Drug and Chemical Toxicology

ISSN: 0148-0545 (Print) 1525-6014 (Online) Journal homepage: http://www.tandfonline.com/loi/idct20

Pulmonary Adenomas in A/J Mice Treated with Silica Daniel A. McNeill, Clarence E. Chrisp & Gerald L. Fisher To cite this article: Daniel A. McNeill, Clarence E. Chrisp & Gerald L. Fisher (1990) Pulmonary Adenomas in A/J Mice Treated with Silica, Drug and Chemical Toxicology, 13:1, 87-92, DOI: 10.3109/01480549009011071 To link to this article: http://dx.doi.org/10.3109/01480549009011071

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DRUG AND CHEMICAL TOXICOLOGY, 13(1), 87-92 (1990)

BRIEF NOTE

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PULMONARY ADENOMAS IN A/J MICE TREATED WITH SILICA Daniel A. McNeill', Clarence E. Chrisp2, and Gerald L. F i ~ h e r ' ' ~ 'Battelle, 505 King Avenue, Columbus, Ohio 43201, and 'Laboratory Unit for Animal Medicine, University of Michigan, Ann Arbor, Michigan 48109

ABSTRACT This study was designed to test the pulmonary tumor response to intratracheally instilled silica in Strain A mice. Urethane was used as a positive control. Silica treatment was utilized to evaluate the effect of a potent fibrogen on pulmonary adenoma formation in this unique animal model. Urethane produced an increase in pulmonary tumor response in this study in agreement with previous investigations. Also, the background incidence of adenomas was comparable to other studies. Silica treatment did not affect tumor incidence either in terms of percent of mice with adenomas or average number of adenomas per mouse. INTRODUCTION The pulmonary adenoma response of Strain A mice has been reported to be a rapid and efficient predictor of carcinogenic potential for a variety of chemicad'). In a previous study(*),we evaluated the pulmonary adenoma production

90whom correspondence should be sent. Present address: Sandoz Research Inst., 59 Route 10, E. Hanover, NJ 07936 a7 Copyright 0 1990 by Marcel Dekker, Inc

aa

McNEILL, C H R I S P , AND FISHER

in Strain A mice using urethane as a positive control and nickel subsulfide as the test article. Although urethane produced an increased incidence of lung adenoma by both the intratracheal and intraperitoneal routes of exposure, no increase in incidence of pulmonary adenoma was observed with nickel subsulfide using either

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route of exposure. Since nickel subsulfide is a potent

which has

produced tumors by several routes of exposure yet failed to elicit a positive response in the Strain A pulmonary adenomas assay, it was decided that additional evaluation of this model was needed. Because our previous studies demonstrated nickel subsulfide to be a fibrogenic agent after intratrachealinstillation, we evaluated the effect of silica, a potent fibrogen, on pulmonary adenoma formation. MATERIALS AND METHODS Silica (Minusil 216 quartz, 1-5 pm) was purchased from Whittaker, Clark and Daniels, Inc. (So. Plainfield, NJ). Reagent grade urethane (Mallinckrodt;

St. Louis, MO) was dissolved in sterile saline and diluted to the desired concentration. For intratracheal instillations (i.t.), a 1” x 23 gauge sterile blunt needle was attached to the pipet and a 20 pl sample of the silica suspension was withdrawn. For intraperitoneal injections (Lp.), a sterile low-dose tuberculin syringe (0.5 cc) was used to deliver 0.1 ml to each animal. Male StrainN J mice, 11 to 13 weeks old (Jackson Laboratories, Bar Harbor, ME), were evaluated. Upon arrival, animals were housed 5 per cage on Absorb-dri@ bedding. Water containing0.2 mg/ml tetracycline hydrochloride (American Cyanamid Co.) was available ad libitum. Mice were anesthetized using methoxyflurane (Pittman Moore). Anesthetized mice were placed on specially made holders as described by Ho and

PULMONARY ADENOMAS I N A f J M I C E

89

Furd5) and presented in the companion manuscript"'. At necropsy, 20 weeks after study initiation, lungs were removed and the airways perfused with 10% buffered formalin and placed in a vial of 10% buffered formalin for about 1 week. A 2x2 contingency table was used for the basis statistical analyses with the method

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described by Fisher to compute the exact test of significance(6).

RESULTS

Animals were treated 15X (l/wk) with silica (9.75 mg/kg). The dose of silica given (2.9 mg/mouse) was derived from studies by Chvapif7' which showed adoubling of lung collagen 6 days after i.t. administration of 30 mg of silica in rats. A single i.p. dose of urethane (64 mg/kg) was used(g). Mice treated with silica had tumor incidence similar to the vehicle control groups (Table 1). The background incidence of adenomas for the vehicle control group was comparable to other studies"). Mice that received urethane i.t. (positive control) had a significantly higher (p < 0.05) number of adenomas and a significant increase (p < 0.01) in the number of adenomas per mouse. The lungs from the urethane treatment groups were grossly normal in appearance. Lungs from mice that received silica treatments were generally mottled in appearance but had no other grossly visual abnormalities. DISCUSSION Urethane produced an increase in pulmonary tumor response in this study (p < 0.01). This response was elicited after i.t. instillation rather than the usual i.p. injection. The pulmonary tumor response to urethane is apparently not related to the route of administration.

20120

15 (l/wk)

a

Significantly different from vehicle control (p < 0.01).

Significantly different from vehicle control (p < 0.05).

Silica

9.75

30130

1

64.1

Urethane

29/30

15 (llwk)

0

Survival

Vehicle Control

Frequency

(mgIk9)

Treatment

Dose

20

ma

31

(%I

Mice with Lung Adenomas

Strain a Mouse Survival and Lung Adenoma Incidence After lntratracheal Treatment with Silica or Urethane

TABLE 1.

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0.31 (.09)

Av. No. of AdenomadMouse (t S.E.)

Q

x

P H cn

PULMONARY ADENOMAS IN A/J MICE

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In an earlier study with Strain A mice, McNeill et al.(2Jfound that nickel subsulfide, produced an early fibrogenic lung response, but did not increase the incidence of adenomas. Rather a significant decrease in adenoma incidence was observed relative to untreated control animals. Silica was therefore evaluated to

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determine the influence of a non-carcinogenic, fibrogenic material on the progression of adenoma formation in the Strain A mouse. Silica did not affect the incidence of pulmonary adenomas compared to the vehicle control groups. Therefore, the failure of nickel subsulfide to produce tumors in Strain A mice does not appear to be the result of its fibrogenic potency. ACKNOWLEDGEMENTS This work was supported by the Electric Power Research Institute Contract No. RP1639-02. The authors are indebted to Ms. K.L. McNeill for support in manuscript preparation. REFERENCES (1)

Shimkin, M.B., and G.D. Stoner, “Lung Tumors in Mice: Application to Carcinogenesis Bioassay,” Advan. Cancer Res., 21, 1-58 (1975).

(2)

McNeill, D.A., C.E. Chrisp, and G.L. Fisher, Drug and Chern. Tox., submitted.

(3)

Sunderman, F.W., Jr., “Carcinogenic Effects of Metals,” Fed. Proc., 37, 40-46 (1978).

(4)

Sunderman, F.W., Jr., “Mechanisms of Nickel Carcinogenesis,” Scand. J. Work Environ. Health, l5, 1-12 (1989).

(5)

Ho, W., and A. Furst, “lntratracheal Instillation Method for Mouse Lungs,”

Oncol., 27, 385-393 (1973).

(6) Finney, D.J., R. Latscha, and B.M. Bennet, “Tables for Testing Significance in a 2x2 Contingency Table,” Cambridge University Press, New York, 1963.

McNEILL, CHRISP, AND FISHER

92

(7)

Chvapil, M., C.D. Eskelson, V. Stiffel, and J.A. Owen, "Early Changes in the Chemical Composition of the Rat Lung after Silica Administration," Arch. Environ. Health, 34, 402-406 (1979).

(8)

Poirier, L.A., G.D. Stoner, and M.B. Shimkin, "Bioassay of Alkyl Halides and

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Nucleotide Base Analogs by Pulmonary Tumor Response in Strain A Mice," Cancer Res. 35, 1411-1415 (1975).

(9)

Stoner, G.D., M.B. Shimkin, M.C. Troxell, T.L. Thompson, and L.S. Terry, "Test for Carcinogenicityof Metallic Compounds by the Pulmonary Tumor Response in Strain A Mice," Cancer Res., 36, 1744-1747 (1976).

J mice treated with silica.

This study was designed to test the pulmonary tumor response to intratracheally instilled silica in Strain A mice. Urethane was used as a positive con...
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