SUMMARY OF THE EVIDENCE AND FINDINGS AND CONCLUSIONS CONCERNING THE ADVERSE HEALTH EFFECTS OF SNUFF GOVERNMENT DOCUMENTS COLLECTION APR 27 1987 University of Massachusetts Depository Copy MASSACHUSETTS DEPARTMENT OF PUBLIC HEALTH EXECUTIVE OFFICE OF HUMAN SERVICES COMMONWEALTH OF MASSACHUSETTS July, 1985 Digitized by the Internet Archive in 2014 https://archive.org/details/summaryofevidencOOmass -2- Table of Contents Page I. Introduction/Executive Summary 3 II. Authority 7 III. Description of Snuff and Reports on Use 9 IV. Oral Cancer 12 A. Epidemiological Evidence 12 B. Histopathological Evidence 18 C. Experimental Evidence and Mechanisms of Carcinogenisis 24 V. Periodontal Disease 33 VI. Nicotine Dependence/Addiction 35 VII. Public Knowledge of Adverse Health Effects of Snuff 41 VIII. Summary of Findings 44 IX. Regulations 46 X. Appendix A. Agency Positions B. References C. Summary of Testimony INTRODDCTION/EXECOTIVE SUMMARY On February 6 and 7, 1985, the Massachusetts Department of Public Health conducted public hearings on proposed regulations declaring snuff, a smoke- less tobacco product, to be a hazardous substance and requiring the following health warning label on containers of snuff sold in the Commonweal th: WARNING: Snuff is addictive and may cause mouth cancer and other mouth disorders. The Department is under no legal obligation to prepare a summary of testi- mony and findings prior to the adoption of regulations. However, given the public interest in this matter, the Department has prepared a brief summary of the evidence and of certain findings and conclusions concerning several issues raised by the testimony received. This summary is not intended to be exhaustive, and the regulations as adopted are not necessarily based solely on these findings alone to the exclusion of other conceivable evidence. To provide an overview this introduction will consist of a brief outline of each of the topics reviewed in the order in which they appear in the report. Section II summarizes the Department's authority to promulgate a regulation requiring a health warning label on snuff containers. Section III contains a discussion of the definition of snuff, and presents information on sales and use including a number of studies on use by ado- -4- lescent males. The Massachusetts study of 5,000 high school students found that 15 percent tried smokeless tobacco during the last year, and 12 per- cent of the boys used it very often or several times. Section IV reviews the testimony and evidence concerning the association between snuff and oral cancer. This section is divided into three parts. Part A of Section IV deals with the epidemiological evidence. Over 40 case series, case control and cohort studies are presented. The studies showed consistency, specificity and strength for the association between smokeless tobacco use and human oral cancer. Risk for oral cancer was found to increase fourfold for snuff users, and up to fiftyfold for long term users. Opponents to the regulation challenged the association and referenced -the Smith study, a ten year follow-up study of 1,751 users that found no oral cancer among the group. However, the Smith study failed to follow-up on 201 of the study participants. Two epidemiologists who testified stated that this methodologic flaw raises serious questions about the value of the study's findings. Part 3 reviews the clinical evidence that demonstrates snuff use produces "leukoplakia" or white patches in the mouth of some users at the site the tobacco is held, and that a significant percent of these transform into malignant cancer over time. This position was also challenged. Opponents argued that the causes of leukoplakia are unknown, and snuff-associated leukoplakias have not been scientifically shown to develop into cancer. However, the scientific evidence submitted to the Department demonstrated that snuff is an etiologic agent in the formation of leukoplakia. This -5- conclusion is in accord with the position of several concerned agencies, such as the World Health Organization (W.H.O.). Part C examines animal studies which demonstrate that the nitrosamines con- tained in snuff induce tumor development in animals, including the oral cavity. Opponents of the proposed regulations acknowledged that these com- pounds produce tumors in animals. Epidemiologic, animal experimentation and clinical evidence presented in section IV support the conclusion that a strong causal relationship exists between snuff use and oral cancer. Based on this evidence both the National Cancer Advisory Board (NCAB) to the National Cancer Institute and the International Agency for Research on Cancer (IAHC) of W.H.O. state une- quivocably that snuff is a human carcinogen. In February of 1985, NCAB stated, "there is a cause and effect relationship between smokeless tobacco use and human cancer." In November 1984, IARC 'concluded, "there is suf- ficient evidence that oral use of snuffs of the types commonly used in North America and Western Europe is carcinogenic to humans." Section V of the report presents evidence that use of snuff causes periodontal disease at the site in the mouth where the tobacco is held. Section VI discusses nicotine's potential to produce addiction. Snuff produces blood nicotine levels equivalent to those produced from smoking. Evidence was submitted which demonstrated that nicotine at these levels produces effects similar to that produced by other drugs of abuse, can be dependence-producing and can result in addictive behavior. -6- Those opposed Co Che Departments labeling proposal challenged classifica- Cion of nicocine as dependence-producing and addictive. They argued chat addictive drugs must produce life ChreaCening wichdrawal sympCoras, resulC in occupacional or social impairment, and ChaC users must require clinical CreacmenC Co quic. However, a review of Che criceria of Che Nacional InsCiCuCe of Drug Abuse, W.H.O. and Che American PsychiaCric Associacion found ChaC Chese condicions are not accepted criceria for classifying Cobacco as a dependence-producing subsCance. SecCion VII reviews Che Cescimony on indusCry advercising and knowledge of adverse healch effeccs among users. IndusCry advercising was found Co porcray "going smokeless" as a safe, healchy habic and Co lack any healch warnings. A number of young consumers Cescified ChaC Chey did noC know of. healch problems associaCed wich snuff. In addicion, ic was Che opinion of several scace and nacional governmenCal and volunCary agencies ChaC Che public is not informed of possible healch problems caused by snuff. SecCion VTII presencs Che Deparcmenc:s findings and declaracions concerning snuff. Section IX includes a brief discussion of the changes made in the proposed regulations following the public hearing process and a copy of the final version of the regulations. A brief summary of the testimony and a list of agency positions are included in the Appendix. -7- II. Authority Pursuant to G.L. C.94B, the Commissioner of Public Health may, by reaso- nable rules and regulations, declare a substance to be hazardous and require special labeling requirements which are found to be necessary for the protection of the public health and safety. The Smokeless Tobacco Council argued that Massachusetts cannot impose a label requirement on containers of snuff because the area of tobacco regulation has been preempted by the federal government .( 1 ) However, there is no federal statute or regulation which governs the labeling of snuff. Nor has Congress expressed an intent to remove the labeling of snuff from state regulation. In the absence of Congressional action, the fact that Congress could require warning labels on snuff but has not done so does not foreclose the Commonwealth from requiring a label to protect the health and safety of its residents. Testimony was also received from the Smokeless Tobacco Council, the Byfield Snuff Company and the National Association of Tobacco Distributers (NATD) concerning the burden that a label requirement would impose on the industry and interstate commerce. (2-4) The President of the Byfield Snuff Company, the only Massachusetts manufacturer of snuff, stated that it would not be economically feasible for a small business to compete with larger manufac- turers if a label was required. The Smokeless Tobacco Council and NATD claimed that imposition of a labeling requirement on snuff would disrupt interstate tobacco snuff distribution because labeled products would have to be targeted for Massachusetts, thereby increasing costs for manufac- -8- turers and distributers. However, the industry reported that the share of the market affected by the label would be negligible - one quarter of one percent of the total national sales of snuff. (5) Testimony was also pre- sented concerning the need for a national approach. It is recognized that the label requirement may force changes in the distribution system for snuff and may cause some additional expense for manufacturers and distributors of the product. However, legal precedent has established that where a state acts to protect the health interests of its citizens, the resulting burden on interstate commerce is not unreason- able or impermissable under the Commerce Clause. Conclusion The authority of the Commissioner of the Department of Public Health to require a warning label on snuff is not preempted by federal law or regula- tion. Based on the evidence summarized in this report, the Commissioner has concluded that the benefits of preventing and reducing disease caused by the use of snuff far outweigh the additional expense to the industry of providing a health warning label to consumers. -9- III . Description of Snuff and Reports on Use Snuff is a cured, ground tobacco that is consumed orally or nasally. It is dry or moist and is produced in three forms. (6) Dry snuff is made from fire- cured tobacco that is ground and pulverized to a flour-like consistency to which other ingredients are added, including spices for flavor. In normal con- sumption the user places a small pinch between gum and cheek where it comes into contact with the oral tissue. The tobacco mixes with saliva and nico- tine is absorbed through the oral mucosa into the blood stream. Moist snuff is finely cut tobacco with a high moisture content. Fine cut tobacco is the third type of snuff which was classified as chewing tobacco until 1980 by the United States Department of Agriculture. Dry snuff has traditionally been used among female textile workers from the South. Other occupations where use of smokeless tobacco is common include steel, mining, logging and farming. In recent years use has increased among young white males I According to the Tobacco Encyclopedia, "In the 80 ' s (the) market bagan to gravitate toward the white collar, 18-35 year old age group, of whom college students are an important factor. "(7) Recent surveys on use indicate that smokeless tobacco is becoming popular among adolescents. Snuff is used in Britain through nasal sniffing, and in Scandinavia, the United States and North Africa orally. Prior to the invention of the cigarette, smokeless tobacco was the most popular form of tobacco used in the United states. Estimates for the number of users nationally ranges from seven million to 22 million. (8 , 9 ) -10- Table I presents eight different studies done throughout the United States on use by male high school and college students. The studies indicate that a significant percentage of adolescent males report regular use of smoke- less tobacco. A 1984 Massachusetts survey of 5,000 male and female high school students found that 15 percent reported trying smokeless tobacco during the last year. Twenty-eight percent of the boys had tried it at least once and 12 percent reported using it several times or very often. TABLE I SURVEYS ON USE OF SMOKELESS TOBACCO AMONG MALE ADOLESCENTS Source Greer (1983) Offenbacher (1983) Hunter (1983) McCarty (1984) Severson (1983) Glover (1983) Edwards (1984) Glover (1985) State Colorado Georgia Louisiana Massachuse tts Oregon Texas Utah National Age 14-18 10- 16 8-9 12-17 12-16 11- 18 10-18 17-21 Percent Users 112 (R) 202 (U) 212 (U) 122 (R) 142 (R) 92 (R) 102 (LW) 122 (R) Regular Use U ■ Frquency of Use Unavailable LW ■ Use During Last Week Smokeless tobacco consumption among young males is increasing. The 1975 Hunter study of Louisianna youth found four percent using snuff. A follow-up study of the same age group in 1982 found a 24 percent use rate, a fivefold increase. (10) During the same period Hunter reported a decline in cigarette smoking. Sales figures also indicate an upward trend par- ticularly for'Tnoist and fine cut snuff. As shown in Table II, sales for moist snuff have risen substantially from 23.7 million pounds in 1978 to -11- 37.1 million pounds in 1984, a 55 percent increase. During the same period, sales for cigarettes fell, while sales for chewing tobacco rose approximately ten percent. TABLE II DOMESTIC SALES OF CHEWING TOBACCO, MOIST SNUFF AND CIGARETTES 1978 1980 1982 1984* Moist Snuff (1) 23.0 27.3 32.7 37.1 Chewing Tobacco (1) 80.7 89.0 88.0 88.9 Dry Snuff (1) 13.0 12.7 11.2 10.1 Cigarettes (2) 615.3 628.2 600.0 593.0 * Projected annual sales based on first nine months. (1) In Millions of Pounds (2) In Billions of Cigarettes Source: United States Department of Agriculture 1984 -12- IV. Oral Cancer It is well established that epidemiologic evidence can demonstrate causa- lity and criteria have been developed to determine if an association bet- ween a particular agent and disease is causal. The criteria include consistency, strength, specificity, temporal relationship, and coherence for the association that exposure to the agent is causally related to the disease. (11) If these criteria are met the clinical and experimental evi- dence must also support the association. The age adjusted annual incidence rate for oral cancer is 11 cases per 100,000 persons. This rate has not significantly changed during the last twenty years. Males experience a rate three times greater than females 17.2/100,000 versus 5.6/100,000. There are approximately 27,000 new cases each year in the country and 9000 deaths. (12) In Massachusetts there are an average of 900 new cases and 300 deaths each year. It is the sixth common form of cancer in the state. (13) The most common oral cancer is squamous cell carcinoma. Tobacco smoking has been determined to be a major casue of cancers of the mouth and alcohol use acts synergis tical ly with smoking to increase risk. (14) There are two types of oral cancer associated with snuff. The first is verru- cous cancer which is a locally invasive lesion that does not easily metas- tasize. The second is squamous cell carcinoma which is an aggressive lesion that readily spreads. Individuals with this lesion have a five year survi- val rate of less than fifty percent. Many early studies report that snuff use is associated with induction of verrucous cancers and not squamous cell. However, more recent evidence -13- shovs that squamous cell may be the predominant lesion. McQuirt reports that of 57 patients with oral cancer who used snuff to the exclusion of cigarettes, pipes, and alcohol, the majority of cancers were squamous cell lesions. Of 24 that clinically appeared verrucoid, 24 were found to be well differentiated squamous cell lesions on histological evaluation. (McQuirt reference Appendix B, Table IXI-VXI; Appendix B, Table III-VII references. ) A. Epidemiological Evidence The earliest report in the medical literature postulating an association between snuff and cancer was made by Dr. John Hill of England in 1761.(15) In the United States, Dr. Warren of Massachusetts reported on tongue cancer in a male tobacco chewer in 1837.(16) Since then numerous epidemiologic studies have been conducted on the asso- ciation. Tables III - VIII summarize 43 studies. Table III presents 18 case series studies that show a high proportion of patients with oral cancer had been users of smokeless tobacco. Nine studies reported more than 50 percent of the cases having a history of smokeless tobacco use, and six studies reported from 25 to 49 percent. • Table V presents four case control studies showing that smokeless tobacco users had a significant increase in risk to oral cancer. However, smoking was not controlled for in a majority of them and the type of smokeless tobacco used was not specified. Table VI lists five case control studies in which smolclng was controlled for in four and use of snuff was found to significantly increase risk to oral cancer. Table VTI presents six follow- n c o ■ c ■ ww e i» o - •» I* o ■ ff s! • ■ < • 3 9 »"■ 3 c « «c ■ 9" 9* — - « ST 0 c 3 1 < 0 — • O w • — — -» — < w w ^ a la «« a >» c <• — — ^ — — • -y • — • 9 9 • 9 ■» «* - - ■ • ■< • 9 C C ■ < — — m f ~ V 9* 9 y a « < « \ • CO x a y • • c • n •* » o - c on ■ 0 ■ •<3 n n • 0 • - •» rt 1 s c ■ »» • 9- urucoui carclnoaa ja cancar :ancar of oial ■opharyna a C o — ^ «» 3- 9- s -3 1 1 ft ft ft n 9" T3 a 3 O s. ? •» o o •» o 0 o 3 1 n g 9* • ft c — • 59 ft, r» ft 0 sr s o c O "» o " » o c — er n » • o n • o o a •» o — o o 7 a a 9 C o r — ^ w — a ^ a> -j o 3 m • » • o a o o o o * — v • -J *> * a • • _ a 5 5 9 7 < a o- *» c a n x o • y -» — c • «< * n 9 n y c ■ e a • • ^ 1 3 • m — a n w ft a — a " in a •< A a ? ■ 3 "2 0 a f • ~ « — a oca 3 W a 3 " 1 ft • - a - ft r> c o • c » c « - • ^. 2 e t li ■ - S • ar e 8 ™ • o w r » ■< a* 3 • - •* a o o C • B • • J - — • f O ft O O — — •an • • a o » a — * • a 7 c « o — 3 7 E 2 O 7 • 0 a . ft c ■— a ft • — — e o = c "2 8 Si •» •» r* » a • « al : z • n o 0 o ft n • 7 • C ? 3 0 • s* * ■ c a o — o » 7 — c • — ■— • n ir • — C a »» o o e a • • n a — ft a — m a • • • n • — • 0* • • a •» n o • ■q * w a c a o •» o <• £ ' ■ c • •< •% • » n -a o c ■ » " I C C 7 ■ 0 who o n • 7 — C " • 7 ft • S8 r ^ : c » — ir a c ( • n ft • o — 7 a • o n ■ o n ? 8 o •» t • a S 2 u ■ - — 0 M O U O - u *• • « C J »"> O O — e a o o 1 S ■ - c a z e 1- - e o — • •» j a c • l. • -3 • 0 - — O. ■w w 0 3 c 1c 2 0 c — 0» u o s s e — o o u o • • S 8 u — • e > 3 — O • "o & c >» — « u • a e o • u 3 — «S • 8 ^ 1 - \ ■% e - c — • S u • >> 1- is m c o «• u o • 2 3 • — • • 0 •-> 22 u 5 u O • -o • 0> — 4 0 c • - - > 8» — — U u e u u - a e m ■ « • — - • e « • *• » — o 1- >• ■ • - C u — >• 3C > u « « « — u u — I - *J » 0 • C U o — » — — - C £ C >• 0 • • H • • o — o • o ■ • 2 * *■ • 2 3 . — - r. >. - * • — • — w > — .c s c • - - 0 - a O • - •* x O • •J W \ - - >. fj — C I I* c — c • 03 ■ ■ C • ■ o o <■» I o o 1 2 at • — v. « » ■ a ' - 3 a • • » £ — 'j •a «■ — C e a 3 • • -if- to a s •w « * a a • o o — - e • 32 32 ■ 2 ■ — to — O >• 3 e IS -14- up studies of which four showed an increased risk up to threefold for cancer of the mouth, pharynx, esophagus and other sites. Dr. James Smith and Dr. Deborah Winn conducted epidemiological studies which have been heavily referenced by experts who have studied this association. (17, 18) The Smith study was frequently referenced by opponents of the regulation as pathological and epidemiological evidence that snuff-induced leukoplakia do not transform into malignant lesions and that large groups of snuff users do not experience higher than expected rates of oral cancer. (19) The Smith study reported on a population of 15,000 snuff users and tobacco chewers. Of these, 1,651 were observed for cytological , histological and clinical evaluation for ten years. Of the original group of 1,751 cases, 1,550 received follow-up examinations and showed no cancer or serious oral mucosal changes after ten years. According to Dr. William Blot of the National Cancer Institute, Smith did not conduct a careful follow-up study. (20) The failure to account for 201 of the 1,751 cases seriously weakened the results of the study since it is possible that many of the 201 had died and that some had died of oral cancer. Dr. Kupper, an epidemiologist who testified for the Smokeless Tobacco Council, agreed with this analysis. In evaluating the Smith study, Kupper stated "it is important to point out that only 1,751 of the original snuff users were followed for any appreciable time (between 5i and 10 years). Of these, a large number (201) were lost. These small numbers, coupled with the rarity of oral cancer and the shortness of the follow up period, make it hard to interpret the findings from (thi3 study). "(21) Consequently, — 3 - 3 • : : : no* • o — C 3 O f x ft — • • <• o • 7 • ft • — 3 ■ O c ■ • 9- f m - • • 3 <• W 0 — o 9 0 » 1 » • — o ■a t . - - o • • VI 3 c i (lo- an* x • ■» ^ ■ m c — n ■ O 3 7 1 — c - 3 n ■ ■ - 3 — O "2 - — o il 3" - O C x ■ • tr o : r — o ■ o • • n o ft 3 ■0 "I ■o 0 o ^ — - • r — - 9 • ^ w OX. • -< X) -t 3 0 » 9*0 0 • C 3 • T 3 • W -. » — • » x O " e i ; s • o c wo* - 0 o m 3 » • #» x e m o x O - 6 n ft — o - • 9 »• «J O x in • 0 m m — » u ^ » * • ■ a n ui - S 3 -J ft 7 • - • o n a • — x • w x 9 p 9 M xt c — n 3 • • V ■ « n x #» ^ « o • ■ 97 «x -» • • x f 0 X Xt — B> ^ Xt • » #» 3-9 ^ » » « • - n w ■ 9 ■— n 5 I o r e> x» C 9 x n c • o •» 9 » •» t " e 7 ■ • • e • « » • c •» o •» o ft o — • • ^ 9 »» — o • • • ft O X • ■ c ft — ft "» 9" •C • 0 !» X n • • § SS ft 7 • C • • O x x 9 O n c • ■ a- < 5 > X O O ; r n < XI xt > n e • o >. neb • V *. a. e > 0 a. — • ^ » • to lO > 4 C • — to — * • — 3 «• C — — 0 0 u — to c MM o aw u • e a - a - SON 1 %* m Sm c • co*. — « o «. • — - a • O to C C — — „ - « | • e — %• a ••••OS .Oca — — U to to — • a • a — a 4 > 1 — 3 • V O 1J O c & • V 3 u n I — -. o • o — to — 0 - to O • C • — 1 u • — • c 6 i to c • • * O • (J O ■ C £ "3 — TJ - "a a — • to U to — T3 « • O 3 • 0 • 3 • — u n o c > >■ to • • 0> O > 'j a x • e > £ • • S — *» • O • *J • — « — ■ — > ■ > — • 3 • - 0 - O to — • %» O i u> • a e - - « • < a> u a c y} e • o> o to O >. — £. ■ • O — " a 2 3 2 1 e» • a — u o ■ c • O • to C to U >> • ■ — • — • £. to £. v s> u — «j o • • • «• >a • A " a 0 — — • w > to O • U to to u « a • « u • a C to to a o u u «. c • c a — — -2 •3 • «-i • to . ■ • • r% C • ■ >- • a o to to • • o a — £ e • at a "to « O ra to o o o to. to a to 0—0 <"> « aj ». 3 . • to > 01 - M I to Oj ■ o> a s ? 1 2 Oj — n m ~ e e •» O • ». — C a » o» C • — a — — o - 3 ^> • trt to to — 00 3 1 • S o o • O to o • to e • a o e x a u 3 a £ • j -15- the absence of malignancies in the Smith study does not negate the conclu- sions reached in numerous other studies that the use of snuff is asso- ciated with a significant increased risk to oral cancer. The Winn study was a case control study of 250 women with oral cancer. It controlled for multiple risk factors such as, age, race, residence, occupa- tion, smoking and alcohol consumption, and found a fourfold increase in risk attributed to snuff alone. The Winn study was criticized by opponents of the regulation for use of proxy respondents in cases where the patient had died. (22) However, when use of proxy respondents was taken into account, the magnitude of the association did not change. Dr. Kupper of the University of North Carolina acknowledged that the Winn study, in con- juntion with other evidence, established use of snuff as a risk factor for oral cancer at the site of contact. However, Kupper maintained that the association had been demonstrated for Southern rural women only, and was not causal . (23 ) Causal Significance of the Association 1 . Consistency of the Aaaociation As referenced earlier, of the 18 cases series studies presented in Table V, 15 reported that 25 percent or more of the patients with cancer used smoke- less tobacco. Of the 15 case control and cohort studies, 13 found a posi- tive association between use and cancer. These studies were done in different geographic areas in the United States and Europe, and involved different study groups and study methods. The studies almost uniformly -16- demons trace a consistent association between smokeless tobacco use and oral cancer. 2. Strength of the Association As shown in Tables V, VI and VII, the risk to oral cancer is significantly higher for smokeless tobacco users than nonusers. The four studies that computed relative risk (Winn et al , Schuman, Heuch and Schuman, and Winn) found the increase in risk to be from 1.3 to 4.2. The Winn, et al., and Williams and Horn studies examined dose response relationship. Winn found long term users (50 years or more) to have a risk 50 times greater than nonusers. Williams found heavy smokeless tobacco users to have a risk of 6.7 versus 3.9 for moderate users. 3. Specificity of the Aaaociation Table IV presents ten case histories and case series; nine of these show that the cancer occurred in the mouth at the site the tobacco was held. One interesting case supporting the specificity of the association involves a Minnesota farmer who developed cancer in his ear after placing snuff there for 42 years. 4. Temporal Relationship of the Aaaociation Two cohort studies (Schuman, and Schuman and Heuch) showed occurence of cancer among a significant number of users over a long (15 years, and 12 years) follow up period. Histologic evidence supports this relationship. As will be discussed in Section IVB, use of snuff produces clinical -17- leukoplakia, and a significant percent of leukoplakia have been shown to transform into cancer over time further supporting the temporal rela- tionship. (24) 5 . Coherence of the Association Dose Response Relationship As referenced earlier, a dose response relationship has been established for use of smokeless tobacco and oral cancer and supports the coherence of the association. Correlation of Sex Differences in Oral Cancer Oral cancer is predominantly a disease of males. However, females from the Southeast of the United States have rates similar to that of males. In that section of the country, snuff is heavily used by females and is reported to be a factor for this unexpected level of oral cancer. Correlation of Oral Cancer Incidence Among Populations With Different Smokeless Tobacco Habita International surveys indicate the United States has about one-third the oral cancer incidence of India, which has the world's highest rate. (24) Although Indians smoke and chew a variety of substances, cancerous and pre- cancerous lesions are found predominatly among those who use smokeless tobacco. The high incidence of oral cancer in India is attributed to the widespread use of chewing tobacco (47 to 73 percent of the population) -18- rather than to a difference in the rate at which tobacco users develop cancerous lesions. Studies of Indian populations indicate that oral cancer risk is greater for smokeless tobacco users than for smokers and increases with duration of smokeless tobacco use. (25, 26,27) Experimental Studies There is experimental evidence that show nitrosamines contained in snuff are capable of inducing malignant tumors in the mouths of animals. This evidence is presented in Section IV C. Conclusion An evaluation of the epidemiological evidence presented to the Department shows that use of snuff significantly increases oral cancer risk. IVB. His topathological Evidence Leukoplakia is a clinical term that describes a patch or plaque in the mouth that cannot be characterized clinically or pathologically as any other disease. (28) Clinical reports of snuff induced leukoplakia show the tissue to have a white appearance and often to be wrinkled or fissured. Because of the inability to predict cellular changes from clinical obser- vations, microscopic evaluations of biopsies of leukoplakias are necessary to determine the pathologic state of the tissue. On biopsy, 90 percent of leukoplakia show benign changes including hyperkeratosis or thickening of the epithelium, chronic inflammation of the connective tissue, or cellular degeneration. In the remainder premalignant dysplasias or malignant cancer may be present. (29) o cr » O * « ■ < • • * x a a • <* -« • i tm m o ib ■ 1 • : "8 ■ • •J IB ■ a • 2 5 o »» «» ?iS i : s s . & 5 * 1 * 2 g ? I ** tw O O . s It s : c • • — * i *■ * «i * — • «• »» » 4 «t O «4 r* • OB I cr >%•««• « ■I » % a or o • f* a • •» 8» • <» » c i» h op S— m • fc f» B B B OS I B B B B B B «* a 9 B •» OB B r» •% *> I I 8 g 5 s ? ? <— B • • e •I * •< >- «- * * 9 b a i B •» J rf> r» O b cr « 5 O B Sr e i* B •* - i: * ? B B ■ B 7 ■ P -3 > r i »» BOO n <- ■ B B IBs »» «* • « o " c -» »- o n « « c — -tB B B »- O Q. 9 — — o B O 9 § ^ 1 r » »♦ 5 — e i b b • «-•■« • — « « B> • — - -< • 3 -ST5 8, S £ ? . B B *• H e 9 n m t» o m -» 9 ~ • B Or* O 0><4 O B B »» «1 • • O -4 "2 « o> •* y e b n a «♦ 1 9" >- c . 1 1 " •— »B» I " B 3- B B B 5? B — B 4 B A b or -< cr e b 81 >B> ;! o B B O CT ►» e b n w n «» a B 7 1 o T3 O • 7*9 O B cr • i «- ^ • n >- r» <• — 9* 4 • B if l»5 H — — 3- ■ 9 — ■ S 1 C „ rf • 2 • « ■ S • • 3 •o m n Elf ^9-9 O O O 9- B >■ 0 >r 9 9 • " (1—0 1 9 »» • 0 • ^ 5 Z m - — 4 — 9" o> o < s • s 5 — c B B O B B J b — a* o ar o B — ►-9-3 73 • T3 9 • O 1 — 9* O " — 3 O O o »• »1 a o >- b e * n o r» B sr m B 9T si x n B B jr >— B >- X •« a ? I a n »" IT ' I o ar i? :? is BOO • — • «< ar 0 ►« sr £ B cr 1 * rT . s & «o o V o o BOB B B »» s I: a n 9) 9- • s n < ir 7 a 8 m „ J 1 owe wax ^ e s> •H • C • ato z x ■* CP 53 CP 3 — • a. x -19- An analysis of 3,256 cases of leukoplakia showed 80.1 percent were simple hyperkeratosis (thickened cells with retained nuclei), 12.2 percent mild to moderate dysplasias (cellular conditions that point toward malignant transformation), 4.5 percent carcinoma in situ and 3.1 percent invasive carcinoma. (30 ) Over time three to six percent of leukoplakia become cancerous . (31 ) Snuff mM a Cause of Leukoplakia The World Health Organization's Center for Oral Precancerous Lesions has determined that tobacco is an etiological agent for formation of oral leukoplakia. (32 ) This is demonstrated by numerous studies that show occurence of leukoplakia at the site tobacco is held, and remission of the lesion when use is stopped. Clinical severity has been found to be directly proportional to exposure, that is, the longer the use of snuff, the more intense the clinical change. (33) Table VIII presents ten case series studies that show a high proportion of leukoplakia among snuff users. All of the studies demonstrate significant cellular changes in Che oral mucosa of users at the site the snuff was held. Cellular changes that are reported range from simple hyperkeratosis to mild dysplasia. One English study reported a 7.9 percent incidence of leukoplakia among tobacco chewers and smokers. (34) Five other studies among adults which reported that the use of tobacco was associated with oral leukoplakia are also summarized in Table IX. In addition, Table IX includes three studies done in the United States on adolescents which show over 50 percent of smoke- -20- less tobacco users with oral leukoplakia at or near the site where the tobacco was held. These studies demonstrate that a significant portion of snuff users develop clinical leukoplakia at the site where the quid of tobacco is placed. Speakers in opposition to the proposed regulation questioned the signifi- cance of the oral changes induced by snuff and challenged the relationship between leukoplakia and snuff use. Dr. Mincer of the University of Tennessee relied on a study by Frithiof(35) for the proposition that lesions caused by snuff "were too superficial and easily reversible to warrant the designation of leukoplakia. "(36 ) However, a review of Frithiof's study shows that his decision not to use the term leukoplakia was based on his opinion that as a clinical term, leukoplakia should not be used in a diagnostic context. Because Frithiof determined the lesions he found to be caused by snuff use, he did not describe the lesions as leukopla- kia. In five out of 21 cases where lesions were found, Frithiof reported mild dysplasia which are potentially cancerous lesions. Further, Frithiof concluded that each year in Sweden a number of cases of oral cancer develop among Swedish snuff users where the snuff is held. Dr. Furst of the University of San Francisco challenged the finding that snuff use causes leukoplakia. (37 ) He cited Shafer, ec al . , (38 ) to support his premise that the etiology of leukoplakia is unknown. The reference given by Dr. Furst for Shafer was not up-to-date. (39 ) In Shafer 's most recent text on oral pathology published in 1983, he states that tobacco is generally accepted as an extrinsic factor that can cause leukoplakia. -21- Leukoplakia and Oral Cancer According to the W.H.O.'s 1978 Report, a significant percent of leukoplakia transform into malignant lesions. Malignant transformations are reported among tobacco and non-tobacco induced leukoplakia. A long exposure time is generally required before malignant transformations occur, but some may occur without warning. Oral cancer may also occur in the absence of leukoplakia. Leukoplakias that show cellular dysplasia on biopsy are at a greater risk to malignant transformation than ones that do not. (40) Table IV includes ten case series studies of smokeless tobacco users with oral cancer. Six of the studies reported that leukoplakia was common in the mouths of cancer patients. Table IX shows 11 studies that followed patients with oral leukoplakia for a number of years and found malignant transformation rates from 1.3 to 8.7 percent depending on years of exposure. Frithiof, Hirsch, Pindborg and Roed-Peterson have reported dysplasia in biopsies of snuff induced leukoplakia. (41-44 ) Dr. Furst challenged the finding that some leukoplakia transforms into malignancies and referenced studies by Axell, Smith, Banoczy, Einhorn and Silverman as evidence that the relationship has not been proven. (45-49 ) A thorough review of these references supports the opposite view, that snuff use causes leukoplakia and a significant number of leukoplakia transform into malignancies over time. -22- With regard to the Axell study, Dr. Furst stated that Axell found no "cellular or epithelial dysplasia... among 114 men." (50) The Axell study involved biopsy of 114 lesions found in 1,200 snuff dippers. (The clinical diagnosis of snuff dippers' lesions was determined when a lesion on the oral mucosa was found to be at the exact site the snuff was placed. ) In all 114 cases Axell found significant histopathological changes. Axell did not find dysplasia or cancer among the 114 persons. This is not surprising given the small number of persons biopsied and long exposure time asso- ciated with snuff induced cancer. Dr. Kupper of the University of North Carolina who testified on behalf of the Smokeless Tobacco Council, com- mented on the Axell study. According to Kupper, "The negative findings from the Axell (1976) study are of interest. However, since the results are based on such a short time period, and since the study takes place in another culture, it cannot be said to provide evidence against the reason- ably consistent findings in the United States studies, that Southern rural white women who are long-term snuff users apparently are at increased risk for developing oral cancer. "(52) It is important to note that a later 1978 follow-up study by Axell did find a five-sixfold increase in risk to oral cancer among snuff users. (53) A review of the Banoczy and Sugar 1972 article found the following state- ment: "Follow-up examinations of 520 patients with oral leukoplakia during a 25-year period showed cancer development in 31 cases, i.e., 5.9 percent. "(54) In an subsequent 1977 article, Banoczy reported "examination of 670 patients with oral leukoplakia during a 30-year follow- up showed cancer development in 40 cases, 6 percent. Dysplasia was -23- observed in 24 percent of the histologically examined leukoplakia; 13 per- cent of the dysplasia cases subsequently showed development of carcinoma. "(55 ) Dr. Furst references the Einhorn and Wersall study which reported a 2.4 percent cancer development after ten years among patients with leukoplakia and reported a 4 percent prevalence of malignant transformation after 20 years in the same study. He also reported on the Silverman study in which six or .13 percent of 6,718 persons with leukoplakia were found with cancer. (56) Given the fact that the general population rate of oral cancer is 11 cases / 100 , 000 per year, the levels reported in all four studies are significantly higher than would be expected by chance, and strongly support the association between leukoplakia and oral cancer. The methodological flaws of the Smith study are discussed in Section IVA. Because of these flaws, the validity of Smith findings have been questioned by other scientists. Some speakers argued that non-snuff induced leukoplakia have a higher malignant transformation rate than snuff induced leukoplakia. (57 ) This finding does not alter the fact that a significant percentage of tobacco induced leukoplakia do become malignant. Testimony was also submitted which asserted that other factors such as deficiencies in the immune system, diet, dental hygiene, and genetics play a possible role in formation of leukoplakia and oral cancer, and that con- sequently, one factor cannot be singled out as a cause. (58, 59) It is recognized that many factors singly or in combination may be associated with leukoplakia. However, it has been well established by scientific evi- -24- dence that tobacco use alone significantly increases risk to oral leukopla- kia and oral cancer. Conclusion Expert testimony established that the use of snuff is an etiologic factor in formation of oral leukoplakia, that leukoplakia formed by snuff is a po- tentially cancerous lesion and that a significant percent of these lesions transform into oral malignancies. IVC. Experimental Evidence and Mechanism of Carcinogenesis A number of toxic and tumorgenic substances have been identified in tobacco smoke that may act as tumor initiators and promoters. Since snuff is not combusted, users are not exposed to smoke particulates such as poly- cyclic aromatic hydrocarbons or tar. (60) However, they are exposed to tobacco specific nitrosamines as well as other N-nitroso compounds, such as nitroaomorpholine . Over 250 nitrosamine compounds have been shown to pro- duce cancer in animals. (61) Nitrosamines are chemical compounds formed through the ni^osation of amino substances, such as, amines, ureas and amides. The nitrosating agent may include nitrites, nitrogen oxide, organic nitrite or other nitroso com- pounds. In the case of snuff, they are formed during the processing of the tobacco from the amino substances present in the plant and nitrates deli- vered through fertilization. (62) N-nitroso compounds can also form endoge- nously in the mouth of snuff users through reaction between saliva and tobacco products. (63 ) -25- Nitrosamines are found in other consumer products such as, cosmetics, beer, cured meats and processed rubber products. Certain occupational settings, including, rubber, steel, and leather processing plants can be a source of exposure. Based on experimental evidence, the Federal Food and Drug Administration and Department of Agriculture have set strict action levels for human exposure to these compounds. The action level for NDMA (dimethyl- nitrosamine) in beer is 10 parts per billion (ppb), for total volatile nitrosamines in baby bottle nipples 10 ppb, and for cured meats 5 ppb. (64, 65) The total concentration of the four most common nitrosamines found in snuff sold in the United States ranges from 2,000 ppb to 80,000 ppb. (66) (Tolerance limits have not been set for snuff since Congress has restricted the FDA and USDA from regulating tobacco products.) The four most common tobacco specific nitrosamine compounds (TSNA) found in snuff are N- ni trosonornicotine (NNN), N-nitrosoanabasine (NAB), N-nitrosoanatabine (NAT), and 4-(methyl N-nitrosamino ) 1- (3-pyridyl )-l-butanone (NNK). Carcinogenicity of Nitrosamines Contained in Snuff NNK and NMOR have been shown to be potent animal carcinogens. NNN is moderately active; NAB is weak; and NAT has been found to be inactive in one animal study. (68-71) Dr. Stephen Hecht presented evidence on the carcinogenicity of ni trosomi ne s . Table X summarizes the results of thirteen studies done on three different animal species that show pro- duction of benign and malignant tumors in seven different organ sites through exposure to tobacco specific nitrosamines. The studies and other evidence show a dose response relationship exists for exposure to nitrosa- mines and induction of cancer. (72) The more frequent the daily or weekly -26- dose, the sooner the tumor arises; the higher the concentration of nitrosa- mine, the greater the incidence of tumor formation. In general tumor onset occurs from two months to a year after initial exposure. With the exception of the A/ J mouse, spontaneous tumors do not occur in the target organ of the animals studies. The studies show that the tumors occur almost exclusively in the target tissue of exposed animals and not the controls indicating that the N-nitrosocompound is the carcinogenic agent. -27- TABLE X Carcinogenicity of Tobacco-Specific Nitrosamines Species Route Principal Nitros- and of Target amine Strains Application* Organs Dose Re f erence A / T mr\ 1 1 a a ri J ulij use 1 ■L m p* lung Ci 1 Mm i~i 1 / mAii a a 1 -3 F344 rat a. c. nasal cavity 4-6 esophagus 0.2-3.4 mmol/rat ?• o • esophagus u.i — j.o nmoi/rat A 7 ft nasal cavity S pr ague- Daw 1 ey ?• 0 . nasal cavity ft ft — — 1 / — r. f 5.3 mmo i / r a t o rat Syrian golden s. c. trachea 0. 9-2. 1 nmol/ 10-12 hams ter nasal cavity hams ter JfNK A/J mouse i. p. lung 0.12 nmol; mouse 2,3 F344 rat nasal cavity 0.2-2.8 mmol/rat 5,6 lung, liver Syrian golden s . c . trachea, lung 0.9 mmol/hams ter 11 hams ter nasal cavity 0.005 mmol/hamster NAT F344 rat s. c. none 0.2-2.8 mmol/rat 6 NA3 F344 rat p- 0. esophagus 3-12 mmol/rat 6, 14 Syrian golden s. c. none 2 mmol/hamster 10 hamster NNA A/J mouse i. p- none 0. 12 mmol/mouse (Testimony submitted by Dr. Hecht) (*) I. P. - Intraperitoneal injection S.C. - Subcutaneous injection P.O. - Administered orally Dr. William Lijinsky of Litton Bionetrics reported formation of oral and liver tumors among female F344 rats after 50 weeks of exposure to a con- centration of 0.45ppm of nitro8omorpholine (NMOR). He found that as the concentration of NMOR increased so did tumor incidence .( 73 ) -28- Dr. Stephen Hecht of the American Health Foundation presented the results of two studies that demonstrated NNK and NNN can produce oral tumors in hamsters and rats. (74) Table XI summarizes the results of the hamster study. In the second study tumors were produced in the tongue of rats though the esophagus was the major target tissue. TABLE XI Carcinogenicity of NNK, administered by oral swabbing in Syrian golden hamsters Number of Animal s With Tumors Number of Nasal Animals Cheek Pouch Cavi c v Larvnx Trachea Lung NNK 23 4a lib 6a 10c 20d Control 24 • 0 0 0 0 0 a) all in male hamsters b) 6 male, 5 female c) 7 male, 3 female d) 10 male, 10 female (Testimony submitted by Dr. Hecht) Both NNN and NNK have been found to be mutagenic in salmonella typhimumium. They also induce unscheduled DNA synthesis in primary cultures of rat hepa- tocytes. When metabolized these compounds form biologically active inter- mediates that modiyfy DNA to cause point mutations that can initiate the carcinogenic process. (75-77 ) Of particular interest is the formation of the electrophilic intermediate methyldiazohydroxide , upon metabolism of NNK(78). This intermediate is well known in chemical carcinogenesis for its ability to methylate DNA in -29- vivo. One of the products of DNA methylation of O^-methylguanine , which has' been unequivocally shown to be capable of inducing miscoding in DNA(79). It has frequently been observed that persistence of O^-methylguanine in tissues of animals treated with methylating carcinogens such as N-methyl- N-nitrosourea , dimethylnitrosamine , or 1 , 2-dimethyl-hydrazine is associated with tumor development in those tissues(80). Thus, the observation that treatment of animals with NNK leads to formation of 06"met:hy1 guanine in their target tissues is impor tant ( 8 1 , 82 ) . The metabolic processes leading to DNA methylation by NNK also have been shown to occur in human tissues including the buccal mucosa(83). Additional metabolic reactions also occur in animal and human tissues(84). The formation of 06 — methylguanine in DNA, upon exposure to NNK, provides a mechanistic link between nicotine, the major habituating agent in snuff and source of the methyl group, and initiation of the carcinogenic process. Human Exposure to Nitrosamines from Snuff 1 A human who consumes one-third of a can (10 grams) of snuff daily will be exposed to approximately 164 ug of nitrosamines. As shown in Table XII, this level is approximately 10 times greater than that received from smoking and 100 times greater than that from other known environmental sources. Over the course of 30 years, the ten gram user will conceivably receive a dose that has been shown to produce a statistically significant, positive trend in liver cancer for animals exposed to a similar con- centration of a comparable nitrosamine, N-nitrosodimethylamine (DMN).(85) Dr. Lijinsky reported that he found tumor production to occur for NMOR at exposure levels experienced by human snuff users. (86) -30- TABLE XII Estimated Exposure of U.S. Residents to Nitrosamines ( 15 ) Source of Exposure Nitrosamines Primary Exposure Route Daily Intake ug/Person Beer NDMA Ingestion 0.34 Cosmetics NDELA Dermal Absorption 0.41 Cured meat: cooked bacon NPYR Ingestion 0. 17 Scotch whiskey NDMA Ingestion 0.03 Cigarette smoking VNA(16) Inhalation 0.3 NDELA Inhalation 0.5 NNN Inhalation 6. 1 NNK Inhalation 2. 9 NAT-fNAB Inhalation 7.2 TOTAL 16.2 Snuff Dipping(17) VNA Ingestion 3.1 NDELA Ingestion 6.6 TOTAL NNN . Ingestion 75.0 164.5 NNK Ingestion 16.1 NAT+NAB Ingestion 73.4 -31- The Smokeless Tobacco Council submitted testimony challenging some of these findings. Dr. Grasso of Rubins Institute agreed that N-nitroso compounds are present in snuff and induce cancer in laboratory animals. (87) However, he asserted that animal studies do not show that oral tumors are produced by exposure to nitrosamines and that nitrosamines are site specific and not "contact" carcinogens. As referenced earlier, animal studies were cited which show that nitrosamines induce tumors in the oral cavity of animals. In addition, studies have shown that oral administration of N-nitroso com- pounds can produce tumors in the esophagus of animals. Dr. Grasso argued that there is no epidemiologic evidence to show that nitrosamines cause cancer in humans. (88) For ethical reasons such studies may be impossible to conduct. The absence of direct human studies does not diminish the concern that exposure to N-nitroso compounds can increase cancer risk in humans. Scientific opinion supports the concept that animal data on nitrosamines should be viewed as evidence that nitrosamines are capable of producing similar effects in humans. In the absence of human studies, the World Health Organization (W.H.O.) International Agency for Research on Cancer concluded that nitrosamines proven to cause cancer in two species of laboratory animals "should be regarded for practical pur- poses as if they were carcinogenic to humans. "(89) Hirsch has reported malignant tumor formation in rats that were exposed to snuff alone placed in a surgically created test canal in the mouth of the animal. (90) Hirsch found that after nine months one rat out of 55 deve- loped a squamous cell cancer in the mouth. -32- Dr. Furst of the University of San Francisco criticized the Hirsch study, claiming that the rat species used is known to develop spontaneous tumors. (91) However, this claim cannot be substantiated. In a com- munication from Dr. Hirsch to the Department, Hirsch stated "In our preli- minary studies, it was possible to induce tumors in the oral cavity in the rats. Tumors appeared only in rats exposed to snuff. Sprague Dawley rats that were used in the experiments are not known to develop spontaneous tumors. We have performed intraoral experiments with potent carcinogens at our laboratory during the last 20 years and not once seen spontaneous tumors in the oral cavity. "(92) Conclusion The overwhelming majority of testimony on the exper iemental evidence indi- cates that the nitrosamines contained in snuff are potent animal car- cinogens which significantly increase cancer risk in humans. Summary Conclusion on Oral Cancer Based on epidemiological, histopathological and experimental evidence sub- mitted to the Department, it has been shown that snuff is a human car- cinogen and that the use of snuff is causally related to oral cancer in humans. This conclusion is consistent with a similar finding of the W.H.O.'s International Agency for Research on Cancer and the National Cancer Institute's National Advisory Board (see Appendix B). -33- PERIODONTAL DISEASE Snuff is a major risk factor in periodontal disease because it has been shown to produce pathological changes in the soft tissues of the mouth. (Section IVB discusses soft tissue changes that occur in snuff induced oral leukoplakia. ) The most common form of periodontal damage is destruction of the gum tissue that is attached to the tooth surface where the snuff is held. Dr. Christen of the Indiana University School of Dental Medicine and Dr. Mehta of the Tufts Dental School testified that the gingival tissue which is adjacent to the tooth is chronically inflamed by the injurious proper- ties of snuff and recedes from the tooth surface over time. (93,94) Greer and Poulson have defined this type of periodontal problem caused by smoke- less tobacco as "site-specific gingival recession with apical migration of the gingiva to or beyond the cementoename 1 junction with or without clini- cal evidence of inflammation. "( 95 ) Tooth loss may result, and the exposed root surface is prone to decay. A number of case histories and clinical studies were presented showing periodontal problems to occur at the site where smokeless tobacco was held. They include a 1966 study by Van Wyk of South Africa where he reported chronic inflammation of periodontal tissue brought about by the use of snuff. (96) In a Swedish study, long-term snuff users were found to have gingival recession and periodontal destruction around the anterior teeth where the tobacco was held. (97) Four other case reports ( 98—10 i ) were presented showing periodontal breakdown among smokeless tobacco users. -34- Three case series reports were presented on young male users all showing high levels of periodontal disease. A Texas study of 14 college students done by Christen found 57 percent of the users to have gingival recession where the snuff was held. (102) A Colorado study of 117 high school student users found that 20 percent had periodontal or mucosal lesions in their mouth. (103) A second Colorado survey of 56 rural teenagers found four per- cent had periodontal lesions and 23 percent both mucosal lesions and periodontal des true tion. ( 104 ) In the majority of these studies, use of snuff was implicated as the etiologic agent. Dr. Weathers of the Emory University Dental School presented the results of his study of 500 Atlanta school children, in which he found no difference in the incidence of gingival recession, mucosal pathology or decay between users and nonusers of smokeless tobacco as long as the mouths of the ado- lescents were clean and free of gum inflammation. ( 105 ) His finding is not in keeping with Greer's conclusion referenced earlier that loss of periodontal attachment occurred without inflammation. Dr. Weathers did not submit a copy of his study for review or a reference for the study. Conclusion The use of snuff significantly increases risk of periodontal disease and can cause irreversible loss of gingival tissue attachment adjacent to the site where the snuff is held. -35- VI. NICOTINE DEPENDENCE/ ADDICTION Snuff is a dependence inducing substance which can lead to addictive beha- vior. The use of snuff results in elevated nicotine levels in the blood stream of a user similar to that obtained from cigarette smoking. The effect of nicotine levels produced by smoking has been shown through human and experimental studies to satisfy all the criteria for dependence. Commonalities exist between use of snuff and other drugs of abuse that sup- port the finding that snuff is a dependence inducing substance. Clinical criteria have been developed for diagnosis and treatment of tobacco depen- dence by the American Psychiatric Association. Snuff as a Source of Nicotine The mean concentration of nicotine in moist snuff has been found to range from 6.9 mg/g. to 14.4 mg/g.(106) The concentration for cigarettes has been reported to be from 0.06 mg/g. to 2.2 mg/g. (107) Use of snuff has been shown to produce blood nicotine levels equivalent to those produced by smoking. (108 ) In a study by Gritz, e_t a_l . subjects consumed about one third of a can of moist ground snuff (10.8 gm) in eight dips spaced throughout an eight hour period. In this study, "nicotine absorption was observed and resulted in an increase in mean plasma concentration from 2.9 ng/ml after overnight abstinence to 21.6 ng/ml after 6 to 8 hours of consumption ad libitum was recorded. Plasma cotinine concentrations rose from a morning mean of 137.3 ng/ml to an afternoon mean of 197.2 ng/ml, concentrations that are typical of those reached in regular cigarette smokers." -36- Sicotine as a Dependence Producing Drug According to Che National Institute of Drug Abuse (NIDA), three criteria define a drug as having the potential for producing dependence. First, the drug is psychoactive. Second, it produces euphoric effects that can be objectively defined and, finally, it is a biologic reinforcer, that is, the chemical activity of the drug is sufficient to establish and maintain com- pulsive ingestion. ( 109 ) Nicotine has been shown to produce these effects in humans and is classified as a dependence producing drug. (110) A recent article by Pomerleau reviewed a number of studies that demonstrate the psychoactive and euphoric effects of nicotine .( 1 1 1 ) Other studies were presented that showed that nicotine produces euphoric effects similar to other drugs of abuse . ( 1 1 2 , 1 1 3 ) Additional studies showed nicotine to be a reinforcer, and that users developed patterns of self administration because of the rein- forcing effects of the drug that lead to compulsive use. (114) Dr. Jack Henning- field of the National Institute of Drug Abuse (NIDA) reported that history and science leave no doubt that tobacco, in a variety of forms, can be an addictive drug, and that the nicotine delivered by tobacco is a dependence producing drug and a prototypic drug of abuse. (Dr. Henningfield explained that the terms "addiction", "dependence" and "abuse" although they may have a different focus, are used interchangeably. )( 115 ) Commonalities Between Nicotine Use and Other Drugs of Dependence According to the NIDA drug dependency is a state in which a person's free- dom of choice has been compromised by the physical effects of the drug on the brain and nervous system. (116) -37- Nicotine and other drugs Chat produce dependence such as alcohol, cocaine and morphine have four common characteristics. First, they are psychoac- tive, that is they affect the chemistry of the brain and central nervous system. Second, they produce dependence and lead to compulsive use. Third, when one attempts to abruptly stop use, physiological and psycholo- gical distress may occur depending on the drug or individual. Finally, there is a tendency of users who have stopped to relapse and go back to use despite their desire to quit. NIDA has concluded that smoking is the most widespread form of drug dependence in the nation and as Henningfield stated, "any form of nicotine should be considered to have the potential to produce dependence until proven otherwi se . "( 1 1 7 ) Clinical Criteria for Tobacco Dependence The American Psychiatric Association's Diagnostic and Statistical Manual of Mental Disorders (DSM-III ) ( 1 18 ) also recognizes the addictive potential of nicotine and states that the essential features for tobacco dependence are continuous use of tobacco for at least one month with either (1) unsuccess- ful attempts to stop or significantly reduce the amount of tobacco use on a permanent basis, (2) the development of tobacco withdrawal, or (3) the pre- sence of a serious physical disorder (e.g., respiratory or cardiovascular disease) that the individual knows is exacerbated by tobacco use. If the criteria are met, the individual is diagnosed as being dependent. Five smokeless tobacco users testified, many of whom used the word "hooked" to describe their dependence. All expressed great difficulties in quitting implying that they were dependent. One 18 year old Massachusetts high -38- achool student reported that he started chewing tobacco at thirteen and switched to snuff at fifteen. He reported using two cans of snuff a day last spring and stated, "when I tried to stop dipping, I couldn't do it. "(119) Another high school senior started using snuff when he was 16 years old. He said that when he first tried it, he felt a little bit of dizziness and a little light headedness. "Kids in sports," he said, "do it not as a once- in-awhile, but as an everyday thing." He stated, "I tried to quit and I just couldn't stop. "(120) A 30 year old male stated that he was introduced to snuff as a healthful alternative to smoking over twenty years ago. He said, "I've tried to quit countless times, usually smoking cigarettes to replace my desire to dip snuff. "(121) A Brockton high school student used snuff for two years and reported, "I tried to quit and I just stopped for a day, and then I start getting the . . . well, I start feeling that I wanted another dip. It's addictive." He said that his friends have trouble quitting because "sometimes when you get all nervous, you just feel like a dip or a chew, it just relaxes you and calms you down." He added that he would never think of smoking because, "If you play sports, you just don't smoke. "(122) Dr. Nathaniel Rowe of the University of Michigan testified that of four patients who had oral surgery to remove tumors of the mouth caused by smoke- less tobacco, two continued to use smokeless tobacco following surgical treatment despite the life threatening nature of the tumors that were removed. Dr. Rowe described this continued use as addiction. ( 123 ) -39- Several speakers challenged classifying smokeless tobacco as addictive for a number of reasons. Mr. John Curtin, representing the Smokeless Tobacco Council, stated that in 1964, the Surgeon General's Advisory Committee concluded that tobacco use is not addictive and little has occurred since then to change this. (124) The weight of the evidence does not support this position. Considerable research has been conducted since 1964 that supports the finding that nico- tine is addictive and major health agencies have taken positions that nico- tine is a dependence producing drug. Dr. Arthur Furst and Father Joseph Martin, President of Ashley Treatment Center, testified that in order for a drug to be addictive, it must produce 1 i f e-threatenting withdrawal symptoms .( 125 , 126 ) Dr. Powell, President of Educational Training Programs in Connecticut, stated "dependence (addiction) . . . involves impairment of one's social and/or occupational functioning. "( 127 ) However, according to the diagnosis criteria of the American Psychiatric Association, neither life threatening withdrawal symp- toms nor social/occupational impairment are criteria for establishing tobacco dependence .( 128 ) Further, Father Joseph Martin and Dr. David Powell challenged classifica- tion of smokeless tobacco as addictive because, in their experience, indi- viduals had not been treated clinically to quit as in the case for alcohol, morphine or cocaine .( 129 , 130 ) However, even though treatment is not a criteria for diagnosing dependence, Dr. Glover, of the East Carolina University, reported that he has conducted -40- two smokeless tobacco clinics and could not get one person to stop using snuff for more than half a day. (131) Further, there are numerous smoking cessation programs throughout the state and nation that assist individuals who wish to quit smoking. Individuals are treated clinically by physicians and many are prescribed nicorette gum (a prescription drug) as part of cli- nical therapy. Since nicotine can produce dependence regardless of the method of delivery, there is no reason to believe that individuals who use smokeless tobacco would require anything less than what is available to cigarette smokers in order to stop. In addition, as use of smokeless tobacco increases, it is probable that programs similar to the cigarette cessation program will be developed for smokeless tobacco. The National Cancer Institutes will be awarding grants in 1985 to develop and test smo- keless tobacco cessation programs. (132) Conclusions « Testimony supports the view that snuff tobacco delivers nicotine to the blood stream of users in concentrations similar to that of smokers. Nicotine is a prototypic drug of abuse which has been shown to produce dependence and addictive behavior in the user. For this reason, snuff is classified as a potentially addictive substance. -41- VII. PUBLIC KNOWLEDGE OF THE ADVERSE HEALTH EFFECTS OF SNUFF Testimony was submitted by several individuals and organizations which related to both consumer knowledge of the adverse health effects of snuff and the industry's promotional activities to increase consumer acceptance of this product. Several speakers attributed increased use of snuff to television advertisements which use popular sports figures to promote the product. A number of television and print advertisements were reviewed. One witness testified that the ads instructed nonusers on how to use snuff, implied that use was a safe alternative to smoking, and used subliminal messages to imply that use added to athletic prowess and was a clean, healthy, and safe practice. ( 133 ) Several speakers criticized these commercials for ignoring known health problems .( 134 , 135 ) For example, one ad instructs the viewer how to use snuff and states, "at first you could feel a slight irritation on the gum, ...but learning is part of the fun, and these things pass with practice. Two weeks should make you a pro. "(136) Although the ad acknowleges gum irritation, it goes on to instruct the user to ignore it. Representatives of the Smokeless Tobacco Council testified that the industry does not intentionally direct its ads to youth, and that industry adheres to a voluntary code which prohibits advertisements in print or media programs aimed primarily at the youth market. The Council also stated that it supports current legislation to raise the sales age in Massachusetts to 18.(137) At the hearing, testimony from students, teachers and parents indicated that there was a general lack of knowledge of the potentially harmful effects which may result from the use of snuff. -42- Dr. Glover of East Carolina University discussed the results of studies he had done on high school students from the Southwest. He found that a majority of students did not think the use of snuff was a health hazard or the use of snuff was as dangerous as smoking. He attributed this in part Co the lack of educational programs at the high school level similar to cigarette smoking prevention programs .( 138 ) Mrs. Marsee, the mother of a boy from Oklahoma who used snuff heavily until he developed tongue cancer at age 18, stated that her son, Sean, was not aware of any adverse health consequences. She testified that Sean was a track athlete before his death, that he did not smoke cigarettes, and that he considered snuff a safe alternative to smoking based on the promotion of snuff by sports personalities and the lack of a warning label similar to that on cigarettes .( 139 ) Students from North Easton, Taunton and Brockton high schools testified that they did not know that snuff could cause adverse health effects when they first started. The students from North Easton stated that they would not have started to use snuff if they had known of the potential health problems. (140-143) The coordinator for health education at Brockton High School testified that many students are unaware of the dangers of smokeless tobacco and that there were no curriculum materials available on the subject. (144) Ms. Anne Hughes of North Easton, Massachusetts, testified that few parents know anything about smokeless tobacco and little information is available on the hazards . ( 145 ) -43- A dental hygienist from Phillips Academy testified that many students at the school are using the product and that they have a complete lack of knowledge of the potential health ef f ects. ( 146 ) Two private dentists testified that many adolescent snuff users are not aware of the potential health problems associated with smokeless tobacco. ( 147 , 148 ) Conclusion Testimony indicated that adults and adolescents are not knowledgeable about the potential harmful effects of snuff and that promotional campaigns by the industry to encourage use of the product provide no information of potential adverse health consequences. -44- VIII. SUMMARY OF FINDINGS Some of the testimony and evidence referred to "smokeless tobacco", and did not specify whether the tobacco was snuff or chewing tobacco. In general, the testimony implicated tobacco as the noxious agent and stated that the form in which it was delivered was incidental to its action. However, the critical experimental, clinical and epidemiologic evidence presented did identify snuff to be a prime offending agent. For this reason, the findings will deal with snuff only. The following findings are made: 1. Snuff contains nitrosamines which have been shown to cause cancer in laboratory animals, and have been classified as potential human carcinogens. 2. The use of snuff has been shown to form oral leukoplakia, which in a signi- ficant percentage of cases transform into cancerous lesions. 3. The epidemiological, histopathological and experimental evidence has shown use of snuff to be causally related to oral cancer, and snuff to be a human carcinogen. 4. The nicotine contained in snuff is a prototypic drug of abuse that can lead to dependence (addiction). 5. Based on findings (1) - (3), snuff is toxic under the Massachusetts Hazardous Substance Act, G.L. c.94B, SI (Hazardous Substance Act) as a substance which has the capacity to produce personal injury or illness to man through ingestion or absorption through body surfaces. 6. Snuff induces localized inflammation of oral tissues on prolonged or repet- itive contact, causing in some cases periodontal disease which may result in tooth loss and other gum disorders. -45- 7. Based on finding (6), snuff is an irritant under the Hazardous Substance Act, section one, as a substance not corrosive which on immediate, prolonged or repetitive contact with normal living tissue will induce a local inflam- matory reaction. 8. Based on the determination that snuff is toxic and an irritant, it is a hazardous substance within the meaning of the Hazardous Substance Act, sec- tion one. 9. Advertisements for the use of snuff provide no information concerning the possible adverse health consequences of snuff use. 10. In general, the public is not knowledgeable concerning the possible adverse health consequences of snuff use. 11. The labeling requirements of section one' of the Hazardous Substance Act alone are not adequate for the protection of the public health and safety in view of the special hazard presented by snuff. 12. Requiring a health warning label on snuff is not preempted by federal regu- lation or statute and does not constitute an impermissable burden on interstate commerce. -46- IX. REGULATIONS Following a review of Che testimony and written comments submitted in response to the proposed regulations, the Department has determined that a sufficient basis exists for requiring a warning label on snuff containers sold in Massachusetts. In response to the testimony and comments to the testimony and comments recieved during the public hearing process, the proposed regulations have been modified in several respects. First, the definition of snuff has been refined to more accurately describe this particular form of smokeless tobacco and to exclude snuff used in the nasal cavity. (Section 650.005) Second, the label has been changed to warn that snuff "can be" addictive rather than "is" addictive, and "can cause" mouth cancer rather than "may cause" mouth cancer. In addition, the final regulation contains greater specificity concerning the type, location and size of the required label. (Section 650.105) Finally, the regulations contain an effective date of December 1, 1985. (Section 650.105) (Although testimony was requested on label size and placement, as well as effective date, no testimony was submitted on these issues.) -47- 105 CMR: DEPARTMENT OF PUBLIC HEALTH 105 CMR 650.000 is amended in Che following manner: [1] Section 650.005 Supplemental Definitions is amended by adding: (3) "Snuff," is a form of smokeless tobacco, often referred to as such, whi is a finely ground or cut tobacco mixture that is intended to be placed in the oral cavity. [2] Section 650.015: Listing of Toxic Substances is amended by adding: (3) Snuff. [3] Section 650.016: Listing of Irritants is amended by adding: (3) Snuff. [4] Section 650.017: Listing of Hazardous Substances is amended by adding: (3) Snuff. [5] Adding the following section after 650.100: 650.105: Labeling of Snuff (1) Any container -or package of snuff shall be deemed Co be oisbranded as of December 1, 1985 unless: (a) It meets the requirements set forth at 105 CMR 650.004(20)(a) and (b); and (b) It bears the following label conspicuously placed, either on the top or side of the container or package: WARNING: Use of snuff can be addictive and can cause mouth cancer and other mouth disorders. (2) The label required in subsection (1) shall be white with nine (9) point, bold type black lettering and shall be no smaller than iinch by lHnches. (3) The label required in subsection (1) may be either printed directly on the container or preprinted provided that any preprinted label is: -48- (a) connnerc ial ly printed; and (b) has adherence and/or surface retention such that the surface of the label is destroyed before the label can be removed from the container . REGULATORY AUTHORITY 105 CMR 650.000: M.G.L. C.94B and M.G.L. c.lll, $5. APPENDIX A NOTE: These statements are extremely abbreviated and do not reflect the entirety of the various position statements that were received as testimony. Conse- quently, interested persons are advised to read the oral and written transcript of the hearing for a complete and accurate understanding of the Agency's positions. Organizations Testifying In Suuuort of "emulation 1 . Action for Children's Television Strongly supports health warning labels for snuff. 2 . Association of State and Territorial Dental Directors Supports warning labels on snoke less tobacco 3 . American Cancer Society Risk. of oral cancer is substantially greater among users of smokeless tobacco. Fully supports the health warning labels. 4 . American Dental Association Supports the proposed health warning labels for snuff. Correlation between smokeless tobacco and oral cancer is strong. Potentially precancerous lesions are commonly found in mouths of smokeless tobacco users. Periodontal disease is seen in mouths of smokeless tobacco users. 5 . American Heart Association Nicotine increases risk of heart disease and stroke. Urges labeling of all smokeless tobacco products. 6 . American Lung Association Encourages requiring health warning labels on smokeless tobacco products. Nicotine is an addictive substance. 7 . Mayor's Office of Consumers Affairs - City of Boston Supports regulation for health warning labels. 8 . Boston Department of Health and Hospitals - City of Boston Proposed regulations should be implemented. 9 . Coalition on Smoking or Health Represents nationally American Heart Association, American Lung Association, American Cancer Society and 24 additional agencies. Scientific evidence supports the conclusion the use of tobacco containing nicotine is addictive and the use of snuff is directly linked to oral cancer and other diseases. The Coalition and member agencies endorse the proposed regulation and urge Massachusetts to act now and require health warning labels. 10 . Federal Centers for Disease Control Available evidence indicates chronic use could have serious consequenc ie s including oral cancer. Commends Massachusetts for addressing issue. 1 1 . Group Against Smoking Pollution Massachusetts should require health warning labels on smokeless tobacco products. 1 2 . Massachusetts Society of Dentistry for Children and Massachusetts Acadeny of Pediatric Dentistry Scientific research has adequately documented the harmful and carcinogenic effects which tobacco produces in the human oral nucosa . 1 3 . Massachusetts Dental Hy^ienists' Association. Inc. Supports the proposed regulation to require warning labels on snuff . 1 4 . Massachusetts Society of Oral Maxillofacial Surgeons Urges the adoption of the regulation declaring snuff to be a hazardous substance and requiring a health warning label on cans of snuff. Preraa lignant lesions of the oral cavity, oral cancer, periodontal disease and dental erosions are directly attributable to use of this product. 1 5 . Massachusetts Public Health Association Nicotine is an addictive drug. Smokeless tobacco has been implicated in the etiology of oral cancer and periodontal disease. Massachusetts should require warning labels on snuff . 1 6 . National Institute on Drug Abuse National Institutes for Health Nicotine is a prototypic drug of abuse. 1 7 . National Cancer Advisory Board National Cancer Institute National Institutes of Health There is sufficient evidence of a cause and effect relationship - between smokeless tobacco use and human oral cancer. Smokeless tobacco produces leukoplakia and damage to periodontal tissue. Smokeless tobacco contains sufficient nicotine to produce addiction. The Advisory Board supports labeling of smokeless tobacco products. 1 8 . United States Department of Health and Human Services. Office of the Surgeon General Smokeless tobacco including snuff does indeed pose a cancer threat and is associated as well with certain other pathological oral conditions. Supports the public's right to be aware of the negative health consequences from using snuff and chewing tobacco. 19. Public Citizen Health Research Group Smokeless tobacco has been shown to be addictive, and has been shown to cause oral cancer. Urges Massachusetts to adopt warning label. 20 . World Health Organization International Agency for Research on Cancer Snuff of the type sold in the United States is a human care inogen . Organizations Testify in,, in Opposition Co r. e , ; u 1 a c 1 o : i 1 . llassachusetts Candy and Tobacco Distributors Association National Association of Tobacco Distributors Opposes state by state approach of product labeling. Supports national approval. 2 . Smokeless Tobacco Council. Inc. Use of smokeless tobacco has not been proven scientifically to cause any health problems including oral cancer. Massachusetts Department of Public Health lacks authority to require a warning label. Supports raising sales age to 18. Massachusetts should defer this issue to appropriate federal agency. APPENDIX B References 1. Table I 2. Tables III-VII 3. Table VIII 4. Table IX 5. Tables X-XI 6. General References NOTE: Where the written statements of the witness is referenced, the name of the presenter is given first, next (w) appears indicating written testi- mony, and the number of the page of the written statement last. In the case of oral statements, the page of the oral transcript is given. Both the written statements and copy of the oral transcripts are available for review from the Department. REFERENCES TADLE I Edwards, G.: Utah School-Based Smokeless Survey. Fall 1984, Utah Department of Public Health. Glover, E.D.: "Preliminary Results: Use and Knowledge of Smokeless Tobacco: A 1933 Survey of Students in Texas Schools." Presentation Texas School Health Association Annual Meeting, March 8-10, 1984. Glover, E.D., Johnson, R., et a 1 : Study Conducted, National Collegiate Smokeless Tobacco Survey. Greer, Jr., R.O. and Paulson, T.C.: "Oral Tissue Alterations Associated Uith the Use of Smokeless Tobacco by Teenagers, Part I, Clinical Findings." Oral Surg., 56: 275, Sept. 1983. Hunter, S. M a c D . , Parker, F.C., et a 1 : "Longitudinal Patterns of Cigarette Smoking and Smokeless Tobacco Use in Adolescents — The Bogalusa Heart Study," Submitted 01.25.85 McCarty, D. and Krakow, W. : "More Than 'Just a Pinch': The Use of Smokeless Tobacco Among Massachusetts High School Students," January 28, 1985 Report by Massachusetts Department of Public Health, Division of Drug Rehabilitation. Offenbacher, S., Weathers, D.R.: "Effect of Smokeless Tobacco on the Periodontium of Adolescent Males," J. Dent. Res., 62:662, 1983. Severson, H.H., Lichenstein, E., et a 1 : "Analysis of the Use of Smokeless. Tobacco by Adolescents," Presented at the Fifth World Conference on Smoking and Health, Winnipeg, Canada, July 10-15, 1983. REFERENCES TABLES III-VII Abbe,- El. (1915). Cancer of the nouth: The case against tooacco. II . Y . Med . J . . 102. 1-2. Ackerman, L.V. (1948) Verrucous carcinoaa of' cavity. Sur". 23., 670-678 . * Ah 1 bom, 11. E. (1937) Pradisponierende faktoren fur plattenepithe lkarzinom in aund , hals und speiserohre. Eine statistische untersuchung am material des Rad iumhemme t s , Stockholm. Acta Radiologica. 1 8 . 163-1 85 (Swedish). Axell, T., Mornstad, H., & Sundstrom, B. (1976) The relation of the clinical picture to the histopatho logy of snuff dipper's lesions in a Swedish population. J . Ora 1 Path . . 5 , 229-236 . Axell, T., Mornstad, H., & Sundstrom, B. (1978) Snusning och munha lecance r - en retrospektiv studie. Lakart idn ingen . 7 5 . 2224-2226 (Swedish). Blot, W.J. & Fraumeni, J.F., Jr. (1977) Geographic patterns of oral cancer in the United States: Etiologic Implications. J . Chronic Pis . . 30, 745-757. Blot, W.J., Winn, D.M., & Fraumeni, J.F., Jr. (1983) Oral cancer and mouthwash. J. Natl. Cancer Inst.. 70, 251-253. Brinton, L.S., Blot, W.J., Becker, J.S., Winn, D.M., Browder, J. P., Farmer, J.C., Jr., & Fraumeni, J.F., Jr. ( 1984) A case-control study of cancers of the nasal cavity and paranasal sinuses. Amer. J. Epidemiol.. 119, 896-906. Brown, R.L., Suk, J.M., Scarborough, J.E., Wilkins, S.A., & Smith, R.R. (1965) Snuff dippers' intraoral cancer: clinical characteristics and response to therapy. Cancer . 1 8 . 2-13. Browne, R.M., Camsey, M.C., Waterhouse, J. A., & Manning, G.L. (1977) Etiological factors in oral squamous cell carcinoma. Community Dent. Oral Epidemiol.. ,5 301-306. Christen, A.G., Svanion, B.2., Glover, E.D., & Henderson, A.H. (1982) Smokeless tobacco: the folklore and social history of snuffing, sneezing, dippping, and chewing. JADA . 105 , 821-829 . Cole, P., Monson, R.R., Haning, H., & Friedell, G.H. (1971) Smoking and cancer of the lower urinary tract. Hew Engl. J. Med. , 284,, 129-134. Coleman, C.C. (1965) Surgical treatment of extensive cancers of the mouth and pharynx. Ann . Surg . . 161. 634-644. Dunn, W.I. & Dykstra, C.L. (1967) Tobacco habits in carcinoma of the upper respiratory tract. Arch Oto larvng . . 86 . 105-107 . Jayanc, Iv . (1977) Statistical appraisal of the association of snoUinc and chewing habits to oral and pharyngeal cancers. India J. Cancer, 14, 293-299. Keen, P., delloor, N . G., Shapiro, II. P., & Cohen, L. ( 1 9 5 5 ) The aetiology of respiratory tract cancer in the South African Bantu. Br . J . Cancer . 2, 528-538 . Kraus, F. T. h Perez-Mesa, C. (1966) Verrucous carcinoma: Clinical and pathologic study of 105 cases involving oral cavity, larynx, and genitalia. 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(1969) Verrucous squamous cell carcinoma of the oral cavity. Cancer 23, 152-160. Friedell, H.L. & Rosenthal, L.M. (1941) The etiologic role of chewing tobacco in cancer of the mouth. JAMA . 116. 2130-2135. Frithiof, L . , Anneroth, G., Lasson, U., & Awsweholm, C. (1983) The snuff-induced lesion. Acta Odont. Scand. . 41, 53-64. Goethals, P.L., Harrison, E.G., & Devine, K . D . (1963) Verrucous squamous carcinoma of the oral cavity. Ame r . J . Sure.. 106. 845-851 . Graham, S., Dayal, J., Rohrer, T.R., Swanson, M . , Sultz, H., Shedd, D., & Fischman, S. (1977) Dentition, Diet, Tobacco and Alcohol in the epidemiology of oral cancer. J. Natl. Cancer Inst . . 59, 1611-1618. Gupta, P. C, Pindborg, J.J., & Mehta, F.S. ( 1982 ) Comparison of carcinogenicity of betel quid with and without tobacco: An epidemiological review. E c o 1 . Pis.. 1, 213-219. Hankey, B.F. Cancers of the buccal cavity and pharynx. In: Axtell, L.M., Aaire, A.J., Myers, M.H. (eds). Cancer Patient _ Survival. Report Number 5. DHHS (NIH) 77-992. Washington, D.C., U.S. Government Printing Office, 1976. Hartge, P., Hoover, R., & Kantor, A. Bladder cancer risk, and pipes, cigars, and smokeless tobacco. Cancer . in press. Hartselle, M.L. (1977) Oral carcinoma as related to the use of tobacco. Ala . J . Med . Sc i . . 14 . 188-194. ■•^ Heuch, I., Kvale, G., Jacobsen, B.K., Bjelke, E. (1983) Use of alcohol, tobacco, and coffee, and risk of pancreatic cancer. Br . J. Cancer. 48 . 637-643. Higginson, J., Oettle, A.G. (1960) Cancer incidence in the Bantu and "Cape Colored" races of South Africa: Report of a cancer survey in the Transvaal. J. Natl. Cancer Inst.. .24, 589-671. Hou-Jensen, K. (1964) On the occurrence of post nasal space tumors in Kenya. Br . J . Cancer . 1 8 . 58-68. Howe, G.R., Burch, J.D., Miller, A.B., Cook, G.M., Esteve, J., Morrison, B., Gordon, P., Chambers, L.V., Fodor, G. , & Winsor, G.M., (1980) Tobacco use, occupation, coffee, various nutrients, and bladder cancer. J. Natl. 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Pottern, L.M., Morris, L.E., Blot, W.J., Zeigler, R.G., & Fraumeni, J.F., Jr. (1981) Esophageal cancer among black men in Washington, D.C. I. Alcohol, Tobacco, and other risk factors. J . Nat 1 . Cancer Inst. . 6 7 . 777-783 . Redmond, D.E., Jr. (1970) Tobacco and cancer: The first clinical report, 1,761. Hew Engl J . Med . . 282 . 18-23. Roed-Peter sen , B. & Pindborg, J.J. ( 1973 ) A study of Danish snuff-induced oral leukoplakias. J. Oral Pathol.. 2, 301-313. Root, H.D., Aust, J.B., & Sullivan, A., Jr. (1960) Snuff and cancer of the ear. New Engl. J . Med . . 26 2. 819-820 . Rosenfeld, L. & Callaway, J. (1963) Snuff dipper's cancer. Am . J . Surg . . 106 . 840-844. Rothman, K.J. (1978) Epidemiology of head and neck cancer. Larvngo scope . 88, 435-438. Schuman, L.M., Bjel~ke, E., Gibson, R.W., & Watt, G.D. Cancer among chevers of snuf f/ tobacco : International cohort comparisons for Norway and the United States. Proceedings of the 13th International Congress on Cancer, 1982, #267. Shapiro, M.P., Kecn^ P., Cohen, L . , & de Moor, N.G. (1955) Malignant disease in the Transvaal. III. Cancer of the respiratory tract. S . Ar . Med . J . . 29 . 95-101. Smith, J.F., Mincer, H.A., Hopkins, K.P., & Bell, J. (1970) Snuff-dippers lesion: A cytological and pathological study in a large population. Arch . Oto larvng . . 92 . 450-456 . Smith, J.F. (1975) Snuff-dippers lesions: A ten-year follow-up. Arch. Otolaryngol.. 101 . 276-277. Sorger, K. & Myrden, J. A. (I960 ) Verrucous carcinoma of the buccal mucosa in tobacco chevers. Canad. Med. Assoc. J.. 83,, 1413-1417. Stecker, R.H., Devine, K.D., & Harrison, E.G. (1964) Verrucose "snuff dipper's" carcinoma of the oral cavity. JAMA . 189. 144-146 . REFERENCES TABLE VIII Axell, J., Hornstad, II. and Sundstron, D . : "The Relationship of the Clinical Picture to the H is t opa c ho logy of Snuff Dipper's Lesions in a Swedish Population," J. Oral Path. 5: 229-236, 1976. 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In addition it has been established that upon inhalation of the air in cars with new upholstery one is exposed daily to 0.50 Hg of N D MA and 0.20 Hg of NDEA. NDEA + NPYR . Brunnemann, K.D., Scott Y. N-N i t r o somor pho 1 ine and other volatile snuff tobacco. Carcinogenesis (London) VNA, N DMA ♦ NEMA ♦ C. and Hoffman, D. N-N i c r o s am i n e a in 3:693-696, 1982. Brunnemann, et al fine-cut tobaccos daily consumption Carcinogenesis (London) 3_:693-696 , 1982. : Average values for the leading 5 U.S. used for snuff dipping in 1981; assumed 10 g/day; VNA - NDMA ♦ NPYR ♦ NMOR. References General 1. Curt.in (w) page 30 - 46. 2. Curtin (w) page 46 - 60. 3. Pearson (o) page 232 - 233. 4. Gifford (o) page 227 - 229. 5. Kerrigan (w) page 243. 6. Vagues, E., Tobacco Encyclopedia, Tobacco Journal International Mainz, Germany 1984 page 437. 7. Ibid, page 439. 8. Kerrigan (o) page 242. 9. Meyers (o) page 91. 10. Hunter, S.M. et al . 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Journ. of Oral Pathol. 1976:5 page 2229. Op. cit. Smith Banoczy, J. and Sugar, L. , Longitudinal studies in oral leukoplakias. Journal of Oral Pathology, VI 1972, pages 265-272. Einhorn, J. and Wesall, J., Incidence of oral carcinoma in patients with leukoplakia of the oral mucosa. Cancer , Vol. 29, pages 2181 - 2193 Den. 1967. Silverman et al . (1976). Furst (o) page 259. Kupper (w) page 21. Op. cit. Axell 1976. Axell, T. et al. Snuff and cancer of the oral cavity. Lakartidningen 75 2224-2226, 1978. Op. cit. Banoczy 1972. Banoczy, J. and Sugar, L. Follow-up studies in oral leukoplakia. J. Max Fac. Surg. 5(1977) 69-75. Op. cit. Silverman 1976. Mincer (o) page 5. Weathers (w) page 2-3. Mincer (w) pages 6-10. Lijinsky (o) page 120. Op. cit. (o) page 119. Brunneman, K.D. et al . N-nitrosamines environmental occurrence In Vivo formation and metabolism. Toxicol . -Clin . Toxicol. 19(6 & 7), 661-(1982- 1983). Hoffman, et al . 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Nicotine derived N-nitrosamines in tobacco related cancer: Current status and future directions. Cancer Res. 45 935-944, 1985. Lijinsky (w) pages 1-4. Lijinsky (w) pages 1-6. Castonguay, A., . Rivenson , A. , Trushin, N., Reinhardt, J., Spathopoulos , S., Reiss, B. , and Hecht, S. Effects of chronic ethanol consumption on the metabolism and carcinogenicity of N-nitrosonornicotine in F344 rats. Cancer Res. 44:2285-2290, 1984. Hecht, S.S., Linn, D., Castonguay, A. Effects of alpha deterium substitution on the nutagenesis of 4- ( N-methyl-N-nitrosamino ) -1 ( 3-pyridyl ) -1 ( 3-pyridyl ) - 1-butanone. Carcinogenesis Vol. 4:305-310, 1983. William G.M., Laspia, M.F. The detection of various N-nitrosamines in the rat hepatocyte primary culture 1 DNA repair test. Cancer Letters Vol . 6 pages 199-206. Chung, F.L., Wang, M. , and Hecht, S.S. Effects of dietary indoles and isothiocynates on 4- (N-methyl-N-nitrosamino ) -1 ( 3-pyridyl ) -1-butanone alpha hydroxy lation and DNA methylation in rat liver. Carcinogenesis Vol. 6: 539-543, 1985. Hecht, S.S., Young, R., and Chen, C.B. Metabolism in the F344 rat of 4- ( N-methyl-N-nitrosamino ) -l-( 3-pyridyl ) -1-butanone , a tobacco specific carcinogen. Cancer Res 40 : 4144-4150 , 1980. Loechler, E.L. , Green, C.L., and Essigmann, J.M. In vivo mutagenesis by 06-methylguanine built into a unique site in a viral genome. Proc. Natl Acad Sci USA 81:6271 (1984). 80. Singer, B. and Grunberger, D. Molecular Biology of Mutagens and Carcinogens, pp. 221-253, New York, Plenum Publishing Corp., 1983. 81. Castonguay, A., Tharp, R . , and Hecht, S.S. Kinetics of DNA methy lation by the tobacco-specific carcinogen 4- ( methy 1-nitrosamino ) -1 -( 3-pyr idyl ) -1 -butanone in F344 rats. In: I.K. O'Neill, R.C. Von Borstel, C.T. Miller, J. Long, and H. Bartsch, eds . N-Nitroso Compounds: Occurrence, Biological Effects and Relevance to Human Cancer. IARC Scientific Publications, No. 57, International Agency for Research on Cancer, Lyon, France, 1984, pp. 805- 810. 82. Chung, F-L. , Wang, M. , and Hecht, S.S. Effects of dietary indoles and isothiocyanates on N-nitrosodimethy lamine and 4-(methylnitrosamino ) -1- ( 3-pyridyl ) -1-butanone a-hydroxy lation and DNA methylation in rat liver. Carcinogenesis. 6_: 539-543, 1985. 83. Castonguay, A., Stoner, G.D., Schut, H.A.J. , and Hecht, S.S. Metabolism of tobacco-specific N-nitrosamines by cultured human tissues. Proc. Natl Acad Sci USA 80:6694-6697, 1983. 84. Hoffmann, 0 . , and Hecht, S.S. Nicotine derived N-nitrosamines and tobacco-related cancer: current status and future directions. Cancer Res. 45:935-944, 1985. 85. Hecht (w) pages 5-6. 86. Lijinsky (w) page 4. 87. Grasso (w) pages 2-4. 88. Grasso (w) page. 16. 89. International Agency for Research on Cancer (IARC) Evaluation of carcinogenic risk of chemicals to humans. Vol. 17, page 365, 1978. 90. Hirsch, J.M. , Johanson, S.L., Effect of long-term applications of snuff on the oral mucosa: An experimental study in the rat. J. Oral Pathol. 12(3) :187 June 1983. 91. Furst (o) page 264. 92. Hirsch letter to A. Greenberg March 1985. 93. Christen (o) pages 25-27. 94. Mehta (o) page 139. 95. Greer, R.O. and Poulson, T.C. Oral tissue alterations associated with the use of smokeless tobacco by teen-agers. Part I. Clinical findings. Oral Surg., Oral Med., Oral Path. 56:275-284, September 1983. 96. Van Wyck, C.W. The oral lesions caused by snuff: A clinico-pathological study. Med. Proc. 11:531-537, October 1965. 97. Moore, R., and Terec, V. Dentistry in "the Land of the Midnight Sun," Dent. Surv. 56;69-70, April 1980. 98. Zitterbart, P. A., Marlin, D.C. and Christen, A.G. Dental and oral effects observed in a long-term tobacco chewer: Case report. J. Indiana Dent. Assoc. 62:17-18, July/August 1983. 99. Croft, L. Smokeless tobacco: Case report II. Texas Dent. J. 100:14-15, December 1983. 100. Croft, L. Smokeless tobacco: A case report. Texas Dent. J. 99:15-16, December 1981. 101. Hoge, B.W. and Kirkham, D.B. Clinical management and soft tissue reconstruction of periodontal damage resulting from habitual use of snuff. J. Amer. Dent. Assoc. 197:744-745, November 1983. 102. Christen, A.G., McDaniel , R.K. and Doran, J.E. Snuff dipping and tobacco chewing in a group of Texas college athletes. Texas Dent. J. 97:6-10, February 1979. 103. Greer Op. cit. 104. Poulson, T.C., Lindenmuth, J.E. and Greer, R.O. A comparison of the use of smokeless tobacco in rural and urban teenagers. Ca-A Cancer J. for Clinicians 34:248-261, September/October 1984. 105. Weathers (w) page 5. 106. Kozlowski, L.T. et al . Nicotine a prescribable drug available without a prescription. Lancet, Feb. 6, 1982 page 334. 107. Op. Cit. Health Consequences of Smoking page 215. 108. Gritz , E.R. et al . Plasma nicotine and cotinine concentrations in habitual smokeless tobacco users. Clini. Pharmacol. Ther. August 1981 Vol. 30, no 2 pages 201-209. 109. National Institutes on Drug Abuse, DHHS: Drug abuse and drug abuse research, the first in a series of triennial reports to Congress from the Secretary. Department of Health and Human Services, January 1984. 110. Henningfield (o) pages 34-37. 111. Pomerleau, O.F. and Pomerleau, C.S. Neuroregulators and the reinforcement of smoking: Towards a behavioral explanation. Neuroscience & Behav. Rev. , Vol. 8 pages 503-513, 1984. 112. Jasinski, D.R., Johnson, R.E. and Henningfield, J.E. Abuse liability assessment in human subjects. Trends in Pharmalogical Sciences. May 1984 vol. 5, no. 5 pages 196-200. 113 . Henningfield, J.E. Pharmalogical basis and treatment of cigarette smoking. J. Clin. Psychiatry 45:12(sec. 2) Dec. 1984 pages 24-39. 114. Op. cit. NIDA. Drug abuse and drug abuse research. 115. Henningfield (o) pages 36-38. 116. USDHHS/NIDA Why people smoke. U.S. Government Printing Office:1983 pages 399-722. 117. Henningfield (o) page 4. 118. American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders. Third edition Washington D.C. APA 1980 page 178. 119. Hughes (o) page 71. 120. Lawrence (o) page 73. 121. Foster (o) page 168. 122. Riccardo, M. (o) page 205. 123. Rowe (o) page 24. 124. Curtin (w) page 2. 125. Furst (o)-page 268. 126. Martin (w) page 2. 127. Powell (w) page 2. 128. Op. cit. American Psychiatric Association. 129. Martin (w) page 2. 130. Powell (w) page 2. 131. Glover (o) page 59. 132. National Cancer Institutes, Announcement Request for Application December 1, 1985. 133. Charren (o) page 98. 134. Dietz (o) page 175. 135. Amick (o) page 178. 136. Christen (w) page 3. 137. Kerrigan (o) pages 251-252. 138. Glover (o) page 6. 139. Marsee (o) page 63. 140. Hughes (o) page 71. 141. Lawrence (o) page 72. 142. Shubbuck (o) page 203. 143. Riccardi, M. (o) page 209 144. Riccardi, V. (o) page 203 145. Hughes (o) page 76. 146. Walsh (o) page 207. 147. Doherty (o) page 79. 148. Lonborg (o) page 101. APPENDIX C SUMMARY OF TESTIMONY NOTE: These summaries are extremely abbreviated and do not reflect the entirety of the various statements and written submissions received. Consequently, interested persons are advised to read the transcript of the hearing and the text of the written submissions for a complete and accurate understand- ing of the testimony. These documents are available at the office of the Department. * WINN, Deborah, Ph.D. Senior Staff Fellow Epidemiology and B i o s t a t i s t i c s Program National Cancer Institute v e r b a 1 / wr i 1 1 e n - 2. 6. 85 In certain regions of the country many oral cancer deaths are caused by smokeless tobacco. Oral cancer usually occurs at location in mouth where tobacco is held. Three case control studies link chewing tobacco habits with oral cancer. Four case control studies show an association for oral cancer and snuff use only. Winn study shows use of snuff increases risk to cancer fourfold, and for long-term users fiftyfold. Dose response relationship was found. In the study no other characteristic could eliminate snuff as a risk factor including alcohol, diet and ill-fitting dentures. Controlling for use of next of kin interviews did not affect the results. Smith study is inconclusive due to weak follow-up. Three cohort studies show two to threefold increase in risk to. oral cancer from snuff. HECHT, Stephen, Ph.D. Division Chief of Chemical Carcinogenesis American Health Foundation ve r ba 1 / wr i 1 1 en - 2.6.85 Snuff contains high levels of nitrosamines which induce cancer in animals. The types are termed NNN , NAT, NAB and NNK . Concentration of nitrosamines in snuff is 1,000 times greater than that in bacon. Average daily intake of nitrosamines from beer, meat and cosmetics, range from .2 to .7 micrograms. For a snuff dipper using 10 grams of snuff, the daily level of nitrosamine intake is 330 micrograms. This level has been shown to produce tumors in animals. NNK and HUM have been shown to produce cancer in the raouths of animals. ROUE, Nathaniel, D.D.S., II . S . D . Professor of Oral Pathology and Pathology Schools of Dentistry and Medicine University of Michigan verbal - 2.6.85 °?t .of 33 oral cancer cases reported to University of Michigan biopsy service, four were from smokeless tobacco users. Three used snuff and one "tobacco." Two of the four had no history of smoking or alcohol use . Two patients couldn't stop using tobacco following extensive mouth surgery. They are addicted. Use of smokeless tobacco increases risk to oral cancer. CHRISTEN, Arden G . , D.D.S. Chairman and Associate Professor Department of Preventive Dentistry Oral Health Research Institute Indiana University School of Dentistry verbal/written - 2.6.85 Gingival recession, periodontal breakdown and tooth loss can occur as a result of use of smokeless tobacco. Use of smokeless Tobacco can produce leukoplakia that has the potential to transform into cancer. Use of smokeless tobacco can cause tooth abrasion. HENNINGFIELD , Jack, Ph.D. Acting Chief, Human Performance Laboratory Addiction Research Center National Institute on Drug Abuse John Hopkins University School of Medicine verbal/written - 2.7.85 Nicotine is a prototypic drug of abuse that may lead to compulsive use equivalent to alcohol, cocaine and morphine use. A similar position on nicotine is held by the National Institute on Drug Abuse, World Health Organization and American Psychiatric Association. Common misconceptions about drug dependence exist that classify it is immoral, elicit behavior or that withdrawal is life threatening. The terms addiction, dependence and abuse are used somewhat interchangeably but all have a different focus. Nicotine is contained in all tobacro products. Nicotine is a potent pharno logica 1 agent that affects r.iood anc behaviour . According to animal and human studies, nicotine is psychoactive. It is an euphoriant and it is a biological reinforcer. In combination these three factors classify nicotine as a prototypic dependency produc ing drug . Smokeless tobacco delivers significant quantities of nicotine to the system of the user. Therefore, it has the potential to produce dependence. There is no technical or scientific difference between the terms addiction and dependency. They both mean compulsive use of a substance in the face of danger. GREENBERG, Allen, Esq. Staff Attorney Public Citizen Health Research Group verba 1/written - 2.6.85 Industry advertising fails to convey information that smokeless tobacco is harmful. Surgeon General's investigation is not needed for Federal Trade Commission or Massachusetts to require warning, labels. Sufficient evidence already exists. Surgeon General Koop has stated smokeless tobacco poses a cancer threat and the World Health Organization recently concluded that snuff is a human carcinogen. The conclusion of the Smith study is not meaningful because he failed to follow up drop outs. Warning label should be required. GLOVER, Elbert, Ph.D. Associate Professor Department of Community Health East Carolina University verbal/written - 2.6.85 Texas Public School Survey found nine percent of the students responding used smokeless tobacco. Many teenagers did not know dangers of use. An Oklahoma public school survey found a linear relationship between use of smokeless tobacco and age. Twenty-two percent of students in the 11th grade used snuff. National co 1 legiate survey found 12 percent of those surveyed used sraoke less tobacco. Use is up in the nation and many persons are not aware of the potential health problems. It is extremely hard to get users to stop once they are "hocked." Use should not be viewed as a passing fad. MARSEE, Betty Anne Parent Ada , Ok lahoma verbal - 2.6.85 Sean Marsee, son of testifier, used moist snuff from age 12 to 18. He developed oral cancer of the tongue near where the snuff was held and died from complications of the cancer in February of 1984. Sean Marsee felt smoking was dangerous and snuff use was not because cigarette packages had warning label on them and snuff packages didn't. Sean Marsee had no other habits which could result in oral cancer. Cancer developed because of snuff and supports warning labels. Warning labels should be required. SALMON, Thomas, M.S., M.P.H. Director Division of Drug Rehab i 1 ia t ion Massachusetts Department of Public Health verbal/written - 2.6.85 Massachusetts survey found 15 percent of Massachusetts high school students used smokeless tobacco during the past year; 6.2 percent used it several times or very often. Twenty-eight percent of the males surveyed used it during last year. Warning labels should be required. HUGHES , Paul High school student North Easton, MA verbal/written testimony - 2.6.85 Used chewing tobacco since eighth grade and snuff since sophomore year of high school. As a result of this, lost appetite and weight. Tried to stop many times but couldn't. In spring of last year used two cans of snuff per day and developed white lines in his mouth that would become sore. Many of his friends dip and are "addicted" to snuff. People don't realize the health problems. The product should be labeled. LAWRENCE, Alan High school student Taunton, MA verbal - 2.6.85 Started chewing tobacco at age 16 did not consider product harmful. Stated he is addicted and is unable to quit the habit. HUGHES, Ann Parent North Easton, MA verbal - 2.6.85 Educational information concerning smokeless tobacco is not available to parents. Her son, Paul Hughes, was unable to stop using snuff. Warning labels should be required. DOHERTY, Mark, D.M.D. Denta 1 Director Dorchester House Health Center verbal - 2.6.85 When he asked young athletes about snuff none were aware it was harmful. Students reported their only exposure to snuff was from peer pressure, emulation of pro-athletes and favorable TV advert isment . Labels should be required so young people can make responsible decisions whether to use snuff or not. MECKLENBURG, Robert, D.D.5., M.P.H. Chief Dental Office United States Public Health Service Office of the Surgeon General verbal/written - 2.6.85 Supports warning health labels. According to Dr. Mecklenburg industry says nothing should be done because there is as yet no ultimate proof and no direct cause Dr. Mecklenburg has seen cancer and periodontal disease anong smokeless tobacco users. Use of smokeless tobacco is very heavy anong American Indian children. Industry implies that use is safe alternative to soo king . The increase in use is attributable to heavy media advert is ing . I believe absolutely that adequate evidence of harm already exists. Stronger evidence is coming. Action should be taken now and advising the public of risk is our responsibility. Surgeon General's position is "Smokeless tobacco, including snuff does indeed pose a cancer threat." MYERS , Matthew L. Executive Director Coalition on Smoking or Health verbal/written - 2.6.85 Supports labeling by the Department of Public Health. The users of smokeless tobacco are at risk to be addicted to it. Use has increased substantially among youth in the nation. Use of snuff is directly linked to oral cancer. CORBIN, Stephen, D.D.S. M.P.H. Acting Chief of Dental Disease Prevention Activity Centers for Disease Control Testifying for J. Michael Lane, M.D. Director, Center for Preventive Services verbal/written - 2.6.85 Chronic use of smokeless tobacco is harmful including potentially causing oral cancer. Commends Massachusetts for taking action. CHARREN, Peggy Pres ident Action for Children's Television verbal/written - 2. 6. 85 Tobacco companies "know how to sell the public a bill of goods". Children watch 26 hours of TV each week; 80 percent of the time they watch adult TV programming. Tobacco companies know use of sports figures in short spots have impact on young people; it manipulates attitudes and values. ACT will petitioning the FTC and FCC to ban advertising of smokeless tobacco products. ACT strongly supports the labeling requirement. LONBORG, James, D.M.D. Private practice former professional baseball pitcher verbal - 2.6.85 Dr. Lonborg is concerned as a dentist and e x -p r o b a s e b a 1 1 player. The hazards associated with smokeless tobacco are not well-known to the consuming public. Dr. Lonborg has treated patients with dental problems caused by smokeless tobacco. Professional athletes would not appear in ads if they knew dangers. Warning labels should be required. DEVANEY, Thomas, D.D.S. Member, Council on Dental Health and Health Planning American Dental Society verbal/written - 2.6.85 "The correlation between oral cancer and long-term imokeless tobacco use is too strong to be ignored." There is damage to oral tissues in long-term snuff user 8 . ADA and Massachusetts Dental Society support warning labels. CONNOLLY, Gregory N., D.M.D. , M.P.H. Director, Division of Dental Health Massachusetts Department of Public Health ve r ba 1 / wr i t t en - 2.6.85 The Division of Dental Health is responsible for investigating smokeless tobacco. Enters scientific studies into the record. Twenty-six studies fron 1915 to present indicate 1,206 cases of oral cancer in long-teria snuff users with a 40-50 percent mortality rate. Scientific evidence clearly shows need for warning labels to read "Warning. Use of Snuff is Addictive, May Cause Mouth Cancer and Other Dental Problems." GUPTA , Prakash C . , D . S . Talcemi Research Fellow School of Public Health Harvard University ve r ba 1 / wr i 1 1 e n - 2.7.85 Oral cancer is the most common form of cancer in India and tobacco chewing is principle cause. Oral cancer is often preceded by white lesions and a very high correlation has been found between tobacco chewing, white lesions and oral cancer. There is sufficient evidence that smokeless tobacco used in the United States is carcinogenic and is causally related to oral cancer. LIJINSKY, William, Ph.D. Litton Bionetics Under contract to National Cancer Institute Chief Laboratory of Chemical and. Physical Ca r c ino g en i s i s ve r ba 1 / wr i t t en - 2.7.85 N-nitrosamines are present in high levels of snuff and have produced cancer in the mouth and other body parts o f anioa Is. An animal study in progress has produced cancer in the mouth at 1 ppm, a NNN level equivalent to that in snuff. It would be unrealistic to assume man is the only species not affected and exposure to snuff does increase risk to cancer. GUINTA, John, D.M.D., M.S. Professor of Oral Pathology Tufts University, School of Dental Medicine verbal/written - 2.7.85 Oral effects of smokeless tobacco include discolored teeth, bad breath, tooth abrasion, decay, decreased sensory perception, gum disease and leukoplakia. Smokeless tobacco produces leukoplakia, a clinical term. Upon biopsy, leukoplakia can be a simple callous, epithelea dysplasia or cancer. TSAMPROURIS , Anthi, D.M.D., M.S. Associate Professor Tufts University School of Dental Medicine Representing Massachusetts Academy of Pediatric Dentistry and Massachusetts Society of Dentistry for Children verbal/written - 2.7.85 Scientific evidence has documented that smokeless tobacco causes cancer. Condemns use of smokeless tobacco. MEHTA, Nashir, D.M.D. Associate Professor Department of P e r i o d o n t o 1 o g y Tufts University School of Dental Medicine ve r b a 1 / wr i 1 1 en - 2.7.85 Long term use of smokeless tobacco is directly linked to oral leukoplakia, gingival recession and gum disease. Three to six percent of oral leukoplakias become cancerous. KELLY, John, D.M.D. , M.D. Assistant Professor of Oral and Maxillofacial Surgery Harvard University School of Medicine Oral and Maxillofacial Department Massachusetts General Hospital verbal- 2.7.85 Surgical treatment of oral cancer results in significant disfigurement and disability. Cost of hospital and surgical care of oral cancer case $20,000 to $25,000. SHAFFER, Howard, Ph.D. Assistant Professor of Psychology Department of Psychology Harvard University School of Medicine Cambridge Hospital North Charles Institute for the Addiction verbal - 2.7.85 Supports warning label, recommends that word addictive be changed to chemical dependence and feels that warning labels will have limited impact. Nicotine produces chemical dependence, withdrawal syndrome and behavioral craving. Addiction and dependence are not synonymous and should not be interchanged. PALLADINO, George, Lt. Col., Ph.D. Professor of Chemistry United States Military Academy verbal/written - 2.7.85 Nicotine in smokeless tobacco is addictive. Nitrosaoines in snuff have been shown to cause cancer. Supports health warning label of snuff. FOSTER, Ken Con s ume r verbal - 2.7.85 Used snuff for more than 20 years. It was recommended as safe alternative to smoking. Did not know snuff could cause cancer. Tried to quit but couldn't. Supports warning label. BERNAYS, Edward L. Public Relations Counsel Cambridge , MA verba 1 - 2.7.85 Tobacco taken by mouth should be labeled. DIETZ, William H., Jr., M.D., Ph.D. Pediatrician Tufts University School of Medicine Member, American Academy of Pediatrics Task Force on Children's Television verbal/written - 2.7.85 . Ads for smokeless tobacco promote it at an alternative to smoking. Use of professional athletes in ads are directed to receptive adolescents. Supports warning labels. AMI CK , Carol C, M.P.A. Senator, Massachusetts State Senate Former newspaper editor verbal/written 2.7.85 Ads for snuff aimed at adolescent males. They use subliminal messages to seduce youth and use sports figures in ad ve r t i smen t s . 11 Supports warning labels. 33 . BOYD , Gay le , Ph.D. Division of Cancer Prevention and Control National Cancer Institute verbal/written - 2.7.85 The National Cancer Advisory Board has concluded there is sufficient scientific evidence for a cause and effect relationship between snuff and cancer. Smokeless tobacco contains sufficient nicotine to be addict ive . Public awareness of the health effects of snuff is limited . Recommends health warning labels. 34. ALLUKI AN , Myron, D.D.S., H.P.H. Assistant Deputy Commissioner Director, Bureau of Community Dental Programs Department of Health and Hospitals City of Bo 8 t on. ' ' verbal - 2.7.85 Smokeless tobacco may act as a chronic irritant. State -has the responsibility to inform adults and children of potential harm from smokeless tobacco. 35. BERTONAZZI, Louis R. Senator, Massachusetts State Senate Vice Chairman, Joint Committee on Health Care verbal/written - 2.7.85 Evidence is overwhelming showing nicotine addictive. Evidence is targeted to youth. Snuff advertising is targeted to youth. Strongly recommend health warning labels. 36. DAYNARD, Richard, Esq. Professor Northeastern University School of Law President GASP (Group Against Smoking Pollution) of Massachusetts Co-Chairman, Tobacco Products Liability Project verbal/written - 2.7.85 Tobacco Liability Project supports suits against tobacco industry for health problems associated with tobacco use . SMITH, Robert, D.M.D. President, Massachusetts Society of Oral ilaxio 1 1 f a c ia 1 Surgeons verbal/written - 2. 7. 85 Use of snuff is directly linked to prenalignant lesions of the oral cavity, oral cancer and periodontal disease. Supports health warning labels. MODICA, Diane Commissioner, Mayor's Office of Consumer Affairs and Licensing Boston verbal/written - 2.7.85 Snuff is gaining popularity among young people and no information about health risks is available to them. Supports health warning labels. SCHNIPPER, Lowell, M.D. Beth Israel Hospital President-Elect American Cancer Society, Massachusetts Division verbal/written - 2.7.85 Use of smokeless tobaccj causes oral leukoplakia and three to five percent of these become cancerous. Risk of oral cancer is far greater among snuff users than no n - users . Young people habituated to nicotine from smokeless tobacco may switch to cigarettes later in life. Supports warning label. S WED A , Edward, Esq. Legislative Secretary, GASP verbal/written - 2.7.85 Smokeless tobacco serves as a gateway to smoking. Snuff advertising hides the fact the product is harmful. Supports warning label. RICCARDI, Vincent Coordinator of Health Education Brockton High School verbal/written - 2.7.85 Many of the high s tobacco but are not Supports educationa chool students in knowledgeable of 1 program to curb sports use smokeless dangers. use of snuff. SCHUBBUCil, Ralph Student, Brockton High School verbal/ written - 2. 7. 85 Had no knowledge of health problems associated with snuff when he started using it. After using it, he developed sores in his mouth. Started to use snuff because others on sport team did, and athletes used it on television. He found it hard to stop using snuff. RICCARDI, Hark Student, Brockton High School verbal - 2.7.85 Used smokeless tobacco for two years and tried to quit but had trouble because it is addictive. Athletes at Brockton High School would never consider smoking. Teachers and students alike were unaware of snuff's potential hazards. WALSH, Joan, R.D.H. Infirmary, Phillips Academy A n d o v e r , MA verbal - 2.7.85, written - 2.12.85 Students use smokeless tobacco at Phillips Andover but don't know the health effects or dangers. Supports warning label. There is a growing trend among teenagers to use snuff nat iona 1 ly . LANIDES, Maria Concerned Citizen Albany, New York verbal - 2.7.85 There is heavy use of snuff by students in New York, because of heavy advertising. Supports warning label. JOHNSON, Elizabeth Director, Environmental Program American Lung Association of Massachusetts ve r ba 1 / wr i t t en - 2.7.85 Massachusetts students have reported switching fron cigarettes to snokeless tobacco because they think it is safe. Supports warning label. SILVESTRI, Ronald, I! . D . Pulmonary Physician New England Deaconess Hospital Member, Massachusetts Thoracic Society verbal - 2.7.85 Concerned over high addictive potential to nicotine from smokeless tobacco. Supports warning label. CARLSON , Craig D . , Representing Massachusetts Dental Hygienists1 Association, Inc. ve r ba 1 / wr i 1 1 en - 2.7.85 Supports proposed regulation. Recommends ban on television advertising. Recommends listing ingredients of smokeless tobacco (nitrosamines, cyanide, nicotine, insect residues) on package. ROSEN, Robert, M.D. Phy s ic ian Rhode I s land verbal - 2.7.85 Use of smokeless tobacco will increase risk of oral cancer . DUANE , Barney Director of Public Relations American Heart Association, Massachusetts Affiliate Representing W. John Powell, M.D. President, American Heart Association, Massachusetts Affiliate verbal/written - 2.7.85 Ingestion of tobacco affects blood press are, heart rate and blood clotting, thus increasing risk of heart attacks. Cancer, gum disease and tooth loss are linked to smokeless tobacco use. Support health warning labels. uOTElchuc:: , ;:iiton, Ph.D. , ;:.?.;:. President, iiassachusetts Public Health verbal/ written - 2.7.G5 Association Use of smokeless tobacco is a threat to health. Nicotine is an addictive drug. Supports warning label. PIERSOH, Benjanin, Jr. President Byfield Snuff Company B y f i e 1 d , HA verbal/written - 2.7.85 Opposes regulations. It is econonically not feasible for a snail business to compete with larger manufacturers if a label is required . If a label is required, it should be done at federal level. CURTIN, John, Esq. Partner Bingham, Dana and Gould (law firm) Representing Smokeless Tobacco Council, Inc. verbal - 2.7.85, written - 2.22.85 The Smokeless Tobacco Industry was not given sufficient time to prepare for the hearing and was not consulted prior to the Department of Public Health's decision to proceed with warning label. Snuff is not addictive and has not been scientifically established to cause disease. The Federal government is considering the smokeless tobacco issue and Massachusetts should defer to the federal government. Massachusetts' Hazardous Substance Labeling Act is based on the federal law and federal law does not encompass tobacco. Therefore, the Commissioner of Public Health does not have the authority over smokeless tobacco. A warning label requirement in Massachusetts would impose an undue burden on interstate commerce and be in conflict with United States Constitution. UERRIGAI1, tlichael J. President, Suokeless Tobacco Council, Inc. Washington, D.C. verbal/uritten - 2.7.35 Smokeless Tobacco Council opposes warning labels. Use of snuff has declined over the last 50 years and seven million Americans use it today. Ma s s a c hu s e t t s use is one-fourth of one percent of the total United States usage . Smokeless tobacco has not been proven scientifically to cause any health problem. The issue is best left at the federal level where there are proper checks and balances. Animal studies have not found smokeless tobacco to cause cancer . Snuff use may become a settled practice, but it is not addictive. The industry has set up the Smokeless Tobacco Research Council to conduct research on health effects. Smokeless tobacco advertising is not aimed at youth. The target audience for advertising is males 18-49. The Smokeless Tobacco Council supports sales restrictions to those under 18. If smokeless tobacco is required to carry a health warning label, eggs and red meat should also be required to do so . ROMARY, Paul Legislative Aide Representing Representative John McNeil Co-Chairman, Joint Committee on Health Care verbal/written - 2.7.85 Rep. McNeil applauds the Department of Public Health for bringing the issue to the public's attention. There is enough scientific evidence available to recognize the potential risk of smokeless tobacco. In Winthrop, Massachusetts the superintendent of schools adopted a smokeless tobacco ban because of the high use by students in school. In Maiden the use is low. 17 55. FUT.ST, Arthur, Ph.D., Sc.D. Distinguished University Professor Director C Ei.i e r i t u s ) Institute of Chemical Biology University of San Francisco President Anerican College of Toxicology Snoke less tobacco cannot be classified as addictive. Tolerance of a certain level of a substance is produced in an addicted persons and more of that substance is needed. This is not true for smokeless tobacco. Epidenio logica 1 or statistical studies do not demonstrate causal relationships. They provide hypothesis which researchers can explore through experimental or clinical studies. Leukoplakia is a clinical tern. Three studies have found no significant cellular changes among the "leukoplakia" of snuff dippers. It is not a premalignant condition. Smokeless tobacco has not been shown to cause leukoplakia. Other factors such as nutrition and poor oral hygiene play an important role in oral leukoplakia. The Winn study failed to control for "ill fitting dental appliances," poor nutrition or socioeconomic status. He questions the validity of this study's findings. Animal studies have not produced oral cancer following exposure to snuff except in the Hirsch study. However, only one animal out of 52 exposed to snuff produced a tumor, and the animal used was susceptible to tumors. Hirsch concedes that the tumor may have developed spontaneous ly . A few N-nitroso compounds have been found in snuff but none have induced oral cancer in test animals. Indian studies report oral cancer caused by "quids" that contain tobacco, betel nuts and leaves and lime. It is scientifically unsound to single out tobacco since the same lesions are found in those who don't chew. The term premalignant is a misnomer. The Smith study found no oral cancer among 1,550 users followed for ten years. The Axell study found no oral cancer among 114 users with leukoplakia. Based on scientific studies, it is not possible to conclude smokeless tobacco use causes oral cancer. Scientists do not know how a normal cell becomes ma 1 ignant . He cannot make the association that cigarette smoking causes cancer . POVELL , David J . , Ph.D. President Education and Training Pro^raiis , Inc. Hart ford , CT verbal - 2.7.85 Dependency (addiction) neans loss of control over intake of a substance consuned and the inpairoent of one's social and occupational functioning. Smokeless tobacco does not meet the criteria for addiction or dependency. It does not meet the criteria of the American Psychiatric Association or World Health Organization. Use of the word addictive in relation to smokeless tobacco uay mislead youth to believe that truly addictive substances are harmless. Cigarette smoking does not produce dependency. GIFTOS, Peter Vice Pre s iden t National Association of Tobacco Distributors Past President Ha s s a c hu s e t t s Candy and Tobacco Distributors Association verba 1/written - 2.7.85 Groups wishing to testify in opposition to the proposed regulations weren't given sufficient time to prepare for hearing . State by state labeling approach places an unnecessary burden on distributors. He supports a national approach. Manufacturers probably won't bother putting labels on and the distributors will have to instead and will have to bear the cost of this. He questions the ability to enforce this regulation. GRE EN BERG , Allen, Esq. Staff Attorney Public Citizen Health Research Group written 2.19.85 Challenges Dr. Furst's claim that smokeless tobacco does not cause cancer. A causal relationship exists if there is consistency, strength and specificity of the association, and biologic plausibility. Smokeless tobacco fits the criteria. World ileal cancer was Many of Dr. th Or^aniza based solely Furst's Eta tion's find on epidet.ii tements are in^ that ar ological ev □ is leading senic causes i d e n c e . or wr o n g . CARLSON, Robert H., 11 . D . Emergency Care Clinic Birmingham, AL written - 2.20.85 Have not seen significant problems with users of smokeless tobacco. Cigarette smoking and alcohol have been shown to produce significant health problems. Smokeless tobacco has not. Does not support label. HECHT, Stephen, Ph.D. American Health Foundation written - 2.19.85 Dr. Furst contradicted himself on cancer causation. GUINTA , John, D.M.D., M.S. Tufts University School of Dental Medicine written - 2.19.85 Dr. Furst's statements on leukoplakia came from outdated text books. New versions of Shaffer text states the use of tobacco causes leukoplakia. Leukoplakia on biopsy shows histologic changes. Dr. Furst's statements on Axell study misleading. Axell reported all bioposies of leukoplakia showed histologic change s . Dr. Furst does not understand the term "pr ema 1 ignan t . " Epithelial dysplasia (cervical intraepithia 1 neoplasia) is recognized as a precursor to invasive cervical cancer . GUPTA , Prakash C, D.Sc. Takemi Research Fellow Harvard University School of Public Health written - 2.21.85 Rejects Dr. Furst's statement that "epidemiologic or statistical studies ... do not demonstrate causal relations." Cause-and-ef f ect relationships among humans can only be ascertained through epidemiologic reasoning and epidemiologic studies. Animal studies can be supportive of epidemiologic evidence. "ejects Dr. Furst's state ucnt that tobacco does not produce leukoplakia. Tobacco use causes oral leukoplakia and risk of oral cancer much greater auong persons with leukoplakia. Rejects Dr. Furst's statement "that the tern preaalignaat is a misnomer." Uorld Health Organization has defined "precancer as the part of the tissue in which oral cancer is more likely to occur than its normal counterpart." Dr. Furst has misinterpreted results of the six studies he presented. Dr. Gupta personally knows all the authors except two and states they would be surprised by Dr. Furst's interpretation that smokeless tobacco does not cause leukoplakia and increase risk to oral cancer. Rejects Dr. Furst's statement that nutrition and dental hygiene play a role in development of leukoplakia. Rejects Dr. leukop lakia to cont ro 1 ingred ient s be the agent Furst's statement the Indian studies showing and oral cancer among tobacco chewers failed for non-tobacco ingredients. These were controlled for and tobacco was found to STRAUSS , Peter Secretary Rational Association of Tobacco Distributors written 2.19.85 Does not support label. Urges Massachusetts to let federal government deal with labeling. DUFFY, George P. President Massachusetts Candy and Tobacco Distributors, Inc. written 2.22.85 Asks that a hearing be held on economic snd social effects of labeling before regulations are issued. Concerned with criminal sanctions of the lav. CURTIN, John J., Jr., Esq. Dana, Bingham and Gould written - 2.22.85 Hearings did not prove snuff is sddictive nor that it has been scient if ics 1 ly proven to cause human disease. Proposed label is unfair and inaccurate 21 Couuissioner lacks statutory authority to require suc'.i label ins . Regulations are constitutionally defective since federal governuent regulates tobacco. Regulations are invalid because they impose unreasonable and excessive burden on interstate conmerce. 66. BROTMAN , Richard, Ph.D. Professor of Psychiatry New York Medical College written - 2.22.85 Addiction is not a medical term, but a misused popular term. Using the term "addiction" may have a boomerang effect that will attract people particularly, youngsters to use i t . If a label is required, use technical health terms not an alarming one like "addictive." 67. GRASSO, Paul, M.D. Professor of Experimental Pathology Rubens Institute, University of Surrey written 2.22.85 Reviewed animal studies on nitrosamine compounds, found in snuff -NNN, NNK, NAB, NNA and NAT. NNN and NNK are moderately active carcinogens that produce esophageal, lung and other tumors in the body of animals. They have not been shown to produce tumors in the oral cavity, and because of their metabolism are site specific, not contact carcinogens. NAB and NNA are very weak carcinogens and likely to be organ specific, not site specific, and NAT is inactive. No experimental evidence is available to show that nitrosamines in snuff are oral carcinogens, and no direct human evidence shows that nitrosamines cause cancer in humans. 68. JENNINGS , B. R . , Ph.D. Associate Professor of Pathology Director Clinical (Immunology) The Regional Medical Center of Memphis University of Tennessee Medical Center written - 2.22.85 Deficiencies in susceptibility to have been shown the immune system may influence tumors. Tumors of the head and neck to be associated with cellular 22 deficiencies. Ocher factors influence iunune response such as heredity, age, sex, race, alcohol use and pappillona virus . No studies exist associating smokeless tobacco use and oral cancer that have taken into account all risk factors. Therefore, the proposed label is not scientifically warranted. KUPPER, Lawrence L. Professor of D i o s t a t i s t i c s University of North Carolina School of Public Health written - 2.22.85 Reviewed basic principles of epidemiology, case history, case control and follow-up studies done in the United States and Europe on smokeless tobacco including Winn, Smith and Axe 1 1 . Smith study shows no association but it is hard to interpret because of many drop outs and short study period. Axell study does not provide relevant evidence to United States because it is based on short period of time and takes place in another culture. Winn study has three weaknesses. Quality of data is weakened by use of proxy respondents for deceased cases. Statistical methods used are not state of the art today. Recommends reanalysis using conditional logistic regression. Interpretation can only be applied to study group, (i.e., rural white Southern women.) Concludes use of snuff is a risk factor for oral cancer for rural white Southern women only. More research is needed before it can be established as a risk factor for general United States population. LA VIA, Mariano P., M.D. Professor of Laboratory Medicine Director, Division of Diagnostic Immunology University of South Carolina Medical School written 2.22.85 The causes of oral cancer as well as mechanisms for its occurrence are unknown. Immune system plays an important role in pathogenesis and evolution of cancerous lesions, and patients with a malfunctioning system develop cancer more frequently. Dr. LaVia's studies have found vi.tar.iin A in balances in patients v/ith lynphocyte changes and oral lesions. His studies have shov/n no correlation between smokeless tobacco use and oral lesions. There cay be some statistical relationship between smokeless tobacco and oral cancer, but more experimental studies are needed before conclusions can be made. MARTIN, Joseph C. Reverend President Ashley Treatment Center written 2.22.S5 Alcohol addiction is the compulsive use of a sedative drug that results in serious life problems, and cannot be stopped unaided. Physical and mental dependence result from this use. Smokeless tobacco use doesn't fit the criteria for addiction. The word addiction should be reserved for alcohol, heroin or cocaine. Warning label using the word addiction is unwarranted and provides no useful purpose. MINCER, Harry H . , D.D.S., M.S., Ph.D. Prof essor of Oral Pathology University of Tennessee written 2.22.85 Scientific studies have not established that the use of snuff will produce serious changes in oral tissues including oral cancer. Leukoplakia is a clinical term that shows on biopsy four conditions, hyperplasia (chickening of the tissue), atrophy (thinning of the deeper layers), dysplasia and cancer. Dr. Mincer's studies on persons who smoke, use snuff, chew tobacco or use no tobacco found no relationship between leukoplakia and histological conditions. Leukoplakia does not progress in orderly fashion to dysplasia or oral cancer. Dysplasia may transform into cancer, but at a low rate (10 percent). The Smith study does not support a statistical association between use of snuff and oral cancer. • * . **' Other factors such* as heredity, deficiencies with immune system, diet, alcohol , viruses and yeast nay play a greater role in formation of oral cancer than tobacco. There may be a statistical association between snuff use and oral cancer, but the cause is unknown. POWELL, David J., Ph.D. President > Education and Training Programs , Inc. written - 2.22.85 Does not support use of term addictive, it is not accurate. Dependence (addiction) means loss of control over intake of a substance quantity consumed and impairment of one's social and occupational functioning. Smokeless tobacco does not meet criteria for addiction or dependence. It does not meet criteria of the American Psychiatric Association or World Health Organ i za t ion . Use of the word addictive in connection with smokeless tobacco raises major concerns for children reading the labe 1 . WEATHERS, Dwight R . , D.D.S., M.S.D. Cha irman Department of Oral Pathology Emory University School of Dentistry written - 2.22.85 Oral cancer is a multifactoral disease, the cause of which is unknown. There appears to be an association between smokeless tobacco and leukoplakia. Leukoplakia is a clinical term and is not a predictor of cancer. Dr. Weathers' study on 500 schoolchildren found that smokeless tobacco did not change the level of gum disease or tooth decay if the children had clean mouths.