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Report P 0500/3068 Skin Tumorigenicity of Mainstream and Sidestream Whole Smoke Condensate of Standard Reference Cigarette 2R1, 80-Week Dermal Application Study with CD1( ICR)BR and B6C3F1 Mice

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