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IF

1

COPY NO .

TOBACCO AND HEALTH-R&D APPROfiC~~

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Presentation to R & D Committee

by Dr. H. Wakeham

at meeting held in New York Of fi ce

on

November 1'5y 101

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t I

a

Partial List of Compounds in Cigarette Smoke

also Identified as Carcinogens . . . . . . . . . . . . 9Cancer Promoting Agents in Cigarette Smoke . . . . . . . 1 0

Phenols 'ui Cigarette Smoke . . . . . . . . . . . . . . . . . 11 !

Anti-Carcinogens . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 2

I I I . Sznoking and Cardiovasc ular Diseases . . . . . . . . . . . . . . . . . 13

IV . R & D Program Lead ing to a Medically Acce ptable-

TOBACCO AND HEALTH - R & D APPROACHPaae

_Chemistry of Cigarette Smoke . . . . . . . . . . . . . . . . . . . . . . . . . 1

Composition of Mainstream Smoke . . . . . . . . . . . . . . . . : 2

Major Constituents of Mainstream

Particulate Phase . . . . . . . . . . . . . . . . . . . . . . . . 3

Flavor and Irritation Studies . . . . . . . . . . . . . . . . . . . . . . . 4

The Cancer Controversy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5

Evidence Linking Cancer and Tobacco . . . . . . . . . . . . . . 6

The Problem of Carcinogen Identification . . . . . . . . . . . 7

Relative Potency of Carcinogens to the Skin

of Mice ; Comparison of Different Systems

of Grading . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8

C i g a r e t t e . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 4

Reduction of Irritating Factors in Smoke . . . . . . . . . . . 1 5

Controlled Nicotine in Filler and Smoke . . . . . . . . . . . . 1 6

Reduction of Carcinogens in Smoke . . . . . . . . . . . : . . . 1 7

The Production of Polycyclic Hydrocarbons

frorn Tobacco vs . Cigarette Paper . . . . . . . . 18

Polycyclic Hydrocar bons from Tobacco

Constituents . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19

Some Possible Ways to Reduce Carcinog ens

in Tobacco Srnoke . . . . . . . . . . . . . . . . . . . . . . . 20

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o more than 4Q0 compound,g of which about 50 have been~I d e n t i f i e d f o r t h e f i r a t t t n , a r , y + t i e r x .,,- . . _ri1111P morris Kesearch Cen!ter .

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: THE CANCER CONTROVERSY

. TUMOR

Some Definitions

a malignant growth arising from

epithelial tissue (sk in, gastric or

intestinal mucosa, lungs, etc . )

a malignant growth arising from

connective or muscle tissues (musc les,

lymph, etc . )

d b l o o d v e s s e l s , c a r t i l a g e , b o n e , _ : . '

a substance which applied to the tissue

of a test animal gives rise to tu mor _

formation . I n t e s t s f o r c a r c i n o g e n s I t

is assumed that tumors u ltimately lead -

to cancerou s growths and that a_

carcinogen so demonstrated in test

animals is dangerous to man .

P R O M O T ER - a substanc e which by itself does not

show carcinogenic ac tivity but which

applied before or c oncurrently with a

., c arcinogen enhances the effect of the

. l a t t e r .

activity of a carc inogen in a test animal .

ANTICARCINOGEN- a sub stanc e which Inhib its the norm al -

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S t a t i s t i c a 1 e v i d e n c e t h a t c e r t a i n d i s e a s e s a r e m o r e

prevalent among smokers than non-smokers .

P h y s i o 1 o g i c a 1 t e s t s i n w h i c h a n i m a l s t r e a t e d w i t h

smoke condensates, extracts, or compounds therefrom,

suffer from increased tumor frequency . Most tests ' .

involve skin painting or injections on special strains of

, m i c e . Smoke inhalation experiments . h a v e f a i l e d

produce lung cancer. , _ . . . . .

CO 1

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: THE PROBLEM OF CARCiNOGEN IDENTIFTCATION

Green ste in, Bioche mistry of Cancer - "The carc inog enic. J . P .

Many fac tors ne ed to be considered in studying carcinogenesis .

~

(a) The dosage, t he nature of th e vehicle, the mode and

alone but is a function of the following factor s :

potency of an agent does not reside in the nature o f the agent

length of t ime of administrat ion of the ag ent ;

(c) The site of application, the presenc e of c oncomitant ; = :

test animals ;

(b) The strain, the species, the sex, and the age of the

factors s uch as the level of essential dietary c onstituents

and the number of andmals kept in a caqe . "

2. One in five of all ran domly per form ed chro nic toxicity tes ts

reveals the presence of a carcinogen .

Hartw ell, Survey o f Compounds Which Have Been Tested for

Ca .rc inoa enic Activity, U . S. Public Health Service - About

one-ha li 8 of the new ca rcinogens belongs t o five cheinical

classes as follows :

C 1 , _ a s s : New Compounds CarcinogensAlipha tic Carba mat es

Tricyclic Aminofluo ren es 1 4

Tetracy clic Cyclopent enophe nanthr enes 1 4

Azo compoun ds 88

Hete roc yclic Benzacridine 22 .

CpNFI' O Ej q - n AL

1 5 '

1 2

6

- 3 6

1 4

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.

Araenic .

Beni. o ( a ) p y r e n e + + + +

Benzo(e)py rene +

Beazo(c)py rene + :

Henz(o) anthraceBe

; : 8enzo{YK luoranthene +

Benzo(b)f luorsnthene ++

: :Benzene

p-Benzoquinone `

n-Butyric acid

: - B e n z o ( q , h , i ) p e r y l e n e + -

Chryscne

C h r om i um

Cobalt.

5 , 8 - C y c l o p e n t e n o -

1 , 2 - b e n z a n t h r a c e n e

8 , 7 - C y c l o p e n t e n o -

t . 1 , 2 - b e n z a n t h r a ce n e

D i b e n z ( a , h ) a n t h r a c e n e + + t

,

l'

PARTIAL LIST OF COMPOUNDS IN QGARETTE SMO$E_ AL3'J IDENTIFIED AS C ARCINOGENS

~ . .. - . . . '~

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rFb . ' 1 1 0 1 5O L i Q u i d p m r s l f l n l y C i r o c a r b o o s

Orqanic acid sters

Fats

: O~e a t e s_. ' ~hagMY y . _ . 1 A. ~_

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R & D PROGRAM LEADING TO A

c h e m i s t r y , f l a v o r a n d I r r i t a t i o n s t u d i e s , a n d s e l e c t i v e

T h i s i n v o l v e s e x t e n s i o n o f c u r r e n t w o r k i n t o b a c c o

g a s p h a s e f i l t r a t i o n . Cost questimat . e : $ 3 , 0 0 0 , 0 0 0 . . :

MEDICALLY ACCEPTABLE CIGARETTEPresent knowledge and current r esearch indicate three main

approaches :

I . : R e d u c t i o n o f I r r i i a i i n q 7 a c t o r s i n S m o k e .

C o n t r o l l e d N i c o t i n e i n F i l l e r a n d S m o k e .

s m a l l p i l o t p l a n t a t a y e ) : $ 1 , 0 0 0 , 0 0 0 .

f i n i s h e d i n 1 8 - 2 4 m o n t h s . Cost questimate (to

This program is pe. r t i a l l y c o m p l e t e a n d c o u l d b e

Reduction of the General Level of Carcinogenic 3ubstances

in Smoke (bui without Complete Elimination of More than a

Few Specific Co mpounds . )

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*

PEDrUC'I"!ON OF IRFUTA'~'IN4 FAC'T'4RS IN SMOKS~~r~~~A. This approach ia bssed on the hypotbeaia that

p h y a i o l o q i c a l i r r , i t a t i o n s a r e a g r a t s t e p I n t h e

. i n i t i a t i o n o f m o r e s e r i o u s a i l m e n t a .

:L Development of objecti ve teat for irritatiou .

_ 2 . I d e n t i f i c a t i o n o f i r r i t a z i n q c o n a t i t u e a t a . . : ' . ~

. 9 . Selective elimiaation of frritanta from smoke .

a . B y a e l e c t i v e f i l t r s t i o n o f q z s p h a a e .

.b . By modificP. t i o n o f c i g a r e t t e c h e m i s t r y

throuqh;

( 1 ) Ad d i t i v e s t o c o n t r o l p y r o l y s i a r e a c t i o n s

: (2) Selection of fillor blends ~.

: . . . . . _ . - _ _. ., _ . _ - . . _ : . .C. This program Is closely related to flavor' improvement; ` a a d i n c r e a s e d c o n s u m e r a c c E i ~ t a b i l i t y ; h en c e I t h as a

d o u b l e a . d v s nt a q e t o p r o d u c t t - t i a , n c e m e n t .

f

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~_NTR4LIED NICOT'II1E IN FILLER AND SMOKE

burley or brights

d e s i q n a s m a l l p i l o t p l s n t , a p p l i c a b l e t o e i t h e r

( r . ) . T o p r o v i d e e n g i n e e r i n g p r o c e s s d a t a u a e f u l

f o r u p s c c l i n q i f d e s i r e d . . .

( b ) T o s e r v e a s a s t a n d b y u n i t s u i t a b l e f o r p r o - _ ~ :

d u c t i o n o f a m i n o r b r a n d w h i c h c o u l d b e

-introduced in response to public demand .

u s e o f l o w - n i c o t i n e t o b a . c c o s w i l l a l s o b e c o n s i d e r e d .

t

a c c e p t a b i l i t y , a r e d u c t i o n i n l e v e l m a y b e d e s i r a b l e

. , E v e n t h o u q h n i c o t i n e I s b e l i e v e d e s s e n t i a l t o c i g a r e t t e

for medical reasons .

Pr o b l e m a :

tobacco :

. -. -- . . . . , _ . . - - . . .T w o p r o c e a s e s a v a i l a b l e f o r f l a v o r h t l , l o w n i c o t i n e

How much nicotine reduction will be acceptable

.low nicotine product of maximum consumer

I s i t b e t t e r t o e x t r a c t b u r l e y , b r i g h t , o r b o t h f o r

'to the smok er?

W h a t t a s t e d i f f e r e n c e w i l l b e t o l e r a t e d ?

a c c e p t a b i l i t y ?

Consumer tests are under w ay to answer these questions .

8 . The MLK extrac tion pr ocess -it is pla nned to '

I . Th2 Rosentha l process- -now bein g negotiated .

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REDUCTION OF CA.RCINOGENS IN SMOKE

. T o a c h i e v e t h i s o b j e c t i v e w i l l r e q u i r e a m a j o r

r e s e a r c h e f f o r t , b e c a u s e

. C a r c i n o q e n s a r e f o u n d i n p r a c t i c a l l y e v e r y

class of compounds in smoke .

T h i s f a c t p r o h i b i t s c o m p l e t e s o l u t i o n o f t h e

problem by eliminating one or tw o classes

of compounds .

T h e b e s t w e c a n h o p e f o r I s t o r e d u c e a

p a r t i c u l a r l y b a d c l a s s , i . e . , t h e p o l y n u c l e a r -

hy drocarbons, or phenols. -Pr esent technology does not permit selective

filtrat ion of part iculate smoke . . ,Flavor substances and carcinoqenic substances

come from th e same classes, in many inst ances.

i n t o b a c c o . -Many pYi'olycls products have multiple precuraors

CONFiDENT1AL

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PRADUCTION OF POLYCYCLIC HYDROCARBONS FROM TOBACCO

i n c i g a r e t t e a m o k e .

CONFIDEN-TIM-

AMOUNTFROM TOBACCO

VLlues are Srluq CiqareLiea

2 0 . 5 *

48 . 0

5 5 . 0

4 .0

0. 5

C OIdCLUSION : Tobacco is the main source of polynuclear hydrocarbona

VS. CIGARETTE PAPER

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POLYCYCLIC HYDROCARBONS CONiE FROMMANY TOBACCO~ CONSTITUENTS

L 2-Benzanthracene

1 :2-Benzpyrene

' 3 :4-Benzpyrene

Cellulose LS in Pectin,

9 . 0 3 . 5 1 0 . 7

1 6 0 8 0 20

584 8000 2 8 7

337 5 4 4 539

2 1 9 33 133

1 6 4 5 8 1 5 2

1 3 1 - 29

. 1 8 6 4 4 2 7 3

65 22 34 `

7 8 47 4 5

4 . 0 1 1 . 0

56 2 7

32 7

1 0 4 3 6 _

35 66

94 4 5

1 1 1

. 1 1 6 . 4 3

4 1 1

1 7 29

CONCLUSION: Removal of any single precursor will not eliminatepolycyclic hydrocarbons from smoke .

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SOME PO3SIBLE WAYS TO REDUCECARCINOGENB IN TOBACCO SMOKEDiscover ma jor precursors for carcinogens

aWor cancer promoters .

Discover mechsnism or conditions by which

aarcinoqens are produced and modify those

c o n d i t i o n s. - . , . .8 e l e c t e x p e ri m e n t a I t o h a . c c o s w h i c h p r o d u c e a .

minimum of carcinoqens .

. Add enticarcfnoqens .

D i s c o v e r d i f f e r e n c e s i n p a r t i c u l a t e f r a c t i o n s

w h i c h w i l l p e r m i t s e p a r a t i o n o f c a r c i n o q e n s '

i n s m o ke :.

GD ~F1D ~~~t~L

.

. 2 0

'S,

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