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si?!?**! r( ( Xfchives of Environmental Health is published by Heldref Publications, 4000 Albemarle St., N.W., Washington, DC 20016. Biological Effects of Ingested ^ Amosite Asbestos, Taconite Tailings, Diatomaceous Earth and Lake Superior Water in fi[ats w ! l ANDERSON CJUfLDING, M.D., Ph.D.* z Research Laboratory z-St. Lake's HvspGEal -Duluth, Minnesota:55805 ^DAVlfTA. ISLEfiNG, M.D. ^DepaQment ofOtolaryngology ~Abrafjarfl LincoltSSchool of Medicine jUnivasPjy of lllitois at the Medical Center TChicagojIllinoi* coCv --i w m 5 CN Su. uo. gCN ** ** CN DONALD M. LARSON, M.l ARTHUR C. AUFDERHEI1 Department of Pathology St. Luke's Hospital Duluth, Minnesota and Department of Pathology and Laboratory Medicine University of Minnesota School of Medicine Duluth, Minnesota S5812 -t^yr ififcipal water supplies from the lake. When crushed J - _J -- (J^BSTf^ACT. ;SecuSe arsphibole fibers were found in^ketQ\ fMc*lUidd,, many amphibole minerals produce microscoppicc- ize SRUXfio* and in Dututh municipal water, this study wasj^y-. bU AboPs that are similar to one another in size and shape. ]The iatl togivalmQethe Carcinogenicity of ingested asbestos^ 25 cunwiingtonite-grunerite mineral series (found in tacon te GroypsSjfragueDa wley rats were fed asbestos5$dT*S? *jjore) anc* amosite asbestos, suitable for commercial rflaied materials during their lifetime and were examiriSHt *5? are amphibole minerals. The term "amphibole a"tito"psySi^fter spontaneou^s dieath. Test materials were unf__i_lflkare 11 fsibr eitrrsa,d" ians tuLsi>e-drfiini/tluhis study, refer<s to the wto-- talI _n_u__m__Ib__e_ of tored Duloth city tip water, municipal water reservoir sedi such fibers in the suspension without implication regar ling rmnt suspension, taconite plant tailings, amosite asbestos (a their mineral source, whether it be cummingtonite-gruner- "tow-dose" grdiip at 20 mg/rat - day and a high-dose group ite or amosite asbestos. Although the carcinogenicity a300 mg/rat .day) and diatomaceous earth; a control group inhaled asbestos was well established,*"T the incident l dfiank fiber-free well water or filtered city tap water. Autop- focused attention on how little was known of the biciog- studies revealed nonsignificant increase in the incidence of ical effects, especially on gastrointestinal mucosa of Ingest malignant tumors in any experimental group compared with ed asbestos.'' Workers inspiring considerable asbe^os th>t in the con&ol group. dust probably suffer some gastrointestinal exposure/by swallowing mucus containing asbestos fibers cleared from the bronchial tree by ciliary action,but there was no IN 1973 thealiscovery of amphibole fibers in Lake assurance that this was the equivalent to direct Ingestion of amphibole-contaminated water. The presence of asbestos Superiorjand ifta taconite iron ore plant's tailings exhaust fibers in commercial beverages and other municipal water ed into thcSIake,1^4 caused public alarm in residents of systems, possibly resulting from the use of asbestos filters Duluth anctother lakeshore communities drawing tneir in the first instance and asbestos-lined pipes/n the second, caused concern about the carcinogenicity of ingested asbes tos at the national level.16 Accordingly,in1973 we init 'Dec total z iated an animal study to determine wh/ther ingested min- Archlves of Environmental Health D:\PA003597\002\18030588.TIF Archives of Environmental Health is published by Heldref Publications, 4000 Albemarle St., N.W., Washington, DC 20016. Biological Effects of Ingested Amosite Asbestos, Taconite Tailings, Diatomaceous Earth and Lake Superior Water in Rats ANDERSON C. HILDING, M.D., Ph.D.* Research Laboratory St. Luke's Hospital Duluth, Minnesota 55805 DAVID A. HILDING, t ..D. Department of Otolaryngology Abraham Lincoln School of Medicine University of Illinois at the Medical Center Chicago, Illinois DONALD M. LARSON, M.D. ARTHUR C. AUFDERHEIDE, M.D. Department of Pathology St. Luke's Hospital Duluth, Minnesota and Department of Pathology and Laboratory Medicine University of Minnesota School of Medicine Duluth, Minnesota 55812 ABSTRACT. Because amphibole fibers were found in Lake Superior and in Duluth municipal water, this study was init iated to evaluate the carcinogenicity of ingested asbestos. Groups of 22-30 Sprague-Dawley rats were fed asbestos and related materials during their lifetime and were examined at autopsy after spontaneous death. Test materials were unfil tered Duluth city tap water, municipal water reservoir sedi ment suspension, taconite plant tailings, amosite asbestos (a "low-dose" group at 20 mg/rat - day and a high-dose group at 300 mg/rat - day) and diatomaceous earth; a control group drank fiber-free well water or filtered city tap water. Autop sy studies revealed no significant increase in the incidence of malignant tumors in any experimental group compared with that in the control group. IN 1973 the discovery of amphibole fibers in Lake Superior, and in a taconite iron ore plant's tailings exhaust ed into the lake,1-4 caused public alarm in residents of Duluth and other lakeshore communities drawing tneir 'Dec rased municipal water supplies from the lake. When crushed or milled, many amphibole minerals produce microscopic-size fibers that are similar to one another in size and shape. The cummingtonite-grunerite mineral series (found in taconite iron ore) and amosite asbestos, suitable for commercial mining, are amphibole minerals. The term "amphibole fibers," as used in this study, refers to the total number of such fibers in the suspension without implication regarding their mineral source, whether it be cummingtonite-gruner ite or amosite asbestos. Although the carcinogenicity of inhaled asbestos was well established,5-7 the incident focused attention on how little was known of the biolog ical effects, especially on gastrointestinal mucosa of ingest ed asbestos.* ' Workers inspiring considerable asbestos dust probably suffer some gastrointestinal exposure by swallowing mucus containing asbestos fibers cleared from the bronchial tree by ciliary action,,-1! but there was no assurance that this was the equivalent to direct ingestion of amphibole-contaminated water. The presence of asbestos fibers in commercial beverages and other municipal water systems, possibly resulting from the use of asbestos filters in the first instance and asbestos-lined pipes in the second, caused concern about the carcinogenicity of ingested asbes tos at the national level.16 Accordingly, in 1973 we init iated an animal study to determine whether ingested min 298 Archives of Environmental Health eral fibers in various forms are carcinogenic to the rat gas trointestinal tract or to other rat tissues. MATERIALS AND METHODS One hundred ninety weanling Sprague-Dawley rats ate commercial rat chow as their basic nutrient. They were housed, five to a standard rat cage, until each rat died. A complete gross and microscopic thoracic and abdominal autopsy was performed on each animal. The gastrointestinal tract received special attention: the entire tract from esoph agus to anus was removed, opened, washed, inspected, and transilluminaied; tissue specimens were then removed from representative pre-selected sites in the tract and from all abnormal areas. The amphibole fiber counts on the samples were per formed using electron microscopy. They were conducted by the staff at the Environmental Research Laboratory, Duluth, of the Environmental Protection Agency. This lab oratory and this agency were not consulted by us for any other part of this study, therefore, they are not responsible for any conclusions or interpretations of our findings expressed herein. The animals were divided into various groups, as follows. Control Group. Twenty-eight rats drank fiber-free well water for 9 months after birth. For the remainder of their lives, they drank filtered Duluth municipal (Lake Superior) tap water that had an amphibole fiber count averaging one million fibers/L (mfl). Commercial rat chow was their only source of food. Duluth municipal tap water (unfiltered). Thirty rats drank only unfiltered Duluth municipal tap water contain ing an average of 100 mfl, and ate only commercial rat chow. Lake Superior water sediment. Twenty-two rats drank a suspension of Lake Superior sediment. The municipal water supply is drawn from Lake Superior and is stored in a four million gallon reservoir, which had not been cleaned for 14 yr prior to our sample procurement. A 2-L bucket was filled with sediment by dragging it along the bottom of the reservoir, the contents of which were diluted to 40 L with distilled water; this mixture was then shaken vigorously and allowed to settle overnight. The supernatant suspension, averaging 5,000 mfl, served as the sole drinking water source. These rats ate only commercial rat chow. Taconite plant tailings. Some microscopic-size fibers of the cummingtonite-grunerite mineral series (found with taconite ore) are similar in size and shape to fibers found in Lake Superior, as well as to those of amosite asbestos. Therefore, 30 rats were exposed to taconite tailings. Thirtyliter samples of taconite tailings were obtained from the west launder of a taconite plant in Silver Bay, Minnesota. After 7 hr of settling, the top third of the sample was siph oned into glass containers; this decanted fraction of the sample contained an average of 100,000 mfl. For the init ial 16 months of the study, the suspended tailings were mixed with cottage cheese (four parts tailings and one part cheese) and fed ad libitum to the 30 rats. Following its consumption (which proved to be prompt), commercial rat chow was offered. Beginning with the 17th month, and continuing for the remainder of the study, the tailings suspension (no longer mixed with cottage cheese) served as the sole source of drinking water. Low-dose asbestos. Each of the 30 rats was offered a daily feeding of 20 mg asbestos mixed with cottage cheese (5 mg asbestos/g cheese). This asbestos-cheese mixture was offered to the rats in each cage in a single dish holding an amount sufficient to supply each animal with the desig nated dose. Following its consumption, commercial rat chow was available ad libitum. These rats drank only filtered Duluth municipal tap water. Chrysotile asbestos (Paperbestos No. 5, Johns Manville Co., Denver, CO) was used during the first 7 months. Beginning at 8 months, and con tinuing for the remainder of the study, the chrysotile was replaced by UICC Standard Reference Amosite Asbestos, which became available at this time from R.E.G. Rendall, Pneumoconiosis Research Unit, Johannesburg, South Africa; it was prepared as described by Timbrell.17 The fibers in Lake Superior water and in taconite tailings resemble those of amosite asbestos. In Lake Superior water, the proportion of amphibole fibers exceeding 5 pm in length (approximate ly 6% of total amphibole fibers) is similar to that in amosite asbestos reference samples. High-dose asbestos. This group of 20 rats was treated in a manner identical with tu.'t of the low-dose asbestos group, except that: (1) the amount of asbestos offered was differ ent, and (2) this group did not receive chrysotile asbestos at anytime. Each rat ate a daily average of 300 mg of amosite asbestos mixed with cottage cheese to a concentration of 50 mg asbestos/g cottage cheese. Diatomaceous earth. This group of 30 rats was also treated in a manner identical to that in the two asbestos groups except for the test material used. Each rat was fed a daily average of 20 mg diatomaceous earth (Johns Manville Co., Denver, CO) mixed with cottage cheese to a concentra tion of 5 mg diatomaceous earth/g cottage cheese. Diatom aceous earth was included among our test substances because it was a constituent of water filters commonly used in Duluth, Minnesota following the discovery of mineral fibers in Lake Superior. RESULTS Detailed autopsies were performed on 187 of the 190 rats included in this study. Postmortem autolysis and occa sional cannibalism precluded valid autopsy studies on three rats. The frequency of cancer in the various groups is detailed in Table 1. No animal had more than one malignant tumor. Statistical evaluation of the results was provided by the Division of Biometry, School of Public Health of the Uni versity of Minnesota, Minneapolis. Analysis of the frequen cy of cancer in any of our test groups compared to that of our control group used the 2 X k contingency table described by Armitage.1 The departures from the null hypothesis of no difference were not statistically significant at the 5% level (0.25 <P< .5). Breast fibroadenomas, encountered in every group, are common in aging Sprague-Dawley rats. None of these benign tumors showed evidence of transformation into a malignant tumor. The morphology and location of the sarcomas in the STO279206 Novtmber/Decembtr 1981 (Vot. 36 (No. 6fJ 299 Table 1 .-Frequency of Malignant and Benign Tumors after Exposure to Various Test Materials (in the Authors' Study) Ti Material Control (filtered tap water) Duluth city up water, unfiltered Mean Exposure Dose Time (Days) 1 mfl ad lib 100 mfl ad lib 690 960 Lake Superior water sediment Taconite tailings 5,000 mfl ad lib 100,000 mfl 840 870 Asbestos, low dose 20 mg/day 870 Asbestos, high dose Diatomaceous earth 300 mg/day 750 20 mg/day 840 No. Rats Initial/Final 28/27 30/28 22/22 30/30 30/30 20/20 30/30 Malignant Tumors No. Location/Tvoet Benign Tumon __ Ka___Lotation/Tvpet 3 1 Lung(C), 1 Ovary(C) 1 Forestomach(C) 5 Breast(F) 4 1 Salivary gUnd(C), 1 Skin- facc(C), t Utarus(S) 1 Medlastinum(L) 9 BrustfF) 3 1 Lung(C), 1 Skln-Ear(C) 1 Uterus(S) 5 1 Neck(S), 1 Chest Wali(S) 1 Medlastinum(L) 7 5 Breast(F), 2 Pancreas (Adenoma) 1 1 9 Breast(F), 1 Adrenal (Pheoctiromocytoma) 1 Pancreas (Adenoma) 7 1 Breast(C), 2 Skin k Neck 15 Breast(F) (Fibrous Histiocytoma), 1 Skin- Face(C), 1 Medlastlmjm(L) 1 Chest Wad (Mesothelioma) 1 Blood(Leukemia) 11 10 Breast(F), 1 Ileum (Leiomyoma) 5 I Salivary Gland(C), 2 Uterus(S) 13 9 Breast(F), 1 Adrenal 1 Skin(C), 1 Peritoneum (Phoechromocytoma) (Mesothelioma) 3 Pancreas (Adenoma) NOTE: Cancer frequency is not significantly greater in any test group than in the control group; departures from null hypothesis of no difference are not statistically significant at the 5% level (0.25 < P < .5) by x mfl Million amphibole flbers/L. t(C| Carcinoma, (S) = Sarcoma, (L) - Lymphoma. t(F) * Fibroadenoma. rats suggested a myogenic origin. In every instance, these tumors behaved aggressively, infiltrating locally, but metastases were rare. In our rats, only two tumors (chest wall in an asbestos-exposed group and peritoneum in the group exposed to diatomaceous earth) demonstrated the histo logic characteristics of a mesothelioma as described by Kannerstein et al.1* The remaining malignant tumors had a conventional histologic structure. DISCUSSION The most significant finding in our study was the total absence of gastrointestinal cancer in the animals exposed to the test materials. Any direct carcinogenic action of ingested asbestos fibers should have its primary impact on the gastrointestinal mucosa. Several long-term animal studies (most of them published since 1973) fail to identify with certainty any carcinogenic effect of ingested asbestos on the gastrointestinal tract (Table 2).2,3,30-14 The one possible exception is the study by Ward et al.,25 in which the authors concluded that "the experimental evidence sug gested but did not prove that oral asbestos exposure in F344 rats may have increased the incidence of intestinal tumors occurring naturally." Intestinal tumors occurred in 32% of the rats receiving only intragastric amosite 3 times a week for 10 wk. This lifetime experiment lacked a con trol group, but according to the author, spontaneous intes tinal tumors are rare in this animal strain. A large lifetime asbestos-feeding experiment is currently being conducted under the auspices of the National Institute of Environ mental Health Sciences and the Environmental Protection Agency and directed by the recently established National Toxicology Program, using chrysotile, amosite and other forms of asbestos, F344 rats and hamsters. The final results of this study are expected to be published in the latter part of 1981 .'* In humans, two epidemiologic surveys of populations drinking amphibole-contaminated water revealed no con vincing increase in gastrointestinal cancer,2**2* but several others showed an increased frequency of gastrointestinal carcinoma in working populations exposed to excessive amounts of airborne asbestos.2**31 Inhaled asbestos is trans ported by the mucociliary mechanism of the respiratory tract, eventually reaching the pharynx, where a significant portion of the inhaled particulates is then swallowed. If these inhaled and then swallowed fibers or the orally ingested asbestos fibers can penetrate the mucosa of the gastrointestinal tract, they might migrate to distant sites. Conceivably, the fibers could induce malignant transforma tion by direct action on the target tissues, or they might cause cancer indirectly by suppressing the immune defenses.52*34 Investigations addressing the questions of gut mucosal penetration by asbestos fibers3',,20,1I'2*'47 have produced conflicting results. Some experiments, employing intragas tric injection of asbestos at laparotomy26'42 demonstrated apparent gut penetration, but were later shown to be suscep tible to unsuspected leakage of the injected material.46 Gross et al.* fed asbestos to rats and found no evidence BOSeV'i' i> ST0279207 300 Archives of Environment!) Health Table 1-Svninw # L*nf-Tan (> 1 2 Month*) Abla Ingestion Sd Pr*Mosl> fteporwd A LiMrtrwr* Author T*M Material Oo*t Exposure Tim* (Days) Animat Type* MO. Malignant T gmon NO. Local >00/1 y p t Smith1* (1965) Amovu or chrytOlik Coot/of Gross* (1974) Chrysolite Control i%dkt ad lib 0 5% dct ad lib 0 "I'lr" ''Life1' 630 630 M 45 M 15 A to It 5 3 1 Lt*r|C|. 1 MesenteryfCl l Rancra(U 0 0 0 Chfvuiiif CrocidoUie Croctdelite Control 10 mg/wk 5 mg/wk 10 mg/wk 0 u> 511 10 616 to 616 to 644 ft 11 R )) R 34 R 24 2 8fau(C) 0 1 Mode (LI 5 3 &reatt(C). 1 Thigh(5) 1 NodefLl Comments 75 mg asbestos imected inirapkurally t 1 uuo cun animal t Asbestos fed irmial 112 days. Gibcl" (1 9 761 ChrssotMc Talcum Control Cunningham*' (197?) Chrysolite Control OrvMdif 20 mg/day 20 mg/day 0 1% diet ad hb 441 ML* 649 ML 702 ML to 7 20 \ diet ad lib to 720 to 900 Control 0 to 900 1 Wagner*4 II93?) Chrvsoti'e 100 mg/'dav j ! 1-------------------------------------- Smith1 (19791 Talc Control A mover Amovtr 100 mg,'day 0 0 5 mg/L ad lib 5 mg/L ad I'b Amoute Tacomte tailings Taconite tailings Ttconitt Utltftfi Control 50 mg/L ad lib 0.5 mg/L ad I'b 5 mg/L ad ii* 50 mg/L ad ib 0 619 ML 6U ML 641 ML to 690 to 690 to 690 to 690 to 690 to 690 <0 690 f>onh*fn*' (19901 Cbrysotik Control Control 10V diet 10% diet 0 to 960 lo 960 . to 960 Ward ** I90t Aaoavmeiha'it A/ox ymetharx and Amosiff Saline and A movie 7 4 mg/kg . I0k to 665 7.4 mg/kj wk and 10 mg 3i/wk 10 wk 1 /wk and 10 mg 3x/wk 10 wk to 665 to 665 R 42 R 4$ R 49 R7 RI R 36 RU R 32 K J2 ft 16 H 60 H 60 H 60 H 60 H *0 H 60 H 120 R 240 R 242 R :i R 50 R 50 R 50 12 1 LungfC), 4 Kidrsey(C) 3 Mode(L). 4 Liwr(C) 3 L t*r{C) 2 LfvertC 1 20 mg filler was 53% cftrysotllc, 47% not dearly specified. 6 l Bretn<S). 1 AtiutiarylCI 1 Nod{L|. 2 Kidnry(C) 1 PentoneumfS | t Ptntoneum(S) Asbestos feedings for 2 yr. 11 2 Thyrotd(C). 1 Thyroid(S) 1 Chemodectoma iuguUr Body. 1 Lt*(CJ, 1 lleum(S), 1 Colon(Cl 1 Adrtnal(C). 2 NodeUI. 1 Bone<S) 11 1 Thyroid(C), i lnwlCI.2 Adrenal(C). 1 Kldney(C), l NodelLI, S Pat(S) 3 1 Slorrucb(S), 1 Ulefus(S) 1 Node (L) 3 1 Slomech(S), 2 Uterus(S) 0 Asbestos feeding for 101 days of first 5 mo. of experiment. 1 Lung(C) 3 2 Slomach(C), 1 Peritoneum- Mesothelioma 0 1 UterusiS) 0 0 Node! L) 4 J Colon(C). 1 Abdominal Mesothelioma 2 Colon(C) 3 Coton(C) 39 '2 HcumfC!, ?7 Colon(C) 44 15 lieum(C), 29 Coion(C) > 30 mfl 1.300 mfl 1 3 .000 mil 45 mfl 4S0 mfl 4,500 mfl Aroaymethane and saline administered subcutaneously , amosite administered miragestricalty 17 1 lkum(C}, 16Colon(C) ML * Mean life *M * Hamster, R - Rat. |(C] * Carcinoma. IS) * Sarcoma. (L1 ( mfl * Million amphibo'e fibers/L. Lymphoma. ST0279208 that fibers penetrated the mucosa or migrated. Cunningham et al.,37 however, fed asbestos to rats and found numerous fibers in tissue suspensions of omentum, lungs, and kidney studied by electron microscopy. Storeygard and Brown44 exposed the mucosa of a closed loop of bowel to amosite in suspension. In their subsequent study of the mucosa with a scanning electron microscope they reported fibers in the process of penetrating the mucosa. Sebastien, Masse, and Bignon43 administered asbestos (chrysotile or crocidolite) in gelatin capsules by gavage to November/December 1981 [Vol. 36 (No. 6)) 301 rats, and then monitored mediastinal lymph fluid for asbes tos fibers. After a single dose, fibers were detected in the mediastinal lymph fluid in all five animals receiving chrysotile and in three of five receiving crocidolite. Fibers were also detected in the abdominal lymph fluid of the majority of animals receiving a synthetic diet containing chrysolite asbestos for 3 to 12 days. The recovery rates were highest in animals receiving a larger amount of long fiber asbestos. Although less than 1% of the administered fibers were recovered, most of these were found in the lymph in the first 16 hr after ingestion; therefore, gut penetration result ing from mucosal cell damage seemed unlikely. Amphibole fibers have been found in the urine of humans drinking amphibole-contaminated water.4*-50 At this time, experimental evidence suggests that asbes tos fibers may, at least under some circumstances, pene trate the gastrointestinal mucosa. Although these studies suggest that ingested asbestos might migrate to other tissues and prove to be carcino genic to them, no pattern of tissue susceptibility is clear in the review of non-gastrointestinal cancers (Table 2). Only Gibel's study13 shows an increase in cancer frequency. In this experiment, nearly half of the chrysotile filter test material is not clearly identified, and the number of ani mals with tumors is not specified; only the number of tumors is reported. In our study, the frequency of nongastrointestinal cancers in the exposed animals is not signif icantly different from that in the control group (Table 1). Under the conditions of our study, ingested asbestos, laconite tailings, unfiltered Duluth (Lake Superior) tap water, Lake Superior reservoir sediment and diatomaceous earth had no demonstrable carcinogenic effect on the gas trointestinal tract or on other body tissues of the rat. The current research was housed and supported by St. Luke's Hospital, Ouluth, MN 55805. The authors wish to acknowledge their deepest debt and grati tude to Ms. Catherine Vince for the laboratory, secretarial, and medical literature services she supplied in this study, and her total commitment to the many other similar studies carried out by Dr. Anderson Hilding during his active and productive life. Submitted for publication July 2, 1981; accepted for publi cation, | uly 31, 1981. Requests for reprints should be sent to: Donald M. Larson, Department of Pathology and Laboratory Medicine, School of Medicine, University of Minnesota-Duluth, Duluth, MN 5581 2. REFERENCES 1. 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