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,
From the * Department of Environmental Health
Sciences, University of Michigan, Ann Arbor, Michigan; the
Centers for Disease and Control and
Prevention, Atlanta, Georgia; the Department
of Environmental Health, Harvard School of Public Health, Boston,
Massachusetts; and the Vincent Memorial
Obstetrics and Gynecology Service, Andrology Laboratory and In Vitro
Fertilization Unit, Massachusetts General Hospital, Boston,
Massachusetts.
| Correspondence to: Dr John Meeker, Department of Environmental Health Sciences, University of Michigan School of Public Health, 6635 SPH Tower, 109 S Observatory St, Ann Arbor, MI 48109 (e-mail: meekerj{at}umich.edu). |
| Received for publication July 25, 2008; accepted for publication December 1, 2008. |
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Abstract |
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Key words: Androgen, biomarker, endocrine, environment, human, estrogen, male reproduction, testosterone
Phthalates have a wide range of industrial and commercial uses, resulting in widespread human exposure through various pathways. High-molecular-weight phthalates (eg, di(2-ethylhexyl) phthalate [DEHP], diisononyl phthalate, and di(n-octyl) phthalate) are used primarily as plasticizers in the manufacture of flexible vinyl, which, in turn, is used in consumer products, flooring and wall coverings, food contact applications, and medical devices (David et al, 2001; ATSDR 2002). Low-molecular-weight phthalates (eg, diethyl phthalate [DEP] and dibutyl phthalate [DBP]) can be used in personal-care products (eg, perfumes, lotions, cosmetics), as solvents and plasticizers for cellulose acetate, and in making lacquers, varnishes, and coatings, including those used to provide timed releases in some pharmaceuticals (ATSDR, 1995, 2001; David et al, 2001). The Centers for Disease Control and Prevention's (CDC's) Third National Report on Human Exposure to Environmental Chemicals showed that the majority of males in the United States have detectable concentrations of several phthalate monoesters in urine (monoethyl phthalate [MEP], mono(2-ethylhexyl) phthalate [MEHP], mono-butyl phthalate [MBP], and monobenzyl phthalate [MBzP]), demonstrating that exposure to the parent diester compounds is common among the general population (CDC, 2005). Two oxidized metabolites of DEHP, mono(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP) and mono(2-ethyl-5-oxohexyl) phthalate (MEOHP), were present in most subjects at urinary concentrations higher than those of MEHP, the hydrolytic metabolite of DEHP (CDC, 2005).
Although experimental studies have demonstrated antiandrogenic activity and male reproductive toxicity in relation to several phthalates (Foster, 2006; Ge et al, 2007), only limited human studies have investigated associations between exposure to phthalates and circulating hormone levels. A relationship between phthalates and hormone levels in infants has been reported. Within a Danish/Finnish cohort on cryptorchidism, Main et al (2006) analyzed breast milk samples for phthalate metabolites and measured reproductive serum hormone levels in 3-month-old breastfeeding boys. The authors reported positive associations of MEP, monomethyl phthalate, and MBP with luteinizing hormone (LH):free testosterone ratio, which is a measure of Leydig cell function. There were also positive associations among MEP, MBP, and sex hormone–binding globulin (SHBG) and between monoisononyl phthalate and LH, and an inverse association between MBP and free testosterone. One US study among male infants found inverse associations between urinary MBP, MBzP, MEP, and monoisobutyl phthalate and anogenital distance, which is thought to be a sensitive marker for androgen activity (Swan et al, 2005).
Among a group of adult Chinese workers producing PVC flooring with high exposure to DEHP and DBP, urinary concentrations of metabolites of these phthalates were inversely associated with free testosterone levels (Pan et al, 2006). In a study of 295 men from a Massachusetts infertility clinic, we previously reported a suggestive (though not statistically significant) inverse association between urinary MEHP and testosterone, along with a statistically significant positive association between urinary MBP (a urinary metabolite of DBP) and inhibin B (P < .05), and a statistically significant inverse association between urinary MBzP and follicle-stimulating hormone (FSH) (Duty et al, 2005). However, the significant results for MBP and MBzP and hormone levels were in patterns inconsistent with our study hypotheses. Finally, a study of 234 young Swedish men found an inverse association between urinary MEP (the main DEP metabolite) and LH but no association between MEP, MEHP, or other phthalate metabolites in urine and FSH, testosterone, estradiol, or inhibin B (Jonsson et al, 2005).
The present study extends our previous analysis (Duty et al, 2005) by including a much larger sample size, by expanding the range of hormones measured to include estradiol, prolactin, and testosterone:LH ratio (a measure of Leydig cell function), and by expanding the phthalate metabolites that were measured by also including 2 oxidized DEHP metabolites: MEHHP and MEOHP.
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Materials and Methods |
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Phthalate Metabolites in Urine
A single spot urine sample was collected from each subject on the day of
their clinic visit in a sterile specimen cup prescreened for phthalate
metabolites. Phthalate metabolites were measured in urine because of potential
sample contamination from the parent diester and because the metabolites, as
opposed to the parent diesters, are believed to be the active toxicants
(Li et al, 1998;
Peck and Albro 1982). The
analytical approach for the analysis of the urinary phthalate monoester
metabolites (ie, MEHP, MBP, MBzP, and MEP) and 2 oxidized metabolites of DEHP
(ie, MEHHP and MEOHP) involved enzymatic deconjugation of the metabolites from
their glucuronidated form, solid-phase extraction, separation with
high-performance liquid chromatography, and detection by isotope-dilution
tandem mass spectrometry (Blount et al,
2000; Silva et al,
2003,
2004a). Detection limits were
in the low nanogram per milliliter range and varied slightly depending on the
analytical method used (Blount et al,
2000; Silva et al,
2003,
2004a) for each phthalate
metabolite (MEP, 1.00 to 1.21 ng/ml; MBP, 0.60 to 1.07 ng/ml; MBzP, 0.47 to
1.0 ng/ml; MEHP, 0.87 to 1.20 ng/ml; MEHHP, 0.95 to 1.60 ng/ml; MEOHP, 1.07 to
1.20 ng/ml). Isotopically labeled internal standards and conjugated internal
standards were used to increase precision of measurements. Along with the
unknown samples, each analytical run included calibration standards, reagent
blanks, and quality control materials of high and low concentration to monitor
for accuracy and precision. Analysts at the CDC, Atlanta, Georgia, were blind
to all information concerning subjects. Urinary phthalate metabolite
concentrations were adjusted for urine dilution by specific gravity (SG) using
the following formula: Pc = P[(1.024 – 1)/(SG – 1)],
where Pc is the SG-adjusted phthalate metabolite concentration
(ng/ml), P is the observed phthalate metabolite concentration, and SG is the
SG of the urine sample. SG was measured using a handheld refractometer
(National Instrument Company Inc, Baltimore, Maryland).
We calculated (in nanomoles per milliliter) the sum of DEHP metabolites that were measured (ie, MEHP, MEHHP, and MEOHP). These values were also used to calculate the percentage of these DEHP metabolites excreted as MEHP. We refer to this as MEHP% and consider it a phenotypic marker of the proportion of DEHP metabolized to and excreted in the urine as MEHP (Hauser et al, 2006, 2007; Meeker et al, 2007). The greater the MEHP%, the larger the percentage of DEHP excreted as MEHP relative to the excretion of the 2 oxidized metabolites. To calculate MEHP%, we converted MEHP, MEHHP, and MEOHP concentrations to nanomoles per milliliter, divided MEHP concentrations by the sum of concentrations of MEOHP, MEHHP, and MEHP, and multiplied by 100.
Serum Hormones
One nonfasting blood sample was drawn between the hours of 9 AM
and 4 PM on the same day that the semen sample was collected. Semen
analysis procedures and relationships between semen parameters and phthalate
metabolites were described in a previous report
(Hauser et al, 2006). Blood
samples were centrifuged and the resulting serum was stored at –80°C
until analysis. Testosterone was measured directly using the Coat-A-Count RIA
kit (Diagnostics Products, Los Angeles, California), which has interassay and
intra-assay coefficients of variation (CVs) of 12% and 10%, respectively, with
a sensitivity of 4 ng/dL (0.139 nmol/L). The free androgen index (FAI) was
calculated as the molar ratio of total testosterone to SHBG. SHBG was measured
using a fully automated system (Immulite; DPC Inc, Los Angeles, California)
that uses a solid-phase 2-site chemiluminescent enzyme immunometric assay and
has an interassay CV of less than 8%. Inhibin B was measured using a
commercially available, double antibody, enzyme-linked immunosorbent assay
(Oxford Bioinnovation, Oxford, United Kingdom) with interassay and intra-assay
CVs of 20% and 8%, respectively, limit of detection (LOD) of 15.6 pg/mL and a
functional sensitivity (20% CV) of 50 pg/mL. Serum LH, FSH, estradiol, and
prolactin concentrations were determined by microparticle enzyme immunoassay
using an automated Abbott AxSYM system (Abbott Laboratories, Chicago,
Illinois). The Second International Reference Preparation (WHO 71/223) was
used as the reference standard. The assay sensitivities for LH and FSH were
1.2 IU/L and 1.1 IU/L, respectively. The intra-assay CVs for LH and FSH were
less than 5% and less than 3%, respectively, with interassay CVs for both
hormones of less than 9%. The testosterone:LH ratio, a measure of Leydig cell
function, was calculated by dividing testosterone (nmol/L) by LH (IU/L). The
assay sensitivities for estradiol and prolactin were 20 pg/mL and 0.6 ng/mL,
respectively. For estradiol the within-run CV was between 3% and 11%, and the
total CV was between 5% and 15%. For prolactin the within-run CV was 
3%
and the total CV was 6%.
Statistical Analysis
Data analysis was performed using SAS version 9.1 (SAS Institute Inc, Cary,
North Carolina). Descriptive statistics on subject demographics were
tabulated, along with the distributions of phthalate metabolite concentrations
and reproductive hormones. For phthalate metabolite concentrations or hormone
levels below the LOD, an imputed value equal to one-half the LOD was used. In
preliminary data analysis, hormone and phthalate metabolite concentrations
were stratified by demographic categories to investigate the potential for
confounding. Multivariable linear regression was used to explore relationships
between urinary phthalate metabolite and hormone concentrations.
Concentrations of inhibin B, testosterone, and estradiol closely approximated
normality and were used in statistical models untransformed, whereas the
distributions of FSH, LH, SHBG, FAI, T:LH ratio, and prolactin were skewed
left and transformed by the natural logarithm for statistical analyses.
SG-adjusted phthalate metabolite concentrations were also ln-transformed.
Inclusion of covariates was based on statistical and biologic considerations
(Kleinbaum et al, 1998). Age
and body mass index (BMI) were modeled as a continuous variable, smoking
status was dichotomized by current smoker vs never smoked or former smoker,
and race was categorized into 4 groups: white, African American, Hispanic, and
other. Previous exam for infertility (yes or no), prior ability to impregnate
a partner (yes or no), and timing of blood/urine samples by season (winter vs
spring, summer, or fall) and time of day (9:00 AM–12:59
PM vs 1:00 PM–4:00 PM) were considered
for inclusion in the models as dichotomous variables. To improve
interpretability, the regression coefficients were back transformed and
expressed as a change in the dependent variable (ie, hormone levels) for an
interquartile range (IQR) increase in phthalate metabolite concentrations.
For MEHP, we also included MEHHP, MEOHP, or MEHP% in the models to explore evidence of whether individual differences in DEHP metabolism alter susceptibility to MEHP. We also explored the possibility of effect modification of MEHP-hormone associations by MEHP%. Our hypothesis is that the concentrations of MEHHP (or MEOHP) and/or MEHP% may represent phenotypic markers for efficient or inefficient metabolism of DEHP to its oxidized metabolites (Hauser et al, 2007; Meeker et al, 2007). In secondary sensitivity analyses, the multivariable models were rerun after excluding men with highly concentrated or highly dilute urine samples (SG above 1.03 or below 1.01) (Teass et al, 1998), and rerun among the strata of men with sperm concentration, motility, and morphology all above reference values (Hauser et al, 2006). Finally, we assessed nonlinear relationships between phthalate metabolite concentrations and hormones by regressing the hormones on tertiles or quintiles of phthalate metabolites. We also assessed whether phthalate metabolite tertiles or quintiles predicted low steroid hormone levels, where the odds of being in the lowest quartile for testosterone, estradiol, or FAI were calculated using multiple logistic regression.
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Results |
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FAI and estradiol were both inversely associated with age (Spearman correlation coefficients = –0.2 and –0.1, respectively; both P < .05), but positively associated with BMI (Spearman coefficients = 0.2 and 0.1, respectively; P < .05). BMI was inversely associated with inhibin B, testosterone, and SHBG, but positively associated with MBzP and MEOHP (all P < .05). Current smokers had lower median prolactin levels (9.2 ng/mL) than never smokers (11.7 ng/mL). Current smokers also had higher median concentrations of MEP but lower concentrations of MEHHP and MEOHP compared with never smokers. Median inhibin B was higher in samples collected in the morning compared with samples collected in the afternoon (166 vs 155 pg/mL), but morning samples had lower median estradiol (29 vs 30 pg/mL) and prolactin (9.9 vs 12.7 ng/mL) compared with afternoon samples. As previously observed (Silva et al, 2004b), median MEHP concentration was also higher among men whose urine sample was collected in the afternoon (9.0 ng/mL) vs men providing the urine sample in the morning (6.9 ng/mL). Finally, urine samples collected in the winter had median inhibin B concentrations that were lower than those collected in spring, summer, or fall (143 vs 168 pg/mL), but a median FAI that was slightly higher (0.55 vs 0.52). Samples collected in the winter also had slightly higher concentrations of MEHHP and MEOHP, but also a higher MEHP%, than samples collected in spring, summer, or fall.
All linear regression results in Table 3 were adjusted for age, BMI, smoking, and time of day blood/urine samples were collected. Crude regression results (not shown) were similar to the adjusted results presented in Table 3, though the relationship between MEHP and FAI became somewhat less statistically significant in the adjusted model (P < .05 in the crude model, .1 in the adjusted model). In adjusted models (Table 3), there was an inverse association between SG-adjusted urinary MEHP concentration and serum testosterone levels, where an IQR increase in MEHP was associated with a 14.9 ng/dL decrease in testosterone (95% confidence interval [CI], –27.5 to –2.30 ng/dL; P = .02). For the median level of testosterone (408 ng/dL), this represents a 3.7% (–6.8% to –0.5%) decrease in testosterone for an IQR increase in MEHP (IQR, 3.18 to 20.7 ng/dL). SG-adjusted MEHP was also inversely associated with estradiol, where an IQR increase in MEHP was associated with a 6.8% decline (95% CI, –11.2% to –2.4%) in estradiol relative to the population median estradiol level (30 pg/mL).
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In sensitivity analyses, effect estimates from the multivariable models were similar when only men with SG between 1.01 and 1.03 were included (n = 343, results not shown). The effect estimates were also similar when limiting the analyses to men with above reference ("normal") semen quality measures (data not shown). This provided limited evidence that the relationships between MEHP and reproductive hormones among men with semen parameters above reference values are similar to those among men with below-reference semen parameters. This suggests that the associations reported may be generalizable to men with normal fertility, recognizing, however, that even men with above reference semen parameters may be infertile.
When the analysis was limited to the subset of men with oxidized DEHP metabolite measures (n = 221), there was no evidence of strengthened associations between MEHP and hormone levels when additionally adjusting for MEHHP, MEOHP, or MEHP%, as we previously reported for sperm DNA damage and thyroid hormone levels (Hauser et al, 2007; Meeker et al, 2007). However, both MEHHP and MEOHP were inversely associated with FAI when modeled without MEHP. For both metabolites an IQR increase was associated with a 5% decline in FAI (Table 3). Likewise, the sum of measured DEHP metabolites was associated with a statistically significant 4% decline in FAI. There was also an inverse association between MEHP% and estradiol. Because MEHP% was associated with estradiol but not testosterone, an additional secondary analysis involved exploring associations with the ratio of testosterone to estradiol (T:E2; a measure of aromatase activity). In this analysis MEHP% was positively associated with T:E2 ratio; an IQR increase in MEHP% was associated with a 14% increase in T:E2 (95% CI, 4% to 25%; P = .007). There was also a suggestive positive association between MEHP and T:E2 in the full dataset (n = 425), where an IQR increase in MEHP was associated with a 6% increase in T:E2 (95% CI, –0.4% to 12%; P = .07).
To assess the robustness of the associations between phthalate metabolite concentrations and steroid hormones, and potential nonlinear relationships, we divided SG-adjusted phthalate concentrations into categories. In quintile analysis among the full cohort (n = 425) there were significant but nonmonotonic trends in the associations between MEHP and testosterone and between MEHP and estradiol (Figure 1a and 1b). There was a sharp decline in the regression coefficient for change in testosterone among the highest MEHP quintile, whereas the regression coefficients for declined estradiol among increasing quintiles of MEHP appeared to plateau at quintile 4. The lack of a monotonic trend could perhaps be a result of unequal bin widths stemming from a skewed-right distribution, where the occurrence of exposure misclassification may be more likely in the lower quintiles where cutoff values are closer together. Conversely, there was no trend in FAI in relation to MEHP quintiles (results not shown; P for trend = .33). However, in multiple logistic regression for low FAI, there was a significant increasing trend in the adjusted odds of being in the lowest FAI quartile among increasing MEHP quintiles (P for trend = .01; Figure 2a). When limiting this analysis to the 221 men with oxidized metabolite measures the trend became weaker (P for trend = .13 among MEHP tertiles; tertiles were used instead of quintiles because of the smaller sample size). However, there was evidence of effect modification by MEHP% in this relationship, as an MEHP-FAI trend was present among men with MEHP% above the median but not among men with MEHP% below the median (Figure 2b). The odds ratio for low FAI among men in the highest MEHP tertile and with high MEHP% was 11.2 (95% CI, 1.3 to 97.1). There was no clear evidence of effect modification by MEHP% in the other MEHP-hormone relationships, but the number of men with DEHP oxidized metabolite measures (n = 221), and thus a calculable MEHP%, limited statistical power for detecting interactions. Among the full 425 men there were also increased adjusted odds for low (lowest quartile) testosterone and estradiol among increasing MEHP quintiles (results not shown; P for trend = .04 and .02, respectively).
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Discussion |
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Only a limited number of studies have investigated the relationship between human phthalate exposure and circulating reproductive hormone levels or hormone indicators (Jonsson et al, 2005; Swan et al, 2005; Main et al, 2006; Pan et al, 2006), and only 2 other previous studies have been conducted among men (Jonsson et al, 2005; Pan et al, 2006). Pan et al (2006) studied 74 workers in a Chinese factory exposed to high levels of DEHP and DBP in the production of unfoamed PVC and 64 unexposed workers. The authors reported inverse associations between urinary MBP and MEHP concentrations and free testosterone among the workers, but no relationship between the phthalate metabolites and estradiol. Interestingly, although MEHP concentrations in the present study among non–occupationally exposed men were several orders of magnitude lower than those measured in the Chinese workers with occupational exposure (Pan et al, 2006), the evidence for decreased testosterone in relation to DEHP and/or MEHP was consistent between the 2 studies.
Conversely, the findings in the present study were inconsistent with those reported in the other study of non–occupationally exposed Swedish men by Jonsson and colleagues (2005). In that study no associations between urinary MEHP and testosterone or estradiol were observed. It is possible that the discrepancies in findings between studies may be explained by differences in study design or laboratory methods. For example, there were large differences in the ages of the study populations and the methods of recruitment. The Swedish study population consisted of young men (median age 18 years; range, 18–21 years) undergoing a medical examination before military service. Because approximately 95% of young men in Sweden undergo the conscript examination, these young men reflected the general population of young Swedish males. In contrast, in the present study the median age was 35.5 years, and ages ranged from 22 to 54 years. However, it is unclear whether men presenting to an infertility clinic are more susceptible to exposure to reproductive toxicants than men from the general population or whether older men are more susceptible to reproductive toxicants because of an age-related response. Other differences between the 2 studies include major differences in participation rates (14% in the Swedish study and 65% in the US study) and differences in the analytical methods used to measure urinary phthalate metabolites, where the method in the present study was more sensitive than that used in the Swedish study.
Consistent with our findings, animal and in vitro studies have demonstrated that several phthalates, including DEHP or its metabolites, are endocrine-disrupting chemicals that possess antiandrogenic activity and reduce testosterone and estradiol levels (ATSDR, 2002). The mechanisms by which these alterations are occurring are not fully established. Recent evidence suggests that phthalates may inhibit expression of genes or proteins related to steroidogenesis, such as steroidogenic acute regulated protein, peripheral benzodiazepine receptor, and P450 side chain cleavage in Leydig cells (Borch et al, 2006). However, this and most other studies of DEHP or MEHP antiandrogenic activity that have been conducted to date were performed in rat fetal testis and thus may not reflect what occurs in adult humans. Additional research is needed on reproductive health effects from phthalate exposures in adulthood, and the involvement of alternative mechanisms, such as hepatic SHBG transcription activity and altered pituitary function, should be considered.
We found limited evidence for interaction by MEHP% of the inverse association between MEHP and FAI. In multiple logistic models for having FAI in the lowest quartile, the association was much stronger among men with high MEHP%. This was consistent with our a priori hypothesis that a high percentage of MEHP, a bioactive hydrolytic metabolite of DEHP, in the sum of all measured DEHP metabolites reflects increased susceptibility to DEHP exposure because of less efficient oxidation and excretion of DEHP and/or MEHP. However, we did not find evidence for modification of the other observed associations by MEHP%, though this may be because of the small number of men with oxidized DEHP metabolites measured (n = 221). The possibility of effect modification by MEHP% should be tested in future epidemiological studies with larger sample sizes.
Another secondary finding from the present study was a suggestive positive
association between T:E2 ratio and MEHP, and a strong positive
association between T:E2 ratio and MEHP%. A larger T:E2
ratio is a marker for reduced aromatase activity. Consistent with these
findings, animal and in vitro studies have demonstrated that DEHP and/or MEHP
can suppress aromatase in a human adrenocortical carcinoma cell line, in
cultured rat ovarian granulosa cells, and in the brain and testes of young
male rats (Davis et al, 1994;
Lovekamp and Davis, 2001;
Kim et al, 2003;
Andrade et al, 2006;
Noda et al, 2007). Although
suggested as a potential treatment for certain cases of male infertility
(Liu and Handelsman, 2003;
Schiff et al, 2007), aromatase
suppression could be associated with adverse effects on male reproduction
(Carreau et al, 2006). A
potential alternative explanation for an increased T:E2 ratio in
relation to DEHP and/or its metabolites in the present study could be through
an increase in estradiol metabolism through PPAR
-dependent mechanisms
(Corton et al, 1997).
Recent experimental evidence has suggested that estradiol plays an important role in spermatogenesis and male reproduction, and that estradiol is a potent inhibitor of male germ cell death (Hess et al, 1997; Pentikainen et al, 2000). We also recently reported strong inverse associations between estradiol levels and human sperm DNA damage (Meeker et al, 2008). Thus, it is possible that a decrease in estradiol levels and/or aromatase activity may explain our previous observation of a significant increase in sperm DNA damage associated with increased urinary MEHP when accounting for oxidized DEHP metabolites (Hauser et al, 2007). Alternatively, the significant positive association between MEHP% and T:E2 ratio may reflect relationships between aromatase and enzymes involved in efficient DEHP or MEHP metabolism. Future research is needed to help explain these findings.
A potential limitation of the present study is the measurement of urinary phthalate metabolites and serum hormones at a single point in time. Phthalates are rapidly metabolized and excreted, and metabolite concentrations in urine reflect exposure in only the preceding 1 or 2 days. Several studies have explored temporal variability of urinary phthalate metabolites, where high within-individual variability has been reported over the course of several days to months (Hoppin et al, 2002; Fromme et al, 2007; Teitelbaum et al, 2008). Nevertheless, we demonstrated that a single sample may adequately predict average monoester concentrations over a 3-month period in adult men (Hauser et al, 2004). Serum hormone levels may also vary within an individual over time, but a single measure has been shown to provide a reliable measure in population studies (Bain et al, 1988; Vermeulen and Verdonck, 1992; Schrader et al, 1993; Bjornerem et al, 2006). In addition, requiring multiple blood samples from participants may result in a reduced participation rate and lower statistical power.
Concentrations of (unadjusted) urinary phthalate metabolites measured in the present study were compared with those among US males measured as part of the 2003–2004 National Health and Nutrition Examination Survey (NHANES) (CDC, 2008). Metabolite distributions were generally similar between the present study and the national data, although in the present study concentrations of MEP, MBP, and MBzP were slightly lower, and concentrations of MEHP, MEHHP, and MEOHP were somewhat higher. For example, the median and 95th percentile values for MEHP (unadjusted for SG) in the present study were 6.0 and 112 ng/ml, respectively, compared with 2.2 and 33.3 ng/ml in males from NHANES 2003–2004.
In conclusion, the present study found that urinary DEHP metabolites, at levels that are representative of those found among the general US population, may be associated with altered steroid hormone levels and perhaps aromatase activity. Additional work is needed to confirm these findings and determine clinical implications of subclinical alterations in hormone levels in adult men following exposure to environmental EDCs.
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Acknowledgments |
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Footnotes |
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Disclaimer: The findings and conclusions in this report are those of the authors and do not necessarily represent the views of the CDC.
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