January 26, 2004
Marian K. Stanley
Senior Director, Phthalates Esters Panel
CHEMSTAR
American Chemistry Council
1300 Wilson Boulevard
Arlington, VA 22709
RE: Your letter of November 24, 2003 regarding phthalates and breast cancer
Dear Ms. Stanely:
Your letter reached me both by e-mail and Federal Express. I appreciate your offer of assistance with the issues with which we are dealing. However, the information you provide leads me to conclude that we should look elsewhere for help on our concerns related to phthalates.
Your letter correctly quotes our ad in the New York Times as stating that “because phthalates are also endocrine disruptors, concerns have been raised as well about their association with breast cancer.” You then dispute a claim we did not make in our ad: that phthalates are estrogenic. We did not make this statement because we know that, while phthalates are hormonally active, their activity does not appear to be on the estrogen receptor directly. And while it remains unclear how the hormonal activity of phthalates might affect the initiation or progression of breast cancer, the fact that breast cancer is a hormonally mediated cancer and that phthalates interrupt androgen signaling does give us cause for concern.
As you know, there is strong evidence showing that phthalates cause testicular and ovarian toxicity at higher doses and that they interfere with the development of the male reproductive tract at lower doses, and that in both instances the mechanism has been shown to involve interference with normal androgen hormone signaling1-8. In addition, recent research has shown that phthalates increase circulating levels of testosterone and estrogen9. Circulating levels of estrogen, testosterone, and other hormones have been studied in relation to breast cancer, and everything we know about risk factors for breast cancer points to the importance of hormonal factors10-12.
Your reassurance about the general population phthalate exposures being below EPA safety levels is similarly unhelpful. First of all, EPA “safety levels” are extremely outdated. The EPA reference dose for dibutyl phthalate, for example, is based on a rat mortality study published in 195313. The reference dose does not reflect any of the studies published over the last 5 years that have demonstrated effects on developing reproductive systems. A revised risk assessment based on new studies is likely to result in a lower “safe” dose. Second, while general population exposures appear to be below the reference dose, we are concerned about exposures that are much higher than average but still common. Maximum concentrations reported by US CDC are above the EPA reference dose14. Your focus on protecting 95% of the population still leaves 5% potentially at risk. If you think about inviting 100 of your closest family and friends to a wedding or bat-mitzvah, that’s 5 of them you would decide it was okay not to protect.
While you assert that phthalates have been extensively studied, the studies done have not been the kind that would illuminate the effects we are most concerned with, which would require multiple studies of in utero exposures with long-term follow up to determine the effects on breast cancer, fertility or asthma, or a study looking at these same health effects following exposure during puberty. Neither breast cancer nor the endocrine toxicity of phthalates are well-enough understood to conclude that exposure to these ubiquitous compounds does not affect the initiation and progression of the cancer about which women are most concerned, and whose incidence is skyrocketing.
Your offer to address our concerns about phthalates is a generous one, but one that I must decline absent additional evidence that you are truly committed to advancing the effort to understand how these chemicals are affecting public health.
Sincerely,
Barbara A. Brenner
Executive Director
1 Lovekamp, T. and B.J. Davis, Mechanisms of phthalate ester toxicity in the female reproductive biosystem. Environmental Health Perspectives, 2002: p. doi:10.1289/ehp.5658 [Online October 28, 2002].
2 Duty, S.M., et al., The relationship between environmental exposures to phthalates and DNA damage in human sperm using the neutral comet assay. Environmental Health Perspectives, 2002. doi:10.1289/ehp.5756 (available at http://dx.doi.org/) online 6 December 2002.
3 Parks, L.G., et al., The Plasticizer Diethylhexyl Phthalate Induces Malformations by Decreasing Fetal Testosterone Synthesis during Sexual Differentiation in the Male Rat. Toxicol. Sci., 2000. 58(2): p. 339-349.
4 Mylchreest, E., et al., Dose-Dependent Alterations in Androgen-Regulated Male Reproductive Development in Rats Exposed to Di(n-butyl) Phthalate during Late Gestation. Toxicological sciences, 2000. 55(1): p. 143-151.
5 Gray, L.E., Jr., et al., Perinatal Exposure to the Phthalates DEHP, BBP, and DINP, but Not DEP, DMP, or DOTP, Alters Sexual Differentiation of the Male Rat. Toxicol. Sci., 2000. 58(2): p. 350-365.
6 National Toxicology Program (NTP), NTP-CERHR Expert Panel Report on butyl benzyl phthalate. 2000, US Department of Health and Human Services, National Toxicology Program (NTP), Center for the Evaluation of Risks to Human Reproduction (CERHR): Alexandria, VA. p. 42.
7 National Toxicology Program (NTP), NTP-CERHR Expert Panel Report on di-n-butyl phthalate. 2000, US Department of Health and Human Services, National Toxicology Program (NTP), Center for the Evaluation of Risks to Human Reproduction (CERHR): Alexandria, VA. p. 60.
8 National Toxicology Program (NTP), NTP-CERHR Expert Panel Report on di(2-ethylhexyl) phthalate. 2000, US Department of Health and Human Services, National Toxicology Program (NTP), Center for the Evaluation of Risks to Human Reproduction (CERHR): Alexandria, VA. p. 150.
9 Akingbemi, B., et al., Phthalate-induced Leydig cell hyperplasia is associated with multiple endocrine disturbances. PNAS, 2004.
10 Wang, D.Y., et al., Urinary androgens and breast cancer risk: results from a long-term prospective study based in Guernsey. British Journal of Cancer, 2000. 82(9): p. 1577-1584.
11 Secreto, G., et al., Serum and urinary androgens and risk of breast cancer in postmenopausal women. Cancer Research, 1991. 51(10): p. 2572-2576.
12 Bernstein, L., Epidemiology of endocrine-related risk factors for breast cancer. Journal of Mammary Gland Biology and Neoplasia, 2002. 7(1): p. 3-15.
13 US Environmental Protection Agency, Integrated Risk Information System. 1999: http://www.epa.gov/ngispgm3/iris.
14 National Center for Health Statistics, National Health and Nutrition Examination Survey: NHANES 1999-2000 Data Files. 2000, US Centers for Disease Control and Prevention.