This summary provides an overview of key information from the document: 1) The document reviews several epidemiological studies that examine the relationship between smokeless tobacco use and oral cancer risk. Case control and cohort studies from Sweden, India, and Norway generally found increased risks, though the magnitude of risk depended on the type of smokeless tobacco. 2) A review of 21 studies found that chewing tobacco and moist snuff carried low cancer risks under 2, while dry snuff was associated with higher relative risks from 4 to 13. However, studies may have overestimated risks by not adequately controlling for smoking and drinking. 3) Another review of 65 studies also noted small increased risks from case control studies, but cohort studies

1. Smokeless Tobacco and Oral Cancer
Jakala Reese
Oral cancer is considered cancer of the mouth and the back of the throat, or the pharynx.
Patients with oral cancer present noticeable symptoms, such as white or red patch in the mouth
or numbness in the the tongue or other areas of the mouth. If those sorts of symptoms persist for
more than two weeks, patients usually see a doctor or dentist for an oral cancer exam. If oral
cancer is detected early, it can be treated more effectively.¹

2. The Surveillance, Epidemiology, and End Results (SEER) Program (derived from the
National Cancer Institute) submitted data in November of 2008 on the incidence of oral cancer.
10.5 per 100,000 people have or will develop oral cancer. Oral cancer rates are much higher in
males than females, with the rates being 15.5 per 100,000 versus 6.1 per 100,000. Cancer rates
vary in individual populations. The highest highest rates occur in the white, non-hispanic
population (16.7 per 100,000). Incidence of oral cancer increases between the ages of 50-70,
with the highest cancer rates observed in the age group of 70-79 at 40.2 per 100,000.² In 2004,
244,473 people had oral cancer. There were 157,250 (11 percent) men with oral cancer, and
87,000 (0.07 percent) women with oral cancer.³ For decades, the usage of smokeless tobacco has
been associated with increased risk of oral cancer. This paper will review previous, published
evidence to examine if a causal relationship, as described by Hill’s criteria, between smokeless
tobacco and oral cancer exists.
The strength of an association speaks to the size of the association, which is measured
through tailored study designs, such as cohort studies, and statistical testing. The higher the
association, the more likely the relationship is causal. The following two studies were examined
to evaluate the strength of smokeless tobacco and the increased risk for oral cancer.
A study was conducted in Sweden to examine the risks for oral, lung, and pancreatic
cancer after having used smokeless tobacco, also known as snuff. It is widely used in
Scandinavian culture, and it has been suggested that it is a safer alternative to smoking.
However, it has still been classified as a carcinogen. There is not much data on the effects of
snuff and the development of site-specific cancers.⁵ This study was conducted using a
retrospective cohort study design. This article is important because cohort studies are very
instrumental in determining strength of a relationship.
The conductors of the study collected detailed information about snuff and smoked
tobacco use from 279, 897 construction workers in Sweden during the years of 1978-1992. THe
average age of the men at the initial data collection period was 35. At the initial collection, the
data received determined which cohort the men were placed in. They were asked about snuff use,
amount of snuff consumer per day if used, and body mass index. Follow-ups were conducted
through the year 2004 via health registries and links with the population. There were 125, 576
workers who were reported as never-smokers. In order to identify the effects of using snuff,
these workers were compared over the years to the workers who smoked. At the conclusion of
the data collection, researchers identified 60 cases of oral cancer, 154 cases of lung cancer, and
83 cases of pancreatic cancers in workers who had never smoked. The researchers were only able
to independently associate snuff with the increased risk of pancreatic cancer. They were not able
to do so with oral or lung cancer. The relative risk was the same for both types of cancers in
never- and ever-users, 0.7. For pancreatic cancer, in ever-users, the relative risk was 0.9
compared to 1.2 in never-users.The study concluded that snuff should be regarded as a risk factor
for pancreatic cancer.⁵
Case control studies are frequently used to assess the relationship of smokeless tobacco
and oral cancer, but they have limitations, such as selection bias. One group of researchers

3. decided to study this health outcome and the exposure using a nested case-control study in an
attempt to eliminate such limitations. This is important because these two variable are not
usually assessed this way; this provides a different perspective on the strength of the
association.⁷
The group of subjects were taken from a previous, cluster-randomised control trial done
in Kerala, India. The study examined the effect of screening on oral cancer mortality. From this
study, only the healthy individuals over the age of 35 were included; those who already had oral
cancer were not. Individuals were placed into categories according to the performance or
avoidance of three behaviors: alcohol use, smoking, and chewing tobacco. When the data was
analyzed after the study period, only the incidence cases were included and the controls were
selected from the non-cancer individuals. The controls were similar in age, sex, place of
residence, and response status.⁷
There were 282 new cases of oral cancer during the study, and 202 of the cases were
currently chewing or had chewed tobacco before. Odds ratios were recorded for past chewers; it
was 5.9 for men and 39.0 for women. They were also calculated for current users; it was 11.8 for
male and 23.3 for females. All odds ratios had a confidence interval of 95%. This study also
examined the risks of alcohol usage, another factor associated with oral cancer, but did not find a
significant increased risk (once adjusted for smoking and chewing tobacco behaviors).⁷
Before a causal relationship can be determined, consistency must also be demonstrated.
In order for an association can be deemed consistent, different studies must be done on different
populations; the studies must yield the same results. The following two studies were examined to
evaluate the consistency of smokeless tobacco and the increased risk for oral cancer.
A review of the risks and determinants of oral cancer in regards to smokeless tobacco use
was conducted by Rodu and Jansson. This article is important because it closely examines the
validity of results from epidemiological research concerning oral cancer and smokeless tobacco.
The pair identified and reviewed 21 studies that assessed the risk of using smokeless tobacco and
contracting oral cancer. Several conclusions were made in the review. To begin, there are three
types of smokeless tobacco: moist snuff, dry snuff, and loose-leaf chewing tobacco.The
reviewers identified that different types of smokeless tobacco products yield different relative
risks. For those who use chewing tobacco and moist snuff, there are very low risks for cancers.
The relative risks for the are under 2. Dry snuff yields a relative risk from 4 to 13. Overall,
smokeless tobacco's average relative risk ranges from 1.5 to 2.8. The review also concluded that
the risk for certain smokeless tobacco products are high, but the high risk is an exaggeration. The
authors state that over the years studies have overestimated the presence of tobacco-specific-
nitrosamines (TSNAs) in these products. Although these compounds are harmful, they are
present in very low levels. The articles also points out that previously conducted studies were not
very efficient. The studies did not control for confounding factors such as cigarette smoking or
alcohol use, two others factors that have been associated with increased risk for oral cancer.
Claims in previous studies have also been made about other carcinogens that are in smokeless
tobacco products such as lead, cadmium, polonium-220, and formaldehyde. The articles claims

4. that more discussion of the concentrations and exposures of these carcinogens in these tobacco
products. The authors state that the same, or even less, amounts of these carcinogens can be
found in food. ⁴
Another epidemiological review of the health effects of smokeless tobacco and cancer
was conducted. 65 studies were reviewed based on following criterion: usage of an analytic
epidemiological study design, sufficient sample size, primary data analysis, usage of appropriate
statistical methods, and population in Scandinavia and United States. Studies were retrieved from
Medline and other literature databases.⁶
The reviewer concludes that of the case control studies (11) that have been published,
which would determine strength, there is an increased risk of cancer and mortality. It also states
that the risk is very small. The author also notes that the Swedish studies, which are popular, may
not be entirely credible. This is because mid-follow-up, the concentration of TSNAs were
lowered. This may affect cancer and mortality rates. The author examined three different studies
that associated smokeless tobacco with oral cancer; it was then noted that these studies may not
be generalizable since they were hospital-based, and confounding factors (alcohol use and
smoking) were not controlled for. There were also two additional cohort studies that showed no
association of smokeless tobacco and cancer once the results were adjusted for age and alcohol
use. Of the cohort studies (11) examined, the reviewer was able to determine that the risk of oral
cancer depended strongly on the type of smokeless tobacco being used. In the cohorts previously
studied, dating back to 1966, moist snuff and chewing tobacco from the United States present
minimal risk of oral cancer (as long as it not excessively consumed). The reviewer does
acknowledge the risks of smokeless tobacco but also suggests that a switch from smoked tobacco
to smokeless tobacco may serve a benefit to the health of the public.⁶
In determining causal relationships, temporality must also be examined. In trying to
prove that an exposure causes an outcome, studies must show that the exposure precedes the
health outcome. The following two studies were observed to evaluate the temporality of oral
cancer rates and the usage of smokeless tobacco.
A prospective cohort study conducted on Norwegian men from 1964 to 1967. 10,136
men participated in the study that aimed to examine the effects of smokeless tobacco on different
types of cancer rates, including oral cancer. The subjects were obtained from a systematic sample
of the Norwegian population via the 1960 census. Also included in the study were relatives of
Norwegian migrants who had gone to the United States. All participants completed a detailed
questionnaire about their consumption of smokeless tobacco, dietary habits, any tobacco
smoking behavior, alcohol consumption, and other factors not mentioned. Follow up was
conducted by way of national cancer and death registries. Follow up was discontinued once the
subject was diagnosed with cancer, left the country, or died.¹⁰
The participants were placed into the following categories: current users, never or
occasional users, or regular former users. During the study period, there 34 incident cases of oral
cancer, with 25 of those being never users. 9 were ever users (6 were former users, and three
were current users). The relative risk was 1.10 for never users. ¹⁰

5. A study conducted at the Kasturba Medical Hospital in India over the course of 5 months
(March 2013 to July 2013 aimed to study the health effects of exposure to gutka, a form of
smokeless tobacco, and other tobacco products on the rates of oral cancer. This study is
important because it examines a form of smokeless tobacco that has been deemed more intense
than other forms. This study was a case-control study that included 134 cases (80% male and
20% female) and 268 controls (90% male and 10% male). Included in the case group were
individuals who were over the age of 18 who had oral cancer and visited the hospital during the
study period. Included in the control group were persons 18 and above with no history of oral
cancer who had visited the hospital during the study period. The average age of the participants
was 46 years old.¹¹
Participants were administered a detailed questionnaire which inquired about their
demographic characteristics, occupation, diagnosis date, oral hygiene rituals, and and habits that
could serve as risk factors, such as smoking, drinking, chewing tobacco, etc,. The data was
analyzed, and the researchers did include that people who consumed smokeless tobacco whether
chewed or dipped were at an increased risk for oral cancers. Consumers of gutka were 5.1 times
more likely to develop oral cancer, and consumers who chewed tobacco were 6 times more likely
to develop oral cancer compared to people who did not consume gutka or chew tobacco.¹¹
Biological gradient is otherwise known as the dose-response relationship. Simply put, as
the exposure increases, so does the risk or occurrence of the health outcome. In trying to prove
causality this is important because it demonstrates the association of the two variables. The
following two studies were examined to evaluate the dose-response relationship of smokeless
tobacco and oral cancer.
The first study took place during the time period of 1990 to 1997. 78, 140 women aged
30-84 in Karunagappally, India were included in the study. Only women who were over 30 and
below 85 years of age, were not employed at the Rare Earth factory (other carcinogenic
exposures may have occured), cancer-free, and did not die within three years of the interview
were included in the study. The study aimed to analyze cancer incidence in regards to tobacco
chewing. Alcohol use and smoking behaviors were rare in this particular population of women.⁸
Initial baseline data was collected in 1990 about sociodemographic factors, religion,
income, educational level, occupation, lifestyle and other factors not mentioned. The women
were then categorized into groups based on performance or avoidance of tobacco chewing
behaviors, which were: never chewed tobacco, habitually chewed in the past, or currently
habitually chewed. Information on daily consumption, age at starting or stopping point of the
behavior were taken. ⁸
Cancer incidence was obtained by the cancer registry in the area. Of the women studied,
92 cases of oral cancer were identified; these were the cases identified after control for alcohol
and smoking behavior. Incidence of cancer in this study was associated with daily consumption
of smokeless tobacco. Women who chewed tobacco 10 or more times a day were 9.2 times more
likely to develop oral cancer. The risk is expected to increase during the first 20 years of chewing
tobacco.⁸

6. A case control study conducted in 67 counties from 1971 to 1978 in central North
Carolina sought to examine the risk of oral cancer in women who used smokeless tobacco
(dipped or moist snuff). Identified cases were obtained from the hospitals in the area and death
certificates. For the 255 cases identified (156 from the hospital and 99 from death certificates),
two controls were selected for each;there were a total of 502 controls. Controls were similar in
age, race, place the case identification was obtained from (hospital), or residence at the time of
death. Excluded from this study were those with mental disease, neoplasm in the oral cavity,
esophageal or laryngeal cancer, or any other disease in the mouth and throat region. Information
was obtained from both the cases and the controls about their usage of tobacco, alcohol, and
occupational exposures. Other factors were inquired about but not mentioned.⁹
After analyzing the data, the researchers concluded that snuff users were 4 times more
likely to develop oral cancer, and long term users were 50 times more likely to develop oral
cancer and the tumors associated with it. ⁹
Because I did not observe all of Hill’s criteria in examining the relationship of smokeless
tobacco and oral cancer, I can not definitively say that there is a causal relationship between the
two. I can only give an informed critique of the information I reviewed.
I would say there is a weak, potential causal relationship. In studying the literature,
previous studies were not able to identify significant strength of the association. Researchers
were able to find an increased risk in smokeless tobacco users in developing oral cancer, but the
risk was not significant compared to others who had never used it. Another factor that influences
my opinion is the consistency of the results. There was evidence that claims that all studies done
on the topic may not be credible because of non-standardized practices, such as what does or
does not count towards the behavior, selection bias in case-control, assumed high risk of all
smokeless tobacco products, and inadequate sample sizes. Also, earlier studies did not do a
sufficient job in controlling for confounding factors of other known contributors to oral cancers.
All of these things lead to different, or invalid and inaccurate results. The temporality was
adequately displayed in the retrospective cohort studies that I displayed, and so was the
biological gradient. Both criterion had strong evidence to support the association. However,
because of the lack of evidence to support the strength and consistency (and the omission of the
other criterion), I can not say there is a causal relationship between smokeless tobacco use and
oral cancer--on a potential weak, positive relationship.

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