PLASMA ORGANOCHLORINE LEVELS AND THE RISK OF BREAST CANCER: AN EXTENDED FOLLOW-UP IN THE NURSES’ HEALTH STUDY Francine LADEN 1 * , Susan E. HANKINSON 1,2 , Mary S. WOLFF 3 , Graham A. COLDITZ 1,2,4 , Walter C. WILLETT 1,2,5 , Frank E. SPEIZER 1,6 and David J. HUNTER 1,2,4,5 1 Channing Laboratory, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA 2 Department of Epidemiology, Harvard School of Public Health, Boston, MA, USA 3 Department of Community and Preventive Medicine, Environmental and Occupational Medicine, Mount Sinai School of Medicine, New York, NY, USA 4 Center for Cancer Prevention, Harvard School of Public Health, Boston, MA, USA 5 Department of Nutrition, Harvard School of Public Health, Boston, MA, USA 6 Department of Environmental Health, Harvard School of Public Health, Boston, MA, USA The environmental organochlorines 2,2-bis(p-chlorophenyl)- 1,1,1,trichloroethane (DDT) and polychlorinated biphenyls (PCBs) have been implicated as potential causes of female breast cancer. We continued follow-up of our 1997 case-control study nested in the Nurses’ Health Study cohort, adding 143 postmenopausal cases and controls to the original 238 pairs, and examining specific PCB congeners for the first time. We measured plasma levels of 2,2-bis(p-chlorophenyl)ethylene (DDE), the major metabolite of DDT, and PCBs prospectively, comparing women who were diagnosed with breast cancer between 1 month and 4 years after blood collection with con- trol women in whom breast cancer did not develop. Median concentrations of lipid-adjusted DDE, total PCBs, and PCB numbers 118, 138, 153 and 180, assessed individually, were similar among the cases and controls. The multivariate relative risk of breast cancer for women in the highest quintile of expo- sure as compared with women in the lowest quintile was 0.82 for DDE (95% confidence interval [CI]: 0.49 –1.37) and 0.84 for total PCBs (95% CI: 0.47–1.52), 0.69 for PCB 118 (95% CI: 0.39 –1.22), 0.87 for PCB 138 (95% CI: 0.50 –1.50), 0.83 for PCB 153 (95% CI: 0.47–1.48), and 0.98 for PCB 180 (95% CI: 0.55– 1.75). Sub-group analyses were also performed. Overall, our results do not support the hypothesis that exposure to DDT and PCBs increases the risk of breast cancer. © 2001 Wiley-Liss, Inc. Key words: breast cancer; DDE; PCBs; DDT; organochlorine; plasma The environmental organochlorines 2,2-bis(p-chlorophenyl)- 1,1,1,trichloroethane (DDT) and polychlorinated biphenyls (PCBs) have been implicated as potential causes of female breast cancer. Some of these compounds have demonstrated weak estro- genic properties in vitro 1,2 and have been shown to adversely affect reproduction and sex determination in wildlife. 3,4 Others have dioxin-like activity and are considered anti-estrogenic. 5 Some PCBs have been observed to induce P450 metabolizing enzymes 6 or affect the immune system 7 in animal experiments. Although use and manufacture of DDT and PCBs were banned in the United States in 1972 and 1977, respectively; the compounds persist in the environment. Furthermore, PCBs and 1,1-dichloro-2,2-bis(p-chlo- rophenyl)ethylene (DDE), the main metabolite of DDT, are lipid soluble and stored in adipose tissue, in the lipid components of blood and in breast milk. Because they are resistant to metabolism and have long half-lives, measurements of these organochlorines in these biological media represent cumulative exposures over time. 8,9 Thirteen large epidemiological studies (each with at least 50 cases) have been published that assessed exposure to DDE and PCBs in either blood (plasma or serum) or in adipose tissue in relation to risk of breast cancer, including one from our group. 10 –22 A prospective study of breast cancer cases in New York found a significant increase in the risk of breast cancer with higher serum levels of DDE and a nonsignificant positive association with PCBs collected 1– 6 months prior to diagnosis. 20 In a San Francisco Bay area study of incident breast cancer cases diagnosed from 6 months to 20 years after blood collection, there was a nonsignificant elevated risk associated with DDE among African Americans and whites in ethnicity-specific analyses, but the risk in Asians and all participants combined was not elevated. 15 Findings from subsequent studies have been inconsistent. Re- sults from a retrospective case-control study in western New York state suggested an association between highly chlorinated PCBs and postmenopausal breast cancer risk among parous women who had never breast-fed. 17 A Canadian study comparing levels of organochlorines in adipose tissue from breast cancer cases and benign breast disease controls observed a similar association in the same subgroup for Mirex, an organochlorine insecticide, but not for PCBs. 10 These authors did observe elevated breast cancer risk with higher levels of PCB congeners 105 and 118 among pre- menopausal women (71 cases) and with higher levels of congeners 170 and 180 among postmenopausal women (143 cases). 10 A case-control study of serum levels in a population in Colombia suggested an increased risk associated with elevated levels of DDE. 18 However, most studies have not supported the hypothesis that exposure to DDT and PCBs increases the risk of breast cancer overall. 11–14,16,17,19,21,22 In the largest prospective study published to date, Helzlsouer et al. 12 did not observe an elevated risk of breast cancer associated with PCBs and DDE, regardless of lacta- tion status or decade of blood collection. In 1997, we published an analysis of DDE and PCBs and breast cancer risk in a case-control study of 238 incident cases, nested in the Nurses’ Health Study. We did not observe any evidence of an increased risk of breast cancer among women with relatively high levels of plasma DDE or PCBs. 14 In the current analysis we expand the period of follow-up to include an additional 143 cases of invasive postmenopausal breast cancer. In this larger sample, we have assessed the association of breast cancer risk with specific PCB congeners, as well as total PCBs and DDE. We also evaluated risk in potentially susceptible sub-groups, including those defined by lactation, body mass index and other breast cancer risk factors. Our previous publication was criticized because we had not ad- justed plasma organochlorines for triglycerides in addition to Grant sponsor: National Institutes of Health; Grant numbers: UO1 CA/ES62984, CA40356 and CA49449; Grant sponsor: National Institute of Health National Research Service; Grant number: T32HL07427. (F. Laden) *Correspondence to: Channing Laboratory, 181 Longwood Ave., Bos- ton, MA 02115, USA. Fax: (617) 731-1541. E-mail: francine.laden@ channing.harvard.edu Received 7 March 2000; Revised 23 June 2000; Accepted 5 September 2000 Published online 3 January 2001 Int. J. Cancer: 91, 568 –574 (2001) © 2001 Wiley-Liss, Inc. Publication of the International Union Against Cancer