Skip to content

Environmental Health Perspectives

Facebook Page EHP Twitter Feed Open Access icon  

Research November 2012 | Volume 120 | Issue 11

Environ Health Perspect; DOI:10.1289/ehp.1104748

Exposures to Endocrine-Disrupting Chemicals and Age of Menarche in Adolescent Girls in NHANES (2003–2008)

Danielle E. Buttke, Kanta Sircar, and Colleen Martin

Author Affiliations open
National Center for Environmental Health, Centers for Disease Control and Prevention, Atlanta, Georgia, USA

PDF icon PDF Version (225 Kb)

  • Background: The observed age of menarche has fallen, which may have important adverse social and health consequences. Increased exposure to endocrine-disrupting compounds (EDCs) has been associated with adverse reproductive outcomes.

    Objective: Our objective was to assess the relationship between EDC exposure and the age of menarche in adolescent girls.

    Methods: We used data from female participants 12–16 years of age who had completed the reproductive health questionnaire and laboratory examination for the Centers for Disease Control and Prevention’s National Health and Nutrition Examination Survey (NHANES) for years 2003–2008 (2005–2008 for analyses of phthalates and parabens). Exposures were assessed based on creatinine-corrected natural log urine concentrations of selected environmental chemicals and metabolites found in at least 75% of samples in our study sample. We used Cox proportional hazards analysis in SAS 9.2 survey procedures to estimate associations after accounting for censored data among participants who had not reached menarche. We evaluated body mass index (BMI; kilograms per meter squared), family income-to-poverty ratio, race/ethnicity, mother’s smoking status during pregnancy, and birth weight as potential confounders.

    Results: The weighted mean age of menarche was 12.0 years of age. Among 440 girls with both reproductive health and laboratory data, after accounting for BMI and race/ethnicity, we found that 2, 5-dichlorophenol (2, 5-DCP) and summed environmental phenols (2, 5-DCP and 2, 4-DCP) were inversely associated with age of menarche [hazard ratios of 1.10; 95% confidence interval (CI): 1.01, 1.19 and 1.09; 95% CI: 1.01, 1.19, respectively]. Other exposures (total parabens, bisphenol A, triclosan, benzophenone-3, total phthalates, and 2, 4-DCP) were not significantly associated with age of menarche.

    Conclusions: Our findings suggest an association between 2, 5-DCP, a potential EDC, and earlier age of menarche in the general U.S. population.

  • Citation: Buttke DE, Sircar K, Martin C. 2012. Exposures to Endocrine-Disrupting Chemicals and Age of Menarche in Adolescent Girls in NHANES (2003–2008). Environ Health Perspect 120:1613–1618;

    Address correspondence to D. Buttke, Epidemic Intelligence Service Officer, National Center for Environmental Health, 4770 Buford Hwy, Mailstop F-57, Chamblee, GA 30341 USA. Telephone: (770) 488-3418. Fax: (770) 488-3450. E-mail:

    This work was supported by the National Center for Environmental Health, Centers for Disease Control and Prevention (CDC).

    The findings and conclusions in this report are those of the author(s) and do not necessarily represent the views of the CDC.

    The authors declare they have no actual or potential competing financial interests.

    Received: 15 November 2011
    Accepted: 13 August 2012
    Advance Publication: 14 August 2012
    Final Publication: 1 November 2012

Over the past century, the average age of menarche has declined worldwide, from 16–17 years to < 13 years of age (Euling et al. 2008). This documented trend toward a younger age of menarche has been observed consistently across socioeconomic and race/ethnicity groups (Lee et al. 2001; Wronka 2010) and cannot be attributed to increased nutritional status alone (Himes et al. 2009; Wang 2002).

An earlier onset of menarche is associated with many adverse health and social outcomes (Zuckerman 2001). Earlier menarche has been associated with increased breast cancer risk (Iwasaki et al. 2007; Maskarinec et al. 2006; Stavraky and Emmons 1974), adult-onset asthma (Al-Sahab et al. 2010; Macsali et al. 2011), shorter adult stature (Carel 2006; Partsch and Sippell 2001), hyperinsulinemia and metabolic syndrome (Frontini et al. 2003), type 2 diabetes (He et al. 2010), and reproductive tract cancers (Dossus et al. 2010; Elwood et al. 1977; Fujita et al. 2008). Furthermore, decreased age of menarche has been associated with behavioral and psychosocial disorders, as well as with increased risk of sexual abuse, depression, and teen pregnancy (Deardorff et al. 2005; Jacobson-Dickman and Lee 2009; Joinson et al. 2011; Phinney et al. 1990).

Scientists have proposed many theories to explain the progressive decline in age of onset of menarche (Zuckerman 2001). No consistent relationship between age of menarche and smoking status, socioeconomic status, family structure, or formula feeding has been seen (Rokade and Mane 2009). Another hypothesis regarding the cause of earlier puberty and menarche is increased environmental exposure to endocrine-disrupting compounds (EDCs) in household and personal care products (Buck Louis et al. 2008; Chen et al. 2011; Ozen et al. 2012; Schell and Gallo 2010). EDCs are synthetic or natural compounds that can mimic, alter, or attenuate the action of natural hormones found in the body.

Several compounds to which the general U.S. population is regularly exposed have been implicated as affecting endocrine function or development. For example, certain benzophenones, dichlorophenols, parabens, and the compound triclosan have been shown to disrupt estrogen receptor signaling in animal and in vitro models either by binding directly to the receptor itself or through modulation of downstream signaling processes (Akahori et al. 2008; Craig et al. 2011; Kawaguchi et al 2009; Shaw and deCatanzaro 2009; Stoker et al. 2010; Vo et al. 2010; Yamasaki et al. 2005). Conversely, compounds such as phthalates and bisphenol A have been shown in human and animal studies to disrupt androgen-dependent processes (Howdeshell et al. 2008; Miao et al 2011; Svechnikov et al. 2010), with bisphenol A implicated in both anti-androgenic and estrogenic responses (Chao et al. 2012). Each of these chemicals is manufactured at high volumes for use in household products such as plastic food containers, personal care products, and household cleaners and deodorizers, allowing potentially high exposures to occur in the general public through daily activities and behaviors.

Our objective was to use the 2003–2008 National Health and Nutrition Examination Survey (NHANES) data to assess the potential association between environmental exposures to synthetic EDCs, as assessed by urinary biomarkers, and age of menarche after adjusting for various demographic and health-related factors. We evaluated chemicals previously identified as potential endocrine disruptors that are found in most of the U.S. population and were measured in NHANES participants during at least 3 consecutive years.


Study population. NHANES is a cross-sectional, multistage, stratified, cluster sampling survey conducted by the Centers for Disease Control and Prevention’s (CDC) National Center for Health Statistics. NHANES uses a complex sampling design that includes questionnaires about demographics and health-related behaviors, as well as laboratory and clinical measurements (CDC 2011). We limited our analysis to participants between 12 and 16 years of age to capture exposures close to the age of menarche among those who completed reproductive heath questionnaires (administered beginning at age 12). Reproductive health questionnaires were administered through a proxy of parent or guardian to females 12 years of age, the lower age limit in our analysis, to 16 years. All procedures were approved by the NCHS Institutional Review Board, and all participants provided written informed consent. During 2003–2004, NHANES sampled urinary phenols and phthalates in two separate one-third subsets, and a single one-third subset was analyzed for phenols, phthalates, and parabens from 2005 through 2008. In each case, subsets were a representative sample of NHANES participants ≥ 6 years of age from each 2-year study cycle. Therefore, data presented for phenols and phthalates are from years 2003–2008, whereas data from parabens are from years 2005–2008 only. Laboratory samples were collected on the same day the questionnaire was administered.

Measurement of urinary phenols, parabens, and phthalates. Phenols and parabens. Environmental phenols considered for inclusion were bisphenol A (BPA), 4-tert-octyl phenol, 2,4,4´-trichloro-2´-hydroxyphenyl ether (triclosan), 2-hydroxy-4-metoxybenzophenone (benzophenone-3). Parabens considered for inclusion were propyl-, butyl-, ethyl-, and methyl-paraben, 2,4-dichlorophenol (2,4-DCP), o-phenyl phenol, 2,5-dichlorophenol (2,5-DCP), 2,4,5-trichlorophenol, and 2,4,6-trichlorophenol (CDC 2011). These substances were quantified in urine by use of solid phase extraction (SPE) coupled on-line to high performance liquid chromatography–tandem mass spectrometry (HPLC-MS/MS) (Ye et al. 2005, 2006). In addition we evaluated the phenol metabolites 2,4-DCP, o-phenyl phenol, 2,5-DCP, 2,4,5-trichlorophenol, and 2,4,6-trichlorophenol, which were measured in urine by use of SPE-HPLC followed by atmospheric pressure chemical ionization–high-performance liquid chromatography–isotope dilution tandem mass spectrometry (APCI-MS/MS) (Ye et al. 2005).

Phthalate metabolites. We used HPLC-MS/MS with electrospray ionization to quantify the following phthalate metabolites in urine: monomethyl phthalate, monoethyl phthalate, monobutyl phthalate, mono-isobutyl phthalate, mono(3-carboxypropyl) phthalate, monocyclohexyl phthalate, mono(2-ethylhexyl) phthalate, monooctyl phthalate, monobenzyl phthalate, monoisononyl phthalate, mono(2-ethyl-5-oxohexyl) phthalate, mono(2-ethyl-5-hydroxyhexyl) phthalate, mono(2-ethyl-5-carboxypentyl) phthalate, monocarboxyoctyl phthalate, and monocarboxynonyl phthalate (CDC 2011).Before analysis by HPLC-MS/MS, the urine samples were processed through use of enzymatic deconjugation of the glucuronidated phthalate monoesters, followed by on-line SPE (Kato et al. 2005; Silva et al. 2007).

Data analysis. We included female 2003–2008 NHANES study participants 12–16 years of age who had completed the reproductive health questionnaire and physical examination, and for whom data regarding age of menarche, defined by NHANES as age of first menstruation, were available. Of the 1,598 individuals 12–16 years of age who had completed the reproductive health questionnaire, 1,420 participants had complete data on body mass index (BMI) and age of menarche (age or not yet reached). Of these, 461 were included in NHANES subsamples with urinary phenol and phthalate measurements. We used the one-third subsample weighting variables for each 2-year subset of data. Nonmissing values for urine concentrations below the limit of detection (LOD) were replaced with the value of the LOD divided by the square root of 2. In our analysis, all urinary compounds and metabolites were creatinine-corrected by dividing urine concentrations by creatinine concentrations to give micrograms per gram of creatinine as the final units. Urine samples with creatinine levels > 300 mg/dL or < 30 mg/dL were excluded because they were too dilute or too concentrated for accurate analysis (n = 11) (Sata et al. 1995).

We used SAS 9.2 for data analysis, and calculated means and percentiles of the EDCs and demographic factors by use of the PROC SURVEYMEANS (weighted geometric means) procedure to account for the complex sampling design of NHANES. We calculated the weighted mean self-reported age of menarche using PROC LIFETEST (Kaplan–Meier censored survival estimates) to account for censoring at the age of participation among 43 individuals who had not reached menarche at the time of participation (all programs from SAS Institute Inc., Cary, NC). We used the Taylor series (linearization) method to estimate standard errors and confidence intervals. We calculated BMI percentile for age in months using the standardized CDC growth charts (Grummer-Strawn et al. 2010). We set significance at α = 0.05 for two-sided p-values.

To estimate associations between EDCs and age of menarche, we used the PROC SURVEYPHREG (Cox-proportional hazards model with censored data) procedure and the efron method of ties handling, after confirming the proportional hazards assumption. We modeled the natural log of creatinine-corrected urine analyte concentrations to normalize distributions in our data and, in accordance with NHANES analytic guidelines, we excluded 10 observations with outlier values > 3 SDs for deviance residuals of the log-transformed weighted values, as determined by a probability plot of residuals (CDC 2011). These adjustments left a sample size of 440 for our phenol analysis, 437 for phthalate analysis, and 287 individuals for parabens analysis.

We assessed the urinary concentration of 18 EDCs found above the LOD in at least 75% of study participants as exposures in our model, out of a total of 27 phthalate, phenol, and pesticide compounds or metabolites evaluated in urine in NHANES. These compounds were then analyzed either as single compounds (benzophenone-3, triclosan, BPA, 2,4-DCP, and 2,5-DCP) or as the sum of urinary analyte concentrations within a class of compounds (parabens, phthalates, and environmental phenols), again including only those compounds found above the LOD in at least 75% of study participants. We converted compounds to molar weights for summing to adjust for the different molecular weights of compounds and used micrograms per gram of creatinine as the unit in our models. We identified potential confounders from the literature (mother’s age at birth of girl, mother’s smoking status during pregnancy, birth weight < 5.5 pounds (yes or no), birth weight > 9.0 pounds (yes or no), family income (1–12 categories based on NHANES categories of $0–4,999 to ≥ $75,000), family income-to-poverty ratio (0–5), self-defined race/ethnicity, BMI (continuous) as calculated by measurements taken during the NHANES examination, and BMI percentile for sex and age in months (0–100) as calculated using CDC standardized growth charts) (Grummer-Strawn et al. 2010) and included them in our final models if they either predicted the outcome with p < 0.05 or there was a > 10% change in the hazard ratio for the exposure–menarche association when they were removed from the model. Insufficient observations existed for birth weight to include in model building. Backward and forward selection resulted in the same final model.

We evaluated BMI and race/ethnicity as effect modifiers by evaluating stratum-specific hazard ratios because differences in age of menarche among ethnicities are well established (Himes et al. 2009). Interactions between race/ethnicity and urinary phenol concentrations were evaluated using interaction terms in the model, with p < 0.10 for the interaction term used to evaluate significance of the interaction.


Most participants included in our analysis (63.1%) were of non-Hispanic white ethnicity (Table 1). Of the 342 with complete information on mother’s smoking status, 13.9% had mothers who smoked during pregnancy. The mean family income-to-poverty ratio was 2.6 [95% confidence interval (CI): 2.4, 2.7], the mean mother’s age at the participant’s birth was 26.8 years (95% CI: 26.3, 27.3), the mean BMI was 22.8 (95% CI: 22.2, 23.4), and the average age of menarche was 12.0 years (95% CI: 11.8, 12.1). Age of menarche ranged from 8 to 16 years, with 43 individuals not having attained menarche by the time of survey.

Table 1Table 1 – Descriptive statistics for age at menarche and selected covariates among girls 12–16 years of age in NHANES 2003–2008.

View larger image (TIF File)

Mean BMI was higher among non-Hispanic black girls than among non-Hispanic white girls and girls of other, multiracial ethnicities (Table 2). The mean age of menarche was significantly lower among non-Hispanic black adolescent girls than among non-Hispanic white adolescent girls.

Table 2Table 2 – Weighted mean BMI and self-reported age of menarche by race/ethnicity among girls 12–16  years of age in NHANES 2003–2008 (n  =  440).

View larger image (TIF File)

Three phenols, BPA, benzophenone-3, and triclosan, were each above the LOD in at least 75% of study participants and were evaluated as single compounds in our analysis. The parabens propyl paraben and methyl paraben were above the LOD in at least 75% of study participants and were summed as total parabens for analysis. The phthalate metabolites monoethyl phthalate, monobutyl phthalate, mono-isobutyl phthalate, mono(3-carboxypropyl) phthalate, mono(2-ethylhexyl) phthalate, monobenzyl phthalate, mono(2-ethyl-5-oxohexyl) phthalate, mono(2-ethyl-5-hydroxyhexyl) phthalate, mono(2-ethyl-5-carboxypentyl) phthalate, monocarboxyoctyl phthalate, and monocarboxynonyl phthalate were above the LOD in at least 75% of study participants and were summed as total phthalates for analysis. The phenol metabolites 2, 4-DCP and 2, 5-DCP were above the LOD in 99.8% and 91.8% of study participants, respectively, and were evaluated both as separate compounds and summed as total phenol metabolites. Geometric means and 95% CIs of urinary creatinine-adjusted EDC levels are reported in Table 3.

Table 3Table 3 – Estimated creatinine-corrected weighted geometric means (µg/g creatinine) of selected EDCs and EDC metabolites among girls 12–16 years of age in NHANES 2003–2008 by race/ethnicity.

View larger image (TIF File)

Consistent with observations from the complete NHANES data set, the mean environmental phenol concentration differed by race/ethnicity, with non-Hispanic white girls (n = 124; mean = 7.07 µg/g; 95% CI: 5.53, 9.03) having statistically significantly lower environmental phenol concentrations than non-Hispanic black (n = 136, mean = 26.8 µg/L; 95% CI: 17.0, 42.0) on the basis of nonoverlapping CIs (Table 3). Concentrations of other compounds did not differ significantly by race/ethnicity (data not shown).

Family income-to-poverty ratio, mother’s age at the participant’s birth, and the mother’s smoking status during pregnancy were not retained in our model because they were not significant predictors of menarche.

Total parabens, BPA, triclosan, benzophenone-3, and total phthalates were not significantly associated with age of menarche, either before or after adjustment for BMI and race/ethnicity (Table 4). However, a 1-unit increase in log-transformed creatinine-corrected urine phenol concentration was associated with a 0.7-month decrease in average age of menarche (adjusted hazard ratio = 1.10; 95% CI: 1.02, 1.20; p = 0.01). 2, 5-DCP was the only individual compound that was significantly associated with age of menarche (adjusted hazard ratio = 1.10; 95% CI: 1.01, 1.19; p = 0.025). The association (hazard ratios) between urinary 2, 5-DCP or total environmental phenol concentration and age of menarche did not differ by race/ethnicity (data not shown).

Table 4Table 4 – Weighted survival analysis model estimates and parameters of time of menarche and log creatinine-corrected urinary concentrations (µg/g creatinine) of potential EDCs among girls 12–16 years of age in NHANES 2003–2008 participating in the reproductive health questionnaire and environmental phenol laboratory analysis.

View larger image (TIF File)

When we considered the total environmental phenol concentration for adolescent girls above the 75th percentile, the average age of menarche was 11.8 years (95% CI: 11.6, 12.0). In comparison, the average age of menarche for adolescent girls below the 25th percentile of total environmental phenol urine concentration was 12.4 years (95% CI: 12.2, 12.6) (Table 5).

Table 5Table 5 – Weighted mean self-reported age of menarche by percentile of creatinine-corrected urinary environmental phenol concentration in girls 12–16 years of age in NHANES 2003–2008 (n  =  440).

View larger image (TIF File)


Levels of urinary EDCs in our study population were comparable to levels reported in the 6–11 and 12–19 years age groups in the overall 2005–2008 NHANES population (CDC 2011).

A significant, inverse relationship was seen between age of menarche and urinary environmental phenols and 2,5-DCP. Girls with urinary environmental phenol concentrations above the 75th percentile had a significantly lower age of menarche than girls below the 75th percentile. No other significant associations were seen between urinary EDC biomarkers and age of menarche. The difference in age of menarche between those in the highest percentile of exposure and those in the lowest percentile of exposure was small and may not be clinically significant, but if the association was causal it suggests a physiologic effect.

We found an association between 2,5-DCP, as assessed by urinary biomarkers, and age of menarche in a representative sample of the U.S. population. Another cross-sectional study reported an association between serum PBDEs (polybrominated diphenyl ethers) and age of menarche in adolescent girls (Chen et al. 2011). Three cohort studies have examined relationships between EDC biomarkers and early menarche. A study of 151 women living in the Great Lakes region of the United States reported an association between in utero exposure to the DDT (dichlorodiphenyltrichloroethane) metabolite DDE (dichlorodiphenyldichloroethylene) and early menarche (Vasiliu et al. 2004). Among a cohort of Michigan women exposed to polybrominated biphenyl (PBB) flame retardants from contaminated dairy and beef there was an association between in utero PBB exposure and early menarche among their female children (Blanck et al. 2000). In a retrospective study, serum DDT levels were associated with early puberty in a retrospective cohort study of children in Belgium, but the association was limited to 145 children who were born outside of Belgium, and confounding by factors related to place of birth or related factors could not be ruled out (Krstevska-Konstantinova et al. 2001). Blood lead levels have been associated with delayed puberty in boys and girls (Hauser et al. 2008; Selevan et al. 2003), and exposures to dioxins have been associated with delayed puberty in boys (Korrick et al. 2011).

2,5-DCP is the major metabolite of dichlorobenzene (DCB), a common fumigant also used in mothballs, insect repellants, deodorizers, and toilet bowl disinfectants. 2,5-DCP can be used to estimate exposure to the putative endocrine disruptor DCB in the previous 6–12 months, which is particularly important when interpreting an end point such as age of menarche that is dependent on earlier changes in the neuroendocrine axis of the brain (Teitelbaum et al. 2008). DCB is found in drinking water at concentrations up to 1 mg/L and in food at levels up to 10 mg/kg (Barber et al. 2009). The U.S. population was exposed to a nearly constant level of 25 µg/m3 DCB in indoor air, according to a longitudinal study of homes in 1987 (Wallace 1991a, 1991b; Wallace and Pellizzari 1995), and, although air concentrations may have declined since these studies, DCB was still readily detected in amniotic fluid (Bradman et al. 2003) and human breast milk at concentrations of 5–30 mg/kg nearly 20 years after the indoor air study (Ye et al. 2006).

Like benzophenones, phenols, and parabens, DCB has been reported to have both in vitro EDC activity and EDC effects in laboratory animals [Darbre and Harvey 2008; Fang et al. 2000; Hershberger et al. 2005; Makita 2008; Marsman 1995; Molina-Molina et al. 2008; National Toxicology Program (NTP) 2008; Takahashi et al. 2011; Versonnen et al. 2003]. The levels of DCB at which EDC activity was evident were consistent with levels observed for human daily exposures as well as at higher levels of exposure. DCB has been associated with low birth weight and low maternal weight gain in rats (Marsman 1995) and sperm abnormalities in male mice and rats (Takahashi et al. 2011). In a study of 404 pregnant women, urinary levels of 2,5-DCP during the third trimester of pregnancy were associated with low birth weight and length in male humans (Wolff et al. 2008). DCB is hepatotoxic and hepatocarcinogenic to rats and mice (NTP 1987, 2002), and it reduces plasma levels of thyroxine in rats (den Besten et al. 1991). DCB is currently undergoing tier 1 testing for endocrine-disrupting potential by the U.S. Environmental Protection Agency (2010).

The present study has several limitations. First, questionnaire data are self-reported and may be subject to misclassification. Second, we cannot rule out potential confounding by unmeasured factors associated with DCB exposure and the timing of puberty and menarche. In addition, exposures were measured at a single point in time after the onset of menarche in all but 43 participants; ideally, we would measure urinary EDCs several times during the 6–36 months before menarche, and adjust for BMI before menarche only. Age of menarche was recorded as age in years at first menstrual period. This limitation is further complicated by the half-life of these compounds. Although the U.S. population is continuously exposed to compounds such as BPA, dichlorophenols, and certain phthalates, resulting in relatively constant levels of these compounds in serum and urine (CDC 2011), the relatively short half-lives of these compounds limits our ability to predict exposures before menarche using a single urine sample. Differences in urine 2,5-DCP concentrations also may reflect differences in metabolism, rather than direct differences in individual exposures. Finally, we cannot rule out chance findings due to multiple comparisons, and it is possible that the association between 2,5-DCP and decreased age of menarche could reflect changes in personal habits, pharmacokinetics, or metabolism after menarche.


We estimated an inverse association between urinary 2,5-DCP concentration and age of menarche in girls 12–16 years of age who participated in the NHANES study during 2003–2008. To our knowledge, ours is the first population-based study to report an association between exposure to the putative environmental EDC dichlorobenzene and age of menarche, an outcome that may reflect endocrine-disrupting effects. Although this finding must be interpreted with caution given study limitations, it highlights the need for more research into the potential role of environmental exposures to potential EDCs and adverse endocrine and reproductive health outcomes in humans.


Akahori Y, Nakai M, Yamasaki K, Takatsuki M, Shimohigashi Y, Ohtaki M. 2008. Relationship between the results of in vitro receptor binding assay to human estrogen receptor alpha and in vivo uterotrophic assay: comparative study with 65 selected chemicals. Toxicol In Vitro (1):225–231.

Al-Sahab B, Hamadeh MJ, Ardern CI, Tamim H. 2010. Early menarche predicts incidence of asthma in early adulthood. Am J Epidemiol 173(1):64–70.

Barber LB, Keefe SH, Leblanc DR, Bradley PM, Chapelle FH, Meyer MT, et al. 2009. Fate of sulfamethoxazole, 4-nonylphenol, and 17β-estradiol in groundwater contaminated by wastewater treatment plant effluent. Environ Sci Technol 43(13):4843–4850.

Blanck HM, Marcus M, Tolbert PE, Rubin C, Henderson AK, Hertzberg VS, et al. 2000. Age at menarche and Tanner stage in girls exposed in utero and postnatally to polybrominated biphenyl. Epidemiology 11(6):641–647.

Bradman A, Barr DB, Claus Henn BG, Drumheller T, Drumheller T, Curry C, et al. 2003. Measurement of pesticides and other toxicants in amniotic fluid as a potential biomarker of prenatal exposure: a validation study. Environ Health Perspect 111:1779–1782.

Buck Louis GM, Gray LE Jr, Marcus M, Ojeda SR, Pescovitz OH, Witchel SF, et al. 2008. Environmental factors and puberty timing: expert panel research needs. Pediatrics 121(suppl 3):S192–S207.

Carel JC. 2006. Management of short stature with GnRH agonist and co-treatment with growth hormone: a controversial issue. Mol Cell Endocrinol 254–255:226–233.

CDC (Centers for Disease Control and Prevention). 2011. Fourth National Report on Human Exposure to Environmental Chemicals 2009 and the Updated Tables, February 2011. Available: [accessed 6 May 2011].

Chao HH, Zhang XF, Chen B, Pan B, Zhang LJ, Li L, et al. 2012. Bisphenol A exposure modifies methylation of imprinted genes in mouse oocytes via the estrogen receptor signaling pathway. Histochem Cell Biol 137(2):249–259.

Chen A, Chung E, DeFranco EA, Pinney SM, Dietrich KN. 2011. Serum PBDEs and age at menarche in adolescent girls: analysis of the National Health and Nutrition Examination Survey 2003–2004. Environ Res 111(6):831–837.

Craig ZR, Wang W, Flaws JA. 2011. Endocrine-disrupting chemicals in ovarian function: effects on steroidogenesis, metabolism and nuclear receptor signaling. Reproduction 142(5):633–646.

Darbre PD, Harvey PW. 2008. Paraben esters: review of recent studies of endocrine toxicity, absorption, esterase and human exposure, and discussion of potential human health risks. J Appl Toxicol 28(5):561–578.

Deardorff J, Gonzales NA, Christopher FS, Roosa MW, Millsap RE. 2005. Early puberty and adolescent pregnancy: the influence of alcohol use. Pediatrics 116(6):1451–1456.

den Besten C, Vet JJ, Besselink HT, Kiel GS, van Berkel BJ, Beems R, et al. 1991. The liver, kidney, and thyroid toxicity of chlorinated benzenes. Toxicol Appl Pharmacol 111(1):69–81.

Dossus L, Allen N, Kaaks R, Bakken K, Lund E, Tjonneland A, et al. 2010. Reproductive risk factors and endometrial cancer: the European Prospective Investigation into Cancer and Nutrition. Int J Cancer 127(2):442–451.

Elwood JM, Cole P, Rothman KJ, Kaplan SD. 1977. Epidemiology of endometrial cancer. J Natl Cancer Inst 59(4):1055–1060.

Euling SY, Selevan SG, Pescovitz OH, Skakkebaek NE. 2008. Role of environmental factors in the timing of puberty. Pediatrics 121(suppl 3):S167–S171.

Fang H, Tong W, Perkins R, Soto AM, Prechtl NV, Sheehan DM. 2000. Quantitative comparisons of in vitro assays for estrogenic activities. Environ Health Perspect 108:723–729.

Frontini MG, Srinivasan SR, Berenson GS. 2003. Longitudinal changes in risk variables underlying metabolic Syndrome X from childhood to young adulthood in female subjects with a history of early menarche: the Bogalusa Heart Study. Int J Obes Relat Metab Disord 27(11):1398–1404.

Fujita M, Tase T, Kakugawa Y, Hoshi S, Nishino Y, Nagase S, et al. 2008. Smoking, earlier menarche and low parity as independent risk factors for gynecologic cancers in Japanese: a case-control study. Tohoku J Exp Med 216(4):297–307.

Grummer-Strawn LM, Reinold C, Krebs NF. 2010. Use of World Health Organization and CDC growth charts for children aged 0–59 months in the United States. Morb Mortal Wkly Rep MMWR 59(rr09):1–15.

Hauser R, Sergeyev O, Korrick S, Lee MM, Revich B, Gitin E, et al. 2008. Association of blood lead levels with onset of puberty in Russian boys. Environ Health Perspect 116:976–980.

He C, Zhang C, Hunter DJ, Hankinson SE, Buck Louis GM, Hediger ML, et al. 2010. Age at menarche and risk of type 2 diabetes: results from 2 large prospective cohort studies. Am J Epidemiol 171(3):334–344.

Hershberger PA, Vasquez AC, Kanterewicz B, Land S, Siegfried JM, Nichols M. 2005. Regulation of endogenous gene expression in human non-small cell lung cancer cells by estrogen receptor ligands. Cancer Res 65(4):1598–1605.

Himes JH, Park K, Styne D. 2009. Menarche and assessment of body mass index in adolescent girls. J Pediatr 155(3):393–397.

Howdeshell KL, Rider CV, Wilson VS, Gray LE Jr. 2008. Mechanisms of action of phthalate esters, individually and in combination, to induce abnormal reproductive development in male laboratory rats. Environ Res 108(2):168–176.

Iwasaki M, Otani T, Inoue M, Sasazuki S, Tsugane S. 2007. Role and impact of menstrual and reproductive factors on breast cancer risk in Japan. Eur J Cancer Prev 16(2):116–123.

Jacobson-Dickman E, Lee MM. 2009. The influence of endocrine disruptors on pubertal timing. Curr Opin Endocrinol Diabetes Obes 16(1):25–30.

Joinson C, Heron J, Lewis G, Croudace T, Araya R. 2011. Timing of menarche and depressive symptoms in adolescent girls from a UK cohort. Br J Psychiatry 198(1):17–23, sup 1–2.

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(9):2985–2991.

Kawaguchi M, Morohoshi K, Masuda J, Watanabe G, Morita M, Imai H, et al. 2009. Maternal isobutyl-paraben exposure decreases the plasma corticosterone level in dams and sensitivity to estrogen in female offspring rats. J Vet Med Sci 71(8):1027–1033.

Korrick SA, Lee MM, Williams PL, Sergeyev O, Burns JS, Patterson DG, et al. 2011. Dioxin exposure and age of pubertal onset among Russian boys. Environ Health Perspect 119:1339–1344.

Krstevska-Konstantinova M, Charlier C, Craen M, Du Caju M, Heinrichs C, de Beaufort C, et al. 2001. Sexual precocity after immigration from developing countries to Belgium: evidence of previous exposure to organochlorine pesticides. Hum Reprod 16(5):1020–1026.

Lee PA, Guo SS, Kulin HE. 2001. Age of puberty: data from the United States of America. APMIS 109(2):81–88.

Macsali F, Real FG, Plana E, Sunyer J, Anto J, Dratva J, et al. 2011. Early age of menarche, lung function and adult asthma. Am J Respir Crit Care Med 183(1):8–14.

Makita Y. 2008. Effects of perinatal, combined exposure to 1, 4-dichlorobenzene and 1, 1-dichloro-2, 2-bis(p-chlorophenyl)ethylene on rat female reproductive system. Basic Clin Pharmacol Toxicol 102(4):360–364.

Marsman D. 1995. NTP Technical Report on the Toxicity Studies of Dibutyl Phthalate (Cas No. 84-74-2) Administered in Feed to F344/N Rats and B6C3F1 Mice. Toxicity Report Series 30: Available: [accessed 1 October 2012].

Maskarinec G, Zhang Y, Takata Y, Pagano I, Shumay DM, Goodman MT, et al. 2006. Trends of breast cancer incidence and risk factor prevalence over 25 years. Breast Cancer Res Treat 98(1):45–55.

Miao M, Yuan W, He Y, Zhou Z, Wang J, Gao E, et al. 2011. In utero exposure to bisphenol-A and anogenital distance of male offspring. Birth Defects Res A Clin Mol Teratol 91(10):867–872.

Molina-Molina JM, Escande A, Pillon A, Gomez E, Pakdel F, Cavailles V, et al. 2008. Profiling of benzophenone derivatives using fish and human estrogen receptor-specific in vitro bioassays. Toxicol Appl Pharmacol 232(3):384–395.

NTP (National Toxicology Program). 1987. Toxicology and Carcinogenesis Studies of 1,4-Dichlorobenzene (CAS No. 106-46-7) in F344/N Rats and B6C3F1 Mice (Gavage Studies). Technical Report Series 319. Available: [accessed 1 October 2012].

NTP (National Toxicology Program). 2002. 1,4-Dichlorobenzene. Rep Carcinog 10:84–85.

NTP (National Toxicology Program). 2008. Final amended report on the safety assessment of methylparaben, ethylparaben, propylparaben, isopropylparaben, butylparaben, isobutylparaben, and benzylparaben as used in cosmetic products. Int J Toxicol 27(suppl 4):1–82.

Ozen S, Darcan S, Bayindir P, Karasulu E, Simsek DG, Gurler T. 2012. Effects of pesticides used in agriculture on the development of precocious puberty. Environ Monit Assess 184(7):4223–4232.

Partsch CJ, Sippell WG. 2001. Pathogenesis and epidemiology of precocious puberty. Effects of exogenous oestrogens. Hum Reprod Update 7(3):292–302.

Phinney VG, Jensen LC, Olsen JA, Cundick B. 1990. The relationship between early development and psychosexual behaviors in adolescent females. Adolescence 25(98):321–332.

Rokade SA, Mane AK. 2009. A study of age at menarche, the secular trend and factors associated with it. Internet J Biol Anthropol 3(2). Available: [accessed 10 October 2010].

Sata F, Araki S, Yokoyama K, Murata K. 1995. Adjustment of creatinine-adjusted values in urine to urinary flow rate: a study of eleven heavy metals and organic substances. Int Arch Occup Environ Health 68(1):64–68.

Schell LM, Gallo MV. 2010. Relationships of putative endocrine disruptors to human sexual maturation and thyroid activity in youth. Physiol Behav 99(2):246–253.

Selevan SG, Rice DC, Hogan KA, Euling SY, Pfahles-Hutchens A, Bethel J. 2003. Blood lead concentration and delayed puberty in girls. N Engl J Med 348(16):1527–1536.

Shaw J, deCatanzaro D. 2009. Estrogenicity of parabens revisited: impact of parabens on early pregnancy and an uterotrophic assay in mice. Reprod Toxicol 28(1):26–31.

Silva MJ, Samandar E, Preau JL Jr, Reidy JA, Needham LL, Calafat AM. 2007. Quantification of 22 phthalate metabolites in human urine. J Chromatogr B Analyt Technol Biomed Life Sci 860(1):106–112.

Stavraky K, Emmons S. 1974. Breast cancer in premenopausal and postmenopausal women. J Natl Cancer Inst 53(3):647–654.

Stoker TE, Gibson EK, Zorrilla LM. 2010. Triclosan exposure modulates estrogen-dependent responses in the female Wistar rat. Toxicol Sci 117(1):45–53.

Svechnikov K, Izzo G, Landreh L, Weisser J, Söder O. 2010. Endocrine disruptors and Leydig cell function. J Biomed Biotechnol; doi:10.1155/2010/684504 [Online 23 June 2010].

Takahashi O, Ohashi N, Nakae D, Ogata A. 2011. Parenteral paradichlorobenzene exposure reduces sperm production, alters sperm morphology and exhibits an androgenic effect in rats and mice. Food and Chemical Toxicology 49(1):49–56.

Teitelbaum SL, Britton JA, Calafat AM, Ye X, Silva MJ, Reidy JA, et al. 2008. Temporal variability in urinary concentrations of phthalate metabolites, phytoestrogens and phenols among minority children in the United States. Environ Res 106(2):257–269.

U.S. Environmental Protection Agency. 2010. Endocrine disruptor screening program; second list of chemicals for tier 1 screening. Fed Reg 75(221):70248–70254.

Vasiliu O, Muttineni J, Karmaus W. 2004. In utero exposure to organochlorines and age at menarche. Hum Reprod 19(7):1506–1512.

Versonnen BJ, Arijs K, Verslycke T, Lema W, Janssen CR. 2003. in vitro and in vivo estrogenicity and toxicity of o-, m-, and p-dichlorobenzene. Environ Toxicol Chem 22(2):329–335.

Vo TT, Yoo YM, Choi KC, Jeung EB. 2010. Potential estrogenic effect(s) of parabens at the prepubertal stage of a postnatal female rat model. Reprod Toxicol 29(3):306–316.

Wallace LA. 1991a. Comparison of risks from outdoor and indoor exposure to toxic chemicals. Environ Health Perspect 95:7–13.

Wallace LA. 1991b. Personal exposure to 25 volatile organic compounds. EPA’s 1987 team study in Los Angeles, California. Toxicol Ind Health 7(5–6):203–208.

Wallace LA, Pellizzari ED. 1995. Recent advances in measuring exhaled breath and estimating exposure and body burden for volatile organic compounds (VOCs). Environ Health Perspect 103(suppl 3):95–98.

Wang Y. 2002. Is obesity associated with early sexual maturation? A comparison of the association in American boys versus girls. Pediatrics 110(5):903–910.

Wolff MS, Britton JA, Boguski L, Hochman S, Maloney N, Serra N, et al. 2008. Environmental exposures and puberty in inner-city girls. Environ Res 107(3):393–400.

Wronka I. 2010. Association between BMI and age at menarche in girls from different socio-economic groups. Anthropol Anz 68(1):43–52.

Yamasaki K, Takahashi M, Yasuda M. 2005. Two-generation reproductive toxicity studies in rats with extra parameters for detecting endocrine disrupting activity: introductory overview of results for nine chemicals. J Toxicol Sci 30(spec no):1–4.

Ye X, Kuklenyik Z, Needham LL, Calafat AM. 2005. Automated on-line column-switching HPLC-MS/MS method with peak focusing for the determination of nine environmental phenols in urine. Anal Chem 77(16):5407–5413.

Ye X, Kuklenyik Z, Needham LL, Calafat AM. 2006. Measuring environmental phenols and chlorinated organic chemicals in breast milk using automated on-line column-switching-high performance liquid chromatography-isotope dilution tandem mass spectrometry. J Chromatogr B 831(1–2):110–115.

Zuckerman D. 2001. When Little Girls Become Women: Early Onset of Puberty in Girls. The Ribbon 6. Available: [accessed 1 October 2012].

WP-Backgrounds Lite by InoPlugs Web Design and Juwelier Schönmann 1010 Wien