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. 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