Document zzDQBY4zXzkVm6ejEqw8Nv4ra

1 / * Rtillippe Douillet 0he Holyoke lane Stony Brook, New York 11790 Re : Docket No. 83P-0404 Deer Mr. Doulllet: This responds to your November 8, 1983, petition requesting that cosmetic talc be labeled with an asbestos warning statement, information an asbestos particle -rise, and the proportion of talc impurities in the product. You assert that, because the mining of talc almost invariably includes the mining of asbestos as well, cosmetic talc ma y contain significant amounts of asbestos particles that present an inhalation hazard to humans. Also, you cite references to substantiate that significant amounts of asbestos have been found in commercial talc samples, that asbestos inhalation is hazardous to hurons, and that asbestos contaminants in talc will produce toxicological responses when inhaled. FDA recognizes that asbestos inhalation over extended periods is hazardous to lumens. The agency is also aware that sane cosmetic talc produced in the 1960s and early 1970s did contain asbestiform minerals. However, your petition has not persuaded us that the cosmetic talc, that is presently being produced contains significant amounts of asbestiform minerals. TXrring the early 1970s, FDA became concern ed about the possibility that cosmetic talc did aontain significant amounts of this material. The agency received several reports about such contamination. However, at that time, the analytical procedures for determining asbestos in talc were not fully developed, and most of the analytical work was conducted without scientific agreement as to vhich methods were well-suited for the identification of asbestiform minerals in talc. Consequently, FDA considered sll analytical results to be of questionable reliability. This assessment proved to be correct because many questions were subsequently raised about results reported in the literature in the early 1970s (see enclosed oopy of National Bureau of Standards Special Publication 506 entitled "^identification of Asbestos in Talc"). Because of the questionable nature of the analytical results, the agency m b s rot able to assess reliably the levels of asbestiform minerals In cosmetic talc then in Che marketplace. P0Hi i Mr. Ihillippe Ebuillet - Page 2 Under these circumstances, FDA decided that the most: appropriate actions that It could take to protect the public health would be to make the reports public and to request assistance fro the affected industry in developing acceptable analytical procedures. This approach apparently has led to considerable improvement in the quality of this talc. After FD A took these actions, raarrv cosmetic manufactu rers began to analyze their talc for beatifora minerals as part of their quality control program s , and talc suppliers began to sell higher purity talcs to the cosmetic industry. By 1976, asbestos analytical methodology was sufficiently developed that the Cosmetic, Toiletry, and Fragrance Association (CIF) could issue a specification (copy enclosed) for cosmetic talc. This specification required that such talc b e free of fibrous astfhibole (e.g., asbestos in the form of asbestifora tremolite) using s CTFA method of analysis that is capable of detecting 0.5 percen t of amphibole asbestos. This specification contributed to the continued improvement of cosmetic talc quality. Tn addition, FDA surveillance activities that were conducted in the latter portion of the 1970s showed that the quality of cosmetic talc had significantly improved, and that w e n when asbestos was present, the levels were so low that no health hazard existed. Our scientists recently reviewed data from these surveillance activities and concluded that the risk from a worst-case estimate of escposure to asbestos from cosmetic talc would be less than the risk from environmental background levels of exposure to asbestos (non-ocrrupational exposure) over a lifetime. Consequently, wp 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. Without evidence of such a hazard, the agency concludes that there Is ro need to require a warning label on cosaetic talc. FCA. should "Iso point out that, in reviewing your petition, w p found several problems with the information on which you relied. The publication "Aabestiforn Impurities In Commercial Talcum Powders," which you cite in your petition, appears to contain a number of significant errors that lead us to question the accuracy of the findings that vere reported. For your information, we have enclosed a copy of a June 8, 1973, rebuttal of this publication that wna written b y the Chief Minerologist of the Colorado School of Mines Research Institute in Golden, Colorado. Also, your petition's 1978 book reference to the Mt. Sinai School of Medicine findings is too old to reflect present contamination levels. Further, we are not convinced that the Mt. Sinai findings pertained to cosmetic talc. Your reference states that ccnmon ccnmercial talcs were analyzed, but it does not specify whether these commercial talcs were industrial, grade nr cosmetic talc. Mr. ihillippe Donili et - Page 3 t For all of these reasons, your petition la denied. This denial is without preludio to the future filing of a petition on this matter, accompanied by all relevant data in support of the petition. Sincerely yours, Cj g a V A -- ^ Acting Associate Cbwlssioner for Regulatory Affairs Enclosures m cc: HFC-1 HPC-200 (#G-86-182) HFC-220 (Rogers/file) HFF-1 HFF-100 HFF-152 HFF-300 _JW-3G2 ' HFF-310 ' HFF-440 GCF-1 (Horton/Derfler) HFA-224 HFA-305 Prepared:JRTaylor:5/15/86 Initialled:JRTaylor:5/15/86, 6/5/86 EJCampbell:5/15/86, 6/5/86 HJEiermann:5/16/86, 6/9/86 JAWenninger:5/19/86 WGFlanm:5/29/86, 6/9/86 LRLake:5/29/86, 6/12/86 RJLenahan:5/29/86, 6/10/86 LBBrock: 6/10/86 RWGill:6/12/86 F/T:JRTaylor:sag:6/4/86 Concurred rEBrisson:6/27/86 Retype:RISpencer:cdk:6/27/86:disk-26 (#1.32) Revised:PSDerfler:7/3/86 Retype:RLSpencer:cdk;7/7/86 Concurred:PDerfler:7/8/86 Revised:Concurred:LHorton:7:9/86 F/T:RLSpencer :bka:7/10/86 CTFA A oopled Name: TALC COSMETIC TALC CTFA Specification TALC COSMETIC issue;- 6-1-42 Revise; 3-23-62 6-3"'-'' ' ^^ DEFINITION: Cosmetic Talc is an essentially white, odorless, fine powder, ground from naturally occurring rock ore. It consists typically of 90% hydrateo magnesium silicate. having the ideal formula Mg6[S with tne remainder consisting of naturally associated minerals such as calcite, chlorite. Dolomite, kaolin and mag nesite. and containing no detectable fibrous, asbestos minerals. TEST C o lo r............................................... Odor ............................................... Identification ................................. Slip ................................................. Lustre ............................................. Water-Soluble Iron ........................ Screen T e s t.................................... Water Soluble Substances .......... Acid Soluble Substances.............. Loss of Ignition .............................. Arsenic (as As) .............................. Lead (as Pb) .................................. Fibrous Amphibole ........................ (Asbestiform Tremolite et al) Free Crystalline Silica.................... (Quartz) SPECIFICATION As specified by the buyer and showing no change after heating As specified by the buyer Positive: 1. Close match to CTFA Spectrum-- !R with no indication of foreion materials OR ~ 2. (Alternate) Close match to X-ray Powder Diffraction File No. 19-770, published by ASTM, showing the most intense reflections at d values about 9.35, 1.53 and 4.59 A As specified by the buyer Do. Passes test 100% through 100 mesh 98% minimum through 200 mesh Finer grades: as specified by the buyer 0.1% maximum As specified by the buyer 6.0% maximum 5.0% maximum 3 ppm maximum 20 ppm maximum None detected As specified by the buyer ***** METHOD Heat 1 to 2 g at 200C for 5 minutes CTFA G 3-1 ASTM D 934-74 USP XIX, page 487 CTFA C 6-1 USP XIX, page 487 See test for "Reaction and Soluble Substances" CTFA E 32-1 USP XIX, page 487 CTFA F 1-1, Parts l-A and I CTFA F 2-1, Parts l-A and I CTFA J 4-1 CTFA J 5-1 (DTA) Alternate: CTFA J 6-1 (X-ra Copyright 1976 The Cosmetic. Toiletry and Fragrance Association, tnc. No portion ot the C V A Standards, in whole or in part, may be repnnted without permission from The Cosmetic, Toiletry end Fragrance Association, Inc. 7133 Fifteenth Street, N. tv.. Washington, D. C. 2000S National Bureau of Standards Special Publication 506. Proceedings of the Workshop on :>n. lat Asbestos: Definitions and Measurement Methods held at NBS, Gaithersburg, MD, July 18-20, 1977. (Issued November 1978) , j Ic as -OS M1SIDENTIFICATI0N OF ASBESTOS IN TALC ?.r-e Jerome B. Krause J C. 1 :le to :i- Colorado School of Mines Research Institute Golden, Colorado 80401 ;or ;r- and >P > for William H. Ashton Johnson & Johnson ion Raritan, New Jersey 08869 :es Abstract iot lat I av Both optical microscopy and x-ray diffraction (XRD) are widely used to detect minerals associated with talc. Optical microscopy can determine the morphology of a particle, but cannot always fully identify the specific mineral. Although XRD is an excellent screening technique `ii for the detection of minerals associated with talc, the method can misidentify minerals due to interferences, interpretive errors, and the inability to determine morphology. Methods for reduction or elimination of these problems include special techniques of sample preparation and x-ray diffraction, combined .nd with microscopic examination (both optical and electron). Key Words: Amphiboles; asbestos; chlorite; electron microscopy; fibermorphology; optical microscopy; x-ray diffraction; talc. Introduction There are many ways to analyze and study any naturally occurring material. The conclusions reached will often vary widely depending on the expertise and specific interest of the investigator. That situation sums up the present status of "asbestos"; it is also the status of minerals which are associated with "asbestos"; and it is becoming the status of other minerals which can be naturally associated with talc. Popular methods of analysis can give the wrong answer - namely that asbestos is present when it certainly is not. That problem (misidentification) is not so much one of limitations of the methods, but rather one of misinterpretation of data, and failure to recognize the mineralogical background required to certify mineral purity, for example, when analyzing sheet silicates for asbestos. Unfortunately, one main factor is that asbestos has now developed variable definitions, depending on whether the point of view is mineralogical, industrial, medical, or regulatory. The medical definition is most concerned with whether or not the particles are biologically active; the industrial definition is dependent upon flexibility and weavability; the mineralogical definition upon crystallography; and the regulatory definition upon size and aspect ratio. The word "asbestos" stems from ancient Greek and has always referred to a very fibrous industrial mineral product. Since asbestos has historically related to a mineral exploited as an important industrial commodity, we think a combined mineralogical and industrial definition should take precedence [1.2]1. Other presentations during this figu r e s in brackets indicate the literature references at the end of this paper. 339 SMSf*** ill workshop have amply covered the aspects of asbestos terminology, and it is not our intent to provide comprehensive coverage of that subject. Our primary objective is to review some of the basic principles of analysis, and to point out problem areas where identification of "asbestos" has been abused. Analysis Methods and Misidentification of Asbestos It is useful to categorize the various analytical methods which have been applied to talc to highlight inherent principles which lead to misidentifying asbestos as being present. We offer the following general comments on the three principle determinative properties (chemical composition, morphology, structure). Chemical Composition It is well known that every mineral has a specific chemical composition, and that each mineral has an ideal theoretical chemical formula (configuration). Unfortunately, many investigators overlook the fundamental point that chemical composition does not identify a specific mineral. A simple example will bring that point into focus: A pearl, an oyster shell, a slab of marble, a piece of chalk, and the minerals aragonite and calcite are obviously different materials, and yet each will be identified as calcium carbonate. That is to say, chemical analyses will identify them all as the same substance, where everyone knows that a pearl is not a piece of chalk. The same situation exists in certain phases of asbestos analysis. For example, chrysotile, antigprite, lizardite, sepiolite, chlorite, and talc are all hydrous magnesium silicates. But a Meerschaum pipe (sepiolite) is certainly not chrysotile asbestos in spite of the fact that chemical analysis alone could lead to that misidentification. Accordingly, chemistry alone does not identify a mineral, nor do those sophisticated instrumental methods which are based on chemical principles, such as: Wet Chemical Analysis Classical (gravimetric, volumetric) Instrumental (atomic absorption, flame emission) Microprobe (electron and ion) Emission Spectrograph Mass Spectrograph X-Ray Fluorescence Morphology Although the shape of a mineral particle is one of the key characteristics in the identification of a mineral, shape alone cannot be the sole determinant of a specific mineral species. There are hosts of minerals in different mineral classes whose particles have the same shape. They exist across the spectrum of all classes of minerals and the possibilities are beyond comprehension. Even if we limit ourselves to minerals which occur in the true fibrous state, we would estimate there are up to 100. There have been instances where nonasbestos particles have been misidentified as chrysotile in talc because shape alone was the index used. Methods based on morphology include: Optical Microscopy Automated Image Analyzers Electron Microscopy (SEM and TEM) 340 Structure / The configuration of atoms in the crystal lattice of a mineral does not necessarily determine a mineral species. The atomic arrangement at the molecular level does not always carry through to the external visible physical form. That is to say that methods based on molecular structure can misidentify a mineral. For example, chrysotile asbestos is classified with the sheet silicates because of'its crystal structure arrangement, but it certainly does not occur in flat sheets like the micas or its sibling, antigorite. Methods of identification which relate to molecular structure are: Infrared Spectroscopy Differential Thermal Analysis X-ray Diffraction Electron Diffraction In general then, no single property defines a mineral, and no single method which depends on one property can identify a specific mineral. Conversely, methods which depend on a single factor or characteristic of a mineral can give misidentifications. Two Popular Methods Optical microscopy and x-ray diffraction methods require some additional discussion primarily because they have received widespread attention by industry and government laboratories as possible monitoring techniques. Although.both these methods are fundamental to the science of mineralogy and are highly reliable in the hands of experts, complications arise when shortcuts are taken in the professional procedures. Optical Microscopy When an experienced optical mineralogist or crystallographer identifies a mineral with a petrographic microscope, he can come to a remarkably accurate conclusion. The reason for high accuracy is that not one but several specific properties are determined, such as refractive indices, extinction angle, birefringence, and optical orientation. Specific training and wide mineralogical background are required to get the right answer. In contrast, current optical methods in federal regulatory proposals relating to asbestos presume that asbestos is present in the first place. The analyst then merely observes the mineral particle for size/shape. Consequently, those methods which depend solely on aspect ratio give misidentification. They misidentify the presence of asbestos by such simple oversights as looking at a platelet on edge and counting it as an asbestiform particle. It is not necessary to elaborate on the other shortcomings of those methods in view of the recent NBS report on the analysis of 80 industrial talcs [3] evaluating that methodology. The same shortcomings were also recently corroborated in a study conducted by Harvard University and NIOSH [4]. However, there are a few rare cases where abnormal crystal habit can be misleading and subtly can lead to a misidentification. Optical microscopy is most vulnerable to this type of misidentification. For example, talc normally occurs as micaceous plates, but rare acicular talc does exist, and one must be very careful to avoid misidentifying the rare occurrence as asbestos. As an example, our XRD examination of an industrial acicular talc sample has identified the presence of significant amphibole (probably tremolite). However, when the material was subjected to thorough petrographic examination it was found to be. composed of free grains of columnar amphibole and acicular talc and composite talcamphibole. The significance is that an erroneous conclusion could be reached by misidentifying such a rare talc variety as asbestos, if only aspect ratio and simple optical microscopy were used. 341 Thus, simple optical microscopy can determ ine 'the morphology of a particle, but if used alone it cannot always fully identify the specific mineral observed. X-Ray Diffraction , Although x-ray diffraction (XRD) is a valuable technique, it cannot determine the physical shape of a mineral particle, and for that reason it cannot determine whether or not a sample is asbestos. Furthermore, it cannot distinguish between two mineral varieties in the same mineral class in cases such as the asbestos minerals and their nonasbestiform analogues. It is surprising that such a basic shortcoming continues to be overlooked by responsible investigators alleging to have identified asbestos by XRD. One result of the inability of powder XRD to differentiate between the asbestiform and nonasbestiform varieties of a mineral is the potential error of prejudging an XRD detected phase to be the asbestiform variety. For example, preparing calibration standards of mixtures of talc plus chrysotile could have the effect of causing a serpentine peak in an unknown sample to be prejudged as the asbestiform variety, i.e., chrysotile. A mixture of talc spiked with the serpentine mineral chrysotile will give the same XRD pattern as a mixture of talc spiked with the very common platy serpentine mineral antigorite. It should be obvious that an unknown talc showing a serpentine peak cannot be prejudged or branded as containing chrysotile asbestos under such circumstances. Unfortunately, the literature has articles by responsible authors who have overlooked that error in logic [5,6,7], For research purposes only, single crystal XRD can provide information as to whether or not the specimen could be asbestos. However, due to the difficulty of handling minute specimens, single crystal XRD is inadequate for particles smaller than about 20 x 5 pm, and, of course, is also inadequate for routine monitoring procedures. Amphiboles Each of the five amphibole minerals, anthophyllite, cummingtonite-grunerite, riebeckite, tremolite, and actinolite has an asbestiform variety, namely anthophyllite asbestos, amosite, crocidolite, tremolite asbestos, and actinolite asbestos, respectively. Tremolite asbestos is quite rare, and actinolite asbestos is so rare that a recent NIOSH project to prepare reference standard minerals has been unable to locate a source of pure actinolite asbestos [8]. The amphiboles (named from the Greek "amphibolos," meaning ambiguous) are characterized by similar crystal structure and wide variation in chemical composition and appearance. All amphiboles have XRD patterns which are similar,,and are characterized by having their (110) or (210) diffraction peaks occur within 0.2A of each other (Table 1, Figure 1). Reliable identification of individual amphibole species is difficult in the absence of confirming composition data. Examination of Table 1 and Figure 1 illustrates that attempted identification of a specific amphibole on the basis of d 10} or d ^ K ^ has good potential for being in error. For example, selection of Joint Committee on Powder Diffraction Standards (JCPDS) card 13-437 as being definitive of tremolite presents serious problems. Twenty-nine additional JCPDS amphiboles have their (110) or (210) peaks within 0.126 of this tremolite (110) peak at 10.5626. Identification of an amphibole as tremolite on the basis of a peak at 10.5628 is obviously an identification with very low reliability. In other words, a peak at that location is not necessarily the mineral tremolite since it could be one of 29 other minerals. 342 'j . .i if X \ l Table 1. JCPDS card # X* Amphibole JCPDS Card relative intensity. No's, * d (110) or d (210) peak Ps1t'ion' and 1 2e(Cu) i Name ie r 1 ii r e m :D -n a e 1 e t r e > &' u y a 2 \ ) < 23-118 10-456 20-734 20-378 14-633 21-149 19-467 20-982 23-665 23-664 23-667 23-663 9-434 13-499 20-656 20-470 23-666 20-469 23-1405 23-1406 20-1310 10-428 23-603 10-431 19-1061 20-481 20-1390 23-302 19-1063 13-437 17-478 23-495 9-330 17-750 20-386 22-531 16-401 17-725 17-745 20-376 17-726 20-484 13-506 23-679 9-455 20-453 11-253 23-310 13-401 8.58(1) 8.55(1) 8.53(1) 8.52(1) 8.51(1) 8.51(1) 8.50(1) 8.50(1) 8.48(1) 8.47(1) 8.47(1) 8.46(1) 8.45(1) 8.45(1) 8.45(1) 8.44(1) 8.44(1) 8.43(1) 8.43(1) 8.43(1) 8.43(1) 8.42(1) 8.42(1) 8.41(1) 8.40(1) 8.40(1) 8.40(1) 8.40(1) 8.39(1) 8.38(1) 8.38(1) 8.38(1) 8.37(1) 8.36(1) 8.35(1) 8.35(1) 8.33(2) 8.33(1) 8.33(1) 8.31(1) 8.30(1) 8.29(1) 8.27(2) 8.27(1) 8.26(2) 8.26(1) 8.23(2) 8.20(1) 8.11(2) 10.31 10.35 10.37 10.38 10.39 10.39 10.41 10.41 10.43 10.44 10.44 10.46 10.47 10.47 10.47 10.48 10.48 10.49 10.49 10.49 10.49 10.51 10.51 10.52 10.53 10.53 10.53 10.53 10.54 10.56 10.56 10.56 10.57 10.58 10.59 10.59 10.62 10.62 10.62 10.65 10.66 10.67 10.70 10.70 10.71 10.71 10.75 10.79 10.91 *100 100 70 100 70 55 100 65 45 35 45 40 50 100 100 100 40 100 80 40 40 100 100 80 100 100 90 100 70 100 65 80 100 25 40 30 70 100 100 100 100 100 80 90 55 100 100 75 100 prieskaite richterite mboziite dashkesanite arfvedsonite hornblende ferropargasite, syn richterite, syn richterite, calcian, syn edenite, sodi an, syn richterite, calcian, syn eckermanite, calcian, syn hornblende magnesi oriebeckite magnes iori ebeckite crossi te tremoli te, sodian, syn hastingsite edenite paragasite . tremoli te, syn richterite, fluor, syn tirodite edenite, fluor, syn riebeckite hornblende winchite cummingtonite, mangoan richterite tremoli te kaersutite eckermanite tremoli te, fluor, syn richterite, ferrian eckermanite, syn joesmithite anthophyllite, magnesian, syn gruneri te gruneri te erossi te cummingtonite richterite gedrite glaucophane anthophyllite glaucophane ferrogedrite richterite, ferrian holmquistite 8 ( H O ) 1 or (210) 2 Maximum A26(Cu) = 10.91 - 10.31 = 0.6 Table 1 illustrates the very close proximity of the (210) or (110) XRD peak of all amphiboles, showing the inability to identify a specific amphibole on the basis of d (210) or d(110)* I 'I 11 1 10.3 104 10.5 10.6 10.7 10.6 10.9 ZBDEGREES (CuKCC) Figure 1. Amphibole d ^ g or d ^ g ) -- peak positions (2e for CuK ) and relative intensity. An additional problem further affecting the reliability of identification by XRD is the effect of shift in peak position caused by slight irispositioning of the sample surface in the instrument. For example, a 100 pm mispositioning of the specimen surface will result in a shift of approximately 0.6-0.7 A in d-spacing at low 26 angles [9]. A slight shift in the position of the peak (from a different amphibole or mispositioning of the sample surface, for example) could go unnoticed, resulting in mi sidentification of an amphibole that is not even present. In order to conclusively identify an amphibole by XRD, it is necessary to have an essentially complete diffraction pattern. In order to obtain such an XRD pattern, the sample must have a relatively high amphibole content and the pattern must be acquired with a time-consuming slow scan. Acquisition and interpretation of such patterns is time consuming, and discourages proper application of the full procedure, especially for routine monitoring where large numbers of samples require analysis. Shortened procedures, such ^ as single peak identification of amphiboles, provide good opportunity for misidentification. The shortened procedure of single peak identification was apparently used in a 1972 paper [7], where our examination of some of the same samples disagreed with identifications of serpentine, tremolite-actinolite anthophyllite, and anhydrite. 344  . __ -- ` -- --. _ --: --* -- ___ --; -- -- y. , *. . 1 Chiorite^Serpenti ne Chlorite is one of the most common accessory minerals found associated with talcs. The chlorite group of minerals are somewhat analogous to amphiboles in that they exhibit a wide variation in chemical composition and all have a similar crystal structure. The diagnostic chlorite basal XRD peaks (001), (00), and (004) are characteristic, and occur at about 14A, 7A, and 3.5&, respectively. As in the case for the amphiboles, specific identification of a particular chlorite species by XRD is difficult. The XRD problem with chloritfc talcs is that the serpentine first order basal peak overlaps the chlorite (002) peak, and the corresponding serpentine second order basal peak overlaps the chlorite (004) peak. Generally, however, the chlorite (004) and serpentine second order peaks are separate enough to allow unambiguous determination of the presence of both phases when present in adequate amounts to give definable peaks. Tables 2 and 3 and Figures 2, 3, and 4 are compilations of JCPDS data for the positions of the (004) basal peak for chlorites and (002), (004), or (0012) basal peak for serpentines, respectively. Table 2. Chlorite JCPDS Card No's. relative intensity. Peak positions, and JCPDS card # 0 A 2e(Cu) I Name 10-183 3.60 24.73 100 penninite 20-671 3.60 24.73a 90 kmmererite. 16-351 3.59 24.80 70 chlorite lb 12-185 3.57 24.94 85 kotschubeite 7-160 3.58 24.87 60 kotschubeite 19-749 3.56 25.01 80 clinochlore 7-77 3.558 25.03 50 sheridanite 16-362 3.55 25.08 80 chlorite la 19-751 3.55 25.08 65 sudoite 22-712 3.55 25.08 45 nimite 7-165 3.545 25.12 60 grochauite 7-78 3.541 25.15 60 thuringite 7-171 3.541 25.15 80 diabantite 12-242 3.54 25.16 100 leuchtenbergite 7-76 3.537 25.18 50 ripidolite 13-29 3.53 25.23 80 thuringite 7-166 3.523 25.28 50 daphnite 12-243 3.52 25.30 92 aphrosiderite 21-1227 3.52 25.30 100 thuringite 3-67 3.49 25.52 100 thuringite aA d (n5)* Table 2 illustrates variation in position of the chlorite d ^ ^ XRD peak. Table 2 should be compared with Table 3 to see that the chlorite and - serpentine XRD peaks overlap and interfere with each other. Identification and quantification of serpentine in the presence of chlorite is extremely difficult at best. 345 Figure 2 Chlorite d(00 4 ) " Peak positions and relative intensity. The data of Table 2 are presented in graphical form showing the variation in position of the d^0Q/Jj XRD peaks for different chlorites. Selection of JCPDS card 16-362 as diagnostic for chlorite can obviously result in njisidentification. Table 3. Serpentine, Kaolinite, Halloysite, and Dickite JCPDS Card Nos., peak position, miller index (hkl), and relative intensity. JCPDS Card # 18-779 9-444 21-543 7-417 11-386 21-963 12-583 13-4 7-339 11-388 7-315 9-493 C A 3.67 3.66 3.65 3.63 3.62 3.61 3.56 3.56 3.55 3.55 3.52 3.52 2e(Cu) 24.25 24.32 24.39 24.52 24.59 24.66 25.01 25.01 25.08 25.08 25.30 25.30 I (hkl) 80 * (002) 100 (0012) 70 (004) 300 (102) 60 (002) 80 (002) 80 (0012) 70 (0012) 100 (002) 100 (0012) 100 (002) 100 (004) Serpentines Hzardite, 1M antigorite, 6 chrysotile, 2M antigorite, 6M lizardite, 10, aluminian antigorite, 6M antigorite, 60_, aluminian antigorite, 60, aluminian berthierine antigorite, 60^, syn berthierine amesite 6-221 14-164 12-447 3.'58 3.579 3.56 24.87 24.88 25.01 100+ 80 50 (002) (002) (002) Kaolinites kaolinite, lMd kaolinite, IT kaolinite, IT 9-453 3.63 24.52 90 (002) Halloysite halloysite, dehydrated 10-446 3.58 24.87 100+ (004) Chlorite 2e Range: 24.73 - 25.52 Dickite dickite 2Mj Table 3 illustrates variation in position of XRD peaks of serpentine, kaolinite, halloysite, and dickite. The XRD patterns of these minerals interfere with each other and with chlorite (see Table 2). l \ -- SERPENTINE <Vx*).*x>4>.x> S3S33KA0LINITE d ^ , naaa HALLOYSITE 6m2) cr'r-iDICKITE d#**, DEGREES 29 (C.KI Figure 3. Peak positions and relative Intensities. The data of Table 3 are presented 1n graphical form to Illustrate the variation In position and Interfering overlap of XRD peaks of serpentine, kaollnlte, halloyslte, and dlcklte. IOOr_ 80 " 60 40 20 oL100 80 - 60 - 40 20 * 0>- ------ CHLORITE d(oo4) KAOLINITE d^o, = SERPENTINE d^02).(0oA).*ooi2 -- HALLOYSITE d**, -- DICKITE d***, CHLORITE 16-362 RELATIVE INTENSITY Figure A. Peak positions and relative Intensities. The data of Tables 2 and 3 are presented combined, Illustrating the problems of XRD Identification when chlorite and serpentine, and possibly kaollnlte, halloyslte, or dlcklte are also present. / Three essential features are demonstrated in Tables 2 and 3, and Figures 2, 3, and 4: 1. The diagnostic peaks show considerable variation in the position in which they occur (A26=0.79 for chlorites and 1.05 for serpentines). 2. The chlorites and serpentines overlap and interfere with each other. 3. Basal peaks of the clay minerals kaolinite, halloysite, and dickite overlap the positions of the chlorite and serpentine peaks, and will interfere when present. The significance of the chlorite-serpentine interference is increased by the fact that chlorite is a very common accessory mineral associated with talcs, whereas serpentine is much less commonly associated. In spite of the chlorite-serpentine problem, numerous investigators have performed XRD identification and/or quantification of serpentine in chloritic talcs. It is obvious to us that they have misidentified asbestos as being present by overlooking the chlorite/serpentine interference and by misconcluding that a chlorite peak was serpentine. Other Methods Infrared Spectroscopy (IR) The infrared absorption spectrum of a material results from vibrational and bending frequencies of various atomic bonds within the structure. For example, Si-0 stretching frequencies produce similar IR peaks for all silicate minerals. As a result, IR spectra are not particularly useful for identifying the minerals present in a mixture, and the method certainly is not capable of determining whether or not a detected mineral is the asbestiform variety. Differential Thermal Analysis (DTA) The rearrangement or decomposition of mineral crystal structures due to thermal heating is a characteristic and reproducible reaction. It follows that DTA can identify specific minerals in a mixture but the method is not capable of determining morphology. Therefore, any DTA data which might point to the presence of a serpentine mineral could lead to misidenfying chrysotile asbestos in a talc when the mineral could well be a normally occurring platy antigorite having the same DTA pattern. Electron Microscopy Electron microscopic techniques of identification of asbestos have been amply covered in other presentations during this workshop. We do not intend to cover that subject again, but rather to point out some areas where asbestos can be misidentified. The high magnification attainable with electron microscopy is, in itself, inadequate as the sole index of mineral identity. For example, chrysotile is often identified by the presence of a hollow central core and streaked electron diffraction spots. But the clay mineral halloysite also crystallizes in that form and will produce a similar electron diffraction pattern. Therefore, in the absence of exact chemical composition, halloysite can be misidentified as asbestos. Similar care must be exercised to avoid misidentifying other fibrous clay minerals as asbestos, e.g., attapulgite and alpha sepiolite. In addition, talc ribbons can be mistaken to be asbestos, especially when some talcs have particles which roll up into spiral tubes giving the appearance of a chrysotile particle. Selected area electron diffraction is routinely used to identify a mineral particle as amphibole. Many investigators simply observe the electron diffraction pattern in the microscope and decide on the basis of general pattern geometry whether or not the particle is an amphibole. This can lead to misidentification, since numerous other minerals can give electron diffraction patterns with amphibole pattern geometry [10,11], Careful measurement of an electron diffraction pattern is required in order to identify the type 350 of mineral which produced the pattern. Chemical composition is further required in order to have a chance at identifying the particular species when the mineral is a member of a complex group such as the amphiboles. Otherwise, mi.sidentification will result. Cosmetic Talc Free from Asbestos In the United States, we have a self-regulating association known as the Cosmetic Toiletry and Fragrance Association. In certifying the purity of the talcs which they use, they are aware that no single method can identify asbestos and their most recent spec ification for cosmetic talc [12] combines two methods (XRD and optical microscopy) for monitoring their types of talc. The rationale is that a talc is first examined by XRD, and if even the smallest amount of amphibole is indicated, then the test proceeds into optical microscopy using a dispersion staining technique to determine whether or not the material contains asbestiform particles in the amphibole group. Summary This paper has categorized the main methods which have been used for detection of asbestos in talcs. The basic principles of the various methods were categorized to explain how asbestos has been and can be misidentified in talc. Generally, misidentifications arise by jumping to a conclusion from a single mineral characteristic, when, in fact, many characteristics are required to fully identify a mineral species and/or its variety. Both optical microscopy and XRD required a more detailed review than other methods since they have refceived the most attention from a monitoring point of view. This review is presented with the hope that our guidelines will enable analysts to avoid the mis identification of asbestos in talcs. References [1] Ampian, S. C. , Asbestos minerals and their nonasbestos analogs. Mineral Fibers Session, Electron Microscopy of Microfibers Symposium, Penn State Univ., August, 1976. [2] Thompson, C. S . , Discussion of the mineralogy of industrial talcs. U.S. Bureau of Mines Information Circular 8639, Proceedings of the Symposium on Talc, Washington, D.C., May 8, 1973. [3] National Bureau of Standards Staff, A report on the fiber content of eighty industrial talc samples obtained from, and using the procedures of, the Occupational Safety and Health Administration, 51 pp. (1977). [4] Bowndy, M. G . , Gold, K., Burgers, W. A., and Dement, J. M . , Exposure to industrial talc in Vermont talc mines and mills: AIHA Conference presentation, May 1977. [5] Rohl, A. N . , Langer, A. M . , Selikoff, I. J . , Tordini, A., Klimentidis, R., Bowes, D. R., and Skinner, D. L., Consumer talcums and powders: mineral and chemical characteriza tion, Jour, of Toxicology and Environmental Health, 2, 255-284 (1976). [6] Rohl, A. N. and Langer, A. M . , Identification and quantification of asbestos in talc, Environmental Health Perspectives, 9, 95-109 (1974). [7] Snider, D. W . , Pfeiffer, D. E., and Mancuso, J. J . , Asbestos form impurities in commercial talcum powders, Compass of Sigma Gamma Epsilon, 49, 65-67 (1972). [8] Scholl, R. and Drafts, R . , 1977, XRD characterization of asbestiform reference minerals. Symposium on Electron Microscopy and X-Ray Applications to Environmental arid Occupational Health Analyses, April 1977. 351 [9] Jenkins, R., A review of x-ray diffraction procedures as related to the quantitative analysis of air particulates. Symposium on Electron Microscopy and X-Ray Applications to Environmental and Occupational Health Analyses, April 1977. [10] Zoltai, T. and Stout, J. H. , Comments on asbestiform and fibrous mineral fragments, relative to Reserve Mining Company taconite deposits: Report to Minnesota Pollution Control Agency, 89 pp. (1976). ` . [11] Lee, R. , Electron optical identification of particulates: Symposium on Electron Microscopy and X-Ray Applications to Environmental and Occupational Health Analyses, April 1977. [12] CTFA Specification - COSMETIC TALC Issued 10/7/76, The Cosmetic, Toiletry and Fragrance Association, Inc. Discussion A. WILEY: You said that instantaneous recognition of SAD patterns is difficult. Could you give some examples as to what kind of confusions could exist in this? Can you confuse amphibole with serpentine or amphibole with talc, or is that kind of a gross mistake possible? J. KRAUSE: Those kinds of mistakes probably would not generally happen if you are looking at pyroxenes or olivine. Electron diffraction is not one of my areas of real expertise, but I think that you could possibly get feldspars that would give confusing patterns, depending upon their orientation in the microscope. L. MADSEN: r We are using all the methods that have been talked about today for identi fication for asbestos materials and do not in any way limit ourselves to fiber length and aspect ratios. _ J. WAGMAN: I would like to comment that it is possible by x-ray diffraction and through a special technique to identify and measure the presence of asbestos fibers even when they are in the presence of their non-fibrous counterparts. About two years ago this was demonstrated in a study which we supported at the Naval Research Laboratory in which samples were pre-treated so that fibers were first aligned and then the x-ray diffraction intensities measured at two different orientations with respect to the x-ray beam and in this way the intensity due to the non-fibrous counterparts could be subtracted from the total diffraction intensities. KRAUSE: You were putting the fibers in some specific preferred orientation in the sample and then looking for those orientations by XRD. WAGMAN: That is correct, and this had the advantage of not only making possible corrections, that is correcting for the non-fibrous material present, but also it greatly enhances the detectability for the fibers themselves. KRAUSE: Is this method being currently used? WAGMAN: This is a method whose feasibility was demonstrated and there are two publica tions on this in the literature. Actually our objective was to apply this method to airborne samples, which is a much more difficult application incidently, I should think than in the case of talc. The problem here is a preparative problem in that an air sample usually has a lot of organic material, sticky material present which interferes with the ability to orient the fibers. This is a preparative problem which will have to be overcome. But I should think that in the case of talc samples you probably would not have that problem. 352 CHOOL o f M i n e s R P.O. Box 112 G o l d e n , C o l o r a d o 8040! xCH I n s t i t u t e W. H. Ashton W. T. Caneer EC, Meeting with Bowling Green State University Geological Staff P R O J E C T NO. June 8, 1973 C 10704 A paper entitled "A sbestosform Impurities in C om m ercial Talcum Powders," published in the January 1972 issu e of The Compass of Sigma Gamma Epsilon (Vol. 49, No. 2) stated that 18 com m ercial talcum powders exam ined contained from 4% to 46% asbestiform m inerals. The average a sb estiform content was 18%. The data in this paper has subsequently been .quoted and has been a source of inquiry by interested individuals both in and outside of government agencies. The amount of asbestiform m inerals reported is so large that the data could initiate costly FDA hearings on the m atter. Since our general observations at the Research Institute relative to asbestiform _ m inerals in talc are at such a large variance toihose reported in the paper, an investigation of the paper was undertaken. To date we have reviewed the paper and have discussed the data with the authors. The people involved in the investigation were W. T. Caneer and Dr. Jerry Krause of the R esearch Institute and Dr. Maynard Slaughter of the Colorado School of Mines. REVIEW OF THE PAPER A review of the paper suggested that a number of errors are present. Some of these apparent erro rs may be illustrated by the follow ing table which appeared in the paper: . c . D O S C H O O L OF M I N E S RESE^ memo to W. H. Ashton Page 2 INSTITUTE June 8, 1973 Table I Qualitative Mineral A nalyses by X-ray Diffraction Sample Asbestosform Minerals Anhy- Clay Mise Number Talc (Serp- Trem -A ct. Anth. ) Carbonates drite (Mica) Mins. 1 XX X 2 XX 3 XX 4 XX X X 5 XX X 6 XX X 7 XX 8 XX X X 9 X 1X 10 X X 11 X X 12 X 13 X XX 14 X X 15 X X X 16 X X 17 X XX 18 X X X XXX XXX XX X X XXX XXX X XXX XXX X X X. X XX XXX X XXX X X XX X XX X XXX XXX X XXX XXX ^Additives and inert m inerals and compounds. According to this table, asbestiform m inerals were identified byX-ray dif fraction. By the method of X-ray diffraction used, one could only expect to identify m ineral groups to which asbestiform m inerals belong. Numerous common non-asbestiform m inerals also occur in these groups. A differentiation is shown for trem olite-actinolite and anthophyllite. It is not likely that these m inerals could be differentiated by the X -ray methods used. The m ineral anhydrite (CaS04) is a lso reported by X -ray diffraction for all except three of the sam ples. We have never found anhydrite in any talc sam p le s exam ined at the R esearch Institute. Furtherm ore, from the standpoint of geological occurrences and rock gen esis, one would not expect to find anhydrite associated with talc. 'With these factors in mind, a study was made to determ ine how one may possibly make an identification of anhydrite in talc. m e m o to W. H. Ashton Page 3 June 8, 1973 It soon became apparent that a talc k-beta diffraction peak was being inter preted as belonging to anhydrite. A filter is used to screen out k-beta radiation in X -ray diffraction analysis. However, the filter is not 100% efficient and some of the k-beta p asses through the filter and can lead to erroneous interpretation. The table also shows serpentine as one of the asbestiform m inerals identified by X -ray diffraction for m ost of the sam ples. This is usually based on the occurrence of a 7-angstrom peak. However, chlorite also gives a 7-angstrom peak and chlorite is a common constituent of talc. A differentiation of the two m inerals can usually be made based on other diffraction pe.aks. Since chlorite is a common constituent of talc and none was reported for the 18 sam ples, it is likely that chlorite was m is identified as serpentine. Table II was presented in the paper and shows quantitative m ineral analyses by petrographic m icroscopic techniques. ' *t Table II Quantitative Mineral Analyses by Petrographic Microscope (Volume Percent)* mple mber Percent Talc Flakes Percent Carbonate Grains Percent Asbestosform M inerals 1 73 2 92 3 **79 4 57 5 82 6 72 7 89 8 61 9 80 10 92 11 . 86 12 76 13 48 14 90 15 74 16 80 17 70 18 76 *L ess than 1 percent. 5 *trace trace 20 trace to 1 13 5 5 4 4 trace 20 6 4 4 trace 6 trace 22 8 21 23 18 15 6 34 16 4 14 4 46 6 22 20 24 24 "'Includes m uscovite. jO S C H O O L OF M I N E S RESE memo to W. H. Ashton Page 4 t ST IT U T E June 8, 1973 It is perhaps significant that no anhydrite was observed by m icroscopic techniques even though it was reported in 15 of the 18 sam ples by X -ray diffraction. It is perhaps also significant that no sp ecific asbestiform m inerals were reported in Table II -- only a total percent of asbestiform m in erals. This led us to suspect that any grain with a high length to thick n ess ratio observed under the m icroscope would be cla ssified as a sb esti form . This could lead to the m is identification of the edges of talc plates and of talc shards as asbestiform m inerals. DISCUSSIONS WITH THE AUTHORS Of the three authors, two were graduate students (Snider and Pfeiffer) at the tim e the paper was written. J. Mancuso is on the Geology Department staff and acted as advisor for the research and the paper. Snider is p res ently with the Michigan G eological Survey in Mt. Pleasant, Michigan, and P feiffer is a geologist for Texaco in Midland, Texas. We discussed the paper with Mancuso in Bowling Green and held telephone conversations with Snider and P feiffer. We made it clear to these people that the data presented in their paper could lead to very serious charges against the products. Theyreadily agreed that their data could easily have er ro r s, and if so it would save them much p ossible em barrassm ent at a later date by co rrecting their errors now. Apparently the paper was submitted for publication to f ill an issu e of the journal which was being devoted entirely to the Bowling Green Geology Depart m ent. Apparently a Dr. I. I. O ster (a fruit fly expert in the Biology Depart ment) told them that he had been conducting experiments related to the injection of talc products into m ice for the purpose of determining the effects of the injections upon the m ice. He requested that the Geology Department make m ineralogical determinations of the asbestiform m inerals in the talc products. None of the three authors had had any previous experience with talc m ineralogy, but they decided that it would be a suitable subject for a paper. Our d iscu ssion s yielded the following significant resu lts. 1. A ll three authors readily admitted that they did a "rush-job." About 2 weeks was spent in gathering data for the paper. 2. They agreed that asbestiform m inerals cannot be identified by X -ray dif fraction. X -ray diffraction is capable only of identification of a m ineral group which contains both asbestiform and non-asbestiform m inerals. 3. They admitted that they did not adequately check the "talc edge effect" which could lead to the m is identification of talc plate edges as asbestiform m inerals by microscopic analysis. fCO L \ D O S C H O O L OF M I N E S R E S E A R = I N S T I T U T E m em o to W. H. Ashton Page 5 June 8, 1973 4. They did not take into account the possible presence of chlorite in the talc and could have w ell m isidentified chlorite as serpentine (which of course includes chrysotile). 5. Relative to the identification of anhydrite, they admitted that they prob ably m isidentified a k-beta talc peak. ' 6. They counted only 100 grains for their quantitative m icroscopic analy se s. Though their data is presented in term s of volume percent they neither m easured the siz e of the grains counted nor considered the dif ference in the volume of a fiber as opposed to a plate. We pointed out that the statistics involved are totally unacceptable. 7. They admitted that they probably made many erro rs in conducting the project and seem anxious to rectify them before there is a possible accounting with the FDA or some other agency. ' f 8. The following lis t identifies the talc products examined in the Bowling Green Study. Sample No- ___________ Brand Name___________ Quoted % Asbestiform Minerals 1 Mennen Talc Powder 2 J &J Baby Powder 3 Com Silk 4 E stee Lauder 5 Cuticura (South Africa) 6 Coty-Muquist de Boio 7 April Showers (N. Y .) 8 Remington Shave Talc 9 Cashmere Bouquet 10 . Imprevu . 11 Avons Sachete Occur 12 Bteaven's Scent 13 Excalibur Spray (Avon) 14 Loves F resh Lemon 15 Mennens Baby Magic 16 Ammens Medicated Powder (ZnO) 17 ZBT Baby Powder 18 ` Cuticura (U .S. A .) . 22 8 . 21 23 18 15 6 34 16 4 14 4 46 6 22 20 24 24 C O L DO S C H O O L OF MI NES RESEARCH N ST IT U T E memo to W. H. Ashton Page 6 June 8. 1973 9. About a year ago Howard Jack, who was with the Am erican G eological Institute at the time, requested and got the lis t of various brands of talc examined in the Bowling Green study. His motivation is unknown to us. We have determined that Jack is now apparently with som e governmental agency and we are trying to determine his interest in the sam ples. " We asked to see their X -ray diffraction patterns and also requested sp lits of the sam ples. They could not locate the diffraction patterns and found only two sam ples (Nos. 8 and 13) -while we were there. They are s till try ing to locate the others and said that they would send them to us when and if they find them. They spent an inadequate amount of time and have admitted to making errors relative to the identification and amount of asbestiform m inerals. They apparently w ill not stand behind the data presented in the paper if they are p ressed to do so. ' I also believe that they w ill retract the data after we p re sent them our data and after they have had time to do som e checking on their own. /nkr A :DEPARTMENT OF I T H & HUMAN SERVICES Date * Prom June 6, 1985 QRAC (Quantitative Risk Assessment Committee) / r <. Public Health Service Memorandum Subject Asbestos in Talc W. Gary Flamm, Ph.D. Director, Office of Toxicological Sciences (HFF-100) Using Linda Taylor's report [1] and other information on asbes tos and talc, we conclude that the added human risk of lung cancer --8 and mesothelioma from possible asbestos in talc is less than 10 lifetime risk and quite possibly orders of magnitude less. We have used, as our population at risk, infants that may be routinely dusted with talcum powder for an estimated period of 2 years. Infant Dose and Worker Exposure: Based upon one experimental 2 yr. exposure scenario for talcum powder dusting, babies would apparently inhale no more than about 3 6.5 x 10 asbestiform fibers per year (4.95 talc fibers/cc x 1000cc/l x .58 1/min. breathing rate x 43.8 min/wk powdering x 52 wk/yr. x .1% asbestos in talc). The asbestiform fibers are difficult to detect, poorly defined in shape, and of a highly variable subtype. We assume .1% tremolite or anthophyllite asbestos in talc based on 1977 FDA measurements and other recent samples [1, 10, 11]. To be called asbestiform fibers, the fibrous silicates must be greater than 5 urn. and have length/width ratio greater than 3. These inherent detection and geometrical measurement limitations for asbestos in talc make comparisons with worker exposure to a different type (mainly amosite, crocidolite and chrysotile) and shape of asbestos highly problematical [5]. In fact there is a V. Gary Flamm,^^.D. -2- general consensus that current talc mines are virtually free of asbestos (offending mines have gradually been abandoned) and that any residual silicates in talc are so finely and smoothly ground as to represent virtually no risk to humans whatsoever even where an occasional fiber just barely satisfies the technical definition for asbestlform fibers. However, this consensus belief would require better geometric measurements than currently exist for both current commercial talc fibers and for workplace asbestos fibers during the past 50 years. Nevertheless, baby exposure in fibers per year is crudely estimated at about 0.3 x 10-^ times that of worker exposure in several well known epidemiological studies (e.g., Selikoff study: 15 f/ml in workplace x 12,000 ml/min breathing rate x 60 min/hr x 8 hr/day x 5 days/wk x 50 wks./yr. * 2.16 x 10^f/yr. vs 6.5 x 10^f/yr for baby) [1]. A complicating factor, however, is that human cancer risk from these studies seems to follow different time-dose response patterns for the two main cancer endpoints (lung cancer and mesothelioma). Although several human epidemiological studies exist which could be utilized for quantitative risk assessment purposes, it is most illustrative to ccr.staer the largest of these occupational studies, namely, that of Selikoff, et. al. [7,8] in which 17,800 insulation workers were exposed to a mixed variety of asbestos fibers (mainly amosite and chrysotile) for about 25 years on average. Through 1976, 2,271 deaths (12.7% of total) had occurred. Lung Cancer: Lung cancer rates were about A.6 times average (486 observed/106 expected). Since this nearly 360% excess lung tumor W. Gary Flamn^Bi.D. -3- rate seems to apply to nonsmokers alone as veil as smokers and nonsmokers combined [6], then, assuming hypothetically that one can extend excess relative risks to very low asbestos exposures, one would expect to see an excess lifetime lung tumor rate among asbes tos exposed nonsmokers of about 1.8% (360Z x the normal lifetime nonsmoker lung tumor rate of about .51 - integrating 1979 survival rates against Garfinkel's 1960-1972 nonsmoker age-specific lung tumor rates [12, 13]). Excess lung cancer rates appear to be proportional to dose and duration of exposure, but not to some high power of time-since-first-asbestos exposure [6]. Thus, excess lifetime lung cancer risk for talc exposed babies who will never smoke would appear to be approximately the product of 1) an excess 1.8% lifetime risk for nonsmoking asbestos exposed workers, 2) a baby/worker yearly exposure ratio of 0.3 x 10 and 3) a baby/worker exposure duration ratio of 2 yrs/25 yrs. This product _9 yields a value of . A x 10 added lifetime risk for lung tumors. Similarly, averaging eventual smokers in with the lifelong nonsmokers assumed above, the average added lifetime lung cancer risk for the talc exposed baby will be at worst about 10 times higher or about .A x 10 . We note that current (1979) lifetime total respiratory cancer rates are about 5% and have nearly doubled since 1960, possibly reflecting rapidly changing smoking patterns during and after World War II, primarily among women. However, decreased tar levels in cigarettes and decreased per capita use of cigarettes since about 1965 should result in a gradual leveling off or decline in the total respiratory and/or lung cancer rate of the general population [14]. -4- Meaothelima: The estimation of lifetime risk of mesothelioma is somewhat more difficult since the mesothelioma response data appears quite nonlinear in time since first exposure. We have investigated four different methods of mathematically modelling the nonlinear mesothelioma data. They all indicate an upper bound on lifetime --8 risk for talc powdered infants of about 10 risk and quite possibly a much lower upper bound if the conservative assumptions upon which they were based do not hold. These four methods consisted of mathematically treating mesothelioma as 1) a nonincidental tumor with no time lag between tumor initiation and death, 2) a nonincidental tumor with a 10 year time lag between tumor initiation and clinical observation, 3) an Incidental tumor, and 4) treating asbestos as a first stage intervener in an Armitage-Doll multistage carcinogenic process [9]. In fact methods 1-3 yielded virtually identical risks (.5-.75 x 10' risk). While method 4 yielded a risk 2-3 times higher (1.5 x 10 risk), it could easily have yielded a risk up to several orders of magnitude lover than 10 " if we had simply assumed asbestos intervenes at a later stage of the carcinogenic process in this hypothetical Armitage-Doll multistage model. There was general concurrence among these four methods, and it suffices to briefly summarize Method 1. 3.1 Method 1: based upon fitting bt (nonincidental analysis) to a 1922-1946 cohort of the Selikoff, et. al. data. A reasonably simple way to estimate the median life (ML) risk to median survival age 77 (in 1979) for humans exposed 2 yrs. to talcum V. Gary Flamm^^h.D. -5- powder during Infancy is given by the product of the following terms: (a) (77 yrs. since first exposure for lnfants/37 yrs. since first exposure for 1922-46 cohort as of 1978+)^'* 9.70. (b) (2 yr. Infant exposure duration/34 yrs. approx, worker exposure duration for 1922-1946 worker cohort) * .059. (c) (infant/worker) yearly exposure ratio * 0.3 x 10 (d) 1922-1946 cohort cumulative mesothelioma response of 3.75% (180 mesotheliomas/4,800 cohort members). This product yields a median life risk of --8 0.64 x 10 . Tumors other than Lung and Mesothelioma: (Selikoff study) Although significant tumor increases were observed at other sites in the workers (e.g., esophagus, stomach and colon), their risk is --9 --8 dominated by that of the lung (less than 10 or 10 risk, depending upon whether or not the baby becomes a smoker) and by --8 mesothelioma risk (less than 10 risk). Other Comments on Total Cancer Risk: These estimates of added lifetime human cancer risk are 2 orders of magnitude below those implied in Linda Taylor's memo 1) due to the fact that the more recent detection studies suggest .IX or less asbestos in talc on average rather than the 1% assumed by Dr. Taylor.' and 2) due tc a 10 fold conversion error going from fibers/cc in the air to fibers inhaled/yr by the infant. Although mothers may receive an exposure for each infant powdered, their added lifetime risk from talc should be relatively smaller than the infant's since their mouths and noses are considerably further from the densest portion of the talc cloud than is the case for the captive infant during the daily powdering period (the inverse square law for exposure may apply). W. Gary FI Ih.D. -6- Finally, the risks implied by the Selikoff study are generally on the high side of those implied by the other smaller epidemiological studies and we see little value in repeating calculations here for those studies (see reference 6 for details). Ovarian Talc Study: For completeness, a discussion is presented on a human epidemi ological study purporting to show an association between talc use (talcum powder used for genital dusting on the perineum or on sanitary napkins) and ovarian cancer. The Cramer et.al. study [2], which purported to show a significantly increased relative risk for ovarian cancer associated with talc use, 1) appears to have been misinterpreted statistically, 2) was uncorrected for several likely biasing factors and 3) appears to have been strongly contradicted by another study showing a reduced relative risk as signi ficant in the negative direction as the Cramer study was in the positive direction. The Cramer study's most prominent analysis (Mantel-Haenszel) was adjusted for only 2 factors and gave a relative risk (RR) of around 1.92 (p less than .003) and 95% confidence limits of 1.27 to 2.89 for 215 cases (talc users for genital or sanitary napkin dusting'! vs 215 controls. Cramer's more comprehensively adjusted but seemingly de emphasized multivariate regression analysis for 9 possible simulta neously confounding variables yielded a smaller and much less significant relative risk of 1.61 (p=.03), with 95% confidence limits of 1.04-2.49. It should be noted that the crude relative risk with no adjustments whatsoever was 1.89. In any case, if the authors had limited their logistic regression analysis as they subsequently did for their Mantel-Haenszel analysis, to those 121 cases where the first chosen control did not refuse to participate V. Gary Flamm,^fci.D. -7- (refusal bias), then the resulting p-value can be predicted through extrapolation of the other reported analyses to be greater than .05 and perhaps greater than .1. Unfortunately, the authors did not report this analysis. Instead they selectively chose to point out only that the relative risk of those exposed to talc both as a genital dusting powder and through sanitary napkins declined from a relative risk of 3.28 (p less than .001) to 2.44 (p less than .05) when the potentially biasing control refusals were eliminated from analysis. Apparently the authors felt it unnecessary to report those p-values that were greater than .05. Since there were twice as many singles among the cases (21Z) as among the controls (11Z), the life style of singles might easily have biased the original overall relative risk of 1.92 [3]. However, the multivariate logistic analysis (RR=1.61) using all of the original 215 cases and 215 controls clearly adjusted for marital status along with such variables as religion, educational level, ponderal index, age at menarche, exact parity, oral contraceptive or menopausal hormone use, and smoking. The partially adjusted Mantel-Haenszel analysis (RR=1.92) only adjusted for menopausal status and crude parity. Furthermore, it is generally assumed that any real positive cancer effect will show an increased risk with increased dose. Cramer only reported one subanalysis where he crudely considered dose response. He divided the small group of talc-dusted diaphragm users into those using diaphragms less than 5 years and into those using diaphragms more than five years. However, rather than showing an increased relative risk with increased dose (increased length of usage), the relative risk actually decreased noticeably V. Gary Flaan h . D . ^ -8- though not in a ''statistically significant" fashion from 1.82 to 1.23 as diaphragm use increased from less than 5 years to more than 5 years. In addition to the above interpretations of Cramer's own results, several potentially biasing factors could not be adjusted for by the logistic analysis. First, a possible positive correlation between talc use and ovarian disease etiology due to patient-perceived hygenic or cosmetic reasons would bias the relative risk upwards [4]. Second, a recall bias among hospital cases relative to community controls is quite plausible since cases may have greater incentive as well as opportunity to recall whether they should classify themselves as talc users [3]. Talc users from the community may well be modest In either participating as controls (the refusal bias already discussed) or in subsequently admitting talc use as a control subject. The recall bias might be expected to be even greater - as was possibly observed - for estimation of the relative risk for those using talc both on sanitary napkins and as a dusting powder (RF=3.28, p less than .001; or RR=2.44, p less than 0.05, after the refusal bias is eliminated) than for those engaged in only a single type of use. Finally a talc and ovarian cancer study by Hartge, et. al. [4], appears to strongly contradict the reportedly positive Cramer study. Overall 135 cases and 171 control women matched by age, race and hospital were questioned on talc use. The estimated relative risk of ovarian cancer by talc users was reported to be 0.7 (95% confidence interval of 0.4 to 1.1). Adjustments for race, age, and gravidity (pregnancy) had no effect upon the estimate. No subanalyses V. Gary Flamm^Ki.D. -9- resulted in relative risks significantly greater than 1. It would appear that no refusal bias was operative in the Hartge study since none was reported. Also it would appear that recall bias was non existent since there appeared to be no recall bias on the use or nonuse of douching. SUMMARY In summary, any hypothetical systemic added lifetime cancer risk (e.g., mesothelioma and lung cancer) to humans due to asbestos fibers in talc (principally for babies subject to 2 years of talc dusting) appears to be less than 10-- 8 added lifetime risk and possibly several orders of magnitude lower risk still, depending upon assumptions and uncertainties alluded to above, especially those regarding geometrical shape of any possible asbestos fibers in talc, and limits of detection for asbestos in talc. In addition, there appears to be no association between customary human talc use per se and ovarian cancer. Saoua* Robert Brown ATTACHMENT: Signature Page W. Gary Flamm, Ph.D. REFERENCES 10 - 1. L. Taylor, "Request for CAC Evaluation of the Hazard of Asbestos Contamination of Cosmetic Talc," FDA memo, Nov. 15, 1984. 2. D.W. Cramer, MD, W.R. Welch, R.E. Scully, C.A. Wojclechowski, "Ovarian Cancer and Talc - A Case Control Study," Cancer, July 15, 1982. 3. L. Tollefson, "Review of reports of increased risk of ovarian cancer from talc use," FDA memo, Jan. 30, 1985. 4. P. Hartge, R. Hoover, L. Lesher, L. McGowan, "Talc and Ovarian Cancer," JAMA, Oct. 14, 1983. 5. L. Tollefson and F. Cordle, "Review of an assessment concerning asbestos contamination of cosmetic talc," FDA memo, Dec. 17, 1984. 6. Chronic Hazard Advisory Panel on Asbestos, Report to the D.S. Consumer Product Safety Commission, July, 1983. 7. Selikoff, I.J., Hammond, E.C., Seidman, H., Mortality Experience of Insulation Workers in the United States and Canada, 1943-1976, Annals of the N.Y. Academy of Sciences, 1979, 91-116. 8. Peto, J., Seidman, H., Selikoff, I.J., Mesothelioma Mortality in Asbestos Workers: Implications for Models of Carcinogenesis and Risk Assessment, Br. Jour, of Cancer (1982) 45, 124-135. 9. Day, K.E., Brown, C.C., Multistage Models and Primary Prevention of Cancer, JNCI, 64, 977-989 (1980). 10. Eiermann, Heinz J., "Health Research Group Inquiry on Talc Safety," FDA memo, Aug. 28, 1978. 11. Wenr.inger, John A., "Denial of Petition for 'Labelling of Warning of the Hazardous Effects Produced by Asbestos in Cosmetics Talc' froir Philippe Douillet," FDA memo, July 11 , 1984. 12. Garfinkel, L., "Time Trends in Lung Cancer Mortality Among Nonsmokers and a Note on Passive Smoking," JNCI, j66^, 1061-1066. 13. Vital Statistics of the United States, Mortality, Part A, 1979, published by the U.S. Dept, of Health and Human Services. 14. U.S. Dept, of Health and Human Services, PHS, "The Health Consequences of Smoking: Cardiovascular Disease," a report of the Surgeon General, 1983. W. Gary Flamm, Ph.D. Committee Members: SIGNATURE PAGE James Winbush Ronald Lorentzen Herbert Blumenthal Robert Scheuplein Frank Cordle ______ r Patricia Schwartz S. i j n /g s - Robert Brown R j A v t f S a a u J -V ^ _____ 4 7 [ i j S S L -- Other Participants: Marcia Van Gemert Linda Taylor Linda Tollefson Janet Springer Sara Henry DEPARTMENT OF LTH & HUMAN SERVICES 0 1. /t Public Health Service Date * From Subject To Memorandum May 21. 1985 Robert Brown BRABf Division of Mathematics (HFF-118) Four methods of quantitating mesothelioma risk based on the Selikoff, et. al., insulation workers asbestos study. Technical support for QRAC's asbestos risk assessment. QRAC In fig. 1 we have plotted on a log-log scale Selikoff's original mesothelioma incidence data vs. years since first exposure to asbestos. Incidence is defined as number of mesotheliomas/man-years exposure. The data do not seem to fit a single straight line. Uncertainties of exposure in the early part of the century and the general decline in intensity of asbestos exposure after World War II are possible sources of error. For these reasons, as well as general lack of fit of both recent data and distant past data, Peto recommended use of a more homogeneous subset of workers for quantitative purposes, namely those workers first exposed between 1922 and 1946 [8]. It can be inferred from Selikoff's report that this subset consists of about 4800 workers. Peto reports 180 mesotheliomas (3.75%) among this subgroup out of a total of 236 mesotheliomas for all 17,800 workers followed from 1967 until about 1978 or 1979. Note that Selikoff only reported 175 mesotheliomas total; however, his reported follow-up period was also shorter (1967-1976). Plotting Peto's homogeneous 1922-46 cohort subset, we see that bt 3 '1 nicely fits the data (expressed as a straight line on log-log 21 paper with a slope of 3.1). We also see that b(t-10) ' nicely fits the data (with a different value for the constant b) and may be a reasonable QRAC - 2- way of looking at mesotheliomas since the time lag from mesothelioma induction to death is not zero. The time of mesothelioma induction is not even a well defined concept and may be intimately entertwined with the concept of stage definition in, for example, a multistage cancer process. Nevertheless, both these model fits assume mesothelioma to be a nonincidental tumor (i.e., a life table where incidence is the ratio #tumor bearers/#survivors, re-expressed in man-years, per time interval). If we assume mesothelioma annual incidence to be better approximated by a prevalence or incidental definition, (Itumor hearers/#dead in interval), then bt 1*64 seems to be a rough though not very tight fit to the original Selikoff data. Peto's reported 1922-1946 data set does not easily allow determination of a prevalence fit. However, since the prevalence denominator is defined in terms of deaths per time interval rather than the much larger number of survivors to date, the first 2,271 deaths (12.7Z of 17,800 workers) reported by Selikoff are very heavily weighted with the 1922-1946 cohort used exclusively in the two nonincidental curve fits above. Therefore comparisons of slightly different cohort subsets may still be useful. We estimate that the average time since first exposure for the Peto subset (1922-1946 first exposure) is about 37 years (Peto's 1978+ follow-up) or 35 years (Selikoff's 1976 follow-up). This compares to 25 years average time since first exposure usually reported for all 17,800 workers. We also make the assumption that workers ceased exposure on average 3 years before death. QRAC - 3- 31 Method 1: based upon fitting bt * (nonincidental analysis) to a 1922-1946 cohort of the Selikoff, et. al. data. A reasonably simple way to estimate the median life (ML) risk to median survival age 77 (in 1979) for humans exposed 2 yrs. to talcum powder during infancy is given by the product of the following terms: (a) (77 yrs. since first exposure for infants/37 yrs. since first + 31 exposure for 1922-46 cohort as of 1978 ) * 9.70. (b) (2 yr. infant exposure duration/34 yrs. approx, worker exposure duration for 1922-1946 worker cohort) .059. (c) (infant/worker) yearly exposure ratio 0.3 x 10 (d) 1922-1946 cohort cumulative mesothelioma response of 3.75% (180 mesotheliomas/4,800 cohort members). This product yields a median life risk of --8 = 0.64 x 10 . 21 Method 2: based upon b(t-10) * (delayed observation or time lagged nonincidental analysis). Note that to estimate real mesothelioma incidence (time of mesothelioma induction - the last stage of the multistage cancer process) at age x, the worker must be assumed to have been autopsied or surgically inspected at some average age, say x+10. Thus, assumming the worker stops exposure 3 years before death, the component relative and absolute risk factors for incidence at age 77 now are the following: (a) ((87 yrs.-10 yrs.)/(37 yrs.-10 yrs.)^"1 = 9.03. (b) (2 yr. infant exposure duration/(37-10) yr. worker exposure duration) *= .074. (c) (infant/worker) exposure rate ratio * 0.3 x 10 (d) 3.75% mesothelioma response in 1922-1946 cohort Thus - 0.75 x 10'2*8 . QRAC - 4- 1 64 Method 3: based upon bt * (prevalence or Incidental analysis): The relative and absolute risk product factors are: (a) (77 yrs. since first exposure for infant/35 yrs. since first 1 64 exposure for the 2,271 deaths to 1976) ' 3.64. (b) (2 yr. infant exposure/34 yr. ave. worker exposure duration for 2,271 deaths to 1976) .059. (c) (infant/worker) exposure rate ratio - 0.3 x 10 (d) 1.71 mesothelioma cumulative prevalence to 1976 (175 mesotheliomas/2,271 deaths). Thus = 0.50 x 10 31 Method 4: based upon bt * (nonincidental analysis) and a first stage effect in a generalized multistage process. k-1 We assume that bt fits the time-response data of a nonincidental tumor and is consistent with a first-stage-only effect in a generalized multistage process (with K stages), where biological time t starts at age of first exposure and continues until death [9]. Although this is not precisely true for the 1922-46 asbestos worker cohort, it appears to be approximately true. Moreover the time lag from cessation of exposure to end of followup (1976 or 1978+) is assumed to be small compared to total duration of exposure (i.e., exposure duration is a large fraction of time since first exposure). However, the exposure duration for infants is very small compared to median lifespan. Thus, while we fit * k-1 worker yearly incidence data to bt we should extrapolate yearly incidence (I) for exposed infants using the expression I b(tK -1 (t-d)K -1 ) for a K stage multistage process with duration of exposure d and time since first exposure t [9]. QRAC - 5- Nov K-l > 3 . 1 from Fig. 1 and b can be written as the product of a constant K and f where f is the time adjusted yearly dose of asbestos in fibers in ml-yrs. K^ is a constant dependent upon the type and dimen sions of the asbestos. Since f - 3.A3 f/ml-yr. (15 ave. f/ml in workplace (1922-1946) x 8 hrs./24 hrs. x 5 days/7 days x 50 vks/52 wks) for the Selikoff study, R can be computed from the plot of I K f t3'1 mm -A in Fig. 1. At t 20 yrs, I 5.6 x 10 , implying that the InK In m (5.6 x 10"4)-ln(3.43)-3.1(ln 20) -7.49-1.23-9.29-- 18.01. Thus K * 1.51 x 10-*8 (same as Peto obtains). Continuing, I * m K f(tK *-(t-d)K *) K ftK ^(1-- (1--d/t)K *) which roughly mm K ftK-- 1(d/t)(K-l) for d much less than t (using Taylor expansions), m K-2 Thus yearly incidence is approximately IK fd(K-l)t . Integrating (without correcting for decreasing survival) over a total of T years K-l yields a cumulative incidence of about I * K^fdT . If d * 2 yrs. infant exposure duration, T = 77 yrs., K-l = 3.1, f > 3.A3 f/ml-yr. for worker x 0.3 x 10 ^ (infant/worker exposure ratio) = 1.03 x 10 ^ f/ml-yr., and K = 1.51 x 10, then 1 = 2.2x10 mc However, this figure assumes no mortality from competing causes of death and does not even adjust for the effect of previous mesothelioma related deaths. Factoring in a standard population age-specific mortal ity or corresponding survival function into the above integral would --8 yield a median life risk of about 752 of 2.2x10 or --8 > 1.6x10 . This correction for survival can vary depending upon the limits of integration and what functional forms are under the integral, but for median life risk estimates the correction ranges from 1.0 down to .5 at worst. We also note that integrating I out to 100 yrs. of life with QRAC -6- respect to a standard mortality curve should yield approximately the same risk as cumulative incidence to median age 77 yrs. without any mortality adjustments. These approximately cancelling effects of two mathematical refinements may support the utility of using the median lifespan in simple calculations. Comments on the 4 Mesothelioma extrapolation methods: First and most importantly, it should be noted that the first 3 methods yield virtually identical median lifespan risks for babies --8 exposed to talc for 2 years (.5-.75x10 ). Thus many of the debates over the "correct model" appear somewhat superfluous. In particular heated debates over whether mesothelioma rates follow given high or low powers of time appear to be superfluous since the power of time is compensatingly related to other poorly defined and difficult to measure conceptual model parameters (e.g., tumor stage initiation and consequent time lag to clinical detection or death, and context of tumor observation (incidental or nonincidental)). Furthermore, small perturbations of the rough estimates of worker exposure or the power of time (K) have only a small effect on the overall risk. All the above models appear to be reasonable summary descriptors of the observable data and result in simple extrapolatory tools for the given problem of inferring median lifetime risk from infant exposure. One can always make method 4 computationally more difficult if one avoids use of the approximations. A second observation is that the rough mutual agreement of the results of the 4 extrapolation methods does not necessarily imply that QRAC - 7- the obtained excess median life risk is accurate even if the infant and worker exposure were to the same type and dimension of asbestos fiber. For example, none of the four models take into account the possibility that accumulated dose rather than yearly dose rate might more accurately reflect the biological burden of asbestos due, for example, to its ability to reside in vivo in the lung, pleural or peritoneal lining for years without being excreted (although encystment may be possible). Note also that we did not define dose on a mg/kg body weight basis. Although, we prefer such a definition for routine compounds that are ingested and metabolized, we strongly suspect that routine approach to be inappropriate for asbestos. In addition, all A methods assume linearity in response vs. dose at all dose levels. However, we have virtually no reliable dose response data from any of the epidemiological studies. Furthermore, some investigators have suggested that the nonconstant accumulated asbestos dose may be as conceptually consistent with a late stage multistage carcinogenic process as the more usually defined yearly asbestos dose rate appears to be consistent with a first stage Armitage-Doll multistage process [9], Although the theory and computa tions are more complicated for nonconstant exposures, it does appear that median life risks from infant exposure to asbestos affecting only a late stage in the carcinogenic process will generally result in much smaller risks than those calculated above for a first-stage-only effect in the carcinogenic process. QRAC - 8- Our third observation which we have just hinted at is that method 4 above (the first-stage-only effect in a multistage model) may be just another way of implementing method 1, but just slightly more computation ally difficult and having a slightly higher risk, partially because it substitutes a theoretical risk integration against the current (1979) U.S. population's standard survival function for the Implicitly observ able but poorer asbestos worker's cumulative survival of an earlier era in a more toxic environment. For example, the method 4 risk is about 2.6 times greater than the average risk of methods 1-3. There are probably other reasons for this 2.6 fold increase in risk over methods 1-3. However, since even partial intervention of asbestos fibers at later stages of the carcinogenic process in the Armitage-Doll multistage model imply lower overall risks, we prefer the simpler methods 1-3 at this moment to the more complicated multistage models whose proper application with respect to the stage or stages affected is still very much in doubt. In general, we do not put a lot of faith in mechanical use of sophisticated but unverifiable models, but we will occasionally refer to them as in method 4 where we can suggest implicit and perhaps elucidative connections to apparently more humble and simpler procedures. QRAC - 9- Summary; All four mathematical methods of modelling the nonlinear mesothelioma response data from the Selikoff study indicate a lifetime added human risk to infants exposed 2 years to talc powdering of at most --8 about 10 risk, and quite probably far less risk, if for example, asbestos intervenes in the carcinogenic process at a later stage than the first stage which was assumed in method A for the Armitage-Doll multistage process. Robert N. Brown QRAC REFERENCES - 10 - 1. L. Taylor, "Request for CAC Evaluation of the Hazard of Asbestos Contamination of Cosmetic Talc," FDA memo, Nov. 15, 1984. 2. D.W. Cramer, MD, W.R. Welch, R.E. Scully, C.A. Wojciechowski, "Ovarian Cancer and Talc - A Case Control Study," Cancer, July 15, 1982. 3. L. Tollefson, "Review of reports of increased risk of ovarian cancer from talc use," FDA memo, Jan. 30, 1985. 4. P. Hartge, R. Hoover, L. Lesher, L. McGowan, "Talc and Ovarian Cancer," JAMA, Oct. 14, 1983. 5. L. Tollefson and F. Cordle, "Review of an assessment concerning asbestos contamination of cosmetic talc," FDA memo, Dec. 17, 1984. 6. Chronic Hazard Advisory Panel on Asbestos, Report to the D.S. Consumer Product Safety Commission, July, 1983. 7. Selikoff, I.J., Hammond, E.C., Seidman, H., Mortality Experience of Insulation Workers in the United States and Canada, 1943-1976, Annals of the N.Y. Academy of Sciences, 1979, 91-116. 8. Peto, J., Seidman, H., Selikoff, I.J., Mesothelioma Mortality in Asbestos Workers: Implications for Models of Carcinogenesis and Risk Assessment, Br. Jour, of Cancer (1982) 45, 124-135. 9. Day, N.E., Brown, C.C., Multistage Models and Primary Prevention of Cancer, JNCI, 64, 977-989 (1980). 10. Eiermann, Heinz J., "Health Research Group Inquiry on Talc Safety," FDA memo, Aug. 28, 1978. 11. Wenninger, John A., "Denial of Petition for 'Labelling of Warning of the Hazardous Effects Produced by Asbestos in Cosmetics Talc' from Philippe Douillet," FDA memo, July 11, 1984. 12. Garfinkel, L . , "Time Trends in Lung Cancer Mortality Among Nonsmokers and a Note on Passive Smoking," JNC1, 66^, 1061-1066. 13. Vital Statistics of the United States, Mortality, Part A, 1979, published by the U.S. Dept, of Health and Human Services. 14. U.S. Dept, of Health and Human Services, PHS, "The Health Consequences of Smoking: Cardiovascular Disease," a report of the Surgeon General, 1983. Oy -.oTM! o lo f * 3 * 4 / 6 '. K*-L_ LKOfGMAMHm*iFMSMSIP <- S0i ."YniCMliinSs* F i q#- 1 Sei iKf-f A_s_k^st S ----------^ s a t U l l o w S l 46 7520 _^ -- S t u d y 01,900 dM asbe&fbS * roles s e-f T*. 1 ,1147) '. ^ . , Peto's tfowoje.ieou s i o b s t t _ __ 19* ut'vyvso ' * w V>vo5cidl?vi\'0 l " cc ^J i ;- /k .' mf f--ff''sc vOv volJuua t ' v r r P r , ,,,./, f m f i M i f f * . T v m u S rvji" Ir# . O r / j1 /rt-f ao 3 456789 3 4 5 6 7 891 Pt ( f t l l ~ H&7 fWst e r p o s u V e ) i . l , i i l l l ! ,1 k y U H & i f e. O <Lrf2) fosa)1 :.5^) J/3^) J*o <m ) . ,JllJJtl /s' ao jo ho so 1 M O tiVMC- I X / jr. t i w e 1 * 3 IS JO 30 Ho so V f O V ' S s/>cc f i v s t Xf>o^i*'s` e November 15, 1984 Food Additives Evaluation Branch (HFF-156) Request for Quantitative Analysis of Risk from Potential Exposure to Asbestos from Cosmetic Talc Use. Quantitative Risk Assessment Ccnmittee Attention: Ronald Lorentzen, Ph.D. (HFF-100) CITIZEN'S PETITION 83P-0404 Philip Douillet 1 Holyoke Lane Stony Brook, N.Y. 11790 Mr. Philip Douillet has submitted a petition requesting certain mandatory labeling on cosmetic talcs to warn consumers of asbestos hazards associated with such products. , BACKGROUND Cosmetic talc is used as a face powder and body powder by both adults and children to lubricate the skin and prevent chafing and discomfort caused by moisture and heat. The normal use of cosmetic talc in infants has not been reported to be harmful , although the accidental aspiration of excessive amounts in infants has been reported to cause serious but reversible acutsj_espiratory disease in sane instances and death in isolated cases. As discussed below, talc, a hydrous magnesium silicate, occurs fairly ccmronly in nature. Table 1 lists the minerals that are conmonly found in talc deposits. FDA STATUS There cure no regulations concerning the use of talc as an ingredient in cosmetic products. Under current law, the burden of proof that a cosmetic may be harmful in that it contains a harmful substance rest5 with FDA. FDA must have data or other information demonstrating that a product contains a poisonous or deleterious substance that is harmful under custcmary conditions of use before any action can be taken either to restrict or prohibit the use of an ingredient or product. TABLE I C aitjo nates Am pfttooles S e rp e n tin e O thers M ineral C alote Dotormt M ag n aaita Trem olite AnthophylMe Antigonta Chryaotile (uncommon) LizanM e (uncommon) Q u a rtz M ica. e.g. PWogopite Chlonte. a.g. Panmrota (/> * Ideal formula CaCOo, C aM g (C 03)2 MgCOj C a ,M g ,S .,0 22(O H )2 (F e M g j^ O jjtO H jj M g jS ij0 5(O H )4 M g jS ij0 5(O H )4 Mg3Si2O j(O H)4 K jlM g .F aJJS ijA ljO ^K O H ), (M g.A l.Fa) 12[S i.AI)| Oj0](O H ) ,4 3- - IDENTITY Talc Talc as a pure chemical compound is defined as hydrous magnesium silicate, Mg-Si, 0,q (OH)2 and consists of a brucite sheet containing magnesium ions Sanowiched between silica sheets that are held together by relatively weak forces. A variety of elements such as nickel and iron may be included in the talc particle lattice but are so bound within,the particle that they are not free to exert any biological action0 . Talc can be tubular, granular, fibrous, or platy, but it is usually crystalline, flexible, and soft. Talc is a member of the family of silicate minerals that have a similar atomic structure and occur widely in a large number of different varieties. These silicate minerals are derived from metamorphic alteration of mineral rocks that sometimes include the amphibole and serpentine groups of asbestos after their exposure to specific temperatures, pressures, and circulating liquid solutions. Talc may be formed also by the thermal metamorphism of silicon dolomites. The purity and physical form of any sample of talc dust as well as the other minerals that are associated with it are, therefore, directly related to the source of the talc and to the minerals found in the ore body from which it is mined. Talc conmonly contains chlorites and carbonates, the former being sheet silicate minerals containing magnesium, aluminum, and iron. The carbonate mineral components of talc are mainly magnesite, dolomite, and calcite. Quartz (free silica), iron oxides, sulphides, and various silicates can also be associated with talc. Since serpentine is one of the minerals from which talc has evolved, it can be associated with talc and is sometimes a contaminant of talc dust. Tremolite, a menber of the amphibole group of asbestos, and chrysotile or antigorite of the serpentine group, are the comncn est asbestos contaminants of industrial talc dust, although (according to Pooley, F . D . , 1975) chrysotile has never been reported to be present in the high-grade talc used in health and cosmetic talc. As talc dusts are obtained from different sources, the amount and specific form of talc, as well as the amount and nature of mineral contaminants, will be different for each dust. The U,S. Department of the Interior, in a letter dated February 24, 1984, indicated that, with regard to talc deposits and whether any were asbestos free, talc deposits can contain the mineral tremolite. However, even for those deposits that do contain tremolite, it was stated that it is important to understand the distinction between non-fibrous (non-asbestifom) tremolite, which may be cannon to same talc deposits, and fibrous, asbestiform, tremolite, which is a very rare 4- - form for that mineral. Similarly, actinolite and anthophyllite only very rarely have fibrous forms. Therefore, the presence of tremolite, actinolite, or anthophyllite in a talc deposit does not necessarily indicate the presence of asbestos, because they usually are not fibrous. Additionally, it was stated in the letter that the minerals crocidolite and amosite do not form in the same geological environment as talc; therefore, it is extremely unlikely that they would be found in any talc deposits. However, it is possible that chrysotile might occur in rocks in or around some talc deposits, but it would probably be in only very minor amounts. As to what percentage of talc deposits might contain 0.5Z or greater of asbestos, this would have to be evaluated for individual deposits. It is also stated that asbestos cannot be formed by shearing during mining. If asbestos minerals are not present to begin with, they will not be formed by mechanical means during mining or crushing operations. This last point is disputed by others. Asbestos Asbestos is not one mineral but a generic term used to describe a family of naturally occurring fibrous hydrated silicates divided on the basis of mineralogical features into two groups: serpentines and amphiboles. The important property of asbestos as compared to non-asbestiform varieties of silicates is the presence of mineralogically long, thin fibers that can be easily separated. According to some definitions, there are as many as thirty varieties of asbestos, but only six are of commercial importance. These, together with their chemical composition, are shown in Figure 2.1. The word "asbestos" is derived from the Greek word meaning "inextinguishable", and the origin of its name reflects one of its principle characteristics: fire resistance. But asbestos has many other qualities that enhance its conmercial utility, among them tensile strength, durability, flexibility, and resistance to heat, wear, and corrosion. As an aside, because of its many uses (insulation material, as a fire retardant, linings for brakes and clutch facings, reinforcing agent in cement and pipes, as filters, etc.) and its natural occurrence, it is not surprising that asbestos is found in ambient air, in drinking water, and in foods. The mineralogical classification of what is and what is not asbestos is complex, and as a result, many definitions of asbestos have appeared in the scientific literature. One definition of the term, asbestos, was published in the Federal Register in 1975 by the U.S. Occupational Safety and Health Administration (October 9, 1975, pp. 47652, 47760). According to this definition, asbestos is considered to include the naturally occurring minerals chrysotile, amosite, crocidolite, a/ 76 Chapter 2 Figure 2.1 Principal Varieties of Asbestos Asbestos r1 Se^Denffne AmobiboleS 4. Chrvsotiie " 1 >i 1" White Asoestos Mg3 ' S'2^5 fOHI A n tn o p n v U 'te Mg, c `- ' S ' g O ^ 1 0 h 2 romci te 'Siq022' 'Oh C'oc oo"te 9iue Asoestos '.j-''**' V"- I- 5 ^ Act:nonte Ca2 Mg. tg S'gO^> OH^ a ~os.-? Pa Vio - S oO"- 2* - SOURCE Or Eric J Chatfieid. 'The Prooiems of M easurem ent of Asoestos. ' >n Ontario. Roval Commission on Asoestos. Proceedings o f The Poval Commission on Asoestos. Second Public M eeting, cndev. Decem ber ' 2. >990. -eoorteo Ov Iv d ia Ootto i Toronto- Roval Commission on Asoestos '9 81 1 Aooenaix A cigure 1 o2 6- - trenolite, actinolite, and anthophyllite, if the individual crystals or fragments are greater than 5 micrometers in diameter, and have a length to diameter ratio of 3 or greater. Each of these six minerals included in OSHA' s asbestos standard occurs in both an asbestiform and a non-asbestiform variety. Three of the six minerals have been given different names for each of their two forms. Chrysotile in its non-asbestiform variety is called antigorite. Crocidolite is called riebeckite. Amosite is called cunmingtonite-grunerite. The other three minerals-- because they occur in their asbestiform varieties so rarely in nature-- are each called by only one name, regardless of their form. Tremolite, anthophyllite, and actinolite are labeled asbestos by OSHA in both their forms. According to mineralogists, this is incorrect, and it is poor science. HEALTH EFFECTS Evaluation of potential health effects from exposure to talc contaminated with asbestos and from other nonoccupational exposures to asbestiform fibers depends primarily on the results of epidemiological studies of occupational groups exposed to asbestos. Most of the data come from cohort studies (see Appendix I) of workers exposed to asbestos of various types and in a variety of industries and occupations. Much information has been obtained from these studies. However, they also suffer from limitations common to many epidemiological studies and from some additional problems related to determining dose (exposure) and response (health end point, such as death from a specific cause). Despite the limitations of individual studies, when all the studies are considered, exposure to asbestos increases the risk of developing lung cancer, mesothelioma, asbestosis, and possibly other cancers. To quantify health risks from an exposure, it is necessary to obtain dose-response data, but exposure measurements are particularly difficult to obtain. Because of the long latency period for asbestos-associated diseases, investigators have found it necessary to try to reconstruct past exposures. Techniques of measurement vary from place to place and over time0 *9 . For example, fiber counts obtained by light microscope in various industrial settings may need to be multiplied by a factor varying from 2 to 8 to obtain a true count of fibers longer than 5 un. Typically, a cumulative dose measurement is used. This does not take into account the time lapsed since last exposure nor does it distinguish between short exposures of high intensity and long exposures to low dust concentrations. In addition, a cumulative dose measurement does not change when exposure ceases. Variability in these exposure-related factors affects mortality responses in occupational cohorts. In some studies, exposure surrogates, such as type of job and duration of employment, are used to estimate exposure. These estimates may be less precise thin actual measurements. f Asbestos and Disease 95 Figur 2.4 Principal A *ba*tos-Ralatad Diaaasas and Condition* and Thair Sita* in tha Human Body ( k I * fr t p r 24 ^ t * * - 8- a- There may also be variability in reporting causes of death, ascertainment of deaths, and diagnostic accuracy of the reported cause of death. ,Inaccuracies are particularly likely for mesothelioma and asbestosis1 . Methodological differences are a major source of variation in comparing studies11. For example, the results obtained will depend on the criteria for selecting the cohort, the choice of comparison groups, the influence of other environmental factors that may introduce competing disease risks, and the records available. In addition, heterogeneity in the time at which onset of exposure begins can introduce additional distortion in the observed relative risks1 , especially because the types of exposure experienced by some workers in the distant past may differ from exposures experienced only more recently. Weiss also discussed how the results of lung cancer studies can be affected if persons who left a job are not included in the study cohort. He found that the exclusion of these workers could affect the relative risk by a factor of 2 to 3. An additional difficulty is encountered when comparing dose-response results from mortality and morbidity studies, particularly if the morbidity studies are confined to active workers, which is usually the case. A bias is introduced in studies of active workers, since those with severe disease have probably already left employment. However,,, asbestosis generally progresses after cessation of dust exposures1'5' . Numerous follow-up studies of asbestos-related mortality have been conducted on cohorts with varying intensity and duration of exposure, type of exposure, type of work, time and duration of follow-up periods, differences in the completeness of the cohort, completeness of mortality ascertainment, availability of smoking histories, geographic area of analysis. Because of the variations noted, it is not surprising that the standardized mortality ratios (SMRs) and dose-response results differ greatly among studies. In general, however, the same major diseases-- lung cancer, mesothelioma, and asbestosis-- have been observed, although not all investigators conducting these studies have reported or detected excesses of all three of these diseases. Talc The health effects of talCchave been studied only in relation to occupational exposures1'5- . Data available on the health hazards associated with occupational exposure to talc are not extensive. Exposure to talc itself in high concentrations has been shewn to produce excess mortality, mainly due to respiratory diseases. 9- - Workers from different geographic regions containing talc with or without fibers have been studied to determine if any adverse health effects are associated with the asbestiform fiber content of talc. Adverse effects have been found in some studies among workers exposed to talc both with and without fibers. These studies are discussed in the following paragraphs. Epidemiological studies on workers exposed to talc containing fibers have demonstrated adverse effects on pulmonary function. In a study of 121 New York miners and millers exposed to talc containing tremolite and anthophyllite fibers, pulmonary function was found to be significantly decreased. Reductions in forced vital capacity (FVC) and 1-second forced expiratory volume (FEV,) were associated with employment duration and the amount of fiber present. Increased pleural thickening and calcification were detected in talc workers with 15 or more years of employment . A mortality study of 398 New York miners exposed to talc containing fibers has demonstrated excess mortality from nonmalignant respiratory disease, excluding influenza, bronchitis, or pneumonia (5 observed/1.3 expected) . An excess in lung cancer with an average latency of 20 years was also observed (9 observed/3.3 expected). Additional studies have had conflicting results. Some investigators have found no significant increases in lung cancer and nonmalignant respiratory disease , whereas others have reported significant increases in lung cancer, attributed to the silica content of talc. ' Morbidity and mortality studies have also been conducted on workers exposed to talc with low or undetectable levels of fibers. A study on the respiratory function of 103 Vermont talc workers indicated that there was a reduction in pulmonary function in smokers'31. After adjusting for smoking, the effect of the exposure to talc was not statistically significant, although there was evidence of an exposure-related effect in workers with an annual dust exposure of approximately 1.5 mg/m . Exposure to talc dust was also associated with small opacities seen on chest radiographs. 26 Ganble t t a l . conducted a cross-sectional study of 299 workers from Montana*7~exas, and North Carolina who were exposed to talc containing low levels of silica and fiber. There was no significant difference in lung function, respiratory symptoms, or pneumoconiosis between workers and controls, although there was a significant increase in bilateral pleural thickening among the workers. Results of pulmonary pathology studies also have provided evidence of fibrosis in workers exposed to talc that does not contain fibers . A mortality study of 392 Vermont workers exposed to talc not containing fibers showed that there were excess deaths from nonmalignant - 10 - respiratory disease, excluding influenza and pneumonia, among millers (11 observed/1.79 expected) . This excess mortality was associated with small opacities seen on chest radiographs. An excess of respiratory cancer mortality among miners was also noted (5 observed/1.15 expected) but was attributed to exposures other than talc. 37 In a recent case-control study , increased risk of ovarian cancer was shown for women who regularly used talc either (or both) as a dusting powder on the perineum or on sanitary napkins compared to women vfoo did not engage in either practice (See Table A). No data with regard to asbestos contamination of the talc were provided. Studies of female asbestos workers are presented in Appendix I. - 11 - Table 4: Relative Risks (RR) for Cannon Epithelial Ovarian Cancers Associated with Talc Exposure in Perineal Hygiene Types of Perineal Exposure No perineal exposure As dusting powder On napkins but Any perineal but not on not as dusting Both on napkins and exposure________ napkins____________ powder________ as dusting powder Cases (Total = 215) Controls (Total - 215) Crude rr Adjusted RR* 95% confidence limits 123(57.2%) 154(71.6%) 1 - - 92(42.8%) 61(28.4%) 1.89 1.92 (1.27-2.89) 43(20.0%) 17(7.9%) 34(15.8%) l v58 v-- 1.55 14(6.5%) 1.52 j (0.98-2.47) 32(14.9%) 13(6.0%) 3.08 3.28 (1.68-6.42) *djusted for parity and menopausal status - 12 - Note: A study (reviewed in Appendix II) of mesothelioma incidence in domestic dogs concluded that there was an association between the incidence of mesothelioma and asbestos exposure; the source of exposure of the dogs was from the use of flea powders and/or the owners asbestos-related occupations (hobbies). Additionally, an animal inhalation study (reviewed in Appendix II) with talc (Italian 00000 grade) did not indicate talc to be carcinogenic. Asbestos Asbestos associated diseases generally have been related to occupational exposures, such as those experienced by some miners, insulators, and factory workers (see Appendix I). Recently, however, there has been concern that exposures to asbestos and related fibers may present a health hazard to the general public. Because asbestos and other asbestiform fibers appear to be ubiquitous, virtually everybody is exposed to some extent. During autopsy, asbestos fibers have been detected in the lungs of most urban residents studied. Reported concentrations of asbestos in urban air are shown in Table 7-6. Exposure to the general public is of concern because the population involved is large and includes unhealthy persons. Also, exposure may begin in childhood (as with baby powder application), leaving a longer time for the development of adverse effects. Additionally, asbestos may enhance the carcinogenic effects of other materials. There is little information about the health effects of most nonoccupational exposures to asbestos (see NAS report, Ref. 100). Although babies have been powdered with talc powder for many years, there is no evidence that this has resulted in an increase in asbestos-related disease. Three principal diseases are related to exposure to one or more of the commercial asbestos minerals. These are: (1) lung cancer, which includes cancer of the trachea, bronchus, and the lung proper; (2) mesothelioma, a cancer of the pleural and peritoneal menbranes that invest the lung and abdominal cavities, respectively; and (3) asbestosis, a diffuse interstitial fibrosis of the lung tissue often leading after long exposure to severe loss of lung function and respiratory failure. These diseases are not equally prevalent in the various groups of asbestos workers that have been studied; the amount and type of disease depend on the duration of exposure, on the intensity of exposure, and possibly on the type or types of asbestos to which the individual was exposed. Only lung cancer and mesothelioma will be considered here. Asbestos appears to act principally as a late stage carcinogen (promoting agent) that multiplies the underlying risk of lung cancer that occurs in the absence of asbestos exposure. The nature of the dose-response relationship for asbestos-related diseases is discussed below. 220 TABLE 7-6. Summary of Environmental Aabeatoa Expoaure Saaplea* Sample Seta 1. Paria air No. of Samplea 161 Meaaured Concentration (ng/a^)________ 90th PerMedian cantile Equivalent Concentra tion (fibera/c3)b 90th PerMedian cantile 0.7 3.2 0.00002 0.00011 Reference Sebaatien et al., 1980 2. Paria (outdoor control) 19 0.7 5.2 0.00002 0.00017 Sebaatien et al., 1980 3. Outdoor control aaaplea, for U.S. achoola 31 0.9 9.8 0.00003 0.00033 Conetant et al., 1982 4. Air of 48 U<S. citie* 187 1.6 6.8 0.00005 0.00023 Nicholaon, 1971 5. Air of U.S. citiea 127 2.3 7.8 0.00008 0.00026 U.S. Environmental Protect ion Agency, 1974 6. Air of five U.S. citiea (outdoor control aaaple) 7. New York City air 34 22 6.7 31.9 13.7 42.9 0.00022 0.00106 0.00046 0.00143 Nicholaon et al., 1975, 1976 Nicholaon et al., 1971 8. Air 0.5 aile (0.8 ka) from aabeatoa apraying 9. Air in U.S. achoolrooaa with out aabeatoa 17 31 22.5 82.6 16.3 72.7 0.00075 0.00275 0.00054 0.00242 Nicholaon et al., 1971 Conatant et al., 1982 10. Air in Paria buildinga with aabeatoa aurfacea 135 1.8 32.2 0.00006 0.00107 Sebaatien et al., 1980 11. Air in U.S. buildinga with ceaentitioua aabeatoa 12. Air in U.S. buildinga with friable aabeatoa 13. Air in U.S. achoolrooaa with aabeatoa aurfacea 28 54 54 7.9 19.1 0.00026 0.00064 19.2 96.2 62.5 550 0.00064 0.00321 0.00208 0.01833 Nicholaon et al., 1975, 1976 Nicholaon et al., 1975, 1976 Conatant et al., 1982 14. Air in U.S. achoola with damaged aabeatoa aurfacing material 27 121.5 465 0.00405 0.01550 Nicholaon et al., 1978 Adapted from Nicholaon, 1983. bBaied on converaion factor of 30 ug/3 1 fiber/ca^. - 14 - (1) Lung Cancer Most epidemiological studies (reviewed in Appendix II) of asbestos workers that have demonstrated an excess lung cancer risk associated with the inhalation of asbestos have produced results consistent not only with a linear relationship between cumulative dose and mortality, but also consistent with the absence of a threshold. In all of these studies, there appears to be a progressive and proportional increase in the SMR (standard mortality ratio) for lung cancer with increasing dose and no evidence of a threshold level. This evidence cannot be accepted without some qualification, however. All of the studies have the intractable difficulty of separating out the effects of cumulative dose from duration of exposure. Persons exposed to asbestos nonoccupationally can be at increased risk of contracting these asbestos-associated cancers. In one of the first studies linking asbestos exposure and mesothelioma, the disease was found among residents of an asbestos mining area in South Africa. These subjects had presumably inhaled the material in the surrounding air. In another study, persons living in households with asbestos factory workers in New Jersey were reported to be at increased risk of asbestos-associated disease. There is debate about the carcinogenic risk at low exposure levels of asbestos because lung cancer risks at low doses over a working lifetime have not been estimated to date by observation but rather b y ^ extrapolation from observed risks at higher exposure levels. Accordingly, there is no direct evidence of the existence or absence of a threshold for lung cancer. It may arguably be the case that with further inquiry and better information the scientific comnunity will be able to demonstrate that there is a dose level for asbestos for which the body's defense mechanisms are effective, or that asbestos acts differently at lower rather than higher doses, thus demonstrating a threshold level for the induction of cancer. At the present time, that information does not appear to exist. Since a threshold dose level for asbestos-related lung cancer has not been established, many investigators conclude that it is prudent, to assume that there is none and that any dose may induce lung cancer. A linear non-threshold model is less likely to underestimate the risk at lew doses than any other plausible model. (2) Malignant mesotheliomas are rare cancers that appear as thick, diffngp Tnassgfi rnsidp any of the serous menbranes (mesothelia) that line body cavities. Epidemiologic research has shown that exposure to asbestos can produce mesothelioma at two sites: the pleura (the serous menforane that surrounds the lungs and lines the thorax) and the peritoneum (the serous membrane that surrounds the abdominal organs and lines the abdominal and pelvic cavities). - 15 - The status of pleural and peritoneal mesothelioma as marker diseases for asbestos exposure stems from the fact that these diseases seldom occur in people who have not been exposed to asbestos in excess of normal ambient levels. The nature of the dose-response relationship for mesothelioma has been less firmly established than that for either lung cancer or asbestosis. Indeed, it has been suggested that very trivial doses of asbestos are capable of inducing the disease and that as a result,there is no dose-response relationship for mesothelioma at all. That mesothelioma is associated with low levels of exposure for brief periods of time appears to be based upon isolated anecdotal case reports and upon more systematic case-series reports of mesothelioma arising-,from nonroccupational household or neighborhood exposures. ' Newhouse et al.~* reported nine cases of mesothelioma in family contacts of asbestos workers and eleven cases among individuals whose only identified asbestos exposure was associated with living within one-half mile of an asbestos factory. In these cases of non-occupational exposure, pleural mesotheliomas predominated over peritoneal mesothelioma. The evidence is not inconsistent with the existence of a dose-response relationship for mesothelioma. Although deaths from mesothelioma have been reported after what appear to have been brief (for gas mask workers) or low (for family contact and neighborhood cases) exposures, the Ontario Conmission*y concluded that the evidence suggests that the actual exposures approached or were equivalent to,corresponding occupational exposures; it further agreed with the IARCr conclusion that there is no evidence of risk of mesothelioma to the general population. There is a time interval between the initial exposure to asbestos and the clinical manifestation of the diseases it causes. The latency period for cancer is thought to be long; rarely less than 10 years and often more than 20 years. Mesothelioma appears to have the widest range of latency-- again, they rarely occur less than 10 years from the time of first exposure to asbestos, but they can occur as many as 40 years or more from the onset of exposure. It has been suggested that the death rates from mesothelioma appear to rise at an exponential rate from the time since first exposure; death rate appears to rise at,a rate between the third and fourth power of time,since first exposure; ' ^ other work suggests the fifth power of time.'5 What the data demonstrate is that the incidence of mesothelioma rises rapidly the longer the time period since a person is first exposed to asbestos. As a result, the age at vhich a person is first exposed to asbestos becomes a very significant factor in determining the overall risk of contacting mesothelioma. While the mesothelioma incidence rates appear to be independent of the age at which exposure first took place, the practical result is that the risk of contacting mesothelioma is greater the earlier in life one is first exposed. (This is important to keep in mind when considering baby - 16 - powder exposure. ) The magnitude of the risk will still depend on the amount and duration of exposure (and, possibly, fiber type); and where that exposure is minimal, the risk, albeit greater for exposures earlier rather than later in life, will also be minimal. The disease rate of lung cancer among persons exposed to asbestos appears to be quite unlike that of mesothelioma. Rather than,-being time-dependent, lung cancer rates appear to be age-dependent. The majority of lung cancer deaths, both in smokers and non-smokers, occur after age 50 and over half occur after age 60, irrespective of the time of first exposure. This suggests that the risk of contracting lung cancer is much greater in older groups than in younger groups. Asbestos exposure appears to have the effect of multiplying the risk of lung cancer that exists apart from that exposure; and the risk of lung cancer contributed to b y asbestos exposure appears to be virtually independent of the age when that exposure took place and will be simply proportional to cumulative dose. The consistency of an increased cancer risk at extrathoracic sites and its magnitude are less for cancer at other sites than for lung cancer. Nevertheless, many studies document significant cancer risks at various GI sites. Cancer of the kidney has also been found to be significantly elevated. Among female workers, ovarian cancer has been found in excess (Appendix I, #16). While no other specific sites have been shewn to be elevated at the 0.05 level of significance, the category of "all cancers other than lung, GI tract, or msothlial" is significantly elevated. Several epidemiological investigations reported in the literature provide data on exposure levels of asbestos related to mortality and specific cause of death, while most do not provide exposure data. Those with relevant data are reviewed in Appendix I (see Summary table). In these investigations, different epidemiological approaches were used, various definitions of the study groups were adopted, observations took place over different periods of time, types of controls varied, time interval from first exposure was unknown, some workers exposed to more than one type of fiber, etc. Several studies are briefly described below: Mining and Milling Chrysotile. Three cohorts occupationally exposed to chrysotile asbestos during mining and milling operations had a moderately increased risk for lung cancer (SMRs from*.1.0 to 2.6). In the largest investigation, McDonald et al. (1980)3 ' studied all employees who had worked for at least 1 month in Quebec mines. From 1950 to 1975, 3,291 deaths occurred among the 9,850 male employees successfully traced and followed for 20 years or more after initial employment. An increase in lung cancer - 17 - mortality was observed (SMR = 1 . 3 , 230 observed vs. 184 expected), and the risk increased with duration of employment (SMR = 1 . 0 for < 1 year to 1.6 for > 20 years) and level of exposure (SMR = 0.9 for < 30 mppcf(yr) to 2.3 for 300 mppcf(yr). Eleven cases of mesothelioma were observed. Anthophyllite. Male and female employees of anthophyllite asbestos mines in Finland were studied by Meurman et al. (1974, 1979) , who reported a two-fold increase in lung cancer mortality (44 observed vs. 22.4 expected) and no mesotheliomas among the 1,045 persons successfully traced. All lung cancer deaths occurred among the male employees, and the risk was associated with estimated intensity of exposure (SMR = 1 . 4 vs. 3.3 for low and heavy exposures, respectively). Lung cancer risk among nonsmoking asbestos-exposed employees was 1.4 compared to a relative risk of 17.0 for the asbestos-exposed enployees who smoked. Crocidolite. For exposure associated with crocidolite mining in Western Australia, there was a similar increase in risk of lung cancer (SMR = 1.6, 60 observed vs. 38.2 expected) and a strong association with mesothelioma. Twenty-six cases of pleural mesothelioma were observed among the 526 deaths, and the mesothelioma risk increased with increased duration and intensity of exposure. Follow-up period was relatively short. No increases in gastrointestinal cancer were observed for any of the mining and milling cohorts reviewed. Manufacturing Chrysotile. Most asbestos exposures associated with manufacturing processes involve mixed fiber types, but Dement et al. (1982, 1983a,b)y,0i,0Z examined the risks associated with exposure to chrysotile asbestos in textile factory workers. They observed a marked increase in lung cancer mortality (SMR = 3.2, 35 observed/11.1 expected), and the risk was strongly correlated with exposure level. There was also one peritoneal mesothelioma. Increased risks for both lung cancer and nonmalignant respiratory disease were observed at exposure levels lower than those reported in other studies. Anosite. Mortality due to lung cancer was increased three- to four-fold (83 observed /22.8 expected) for 820 factory workers exposed to amosite asbestos.0-3 The higher risks were observed for the subgroup followed 20 years or longer after initial employment (SMR = 5.1, 52 observed/10.1 expected). This cohort is a sometdiat unusual population because of its limited duration of intense work exposure (1941-1945) and long period of observation. Other excess cancers, including 14 mesotheliomas, were also reported. - 18 - 64 Mixed. Newhouse and Berry (1979) reported increased risks of lung cancer mortality for both males (SMB. = 2.4, 103 observed/43.2 expected) and females (SMR = 8 . 4 , 27 observed/3.2 expected) in a follcw-up study of 4,600 male and 922 female enployees of an East London asbestos factory in which crocidolite and amosite were used. Approximately 10% of all deaths resulted either from pleural or peritoneal mesothelioma. Except for 10 cases of mesothelioma, no increased cancer mortality was observed among more than 11,000 males and females employed during 1941 or later at a British factory producing friction materials. 3,00 In a case-control study that corrected for total asbestos exposure, 5 of 6 cases had definitely worked with crocidolite, whereas 2 of 10 controls had. A cohort of 1,345 retired asbestos products workers enployed from 1941 to 1967 had increased risks for lung cancer (SMR = 2 . 7 , 63 observed/23.3 expected) and gastrointestinal cancer mortality (SMR = 1.4, 55 observed/39.3 expected). Overall mortality among the 1,075 retirees successfully traced to 1973 was 73%. The lung cancer risk was strongly associated with the amount of exposure, expressed as million particles per cubic foot multiplied by number of years of exposure (mppcf-yr), ranging from a SMR of 2.0 up to 7.8. lung cancer risk differed by type of asbestos exposure (SMR of 2.5 for chrysotile alone vs. 5.2 for mixed chrysotile and crocidolite exposures). Five mesothelioma deaths were observed. Study results suggest that effects of asbestos exposure on lung cancer risk may continue long after the termination of exposure. Studies of a retiree cohort may result in an underestimation of actual risks, since deaths among enployees under-age 65 would be emitted. The Consumer Product Safety Commission (1983) suggests that the risks may be understated by as much as two-fold. No increase in lung cancer mortality or cancer of any other site, except mesothelioma, was observed in the cohort of 5,645 enployees of an asbestos-cement product manufacturing facility studied by Hughes and Weill (1980). In the high exposure subgroup, lung cancer risk was increased for employees exposed to crocidolite, and two mesothelioma deaths were reported. The low overall mortality, 10.6%, and the low tracing rate, approximately 75%, suggest that this study may have resulted in an underestimate of mortality risks. Fihkelstein (1983)7^ studied 328 asbestos-cement workers hired before 1960 and employed for a nrininim of 9 years. Mesothelioma was strongly associated with exposure level for production workers, whereas a dose-response relationship was not observed for lung cancer. Excess lung and gastrointestinal cancers were observed. Clemmesen and Hjalgrim-Jenson (1981)7* studied cancer incidence among 6,372 Danish males who worked in asbestos-cement factories between 1944 and 1976. There were 55 cases of respiratory cancer compared to 33 - 19 - expected, based on Danish Cancer Registry incidence rates. Three mesotheliomas were observed in addition to excess prostate, laryngeal, and stomach cancers. Cancer incidence in the unexposed employees at the same factories was not increased. Jones et al. (1980b) studied a cohort of 578 females exposed to crocidolite from western Australia during the manufacture of gas masks. The 12 cases of lung cancer (SMR = 1.9, 12 observed/6.3 expected) and the 17 mesothelioma cases (13 pleural and 4 peritoneal) were all exposed to crocidolite, whereas no cases of mesothelioma or lung cancer occurred among the 102 females exposed only to chrysotile. Overall, 10Z of deaths were due to mesothelioma. Risk of mesthelioma was strongly associated with duration of exposure, although no dose-response relationship was observed for lung cancer. Similar results were reported among 1,304 females who manufactured gas masks at three locations followed from 1951 to June 30, 1980. Deaths from lung cancer (SMR = 2.0, 22 observed/11 expected) and ovarian cancer (SMR = 2.2, 17 observed/7.8 expected) were increased. Lung cancer excess was higher for those exposed predominantly to crocidolite compared to those exposed predominantly to chrysotile. Five of the six mesotheliomas occurred in those exposed predominantly to crocidolite. All studies of occupational cohorts exposed to asbestos during manufacturing processes had an overall increased risk ofglung cancer or a dose-response relationship in the exposure subgroups. ' Elevated risk ratios ( 1.1) for gaslp^intestinal cancer were observed in six of the nine cohorts reviewed?52'5 3 '65,67'7 0 , 7 r Insulation Mixed. All three of the cohorts involved in end product use of asbestos as insulators were exposed to mixed types of asbestos. One of the largest studies is that of Selikoff et al. (1979), H who studied 17,800 members of an insulator's union. Overall mortality in this cohort was 12.8Z; 2,271 deaths were reported through 1976. Lung cancer risk was increased four-fold (429 observed/105.6 expected) and increases were observed for gastrointestinal cancer (SMR * 1.6, 94 observed/59.4 expected), cancer of the larynx, pharynx, buccal cavity (SMR = 1.7, 25 observed/14.8 expected), and kidney (SMR = 2.2, 18 observed/8.1 expected). Dose-response relationships were not examined because of the lack of exposure data. Mesotheliomas (63 pleural and 112 peritoneal) accounted for 7.7Z of the deaths. Analysis of the relationship between smoking and lung cancer risk vising data from the American Cancer Society indicated a consistent multiplicative effect, in that a 10-fold increase in risk of lung cancer was associated with smoking in both asbestos-exposed and unexposed groups. A five-fold increase in lung cancer risk,was associated with asbestos exposure in both smokers and nonsmokers.1 - 20 - Elmes and Simpson (1977) ^ reported an unusually high risk of lung cancer (SMR = 7 . 0 , 35 observed/5 expected) and gastrointestinal cancer (SMR = 5 . 9 , 13 observed/2.2 expected) for a cohort of 162 insulators and pipe coverers employed in Northern Ireland during 1940. Overall mortality in this cohort was 75.3% by 1975; 54% of the deaths were due to cancer. Thirteen cases of mesothelioma (eight pleural and five peritoneal) were reported. No difference in cancer risk was apparent for workers first employed before or after 1933. Ascertainment bias is unlikely to explain the magnitude of the risks reported for this cohort. Shipyards Mixed exposures. Rossiter and Coles (1980)^ studied 6,076 dockyard workers employed before 1947. They reported no increase in lung cancer mortality (SMR = 0.7, 84 observed/119.7 expected) or gastrointestinal cancer (SMR = 0.8, 63 observed/83.3 expected). Mesothelioma was reported for 31 (3%) of the 1,043 deaths. Hcwever, since less than 20% of this cohort have died, excess cancers may not be fully apparent. In a study of 2,190 Italian dockworkers, Puntoni et al. (1979)^ observed increased risks for lung cancer (SMR = 277,"T23 bbserved/54.9 expected), gastrointestinal cancer (SMR = 1.3, 74 cbserved/58.6 expected), laryngeal cancer (SMR = 1.9, 15 observed/7.7 expected), and kidney cancer (SMR = 2.0, 29 observed/14.7 expected). EXPOSURE Talc Values between 800,000 and 960,000 tons have beej^renorted as the amount of talc used cccmercially in the U.S. each year. ' Talc is used in a number of industries, for a variety of purposes; e.g., the manufacture of ceramics, paints, paper, rubber, roofing, insecticides, stucco, plastics, textiles, and soaps. Pulverized talc is also used as an ingredient in such consumer products as cosmetic talcums, paper mache, and modeling compounds, in spackling, patching compounds and putties, in automotive and boat body repair fillers, and caulking compounds. The uses of talc in food products include rice coating, peanut polishing, candy molding, and salami dusting. It is also used as a filler and excipient for pharmaceutical pills, and for dusting contraceptive diaphragms. Each product carries with it a distinct and individual inhalation and/or ingestion potential of the mineral components. An estimated 30,000 tons of cosmetic-grade talc are used in cosmetic, pharmaceutical, and food products. - 21 - Talc Contamination The table belcw shews theggrincipal minerals that can be combined with talc in natural deposits. ~ MINERALS CCMCNLY ASSOCIATED WITH TALC IN NATURAL DEPOSITS Carbonates: Amphiboles : Serpentines : Others: calcite, dolomite, magnesite tremolite, anthophyllite chrysotile, antigorite, lizardite quartz, mica, chlorite, rutile, pyrophyllite 92 A 1968 study conducted by United States researchers on 22 talc sanples for cosmetic use shewed values between 8 and 391 fibrous particles, whereas a similar study on 80 industrial talc samples conducted by N.B.S. researchers^-3 indicated the presence of fibrous particles in the samples in percentages which vary from 2 to 30Z. In both cases the fraction of these percentages made up of asbestos was not specified. Research conducted in Great Britain on talc powders for various uses has shown that of the 27 samples examined, 3 contained tremolite. More complete and significant data are indicated for 20 talcs for cosmetic use and one talc for pharmaceutical use sampled in the New York area from 1971 to 1975: of the cosmetic products analyzed, 10 contained tremolite and anthophyllite in amounts varying from 0.1 to 14 wt.Z, and shewed a detectable quantity of chrysotile. (This is in conflict with Pooley who stated that no chrysotile has-been found in cosmetic talc.) In an Italian article published in 1982 , 15 samples of talc products (for industrial, cosmetic, and pharmaceutical uses) were analyzed for asbestos contamination using transmission electron microscopy and the associated analytical techniques such as electron diffraction and x-ray microanalysis. In eight of the 15 sanples, the presence of asbestos was detected; in seven cases tremolite fibers were observed and in one case, chrysotile (see Table 9). - 22 - TABLE 9. PERCENTAGE OF FIBROUS PARTICLES AND ASBESTOS FIBERS IN SCME COSMETIC TALCS. KEY: (a) 1 fiber in the particular matter (b) 1 fiber 5 u m in the particular matter (c) % asbestos fiber in the total fiber (d) 7. asbestos fiber in the particular matter, and (e) variety of asbestos (a) (b) (c) (d) (e) A 6.10.9 B 21.61.6 C ll.lil.l D 4.90.5 E 10.30.7 F 5.10.6 1.60.5 5.00.9 3.20.6 0 . 7 0 .2 3.20.4 1.80.4 <2 <2 <2 324.7 <2 103 <0.1 <0.4 <0.2 1.60.3 <0.2 0.50.2 --- Tremolite -- Tremolite Consuner talc products marketed before 1973 were variably contaminated by asbestos. In October, 1976, the Cosmetic, Toiletry, and Fragrance Association (CTFAr 7 revised their guidelines for talc and recommended that no sample containing asbestos detectable by x-ray diffraction and optical microscopy with dispersion staining should be sold. Adherence to the revised CTFA guidelines is voluntary and monitoring of samples is left to individual manufacturers. Samples of cosmetic talc products were analyzed in 1979 by the Division of Cosmetics Technology using x-ray diffraction (XRD). Simples found to be contaminated with tremolite or anthophyllite by XRD were also examined by optical microscopy (CM) to determine crystal morphology. In all cases, the amphiboles found (tremolite and anthophyllite) were present in the massive (non-fibrous) form. The level of detectability is approximately 0.1Z for tremolite and 21 for anthophyllite. None of the sanples was found to contain serpentine at a detectability limit of 1-2Z (XRD). These samples were submitted for SEM analysis and, if fibers were found, the samples were to be examined by energy dispersive x-ray analysis (EDXA) to determine the nature of any fiber-like particle detected. The results of the latter (SEM and EDXA) analyses are not known to this reviewer. No analyses of cosmetic talc have been performed by FDA since 1979. As noted previously, there are non-fibrous forms of minerals with essentially the same chemical composition as the asbestos varieties. In some cases the non-fibrous form has the same name as its fibrous counterpart; e.g., tremolite. According to the U.S. Department of the Interior, non-fibrous (non-asbestiform) tremolite is the cannon form of this mineral, vrtiile fibrous tremolite (asbestiform) is a very rare form for this mineral. - 23 - if. Asbestos As stated above, asbestos bodies can be recovered from the lungs of virtually everyone in the population, on autopsy. These observations suggest that the entire population is being exposed to asbestos. Several studies have assessed the environmental air pollution by asbestos using the transmission electron microscope (TEK) or the scanning electron microscope (SEK). European cities have shewn levels as follows: 0.1-1 ng (10_ygpfJ or ng_J) of chrysotile asbestos in English cities, 10 -104 asbestos fibers per cubic meter of air in Dsseldorf, and 0.1-10 n g ^ of chrysotile asbestos in Paris. Higher concentrations (0.1-100 ng-J of chrysotile asbestos) have been found in U.S. cities. The highest concentrations have been found in New York City (see Table 7-6). -3 Asbestos fibers have been detected in rural locations (0.01-0.1 ng m ) removed from known sources of emission suggesting the existence of background air pollution by asbestos fibers (especially chrysotile) in industrial countries. It is to be noted that an appreciation of the extent of air contamination by asbestos depends upon which of two approaches to its measurement is adopted. If the conventional practice of counting only fibers longer than 5 u m is followed, the concentrations away from imnediate industrial activities are lew or undetectable and even some of those in and around asbestos industries approach tolerable levels. But, if the concentration of smaller fibers is taken into account and particularly the mass concentrations revealed by electron microscopy, the situation changes. Up to 10 ng/nr seems to be virtually ubiquitous in urban conmunities. It is to be noted also that analysis of ambient air samples for asbestos has utilized techniques different from those used in occupational ^ circumstances because typical urban air may contain up to 100 ug/nr of particulate matter in which one is^attempting to quantify asbestos concentrations from about 0.1 ng/nr to perhaps 1000 ng/m . Thus asbestos may constitute only 0.0001 to 11 of the particulate matter in a given sample. It is difficult to make quantitative estimates of exposure to asbestos. A common unit of cumulative dose for occupational exposures is obtained by multiplying the average concentration of fibers in workplace air by the number of years that an individual worked there (full-time equivalent). The concentration of fibers in workplace air is expressed as fibers > 5 ;um long/cm , as counted by the light microscope (IK) under specified conditions ((U.S. National Institute for Occupational Safety and Health, 1977); (fibers/enr) yr. It is to be noted that cumulative exposure measures do not take into account dose rate per unit time, - 24 - duration of exposure, and ages at exposure. These three factors, particularly the third one, could be very important in determining effects on health. Another measure of exposure that allows comparison of different exposure situations is expressed as "lifetime fibers." This quantity is derived by integrating over time the product of fiber concentration in air (the only source of exposure considered here) and the intake rate. When interpreting health-effects information obtained from occupational studies, it may be necessary to convert nonoccupational exposures to equivalent occupational dose expressed in (fibers/cnr) yr. Assuming an inhalation rate of 12000ml/minutej an 8-hour work day; 5 days/week; 50 weeks/year, the amounts of inhaled fibers workers could accutriilate in one year, according to work group, are shown below. worker group exposure level duration exposure per year insulation workers (amosite, chrysotile) 15 f/ml 25 yrs 2.16 x 1010 f/yr total life-time exposure 5.4 x 1011 : British textile workers (chryso tile) 15-30 f/ml 20 yrs 2.16-4.32 x 1010 f/yr 4.32-8.64 x : amosite factory workers 35 f/ml 1.46 yrs 5.04 x 1010 f/yr 7.36 x 1010 cement workers (chrysotile, crocidolite) 9 f/ml 12 yrs 1.296 x 1010 f/yr 1.56 x 1011 Similar calculations for the general population are shown below: O If ambient air concentrations are assumed to be 10 ng/m , using the EPA conversion factor_of 30 fibers (f)/ng, the population as a whole is exposed to 3 x 10 4 f/ml. Using the further assumptions: (1) average breathing rate - 12.72 liters/min. (2) 24 hours per day, and (3) 52 weeks per year as the exposure duration; It is calculated that an individual is exposed to 2.0 x 10^ f/year. - 25 - Using the assunptions and the data generated in the baby-powdering e x p e r i m e n t TM (concentration - 8.58 f/cc during powdering; 4.38 f/cc during settling; with 13.6Z and 86.4Z, respectively, of the time - with exposure time of 43.8 minutes per week; breathing rata of 0 5.8 1/min.), exposure of a baby from baby powder could be 6.6 x 10 f/year. It is to be noted that these calculations assume that all of the talc is asbestos. If a more realistic value of 1Z asbestos is vised, the number of fibers is calculated to be 6.6 x 10* f/yr. The carcinogenic potential and the hazards of exposure to asbestos have been well documented. Also, several types of asbestos are known to be geological contaminants in talc ore. Since the accepted best index of exposure to asbestos requires counting the respirable fibers in the worker's breathing zone, a problem arises in the methodology of distinguishing asbestos fibers from talc. Characteristically, talc has a tendency to curl and stand on its edge which may result in many erroneous counts by optical microscopy. The latest USPHS/NIOSH method for counting asbestos fibers requires phase contrast microscopy at X400-500 magnification, and arbitrarily defines a fiber as a particulate with a length to width ratio of 2a 1 or greater, and a max-inum width and minimum length of 5 micrometers. This method is a crude determination of total fiber exposure because of tiie resolution limitations of optical microscopy. Most airborne asbestos fibers are less than 5 v m in length, and those that are longer nay have diameters too small to be resolved by phase contrast microscopy. With regard to the measurement of asbestos exposure from talc, some authors have stated that scanning electron microscopy (SEM) should be considered as an adjunct to the USPHS/NIOSH method when counting fibers in a dust environment. Phase contrast microscopy may suffice in an asbestos environment, but the resolution limitations of optical microscopy and the inability to distinguish rolled talc particles and talc "shards" from actual asbestos fibers will allow only a crude determination of the total fiber exposure. Other than what was presented above, it is not known whether cosmetic talc (used today) is contaminated with asbestos or asbestiform minerals, what form is involved (tremolite-fibrous or nonfibrous), or what levels of asbestos, if contaminated. In a recent (August, 1984) report`d b y the NAS Conmittee on Nonoccupational Health Risks of Asbestiform Fibers, who evaluated the human health risks associated with nonoccupational exposure to asbestiform fibers with enphasis on inhalation of outdoor and indoor air, it was concluded that nonoccupational exposure to asbestiform fibers i n air presents a risk to human health. The Conmittee made a quantitative estimate of the risk of excess lung cancer and mesothelioma that might occur in persons breathing low levels of asbestos in the air. A concentration of 0.0004 fibers/an3 was deemed reasonable to use in - 26 - such calculations because a variety of~measurements of indoor and outdoor air indicated that 0.0004 f/cm is the approximate average level that may be encountered. If a person inhaled air containing asbestos at that level throughout a 73-year lifetime, the committee's best judgement is that the lifetime risk of mesothelioma would be approximately nine in a million (range 0 to 350 per million, depending on assumptions regarding the relationship of dose to risk). Risks for continuous lifetime exposures to higher or lower levels would be proportionately higher or lower. Epidemiological data and the estimates derived from them indicate that the corresponding lifetime risk for lung cancer would be about 64 in a million for male smokers (range 0 to 290), 23 in a million for female smokers (0 to 110), and 6 and 3 in a million, respectively, for male and female nonsmokers. The risk to nonsmbkers appears greater for mesothelioma than for lung cancer. The Caimittee also emphasized the strong dependence of mesothelioma rates on time from first exposure and exposure of children to asbestos (although mainly from school exposure). (See NAS Risk Assessment - Attachment III.) The only information available on cosmetic exposure is that of baby powder use noted above. Infants exposed to asbestos from talc could be exposed to an additional amount above background of the order of 0.04 to 0.08 f/cc for approximately 2 years. This would result in an increase ofg0.05% in the cumulative lifetime exposure of 1.95 x 10f to 1.951 x 10 f, with a similar increase in the lifetime risk (e.g., 9 to 9.0045 mesotheliomas per million). However this estimate is based on a linear dose response function, assuming no dose-rate effect. Cumulative exposure measures do not take into account dose rate, duration of exposure, or age at exposure. Although the cumulative amount of asbestos would appear to be of no consequence, the estimated exposure level is 100 to 200 times greater than background. Data on acute exposures of this magnitude are not available. This memo is to request a risk assessment of the potential exposure to asbestos from use of cosmetic talc APPENDIX I Epidemiological Studies on Asbestos 1. In a follow-up study"^ of a birth cohort consisting of 10,939 men and 440 women (exposed for at least one month), dust exposure and mortality of chrysotile miners were analyzed using the ''man-years" method and the "case- and multiple-control" approach. Among men the overall excess mortality was 2% at Asbestos and 10% at Thetford Mines, which was the dustier region (see Table 2). The women, mostly employed at Asbestos, had a standardized mortality ratio (SMR) of 0.90. During the five decades, 1926-75, 4350 men died compared with 4107 expected on the basis of Quebec age- and year-specific death rates, a SMR of 1.06. There had been a net excess of 33.9 deaths at Asbestos (1.6% of the 2074.1 expected) and 208.8 at Thetford Mines (10.3% of the 2033.2 expected); SMRs of 1.02 and 1.10, respectively. Table 2 provides data on deaths of the men b y age and cause of death. Four exposure levels were used in these analyses; the mean concentrations were: low: 2.5 to 4.2; medium: 4.3 to 9.4; high: 14.4 to 23.6; very high: 46.8 to 82.6 million particles per cubic foot (mppcf). Quantitative exposure was estimated as cumulative dust exposure during the first 20 years from onset of employment. Tables 6 and 7 analyze the 3291 deaths, 20 or more years after first employment, occurring from 1951 to 1975. Comparison with Table 2 shows that, although 26.3% of all observed deaths were thus excluded from the analysis because they occurred before 1951 or within 20 years of first eqoloyment, over 90% of deaths from pneumoconiosis and from lung cancer were included, and percentages were also high for malignant neoplasms of other sites (except the larynx) and stroke. When account is taken only of length of service (Table 6), trends of risk, as measured by the ratios of observed to expected deaths-- that i s , SMRs in which the standardization was by both age and era-- were generally without clear trends, probably reflecting differences in selection and other factors. Exceptions were deaths attributed to pneumoconiosis and accidents: of the 42 deaths from pneumoconiosis, 36 were in men with at least 20 years' service. TABLE 2. Deaths of , by year, age, and certified cause of death Cause of death (ICD code*) Age at death Year of death Before 1946 1946-55 1956-65 1966-75 Total All causes Pneumoconiosis (523-524) Malignant neoplasms: Lung (162-164) Oesophagus and stomach (150-151) Colon and rectum (152-154) Other abdominal (155-159) Larynx (161) <45 45-64 >65 <45 45-64 65 <45 45-64 >65 <45 45-64 >65 <45 45-64 >65 <45 45-64 65 <45 45-64 564 136 54 754 >| J111 438 842 702 2093 L 4463 -- -- 389 1227 1616 1 0 01 1 -\ 1 6 10 13 30 V 46 -- -- 7 8 15 -) 2 22 6 0 12 51 72 135 v 250 -- -- 20 89 109 ,J 5 2 1 __ 8 4 22 34 17 77 V 154 -- -- 12 57 69 ./ 4 1 0 __ 5 J1 8 20 18 47 V 88 -- -- 6 30 36 5 2 1 __ 8 ) 1 6 15 14 36 V 80 J-- -- 6 30 36 0 0 0-- 0 y2 5 6 5 18 2i \ - 2a - Other (140-148; 160; 165-205) Heart disease (400-443) Respiratory tuberculosis (001-008) Other respiratory (470-522; 525-527) Cerebrovascular (330-334) Accidents (800-999) All other known causes Cause not known 45 45-64 65 45 45-64 65 45 45-64 65 45 45-64 65 45 45-64 65 45 45-64 65 45 45-64 65 45 45-64 65 12 4 1 -2 28 52 48 -- -- 28 101 28 25 18 __ 25 154 355 285 -- -- 166 487 118 30 1 20 31 27 7 -- - - 5 9 60 3 0 5 12 28 37 -- -- 17 72 6 23 4 12 42 38 -- -- 39 122 170 41 17 18 44 71 51 -- -- 9 40 114 23 9 25 82 112 82 -- -- 67 155 40 1 0 3 16 19 15 -- -- 6 25 *Code in the 7th revision of the International Classification of Diseases 17 130 129 71 819 653 149 85 14 63 82 89 11 96 161 228 184 49 146 301 222 41 53 31 -3- TABLE 6. Deaths, by cause, in relation to duration of service Cause of death (see table 2) Length of gross service <yr) Very short ( 1) 0 SMR Short (1 5) Medium (5- 20) 0 SMR 0 SMR Long ( 20) 0 SMR Complete cohort 0 SMR All causes Pneumoconiosis Malignant neoplasms: Lung Oesophagus and stomach Colon and rectun Other abdominal Larynx Other Heart disease Respiratory tuberculosis Other respiratory Cerebrovascular Accidents All other known causes Cause not known 885 1.07 629 1.09 679 1.15 1098 1.07 3291 1.09 1 1.15 3 5.00 2 3.39 36 34.62 42 13.55 47 0.97 29 0.83 50 1.37 104 1.61 230 1.25 37 1.30 25 1.27 18 0.91 50 1.47 130 1.27 22 0.78 13 0.67 23 1.16 21 0.62 79 0.78 20 1.98 12 0.92 14 1.04 21 0.90 67 0.98 6 1.48 5 1.75 1 0.34 4 0.78 16 1.07 67 1.12 43 1.04 48 1.13 79 1.08 237 1.09 370 1.06 251 1.02 287 1.15 424 0.97 1332 1.04 7 0.62 7 0.89 21 2.68 22 1.56 57 1.39 29 0.66 46 1.52 22 0.71 59 1.12 156 0.99 62 0.95 49 1.12 50 1.13 82 1.11 243 1.07 52 1.36 38 1.32 37 1.18 56 0.96 183 1.17 130 1.03 94 1.07 94 1.05 132 0.85 450 0.98 35 14 " " 12 8 69 -- Columns headed 0 give the nurbers of deaths of men, 20 years or more after first employment, occurring during 1951-75; figures under headings SMR are ratios of deaths observed to those expected on basis of male mortality in Quebec. > -4 - TABLE 7. Deaths, by cause, in relation to dust concentration (a) Gross service: less than one year Cause of death (see table 2) Accumulated dust exposure (see table 4) Lew 0 SMR Medium 0 SMR High 0 SMR Very high 0 SMR All causes Pneumoconiosis Malignant neoplasms: Lung Oesophagus and stomach Colon and rectum Other abdominal Larynx Other Heart disease Respiratory tuberculosis Other respiratory Cerebrovascular Accidents All other known causes Cause not known 311 1.12 00 19 1.17 12 1.24 5 0.52 3 0.48 2 1.45 20 0.99 136 1.15 4 1.05 11 0.74 25 1.14 16 1.30 45 1.06 13 * -- 260 1.13 00 12 0.91 12 1.50 7 0.88 6 1.17 2 1.77 23 1.38 112 1.15 1 0.32 10 0.82 18 0.98 19 1.86 29 0.82 9 162 0.95 1 5.66 9 0.88 9 1.54 6 1.03 4 1.04 1 1.19 13 1.05 63 0.87 1 0.44 3 0.33 9 0.67 10 1.27 26 1.00 7 152 1.03 00 7 0.80 4 0.81 4 0.81 7 2.12 1 1.40 11 1.04 59 0.94 1 0.48 5 0.66 10 0.90 7 0.90 30 1.33 6 See footnote to table 6 -5 7(b) Gross service: one year, less than five years Cause of death (see table 2) Accumulated dust exposure (see table 4) All causes Pneumoconiosis Malignant neoplasms: Lung Oesophagus and stomach Colon and rectun Other abdominal Larynx Other Heart disease Respiratory tuberculosis Other respiratory Cerebrovascular Accidents All other known causes Cause not known See footnote to table 6 low 0 SMR 141 1.12 00 5 0.66 8 1.83 2 0.46 2 0.70 2 3.17 14 1.53 51 0.95 00 10 1.49 18 1.83 11 1.89 16 0.83 2 Meditci 0 SMR 246 1.09 3 12.80 13 0.95 7 0.90 4 0.52 7 1.37 1 0.89 16 0.98 99 1.03 5 1.64 16 1.34 17 0.98 12 1.10 40 1.16 6 High 0 SMR 130 1.12 00 6 0.82 4 1.03 4 1.04 2 0.75 1 1.71 9 1.08 59 1.19 1 0.61 10 1.66 10 1.19 3 0.47 16 0.91 5 ---- Very high 0 SMR 112 1.04 00 5 0.78 6 1.64 3 0.82 1 0.41 1 1.90 4 0.52 42 0.92 1 0.65 10 1.78 4 0.49 12 2.14 22 1.33 1 7(c) Gross service: five years, less than 20 years Cause of death (see table 2) Accumulated dust exposure (see table 4) All causes Pneumoconiosis Malignant neoplasms: Lung Oesophagus and stomach Colon and rectum Other abdominal Larynx Other Heart disease Respiratory tuberculosis Other respiratory Cerebrovascular Accidents All other known causes Cause not known Low 0 SMR 161 1.10 00 13 1.41 6 1.21 4 0.81 6 1.78 00 9 0.85 66 1.06 3 1.55 5 0.64 8 0.73 8 1.07 29 1.30 4 Medium 0 SMR 194 1.07 00 14 1.22 6 0.99 7 1.14 3 0.72 00 19 1.44 81 1.05 9 3.94 5 0.51 13 0.94 10 1.06 21 0.77 6 High 0 SMR 170 1.22 1 7.36 7 0.83 5 1.07 9 1.92 3 0.95 1 1.44 11 1.10 72 1.22 5 2.64 5 0.69 14 1.34 10 1.33 25 1.17 2 Very high 0 SMR 154 1.26 1 8.42 16 2.17 1 0.25 3 0.74 2 0.75 00 9 1.03 68 1.31 4 2.28 7 1.12 15 1.67 9 1.28 19 1.01 0 a See footnote to table 6  -7- 7(d) Gross service: 20 or more years Cause of death (see table 2) Accunilated dust exposure (see table 4) All causes Pneumoconiosis Malignant neoplasma: Lung Oesophagus and stomach Colon and rectum Other abdominal Larynx Other Heart disease Respiratory tuberculosis Other respiratory Cerebrovascular Accidents All other known causes Cause not known Low 0 SMR 367 0.98 4 10.49 28 1.21 17 1.36 7 0.56 10 1.18 2 1.07 33 1.23 138 0.87 5 1.01 18 0.92 32 1.15 16 0.82 52 0.92 5 Medium 0 SMR 253 0.89 7 23.75 20 1.08 6 0.64 4 0.43 3 0.46 1 0.69 16 0.79 115 0.95 5 1.31 10 0.68 18 0.89 19 1.16 29 0.68 0 High 0 SMR 183 1.07 5 30.10 24 2.20 8 1.44 1 0.18 2 0.51 00 11 0.90 77 1.06 3 1.27 14 1.62 10 0.84 9 0.85 18 0.70 1 Very high o a 295 1.50 20 101.52 32 2.65 19 2.89 9 1.39 6 1.35 1 1.03 19 1.36 94 1.12 9 3.06 17 1.74 22 1.58 12 1.01 33 1.10 2 See footnote to table 6 -8 - Among those in the very short and short service groups (those with gross service of less than 5 years (Tables 7(a) and (b))), careful study of differences between groups according to severity of exposure showed no consistent pattern. Table 7(c) deals with men with gross service between 5 and 20 years; their service had also been completed before the start of the study interval. There were fairly consistent trends for higher SMRs the greater the dust exposure for total mortality, for pneunoconiosis (although based on only 2 deaths), heart disease, and stroke. In addition SMRs were highest in the group with the most severe exposure, for lung cancer and "other" respiratory diseases. The authors stated that all these findings are understandable as pulmonary fibrosis could well contribute directly to cardio-pulmonary disease and, in addition, might adversely affect the probability of survival in any life-threatening condition. Table 7(d) concerns 3105 men with at least 20 years service, and an average of almost 32 years of employment. Here the most severely exposed had the highest SMR not only for total mortality but for all listed causes otter than laryngeal cancer and accidents. Further, the tendency for increased risk with each augmentation in exposure was completely consistent for pneumoconiosis and for heart disease, and positive, although rather less consistent, for total mortality, lung cancer, respiratory tuberculosis, and other respiratory diseases. The otter form of a priori analysis, with exposure calculated to age 45 at which age the study interval started, is summarized in Table 8. The total nurber of deaths observed in this analysis was 3448 (77.3% of the deaths), with SMR * 1.07, very close to that for all causes in the complete cohort as seen in Table 6. Indeed, for each cause of death, SMRs from both methods of analysis were always close. Clear trends were found for SMRs to be higher the heavier the exposure, for total mortality, pneumoconiosis, lung cancer, cancer of the colon and rectum, respiratory tuberculosis, otter respiratory diseases and stroke. The trends were most clear-cut in pneumoconiosis and lung cancer. The lung cancer trend was essentially linear as shewn in the Figure be lew, where exposures of 30 mppef-year or more have been broken down further, into 4 classes. The trend for respiratory tuberculosis was also consistent in the two areas, but not those for the other causes listed. -9 - Dust exposure and mortality in chrysotile mining, 1910-75 TABLE 8. Deaths, by cause, in relation to dust exposure accumulated to age 45 Cause of death (see table 2) Dust exposure (tnpcf-y) accumulated to age 45 <30 0 SMR 30 < 300 0 SMR > 300 0 SMR All causes Pneumoconiosis Malignant neoplasms: Lung Oesophagus and stomach Colon and rectum Other abdominal Larynx Other Heart disease Respiratory tuberculosis Other respiratory Cerebrovascular Accidents All other known causes Cause not known 1668 1.02 5 2.98 91 0.93 68 1.22 34 0.62 37 1.00 9 1.11 129 1.10 696 1.06 21 0.94 71 0.84 119 0.96 104 1.28 237 0.95 47 1138 1.04 12 10.81 81 1.18 42 1.14 28 0.77 21 0.84 6 1.08 83 1.06 463 0.99 25 1.67 55 0.98 86 1.08 60 1.00 154 0.92 22 mmmm 642 1.30 27 54.00 70 2.25 26 1.58 18 1.11 10 0.88 2 0.81 38 1.08 240 1.14 15 2.20 40 1.62 46 1.32 33 1.16 74 0.99 3 See footnote to table 6 L o n g c a n c e r S M R t In re la tio n to d a r t e x p o s u re a c cu m u la te d ta a g e 4 S . T h e lin t b a s b e e n f in e d b y m m o d ifie d le a s t- s q u a re s te c h n iq u e . - 10 - Table 9 shews deaths from lung cancer. TABLE 9. Deaths from lung cancer in relation to dust exposure and smoking habit Smoking habit Dust exposure (npcf.y) accumulated to age 45 <30 0 SMR 30 < 300 0 3iR > 300 0 SMR All 0 SMR Non-smokers Moderate smokers Heavy smokers All smoking habits 5 0.18 73 1.14 13 2.12 91 0.93 6 0.36 8 1.24 19 0.38 64 1.35 52 2.31 189 1.41 11 2.39 10 4.50 34 2.63 81 1.18 70 2.25 242 1.23 See footnote to table 6 Table 10 summarizes the findings from the Miettinen approach-- that is, more than one control for each case, excluding those for smoking habit; the - 11 - TABLE 10: Dust exposure in deaths from pneunoccniosis and from malignant disease and in controls nunbers of deaths areas table 2 (but see Dust exposure (npcf.y) accumulated up to nine years before death of case 30 30 300 300 1000 1000 All Pneunoconiosis Deaths 79 Controls(3)* , 63 49 Relative Risk+ 1 1.65 Lung cancer Deaths** Controls(3) Relative risk 89 73 333 243 1 1.12 Cancer of oesophagus and stomach Deaths 74 41 Controls(2) 143 105 Relative risk 1 0.75 Cancer of colon and rectun Deaths 39 Controls(2) 88 Relative risk 1 29 70 0.93 Other abdominal cancers Deaths 43 Controls(2) 83 Relative risk 1 25 46 1.05 Cancer of larynx Deatiu 13 6 Controls(3) 36 21 Relative risk 1 0.79 13 21 5.57 56 127 1.65 22 53 0.90 13 15 1.96 7 26 0.52 2 5 1.11 17 5 30.60 46 138 -- 27 32 3.16 245 735 17 7 4.69 154 308 7 3 5.26 88 176 5 5 1.93 80 160 -- 0 1 0.00 21 63 selecting controls is described in text; those reported here were not matched for smoking habit. +Risk calculated by method of Doll in relation to those with exposure less than 30 npcf .y. **Excluding five deaths coded to 162-164, but found to be due to malignant mesothelioma. - 12 - rurisers of deaths are as in Table 2 (but see footnote ** in Table 10) because there were no restrictions on the start of the study interval. Four groups of dust exposure are distinguished, and the data are presented without regard to the matching. Matching was taken into account in the full analysis, hcwever, vrtiich generally confirmed the tendencies shown in the two a priori approaches and relative risks were fairly similar at Asbestos and Thetford Mines. Linear dose-respcnse relations have been fitted (Berry, G . , unpublished) for lung cancer (without regard to smoking habits); using the data on which Table 10 is based, but taking into account the matching of controls for each case in terms of date of birth and place of employment, the fitted line was: Relative risk * 1 + 0.0014 (mppcf-y) the standard error of the estimate of the slope being 0.0005. The linear fit accounted for X , with cue degree of freedom, of 21.37, leaving only a very low value for deviations from linearity. There were in all 11 deaths (including one women) from malignant mesothelioma observed to the end of 1975. All were of the pleura and appeared to follow a clear exposure trend. The authors concluded that essentially linear relations have been shown between indices of exposure, based on dust concentration (mppcf) multiplied by length of service, and lung cancer, pneumoconiosis, and total mutter of deaths. Because of concern regarding the risk from concentrations of asbestos dust nearer current standards, the data for the 1904 men in the cohort employed for at least 20 years in the low and medium dust exposure groups were analyzed. The concentrations to which these men were exposed (Table 4) averaged 6.6 mppcf, or perhaps 20 f/ml. The total mortality was 620 deaths, and the SMR was 0.94. The authors stated that this might be a true healthy worker effect, but not all cause-specific SMRs were below unity. There^were excesses foa: pneumoconiosis (10.3 excess deaths, leading to YT on the usual basis, and.id.th one degree of freedom, of 159.27), for lung cancer (6.4, X z = 0 .9 9 ); cancer of esophagus and stomach (1.1, Yr - 0.06); "other" cancers (1.7, X 2 = 0.06); respiratory tuberculosis (1.3, YT * 0.17); and stroke (1.8, YT - 0.07). Apart from pneumoconiosis, these values of X^ are so lew, even for lung cancer (where the associated p-value is 32.0%), that the observed excesses do not reach conventional levels of statistical significance. Moreover, the lung cancer SMR for the low dust exposure roup (1.21) was higher than that of the medium exposure group (1.08); the authors stated that only the greatly enhanced SMRs for those with high and very high exposure allow the conclusion that there was a response to exposure. Nevertheless, the lung cancer SMR for all 1904 men was 1.15, in close conformity with that which might be predicted from the figure (about 1.20) or the relative risk of 1.16 from the fitted line (Berry, G . , unpublished). It is noted that exposure to asbestos was presented as dust exposure in mppcf. The current trend is towards providing information in terms of fibers rather that dust counts, although there is an almost coup lete lack of epidemiological data based on fiber measurements. The problem with this is there is no easy conversion. The authors note that studies shewed that, at relevant dust levels, the conversion factors range from about 3 to 7 fibers/mL for each mppcf; although other data point to a lower range, 1 to 5. This is a recurring problem. OONCLUSION: The study suggests an overall small increase in lung cancer associated with asbestos exposure. A consistent dose-response gradient was observed: SMR of 0.9 (lew exposure 30 mppcf-yrs) to 2.3 for highest exposure category ( 300 mppcf-yrs.). 2. In this cohort study*of chrysotile miners and millers, only workers with at least 20 years of employment were chosen. Dust measurements after 1969 were reviewed but no quantitative exposure data were provided. Fiber concentrations for various areas of the mills and mines ranged from 9 to 36 fibers longer than 5 micrometers/ml of air. Table 4 shews the various causes of death observed in 130 deaths. - 14 - TABLE 4: Categorization of causes of death according to death certificate information compared with categorization following review of all available medical records and pathological material in 130 cases Underlying Cause of Death as Categorized on Certificate of Death, (DC)* Cause of Death as Ascertained (BE)* All Asbestosis All Lung Other Including Othe: N. Cancer Mesothelioma Cancer Pneunoconiosis Causi Lung cancer Mesothelioma All other cancer Asbestosis All other causes Totals 25 1 18 24 62 130 18 1 3 22 32 1 17 14 11 1 21 17 2 7 60 69 *B - best evidence DC - death certificate cause The expected mortality experience was calculated using national rates of Canada (Table 5). TABLE 5: Expected and Observed Deaths Among 544 Asbestos Miners and Millers, Thetford Mines, Quebec, Jan.-Nov., 1961 ADG, 1977* Total Total deaths Total cancer all sites Lung cancer Pleural mesothelioma Cancer of the gastrointestinal tract All other cancers Total Noninfectious pulmonary diseases Asbestosis All other causes Person-years Exp. 159.9 36.7 11.1 ** 9.5 16.1 6.7 ** 116.5 Obs. 178 49 28 1 10 10 30 26 99 7,408 0/E 1.11 1.34 2.52 -- 1.05 0.62 4.48 -- 0.85 Canadian white males. **Death rates not available but these have been rare causes of death in the general population. - 15 - Asbestosis and lung cancer were major causes of death among these workers. Table 7 details the mortality experience according to time from onset of exposure and shows an increase in mortality between 30 and 50 years from first exposure to asbestos. There is, however, little excess mortality after 50 or more years from first exposure. The authors stated that perhaps this occurred as individuals at high risk of death (because of their particular susceptibility or because of other associated factors, as cigarette smoking) may have died preferentially in earlier years. TABLE 7: Ratios of Observed to Expected Deaths Among 544 Asbestos Miners and Millers, Thetford Mines, Quebec, Jan.-Nov. 1961 Aug. 1977 Ratio of Observed to Expected Deaths (Number of Deaths in Parentheses) Years from Onset of Employment 20-29 30-39 40-49 50 + Total deaths Total cancer Lung cancer Noninfectious pulmonary diseases (incl. asbestosis) Causes other than cancer or noninfectious pulmonary diseases 0.65 (8) 0.00 (0) 0.00 (0) -- (4) 0.42 (4) 1.27 (60) 0.98 (ID 1.94 (7) 5.29 (9) 1.16 (40) 1.28 (66) 1.95 (24) 4.19 (16) 3.64 (8) 0.91 (34) 0.91 (44) 1.30 (14) 1.67 (5) 3.60 (9) 0.59 (21) Number of deaths Asbestosis Mesothelioma Person-years of observation 3 0 1,623 8 0 3,067 8 1 1,805 7 0 914 - 16 - CONCLUSION: The study results indicate that a small increase in lung cancer risk occurs as asbestos exposure increases, but the lack of quantitative exposure data makes it difficult to evaluate this association. 82 3. Mortality of Italian chrysotile asbestos workers was studied using two different reference groups. In the first analysis the observed Tauber of deaths was compared with the expected number in the population of all Italy. Person-years of observation were calculated according to the method of Case and Lea"53 and multiplied by age-specific death rates to compute the expected timber of deaths. Secondly, a case control study of carcinoma of lung and larynx was undertaken. Only two exposure categories were considered, the first with cumulative exposure up to 100 fiber-years and the second, all those with a cumulative exposure greater than 100 f/yr. (The lower of the two exposures corresponds to the British standard of 2f/cc for 50 years' working life). In Table 3 the mortality of the cohort is divided into 2 groups according to period since first employment: deaths occurring up to 19 years since first employment and deaths occurring over 20 years since first employment. The overall mortality compared to the national figures is also shown. One death from pleural mesothelioma occurred 35 years after starting employment in a worker with 33 years exposure. A significant excess of laryngeal cancer is seen when examining mortality over the whole period of observation. Four of these deaths occurred after 20 years since first employment. Two of the six workers dying from laryngeal cancer had less than one year of exposure. There is also a marked excess of respiratory diseases, both influenza and pneumonia and "other" respiratory diseases, consisting chiefly of chronic obstructive lung disease. Asbestosis was reported in 9 cases. Mortality from lung cancer is shewn in Table 4. No deaths were observed before 1961, nor did any deaths occur from this cause in subjects under the age of 50. However, among those of 50 years or more, the SMR rises to 111 in the quinquennium 1966-70 and reaches 226 between 1971 and 1975; for men of all ages it is 206 in the same period. - 17 - TABLE 3: Nurrber of deaths observed and expected by period since first exposure, and cause. (Period of observation from 1946 to 1975) Period since first exposure (yr) over Total Up to 19 20 and Person-years observation 12683 8776 21459 Cause of death Observed Expected SMR Observed Expected SMR Observed Expected SMR All causes 112 All malignant neoplasms (140-205) Lung and pleura (162-163) Larynx (161) Gastrointestinal (151-159) Other sites 12 1 2 4 5 Non-tnalignant respiratory diseases (470-527) Influenza and pneumonia (480-483) Other respiratory diseases(470-475, 500-527) Asbestosis (523.2) 12 8 4 2 TXberculosis of the lung (001-008) Cardiovascular diseases (400-468) Cirrhosis of the liver (581) Accidents (800-999) All other causes Unknown 13 22 9 30 9 5 / A AUTlWt / A rtl----------------- 54.2 10.0 1.7 0.4 4.8 3.1 2.3 1.6 0.7 -- 3.9 14.8 2.1 7.8 13.3 mm-- 207** 120 59 500 83 161 220 38, 10+ 4 15 9 522** 500** 20 4 571** -- 16 7 333** 149 429** 385** 68 *" 5 100 22 15 17 3 160.2 37.0 8.7 1.5 14.5 12.3 11.8 4.6 7.2 -- 3.3 67.7 7.8 9.5 23.1 +These nunbers include one suspected case of mesothelioma of the pleura Figures in parentheses are ICD (7th Revision) code timbers 137** 332 103 50. 115 11+ 267 6 103 19 73 14 214.4 47.0 10.4 1.9 19.3 15.4 169* 87 32 12 222** 20 --9 152 148** 282** 158 74 18 122 31 45 26 8 ` 14.1 6.2 7.9 -- 7.2 82.5 9.9 17.3 36.4 155** 106 106 316* 98 91 227** 194* 253** -- 150** 148* 313** 260** 71 - 18 - TABLE 4: Cbserved and expected deaths from lung cancer (162-163) by age and calendar time Age Calendar years of follow-up 1946-60 1961-65 1966-70 1971-75 1946-75 Up to 49 50 and over All ages Observed Expected SMR Observed Expected SMR Observed Expected SMR 0 0.5 -- 0 1.7 -- 0 2.2 0 0.2 -- 1 1.6 63 1 1.8 56 0 0.3 -- 3 2.7 111 3 3.0 100 0 0.3 -- 7* 3.1 226 7* 3.4 206 0 1.3 -- 11 9.1 121 11 10.4 106 *These rtmbers include one suspected case of mesothelioma of the pleura Table 5 shows the distribution of the deaths of men with lung cancer and their controls in the two exposure categories, in the upper part of the table, and the deaths from laryngeal cancer with their controls, in the lower half of the table. Ten of the deaths from lung cancer are in the higher exposure group with a relative risk of 2.89. However, tests of the significance of the association of lung cancer and high exposure gave a two-tailed P value of 0.18, thus demonstrating no statistically significant difference between the proportion of cases and controls reaching the higher exposure level. Nor is there a statistically significant excess of laryngeal cancer in the higher exposure categories (relative risk 3.33, two-tailed P value 0.28), although all but one of the deaths occurred in this group. - 19 - TABLE 5: Distribution of patients with lung and laryngeal cancer and their matched controls according to cumulative dust exposure. Subjects Dust exposure Up to 100 fibre/yr 101 and over fibre/yr Lung cancer Controls Relative risk Laryngeal cancer Controls Relative risk 2 22 1 1 12 1 10+ 38 2.89* 5 18 3.33** reported in death certificate as "cardiac failure" and one suspected case of mesothelioma of the pleura. *two-tailed p value 0.18 **two-tailed p value 0.28 Table 7 shows the distribution of the whole cohort according to the selected exposure categories. For this analysis, workers included in the higher exposure category contributed to person-years observation in the lower category "up to 100 fibre/years" from the date of first employment to the date they reached the emulative dust exposure of "more than 100 fibre/yr," after which they contributed to the higher category. The mean value of emulative dust exposure in the higher category was about five times that in the lower (75 fibre/yr compared with 376 fibre/yr). About two-thirds of the cohort reached the higher exposure category. In Tables 7 and 8, man-years from 1 January 1946 only are included in the total. Thus, those who had accuiulated a dose of 100 fibre/yr b y 1946, immediately entered the higher exposure category. The age-standardized death rates and the associate measure of risk for overall mortality and some selected causes of death are shewn in Table 8. The relative risk for lung cancer obtained by examining the whole cohort (2.54) is similar to that calculated for the case control study (2.89, Table 5). A higher death rate for laryngeal and gastrointestinal cancer is also seen in the more highly exposed group, although comparison with the national statistics showed no - 20 - excess for gastrointestinal cancers. Non-malignant respiratory diseases, including asbestosis, tuberculosis and cardiovascular diseases, showed an increase in relative risk, whereas death rates for all other causes were almost equal in the two exposure groups. TABLE 7: Distribution of workers according to cumulative dust exposure. Period of observation from 1946 to 1975 Dust exposure as fibre/yr Up to 101 and over Unknown 100 fibre/yr fibre/yr Mean value within categories Number in study Person-years observation 74.7 927* 8365 376.2 611 12976 -- 6** 118 rr---- : irrm--- fibre/yr" before they had reached such cumulative exposure. Person-years are additive, whereas number of workers are not. **Including 4 dead - 21 - TABLE 8: Crude and age-standardised death rates per 1000 person-years and relative risks by selected causes. emulative dust exposure Cause of death Up to 100 fibre/yr Death rate 101 and over fibre Death rate Relative risk* Crude Age-standardised Crude Age-standardized All causes 11.72 13.31 Lung cancer (162-163) 0.24 Laryngeal cancer (161) 0.12 Gastrointestinal cancer (151-159) 0.48 Non-malignant respiratory diseases excluding influenza and pneumonia (470-475, 500-527) 0.48 Tuberculosis of the lung (001-008) 0.48 Cardiovascular diseases (400-468) 4.06 All other causes 5.86 0.28 0.14 0.57 0.46 0.46 4.68 6.60 *Based on age-standardised death rates 17.73 0.77 0.39 1.16 16.73 0.71 0.36 1.09 1.39 1.08 6.47 6.47 1.28 1.10 5.94 6.24 1.26 2.54 2.57 1.91 2.21 2.39 1.27 0.95 CONCLUSION: The gradient of risk for lung cancer with time since onset of exposure (SMR 0.6 for < 20 years vs. 1.2 for > 20 years) and calendar tine (SMR 0.6 for 1961 - 1 ^ 5 vs. 2.1 for 1971-1975) was observed. Significantly higher risk was noted only for laryngeal cancer. Increased relative risk for lung cancer (2.9) and laryngeal cancer (3.3) was found when case-control groups were compared by exposure level. - 22 - MattflEty4. of workers nanufacturing friction materials using chrysotile was studied03 on a population of 13A60 workers. Exposure conditions are shown in Table 1. Table 1 Mean concentration o f asbestos in air Ifim l) P erio d Pre-1*>31 1932-V) IV5I-09 1970-TV O ffice/ la b o ra to ry 10-20 <0-5 <0 5 <0 5 S to ra g e ! ( i rin din g d istribu tion >20 2-5 0 5~t >20 5-10 2-5 0 5-1 F orm in g >20 2-5 1-2 0-5-1 *H The observed mortality was compared with that expected, based on i Jsex-, age-, and period-specific death rates for England and W a l e s ^ t using the subject-years method. Attention was restricted to the period following 10 years exposure, and follow-up was to the end of 1979. In addition to mortality from all causes, the separate causes of death considered were cancer of lung and pleura, cancer of the gastrointestinal tract, and all other cancers. Table 7 shows the total mortality. Apart from 10 pleural mesotheliomas there was no sign of any excess mortality. fdhlv 7 C run mi) h s c r \ e J n r n i e i / i n le i l i n o r i d i l i a f t e r I d h< n h r \i e x p o M ire I \ u m h e i o f p le u r a l n ie a ith e h o m a s h ille d in parenlhese\l ( u u s r o f truth \<> \u b t c r ur * \trfi *4*4 104 ta t W rwm*M m s *\M in \H ia u x s 1 u n ftjm j picui tU jn u 'r ( M s tr o tn io ltr u ! vjmi-r <Mhcr can crr( )ih.-r nbs |m 1" 1 (* nn *? turn / 1r 1K 1VI * iu 7 ; H** " HO** 4 ( tbs Jvni *i2> .Ml b tr v s it 11 * N t (1 :;y * Whirl the subjects were divided into groups according to duration of exposure, there was still no sign of excess mortality nor of any trend in mortality with duration of employment. Dividing the subjects according to the period of first employment again shewed no excess mortality apart from the pleural mesotheliomas. This applied even to those with 30 years' follcw-up who were first employed before 1950, when dust levels were high (Table 1). Anoc"8eaths from other cancers, there were 2 in men due to cancer of the larynx (3.6 expected). Eight of the women died of cancer of the ovary (8.1 expected), and 22 of cancer of the breast (24.4 expected). The mortality experience of workers who completed 10 years' service is shown in Table 8. I .it'll.- S (</( > h \ e r \ u r til I i / n - i t c . l m o r m l t n n f l e r i u m p l e t i n v I I I i cun nirm / i > H t m n f > lilit'r III i itr* \i * w ifrtet t-\t a r ' ( < m \ f itt i t f u i h > \ l l V.lllM. N 1 u h L .iiKi p k t i r . i l u i u c r ( i A iio m k N ttn .il c.tik i r ( )tiii t i .i i h c r s * < M III f H U M n rl i n 1 4 M 4 2 / -SHI Oh\ t \r I S ' |W ' 1 : :i ' Ih l i : '> i7 i ^ m f.'MS'iVO ( *h\ / 17 \M ~ 2* :i 4S<i x r4 KX 2> 2 ; u 4 n il-iO * 2 " < i /% 14 II 1< \ 11 / / :i ' ti ~ 1X 4N U1 A l-- ( f lf ~i 2` N 14 N' rv> 22 N* "" i ' <J Except for deaths from mesothelioma, there was no excess in this ^ group, even 10 years after coupleting 10 years' employment. A - similar result was obtained vhen restricting attention to those who had completed 20 years' exposure. ;; -V A n additional 187 deaths have occurred since the original analysis. Only one of 40 deaths in women and 12 of 147 in men were due to lung cancer. One of the men certified as dying from pleural mesothelioma was 50 and had worked at the factory for two weeks in 1960 (when aged 29) as a grinder exposed to chrysotile (only known asbestos exposure). With regard to mesothelioma, the cases observed here were analyzed in a case-control study using tide method of Liddell, et al. The effect of exposure to crocidolite was examined. Four matched controls were chosen for each mesothelioma, where matching was for (1) sex, (2) year started work in factory ( 1 year), (3) year of birth ( 4 years), (4) survival up to time of death of mesothelioma, and (5) employed at factory during crocidolite period for same time as case. Eighty percent of those dying of mesothelioma had worked on the crocidolite contract compared with only 81 of the controls. Those wittffeteothelioma, however, had also been exposed to higher levels of^Sjgrsotile than the controls; 90Z had been exposed to more than 5 f/u^dUipared with 25Z of the controls. The confounding effect of exposure to chrysotile was eliminated by considering only cases of mesothelioma and their controls who had been exposed to chrysotile at a level of at least 5 f/ml. This left 6 cases with 10 controls. Five of the 6 had had definite crocidolite exposure. A case-control study of deaths due to lung cancer was carried out for males had started work before the end of 1960 and who survived for at least 10 years after start of exposure. There were J8L- - 24 - ldo <h&ths fran lung cancer satisfying these criteria, and three controls were chosen for each case, matched for: (1) year started at factory; (2) date of birth; and (3) survival up to time of death from lung cancer. Within the restricted set of men there were 86 who had died of gastrointestinal cancer, who were also included in this study (without additional controls). Each occupational history was integrated with respect to time to give the cumulative exposure up to the date of death for the cases, and for controls up to the date of death of the corresponding case of lung cancer. The total duration was also calculated. These two measures were also evaluated up to 9 years before the above dates, on the basis that recent exposure is irrevalent to the risk of lung cancer. A fifth measure evaluated was the cumulative dose weighted by the H m > elapsed since the exposure occurred. This measure was evaluated up to the date of death and attaches most importance to the earliest exposure. The distribution of duration of exposure and emulative exposure to death are given in Tables 13 and 14. Ijhle Il / ut> i \ tr th u ii n iis J u r a t i o n n l e x p o s u r e u p l o death i h i f u t t n n <t 1 X(U>\utc \ear\i iv o M 1 -4 M s g li |*> g us V t>t w iftfi'i t KMIMIN "4 Mh -' / u*nr t sr\ -*> 2*t i' h* i t i H u 'rx H' .' 4 g > 11 V' < raion una </ffl r r 1 <11 0 Uh (1 M 1O' 0 N' l M A W nm om ui tun et 1 tit 1> 1 4^ 1 'h H g* 1.iblc 14 /> t\tri*mt/onx o\ (u m t t h i u v r t \ p o \ u r r nxhtith C u m u ia m e exposure < t-\ m lt o-g lift-4M so. MM IIIKlVl rirai S o o f \ u b f e ri> t nntruLs n: IM 40 IS Mr l ttntt ta m e n Yf M s mv (iastroinievnmii canert 40 g l Wt O dds-ratios Lune tan. e t \ CU 0 7M 0 h 1)KM (t u s i n infettino/ cancer 1(II 1 IK 0 0 :4 B jrn (ft u m ir o ls -v carv m l luri|c c a n c e l ) i n t o m u t i o n a v a ila b le m d i m lev e l* w av in M ifh c ie m t o c a lc u la te c u m u la tiv e e x p o s u re The odds ratio, i.e., the approximate risks of cancer, relative to the lowest exposure group, are also given. For lung cancer there is no indication of an increased risk with either duration of exposure or cumulative exposure. For gastrointestinal cancer, there is no sign of an increased risk with cumulative exposure, and although there appears to be a trend with duration of exposure up to 20 years, this trend is not supported by - 25 - 9T -f T T ' the riCKers with more than 20 years' exposure and could have occurred by chance. There was also no sign of increased risk with duration of exposure or with emulative exposure calculated to nine years before death or with the measure of exposure weighted by elapsed time (tables not given). Restricting the analysis to cases who survived for at least 15 years after first exposure also did not shew any dose-response relationship. For lung cancers, a linear relationship between relative risk and cumulative exposure was fitted using methods appropriate to matched data. The coefficient was estimated as 0.00058 per fiber-year/ml. That is, for a e m u l a t i v e exposure of 100 fibers-years/ml, the . .relative risk was estimated as 1.06; the upper confidence limit was 1 80 CONCLUSION: No gradient of risk was observed with quantitative exposure level? No evidence of excess mortality due to cancer at any site, except : mesothelioma, even when examined by duration of exposure or periods of initial enployment. No increased risk of lung cancer or gastrointestinal cancer was associated with either duration or emulative exposure in the case-control analysis. 83 5. A report on dust exposure and mortality of workers in a chrysotile asbestos friction products plant consisted of data on a cohort of 3641 men employed for at least one month. Individual exposures were estimated (in nppcf-years) from impinger measurements. Table 1 shews deaths by cause and age at death. Tabic I Malt deaths b \ age and terufied cause C a u se o f d e a th ( I C O co d e ) Age at death (y) <45 set nan* n e o p la s m s ! 162-0-11 O e s o p h a g u s an d sto m a c h ( |5 t> -S |) C o lo n a n a n v ta m (1 5 2- > 4j O t h e r a b d o m in a l ( ) 55- 5 9 ) L arynx (1 6 1 ) O th e r(140-4,5 .*. 165-205) Heart Oisesie !400-443) R e s p i r a t o r y tuberculosis ( 0 0 1 -O O tt) O th e r resp irato ry (4 7 0 -5 2 2 . 5 2 5 -5 2 7 ) P n eu m o co n tu sas (5 2 V- 2 ) C e r e b r o v a s c u la r < } .'0 -3 4 1 A ccid en ts (800-99*) O th er know n causes C ause not know n 'Including one age unknown 139 1 0 J 4 0 II 39 1 2 0 5 35 30 6 45-64 16 47 12 9 9 3 50 2736 27 7 30 42 87 14 *65 511 41 13 20 12 I 40 198 24 5 56 15 66 18 Total 1267 89 25 32 25 4 101 510 11 53 12 91 92 183 39- Information is presented in Tables 2 and 3. Table 2 F iu tn u ite d u v e r a g t J u s t io n c v n tr a tio n s ( m p c f) f o r rruttn p r o t T w t x f 9 .U ) - 7 0 P ulv erisin g a s te a sb e sto s p ro d u cts S h eet p ack in g s F ibre ro o m M ixing O th er M illb o ard w et m ac h in e s W ire m o u ld e x tru d e d b ra k e lin in g M ixing O th er Paper A u to tran sm issm n etc N o v ab esto s p ro cess G ro o v in g M etal fa b ric a tio n B rake shoes C ore D isc b ra k e T re atc u re B rak e finixtvhur p ress D ry m o u ld m ut G rin d in g O th er R ing h m sh (g rin d in g ) P ack in g W arehouse 6 134 24 20 31 82 1 -- -- -- -- -- -I 2 2A 4 15 56 *1 W 0-V 4 to 2 15 i -- -- -- -- -- -- 15 15 10 3 15 4 *1 /9.50-9 > s 15 1 2 0-5 05 02 05 1 05 05 1 1 7-5 2 1 05 02 Table 3 Age at start, duration o f employment, and dust exposure <men onlyl No A v e r a g e a g e a t s ta r t (y> ' G ross serv ice (y i N et service <y) A verage d u st co n cen tratio n (m pcfl Uurtaon of gross servit e (y) <1 1253 2962 038 0 37 /-< 3 038 31 9 0 2 53 2 12 2 28 2 0b -<20 577 3W 5 1058 9 -0 0 1 56 20 747 2 9 -M 3059 28 82 1 '0 6 1900-9 1 6 1 05 05 1 02 02 02 02 05 02 02 05 05 5 1 05 1 Ol Ol f'^ a Total 3515 3095 9 05 804 1 84 Table 4 simnarizes the mortality experience of the cohort by duration of work. The SMR based on Connecticut rates was 108.5 (107.9 on U.S. rates). The excess was mainly due to people who had worked for less than 1 year (SMR 129.9); those who worked one or rs had an SMR of 101.2. The lowest SMR (97.2) was for those worked 20 or more years. SMRs were raised for the three js of malignant neoplasms. Again this was mainly due to in men enployed for less than one year; in none was there evidence of increasing risk with increasing duration of exposure. No mesotheliomas were observed.