Research Association of Exposure to Phthalates with Endometriosis and Uterine Leiomyomata: Findings from NHANES, 1999–2004 Jennifer Weuve,1,2 Russ Hauser,2,3 Antonia M. Calafat,4 Stacey A. Missmer,5,6,7 and Lauren A. Wise 8 1Rush Institute for Healthy Aging, Rush University Medical Center, Chicago, Illinois, USA; 2Department of Environmental Health, Harvard School of Public Health, Boston, Massachusetts, USA; 3Vincent Memorial Obstetrics and Gynecology Service, Andrology Laboratory and In Vitro Fertilization Unit, Massachusetts General Hospital, Boston, Massachusetts, USA; 4Centers for Disease Control and Prevention, Atlanta, Georgia, USA; 5Department of Obstetrics, Gynecology, and Reproductive Medicine, and 6Channing Laboratory, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA; 7Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA; 8Slone Epidemiology Center, Boston University, Boston, Massachusetts, USA Background : Phthalates are ubiquitous chemicals used in consumer products. Some phthalates are reproductive toxicants in experimental animals, but human data are limited. o Bjectiv : We conducted a cross-sectional study of urinary phthalate metabolite concentrations in relation to self-reported history of endometriosis and uterine leiomyomata among 1,227 women 20–54 years of age from three cycles of the National Health and Nutrition Examination Survey (NHANES), 1999–2004. Methods : We examined four phthalate metabolites: mono(2-ethylhexyl) phthalate (MEHP), monobutyl phthalate (MBP), monoethyl phthalate (MEP), and monobenzyl phthalate (MBzP). From the last two NHANES cycles, we also examined mono(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP) and mono(2-ethyl-5-oxohexyl) phthalate (MEOHP). We used logistic regression to esti- mate odds ratios (ORs) and 95% confidence intervals (CIs), adjusting for potential confounders. r esult : Eighty-seven (7%) and 151 (12%) women reported diagnoses of endometriosis and leiomyomata, respectively. The ORs comparing the highest versus lowest three quartiles of urinary MBP were 1.36 (95% CI, 0.77–2.41) for endometriosis, 1.56 (95% CI, 0.93–2.61) for leiomyo- mata, and 1.71 (95% CI, 1.07–2.75) for both conditions combined. The corresponding ORs for MEHP were 0.44 (95% CI, 0.19–1.02) for endometriosis, 0.63 (95% CI, 0.35–1.12) for leio- myomata, and 0.59 (95% CI, 0.37–0.95) for both conditions combined. Findings for MEHHP and MEOHP agreed with findings for MEHP with respect to endometriosis only. We observed associations for MEP and MBzP. Associations were similar when we excluded women diagnosed > 7 years before their NHANES evaluation. c onclusi : The positive associations for MBP and inverse associations for MEHP in relation to endometriosis and leiomyomata warrant investigation in prospective studies. k ey words : dibutyl phthalate, di(2-ethylhexyl) phthalate, endometriosis, leiomyomata, mono- benzyl phthalate, monobutyl phthalate, monoethyl phthalate, mono(2-ethyl-5-hydroxyhexyl) phthalate, mono(2-ethyl-5-oxohexyl) phthalate, mono(2-ethylhexyl) phthalate. Environ Health Perspect 118:825–832 (2010). doi:10.1289/ehp.0901543 [Online 25 February 2010] Phthalates are a class of organic chemicals that have been used as plasticizers for polyvinyl- chloride formulations since the 1930s. These chemicals have been widely used in food pack- aging, medical devices and medications, toys, and building materials, as well as cosmetics and personal care products commonly used by women, such as perfume, lotion, and nail polish (Blount et al. 2000b). There is increas- ing concern that phthalates may have negative effects on human fertility and reproductive health, although there have been few studies on this topic. Moreover, most of the human studies suggesting an effect of phthalates on reproductive health have focused on males and have found deleterious effects on testicu- lar function and spermatogenesis (Hauser and Calafat 2005). Several studies in experimental animals suggest that phthalates possess endocrine- disrupting properties and can adversely affect reproductive function by antagonizing or altering the effects of endogenous sex ste- roid hormones (Agarwal et al. 1985, 1989; Arcadi et al. 1998; Berman and Laskey 1993; Davis et al. 1994a, 1994b; Lamb et al. 1987; Laskey and Berman 1993; Lovekamp and Davis 2001), and an emerging literature has begun to identify potential effects on female animals. Specifically, studies of sexually mature rats have found that exposure to di(2- ethylhexyl) phthalate (DEHP) and one of its metabolites, mono(2-ethylhexyl) phthalate (MEHP), is associated with smaller preovula- tory follicles, anovulation or delayed ovulation, longer estrous cycles, decreased synthesis of estradiol, decreased serum progesterone levels, and increased serum follicle-stimulating hor- mone (FSH) levels (Davis et al. 1994a, 1994b; Lovekamp and Davis 2001). In addition, stud- ies in pregnant and pseudopregnant rats have found associations between exposures to dibu- tyl phthalate (DBP) and benzyl butyl phthalate (BzBP) and impaired implantation in mated females (Ema et al. 1998, 2000), suggesting a possible link between phthalates and altera- tions in the endogenous hormonal milieu. In these studies, monobutyl phthalate (MBP), the main metabolite of DBP, and other phthalate metabolites, including monomethyl phthalate, Environmental Health Perspectives • volume 118 | number 6 | June 2010 monoethyl phthalate (MEP), monopropyl phthalate, and monopentyl phthalate, had no effect on estradiol synthesis (Lovekamp and Davis 2001). Given that some phthalates have anti- estrogenic activities (Davis et al. 1994a, 1994b; Lamb et al. 1987), and some have been shown to have weak estrogenic activity in vitro (Harris et al. 1997; Picard et al. 2001), there is biologic plausibility for an effect of phtha- lates on the incidence of hormone-responsive conditions such as endometriosis and uterine leiomyomata (fibroids). Endometriosis and uterine leiomyomata are common disorders among reproductive-age women and are asso- ciated with considerable morbidity, includ- ing pelvic pain, menorrhagia, and infertility (Eskenazi and Warner 1997; Schwartz et al. 2000; Velebil et al. 1995). Endometriosis is characterized by growth beyond or outside the uterus of tissue resembling the endometrium. Uterine leiomyomata are benign neoplasms composed of smooth muscle cells, growing within or around the myometrium. Prevalence estimates of clinically relevant endometriosis and leiomyomata in premenopausal women are approximately 10% and 30%, respectively (Baird et al. 2003; Missmer and Mohllajee 2008; Schwartz et al. 2000). Both conditions are leading indications for hysterectomy in the United States (Farquhar and Steiner 2002; Address correspondence to J. Weuve, Rush Institute for Healthy Aging, Department of Internal Medicine, Rush University Medical Center, 645 W. Jackson Blvd., Suite 675, Chicago, IL 60612 USA. Telephone: (312) 942-3350. Fax: (312) 942-2861. E-mail: Jennifer_Weuve@rush.edu We thank the many contributors to the National Health and Nutrition Examination Survey (NHANES) data we have examined, particularly the staff at the National Center for Health Statistics of the Centers for Disease Control and Prevention (CDC) for adminis- tering the survey, and M. Silva, E. Samandar, J. Preau, J. Reidy, and others at the Division of Laboratory Sciences, National Center for Environmental Health, CDC, for the measurements of the phthalate metabo- lites. We also thank L.W. Jackson at Case Western Reserve University for her guidance in defining nulli- parity in the NHANES data. The findings and conclusions in this report are those of the authors and do not necessarily represent the views of the CDC. The authors declare they have no actual or potential competing financial interests. Received 6 October 2009; accepted 25 February 2010. 825