State of the Evidence on Phthalates

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CATEGORY*: Endocrine disruptor
FOUND IN: Plastics, cosmetics, fragrance in cosmetics and household cleaners
THE GIST: Phthalates, pronounced THAL-ates, soften plastics and are known to disrupt the body’s hormones. A 2012 study found that women working in the automotive and food-canning industries have nearly a fivefold increase in risk for premenopausal breast cancer, likely because of their exposure to phthalates, BPA and flame-retardants. Phthalates have also been linked to birth defects, asthma, neurodevelopmental problems in newborns, fertility issues and obesity. Though phthalates are banned in children's toys, they can still be found in school supplies, cosmetics and personal care products such as nail polish and shampoo.
Phthalates are a group of endocrine-disrupting chemicals commonly used to render plastics soft and flexible. They are found in a wide variety of common products including plastics, textile, cosmeticspharmaceuticals, baby care products, building materials, modeling clay, automobiles, cleaning materials and insecticides. Phthalates are readily absorbed through the skin (Janjua, 2008) and can also enter the body through inhalation or medical injection procedures (Schettler, 2005).
Look for plastic products marked "phthalate-free" or "PVC-free" and avoid plastics with recycling code #3. Avoid household cleaners and cosmetics with "fragrance" on the label.
Another major source of at least one phthalate, di(2-ethylhexyl)phthalate (DEHP), is food packaging. A 2011 studydemonstrated that just a three-day period of limiting intake of packaged foods decreased by half the concentrations of DEHP found in urine (Rudel, 2011). Another dietary intervention in which study participants followed a five-day monastic lifestyle, including a vegetarian diet, led to a statistically significant decrease in urinary phthalate levels (Ji, 2010). Substantial levels of DEHP and another phthalate used in food packaging, di-n-butylphthalate (DNP), were found in cooked foods, both before and after packaging, that were served to children through school meal programs (Cirillo, 2011).
Phthalates have been found in indoor air and dust (Rudel, 2001) and in human urine and blood samples from children, adolescents and adults (Calafat, 2011; Frederiksen, 2011; Kato, 2003; Rudel, 2011). National data collected by the Centers for Disease Control and Prevention show that levels are highest in children ages 6 to 11 and in women, and that blacks have higher levels of phthalates than do whites (CDC, 2005). Phthalates have also been detected in human breast milk and urine (Hines, 2009; Meeker, 2009). Phthalates cross the human placenta, exposing fetuses to the hazards associated with exposure to an important class of endocrine-disrupting compoundsduring this critical period of development (Wittassek, 2009). Young infants are also exposed to high levels of phthalates, with measurable levels of seven different phthalates being found in infants born between 2000 and 2005 (Sathyanarayahna, 2008).
A 2012 study examined whether or not there is a relationship between urinary levels of nine different phthalates and the incidence of breast cancer. In this study, urinary phthalate metaboliteswere detected in 82 percent of the women, whether or not they had been diagnosed with breast cancer. Monoethyl phthalate (MEP), a urinary metabolite of the parent compound diethyl phthalate (DEP; often used in fragrance), was elevated in women with breast cancer. This association was most profound in pre-menopausal women. Metabolites of two other common phthalates (butyl benzyl phthalate, BBP; and di-n-octyl phthalate, DOP) were negatively associated with breast cancer risk in this study (Lopez-Carrillo, 2010). Higher levels of urinary MEHP, a marker of DEHP body burden, has also been associated with increased pregnancy loss in a study of Danish women (Toft, 2012).
Phthalates are considered to be endocrine disruptors because of their complex effects on several hormonal systems including the estrogen and androgen hormone systems. Some phthalates, including BBP and di-n-butyl phthalate (DBP), act as weak estrogens in cell culture systems. They can bind to estrogen receptors (ER), induce estrogen-appropriate cellular responses and act additively with the natural estrogen estradiol in altering these systems (Jobling, 1995; Kang, 2005). Phthalates also bind weakly to the androgen receptor, disrupting the cellular actions ordinarily initiated by the androgens (Borch, 2006). Those that bind most strongly to the androgen receptor, and therefore might be expected to exert the greatest effects through this pathway, include DBP, di-i-butyl phthalate (DiBP) and BBP (Fang, 2003). In addition to their direct effects regulated through interactions with steroid hormone receptors, phthalates can also induce proliferation, malignant invasion, and tumor formation in breast cancer cell lines that are are low in or lack hormone receptors This indicates that at least some effects of these compounds are independent of their direct estrogenic or androgenic effects (Hsieh, 2012).
The endocrine-disrupting properties of this class of chemicals have been well established in the offspring of mother rats who were treated with phthalates while pregnant. Phthalates have been shown to disrupt the development and functioning of male and female reproductive systems by interfering with the production of testosterone and estradiol, respectively (Jiang, 2007; Lovekamp-Swan, 2003). Abnormalities in male offspring exposed prenatally included nipple retention, shortened ano-genital distance and increased cryptorchidism (undescended testes) (Foster, 2005; Latini, 2006). Exposure of human mothers to phthalates, as measured by analysis of their urine samples, has also been associated with shortened ano-genital distance in their newborn sons—a measure of feminization of external genitalia (Swan, 2005).
A recent case-control study examined phthalate levels in apparently healthy girls who went through thelarche (breast development) before the age of 8, as compared with girls who underwent precocious puberty because of abnormalities in their neuroendocrine systems and with girls who were progressing through puberty at normal ages. Increased levels of monomethyl phthalate were associated with early thelarche group, but not with either of the comparison groups (Chou, 2009). Early breast development in otherwise healthy girls is associated with an increased risk for breast cancer (Steingraber, 2007).
Exposure of very young rats to BBP resulted in increased cellular proliferation in the terminal end buds of mammary tissue. BBP-induced changes in the activity of mammary-cell genes that are involved in the regulation of  cell differentiation and proliferation, as well as cell-to-cell communication (Moral, 2007). Similar structural irregularities were observed in the postnatal development of mammary tissues in rats exposed to the BBP only in utero, when their mothers were fed low levels of the compound during the second half of their pregnancies (Moral, 2011).
With in vitro cell systems, BBP, DBP and DEHP significantly increased cell proliferation in human breast tumor cells (MCF-7 cells). In addition, these three phthalates inhibited the anti-tumor action of Tamoxifen in MCF-7 breast cancer cells (Kim, 2004a). In another cell study, exposure of normal human breast epithelial cells to DBP resulted in changes in gene expression in pathways related to a number of systems, including immune responses, cell cycle regulation and antioxidant status of the cell (Gwinn, 2007).


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