Abstract
This 502-page scientific report was done at INBIFO, Philip Morris's biological research lab in Europe, and was sent to Ragnar Rylander, a scientist who worked on contract for PM. It is an extensive report on mouse skin painting tests done to determine the carcinogenicity of secondhand (sidestream or "SS") smoke compared with that of mainstream ("MS") smoke. For the test, solids (or "condensate)" were derived from the particulate matter in both mainstream and sidestream smoke and painted onto the skin of 2,625 mice over an 80-week period to gauge the biological reaction.
On page 12, Bates No. 2026051129, under "Condensates," the report states that
"The concentrations of the nitrosamines NNN, NATB, NNK, NAB, NPY, and DMNA were between 0.01 and 1.9 milligrams/liter for [mainstream smoke]and between 0.08 and 6.1 milligrams/liter for [sidestream smoke]. The main differences between [mainstream] and [sidestream smoke] were the higher concentrations: of NNK, NPY, and DMNA for [sidestream]."
It also states that,
"The sum of all PAH [polycyclic aromatic hydrocarbons] were 5-fold higher for [sidestream smoke] than for [mainstream smoke]."
and, on page 14, (Bates No. 2026051131) it states that "The number of mice with signs of intoxication was higher in the [sidestream] than in [mainstream] treated groups."
It also states that:
"The comparison of the mortality of [mainstream] and [sidestream] treated mice showed a statistically significantly higher mortality in the [sidestream]treated groups. This is considered to be biologically relevant."
The "Conclusions" section on page 22 (Bates No.2026051139) states that Sidestream Whole Smoke Condensate collected with an impaction trap (SWSC-I) showed 2 to 6 times higher skin tumorigenicity than Mainstream Whole Smoke Condensate collected in the same manner (MWSC-I). Here is the quote:
"SWSC-I assayed for complete tumorigenic activity, i. e., without DMBA pretreatment, showed a 2- to 6-fold higher skin tumorigenicity than MWSC-I."
The section entitled "Mortality" on Page 14 (Bates No. 2026051131) states that,
"The comparison of the mortality of the [mainstream] and [sidestream] treated CD1 and B6C3FI mice showed a statistically significantly higher mortality in the [sidestream] treated groups. This is considered to be biological relevant."
On Page 17 (Bates No. 2026051134), a section entitled "Skin Irritations" states,
"The comparison of skin irritations in [mainstream] and [sidestream] treated CD1 mice showed a statistically significantly higher number of mice with skin irritations in the [sidestream] treated groups. This is considered to be biologically relevant."
On Page 21 (Bates No. 2026051138) a section describing "Pathological Findings" states that,
"The relative skin tumor rate (b), was statistically significantly higher in
(1) [Sidestream treated mice] without and with DMBA pretreatment than in [mainstream treated mice] without and with DMBA pretreatment...These effects are considered to be biologically relevant."
NOTE: Some of the mice were pre-treated with an "initiator" (DMBA), a chemical that was believed to help tumors start forming, but which does not to promote them once they are formed.
The report, dated 26 October 1987, seems to show that Philip Morris had done biological testing on secondhand smoke and found that secondhand smoke was more biologically active than mainstream smoke.
Fields
- Notes
Page 7 of the document (Bates No. 2026051124) contains a glossary of abbreviations which is very helpful. This document was used as a Trial Exhibit in Minnesota's case against the industry.
- Quotes
ABBREVIATIONS
DBMA - 7,12-dimethylbenz(a)anthracene (a tumor initiator used in pretreating some mice)
MSW - Mainstream smoke
SS - Sidestream smoke
WSC - Whole smoke condensate
MWSC-C - Mainstream whole smoke condensate collected with cool trap
MWSC-I - Mainstream whole smoke condensate collected with impaction trap
SWSC - Sidstream whole smoke condensate
SWSC-I - Sidestream whole smoke condensate collection with impaction trap
[From Page 21, 2026051138]
The relative skin tumor rate (b), was statistically significantly higher in (1) SWSC-I without and with DMBA pretreatment than in MWSC-I without and with DMBA pretetreatment...These effects are considered to be biologically relevant.
[From Page 22, 2026051139
Conclusions...
...From the results obtained in the present study, the following is concluded for the skin tumorigenicity, i. e., tumor probability, tumor multiplicity, and malignancy of WSC-I of the standard refer- ence cigarette type 2RI: (
I) SWSC-I assayed for complete tumorigenic activity, i. e., without DMBA pretreatment, showed a 2- to 6- fold higher skin tumorigenicity than MWSC-I. SWSC-I with DMBA pretreatment showed a 2- to 3-fold higher skin tumorigenicity than MWSC-I with DMBA pretreatment indicating a higher promoting activity of the SWSC-I;
[From Page 25, 2026051142]
Laboratory studies can contribute to a better understanding of the factors and mechanisms involved in the induction of disease by environmental agents. There have been numerous bioassays conducted on mainstream smoke (MS). In examining the effects of MS, many research workers have used condensates of the smoke painted on the shaved skin of mice. This contrasts with the human exposure that occurs mainly in the respiratory tract. Skin painting with WSC serves as a model for skin tumorigenicity of tobacco smoke. Nonetheless, these skin painting studies have been useful in examining the carcinogenicity of different tobacco constituents and thus increases knowledge of the actions of MS. Similar skin painting work has not been sufficiently done with sidestream smoke (SS) condensate and would be of value for assessing the differential tumorigenicity of SS condensate and MS condensate. The burning of tobacco products leads to the formation of MS and SS. MS from cigarettes is generated during puff-drawing in the burning cone and hot zones. It travels through the tobacco column and exits from the mouthpiece. SS is formed, in between puff-drawing and is emitted freely from the smouldering tobacco product into the ambient air, and vapor phase components diffuse through the cigarette paper (a). SS is known to have a different composition than MS (see TABLES A and B) in its vapor phase as well as in its particulate phase. It was found that the level of carbon monoxide, carbon dioxide, pyridine, ammonia, nitrogen oxides, nitrosamines, phenols, amines, polycyclic aromatic hydrocarbons such as benzo(a)pyrene and benz(a)ianthracene was much higher in SS than in MS...
- Company
- Philip Morris
- Author
- Gerstenberg, B. (Food chemist, INBIFO, c. 1987)
- Kuhn, D. (Study Director (mouse skin painting) INBIFO c. 1987)
- Romer, Ewald (Quality Assurance Biologist, INBIFO, c. 1987)
- Teredesai, A. (Pathologist, INBIFO, c. 1987)
- Tewes, F. (Biologist at INBIFO c. 1987)
- Thomas, C.
- Recipient
- Rylander, Ragnar, M.D. (PM contractor, Environmental Hygienist, U of Gothenburg)
Professor of Environmental Hygiene, University of Gothenburg, Sweden. Worked on contract to Philip Morris overseeing biological laboratory work being performed at INBIFO, PM's biological labs in Cologne, Germany. PM paid Rylander $150,000 per year (salary determined from Bliley PM doc 2022850392, from 1992)
- Region
- Switzerland
- Type
- SCRT, REPORT, SCIENTIFIC
- BIBL, BIBLIOGRAPHY
- CHAR, CHART, GRAPH, TABLE, MAPS
- DRAW, DRAWING
- FOOT, FOOTNOTES
- Litigation
- Stmn/Produced
- Stmn/Trial Exhibit P-11753
- Named Person
- Wynder
- Armitage
- Chouroulinkov
- Decoulon
- Downs
- Eaton
- Ehrenstorfer, S.
- Faccini
- Festing
- Fischer, K.
- Forsbach
- Foster
- Grimmer
- Hauschka
- Hoffmann
- Homburger
- Horter, R.
- Kraft
- Lazar
- Levins
- Lynch, C.
- Mirand, E.
- Parker
- Percy
- Peto
- Pullinger
- Richter
- Schahl, R.
- Schonherr
- Tattersall
- Ward
- Windholz
- Operation/Project
- Testing done on sidstream smoke at INBIFO
- Named Organization
- Aesculap
- Auergesellschaft
- Baker Chemikalien
- Bandelin
- Beckman Instruments
- Buchi
- Camag
- Carl Platz
- Carworth Europe
- Diversey
- Dr Henning
- E Merck
- Erba Science
- Fachtierarzt Fur Bakteriologie Und Serol
- Faust
- Fluka
- Forma Scientific
- Ftr, Fabriques De Tabac Reunies S.A.
- Gerhard Teck
- German Futtermittelverordnung
- H Eggersmann
- H Waldner
- Hamilton
- Hartmann Essen
- Henkel Und Cie
- Hermle Laborgerate
- Hewlett Packard
- HRI, Health Research Inst. Roswell Park
- International Agency for Research on Cancer (IARC) (WHO cancer research arm)
International Agency for Research on Cancer - The cancer research arm of the WHO. Conducted a multi-center epidemiology study on ETS, initiated in 1988, data collection completed in 1994 and results were published in 1998
- Ict Handels
- INBIFO, Intitut Fur Biologische Forschung (Philip Morris' secret biological research lab in Europe)
"INBIFO" stands for Institut Fur Biologische Forschung, or Institute for Biological Research. It is located in Germany. Philip Morris acquired Inbifo on June 30, 1971. Its stated mission was "quantitative biological product evaluation" by using "comprehensive toxicological and physiological testing. Major activities are listed as: product evaluation and modifications, product ingredients and ETS-related technical knowledge and smoke components. Inhalation toxicology was a key feature of Inbifo. (Derived from Bates No. 2505235055/5088)
- Inst for Cancer Research Philadelphia
- Isconlab
- Janke Kunkel
- K Neuberger
- Leybold Heraeus
- Linde
- Macherey Nagel
- Metrawatt
- Miele Cie
- Natl Toxicology Program
- Osram
- Packard Instrument
- Philips
- Rockefeller Inst
- Sartorius
- Serva Feinbiochemica
- Shimadzu
- Sigma Chemical
- Teletype
- Thermo Electron
- Vollwood
- A Popp
- INBIFO, Intitut Fur Biologische Forschung (Philip Morris' secret biological research lab in Europe)
"INBIFO" stands for Institut Fur Biologische Forschung, or Institute for Biological Research. It is located in Germany. Philip Morris acquired Inbifo on June 30, 1971. Its stated mission was "quantitative biological product evaluation" by using "comprehensive toxicological and physiological testing. Major activities are listed as: product evaluation and modifications, product ingredients and ETS-related technical knowledge and smoke components. Inhalation toxicology was a key feature of Inbifo. (Derived from Bates No. 2505235055/5088)
- Subject
- secondhand smoke
- secondhand smoke/health effects
- animal research
- animal subject
- mouse skin painting
- Secondhand Smoke/Constituents
Document Images
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IPJ"1'L'lik/i'1'1Nli kEPUk'1" Y 0500/.iUbt3 UBE141RA6 7295 PAGE 1-4
lent to 51 micrograms) per mouse. Both CD1 and B6C3F1 mice re-
ceived the same DMBA dose. 10 days later (a) WSC-I application was
started. To CD1 mice either 60, or 90, or 120 milligrams/(mouse x
week) of processed MWSC-I or SWSC-I prepared in acetone or acetone
alone were applied on 5 consecutive days per week. The application
volume was 100 microliters/(mouse x application). B6C3F1 mice
showed an approx. 30 percent lower body weight than CD1 mice
throughout their lifetime. Therefore, B6C3F1 mice received MWSC-I
doses reduced by approx. 30 percent compared with the doses for
CD1 mice (reduction of the applicatiom volume to 70 microliters/
(mouse x application)). 1 dose was equal for both strains (60
milligrams/(mouse x application)). Considering the strain-de-
pendent reduced body weight, the B6C3F1 mice received the same
doses (mg/kg body weight) as the CD1 mice.
The mice were checked for general condition, behavior, and mor-
tality. The body weight was determined at least fortnightly up to
week 20 of the condensate application period and every 4th week
thereafter. Visual examinations of the skin for macroscopic tumors
and ulcers were performed weekly.
All surviving mice were sacrificed 80 weeks after the 1st conden-
sate application. All mice sacrificed at that time and those that
died "spontaneously" were examined for skin lesions. The skin of
the application area and those sites outside the application area
with lesions were removed and fixed with formaldehyde solution.
Each lesion and 50, skin samples from the application areas without
any macroscopic finding were trimmed, processed, and individually
stained with hematoxylin eosin. The slides were examined and
evaluated histopathologically.
Life table estimates of the histologically confirmed skin tumor
rates (tumor probabilites) were calculated according to Armitage
(1971). For the statistical evaluation of the tumor probability
the chi-square test of life table-adjusted incidences according to
Peto et al. (1980) was used.
(a) no applications in between
..q~
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_ _- -_ - - ---- -----
INTEGRA''1NG REPORT P 0500/3U68 UBE141RA7 --7295 P_AGE 1-5
1.4 Results
1.4.1 Condensates
For this study 176 batches of MWSC-I and 175 batches of SWSC-I
were prepared from approx. 320000 cigarettes (standard ref-
erence cigarette 2R1 ), .
For MS the yield of crude and processed condensate (a) was 48.5
and 39.6 milligrams per cigarette respectively, for SS 22.1 and
19.4 milligrams per cigarette respectively. Thus the yield of the
processed condensate was twice as high for MS as for SS.
The MS application solution was slightly more acidic than the
SS application solution: the pH values were 6.0 and 6.5.
The nicotine concentration for MS was 20.8 grams/liter, and thus
about 20 percent lower than that of SS at 25.1 grams/liter.
The catechol concentration was nearly identical: 1.21 grams/
liter for MS and 1.10 grams/liter for SS.
The concentrations of the nitrosamines NNN, NATB, NNK, NAB,
NPY, and DMNA were between 0.01 and 1.9 milligrams/liter for MS
and between 0.08 and 6.1 millig,rams/liter for SS. The main dif-
ferences between MS and SS were the higher concentrations of NNK,
NPY, and DMNA for SS.
Benzo(a)pyrene, dibenz(a,h)anthracene, and the benzofluoranthenes
may be the most relevant PAH for the mouse skin carcinogenic
activity. Their concentrations were 0.18, 0.01, and 0.17 milli-
grams/liter for MS and 1.25, 0.07, and 1.42 milligrams/liter for
SS. The sum of all PAH were 5-fold higher for SS than for MS.
(a) defined by the procedure of preparation (see SUBREPORT AC
FIGURE A)
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INTEGRATING REPORT P 0500/3068 UBE141RA8 7295 PAGE 1-6
The comparison of volatile components in MS and SS (headspace
chromatography) showed a higher number and concentration in the
former MS than in: the latter SS as well as in the crude and in
the processed condensate. Processing caused a reduction of the
volatile components.
The reproducibility of the condensate preparation was very good
with a relative standard deviation for the processed condensate
yield of 4.7 percent for MWSC-I and 6.1 percent for SWSC-I. No
fluctuations of the concentration of condensate components over
the whole time of condensate preparation (approx. 80 weeks) were
observed. The crude condensate and nicotine yields for MS were in
good accordance with the d ata provided by the client. For SS, data
were not provided by the client.
Concerning the relevance of all condensate data, it has to be
mentioned that condensate characteristics depend on their pre-
paration method. This is especially true for SS condensate as
there are more variables in the generation process than that for
MS.
1.4.2 General-condition-and behavior
In CD1 mice, signs of intoxication were observed from approx.
5 weeks after the start of the application period up to approx.
the 25th application week in the WSC-I treated groups. Only in the
SWSC-I-treated groups did acute signs of intoxication occur up to
the end of the study. The intensity of these signs decreased with
time. The main signs of intoxication were spontaneous activity
which increased immediately after application and later decreased,
prone position, dyspnea, decreased body temperature, and either
a partial or complete closing of the palpebral fissure. The signs
of intoxication increased with ascending doses. Dose groups with
strong signs of intoxication showed high mortality.
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INTEGRATING REPORT P 0500/3068 UBE141RA9 7295 PAGE 1-7
The comparison of the general condition and behavior of CD1 mice
treated with MWSC-I and those with SWSC-I showed differences in
the proportion of signs of intoxication. The number of mice with
signs of intoxication was higher in SWSC-I- than in MWSC-I-treated
groups.
No differences were seen in the general condition and behavior of
both mouse strains which were pretreated with DMBA.
Signs of intoxication were observed in CD1 but not in B6C3F1
mice.
The comparison of the general condition and behavior of CD1
mice did not result in differences depending on whether MWSC-I was
stored before application at 4 or at -75 degrees centigrad~e.
1.4.3 Mortality
The comparison of the mortality of MWSC-I- and SWSC-I-treated CD1
mice showed a statistically significantly higher mortality in the
SWSC-I-treated groups. This is considered to be biologically rele-
vant.
In CD1 mice the pretreatment with an initiating dose of DMBA re-
sulted in a statistically significantly higher mortality in the
SWSC-I dose groups. This statistical significance is considered
to be biologically relevant. In B6C3F1 mice a slightly higher
mortality was seen in the DMBA pretreated: groups which was sta-
tistically significant in the medium- and high-dose groups. This
statistical significance is considered to have no biological
relevance.
The comparison of the mortality of the MWSC-I-treated CD1 and
B6C3F1 mice showed a statistically significantly higher mortality
for CD1 mice. This is considered to be biological relevant.
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1N'1'EGttAY'iNG REPUI2T P 0500/3068 UBE141'RA10 7295 PAGE 1-8
The comparison of the mortality for CD1 mice showed no difference
depending on whether MWSC-I was stored before application, at 4 or
at -75 degrees centigrade.
The proportion of dead CD1 mice with macroscopic skin tumors did
not generally exceed that without skin tumors. Also the overall
mortality of mice with macroscopic skin tumors did not increase,
i. e., the mortality did not increase in relation to: the appear-
ance of skin tumors. Therefore, the reason for the higher mor-
tality in the WSC-I-treated groups is not known.
1.4.4 B'ody-weiSht
Beginning in the 1st third of the study the mean body weight of
both mouse strains of all condensate-treated groups was slight-
ly lower (in application week 80 a maximum of 13 percent in CD1
mice and 9 percent in B6C3F1 mice) than the body weight of the
corresponding control groups. This is considered to be biological-
ly relevant, indicating a slight toxic effect. The toxicity is
thought to be caused by nicotine in the condensate, but other
components may also be relevant. The body weight reduction indi-
cates an appropriate WSC-I dose selection with the highest dose at
the maximum tolerated dose (MTD:), i. e., a dose causing an approx.
10-percent reduction in body weight gain.
The comparison of the body weights of CD1 mice with respect to
MWSC-I and SWSC-I showed no differences.
The pretreatment with an initiating dose of DMBA did not result
in a difference in the body weight of both.mouse strains.
3285
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INTEGRATING REPORT'P 0500/3068 UBE141RA11 7295 PAGE 1-9:
The body weight of the CD1 mice is strain-dependently higher
than that of the B6C3F1 mice. The relative body weight reduction
in the MWSC-I-treated groups was the same in both mouse strains
(-7 percent).
The comparison of body weight in CD1 mice showed no difference
depending on whether MWSC-I was stored before application at 4 or
at -75 degrees centigrade.
1.4.5 Develoement_of_macroscopic_skin_tumors
No macroscopic skin tumors were found in the acetone control
groups. In WSC-I-treated groups the 1st macroscopic skin tumors
were recorded in CD1 mice between WSC-I application weeks 14 and
54 and in B6C3F1 mice between WSC-I application weeks 18 and 66.
At the time when a 10-percent macroscopic tumor rate (MTR) was
reached, a strong dose dependency was observed in CD1 mice treated
with SWSC-I and in B6C3F1 mice treated with DMBA plus MWSC-I.
1.4.6 Skin_irritations_imacroscoLic_diagnosis)
---- ----------- -----
No skin irritations were found in CD1 mice in the control groups.
The 1st skin irritations (translucent and/or reddened skin): in
CD1 mice were detected approx. 2 weeks after the start of the
WSC-I application. The number of mice with skin irritations
reached a maximum during the 4th and 5th week of WSC-I applica-
tion, i. e., after approx. 15 to 25 applications. In the high-dose
groups, skin irritations occurred earlier. Approx. 10!weeks after
the beginning of the WSC-I applications, skin irritations were no
longer observed.
P~
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INTEGRATING REPORT P 0500/3068 UBE:141RA12 7295 PAGE 11-10
The comparison of skin irritations in MWSC-I- and SWSC-I-treated
CD1 mice showed a statistically significantly higher number of
mice with skin irritations in the SWSC-i-treated groups. This is
considered to be biologically relevant.
In CD1 mice the pretreatment with an initiating dose of DMBA re-
sulted in a statistically significantly lower number of mice with
skin irritations both in the MWSC-I- and in the SWSC-I-treated
groups. This effect is considered to be biologically relevant. The
reduced number of mice with skin irritations in the DMBA-pre-
treated WSC-I groups is unexplainable. In B6C3F1 mice no differ-
ence was seen between the MWSC-I-treated groups without and with
DMBA pretreatment.
The comparison of skin irritations between the MWSC-I-treated CD1
and B6C3F1 mice showed a statistically significantly higher number
of mice with skin irritations in the CD1 mouse strain. This, how-
ever, is not considered to be biologically relevant, because the
skin inspection and scoring of skin irritations were hindered by
the brown pigmentation of the skin in B6C3F1 mice.
The comparison of the number of mice with skin irritations in
CD1 mice showed no difference depending on whether MWSC-I was
stored before application at 4 or at -75 degrees centigrade.
1.4.7 Prediction of the microscopic tumor probability in future
studies
For the prediction of the microscopic probability at an early
stage of the experiment, the microscopic tumor probability was
compared with the macroscopic skin irritation, the week of the
-pr.
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INTEGRATING REPORT P 0500/3068 UBE141RB28 7295 PAGE 1-11
tumor onset, the week when 5-percent tumor probability was reached,
and the macroscopic tumor probability of application weeks 30 and
40 in CD1 and B6C3F1 mice. In CD1 mice all macroscopic "short-term"
parameters correlated well with the 80-week microscopic tumor pro-
bability (correlation coefficients 0.93 to 0.68). The macroscopic
parameters, such as the tumor onset, the 5-percent tumor proba-
bility, and the tumor probability in application weeks 30 and 40
were superior to the skin irritation for the predictability of the
microscopic tumor probability. Therefore, for this type of experi-
ment and for comparable test materials, the microscopic tumor pro-
bability can be predicted by the macroscopic tumor probability as
early as after 30 weeks of WSC-I application or by the skin irrita-
tion and the histopathological examination for "hyperkeratosis" (a)
as early as after 5 weeks of WSC-I application. Also in B6C3F1 mice
all macroscopic "short-term" parameters (b)~ correlated well with
the 80-week microscopic probability (correlation coefficients 0.911
to 0.77). The macroscopic parameters, such as the 5-percent tumor
probability and the tumor probability in application weeks 30 and
40 were superior to the tumor onset for the predictability of the
microscopic tumor probability.
1.4.8 Microbialoqical_findincs
The microbiological screening of the CD,1 and B6C3F1 mice showed
significant antibody titers to 4 mouse-related viruses, but no
influence on the results of the study was observed. In addition,
(a) INBIFO study P 0500/3117 (1986)
(b) In B6C3F1 mice skin irritations could not be used for the
prediction, because due to the brown pigmentation of skin such
changes were not observed.
1,8~
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INTEGRATING REPORT P 0'50U/3-068' UBE141RA14 7295 PAGE 1-12
the results of the bacteriological analyses of the mice and the
environment within the animal laboratory units were in agreement
with the microbial flora acceptable for optimal hygienic condi-
tions during long-term studies on mice.
1.4.9 Pathological_findings
50 skin samples from the application, area without any macroscopic
findings were randomly selected f rom various groups and showed no
histopathological findings.
Macroscopic skin lesions consisting of ulcerated and/or nonulce-
rated tumors, ulcers, and pachyd'ermia were observed in many CD1
and B6C3F1i mice in the WSC-I-treated groups, in few CD1 and many
B6C3F1i mice in the DMBA pretreatment acetone control groups, and
rarely in mice of both strains in the acetone control groups.
Almost all of these lesions were confirmed histopathologically.
With few exceptions, the incidence of mice with macroscopic tumors
correlated well (approx. 80 percent) with the incidence of mice
with histopathologically confirmed tumors in the various groups.
Histopathologically, CD1 and B6C3F1 mice in the acetone control
groups showed no skin neoplasms after 80 weeks of WSC-I applica-
tion. In DMBA-pretreated acetone control groups benign as well as
malignant epithelial tumors (papillomas, acanthomas, carcinomas)
were observed in B6C3F1 and only benign epithelial skin tumors in
CD1 mice. Therefore, the chosen DMBA dose was too high to be only
initiating, but the general concept of this study is not inva-
lidated by the DMBA overdosing. The incidence of epidermal hyper-
plasia and of dermal inflammatory changes was low (1 to 3 percent)
in both mouse strains.
1285
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1... ., .. . ., -....1 iru. i ~.~....~~......J' tVUl11
INTEGRATING REPORT P 0500/3068 UBE191RA15 7296 PAGE 1-13'
The mice of the WSC-I-treated groups without and with DMBA pre-
treatment showed neoplastic and monneoplasttiic skin changes in the
application area which are usually expected after repeated appli-
cation of whole smoke condensate. The neoplastic changes consisted
mainly of benign (papilloma, acanth:oma) and mal~ignant (carcinoma)
epithelial neoplasms. In addition to these epithelial neoplasms
sporadically benign (hemangioma) and a few malignant (fibrosarcoma)
mesenchymal skin neoplasms mainly in SWSC-I groups without and
with DMBA pretreatment were also observed. The incidence of these
mesenchymal neoplasms was low (below 3 percent). A similar inci-
d~ence was also observed in former skin tumorigenicity studies:
The incidence of spontaneous mesenchymal skin tumors in CD1 mice
as mentioned in the literature does not exceed 1 percent (Hombur-
ger et al., 1975, Faccini et al., 1981). Cigarette smoke conden-
sate (CSC) usually induces both benign and malignant tumors of
epidermal origin on mouse skin. Induction of mesenchymal tumors,
however, has not been reported in the literature. Though they are
observed in WSC-I-treated groups in the present and previous
INBIFO studies their association with WSC-I treatment is of doubt-
ful biological relevance. Leukemic infiltrations were sporadically
observed in CD1 mice in all WSC-I-treated groups. The incidence
ranged between 1 to 5 percent in different groups. A dose-dependent
increased incidence was observed in SWSC-I with DMBA pretreatment.
Mouse skin painting studies with CSC reported to date have not
shown a linkage between CSC application and incidence of leukemic
infiltration. Such a linkage, however, was described between CSC
application and the low but significant incidence of cutaneous
mastocytomas and diffuse dermal mast-cell infiltration. This
information may make a reevaluation necessary.
With few exceptions, at comparable dose levels, numerically an
earlier tumor onset, a higher skin tumor probability for total
epithelial tumors as well as for benign and malignant epithelial
tumors, a higher multiplicity and more malignant epithelial tumors
p,
