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COPY NO . 4

F
TOBACCO AND HEALTH-R&D APPROfiC~~
Presentation to R & D Committee
by Dr . H. Wakeham
I at meeting held in New York Offi ce
on
November 1'5y 1°01

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[
TOBACCO AND HEALTH - R & D APPROACH
F Paae
_Chemistry of Cigarette Smoke. . . . . . . . . . . . . . . . . . . . . . . . . 1
Composition of Mainstream Smoke . . . . . . . . . . . . . . . . : 2
Major Constituents of Mainstream
Particulate Phase . . . . . . . . . . . . . . . . . . . . . . . . 3
f 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
L of Mice ; Comparison of Different Systems
of Grading . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
Partial List of Compounds in Cigarette Smoke
also Identified as Carcinogens . . . . . . . . . . . . 9
Cancer Promoting Agents in Cigarette Smoke . . . . . . . 10
Phenols 'ui Cigarette Smoke . . . . . . . . . . . . . . . . . 11!
I' Anti-Carcinogens . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12

i III. Sznoking and Cardiovascular Diseases . . . . . . . . . . . . . . . . . 13

IV . R & D Program Leading to a Medically Acceptable-

Cigarette . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
Reduction of Irritating Factors in Smoke . . . . . . . . . . . 15
Controlled Nicotine in Filler and Smoke . . . . . . . . . . . . 16
Reduction of Carcinogens in Smoke . . . . . . . . • . . . : . . . 17
The Production of Polycyclic Hydrocarbons
frorn Tobacco vs . Cigarette Paper . . . . . . . . 18
Polycyclic Hydrocarbons from Tobacco
Constituents . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
Some Possible Ways to Reduce Carcinogens
a
in Tobacco Srnoke . . . . . . . . . . . . . . . . . . . . . . . 20
 o more than 4Q0 compound,g of which about 50 have been~
Identified for the firat ttn,a r,y +tie ri1111
rx .,,- . ._
P morris Kesearch Cen!ter .
-_ ~~
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44r.
 : THE CANCER CONTROVERSY

Some Definitions

a malignant growth arising from

epithelial tissue (skin, gastric or
intestinal mucosa, lungs, etc . )

a malignant growth arising from

connective or muscle tissues (muscles,
d blood vessels, cartilage, bone, _ : . '
lymph, etc . )

a substance which applied to the tissue

of a test animal gives rise to tumor _
formation . In tests for carcinogens It
is assumed that tumors ultimately lead -
to cancerous growths and that a_
carcinogen so demonstrated in test
animals is dangerous to man .

. TUMOR
P R O M O T ER - a substance which by itself does not
show carcinogenic activity but which
applied before or concurrently with a
., carcinogen enhances the effect of the
. latter .

ANTICARCINOGEN- a substance which Inhibits the normal -

activity of a carcinogen in a test animal .
S t a t i s t i c a 1 evidence that certain diseases are more
prevalent among smokers than non-smokers .

P h y s i o 1 o g i c a 1 tests in which animals treated with

smoke condensates, extracts, or compounds therefrom,
suffer from increased tumor frequency . Most tests ' .
involve skin painting or injections on special strains of
, mice. Smoke inhalation experiments . have failed
produce lung cancer . , _ . . .. .

1
CO
 : THE PROBLEM OF CARCiNOGEN IDENTIFTCATION

Many factors need to be considered in studying carcinogenesis .

'. J. P. ~ Greenstein, Biochemistry of Cancer - "The carcinogenic
potency of an agent does not reside in the nature of the agent
alone but is a function of the following factors :
(a) The dosage, the nature of the vehicle, the mode and
length of time of administration of the agent ;
(b) The strain, the species, the sex, and the age of the
test animals ;
(c) The site of application, the presence of concomitant ;= :
factors such as the level of essential dietary constituents
and the number of andmals kept in a caqe ."

2. One in five of all randomly performed chronic toxicity tests

reveals the presence of a carcinogen .
Hartwell, Survey of Compounds Which Have Been Tested for
Ca .rcinoaenic Activity, U . S. Public Health Service - About
one-hali 8 of the new carcinogens belongs to five cheinical
classes as follows:

C 1,_ a s s : New Compounds Carcinogens

Aliphatic Carbamates 15 '
Tricyclic Aminofluorenes 14 12
Tetracyclic Cyclopentenophenanthrenes 14 6
Azo compounds 88 - 36
Heterocyclic Benzacridine 22 . 14

CpNFI'OEjq-n AL
1

. PARTIAL LIST OF COMPOUNDS IN QGARETTE SMO$E

_ AL3'J IDENTIFIED AS CARCINOGENS r:
>. . I

Araenic .
Beni.o(a)pyrene ++++
Benzo(e)pyrene +
Beazo(c)pyrene + :
Henz(o)anthraceBe ti,

; : 8enzo{YKluoranthene +
Benzo(b)fluorsnthene ++
Benzene : :
p-Benzoquinone `
n-Butyric acid
: - Benzo(q, h, i)perylene + -
Chryscne •
Chromium .
Cobalt - I
5, 8-Cyclopenteno-
1, 2-benzanthracene
8, 7-Cyclopenteno-
t . 1, 2-benzanthracene
Dibenz(a, h)anthracene ++t

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rFb .'11015
OLiQuid pmrslfln lyCirocarboos
Orqanic acid •sters
Fats -
: Oleates~

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I
 R & D PROGRAM LEADING TO A
MEDICALLY ACCEPTABLE CIGARETTE

Present knowledge and current research indicate three main

approaches :

I. : Reduction ofIrriiaiinq 7actors in Smoke .

This involves extension of current work in tobacco
chemistry, flavor and Irritation studies, and selective
gas phase filtration . Cost questimat.e: $3, 000, 000. . :
Controlled Nicotine in Filler and Smoke .
This program is pe.rtially complete and could be
finished in 18-24 months . Cost questimate (to
small pilot plant ataye) : $1, 000, 000.

Reduction of the General Level of Carcinogenic 3ubstances

in Smoke (bui without Complete Elimination of More than a
Few Specific Compounds . )
 f

PEDrUC'I"!ON OF IRFUTA'~'IN4 FAC'T'4RS IN SMOKS

~~r~.~~

A. This approach ia bssed on the hypotbeaia that

phyaioloqical irr,itations are a grat step In the
. initiation of more serious ailmenta .

P-* :L Development of objective teat for irritatiou .

_ 2. Identification of irritazinq conatitueata . . :' .~
. 9. Selective elimiaation of frritanta from smoke .

a. By aelective filtrstion of qzs phaae .

` b. By modificP.tion of cigarette chemistry .
throuqh ;
(1) Additives to control pyrolysia reactions
: (2) Selection of fillor blends ~
. . ., ._ : . . . .. _ . . ._--
. .. _ _
:. _
C. This program Is closely related to flavor' improvement
;`aad increased consumer accEi ~tability ; hence It has a
double a.dvsntaqe to product t-»tia,ncement .
 ~_NTR4LIED NICOT'II1E IN FILLER AND SMOKE

., Even thouqh nicotine Is believed essential to cigarette

acceptability, a reduction in level may be desirable
for medical reasons .
Problema :
I How much nicotine reduction will be acceptable
'to the smoker?
What taste difference will be tolerated?
Is it better to extract burley, bright, or both for
.low nicotine product of maximum consumer
acceptability?
Consumer tests are under way to answer these questions .
.-. - .- .. . .,_ . . -- . .. .
Two proceases available for flavorhtl, low nicotine
tobacco :
I. Th2 Rosenthal process--now being negotiated.
8. The MLK extraction process-•it is planned to'
desiqn a small pilot plsnt, applicable to either
burley or brights
(r.) . T o provide engineering process data uaeful
for upscclinq if desired . . .
(b) To serve as a standby unit suitable for pro- •_~ :
duction of a minor brand which could be
-introduced in response to public demand .
use of low-nicotine toba .ccos will also be considered .

t
 REDUCTION OF CA.RCINOGENS IN SMOKE

. To achieve this objective will require a major

research effort, because

. Carcinoqens are found in practically every

class of compounds in smoke .
This fact prohibits complete solution of the
I problem by eliminating one or two classes
of compounds .
The best we can hope for Is to reduce a
particularly bad class, i . e ., the polynuclear -
hydrocarbons, or phenols . -

Present technology does not permit selective

filtration of particulate smoke . . ,
Flavor substances and carcinoqenic substances
come from the same classes, in many instances.
Many pYi'olycls products have multiple precuraors
in tobacco. -

CONFiDENT1AL
 PRADUCTION OF POLYCYCLIC HYDROCARBONS FROM TOBACCO
VS. CIGARETTE PAPER

AMOUNT
FROM TOBACCO

20. 5*
48.0
55.0
4.0
A 0.5

VLlues are Srluq CiqareLiea

C OIdCLUSION: Tobacco is the main source of polynuclear hydrocarbona

in cigarette amoke .

CONFIDEN-TIM-

i
 POLYCYCLIC HYDROCARBONS CONiE FROM
MANY TOBACCO~ CONSTITUENTS

Cellulose LS in Pectin,

9.0 3.5 10.7 4 .0 11. 0

160 80 20 56 27

584 8000 287 32 7

337 544 539 104 36 _

219 33 133 35 66

164 58 152 94 45

131 - 29 11 1

L• 2-Benzanthracene .186 44 273 .116 . 43

1:2-Benzpyrene 65 22 34 ` 4 11

'3 :4-Benzpyrene 78 47 45 17 29

CONCLUSION : Removal of any single precursor will not eliminate

polycyclic hydrocarbons from smoke .
 .
.20

.t

SOME PO3SIBLE WAYS TO REDUCE

W
CARCINOGENB IN TOBACCO SMOKE
T

Discover ma jor precursors for carcinogens

aWor cancer promoters.

Discover mechsnism or conditions by which

aarcinoqens are produced and modify those
conditions . - . , . ..

8elect experimentaI toha.ccos which produce a .

minimum of carcinoqens.

. Add enticarcfnoqens .

Discover differences in particulate fractions

which will permit separation of carcinoqens '
in smoke : .

GD~F1D~~~t~L

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