compared is almost certainly substantially greater with measures of
absorption than with atmospheric measures.
Tobacco smoke contains many substances, but only a few have
been measured in human biological fluids. of the g-w compo-
nents, markers include carbon monoxide and thiocyanate. The latter
is not a gas but a metabolite of gaseous hydrogen cyanide. Concentra-
tions of nicotine and its metabolite cotinine are markers of nicotine
uptake. In mainstream smoke, nicotine uptake reflects exposure to
particulates. In environmental tobaccc smoke, nicotine becomes
vaporized and therefore reflects gas phase expcsure @udy et al.
1985). Quantitating tar consumption is more difficult urinary
mutagenic activity has been used as an indirect marker.

The relative exposures of nonsmokers to various tobacco smoke
constituents differs from that of smokers. Assuming that exposure to
a single tobacco smoke constituent accurately quantifies the expo-
sure of both smokers and nonsmokers to other constituents is
inaccurate because mainstream smoke and environmental tobacco
smoke differ in composition (see Chapter 3).

To understand the usefulness and limitations of various biochemi-
cal markers, it is important to appreciate the factors that influence
their absorption by the body and their disposition kinetics within it.

Carbon Monoxide

Carbon monoxide is absorbed in the lungs, where it dZfuses across
the alveolar membrane (Lawther 1975; Stewart 1975). It is not
appreciably absorbed across mucous membranes or bronchioles.
Within the body, carbon monoxide binds, as does oxygen, to
hemoglobin, where it can be measured as carboxyhemoglobin.
Carbon monoxide may also be bound to myoglobin and to the
cytochrome enzyme system, although quantitative details of binding
to the latter sites are not available. Carbon monoxide is eliminated
primarily by respiration. The amount of ventilation influences the
rate of elimination. Thus, the half-life of carbon monoxide during
exercise may be less than 1 hour, whereas during sleep it may be
greater than 8 hours (Castleden and Cole 1974). At rest, the half-life
is3to4hour-s.
The disposition kinetics of carbon monoxide explain the temporal
variation of carbon monoxide concentration in active smokers during
a day of regular smoking. With a half-life averaging 3 hours and a
reasonably constant dosing (that is, a regular smoking rate), carbon
monoxide levels will plateau after 9 tc 12 hours of cigarette smoking.
This has been observed in studies of circadian variation of carbon
monoxide concentrations in cigarette smokers (Benowitx, Kuyt et al.
1982). Smoking is not a constant exposure source, but results in
pulsed dosing. There is a smsll increment in carboxyhemoglobin
level immediately after smoking a single cigarette, which then

201


declines mta tie next, cig~tt.e is smoked. But after several hours of
smou, the m@t&e of rise and faR is small compared with the
trough vahres. For this reason, carboxyhemoglobm levels at the end
of a day of smoking are satisfactory indicators of carbon monoxide
exposure during that day.

&bn monoi& e-m may be more'constant during environ-
mental ~~CCCB m&e exposure than during active smoking. The
major limitation m using carbon monoxide as a means of measuring
hrvohmtary smoke exposure is its lack of specificity. Endogenous
carbcn monoxide generation from the metabolism of hemoglobin
results in a low level of carbo~hemoglobin (up to 1 percent)
(Lawther 1975; Stewart 1975). Carbon monoxide is generated by any
source of combustion, including gas stoves, machinery, and automo
bile exhaust. Thus, nonsmokers in a community with moderate home
and industrial carbon monoxide sources may have carboxyhemogb
bin levels of 2 or 3 percent (Woebkenberg et al. 1981). A carbon
monoxide level of 10 in room air results in an increment of 0.4 and
1.4 percent carboxyhemoglobin at 1 and 8 hours of exposure time,
respectively (Lawther 1975; Stewart 1975). Thus, small increments of
carhcn monoxide due to environmental tobacco smoke may be
indistinguishable from that due to endogenous and non-tobacco
related sources.

Measurement of carbon monoxide is straightforward and i,nexpen-
sive. &dar carbon monoxide pressures are proportional to the
concentration of carhoxyhemoglobin in blood, therefore, end&~
carbon monoxide tension accurately reflects blood carboxyhemoglo
bin (Jti and Russell 1980). Expired carbon monofide - &
measured Using an instrument (Ecolyzer) that measures the rate of
conversion of carbon monoxide to carbon &&de 88 it pm over a
catalytically active electrode. Blood carboxyhemoglobin - b
xm~~ured ~~1~ ad quickly wing a differential spectropho~m~
ter.

Hydrogen cyanide is metabolized by the liver to thiooyanate. In
addition to tobacco smoke, certain foods, particularly leafy vegeta-
bles and some nuts, are sources of cyanide. Cyanide is also present in
beer.
Thiocyanatc is distributed in extracellular fluid and is eliminated
slowly by the kidneys. The half-life of thiocyanate is long, about 7 to
14 days. Thiocyanate is also secreted into saliva, with salivary levels
about 10 times that of plasma levels (Haley et al. 1983). The long
half-life of thiocyanate means that there is little flu&ration in
plasma thiocyanate concentrations during a day or from day to day.
Thus, the time of sampling is not critical. On the other hand, a given
level of thiocyanate reflects exposure to hydrogen cyanide over


several we&~ ~mceding the time of sampling. When a smoker stops
smoking, it takes an estimated 3 to 6 weeks for thiocyanate levels to
reach that individual's nonsmoking level.
Because of the presence of cyanide in foods, chiocyanate is not
specific for exposure to cigarette smoke. Although active smokers
have plasma levels of thiocyanate two to four times those of
nonsmokers (vogt et al. 1979, Jacob et al. 1981), light smokers or
involuntary smokers may have little or no elevation of thiocyanate.
When thousands of subjects are studied, involuntary smokers have
been found to have slightly higher thiooyanate levels than those
without exposure (Friedman et al. 1983). Other studies of smaller
numbers of subjects have shown no difference in thiocyanate level
between exposed or nonexposed nonsmokers (Jarvis et al. 1984).

Serum or plasma thiocyanate levels can be measured using
spedrophotometric methods or, alternatively, gas chromatography.

Nicotine

Nicotine ia absorbed through the mucous membranes of the mouth
and bronchial tree as well as across the alveolar capillary mem-
brane. The extent of mucosal absorption varies with the pH of the
smoke, such that nicotine is absorbed in the mouth from alkaline
(cigar) smoke or buffered chewing gum, but very little is absorbed
from acidic (cigarette) mainstream smoke (Armitage and Turner
1970). With aging, environmental tobacco smoke becomes less acidic;
pH may rise to 7.5, and buccal or nasal absorption of nicotine by the
nonsmoker could occur (see Chapter 3).
Nicotine is distributed rapidly to body tissues and is rapidly and
extensively metabolized by the liver. Urinary excretion of unmetabo-
lized nicotine is responsible for from 2 to 25 percent of total nicotine
ehnrination in alkaline and acid urine, respectively; nicotine excre-
tion also varies with urine flow (Rosenberg et al. 1980). Exposure to
environmental tobacco smoke, active smoking, and use of smokeless
tobacco markedly elevate salivary nicotine transiently out of propor-
tion to serum and urinary levels (Hoffiann et al. 1984). Nicotine is
present in breast milk (Luck and Nau 1985), and the concentration
in the milk is almost three times the serum concentration in the
mother (Luck and Nau 1984).
The rate of nicotine metabolism varies considerably, as much as
fourfold among smokers (Benowitz, Jacob et al. 1982). There is
evidence that nicotine is metabolized less rapidly by nonsmokers
than by smokers (Kyerematen et al. 1982). A given level of nicotine
in the body reflects the balance between nicotine absorption and the
metabolism and excretion rates. Thus, in comparing two persons
with the same average blood concentration of nicotine, a rapid
metabolizer may be absorbing up to four times as much nicotine as a
slow metabolizer. To determine daily uptake of nicotine directly,

203


both the nicotine blood concentrations and the rates of metabolism
and excretion must be known. These variables can he measured in
experimental studies (Renowitz and Jacob 1984; Feyerabend et al.
1985), but are not feasible for large-scale epidemiologic studies.
The time course of the decline of blood concentrations of nicotine is
multiexponential. Following the smoking of a. single cigarette or an
intravenous injection of nicotine, blood concentrations of nicotine
decline rapidly owing to tissue uptake, with a half-life of 5 to 10
minutes. If concentrations are followed over a longer period of time
or if multiple doses are consumed so that the tissues are saturated, a
longer elimination half-life of about 2 hours becomes apparent
(Renowitz, Jacob et al. 1982; Feyerabend et al. 1985). Because of the
rapid and extensive distribution in the tissues, there is considerable
fluctuation in nicotine levels in cigarette smokers during and after
smoking. As predicted by the Z-hour half-life, nicotine blood concen-
trations increase progressively and plateau after 6 to 8 hours of
regular smoking (Renowitz, Kuyt et al. 1982). Nicotine concentra-
tions have been sampled in the afternoon in studies of nicotine
uptake during active cigarette smoking (Renowitz and Jacob 1964,
and similar timing might be appropriate in assessing the plateau
levels that result from continuous ETS exposure, such as during a
workday.

Russell and colleagues (1965) quantitated nicotine exposure by
comparing blood nicotine concentrations during intravenous infu-
sions (0.5 to 1.0 mg over 60 minutes) in nonsmokers to the blood
nicotine concentrations in nonsmokers exposed to environmental
tobacco smoke. The data suggest that nicotine uptake in a smoky bar
in 2 hours averaged 0.20 mg per hour.  ..
The presence of nicotine in biologic fluids is highly specific for.
tobacco or tobacco smoke exposure. Nicotine concentration is sensi-
tive to recent exposure because of nicotine's relatively rapid and
extensive tissue distribution and its rapid metabolism. Urinary
nicotine concentration has been examined in a number of studies of
environmental tobacco smoke exposure. Although influenced by
urine pH and flow rate, the excretion rate of nicotine in the urine
reflects the concentration of nicotine in the blood -over the time
period of urine sampling. In other words, nicotine excretion in a
timed urine collection is an integrated measure of the body's
exposure to nicotine during that time. When timed urine collections
are not available, nicotine excretion is commonly expressed as a
ratio of urinary nicotine to urinary creatinine, which is excreted at a
relatively constant rate throughout the day. Urinary nicotine
excretion is highly sensitive to environmental tobacco smoke expo
-sure (Hoffmann et al. 1984; Russell and Feyerabend 1975). Saliva
levels of nicotine rise rapidly during exposure to sidestream smoke
and fall rapidly after exposure has ended (Hoffmann et al. 1984).

204


Presumably, this the course reflects local mouth contamination,
followed by absorption or the swallowing of dcotine.

Blood, urine, or saliva concentrations of nicotine can be measured
by gas chromatography, radioimmunoaaeay, or high pressure liquid
chromatography- sample preparation is problematic in that contam-
ination of samples with even small amounts of tobacco smoke c8n
substantially elevate the normally low concentrations of nicotine in
the blood. Thus, careful Precautions against contamination during
sample collection and processing for analysis are essential. &cause
the concentrations are so low, the measurement of nicotine in blood
has been difficult for many laboratories in the past, but with
currently available assays, it is feasible for largescale epidemiologic
StUdiM.

C&nine

Cotinine, the major metabolite of nicotine, is distributed to body
tissues to a much lesser extent than nicotine, Cotmine is eljmmated
primarily by metabolism, with 15 to 20 percent excreted unchanged
in the urine (Benowitz et al. 1983). Urinary pH does affect the r-end
elimination of cotinine, but the effect is not as great as for nicotine.
Since renal clearance of cotinine is much less variable than that of
nicotine, urinary cotinine levels reflect blood coti.&e levels better
than urinary nicotine levels reflect blood nicotine levels. Plasma,
urine, and saliva cotinine concentrations correlate strongly with one
another (Haley et al. 1983; Jarvis et al. 1984).
The elimination half-life for cotinine averagea 20 hours (range, 10
to 37 hours) (Benowitz et al. 1983). Because of the relatively long
half-life of cotinine, blood concentrations are relatively stable
throughout the day for the active smoker, reaching a maximum near
the end of the day. Because each cigarette adds relatively little to the
overall cotinine level, sampling time with respect to smoking is not
critical. Assuming that smoke exposure occurs throughout the day, a
midafterrmcm or late afternoon level reflect8 the average wtinine
concentration.
The specificity of cotinine as a marker for cigarette smoking ie
excellent. Because of its long -half-life and its high specificity,
cotinine measurements have become the most widely accepted
m&hod for assessing the uptake of nicotine from tobacco, for both
active and involuntary smoking.
Gotinine levels can be used to generate quantitative estimates of
nicotine absorption. Galeazzi and colleagues (1985) defined a linear
relationship between nicotine uptake and plasma cotinine levels in
six healthy volunteers who received several i.v. doses of nicotine
( 5 480 &kg/day) for 4 days. The ability to extrapolate from this
model to levels in nonsmokers is limited, however, because the
elimination half-life of cotinine may be shorter in smokers than in


nsmokers, as is the elimination ha&life of nicotine (Kyerematen
1; al. 1982).
Cotinine can be assayed by radioimmunoassay, gas chromatogra-
phy, and high pressure liquid chromatography.

Urinary Mutagenicity

TO&~ smoke condensate is strongly mutagenic in bacterial test
s-m (ties test) (Kier et al. 1974). A number of compourids,
j&u&g polycyclic aromatic hydrocarbons, contribute to this
mutagenicity. The urine of cigarette smokers has been found to he
mutagenic, and the number of bacterial revertants per test plate is
r&ted to the number of cigarettes smoked per day Wamasaki and
Ames 1977). Urinary mutagenicity disappears within 24 hours after
smoking the last cigarette &do et al. 1986).
For several reasons, the measurement of mutagenic activity of the
urine is not a good quantitative measure of tar absorption. Individu-
als metabolize polycyclic aromatic hydrocarbons and other mutagen-
ic substances differently. Only a small percentage of what is
absorbed is excreted in the urine as mutagenic chemicals. The
bacterial system is differentially sensitive to different mutagenic
compounds. The urine of smokers presumably contains a mixture of
many mutagenic compounds. In addition, the test lacks speciEcity, in
that other environmental exposures result in urinary mutagenicity.
The test may also be insensitive to very low exposures such as
mvobmtary smoking. However, one study, by Bos and colleagues
(1983), indicated slightly increased mutagenic activity in the urine of
nonsmokers following tobacco smoke exposure.
The presence of bedalpyrene and 4-amino biphenyi covalently
bound to DNA and hemoglobin in smokers (Tannenbaum et al., in
press) suggests other potential measures of carcinogenic exposure.
Whether such measures will be sensitive to HIS exposure is
unknown. The development of specific chemical assays for human
exposure to componenta of cigarette tar remains an important
researchgoal.

Populations in Which Exposure Has Been Demonstrated
Absorption of tobacco smoke components by nonsmokers has been
demonstrated in experimental and natural exposure conditions.

Experimental Studies

Nonsmokers have been studied after exposures in tobaccosmoke-
Clled rooms. The smoke may be generated by a cigarette smoking
machine or by active smokers placed in the room by the investigator,
or the location may be a predictably smoke-filled environment such
as a bar. The level of environmental smoke has most often been


quantitated by measuring ambient carbon monoxide concentrations.
In nonsmokers exposed for 1 hour in a test room with a carbon
monoxide level of 33 ppm, carboxyhemoglobin levels increased by 1
percent and urinary nicotine increased about eightfold (Russell and
Feyerabend 1975). Seven subjects in a similar study sat for 2 hours in
a public house (bar) with a carbon monoxide level of 13 ppm; their
expired carbon monoxide increased twofold and their urinary
nicotine excretion increased ninefold (Jarvis et al. 1983). In a study
exposing eight nonsmokers to a smoke-filled room for 6 hours, a
small increase in urinary mutagenic activity was measured (Bos et
al. 1983).

Nonexperimental Exposures

Exposure studies performed in real-life situations have compared
biochemical markers of tobacco smoke exposure in different imiivid-
uals with different self-reported exposures to tobacco smoke. Absorp
tion of nicotine (indicated by urinary cotinine levels) was found to be
increased in adult nonsmokers if the spouse was a smoker (Wald and
Ritchie 1934). In another study (Matsukura et al. I984), urinary
cotinine levels in nonsmokers were increased in proportion to the
presence of smokers and the number of cigarettes smoked at home
and the presence and number of smokers at work. Blood and urinary
nicotine levels were increased after occupational exposure to ETS
such as a transoceanic flight by commercial airline flight attendants
(Foliart et al. 1983). Nicotine absorption, documented by increased
salivary cotinine concentration, has been shown in schoolchildren in
relationship to the smoking habits of the parents (Jarvis et al. 1985),
and using plasma, urinary, and saliva measures, in infants in
relation to the smoking habits of the mother (Greenberg et al. 1934;
Luck and Nau 1985; Pattishall et al. 1935).

Quantification of Absorption
Evidence of Absorption in Different Populations

One questionnaire survey indicated that 63 percent of individuals
report exposure to some tobacco smoke (Friedman et al. 1983).
Thirty-four percent were exposed for 10 hours and 16 percent for 40
or more hours per week. The distribution of cotinine levels in a few
populations has been reported. In men attending a medical screening
examination, there was a tenfold difference in mean urinary
cotinine in nonsmokers with heavy exposure (20 to 80 hours per
week) compared with those who reported no ETS exposure (wald et
al. 1984). The median and 90th percentile urinary cotinine concen-
trations for all nonsmokers who reported exposure to other people's
smoke were 6.0 and 22.0 ng/mL, respectively, compared with a
median of 1645 ng/mL for active smokers, In 569 nonsmoking

207


schoolchildren, salivary cotinine concentrations were widely distrib-
uted. Values were strongly influenced by parental smoking habits
(Jarvis et al. 1985). The median and 25 to 75 percent ranges (in
ng/mL) were 0.20 (O-0.5), 1.0 (O&1.8), 1.35 (0.7-2.71, and 2.7 (l.M.4)
for children whose parents did not smoke or whose father only,
mother only, or both parents smoked, respectively.

Quantification of Exposure

Expired carbon monoxide, carboxyhemoglobin, plasma thiocya-
nate, plasma or urinary nicotine, and plasma, urinary, or salivary
cotinine have been used to evaluate exposure to ETS. However,
successful attempts to quantify the degree of exposure have been
limited largely to measurements of nicotine and cotinine. Expired
carbon monoxide and carboxyhemoglobin have been found to be
increased up to twofold after experimental or natural exposures
(Russell et al. 19731, `but not in more casually exposed subjecta.
Thiocyanate was slightly increased in one very large study of heavily
exposed individuals (Friedman et al. 1983), but most studies report
no differences as a function of involuntary smoking exposure. The
most useful measures appear to be nicotine and cotinine. The data on
nicotine and cotinine measurements are presented in Tables 6 and 7
and suggest the following:

(1) Both nicotine and cotinine are sensitive measures of environ-
mental tobacco smoke exposure. Levels in body fluids may be
elevated 10 or more times in the most heavily exposed groups
compared with the least exposed groups.

(2) The tune course of change in the levels of biochemical markers
depends on which marker is selected and which fluid is sampled.
There ia a lag between peak blood levels of nicotine and peak blood
levels of cotinine, owing to the time required for metabolism
(Hoffmann et al. 1984). Salivary levels of nicotine, because of the
local deposition of smoke in the nose and mouth, peak early and
decline rapidly.

(3) With nicotine, salivary levels increase considerably after
environmental tobacco smoke exposure, but decline rapidly follow-
ing the end of exposure. Blood nicotine levels are too low to be very
useful in quantitating environmental nicotine exposure. Urinary
nicotine is a sensitive indicator of passive smoke exposure, but
because of its relatively short half-life, urinary nicotine levels
decline within several hours of the time of exposure.

(4) Cotinine levels are less susceptible than nicotine to transient
fluctuations in smoke exposure. Blood or plasma, urine, and saliva
concentrations correlate strongly with one another. Because of the
stability of cotinine levels measured at different times during an
exposure and the availability of noninvasive (i.e., urine or saliva)

203


TABLE 6,Nicotine measurea in nonsmokers with environmental tobacco smoke (EIB) sxponve and
      comparisons with active smoking

Numberof Smoking

eubjecta    et&Ii     Rxposum level      BefOr     After    Mom        After        Before     Ahr

Ruassll and
Feyerebend
U~6)



Feyerabend
et al. (1982)







Foliart et al.
M89)

12       NS


14       NS
13       NS
18       S

26       NS
90       NS
8       S
16       S
32       S
27       5

6       Ns

18 min in
enlokem2d room
Hoepad
~~~lw=u
Averege 24 cigdday
No S eqxnum
Work expmum
Nonlnhelem
slight inhalere
Medium bIbden
Dwp inhdm
Flight attendNIb

0.73       0.90

-


- -

        -
        -
-


-
        -
  (1E.S)

-     80 w-2rs)           - -


    12.4 (O&64.3)           - -
    8.9 (o-26)            - -
-    1236 (104-2799)          - -

-     1.5                     lb.9
    21.6                     10.1
     w                    ls2
    1261                    421
    1949                   (64
    1527                     o(#

    lb.2 (8.Sr.4)          - -

.

JAetal.       7       NS     s&m, 1Mo can.        0.8       2.6        10.6.   92.6                1.9    49.6

After, public houm x
2hr

HolTmann et al.     10       NS     Rxpimental chamber
(1980                   2cigaburned          1.1        1.1        24'    Sl'                0     427
                     3cigebumed          ND       1.3        20    94                 1     ma
                     4 cigc burned          0.2       0.5       17    loo               3     790


E  TABLE i&fhntinued
0

                                                Mean or median conoentration and range

Study

Number of   Smoking
subjects      etatus

Expmure level

Plasma nicotine
   ht/mL,


Before      After

     Urine nicotine          Saliva nicotine
     bf+u             WmL,


Before       At&        EdOR     After

Jarvia et al.
ww






Greenberg
et al. (1984)

Luck and Nau
(1986)

48
27
20
7
94

32
19

10
10


10
9

       Hospital clinic patients
  NS     No expmure           -        1.0        -     3.9                -     3.8
  NS     Little expceure         -        0.8             12.2                     4.8
  NS     Some expcmm         -       0.7        -    11.9                    4.4
  NS     Lot of exposure         -        0.9       -    12.2                     12.1
  S                        -       14.8            1760                -     872

  NS     Infanta, mother S        -                 -     as' (O-370)             12.7 (O-188)
  NS     infant, mother NS       -                 -     0 o-89)            -     0 (O-17)
NS, neonates   No exposure           -                 -     0' @14)           - -
NS, neonates  Nuraad by S mother:      -                   14 (&llO)           - -
       no Em expomre
NS, infants   S mother, not nursed      -                 -     36 (4-218)           - -
NS, infants   Nureed by S mother;      -                 -     12 (s-42)            - -
       Em exposure

1 nglmg creatinins.


TABLE V.-Cotini.ne measures in nonsmokers with environmental smoke exposure and comparisons
      with active smoking

                                     ban or median concentration and -
                                        Plaema &hine
        Number                                               Urine cutinine
                                     WmL)                           salivaootin&

         Of    Smoking                                     WmL)           WmL)
Study    eubjecta     atatw        Expoeure level        Before     After     Before        After         More     After


Jarvis       7      NS       Before, 1150 a.m.            1.1 7.3
et al.                                                           4.8       12.9             1.6    8.0
                  After, public houae x 2 hr
GBw

Jarvis                 Hcepital clinic patients
et al.      48      NS       No expmure                     0.8
ww      27     NS                                                    1.6                  0.7
                    Litie expmum                                                     -
                                               -     1.8         -
         20     NS                                                       6.6                   2.2
                   Some expoeure                                                     -
                                               -     2.6         -         8.6
         7      NS                                                                          2.8
                   Lot of expmure                                                    -
                                                     1.8         -         9.4
        94     S                                                                        26
                                               -     276        -        1391             -     810

Hoffmann 10      NS       Rperlmental chamber
et al.                 2 ciga burned              1.7    2.6 (peak     14        21              1.2     28
ww                 Scignburned              1.0    3.0 chenge) 14        88             1.7     2.6
                   4eigsburned              0.9 9.9         14        66             1.0     1.4

Wald and   101      NS        Wife abstinent              - -        8.6 (median 6.0)
Ritchie     20      NS        Wife uaoker               - -        26.2 (median 9.0)


TABLE `I.--continued






        Number
         of    Smoking
Study     subjecte     etatue

Ekpceure level

M~I or median amcantration and raage

       Urine wtinine          sdh mtininc
       b6ld.J           WmL)


BdOl-fJ        After         hf0m    After

Wald
et al.
(1984)

221     NS
43     NS
47      NS

        43     NS
        43     NS
        46     NS
        131      S
        69     S
        42     S

Mataukura  200     NS
et al.      272     NS
ww
        25     NS
        67     NS
        99     NS
         38     NS
         28     NS

        472     NS
        392     S

Med scraening clinic patients
-   ch colleeguex
O-l.6 hr JTTS expaeurejwk
1.6-4.6 hr El?3 exposumlwk
4.5-8.6 hr El% expumlwk
8.6-20 hr ~3% expwlwk
XI-W hr E%?J expmlwk
cigarettes
wm
Pips

No home exposure
All home exposure
Home expmure:
l-9 &/day
lo-19 CigldaY
20-29 CisldaY
So-39 ciglday
> 40 ciglday

All
All

76     NS
201      NS

No workplace exposure
Workplace exposure

-        11.2
-         2.8
         3.4
         6.3
         14.7
        29.6
-        1646 (637-3326)
-         398 (613139)

-      1920 MmS-46@)

-        610 '

790

        310
        4m
-        870
-        1030
        1680

-        880
-        8620

-        220
         720


TABLE 7.-Continued

Mean or median concentration and range

Study

Number
of
aubjocta

Smoking
etatua

Expmure level

Plasma cotinine
   (nghL)

Before     After

Before

urine c&nine
ww

     After

Saliva cotinine
   b&IlL)

Before ARer

Greenberg 32
et al.      19
(1984)

NS, infants

S mother                                   361 (41-1885)        -
NS mother                                                   9 @-261
                                     -        4 0-125)         -    0 6x3)

Jarvie
et al.      269
(1965)
        98
        76
        128

Luck and 10
Nau       19
NW
         10
         9

       Children aged 11-16
NS       Neither parent SM                                                  -     0.4
                                                                     (median 0.2)
NS        SM father                                                       1.9 (1.0)
NS        SM mother                                                       2.0 (1.7)
NS       Both parents SM                                                    -     3.4 (2.4)

NS, neonates  No exposure               - -         -        0' @-w               -
NS, neonates  Nursed by S mother;          -     -                loo Qo-666)         -
       no Fps exposure
NS, infants   S mother, not nursed          - -               327 (117-780)
NS. infants    S mother, nursed;            - -               660 (226870)              -

ITS exp&ure

Serum mtinine

Pattishall 20
et al.       18

NS, children   Smokers in home                4.1                                      -
                                                                      -
NS, children   No smokers in home                1.0         -


E  TABLE CI.-Continued

Mean or median concentration nnd range

Study

Number
of
subjects

Smoking
statue

Expoeure level

PI- cotinhe
   b&W


Before     After

Before

Urine cotinine
wmu

     After

coulta8     88     NSaBed (6   No emokera in home
et al.      41    NS aged (6   1 smoker in home
w66)      21     NS aged <6   2 or more smokera in home
        200     NS aged Cl7  No smokers in home
        98     NS aged 6-17  1 smoker in home
        26     NS aged 617  2 or more mnokem in home
        316     NSaged >17  No smokers in home
        80     NSaged >17  1 emoker in home
        12     NSaged >17  2 or more smokers in home

-     -                      -          -    0, 1.7'
-     -         7                       -    3.8, 4.1
-     -                      -          -    6.4, 6.6
-     -                                0, 1.3
-                            -          -     1.6, 2.4
-     -                      -          -    6.3, 6.8
     -                      -          -    0, 1.6
-     -         -            -          -     0.6. 2.8
-     -         -            -          -     0, 3.7

`rag/me creatinine.
*median. mean.


meats-men% &i&e appears to be the short-term marker of
choice for epidemiological studies.

(6) Mean levels of urinary nicotiue and of cotinine in body fluids
increase with an increasing seKreported E!l'S exposure and with an
increasing number of cigarettes smoked per day. There is consider-
able variability in levels among individuals at any given level of self-
reported exposure.

Comparison Of Abeorption From Environmental Tobacco
Smoke and From Active Smoking

&idemiologic studies show a dose-responss r&tiomGp between
number of cigarettes smoked and lung cancer, coronary artery
disease, and other smoking-related d&eases. Aseuming that dose-
response relationships hold at the lower dose end of the expoeure-
respome curve, risks for nonsmokers can be estimated by using
measures of absorption of tobacco smoke constituenta to compare the
relative exposures of active smokers and involuntary smokers.

As diSCUSStd PreviOuSly, measures Of nicotine uptake (i.e., r&&&e
or cotinine) are the most specific markers for El% exposure a&
provide the best quantitative estimates of the dose of expoeum.
Although the ratio of nicotine to other tobacco smoke constituents
differs in mainstream smoke and sidestream smoke, nicotine uptake
may still be a valid marker of total ETS exposure. Nic@ne uptake in
nonsmokers can be estimated in several ways.

Russell and colleagues (1965) infused nicotine intravenously to
nonsmokers and compared resultant plasma and urine nicotine
levels with those observed iu nonsmokers with E'l'S exposure. An
infusion of 1 mg nicotine over 60 minutes resulted in an average
plasma nicotine concentration of 6.6 ng/mL and an average urinary
mcotine concentration of 224 ng/mL. Using these data in combina-
tion with measured plasma and urinary nicotine levels in nonsmok-
ers after 2 hours in a smoky bar, nicotine uptake was estimated as
0.22 mg per hour. Since the average nicotine uptake per cigarette is
1.0 mg (Renowitz and Jacob 19&i, Feyerabend et al. 1965), 0.22 mg of
nicotine is equivalent to smoking about onefifth of a cigarette per
hour. In m&.ng these calculations, it is assumed that the disposition
~etics of inhaled and intravenous nicotine are similar and that the
rate of nicotine expowre from ETS ifs constant.

Steady state blood cotinine concentrations can also be used to
estimate nicotine uptake. Galeazzi and colleagues (1985) measured
c(ginj.ne levels in smokers receiving various doses of intravenous
nicotine, simulating cigarette smoking, for 4 days. They described
the relationship: [steady state plasma cotinine concentration]
(ng/mL) = (0.783) x [daily nicotine uptake] (w/kg/day). With such
data, a 70 kg nonsmoker with a plasma cotinine concentration of 2.5
ng/mL would have an estimated uptake of 3.2 )~g nicotine/kg/day, or

215


0.22 mg nicotine/day, equivalent to one-f* of a cigarette. This
approach assumes that the half-life for cotinine and nicotine
ewt,iom is similar in smokers and nonsmokers, an assumption
that may not be correct Wyerematen et al. 1982).
A third approach is to compare cotinine levels in nonsmokers with
those in smokers. Jarvis and colleagues (1984) measured plasma,
saliva, and urine nicotine and cotinine levels in 100 nonsmokers
selected from outpatient medical clinics and in 94 smokers. Ratios of
average values for nonsmokers compared with smokers were as
follows: plasma cotinine, 0.6 percent; saliva cotinine, 0.6 percent;
urine &nine, 0.4 percent; urine nicotine, 0.6 percent; and saliva
nicotine, 0.7 percent. These data suggest that, on average, nonsmok-
em absorb 0.5 percent of the amount of nicotine absorbed by
smokers. Assuming that the average smoker consumes 30 mg
nicotine per day (Benowitx and Jacob 1984), this ratio predicts an
exposure of 0.15 mg nicotine, or onesixth of a cigarette per day. The
most heavily exposed group of nonsmokers had levels almost twice
the overall mean for nonsmokers, indicating that their exposure was
quivslent to one-fourth of a cigarette per day. Most studies (see
l'ables 6 and `7) report similar ratios when comparing nonsmokers
with smokers. The exception is Matsukura and colleagues (1984),
who reported urine cotinine ratios of. nonsmokers to smokers of 6
percent. The reason for such high values in this one study is
UllhOWIl.

Personal air monitoring data for nicotine exposure can also be
used to estimate nicotine uptake. For example, Muramatsu and
colleagues (1984) used a pocketable personal air monitor to study
environmental nicotine exposures in various living environments.
They reported air levels of from 2 to 48 cog nicotine/ma. Assuming
that respiration is 0.48 ms per hour and exposure is for 8 hours per
day, nicotine uptake is estimated to range from 8 to 320 w per day.
The average values are consistent with other estimates of onegixth
to onethird cigarette equivalents per day in general populations of
nonsmokers exposed to ETS.
Aa noted before, these estimates must be interpreted with caution.
Rddh absorption of nicotine in smokers and nonsmokers may
substantially underestimate exposure to other components of ETS.

Conclusions

1. Absorption of tobacco-specific smoke constituents (i.e., nicotine)
from environmental tobacco smoke exposures has been docu-
mented in a number of samples of the general population of
developed countries, suggesting that measurable exposure to
environmental tobacco smoke is common.

216


2. Mean levels of nicotine and c&nine in body fluids increase
with self+ep0rted EXS exposure.

3. Because Of the stability of cotinine levels measured at different
times during exposure and the availability of noninvasive
sampling techniques, cotinine appears to be the short-term
marker of choice in epidemiological studies,
4.Both mathematical modeling techniques and experimental
data suggest that 10 to ZO percent of the particulate fraction of
sidestream smoke would be deposited in the airway.
5. The development of specific chemical assays for human ew
sure to the components of cigarette tar is an imp0rtant
research goal.

217


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224


CHAPTER 5

     TOXICITY,
ACUTE IRRITANT EFFECTS,
AND CARCINOGENICITY
  OF ENVIRONMENTAL
   TOBACCO SMOKE