Ref. #15101
Chlorine Chemistry Council
May 1997


Breast Cancer - Environmental Factors and Women's Health

A Review of Chlorine-Related Research


In the search for ways to prevent breast cancer, some scientists and advocates have raised questions about possible environmental links, including hypotheses about exposure to some chemicals that contain chlorine. The questions raised are important and deserve - and are receiving - investigation.

A recent hypothesis focuses on how some naturally occurring and synthetic chemicals in the environment might mimic the effects of one of the body's own natural hormones, estrogen, and thereby contribute to breast cancer. At the heart of the chlorinated chemical/breast cancer hypothesis is the suggested link between estrogen and the development of breast cancer. Hormones produced by a woman's ovaries, especially estrogen, have been shown to cause breast cancer cells to proliferate. This indicates that the cancer is sensitive to hormones, but it may not mean that the cancer is directly caused by the hormone.

Certain chlorinated chemicals - including many natural and man-made substances - may exhibit estrogen-like (estrogenic) properties. Scientists and advocates have raised the question - a hypothesis - of a possible relationship between specific chlorine-based chemicals and breast cancer.

While the weight of scientific evidence does not support the hypothesis of a relationship between chlorinated chemicals and breast cancer, there has been an increase in the incidence of breast cancer over time that is not explained by known risk factors. This is of concern to us all.

This paper reviews the leading scientific research examining the hypothesis that environmental exposures to chlorine-based chemicals may explain increases in the rates of breast cancer. First, however, it examines both what is meant by the "weight of scientific evidence" and what we know about the rates and causes of breast cancer.

UNDERSTANDING THE WEIGHT OF SCIENTIFIC EVIDENCE ON ENVIRONMENTAL EXPOSURES

In searching for answers to hypotheses such as the suggested link between environmental chemical exposures and cancer, the scientific community evaluates all available research, including studies that first generate the hypothesis as well as ones that later test it. In making decisions, scientists rely on findings from studies with different study designs, conducted by researchers using scientifically appropriate methods and practices.

When conducting research on humans exposed to chemicals that may cause cancer, scientists consider a number of factors. They try to establish, for example:

Scientists also look at available research - including studies of humans and laboratory animals - to determine what is known and what are critical gaps in knowledge.

Taken together, all of these considerations paint a larger picture - known as the "weight of evidence." Scientifically valid conclusions can rarely be drawn from a single study. They can only be drawn from the composite evidence - the weight of evidence - that takes all available and scientifically valid studies into account.

BREAST CANCER IN THE U.S. TODAY

According to the American Cancer Society (ACS), an estimated 184,300 new invasive cases of breast cancer will be diagnosed among women in the U.S. in 1996. ACS reports that breast cancer incidence rates for women increased about four percent each year between 1982 and 1987, but recently have leveled off at about 110 new cases of breast cancer per 100,000 women. [1] National Cancer Institute (NCI) data collected through 1994 also report that breast cancer incidences have leveled off. [2] NCI estimates that among women who reach the age of 85, one in nine will develop breast cancer. [3]

Both ACS and NCI acknowledge that most of the recent increase in rates is believed to be due to marked increases in mammography utilization. [3,4] However, the reasons for longer-term trends in breast cancer are not fully understood.

Recent research on breast cancer incidence by the NCI suggests that a "substantial proportion of breast cancer cases in the U.S. are explained by well-established risk factors [i.e., later age at first birth, never giving birth, family history of breast cancer and higher socioeconomic level]."[5] Study researchers attributed approximately 41 percent of all breast cancer cases in the U.S. to these risk factors.

A second NCI study published in 1995 evaluated geographic factors in the risk of breast cancer. [6] An editorial accompanying the study's publication in the Journal of the National Cancer Institute noted that with every year of delay in giving birth to the first child, the risk of breast cancer increases in women over the age of 30 by as much as 7 or 8 percent. The editorial authors noted that most of the geographic variation in breast cancer mortality among American women appears due to variations in known reproductive and other risk factors. "The findings of the NCI should help allay fears that unknown environmental hazards are responsible for the clustering of elevated breast cancer mortality in the Northeast," according to the editorial. [7]

In acknowledging that known risk factors do not explain roughly half of the incidences of breast cancer, NCI researchers concluded, "If the genetic, hormonal and other biological exposures and traits underlying breast cancer risk factors can be understood, these determinants may be responsible for a considerable part of the current unexplained fraction of breast cancer cases as well."

IN THE SEARCH FOR ADDITIONAL ANSWERS:
Assessing the Environmental Exposure Hypothesis

In the search for additional answers to what causes and how to prevent breast cancer, some scientists and advocates have raised questions about possible environmental links, including hypotheses about some chemicals that contain chlorine.

Mount Sinai/Wolff Study

In a 1993 study, Dr. Mary S. Wolff of the Mount Sinai School of Medicine addressed the chlorinated chemical/breast cancer hypothesis. [8] Dr. Wolff,s study examined two chlorinated compounds - PCBs (polychlorinated biphenyls) and DDE (dichlorodiphenyl dichloroethylene, a breakdown product of the now-banned pesticide DDT - dichlorodiphenyl trichlorethane) - in the blood of women undergoing diagnostic testing for breast cancer.

By comparing blood levels of these chemicals in women who did not have breast cancer with those of women with the disease, Dr. Wolff concluded that there may be a link with DDE. However, she concluded it is unlikely that there is a link between PCBs and breast cancer.

The researchers assumed that levels of DDE and PCBs measured in blood samples at the time of the study represented actual levels in the blood 10, 20, or more years ago, before the women developed breast cancer. However, it is unclear whether current measurements actually reflected past exposures to DDT.

In a letter published in the Journal of the National Cancer Institute, Dr. Stephen S. Sternberg, a pathologist at Memorial Sloan Kettering Cancer Center, noted that Dr. Wolff cited an Israeli study conducted by Westin and Richter as support for conclusions in the Mt. Sinai study. [9] The Israeli study reported a decrease in breast cancer deaths after the country restricted use of some chlorinated pesticides, including DDT. "Unfortunately, Wolff et al, failed to indicate that the rapid decline was never preceded by a steep rise in breast cancer mortality subsequent to the introduction of these chemicals," said Dr. Sternberg. He added that the decrease in breast cancer deaths actually began shortly before DDT use became restricted in Israel.

Kaiser/Krieger Study

A larger and more definitive chlorine-related study was specifically designed to test Dr. Wolff,s hypo-thesis. Led by Dr. Nancy Krieger of the Kaiser Foundation Research Institute, this study did not support a relationship between exposure to DDE or PCBs and increased risk of breast cancer. [10] The Kaiser study included Dr. Wolff as a key researcher.

The Kaiser study represents an important test for the chlorinated chemical/breast cancer hypothesis. Unlike the Mt. Sinai study, researchers analyzed blood samples taken from women during routine examinations in the late 1960s, when DDT use was prevalent. They then compared the DDE levels in their patients' blood with the incidence of breast cancer occurring after nearly two decades.

An article in Public Health and Epidemiology Reports of Ontario noted that the women in the Kaiser study had DDE levels in their blood samples four times greater than those in the Mt. Sinai study, and yet, the Kaiser researchers found no association between exposure to these chemicals and risk of breast cancer. [11] In the article, Dr. Leonard Ritter, Canadian Network of Toxicology Centres, concluded, "The results of this (Kaiser) study are more convincing than the Wolff study because the sample size is larger, it is a true prospective study with an average period of 14 years from the time of sampling to development of the disease, compared with a very short 1-6 month period in the Wolff study, and the samples were taken prior to the 1972 ban on DDT when women were exposed to much higher residue levels than they are today."

In an analysis accompanying the publication of the Kaiser study in the Journal of the National Cancer Institute, Dr. Brian MacMahon, Harvard School of Public Health, also noted that the Kaiser research is stronger scientifically than previous studies, in part because it contains more subjects and greater racial and ethnic diversity. [12] "The Kaiser study has a number of features that favor its conclusions," observed Dr. MacMahon.

The Harvard School of Public Health Review

A comprehensive review by the Harvard School of Public Health examines the science of possible environmental causes of breast cancer. [13] The review also looks at possible environmental effects on endometrial tissue - the lining of the uterus - which is much more sensitive to estrogenic effects than breast tissue.

Under a grant from the Chlorine Chemistry Council (CCC), a business council of the Chemical Manufacturers Association, Harvard convened a panel of reviewers - including researchers from Harvard, Dartmouth College, Uppsala University in Sweden and Karolinska Institute in Sweden. They analyzed available scientific data - including animal tests and occupational and other epidemiological studies - to determine whether background levels of organochlorines in the general population are high enough to cause adverse effects.

In their review, neither ecological data nor occupational studies provide clear support for an association between organochlorine exposure and the occurrence of breast or endometrial cancer. "Available data do not indicate that organochlorines will affect risk of [breast cancer or endometrial cancer]," they concluded.

However, the reviewers also found that the hypothesis of an environmental link to cancer could not be rejected, and suggested that further research should focus on possible environmental effects on endometrial tissue. Based on this recommendation, the CCC is supporting an international research project led by Dartmouth University that is investigating a possible association between certain organochlorines and endometrial cancer.

Endometrial Cancer Studies

Available research on endometrial cancer provides important clues in evaluating the chlorinated chemicals/breast cancer hypothesis. Early forms of estrogen replacement therapy, involving far higher doses of synthetic estrogen than are used today, increased the risk of endometrial cancer in some women. If DDT increases the risk of breast cancer while being only mildly estrogenic, then scientists expect it to have similar effects on the endometrium. Investigators in the Mount Sinai study suggested no such link; nor has endometrial cancer increased among the U.S. population.

In a 1993 article in Environmental Health Perspectives, Richard DiAugustine of the National Institute of Environmental Health Sciences, cautioned that if heavily chlorinated pesticides were potent enough estrogens to increase breast cancer rates, endometrial cancer rates would be soaring, and they are not. [14]

A single study of monkeys chronically exposed to dioxin in their diet has been the basis for a claimed link between exposure to dioxin and endometriosis. [15] However, reviews of the study showed shortcomings, suggesting that monkeys may not be a suitable surrogate species for testing this hypothesis. For example, researchers involved in the Harvard School of Public Health Review evaluated the study and concluded "the prevalence of spontaneous endometriosis among TCDD-[the most toxic form of dioxin] unexposed monkeys was about 30 percent, considerably higher than among women, suggesting that rhesus monkeys may be more susceptible to endometriosis than are humans." [13]

Studies of Fatty Tissue

The Mount Sinai and Kaiser studies measured concentrations of DDE and PCBs in blood. A study by Dewailly, published in the February 1994 issue of the Journal of the National Cancer Institute, found higher concentrations of DDE in the fatty tissue of certain breast cancer patients, leading the authors to associate chlorinated organic chemicals with possible increased breast cancer risk. [16] How-ever, fatty-tissue studies to date yield inconsistent results.

Of the four similar studies evaluating an association between breast cancer and fatty tissue concentration of chlorinated chemicals, three studies found no association and one study suggested an association. A study by Mussalo-Rauhamaa, published in Cancer in 1990, found no association between breast fatty tissue concentrations of DDT, DDE and PCBs and breast cancer. [17] A 1992 study by Falck did suggest a correlation between concentrations of these compounds and increased risk of breast cancer. [18] Studies by Davies [19] and Unger [20], however, found no association.

Workplace Studies of PCBs

The lack of a link between PCBs and breast cancer in the Mount Sinai and Kaiser studies parallels results from earlier research involving women exposed in the workplace to high levels of PCBs. None of these occupational studies found a link between PCB exposure and elevated breast cancer risk. [21, 22, 23, 24] In fact, these studies actually found fewer cases of breast cancer among the exposed workers than expected in a normal or control population.

Clues from Animal Research

If exposure to DDT is linked to increased breast cancer risk, scientists expect similar results from studies of laboratory animals exposed to high levels of DDT throughout their lifetimes. However, the majority of research with laboratory animals indicates no increased incidence of mammary tumors. [25, 26, 27, 28, 29, 30, 31] In fact, a number of studies found the opposite effect; exposure to DDT actually resulted in fewer than expected tumors in the test animals' mammary tissue. [32, 33]

Preliminary research findings with laboratory animals suggest that dioxin, known to have anti- estrogenic properties, may actually decrease the incidence of breast cancer. This new research by Dr. William F. Greenlee of the University of Massachusetts suggests the possibility of developing a pharmaceutical product that stimulates these anti-estrogenic properties to help prevent breast cancer. [34]

INTRPRETING THE SCIENTIFIC FINDINGS

Additional insights on Estrogen, Sources of Estrogen and Breast Cancer Risks

At the heart of the chlorinated chemical/breast cancer hypothesis is the suggested link between estrogen and the development of breast cancer. The role of both synthetic (those not produced naturally by the body) and naturally occurring estrogens in breast cancer is uncertain. It is the subject of much current study and debate.

Dozens of studies of women using oral contraceptives or undergoing estrogen replacement therapy (commonly called HRT or hormone replacement therapy) have found no firmly established link between significant doses of therapeutic estrogens taken daily for years and increased breast cancer risk. In fact, a 1996 analysis of nearly all studies on the subject of "the pill" and its potential relationship to breast cancer concluded that the pill does not appear to increase the risk of breast cancer in women 10 to 20 years after they stop using it. [35]

Scientific evidence on oral contraceptives and estrogen replacement therapy provides important clues in evaluating possible risks to people from environmental exposures to estrogen. Under medical prescription, women ingest significantly higher doses of estrogen than those which occur from dietary or environmental exposure. DDT, for example, is only weakly estrogenic - about one-thousand to one-million times less estrogenic than medically prescribed estrogen replacement therapy.

Dr. Karl T. Kelsey of the Harvard School of Public Health noted in a September 1993 article in Scientific American, "although PCBs and DDT metabolites [breakdown products such as DDE] have been shown to have estrogen-like activity, other compounds such as birth control pills that have orders of magnitude more activity have not been definitively associated with breast cancer. So it is hard to understand how these compounds could be active when those others are not." [36]

Dr. Stephen Safe of Texas A&M University takes this line of inquiry even further to include natural estrogens in the food supply. Dr. Safe estimated that people consume 40 million-fold higher levels of natural estrogens in food daily than they receive from typical exposures to industrial compounds that are considered estrogenic. Safe concluded, "The suggestion that industrial estrogenic chemicals contribute to an increased incidence of breast cancer in women ... is not plausible." [37]

According to Dr. Safe, synthetic estrogens in drugs and naturally occurring in food are far more potent than the estrogenic activity from certain chemical compounds. The comparisons below estimate daily doses in terms of estrogen equivalents:

Morning after pill 333,500 times
Birth control pill 16,675 times
Post-menopausal therapy 3,350 times
Flavonoids(Naturally occurring estrogens in food 102 times
Environmental organochlorine estrogens 0.0000025 times

Safe concluded that "(this illustrates) the minimal potential of these industrial estrogens to cause an adverse endocrine-related response in humans." [37]

More recently, a 1996 report from the National Academy of Sciences, although not limited to breast cancer, concluded that (1) the risk of cancer from naturally occurring chemicals is much greater than the risk from synthetic chemicals in the environment and (2) for the majority of natural and synthetic chemicals found in food, the levels are far too low to pose a measurable cancer risk. [38]

IN FURTHER PURSUIT OF A BETTER UNDERSTANDING

While the weight of scientific evidence does not support the hypothesis of a relationship between chlorinated chemicals and breast cancer, the Chlorine Chemistry Council and its member companies encourage and are supporting additional research.

Ongoing CCC-supported studies include:

The CCC is committed to furthering public dialogue on breast cancer. As part of that commitment, the Council will continue to disseminate information and support research to help us understand and find ways to prevent breast cancer.

BIBLIOGRAPHY

1. American Cancer Society, Cancer Facts & Figures 1996, P. 7.

2. Ries L.A.G., Kosary C.L., Hankey B.F., Miller B.A., Harras A., Edwards B.K. (eds). SEER Cancer Statistics Review, 1973-1994, National Cancer Institute, NIH Pub. No. 97-2789, Bethesda, MD, 1997.

3. Devesa S.S., Blot W.J., Stone B.J., Miller B.A., Tarone R.E., Fraumeni Jr. J.F., "Recent Cancer Trends in the United States," Journal of the National Cancer Institute, 1995, 87(3):175-182.

4. American Cancer Society, Breast Cancer Facts & Figures - 1996, P. 3.

5. Madigan M.P., Ziegler R.G., Benichou J., Byrne C., Hoover R.N., "Proportion of Breast Cancer Cases in the United States Explained by Well-Established Risk Factors," Journal of the National Cancer Institute, 1995, 87(22):1681-1685.

6. Sturgeon S.R., Schairer C., Gail M., McAdams M., Brinton L.A., Hoover R.N., "Geographic Variation in Mortality From Breast Cancer Among White Women in the United States," Journal of the National Cancer Institute, 1995, 87(24):1846-1853.

7. Blot W.J., McLaughlin J.K., "Geographic Patterns of Breast Cancer Among American Women," Journal of the National Cancer Institute, 1995, 87(24):1819-1820.

8. Wolff M.S., Toniolo P.G., Lee E.W., Rivera M., Dubin N., "Blood Levels of Organochlorine Residues and Risk of Breast Cancer," Journal of the National Cancer Institute, 1993, 85(8):648-652.

9. Westin J.B., Richter E., "The Israeli Breast-Cancer Anomaly," Ann. NY Acad.Sci., 1990, 609:269-279.

10. Krieger N., Wolff M.S., Hiatt R.A., Rivera M., Vogelman J., Orentreich N., "Breast Cancer and Serum Organochlorines: A Prospective Study Among White, Black, and Asian Women," Journal of the National Cancer Institute, 1994, 86(8):589-599.

11. Ritter L., "Organochlorine Residues and Risk of Breast Cancer," Public Health and Epidemiology Reports of Ontario, 1994, 5(8):176-183.

12. MacMahon B., "Pesticide Residues and Breast Cancer?" Journal of the National Cancer Institute, 1994, 86(8):572-573.

13. Ahlborg U.G., Lipworth L., Titus-Ernstoff L., Hsieh C., Hanberg A., Baron J., Trichopoulos D., Adami H., "Organochlorine Compounds in Relation to Breast Cancer, Endometrial Cancer, and Endometriosis: An Assessment of the Biological and Epidemiological Evidence," Critical Reviews in Toxicology, 1995, 25(6):463-531 and "Organochlorine Compounds and Estrogen-Related Cancers in Women," Cancer Causes and Control, 1995, 6:551-566.

14. Pollner F., "A Holistic Approach to Breast Cancer Research," Environmental Health Perspectives, 1993, Vol. 101, No. 2.

15. Rier S.E., Martin D.C., Bowman R.E., Dmowski W.P., Becker J.L., "Endometriosis in Rhesus Monkeys (Macaca Mulatta) Following Chronic Exposure to 2,3,7,8-Tetrachlorodibenzo-p-dioxin," Fundam. Appl. Toxicolo., 1993, 21:433-441.

16. Dewailly E., Dodin S., Verreault R., Ayotte P., Sauve L., Morin J., Brisson J., "High Organochlorine Body Burdens in Women With Estrogen Receptor-Positive Breast Cancer," Journal of the National Cancer Institute, 1994, 86(3):232-234.

17. Mussalo-Rauhamaa H., Hasanen E., Pyysalo H., Antervo K., Kauppila R., Pantzar P., "Occurrence of Beta-hexachlorocyclohexane in Breast Cancer Patients," Cancer, 1990, 66:2124-2128.

18. Falck F., Ricci A. Jr., Wolff M.S., Godbold J., Deckers P., "Pesticides and Polychlorinated Biphenyl Residues in Human Breast Lipids and Their Relation to Breast Cancer," Arch. Environ. Health, 1992, 47(2):143-146.

19. Davies J.E., Barquet A., Morgade C. and Raffonelli A., "Epidemiologic Studies of DDT and Dieldrin Residues and Their Relationship to Human Carcinogenesis," Proceedings of the International Symposium on Recent Advances in the Assessment of the Health Effects of Environmental Pollution, Volume II, Symposium sponsored by the Commission of the European Communities and the U.S. Environmental Protection Agency, 1975.

20. Unger M., Kiaer H., Blichert-Toft M., Olsen J., Clausen J., "Organochlorine Compounds in Human Breast Fat From Deceased With and Without Breast Cancer and In a Biopsy Material From Newly Diagnosed Patients Undergoing Breast Surgery," Environ. Res., 1984, 34:24-28.

21. Bertazzi P.A., Riboldi L., Pesatori A., Radice L., Zocchetti C., "Cancer Mortality of Capacitor Manufacturing Workers," Amer. Jour. Ind. Med., 1987, 11:165-175.

22. Brown D.P., "Mortality of Workers Exposed to Polychlorinated Biphenyls - An Update," Arch. Environ. Health, 1987, 42:333-339.

23. Sinks T., Personal Communication re: Sinks T., Steele G., Smith A.B., Watkins K., Shults R.A., "Mortality Among Workers Exposed to Polychlorinated Biphenyls," Amer. J. Epidemiol., 1992, 136:389-398.

24. Taylor P.R., "The Relation of Occupational Polychlorinated Biphenyl Exposure to Cancer and Total Mortality," Doctoral Dissertation. Harvard School of Public Health, 1989.

25. Abramson R.H., Sieber S.M., "The Use of Nonhuman Primates for Chemical Carcinogenesis Studies," Exotoxicol. Environ. Qual., 1979, 2:275-296. Cited In: EPA, 1992, IRIS on-line database, DDT, March 6, 1992.

26. Abramson R.H., Sieber S.M., "Chemical Carcinogenesis Studies in Nonhuman Primates," Basic Life Sci., 1983, 24:129-156. Cited In: EPA, 1992, IRIS on-line database, DDT, March 6, 1992.

27. Fitzhugh O.G., Nelson A.A., "The Chronic Oral Toxicity of DDT," J. Pharmacol., 1946, 89:18-30.

28. International Agency for Research on Cancer: "Occupational Exposures in Insecticide Application, and Some Pesticides," IARC Monogr. Eval. Carcinog. Risk Chem. Man., 1991, 53:179-249.

29. Lehman A.J., "Chemical in Foods. A Report to the Association of Food and Drug Officials on Current Developments," Part II, Pesticides. Section V. Pathology. Q. Bull. Assoc. Food Drug Off., 1951, 15:126-132. Cited In: EPA, 1992, IRIS on-line database, DDT, March 6, 1992.

30. Lehman A.J., "Summaries of Pesticide Toxicity," Association of Food and Drug Officials of the United States, Topeka, Kansas, 1965. Cited In: EPA, 1992, IRIS on-line database, DDT, March 6, 1992.

31. Silverhorn E.M., Glauert H.P., Robertson L.W., "Carcinogenicity of Polyhalogenated Biphenyls: PCBs and PBBs," Crit. Rev. Toxicol., 1990, 20(6):440-496.

32. Cabral J.R.P., Hall R.K., Rossi L., Broncyzk S.A., Shubik P., "Effects of Long-term Intake of DDT on Rats," Tumorigenesis, 1982, 68:11-17.

33. Rossi L., Ravera M., Repetti G., Santi L., "Long-term Administration of DDT or Phenobarbital in Wistar Rats," Int. J. Cancer, 1977, 19:179-185.

34. Greenlee, William F. et.al., "Expression of Cytochrome P450 CYP1B1 in Breast Cancer," Federation of European Biochemical Societies Letters," 1995, 374:270-272.

35. Contraception (suppl.), "Breast Cancer and Hormonal Contraceptives," September 1996, 54(3):1S-106S.

36. Rennie, John, Scientific American, September 1993.

37. Safe S.H., "Environmental and Dietary Estrogens and Human Health: Is There a Problem?" Environ. Health Perspec., 1995, 103(4):346-351.

38. National Research Council, "Carcinogens and Anti-carcinogens in the Human Diet: A Comparison of Naturally Occurring and Synthetic Substances," 1996.