Anne Landman's Collection
Biological Effects of Smokeless Tobacco Products
Abstract
This 1982 Philip Morris (PM) memo was written after PM's Chief Executive Officer (Hugh Cullman) asked Thomas Osdene (Director of PM's research department) to investigate the biological effects of smokeless tobacco, and report back. After researching the literature regarding smokeless tobacco, Osdene wrote back to Cullman (in the cover memo for this report) saying, "I believe the correlation between use of [smokeless tobacco] and oral cancer is quite strong..." (PM Bates No. 2001207640). The body of the report states,
"Retrospective surveys have implicated snuff as a major risk factor in oral cancer particularly in females. The geographic distribution of this cancer correlates directly with geographical areas of widespread snuff use. The most conclusive studies have shown that approximately 90% of the women in the rural Southeastern United States who develop cancers of the buccal mucosa are snuff users."
* Histopathological studies have shown that snuff use is associated with a distinctive verrucose squamous carcinoma of the buccal cavity.
Thus this memo shows that in 1982 Philip Morris knew the extent of the carcinogenic threat chewing tobacco posed to users. (The company did not manufacture chewing tobacco.) They also were aware that nicotine-dependent people commonly used chewing tobacco as a substitute for smoking.
Fields
- Quotes
Snuff has been proposed as an acceptable alternative to smoking because of the rapid absorption of nicotine through the buccal mucosa.
* Snuff users experience elevations in blood pressure and heart rate, probably due to the rapid absorption of nicotine.
* Retrospective surveys have implicated snuff as a major risk factor in oral cancer particularly in females. The geographic distribution of this cancer correlates directly with geographical areas of widespread snuff use. The most conclusive studies have shown that approximately 90% of the women in the rural Southeastern United States who develop cancers of the buccal mucosa are snuff users.
* Histopathological studies have shown that snuff use is associated with a distinctive verrucose squamous carcinoma of the buccal cavity.
The rapid absorption of nicotine from snuff is one reason why several investigators have proposed snuff as a satisfying alternative for nicotine-dependent smokers...
Switching from cigarettes to snuff would reduce the risk of lung cancer, bronchitis, and emphysema at the cost of a lesser increase in the risk of cancer oral cavity or nasopharynx...
- Company
- Philip Morris (A division of Altria Group)
- Author
- John, Judith E. (PM scientist)Judy E. John was a Philip Morris Scientist. (PMI's Introduction to Privilege Log and Glossary of Names, Estate of Burl Butler v. PMI, et al, April 19, 1996)
- Recipient
- Osdene, Thomas Stefan, Ph.D. (Director of Science and Technology, Philip Morris [1986])Ph.D. in Organic Chemistry. Ten years of research when he started with PM in 1965. Worked in Chemical Research Division of PM 1965-66; Chemical and Biological Research Division 1966-69; Director of Research 1969-1984, also assumed independent position as Director of Research and Extramural Studies during these years; became Director of Science and Technology in 1984, reporting directly to Philip Morris USA Executive VP Mark Serrano. Involved with Center for Indoor Air Research (CIAR) 1988. Attended PM's Operation Downunder Conference in June, 1987. Retired 1993.
Plaintiff
Institute of Psychiatry, Addiction Research Unit, Bethlem & Mausley Hospital, London, England
Johns Hopkins animal pathologist - does work for the tobacco co's
Document Images
PHILIP MORRIS U. S. A.
INTER-OFFICE CORRESPONDENCE
R{CII'NOND, VJ RGIttIA
To: . Dr. T. S. Osdene Date: Apri l! 8, 1:982
From: . J. John
Subject: . Btological: Effects of Smokeless Tobacco Products
SUMMARY
* Snuff contains tobacco specific nitrosamines (TSNA) which are formed
' during curing and manufacture of tobacco. Additional TSNA are formed in
the saliva of the snuff user. There is wide variation in the levels of
TSNA in snuff and in the saliva of snuff users.
* Snuff has been proposed as an acceptable alternative to smoking because
of the rapid absorption of nicotine through the buccal mucosa.
* Snuff users experience elevations in blood pressure and heart rate,
probably due to the rapid absorption of nicotine.
* Retrospective surveys have implicated snuff as a major risk factor in
oral cancer particularly in females. The geographic distribution of this
cancer correlates directly with geographical areas of widespread snuff
use. The most conclusive stud:es have shown that approximately 90% of
the women in the rural Southeastern United States who develop cancers of
the b,ccal mucosa are snuff users.
* Histopathological studies have shown that snuff use is associated with a
distinctive verrucose squamous carcinoma of the buccal cavity. It is not
clear whether snuff acts as a promotor or initiatorfor this tumor.
* Snuff has not been shown to induce oral cancer in any animal models.
INTRODUCTION
The practice of placing a small amount of powdered tobacco in the gingivobuccal
groove and leaving it there for extended periods of time iis known as "snuff
di'pping". In Britain, snuffing consists of inserting powdered tobacco into the
nose. Snuff has beeni suggested by Russell to be a satisfactory alternative for
cigarette smokers dependent on nicotine. Nicotine is rapidly absorbed through
buccal mucosa in oral snuffing and through the nasal mucosa in nasal snuffing.
Snuffing provides the smoker with an easily absorbed source of nicotine.
The use of snuff is on the increase in the United States and in Britain. One
estimate is that snuff may be used by at least one in every 12 to 15 people in
the U.S., and by about 500,000 people in Britain. Sales of oral tobacco
products have increased by more than 25% since 1976, especially among younger
adults. Snuffing is very popular among women in the Southeastern United
States.
The chemistry and pharmacological effects' of snuff will1 be reviewed in this
paper. In addition, the health effects of snuff in animal and humans will also
be discussed.
Chemistry of Snuff
In order to determine the carcinogenic potential of snuff, Hoffman et al
analyzed popular snuff products from the United' States, Germany, Sweden and
Denmark for tobacco specific N-nitrosoamines (TSNA). These compounds are
formed~ during the manufacture and curing of tobacco from nicotine, nornicotine,
and anatabine and represent the only known carcinogens in snuff. Earlier
studies had shown that nicotine and nornicotine are effective precursors in
vitro for N°-nitrosonornicotine (NNN), 4-(N-methyl-N-nitrosamino)-4-(3-pyridyl)-
butanal (NNA)~, and~ 4-(N!-methyl-N-nitrosamino)~-1-(3-pyridyl')-1-butanone (NNK).
(Hecht, 1978).
The results of this study are shown in Table I.
Table I
N
Levels of TSNA in Snuff O
O
Product
Total TSNA
NNN
NNK NNT N
N
Snuff
5.5-1.06 ppm
3.5-77 ppm
0.6-7.0 ppm: 0.8-44 ppm O
~
Cig. Tobacco
0.3-5.0 ppm Cn
~
N
Cig. Smoke 0.3-5.&ug/cig.
A recently introduced U.S. brand of snuff contained only 6.6 ppml total TSNA,
which indicates that a change in manufacture can lead to reduced TSNA yield.
This study also shows that the concentration of alkaloids, especially nicotine,
is not a rate-determining factor in the formation of TSNA.
In addition to the TSNA naturally occurring i'n dry snuff, additional amounts of
TSNA can be formed in the saliva during snuff dipping. In the saliva of women
who were long-term snuff dippers, there was a wide range in the concentrations
of TSNA in the saliva of individual snuff dippers. During snuff use, TSNA
appears to be extracted from the -tobacco plug at varying rates. Hoffman
calculated that the women were exposed to 1-20 ug of TSNA during 1 hour of snuff
dipping. The results are shown in Table II.
Table II,
TSNA in Saliva of Snuff-Dippers
No. Ace NNN NNK NAT
1 45 840 5.0 7.5 6.6
2 43 900 27.1 20.1 14.2
3 40 1500 21.7 2.1 28.8
4 53 1600 125.0 201.0 147.0
i
This study presents experimental support for the correlation of snuff dipptng
with~ cancer of the gum and buccal mucosa in snuff dippers. However, there is
very wide variation in the levels of TSNA in dry snuff and in the saliva of
snuff dippers. The study is significant because TSNA are the only known carcin-
ogens in snuff, and are therefore the presumed source of risk of oral cancer in
snuff dippers.
New manufacturing methods and airtight wrappings of individual portions of snuff
can reduce the concentrations of TSNA in snuff. Hoffman, 1981).
Another nitrosamine, N-nitrosodiethanolamine (NDELA) is found in many environ-
mental sources, including tobacco products and smoke. NDELA arises from the
treatment of tobacco with the sucker grouth inhibitor maleic hydrazide-diethano-
lamine (MH-DELA). NDELA is formed furing tobacco processing. Snuff tobacco,
which goes through a long-term fermentation process contains much higher amounts
of NDELA (3.2 - 6.8 ppm) than does smoking tobacco after curing (0.1 - 0.4 ppm)1.
The longer fermentation process also leads to higher level!s of other TSNA.
(Brunnemann, 1981).
Pharmacologi'c Effects of Snuff
Effects of Nicotine in Snuff
The rapid absorption of nicotine from snuff is one reason why several investiga-
tors have proposed snuff as a satisfying alternative for nicotine-dependent
smokers. Russell compared blood nicotine 1!evels for non-inhaling cigar smokers
with those of snuff users. The bucccal absorption of nicotine was very slow
even when a cigar was smoked in such a way as to maximize absorption. However,
the rate of nicotine absorption from snuff is very rapid. The blood-nicotiine ~
level of over 40 ng/ml matches the peak levels found iin heavy cigarette smokers, p
whi,ch average about 35 ngJml. Although the user does not get the puff-by-puff O
high nictoine boli obtained by inhaling cigarette smoke, it takes the smokerF,
about 10 minutes to reach a peak nicotine level compared with 5 minutes or less O
for the snuff user. (Russell, 1980). ~
~
W
In a later study, RusselT' measured blood nicotine and cotinine concentration in
27 volunteers before and after taking snuff. These results confirm -his earlier
conclusions on the very rapid absorption of nicotine by snuff users. Wi'th~in 10
minutes after snuffing blood nicotine, concentrations were comparable to those
obtained after 10 minutes of smoking a cigarette. Nicotine intake correlated
directly with the length of experience of the snuffer, as shown below.
Taple III
Comparison of Plasma Nicotine and Cotinine Concentrations
Experience Plasma Nicotine (nmol/1) Plasma Cotinine (nmol/1)
Novice 37.9 202.8
Occasional 121.3 1200.6
Daily 222.6 2352.5
,Multiple Dose ,
Snuffing .464.9 2575.2,
Cigarette Smoking: 226.3 1913.3
Rapid Smoking 296.5 Not Given:
The increase in plasma nicotine levels of daily snuffers was comparable to the
average increase obtained by a single cigarette by a group of heavy smokers.
The peak nicotine concentrations in the daily snuffers were also similar to the
peak values of heavy smokers. Unusual multiple-dose snuffing produced' massive
increases in plasma nicotine concentrations that have never been seen in
smokers. Although the plasma cotinine values correlated with increases in
plasma nicotine, the plasma cotinine of daily snuffers averages 23% higher than
those of heavy smokers while the average nicotine levels were similar.
The study suggests that the plasma nicotine concentration has some controlling!
influence over the self-regulation of these two different forms of tobacco use.
The authors conclude that rapid absorption of nicotine from snuff confirms its
potential as an acceptable substitute for smoking. Switching from cigarettes to
snuff-would reduce the risk of lung cancer, bronchitis, and emphysema at the
cost of a lesser increase in the risk of cancer oral cavity or nasopharynx.
(Russell, 1981)
Cardiovascular Effects of Snuff N
The rapid absorption of nicotine through, the oral mucosa i'.s thought to be 0
responsible for the cardiovascular effects that have been observed in snuff ~a
users. N
O
Squires et al evaluated the effect of snuff on the blood pressure of 20 male ~
athlete volunteers, ten of whom were users of oral tobacco and 10 of whom were ~
not. Alil volunteers abstained fromitobacco use for 72 hours, baseline electro- ~'
cardiograph and blood pressure measurements were taken and then a 2.5 g pinch of ~
tobacco was placed in each. man's mouth. Within 20 minutes, heart rates
increased from a mean-of 69 `to 88 beats/minute. Mean blood'i pressure values rose
approximately 9%, from 118/72 to 126/78 mm Hg. Both heart rate and blood pres-
sure returned to normal after the tobacco was removed. The authors conclude
that snuff use`can produce'significant cardiovascular effects, particularl!y in
those persons predisposed to hypertension. (Squires, 1982).
Animal Studies on the Health Effects of Snuff
Results of animal studies linking oral cancer with snuff are not conclusive, in
part because there :is' not:_.a-_g'ood animal mode:l. Shat ` dupli.cates snuff use in
humans and because of chemical variations in snuff. Tobacco specific nitro-
sami nes, whi ch are .._found . i.n,-.snuff, have i nduced cancer i n mi ce (Hecht, 1978).
Peacock placed snuff in the cheek pouches of hamsters for one year, but none of
the animals developed cancer (Peacock, 1959).
Another investigation on the carcinogenic potential of snuff showed no adverse
effects in hamsters exposed for 51 weeks to d'aily periods of snuff inserted into
their oral cavities by means of a special bit. (Homberger, 1971) A second
study was designed to determine whether snuff in the diet was carcinogenic or
cocarcinogenic when administered with a known carcinogen, 20-methylcholanthrene
(MC). The diet contained 20% snuff as powdered tobacco given by gavage. These
chronic feeding studies did not show any carcinogenic or cocarcinogenic effects
of snuff. The only effect of snuff was a slower growth of the animals in one of
the inbred lines, due to a reduced food consumption. The presence of cotinine
in the serum: was considered proof of the absorption of nicotine from the
ingested'snuff. (Homberger, 1976).
In another attempt to develop an animal model, Smith placed snuff in the cheeks
of monkeys for over 7 years. Again, there was no evidence of tumor development
in these animals (Smith, 1970).
One implication of this study is that gastric epithelium, is not as susceptible
to the carcinogenic effects of snuff that have been impl,icated for humans. In
addition, the carcinogenic effects of snuff might be species specific.
Correlation of Oral Cancer with Snuff in Humans
Several case reports and broader epidemiologic studies have pointed to the cor-
rellation of the high incidence of cancer of the lip and buccal mucosa in various
parts of the world with, the use of snuff, chewing tobacco, betel, or quid.
These buccal carcinomas are usually located in those areas where chewing tobacco
or snuff is held in the mouth. An early report linked chewing tobacco with aa
distinct squamous carcinoma of the oral cavity. (Friedell, 1941) In a later
study, _11 or 18 patients with lesions of the buccal mucosa were reported to be
tobacco chewers. (Ackerman, 1948). Other case reports have implicated snuff use
with the development of an invasive, verrucose, squamous carcinoma of the buccal
mucosa with leukoplakia and invasion of underlying tissue, including bone. One
investigator 1'abelled snuff use as "self-induced carcinogeneis". (St reker,
1964)~.
Further characterization of the pathology of lesions found in snuff users was
carried't out by Pindborg. In 12 biopsy speciments of Danish snuff users, snuff-
induced' labial mucosa leukoplakias showed a characteristic chevron pattern of
keratinization with very hyperplastic epithelium. This chevron keratinization
was also found in other types of tobacco usage. It is significant that not a
single case of epithelial dysplasia was found'among the 50 cases of chevron-type
keratinization. The authors were unable to explain the benign nature of this
snuff-association pathology of keratinization. (Pindborg, 1980).
It appears that in humans tobacco and snuff may have promoting of oral cancer.
Pindborg biopsied the side of the cheek where snuff was held in 12 male
patients. They found hyperplasia of the epithelium in all 12 specimens. They
concluded that tobacco promotes epithelial proliferation of the oral mucosa
regardless of the manner in which it is used. (Pindborg, 1963).
Epid'eniiology of Oral Cancer in Relation to Snuff Use ~
The use of snuff has been suggested as a' risk factor in cancer of the oral
cavity and pharynx due to distinctive sex and geographic distribution of mortal-
ity from these cancers. The strongest evidence of this association are the
results of the study by Winn on snuff-using women in North Carolina carried out
in 1981.
The results of this study involving 255 women with oral and pharyngeal cancer
and 502 controls indicates that the excess mortality from these neoplasms in the
South results from the use of snuff. The increased risk of oral and pharyngeal
cancer was fourfold among snuff users. For cancers arising in the and buccal
mucosa, the risk was nearly 50-fold among long-term users and at least 87%' of
these tumors were attri butabl e to snuff use. The risk of cancers el sewhere i n
the oral cavity and pharynx was also elevated among snuff dippers, but to a less
degree and with no dose-response relationship (Winn, 1981).
"Snufif Dipper's Carcinoma" was evaluated by Westbrook using hospital records in
Arkansas. Of the 55 female patients with cancer of the buccal mucosa or gums,
50 had a history of dipping snuff. Most of the cancers originated in~the buccal
mucosa, with the lower gum as the primary site. Most lesions were well differ-
entiated squamous cell carcinomas. These authors admit that the lesions they
encountered'were more varied and more severe than those mentioned in the litera-
ture. The excess of risk of oral cancer among snuff users in the Southeastern
United States is similar to that observed among users of tobacco chews and
powders such as "khaini" and "pan" in India and Southeast Asia and "nass" in
certain Soviet republic. (Mahboubi, 1977).
The results of the Third! National Cancer Survey showed position assoications
between the use of cigar, pipe and chewing or snuff tobacco and cancer of the
oral cavity and': larynx, and with cancer of the stomach, colon, testis, andN
uterus (Williams, 1977). Chewing and snuff tobacco seem to pllay a primary role0
because they showed~ the strongest associatiom with cancers of the gum an1i
mouth. N,
O
~
~
~
0~
A survey of bucca1 cavity and pharynx cancer mortality in the United States
counties, 1950-1969, reveated elevated rates in urban males throughout the
country and among females in the rural South. Tobacco smoking and al'cohol, con-
sumption were the. major factors for: urban~ males. But the cluster -of Southern
females conforms to the geographic pattern of clinical reports of "snuff
dipper's cancer" in Georgia and North Carolina. In Georgia, one study reported
that 39% of the urban women and 72%-,of, the rural women with oral cancer used
snuff, compared tq control -figures.that were below 5% and 20%, respectively.
(Peacock, 1963).
In summary, these retrospective studies of patients with oral cancer can be
used to draw the following conclusions:
* Cancer of the gingivobuccal 'area is more common in femals than in males.
* Approximately 90% of the women with this lesion, particularly in South-
eastern eastern United States,-use snuff.
* There is a correlation between snuff use and verrucose squamous dell
carcinoma.
* The histopathology of oral cavity of snuff dipper's shows primarily
leukoplakia and epithelial hyperplasia or dysplasia. This hi'stopathology
is not conclusive evidence of premalignant changes.
* Despite a strong epidemiologic association, there is not agreement in the
literature that snuff is the primary cause of buccal mucosal cancer.
More than likely, snuff acts as one of many promoting substances in the
oral cavity. Another reason for this discrepancy is that all snuffs are
not alike chemically and probably have different potentials for carcino-
genicity in humans.
REFERENCES
1. Harrison, D.
Snuff - Its use and abuse. British Medical J. 2:1'649-1G511, 1964.
2. Hoffman, D.
Carcinogenic tobacco-specific N-nitrosamines in snuff and i'n the saliva
of snuff dippers. Cancer Research, 41(11), Pt 1, 4305-4308, 1981.
3. Hecht, S.
Tobacco-specific nitrosmaines: formation from nicotine in vitro an6
du!ring tobacco curing and carcinogenicity in Strain A mice. J. Nati
Cancer Inst. 60(4), 819-824, April, 1978.
4. Hecht, S., Chen, C.
Chemical studies on tobacco smoke. LVI. Tobacco specific nitro-
samines: origins, carcinogenicity and metabolism. IARC Sci Publ; (19)
: 395-413, 1978.
5. Brunnemann, D., Hoffman, D.
Assessment of the carcinogenic N-nitrosodiethanol!amine in tobacco
products and tobacco smoke. Carcinogenesis (London); 2(11), 1123-1127,
1981.
6. Russell, M. A. FI., Jarvis, M., Feyerabend~, C.
. A new age for snuff? Lancet, 1 March, 1980.
7. Russell, M. A. H.
Nicotine intake by
September, 1981.
snuff users. British Medical J. 283, 814-817, 26
8. Gunby, P.
Snu." gives heart rate, blood pressure a kick. JAMA 247(7), 947, 19
February 1982.
9. Homberger, F., Hsdeh, S., Russfield, A.
Absence of carcinogenic effects of chronic feeding of snuff in inbred
Syrian hamsters. Toxicol. Appl. Pharmacology, 35(3): 515-521, 1976.
10. Streker, R., Devine, K., Harrison, E.
Verrucose "snuff dipper's" carcinoma of the oral cavity. A case of
self-induced carcinogenesis. JAMA 189(11): 838-840, 1964.
11. Rosenfeld, L, Callaway, J.
Snuff Dipper's Cancer. Amer J. Surg. 106: 840-844, November, 1963. O
12. Schottenfeld, D. ~
~
'
s cancer. New Eng. J. Med. 304(13), 26 March, 1981.
Snuff dipper
13. Gonzalez, E.
Snuffing out the cigarette habit: how about another source of nico-
tine? JAMA 244(2), 112-114, 11 July 1980.
14. Mahboubi, E.
The epidemiology of oral cavity, pharyngeal and esophageal cancer out-
side of North American and Western Europe. Cancer 40: 1879-1886,
1977.
15. Winn, D., Blot, W., Shy, C.
Snuff dipping and oral cancer among women in the Southern United
States. New Eng. J. Med. 304(13), 745-749, 26 March 1981.
16. Williams, R., Horm, J. '
Association of cancer sites with tobacco and alcohol consumption and
socioeconomic status of patients: interview study from the Third
National Cancer Survey. J. Natl..Cancer Inst. 58(5), 525-547, 3 March
1977.
17. Goldsmith, D., Winn, D.
Hazards with snuff. Lancet (England) 1/8172, 825, 12 April 1980.
18. Joint Iran-International Agency for Research, on Cancer Study Group
Esophageal cancer studies in the Caspian Littoral of Iran: Results of
populaton studies - a prodome. 59(4), 1127-1138, 4 October 1977.
19. Fonts, E., Greenlaw, R. Rush, B.
Verucous squamous cell carcinoma of the oral cavity. Cancer, 23(11),
152-160, 1969.
20. Pindborg, J., Reibel, J., Roed-Petersen, B.
Tobrrco-induced changes in oral leukoplakic epithelium. Cancer, 45(9),
233.`-2336, 1 May 1980.
21. Westbrook, K., Suen, J., Hawkins, J.
Snuff dipper's carcinoma: fact or fiction? Prevention and Detection
of Cancer, Part II, Detection, Vol. 2, International Symposium on
Detection and Prevention of Cancer held in New York, NY, April 26,
1976, Nieburgs, HE, ed. New York, Narcel Dekker, Inc., (pp 1367-1371)
1153 pages, 1980.
22. Ackerman, L.
Verrucous carcinoma of the oral cavity. Surg. 23: 0-678, 1948.
N
24. Peacock, E., Brawley, B. 0
An evaluation of snuff and tobacco in the production of mouth cancer. ~
Plastic and Reconstructive Surgery and the Transplantation Bul!letin. N
23:628-635, 11959. O
NI
25. Peacock, E., Greenberg, B., Brawley, B. Q)
The effect of snuff and tobacco on the production of oral carcinoma:K~b
an experimental and epidemiological study. Ann. of Surg. 151:542-550, CD
1960.
26. Pindborg, J., Renstrup, G.
Studies in oral leukoplakias. Acta Dermato-Venereologica, 43:271-276,
1963.
27. Smith, J., Minder, H., Hopkins, K.
Snuff dipper's lesion: a cytological and pathological study in a 1!a.rge
popu1ation. Archives Otolaryngology 92:450-456, 1970.
28. Blot, W., Fraumeni, J.
Geographic patterns of oral cancer in the United States: etiological
implications. J. Chronic Dis. 30(11), 745-757, 1978.
29. Christen, A., McDaniel, R., Doran, J.
Snuff dipping and tobacco chewing in a group of Texas college athletes.
Texas Dental! J. 6-10, February, 1979.
30.-Axell, T., Mornstad, H., Sundstrom, B.',
The relation of the clinical picture of the histopathology of snuff
dipper's lesions in a Swedish population. J. Oral Path. 5: 229-236,
1976.
31. Roed-Petersen, B., Pindborg, J.
A study of Danish snuff-induced oral leukoplakias. J. Oral Path.
2:301-313, 1973.
32. Vun:::is, H., Jarvik, M.
Plasma nicotine and cotinine concentrations in habitual smokeless
tobacco users. Clin. Pharmacol. Ther. 30:201-209, August, 1981.
IF
