The Ribbon Newsletter

Suzanne Snedeker, Ph.D.
BCERF Associate Director for Translational Research

The breast is unique because most of its development occurs after birth, during the pre-pubertal years through puberty. Researchers are interested in how early life exposures to chemicals, especially those that may affect breast development, may ultimately affect the cancer process. The papers discussed below illustrate how a multi-disciplinary approach is needed to fully understand to what extent young girls are exposed to chemicals of concern, how animal models can be used to tease out whether such exposures influence how the mammary gland develops, and if early exposures to certain environmental chemicals can lead to changes that ultimately affect breast cancer risk later in life.

Although we have known for over seventy years that the environmental chemical bisphenol A (BPA) is an environmental estrogen (Dodds and Lawson, 1938), until recently we have known very little about levels in people. Since this chemical is processed by the body relatively quickly and excreted, levels in the urine are used as biological marker (biomarker) of recent exposure. Less than three dozen papers are available on urinary levels of BPA in humans (most published since 2000), and only a few of these studies document urinary levels of young children during the period of time when breast tissue is starting to develop.

One of these studies was recently published in the January 2007 issue of Environmental Health Perspectives, entitled "Pilot study of urinary biomarkers of phytoestrogens, phthalates, and phenols in girls," by a consortium of three Centers devoted to determining if early environmental exposures affect the development of puberty in girls (Wolff et al., 2007). These NIH-funded centers, called the Breast Cancer and the Environment Research Centers (BCERC), will also determine if early exposure to environmental stressors can affect subsequent breast tumor development in laboratory animal models (see http://envirocancer.cornell.edu/Research/BCERC/ for an overview of these Centers).

This pilot study analyzed urinary samples from 90 girls (average age, seven years old) of different ethnic backgrounds from New York City, Cincinnati, and the San Francisco Bay area (30 samples from each location) for a variety of environmental chemicals. The chemicals of interest included both synthetic chemicals and naturally occurring chemicals (phytoestrogens). This study's most basic question was this: of the target environmental compounds these researchers would like to follow in young girls because they may affect pubertal development, which ones can be detected with current methods, and how do levels detected compare to any known values for girls of similar ages? Secondly, would these preliminary results show any variation in levels of the chemicals by geographic location, ethnicity, or one marker of puberty, weight for height (as measured by body mass index)?

All of these 25 chemicals have been identified as having some capacity to disrupt hormones, especially estrogens or androgens.

To do this study, researchers collaborated with the Centers for Disease Control and Prevention (CDC), which has laboratory facilities with the capability of analyzing blood and urine samples for biomarkers of chemical exposures. The CDC launched a national biomonitoring program to track levels of environmental chemicals in the U.S. population in 2001. The CDC biomonitoring program is one of the few sources of information on current levels of environmental chemicals in the general U.S. population.

Researchers conducting this puberty study found that 18 out of the 25 chemicals studied were detectable in the 95% of the urine samples. The chemical with the highest median values (the median is where half the values are above and half below) in each class of chemicals was enterolactone for phytoestrogens, monoethylphthalate (MEP) for the phthalates, and a benzophenone-3, a component of sunscreens, for the phenols.

This is one of the few studies that have reported levels of BPA in young girls; the levels for BPA in this puberty study were similar to values reported by the CDC in their 2005 biomonitoring study. Both the phytoestrogen enterolactone, and the environmental estrogen BPA tended to be higher in girls that were not obese (less than the 85th percentile for body mass index); no explanation was given for these trends.

While there was some variation in levels of several phthalates with ethnicity and geographic location, it is difficult to interpret the significance of these findings because questionnaire data from this study have not been fully analyzed yet. Questionnaire data may provide information on possible sources of exposure, including the girls' diet and use of personal care products.

In the same issue of Environmental Health Perspectives, a study from the laboratory of Drs. Ana Soto and Carlos Sonnenschein evaluated whether pubertal exposures to BPA in female rats affected the development of the mammary gland and looked to see if any pre-cancerous changes occurred as the BPA-treated animals got older (Durando et al., 2007) . The most striking result from this study was that early, pubertal exposures to BPA (for rats, exposure started at 50 days of age) resulted in a higher percentage of the BPA-exposed animals having pre-cancerous lesions in the mammary gland. These lesions, called hyperplasias, were not observed until the BPA-treated animals were 180 days of age (young adults rats). The size of the treatment groups in this study were small, and the animals were only followed for six months, so further research is needed to determine if these pre-cancerous lesions persist as the animals age. While there is some indication in these studies that BPA may make the animals more sensitive to other chemicals known to be mammary carcinogens, the animals were not followed for a sufficient length of time to make strong conclusions. But, since cancer is a process, the finding of a higher number of mammary hyperplasias with pubertal BPA exposures would support the need to determine how early exposures to environmental chemicals may "imprint" the mammary gland and affect the cancer process.

In support of this thesis are studies from the laboratories of Drs. Gail Prins and Shuk-Mei Ho (Ho et al., 2006) which show that early exposures to BPA during prostate gland development induces prostate hyperplasias in male rats. These changes appear to be tied to a gene-induced change in DNA-methylation patterns, which may be an important factor in the development of prostate tumors as these BPA-treated animals age. This evidence of an imprinting effect with early life exposures to BPA during mammary and prostate development indicates that both glands have critical windows of susceptibility, and that early exposure to environmental estrogens may affect the cancer process.

Other studies are needed to more fully characterize routes of exposure to chemicals like BPA during critical times of mammary and prostate gland development. One highly quoted study was conducted by food regulatory authorities in Singapore (Onn et al., 2005). BPA was detected in 19 out of 28 brands of polycarbonate baby bottles tested. Calculated daily intakes of BPA for infants from the baby bottles were below the maximum limit recommended by the Environmental Protection Agency (EPA) of 0.05 milligrams/kilogram body weight per day. The European Union's (EU) tolerable daily intake for BPA is 0.01 mg/kg/day, and while one Norwegian study found that BPA leached out of polycarbonate baby bottles after dishwashing, boiling and brushing, the levels did not exceed the EU limits (Brede et al., 2003).

In one the few studies on children in daycare centers, preschoolers' exposure to BPA appeared to be primarily through food (Wilson et al., 2003). A more recent study on exposures of preschool children to BPA at home and in daycare facilities reported similar results. BPA was detected in 68% of the children's liquid food and in 83% of the solid food samples, and in virtually all hand swipe samples taken from the children. Overall, 99% of the BPA exposure was through the dietary intake route (Wilson et al., 2007). Research from other laboratories suggest that most of the transfer of BPA from epoxy resins (used to line food cans) to the food occurs during the high-heat canning process (Goodson et al., 2004; Kang et al., 2006; Sajiki et al., 2007).

To what extent BPA exposure is from consuming canned food versus other sources in older children is not known. Few published studies have evaluated leaching from polycarbonate sports bottles or from landfills that contain degrading polycarbonate plastics that may leach BPA. BPA has also been found in paperboard food containers, and paper towels made from recycled products (Ozaki et al., 2004; Vinggaard et al., 2000). Carbonless paper, photosensitive fax paper, and various photographic inks may be sources for BPA that makes its way from recycled office paper products to recycled paper board used for food containers.

With regard to exposures that may occur during the puberty years, Duty and colleagues (Duty et al., 2005) reported that the use of personal care products predicts urinary concentrations of some phthalate monoesters (many types of phthalates are metabolized and found as monoesters in the urine). While this study was done in men, the study results did support a relationship between use of personal care products (cologne or aftershave) and urinary levels of monoethyl phthalate. Similar studies characterizing personal care product use (fragrances, hair and body care, nail polish) and exposure to phthalate monoesters in girls are needed.

When the full results of the early life exposure-pubertal study from the three Centers become available, it may be one of the first studies to not only characterize pubertal urinary levels of environmental agents and probable sources, but to also give us important data on whether these contaminants, dietary factors, or body size are influencing the onset of breast development and other hallmarks of puberty in young girls.

Studies confirming the Soto lab's findings of a higher incidence of pre-cancerous hyperplastic lesions in the mammary gland after low level pubertal exposures to BPA need to be confirmed by other laboratories. Other studies are needed to determine if this effect is due to an inherent characteristic of BPA, or if equivalent doses of other environmental estrogens also are able to imprint on the developing mammary gland and cause pre-cancerous lesions. Ultimately, studies will need to go beyond showing visual changes (lesions), and need to document whether early exposures to BPA or other environmental chemicals affects genes related to the cancer process.

Real-life exposures to environmental agents are not to limited to one chemical, but are more likely to result from low-level exposures to several or even dozens of environmental estrogens. While exposure studies have documented levels below current EPA and EU limits for single chemicals like BPA, a "risk cup" assessment of how additive effects to multiple environmental estrogens affects puberty, including the onset of breast development, is important. Knowing how environmental stressors affect early breast development needs to be studied at many levels. This includes determining actual levels in urine and current sources of exposure in different ethnic populations, to deciphering the biological basis of any changes that affect puberty or cancer risk at the structural and molecular level.

Brede, C., Fjeldal, P., Skjevak, I., and Herikstad, H. (2003). Increased migration levels of bisphenol A from polycarbonate baby bottles after dishwashing, boiling and brushing. Food Additives and Contaminants 20, 684-689.

Dodds, E.C., and Lawson, W. (1938). Molecular structure in relation to oestrogenic activity: compounds without a phenanthrene nucleus. Proceedings of the Royal Society. London B. 122, 222-232.

Durando, M., Kass, L., Piva, J., Sonnenschein, C., Soto, A.M., Luque, E.H., and Muñoz-de-Toro, M. (2007). Prenatal bisphenol A exposure induces preneoplastic lesions in the mammary gland in Wistar rats. Environmental Health Perspectives 115, 80-86.

Duty, S.M., Ackerman, R.M., Calafat, A.M., and Hauser, R. (2005). Personal care product use predicts urinary concentrations of some phthalate monoesters. Environmental Health Perspectives 113, 1530-1535.

Goodson, A., Robin, H., Summerfield, W., and Cooper, I. (2004). Migration of bisphenol A from can coatings - effects of damage, storage conditions and heating. Food Additives and Contaminants 21, 1015-1026.

Ho, S.-M., Tang, W.-Y., Belmonte de Frausto, J., and Prins, G.S. (2006). Developmental exposure to estradiol and bisphenol A increases susceptibility to prostate carcinogenesis and epigenetically regulates phosphodiesterase type 4 variant 4. Cancer Research 66, 5624-5632.

Kang, J.-H., Kondo, F., and Katayama, Y. (2006). Human exposure to bisphenol A. Toxicology 226, 79-89.

Onn, W.K., Woon, L.L., and Leng, S.H. (2005). Dietary exposure assessment of infants to bisphenol A from the use of polycarbonate baby milk bottles. Food Additives and Contaminants 22, 280-288.

Ozaki, A., Yamaguchi, Y., Fujita, T., Kuroda, K., and Endo, G. (2004). Chemical analysis and genotoxicological safety assessment of paper and paperboard used for food packaging. Food and Chemical Toxicology 42, 1323-1337.

Sajiki, J., Miyamoto, F., Fukata, H., Mori, C., Yonekubo, J., and Hayakawa, K. (2007). Bisphenol A (BPA) and is source in foods in Japanese markets. Food Additives and Contaminants 24, 103-112.

Vinggaard, A.M., Korner, W., Lund, K.H., Bolz, U., and Petersen, J.H. (2000). Identification and quantification of estrogenic compounds in recycled and virgin paper for household use as determined by an in vitro yeast estrogen screen and chemical analysis. Chemical Research in Toxicology 13, 1214-1222.

Wilson, N.K., Chuang, J.C., Lyu, C., Menton, R., and Morgan, M.K. (2003). Aggregate exposures of nine preschool children to persistent organic pollutants at day care and at home. Journal of Exposure Analysis and Environmental Epidemiology 13, 187-202.

Wilson, N.K., Chuang, J.C., Morgan, M.K., Lordo, R.A., and Sheldon, L.S. (2007). An observational study of the potential exposures of preschool children to pentachlorophenol, bisphenol-A, and nonylphenol at home and daycare. Environmental Research 103, 9-20.

Wolff, M.S., Teitelbaum, S.L., Windham, G., Pinney, S.M., Britton, J.A., Chelimo, C., Godbold, J., Biro, F., Kushi, L.H., Pfeiffer, C.M., and Calafat, A.M. (2007). Pilot study of urinary biomarkers of phytoestrogens, phthalates, and phenols in girls. Environmental Health Perspectives 115, 116-121.

Environmental Estrogens: Affects on Puberty and Cancer Risk The Ribbon

Environmental Estrogens: Affects on Puberty and Cancer Risk
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