Affiliations of authors: D. M. Gertig, F. E. Speizer,Channing Laboratory, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA; D. J. Hunter, G. A. Colditz, Channing Laboratory, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, and Department of Epidemiology, Harvard School of Public Health, Boston, and Harvard Center for Cancer Prevention, Boston; D. W. Cramer, Obstetrics and Gynecology Epidemiology Center, Brigham and Women's Hospital; W. C. Willett, Channing Laboratory, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, and Departments of Epidemiology and Nutrition, Harvard School of Public Health; S. E. Hankinson, Channing Laboratory, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, and Department of Epidemiology, Harvard School of Public Health.
Correspondence to: Dorota M. Gertig, MB.BS., MHSc., ScD., Centre for Genetic Epidemiology, University of Melbourne, 200 Berkeley St., Carlton 3053, Australia (e-mail: Dorota.Gertig{at}channing.harvard.edu).
![]() |
ABSTRACT |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
![]() |
INTRODUCTION |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
![]() |
METHODS |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Ascertainment of cases. We sought medical records from all women who reported a diagnosis of ovarian cancer or who were deceased in each follow-up cycle. Records were reviewed by physicians unaware of exposure status. Histologic subtypes were determined from pathology reports, and epithelial ovarian cancers were classified as serous cancers (including cystadenocarcinoma and papillary adenocarcinoma), mucinous cancers (including adenocarcinoma and mucinous papillary adenocarcinoma), and endometrioid cancers (clear cell and other types, including mixed epithelial tumors). Borderline histologic tumors are included in the analysis. Deaths are reported by relatives and postal authorities, as well as a search of the National Death Index. Mortality follow-up is estimated to be 98% complete in this cohort (14). Cases of epithelial ovarian cancer (International Classification of Diseases Code, ICD183.0), confirmed by medical record review or death certificate, occurring between the return of the 1982 questionnaire and June 1, 1996, were included in the analysis.
Exclusions. Women who did not respond to the question on talc use in 1982 were excluded from this analysis. We also excluded women who had reported a diagnosis of cancer (other than nonmelanoma skin cancer) before 1982, as well as women who reported bilateral oophorectomy, surgery with an unknown number of ovaries removed, and a history of radiation therapy. Validity of self-reported surgical menopause has been assessed previously, and agreement with medical records was more than 97% (15). These exclusions were updated every 2 years. At baseline, 78 630 women were eligible for the analysis. The resulting population after exclusions contributed 984 212 person-years of follow-up and 307 cases of epithelial ovarian cancer.
Ascertainment of talc exposure. Use of talcum powder was ascertained on the 1982 questionnaire in the following ways: "Have you ever commonly used talcum, baby powder, or deodorizing powder a) to apply to perineal (private) area? No, daily, one to six times per week, or less than once per week or b) to apply on sanitary napkins? No, Yes." We classified "ever talc use" as ever talc use on either the perineal area or sanitary napkins.
Other covariates. Potential risk factors and confounders of the association between ovarian cancer and exposures of interest in this analysis also were obtained from the biennial questionnaires and were updated every 2 years where relevant. Oral contraceptive use was asked every 2 years from 1976 through 1982, by which time use was rare. Tubal ligation history was asked as part of a question on methods of contraception from 1976 through 1984, and, in 1994, women were asked if they had ever had a tubal ligation and, if so, at what age. Family history of ovarian cancer was not asked until 1992. Parity was defined as the number of pregnancies lasting 6 months or more and was asked through 1984.
Statistical analysis. Incidence rates (number of cases for each category of exposure
divided by person months of follow-up in that cycle) were calculated for each category, adjusting
for age in 5-year intervals. Proportional hazards models by use of pooled logistic regression were
used to derive relative risks (RRs) and 95% confidence intervals (CIs) of disease for each
exposure category (16). For age-adjusted analyses, we categorized
variables as follows: parity (0, 1-2, or 3), oral contraceptive use (never, past, or current),
tubal ligation (yes or no), postmenopausal hormone use (never, past, or current), cigarette
smoking (never, past, or current), and body mass index, i.e., weight in kilograms/height in meters
squared (<21, 21.0-22.9, 23.0-24.9, 25.0-28.9, or
29 kg/m2). In
multivariate analyses, we adjusted for age (years) and for potential risk factors by use of indicator
variables for each category as described above, except for parity (0, 1-2, 3-4, or
5) and
duration of oral contraceptive use (never or <3, 3-5, or >5 years), for which we used a
larger number of categories to more appropriately control for confounding. In addition we
controlled for age at menarche, duration of breast-feeding, and age at menopause. However, since
this did not alter the estimates for talc use, further models did not control for these variables.
Body mass index and duration of oral contraceptive use were also entered as continuous
variables, and similar estimates were obtained. All RRs reported are multivariate unless
otherwise stated. P values reported are two-sided.
![]() |
RESULTS |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
|
|
|
Cosmetic talc may have been more likely to contain asbestos fibers prior to 1976, before voluntary guidelines were proposed (9). As a proxy for early talc use, we assessed risk among women 45 years old or older in 1982. There was no evidence that older women in 1982 were at greater risk of ovarian cancer overall; the RR for ever talc use compared with never talc use for women under 45 years was 0.95 (95% CI = 0.59-1.53) and among women 45 years old or older was 1.13 (95% CI = 0.86-1.47). However, women 45 years old or older in 1982 who ever used talc had a higher risk of serous invasive cancer (RR = 1.51; 95% CI = 1.07-2.15). There was no evidence of effect modification by oral contraceptive use, body mass index, or cigarette smoking for epithelial cancers overall.
![]() |
DISCUSSION |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
However, there are several important limitations to our study. The questions on talcum powder use referred to ever use, and we cannot determine the age at which women began using talc or the duration of use. Thus, we were unable to assess the potential effect of talc use before first pregnancy, which has been shown to be a stronger risk factor for ovarian cancer than use after pregnancy in one study (13). The number of lifetime applications of talc has also been associated with increased risk of ovarian cancer in some previous studies (9,13). Our relatively short follow-up period may be inadequate to detect an association if the latency for development of ovarian cancer is more than 15 years. Although we controlled for tubal ligation history, the tubal ligation question was asked as part of a question on contraceptive use; therefore, postmenopausal women and some premenopausal women who were not sexually active may not have responded to the question. Substantial residual confounding is unlikely, since there was no overall association between talc use and tubal ligation in this study. In addition, we excluded women who were postmenopausal in 1976 from analyses stratified by tubal ligation history. Finally, the prevalence of talc use in our study is somewhat higher than that in other studies and may reflect the fact that we asked about frequency of ever use rather than current regular use; this may have contributed to an attenuation of risk due to misclassification of exposure.
The potential effect of talc on the ovaries depends on migration of talc fibers through a patent genital tract, and we would, therefore, expect a stronger association among women without a tubal ligation who had used talc. However, no effect modification was seen by history of tubal ligation. Because we did not have the date of tubal ligation, some women may have begun talc use only after tubal ligation, potentially resulting in misclassification of talc use and attenuation of the RRs.
Since the first study showing an almost twofold increase in risk of ovarian cancer with any perineal talc use (4), most case-control studies have demonstrated positive associations with talc use (4-13), although not all have been statistically significant (5,6,8). Several studies (9,17-20) found no overall association between any genital talc use and ovarian cancer. We did not observe a dose-response relationship with talc use, and previous studies also have been inconsistent in this regard. Some studies (9,13,17) have demonstrated statistically insignificant trends in risk with increased frequency of talc use, duration of use, and measures of "total lifetime applications," while other studies (6,8) have not observed a statistically significant dose response.
With regard to histologic subtypes, a recent study by Cramer et al. (13) observed the greatest risk for talc use and invasive serous cancer; however, other studies found increased risks for endometrioid cancers (9,12), serous cancers (7), and invasive cancers of all subtypes (12). Since serous cancers, which account for more than half of all invasive ovarian cancers, most resemble mesotheliomas, it could be hypothesized that this subtype may be most likely associated with talc use. In our stratification by subtype, we did observe a modest positive association with serous invasive cancers and ever talc use as well as a borderline significant trend for increasing frequency of ever use.
The biologic evidence for the association of talc and ovarian cancer is incomplete. Asbestos has been linked to ovarian cancer in occupational settings and is associated with peritoneal tumors similar to ovarian cancer (2,3,21). Because of the chemical similarity of talc and asbestos, talc also has been implicated as a possible ovarian carcinogen. Talc is able to migrate through the genital tract and gain access to the ovaries because talc fibers have been detected in benign and malignant ovarian tissue (22), although no relation between reported levels of talc exposure and ovarian talc counts has been observed (23). There have been few studies (24,25) of talc exposure in animals, and these studies have not demonstrated an increase in ovarian cancer among animals subjected to chronic talc exposure. These data should be interpreted cautiously because there are important anatomic and physiologic differences between rodents and humans, and talc in animals is often administered at high dose via aerosol exposure (24).
In summary, we did not observe an overall association between epithelial ovarian cancer and ever use of talc, and there was no apparent dose response, although we lacked information on duration of talc use. In analyses stratified by histologic subtype, we observed a modest positive association between invasive serous cancer and ever talc use. Our results provide little support for any substantial association between perineal talc use and ovarian cancer risk overall; however, perineal talc use may modestly increase the risk of invasive serous ovarian cancers.
![]() |
NOTES |
---|
We thank Karen Corsano and Barbara Egan for their expert assistance with the study and Kathleen Fairfield for her help with analysis. We also thank the Nurses' Health Study participants for their continuing dedication and commitment.
![]() |
REFERENCES |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
1 Harlow BL, Hartge PA. A review of perineal talc exposure and risk of ovarian cancer. Regul Toxicol Pharmacol 1995;21:254-60.[Medline]
2 Keal E. Asbestosis and abdominal neoplasms. Lancet 1960;2:1211-6.[Medline]
3 Acheson ED, Gardner MJ, Pippard EC, Grime LP. Mortality of two groups of women who manufactured gas masks from chrysotile and crocodilite asbestos: a 40 year follow-up. Br J Indust Med 1982;39:344-8.[Medline]
4 Cramer DW, Welch WR, Scully RE, Wojciechowski CA. Ovarian cancer and talc: a casecontrol study. Cancer 1982;50:372-6.[Medline]
5 Chen Y, Wu PC, Lang JH, Ge WY, Hartge P, Brinton LA. Risk factors for epithelial ovarian cancer in Beijing, China. Int J Epidemiol 1992;21:23-9.[Abstract]
6 Whittemore AS, Wu ML, Paffenbarger RS Jr, Sarles DL, Kampert JB, Grosser S, et al. Personal and environmental characteristics related to epithelial ovarian cancer. II. Exposures to talcum powder, tobacco, alcohol, and coffee. Am J Epidemiol 1988;128:1228-40.[Abstract]
7 Cook LS, Kamb ML, Weiss NS. Perineal powder exposure and the risk of ovarian cancer. Am J Epidemiol 1997;145:459-65.[Abstract]
8 Booth M, Beral V, Smith P. Risk factors for ovarian cancer: a case-control study. Br J Cancer 1989;60:592-8.[Medline]
9 Harlow BL, Cramer DW, Bell DA, Welch WR. Perineal exposure to talc and ovarian cancer risk. Obstet Gynecol 1992;80:19-26.[Abstract]
10 Purdie D, Green A, Bain C, Siskind V, Ward B, Hacker N, et al. Reproductive and other factors and risk of epithelial ovarian cancer: an Australian case-control study. Int J Cancer 1995;62:678-84.[Medline]
11 Shushan A, Paltiel O, Iscovich J, Elchalal U, Peretz T, Schenker J. Human menopausal gonadotropin and the risk of epithelial ovarian cancer. Fertil Steril 1996;65:13-8. [Medline]
12 Chang S, Risch HA. Perineal talc exposure and risk of ovarian carcinoma. Cancer 1997;79:2396-401.[Medline]
13 Cramer DW, Liberman RE, Titus-Ernstoff L, Welch WR, Greenberg ER, Baron JA, et al. Genital talc exposure and risk of ovarian cancer. Int J Cancer 1999;81:351-6.[Medline]
14 Stampfer MJ, Willett WC, Speizer FE, Sysert DC, Lipnick R, Rosner B, et al. Test of the National Death Index. Am J Epidemiol 1984;119:837-9.[Medline]
15 Hankinson SE, Hunter DJ, Colditz GA, Willett WC, Stampfer MJ, Rosner B, et al. Tubal ligation, hysterectomy, and risk of ovarian cancer. JAMA 1993;270:2813-8.[Abstract]
16 D'Agostino RB, Lee ML, Balanger AJ, Cupples LA, Anderson K, Kannel WB. Relation of pooled logistic regression to time dependent Cox regression analysis: the Framingham Heart Study. Stat Med 1990;9:1501-15.[Medline]
17 Hartge P, Hoover R, Lesher LP, McGowan L. Talc and ovarian cancer [letter]. JAMA 1983;250:1844.[Medline]
18 Rosenblatt KA, Thomas DB. Lactation and the risk of epithelial ovarian cancer. The WHO Collaborative Study of Neoplasia and Steroid Contraceptives. Int J Epidemiol 1993;22:192-7.[Abstract]
19 Tzonou A, Polychronopoulou A, Hsieh CC, Rebelakos A, Karakatsani A, Trichopoulos D. Hair dyes, analgesics, tranquilizers and perineal talc application as risk factors for ovarian cancer. Int J Cancer 1993;55:508-10.
20
Wong C, Hempling RE, Piver MS, Natarajan N, Mettlin CJ.
Perineal talc exposure and subsequent epithelial ovarian cancer: a case-control study. Obstet Gynecol 1999;93:372-6.
21 Wignall BK, Fox AJ. Mortality of female gas mask assemblers. Br J Indust Med 1982;39:34-8.[Medline]
22 Henderson WJ, Joslin CC, Turnbull AC, Griffiths K. Talc and carcinoma of the ovary and cervix. J Obstet Gynecol 1971;78:266-72.
23 Heller DS, Westhoff C, Gordon RE, Katz N. The relationship between perineal cosmetic talc usage and ovarian talc particle burden. Am J Obstet Gynecol 1996;174:1507-10.[Medline]
24 Boorman GA, Seely JC. The lack of an ovarian effect of lifetime talc exposure in F344/N rats and B6C3F1 mice. Regul Toxicol Pharmacol 1995;21:242-3.[Medline]
25 Hamilton TC, Fox H, Buckley CH, Henderson WJ, Griffiths K. Effects of talc on the rat ovary. Br J Exp Pathol 1984;65:101-6.[Medline]
Manuscript received June 17, 1999; revised November 18, 1999; accepted December 2, 1999.
![]() |
||||
|
Oxford University Press Privacy Policy and Legal Statement |