Systematic review of the relation between smokeless tobacco and non-neoplastic oral diseases in Europe and the United States

1472-6831-8-13 1472-6831 Research article Systematic review of the relation between smokeless tobacco and non-neoplastic oral diseases in Europe and the United States Kallischnigg Gerd Gerd.Kallischnigg@pmintl.com Weitkunat Rolf Rolf.Weitkunat@pmintl.com Lee N Peter PeterLee@pnlee.co.uk

Philip Morris Products S.A., PMI Research & Development, Neuchâtel, Switzerland

P.N. Lee Statistics and Computing Ltd, Surrey, UK

BMC Oral Health 1472-6831 2008 8 1 13 http://www.biomedcentral.com/1472-6831/8/13 18452601 10.1186/1472-6831-8-13 01 11 2007 01 5 2008 01 5 2008 2008 Kallischnigg et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Background

How smokeless tobacco contributes to non-neoplastic oral diseases is unclear. It certainly increases risk of oral mucosal lesions, but reviewers disagree as to other conditions. In some areas, especially South-East Asia, risk is difficult to quantify due to the many products, compositions (including non-tobacco ingredients), and usage practices involved. This review considers studies from Europe (in practice mainly Scandinavia) and from the USA.

Methods

Experimental and epidemiological studies published in 1963–2007 were identified that related risk of oral lesions to smokeless tobacco use. Data were assessed separately for oral mucosal lesions, periodontal and gingival diseases, dental caries and tooth loss, and oral pain.

Results

Oral mucosal lesions: Thirty-three epidemiological studies consistently show a strong dose-related effect of current snuff on oral mucosal lesion prevalence. In Scandinavia, users have a near 100% prevalence of a characteristic "snuff-induced lesion", but prevalence of the varied lesions reported in the USA is lower. Associations with chewing tobacco are weaker. The lack of clear association with former use suggests reversibility following cessation, consistent with experimental studies showing rapid lesion regression on quitting.

Periodontal and gingival diseases: Two of four studies report a significant association of snuff with attachment loss and four out of eight with gingival recession. Snuff is not clearly related to gingivitis or periodontal diseases. Limited evidence suggests chewing tobacco is unrelated to periodontal or gingival diseases.

Tooth loss: Swedish studies show no association with snuff, but one US study reported an association with snuff, and another with chewing tobacco.

Dental caries: Evidence from nine studies suggests a possible relationship with use of smokeless tobacco, particularly chewing tobacco, and the risk of dental caries.

Oral pain: Limited evidence precludes any clear conclusion.

Conclusion

This review confirms the strong association of current use of smokeless tobacco, particularly snuff, with prevalence of oral mucosal lesions. It provides suggestive evidence of an association of snuff use with gingival recession and attachment loss, and of chewing tobacco with dental caries. While smokeless tobacco clearly increases risk of oral mucosal lesions, interpretation for other endpoints is limited by study weaknesses, including poor confounding control.

Background

This review concerns epidemiological studies that relate smokeless tobacco [ST] use to non-neoplastic oral diseases and is based primarily on 50 publications, 20 in Scandinavia 1234567891011121314151617181920, 29 in the USA 2122232425262728293031323334353637383940414243444546474849 and one in England 50. In these countries, usage is mainly oral; nasal use of finely ground "dry snuff" has become rare 51. ST products are traditionally classified as snuff or chewing tobacco (CT) 52. In the USA, CT is typically mixed with saliva and then placed in the buccal pouch, while finely cut "moist snuff" is frequently held in the lower labial fold. In Scandinavia, snuff (or snus in Sweden) is generally placed under the upper or lower lip. As in some other reviews of ST effects 5354555657 results from areas (such as India, South Asia, Africa and Saudi Arabia) where the tobacco chewed is often mixed with other substances, such as betel quid and areca nut are not considered 58. Nor is oral cancer considered, as its relationship with ST has been discussed elsewhere 57.

An earlier review of non-cancerous and precancerous oral health effects associated with ST use was published by the US Surgeon General in 1986 53. This report concluded that "smokeless tobacco is responsible for the development of a portion of oral leukoplakias in both teenage and adult users" and that "dose response effects have been noted by a number of investigators". However, it also noted that "studies of the effects of smokeless tobacco use on gingival and periodontal tissues have resulted in equivocal findings" and that "negative health effects on the teeth from smokeless tobacco use are suspected but unconfirmed". Since that time there have been many reviews of the evidence relating ST use to oral changes 545559606162636465666768697071.

While these reviews are consistent in concluding that ST use is associated with an increased risk of oral mucosal lesions, they are far less consistent with regard to other endpoints. Though various reviews 54606167 comment on a possible relationship with gingival recession, they disagree on whether an association is clearly demonstrated or not. Similarly, views vary over whether associations with periodontal diseases and dental caries have not been demonstrated 60, are possibly related, based on limited evidence 69, or have been shown to exist 5467. A number of these reviews 6364687071 note that "ST-related" oral mucosal lesions reverse on quitting and go on to discuss the extent to which the presence of the lesion modifies the risk of oral cancer. A recent review by the US Surgeon General 72 notes that leukoplakia is a classic precursor lesion of oral cancer, but notes that "the leukoplakia that occurs in cigarette smokers differs morphologically from the keratoses caused by smokeless tobacco; although less common, the leukoplakia induced by cigarettes is more susceptible to malignant transformations," citing a review by Bouquot 73. The importance of distinguishing the oral mucosal lesions induced by ST from oral leukoplakias has also been emphasised by other reviewers 7475.

Our objective, therefore, was to try to clarify the overall picture by conducting a detailed review of the available evidence.

Methods

Study identification and selection

Results were identified from a systematic search of MEDLINE, EMBASE, and SCOPUS through November 2007. The search was not limited by period or language. The main searches were based on combinations of the terms "smokeless tobacco", "chewing tobacco" and "snuff" for exposure, and "oral diseases", "mouth diseases", "periodontal diseases", "leukoplakia", "mucosal lesions", "gingivitis", "gingival recession", "teeth problems", and "dental caries" for outcome. Further articles were identified by inspection of reference lists in individual papers and reviews.

All reports had to satisfy the following Inclusion criteria: published in a peer reviewed journal or publicly available; based on research in humans; of experimental, cohort, case-control design or cross-sectional design; study location specified; conducted in North America or Europe; non-neoplastic form of oral disease (ICD 9 520–529) as the outcome; and CT, orally used moist snuff, or unspecified ST as the exposure. They also had to satisfy the Exclusion criteria: oral cancer, sample included in a more complete or recent study; inappropriate design (case report, qualitative study or review); and appropriate prevalence estimates or odds ratios (ORs) not reported and cannot be computed from the available data.

Data extraction

From each report, details were abstracted relating to the study (design, period, region, population, sample selection, and size), the exposure (method of assessment, type of ST investigated, exposure doses and durations considered), the outcome (type of oral disease and method of diagnosis), and issues relating to analysis (type of effect measure, analysis methods, stratification variables, and adjustment factors).

Data were considered separately under four disease groups: oral mucosal lesions, periodontal and gingival diseases, dental caries and tooth loss, and oral pain. Additionally, a summary description of each study was prepared, sorted by study design.

In some studies, the required estimates of prevalence, or of effect size and precision, were not given by the authors and had to be estimated from data presented. Crude ORs and 95% confidence intervals (CIs) were derived from the relevant 2 × 2 table using standard methods, with, where necessary, numbers estimated from proportions given numerically.

Results

50 principal studies were identified, 20 of snuff, conducted in Scandinavia (two in Denmark, one in Finland and 17 in Sweden), 29 of CT, snuff or overall ST, conducted in the USA, and one of CT, conducted in England. No relevant studies were identified from other parts of North America or Europe. Table 1 (Europe) and Table 2 (USA) give some details of the 50 studies considered. Both tables are sorted by type of study and then by year of publication within type. Six are experimental studies investigating the short-term effect on oral mucosal lesions of quitting ST use, switching to a different brand of snuff, or changing the site of placement of the snuff. Of the 44 epidemiological studies, three are prospective studies and two are case-control studies, though one 5 is a case-control study of oral and oropharyngeal cancer, with only the control group providing data relevant to this report. There are 39 cross-sectional studies, 26 of populations unselected by ST use and 13 of populations selected by ST use and/or presence of oral lesions. Some of the 50 studies are not independent. Thus, two studies 119 involve a subset of subjects selected from those in a third 18, while one study 38 gives combined results from a number of groups of baseball players, the results for two of these being previously reported 3134. Also, three studies 404243 give results for different endpoints using differently selected samples from the third National Health and Nutrition Examination Survey (NHANES III).

Table 1

Details of European studies considered.

First author, year of publication

Location

Study Period ^a

Sex

Age

Population

Further details of study design

Endpoints ^b

Experimental studies

Larsson 1991 [1]

Sweden (Malmö)

3 to 6 months

21 to 70 Mean 36

29 snuff users with degree 2 to 4 mucosal lesions selected from Andersson 1989 [18]

Subjects advised to stop or change their habit

Andersson 1995 [2]

Sweden (Malmö)

12 weeks

Not given

Mean 37

24 users of snuff brand A, 18 users of low-nicotine snuff brand B

Subjects observed for 2 weeks, then brand A users switched to brand B for 10 weeks^c

Andersson 2003 [3]

Sweden (Malmö)

24 weeks

Not given

Mean 34

20 users of snuff brand A with degree 3 or 4 lesions

Subjects switched to brand B with lower pH for 12 weeks, then to brand C with same pH as brand B but lower nicotine^d

Prospective studies

Roosaar 2006 [4]

Sweden (Uppsala county)

1973–1974 to 2002

15+

1115 men with "snus-induced lesions" in 1973–1974 followed up

Selected from 7890 men examined

Case-control studies

Rosenquist 2005 [5]

Sweden (South)

2001 to 2004

M+F

33 to 87

132 cases of oral and oropharyngeal squamous cell carcinomas, 320 population controls

Cases and controls matched on age ± 3 years, sex and county

Cross-sectional studies of populations unselected by ST use

Tyldesley 1971 [50]

England (Lancashire)

Not given

402 coal miners

Modéer 1980 [6]

Sweden (Stockholm)

Not given

M+F

13 to 14 Mean 13.5

232 school children

Jungell 1985 [7]

Finland (Tammisaari)

Not given

17 to 29

441 military recruits

Salonen 1990 [8]

Sweden (Älvsborg county)

1983 To 1984

M^e

20+

477 randomly selected male adults

Hirsch 1991 [9]

Sweden (Gothenburg)

Not given

M+F

14 to 19 Mean 16.8

2145 teenagers attending for dental check-up

Wickholm 2004 [10]

Sweden (National)

1985

M+F

31 to 40

1674 adults born on 20th of month

Bergström 2006 [11]

Sweden (National)

2002 to 2003

26 to 54

84 submariners

PD, DC

Montén 2006 [12]

Sweden (Göteborg)

Not given

103 never smokers

Subsample from larger epidemiological study

Cross-sectional studies of populations selected by ST use and/or presence of oral lesions

Pindborg 1963 [13]

Denmark (Copenhagen)

Not given

39 to 83

12 long-term snuff users

SIL probable inclusion criterion

Roed-Petersen 1973 [14]

Denmark (Copenhagen)

1956 to 1970

M+F

< 20 to 90+ Mean 55

450 oral leukoplakia patients

ML, OP

Axéll 1976 [15]

Sweden (Not given)

Not given

20 to 88 Mean 50

114 snuff users with oral lesions

Hirsch 1982 [16]

Sweden (Gothenburg)

Not given

15 to 84 Mean 41

50 habitual snuff users

SIL probable inclusion criterion

Frithiof 1983 [17]

Sweden (Stockholm)

Not given

31 to 79 Mean 55

21 long-term snuff users referred to dental school for oral lesions

ML, PD

Andersson 1989 [18]

Sweden (Malmö)

1986 to 1987

17 to 80 Mean 36

252 snuff users; construction and shipyard workers and outpatients

ML, PD

Andersson 1994 [19]

Sweden (Malmö)

Not given

21 to 75 Mean 42

45 habitual snuff users and 9 users of CT selected from Andersson 1989 [18]

Loose and portion-bag users matched on consumption and usage

Rolandsson 2005 [20]

Sweden (Värmland)

Not given

16 to 25 Mean 21

80 ice hockey players, of which 40 were snuff users and 40 non users

Snuff users and non users age matched

ML, PD, DC

^aLength of follow-up period for experimental studies, period of follow-up for prospective studies, and time study conducted otherwise

^bDC = dental caries, ML = mucosal lesion, OP = oral pain, PD = periodontal or gingival diseases

^cBrand A 0.8–0.9% nicotine, 8.2–8.5 pH; Brand B 0.4–0.5% nicotine, 7.8–8.2 pH

^dBrand A 0.8% nicotine, 8.6 pH; Brand B 0.8% nicotine, 8.0 pH; Brand C 0.4–0.5% nicotine, 8.0 pH

^eWomen were also studied but none used snuff

Table 2

Details of US studies considered.

First author, year of publication

Location

Study Period ^a

Sex

Age

Population

Further details of study design

Endpoints ^b

Experimental studies

Grasser 1997 [21]

North Carolina

10 days

M+F

18 to 47

214 soldiers

4 ST users with oral leukoplakia advised to stop

Payne 1998 [22]

Nebraska, Iowa

7 days

Mean 25

16 snuff users with oral lesions at habitual sites only

Site of snuff placement changed

Martin 1999 [23]

Texas

6 weeks

17 to 34

3051 air force trainees

119 ST users with oral leukoplakia ordered to stop

Prospective studies

Beck 1995 [24]

North Carolina

1988 to 1991

M+F

65+

818 dentate adults (50% black, 50% white)

Selected from Piedmont study. Reexamined at 18 and 36 months

PD, OP

Dietrich 2007 [25]

National

1986 to 2002

40–75

43112 health professionals dentate and cancer free at baseline

Data on tooth loss recorded every 2 years

Case-control studies

Fisher 2005A [26]

West Virginia

2001 to 2002

M+F

18+

90 cases of oral leukoplakia, 78 controls with periapical cysts and no oral leukoplakia

Subjects identified from biopsy of hyperkeratosis

Cross-sectional studies of populations unselected by ST use

Greer 1983 [27]

Colorado

Not given

M+F

14 to 19

1119 high school students

ML, PD, DC

Poulson 1984 [28]

Colorado

Not given

M+F

14 to 19 Mean 16.7

445 high school students

ML, PD, DC

Offenbacher 1985 [29]

Georgia

Not given

10 to 17 Mean 13.8

565 grammar and high school students

ML, PD, DC

Wolfe 1987 [30]

New Mexico

Not given

M+F

14 to 19 Mean 16.0

226 Native American children at boarding school

ML, PD

Cummings 1989 [31]

New York

1985

22 to 44 Mean 29

25 baseball players and coaches

ML, PD

Creath 1988 [32]

Alabama

Not given

11 to 18

995 adolescent football players

ML, PD

Stewart 1989 [33]

Florida

Not given

10 to 18

114 middle and high school students

5588 M+F interviewed, 182 examined orally, no results for 68F

Ernster 1990 [34]^c

Arizona

1988

M+F

20 to 29 (77%)

1109 professional baseball players

ML, PD, DC

Greene 1992 [35]

Arizona

1989 to 1990

20 to 29 (76%)

894 professional baseball players

Sinusas 1992 [36]

Pennsylvania

1990

17 to 58 Mean 25

206 baseball players and managers

ML, PD, DC

Daughety 1994 [37]

Iowa

Not given

16 to 17

821 11th and 12th grade school students

Robertson 1997 [38]

Arizona

1988 to 1990

20 to 29 (77%)

1846 professional baseball players

Includes subjects in Ernster 1990 [34] and Greene 1992 [35]

ML, PD, DC

Tomar 1997 [39]^d

National

1986 to 1987

M+F

12 to 17

17027 school students

NIDR National Survey of Oral Health

Tomar 1999 [40]

National

1988 to 1994

M+F

18+

14087 dentate adults

Third National Health and Nutrition Examination Survey (NHANES III)

Riley 2004 [41]

Florida

1993 to 2000

M+F

45+

873 adults

Reinterviews occurred over a 48 month period but analyses are all cross-sectional

Shulman 2004 [42]

National

1988 to 1994

M+F

18+

17235 adults

NHANES III, but different endpoints from Tomar 1999 [40]

Fisher 2005B [43]

National

1988 to 1994

M+F

18+

12932 adults

NHANES III, but different endpoints from Tomar 1999 [40] and Shulman 2004 [42]

Sinusas 2006 [44]

Pennsylvania

1991 to 2000

Mean 26

190 to 259 baseball players and coaches examined each year

Men attending spring training. Some men may attend on multiple occasions

Cross-sectional studies of populations selected by ST use and/or presence of oral lesions

Smith 1970 [45]

Tennessee

Not given

M+F

Mean 55

15000 long-term snuff users

Christen 1979 [46]

Texas

Not given

18 to 22 Mean 20

14 college athletes who used ST

ML, PD

Kaugars 1992 [47]

Virginia

Not given

14 to 77 Mean 29

347 ST users recruited by advertising^e

Little 1992 [48]

Oregon, Washington

Not given

15 to 77

245 ST users in Kaiser Permanente Dental Care Program

Also 223 age-matched non ST users

Roberts 1997 [49]

Indiana

1994 to 1995

M+F

Not given

22 snuff users and 19 non users

Oral lesions not recorded in non users

^aLength of follow-up period for experimental studies, period of follow-up for prospective studies, and time study conducted otherwise

^bDC = dental caries, ML = mucosal lesion, OP = oral pain, PD = periodontal or gingival diseases

^cSimilar results are reported by Grady et al [83], Robertson et al [84] and Daniels et al [85]

^dResults from this study are also reported by Kleinman et al [86]

^eAn additional group of 91 non users of ST with no oral lesions provides no useful information and has been ignored

The earliest publication 13 was in 1963, with five studies published in the 1970s, 13 in the 1980s, 18 in the 1990s and 13 since 2000. Many of the studies did not give details on when they were conducted. Of the 50 studies, 24 were of males and females, and 24 of males. Two studies 23 did not give details on the sex of their subjects. Most of the studies were mainly or wholly of adults, but there were 10 cross-sectional studies of children, mainly of school students, but including one of adolescent football players aged 11 to 18 32 and one of teenagers attending dental health check-up 9. Some of the studies of adults involved quite young populations, including air force trainees 23, military recruits 7, college athletes 46, 19 year olds 12 and baseball players 313435363844. Oral mucosal lesions were considered in 40 of the studies, with 19 considering indices of periodontal or gingival diseases, 10 dental caries, and three oral pain.

Oral mucosal lesions

Fifteen of the studies in Scandinavia provided information relating ST use to oral mucosal lesions. As shown in Table 3, 11 of these used the endpoint "snuff-dipper's lesion" as defined by Axéll et al 15 and a further three used an endpoint which appeared to be similar. For convenience we will refer to these 14 studies as being of snuff-induced lesions (SIL). Only in one study 14 was a clearly different endpoint used, of "oral leukoplakia", which could occur both in users and non-users of snuff.

Table 3

Definitions of oral mucosal lesions used in studies in Scandinavia

Definition of Axéll 1976 [15]

Snuff dipper's lesion is a lesion of the oral mucosa at the exact site of the regular placing of snuff. The clinical appearance is graded as follows:

Degree 1. A superficial lesion with a colour similar to the surrounding mucosa, and with slight wrinkling. No obvious mucosal thickening.

Degree 2. A superficial, whitish or yellowish lesion with wrinkling. No obvious thickening.

Degree 3. A whitish-yellowish to brown, wrinkled lesion with intervening furrows of normal mucosal colour. Obvious thickening.

Degree 4. A marked, white-yellowish to brown and heavily wrinkled lesion with intervening, deep and reddened furrows and/or a heavy thickening.

Studies using the Axéll 1976 definition

Larsson 1991 [1], Andersson 1995 [2], Andersson 2003 [3], Roosaar 2006 [4], Rosenquist 2005 [5], Axéll 1976 [15], Hirsch 1982 [16], Salonen 1990 [8]^a, Andersson 1989 [18], Andersson 1994 [19] and Rolandsson 2005 [20]

Studies using other definitions

Jungell 1985 [7] – "snuff-induced lesion", not further defined

Pindborg 1963 [13] – "snuff-induced leukoplakia", characterised by a mucous membrane with "a slightly whitish, sometimes yellowish-brown dry appearance with a very delicately folded or finely grooved appearance"

Roed-Peterson 1973 [14] – "oral leukoplakia", defined as "a white patch not less than 5 mm in diameter which cannot be removed by rubbing, and which cannot be ascribed to any other diagnosable disease"

Frithiof 1983 [17] – "snuff-induced lesion", with "a characteristic whitish appearance frequently with a brown discolouration which clearly contrasted with the neighbouring mucosa"

^a32 other types of oral mucosal lesion were also considered, but results were incompletely presented and their incidence (not shown in Table 4) did not appear to be clearly snuff related

Table 4 summarizes the main results from the Scandinavian studies relating oral mucosal lesions to the use of moist snuff (snus). The single study of oral leukoplakia 14, in Denmark, had no control group so could not compare lesion prevalence in snuff users and non-users, though it reported that only 32 of the 450 oral leukoplakia cases studied used snuff and that the presence of symptoms (such as pain or rough feel to the tongue) was much less prevalent in those who used snuff (3.1%) than in those who did not (23.1%, p < 0.01).

Table 4

Prevalence of oral mucosal lesions in relation to snuff use evidence from Scandinavia

Study

Location

Summary of main results

Experimental studies

Larsson 1991 [1]

Sweden

Of 29 users with degree 2 to 4 lesions, the lesion disappeared in 20 who quit snuff or changed to portion-bags and changed placement of the quid, reduced in 7 who changed to portion-bags and reduced their exposure, and remained in 2 who modified their habits only slightly.

Andersson 1995 [2]

Sweden

100% lesion prevalence initially in 24 users of ordinary snuff and in 18 users of low nicotine snuff. After 2 weeks, severity was non-significantly lower in habitual users of low nicotine brand. After a further 10 weeks, switching to the low nicotine brand was associated with a reduction in lesion severity (p < 0.01), despite an increased intake of 2.5 g/day.

Andersson 2003 [3]

Sweden

The 20 users of brand A (0.8% nicotine, pH 8.6) had a severity distribution of 0/0/16/4 for degrees 1/2/3/4 respectively. Switching to brand B (0.8% nicotine, pH 8.0) for 12 weeks, reduced the severity to 0/7/13/0, and switching to brand C (0.4–0.5% nicotine, pH 8.0) reduced it further to 2/11/7/0.

Prospective studies

Roosaar 2006 [4]

Sweden

Of 176 users with grade 1–4 lesions in 1973–1974 who were re-examined in 1993–1995, the lesion had disappeared in 62/66 = 94% of those who stopped, and remained in 108/110 = 98% of whose who continued (p < 0.001). Grade 3 and 4 lesions were less common in those who switched to portion-bag snuff, 6/42 = 14%, than in those who continued with loose snus, 20/68 = 29% (0.05 < p < 0.1).

Case-control studies

Rosenquist 2005 [5]

Sweden

100% lesion prevalence in 31 population controls who currently used snuff. Lesion severity was significantly associated with hours/day consumed (p = 0.01), but not with daily consumption (p = 0.07), or duration of use (p = 0.8).

Cross-sectional studies of populations unselected by ST use

Jungell 1985 [7]

Finland

63.6% lesion prevalence in 33 snuff users examined. Of the 12 with no lesions, 8 had quit snuff and 4 started snuff in the previous 3 weeks.

Salonen 1990 [8]

Sweden

92 lesions in 58 snuff only users, 29 in 23 mixed smokers and snuff users, 5 in 235 smokers and 0 in 602 with no tobacco habit (frequencies of subjects with lesion not given).

Cross-sectional studies of populations selected by ST use and/or presence of lesions

Pindborg 1963 [13]

Denmark

100% lesion prevalence in 12 long-term snuff users (lesion prevalence probable inclusion criterion).

Roed-Peterson 1973 [14]

Denmark

Among 450 selected patients with oral leukoplakia, the 32 who used snuff experienced fewer symptoms than the other 418 patients.

Axéll 1976 [15]

Sweden

Among 108 selected snuff users with oral lesions, severity increased with consumption (hours/day or grams/day) of snuff.

Hirsch 1982 [16]

Sweden

100% lesion prevalence in 50 habitual snuff users (lesion prevalence probable inclusion criterion). Severity increased with consumption (hours/day or grams/day) of snuff, and also with duration of use.

Frithiof 1983 [17]

Sweden

Among 21 snuff users referred for treatment due to oral lesions, those who quit following advice to do so had marked lesion improvement in two weeks.

Andersson 1989 [18]

Sweden

100% lesion prevalence in 252 snuff users. Severity was significantly less in 68 users of portion-bag snuff than in 184 users of loose snuff. Severity was also clearly associated with consumption (hours/day or grams/day), though less clearly with duration of use.

Andersson 1994 [19]

Sweden

100% lesion prevalence in 45 snuff users. Severity was less in 23 users of portion-bag snuff than in 22 users of loose snuff.

Rolandsson 2005 [20]

Sweden

Lesion prevalence 87.5% in 40 snuff users and 0.0% in 40 non-users (p < 0.001). Prevalence and severity increased with hours/day of snuff and was lower in users of portion-bag snuff.

The remaining 14 studies generally reported a 100% prevalence of SIL in snuff users. Partly this was because in seven studies 13413151617 subjects had been, or appeared to have been, selected on the basis of SIL being present, but this was not always the case 251819. The only exceptions were a study in Finland 7 in which all the users with no lesion had either quit or started snuff in the previous three weeks, and a recent study of ice-hockey players in Sweden 20 which reported no lesions in five users of portion-bag snuff. One study in Sweden 8 reported total numbers of lesions, but prevalence seems likely to have been very high in snuff users.

As is evident from the results of the cross-sectional and case-control studies summarized in Table 4, severity of SIL was clearly associated with the length of time per day snuff was used for and with the amount of snuff consumed per day 515161820, though the statistical significance of these relationships could not always be determined. The relationship of severity with duration of use was less marked 51618. Severity was also lower in users of portion-bag snuff than in users of loose snuff 1920.

A number of the experimental and epidemiological studies investigated the effect of changing snuff habits on the presence and severity of SIL. The data in Table 4 are all consistent with quitting in the short-term reducing the severity of the lesion 17 and in the longer term eliminating the lesion 147, and switching to lower nicotine, lower pH or portion-bag snuff also reducing severity 1234.

While it is clear from the above that SIL occurs in virtually all current users of moist snuff, with severity related to extent of use, the data in Table 4 tell us little about the long-term health implications of the lesion. The study by Roosaar et al 4 provides some additional information. Here 1,115 individuals with SIL were followed-up for 27–29 years, with a total of three incident cases of oral cancer seen, two in concomitant daily smokers. Though this was somewhat higher than expected (standardized incidence rate 2.3, 95% CI 0.5–6.7), none of the three occurred at the site of the original SIL.

Of the 15 Scandinavian studies considered, 14 consider use of moist snuff only and not other types of ST. The study of Andersson et al 19, however, considered nine users of CT as well as 45 snuff users. They noted that seven of the CT users showed leukoedema in the buccal mucosa, and that six who placed the tobacco on a permanent site had degree 1 or 2 (Axéll) lesions at the site of placement.

The single study in England 50, of coal miners, reported that 10 out of 280 CT users, 3.6%, had leukoplakia, as compared to none out of 122 non-chewers (p = 0.05). Here leukoplakia was defined as "a white patch that could not be rubbed off and which could not be diagnosed as being due to any other disease".

Twenty-four US studies provided evidence relating ST use to oral mucosal lesions. As shown in Table 5, the definitions of the endpoint used varied widely. Eight studies 2227283033364448 used a definition modified by Greer and Poulson 27 from that used by Axéll 15, and at least three studies 34353839 used a similar definition. However, in some studies the endpoints were clearly not comparable, including one 42 where the endpoint was any type of oral lesion and one 47 where the definition specifically excluded alterations that resolved rapidly on discontinuation of ST use. Unlike the studies in Scandinavia, the conditions were usually referred to as oral leukoplakia or as oral lesions, with no specific reference to ST or snuff in the name of the condition, as in SIL. An exception was the Tomar et al study 39 which referred to the endpoint as "smokeless tobacco lesions". Indeed it is clear from Table 6, which presents the prevalence of these lesions in relation to ST use, that the endpoint definitions did not exclude the possibility of the lesion being present in non-users of ST. In fact, in all but one of the 15 studies which presented findings separately for users and non-users, including the Tomar et al study, prevalence is greater than zero in the non-users.

Table 5

Definitions of oral mucosal lesions used in studies in the USA

Definition of Greer 1983 [27]

Modified version of Axéll 1976 [15]. Oral mucosal lesion graded for severity as:

Degree 1. A superficial lesion with colour similar to that of the surrounding mucosa with slight wrinkling and no obvious thickening.

Degree 2. A superficial whitish or reddish lesion with moderate wrinkling and no obvious thickening.

Degree 3. A red or white lesion with intervening furrows of normal mucosal coour, obvious thickening and wrinkling.

Studies using the Greer 1983 definition

Payne 1998 [22], Greer 1983 [27], Poulson 1984 [28], Wolfe 1987 [30], Stewart 1989 [33], Sinusas 1992 [36], Sinusas 2006 [44] and Little 1992 [48].

Studies using other definitions

Grasser 1997 [21] – oral leukoplakia; a white patch or plaque that does not wipe off and cannot be characterized clinically or pathologically as any other disease

Martin 1999 [23] – oral leukoplakia; modified from Greer 1983 definition, graded for severity as 1: superficial lesion with slight colour change, slight wrinkling and no obvious thickening, 2: superficial white lesion with moderate wrinkling and no obvious thickening, and 3: white lesion with obvious thickening and wrinkling

Fisher 2005 [26] – oral leukoplakia; based on the international classification of diseases, 9^threvision code (ICD-9) of 528.6 with a biopsy of hyperkeratosis with or without epithelial atypia or dysplasia. A clinical diagnosis of ST keratosis or frictional keratosis was excluded

Offenbacher 1985 [29] – oral mucosal pathology; alterations considered to represent early changes, as reflected by a mild increase in opalescence and whiteness, with slight furrowing

Creath 1988 [32] – oral leukoplakia; not further defined

Cummings 1989 [31] – soft tissue lesions; not further defined

Ernster 1990 [34] and Greene 1992 [35] – oral leukoplakia; any white, opaque, leathery-appearing plaque not clinically characteristic of another type of white lesion, graded for severity as 1: no or only slight colour change, with or without texture change, 2: colour and texture change, but no thickening, 3: colour and texture change with mild to moderate thickening, or 4: no normal colour, severe texture change, and heavy thickening

Daughety 1994 [37] – oral lesions at placement site; from response to question "Have you ever noticed a sore, white patch or gum problem where you held the tobacco in your mouth?"

Robertson 1997 [38] – oral leukoplakia; any white, opaque, leathery-appearing slightly raised, and irregularly corrugated changes in the oral mucosa not characteristic of another white lesion, graded for severity from 1: slight change in colour and texture to 4: no normal colour, severe texture change and heavy thickening

Tomar 1997 [39] – ST lesions; slight to heavy wrinkling of the mucosa with or without obvious thickening, graded for severity as 1: slight, superficial wrinkling of the mucosa. Colour of the mucosa may range from normal to pale white or grey. Mucosa does not appear to be thickened, 2: distinct whitish, greyish, or occasionally reddish colour change. Wrinkling is obvious, but there is no thickening of the mucosa, or 3: mucosa is obviously thickened, with distinct whitish or greyish colour change. Deep furrows are present within the thickened areas

Shulman 2004 [42] – oral mucosal lesions; 49 types of lesion are listed, including candida-related lesions, tobacco-related lesions, acute conditions and various other conditions, but ST use is only given in relation to the overall incidence of any type

Smith 1970 [45] – oral mucous membrane change "which offered criteria for further study"

Christen 1979 [46] – clinical leukoplakia; a white plaque on the mucosa, with mild to moderate defined as a non palpable, smooth, fairly translucent white area, and severe defined as areas appearing thick, white, indurated and fissured

Kaugars 1992 [47] – oral lesion; a visible alteration of the oral mucosa that persisted for at least 7 days after discontinuation of ST use; an alteration with little probability of resolving within 7 days, in the opinion of the investigator, or an alteration occurring in a subject who was unable to return for a recall visit

Roberts 1997 [49] – oral lesion; any visible lesion

Table 6

Prevalence of oral mucosal lesions in relation to ST use – evidence from the USA

% prevalence (n) ^a

Study

Endpoint^b

Exposure^c

Exposed

Unexposed

Statistical tests and other results and comments^d

Experimental studies

Grasser 1977 [21]

Oral leukoplakia

ST ever

13.3 (4)

0.5 (1)

OR 28.2 (3.03–262)

Lesions in users resolved after 10 days quit

Payne 1988 [22]

Greer 1–3

Snuff current

100.0 (16)^e

After switching site of snuff placement and to reference snuff, all 16 subjects had new lesions after 7 days of use, evident in 15 subjects by day 2. After 7 days, the original lesions at the habitual sites had resolved by 1 degree

Martin 1999 [23]

Oral leukoplakia

ST current

39.4 (119)

1.5 (42)^f

OR 41.9 (28.6–61.4)

Snuff current

41.8 (118)

1.5 (42)^f

OR 46.4 (31.5–68.2)

CT current

5.0 (1)

1.5 (42)^f

OR 3.39 (0.44–25.9)

Lesion had completely resolved in 97.2% (106/109) of ST users 6 weeks after tobacco use was prohibited

Case-control studies

Cases

Controls

Fisher 2005 [26]

Oral leukoplakia

ST current

22.5

7.2

OR 9.21 (1.49–57.0)^g

ST former

25.7

12.3

OR 2.73 (0.69–10.8)^g

Snuff current

19.0

2.7

OR 30.1 (2.67–338)^g

Snuff former

11.1

6.6

OR 0.98 (0.17–5.61)^g

CT current

4.2

4.3

OR 0.97 (0.19–4.98)

CT former

20.0

12.0

OR 1.83 (0.76–4.40)

Cross-sectional studies of populations unselected by ST use

Exposed

Unexposed

Greer 1983 [27]

Greer 1–3

ST use

42.7 (50)

Only ST users examined

Poulson 1984 [28]

Greer 1–3

ST use

58.9 (33)

Only ST users examined

Offenbacher 1985 [29]

Oral mucosal pathology

ST use

22.7 (17)

4.7 (23)

OR 5.95 (3.00–11.8)

Wolfe 1987 [30]

Greer 1–3

ST current^h

25.5 (37)

3.7 (3)^f

OR 8.91 (2.65–29.9)

Creath 1988 [32]

Oral leukoplakia

Snuff ever

5.2 (15)

0.1 (1)

OR 38.6 (5.07–294)

Cummings 1989 [31]

Soft tissue lesion

ST current

17.6 (3)

0.0 (0)

Only 6 never users of ST No differences significant

ST former

100.0 (2)

0.0 (0)

Snuff current

21.4 (3)

0.0 (0)

CT current

11.1 (1)

0.0 (0)

Stewart 1989 [33]

Greer 1–3

ST current

29.0 (9)

Prevalence only reported for male current users

Ernster 1990 [34]

Oral leukoplakia

ST current

46.3 (196)

1.4 (7)

OR 59.9 (27.8–129)

ST former^j

1.7 (3)

1.4 (7)

OR 1.19 (0.30–4.65)

Snuff current^k

58.3 (165)

1.4 (7)

OR 97.1 (44.4–212)

CT current^k

17.7 (14)

1.4 (7)

OR 15.0 (5.82–38.4)

Greene 1992 [35]

Oral leukoplakia

ST current

51.7 (167)

2.9

OR 35.8ⁱ

ST former^j

3.5

2.9

OR 1.21ⁱ

Snuff current^k

61.3 (157)

2.9

OR 53.0ⁱ

CT current^k

14.8 (8)

2.9

OR 5.82ⁱ

Sinusas 1992 [36]

Greer 1–3

ST current

37.1 (23)

6.0 (5)

OR 9.32 (3.29–26.4)

ST former^l

6.7 (4)

6.0 (5)

OR 1.13 (0.29–4.39)

Snuff current^k

34.2 (13)

6.0 (5)

OR 8.22 (2.67–25.3)