Document XOMgG8123qk43Bpj0z96G40KR

Fd Cosmet Toxicol Vol 15 pp 121 129Pergamon Press 1977. Printed in Great Britain INHALATION OF TALC BABY POWDER BY HAMSTERS A. P. WEHNER G. M. Zwicker and W. C. Cannon Biology Department Battelle C. R. WATSON Systems Department Battelle Pacific Northwest Laboratories Richland WA 99352 and W. W. CARLTON Department of Microbiology and Pathology School of Veterinary Science and Medicine Purdue University West Lafayette IN 47907. USA Received 25 September 1976 Abstract of 50 male and 50 female Syrian golden hamsters were exposed to talc aerosol for 3. 30 or 150 min 5 days for 30 days or for 30 or 150 day either until they died naturally or for a maximum of 300 days The mean concentration of the respirable aerosol fraction was approximately 8 litre and the mass mean aerodynamic diameter was 6 mFollowing the exposures the animals were observed for the remainder of their lifespan At death lungs trachea larynx liver one kidney stomach uterus one ovary or one testis and all tissues showing gross lesions were collected for histopathological examination Deposition of tale particles in the lungs of the exposed animals was demonstrated by ray fluorescence and by ray diffraction The exposures to talc aerosol had no effect on body weight survival or the type incidence or degree of histopathological change in the exposed groups compared with exposed controls INTRODUCTION Autopsy and radiological findings of induced pneumoconiosis include a heavy accumulation of macrophages varying degrees of diffuse fibrosis pneumoconiotic nodules and asbestos bodies in a large percentage of the cases Worth & Schiller 1954 The presence of asbestos bodies indicates that the talc to which the patients had been exposed contained appreciable quantities of asbestos and probably various other components such as quartz In recent years interest has focussed again on the potential health hazard of the dust commonly referred to as talc Blejer & Arlon 1973 Chodzikowski 1975 Henderson Joslin Turnbull & Griffiths 1971 Kleinfeld Messite Kooyman & Zaki 1967 Kleinfeld Mes- site & Langer 1973 Kleinfeld Messite Shapiro & Swencicki 1965 Kleinfeld Messite & Zaki 1974 Merliss 1971 Miller Tiersfein Bader Bader & Selikoff 1971 Pelfrene & Shubik 1975 Smith 1973 It was considered necessary therefore to determine the biological effects of talc dust by means of inhalation studies in a suitable animal model under controlled laboratory conditions Syrian golden hamsters Mesocricetus auratus were selected because studies in our laboratory have demonstrated the development of pulmonary lesions in these animals following prolonged inhalation of asbestos cobalt and nickoxide dusts and cigarette smoke Exposure to chrysotile asbestos aerosol 7 day 5 days for 11 months mean aerosol concn 23 litre resulted in a 100 incidence of asbestosis in the exposed animals Wehner Busch Olson & Craig 1974b & 1975a Exposure to aerosols of cobalt oxide Wehner et al 1974b or nickel oxide Wehner et al 1974b Wehner Busch Olson & Craig 1975b caused pneumoconiosis and cigarette exposure significantly increased tumour incidence and epithelial lesions of the larynx Wehner Busch & Olson 1974a The positive response of the Syrian golden hamster to a variety of carcinogens has been reported by a number of investigators Dontenwill 1970 Donten & Mohr 1961 Herrold & Dunham 1963 Mohr 1970 Mohr Wieser & Pielsticker 1966 Montesano & Saffiotti 1968 & 1970 Smith 1974 Montesano Saffiotti & Shubik 1970 used this species extensively as an animal model for the study of the pathogenesis of lung cancer and found it markedly susceptible to various respiratory carcinogens and conveniently refractory to chronic pulmonary infections EXPERIMENTAL Experimental design The hamsters used were of the outbred Ela ENG strain from Engle's Laboratory Animais Inc. Farmersburg IN and the experimental design is summarized in Table 1 Three hundred old hamsters were randomly divided into three groups 1. 2 and 3 each of 50 males and 50 females These groups were exposed for 30 days to talc aerosol for 3 30 and 150 min respectively The mean total aerosol concentration was 37 -7.4 SD litre with a respirable fraction of 9.8 -2.4 litre The exposed control group group 6 comprised 25 males and 25 females Two hundred old hamsters were randomly divided 121 Protected Document to Protective Order JNJ 000021023 122 A. P. WEHNER G. M. ZWICKER W. C. CANNON C. R. WATSON and W. W. CARLTON . Table 1. Experimental design for exposure of groups of hamsters to a talc aerosol for various lengths of time Group 1 2 3 4 S 6 control 7 control Exposure regimen No. of min 3 30 150 30 150 150 150 No. of days Calculated cumulative exposure hr mg m 1-5 15 75 150+ 750+ 75+ 750+ 12 120 600 1200+ 6000+ _ _ Animals 50 males and 50 females in groups 1-5 and 25 males and 25 females in groups 6 and 7 were treated on 5 days Desired respirable fraction of talc aerosol = 8 litre Most of these animals died before completion of 300 exposures Sham exposures into two groups 4 and 5 each of 50 males and 50 females and were exposed to talc aerosol for 30 or 150 min respectively for 300 days unless they died sooner Mean total aerosol concentration was 27.4 -3-4 litre with a respirable fraction of 8.1 -10 litre The exposed controls group 7 comprised 25 males and 25 females Aerosol concentrations and exposure times were based partly on results of simulated exposure experiments conducted by F. D. Pooley unpublished data 1973 in which women dusted infant dolls with baby powder as they would dust infants and partly on results of dusting experiments conducted by A. N. Eden unpublished data 1971 and were chosen to simulate in young and adult hamsters as far as was practical multiples of median infant exposure MIE estimated from these data The MIE was later recalculated using the data of Eden who determined in a study involving 72 babies ranging from 1 to 24 months of age that mothers applied talc from one to nine times each day with a median frequency of twice a day and of R. S. Russell unpublished data 1976 who determined the weighted average exposure for one dusting to be 0.1 mg min with a standard error of 0-04 mg min in individual tests on 48 mother pairs Using all frequencies reported by Eden and all the reported one dusting exposure values determined by Russell a computer was used to develop a cumulative frequency distribution of total daily infant exposures by randomly sampling a frequency randomly sampling an exposure and multiplying the two numbers together for a total of 1000 cycles From the resulting cumulative frequency distribution it was possible to determine that the MIE was 0-058 mg wk and the upper 95th percentile corresponded to 0-105 mg wk To prevent contamination the hamsters exposed to talc aerosol and the controls were maintained in separate but identical rooms controlled for temperature 73 -F and humidity 45 -% After completion of the exposures the hamsters were maintained for observation for the remainder of their fiRegisteredtrademark of Johnson & Johnson natural lifespan with the qualification that the experiments were concluded by the killing of all surviving animals when the number of deaths in the group with the most survivors exceeded 90 Moribund animals were killed by ip injection of sodium pentobarbitone and exsanguination The hamsters had free access to Wayne Blox F6 Allied Mills Inc Chicago Ill and water Body weights were measured every 2-3 wk during the growing period and every wk thereafter Figs 1 & 2 and the numbers of deaths were recorded throughout the treatment and observation periods Figs 3 & 4 Aerosol exposure system Each stainless 1500 aerosol exposure chamber Fig 5 was designed for single exposure of four separate ani- mal cages which could be inserted and removed inde- pendently while the aerosol was being generated Each 64 ^ 64 ^ cm stainless mesh cage held 25 hamsters in individual 12.8 ^ cm com- partments the cages being set in cabinet drawers which sealed into the sides of the chamber in either of two positions inserted or fully with- drawn This arrangement allowed the desired aerosol concentration to be established within the chamber prior to insertion of the drawers with the loaded animal cages Animals could then be inserted by closing a drawer with only a relatively small effect on the aerosol concentration within the chamber This facili- tated exposure of animals to given aerosol concen- trations for as little as 3 min Talc powder The talc aerosol was generated from Johnson's Baby Powder lot 228p provided by Johnson & Johnson According to the manufacturers a multi flotation process on Vermont talc is used to provide a grade cosmetic talc for the baby powder lot 228p a normal production lot having been prepared as a part of that process It consists of over 95 w platey talc with trace quantities of carbonates magnesite and dolomite as well as platey chlorite and rutile Aerosol generation and characterization A Wright Dust Feed Mechanism Wright 1950 served as the aerosol generator the talc powder being packed into the cup at a pressure of 263 cmThe mechanism was operated with an air flow of approximately 20 Protected Document to Protective Order JNJ 000021024 Inhalation of talc baby powder by hamsters 123 litres with an upstream air pressure of 5 in. to give a fairly reliable aerosol generation flow rate through the exposure chamber was 208 litres min The concentration of respirable aerosol in the exposure at a sampling rate of 2.5 litres The Casella Type 113A Gravimetric Dust Sampler which included a horizontal elutriator to remove larger particles from the aerosol prior to collection of the respirable particles on a glass filter A sample was taken continuously for the duration of each day's exposure at a sampling rate of 2-5 litres The Whatman GF filters from the sampler were weighed before and after sampling to determine the quantity of talc deposited and the sample volume was measured by the sampler From these data the respirable fraction of the aerosol concentration was determined Total aerosol concentration was measured daily by means of two probes inserted into opposite quadrants of the chamber Two probes were used to moni- tor and ascertain even aerosol distribution within the chamber Each probe sampled for 60 min concurrent with the Casella sampler at a rate of 2-3 litres through a vertically positioned diameter Metricel DM filter paper which was weighed before and after sampling Weekly mean aerosol concentrations were computed from the daily data The mean aerosol concentrations referred to in this paper are the means of the combined weekly means To monitor the accuracy of the gravimetric data filter paper samples were subjected periodically to chemical analysis in addition to being weighed Particle size and particle distribution were determined periodically by collecting aerosol samples in an Andersen Cascade Impactor Andersen 1966 Sham exposures consisted of placing the control animals in an identical exposure chamber for the specified periods of time to simulate the stress of handling Instead of aerosol filtered room air was drawn through the chamber mortem procedures A detailed autopsy was performed on each animal and gross findings were recorded Lungs with trachea and larynx heart liver one kidney stomach one ovary and uterus or one testis and all tissues showing gross lesions were fixed in % buffered formalin embedded in paraffin sectioned at 5 mand stained with haematoxylin and eosin for histopathological examination For this procedure the lungs were gently infused through the trachea with formalin followed by tracheal ligation All histopathological findings were recorded and coded according to the Systematized Nomenclature of Pathology Committee on Nomenclature and Classification of Disease 1969 to facilitate computer analysis of the data Qualitative analysis of lung tissue for talc To identify the particles deposited in the lungs of the exposed hamsters eight particles of talc were processed for scanning electron microscopy photographed and analysed by ray fluorescence Portions of lung tissue from an exposed hamster and from a control animal and particles removed from the lung of an exposed hamster were also processed and analysed by ray fluorescence and diffraction and the results were compared with those from the eight talc par- ticles RESULTS Aerosol exposure data Aerosol data for the 30- and 300 exposures are summarized in Table 2 Clinical signs No clinical signs were observed as a result of the talc exposures Mean body weights as a function of age and treatment are shown in Figs 1 and 2 in which the 95 confidence intervals have been deleted for clarity The exposures had no effect on either male or female hamsters as determined by comparison of the 95 confidence intervals of these means Number of deaths There were no significant differences among the survival times of the exposed groups nor between the exposed groups and the controls Table ) How- ever in all groups the mean survival time of the males was significantly P < 05 longer than that of the females The numbers of deaths in the 30- and day exposure groups are shown in Figs 3 and 4 respectively There was a marked related difference in all groups which became statistically significant at the age of approximately 12 months but no treatment effect was apparent Table 2. Talc aerosol data for 30- and day exposures Particle size distribution Interval Upper limit of intervalt ...m Percentage of total mass in interval Cumulative percentage mass smaller than upper limit size day exposures 1234567 16452 34.1 99.9 1234567 6.7 16.9 65-8 1234567 16452 19.5 48.9 1234567 16452 21-6 29-4 1234567 2.0 4.1 7.8 1234567 = 1-2 3.7 1234567 68 1.0 2.5 68 1.5 1.5 day exposures 1234567 Tanmn 32-6 100-0 1234567 Tanmn 26.9 67.5 1234567 Tanmn 20-3 40-6 1234567 Tanmn 9.5 20-3 1234567 Tanmn 3.0 10.8 1234567 - 2.3 6-8 1234567 0-7 2.6 +5 1234567 83 1.9 1.9 Cumulative composite of 10 for day exposure and 53 for day Andersen Cascade Impactor samples Particle size expressed as aerodynamic equivalent dia- meter Mean aerosol concentrations litre - SD 37-1 -7.4 total and 9.8 -2.4 respirable fraction mass median aerodynamic diameter 49 mdistribution bimodal with peaks at 0-6 and 2-6 m Meanaerosol concentrations litre -SD 27.4 -3.4 total and 8.1 -1.0 respirable fraction mass median aerodynamic diameter 6-0 ...mdistribution bimodal with peaks at 6 and 0 ... F.C.T. 15 Protected Document to Protective Order JNJ 000021025  124 A. P. WEHNER G. M. ZWICKER W. C. Cannon C. R. WATSON and W. W. CARLTON 180 160 140 140 , weight weight body 100 body body Mean Mean 8 Mean 60 40 . /\ ~~. PA a eS. Nae se NA _ 4 WPee=t \ . Y Vw", ~~ Exposure period 20 L Le ! L 1 l } a { \ J 0 50 100 150 200 250 300 400 450 500 550 600 650 Age days Fig 1. Mean body weights of hamsters of groups 1 --- males - fem, ales 2 mal es , -+- fem,ales and 3 ) mal es -----, females exposed to talc aerosol for 30 days and of group 6 males ---~, females the exposed control group 160 : . 140 g , weight weight 120 weight weight g body body body 60 Mean Mean Mean Mean 60 40 20 fe) 1 J l a a ! ! a 1 50 100 150 200 250 300 350 400 450 Exposure period _ __ Age days ____. 1 500 nN 550 L 600 650 Fig 2. Mean body weights of hamsters of groups 4 -- males -- fem,ales and 5 , males ----. females exposed to talc aerosol for 300 days and of group 7 , males --- females the exposed control group Table 3. Mean survival times of groups of hamsters exposed to a talc aerosol and of exposed controls Group Daily aerosol exposure min Actual cumulative exposure mg m-SD Median survival time days -SD Males Females M + F Mean survival time days -SD Males Females M -230 3 -230 30 -230 150 6 0 14-6 -3.6 146 -36 732 -180 0 day exposures 430 370 398 363 434 367 412 381 398 382 388 393 442 -15 415 15 453 -18 426 -17 349 -15 360 -13 372 - 372 -14 396 -12 387 -10 412 399 -8 457 30 457 150 7 0 1210 -150+ 6060 -750+ 0 day exposures 482 400 428 481 396 428 488 354 411 491 462+ 11 485 -21 380 12 405 12 361 -16 436 -10 433 -10 423 -16 In all groups the mean survival time for the males was significantly longer P < 0-05 than that for the females Most of these animals died before completion of the 300 exposures Fig 5 The survivors of groups 4 5 and 7 were killed at the age of 20 months At that time all females were dead and less than 20 of the males were alive The male mean survival times and consequently the combined mean survival times are therefore artificially low ' Protected Document to Protective Order JNJ 000021026 Inhalation of talc baby powder by hamsters 125 8080 T T 7700 % 6060 T deaths wfo} T of 40 40 T No. 30 400 1 500 { 600 Age days Fig 3. Death rates in hamsters exposed for 30 days to talc aerosol for 3 day group : males 1 females 30 min group 2 ---- males ---- females and 150 min group 3 1 males : fem, ales and in the exposed controls group 6 -- - , males , females Qualitative analysis of lung tissue for talc Figure 6 shows a photomicrograph of one of the eight talc particles processed Analysis by ray fluor- escence at 0-5 keV and at 5-10 keV showed that the particle was composed of magnesium silicon and traces of iron Figure 7 is a photomicrograph of lung tissue from a control hamster One of many talc par- ticles found in the lungs of exposed hamsters is shown . in Fig 8 its identity having been confirmed by ray analysis Summary of type and incidence of histopathological findings The type incidence and severity of the observed lesions indicated no trend toward a response relationship and showed no significant differences between the exposed groups and the controls Larynx and trachea Changes found in the larynx in both control and exposed hamsters included calcification of the mucosal tissue calcification of the muscles of the larynx dilation of the glands of the 90 80 70 % 60g death 8 of No 40 30 Experiment terminated 0 100 200 300 Age days 500 600 Fig 4. Death rates in hamsters exposed for 300 days to talc aerosol for 30 min group 4 males fe-m,ales and 150 min group 5 ----, males -- -f,emales and in the exposed controls group 7 ' males females Protected Document to Protective Order JNJ 000021027 A. P. WEHNER G. M. Zwicker W. C. Cannon C. R. WATSON and W. W. CARLTON _ Table 4. Summary of incidence of common pulmonary changes observed in hamsters exposed to a talc aerosol No. of animals affected in group Pulmonary change 1 2 4 S - - oor Orr i MF No. of hamsters examined 49 47 MF 50 49 MF 48 50 MF 49 50 M F 48 48 6 7 > MM F F 25 25 25 25 Alveolar emphysema Interstitial pneumonia Calcification Alveolar hyperplasia Alveolar histiocytosis 16 17 14 + 5 6 8 minta minaa 3 3840 23 25 29 24 22 24 18 26 21 30 14 14 12 3840 21 16 9 7 3 9 7 12 minaa 235 3840 10 5 S 11 6 15 minta minaa 235 3840 4 S 3 2 4 In 966 966 minta 2 4 1 Total affected 588 100 290 101 105 54 Incidence % 17-0 49-0 17.2 17.9 9-2 See Table 1 for the identification of groups 1-7 mucosa and focal inflammation and hyperplasia of the mucosa The most common change was focal mucosal calcification the incidence of which was not a function of exposure time for example the com- bined data for male and female hamsters showed the highest incidence in group 3 150 min for 30 days and the lowest in group 5 which received the longest exposure 150 min for 300 days The incidence of other laryngeal changes were similarly unrelated to treatment Tracheal changes found in both control and exposed hamsters included focal mucosal calcification mucosal dilation and focal mucosal in- flammation The most common alteration was focal calcification of the mucosa No treatment effects were evident in any of the alterations of the trachea the highest incidence combined male and female data of focal mucosal calcification occurred in group , which had received the shortest exposure 3 min for 30 days and the incidences in the other treatment groups did not differ much from the incidence of the combined exposed control groups Lungs Pulmonary changes Table 4 in all groups included interstitial pneumonia focal alveolar and bronchiolar calcification focal alveolar emphysema focal alveolar hyperplasia focal alveolar histiocytosis and pulmonary vasculitis Interstitial pneumonia was the most common lesion the incidence being highest in group 2 and lowest in group 4 and in the sham- exposed controls The other pulmonary changes also varied among the treatment groups without a consistent incidence pattern that could be related to level or duration of talc exposure Alveolar and bronchio- lar calcification and focal alveolar emphysema for example were found most frequently in group 1 and least frequently in group 4 of the treated animals Table 5. Incidence offocal alveolar cell hyperplasia Exposure min Incidence % of lesion in groups exposed for 30 days 300 days 0 3 30 150 18 group 6 15-6 group ) 10-1 group 2 17 group 3 10-0 group 7 _ 25-2 group 4 25.0 group ) See Table 1 for the identification of groups 1-7 The incidence of focal alveolar cell hyperplasia seemed to reflect an effect of treatment as the highest incidences were found in groups 4 and 5 Table 5 However a way weighted analysis of variance of the arcsin transformation of the percentage incidence demonstrated that no significant pattern of incidence of focal alveolar cell hyperplasia was associated with the number of exposure days or with the number of exposure minutes per day Histological examination with the aid of a Nomarski system of a lung section from a randomly selected hamster of group 5 revealed foci of macro- phages containing material resembling talc Fig 9 The hamster was killed 3.5 months after completion of the 300 days of exposure during which it had received a cumulative exposure of 600m0g mIn a lung section from a randomly selected group 3 hamster which died during the 30 days of exposure after a cumulative exposure of 420 mg mno talc was observed Heart Common changes in the heart included valvular endocarditis atrial thrombosis calcification of the coronary vessels and myocardium and focal myo- carditis The incidence of these alterations did not appear to be related to treatment as no consistent pattern of incidences emerged and the incidence was similar for most of the groups Other organs The incidences of hepatic amyloidosis and hepatitis and of renal amyloidosis and nephrosis were high and were similar for the several treatment groups and for the exposed controls Changes observed in the stomach included calcifica- tion of the mucosal tissues and of the tunica muscu- laris No pattern was present to suggest that these alterations were related to the talc exposures Atrophy of the germinal epithelium was common among the treatment groups but no pattern consistent with a treatment effect was found Few changes were found in the uterus and treatment did not have any apparent effect on the incidence of any of these Tumours Only a few neoplasms Table 6 were found They were of several different histological types and their incidence was not related to treat- ment No primary neoplasms were found in the respiratory system DISCUSSION The calcification observed in several organs includ- ing the mucosa of the larynx and trachea alveolar Protected Document to Protective Order JNJ 000021028 Fig 5. Aerosol exposure system Fig 6. Scanning electron micrograph of a talc particle ^ 1800 Protected Document to Protective Order Facing p 125 JNJ 000021029 000021030 Document--Subject to Protective Order 0S9 ~% ansiy OPT Runy X UO ansi1 aponred Suny oye1 jo Jo ydesgonu YdelZoIOW UoNa UOIEJa FuUPIS BUITBDS *f g BLT BLT JNJ 000021030 Fig 9. Photomicrograph of section of hamster lung in Nomarski illumination showing a cluster of alveolar macrophages containing particles believed to be talc The male hamster was killed 3.3 months after completion of the day exposure period during which it had received a cumulative exposure of 6000 mg m Haematoxylin and eosin ^ 870 Fig 10. Transmission electron micrograph of talc particles ^ 8000 Protected Document to Protective Order JNJ 000021031 Inhalation of talc baby powder by hamsters 127 Table 6. Summary of incidence of spontaneous neoplasms found in control and calcexposed hamsters Site and neoplasm No. of affected males and females as specified in groupst MF F FM Total affected Adrenal gland Adenoma Phaeochromocytoma Uterus Leiomyoma Unknown site of origin Carcinoma Lung Carcinoma metastatic Thorax Rhabdomyosarcoma Bone Osteosarcoma Lymph node Malignant lymphoma Liver Osteosarcoma Cholangiocarcinoma Malignant lymphoma metastatic 2 1 {' No neoplasms occurred in either sex in groups 2 and 4 in the males of groups 3 5 and 6 or in the females of groups 1 and 7 See Table 1 for the identification of groups 1 7 and bronchiolar walls myocardium coronary vessels and the gastric mucosa and muscularis is a change commonly associated with ageing Also the renal and hepatic changes are common findings in old hamsters Fortner 1957 The nephrosis could have altered the serum phosphorus balance to a marked degree and contributed to the tissue calcification Some of the cardiac and pulmonary changes were apparently interrelated It appears likely that valvular endocarditis was contributory to the atrial thrombosis and by extension responsible for the inflammatory lesions of the pulmonary vasculature as well as contributory to the development of interstitial pneu- monia Thrombosis of the chambers of the heart of ageing hamsters has been described by Fortner 1957 and Chesterman 1972 Amyloidosis is a common change in the ageing hamster and especially common is renal amyloidosis Fortner 1957 The stimulation to the immune system by persistent infection as seen in the heart valves and lungs could have contributed to the development of the hepatic and renal amyloidosis The incidences of the tissue changes associated with ageing varied greatly among the treatment groups and sham controls and no consistent pattern was dis- cerned to indicate that treatment increased or accen- tuated these changes The hamsters received cumulative exposures rang- ing from about 15 to more than 6000 mg mTable 4 Estimates based on results of a pulmonary deposition study with activated talc show that 0-05 6 gtalc depending on the length of exposure was deposited in the hamster lungs at each exposure Wehner 1976 Estimates based on dusting experiments show according to J. N. Sivertson personal communication 1976 that the weekly hamster exposures expressed in mg m exceeded the aver- age of the weekly infant exposures by some 30 to 1700 times Table 7 Unknown quantities of talc also passed through the intestinal tract of the exposed hamsters This talc comprised quantities deposited on the ciliated surface of the respiratory tract and subsequently brought up by the mucociliary clearance mechanism and swallowed talc licked from the pelt and swallowed and talc deposited on the feed during exposure However there was no evidence of induced lesions in the intestinal tract A gavage study with activated talc is in progress to determine to what degree talc is absorbed during passage through the intestinal tract It is possible that markedly higher exposure levels would have caused talcosis eventually Quick clearance of the talc particles from the lung could be at least partly responsible for the absence of induced lesions but this possibility can only be confirmed by Table 7. Comparative levels of exposure to talc aerosols in different groups of hamsters Hamster group Weekly hamster exposure expressed as multiples of weekly Calculated infant exposuret weekly exposure 50th Upper 95th mg m percentile percentile 1 2 30 19 2 20 300 190 3 100 1700 950 4 20 300 190 5 100 1700 950 See Table 1 for the identification of groups 1-7 N. Sivertson personal communication 1976 Protected Document to Protective Order JNJ 000021032 128 A. P. WEHNER G. M. ZWICKER W. C. CANNON C. R. WATSON and W. W. CARLTON determining the fate of the talc particles in the hamster Early efforts to determine pulmonary deposition and clearance using atomic absorption spectrophotometry were unsuccessful because the relatively high and varying tissue background levels of the elements to be analysed interfered with the measurements A study is now in progress using activated talc to determine pulmonary deposition and clearance The most plausible explanation for the absence of induced lesions in our hamsters appears to lie in the nature of the talc It was cosmetic talc Donten W. 1970 Experimental investigations on the effect of cigarette smoke inhalation on small laboratory animals In Inhalation Carcinogenesis CONF Edited by M. G. Hanna Jr. P. Nettesheim & J. R. Gilbert p 389. NTIS Springfield VA Dontenwill W. u Mohr U. 1961 Carcinome des Respirationstrakts nach Behandlung von Goldhamstern mit Di^/thylnitrosaminZ. Krebsforsch 64. 305 Fortner J. G. 1957 Spontaneous tumors including gastrointestinal neoplasms and malignant melanomas in the Syrian hamster Cancer N.Y. 10 1153 Henderson W. J. Joslin C. A. F. Turnbull A. C. & Grif- Fig 10 in which no asbestos fibres were found In- fiths K. 1971 Talc and carcinoma of the ovary and dustrial talc by comparison contains varying and appreciable quantities of other minerals includ ing asbestos which is a proven fibrogen and carcinogen Our results therefore should not be inter- preted as being in disagreement with the findings in workers engaged in such industries as talc mining and cervix J. Obstet Gynec Br Commonw 78. 266 Herrold K. M. & Dunham L. J. 1963 Induction of tumors in the Syrian golden hamster with diethylnitrosamine nitrosodiethylamine Cancer Res 23 773 Kleinfeld M. Messite .. Kooyman O. & Zaki M. 1967 Mortality among talc miners and millers in New York State Archs envir Hlth 14. 663 milling rubber and cable manufacture and batplate casting in which prior to the initiation of Kleinfeld M. Messite J. & Langer A. M. 1973 A study of workers exposed to asbestiform minerals in commer- protective measures the workers were chronically cial talc manufacture Envir Res 6. 132 exposed to atmospheric concentrations of mine Kleinfeld M. Messite J. Shapiro J. & Swencicki R. dust or industrial tale averaging up to several 1965 Effect of talc dust inhalation on lung function hundred million particles Kleinfeld et al 1967 Archs envir Hlth 10 431 . Some of the controversy and confusion about talc Kleinfeld M. Messite J. & Zaki M. H. 1974 Mortality can be attributed to the loose application of the term experiences among talc workers A follow study J. ws occup Med 16 345 talc for widely varying mixtures of components of Merliss R. R. 1971 treated rice and Japanese sto- different pathogenicity mach cancer Science N.Y. 173 1141 We recommend therefore that a the dust mix- Miller A. Tiersfein A. S. Bader M. E. Bader R. A. & tures now commonly referred to as tale should be analysed and graded uniformly according to the type and quantity of their components b an appropriate nomenclature should reflect the type or quality of the dust mixture in question the term talc being reserved for powder consisting of at least 95 w platey talc and no asbestos with different names e.g. talcoid being assigned to the powder categories of lesser purity and c rather than having one threshold limit value 2 x 107 particles at present for the dust mixtures now collectively referred to as talc different threshold limits should reflect the differences between the adverse biological effects of cosmeticgrade talc and those of different talcoid mixtures con- taining varying degrees of asbestos and quartz Selikoff I. S. 1971 Talc pneumoconiosis Significance of sublight microscopic mineral particles Am J. Med 50 395 Mohr U. 1970 Effects of diethylnitrosamine in the respiratory system of Syrian golden hamsters In Morphology of Experimental Respiratory Carcinogenesis p 255 Edited by P. Nettesheim M. G. Hanna Jr. & J. W. Deatherage Jr. NTIS Springfield VA Mohr U. Wieser O. u Pielsticker K. 1966 Die Minimaldosis f^...rdie Wirkung von Di^/thylnitrosaminauf die Trachea beim Goldhamster Naturwissenschaften 53 229 Montesano A. & Saffiotti U. 1968 Carcinogenic response of the respiratory tract of Syrian golden hamsters to different doses of diethylnitrosamine Cancer Res 28 2197 Montesano R. & Saffiotti U. 1970 Carcinogenic response of hamster respiratory tract to single subcu- Acknowledgements work was performed by Battelle Pacific Northwest Laboratories for the Johnson & John- son Research Foundation under Contract no 212B01060 We would like to express our appreciation to Dr. D. K. Craig for the design of the aerosol exposure chambers to E. M. Milliman and D. Wardell for technical assistance in conducting the experiments to J. A. Mahaffey for statis- tical assistance and to V. M. Lee and J. E. Rehfield for assistance in data reduction and analysis taneous administration of diethylnitrosamine at birth J. natn Cancer Inst 44 413 Montesano R. Saffiotti U. & Shubik P. 1970 The role of topical and systemic factors in experimental respiratory carcinogenesis In Inhalation Carcinogenesis Edited by M. G. Hanna Jr. P. Nettesheim & J. R. Gilbert p 353. NTIS Springfield VA Pelfrene A. & Shubik P. 1975 Is talc a carcinogen A review of present data Presse m^'d4 11 801 Smith W. E. 1973 Asbestos talc and nitrites in relation to gastric cancer Am ind Hyg Ass J. 34. 227 REFERENCES Andersen A. A. 1966 A sampler for respiratory health hazard assessment Am ind Hyg Ass J. 27 160 Blejer H. P. & Arlon R. 1973 A possible occupational and environmental carcinogen J. occup Med 15 92 Chesterman F. C. 1972 Background pathologiyn a col- ony of golden hamsters Prog exp Tumor Res 16 50 Chodzikowski R. J. 1975 Spotlight on talc J. Perfume Chemists 78 56 Smith W. H. 1974 Experimental studies on biological effects of tremolite talc on hamsters In Proceedings of the Symposium on Talc Washington DC May 8 1975 Information circular 8639. p 43. Compiled by A. Good- win US Bureau of Mines Wehner A. P. 1976 Pulmonary Deposition Translocation and Clearance of Inhaled activated Talc in Syrian Golden Hamsters Final Report to Johnson & Johnson Baby Products Company Battelle west Richland WA Committee on Nomenclature and Classification of Disease 1969 Systematized Nomenclature of Pathology 2nd Printing College of American Pathologists Chicago Wehner A. P. Busch R. H. & Olson R. J. 1974al Effect of chronic exposure to cigarette smoke on tumor incidence in the Syrian golden hamster In Experimental Protected Document to Protective Order JNJ 000021033 Inhalation of talc baby powder by hamsters 129 Lung Cancer Carcinogenesis and Bioassays Edited by K. 1975a Chronic inhalation of asbestos and cigarette ; E. Karbe & J. F. Park p 360. Springer New smoke by hamsters Envir Res 10 368 York Wehner A. P. Busch R. H. Olson R. J. & Craig D. Wehner A. P. Busch R. H. Olson R. J. & Craig D. K.1975b Chronic inhalation of nickel oxide and cigar- K. 1974b Investigation of Cocarcinogenicity of ette smoke by hamsters Am ind Hyg Ass J. 36 801 Asbestos Cobalt Oxide Nickel Oxide Diethylnitrosa- Worth G. u Schiller E. 1954 Die Pneumokoniosen Ges- mine and Cigarette Smoke Final Report to National Cancer Institute Northwest Richland WA chichte Pathogenese Morphologie Klinik und Rontgenologie pp 205 & 536. Staufen Verlag Wehner A. P. Busch R. H. Olson R. J. & Craig D. Wright B. M. 1950 A new dust mechanism J. scient Instrum 27. 12 Protected Document to Protective Order JNJ 000021034