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Environmental Health Perspectives < Vol. 53, pp. 3-9,1983
Review of Published Studies of Orally Administered Asbestos
by Lyman W. Condie*
There hu been great public concern about the advene health effect* resulting from the presence of asbestos fibers in municipal drinking water supplies. This article reviews and summarizes the experimental findings of 11 published papen that have evaluated the carcinogenic potential of asbestos following its ingestion. The long-term, high-level ingestion of various types of asbestos fiben in more than one animal species failed to
produce any definite, reproducible, organ-specific carcinogenic effect
Introduction
Prolonged industrial human exposure to asbes tos has been associated with an increase in the incidence ofcertain forms of cancer. The relation ship between inhaled asbestos and mesothe liomas of the pleura and peritoneum or pulmo nary carcinoma is particularly strong; other cancers have also been implicated from inhaled asbestos (2-3). In order to explain why cancer may occur at remote sites following the inhala tion of asbestos, it has been suggested that the asbestos fibers that are cleared from the lungs are swallowed and subsequently migrate through the gastrointestinal wall to the peritoneum where cancer may be initiated.
Originally the question of pathogenicity from asbestos exposure had relevance only to people occupationally exposed, but the discovery of amphibole fibers in municipal water supplies (4) indicated that asbestos was more widely dis persed through the environment than once be lieved. Asbestos from natural sources, as well as from mining activities, has been shown to con taminate bodies of water that are used as sources of drinking water. Asbestos fibers have been de tected in commercial beverages, possibly result ing from the use of asbestos filters. The extensive use of asbestos cement pipe in municipal water systems has concerned officials of the U.S. Envi ronmental Protection Agency. This paper summa
*Tfcrget Organ Ibxicology Branch, Tbxicology and Microbi ology Division, Health Effects Research Laboratory, U.S. EPA, Cincinnati, OH 45268.
rizes the various published asbestos ingestion studies that have attempted to answer the ques tion of whether or not ingested asbestos is a health hazard. Other relevant topics such as gas trointestinal penetration by asbestos, the pres ence of asbestos in municipal drinking water sup plies, and epidemiologic studies will be presented in subsequent papers of this workshop. The de tails of all but one of the cited experimental studies are summarized in Thble 1.
Results of Published Studies
An abstract by Bonser and Clayson (5) initially reported experimental findings from an ingestion study. Asbestos was administered to SpragueDawley rats in their feed at a level of 0.15%. No malignant tumors were observed in the exposed animals, which may have been due to the low level of asbestos administered. The high mortal ity of the rats due to pulmonary infection seri ously compromised the study.
Webster reported the only study conducted with primates (6). Because of lack of experimental detail, the findings of this article were omitted from Table 1. An unreported number of baboons were exposed to "heavy" concentrations of asbes tos in food and drinking water for up to 5 yr. There was no evidence of any peritoneal or gas trointestinal tumors. The 5-yr exposure time ap pears too short for the carcinogenesis process to occur if the time element of the baboon's reaction to asbestos is similar to that of a human.
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REVIEW OF ASBESTOS STUDIES Table 1. Summary of asbeatoa ingestion studies (continued).
Study
Species
Wagner (10) Rat
Test material
Chrysotile
Talc Control
Dose 100 mg/day
lOOmg/day 0
Exposure time
101 days/ 5 mo.
101 days/ Smo.
0
Study duration 619*
614*
641*
Number of animals, Initisl/ Examined 32/32
32132
16/16
Malignant tumors
Number 3
Location
Node Stomach Uterus
Type*
L S S
3 2 Uterus Stomach
S S
0
Smith (11) Hamster Amosite
Amosite
Amosite
Taconite tailings
Taconite tailings
Taconite tailings
Control
0.5 mg/L ad libitum 5 mg/L ad libitum
SO mg/L ad libitum
0.5 mg/L ad libitum
5 mg/L ad libitum
50 mg/L ad libitum 0
To 23 mo. To 23 mo. 60/60 To 23 mo. To 23 mo. 60/60 To 23 mo. To 23 mo. 60/60 To 23 mo. To 23 mo. 60/60 To 23 mo. To 23 mo. 60/60 To 23 mo. To 23 mo. 60/60 0 To 23 mo. 120/120
1 Lung
c
3 2 Stomach
c
Peritoneal
mesothelioma
0
1 Uterus 0
S
0 1 Node
L
Donham (12) Rat
Chrysotile Cellulose fiber Control
10% in diet ad libitum
10% in diet ad libitum
0
To 32 mo. To 32 mo. 240/189 To 32 mo. To 32 mo. 242/197 0 To 32 mo. 121/115
4 3 Colon
C
Abdominal
mesothelioma
2 Colon
C
3 Colon
C
Ward (13)
Rat
Azoxymethane1 7.4 mg/kg wk 10 wk
Azoxymethane plus amosite
7.4 mg/kg wk 10 mg 3/wk
Azoxymethane 7.4 mg/kg wk plus chrysotile 10 mg 3/wk
10 wk 10 wk
34 wk 34 wk 34 wk
21/21 21/18 21/21
12 5 Ileum 7 Colon
10 3 Ileum 7 Colon
10 4 Ileum 6 Colon
c c c c c c
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REVIEW OF ASBESTOS STUDIES Table 1. Summary of asbestos ingestion studies (continued).
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Study
Specie*
Teat material
Doee
Exposure time
Study duration
Number of animala,
Initial/ Examined
Malignant tumora
Number
Location Type*
Bolton (IS)
Rat
Amoaite Crocidolite ` Chryeotile
250mg/wk 250mg/wk 250mg/wk
25 mo. 25 mo. 25 mo.
Life Life Life
24/24 22/22 22/22
* Margarine control
0
0 Life 24/24
Control
0
0 Life 23/23
>Type C - carcinoma; S * sarcoma; L lymphoma. bMean survival time in days.
cAzoxymethane given subcutaneously; saline administered by oral gavage or subcutaneously. *mfl * million amphibole fibera/L
1 Stomach
S
1 Adrenal
C
5 Fat
s
Pleural histio
cytoma, 2 Adrenal
c
Plaimacell
tumor
- 4 2 Adrenal
c
Bladder
c
Peritoneum
s
2 Fat
Lymphoma
s
The results of a series of feeding experiments with different sources ofchrysotile and crocidolite were reported by Gross et al. (7). This paper incorporated data from unpublished results of various studies conducted by three laboratories.
Animals fed asbestos by gavage in butter or mar garine for up to 21 months failed to provide evi dence of a carcinogenic effect. The experiments were flawed for the following reasons: the number
ofrats in the experimental groups was small, the
doses of asbestos were limited, significant infor mation on experimental protocol was missing, and systematic histologic examination was not performed on a significant number of rats.
A study by Gibel et al. (8) was undertaken to feed asbestos filter material to rats because of the
concern of the possible adverse health effects of
erosion of asbestos from the filters used to purify commercial beverages. The filter material was composed of sulfated cellulose, a condensation resin and chrysotile asbestos (53%). The authors
did not provide any information , regarding the size and shape of the asbestos fibers that were incorporated into the filter material. Although 12 malignant tumors were noted in the asbestosexposed group of rats and the mean survival time was decreased in the asbestos-treated group, the authors stated that no conclusions could be made
from their test results regarding the pathogenesis of the tumors caused by the oral intake of asbes
tos material. The relationship of this study to asbestos carcinogenicity was also confounded by the presence of several substances in the filter material, which were not clearly identified.
Cunningham and co-workers (9) conducted two limited feeding studies with male Wistar rats. Chrysotile asbestos (1% with 5% corn oil) was added to rat chow and fed to the animals for 24 months or 30 months. In the first study, 10 rats were exposed to asbestos. Six of the seven rats autopsied were found to have tumors, while only one malignancy was observed in the control ani mals. In the larger study of 80 animals, equal numbers of malignant tumors were noted in the exposed and the control groups. The authors stated that trace amounts of asbestos can pene trate the walls of the gastrointestinal tract, but evidence that asbestos causes cancer by the oral route of administration was inconclusive.
Wagner et al. (10) fed 32 Wistar rats 100 mg/ day of chrysotile or talc in malted milk for 101 days over a 5-month period. A slight decrease in survival time was observed in the two experimen tal groups. One gastric leiomyosarcoma was de-. tected in each exposure group. Interpretation of the results of this experiment is difficult because of the small number of animals included in the study.
A study in Smith's laboratory (22), which was the first study to utilize a large number of ani-
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REVIEW OF ASBESTOS STUDIES
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One can question the suitability of the animal models employed in evaluating the human re sponse to oral exposure to asbestos, since suffi cient time may be lacking between exposure and the development of malignancies during the ani mal's lifetime. However, exposure to asbestos by other routes has induced cancer in rats. For ex ample, Wagner et al. (17) repotted the develop ment of lung cancer and mesothelioma from brief to lengthy inhalation exposure to various types of asbestos, while Gross (18) reported asbestotic lung cancers in 25 of 72 rats that survived 16 months of exposure to chrysotile dust. Based on the carcinogenic effects of asbestos from nonoral exposure routes (2), one would expect to be able to produce a neoplastic response within the life time of conventional laboratory animals with massive doses of ingested asbestos such as those employed in some ofthe studies mentioned in this paper. These studies also cast some doubt on the hypothesis that peritoneal mesotheliomas and gastrointestinal cancers result from the ingestion ofasbestos fibers cleared from the lungs following inhalation exposure.
The research described in this paper has been peer and administratively reviewed by the U.S. Environmental Protec tion Agency and approved for presentation and publication. Mention of trade names or commercial products does not constitute endorsement of recommendation for use.
REFERENCES
1. Bogovski, P., Timbrell, V., Gilson, J. C., and Wagner, J. C. (Eds.). Biological Effects of Asbestos. IARC Scientific Publications, Lyon, 1973.
2. Selikoff, I. J., and Lee, D. H. K. Asbestos and Disease. Academic Press, New York, 1978.
3. Peters, G. A., and Peters, B. J. Sourcebook on Asbestos Diseases. Garland STPM Press, New York, 1980.
4. Cook, P. M., Glass, G. E., and Ttacker, J. H. Asbestiform amphibole minerals: detection and measurement of high concentrations in municipal water supplies. Science 185: 853-855 (1974).
5. Bonser, G. M., and Clayson, D. B. Feeding ofblue asbestos to rats. Brit. Emp. Cancer Campaign, Res. Ann. Rept. 45: 242 (1967).
6. Webster, I. The ingestion of asbestos fibers. Environ. Health Perepect. 9:199-202 (1974).
7. Gross, P., Harley, R. A., Swinburne, L. M., Davis, J. M. G., and Greene, W. B. Ingested mineral fibers. Arch. Environ. Health 29:341-347 (1974).
8. Gibel, W., Lohs, K., Horn, K. H., Wildner, G. P., and Hoffinan, F. Tierexperimentelle Untersuchungen uber eine Kanserogene Wirkung von Asbesfiltermaterial nach oraler Aufnahme (Experimental study on carcinogenic activity of asbestos filters following oral ingestion). Arch. Geschwulstforsch. 46: (6): 437-442 (1976).
9. Cunningham, H. M., Moodie, C. A., Lawrence. G. A., and - Pontefract, R. D. Chronic effects of ingested asbestos in rats. Arch. Environ. Contam. Tbxicol. 6:507-513 (1977).
10. Wagner, J. C., Berry, C., Cook, T. J., Hill, R. J., Pooley, F. D., and Skidmore, J. W. Animal experiments with talc. In: Inhaled Particles IV (W. H. Walton, lid.), Pergamon Press, New York, 1977, pp. 647-654.
11. Smith, W. E., Hubert, D. D., Sobel, H. J., Peters, E. T., and Doerfler, T. E. Health of experimental animals drinking water with and without amosite asbestos and other min eral particles. J. Environ. Pathol. Tbxicol. 3: 277-300 (1980).
12. Donham, K. J., Berg, J. W., Will, L. A., and Leininger, J. R. The effects of long-term ingestion of asbestos on the colon of F344 rats. Cancer 45:1073-1084 (1980).
13. Ward, J. M., Frank, A. L., Wenk, M., Devor, D., and Throne, R. E. Ingested asbestos and intestinal carcinogen esis in F344 rats. J. Environ. Pathol. Tbxicol. 3: 301-312 (1980).
14. Ward, J. M. Dose response to a single injection of azoxymethane in rats. Vet. Pathol. 12:165-177 (1975).
15. Hilding, A. C., Hilding, D. A., and Larson, D. M. Biologi cal effects of ingested amosite asbestos taconite tailings, diatomaceous earth, and Lake Superior water in rats. Arch. Environ. Health 36: 298-303 (1981).
16. Bolton, R. E,, Davis, J. M. G., and Lamb, D. The pathologi cal effects of prolonged asbestos ingestion in rats. Envi ron. Res. 29:134-150 (1982).
17. Wagner, J. C., Berry, G., Skidmore, J. W., and Timbrell, V. The effects of the inhalation of asbestos in rats. Brit. J. Cancer 29: 252-269 (1974).
18. Gross, P., deTVeville, R. T. P., Tblker, E. B., Kaschak, M., and Babyak, M. A. Experimental asbestosis: the develop ment of lung cancer in rats with pulmonary deposits of chrysotile asbestos dust. Arch. Environ. Health 15: 343355 (1967).
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