for race, significance is not indicated
if it was found only for Asians).
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