Medical Hypothesis:
Xenoestrogens As Preventable Causes of Breast Cancer

Environmental Health Perspectives, v.101,  n.5,  Oct93

Devra Lee Davis,¹ H. Leon Bradlow,² Mary Wolff,³ Tracey Woodruff,⁴ David G. Hoel,⁵ and Hoda Anton-Culver⁶

¹Office of the Assistant Secretary for Health, Department of Health and Human Services, Washington, DC 20201 USA; ²Strang Cornell Cancer Research Laboratory, Cornell University Medical Center, Ithaca, NY 10021 USA; ³Department of Environmental and Community Medicine, Mt. Sinai Medical Center, City University of New York, New York, NY 10029 USA; ⁴Institute for Health Policy Research, University of California, San Francisco, CA 94109 USA; ⁵Department of Biometrics and Epidemiology, Medical University of South Carolina, SC 29425 USA; ⁶Epidemiology Program, Department of Medicine, University of California, Irvine, CA 92717 USA

Changes in documented risk factors for breast cancer and rates of screening cannot completely explain recent increases in incidence or mortality. Established risk factors for breast cancer, including genetics, account for at best 30% of cases. Most of these risk factors can be linked to total lifetime exposure to bioavailable estrogens. Experimental evidence reveals that compounds such as some chlorinated organics, polycyclic aromatic hydrocarbons (PAHs), triazine herbicides, and pharmaceuticals affect estrogen production and metabolism and thus function as xenoestrogens. Many of these xenoestrogenic compounds also experimentally induce mammary carcinogenesis. Recent epidemiologic studies have found that breast fat and serum lipids of women with breast cancer contain significantly elevated levels of some chlorinated organics compared with noncancer controls. As the proportion of inherited breast cancer in the population is small, most breast cancers are due to acquired mutations. Thus, the induction of breast cancer in the majority of cases stems from interactions between host factors, including genetics and environmental carcinogens. We hypothesize that substances such as xenoestrogens increase the risk of breast cancer by mechanisms which include interaction with breast-cancer susceptibility genes. A series of major epidemiologic studies need to be developed to evaluate this hypothesis, including studies of estrogen metabolism, the role of specific xenoestrogenic substances in breast cancer, and relevant genetic-environmental interactions. In addition, experimental studies are needed to evaluate biologic markers of suspect xenoestrogens and biologic markers of host susceptibility and identify pathways of estrogenicity that affect the development of breast cancer. If xenoestrogens do play a role in breast cancer, reductions in exposure will provide an opportunity for primary prevention of this growing disease. Tests for estrogenicity could become critical screening tools with which to assess the potential health consequences of new and existing chemicals. Key words: aromatic hydrocarbons, breast cancer, chlorinated organics, genetic susceptibility, pesticides, xenobiotics, xenoestrogens. Environ Health Perspect 101:372-377(1993)

Address correspondence to D.L. Davis, Office of the Assistant Secretary for Health, DHHS, 200 Independence Avenue SW, Washington, DC 20201 USA.

Members of the Breast Cancer Prevention Collaborative Work Group provided constructive comments on the development of this hypothesis at meetings of the International Society for Environmental Epidemiology held at the National Institute for Public Health in Cuernavaca, Mexico, August 1992, and at a workshop sponsored by NIEHS and Health and Welfare Canada, held at the National Research Council, Washington, DC, December 1992. Support for this research was provided to the authors by NIEHS, the National Cancer Institute, and Health and Welfare Canada.

Received 12 May 1993; accepted 28 June 1993