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Smokeless tobacco: The folkIore and social history of snuffing, sneez-
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(2) Schuman, L.M. Patterns of smoking behavior. In: M.E. Jarvick, J.W.
Cullen, E.R. Critz, T.M. Vogt, and L.J. West teds.). Research on smok-
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(3) Shelton, A. Smokeless sales continue to climb. Tobacco Reports, p. 42.
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(4) Maxwell, J.C., Jr. Chewing, snuff is growth segment. Tobacco Reports,
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(5) Winn, D.M. Tobacco chewing and snuff dipping: An association with
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Bartsch (eds.). N-Nitroso Compounds Occurrence, Biological Effects
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(6) Rosenfeld, L., and Cahaway, J. Snuff dipper's cancer. Am. J. Surg. 106:
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(7) Agricultural Market Service. Tobacco in the United States. U.S.
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(8) Davis, D.L. Smokeless tobacco products and their production in the
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Maryland, January 13-15, 1986, and personal correspondence.
(9) Bantle, L.F. Smokeless tobacco-A trend to watch. Ihbak J. Int. 4:
344-346, 1980.

(10) Rizio, D. Smokeless tobacco. Thbak J. Int. 2: 183-184, 1984.
(ll/ U.S. Department of Agriculture, Economic Research Service. Tobacco:
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(12) U.S. Department of Agriculture, Agricultural Marketing Service.
  Annual report on tobacco statistics, 1973. (Statistical Bulletin No. 528).
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(13) U.S. Department of Agriculture, Agricultural Marketing Service.
  Annual report on tobacco statistics, 1976. (Statistical Bulletin No. 570).
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(14) U.S. Department of Agriculture, Agricultural Marketing Service.
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(15) U.S. Department of Agriculture, Agricultural Marketing Service.
  Tobacco stocks, as of January 1, 1983. Washington, D.C., 1983.
(16) U.S. Department of Agriculture, Agricultural Marketing Service.
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(17) U.S. Department of Agriculture, Agricultural Marketing Service.
Tobacco stocks, as of January 1, 1986. Washington, D.C., 1986.

26


(18) National Clearinghouse for Smoking and Health. Use of tobacco: Prac-
tices, attitudes, knowledge, and beliefs. U.S. Fail 1964 and Spring 1966,
  July 1967.

(19) U.S. Department of Health, Education, and Welfare. Smoking and
health-A report to the Surgeon General. Office on Smoking and
  Health (DHEW Publication No. PHS 79-50066). 1979.
(20) National Clearinghouse to3 Smoking and Health. Adult use of tobacco,
1975. U.S. Department of Health, Education, and Welfare, Public
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(21) National Center for Health Statistics. National Health Interview
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(22) Simmons Market Research Bureau, Inc. Study of Media and Markets,
  1980-1985.

(23) Simmons Market Research Bureau, Inc. Simmons National College
  Study, 1983 and 1985.

(24) Office on Smoking and Health. Current Population Survey, 1985
  (unpublished).

(25) Rouse, B.A. National prevalence of smokeless tobacco use. Presented
at the NIH Consensus Development Conference on the Health ImpIica-
  tions of Smokeless Tobacco Use, Bethesda, Maryland, January 13-15,
  1986.

(26) U.S. Department of Commerce, Bureau of the Census. (CP Series P25,
  No. 922), 1982.

(27) Hartge, P., Hoover, R., and Kantor, A. Bladder cancer risk and pipes,
  cigars, and smokeless tobacco. Cancer 55: 901-906, 1985.
(2%) Glover. E.D., O'Brien, K., and Holbert, D. Prevalence of smokeless
  tobacco use in Pitt County, North Carolina. Int. J. Addict. (in press).
(29) Gritz, E.R., Ksir, C.. and McCarthy, W.J. Smokeless tobacco use in the
  United States: Past and future trends. Ann. Behav. Med. 7: 24-27,1985.
(30) Glover, E.D., Johnson, R., Laflin, M., and Christen, A. Smokeless
  tobacco trends in the United States. World Smoking and Health (in
  press).

(31) Marty, P.J., McDermott, R.J., Young, M., and Guyton, R. Prevalence
and psychosocial correlates of dipping and chewing in a group of mraI
  high school students. Health Educ. (in press).
(32) Marty, P.J., McDermott, R.J., and Wihiams, T. Patterns of smokeless
tobacco use in a population of high school students. Am. J. Public
  Health 76: 190-192,1986.
CW Newman, I.M.. and Duryea. E.J. Adolescent cigarette smoking and
  tobacco chewing in Nebraska. Nebr. Med. J. 66: 243-244, 1981.
(34) Bonaguro, J.A., Pugy, M., and Bonaguro, E.W. Multivariate analysis
of smokeless tobacco use by adolescents in grades four through twelve.
  Health Educ. (in press).

(35) Lichtenstein, E., Severson, H.H., Friedman, L.S., and Ary, D.V. Chew-
ing tobacco use by adolescents: Prevalence and relation to cigarette
  smoking. Addict. Behav. (in press).

27


(36) Severson, H., Lichtenstein, E., and Gallison. C. A pinch or a pouch in-
  stead of a puff? Implications of chewing tobacco for addictive pro-
  cesses. Bulletin of Psychologists in Addictive Behaviors 4: 85-92,1985.
137) Jones, R.B. Smokeless tobacco: A challenge for the 80's. Journal of the
  Wisconsin Dental Association 10: 71'7-721, 1985.
(38) Chassin. L., Presson, C.C., and Sherman, S.J. Stepping backward in
  order to step forward: An acquisition oriented approach to primary
prevention. J. Consult. Clin. PsychoL (in press).
(39) Chassin, L., Presson. C.C., Sherman, S.J., McLaughlin, L., and Gioia,
  D. Psychological correlates of adolescent smokeless tobacco use.
  Addict. Behav. (in press).

(40) Greer, R.O., and Poulson, T.C. Oral tissue alterations associated with
the use of smokeless tobacco by teenagers, I. Clinical findings. Oral
  Surg. 56: 275-284, 1983.

(41) Paulson, T.C., Lindenmuth, J.E., and Greer, R.O. A comparison of the
use of smokeless tobacco in rural and urban teenagers. CA 34: 248-261,
  1984.

(42) Hunter, S.M., Croft, J.B., Burke, G.L., Parker, F.C., Webber, L.S., and
Berenson, G.S. Longitudinal patterns of cigarette smoking and smoke
  less tobacco use in youth. Am. J. Public Health 76: 193-195,1986.
(43) Guggenheirner, J., Zullo, T.G., Krupee, D.C., and Verbin, R.S. Chang-
ing trends of tobacco use in a teenage population in western Pennsyl-
  vania. Am J. Public Health 76: 196-197, 1986.
(44) Schaefer, S.D., Henderson, A.H., Glover, E.D., and Christen, A.G. Pat-
  terns of use and incidence of smokeless tobacco consumption in school-
age children. Arch. Otolaryngol. (in press).
(4.5) Young, M., and Williamson, D. Correlates of use and expected use of
smokeless tobacco among kindergarten children. Psychol. Rep. 56:
  63-66,1985.

(46) Boyd, G.M.. et al. Use of smokeless tobacco among children and
  adolescents in the United States. Prev. Med. (in press).
(47) Evans, R.I., Hansen, W.G., and Mittehnark. M.B. Increasing the valid-
ity of self-reports of smoking behavior in children. J. Appl. Psychol. 62:
  521-523. 1977.

(48J Murray, D.M.. O'Connell, C.M., Schmiel. L.A., and Perry, C.P. The
  validity of smoking self-reports by adolescents: A reexamination of the
  logic and pipeline procedure. Addict. Behav. (in press).
(49) Bauman, K.E., and Dent, C.W. Influence of an objective measure on
self-reports of behavior. J. Appl. Psychol. 67: 623-638, 1982.
(50) Office of the Inspector General. Youth use of smokeless tobacco: More
than a pinch of trouble. U.S. Department of Health and Human Ser-
  vices, January 1986.

28


Chapter 2.

CARCINOGENESIS ASSOCIATED WTTH
  SMOKELESS TOBACCO USE


CONTENTS

Introduction.. ................................... ..3 3

Epidemiologic Studies and Case Reports of Oral
CancerinReIationtoSmokelessTbbaccoUse ............. .33
DataFromNorthAmericaandEurope  .............. .33
  DataFromAsia  ................................ .42
summary......................................4 4
  References ................................... ..4 4

Epidemiologic Studies of Other Cancers
inRelationtoSmokeless'I%accoUse ................... .47
  NasalCancer.................................... 8
EsophagealCancer............................... 8
LaryngealCancer................................ 0
  StomachCancer ............................... ..5 1
Urinary'It-actCancer  ............................ .52
  Other Cancers .................................. .54
  summary.. .................................. ..5 5
  References ................................... ..5 6

Chemical Constituents, Including Carcinogens,
of Smokeless Tobacco  ............................... .58
Chemical Composition of Smokeless Tobacco .......... .58
Carcinogens in Smokeless `Ibbacco .................. .58
Summary......................................6 5
  References ................................... ..6 7

Metabolism of Constituents of Smokeless Tobacco .... .70
  Metabolism of NNK ........................ .71
  Metabolism of NNN ........................ .73
  Metabolism of NMOR  ...................... .74
  summary ................................ .75
  References  ............................... .75

Experimental Studies Involving Exposing Laboratory
Animals to Smokeless `Ibbacco or Its Constituents ......... .79
Bioassays With Chewing Tobacco  .................. .79
Bioassays With Snuff. ........................... .83
Bioassays With Constituents of Smokeless Tobacco  .... .86
Mutagenicity Assays and Other Shoti'Ihrrn lb&s ...... .88
Summary.. .................................. ..8 9
  References ................................... ..8 9

cOnclusions........................................92

ResearchNeeds.....................................93

31


This chapter presents the results of a systematic review of the world's
medical literature describing experimental and human evidence perti-
nent to the evaluation of smokeless tobacco as a potential cause of
cancer. Five categories of research relevant to assessing the role of
smokeless tobacco in cancer causation were defined:

1. Epidemiologic studies and case reports of oral cancer in relation
to smokeless tobacco use.

2. Epidemiologic studies of other cancers in relation to smokeless
toba~0 use.

3. Chemical constituents of smokeless tobacco.

4. Metabolism of constituents of smokeless tobacco.

5. Experimental studies involving exposing laboratory animals to
smokeless tobacco or its constituents.

consensus summari es of the literature in each of these categories
were prepared and form the basis of this report. In addition, recommen-
dations for future i-search to clarify suggestive findings or fi.lI gaps in
knowledge are made.

EPIDEMIOLOGIC STUDIES AND CASE REPORTS
OF ORAL CANCER IN RELATION TO
SMOKELESS TOBACCO USE

Because smokeless tobacco products used in different regions of the
world vary considerably in composition and usage patterns, this section
will consider North American and European data separately from
Asian data. Citations to the literature from India and other Asian coun-
tries where quids containing tobacco and other ingredients are com-
monly used orally focus on articles that attempt to distinguish tobacco
from other ingredients in the quids as possible determinants of cancer
risk.

Data From North America and Europe

Although about a dozen informative epidemiologic studies of smoke
less tobacco use and oral cancer in North America or Europe have been
reported, only a few were specifically designed to examine this relation.
There are two major reasons for the relative paucity of studies. Apart
from the recent increased prevalence in use of smokeless tobacco, the
habit has not been widely practiced in America during this century, ex-
cept in localized areas such as parts of the rural South (1,2). Further-
more, cancer of the mouth is uncommon in the Western Hemisphere,

33


exacerbating the difficulty of conducting epidemiologic investigations,
particularly cohort studies, into the relation between smokeless tobacco
and oral cancer. The ageadjusted incidence rate for cancers of the buc-
cal cavity and pharynx in the United States is approximately 11 cases
per 100,000 population per year, with these tumors accounting for
about 3 percent of all cancer deaths (3). Nevertheless, sufficient informa-
tion is available to evaluate whether the use of smokeless tobacco
increases the risk of oral cancer.

case studies

In their review of 566 oral cancer patients treated in two hospitals in
Nashville, Rosenfeld and Callaway (4,5) noted that the proportion of
women (61 percent) with buccal and gingival carcinoma was higher than
the proportion of men (36 percent). Approximately 90 percent of women
with buccal and gingival carcinoma used snuff for 30 to 60 years; in con-
trast, 22 percent of women with cancers in other oral cavity subsites
used snuff. Many of these women began practicing "snuff dipping,"
namely, the placement of tobacco snuff in the gingivobuccal sulcus, be
tween the ages of 10 to 20 years. These reports are typical of numerous
and sometimes large series of cases from the South, which reported that
high percentages of patients with gingivobuccal cancers were snuff dip-
pers or tobacco chewers (613). The articles describing these case series
generally did not use comparison (control) groups, but the authors con-
sistently commented on an apparently high prevalence of the use of
snuff by the cancer patients. Clinicians also noted that the usual male
predominance for epidermoid carcinomas of the oral cavity diminished
or disappeared for the subgroup of gingivobuccal carcinomas occurr@
in geographic areas where there was relatively common use of snuff and
chewing tobacco.

Ahblom reported in the 1930's on a possible association between
smokeless tobacco and cancer in Sweden (14). Among male patients
with cancers of various sites seen at the Ftadiumhemmet (Stockholm),
the use of snuff or chewing tobacco was reported in 70 percent with buc-
cal, gingival, and "mandibuIar" cancers as compared to 26 to 37 percent
with cancers in other oral subsites, the larynx, pharynx, and esophagus.
Ax611 et al. reviewed medical records of male patients with squamous
cell carcinoma in the oral cavity diagnosed between 1962 and 1971 and
recorded in the Register of the Swedish Board of Health and Welfare (Is).
The authors were only able to determine a history for the pattern of use
of snuff in 25 percent of eligible patients but commented that two
thirds of patients who were verified snuff users had oral cancers in
regions where the snuff was generally placed. Reports of a single or a
few cases, usually among male tobacco chewers, in the Northern United
States and Canada also described buccal carcinomas that were often
located precisely in the area where the tobacco was retained in the
mouth (1619)

34


In the early 1940's, Friedell and Rosenthal associated the use of snuff
or chewing tobacco with an exophytic, verrucous type of squamous car-
cinoma of the oral cavity (16). Ackerman described in detail the morpho
logic and clinical features of verrucous carcinoma of the oral cavity (20).
Where the lesions originated in the buccal mucosa, a history of chronic
use of chewing tobacco was elicited in 60 percent of the patients. The
morphologic description was that of a well-differentiated, locally inva-
sive, papillary squamous carcinoma, often in association with leuko
plakia. In more than half of these patients, there was poor oral hygiene
and carious and missing teeth.

In summary, clinical and pathological reports published during the
past four decades in the United States and elsewhere have commented on
the use of smokeless tobacco by oral cancer patients and have described
the entity known as snuffdipper's carcinoma (4,7,11), providing the basis
for the hypothesis that the prolonged use of snuff or chewing tobacco is
associated with an increased risk of low-grade, verrucal or squamous cell
carcinoma of the buccal mucosa and gingivobuccal s&us.

case control studies

Most of the epidemiologic evidence comes from several case-control
studies of oral cancer. The low prevalence of smokeless tobacco use in
most North American populations contributes to a low statistical effi-
ciency in most of these studies. Good information has been obtained,
however, from studies that were either very large, conducted in an area
of high prevalence of smokeless tobacco use, or analyzed according to
site within the oral cavity (since the tissue affected by snuff use appears
to be highly localized). One study, by Winn et al., with these characteris-
tics consequently provides the most informative body of data on the
carcinogenicity of smokeless tobacco in North America (21).

The major concern for validity in the epidemiologic studies of smoke
less tobacco and oral cancer is uncontrolled confounding. A smalI num-
ber of subjects in crucial categories prevented efficient adjustment for
confounding by stratification in many of these studies. Many of the
studies were conducted before the advent of sophisticated epidemic
logic analyses and make no attempt to control confounding. The two
primary confounding factors of concern are alcohol consumption and
smoking (22). Alcohol consumption is a strong risk factor for oral can-
cer. It is not clear on a priori grounds, however, to what extent alcohol
consumption would be correlated with smokeless tobacco use. The rela-
tion between smoking, also a strong risk factor for oral cancer (2), and
smokeless tobacco use may be complex. Users of smokeless tobacco
may be more likely to have been smokers at some time. On the other
hand, heavy users of smokeless tobacco typically cannot be heavy users
of cigarettes, so that smoking is p resumably negatively correlated with
smokeless tobacco use. Failure to control confounding by smoking would
therefore lead to underestimates of the effect of smokeless tobacco.

35


TABLE l.-Smokeless Tobacco and Mouth Cancer,
      Case-Control Data From Moore et al. (23,24)

Smokeless Tobacco      Mouth Cancer Cases

controls

Users                     26                12

Nonusers                    14                26
Totals                      40                38
Crude RR = 4.0      95%.Confidence Interval:       1.6-10

Chronologically, the first casecontrol study of smokeless tobacco
was conducted by Moore et al. in Minnesota (23,24). Patients at the
University of Minnesota `lhrnor Clinic with a diagnosis of cancer of the
mouth were interviewed about tobacco use as part of a general inter-
view procedure for clinic patients. Surgical outpatients who received
the same interviews served as controls. Prom the data that were
reported by these authors, one can calculate a crude relative risk
estimate for mouth cancer among smokeless tobacco users of 4.0 with a
95percent confidence interval of 1.6-10 (table 1). An oddity was an ap-
parent lack of effect for other forms of tobacco use. A partial explana-
tion might be negative confounding between smokeless and smoked
tobacco; indeed, 26 of the 40 cases of mouth cancer chewed tobacco.
Still, the extent of disparity in crude effect estimates for smokeless
tobacco (relative risk estimate 4.0) and smoked tobacco (all relative risk
estimates < 1.0) is surprising.

Wynder et al. reported on a case-control study of squamous cell
cancers of the upper alimentary and respiratory tract that was con-
ducted at Sweden's Radiumhemmet in 1952-55, including 33 tongue
cancer patients, 14 lip cancer patients, 19 gingival cancer patients, and
8 patients with cancer of the buccal mucosa, among others (25). Con-
trols were patients with cancers of the skin, head, and neck other than
squamous cell carcinoma, stomach cancer, lymphoma, salivary-gland
tumors, leukemia, sarcoma, cancers of the colon and rectum, and
cancers of the female genital tract. A variety of risk factors was exam-
ined, including the use of chewing tobacco. The authors state that the
data suggested that an increased risk is associated with the duration of
chewing tobacco for cancers of the gingiva and oral cavity but not for
cancers of the tongue, lip, hypopharynx, esophagus, or larynx, but the
data as presented do not permit an estimation of risk. In addition, data
were not adjusted for other potential confounders, including cigarette
smoking. Wynder and colleagues also reported in 1957 data from a
similar hospital-based casecontrol study of mouth cancer conducted in
New York (26). ?bbacco chewing was found to be more common among
men with oral cavity cancers than among controls; but it was noted that
almost all of these patients also drank alcoholic beverages and smoked
and no further analyses were attempted.

36


TABLE 2.-Smokeless Tobacco and Mouth Cancer,
     CaseControl Data From Peacock et al. (27)

Age

Smokeless
Tobacco

User

Nonuser

Total

  40-49         59-59          60-69

case controls     case controls     Case Controls

0 16       7 13      18 20

5 14       6 16       9 37

5 60      13 29      27 57

RR=0        RR = 1.4       RR = 3.7

RRMH = 2.0     95%.Confidence Interval: 1.0-4.2

Peacock et al. studied 56 cases of mouth cancer, including malignan-
cies of the buccal mucosa, alveolar ridge, and floor of the mouth, and
compared their tobacco histories with those of two control groups: 146
hospitalized controls with diagnoses other than cancer and 217 outpa-
tients (27). Agespecific results using the hospitalized controls are sum-
marized in table 2. The overall relative risk was estimated to be 2.0
(95percent confidence interval 1.0-4.2); the relative risk seemed to in-
crease with age with an estimate of 3.7 for the 60 to 69 age group. The
data were not reported in sufficient detail to control for confounding by
smoking, which presumably led to underestimates of the relative risk.
There was also insufficient detail reported to evaluate the relation be
tween the risk of mouth cancer and the amount or duration of smokeless
tobacco use.

In Atlanta, patients with oral, pharynx, and larynx cancer were com-
pared to three control groups having other mouth diseases, other can-
cers, or no cancer (28. Among urban women, 40 percent of the cases
used snuff compared to 3 percent or less of the controls (table 3). Among
rural women, 75 percent dipped snuff compared to 20 percent or less
among controls. Cigarette smoking was common in urban women and
not specifically controlled for. Few rural female cases smoked cigarettes
(7 percent) so confounding by smoking was minimal. The association
between snuff dipping and oral, pharynx, and larynx cancer in women
was generally evident in most age groups. Among the cases, the propor-
tion of snuff dippers was highest among oral cancer patients: 53/72 were
dippers compared to 2/18 pharynx and larynx cancer patients. Among
men, insufficient information was provided to obtain precise epidemic
logic estimates of the effect of chewing tobacco, although date from one
of the bar charts presented indicate that urban cases were more likely to
be users of smokeless tobacco than controls, that rural men with oral,
pharynx, and larynx cancer or mouth disease were more likely to chew
than controls, and that oral cancer patientu were more likely to chew

37


TABLE 3.-Estimated Relative Risks Associated With Snuff Use for
    Cancers of the Oral Cavity, Pharynx, and Larynx,
    Case.C!ontrol Data From Vogler et aL (2B), Females Only

oral/       Other
PlLSryIlXl      Mouth
Larynx      Disease

Other        No
ClUlCer      Cancer

Urban

User

Nonuser

Crude Relative
  Risk Estimate

RlUal

User

Nonuser
Crude Relative
  Risk Estimate

15           1           5           4

23          56         165         373

60.8         1.7         2.8         1.0*

41           4          26          17

14          33         103         133

22.9         0.9         2.0         1.0*

TABLE 4.-Smokeless Tobacco and Head and Neck Cancer by
     Anatomic Site, CaseControl Data From
     Vincent and Marchetta (29), Males Only

Smokeless
Tobacco Use

User

Nonuser

Total

Relative Risk
Estimate

95%~Confidence
Interval

Control Larynx

  5        2

  95       21

100       23

         1.8

       0.3-9.8

        oral    All Head
Phw   Cavity   and Neck

  3        9        14

30       24       75

33       33       89

1.9       7.1       3.5

0.4-8.3    2.4-21    1.3-9.8

than the pharynx and larynx cancer cases. Among men, confounding by
smoking could not be ruled out.

Vincent and Marchetta reported the results of a case-control study of
head and neck cancer according to anatomic site. Table 4 summarizes
the findings for males (29). The oral cavity seems to be the anatomic site
where the bulk of the effect is noted; only mild increases in risk were
estimated for the larynx and pharynx, whereas users of smokeless
tobacco were estimated to have a sevenfold greater risk for cancer of the
oral cavity. These estimates are imprecise because of the small number
of subjects and are uncontrolled for age and smoking.

38


TABLE 5.-Estimated Relative Risk for Cancer of the Head and Neck
     From Smokeless `lbbacco Use by Anatomic Site,
     Third National Cancer Survey (311, Males Only

Relative Risk Estimate

Anatomic Site         Low Exposure

High Exposure

Gum-Mouth                 5.6               3.9
Pharynx                   0.6                 -

Lip-Tongue                 0.3               1.1
LarYm                    2.0               1.7

Martinez reported on a case-control study in Puerto Rico of risk fac-
tors for cancers of the mouth, pharynx, and esophagus (XI). This
population-based study included 400 cases of epidermoid carcinomas of
those sites and 1,200 controls matched on age ( + 5 years) and sex to the
cases. One control per case was drawn from the same hospital or clinic
and two from the same community. There were 153 cases of mouth
cancer (115 male and 38 female) and 68 cases of pharyngeal cancer (55
male and 13 female). The authors concluded that "Patients with cancer
of the mouth did not often use chewing tobacco disproportionately. "
However, calculation of the relative risks of mouth cancer that are asso
ciated with chewing tobacco based on comparing the use of chewing
tobacco only with no tobacco use suggests a strong effect for oral and
pharyngeal cancer in males (data from table 13 in the paper). The esti-
mated relative risks were 11.9 (95percent confidence interval 2.5-56.4)
for oral cancer and 8.7 (95percent confidence interval 1.4-54.5) for
pharyngeal cancer among chewers. These numbers do not include the
experience of the many study subjects whose use of tobacco was
mixed" (that is, those who used any combination of cigarette, cigar,
and pipe smoking and chewing tobacco), and these calculations were
based on unmatched data.

Further evidence for the site specificity arose from a case-control
analysis of multiple cancers using data from the Third National Cancer
Survey (31). There were few female users of smokeless tobacco and
scanty data by site within the head and neck region even for males; the
findings do seem to indicate that the effect is greater for the site that is
labeled gum-mouth as opposed to other head and neck sites (table 5).

Browne et al. conducted interviews with 75 oral cancer patients, or
(usually) their next of kin, and 150 living sex-, neighborhood-, and
occupation-matched controls in the West Midlands area of the United
Kingdom where oral cancer mortality rates were high and tobacco
chewing was common among miners (32). Controls on average were
born about 10 years earlier than the cases. The proportion of tobacco
chewers was approximately the same among the 16 cases and 43 con-

39


trols who were miners, although data on this variable were missing for
onefourth of the cases, and the authors apparently assumed that all
cases with missing information were nonchewers. If the proportion of
tobacco chewers among the cases with missing information was similar
to those miners with known information, then the data would have
shown a positive association between chewing tobacco and oral cancer.
All of the miners with oral cancer who chewed tobacco also smoked
pipes, further complicating interpretation of this study.

Additional evidence that a carcinogenic effect of smokeless tobacco
may be greatest at the anatomic site of exposure came from Westbrook
et al. who compared the medical records of 55 female patients with
cancers of the alveolar ridge or buccal mucosa who were treated at the
University of Arkansas with those of 55 randomly selected female
hospital controls (33). Fifty of the cases, but only one control, were snuff
dippers, with the tumors among the cases typically appearing at the site
where the snuff was usually placed. No reliable estimates of risk can be
derived from this study because of the strong possibility that them was
not comparable elicitation of exposum information for cases and controls.
`Iwo large case-control studies were not reported in a way that enables

a meaningful quantitative assessment of the effect of smokeless to.
bacco in chewers and dippers compared to tobacco abstainers (34,35).
The first study found that 10 percent, and the second 9 percent, of male
oral cancer cases had ever chewed tobacco, while the corresponding fig-
ure for controls was 9 percent. These studies, like many of the others
cited here, were not undertaken specifically to evaluate the carcino
genicity of smokeless tobacco. Although the data seem to indicate a
weak relation, if any, between smokeless tobacco and cancer of the oral
cavity, the findings are uncontrolled for age, race, geography, and
smoking.
The recent casecontrol study of Winn et al. is by far the most infor-
mative study on the carcinogenicity of smokeless tobacco (21). The case
series comprised 255 women with oral and pharyngeal cancer who were
living in 67 counties in a high-risk (for oral cancer) region of North
Carolina. ?tyo female controls were obtained for all but a few cases and
were individually matched for age, race, source of ascertainment
(hospital or death certificate), and county of residence. There was a four-
fold increased risk of oral-pharyngeal cancer among nonsmoking white
women who dipped snuff. The association could not be explained by
smoking or alcoholic beverage consumption (21), denture wearing or
poor dentition (36), diet (37), or mouthwash use (38). The data provided
evidence for a strong relation between the duration of snuff use and risk
for cancer, as well as a striking localization of the carcinogen&y to the
gum and buccal mucosa (table 6). For long-term chronic users of snuff,
there was nearly a fiftyfold increase in risk for cancers of the gum and
buccal mucosa. Indeed, almost all of the patients with cheek and gum
cancers had dipped snuff.

40


TABLE 6.--Estimated Relative R&k of tipharyngeal Cancer
     According to Duration of Snuff Use and
     Anatomic Site, Winn et al. (21)

Anatomic          Duration of
Site           Snuff use (yrb

Relative Risk
Estimate

95%.
Confidence
IUtelVal

Gum and Buccal
Mucosa

Other Mouth
and Pharynx

  0
1 - 24
25 - 49
  1 50

  0
1 - 24
25 - 49
  2 50

1.0             -
13.8         1.9 -  98
12.6          2.7 -  53
48.0          9.1 - 250

1.0             -
1.7          0.4 - 7.2
3.8          1.5 - 9.6
1.3          0.5 - 3.2

Although some of the exposure information came from interviews
with next of kin, when the analysis was restricted to interviews with
study subjects, the association between snuff and oral cancer was even
stronger @9). Matched conditional logistic analysis yielded similar
results (35). Based on calculations of attributable risk, the authors
estimated that 87 percent of these cancers were due to the patients'
snuff-dipping habits. The authors also provided data that
demonstrated the negative confounding by tobacco smoking in the
population, raising the possibility of a serious validity problem with the
other studies that did not control for smoking. If the negative correla-
tion between the use of smokeless and smoked tobacco holds in other
populations, estimates of the carcinogenic effect of smokeless tobacco
in studies without the control of smoking may be underestimates. The
quantitative information that was provided by the Winn et al. study led
its authors to conclude that the long-standing use of smokeless tobacco
by Southern women was the principal cause of the elevated mortality
from oral cancer among women in the Southern United States.

Cohort Studies

Few cohort studies of smokeless tobacco have been undertaken
because of the rarity of both the exposure (smokeless tobacco use) and
the outcome (oral cancer) of most interest. Bjelke and Schuman (40)
reported on cancer mortality in cohorts of 12,945 Norwegian men and
16,930 American men and found increases in the risk of death for can-
cers of the buccal cavity, pharynx, and esophagus (relative risk
estimates ranged from 2.6 to 3.1(41); no further detail was given). They
noted a negative association between smoking and chewing tobacco,
confirming the pattern that was observed from the case-control
research. In a 16.year followup of U.S. veterans, Winn et al. reported no
deaths from oral or pharyngeal cancer among 951 smokeless tobacco

41


users who did not use other forms of tobacco (about 0.5 deaths were ex-
pected) but a significant increase in both oral and pharyngeal cancers
among smokeless tobacco users who were light smokers (42) These
data, as well as those from Bjelke and Schuman (40). were reported only
as abstracts in scientific journals or proceedings, with little or no detail
as to the methods used, hindering interpretation of the results.

Smith and colleagues followed a group of about 1,500 patients with
changes in the oral mucosa to evaluate the effects of smokeless tobacco
use (43,44). No oral cavity cancers were found in about 16,000 person-
years of followup. Based on the results of other studies, two or three
should have been detected over the study period. Smith gave little docu-
mentation of the methods that were employed for followup; however, 12
percent of the original group (201 subjects) were lost without any data
on outcome, and there was apparently no effort to trace them. It seems
likely that persons who died and persons who developed cancer, includ-
ing some with tumors of the oral cavity, may have been lost to followup.
In fact, no deaths among cohort members were reported, whereas
perhaps as many as 100 or more would have been expected among such
a cohort of middleaged adults, making Smith's data uninterpretable.

Data From Asia

The highest rate-e of oral cancer among the more than 100 that are
listed from population-based registries around the world that report stan-
dadized cancer incidence statistics are found in India (45). In many areas
of Asia, hospital statistics suggest that oral cancer is extremely common
and often accounts for 25 or more percent of all cancers (4649), propor-
tions that are far greater than in most areas of the United States where
oral cancers typically comprise only 3 percent of all malignancies (3). It
has long been thought that the chewing of quids that contain tobacco
and other substances is the cause of the increased risk of oral cancer in
these areas (50).

The smokeless tobacco products that are commonly used include to
bacco with betel leaf, areca nut, and lime mixtures (often referred to as
"pan"); Khaini (powdered tobacco and slaked lime paste); mishri (pow-
dered partially burnt black tobacco); nass (tobacco, ash, and cotton or
sesame oil; lime is used in Iran and certain Soviet Republics); and various
preparations that vary locally throughout the Southeast Asia region.

The inclusion of lime, areca nut, and other ingredients in many of the
smokeless tobacco-containing quids hinders the evaluation of the con-
tribution of tobacco per se to the increased risk of oral tumors. From
five investigations, however, relative risks of oral cancer among
chewers of betel quids with versus without tobacco can be calculated.
Data from these case-control studies, which were conducted in Cal-
cutta, Madras, Karachi, Bombay, and several parts of India and Sri
Lanka (4',51+%), reveal considerably higher risks of oral cancer for the

42


TABLE 7.-Relative Risk of Oral Canax From
     Betel Quid With and Without `Ibbacco
     (With 95Percent Confidence Limit)

Study
Location
(References)

Betel    Betel
Quid .      No
With  W%zut Chewing
Tobacco   Tobacco   Habit Remarks

Calcutta,
India (5054)

Madras,
India (5154)

Karachi.
Pakistan
(5&w

Bombay,
India (53)

India and
SI-iLanka
(47)

Cases         138       46
Controls        61      70
Relative risk     4.3      1.2
estimates   (3.0-6.1)  10.8-1.9)

Cases         219       33
Controls        35      144
Relative risk     25     0.91
estimates   115-41)   10.4-1.6)

135
256

25
99

Smokers not included
in these data. Only
buccal mucosa can-
cers considered.

Smokers not included
in these data. Only
buccaI mucosa and
tongue cancer cases
included. Numbers
reconstructed from
percentages and
totals.

Cases
Controls
ReIative risk
estimates

Cases
Controls
Relative risk
wtimates

cases
Controls
Relative risk
estimates

339
474
(11~~7,

238
513

120
  63
(7.Ot532,

  40
216
3.6
(2.4-5.2)

  44
152
3.0
(2.1-4.3)

  3
  8
2.9
(0.6-14)

88  Smokers not included
1.690  in these data.

129
1.340

6
47

Separate analyses
indicate that ele
vated risks of oral
cancer associated
with tobacco chew-
ing are found among
nonsmokers as well
as smokers.

Smokers not included
in these data. Only
buccaI mucosa
cancer considered.

use of tobacco-containing compared to nontobacco-containing quids
(table 7). The findings thus suggest that the addition of tobacco con-
tributes substantially to the elevated cancer risk among chewers,
although other differences between those who use versus those who do
not use tobacco-containing quids could influence the differences. Smok-
ing, however, is not such a difference, since most of the investigations
referred to in table 7 demonstrated high relative risks of oral cancer
(with excesses among tobacco chewers often exceeding tenfold com-
pared to nonquid users) among chewers who did not smoke, ruling out
confounding by cigarette smoking. The studies also generally found
that the large majority of oral cancer patients had been tobacco chewers
and suggest that the habit of quid chewing accounts for most of the oral
cancers in the diverse populations studied (5.5%).

43


Summary

Numerous case reports, especially in the South, have described oral
cancers among smokeless tobacco users. The tumors often arose at ana-
tomic locations where the tobacco was routinely placed. The number of
epidemiologic investigations evaluating the relation between smokeless
tobacco and oral cancer is not large, and several studies have method-
ologic limitations. The pattern of increased oral cancer risk among
smokeless tobacco users, however, is generally consistent across
studies, with evidence of an increasing risk with increasing duration of
exposure, and with excess risks tending to be greatest for those ana-
tomic sites where tobacco exposures are greatest. The best designed
study was drawn from a female population in the Southern United
States where exposure rates are high and potentially confounding vari-
ables could be taken into account. This study showed that chronic snuff
users were at substantially increased risk of oral cancers and that
nearly all tumors of the cheek and gum were due to snuff use. Evidence
from parts of Asia, where the prevalence of smokeless tobacco use is
high and oral cancer is the most common tumor, indicates a strong asso
ciation between the chewing of quids and oral cancer. Users of quids
that contain tobacco have much higher oral cancer rates than users of
quids that do not, and the association is not confounded by cigarette
smoking, raising the possib&ty that tobacco per se contributes to the
elevated oral cancer risk in this part of the world. In summary, users of
smokeless tobacco face a strongly increased risk of oral cancer, particu-
larly for the tissues that come in contact with the tobacco.

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57, 1981.

(4) Rosenfeld, L., and Callaway, J. Snuff dipper's cancer. Am. J. Surg. l&C
840-844, 1963.

(5) Rosenfeld, L., and Callaway, J. Squamous cell carcinoma of the oral
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(6) Landy, J.L., and White, H.J. Buccogingival carcinoma of snuff dippers.
Arm Surg.27: 442-447, 1961.

(7) Wilkins, S.A., and Vogler, W.R. Cancer of the gingiva. Surg. Gynecol.
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R.R. Snuff dippers intraoral cancer: Clinical characteristics and
response to therapy. Cancer 18: `2-13, 1965.

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(9) Coleman, C.C. Surgical treatment of extensive cancers of the mouth
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squamous cell carcinoma of the oral cavity. Cancer 23: 152-160, 1969.
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(12) McGuirt, W.F. Snuff dipper's carcinoma. Arch. OtoIaryngol. 109:
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(13) McGuirt, W.F. Head and neck cancer in women-a changing profile.
Laryngoscope 93: 106-107, 1983.

(14) Ahblom, H.E. Predisposing factors for epitheliomas of the oral cavity,
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(15) Ax&II, T., et al. Snuff dipping and oral cancer-a retrospective study.
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(16) FriedeII, H.L., and Rosenthal, L.M. The etiologic role of chewing to
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(20) Ackerman L.V. Verrucous carcinoma of the oral cavity. Surgery 23:
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(21) Winn, D.M., Blot, W.J.. Shy, C.M., et aI. Snuff dipping and oral cancer
among women in the Southern United States. N. Engl. J. Med. 304:
  745-749, 1981.

(22) Rothman, K., and Keller, E. The effect of joint exposure to alcohol and
tobacco on risk of cancer of the mouth and pharynx. J. Chron. Dis. 25:
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(23) Moore, G.E., Bissmger, L.L., and ProehI, E.C. Tobacco and intraoral
  cancer. Surg. Forum 3: 685688, 1952.
(ZX#) Moore, G.E., Bissinger, L.L., and Pro&I, EC. Intraoral cancer and the
use of chewing tobacco. J. Am. Geriatr. Sot. 1: 497-506,1953.
(25) Wynder, E.L., H&berg, S., Jacobsen, F., and Bruss, I.J. Environmental
factors in cancer of the upper alimentary tract. Cancer 10: 470-487,1957.
(26) Wynder, E.L., Bruss, I.J., and Feldman R.M. A study of the etiologicaI
  factors in cancer of the mouth. Cancer 10: 1300-1323,1957.
(27) Peacock, E.E., Greenberg, B.G., and Brawley. B.W. The effect of snuff
and tobacco on the production of oral carcinoma. Am. Surg. 151: 542-550,
  1960.

(28 VogIer, W.R., Lloyd. J.W., and Mihnore, B.K. A retrospective study of
etiologicaI factors in cancer of the mouth, pharynx, and Iarynx. Science
  15: 246-258.1962.

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1291 Vincent, R.G., and Marchetta F. The rehrtionship of the use of tobacco
and alcohol to cancer of the oral cavity, pharynx, or Iarynx. Am. J.
h-g. 106: 501-505, 1963.

(30) Martinez, I. Factors associated with cancer of the esophagus, mouth,
and pharynx in Puerto Rico. J. Natl. Cancer Inst. 42: 1069-1094,1969.
(311 WiIIiams, R.R., and Harm, J.W. Association of cancer sites with to
bacco and alcohol consumption and socioeconomic status of patients:
Interview study from the Third National Cancer Survey. J. Natl.
Cancer Inst. 58: 525-547, 1977.

(32) Browne, R.M., Camsey, M.C., Waterhouse, J.A.H., and Manning, G.L.
EtiologicaI factors in oral squamous ceII carcinoma. Community Dent.
Oral Epidemiol. 5: 301-306, 1977.

(33 Westbrook, K.C., Sven, J.Y., Hawkins, J.M., andMcKinney. D.C. Snuff
dipper's carcinoma: Fact or fiction? In: H.E. Nieburg (ed.). Prevention
and Detection of Cancer. New York, Marcel Dekker, 1980. pp.
  1367-1371.

(34) Wynder, E.L., and Stelhnan, S.D. Comparative epidemiology of
tobacco-related cancers. Cancer Res. 37: 46084622, 1977.
(3.5) Wynder, E.L., Kabat, G., Rosenberg, G., and Levenstein, M. Oral can-
cer and mouthwash use. JNCI 70: 255-260, 1983.
(3s Winn, D.M., Blot, W.J., and Fraumeni, J.F. Snuff dipping and oral
cancer. N. Engl. J. Med. 305: 230-231,198l.
(37) Winn, D.M., Ziegler, R.G., Pickle, L.W., GridIey, G., Blot, W.J., and
Hoover, R.N. Diet in the etiology of oral and pharyngeaI cancers among
women from the Southern United States. Cancer Res. 44: 1216-1222,
  1984.

138) Blot, W.J., Winn, D.M., and Fraumeni, J.F. Oral cancer and
  mouthwash. JNCI 70: 251-253, 1983.
(39) Winn, D.M. Smokeless tobacco and oral-pharynx cancer: The role of
cofactors. Banbury Report (in press).
(40) BjeIke, E., and Schuman. L.M. Chewing tobacco and use of snuff: ReIa-
tionships to cancer of the pancreas and other sites in two prospective
studies. Proceedings of the 13th International Congress on Cancer,
  1982. p. 207.

(41) International Agency for Research on Cancer. Tobacco habits other
than smoking: Betelquid and areca-nut chewing and some related
nitrosamines. IARC Monogr. EvaI. Carcinog. Risk Chem. Hum. 37:
  103-104, 1985.

(4.2) Winn, D.M., Wahath, J., Blot, W., and Rogot, E. Chewing tobacco and
snuff in relation to cause of death in a large prospective cohort
(Abstract). Am. J. Epidemiol. 116: 567, 1982.
1431 Smith, J.F., Mincer, H.A., Hopkins, K.P., and Bell, J. Snuff-dippers
lesion: A cytologicaI and pathological study in a large population. Arch
GtohuyngoI 92: 450-456, 1970.

1441 Smith, J.F. Snuff dippers lesion, a ten-year follow-up. Arch. OtoIaryn-
  gol.l01:2767-277, 1975.

46


(45) Waterhouse, J., Muir, C., Shanmugamnam, K., and Powell, J. Cancer
incidence in five continents, Vol. IV. Lyon, France, International
Agency for Research on Cancer, 1982.
(46) Pindborg, J.J. Epidemiologic studies of oral cancer. Int. Dent. J. 27:
  172-178, 1977.

(47) Wahi, P.N. The epidemiology of oral and oropharyngeal cancer. Bull.
  WHO 38: 495-521.1968.

(48) Hirayama, T. An epidemiologic study of oral and pharyngeal cancer in
  Central and Southeast Asia. BulL WHO 34: 41-69, 1966.
(49) Paymaster, J.C. Cancer and its distribution in India. Cancer 17: 1026,
  1964.

(So) Orr, I.M. Oral cancer in betel nut chewers in Travancore. Lancet 2:
  575-580, 1933.

(51) Chandra, A. Different habits and this relation with cheek cancer. Bull.
Cancer Hosp. Natl. Cancer Res. Center 1: 33, 1962.
(52) Shanta, V., and Krishnamurthi, S. A study of aetiological factors in oral
squamous cell carcinoma. Br. J. Cancer 13: 381, 1959.
(537 Jafary, N.A., and Zaidi, S.H. Carcinoma of the oral cavity in Karachi,
Pakistan: An appraisal. Trap. Doct. 6: 63, 1976.
(54) Jus~awdh, D.J.. and Deshpande, V.A. Evaluation of cancer risk in
tobacco chewers and smokers: An epidemiologic assessment. Cancer
  28: 244-252, 1971.

(55) Gupta, P.C., Pindborg, J.J., and Mehta, F.S. Comparison of carcine
genicity of betel quid with and without tobacco. An epidemiological
  review. EcoL Dis. 1: 213-219, 1982.
(56) Jayant. K.. Balakrishnan, V.. S anghvi, L.D., and Jussawalla, D.J.
Quantification of the role of smoking and chewing tobacco in oral,
pharyngeal, and esophageal cancers. Br. J. Cancer 35: 232-235, 1977.

EPIDEMIOLOGIC STUDIES OF OTHER CANCERS
IN RELATION TO SMOKELESS TOBACCO USE

The epidemiologic studies reported in the preceding section that
show an association between the use of smokeless tobacco and oral
cancers, particularly malignancies of the cheek and gum, indicate that
the topical exposure of tissues to tobacco can cause cancers at the site of
the exposure. In the United States, the tissues in direct prolonged con-
tact with the tobacco are generally those of the oral cavity. Smokeless
tobacco may occasionally come in contact with other tissues. One case
has been reported of squamous cell carcinoma that developed in the ear
of an individual in Minnesota who habitually placed snuff in his ear for
42 years at the site where the neoplasm developed (II. Although but a
single report, this highly unusual observation raises the possibility of a
carcinogenic potential of smokeless tobacco at other anatomic sites
when exposure is direct and prolonged.

47


Nasal Cancer

In some areas of the world snuff is inhaled, so that tissues of the nasal
cavity come in contact with the tobacco powder. The earliest report that
links any form of tobacco to cancer was published over two centuries
ago when what were probably nasal cancers were described in several
patients in England who were heavy inhalers of snuff (2). There have
been no systematic evaluations of snuff inhalation and nasal cancer in
the United States, United Kingdom, or other European countries, most
likely because both the sniffing habit and nasal cancer are uncommon,
Sniffing snuff has been reported, however, to be a frequent habit among
Bantu men, whose rates of nasal cancer have been reported to be high (31.
In case-control studies of nasal sinus cancer reported in 1955,80 per-
cent of patients with tumors of the maxillary antrum were prolonged
and heavy snuff users, in contrast to about onethird of Bantu men with
other cancers (4,s). The snuff used by the Bantu is thought to contain
aloe plant ash, trace elements such as nickel and chromium, and other
ingredients in addition to tobacco (6). Snuff use (presumably by inhala-
tion) was reported not to account for the high rates of nasal adenocarci-
noma among furniture makers in studies in England and Denmark, but
evaluations of snuff itself as a risk factor were not undertaken (7,s).

One casecontrol study of cancers of the nasal cavity and paranasal
sinuses in the United States addressed the issue of smokeless tobacco (91.
A total of 193 cases were identified in four hospitals in Virginia and
North Carolina over a lo-year period. No association between sinonasal
cancers and chewing tobacco was found (relative risk 0.7,95-percent con-
fidence interval 0.4-1.5). However, a relative risk of 1.5 was observed for
users of snuff (g&percent confidence interval 082.8). Risk was increased
in snuff users for both adenocarcinomas (relative risk 3.1) and squamous
cell carcinomas (relative risk 1.9) but not for other histologic types
(relative risk 0.6) and was found for both sexes. The implications of the
findings are not clear since the snuff used by the cases and controls was
oral snuff not coming in contact with nasal tissues. Animal experiments,
however, suggest that tumors distant to the site of exposme may l-ealllt
from exposure to constituents of snuff (see the section on animal studies).

An apparent excess of posterior nasal space tumors was reported
among certain tribes in Kenya, and 6 or 12 cases interviewed were
found to be chronic "liquid snuff" users (10). Multiple subsites of the
respiratory tract were considered however, increasing the likelihood of a
chance association No increased risk of nasopharyngeal cancer associ-
ated with snuff use was noted in a casecontrol study in Singapore (11).

Esophageal Cancer

Other tissues that come in contact with constituents of smokeless
tobacco in more dilute concentrations include the linings of the esopha-
gus, larynx (supraglotic portion), and stomach. The results of studies of

48


7I!ABLE l.-Relative Risks of Ektphageal Cancer in
     Pemom Expoeed to Chewing `lbbacco and Snuff:
     Summa@ of Four CaseControl Studies

                                  controle

Fht  zz f3e.x          %          IReldw
AUthtK                   No. Erpud No. Exjmd Risk*

Wynder  Chewing  Any      M    150   20     150   10     2.3
(4         < 1oyrs.             14          4     3.9
        2 iop.              6          6     1.2

Williams  chewing  Level1     M    38    5.2  1,788   5.4    0.9
W    or Snuff  Level2               0          0      -
WYgr  cl=+%  Any       M    183   10.9  2,560   9.0    1.2

      snuff   Any       M          4.4         2.7    1.7

Martinez  t%ewingt Any       M    120    2.5    360   3.6    1.2
(14)                   F     59  `11.9    177   7.3    2.7

*caldatedfrompubliabedrepultifuutpruvidedby~uthur.
tRgtectedtonouamdtea.

cancers of these three sites in relation to smokeless tobacco are inam-
elusive. The studies are gtmemlly of limited power to detect small in-
cxeases in risk, and many did not control for relevant, potentially con-
founding variables. However, some studies of these three cancera do
show au increaseinriskinrelationtotheuseofsmokeless~~.As
shown in table 1, elevated relative risks of esophageal cancer up to
twofold or higher were found in two hospital-based casecontrol studies
in the United States involving 150 and 183 cancer patients (1213) and
one in Puerto Rico (described in the previous section) with 179 casea (I#.
One of the studies by Wynder and colleagues, however, found no
evidence of an incmase in risk with duration of exposure, and all
chewers were also smokers (12). The effect of smoking was not adjusted
for in the other study (13). Another casecontrol study involving 120
black male cases of esophageal cancer was conducted in Washington,
D.C. (15). Few of the cases or controls had used either chewing tobacco
or snuff, suggesting that it did not contribute to the high rates of
esophagealcancerobservedin~eareaFinally,datafromaprospective
(cohort) study of U.S. veterans were analyzed to determine whether
mortalityratesof~cdiseaseswereincreasedinusersofsmokeless
tobacco (16,l. In the absence of smoking, the standardize mortality
ratio for esophageal cancer was found to be 228, but this value was
based on only one death In a cohort study of 12,945 Norwegian and
16,930 American men followed over 10 years, the risk of esophageal
cancer was reported to be significantly increased among men who used

49


chewing tobacco or snuff, after controlling for age, residence, and smok-
ing habits (17,18). Unfortunately, the results of both cohort studies have
been published only as abstracts, so additional details are not available.
Some evidence that the chewing of quids may increase the risk of
esophageal cancer arises from studies in Southeast Asia. In a series of
237 cases of esophageal cancers in Sri Lanka, interview information
from 111 revealed that 90 (81 percent) habitually used betel containing
tobacco leaf (19). This percentage was considerably higher than the fre
quency of betel chewing in the general population (30 percent). Betel
chewing was more common among women. Esophageal cancer also was
more common among women, an unusual observation since this cancer
occurs more frequently among men in almost all areas of the world that
report standardized cancer statistics @Q). Since few women were
reported to smoke or use alcohol, the possibility of an etiologic role of
chewing is increased. However, the potential effects of tobacco as op
posed to other ingredients in the quids cannot be distinguished. In a
case-control investigation in Bombay involving interviews with 305
esophageal cancer patients and nearly 2,000 population controls of age,
sex, and religions similar to all head and neck cancer cases, a 2.5-fold in-
creased risk of esophageal malignancy was observed (p < .Ol) among
nonsmokers who chewed pan, a mixture usually consisting of tobacco,
betel, lime, and other ingredients (21). The excess was higher, however,
among those chewing quids without tobacco (relative risk 3.5) than with
tobacco (relative risk 2.1). A more recent analysis (22) in Bombay based
on 649 patients with esophageal cancer and 649 controls yielded similar
qualitative findings, but the excess among users of pan without tobacco
(relative risk 12.1) was accentuated compared to users of tobacco
containing chews (relative risk 2.81. On the other hand, in an earlier case
control investigation in southern India of several upper digestive tract
tumors, including 93 esophageal cancers, increases in esophageal cancer
risk were much greater among men who used betel with tobacco (c&u-
lated relative risk 11) than without tobacco (calculated relative risk 2) (23,).
The chewing of nass was not associated with esophageal cancer risk
in a case-control study conducted in an area of Iran with among the
world's highest rates for this cancer (24). Of 638 identified cases of
esophageal cancer, interviews were completed with 344 and with 2
neighborhood controls matched to each case. The relative risk associ-
ated with ever using nass was 0.9, with an upper limit of the 95-percent
confidence interval of 1.5, suggesting that any major effect of nass on
the origins of this cancer could be excluded.

Laryngeal Cancer

In a case-control analysis of the interview data from the Third Na-
tional Cancer Survey (TNCS), Williams and Horm compared the prior
use of smokeless tobacco products (in the aggregate) in persons with a

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