Document oeDRbQgE2VxRJvNynX9j3Yo27

FILE NAME: Talc (TALC) DATE: 1992 DOC#: TALC030 DOCUMENT DESCRIPTION: Journal Article - Perineal Exposure to Talc and Ovarian Cancer Risk tw t ; i t< &jfj fTi ittT fiK > r> The material on this page was copied from the collection of the National Library of Medicine by a third party and may be protected by U S Copyright law Perineal Exposure to Talc and Ovarian Cancer Risk BERNARD L. HARLOW, PhD, DANIEL W. CRAMER, M D , ScD, DEBRA A. BELL, M D, A N D WILLIAM R. WELCH, M D O bjective: We sought to determine whether the use of talc in genital hygiene increases the risk for epithelial ovarian cancer. M ethods: We interviewed 235 white women diagnosed with epithelial ovarian cancer between 1984-1987 at ten Boston metropolitan area hospitals and 239 populationbased controls of similar race, age, and residence. R esults: Overall, 49% of cases and 39% of controls re ported exposure to talc, via direct application to the per ineum or to undergarments, sanitary napkins, or dia phragms, which yielded a 1.5 odds ratio (OR) for ovarian cancer (95% confidence interval [Cl] 1.0-2.1). Among women with perineal exposure to talc, the risk was significantly elevated in the subgroups of women who applied it: 1) directly as a body powder (OR 1.7, 95% Cl 1.1-2.7), 2) on a daily basis (OR 1.8, 95% Cl 1.1-3.0), and 3) for more than 10 years (OR 1.6, 95% Cl 1.0-2.7). The greatest ovarian cancer risk associated with perineal talc use was observed in the subgroup of women estimated to have made more than 10,000 applications during years when they were ovulating and had an intact genital tract (OR 2.8, 95% Cl 1.4-5.4); however, this exposure was found in only 14% of the women with ovarian cancer. Conclusions: These data support the concept that a life time pattern of perineal talc use may increase the risk for epithelial ovarian cancer but is unlikely to be the etiology for the majority of epithelial ovarian cancers. (O bstet Gy necol 1992;80:19-26) The theory that human ovarian cancer may be me sotheliomas that originate from asbestos exposure was first proposed by Graham and Graham.1 Later, Parmley and Woodruff2 suggested that effluences that may arise from the vagina, uterus, or tubes might enter the pelvic cavity and interact with ovarian surface epithe- Erom the Obstetrics and Gynecology Epidemiology Center, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachu setts. . Supported by grant R01 CA 42008 from the National Cancer Institute. Hum to induce such mesotheliomas. Longo and < Young3 further speculated that cosmetic talc might act ; in this manner because of its chemical similarity to asbestos. Although there is little doubt that asbestos s. may induce mesotheliomas, the link between genital exposure to talc and ovarian cancer is less clear. The few epidemiologic studies that have examined the association between talc and ovarian cancer re- | ported only modest elevations of risk, but data on all ; potential sources of genital talc exposure were limit- * ed.4"7 The purpose of this report was to present findings from a new case-control study of ovarian . cancer conducted in the Boston metropoHtan area, in . which we considered a variety of modes for perineal talc exposure, the frequency and duration of use, and t various reproductive characteristics that might influ- ence the ability of talc to enter the pelvic cavity and % affect the ovaries. Materials and Methods ; Between July 1984 and September 1987, we identified v 394 women between 18-76 years of age diagnosed with ; borderline or malignant epithelial ovarian cancer at one of ten participating hospitals in the Boston metro- J politan area. Permission to contact each patient was J obtained in advance from the physician of record. An J in-person interview was conducted with 272 (69%) of the 394 cases identified. Thirty-one percent were not interviewed because of physician and/or patient re fusal, patient death, or relocation. The final sample for " analysis was further restricted to the 235 white women , confirmed as having an epithelial ovarian tumor based ; on an independent pathology review conducted by J two of the authors (DAB and WRW). J Controls were selected from the Massachusetts ) Town Books, annual publications that list residents by ( name, age, and address according to voter precincts, j For each new ovarian cancer case interviewed, a ran- j VOL. 80, NO. 1, JULY 1992 ' / 0029-7844/92/$5.00 19 The material on this page was copied from the collection of the National Library of Medicine by a third party and may be protected by U S Copyright law Tabk ' " r p" it0,',, AAnL P' i r `iw Exp08ure* Vari" Can" r M by C l M TM`to Of Study Participants, Boston Cases Controls Total Talc exposure Total Talc exposure Crude OR 95% Cl All subjects Age (y) 235 114 (48.5%) 239 94 (39.3%) 1.5 1.0-2.1 <50 50 Education (y) 96 41 (42.7%) 101 28 (28.0%) 1.9 1.2-3.4 139 73 (52.5%) 138 66 (47.8%) 1.2 0.8-2.1 <12 >12 Marital status 93 51 (54.8%) 115 48 (41.7%) 1.7 1.1-3.0 142 63 (44.4%) 124 46 (37.1%) 1.4 0.9-2.4 Never married Ever married Religion 40 14 (35.0%) 24 6 (25.0%) 195 100 (51.3%) 215 88 (40.9%) 1.6 0.5-5.7 1.5 1.0-2.7 Jewish Non-Jewish Weight (lb) 35 21 (60.0%) 21 12 (57.1%) i.i 0.4-3.9 200 93 (46.5%) 218 82 (37.6%) 1.4 0.9-2.5 <140 140 Use of OCs (mo) 123 53 (43.1%) 125 49 (39.2%) 1.2 0.7-1.9 112 61 (54.5%) 114 45 (39.2%) 1.8 1.1-3.1 3 66 < 3 or never 169 No. of live-born children 31 (47.0%) 82 27 (32.9%) 83 (49.1%) 157 67 (42.7%) 1.8 0.8-4.5 1.3 0.8-2.3 0 79 30 (38.0%) 43 12 (27.9%) 1.6 0.7-4.0 1 31 21 (67.7%) 27 5 (18.5%) 9.2 2.9-46.2 2 40 24 (60.0%) 63 26 (41.3%) 2.1 0.9-3.3 3 85 39 (45.9%) 106 51 (48.1%) 0.9 0.6-1.6 OR --odds ratio; Cl = confidence interval; OCs == oral contraceptives. * Sources of perineal talc exposure include: dusting of underwear, diaphragms, or sanitary napkins; use by partner on his perineal area; use as a body powder. dom number generator selected one page from the town book corresponding to the case's precinct of residence. By working forward in the town book, we selected the first five female subjects within 2 years of age of the case as potential controls. Of these five, the first subject of the same race as the case without a history of a bilateral oophorectomy was asked to par ticipate in the study. Of the 526 controls contacted, 239 interviews were conducted (25% could not be reached, 10% reported a history of bilateral oophorectomy, and 19% declined to participate). Further details of the study methods can be found elsewhere.8 The in-person interview focused on the following: demographic and occupational history; medical and reproductive histories, including pregnancies, hor mones used, and gynecologic operations; dietary his tory; cigarette smoking; and hygienic practices. The hygienic practices included information regarding the use of douches, type of sanitary protection used, and perineal exposure to talc. Queried sources of perineal talc exposure included dusting of underwear, sanitary napkins, and diaphragms; exposure via husband's use of talc; and more direct exposure to the perineum as a body powder. No reliable information on talc exposure during infancy with diapering could be obtained, and women using talc as a body powder on areas other than the perineum were considered nonexposed. For each exposure, we inquired about brands used, age at first use, total years of use, and frequency of use per month, to enable us to estimate the total lifetime number of applications from all sources of exposure. Differences between cases and controls in the distri bution of these various exposures to talc were exam ined both qualitatively and quantitatively. The influ ence of confounders and effect modifiers was assessed first through stratification and then using uncondi tional logistic regression.9 The primary matching vari able, age, was retained in each logistic model. The x1 test for linear trend was calculated based on the change in deviance in models with and without continuous exposure variables.9 Results Table 1 shows the proportion of cases and controls with any reported perineal talc exposure, and the associated crude exposure odds ratio (OR), by certain demographic and reproductive subgroups. Overall, a 20 Harlow et al Talc and Ovarian Cancer Obstetrics & Gynecology The material on this page was copied from the collection of the National Library of Medicine by a third party and may be protected by U S Copyright law oCO Al Table 2. History of Talc Exposure by Types of Application, Brand of Powders, Years and Frequency of Use, and Era of Use Cases Controls Adjusted OR* 95% Cl No genital talc application Any genital talc application Type of application Only via sanitary napkins and/or underwear Via partner or applications to diaphragm* Via dusting powder to perineum* Applications of talc per month <5 5-29 a 30 Years of talc use <10 10-29 . Age (y) at first talc use <20 20-25 >25 Years since last talc use Within last 6 mo Between 6 mo-10 y 10 y or more Era of use* Exclusive use after 1960 Any use before 1960 Brand of application Brand or generic baby powder Deodorizing or other scented powders 121 (51.5%) 114 (48.5%) 9 (3.8%) 20 (8.5%) 85 (36.2%) 32 (13.6%) 24 (10.2%) 58 (24.7%) 14 (6.0%) 49 (20.9%) 51 (21.7%) 66 (28.1%) 27 (11.5%) 21 (8.9%) 48 (20.4%) 36 (15.3%) 30 (12.8%) 29 (12.3%) 75 (31.9%) 91 (38.7%) 16 (6.8%) 145 (60.7%) 94 (39.3%) 12 (5.0%) 21 (8.8%) 61 (25.5%) 28 (11.7%) 25 (10.5%) 41 (16.7%) 15 (6.3%) 39 (16.3%) 40 (16.3%) 50 (20.9%) 26 (10.9%) 18 (7.5%) 27 (11.3%) 39 (16.3%) 28 (11.7%) 30 (12.6%) 57 (23.9%) 72 (30.1%) 17 (7.2%) 1.0 1.5 1.0-2.1 1.1 0.4-2.8 1.2 0.6-2.4 1.7 1.1-2.7 1.5 0.8-2.7 1.2 0.6-2.2 1.8 1.1-3.0 1.2 0.5-2.6 1.6 1.0-2.7 1.6 1.0-2.7 1.7 1.1-2.7 1.2 0.6-2.2 1.6 0.8-3.2 2.3 1.3-4.0 1.1 0.7-1.9 1.4 0.8-2.6 1.1 0.6-2.1 1.7 1.1-2.7 1.6 1.1-2.5 1.2 0.6-2.5 OR = odds ratio; Cl = confidence interval. * Adjusted for parity (0, 1-2, >2), education (<12 years, >12 years), marital status (never married, ever married), religion (Jewish, non-Jewish), use of sanitary napkins (no, yes), douching (no, yes), age (continuous), and weight (<140 lb, >140 lb). * Includes combinations with sanitary napkins or underwear. * Restricted to women older than 10 years in 1960; 100 cases and 118 controls were unexposed and used as the referent group. Excludes seven cases and five controls with unknown powders. Seven cases and four controls reported combinations of more than one brand and were classified according to the brand used most frequently and for the longest period. Specific brands mentioned by cases were: Johnson and Johnson, 71; generic baby powder, 20; Shower to Shower, four; other scented, 12. Specific brands mentioned by controls were: Johnson and Johnson, 54; generic baby powder, 18; Shower to Shower, three; other scented powder, 14. greater percentage of cases (48.5%) than controls (39.3%) reported any perineal exposure to talccontaining powders. Subgroups of controls in which exposure to talc appeared to be more common were women older than 50 years (P = .002), ever married (P = .12), Jewish (P = .08), and parous (P = .05). Controls who reported no oral contraceptive (OC) use also reported greater talc use. However, this interaction may be explained by the older age distribution among controls who reported perineal application of talc. We observed stronger associations between talc and ovar ian cancer risk in the subgroups of cases and controls younger than age 50, less well educated, heavier than 140 lb 5 years before diagnosis, and reporting a history of one or two live births. The number of live births was the only factor that produced statistically significant heterogeneity in the ORs for the talc and ovarian cancer association. Age, education, marital status, re ligion, weight, and parity were considered confound- ers and were included as covariates in subsequent / multivariate models. Use of OCs did not confound the talc-ovarian cancer association. - Table 2 examines the association between talc use and ovarian cancer by variables related to the specific types and kinds of applications, and measures of ; duration including length, frequency, and period of ; use. Compared with women with no genital talc expo sure, women exposed to talc only through use as a dusting powder on sanitary napkins or underwear had no appreciable increased risk for ovarian cancer. There was also no substantial increase in risk among women exposed to talc only through a husband's use or use in the storage of diaphragms, or in combination with applications to sanitary napkins or underwear. The : most frequent method of perineal talc exposure was use as a dusting powder directly to the perineum, V O L. 80, N O . 1, JU LY 1992 Harlow et al Talc and Ovarian Cancer 21 The material on this page was copied from the collection of the National Library of Medicine by a third party and may be protected by U S Copyright law Table 3. Estimated Total Lifetime Perineal Applications of Talc-Containing Powders in Cases and Controls , Applications_______________ Cases Controls Adjusted OR' Total applications None <1000 1000-10,000 >10,000 it2 1d f test for linear trend = 2.85, P = .094' 121 145 18 19 54 44 42 31 Applications excluding use after hysterectomy or tubal ligation None <1000 1000-10,000 >10,000 X 2 t d f test for linear trend = 3.19, P = .077* 121 145 19 19 57 46 38 29 Applications excluding use after hysterectomy or tubal ligation, and use during nonovulatory months* None <1000 1000-10,000 >10,000 X 1d f test for linear trend = 6.15, P = .015' 124 149 24 23 55 51 32 16 1.0 1.3 07 27 1.5 09 24 1.8 1.0-3.0 1.0 1.4 0.7-2 9 1.5 0.9-2.4 1.7 1.0-3.0 1.0 1.5 0.8-2.9 1.3 0.8-2.0 2.8 1.4-5.4 Abbreviations as in Table 2. Adjusted for parity (0, 1-2, >2), education (<12 years, >12 years), marital status (never married, ever married), religion (Jewish, non-Jewish), use of sanitary napkins (no, yes), douching (no, yes), age (continuous), and weight (<140 lb, >140 lb). ' ' Trend test based on actual applications as a continuous variable. Excludes exposures while taking oral contraceptives, while pregnant or breast-feeding, or occurring after menopause. There were three cases and four controls who moved from "exposed" to "nonexposed" in this category, as all of the exposure occurred during oral contraceptive use pregnancies, or after menopause. r ' alone or in combination with either a partner's use or use in the storage of diaphragms. This exposure oc curred in 85 cases (36.2%) and 61 controls (25.5%) (P = .01). Of the application modes studied, direct perineal application produced the greatest risk (OR 1.7, 95% confidence interval [Cl] 1.1-2.7). We also examined the talc-ovarian cancer association by frequency and years of use (Table 2). When monthly frequency was considered as a continuous variable in the logistic model, the linear test of trend was 4.06 (P = .046), indicating that the risk for ovarian cancer increased significantly with increasing fre quency of applications per month. The categorical analysis showed that relative to non-users, the risk was greatest in women who applied talc at least once per day. When years of use was included as a contin uous variable, the test for linear trend was 3.32 (P = .07). The categorical analysis showed that relative to non-users, women who applied talc for more than 10 years were at 60% greater risk for ovarian cancer. Likewise, perineal applications of talc early in life (before age 20) or applications within 6 months of diagnosis (reference age for controls) produced the stronger ORs. To assess whether the risk of ovarian cancer with perineal exposure to talc was affected by the time when talc-containing products were manufactured, we ex amined the association separately in women who only used talcum powder after 1960 and in women who reported any use of talcum powder before 1960 (Table 2). After restricting the population to women older than age 10 in 1960 and adjusting for age, parity, and a number of other demographic characteristics, we found that the association of talc and ovarian cancer was greater in women using talc products before 1960 (P = .025). The last entry in Table 2 shows the risks by brand of powder used. No subjects could recall exclusive use of starch-based powders. Brand or generic 'baby pow der" was used most frequently and was the category associated with a statistically significant risk for ovar ian cancer. With respect to other powders, four cases and three controls reported primary use of deodorizing powders, and 12 cases and 14 controls reported pri mary use of other scented powders. It should be appreciated that, because the period of exposure often occurred over decades, verification of brands was not possible. Table 3 examines the ovarian cancer risk associated with the total number of applications to the perineum, estimated by cumulating frequency and years of use for the various kinds of exposures. An 80% excess risk was associated with an estimated exposure of more than 10,000 applications (equivalent to daily use for 30 22 Harlow et al Talc and Ovarian Cancer Obstetrics & Gynecology a 'iijli i*|y*i>- The material on this page was copied from the collection of the National Library of Medicine by a third party and may be protected by U S Copyright law T' b,e ` f a TM " C" " * * " * * - * P,,S,, C TM - , Cases Total Talc exposure All subjects Mid-cycle pain 235 114 (48.5%) No 181 88 (48.6%) Regular period 54 26 (48.2%) No 26 12 (46.2%) Yes 209 102 (48.8%) PID or ectopic pregnancy No 226 113 (50.0%) Yes 9 1 (11.1%) 1lu pelvic inflammatory disease; other abbreviations as in Table 2. Total 239 184 55 34 205 230 9 Controls Talc exposure 94 (39.3%) 77 (41.9%) 17 (30.9%) 16 (47.1%) 78 (38.1%) 92 (40.0%) 2 (22.2%) Adjusted OR* 1.5 1.4 2 0 1,1 1.7 1.6 0.1 -- 95% Cl 1.0-2.1 09 ?? 0.8-5.2 0.4-3.4 1.1-2.5 1.1-2.4 0.01-7.0 " as a body powder. F g Underwear' d.aphragms, or sanitary napkins; use by partner on his perineal area; use -* *** years) as compared with non-users. When considered as a continuous variable in the logistic model, the x* linear test of trend was 2.85 (P = .094). The remaining entries in Table 3 show how conditions that either close the upper genital tract or are associated with anovulation affect the dose response of number of applications on ovarian cancer risk. The second entry shows the effect of censoring applications that oc curred after tubal ligation or hysterectomy. No appre ciable change in the ORs or the dose response was noted. The third entry shows the effect of censoring applications after hysterectomy and tubal ligation and use during presumed nonovulatory periods. Excluded were exposures occurring while taking OCs, while pregnant or breast-feeding, and after menopause. The risk associated with fewer than 10,000 applications was not substantially altered. However, the risk associated with more than 10,000 applications was nearly three fold and statistically significant. The / test for a linear trend of risk, by number of applications as a continu ous variable, increased to 6.15 (P = .015). Table 4 shows the association of talc exposure and ovarian cancer based on other clinical factors that may predict either ovulation or tubal occlusion. The ORs were greater in women with a history of mid-cycle pain or regular periods--potential clinical predictors of ovu latory cycles. An association between talc and ovarian cancer was absent in women with a history of either pelvic inflammatory disease or ectopic pregnancy-- potential markers of a closed genital tract. However, only nine cases and nine controls reported a history of pelvic inflammatory disease or ectopic pregnancy, and the Cl on the exposure OR was correspondingly wide. Table 5 shows the relative risk for any perineal use of talc when restricted to specific histologic type and grade of ovarian tumors. The greatest association was found in women diagnosed with an endometrioid tumor or borderline ovarian tumor. Discussion Animal and epidemiologic studies have addressed the plausibility of an association between talc and ovarian cancer. Intraperitoneal injection of talc in rodents pro duced papillary changes in the surface epithelium not inconsistent with the first stage in the development of surface papillary epithelial neoplasms.10 However, be cause the ovaries of small rodents are surrounded by a Table 5. H istory of Talc U se by H istologic Type and Grade Histologic type Any use of talc No use of talc Adjusted OR* 95% Cl Controls 94 Histologic type Serous 60 Mucinous 17 Endometrioid 18 Other 19 Histologic grade Borderline 32 Grade 1 6 Grade 2 21 Grade 3 27 Undifferentiated 28 145 1.0 64 1.4 0.9-2.2 25 1.2 0.6-2.5 11 2.8 1.2-6.4 21 1.6 0.8-3.3 30 2.4 1.2-4.5 11 1.0 0.3-2.8 22 1.5 0.7-3.0 24 1.5 0.8-2.8 34 1.2 0.7-2.2 Abbreviations as in Table 2. ` Adjusted for parity (0, 1-2, >2), education (<12 years, >12 years), marital status (never married, ever married), religion (Jewish, non-Jewish), age (continuous), and weight (<140 lb, =rl40 lb). VO L. 80, N O . 1, JULY 1992 Harlow et al Talc and Ovarian Cancer 23 Table 6- of varian Cancer in Relation to Any Perineal Expsure to Taic $ , 03 ; CD ; OC l ' O ' CO - 3 j>a ,-: "0OL> - Oo) I O ; Q. : CD xz .: >. 03 : E i Author(s) (year) Cramer et al4 (1982) Hartge et al (1983)* Whittemore et al5 (1988) Harlow and Weiss6 (1989)* Booth et al7 (1989) Harlow et al (1992) (current study) All studies* Abbreviations as in Table 2. Total 215 135 188 116 217 235 1106 Cases Talc exposure 92 (42.8%) 67 (49.6%) 98 (52.1%) 49 (42.2%) 141 (65.0%) 114 (48.5%) 561 (50.7%) Total 215 171 539 158 434 239 1756 Controls Talc exposure 61 (28.4%) 100 (58.5%) 248 (46.0%) 64 (40.5%) 256 (59.0%) 94 (39.3%) 823 (46.9%) Crude OR 95% Cl 1.9 1.3-2.9 0.7 0.4-1.1 1.4 0.9-2.0 1.1 0.7-2.1 1.3 0.9-1.9 1.5 0.9-1.8 1.3 1.1-1.6 ~ ----------------- a s ' ! ? 86 P' HOOV6r R' LeSher LP/ ^ 3l' Tak 3nd Varian C3nCer (`etter)-JAMA 1983;250:1844- d d s ratio may include nonperineai talc exposure Restricted to borderline ovarian tumors. * Meta-analysis.19 03 / 0Q3_i; CZ ->Qs ; C ^ 5 1 T3 ;. O 03 .' 5 -<C1) "S* * *o C --m O 2 _o<d ' oo $? 0) # Eo T03) <OQJ. </) * 03 - 5 CD ' Ci . 0C3Lar<> * peritoneal bursa which often becomes occluded and distended with follicular fluid after intraperitoneal in jection of foreign bodies,1 it is difficult to distinguish whether the papillary changes are the effects of for eign-body exposure or bursal distention. It would be worthwhile to repeat the talc experiments in guinea pigs or rabbits, the animals used in the original re search of Graham and Graham.1 Is there evidence to suggest that talc can translocate from the vagina to the peritoneal cavity? It is known that red cells and endometrial tissue are capable of retrograde flow from the fallopian tubes.11 Experi ments in rats confirmed the presence of talc in the ovaries after the introduction of a talc suspension into the vagina and cervical os.12 In humans, two studies observed the migration of inert carbon particles13 and radioactively labeled human albumin microspheres14 from the vagina to the fallopian tubes. In addition, several investigators have observed birefringent crys tals embedded in ovarian tissue.15-17 However, critics have argued that these findings resulted from poorly designed studies or lack of precision in measuring particulates, due to leaching of radionucleotide mark ers from the test materials or the introduction of contaminants during tissue processing.18 In six multip arous cynomolgus monkeys separately caged, no translocation of talc was observed after 30 consecutive days of douching with a suspension of neutronactivated talc coupled with weekly injections of oxyto cin.18 However, this study was not able to address the effects of long-term use or coitus, which might facili tate talc translocation. Several epidemiologic studies4-7 have addressed the genital talc-ovarian cancer association (Table 6). Each study has consistently reported little or no association with the use of talc-dusted diaphragms, and stronger associations with direct perineal application. Dose re sponse of perineal talc exposure from all sources by frequency or years of use was not available in the studies by Hartge et al (Hartge P, Hoover R, Lesher LP, et al. Talc and ovarian cancer [letter], JAMA 1983;250:1844), Harlow and Weiss,6 or Cramer et al.4 Whittemore et al5 reported no significant dose re sponse by years or frequency of use, whereas Booth et al7 reported a marginally significant trend with fre quency of use. Using the techniques of meta-analysis, in which ORs from multiple studies are weighted by their variances,19 we calculated a statistically signifi cant OR of 1.3 for any perineal talc exposure and ovarian cancer risk (95% Cl 1.1-1.6) from the various studies. We therefore conclude that there is an associ ation, albeit modest, between ovarian cancer and per ineal talc use. However, insufficient detail has been available to rule out a stronger association in certain subgroups of users. Our study included greater detail on genital talc use, including methods, frequency, and years of use (Table 2). Talc applied as a dusting powder directly to the perineum carried a greater risk than less direct expo sure via a partner's use or the dusting of undergar ments, sanitary napkins, or diaphragms. Current use of talc was associated with a greater ovarian cancer risk than past use. Daily versus less than daily talc use, and talc use for more than 10 years versus less than 10 years, were associated with greater risk for ovarian cancer. Most subjects reported use of "baby powder." We were unable to confirm a previous finding that pow ders with "deodorizing" agents were associated with particular risk.6 Thus, this study failed to answer a key issue in the talc-ovarian cancer association: whether the risk pertains to all cosmetic talcs or only to certain 24 Harlow et al Talc and Ovarian Cancer Obstetrics & Gynecology The material on this page was copied from the collection of the National Library of Medicine by a third party and may be protected by U S Copyright law preparations likely to be contaminated by asbestos. Cralley et al20 and Rohl et al21 found considerable variation in the purity of cosmetic talcs, with fiberform contents varying from less than 1 to 30%. Most of these products were manufactured before 1970 and it is likely that the asbestiform content has decreased since 1976, when manufacturers instituted voluntary guide lines on asbestos contamination. Our finding of a lower ovarian cancer risk in women with exclusive use of talc after 1960 may support this theory. Because of the difficulty in obtaining a complete and detailed history of powders used, the issue of whether risk pertains only to asbestos-contaminated powders may need to be settled by animal experiments. In our analysis, we first calculated all genital appli cations of talc based upon frequency and years of use. As a continuous variable in a multivariate model, no significant dose response was observed between total genital applications of talc and ovarian cancer risk. Because the "translocation" theory assumes an open genital tract, we then excluded application after tubal ligation or hysterectomy, but observed no appreciable change in the dose response. Further restricting talc exposure to months when the women were likely to be ovulatory, we observed a significant dose response, such that women with an intact genital tract and more than 10,000 applications during ovulatory cycles had nearly a threefold increase in risk for ovarian cancer. Some additional evidence that might support an inter action with ovulation includes stronger associations in women with regular periods and mid-cycle pain. Cra mer et al4 suggested that talc contamination around the time of ovulation might lead to the incorporation of talc particulates into inclusion cysts that may form with ovulation. Experiments on foreign-body tumorigenesis have shown that implantation of foreign bodies into the lumens of epithelial-lined organs provides a favor able environment for carcinogenesis.22 Alternatively, Mostafa et al16 speculated that foreign-body exposure might produce cortical "granulomas" whose link to stromal hyperactivity (and hormonally related cancers) is argued in older literature.23 We observed that the talc association was strongest in women with endometrioid or borderline ovarian tumors. However, an earlier study by Cramer et al4 reported no such variation in risk by histologic sub type. It was noted that a greater proportion of women with endometrioid tumors than with other histologic types of ovarian cancer reported more than 10,000 lifetime applications of talc during ovulatory cycles while having an intact genital tract (34 versus 16%). Although this may explain in part the strong talcovarian cancer association noted in women with en dometrioid tumors, it does not explain the strong association noted in women with borderline ovarian tumors, of whom only 13% reported long-term talc exposure. This variation in risk among histologic sub types may reflect a chance finding or a need to examine endometrioid and borderline tumors more carefully for evidence of a foreign-body effect. An unusual observation was the strong association between talc use and ovarian cancer in the subgroup of women with one or two pregnancies but a lower risk in women with either no children or three or more children. Although chance may be the most likely explanation for this finding, we wonder whether this peculiar interaction might reflect, in part, an effect of pregnancy on the degree of openness of the cervical os and its ability to allow translocation of vaginal partic ulates. The parous cervix has a larger os than the nulliparous cervix, and this could explain the greater risk in women with one child compared with women with no live births. At the other extreme, multiple pregnancies may offer other protective mechanisms (such as reduced ovulation as discussed above) that could outweigh this effect. Clearly, this is a very speculative hypothesis but one that might be tested in experimental studies (ie, repeating the vaginal talc experiments in nulliparous and parous mice or pri mates). Noncausal explanations are possible in any epidemi ologic research. We cannot rule out the possibility of differential over- or under-reporting of talc exposure in our cases and controls, especially in those with repro ductive events that enhance ORs. In addition, though we were successful in interviewing 69% of eligible ovarian cancer cases and 81% of eligible controls con tacted, we cannot assess whether the cases and con trols not interviewed could have selectively differed in their reproductive characteristics or in their use of talc-containing powders. Because our associations are based upon responses from participating cases and controls, the validity of our results depends upon the assumption that respondents and non-respondents were similar with respect to talc and other relevant exposures, or that the magnitude of any respondentnon-respondent difference was similar for cases and controls. Because the interview provided the only source of "exposure" information, we were unable to assess the likelihood of this assumption. The extent of this bias, however, is likely to be small because the reproductive characteristics and history of talc expo sure in participating cases and controls are, for the most part, reasonably consistent with earlier epidemi ologic studies of ovarian cancer. Finally, in our attempt to present the most accurate ORs, we made a variety of adjustments to account for the confounding influence of factors associated with both ovarian cancer risk and VO L. 80, N O . 1, JU LY 1992 Harlow et al Talc and Ovarian Cancer 25 $ 03 OO Oo) 0I OJ ' O . V) 03 % - ~ 03 t E T3 1 _(QJJ O . eo OQ_ =. COT; 03 Q- c jC<_ talc exposure. Nevertheless, we cannot rule out the presence of other unknown factors that might have influenced, in part, our observed associations. Because the overall association between genital use of talc and ovarian cancer remains weak, it is unlikely that this exposure-disease pathway is the principal one involved in ovarian cancer etiology. We have previ ously discussed the role of dietary and metabolic factors in a model for ovarian cancer involving gonad otropin stimulation of failing ovaries.8 Even if an etiologic association were to pertain in the subgroups of daily users or users with more than 10,000 applica tions during ovulatory months, we calculate that by applying these ORs to the exposure rate among cas es, the proportion of ovarian cancer incidence attrib utable to this level of talc exposure is about 10%. Nevertheless, given the poor prognosis for ovarian cancer, any potentially harmful exposures should be avoided, particularly those with limited benefits. For this reason, we discourage the use of talc in genital hygiene, particularly as a daily habit. References !. Graham J, Graham R. Ovarian cancer and asbestos. Environ Res 1967;1:115-28. 2. Parmley TH, Woodruff JD. The ovarian mesothelioma. Am J Obstet Gynecol 1974;120:234-41. 3. Longo DL, Young RC. Cosmetic talc and ovarian cancer. Lancet 1979;ii:349-51. 4. Cramer DW, Welch WR, Scully RE, Wojciechowski CA. Ovarian cancer and talc. Cancer 1982;50:372-6. 5. Whittemore AS, Wu ML, Paffenbarger RS, 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. 6. Harlow BL, Weiss NS. A case-control study of borderline ovarian tumors: The influence of perineal exposure to talc. Am J Epide miol 1989;130:39(M. 7. Booth M, Beral V, Smith P. Risk factors for ovarian cancer: A case-control study. Br J Cancer 1989;60:592-8. 8. Cramer DW, Harlow BL, Willett WC, et al. Galactose consump tion and metabolism in relation to the risk of ovarian cancer Lancet 1989;ii:66-71. 9. Breslow NE, Day NE. Statistical methods in cancer research. Vol 1. The analysis of case control studies. IARC scientific publication no 32. Lyon: International Agency for Research on Cancer, 1980. 10 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. 11. Sampson JA. The development of the implantation theory for the origin of endometriosis. Am J Obstet Gynecol 1940;40:549-57 12. Henderson WJ, Hamilton TC, Baylis MS, et al. The demonstra tion of the migration of talc from the vagina and posterior uterus to the ovary in the rat. Environ Res 1986;40:247-50. 13. Egli GE, Newton MD. The transport of carbon particles in the human female reproductive tract. Fertil Steril 1961;12:151-5. 14. Venter PF, Iturralde M. Migration of particulate radioactive tracer from the vagina to the peritoneal cavity and ovaries. S Afr Med I 1979;55:917-9. 15. Henderson WJ, Joslin CAF, Turnbull AC, Griffiths K. Talc and carcinoma of the ovary and cervix. J Obstet Gynaecol Br Cornmonw 1971;78:266-72. 16. Mostafa SAM, Bargeron CB, Flower RW, Rosenshein NB, Parmiey TH, Woodruff JD. Foreign body granulomas in normal ova ries. Obstet Gynecol 1985;66:701-2. 17. Griffiths K, Henderson WJ, Chandler JA, Joslin CAF. Ovarian cancer: Some new analytical approaches. Postgrad Med J 1973;49: 18. Wehner AP, Hall AS, Weller RE, Lepel EA, Schirmer RE. Do particles translocate from the vagina to the oviducts and beyond? Food Chem Toxicol 1985;23:367-72. 19. Greenland S. Quantitative methods in the review of epidemio logic literature. Epidemiol Rev 1987;9:1-30. 20. Cralley LJ, Key MM, Groth DH, Lainhart WS, Ligo RM. Fibrous and mineral content of cosmetic talcum products. Am Ind Hye Assoc J 1968;29:3504. 21. Rohl AN, Langer AM, Selikoff IJ, et al. Consumer talcums and powders: Mineral and chemical characterization. J Toxicol Envi ron Health 1976;2:255-84. 22. Brand KG, Johnson KH, Buoen LC. Foreign body tumorigenesis Crit Rev Toxicol 1976;4:353-94. 23. Woll E, Hertig AT, Smith GVS, et al. The ovary in endometrial carcinoma with notes on the morphological history of the aging ovary. Am J Obstet Gynecol 1948;56:617-33. 24. Rothman KJ. Modern epidemiology. Boston: Little, Brown 1986: 35-40. ' Address reprint requests to: Bernard L. Harlow, PhD Obstetrics and Gynecology Epidemiology Brigham and Women's Hospital Harvard Medical School 221 Longwood Avenue Boston, MA 02115 Center Received January 6, 1992. Received in revised form March 23, 1992. Accepted March 23, 1992. Copyright 1992 by The American College of Obstetricians and Gynecologists. c QJ mm 26 Harlow et al Talc and Ovarian Cancer Obstetrics & Gynecology -