A Committee of the National Research Council’s (NRC’s) Board on Environmental Studies and Toxicology prepared this report in response to requests from two federal government agencies, the Office of Air and Radiation of the Environmental Protection Agency (EPA) and the Office of Smoking and Health of the Department of Health and Human Services. The report evaluates methodologies in epidemiologic and related studies for obtaining measurements of exposure to environmental tobacco smoke (ETS) by nonsmokers and also outlines the possible health effects of such exposures as reported in the published literature. This committee was asked to review original research data and identify research needs but was not charged with preparing policy statements or recommendations for public health actions. In particular, the NRC was asked to:
review the chemical and physical characterizations of the constituents of ETS;
include a toxicological profile of sidestream and environmental tobacco smoke;
review the epidemiologic and related literature on the health effects of exposure to ETS; and
recommend future exposure monitoring, modeling, and epidemiologic research.
To address these and related issues, the NRC formed the Committee on Passive Smoking in the Board on Environmental Studies and Toxicology of the Commission on Life Sciences. The
committee consists of professionals in a variety of fields, including epidemiology, toxicology, biochemistry, atmospheric science, biostatistics, and pulmonary physiology.
The subject of the committee’s report is the use of epidemiology and related disciplines for the study of possible health effects of exposure to ETS by nonsmokers. Smokers are also exposed to ETS, but the health effects of this exposure, which are likely to be less intense than those of active smoking, are not the subject of this report. The primary goal of the studies reviewed in this report is to determine whether there is a relationship between health outcomes in human populations and ETS-exposure of nonsmokers. It is a formidable task to assess exposure to the complex mixture of ETS with enough precision to permit use in analytic studies, including quantitative risk estimation. For some health outcomes the relevant duration of exposure may be minutes, for others it may be decades. Numerous factors, in addition to exposure to smoke, can influence the risk of illness. These other factors must be taken into account if the magnitude of the effects of exposure to ETS is to be evaluated.
ENVIRONMENTAL TOBACCO SMOKE
More than 3,800 compounds have been identified in cigarette smoke. The major source, by far, for ETS is sidestream smoke (SS) which is emitted from the burning end of a cigarette in between puffs. The remainder of ETS consists of exhaled mainstream smoke (MS), smoke which escapes from the burning end during puff-drawing, and gases which diffuse during smoking through the cigarette paper. Each of the mixtures, MS, SS, and ETS, is an aerosol consisting of a particulate phase and a vapor phase. However, the smokes of MS, SS, and ETS differ, as the result of changes in the concentrations of individual constituents, the phase (particulate or vapor) in which the constituents are present, and various secondary reactions that chemically and physically alter (“age”) the composition of the smoke. Undiluted SS contains higher concentrations of some toxic compounds than undiluted MS, including ammonia, volatile amines, volatile nitrosamines, nicotine decomposition products, and aromatic amines. However, concentrations of these SS emissions are considerably diluted in the indoor space where ETS exposures take place. The hydrophobic vapor phase
constituents of ETS are likely to enter the lung of the exposed individual, while the hydrophilic vapor phase constituents are likely to be absorbed in the upper respiratory tract. Particles <2.5 µm (in this report referred to as respirable suspended particulates [RSP]) dominate the particulate phase of ETS and can be inhaled deeply into the lung.
Standard laboratory procedures have been established to assess the physicochemical properties of SS and MS. Research is needed to standardize both the collection and evaluation of ETS so that the effects of ETS can be studied in laboratories and in human populations.
The changes in distribution of particular constituents of ETS as the smoke ages in the indoor environment are largely unknown. For example, it is known that almost all of the nicotine shifts from the particulate phase in MS and fresh SS to the vapor phase in ETS. Consequently, indoor air-cleaning systems designed to remove particles will not greatly alter the nicotine exposure, but may alter the concentrations of other noxious or toxic components. Research is needed to determine the distribution of constituents in the particulate and vapor phases of aged ETS. Also, the efficiency of air-cleaning systems in removing the constituents needs to be studied.
Indoor radon comes from sources in the environment and decays to short-lived radon daughters, which may become bound to the RSP in ETS. However, some long-lived radon daughters come from tobacco itself. Research should be conducted on possible interactions between ETS and radon daughters, especially as radon daughters can adhere to RSP and increase the potential hazard of ETS.
MEASURES OF EXPOSURE
There are currently no direct measures of the dose absorbed of ETS in a population under study. Exposures to ETS, however, can be assessed by questionnaires, air monitoring, modeling of concentrations, or biological markers. Future epidemiologic studies should incorporate into their design several of these exposure assessment methods in order to assess exposures to ETS more accurately and to estimate dose.
The simplest measure of ETS exposure is contained in the reply to the questions: “Are you a cigarette smoker?” and “If you are a nonsmoker, do you live with, or work with, or have regular contact with persons who are smokers?” There are great difficulties in developing uniform questions that elicit unambiguous replies and, more particularly, in using these replies to make firm quantitative estimates of exposure. They can be used, however, as a basis for classifying individuals into broad categories of exposure, recognizing the problems such as incorrectly estimating exposure through errors in reporting of current smoking habits, neglecting exposure to ETS in other environments like workplaces or public places, and reporting an exsmoker as a nonsmoker. Reports of whether or not the subject has smoked can be obtained with reasonable reliability from surrogate respondents. However, quantification of integrated exposure over many years is not likely to be fully reliable or precise. At best, such quantification provides an approximation of exposure, whether the information is obtained from the individual himself or from a surrogate. To estimate integrated exposure to ETS, future studies need to estimate a long-term ETS exposure history, including what fraction of the day is spent in the presence of ETS and at what ages these exposures occurred. The data from such a history should be entered into a specific time-place model, from which cumulative exposure can be estimated.
The use of air monitoring (personal or indoor space) is handicapped by the lack of a clear definition of the physicochemical nature of ETS and the identification of the individual, or target, constituents of ETS associated with the health or comfort effects under study. Proxy, or surrogate, constituents have been measured in a number of studies as indicators of ETS exposure in both personal and indoor space monitoring. RSP, carbon monoxide, nicotine, nitrogen oxides, acrolein, nitroso-compounds, and benzo[a]pyrene are some of the compounds or classes of air contaminants that have been measured under field conditions as indicators of ETS exposure. While some of the ETS constituents, particularly nicotine and RSP, have proved to be useful surrogates
for ETS, no single measure has completely met all the criteria for an ideal ETS surrogate. To facilitate the study of the health effects of ETS exposure, an ideal marker or tracer of exposure to ETS should be unique (or nearly unique) to tobacco smoke, should be a constituent of tobacco smoke that is present in sufficient quantity so it can be measured even at low ETS levels, and should stand in a fairly constant ratio across brands of cigarettes to other tobacco smoke constituents (or contaminants) of interest. Reliable information needs to be obtained on the quantity, transport, and fate of such chemicals in ordinary indoor environments.
A majority of field studies have used RSP as an indicator of exposure to ETS because of the substantial emission of RSP in indoor spaces from tobacco combustion. ETS is the dominant contributor to the indoor levels of RSP. The total RSP, as measured by personal monitors, has been found to be substantially elevated for individuals who reported being exposed to ETS as compared with those who reported no such exposure. Both air monitoring and modeling clearly indicate that RSP concentrations will be elevated over background levels in indoor spaces when even low smoking rates occur. The importance of variation in the input parameters-such as room size, temperature, humidity, air exchange rate, and numbers of cigarettes smoked—should be noted when interpreting the data on the constituents of ETS obtained from personal monitors and indoor space monitors.
In theory, dose of ETS to the tissues or organs could be measured directly through the use of biological markers that accurately indicate uptake in the tissues or organs. Optimal assessment of exposure to ETS should derive from measures made on physiological fluids of exposed persons. Several chemicals found in such fluids may be able to serve as biological markers of recent exposures. The criteria for acceptable biological markers are similar to those for measuring ETS in the external environment.
The biological markers that have been most useful for assessing recent exposures to ETS are nicotine and its metabolite, cotinine. Nicotine and cotinine derive virtually exclusively from tobacco products, of which tobacco smoke is the most important direct source. They can be identified and quantified in saliva, blood, or urine. Generally, the mean concentrations of nicotine
and cotinine in the plasma or urine of nonsmokers exposed to ETS are about 1 percent of the mean values observed in active smokers. Several studies have indicated that urinary cotinine concentrations in infants and children increase as the numbers of reported smokers increase in the home. At present, there may be difficulty in interpreting the relative cotinine levels in nonsmokers compared with smokers because of the reported slower clearance of cotinine in nonsmokers. Absorption, metabolism, and excretion of ETS constituents, including nicotine, need to be carefully studied in order to evaluate whether there are differences between smokers and nonsmokers in these factors. Further epidemiologic studies using biological markers are needed to quantify exposure-dose relationships in nonsmokers.
Thiocyanate, as measured in saliva, serum, or urine, does not appear to be sufficiently sensitive as an indicator of ETS exposure. Similarly, exhaled carbon monoxide and carboxyhemoglobin are not sufficiently sensitive to moderate or low levels of ETS exposure and thus are not particularly useful biological markers for exposure to ETS, except in experimental, acute exposure situations. There are several other sources of carbon monoxide in the environment that equal or exceed the concentrations of carbon monoxide attributable to ETS.
Other suggested biological markers of exposure are N-nitrosoproline, nitrosothioproline, and some of the aromatic amines that are present in high concentrations in SS. However, data on sensitivity and reliability of laboratory procedures for these markers are not sufficient to recommend their use at this time in epidemiologic studies of ETS.
Laboratory assays have shown mutagenic activity in the urine of smokers and ETS-exposed nonsmokers. The mutagenicity of urine is a function of many factors—such as dietary constituents, occupational exposures, and other environmental factors—which render any findings of mutagenicity nonspecific. Research is needed to clarify the appropriate methods for estimating mutagenicity and to isolate and identify the active agents in body fluids of ETS-exposed nonsmokers.
DNA adducts derived from tobacco-related chemicals can be measured in the blood. However, these chemicals, such as benzo[a]pyrene, are not unique to ETS. Studies are needed that can measure adducts of tobacco-specific chemicals.
IN VIVO AND IN VITRO STUDIES
Laboratory studies can contribute to a better understanding of the factors and mechanisms involved in the induction of disease by environmental agents. There have been numerous bioassays conducted on MS. In examining the effects of MS, many research workers have used condensates of the smoke painted on the shaved skin of mice. This contrasts with the human exposure that is mainly in the respiratory tract. Nonetheless, these skin-painting studies have been useful in examining the carcinogenicity of different tobacco constituents and thus advancing knowledge of the actions of MS on a gross exposure level. Similar work with skin painting has not been done with ETS and would be of value for assessing the differential toxicity of ETS and MS.
In constrast to MS exposure, ETS exposure involves proportionately more exposure to gas phase than to particulate phase constituents. There have not, however, been studies of the effects of exposure to aged ETS. The relative in vivo toxicity of MS, SS, and ETS needs to be assessed.
Some studies have attempted to evaluate the gas phase of MS, SS, and ETS in short-term, in vitro assays. A solution of the gas phase of MS has been shown to induce dose-dependent increases in sister-chromatid exchanges in cultured human lymphocytes. Mutagenic activity has been found in the particulate matter of SS and in condensates of ETS. However, the work done to date is too sparse to permit any estimates of the mutagenicity of ETS per se, even though most of ETS consists of SS. Further in vitro assays of ETS are needed.
This report reviews both chronic and acute health effects associated with ETS exposure in nonsmokers. Most epidemiologic studies of chronic health effects have been conducted on persons who have had long-term exposures to ETS from household members. The studies do not directly address chronic health effects in individuals who are exposed at work or have occasional exposures in the home or elsewhere.
Because the physicochemical nature of ETS, MS, and SS differ, the extrapolation of health effects from studies of MS or of
active smokers to nonsmokers exposed to ETS may not be appropriate. However, chemicals known to be toxic and carcinogenic in MS are also present in ETS. Laboratory studies in conjunction with epidemiologic investigations are needed to help clarify possible health effects of exposure to ETS in nonsmokers.
Acute, Noxious Effects
The most common acute effects associated with exposure to ETS are eye, nose, and throat irritation, and objectionable smell of tobacco smoke. Tobacco smoke has a distinct and persistent odor, making control through ventilation particularly difficult. In closed rooms where smoking is allowed, a ventilation rate of greater than 50 cubic feet per minute per occupant is necessary to achieve air quality that is acceptable to more than 80% of adults entering the room as contrasted with rates of less than 10 cubic feet per minute per occupant when there is no smoking or other pollution. Annoyance with noxious tobacco odor largely governs the reactions of visitors, while occupants of smoky rooms are more likely to complain about irritating effects to the eye, nose, or throat. Particle filtration appears to lead to little or no decline in odor and irritation, suggesting that the effects are produced by gas-phase constituents. During exposure to ETS, eye blink rate is correlated with sensory irritation, such as burning eyes and nasal irritation. For some persons, eye tearing can be so intense as to be incapacitating. There is some evidence that nonsmokers are more sensitive to the noxious qualities of cigarette smoke than are smokers. Objective physiological or biochemical indices should be sought to validate reports of noxious reactions and chronic irritation associated with ETS.
Smoke contains immunogens, that is, substances that can activate the immune system. Approximately half of atopic (allergy prone) individuals react to various extracts of tobacco leaf or smoke presented in skin tests. However, the components of the extract that are responsible for this reaction have not been isolated. There is little correlation between positive reactions to skin tests and self-reported complaints of tobacco smoke sensitivity. Research is needed to evaluate the medical importance in atopic persons of these positive reactions to skin tests using ETS extracts and to relate immune response on skin tests to subjective complaints about the noxious, irritating properties of tobacco smoke.
Respiratory Symptoms and Lung Function
Respiratory symptoms, such as wheezing, coughing, and sputum production, are increased in children of smoking parents. These symptoms are more common in children of smokers than children of nonsmokers. The largest studies place the increased risk of 20 to 80%, depending on the symptom being assessed and number of smokers in the household. Also, respiratory infections manifested as pneumonia and bronchitis are significantly increased in infants of smoking parents. Some studies have reported that infants of smoking parents are hospitalized for respiratory infections more frequently than children of nonsmokers. Among children aged under 1 year, studies are remarkably consistent in showing an increased risk of respiratory infections among children living in homes where parents smoke. There is a dose-response relationship that relates more to maternal smoking than paternal smoking. The association persists after allowing for possible confounding factors such as occupational data, respiratory illness in the parents, and birthweight. The mechanisms of the increased risk may either be a direct effect of ETS or due to a higher risk of cross-infection in such homes. Regardless of the mechanism, the exposure of small children to smoking in the home appears to put them at risk of respiratory illness.
Since children exposed to ETS from parental smoking have an increased frequency of pulmonary symptoms and respiratory infections, it is prudent to eliminate ETS exposure from the environments of small children.
There is some evidence that parental smoking may affect the rate of lung growth in children. In children with one or more parents who smoke, lung function increase, which is a normal growth phenomenon, shows a small decrease in the rate of growth. An important issue currently unresolved is whether a child who is affected by exposure to ETS from parental smoking may be at an increased risk for the development of chronic airflow obstruction in adult life. In all studies of children, it is difficult to distinguish between the role of ETS exposure in utero and postnatally. Research is needed to address the issues of ETS exposure during childhood and fetal life and its possible relationship with airway hyperresponsiveness and pulmonary diseases in adult life.
Three studies have shown a small reduction in pulmonary function in normal adults exposed to ETS. Interpretation of these findings is difficult because pulmonary effects in normal adults are likely to reflect the cumulative burden of many environmental and occupational exposures and other insults to the lung. Thus, the effects of ETS on the lungs of adults are likely to be confounded by many other factors, making it difficult to attribute any portion of the effect solely to ETS.
In some studies of asthmatics, in whom pulmonary reactions to ETS should be more readily produced, no effects on lung function were reported. In other studies, asthmatics reported complaints upon exposure to ETS and showed significant pulmonary function changes after experimental smoke exposure. Future studies of asthmatics exposed to ETS should be designed so as to limit the distortion produced by heterogeneous patient groups, varying medication schedules, and psychogenic effects of ETS.
Considering the evidence as a whole, exposure to ETS increases the incidence of lung cancer in nonsmokers. Estimates of the magnitude of the increased risk vary. Among studies of various populations in Europe, Asia, and North America, the risk of lung cancer is roughly 30% higher for nonsmoking spouses of smokers than it is for nonsmoking spouses of nonsmokers. There is consistency among the studies in that all of the studies individually include the 30% increased risk within the 95% confidence intervals. Patterns and extent of exposure may vary in different communities and countries. Based on presently available epidemiologic data, the estimate of the increased risk from the American studies is lower than the average for all the studies, though not significantly so. These estimates are almost exclusively derived from the comparison of persons identified as exposed, or unexposed, on the basis of their spouse’s smoking habits.
Certain errors in the reporting of smoking habits have probably contributed to the risks observed in the epidemiologic studies. Misclassification of current or exsmokers as nonsmokers would tend to produce an observed relative risk that is larger than the true risk. This effect was studied in detail using estimates of the extent of the errors involved and judged to contribute only a portion of the excess risk. Underestimation of the increased risk might also
be introduced because the supposedly unexposed population had some exposure to ETS, although they were classified as unexposed in the studies. Taking both types of errors into account produces an estimate of the excess lung cancer risk for nonsmokers married to smokers compared with completely unexposed individuals that is similar to the relative risk observed in the epidemiologic studies considered.
Since carcinogenic agents contained in ETS are inhaled by nonsmokers, in the absence of a threshold for carcinogenic effects, an increased risk of lung cancer due to ETS exposure is biologically plausible. Laboratory studies would be important in determining the concentrations of carcinogenic constituents of ETS present in typical daily environments. The use of biological markers in epidemiologic studies is recommended to more precisely quantify dose-response relationships between ETS exposure and lung cancer occurrence.
There have been few studies of risk for cancers other than lung in nonsmokers exposed to ETS. Some of the sites considered have been brain, hematopoetic, and all sites combined. The results of these studies have been inconsistent. Whether or not there is an association between ETS exposure and cancers of any site other than lung is an important topic for future epidemiologic inquiries.
Since active smoking has an adverse effect on cardiovascular disease morbidity and mortality, ETS exposure has also become suspect. Reports have noted an excess risk of cardiovascular disease in ETS-exposed nonsmokers; however, methodologic problems in the designs and analyses of these studies preclude any firm conclusions about the results. Studies reporting that ETS can precipitate the onset of angina pectoris among people who already have this condition are subject to the same precautionary note. Exposure to ETS produced no statistically significant effects on heart rate or blood pressure in school-aged children or healthy adult subjects, either during exercise or at rest. Data are not available as to possible adverse cardiovascular effects in susceptible populations, such as infants, elderly, or diseased individuals.
Further experimental and observational studies should be conducted to assess the effect of long-term and acute ETS exposure on cardiac function, blood pressure, and angina in nonsmokers.
Other Health Considerations in Children
Several other health outcomes have been studied that relate to the growth and health of children. For all postnatal outcomes, it is often not possible to differentiate the effect of in utero exposure to ETS from subsequent childhood exposures to ETS.
Nonsmoking pregnant women exposed to smoking spouses have been reported to produce babies of lower birthweight than nonsmoking women with nonsmoking spouses. Some studies have noted a dose-response relationship between the number of cigarettes smoked by fathers and birthweight of the offspring. Additional studies of intrauterine fetal growth retardation associated with ETS exposure of nonsmoking mothers need to be conducted with better assessments of the magnitude of ETS exposure.
Several studies have examined possible relationships between chronic exposure to ETS by children and parameters of growth and development. Growth is an especially difficult phenomenon to study since many factors—such as genetics, nutrition, social class, and ethnicity—play important roles. It is difficult to assign proportional causality to each factor. Moreover, height and weight ratios and other growth measures are not reliably obtained in standard pediatric surveys. A few studies have shown that children of smokers have reduced growth and development, and one study reported a dose-response relationship between reduced height and increasing numbers of cigarettes smoked in the home by either the mother or the father. Further work is needed to determine the nature of this association.
Otitis media is a common occurrence in young children. In several studies, parental smoking, along with several other risk factors, has been linked to increased risk of chronic ear infections in children. Further work is needed to determine whether the association is causal.