We examined the association between six urinary phthalate metabolites and BMI and WC in data from NHANES 1999–2002. Details of this analysis have been described previously (Hatch, 2008
). Briefly, NHANES interviewed and examined participants to assess behavioral and physical characteristics. As part of a biomonitoring program conducted by the U.S. National Center for Environmental Health, blood and urine were collected on a random sample of one-third of the participants. Methods of laboratory analysis of phthalates are reported elsewhere (Silva, 2004
). We analyzed six metabolites detectable in at least 80% of the study population: MEP, mono-2-ethylhexyl (MEHP), MBP, mono-benzyl (MBzP), MEHHP, and mono-(2-ethyl-5-oxohexyl) phthalate (MEOHP). The latter two are further metabolites of MEHP. After exclusions, a total of 4369 subjects were available for the analyses of MEP, MEHP, MBP, and MBzP, and 2286 subjects for the analyses of MEHHP and MEOHP (measured only during 2001–2002).
We used multivariable linear regression models to examine the association between level of phthalates (categorized into quartiles) and BMI and WC for males and females within age-specific categories. Separate regression models were run for each phthalate. We also created a summary variable to estimate exposure to the four primary metabolites (MEP, MEHP, MBP, and MBzP) simultaneously. The summary score variable was computed by the following method: 1) each individual was ranked according to level of each of the four phthalates (from 1 to 4369), 2) the mean of the 4 ranks was calculated, and 3) the resulting distribution of mean ranks for the study population was divided into quartiles.
We controlled for the following potential confounding variables: age, creatinine, race/ethnicity, height, socioeconomic status, diet (percent of calories from total fat, dairy, fruit and vegetable consumption), physical activity (METS/month and TV/video/computer use), smoking, menopausal status, and parity. Tests for trend were performed by treating phthalate category as a linear predictor in the models.
Associations between phthalate metabolites and the outcomes, BMI and WC, differed markedly by gender. For MBzP, there was a strong positive relationship with BMI and WC among adult males aged 20–59 (adjusted mean BMIs from quartile 1 to 4 were 26.7, 27.2, 28.4, and 29.0 respectively (p-trend=0.0002)), but no discernible trends among females. Similarly, for MBP, the patterns in adult males and females were different, with suggestive positive trends among males for both BMI and WC, but inverse trends among females. While MEHP was inversely related to BMI and WC in adolescent and adult females, there were no major trends between MEHP and either BMI or WC among males. Results for MEHHP and MEOHP were similar (as expected due to their high correlation). There were positive associations between both metabolites and BMI and WC among 20–59 year old males, and no important trends in BMI or WC among adult females; for 60–80 year olds the trends were inverse in both genders. Associations seen with MEP were a bit different than with the other metabolites: a positive relationship between MEP quartile and BMI was apparent for adult males (20–59 and 60–80), and for adolescent and adult females (20–59). For example, among adolescent girls, adjusted mean BMIs increased from 22.9, 23.8, 24.1, to 24.7 (p-trend =0.03) across quartiles of MEP, and adjusted mean WCs were 77.4, 79.7, 80.1, and 81.6 (p-trend=0.02). In general, there were few associations of note among children aged 6 to 11 for any of the metabolites.
Results for WC using the summary score variable are shown in and . For adults aged 20–59 (), the notable difference by gender is again apparent, with a marked positive trend among males (p<0.001) and little evidence of any pattern among females. For older adults (60–80) (), subjects in the highest quartile of the summary score variable had smaller WCs than those in the other three quartiles, and there appeared to be a decreasing trend across quartiles in females. Similar results were found for BMI, not surprisingly because of the high correlation between BMI and WC.
Waist circumference by quartile of combined phthalate score (MEP, MBP, MBzP, MEHP), females and males, aged 20–59
Waist circumference by quartile of combined phthalate score (MEP, MBP, MBzP, MEHP), females and males, aged 60–80
The striking contrast in results between males and females, particularly among 20–59 year olds, is biologically plausible. Several phthalates are anti-androgens, and thus it is possible that effects may differ according to levels of endogenous hormones. As discussed previously, higher androgen levels are associated with smaller WC in males, whereas higher androgen levels in females are associated with higher BMI, greater risk for metabolic syndrome, and conditions such as polycystic ovarian disease (Barber, 2006
). Therefore, women with the highest levels of MEHP (the metabolite with the strongest inverse relationship with BMI and WC among females) may have lower levels of androgens or a higher estrogen/androgen ratio, which could explain the inverse relationship between MEHP and BMI. Our results appear more consistent with an antiandrogenic action of certain phthalates than with action on PPAR-gamma or thyroid hormones, which might be expected to have similar effects in males and females. However, other explanations for the associations may be involved, particularly for MEP. lists three possible biologic mechanisms that may be involved in the association between phthalate metabolites and the occurrence of obesity (for original references see Hatch, 2008
, Table 4).
Biological Effects of Phthalates Potentially Related to Obesity
Our exploratory study found several associations between phthalate metabolites and BMI and WC with magnitudes of potential clinical relevance. This study has a number of strengths, including the opportunity to evaluate results separately by gender, the assessment of multiple potential confounding variables (including physical activity and several aspects of diet), and a broad range of exposure levels in the population. Increased exposure to phthalates via diet is unlikely to be an explanation of our findings. There are numerous limitations. Cross-sectional studies cannot make causal inferences about the direction of the association between phthalates and obesity. Although phthalates are rapidly metabolized and do not accumulate in adipose tissue, heavier individuals may conceivably metabolize phthalates differently than individuals with less body fat. In addition, some exposure to phthalates, especially DEP, occurs through dermal absorption. Thus, heavier individuals are apt to have a greater body surface area, and may absorb more phthalates from use of lotions or other cosmetics. Confounding by unmeasured factors, such as medication use or fasting time before urine sample is a possibility, as is residual confounding. Single spot-urine measurement, used to estimate exposure, may not be a good proxy for long-term exposure, although studies of the consistency of phthalate measurements over time have shown moderate to high sensitivity to classify individuals into the highest tertile of exposure (Hauser, 2004
). We were unable to look at exposure to other EDCs, which may have different effects than single exposures (Kortenkamp, 2007
). We evaluated combinations of phthalates using the simplistic approach of combining rankings for individual phthalates into a single exposure variable, but the correct metric is unknown. We could not evaluate exposures throughout the life course, particularly during prenatal and neonatal development.