DDT and Breast Cancer

Environ Health Perspect. doi:10.1289/ehp.11025 available via http://dx.doi.org [Online 27 March 2008]

Referencing: DDT and Breast Cancer in Young Women: New Data on the Significance of Age at Exposure

In a recent article, Cohn et al. (2007) noted an association between increased breast cancer risk and p,p´-DDT [1,1,1-trichloro-2,2-bis(p-chlorophenyl)ethane] exposure early in life. Their article should be interpreted with caution, particularly the estimated 5-fold increase in risk for women born after 1931 the authors reported without qualification in the "Abstract"; this value was repeated in the news article by Manuel (2007). Cohn et al. (2007) evaluated three DDT congeners—that is, p,p´-DDT, o,p´-DDT [1,1,1-trichloro-2(p-chlorophenyl)-2-(o-chlorophenyl)ethane], and p,p´-DDE [1,1-dichloro-2,2-bis(p-chlorophenyl)ethylene]—by various categories of year of birth, yet they found no significantly increased risk estimates for any of the three DDT congeners in multiple comparisons that were not adjusted for the other DDT-related chemicals either in all women or in women born after 1931. The estimated 5-fold increase in risk for the upper tertile of p,p´-DDT serum levels was only observed in subgroup analyses that were both restricted to women born after 1931 and adjusted for serum level of o,p´-DDT. The impact of the adjustment for o,p´-DDT on the risk estimate for p,p´-DDT is remarkable in view of the low o,p´-DDT levels observed (35% were below the limit of detection). A significant inverse association between o,p´-DDT level and breast cancer risk, which was interpreted by Cohn et al. in terms of length of time since DDT exposure, became stronger after adjustment for p,p´-DDT levels; presumably this does not indicate a protective effect of recent DDT exposure.

In view of the absence of evidence for an association between p,p´-DDE levels and breast cancer risk (Lopez-Cervantes et al. 2004), it seems unlikely that DDT exposure increases the risk of breast cancer. Nonetheless, if the effect of DDT exposure early in life on breast cancer risk is large [a possibility suggested by Cohn et al. (2007)], then the decreasing birth cohort trend in breast cancer risk that has been observed for U.S. baby boomers is even more remarkable (Chu et al. 1999; Tarone 2006, 2007; Tarone and Chu 2000). Women born after 1945 would have been exposed to DDT for each of the first 13 years of life, with increasing exposure through the late 1960s (Wolff et al. 2005), but the birth cohort risk of breast cancer showed a marked decrease among U.S. women for over two decades after 1945. DDT exposure would join a list of other breast cancer risk factors predicting increasing breast cancer risk in baby boomers (Tarone 2006); yet the birth cohort risk of breast cancer decreased for women born after 1945. That the hypothesized association between DDT exposure and breast cancer risk has received far more attention than the paradoxical decreasing risk of breast cancer that has actually occurred among young U.S. women says much about the priorities and focus of environmental epidemiology.

The author declares he has no competing financial interest.

References

Chu KC, Tarone RE, Brawley OW. 1999. Breast cancer trends in black women compared with white women. Arch Fam Med 8:521–529.

Cohn BA, Wolff MS, Cirillo PM, Sholtz RI. 2007. DDT and breast cancer in young women: new data on the significance of age at exposure. Environ Health Perspect 115: 1406–1414.

López-Cervantes M, Torre-Sánchez L, Tobias A, López-Carrillo L. 2004. Dichlorodiphenyldichloroethane burden and breast cancer risk: a meta-analysis of the epidemiologic evidence. Environ Health Perspect 112:207–214.

Manuel J. 2007. DDT and breast cancer revisited: new findings in an old debate. Environ Health Perspect 115:A505.

Tarone RE. 2006. Breast cancer trends among young women in the United States. Epidemiology 17: 588–590.

Tarone RE. 2007. Breast cancer trends: the author replies [Letter]. Epidemiology 18:284–285.

Tarone RE, Chu KC. 2000. Age-period-cohort analyses of breast-, ovarian-, endometrial-, and cervical-cancer mortality rates for Caucasian women in the USA. J Epidemiol Biostat 5:221–231.

Wolff MS, Britton JA, Teitelbaum SL, Eng S, Deych E, Ireland K, et al. 2005. Improving organochlorine biomarker models for cancer research. Cancer Epidemiol Biomarkers Prev 14:2224–2236.

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DDT and Breast Cancer: Cohn et al. Respond

Environ Health Perspect. doi:10.1289/ehp.11025R available via http://dx.doi.org [Online 27 March 2008]

We thank Tarone for his letter, as it provides an opportunity to elaborate on analytic strategies for the study of DDT associations with breast cancer.

One feature of our study (Cohn et al. 2007)—assessment of exposure in blood samples collected during active DDT use in the 1960s—provided a unique opportunity to examine three DDT-related compounds singly and in combination. The three DDT-related compounds studied represent distinct aspects of exposure. p,p´-DDT [1,1,1-trichloro-2,2-bis(p-chlorophenyl)ethane] is the primary ingredient of commercial grade DDT. p,p´-DDE [1,1-dichloro-2,2-bis(p-chlorophenyl)ethylene], the most persistent DDT-related compound, is a metabolite of p,p´-DDT that is both made by humans during active exposure, and also ingested directly from food sources where it can be stored for long periods in fat (Morgan and Roan 1975). o,p´-DDT [[1,1,1-trichloro-2(p-chlorophenyl)-2-(o-chlorophenyl)ethane] is a low-concentration contaminant of commercial DDT that is eliminated by humans most quickly, making it a marker of recent exposure (Morgan and Roan 1975). Therefore, absolute and relative DDT/DDE isomer levels may represent different windows of exposure (Wolff et al. 2007).

Unlike our investigation, most other breast cancer studies were conducted long after active use of DDT ceased. Thus the preponderance (> 95%) of their exposure was only p,p´-DDE [see our Figure 1 and Table 1 (Cohn et al. 2007)]. Hence, our study provides new information. An additional dimension is that these compounds have been shown to have distinctly different endocrine activity (Kelce et al. 1995), suggesting potential for differential effects on human outcomes. Therefore, we disagree with Tarone's assertion that the lack of an association between p,p´-DDE and breast cancer risk in young women refutes a role for p,p´-DDT exposure. The timing, origin, and functional activity may differ for each compound.

Concurrent measurements of p,p´-DDT, p,p´-DDE, and o,p´-DDT allow evaluation of potential differences in the effects of these compounds. Other studies have also observed differing associations with cancer risk for p,p´-DDT and its metabolite, p,p´-DDE. McGlynn et al. (2006) reported that the p,p´-DDT association with risk of liver cancer was enhanced when p,p´-DDE was low. We also reported that a higher proportion of p,p´-DDT to p,p´-DDE in maternal serum samples was associated with longer time to pregnancy in their daughters 30 years after exposure in utero (Cohn et al. 2003). In another other breast cancer study, Romieu et al. (2000) showed a significant effect for p,p´-DDE—after adjustment for p,p´-DDT—for predicting breast cancer, particularly in postmenopausal women. We believe that simultaneous adjustment for DDT-related compounds is a strength of our study.

Tarone suggests that subgroup analyses weaken the results of our article (Cohn et al. 2007). However, we pointed out in our article that subgroup analyses, by birth cohort, were planned a priori and were a primary objective of our study. In this setting, subgroup analyses are a strength that enabled us to examine whether age at DDT exposure may be of importance in human breast cancer.

The trends in breast cancer incidence in young women previously presented by Tarone in Table 1 of his article (Tarone 2006) do not refute a possible effect of DDT exposure in childhood. Successive birth cohorts of women diagnosed at 20–39 years of age between 1975 and 2002 (Table 1; Tarone 2006) experienced decreasing DDT exposure in childhood (birth years 1941–1982) because DDT use began in 1945, peaked in 1959, and was banned in 1972 in the United States (U.S. Environmental Protection Agency 1975). Successive birth cohorts of women diagnosed at 40–49 years of age between 1990 and 2002 (Table 1 in Tarone 2006) were all exposed to DDT in childhood (birth years 1941–1962); therefore, breast cancer trends for these birth cohorts are not informative for investigating effects of DDT exposure in childhood. Further, we agree with Weiss (2007) that trends in invasive disease and mortality cannot be interpreted without consideration of the rising incidence of in situ disease and its successful treatment, which would reduce incidence of invasive disease and mortality.

The authors declare they have no competing financial interests.

References

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Cohn BA, Wolff MS, Cirillo P, Sholtz RI. 2007. DDT and breast cancer in young women: new data on the significance of age at exposure. Environ Health Perspect 115: 1406–1414.

Kelce WR, Stone CR, Laws SC, Gray LE, Kemppainen JA, Wilson EM. 1995. Persistent DDT metabolite p,p´-DDE is a potent androgen receptor antagonist. Nature 375:581–585.

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Morgan D, Roan CC. 1975. The metabolism of DDT in man. In: Essays in Toxicology (Hayes WJ, ed). New York: Academic Press, 39–97.

Romieu I, Hernandez-Avila M, Lazcano-Ponce E, Weber JP, Dewailly E. 2000. Breast cancer, lactation history and serum organochlorines. Am J Epidemiol 152(4):363–370.

Tarone RE. 2006. Breast cancer trends among young women in the United States. Epidemiology 17(5): 588–590.

U. S. Environmental Protection Agency. 1975. DDT, A Review of Scientific and Economic Aspects of the Decision to Ban Its Use as a Pesticide. EPA-540/1-75-022. Washington, DC:U.S. Environmental Protection Agency.

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Wolff MS, Anderson HA, Britton JA, Rothman N. 2007. Pharmacokinetic variability and modern epidemiology the example of dichlorodiphenyltrichloroethane, body mass index, and birth cohort. Cancer Epidemiol Biomarkers Prev 16(10):1925–1930.