Experimental Lung Cancer: Carcinogenesis and Bioassays

623 Pages·1974·17.184 MB·English

by  Umberto Saffiotti (auth.), Dr. Eberhard Karbe, Dr. James F. Park (eds.)

Experimental Lung Cancer
Carcinogenesis and Bioassays
International Symposium
Held at the Battelle Seattle Research Center
Seattle, WA, USA, June 23-26, 1974
Edited by
Eberhard Karbe and James F. Park
With 312 Figures and 144 Tables
Springer-Verlag Berlin Heidelberg New York 1974
The Symposium was sponsored by
The Battelle Memorial Institute
The Battelle Institute Life Science Program
The Division of Biomedical and Environmental Research (AEC, USA)
Deutsche Forschungsgemeinschaft, W. Germany
The program was planned with the cooperation of the Carcinogenesis Program
of the National Cancer Institute (NIH, USA)
Dr. Eberhard Karbe
Chief, Toxicology, Physiology and Experimental Medicine Division,
Battelle-Institut e.V., Frankfurt, W. Germany
Privatdozent, Veterinary Pathology, University of Zurich, Zurich, Switzerland
Dr. James F. Park
Associate Manager, Biology Department, Battelle Pacific Northwest Laboratories,
Richland, Wash., USA
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ISBN-13: 978-3-642-61941-0 e-ISBN-13: 978-3-642-61939-7
001: 10.1007/978-3-642-61939-7
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Preface
These are the proceedings of the international symposium on "Experi
mental Respiratory Carcinogenesis and Bioassays", held from 23 to 26
June 1974 at the Battelle Seattle Research Center, Seattle, Wash., USA.
Human lung cancer is already very common in industrialized countries,
and its incidence is increasing. This increase involves mainly epi
dermoid and small-cell carcinoma. Evidence is accumulating that these
tumors are associated with such exogenic factors as automobile exhaust,
asbestos, chemicals, cigarette smoke, and radionuclides. These pro
ceedings are concerned with finding the most suitable experimental
designs for investigating the genesis of these particular types of
tumor, and with the development of specific bioassays to test sus
pected carcinogens.
Spontaneous epidermoid and small-cell carcinomas are extremely rare
in the respiratory organs of animals, and it has proved rather diffi
cult until recently to produce them experimentally. Epidermoid carci
nomas are now readily obtained by using methods of intratracheal in
stillation of carcinogens with particulate materials such as that
described by SAFFIOTTI and co-workers, which is the technique most
frequently mentioned in these proceedings. While the experimental
production of small-cell carcinomas has remained difficult, it is
described by two authors in this volume.
The development of an animal model for studying respiratory carcino
genesis or to test suspected respiratory carcinogens must allow for
both exogenous factors associated with the material and methods of
exposure and factors endogenous to the animal, e.g. particular sensi
tivity to chemical carcinogens, detailed knowledge of genetic make-up,
resistance to respiratory inflammation and CO toxicity, dimensions of
the respiratory tract and life span. Special attention has been fo
cused on the correlation between aryl hydrocarbon hydroxylase activity
and sensitivity to the carcinogenic effect of polycyclic aromatic
hydrocarbons. The induction of a malignant tumor in a simian primate
by a polycyclic aromatic hydrocarbon is reported here for the first
time.
Inhalation experiments with carcinogens carry a high risk of human
exposure, and because of this hazard special precautionary measures
have to be taken. The sophisticated equipment required is available
in only a few laboratories; we are fortunate that these proceedings
include several reports on experiments in this field. Further studies
are necessary to improve the exposure design, especially as regards
bioassays concerned with the deposition and dosimetry of inhaled par
ticulate matter. Other methods of applying carcinogens to the target
tissue, e.g. instillation, injection or implantation, are discussed.
In vitro systems offer unique possibilities for investigating carcino
genesis under defined conditions, and the experiments reported here
indicate that organ cultures are particularly suitable for studying
carcinogenesis at the cellular or molecular level. This approach does
not replace animal experiments; instead, it opens us new avenues in
the study of respiratory carcinogenesis. A topic of very particular
interest is the role of synergistic effects in carcinogenesis. It has
been appreciated during the presentation of papers and in discussions
that superadditive effects may be produced by combinations of carcino
gens, or co-carcinogens, and that promoters may be involved in respi
ratory carcinogenesis. The potentiating effects of components of com
bustion products were discussed, and the need to identify additional
active principles in polluted air was recognized. The deposition pat
tern and clearance rate of carcinogens are affected by particle size
and may significantly influence carcinogenesis.
Cigarette smoke, being a major causative factor of human lung cancer,
received a great deal of attention. The best animal model to test the
carcinogenic activity of inhaled cigarette smoke appears at present
to be the Syrian hamster, which develops epidermoid carcinomas in the
larynx. The disadvantages of this model are a low tumor yield (below
20%) and the fact that the induced respiratory tract tumor is located
only in the larynx.
Another special topic was the effect of inhaled alpha-emitting radio
nuclides on the incidence of lung cancer, as observed in uranium
miners. Various uranium-mine air contaminants are being tested in
rodents and dogs, and it has been demonstrated that radon daughters
alone can cause lung cancer. Pulmonary deposition of other alpha
emitting radionuclides (239pu, 238pu, 244Cm, 241Am, and 210po) in
creases the incidence of pulmonary cancer in rodents. The chemical
form of the isotopes influences distribution of the radiation dose
in the lung; a rather uniformly distributed dose will induce cancer
more readily than a heterogeneously distributed dose from particulate
matter. Alpha-emitting radionuclides induce primarily epithelial tumors
in the lung. At the radiation dose levels studied to date, dogs that
inhaled beta-emitting radionuclides (144Ce and 90Sr ) developed mainly
hemangiosarcomas, i.e. tumors of endothelial origin.
The results of animal experiments on the process of carcinogenesis
and the testing of suspected carcinogens depend on interpretation of
the histopathologic lesions. Because of its key role, the histology
of precancerous and cancerous lesions was discussed in detail during
a three-hour slide session; this discussion is not included in these
proceedings.
We were fortunate in that many outstanding scientists in the field of
experimental lung cancer attended the symposium and contributed to
these proceedings. In particular, we would like to thank Dr. UMBERTO
SAFFIOTTI for introducing the symposium, Drs. WALTER DONTENWILL,
SIDNEY LASKIN, PAUL NETTESHEIM, and MICHAEL SPORN for introducing and
chairing the sessions, and Dr. SWEND NIELSEN for organizing and chair
ing the slide session. These scientists helped to plan the symposium
and made a significant contribution to its success. A wealth of scien
tific information was given in 58 papers by authors from various coun
tries, presenting the state of the art in the field of experimental
lung cancer at an international level. The 103 participants came from
France, Germany, Great Britain, Japan, Switzerland, and the United
States of America.
We are also greatful to numerous people for their technical assistance
in assuring the smooth running of the symposium and the rapid publi
cation of these proceedings. In this respect we would like to acknow
ledge the efforts of SHIRLEY LAKE, who helped to organize the sympo
sium, and ELLEN BRANDT, who helped to edit these proceedings, both in
Seattle. Last but not least, we extend thanks, not only for their
help, but also for their great patience, to our secretaries, INGEBORG
SCHIECHEL in Frankfurt and JUDITH HARRISON in Richland.
Finally, we thank the publisher for publishing these proceedings less
than six months after the symposium took place.
September 1974 Eberhard Karbe
Battelle-Institut e.V.
Frankfurt, W.Germany
James F. Park
Battelle Pacific Northwest
Laboratories
Richland, Wash., USA
Contents
Keynote Address: Progress in Respiratory Carcinogenesis.
U. SAFFIOTTI .•.......•....................................•
SESSION I
Methods in Experimental Respiratory Carcinogenesis and Bioassays.
Chairman: S. LASKIN
Models in Chemical Respiratory Carcinogenesis. S. LASKIN and
A. SELLAKUMAR •.............................................. 7
The Role of the Host in the Development of in vivo Models for
Carcinogenesis Studies. D.E. WHITMIRE, C.F. DEMOISE, and
R.E. KOURI ••..........•.......................•............ 20
The Significance of Aryl Hydrocarbon Hydroxylase Enzyme Systems
in the Selection of Model Systems for Respiratory Carcino-
genesis. R.E. KOURI, C.F. DEMOISE, and C.E. WHITMIRE ....... 48
Pulmonary Carcinogenesis by Two Aryl Hydrocarbons on Three
Mouse Strains. W. HO, K. WILCOX, and A. FURST .............. 62
Cell-Mediated Immunity after Intratracheal Exposure to 3-Methyl
cholanthrene, and its Relationship to Tumor Transplant Growth
in C3H/f Mai Mice. C.F. DEMOISE, R.E. KOURI, and C.E. WHIT-
MIRE ....................................................... 72
The Influence of Carcinogenic Substances Introduced Intratra
cheally to Several Generations of Experimental Rats. L.L.
GRICIUTE ................................................... 81
Large-Volume Intratracheal Instillation of Particulate Suspen-
sions to Hamsters. D.W. BAXTER and C.D. PORT ............... 86
The Intrapleural Route as a Means for Estimating Carcinogeni-
city. W.E. SMITH and D.O. HUBERT ........................... 92
Localized Submucosal Bronchial Injections of Carcinogens in
Dogs. M. OKITA, A.H. COHEN, and J.R. BENFIELD .............. 102
Studies of Intrabronchial Particle Depositlon Using Hollow
Bronchial Casts. R.B. SCHLESINGER, V.R. COHEN, and M. LIPP-
MANN ....................................................... 116
x
The Distribution and Retention of Selected Metals in Rat Tissue
after Inhalation of Cadmium Oxide Aerosols. P.D. KAPLAN, M.
BLACKSTONE, and N. RICHDALE ............................... 128
Conception and Methods of Experimental Studies In Germany to
Estimate the Carcinogenic Burden by Alr Pollution in Man.
D. SCHMAHL and K.G. SCHMIDT............................... 139
Experimental Carcinogeniclty and Bioassays of Automobile Ex
haust Condensate and Its Polycyclic Aromatic Hydrocarbons.
H. BRUNE .................................................. 1 46
SESSION II
Multifactorial Respiratory Carcinogenesis and Related Bioassays.
Chairman: P. NETTESHEIM
Review and Introductory Remarks: Multifactorial Respiratory
Carcinogenesis. P. NETTESHEIM ..........................•.. 157
Morphogenesis of Experimental Lung Tumors in Hamsters: The
Effects of Carrier Dust. F. STENBACK ...................... 161
Role of Particles in Respiratory Carcinogenesis Bioassay. M.C.
HENRY, C. D. PORT, and D. G. KAUFMAN .................•...... 1 73
Effect of Particulate Benzo(a)pyrene Carrier on Carcinogenesis
in the Respiratory Tract of Hamsters. R.L. FARRELL and G.W.
DAVIS..................................................... 186
Chemical Induction of Lung Carcinomas in Rats. W.H. BLAIR .... 199
Synergistic Effects of Benzo(a)pyrene and N-Methyl-N-Nitro
sourea on Respiratory Carcinogenesis in Syrian Golden Ham-
sters. D.G. KAUFMAN and R.M. MADISON ...................... 207
The Effects of Particulates on Respiratory Carcinogenesis by
Diethylnitrosamine. R.L. FARRELL and G.W. DAVIS ........... 219
Respiratory Cocarcinogenesis Studies with Ferric Oxide: A Test
Case of Current Experimental Models. D.A. CREASIA and P.
NETTESHEIM. .•. .. . ... ... ... ... ... ...•.. .•. ..• ... ... .. . ... .. 234
Induction of Pulmonary Tumors in Mice by Oral Administration
of a 5-Nitrofuran Derivative. M. KANISAWA ................. 246
Surface Morphology of Tracheal Epithelium in Vitamin A Defi
ciency and Reversal. C.D. PORT, D.W. BAXTER, and C.C.
HARRIS .............•.•..............................•..... 257
Postinfluenzal Pulmonary Lesions in Vitamin A Deficient Mice.
C.G. LOOSLI, J.D. HARDY, and S.F. STINSON ............•.... 265
Influenza-Virus-Induced Hyperplasia of the Respiratory Tract
of the Hamster. C.D. PORT, D.W. BAXTER, D.G. KAUFMAN, and
V. GENTA ....•.......................•................•.... 274
Inoculation of Owl Monkeys (Aotus trivirgatus) with 7, 12-Dimethyl
benz (a) anthracene and Herpesvirus saimiri. Induction of Epi
dermoid Carcinoma in the Lung. W.E. GIDDENS, Jr ..........• 280
SESSION III
Bioassays of Respiratory Carcinogens in Tobacco Products.
Chairman: W.P. DONTENWILL
Review and Introductory Remarks: B~oassays of Respiratory Car-
cinogens in Tobacco Products. W.P. DONTENWILL ............. 293
A Modified Method for Locating Labeled Smoke Particles in Or-
gans of Syrian Golden and European Hamsters. G. REZNIK and
U. MOHR ...............•...............•................... 300
Dotriacontane-16,17-14C Distribution Pattern in the Respiratory
System of Two Hamster Species after Passive Exposure to Ra-
dioactive Labeled Smoke. N. KMOCH and U. MOHR ............. 309
Cigarette Smoke Inhalation Studies in Inbred Syrian Hamsters.
F. HOMBURGER, P. BERNFELD, and A.B. RUSSFIELD ........•.... 320
Tumorigenic Effect of Chronic Cigarette Smoke Inhalation on
Syrian Golden Hamsters. W.P. DONTENWILL .......•.•......... 331
Effect of Chronic Exposure to Cigarette Smoke on Tumor Incidence
in the Syrian Golden Hamster. A.P. WEHNER, R.H. BUSCH, and
R.J. OLSON ..•....•...........•........•...•............... 360
Carcinogenicity of Inhaled Cigarette Smoke in the NMU-Pretreat-
ed Hamster Larynx. E. KARBE and K. K6sTER ................. 369
Validity of the Sebaceous Gland Test and the Hyperplasia Test
for the Prediction of the Carcinogenicity of Cigarette
Smoke Condensates and Their Fractions. P. LAZAR and I.
CHOUROULINKOV .......................•..................... 383
Squamous Carcinoma of the Lung from Cigarette Smoke Condensate
in Implanted Beeswax Pellets. M.F. STANTON, M.W. LAYARD,
and E. MILLER............................................. 392
SESSION IV
Radiation Carcinogenesis and Bioassays. Chairman: J.F. PARK
Radiation Carcinogenesis. Introductory Remarks. J.F. PARK .... 401
The Effects of Inhaled Uranium Mine Air Contaminants in Beagle
Dogs. R.E. FILIPY, B.O. STUART, R.F. PALMER, H.A. RAGAN,
and P. L. HACKETT ....•..•.•................................ 403
Lesions and Lung Cancers Induced in Rats by Inhaled Radon 222
at Various Equilibriums with Radon Daughters. J. CHAMEAUD,
R. PERRAUD, J. LaFUMA, R. MASSE, and J. PRADEL ............ 411
Studies of Pulmonary Carcinogenesis in Rodents Following Inha
lation of Transuranic Compounds. C.L. SANDERS and G.E. DAGLE 422
Lung Irradiation with Static Plutonium Microspheres. E.C. AN-
DERSON, L.M. HOLLAND, J.R. PRINE, and C.R. RICHMOND ....... 430
XII
Respiratory Carcinogenesis in Rats after Inhalation of Radio
active Aerosols of Actinides and Lanthanides in Various
Physicochemical Forms. J. LaFUMA, J.C. NtNOT, M. MORIN,
R. MASSE, H. METIVIER, D. NOBILE, and W. SKUPINSKI •...... 443
Pulmonary Carcinogenesis and Chronic Beta Irradiation of Lung.
R.K. JONES, F.F. HAHN, C.H. HOBBS, S.A. BENJAMIN, B.B.
BOECKER, R.O. McCLELLAN, and D.O. SLAUSON ............•.•.• 454
Histologic Observations on the Pathogenesis of Lung Cancer in
Hamsters Following Administration of Polonium-210. H. LISCO,
A.R. KENNEDY, and J.B. LITTLE ..............•.........•.... 468
Cellular Localization of Intratracheally Administered 210po in
the Hamster Lung Using Autoradiography of Thin Sections from
Plastic Embedded Tissue. A.R. KENNEDY and J.B. LITTLE ..•.. 475
Experimental Respiratory Carcinogenesis: Interaction between
Alpha Radiation and Benzo(a)pyrene in the Hamster. R.B.
McGANDY, A.R. KENNEDY, M. TERZAGHI, and J.B. LITTLE ......• 485
SESSION V
In vitro Bioassays of Respiratory Carcinogens. Chairman: M.B.
SPORN
Review and Introductory Remarks: The Role of Organ Culture and
Cell Culture Methods in Studies of Respiratory Carcinogene-
sis and Anti-Carcinogenesis. M.B. SPORN ................... 493
Interactions between Radiation and Benzo(a)pyrene in an in vitro
Model for Malignant Transformation. M. TERZAGHI and J.B.
LITTLE .......................................•............ 497
Dose Dependence of Carcinogen-Induced Changes in Tracheal Epi
thelium in Organ Culture. B.P. LANE and S.L. MILLER ....•.. 507
Topical Application of Polycyclic Hydrocarbons to Differenti
ated Respiratory Epithelium in Long-Term Organ Cultures.
B. T. MOSSMAN and J. E. CRAIGHEAD ....•......•............... 51 4
The Bioassay of Carcinogenesis: Effects on the Epithelial Cell
Complement of Rat Tracheae Maintained in vitro. D.W. LINDSAY,
J.R. JONES, W.J. HIGGINS, and P.W. BROWN.................. 521
Effects of Cigarette Smoke Condensate (CSC) on Rat Fetal Lung
in Organ Culture. I. CHOUROULINKOV and M. MICHIELS .......• 532
Tracheal Grafts. R.A. GRIESEMER, J. KENDRICK, and P. NETTES-
HEIM ...................................................... 539
Studies of Ultrastructure, Cytochemistry, and Organ Culture of
Human Bronchial Epithelium. B.F. TRUMP, E.M. McDOWELL, L.A.
BARRET, A.L. FRANK, and C.C. HARRIS....................... 548
Studies on Carcinogen Binding in vitro in Isolated Hamster
Tracheas. D.G. KAUFMAN, V.M. GENTA, and C.C. HARRIS ....... 564