,L
265 9
SRE/PSD/46D-2 (BR Papers) 20th August, 1975
THE UTILIZATION OF CRS, WASTE AND LAMINA TOBACCO:
A REVIEW OF THE TUMORIGENICITY OF CRS AND SOME
RECONSTITUTED TOBACCO SHEETS
SUMKARY AND CONCLUSIONS
By (a) ignoring the evidence from the calibration
groups, and
(b) eliminating the high dose level groups, it is
possible to
determine the tumorigenic ratio of Janus sample B4
(50% CRS) with
resoect to 30 (100% FC lamina). These results
indicate that
the -4rclu-S-ion c--F 501% CRS leads to a 3(YA
reduction in tumorigenic
activity.
Examination of the provisional results from
Experiment B11
shows that when a FIC blend (60% lamina/40% stem)
is manufactured
into PCL the activity is reduced by 20%, while
manufacturing into
SRT reduces condensate activity by 6M..
The TWG experiment shows that Schweitzer stem
sheet, CRS
and AMF stem (plus scrap and strips, ? "fines")
sheet all have
significantly lower activity than the standard
experimental
blend (SEB). Nevertheless, the TWG results are
based on a ranking
of blends using a likelihood ratio and it is not
possible on the
information available to assess any possible
differences between
the CRS and/or the sheet samples. Further, the RTS
samples
produced from the SEB included a variety of
additives or no
additive and were manufactured at various
densities and it is
not possible to rationalise these results at the
present time.
The information clearly shows that significant
reductions in
tumorigenicity can be achieved by the
incorporation of CRS and
even greater reductions achieved by the use of a
paper reconstitut
process. This information does not indicate,
however, whether ster99D
should be utilized as CRS or to produce PRT and no
information
is available to indicate the relative effect of
the PRT process'
on stem and/or fines compared with lamina.
BATCo document for Province of British Columbia 2
November 1999


In the commercial situation it is obvious that
waste tobaccos
will be utilized in the manufacture of PRT even
when PRT is
manufactured at well above waste utilization
levels.
The questions to be answered may be stated as
follows:
(1) should stem be utilized in the blend as CRS
(WT-S) or should
all or part of the stem be incorporated into PRT
along with
the waste;
(2) should some of the lamina be incorporated into
PRT; and
(3) should some of the lamina plus some or all of
the stem be
incorporated?
It is proposed that (1) above should be examined
in a promotion
skin-painting experiment. Since an important
principle is involved
in (2) and (3) above and the materials can be
defined more exactly,
it is considered that the relative contributions
of lamina and stem
in PRT should be examined in a single long-term
experiment.
Proposals for both experiments will be circulated.
C=)
CO
BATCo document for Province of British Columbia 2
November 1999


-3-
A REVIEW OF THE TUMORIGENICITY OF CRS AND SOME
RECONSTITUTED TOBACCO SHEETS
The optimum method of using stem (i.e. as CRS or
incorporated
into a reconstituted tobacco) has been discussed
on a number of
occasions and at a previous BR meeting a request
was made that the
position should be reviewed.
JANUS RESULTS
A long-term mouse skin painting experiment (B4)
has been
undertaken to examine the effect of incorporating
CRS at the 50%,
level into the all-lamina blend used for
experiment BO.
In the report on experiment B4 (Report No. B32)
the response
of the B4 calibration groups was compared with
that found in BO.
This comparison showed that there were significant
differences in
response for the benzpyrene and dibenzanthracene
groups used in
these experiments. On this basis, the results of
experiment B4
cannot be compared directly with those found in
experiment BO.
Some further analysis of these experiments has now
been undertaken,
An initial attempt to fit common Weibull
parameters to the data from
BO and B4 was not succes sful and reinforced the
conclusion based on
the calibration groups. It was considered,
however, that the lack
of fit could be due to differences in the "high
dose anomaly"
between the two experiments. On this basis, common
k and w factors
were fitted to the two lower dose groups from
experiments BO and B4
and to the 50 mg dose level BO condensate group
included in the B5
experiment. A satisfactory fit was obtained and it
was also shown
that for the 50 mg BO groups there was not a
significant difference
between experiments BO and the repeat experiment
B5 (Report No. B33).
C:)
The tumorigenic ratio calculated on this basis for
condensate
B4 (50% FC lamina:50% CRS) with respect to BO
condensate was 0.7
-C
b
BATCo document for Province of British Columbia 2
November 1999


-4-
with 95% confidence limits of 0.63 and 0.76. Thus
the tumorigenic
response from I g B4 condensate is equivalent to
that from 0.7 g
BO (100% PC lamina) condensate.
These results may be summarised together with the
final
provisional values from experiment Bll as set out
below with the
proviso that the "controls" (BO and Ell/1) which
are both put
equal to 1.0 cannot be eauated. Assumed
Rankinq
BO (flue-cured lamina)
B4 (5014 FC lamina/50-- CRS)
B11/1 (60% FC lamina/40% CRS)
B11/2 (PCL made from Bll/l)
B11/3 (SRT made from Bll/l)
1.0 1.0
0.7 0.7
1.0 (say) 0.80
0.81 0.65
0.41 0.33
From this summary it is obvious that the specific
activity of
SRT is much lower than that of a blend containing
501A CRS. if
cross assumotions are made to equate the two
experiments then the
activity ratios for PCL and particularly SRT,
manufactured from
a blend containing 40% CRS, are reduced even
further. Nevertheless
the results, which indicate the probable
advanta-ges of a paper
reconstituted sheet process, do not give any
indication as to
whether the reduction is achieved by processing
the lamina portion
of the blend or the stem.
RESULTS OBTAINED IN OTHER CENTRES
(a) T.R.C. (Harroqate)
In a single experiment condensatcs from FC lamina,
CRS and
RTS were_compared with a FC control blend. The
lamina was
slightly more active (1.12) than the control while
the reduction C=:~
in activity for CRS (0.53) was slightly greater
than that for
the RTS sample (0.62), the latter being only just
significant.
U-1
These results must, however, be treated with some
caution since (--4
N.)
the experiment had to be terminated at week 88.
<:>
BATCo document for Province of British Columbia 2
November 1999


-5-
(b) T.W.G. Experiment
The provisional results of the first large TWG
experiment
provide some guide tothe activity of both CRS and
reconstituted
sheets. This assessment of the results is limited,
however, to
the "Ranking of Blends on Likelihood Ratio
Chi-Squared Tests of
Difference from the Combined Standard
Experlimiental Blend". it
will also be remembered that this ranking is made
much more
difficult in some cases because of the differences
found for the
lour and high dose groups.
T'he TIIG results clearly show that condensate
from CRS is
very much less active than that from the blend and
that from the
lamina. The relative position of the lamina with
respect to the
blend cannot be interpreted; it is ranked more
active at the low
dose level and less active at the higher dose.
The CRS processed into RTS without additives by
Schweitzer
produced condensate with the lowest activity in
the series. The
same CRS was also processed by AMF but the
ingredients included
27% scrap and strip tobacco, invert sugar (5.3%)
and glycerine:
the results for this sample were also
significantly less active
than the standard blend (SEB) but were not ranked
as high as CRS or
the Schweitzer sheet (Table 1).
rQ
BATCo document for Province of BritiSh Columbia 2
November 1999


TABLE 1
T.W.G. RANKINGS
SAMPLE
Schweitzer sheet
CRS
AM Fsheet
SEB
Lamina
RANIKING
LOW DOSE HIGH DOSE
1 1 1
3 2
6
i 22
19 12
U1
L^j
r".)
r10
BATCo document for Province of British Columbia 2
November 1999


SRE/AIW/18.4.74
DARK TOBACCO CIGARETTES
Summary
Although a number of studies have been undertaken,
there is relatively little-information on dark
tobacco cigarettes.
Apart from the interest in cigar tobaccos, this
may be partly due
to the local 'native' nature of dark tobaccos,
which are often
produced from local, or locally naturalised, seed
lines.
Mouse-skin studies show that condensate from dark
tobaccos, including cigar tobacco manufactured
into cigarettes,
are at least as tumorigenic and often more
tumorigenic than that
from flue-cured Burley and oriental tobaccos.
Following a long-term inhalation experiment,
assessed on
the basis of the severity of laryngeal lesions in
hamsters,
Dontenwill concluded that smoke from a "black"
cigarette was
biologically very much less active than smoke from
the reference
cigarette; the latter being a 'standard' German
blend. It should
be noted, however, that the reduction in
biological activity could
be accounted for almost entirely by a lower
accumulated dose from
the "black" cigarette due to a shorter exposure
time 'and the lower
delivery of smoke. A similar reason may also be
advanced for the
marked reductions found for filter tip versions of
the reference
blend.
Because of the publicity which has surrounded the
work of
Passey and his colleagues, this must also be
included in a
'consideration of dark tobacco cigarettes.
Nevertheless, the studies,
which were undertaken under poor experimental
conditions, have been
severely criticised and do not add materially to
our knowledge of
dark tobacco cigarettes.
In conclusion, the hypothesis that smoke from dark
cigarettes is "safer" than that from flue-cured or
blended cigarettes
is certainly not supported by the results of the
mouse-skin painting
experiments and the Dontenwill inhalation study
appears to provide
only shaky supporting evidence. On the present
evidence, it is
suggested that any concept of a lower risk
attached to dark
C:)
cigarettes can, in a given population, only be
associated with a %,o
110
reduced level of inhalation (accumulated dose)
from such productsQn
rIJ
U-4
BATCO document for Province of BritiSh Columbia 2
November 1999


DARK TOBACCO CIGARFTTES
a) Study of Cigar Tobacco Condensate
Followi ng reports Afrom Croninger (1) and
Homburger (2)
which suggested, but di,3 not prove statistically,
that cigar smoke
condensate was more carcinogenic than that from
cigarette smoke,
Davies and Day (3) re-examined the position.
The results obtained after 116 weeks showed that
the
condensate from the cigar was more carcinogenic
than that of
the cigarette manufactured from cigar tobacco or
from flue-cured
tobacco. There was no significant difference in
carcinogenicity
to mouse-skin of the condensates from the two
cigarettes. The
differences in mortality rates were small and the
results were
not affected by age-standardisation.
b) Comparison of Tobacco TVpes
In a further TRC experiment, a number of different
types of tobacco, including an air-cured fermented
(Paraguay)
tobacco, were examined. The tumorigenic ratios and
95% confidence
limits for the condensates from the various
cigarettes compaied
with the flue-cured "control" (TU were:
Sample T16 Air-cured fermented 1.38 (1.14 - 1.65)
T17 Burley 1.07 (0.89 - 1.29)
T18 Oriental 1.11 (0.92 - 1.33)
T19 Indian sun-cured 1.55 (1.29 - 1.90)
T20 Indian flue-cured 1.22 (1.02 - 1.47)
These results show that condensate from air-cured
fermented tobacco is more tumorigenic than the
flue-cured control.
Condensate from Indian sun-cured is also more
tumorigenic, while
that from Indian flue-cured tobacco is just
significantly more
tumorigenic than the control. The differences for
Burley and
oriental tobaccos are not significant.
Subsequently, Imperial Tobacco Ltd. have compared
condensates from Gauloises and other continental
brands with %-0
Embassy cigarettes. Full details are not
available, but all 92
weeks, it was clear that condensate from Gauloises
Caporal plain
M-)
411.
BATCo document for Province of Briti8h Columbia 2
November 1999


-2-
was very much more tumorigenic than that of
Embassy filter.
The ranking was :
Gauloises',~ Belga Rouge filter > Nazionali
Esportazione
Embassy
c) Inhalation Study Dontenwill et al. (4)
In this long-term experiment, smoke from a "black"
cigarette manufactured from a blend of Burley
(15%), Maryland (6%),
and dark tobaccos was compared with a "standard"
German blend and
various other cigarettes.
Comparison of the various cigarettes was based on
the
seveie laryngeal changes found following exposure
of hamsters to
30 cigarettes twice a day for up to two years. On
this basis,
smoke from the "black" cigarette was found to have
only 33%.(stage 5)
or 12% (stage 6) of the activity of the reference
cigarette,
ie. a 67-88% reduction in activity .
Apart from the absence of suitable methods for the
analysis
of such experiments, two main factors should be
considerea in
attempting to put these results into perspective.
1. Cellulose acetate or paper filter versions ot
the
reference cigarette also led to a considerable
reduction in activity;
56-60% (stage 5) and 76-99% (stage 6)
respectively.
2. The condensate delivery from the "black"
cigarette was
nearly 40% lower than that from the reference
cigarette and the
exposure time was also 20% lower. Similarly,
condensate deliveries
from the filter cigarettes were 30 and 33% lower
than that"of the
reference cigarette.
Since the above reduction in condensate
delivery.and
expas7ure time for the "black" cigarette compared
with the
reference cigarette obviously reduce the total
accumulated dose
to the respiratory system, it is considered that
the marked
reduction in biological response should be treated
with considerable,-.o
caution.- C-n
BATCo document for Province of British Columbia 2
November 1999


-3-
Other Inhalation Studies Passey et al. (5)
In two experiments, groups of 12 rats were exposed
to
smoke under what can rnly be considered as poor
experimental
conditions. In one exp,~riment, cigarette smoke
was compared with
smoke from cigarettes manufactured from cigar
tobacco (TRC C2).
A commercial cigar tobacco cigarette (Calypso) and
a cigarette
manufactured from Burley tobacco (TRC T17) were
included in the
second experiment. The rats exposed to smoke from
flue-cured
tobacco died early and with enlarged and severely
diseased lungs.
The conclusions drawnwere that smoke from
flue-cured .
cigarettes is more dangerous to man and to animals
than that from
air-cured tobaccos and that this is related to the
method of
curing (and the sugar content) of the tobaccos.
These experiments have been criticised severely
because
the pathological findings of the rats which died
suddenly could
be related to an inflammatory condition not
regularly encountered
in man: Passey himself stated that chronic
respiratory disease
and bronchiectasis were endemic in the strain of
rats used for
their studies. Passey also undertook some limited
mouse-skin
painting experiments.
Passey's studies have become linked to lung cancer
(because of a limited mouse-skin study) and also
to a theory of
lung cancer induction advanced by Braven and
Fenner M: the
latter because of Passey's contc:ntion that the
sugar conLent of
the tobacco was an important factor. In the samte
review (6), it
is argued that, although the studies of Passey may
conceivably
have some relevance to chronic inflammatory lung
disease in man,
there are no groupds for regarding them as
relevant to lung cancer.
The link with sugar content and Braven and
Fenner's
work is also criticised, since there is no
evidence that cystein
offers protection from cancer inducing effects of
chemical agents.
1%0
Ln
SRE/AIW/19.4.74 Ld-4
rQ
CN
BATCo document for Province of British Columbia 2
November 1999


1. Croninger, .4.B. et Al. Cancer Res. 1958, 18,
1263
2. Homburger, F. et al
3. Davies R.F. et al.
4. Dontenwill, W. et al.
5. Passey, R.D. et al
J. Watn. Cancer Inst. 1963, 31, 1445
Br. J. Cancer, 1969, 23, 363
J. Natn. Cancer Inst. 1973, 51, 1781
Br. med. J. 1971, IV, 198
6. Editorial
7. Braven, J. et al.
B. Fenner, M.L. et al.
Lancet, 1973, 187
Br. J. Cancer, 1967, 21, 623
Br. J. Cancer, 1968, 22, 474
BATCo document for Province of Brit!Sh Columbia 2
November 1999


APPENDIX
Details of Cigarettes and Cigars'used in TRC Cigar
StudY
Table I
Code
1 Length Circum Weight
1 1 Butt Puff
I NVWSC (4)
I
Leng Lh No.
(Mm) (mm) (g) (mm) (mg)
C10) 83 33.7 1.86 25 19.8 37.8
C2 (, ) 70 25.1 0.94 20 8.4 19.4
T4(1) 70 25.3 1.09 20 10.9 26.3
(1) Composite blend cigar tobacco; granulated
wrapper and
binder of natural leaf.
(2) Blend as Cl cut at 50 cpi for cigarette
manufacture
(3) Composite blend of flue-cured tobacco.
(4) Non volatile whole smoke condensate.
Smoking conditions : puf-Z volume 25 ml
duration 2 seconds
one puff per minute
Table 2
Summary of results from Dontenwill Inhalation
Study
Sample Cundens ate Relative Laryngeal Changes
Exposure Relative Potency
Factor
Dry Factor Stage 5 Stage 6
(mg/cig)
Control (1) 33.7 1.0 1.0 1.0 1.0
"Black" (2) 20.9 0.62 0.8 0.33 0.12
Control 23
5 0.70 1.0 0.44 0.06
Acetate Filt .
er
Control 22.7 0.67 1.1 0.40 0.24
.Paper Filter
(1) German blend: 55% flue-cured, 35% oriental and
10% Burley
(2) Black cigarette: 15% Burley, 6% Maryland, 6%
Java,
19% cigar tobacco, 54% other dark tobacco
NO
CO
BATCo document for Province of BritiSh Columbia 2
November 1999