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Vol. 06 Issue 1, Winter 2001

Research Commentary: Identification of Phthalate Esters in the Serum of Young Puerto Rican Girls with Premature Breast Development
The Ribbon 

Colon, I., D. Caro, C.J. Bourdony, and O. Rosario.
Environmental Health Perspectives 108 (2000):895-900.

Gloria D. Jahnke, MS, DVM
Toxicologist and Consultant,
Research Triangle Park, NC

This study examines serum concentrations of a group of phthalate compounds in girls with premature breast development and compares these values to those obtained from an age-matched group of girls with no premature breast development. In Puerto Rico, over approximately the last 20 years, clusters of young girls (eight years old and below) have experienced early thelarche. The author's report that the incidence rate in Puerto Rico is approximately 18.5 fold greater than an incidence reported in a study in the US. An Early Thelarche Registry has been established in Puerto Rico since 1987. Girls were taken from this registry for this study. Girls selected had no other signs of puberty, such as early menarche or pubic hair growth. Using a combination of gas chromatography and mass spectroscopy (GC/MS), the authors looked for pesticides or phthalates in the serum of selected girls, and compared these values to a control group; the hypothesis being that perhaps there was a difference between the groups in environmental chemical exposures leading to early thelarche. No chlorinated pesticides were detected in the serum samples. However, phthalate diesters and monoesters were detected in 28 out of 41 samples from girls with early thelarche and one out of 35 samples of the controls. The monoester metabolite of DEHP, MEHP, was detected in five out of 41 of the experimental and none of the control samples. It is suggested by the authors that a possible association exists between phthalate exposure and premature female breast development.

Phthalate diesters, also known as phthalates, are a class of chemicals used to soften vinyl plastic, hence, are also called 'plasticizers'. Phthalates are ubiquitous in the modern environment, because they are not chemically bound to the plastic polymer and can readily leach out of the plastic. Phthalates are small, fat-soluble chemicals found in PVC-type and other plastics, but not in polyethylene. Some examples of materials that contain phthalates are food products, perfumes, hair sprays, nail polish, garden hoses, car interiors, lotions, and vinyl flooring. Food products are the most common products where humans are exposed to phthalates, because phthalates leach into the food from contact with plastics containing the chemical. Phthalates are poorly absorbed through the skin.

After oral ingestion, phthalates are hydrolyzed from the diester to monoester form by lipases present in saliva, stomach and small intestine. Lipases are also present in breast milk. The monoester form is very rapidly absorbed by the gut. Upon absorption, the chemical is conjugated by the liver and excreted in the urine as a conjugated monoester phthalate. Evidence of oral phthalate exposure would therefore be indicated by the presence of the monoester in the serum or urine. However, if exposure to phthalate diesters is through intravenous tubing, then the diester form would be present in the serum. Based upon this information, it is likely that the serum levels of phthalate diesters reported in this study are assay contaminants and not the result of ingestion of the chemicals. However, in this study, the DEHP monoester, MEHP, was reported in five of the test samples, indicating an oral exposure in these individuals. No other monoester phthalates were reported. More information would be needed from the authors to determine whether other phthalate monoesters were assessed. Exposure data could be estimated from the serum values obtained for the monoester metabolites.

Recently, monoester phthalate levels were measured from spot urine samples taken from the NHANES III study sponsored by the Center for Disease Control (Environmental Health Perspectives, 108 (2000):979-982). Samples from 289 adults were extracted and analyzed by GC/MS. Specifically labeled phthalate monoester internal standards and extensive quality control measures were used. Estimates of actual exposures to several phthalates were calculated based upon these monoester values (ibid. A440-A442).

Investigations have shown that some phthalates can act as "endocrine disrupters".1 The research demonstrated that exposures of rodents to some phthalates (at high doses) prior to development of the reproductive tract affected reproductive tract maturation and fertility. In rodent reproductive studies, some phthalates, when given to the dams during gestation, were found to disrupt sexual development of male mice. Effects on female development were also observed, but at higher chemical doses. The exact pathogenesis of this process has not been elucidated, but is believed to involve a drop in testosterone levels leading to an "antiandrogenic" effect. No evidence of an estrogenic effect from phthalate exposure has been reported in animal studies. Toxicology studies on phthalates have shown that some are carcinogenic in rodents, but only at very high concentrations. In long-term exposure studies, no tumors have been described in the mammary gland nor has there been any reported evidence of abnormal mammary gland development although tumors at other sites, such as the liver and testis, did occur. Therefore, it seems very unlikely that phthalates would affect early development of mammary glands.

If early thelarche is due to an increase in ductal development, then the question arises as to what hormone or hormone-mimic could cause an effect independent of other signs of puberty? Substances that promote prolactin levels in the serum are possible candidates. Because of these concerns, it would have been informative if this study could have examined serum hormone levels such as estradiol, prolactin, testosterone, progesterone, thyroid hormone, growth hormone, cortisol, and insulin in both control and experimental groups. In spite of analytical doubts concerning the exposures of the experimental group in this study, there is a valid concern for determining the causative factor leading to early thelarche. Breast enlargement due to documented ductal development and carefully age and weight matched controls are needed. A detailed epidemiology study documenting lifestyle, family history, and diet is necessary to help determine a cause for early thelarche.

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Last Update 03.30.01