Document v87x2KryZog2wV3Byrr3rd5q

THE COS ME TI C , TOILETRY, AND FRAGRANCE ASSOCIATION June 16, 1995 Dockets Management Branch (HFA-305) Food and Drug Administration Room 1-23 12420 Parklawn Drive Rockville, Maryland 20857 E. EDWARD K A V A NA U G H PRE SI DENT Re: FDA Docket No. 94P-0420/CP 1 Dear Sir or Madam: Enclosed for filing please find comments o f The Cosmetic, Toiletry, and Fragrance Association (CTFA) in response to a Citizen Petition filed on November 17, 1994 by Jill A. Cashen and Samuel S. Epstein, M.D. on behalf o f the Cancer Prevention Coalition ("Petitioner"). Petitioner urges the Food and Drug Administration to require "cosmetic talcum powder" to bear warning labels such as "Talcum Powder causes cancer in laboratory animals. Frequent talc application in the female genital areas increases the risk o f ovarian cancer." As discussed in detail in the enclosed comments, CTFA believes that the Petitioner's arguments are without scientific merit. Much o f the evidence relied upon by Petitioner has already been fully considered by FDA with the conclusion that there is no risk to human health posed by the use o f talc in cosmetic products. New evidence further supports this conclusion. Therefore, the requested label warnings are not necessary to protect the health o f consumers and would unnecessarily alarm consumers regarding the use o f safe cosmetic products. We respectfully request that the petition be denied. c Enclosures ovjo 1101 17TH ST., N.W., SUITE 300 WASHINGTON, D.C. 20036-4702 2 0 2.3 3 1.1 770 fax 202.3 31.196 9 SECURING THE INDUSTRY'S FUTURE SINCE 1894 COMMENTS OF THE COSMETIC, TOILETRY, AND FRAGRANCE ASSOCIATION IN RESPONSE TO A CITIZENS PETITION FILED WITH THE FOOD AND DRUG ADMINISTRATION ON NOVEMBER 17, 1994 WHICH WOULD REQUIRE CARCINOGENIC LABELLING ?, ON ALL COSMETIC TALC PRODUCTS ) - FDA Docket No 94P-0420/CP 1 June 1995 Table of Contents I. INTRODUCTION H. THERE IS NO EVIDENCE TO SUGGEST THAT COSMETIC-GRADE TALC IS A HUMAN CARCINOGEN A. The Contention That Cosmetic-Grade Talc Contains Asbestos is Unsupportable B. Talc is a Rat Carcinogen Only Under Conditions Which Produce Particle Overload and Related Chronic Toxicity C. Consumer Exposure to Respirable Talc Particles is Several Orders of Magnitude Lower Than Exposures Which Result in Rat Lung Tumors HI. THERE IS NO CONVINCING EVIDENCE TO SUPPORT THE CONTENTION THAT FREQUENT TALC APPLICATION IN THE FEMALE GENITAL AREA MAY INCREASE THE RISK OF OVARIAN CANCER A. Evidence for the Role of Intrinsic and Extrinsic Risk Factors in the Etiology of Ovarian Epithelial Cancer is Inconclusive B. Epidemiological Evidence Supports Only a Weak Statistical Association Between Perineal Talc Use and Ovarian Cancer, the Significance of Which is Not Considered Scientifically or Medically Meaningful C. Statistical Arguments are Unsupported by Evidence of a Plausible Biological Mechanism by Which Talc Could Cause Ovarian Cancer IV. CONCLUSIONS V. REFERENCES /. INTRODUCTION The Cosmetic, Toiletry, and Fragrance Association (CTFA)1 is filing these comments in response to a citizens petition filed by Ms. Jill A. Cashen and Samuel S. Epstein, M.D. on behalf of the Cancer Prevention Coalition ("Petitioner") on November 17, 1994 (FDA Docket No. 94P0420/CP 1). Petitioner urges the Food and Drug Administration (FDA) to require "cosmetic talcum powder" products to bear labels with warnings such as "Talcum powder causes cancer in laboratory animals. Frequent talc application in the female genital area increases the risk o f ovarian cancer". CTFA contends that such labelling is without scientific basis and is unnecessary to protect the health of consumers. Talc (CAS No. 14807-96-6) comprises pulverized, natural, foliated, hydrous magnesium silicates (Harvey, 1988). As a pure mineral compound, talc is mineralogically defined as hydrous magnesium silicate, with the approximate chemical formula: Mg3(Si20 5)2(0 H )2 The largest commercial uses o f talc are in industrial applications such as paint, plastics, paper, ceramics, and construction materials. Talc utilized in direct cosmetic applications accounts for a relatively small percentage o f the overall talc market. In 1992, approximately 48,000 tons o f talc were used in the United States for cosmetics, pharmaceuticals, and food products (American Westmin, Inc./Luzenac America, unpublished data). 'The Cosmetic, Toiletry, and Fragrance Association is the national trade association representing the cosmetic, toiletry and fragrance industry in the United States. CTFA, founded in 1894, represents over 500 companies involved in the personal care products industry. CTFA's active members manufacture and distribute the vast majority of personal care products marketed in the United States. CTFA's associate member companies supply goods and services such as raw materials and packaging to the industry's manufacturers and distributors. The personal care products industry prides itself on a long history of providing safe, reliable products to meet the diverse needs and personal tastes of the American consumer. 1 Pharmaceutical tableting and various food applications account for approximately 8% of direct consumer uses of talc products; the greatest proportion (approximately 92%) is used in cosmetic applications. Used for decades in a wide variety of cosmetic and other applications, talc has proven to be among the safest o f all consumer products. The talc industry has adopted stringent quality assurance standards set by the Food Chemical Codex, the United States Pharmacopeia and the Cosmetic, Toiletry and Fragrance Association. The focus o f all three specifications is similar in that they place limits on certain extractable elements and other potential chemical contaminants. Only relatively pure talc products are capable o f meeting these specifications. Petitioner contends that labelling o f cosmetic talc products is required in order to adequately warn consumers o f the risk o f ovarian cancer. However, the available literature and the experience of manufacturers provides no evidence that cosmetic talc, when used as intended, presents any health risk to the consumer. All current available safety information on cosmetic talc has been thoroughly reviewed (Wehner, 1994). Moreover, a panel of experts at a workshop organized by FDA and the International Society of Regulatory Toxicology and Pharmacology (ISRTP) convened to review the latest toxicological and epidemiological studies on talc concluded that the "probability o f human risk [from talc] is likely non-existent under customary conditions o f use "and that "while some weak association between talc exposure and ovarian tumors has been reported, it [is] not sufficient warning for concern" (Carr, 1995). In summary, there is no evidence to suggest that cosmetic-grade talc is a human carcinogen. Specifically, CTFA will show that: the contention that cosmetic-grade talc contains asbestos is unsupportable; talc is a rat carcinogen only under conditions which produce particle overload 2 and related chronic toxicity; consumer exposure to respirable talc particles is several orders o f magnitude lower than exposures which result in rat lung tumors; evidence for the role o f intrinsic and extrinsic risk factors in the etiology o f ovarian epithelial cancer is inconclusive; epidemiological evidence supports only a weak statistical association between perineal talc use and ovarian cancer, the significance o f which is not considered scientifically or medically meaningful; and statistical arguments are unsupported by evidence o f a plausible biological mechanism by which talc could cause ovarian cancer. In short, there is no scientific justification to support the Petitioners contention that cosmetic talc products should bear labels warning that "[tjalcum powder causes cancer in laboratory animals" and that "[fjrequent talc application in the female genital area increases the risk o f ovarian cancer". II. THERE IS NO EVIDENCE TO SUGGEST THA T COSMETIC-GRADE TALC IS A HUMAN CARCINOGEN A. The Contention that Cosmetic-Grade Talc Contains Asbestos is Unsupportable Petitioner contends that talc used in cosmetic applications contains asbestos This contention is based on outdated and erroneous evidence which FDA has previously refuted. Petitioner quotes early mineralogical research done by Cralley et al (1968) and Rohl et al (1976) which sought to identify asbestos contamination in cosmetic talc. During the early 1970's FDA became concerned that 3 cosmetic talc contained significant amounts o f asbestos. However, in response to an earlier Citizens Petition "... FDA considered all analytical results to be o f questionable reliability. This assessment proved to be correct because many questions were subsequently raised about results reported in the literature in the early 1970's" (letter from FDA Acting Associate Commissioner for Regulatory Affairs, 1986). In denying the Petition, FDA noted "we find that there is no basis at this time for the agency to conclude that there is a health hazard attributable to asbestos in cosmetic talc" (Id). The erroneous association between talc and asbestos is an extremely unfortunate one. Precipitated in large part by the use of overly broad definitions o f asbestos and nonspecific analytical techniques (Rohl, 1974; Rohl and Langer, 1974; Krause and Ashton, 1978; Parmentier and Gill, 1978), the idea that asbestos is commonly and intimately associated with talc is simply incorrect. As a retrograde mineral, talc may be found in association with chrysotile in serpentinites and other hydrous minerals. However, the geologic conditions under which talc and asbestos form are dissimilar. Many talc-bearing rocks form from ultramafic rocks, the central core of which is composed o f serpentinite surrounded, successively, by shells o f talc-carbonate rock and talc-bearing steatite (steatite is synonymous with soapstone). Usually a thin wall schistose rock, composed essentially o f chlorite, separates the steatite from the country rock. The serpentinite is composed mostly o f non-fibrous serpentine minerals (lizardite and antigorite), but small amounts o f chrysotile asbestos may also occur within the serpentinite. The talc-carbonate and steatite shells which surround the serpentinite core contain abundant talc but do not contain asbestos. Careful mining procedures enable the serpentinite core to be avoided and thus possible contamination o f talc ore with asbestos is obviated. Confirmation o f the absence o f asbestiform minerals in the finished talc product is established using x-ray diffraction, optical microscopy and electron microscopy techniques (CTFA, 4 1990). B. Talc is a Rat Carcinogen Only Under Conditions Which Produce Particle Overload and Related Chronic Toxicity Petitioner contends that "[t]alc is a carcinogen, with or without the presence o f asbestos-like fibers". In support o f this contention, Petitioner relies on the results o f studies published by the National Toxicology Program (NTP). Petitioner's reliance is misplaced in that NTP showed talc to be a rat (but not a mouse) carcinogen, and only under circumstances indicative o f a secondary mechanism involving particle overload and resultant chronic toxicity. In 1992, NTP reported the results o f 2 year inhalation studies designed to determine the effect o f talc in experimental animals (NTP, 1993); male and female F344/N rats and B6C3F, mice were exposed to target aerosol talc concentrations of 0, 6, or 18 mg/m3for 6 hours/day, 5 days/week, for 2 years. NTP concluded that: Under the conditions o f these inhalation studies, there was some evidence o f carcinogenic activity o f talc in male F344/N rats based on an increased incidence o f benign and malignant pheochromocytomas o f the adrenal gland. There was clear evidence o f carcinogenic activity o f talc in fem ale F344/N rats based on increased incidences o f alveolar/bronchiolar adenomas and carcinomas o f the lung and benign and malignant pheochromocytomas o f the adrenal gland. There was no evidence o f carcinogenic activity o f talc in male or fem ale B6C3F, mice exposed to 6 to 18 m g /m 3. Since its publication, the findings o f NTP have been criticized by several experts in the field of inhalation toxicology with regard to both study design and conduct. Most notably these studies were the subject o f a joint ISRTP/FDA scientific workshop held in 1994 ( Talc: Consumer Uses and 5 Health Perspectives; January 31/February 1, 1994) which discussed the relevance o f the NTP findings with regard to consumer exposure and consumer safety. Criticisms o f the study made at the workshop may be summarized as follows: Test Article/Particle Size: The NTP study has questionable relevance with regard to prediction o f human risk due to consumer exposure since the talc sample utilized in the NTP study was o f a kind which is used in industrial applications, and was not a product that would be used in a cosmetic powder application because o f its extreme fineness (Zazenski et al., 1995). The test material used by NTP is an industrial grade product typically used in specialty coatings and high performance polymeric applications. The median particle size o f the NTP talc sample was approximately 1.2 microns and had a top size o f approximately 10 microns. In contrast, typical commercial loose talc powder has a median particle size o f approximately 10 microns and a top size of approximately 45 microns (Zazenski et al., 1995). Exposure Levels Resulted in Lung Particle Overload: The major criticism o f the NTP study is the failure to include exposure levels which did not lead to lung particle overload The concept of "particle overload" in chronic inhalation studies with highly insoluble particles o f relatively low toxicity is now widely accepted (Morrow, 1988). Typically, exposure concentrations are relatively high and result in retained particulate lung burdens which are also high. Such retained lung burdens lead to a sequence o f inflammatory responses, altered particle-clearance/retention and altered morphology, leading to chronic disease states including fibrosis and the induction o f benign/malignant tumors (see Oberdorster, 1995). Highly insoluble particles deposited in the lower respiratory tract are removed by two important mechanisms (see Oberdorster, 1995). The mucociliary escalator removes particles 6 deposited in the conducting airways; particles deposited in the alveolar region are phagocytosed by alveolar macrophages (AM) which then migrate towards the mucociliary escalator and are removed (Schlesinger, 1985, Oberdorster, 1988; Snipes, 1989). When deposition rate in the alveolar region exceeds the AM-medicated clearance rate, alveolar retention halftime is considerably increased (often irreversibly) and results in excessive accumulation o f particles in the lung. One further consequence of excessive accumulation is increased translocation o f particles to the pulmonary interstitium which eventually results in the induction of pulmonary fibrosis (Adamson et al., 1989; Bowden et al., 1989), activation of macrophages and release o f cytokines resulting in increased epithelial cell proliferation (Driscoll et al., 1990). Based on the actual talc burdens o f exposed rats (ie., as measured by NTP), Oberdorster (1995) has estimated that the pulmonary retention halftimes o f the retained talc particles range between 250 and 300 days, ie., is markedly longer than the normal retention halftime for highly insoluble particles in rat lungs o f ~70 days. Oberdorster has concluded that these results are indicative o f lung particle overload. Oberdorster has also shown that the talc-exposed mice exhibited a marked increase in pulmonary retention halftime for talc particles with increasing lung burdens (i.e,, a severe retardation o f normal AM-mediated particle clearance) compared to a normal retention halftime in mice lungs. In summary, the lung particle clearance was impaired in both rats and mice in the N TP study, resulting in altered accumulation kinetics o f talc particles chronically inhaled at concentrations o f 6 and 18 mg/m3. The rat tumor response is thus very likely a secondary effect of the particle overload phenomenon ie., due to altered lung clearance kinetics resulting in excessively high lung burdens leading to chronic inflammatory and cell proliferative processes (Oberdorster, 1995). Conceivably, the difference in tumor response between male and female rats may be merely 7 temporal since hyperplasia and an interstitial fibrosis was observed in both sexes. Oberdorster attributes the lack of pulmonary tumors in mice to the fact that rat lung tumors associated with a high pulmonary particle load appears to be a very species-specific response to non-fibrous particles (Oberdorster, 1995). Exposure Levels Exceeded the MTD: The highest dose in carcinogenicity studies is generally designed to be equivalent to the maximum tolerated dose (MTD). Although this principle has become increasingly subject to criticism, high-dose testing at the MTD remains the practice o f NTP. In general, the MTD is estimated following a careful analysis o f data from appropriate subchronic toxicity tests. The need to consider a broad range o f biological information when selecting the MTD has become increasingly clear. For example, data concerning changes in body/ organ weight, clinically significant alterations in hematologic, urinary and clinical chemistry measurements, as well as more definitive toxic, gross or histopathologic endpoints can be used to estimate the MTD. For chronic inhalation studies with highly insoluble particles o f low cytotoxicity, the phenomenon of particle overload and the question of exceeding the MTD are intimately interrelated. Recommendations o f a NTP Workshop on Maximal Aerosol Exposure Concentrations in Inhalation Studies (Lewis et al., 1989) included "[the] chronic study should not (emphasis supplied) be performed at the highest technologically feasible concentration, three concentrations should be used o f which only the highest should show some interference with lung defense mechanisms, i.e., clearance impairment, and the two lower concentrations should show no interference with clearance and particle accumulation". Based on these criteria, the MTD was clearly exceeded in the studies conducted by NTP on talc. In the NTP study, talc-induced lung tumors were not detected in male rats, female mice or 8 male mice. In rats, the principal toxic lesions associated with inhalation exposure to talc included chronic granulomatous inflammation, alveolar epithelial hyperplasia, squamous metaplasia and squamous cysts, and interstitial fibrosis o f the lung. These lesions were accompanied by impaired pulmonary function. While the talc burden in the lungs o f males and females was similar, the degree o f chronic toxicity and inflammation was substantially higher in females In mice, inhalation exposure to talc produced some chronic inflammation. In contrast to rats, alveolar epithelial hyperplasia, squamous metaplasia, and interstitial fibrosis were not observed. Overall, markedly less talc-induced lung toxicity was produced in mice than in rats. In summary, it is apparent that an increase in lung tum ors was seen only in the test animals that clearly exhibited the highest degree o f chronic lung toxicity, (ie., the female rats exposed to 18 mg/m3 talc). Similarly, the increased incidence o f pheochromocytomas is most likely attributable to the stressful conditions (eg., as a result o f physiological, metabolic or endocrine changes) to which the test animals were exposed. In addition, the F344/N rat is known to have a high background incidence o f pheochromocytomas (NTP, 1993). The relevance o f these responses with regard to extrapolation to humans is thus highly suspect (Goodman, 1995). The unmistakable conclusion from these observations is that the MTD was exceeded in the female rats exposed to the high dose, and that talc is not expected to cause lung tumors under conditions o f exposure that fail to result in marked chronic lung toxicity (Goodman, 1995). In contrast to Petitioner's characterization o f the results o f the NTP study, clear evidence o f carcinogenic activity o f talc was seen only in female rats (not male or female mice) exposed to the high dose o f talc and only under circumstances in which there was evidence o f particle overload and marked chronic lung toxicity. In summarizing it's assessment o f the NTP study, the panel o f experts at the 9 ISRTP/FDA workshop Talc: Consumer Uses and Health Perspectives characterized the positive results in female F344/N rats as "likely experimental artifact...[a] non-specific generic response o f dust overload of the lungs, and not a reflection o f a direct activity o f talc. Given the gross differences o f rodent and human lungs, the lung clearance capabilities o f humans and the possible conditions of customary human exposures, the NTP bioassay results in F344/N rats cannot be considered as relevant predictors o f human risk" (Carr, 1995) C. Consumer Exposure to Respirable Talc Particles is Several Orders of Magnitude Lower Than Exposures Which Result in Rat Lung Tumors Although Petitioner would require warning labels to the effect that "[tjalcum powder causes cancer in laboratory animals", the implication is that talc exposure constitutes human risk o f cancer. Such an implication is unwarranted since consumer exposure to talc is considerably lower than exposures which result in rat lung tumors. Consumers are exposed to talc during the application and use o f body powders. In this regard, human exposure occurs principally via the dermal route, but primary concern has focused on exposure via the respiratory tract. Talc miners and millers are exposed to long-term, relatively high concentrations o f airborne talc; the results o f human cohort studies involving cosmetic grade talc miners and millers thus provide a useful basis against which pulmonary risk to consumers may be estimated (Scansetti et al., 1963; El-Ghawabi et al., 1970; Rubino et al., 1976; Gamble et al., 1982; Wegman et al., 1982; Leophonte et al., 1983; Wergeland et al., 1990). These studies show that a pneumoconiosis (talcosis) risk does exist but only when respirable talc dust levels are significantly greater than worst-case consumer exposures (described below) and exposure is over an extended period o f time (several years). While there may be disagreement over the amount o f exposure required to induce 10 pneumoconiosis, such studies suggest that talc poses a low to moderate pulmonary risk in an industrial setting. For example, in a mortality and morbidity study o f Italian talc miners and millers, radiographic abnormalities consistent with pneumoconiosis were found among talc workers after an average duration o f exposure for 22 years, with an average respirable dust concentration of approximately 11 mppcf (Rubino, et al., 1976); in contrast, in a study involving French talc workers, no cases o f pneumoconiosis at a level o f 15 mppcf were reported (Leophonte, et a l , 1983). Although it is difficult to reliably convert respirable particle count data (mppcf) into respirable gravimetric data (mg/m3), such levels typically fall into the 1-2 mg/m3 range (e.g., in a study o f Vermont talc miners and millers (Boundy et al., 1979), pneumoconiosis was observed when respirable dust levels ranged from 0.5 to 2.9 mg/m3). Despite the incidence o f pneumoconiosis at high industrial exposure levels it is important to note that an excess prevalence o f lung cancer in talc mining populations has not been observed (Selevan et al 1979; Leophonte et al., 1983, Wergeland et al., 1990; Rubino et al., 1976). Electrostatic, Van der Waal's and valance charges present on the particulate surfaces o f a dry powder such as talc result in substantial particle-to-particle agglomeration, thereby increasing effective mass, diameter, and settling velocity (Carta et al., 1981, Gajewski, 1990). These factors are important with regard to influencing the respirability o f dry particles. Two studies have been conducted to evaluate exposures to respirable particles during application o f talc as an adult body powder and as a baby powder (Russell et al., 1979; Aylott, et al., 1979). In both studies, respirable particles (< 10 microns) were collected usig a cyclone particle fractionation system operating at an air flow rate o f 1.7-1.9 liters/minute. Adult exposure was assessed during normal face/body powdering practices by placing cyclone collection units on shelves at appropriate face height, or by positioning a cyclone attached to a headband near the nose (i.e., in the subjects breathing zone). To 11 evaluate the exposure o f babies to talc, sampling units were placed on the changing table near the infants' (or doll's) heads during normal powdering practices (i.e., while changing a diaper). Talc was dispensed using common twist-top, sprinkle-type containers, or in the case o f face powder, powder puffs. Exposure of adults to respirable particles during application o f talc ranged from 0.48 to 2.03 mg/m3, while the exposure to babies ranged from 0.19 to 0.21 mg/m3. When these numbers are extrapolated to 8-hour time weighted average exposures, they range from <0.001 to 0.005 mg/m3 (Zazenski et al., 1995). For comparison purposes, the current OSHA/ACGIH permissible industrial exposure limit for talc is 2.0 mg/m3 as an 8 hour time-weighted average (ACGIH, 1992), i.e., the industrial permissible limit is approximately 350 times greater than the worst case consumer use of cosmetic grade talc. Based upon the determinations reported in the literature, human exposure to respirable talc particles during normal product use are approximately 2,000-20,000 times lower than those used to expose rats and mice in inhalation studies conducted by the NTP (Zazenski et al., 1995). Although a direct comparison o f the dosimetry o f inhaled materials between rodents and humans is far from simple (Dahl et al., 1991), such a broad difference in exposure level is quite striking. The incidence of tumors resulting from massive exposures such as those involved in the NTP talc inhalation study are more likely to reflect a particle overloading effect in the experimental animals (Morrow, 1988; Morrow, 1992; Oberdorster, 1988) than any genotoxic effect associated with the test material (EndoCapron et al., 1993). As previously noted, the talc sample utilized in the NTP study was not a product that would be used in a cosmetic powder application because of its extreme fineness (SECTION II. B). Further, the NTP talc aerosol was exposed to Kr-85 gamma radiation immediately prior to its introduction 12 into the exposure chambers containing the experimental animals. Use o f ionizing radiation was intended to neutralize the electrical charge imparted on the talc particles during aerosolization. Charge neutralization tends to decrease agglomeration and results in deposition o f particles in the deep lung o f exposed animals. Thus, while selection o f an ultra-fine product combined with procedures designed to maximize particle dispersion may be entirely appropriate from a toxicological perspective, such an artificial environment has questionable relevance with regard to actual human exposure from commercial cosmetic talc products under use conditions SECTION II. SUM M ARY The issues raised by Petitioner with regard to asbestos contamination o f cosmetic-grade talc have previously been addressed by FDA. In 1986, FDA concluded that there was no health hazard attributable to asbestos in cosmetic talc. Since that time no new evidence has arisen which would suggest a conclusion to the contrary; moreover, appropriate selection o f mine site, careful mining procedures and the utilization of modern beneficiation techniques have further safeguarded against asbestos contamination. Accordingly, CTFA believes that FDA's response to the issue o f asbestos contamination raised by Petitioner should be no different than its response in 1986. With regard to Petitioner's assertion that talc is an animal carcinogen, the NTP chronic inhalation study has been subject to severe criticism. The test material used by NTP was characterized by an extremely small particle size and is not characteristic o f material used for cosmetic talc applications. Further, the exposure levels chosen by NTP clearly exceeded the MTD for talc and were such that exposure resulted in impairment of lung clearance mechanisms and a condition known as particle overload. Because any highly persistent particulate compound o f low cytotoxicity has 13 carcinogenic potential, particularly in rats, when chronically inhaled at such high concentrations, the classification o f such particles with respect to pulmonary carcinogenicity must be carefully evaluated. In the absence o f any evidence o f a toxic or genotoxic effect per se, the only reasonable conclusion which may be drawn from the studies conducted by NTP is that the carcinogenic effect o f talc is a secondary phenomenon which does not occur in the absence o f chronic toxicity which is itself a result of particle overload. In summary, the application o f the results o f the NTP study with regard to human risk assessment are highly questionable. Consumer exposure to respirable talc particles is several orders of magnitude lower than exposures which result in rodent tumors. There is no evidence o f chronic toxicity following consumer exposure to talc, thus use o f the lung tumor endpoint in female rats as the basis o f extrapolation to human risk is inappropriate. Clearly, Petitioner's request that FDA require warnings such as "[t]alcum powder causes cancer in laboratory animals", with it's implicit message that talc may cause human risk o f cancer, is both misleading and may cause consumers unnecessary concern. As such, Petitioner's request should be denied. III. THERE IS NO CONVINCING EVIDENCE TO SUPPORT THE CONTENTION THA T FREQUENT TALC APPLICATION IN THE FEMALE GENITAL AREA MAY INCREASE THE RISK OF OVARIAN CANCER A. Evidence For The Role O f Either Intrinsic Or Extrinsic Risk Factors In The Etiology O f Ovarian Epithelial Cancer Is Inconclusive The etiology o f human ovarian epithelial cancer is not clearly understood Ovarian tumors o f epithelial origin, which include serous, mucinous, endometrioid, clear cell and undifferentiated adenocarcinomas and the Brenner tumor, are responsible for the majority o f ovarian malignancies 14 (Cannistra, 1993; Slotman and Roa, 1988). The purported extrinsic and intrinsic risk factors which contribute to the incidence of epithelial cancer of the ovary have been the subject o f numerous reviews (Shoham, 1994; Kelsey et al., 1994; Dietl and Marzusch, 1993; Parazzini et al., 1991; Baylis et al., 1986; Heintz et al., 1985). While a number o f scientists have attempted to identify various extrinsic risk factors, including environmental (e g. tobacco and talc), infectious disease (e g. mumps, rubella), and dietary intake (e g. lactose, animal fat, alcohol, caffeine) as potential etiologic agents, the data are inconclusive. At best, some studies have demonstrated a relationship between dietary factors and the incidence of ovarian epithelial cancer: in particular, an increased risk for ovarian cancer has been reported for women who consume diets which are high in animal fat (Shu et al., 1989; Mori and Miyake, 1988; La Vecchia, et al., 1987) and lactose (Cramer, 1989; Cramer et al., 1989). Research investigating intrinsic risk factors has provided evidence which suggests that reproductive history and molecular factors are strongly linked to carcinogenesis o f the ovarian epithelium. It is well documented that suppression o f ovulation, either by pregnancy or by oral contraceptive use, decreases the risk for developing ovarian cancer (McGowan et al., 1979; Wu et al., 1988; Mori et al., 1988; Booth et al., 1989). Ovulation is a physiologic process which is mediated by hormones (gonadotropins) and results in repeated ruptures in the surface epithelia o f the ovary. Following ovulation, a repair process takes place whereby there is an increase in epithelial cell mitotic activity. The reduced risk afforded by pregnancy or by oral contraceptive use is postulated to be meditated by the subsequent decrease in circulating gonadotropins and/or the suppression of ovulation (Whittemore, et al., 1992). Evidence supporting the etiologic role o f ovulation has been provided by in vitro studies demonstrating that the repeated cell division o f ovarian surface epithelial 15 cells results in a malignant transformation (Godwin et al., 1993). Molecular events associated with the initiation o f ovarian cancer have recently been reviewed (Berek and Martinez-Maza, 1994; Godwin et al., 1993). Genetic mutations are molecular events which can lead to tumor formation. Studies assessing family history have reported a genetic predisposition to ovarian cancer (Patel and Obrams, 1993; Hartge et al., 1989) which appears to be inherited on an autosomal dominant gene (Slotman and Rao, 1988). Specific loss o f a gene at the 6q chromosomal loci has been identified in ovarian tumors (Lee et al., 1990); additionally, genetic alterations on chromosomes 1,3, 14 and 17 have been identified in certain ovarian carcinomas (Daly, 1992). Mutations can result in chromosome alterations and the subsequent inactivation o f a particular gene. Studies conducted by Hoffman and colleagues (1993) have demonstrated a reduced expression o f a cell adhesion molecule (E-cadherin) in an in vitro model o f ovarian epithelial carcinogenesis. Genetic alterations can also lead to the overexpression o f a gene. Proteins encoding certain chemical messengers (cytokines), such as IL-6 (interleukin 6), M-CSG (macrophage colony stimulating factor) and TNF (tumor necrosis factor) have been found to be increased in epithelial ovarian cancer cells (Malik and Balkwill, 1991). In summary, the events which lead to development of ovarian epithelial cancer are not clearly understood A variety of intrinsic and extrinsic risk factors may be involved. However, in light o f the fact that cancer is a disease which evolves at the molecular level, it is likely that research investigating the molecular aspects o f ovarian cancer may provide important insight how such risk factors relate to incidence. It is significant in this respect that a thorough review o f the toxicology o f talc reveals no evidence o f any genotoxicity (Wehner, 1994). 16 B. Epidemiological Evidence Suggests Only a Weak Statistical Association Between Perineal Talc Use and Ovarian Cancer, the Significance of Which is Not Considered Scientifically or Medically Meaningful Although several studies on the possible association between perineal talc use and ovarian cancer have been published, any evidence o f such an association remains equivocal. At most, the statistical association is weak and in the absence o f evidence of a plausible biological mechanism (SECTION III. C) is insufficient to warrant public health concern. There have been seven casecontrol studies and one cohort study that have been published containing information regarding the risk o f ovarian cancer in women using talc in their perineal region (Cramer et al., 1982; Hartge et al., 1983; W hittemore et al., 1988; Booth et al., 1989; Harlow and Weiss, 1989; Harlow et al., 1992; Rosenblatt et al., 1992, Hankinson et al., 1993). Talc exposure was the primary focus in only four o f these studies (Cramer et al., 1982; Hartge et al., 1983; Harlow and Weiss, 1989; Harlow et al., 1992). Cramer et al (1982) investigated whether there is an association between exposure to certain hydrous magnesium silicates (including talc), and the incidence o f ovarian cancer. Population-based matched controls were randomly selected, and stratification and logistic regression were used to accommodate confounders. Overall, 42.8% o f cases and 28.4% o f controls reported exposure to talc, via direct application to the perineum, by dusting sanitary napkins, or both. The unadjusted odds ratio (OR) of ovarian cancer for any perineal exposure as opposed to no perineal exposure was 1.89 (95% Cl 1.27-2.82). Adjustment was then made for parity and menopausal status. Women who used talc on both the perineum and sanitary napkin had an adjusted OR o f 3.28 (95% Cl 1.68-6.42) and for any exposure, 1.61 (95% Cl 1.04-2.49). The reduction in risk from 1.89 to 1.61 for perineal talc exposure due to logistic regression is largely unexplained and may be due to residual confounding. 17 No dose-response or duration data were reported. While a major strength of the study is the use of neighborhood controls, the nonparticipation rate among controls was relatively high (260/475=55%). H artge et al (1983) investigated the association between talc use and the risk of ovarian cancer but reported no significant finding. The cases were women with pathologically confirmed primary epithelial ovarian cancer, while the hospital based controls had non-gynecological conditions (psychiatrically disturbed women, pregnant women, and women with other malignancies were excluded). Controls were frequency matched on age, race and hospital. For the group o f women who did not use talc versus the group of women who did, the unadjusted OR o f ovarian cancer was 0.776 (95% Cl 0.47-1.20). Although no attempt was made to control for potential confounding variables, this nonsignificant odds ratio was unaffected by adjustment for parity, race and age. Lifetime consumption o f coffee, tobacco and alcohol were the principal exposure factors studied by Whittemore et 7/(1988). Women diagnosed with ovarian cancer in the San Francisco Bay area between 1983-5 provided the cases for this study. Matched controls from two groups, hospital and population, were obtained. The hospital controls were selected from the same hospitals as the cases, whereas the population controls were selected using random digit dialing. All controls were matched to cases on age, race, and having at least one ovary. Logistic regression was used to adjust for confounders. While this study examined other potential risk factors as well as talc exposure in relation to ovarian cancer, the study did not find evidence o f an association between genital talc exposure and an increased risk of ovarian cancer. While women who reported regular use o f talc on the perineum showed a marginally significant increase in relative risk, no other differences were noted between cases and controls when considering other types o f perineal talc exposure either alone or taken in combination. The unadjusted OR o f ovarian cancer for any perineal exposure as opposed 18 to no perineal exposure was 1.19 (95% Cl 0.85-1.66). Adjusted for parity, the OR was 1.40 (95% Cl 0.98-1.99). Other odds ratios also failed to produce significant associations. Several sources of bias were identified, including failure to interview all eligible cases, the potential pitfalls in combining hospital and population controls, confounding by differential talc use among women with characteristics predictive o f ovarian cancer and random error in reported talc use tending to attenuate relative risk estimates. The study raises the possibility that a hormonal factor that may place women at a higher risk for the disease may also promote their use o f talc. Booth et al (1989) studied various potential risk factors for ovarian cancer including infertility, oral contraceptive use, parity, age at menopause, and genital talc use. Women with a diagnosis o f ovarian cancer and treated at a London cancer hospital were each age matched to two hospital controls at 15 other hospitals. Non-participation rates were not provided, and one hospital providing more than 25% o f the cases provided no controls. In addition, cases were generally older and in a higher social class than controls. All odds ratios were adjusted for social class in six categories. Maximum likelihood estimates o f the odds ratios with the corresponding 95% confidence intervals were obtained. Logistic regression was used to test for trends. The results were inconclusive since weekly talc use showed a higher OR of ovarian cancer (2.0) than did daily use (1.3), (95% Cl 1.3-3.4 and 0.8-1.9, respectively). Furthermore, there was no significant difference between cases and controls who used talc in conjunction with a diaphragm. The unadjusted OR of ovarian cancer with regard to talc use was a statistically nonsignificant 1.29 (95% Cl 0.92-1.81). Overall, the study does not support the hypothesis that use of perineal talc increases the risk of ovarian cancer. Harlow and Weiss (1989) investigated whether application o f perineal talc application is 19 associated with an increased risk o f serous and mucinous borderline ovarian tumors. Cases (residents o f three urban, western Washington state counties diagnosed as having a serious or mucinous borderline ovarian tumor) were identified from the corresponding population-based cancer reporting system. Controls were population-based and located through random digit dialing. Women who reported any perineal use o f dusting powders had an adjusted OR o f 1.1 (95% Cl 0.7-2.1) for borderline ovarian tumor. The adjustment was for age, parity, and use o f oral contraceptives but not for other possible confounders. Women using deodorizing powder with or without baby powder (the only powder reported by women using a second powder) showed an increased risk o f borderline tumor development, OR o f 2.8 (95% Cl 1.1-11.7). The elevated risk o f borderline ovarian cancer among women who specifically used deodorizing powders may have been due to chance or applicable only to borderline but not malignant tumors. Harlow et al (1992) investigated whether the use o f talc increases the risk for epithelial ovarian cancer. Between July, 1984, and September, 1989, cases were diagnosed with borderline or malignant epithelial ovarian cancer at 10 different Boston metropolitan hospitals. Population controls were age matched and were all Caucasian. The influence o f confounders and effect modifiers was assessed through stratification and logistic regression. Overall, 49% o f cases and 39% o f controls reported exposure to talc, yielding an OR o f 1.5 (95% Cl 1.0-2.1) for ovarian cancer. Among women with perineal exposure to talc, the risk was significantly elevated in subgroups o f women who applied it directly as body powder (OR o f 1.7; 95% Cl 1.1 -2.7). Women with an intact genital tract (and who had at least 10,000 applications while ovulating) showed an OR o f 2.8 (95% Cl 1.4-5.4). Although this study seemingly suggests a small increased risk o f epithelial ovarian cancer due to lifetime use o f perineal talc, the association is still not entirely clear. One important potential 20 confounder that was not accounted for in this study was oral contraceptive use. More controls used oral contraceptives than cases, and oral contraceptive use was associated with less reported talc exposure. Thus, use o f oral contraceptives is a possible strong confounder that, if properly considered, could eliminate any observed effect. Rosenblatt et al (1992) studied the relationship between "fiber" exposure (Note: these investigators mischaracterize talc as "fiber"; other exposures include asbestos and fiberglass) and epithelial ovarian cancer. Controls, who were hospital-based and free o f gynecological and malignant conditions, were matched to cases by age, race and date o f diagnostic admission. Due to the strict inclusion criteria, controls could not be found for each case. Thus although 140 new cases were located and 108 were successfully interviewed, only 77 cases were entered into the study. The OR (adjusted for number o f live births) was 1.0 (95% Cl 0.2-4.0) for women reporting any genital "fiber" use versus those women who were not so exposed; the unadjusted OR was 0.84 (95% Cl 0.27-2.63). An increased risk o f ovarian cancer was observed for women who used talc on their sanitary napkins with an OR o f 4.79 (95% Cl 1.29-17.79). However, among the remaining eight odds ratios, none was statistically significant. While there seems to be an elevated risk o f ovarian cancer in women who used talc on sanitary napkins, this finding is not supported by other studies (eg., Harlow et al., (1992) did not report an elevated risk in this category). The most recent study in which an indirect comparison o f ovarian cancer incidence in talc users versus nonusers can be made was reported by Hankinson et a l (1993). The purpose o f this study was to assess whether tubal ligation and hysterectomy affected subsequent risk o f ovarian cancer based upon the hypothesis that such procedures could prevent translocarion o f talc to the ovaries. In reporting a finding of no association between talc use and an increased risk o f ovarian 21 cancer the authors found that tubal ligation was "highly protective in women who reported never using talc". Such a finding tends to discount the talc translocation hypothesis discussed in SECTION III.C, below). In reviewing evidence o f the proposed association o f talc exposure and ovarian cancer, the panel o f experts at the ISRTP/FDA workshop Talc: Consumer Uses and Health Perspectives found that the "epidemiologic data are conflicting and remain equivocal" (Carr, 1995) The panel noted the problems connected with the epidemiology of weak associations and the fact that any properly designed study to determine the association between perineal talc use and ovarian cancer must account for other possible risk factors. These other factors include (but are not necessarily limited to) age, oral contraceptive use, number o f term pregnancies, menopausal status, and other, environmental factors such as smoking status, alcohol and caffeine consumption. Other confounding variables, such as vulvovaginal diseases and obesity may also be causally related to ovarian cancer (Rosenblatt et al., 1992). In such instances (where talc use is associated with such conditions because o f the degree of comfort it imparts to those affected), any statistical association between talc use and ovarian cancer may be merely coincidental In summary, the results of epidemiological studies are inconsistent and ambiguous. Any reported association between perineal talc use and ovarian cancer is weak and statistically barely significant. The biological significance (and hence public health significance) o f any such weak association remains obscure. C. Statistical Arguments are Unsupported by Evidence of a Plausible Biological Mechanism by Which Talc Could Cause Ovarian Cancer As previously described (SECTION III. B), several investigators have proposed that, based 22 on weak epidemiological evidence, chronic perineal use o f talc, including direct application or application to under garments, sanitary napkins or diaphragms, may increase the risk o f ovarian cancer. In order for this to occur, talc particles (which have no inherent locomotive capability) would have to migrate from the perineum to the ovaries o f exposed individuals. In order to try to identify such a potential translocation process, several studies have been conducted in various species, including humans. Many of these studies are so fraught with problems as to render the results o f such studies ambiguous. Egli and Newton (1961) have claimed that half an hour following vaginal deposition o f carbon black particles, translocation occurred from the vagina to the oviducts in two o f three female patients. The results o f this study are subject to considerable doubt since the investigators failed to utilize either solution or filter blanks as negative controls. Wehner et al (1985) subsequently conducted a similar study in cynomolgus monkeys and found no difference in the number o f carbon black particles in the blanks compared to the oviduct rinse solution. In a study conducted by De Boer (1972), carbon black particles were deposited in the uterus, cervical canal, or vagina o f over 100 patients prior to abdominal surgery. Subsequent evaluation showed that when deposited in the uterus, carbon black particles translocated to the oviducts and beyond; particles placed in the cervical canal migrated to a lesser extent. Translocation from the vagina occurred in only 2 of 37 patients: in both cases the patients were placed in the Trendelenburg position, resulting in a negative intra-abdominal pressure Such negative pressure was considered by the investigator to have been sufficient to draw up material from the vagina, especially when the patient was anesthetized and had a relaxed cervix. Translocation studies have also been performed in laboratory animals. Henderson et al 23 (1986) injected a suspension o f talc particles into the cervical canal o f 8 female ex-breeder SpragueDawley rats. A group o f four animals was sacrificed 5 days later, while the remaining 4 animals received additional installations 6 and 15 days following initial treatment. Two o f these animals were further administered the talc suspension at 22 and 30 days; six other animals received intra-vaginal injections o f talc particles. Subsequent evaluation showed that all animals receiving intrauterine deposition of talc (and 2 o f 6 receiving intra-vaginal administration) resulted in the detection o f talc particles in the ovaries. Wehner (1994) has suggested that the hydrostatic pressure o f the saline solution enhanced the potential for translocation under such conditions. In contrast Phillips et al (1978) found no radiolabel in the ovaries of rabbits given either single or multiple intra-vaginal doses o f 3H-labelled talc. An attempt to quantify the amount o f talc supposedly found in human ovarian tissue (normal ovaries, cystic ovaries, and ovarian adenocarcinomas) has been made by Henderson et al (1979). According to these investigators, normal ovarian tissue contained up to 55,100 particles o f talc per gram o f wet weight o f tissue, while cystic ovaries and ovarian adenocarcinomas contained up to 24,300 particles. However, because talc is ubiquitous, especially in a laboratory or surgical setting, it is difficult to determine if the talc observed in such clinical specimens is due to a specific exposure or contamination. In order to specifically and clearly evaluate the potential for translocation o f talc from the vagina to the ovaries, Wehner et al. (1986) used neutron- activated talc with subsequent gamma-ray analysis in order to rule out contamination These investigators used cynomolgus monkeys since the physiological and anatomical characteristics of this species resembles the human female more closely than any other readily available laboratory animal (cynomolgus monkeys have an estrous cycle o f 28 days and menstruation lasts 2-7 days). Neutron-activated talc was deposited 24 in the vagina for 30 consecutive working days (45 calendar days); thus exposure occurred through at least one menstrual cycle. Oxytocin was administered once per week during the study to induce the type o f uterine contractions thought to occur during coitus and which may enhance the translocation process. The vagina/cervix, uterus, oviduct, ovaries and peritoneal lavage fluid o f exposed animals were subsequently examined. Talc was observed only at the site o f administration (vagina/cervix) and none was found in the ovaries. In the carcinogenicity studies conducted by NTP (see SECTION II. B) male and female F344/N rats and B6C3F1 mice were exposed to target aerosol concentrations o f 0,6 and 18 mg/m3 talc for 6 hours daily, 5 days per week, for two years. Such conditions resulted in exposure via inhalation, oral and dermal (including perineal) routes. Initial tissue examination found no exposurerelated lesions in either rat or mouse ovaries (NTP, 1993). Subsequent histological examination of the ovaries and ovarian bursa from rats confirmed this finding and demonstrated no material consistent with the appearance o f talc in any animals from any group (Boorman and Seely, 1995). In summary, available histologic and physiologic studies provide no concrete basis to conclude that talc can plausibly migrate to the ovaries from the perineal region. In the absence o f such biological evidence, conflicting and equivocal evidence o f a weak statistical association between perineal talc use and ovarian cancer is insufficient to "raise concern at level sufficient to warrant regulatory or public health measures" (Carr, 1995). SECTION III SUMMARY Although several possible intrinsic and extrinsic risk factors have been suggested, the etiology of ovarian epithelial cancer is presently unknown. Critics o f the supposed association between talc 25 and ovarian cancer highlight the reported weak associations and the numerous confounding variables (e g., interview case/control comparisons, failure to adequately address key independent risk factors, etc.) which characterize much o f the epidemiological research in this area Further, experimental studies in which neutron-activated talc was repeatedly introduced into the vagina o f cynomolgus monkeys, failed to demonstrate translocation to the cervix, uterus or ovaries. The results o f these studies in monkeys suggest that any increased risk o f ovarian cancer following perineal exposure to talc is biologically implausible. A causal association between perineal talc application and ovarian cancer is improbable. IV CONCLUSIONS In January 31- February 1, 1994, a workshop organized by FDA and the International Society o f Regulatory Toxicology and Pharmacology (ISRTP) was convened to provide a forum for an updated discussion o f the origins, manufacture, characterization, toxicology and epidemiology of talc.2 The principal focus o f the meeting was on the latest toxicologic and epidemiologic studies and their significance with regard to the safe uses o f talc in consumer products. At the conclusion o f the workshop, a panel o f independent experts were able to reach a series o f unanimous conclusions. With regard to the NTP talc bioassay in rodents, the panel found that "because of the extreme doses and the unrealistic particle sizes o f the talc employed, because o f the negative results in mice and male rats, because o f the lack o f tumor excess at the low doses, and because o f the clear biochemical and cytological markers o f excessive toxicity in female rats, the 2These conclusions are in large part based upon an Executive Summary which prefaced a series of papers published as the proceedings of the FDA/ISRTP Conference, Talc: Consumer Uses and Health Perspectives (Carr, 1995). 26 positive talc bioassay results in female F344/N rats are likely the result o f experimental artifact and a non-specific, generic response of dust overload o f the lungs, and not a reflection o f a direct activity o f talc. Given the gross differences o f rodent and human lungs, the lung clearance capabilities of humans and the possible conditions o f customary human exposures, the NTP bioassay results in F344/N female rats cannot be considered as relevant predictors o f human risk" (Carr, 1995). With regard to the proposed association o f talc exposure and ovarian cancer, the panel found that "epidemiologic data are conflicting and remain equivocal". "Diet, parity, contraceptive use, ovulatory frequency, familial predisposition, age to menarche and menopause amongst other factors [are] associated] strongly (and plausibly) with ovarian cancer incidence" (Carr, 1995). These possible confounders, as well as control selection biases, etc., interviewer and interviewee biases, as well as other factors, may well explain the conflicting results that have appeared in the literature. In summary "...epidemiologic studies have provided weak and conflicting risk signals for [the] association [between talc use and ovarian cancer], and it is unlikely that further studies may prove adequate to raise concern at a level sufficient to warrant regulatory or public health measures " (Carr, 1995). In conclusion, there is no basis to Petitioner's request that cosmetic talc products should bear warning labels to the effect that talcum powder causes cancer in laboratory animals or that "[f] requent talc application in the female genital area increases the risk o f ovarian cancer" When used as intended, talc presents no health risk to the consumer. Accordingly Petitioner's request for warning labels on talc-containing cosmetic products should be denied. 27 V REFERENCES SECTION I. Carr, C.J. (1995). Papers presented at the International Society o f Regulatory Toxicology and Pharmacology/U.S. FDA Workshop on Talc: Consumer Uses and Health Perspectives, Bethesda, Maryland, January 31-February 1, 1994. Workshop participants and Executive Summary. Regul. Toxol. Pharmacol. 21, 211-215. Harvey, A.M. (1988). Talc. In Pigment Handbook (2nd Edition) (Vol. 1. Properties and Economics) (P.A. Lewis, Ed.) pp. 219-225. John Wiley & Sons, Inc., New York, NY. Wehner, A.P. (1994). Biological effects o f cosmetic talc. Fd. Chem. Toxicol. 32(12), 1173-1184. SECTION n . A Cralley, L.L., Key, M.M., Goth, D.H., Lainhart, W.S., and Ligo, R.M. (1968). Fibrous and mineral content o f cosmetic talcum products. Am. In. Hyg. Assoc. J. 29(4), 350-354. CTFA (1990). CTFA Method J4-1, Asbestiform Amphibole Minerals in Cosmetic Talc. In Compendium o f Cosmetic Ingredient Composition. Methods. Cosmetic, Toiletry and Fragrance Association, Washington, D C. Krause, J.B., and Ashton, W.H. (1978). Misidentification o f asbestos in talc. In National Bureau o f Standards Special Publication 506. Proceedings o f the Workshop on Asbestos: Definitions and Measurement M ethods held at NBS, Gaithersburg, MD, July 18-20, 1977, pp. 339-353. Parmentier, C.J. and Gill, G.J. (1978). Practical aspects o f talc and asbestos. In National Bureau o f Standards Special Publication 506. Proceedings o f the Workshop on Asbestos: Definitions and Measurement Methods held at NBS, Gaithersburg, MD, July 18-20, 1977, pp. 403-411. Rohl, A.N. (1974). Asbestos in talc. Environ. Health Perspect. 9, 129-132. Rohl, A.N., and Langer, A.M. (1974). Identification and quantitation o f asbestos in talc. Environ. Health Perspect. 9, 95-109. Rohl, A.N., Langer, A.M., Selikoff, J., Tordini, A., and Klimentidis, R. (1976). Consumer talcums and powders: Mineral and chemical characterization. J. Toxicol. Environ. Health 2, 255-284. 28 SECTION n . B Adamson, I.Y.R., Letoumeau, H.L., and Bowden, D.H. (1989). Enhanced macrophage-fibroblast interactions in the pulmonary interstitium increases fibrosis after silica injection to monocytedepleted mice. Am. J. Pathol. 134(2), 411-418. Bowden, D.H., Hedecock, C., and Adamson, I.Y.R. (1989). Silica-induced pulmonary fibrosis involves the reaction o f particles with interstitial rather than alveolar macrophages. J. Pathol. 158, 73-80. Carr, C.J. (1995). Papers presented at the International Society o f Regulatory Toxicology and Pharmacology/U.S. FDA Workshop on Talc: Consumer Uses and Health Perspectives, Bethesda, Maryland, January 31-February 1, 1994. Workshop participants and Executive Summary. Regul. Toxicol. Pharmacol. 21, 211-215. Driscoll, K.E., Maurer, J.K., and Crosby, L.L. (1990). Overload o f lung clearance is associated with activation o f alveolar macrophage tumor necrosis factor and fibrorectin release. J. Aerosol Med. 3 (Suppl. 1), S83-S91. Lewis, T.R., Morrow, P.E., McClellan, R.O., Raabe, O.B. Kennedy, G.R., Schwetz, B.A., Goehl, T.J., Roycroft, J.H., and Chhabra, R.S. (1989). Establishing aerosol exposure concentrations for inhalation toxicity studies. Toxicol. Appl. Pharmacol. 99, 377-383 Morrow, P.E. (1988). Possible mechanisms to explain dust overloading o f the lungs. Fund. &. Appl. Toxicol. 10, 369-384. National Toxicology Program (NTP) (1993), NTP technical report on the toxicology and carcinogenesis studies o f talc in F344/N and B6C3F1 mice NTP TR 421. U S . Dept. Health and Human Services, National Institute o f Health. Oberdorster, G. (1988). Lung clearance o f inhaled insoluble and soluble particles. J. Aerosol Med. 1(4), 289-330. Oberdorster, G. (1995). The NTP talc inhalation study. A critical appraisal focused on lung particle overload. Regul. Toxicol. Pharmacol. 21, 233-241 Schlesinger, R.B. (1985). Clearance from the respiratory tract. Fund. & Appl. Toxicol. 5, 435-450 Snipes, M.B. (1989). Long-term retention and clearance o f particles inhaled by mammalian species. Toxicol. 20 (3), 175-211 Zazenski, R., Ashton, W.H., Briggs, D., Chudkowski, M., Kelse, J.W., MacEachern, L., McCarthy, E.F., Nordhauser, M.A., Roddy, M.T., Teetsel, N.M., Wells, A.B., and Gettings, S.D 29 (1995). Talc: Occurrence, characterization and consumer applications. Regul. c Toxicol. Pharmacol. 21, 218-229. SECTION H. C. ACGIH (1992). 1992-1993 Threhold Limit Valuesfo r Chemical Substances and Physical Agents and Biological Exposure Indices. American Conference o f Governmental Industrial Hygienists, Cincinnati, OH Aylott, R.I., Byrne, G.A., Middleton, J.D., and Roberts, M E. (1979). Normal use levels o f respirable cosmetic talc: Preliminary study. Ini. J. Cosm. Sci. 1, 177-186. Boundy, M G ., Gold, K., Martin, K.P., Jr., Burgess, W.A., and Dement, J.M. (1979). Occupational exposures to non-asbestiform talc in Vermont. In Dust and Disease (R. Lemen and J.M. Dement, Eds.), pp. 365-378. Pathotox Publishers, Inc., Park Forest South, IL. Carta, M., Alfano, G , Carbini, P., Ciccu, R , and Del Fa', C. (1981). Triboelectric phenomena in mineral processing. Theoretic fundamentals and applications. J. Electrostatics 10, 177-182. Dahl, A.R., Schlesinger, R.B., Heck, H.A., Medinsky, M.A. and Lucier, G.W. (1991). Symposium Overview: Comparative dosimetry o f inhaled materials: Differences among animal species and extrapolation to man. Fund. &Appl. Toxicol. 16, 1-13. El-Ghawabi, S.H., El-Samra, G.H., and Mehasseb, H. (1970). Talc pneumoconiosis. J. Egypt. Med. Assoc. 53, 330-340. Endo-Capron, S., Renier, A., Janson, X., Kheuang, L., and Jaurand, M.C. (1993). In vitro response o f rat pleural mesothelial cells to talc samples in genotoxicity assays (sister chromatatid exchanges and DNA repair). Toxicol. In Vitro 7(1), 7-14. Gamble, J., Greife, A., and Hancock, J. (1982). An epidemiological-industrial hygiene study o f talc workers. Ann. Occup. Hyg. 26(1-4), 841-859. Gajewski, J.B. (1990). Assessment of electrostatic hazards due to the flow o f charged solid particles in pneumatic transport. M aterials Science 16(1-3), 299-305. Leophonte, P., Basset, M.F., Pincemin, J., Louis, A., Pernet, R , and Delaude, A. (1983). Mortalite des travailleurs de talc en France. Etude epidemidologique retrospective. Rev. Fr. Mai. Respir. 11, 489-490. Morrow, P.E. (1988). Possible mechanisms to explain dust overloading o f the lungs. Fund. & Appl. Toxicol. 10, 369-384. 30 M orrow, P.E. (1992). Dust overloading o f the lungs: Update and appraisal. Toxicol. & Appl. Pharmacol. 113, 1-12. Oberdorster, G. (1988). Lung clearance o f inhaled insoluble and soluble particles. J. Aerosol Med. 1(4), 289-330. Rubino, G.F., Scansetti, G. Piolatto, G., and Romano, C.A (1976). Mortality study o f talc miners and millers. J. Occup. Med. 18(3), 186-193. Russell, R.S., Merz, R.D., Sherman, W.T., and Sivertson, J.N. (1979). The determination of respirable particles in talcum powder. Fd. Cosmet. Toxicol. 17, 117-122. Scansetti, G , Rosetti, L., and Ghemi, F. (1963). Clinical and radiological evolution of pneumoconiosis in the talc extracting industry. M edicina del Lxtvoro 54(11), 746-749. Selevan, S.G., Dement, J.M., Wagoner, J.K., and Froines, J.R. (1979). Mortality patterns among miners and millers o f non-asbestiform talc: Preliminary report. In Dusts & Diseases (R. Lemen and J.M. Dement, Eds.), pp. 379-388. Pathotox Publishers, Inc., Park Forest South, IL. Wegman, D.G., Peters, J.M., Boundy, M.G., and Smith, T.J. (1982). Evaluation o f respiratory effects in miners and millers exposed to talc free o f asbestos and silica Br. J. Ind. Med. 39, 233-238. Wehner, A.P. (1994). Biological effects o f cosmetic talc. Fd. Chem. Toxicol. 32(12), 1173-1184. Wergeland, E., Andersen, A., and Baerheim, A. (1990). Morbidity and mortality in talc exposed workers. Am. J. Ind. Med. 17, 505-513. SECTION n . D. Goodman, J.I. (1995). An analysis o f the National Toxicology Program's (NTP) Technical Report (NTP TR 421) on the toxicology and carcinogenesis studies o f talc. Regul. Toxicol. Pharmacol. 21, 244-249. SECTION m . A Baylis, M S., Henderson, W.J., Pierrepoint, C.G., and Griffiths, L. (1986). The aetiology o f ovarian cancer. In Gynecological Oncology, (C.P. Morrow and G.E. Smart, Eds.), pp. 157-165. Springer-Verlag, New York. 31 Berek, J.S. and Martinez-Maza, O. (1994). Molecular and biologic factors in the pathogenesis of ovarian cancer. J. Reprod. Med. 39, 241-248. Booth, M., Beral, V. and Smith, P. (1989). Risk factors for ovarian cancer-control study. Br. J. Cancer 60, 592-598. Cannistra, S.A. (1993). Cancer of the ovary. New England J. Med. 329(21), 1550-1559. Cramer, D.W. (1989). Lactase persistence and milk consumption as determinants o f ovarian cancer risk. Am. J. Epidem. 130(5), 904-910 Cramer, D.W., Willett, W.C., Bell, D.A., Ng, W.G., Harlow, B.L., Welch, W.R., Scully, R.E., and Knapp, R.C. (1989). Galactose consumption and metabolism in relation to the risk of ovarian cancer. Lancet 2, 66-71. Daly, M.B. (1992). The epidemiology of ovarian cancer. Hematol. Oncol. Clin. North Am .6(4), 729-738. Dietl, J., and Marzusch, K. (1993). Ovarian surface epithelian ovarian cancer Gynecol. Obstet. Invest. 35, 129-135. Godwin, A.K., Testa, J.R., and Hamilton, T.C. (1993). The biology o f ovarian cancer development. Cancer Supplement 71(2), 530-536. Hartge, P., Schiffinan, M.H., Hoover, R., McGowan, L., Lesher, L., and Norris, H.J. (1989). A casecontrol study o f epithelial ovarian cancer Am. J. Obstet. Gynecol. 161(1), 10-16. Heintz, A.P., Hacker, N.F., and Lagasse, L.D. (1985). Epidemiology and etiology o f ovarian cancer: A review. Obstet. Gynecol. 66(1), 127-135. Hoffman, A.G., Burghardt, R.C., Tilley, R., and Auersperg, N. (1993). An in vitro model o f ovarian epithelial carcinogenesis: changes in cell-cell communication and adhesion occurring during neoplastic progression. Int. J. Cancer 54, 828-838. Kelsey, J.L. and Whittemore, A S. (1994). Epidemiology and primary prevention o f cancers o f the breast, endometrium, and ovary. A brief overview. Ann. Epidemiol. 4(2), 89-95. La Vecchia, C., Decarli, A., Negri, E., Parazzini, F., Gentile, A., Cecchetti, G., Fasoll, M., and Franceschi, S. (1987). Dietary factors and the risk o f epithelial ovarian cancer. J. Natl. Cancer Inst. 79(4), 663-669. Lee, J.H., Kavanagh, J.J., Wildrick, D M , Wharton, J.T., and Blick, M (1990) Frequent loss of heterozygosity on chromosomes 6q, 11, and 17 in human ovarian carcinomas. Cancer Res. 32 50, 2724-2728. Malik, S., and Balkwill, F. (1991). Epithelial ovarian cancer: a cytokine propelled disease? [editorial] Br. J. Cancer 64, 617-620. Mori, M., Harabuchi, I, Miyake, H., Casagrande, J.T., Henderson, B E., and Ross, R.K. (1988). Reproductive, genetic and dietary risk factors for ovarian cancer Am. J. Epidem. 128(4), 771-777. Mori, M., and Miyake, H. (1988). Dietary and other risk factors o f ovarian cancer among elderly women. Jpn. J. Cancer Res. 79, 997-1004. McGowan, L., Parent, L., Lednar, W., and Norris, H.J. (1979). The women at risk for developing ovarian cancer. Gynecol. Oncol.l, 325-344. Parazzini, F., Franceschi, S., La Vecchia, C , and Fasoli, M. (1991). The epidemiology o f ovarian cancer. Gynecol. Oncol. 43, 9-23. Patel, A.R., and Obrams, G.I. (1993). Epidemiology o f ovarian cancer. Cancer Eidemiol. Biomarkers Prev. 2, 79-83. Shoham, Z. (1994). Epidemiology, etiology, and fertility drugs in ovarian epithelial carcinoma: where are we today? Ferdl. Sleril. 62(3), 433-48. Shu, X.O., Gao., Y.T., Yuan, J.M., Ziegler, R.G., and Brinton, L A. (1989). Dietary factors and epithelial ovarian cancer. Br. J Cancer 59(4), 92-96. Slotman, B.J., and Rao, R. (1988). Ovarian cancer (review). Anticancer Res. 8, 417-434. Wehner, A.P. (1994). Biological effects o f cosmetic talc. Fd. Chem. Toxicol. 32(12), 1173-1184. Whittemore, A S., Harris, R., Itnyre, J., and the Collaborative Ovarian Cancer Group (1992). Characteristics relating to ovarian cancer risk: collaborative analysis o f 12 US case-control studies. Am. J. Epidem. 136(10), 1212-1220. Wu, M L., Whittemore, A S., Paffenbarger, R.S., Jr., Sarles, D.L., Kampert, J.B., Grosser, S., Jung, D.L., Ballon, S., Hendrickson, M., and Mohle-Boetani, J. (1988). Personal and environmental characteristics related to epithelial ovarian cancer. Am. J. Epidem. 128(6), 1216-1227. SECTION m . B Booth, M., Beral, V., and Smith, P (1989) Risk factors for ovarian cancer: A case-control study Br. J. Cancer 60, 592-598. 33 Carr, C.J. (1995). Papers presented at the International Society o f Regulatory Toxicology and Pharmacology/U.S. FDA Workshop on Talc: Consumer Uses and Health Perspectives, Bethesda, Maryland, January 31-February 1, 1994. Workshop participants and Executive Summary. Regul. Toxicol. Pharmacol. 21, 211-215. Cramer, D.W., Welch, W.R., Scully, R.E., and Wojciechowski, C A. (1982). Ovarian cancer and talc: A case-control study. Cancer 50, 372-376. Hankinson, S.E., Hunter, D.J., Colditz, G.A., Willett, W.C., Stampfer, M.J., Rosner, B., Hennekens, C. H., and Speizer, F.E. (1993). Tubal ligation, hysterectomy, and risk o f ovarian cancer: A prospective study. JAMA 270(23), 2813-2818. Harlow, B.L., and Weiss, N.S. (1989). A case-control study o f borderline ovarian tumors: The influence o f perineal exposure to talc. Am. J. Epidemiol. 130(2), 390-394. Harlow, B.L., Cramer, D.W., Bell, D.A., and Welch, W.R. (1992). Perineal exposure to talc and ovarian cancer risk. Obstet. Gynecol. 80(1), 19-26 Hartge, P., Hoover, R., Lesher, L.P., and McGowan, L. (1983). Talc and ovarian cancer. JAMA 250(14), 1844, Rosenblatt, K.A., Szklo, M., and Rosenshein, N.B. (1992). Mineral fiber exposure and the development o f ovarian cancer. Gynecol. Oncol. 45, 20-25. Whittemore, A S., Wu, M L., Paffenbarger, R.S. Jr., Sarles, D.L., Kampert, J.B. Grosser, S., Jung, D. L., Ballon, S., and Hendrickson, M. (1988). Personal and environmental characteristics related to epithelial ovarian cancer. II. Exposures to talcum powder, tobacco, alcohol, and coffee. Am. J. Epidemiol. 128(6), 1228-1240. Whittemore, A.S., Harris, R., Itnyre, J., Halpern, J. and the Collaborative Ovarian Cancer Group (1992). Characteristics relating to ovarian cancer risk: Collaborative analysis o f 12 US casecontrol studies I Methods. Am. J. Epidemiol. 136(10, 1175-1183. SECTION m. c Boorman, G.A., and Seely, J.C. (1995). The lack o f an ovarian effect o f lifteime talc exposure in F344/N rats and B6C3F, mice. Regul. Toxicol. Pharmacol. 21, 242-243. Carr, C.J. (1995). Papers presented at the International Society o f Regulatory Toxicology and Pharmacology/U.S. FDA Workshop on Talc: Consumer Uses and Health Perspectives, Bethesda, Maryland, January 31-February 1, 1994. Workshop participants and Executive Summary. Regul. Toxicol. Pharmacol. 21, 211-215. De Boer, C.H. (1972). Transport o f particulate matter through the human female genital tract. J. 34 R e p r o d . F e rtil. 28, 2 9 5 -2 9 7 . Egli, G.E., and Newton, M.D. (1961). The transport o f carbon particles in the human female reproductive tract. Fertil. Steril. 12, 151-155. Henderson, W.J., Hamilton, T.C., Baylis, M S., Pierrepoint, C.G., and Griffiths, K. (1986). The demonstration o f the migration o f talc from the vagina and posterior uterus to the ovary in the rat. Environ. Res. 40, 247-250. Henderson, W.J., Hamilton, T.C., and Griffiths, K. (1979). Talc in normal and malignant ovarian tissue. Lancet 1, 499. National Toxicology Program (NTP) (1993). NTP technical report on the toxicology and carcinogenesis studies o f talc in F344/N and B6C3F1 mice. NTP TR 421. U S . Dept. Health and Human Services, National Institute o f Health. Phillips, J.C., Young, P.J., Hardy, K., and Gangolli, S.D. (1978). Studies on the absorption and disposition o f 3H-labelled talc in the rat, mouse, guinea-pig and rabbit. Fd. Cosmet. Toxicol. 16, 161-163. Wehner, A.P. (1994). Biological effects o f cosmetic talc. Fd. Chem. Toxicol. 32(12), 1173-1184. Wehner, A.P., Hall, A S., Weller, R.E., Lepel, E.A., and Schirmer, R E (1985). Do particles translocate from the vagina to the oviducts and beyond? Fd. Chem. Toxicol. 23(3), 367-372. Wehner, A.P., and Weller, R.E. (1986). On talc translocation from the vagina to the oviducts and beyond. Fd. Chem. Toxicol. 24(4), 329-338. SECTION IV Carr, C.J. (1995). Papers presented at the International Society o f Regulatory Toxicology and Pharmacology/U.S. FDA Workshop on Talc: Consumer Uses and Health Perspectives, Bethesda, Maryland, January 31-February 1, 1994. Workshop participants and Executive Summary. Regul. Toxicol. Pharmacol. 21, 211-215. 35 REFERENCES (FDA Docket No. 94P-0420/CP 1) SECTION I. thru SECTION II. C