September 29. 1969
COPISIDERATION OF THE METMOLIC ROLES OF NON-TOXINS
IN 17MRACCO-S11OKE
As considerable attention is being gfv-ftn to the
analysis
and filtration of known toxins in tobacco smoke.
our thoughts have
turned toward compounds which have no easily
observed toxic prop-
erties but which might, however, be potentially
hazardous.
It is difficult to make a clear division between
toxins
and non-toxins, since virtually all chemicals in
sufficiently high
concentrations have, toxic effectse while none are
toxic if their
concentration is sufficiently small. At present it
is not necessary
to make an absolute distinction between the two; a
typical classi-
fication. as shm-4n below, will suffice to divide,
arbitrarily,
chemicals into toxins and non-toxins:
1. Extreerely toxic
2. Highly toxic
3. floderately toxic
4. Sliohtly toxic
S. rractically non-tnxic
6. Relatively harmless
I mi/kq or less r),A-1-prnent
1-50 mg/kq
0,11
50-50n mq/kg .. .. ....
.5-5 q/kq
5-15 q/kcj
15 9/kg . .. ...... .... ...
The concentrations shown above are described as
the
levels required to produce 'harmful effo!cts'*.
For our purposes
groups 5 and 5 will he considered as non-texinn.
It is reasonable to assume that the bulk of
non-toxic
smoke constituents.will be metabolised or excreted
by the smoker
with no III effects. It Is possible. however, that
some apparently
harmless substances, may be metabolised by the
body into more toxic
products (toxification) and it Is also possible
that some non-toxic
substances may behave as haptens and produce minor
localised allergic
reactions.
Toxi fi cati an
Examples of toxification are best drawn from the
field
of drugs and pesticides. These examples have no
direct relevance to
human beings or to tobacco smoke and are only
intended to draw
attention to the principle involved.
Essentials of Toxicology, T.A. Loomis, Lea 11
Febiger. Philadelphia 19FF.
Cli
CO
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The Insecticide Malathion Is relatively Inactive.
Insects
are equipped with two enzymes systems for dealing
with Malathion.
The first set, the microswal enzymes, racidly
~7xidise the compound
to Malaoxon which is an active Insecticide. The
second set, the
A-esterases. slowly hydrolyse the oxidised form
Into inactive products.
The net result is that Malsaxon Is formd faster
than the A-esterases
can dispose of It and thus exerts a toxic effect
an the arqanism.
The pesticide Parathion behavessimilarly. It is
enzyr-atically
oxidised to Paraoxon a more active product. A
better known example
Is that of Prontosil, the antibiotic, which is
reduced to sultanila-
ride a product having toxic and antibacterial
properties. The
toxic properties are not lethal and the body
possesses a mechanism
for converting sulfanilamide to acetyl
sulfanilamide a non-toxic
derivative. The first reaction takes place more.
rapidly than the
second thus permitting temporary accumulations of
the antibiotic.
jLaptens
The possibility of the existence of haptens in
smke
has. as far as we know, received no attention. In
drawing attention
to this class of compounds it is necessary to
provide a little back-
ground information. Large molecules (antigens) on
Introduction
Into an animal, give rise, after an induction
period, to new
proteins called antibodies. If the animal Is later
eirposed to
more of the.entigen a specific antibody/antigen
reaction will
take place. This reaction Is made use of in
immunisation against
infectious disease and also provides the body's
defense mechanism
against foreign protein.
Small molecules can achieve much the same effect
by
reacting with endogenous protein to form an
antignn. The small
molecule is ternv4 a haoten. Initial exposure of
an animal to a
hapten mkv lead to sensitisation of the animal.
Exoo,,qu"-s to the
hapten on subsequent occasions will then lead to
formation of the
antigen which reacts with the preformed antibody.
resulting in
cell damage.
~Ta explain why the normal antigens give rise to
smooth
antibody-antigen reactions while the haptens
result in an allergic
type reactions it is postulated that haptens or
Mle u
clens ca se
formation of cell bound antibodies. The immune rea
t on Involving
call bound antibodies Is thought to result in the
liberation of
histamine and damaSe to the cell. Normal antigens
stimulate pro-
duction of serum antibodies which take part In
non-disruptive
Immune reactions.
To perform the function of a hapten the chemical
must
be able to react covalently with proteins.
Compounds with the
following functional groups can have this
property-
00
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Thiol _SH
diazonium -N*-N-
sulfonic acid -Soil
aldehyde -CHO
active halogen
quinone. 0 _j___ NL 0
A number of these functional groups can be found
in
smoke components.
Assuming that compounds which undergo metabolic
toxiffca-
tion and haptens are represented in smoke. how can
they be identified?
It Is suggested that. to investigate the first
class of compounds,
information be gathered about the metabolism of
non-toxic comnounds
in smoke, bearing in mind that synergistic effects
may occur. To
investicate the second class of compounds,
information about low
molecular weiqht haptens should be collected to
see if any of these
do in fact occur In smoke. It is important to find
out whether
persistent exposure to a hapten results in
desensitisation or
whether the allergic response continues. If
haptens are present
in smoke and the allergic reaction persists, it is
possible that
this type of continuous insult could lead to
permanent changes In
the lung and might be linked with lung ailments
like emphysema.
It Is felt that plans for experimental work In
this area
would be premature and that a broad literature
survey should suffice
to substantiate or disprove the hypothesis.
A.,
A(
MAN/39
C_r7
QN
Co . _~
4.1t.,
BATCo document for Province of British Columbia 20
April 1999