March 2, 2004
Breast Cancer Action
55 New Montgomery
Suite 323
San Francisco, CA. 94105
Dear Ms. Brenner:
Thank you for your letter of January 26, 2004, which responded to the Phthalate Esters Panel’s letter of November 24, 2003. The Panel would like to discuss with you our perspective on the science and reiterate its commitment to expanding scientific knowledge to protect public health. The Panel notes in particular your last sentence in which you express doubt that it is “truly committed to advancing the effort to understand how these chemicals are affecting public health”. Our group is fully committed to understanding whether these chemicals are affecting public health, and if so, how. Part of our mission is to critically evaluate the literature and to sponsor toxicology studies that our understanding of the science indicates would be appropriate.
If the Panel understands your letter correctly, your thesis is that any substance that has any hormonal effect under any circumstance is potentially a cause of breast cancer. The Panel believes that many substances can ultimately affect hormone levels if administered at sufficiently high doses. So, in theory, your thesis could label any of these substances as potentially a breast carcinogen. The Panel does not find that premise particularly helpful either in a public health context or as a basis for devising a research strategy. Some means of distinguishing between those substances that are of concern and the many substances that probably are not would seem helpful in targeting limited resources to areas of actual concern.
The Panel’s initial letter to you responded to your suggested links between exposure to phthalates and breast cancer. This is an issue that our group has considered previously. Our basic approach was to assess whether there is any evidence from either human observations or animal studies that would support such a link. Based on the report available on your website (Evans, 2003), we assume that you have taken a similar approach. Your report provides a list of chemicals shown to induce mammary cancer in animals. Phthalates are not on this list, nor were they identified as producing breast cancer in animals in a similar review of cancer studies conducted by the National Toxicology Program (NTP) by Brody and Rudel (2003). Although these reviews were limited to the NTP studies, there are other cancer studies of phthalates, some of which were conducted and published on a voluntary basis by some of the Panel’s member companies (Butala et al., 1996; 1997; Lington et al., 1997; David et al. 2000a,b). These studies, like those discussed above, provide no experimental evidence of elevated breast cancer in rodents. The Panel is unaware of any epidemiology studies linking phthalate exposure to breast cancer in humans. We presume that you are likewise not aware of any such studies, as none were cited in your review nor in your letter. Based on available literature and studies it is our conclusion from this that there is no human evidence of breast cancer resulting from phthalate exposure and no experimental evidence in animals.
Regarding the role of hormones in breast cancer, your website report makes the statement that “women who have prolonged exposure to estrogens are at higher risk for breast cancer” and additional information is provided in that section of the report on the relationship between exposure to estrogen and breast cancer. In the section on phthalates it is stated that…”many phthalates are known to disrupt hormonal processes, raising concern about their implications for breast cancer.” As the report provides no information on hormones other than estrogen, it would be reasonable for the reader to assume that this section on phthalates is referring to estrogen as well. We have dedicated resources to this research area; studies either conducted or sponsored by the Panel and published in the peer-reviewed literature have not shown that phthalate metabolites to interact with the estrogen receptor, nor do they produce other evidence of estrogenic effects under in vivo conditions.
In one reference you cite (Gray et al., 1999), phthalates did not show any evidence of estrogenic effects under in-vivo conditions. The study did show that the particular two phthalates tested (DEHP and DBP) affected androgen-dependent processes. However, it is not clear to us from either your website report or recent letter how you have apparently expanded the linkage between estrogen exposure and breast cancer and broadened it to include hormones generally—the other references that you cited also emphasize the role of estrogens in breast cancer. Androgens can be converted to estrogens, but the androgen role in breast cancer is, at best, unclear (Bernstein, 2002; Secreto et al., 1991; Wang, 2000).
As the Panel understands hormonal theory, an important issue for breast cancer is the potential for substances to elevate levels of estrogen in the breast. We are not aware of any phthalate data on this subject specifically, but there are some interesting data on the effects of phthalates on levels of estrogen in the rat ovary (see for example Lovekamp-Swan and Davis, 2003 that you cited as well as Davis et al., 1994; Lovekamp and Davis, 2001). These studies demonstrate that in the rat, treatment with either DEHP or DBP reduces estradiol levels in the ovary by a process under the control of the Peroxisome Proliferator Activated Receptors (PPAR) a and y. One of the consequences of activation of these receptors is to inhibit aromatase, an enzyme that converts testosterone to estradiol. The y receptor, interestingly, is uniquely found in adipose tissue including the breast. Thus, if phthalates modulate hormonal levels in the breast, the toxicology data suggest that aromatase activity is likely to be inhibited, and further suggest that localized estradiol concentrations would be reduced.
It is our view that these data suggesting PPAR activation and possible reduced estradiol concentrations probably have little public health significance, partly because human exposure levels to phthalates are so low. Davis et al. treated their rats with 2 g/kg DEHP, more than a million times higher than the average DEHP exposure in the human population. Further, rodents are much more sensitive to PPAR a-mediated process than are humans. Thus, under likely human exposures, it is unlikely that any PPAR receptor-mediated processes would be expressed. But, if we take these data at face value and assume they are relevant, there are two reasonable conclusions: (1) if phthalates affect hormonal levels in the breast, available data suggests the effect would be a reduction in estradiol levels, and (2) phthalates should then be protective for breast cancer.
The Panel also would like to speak to the next to last paragraph in your letter in which you call on us to conduct studies of fertility and asthma. We have conducted research in both areas, and have reported these data publicly. The references to these particular studies, as well as other Panel- and member company-sponsored research, can be found on our website, www.phthalates.org.
Sincerely,
Marian K. Stanley
Senior Director, CHEMSTAR
Manager, Phthalate Esters Panel
Bernstein, L., (2002). Epidemiology of endocrine-related risk factors for breast cancer. Journal of Mammary Gland Biology and Neoplasia 7: 3-15.
Brody, J. and Rudel, R. (2003). Environmental Pollutants and Breast Cancer. Environmental Health Perspectives. Online 19 May, 2003.
Butala, J., Moore, M., Cifone, M., Bankston, J., and Astill, B. (1996). Oncogenicity study of di(isononyl) phthalate in rats. The Toxicologist 30: 202.
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Evans, N. (2003). State of the Evidence. What is the connection between chemicals and breast cancer? Updated Edition. Presented by the Breast Cancer Fund and Breast Cancer Action.
Gray, L., Wolf, C., Lambright, C., Mann, P., Price, M., Cooper, R., and Ostby, J. (1999). Administration of potentially antiandrogenic pesticides (procymidone, linuron, iprodione, chlozolinate, p,p’-DDE, and ketoconazole) and toxic substances (dibutyl- and diethylhexyl phthalate, PCB 169, and ethane dimethane sulphonate) during sexual differentiation produces diverse profiles of reproductive malformations in the male rat. Toxicology and Industrial Health 15: 94-118.
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Secreto, G., Toniolo, P., Berrino, F., Recchione, C., Cavalleri, A., Pisani, P., Totis, A., Fariselli, G., and Pietro, S. (1991). Serum and urinary androgens and breast cancer in postmenopausal women. Cancer Research 51: 2572-2576.
Wang,D., Allen,D., De Stavola,B., Fentman, I., Brussen,J., Bulbrook, R., Thomas, B., Hayward, J., and Read, M. (2000). Urinary androgens and breast cancer risk: results from a long-term prospective study based in Guernsey. British Journal of Cancer 82: 1577-1584.