Overall, the epidemiologic data strongly support a relationship between ETS exposure in the home and either acute otitis media with effusion or serous otitis media (middle ear effusion without acute infection), particularly among children under two years of age. Limitations of available data on the chronicity of physical findings, as well as the differing patterns of recruitment in the various studies, make it impossible to distinguish separate relationships between ETS exposure and acute serous otitis media, chronic serous otitis media, and acute infectious otitis media.

Several reports on the relationship between ETS exposure and otitis media have been published since the draft release of the earlier draft of this chapter (Collet et al., 1995; Ey et al., 1995; Kitchens et al., 1995). The results of these investigations (summarized in Table 6.4) are consistent with the conclusions articulated above.

6.1.3.4 Biological Plausibility

Eustachian tube dysfunction (ETD) plays a central role in the pathogenesis of middle ear disease. While the U.S. EPA did not find plausible biological mechanisms for ETS-related acute otitis media, there are at least four mechanisms whereby ETS might produce Eustachian tube dysfunction. These include:

1) Decreased mucociliary clearance

2) Decreased Eustachian tube patency due to adenoidal hyperplasia

3) Decreased patency due to ETS-induced mucosal swelling

6.1.3.5 Dose-response and attributable risk considerations

Etzel et al. (1992) estimated that, with the relative risk of otitis media with effusion (OME) as a function of ETS exposure peaking at 1.62 at age 18 months -- and with an estimated exposure prevalence of 38% (North Carolina) -- some 8% of otitis media episodes occurring between ages 6 and 24 months are attributable to ETS exposure. Iverson (1985) calculated that for Danish children attending day care (estimated ETS exposure prevalence, 60%), 15% of middle ear effusions (MEE) may be smoking-related, with the ETS-attributable fraction actually greater in the 6 to 7 year old group than in younger children. Strachan (1989) computed the odds ratio for MEE in 6.5 to 7.5-year-old children as a function of a doubling of salivary cotinine as 1.14 (crude) or 1.13 (adjusted for gender and housing type). As median cotinine levels in that study varied by a factor of 25 (or 4.5 doublings) between the unexposed children and those living with at least two smokers, odds ratios as high as 1.69 were observed in the more highly-exposed children.

An estimate of yearly physician office visits for early childhood otitis media episodes attributable to ETS exposure in California can be derived as follows:

a = p (R-1) / (p(R-1) +1)

Combining the above data, one obtains an estimate of almost 135,000 (95% confidence limits, 78,615-188,676) office visits per year among California children under age three years for ETS-attributable otitis media episodes:

At the national level, this would roughly correspond to 700,000 to 1.6 million physician office visits annually, assuming approximately 88% of U.S. children under age three reside outside California.

A substantial body of literature addresses the acute and reversible irritative effects of ETS on the upper respiratory tract. Symptoms subsumed in this category include eye, throat, and nasal irritation, rhinorrhea, nasal congestion, hoarseness, and odor "annoyance." ETS-related irritant and annoyance effects were reviewed in both the Surgeon General's and NRC reports (U.S. DHHS, 1986; NRC, 1986), and more recently by Samet et al. (1991). In the period since these reports were written, additional insight has been gained into the pathophysiology of upper airway irritant responses, and progress has been made in developing objective methods to validate ETS-related symptom complaints. In this section we will first review exposure dynamics and pathophysiology before considering the newer epidemiological and experimental literature. Whereas ETS is frequently dealt with as a general cofactor in the study of indoor air quality, this literature review has been restricted to studies in which ETS effects are examined directly.

6.1.4.1 Exposure Dynamics

As noted in the chapter on Exposure Measurements and Prevalence, ETS consists of a complex and dynamic mixture of particulate and vapor phase constituents. There is some evidence that the perceived odor and irritation associated with ETS derives from the vapor, rather than particulate phase; however, the data are not conclusive (Hugod, 1984; Weber, 1984). The chemical constituents of ETS thought responsible for sensory irritation include aldehydes (formaldehyde and acrolein), ammonia, pyridine, toluene, sulfur dioxide, and nitrogen oxides, among others (U.S. DHHS, 1986; Ayer and Yeager, 1982; Triebig and Zober, 1984).

The site of action of various respiratory tract irritants is thought to be governed by three factors: 1) particle size (for irritants adsorbed to particulates), 2) water solubility (for gaseous and vapor-phase inorganics), and 3) lipid solubility (for vapor-phase organics). In general, the larger the particle or the more water soluble the compound, the higher the proportion of the inhaled dose that is likely to be deposited in the upper respiratory tract, particularly during nasal breathing. In addition, for a given deposited dose of an organic compound, higher lipid solubility augments the irritant efficiency of the stimulus, apparently by increasing access to the membrane receptor (Nielsen, 1991). Of note, many of the gaseous and vapor phase irritants in ETS have sufficient water solubility to be active on the upper respiratory tract (i.e., nasal cavity, nasopharynx, and hypopharynx) (U.S. DHHS, 1986).

6.1.4.2 Pathophysiology

ETS stimulates the sensory apparatus of the upper respiratory tract through four structures: the olfactory, trigeminal, glossopharyngeal, and vagus nerves (cranial nerves I, V, IX, and X). The olfactory nerve is responsible for the sense of smell, and projects to areas of the primitive forebrain responsible for emotional arousal, including the amygdala and portions of the frontal and temporal lobes. The nasal and oral cavities are innervated by the trigeminal nerve, the nasopharynx by the glossopharyngeal, and the oro- and hypopharynx by the vagus; these nerves project to various areas of the brainstem. The trigeminal, glossopharyngeal, and vagus nerves are responsible for the perception of touch, temperature, and sensory irritation (or what has been termed the "common chemical sense") in all head and neck mucosae. The two nasal senses -- olfaction and irritant chemoreception -- as well as the related sense of taste, functionally interact to produce an integrated impression of one's chemical environment (Cain, 1974; Cain and Murphy, 1980; Frank and Rabin, 1989).

The olfactory epithelium occupies a total area of approximately 5 cm² bilaterally in the upper reaches of the nasal cavity. The olfactory apparatus is variably stimulated during normal relaxed nasal breathing; "sniffing," or attentive smelling, creates eddy currents which facilitate the delivery of odorant molecules to the olfactory epithelium. Lipophilic molecules diffuse through the nasal mucus layer, probably aided by an olfactory binding protein, to make contact with receptor sites on olfactory receptor cells (Pevsner, 1988). The olfactory receptor cells are the only central nervous system neurons known to regenerate on a regular basis; this may constitute a functional response to the fact that olfactory receptor cells are directly exposed to a variety of environmental insults (Frank and Rabin, 1989).

In contrast to the limited distribution of olfactory receptor cells, trigeminal nerve endings are located throughout the nasal and oral cavities. (The vagus nerve innervates the lower respiratory tract, including the trachea, and tracheobronchial tree.) Trigeminal fibers carry sensory information of a variety of types; of primary interest here is the chemosensory function of irritant perception. Irritant perception involves free nerve endings which terminate a short distance below the mucosal surface. The nerve fiber type thought to be responsible for mediating airborne chemical irritation (both in the upper and lower respiratory tract) is the small-diameter, unmyelinated, capsaicin-sensitive C fiber (Lundberg et al., 1988, 1991; Silver, 1992), although A₂ (delta) fibers have also been implicated in some studies (Hummell, 1992).

Important for purposes of understanding the upper airway response to ETS is the fact that trigeminal stimulation can activate both long and short reflex arcs. The long reflex arc involves the trigeminal nerve for the afferent (perceptual) limb and the facial nerve (cranial nerve VII) for the efferent (effector) limb. Exposure to intense irritants anywhere within the nasal or oral cavities produces reflex rhinorrhea and lacrimation via a long reflex arc, autonomic (cholinergic) response. On provocative irritant testing (e.g., after ingestion of horseradish), subjects typically experience subjective nasal stuffiness and rhinorrhea and have acute increases in nasal airway resistance, dilation of vessels within the nasal mucosa, and increased content of plasma and glandular proteins in nasal secretions. This response is mimicked by local instillation of methacholine (an acetylcholine analog), and is blocked by pretreatment with atropine (an acetylcholine antagonist) (Raphael et al., 1991).

For mild to moderately intense irritant stimuli, local reflexes may predominate over the long-arc autonomic response. The so-called "axonal" response is a local reaction in which neuropeptides (vasoactive peptides including substance P, neurokinin A, gastrin-releasing peptide, and calcitonin gene-related peptide) are released from sensory nerves near the mucosal surface. Interestingly, this reflex involves the sensory limb of the nerve only, and is analogous to the so-called "wheal and flare" reaction observed upon mechanical stimulation of the skin. Depending upon the specific peptides involved, these mediators produce some combination of engorgement of blood vessels, transudation of fluid and plasma proteins into tissues, stimulation of secretions, and migration of inflammatory cells (Baraniuk, 1990; Lundberg, 1991; Silver, 1992; Widdicombe, 1990). Apparent cross-species differences in both the distribution of mediators and their physiological effects have posed a challenge to researchers attempting to understand the axonal response in the human airway (Bascom, 1991). Newer studies of airway responses to ETS should be viewed against a background of more traditional methods in irritant toxicology. Animals exposed to highly water soluble upper respiratory tract irritants reveal predictable changes in respiratory pattern, including slowing of respiration, sneezing, coughing, and increased secretions (Alarie, 1973). In humans, the analogous respiratory pattern is an involuntary pause during inspiration or actual breath-holding (Cain, 1987a). Exposure levels necessary to produce these responses, however, are generally high, and researchers in the field of indoor air quality and ETS have searched for more sensitive indices of respiratory tract irritation. As noted below, evidence of true "allergic" upper airway reactions to ETS is quite limited.

6.1.4.3 Specific Health Effects

Eye Irritation

In several questionnaire studies, eye irritation was the most commonly reported mucous membrane symptom among non-smokers exposed to ETS (Bascom, 1991; Basu, 1978; Shephard, 1979; Speer, 1968; White, 1991). The cornea is richly innervated with trigeminal nerve endings that are sensitive to both mechanical and chemical stimuli, and blinking occurs reflexively in response to corneal stimulation. Experimentally, Weber et al. (1976, 1984, 1987) and Muramatsu et al. (1983) exposed volunteers to progressively increasing concentrations of environmental tobacco smoke; as exposure duration and intensity increased, subjects began to report subjective eye irritation, and blink rate also increased. In another human experimental study, researchers measured precorneal (tear) film breakup time, using fluorescein dye both pre- and post-exposure to ETS. A significant decrease in tear film breakup time occurred after ETS exposure (i.e., the tear film was less stable after ETS exposure) (Basu, 1978). Both blinking and lacrimation act as protective responses to airborne irritants by restoring the protective tear film and diluting any chemical insult. The literature on ETS-induced eye irritation was reviewed in greater detail in the Surgeon General's report (U.S. DHHS, 1986, pp. 234-238).

Nasal Irritation

Bascom (1991) and Willes (1992) identified a subgroup of research subjects who reported a variety of nasal symptoms (congestion, rhinorrhea, sneezing, and postnasal drip) upon prior exposure to ETS. This group comprised approximately one-third of their study population, and were labeled the "historically ETS-sensitive" subgroup in the authors' subsequent provocative testing protocol. Using a climate-controlled exposure chamber, the investigators conducted ETS challenge testing, examining a variety of endpoints. Historically ETS sensitive, but not ETS non-sensitive, subjects showed significant increases in nasal airway resistance (NAR) by rhinomanometry after 15-minute exposures to ETS at levels chosen to simulate a smoking lounge. These changes in objectively measured NAR paralleled the onset of symptoms of nasal stuffiness and rhinorrhea. Although the symptoms described above resemble those of allergic rhinitis, the authors noted that only a small proportion of historically ETS-sensitive subjects have positive skin test reactivity to tobacco-leaf extract (see review of tobacco allergy in Stankus, 1988, pp. 283-285). To investigate the mechanism(s) underlying the responses they observed, Bascom et al. (1991) performed nasal lavage pre- and post-ETS exposure. Although allergy-like nasal symptoms were provoked acutely, traditional markers of allergic nasal response (including histamine, various kinins, and albumin) were not found to be increased post-exposure. These findings were taken as evidence that acute nasal responses to ETS may occur via non-allergic, irritative mechanisms (see discussion of vasoactive peptides, above). Despite a lack of evidence for direct allergic mechanisms, individuals who display both subjective and objective ETS sensitivity are more likely than ETS-insensitive subjects to have documented non-tobacco allergies, implying a modulatory effect of allergy upon the irritant chemoreceptive system (Bascom, 1991; Cummings, 1991).

Alteration of Sensory Thresholds

Chronic exposure to cigarette smoke has the ability to change apparent chemosensory sensitivity to airborne odorants and irritants; in at least one case, these observations extend to passive as well as active smokers. Ahlstrom et al. (1987) tested smokers, nonsmokers, and passive smokers for odor acuity to n-butanol and pyridine (the latter being a constituent of tobacco smoke). Both active and passive smokers reported lower perceived odor intensities (i.e., were less sensitive) than nonsmokers. Cometto-Muñiz (1982) and Dunn (1982) examined the endpoint of altered respiration (reflex transitory inspiratory pause) as a measure of nasal irritant sensitivity. Both researchers reported higher irritation thresholds (i.e., lower sensitivity) among smokers versus nonsmokers exposed to a non-odorant stimulus (high-level carbon dioxide); they did not, however, test passive smokers. Kjaergaard (1990; 1992) exposed smokers and nonsmokers to carbon dioxide by mask to determine eye irritation thresholds, and found no appreciable difference in sensitivity between the two groups; again, passive smokers were not tested. No published studies were identified which examined trigeminal irritant thresholds among passive smokers.

A number of mechanisms could explain observed sensory shifts in active and passive smokers. Decreased odor acuity among smoke-exposed individuals could result from increased nasal secretions, which in turn would pose an increased diffusion barrier to odorant molecules. Alternatively, habituation (in effect, ignoring the stimulus) may explain the odor perception findings; Ahlstrom (1987) emphasized the latter possibility because passive smokers did not differ from nonsmokers in the number of "zero intensity" responses given. Shifts in irritant thresholds could result from depletion of neuropeptides in trigeminal sensory fibers; this phenomenon has been documented after high-level treatment with capsaicin (the irritant constituent in hot peppers) (Lundberg, 1983). As noted above, however, reports of altered irritant thresholds due to ETS exposure have not appeared in the literature to date.

Odor "Annoyance"

"Annoyance" is a subjective state of displeasure resulting from a defined environmental stimulus. In the context of ambient (outdoor) air pollution, citizen reactions to unpleasant odors are responsible for the majority of publicly initiated complaints to air quality management districts in California, and may give rise to so-called "nuisance" abatement actions. ETS contains a number of odorant compounds (e.g., pyridine) which are typically described as unpleasant. It is not surprising, then, that even in the absence of eye or other mucous membrane irritation, nonsmoking citizens often complain of annoyance from the odor of ETS in indoor settings. This endpoint has been discussed extensively in the National Research Council report (NRC, 1986, pp. 166-181) and by Samet et al. (1991, pp. 152-160). In addition to annoyance, indoor air quality researchers have shown that unpleasant odors detract from the sense of well-being of building occupants and interfere with concentration and productivity (Rotton, 1983).

Cain and co-workers (1983) demonstrated that nonsmokers, on the average, are more likely than smokers to complain of an offensive odor when exposed to a given dilution of smoke-contaminated indoor air. They also showed that when smokers and nonsmokers occupy the same air space, air dilution rates required to render odorant levels acceptable to nonsmokers may be unrealistically high from an engineering standpoint. The practical implication of these findings is that apparently only a strict no-smoking policy, or segregation of smokers into areas with separate, nonrecirculating air supplies, protects nonsmoking building occupants from annoyance and associated effects.

6.1.4.4. Dose-response considerations

Cain et al. (1987b), using a climate-controlled exposure chamber, found that 10% of nonsmoking subjects complained of unacceptable air quality (either due to eye irritation or odor annoyance) when ETS raised carbon monoxide (CO) levels by 2 ppm over background, and over 20% expressed dissatisfaction at 5 ppm over background. Muramatsu et al. (1983) reported that nearly 30% of experimental subjects had complaints of moderate-to-severe eye irritation with ETS-derived CO levels 2.5 ppm over background. By comparison, CO levels can reach up to 10 ppm over background in smoking-permitted offices (average, 2.5-2.8 ppm), and as high as 29 ppm (average, 4.8-17 ppm) in taverns (Triebig and Zober, 1984). Although most experimental work on sensory annoyance has been performed using CO as an index of ETS exposure, some investigators believe that CO, itself being odorless and non-irritating, is an insensitive and unreliable surrogate measure for irritant and odorant exposure (Chapelle and Parker, 1977).

6.1.4.5. Summary

ETS exposure produces a variety of irritative symptoms involving the upper respiratory tract and eyes; increasingly, these endpoints are able to be objectively documented and quantified. In addition to irritation, odor annoyance from ETS may detract significantly from subjective well-being and productivity among building occupants. Experimental studies conducted by investigators familiar with building ventilation practice suggest that, short of prohibiting indoor smoking, protection of nonsmokers against both sensory irritation and odor annoyance can only be achieved through extreme engineering measures.

There is considerable evidence that continuing exposure to cigarette smoke results in the induction of asthma in children. Two large cross-sectional studies involving a total of about 8,000 children and adolescents resulted in odds ratios of approximately two for the presence of asthma with parental smoking (Burchfiel et al., 1986) or maternal smoking (greater than 10 cigarettes a day) (Weitzman et al., 1990). In a longitudinal investigation of asthma incidence among 774 children up to 5 years of age at entry, Martinez et al. (1992) reported a relative risk of 2.5 (95% CI = 1.4, 4.6) when maternal smoking exceeded 10 cigarettes/day and the mother had at most a high school education. Another prospective study of 770 school children, however, found no effect of maternal smoking on asthma prevalence at the inception of the study or on incidence during 11 years of follow-up (RR = 1.1, 95% CI = 0.7, 1.7) (Sherman et al., 1990). The U.S. EPA (1992, p. 7-51) reviewed these and other studies and stated that, "The consistency of all the evidence leads to the conclusion that ETS is a risk factor for inducing new cases of asthma. The evidence is suggestive of a causal association but is not conclusive."

To investigate the relationship between ETS exposure and childhood asthma more thoroughly, a meta-analysis of studies purporting to examine this issue was undertaken. We conducted a MEDLINE search to identify all epidemiologic studies published between 1975 and 1995 examining ETS exposure as a risk factor for the induction of childhood asthma. Sixty-eight studies were identified as potentially relevant. Studies were selected for inclusion if they met the following four criteria. First, the endpoint studied must represent the development of asthma in persons < 18 years of age. Because of difficulties related to the diagnosis of asthma, particularly in young children, studies that examined outcomes of "wheezy bronchitis" or "constant wheeze/whistling in chest" were also included and analyzed both separately and jointly with those studies which examined only physician-diagnosed asthma. Second, the exposure studied must represent post-natal household sources of ETS. While studies were not excluded for failure to evaluate separately the effects of post- and pre-natal exposures, they were excluded if they only examined in utero exposures to ETS. Third, odds ratios or relative risks must be reported or sufficient data must be presented to allow for calculation of risk ratios and estimates of their standard errors. Lastly, studies must be independent. If more than one study reported on the same cohort of children, then the study that best met the previous three criteria was selected for inclusion.

Thirty-one studies were excluded for failure to meet one or more of the inclusion criteria. We extracted the risk ratios and standard errors from each of the remaining 37 studies, or calculated them using formulae given by Greenland (1987).

We used the random-effects model proposed by DerSimonian and Laird for this analysis (1986). Under the DerSimonian and Laird model, a pooled risk ratio (pooled RR) is calculated as a weighted average of the risk sizes reported by each study. Each study is weighted by a factor equal to the inverse of the variance of the true underlying effect size (estimated by the among-study variance (t2 ) added to its own within-study variance (s2)). Because significant among-study variance was detected, potential sources of heterogeneity by subset analysis and linear meta-regressions were evaluated. Indicator variables were created a priori to characterize study design (case-control, cohort or cross-sectional), exposure metric (level and method of measurement), outcome metric (wheeze or asthma), method for identifying cases (parental reporting or medical record extraction), year of publication, age of study participants (preschool, school-age, or all ages), location (North America, Europe or elsewhere), and covariates controlled for in the analysis (i.e., age, sex, socio-economic status, family history of atopy/asthma, reporting of parental respiratory symptoms, early childhood respiratory illness, history of breast-feeding and, in studies involving children older than 10 years of age, the children’s own smoking habits). These indicator variables were then used in the subset and meta-regression analyses to explore sources of heterogeneity.

Of the 37 studies included in this analysis, all but three reported a risk ratio (RR) greater than 1.0, albeit many were not statistically significant at a = 0.05. The pooled RR for those studies with clinically diagnosed asthma as the outcome was 1.45 (95% CI = 1.28 - 1.65) and did not significantly differ from that of studies examining "wheezy bronchitis" or "chronic wheeze/whistling in chest" (pooled RR = 1.47, 95% CI = 1.34 - 1.61) (See Figures 5.1 and 5.2). Subset analyses revealed several potentially important sources of heterogeneity. Significantly higher pooled estimates of risk were derived from the subset of case-control studies that used population-based controls (pooled RR = 2.43, 95% CI = 1.67 - 3.53) and the subset of studies of preschool children in North America or Europe (pooled RR = 2.00, 95% CI = 1.58 - 2.54). There was little evidence of heterogeneity in either of these groups. Both subsets, however, consisted of relatively few studies. Stratifying the data on other study characteristics yielded pooled RRs ranging from 1.14 to 1.86. The subset analyses substantially reduced the inter-study heterogeneity, but did not eliminate it.

Because substantial heterogeneity persisted even after the subset analyses, we fit linear meta-regressions to evaluate the influence of the study characteristics simultaneously. This multivariate approach identified several additional sources of heterogeneity. Studies of preschool children yielded approximately 50% higher risk ratios than those that included older children. Studies that adjusted for gender also tended to yield significantly higher risk estimates than those that did not. Furthermore, while studies controlling for a family history of atopy did not yield significantly different estimates of risk than those studies that did not, limiting the study population to atopic children or to children with a family history of atopy yielded approximately 60% higher estimates of risk. The overall fit of the model was reasonably good (p = 0.40), indicating little evidence of unmodeled heterogeneity.

The smoking status of the children being studied was a commonly omitted and potentially important confounder in the studies included in this analysis. To evaluate the influence of this factor on the pooled RRs, the analysis was repeated excluding studies involving children who were 10 years of age or older that did not control for the children’s own smoking. This did not change the results, although the confidence intervals became slightly wider (pooled RR = 1.48, 95% CI = 1.28 -1.71).

Most studies relied on crude measures of ETS exposure, i.e., parental reporting of the presence of household smokers or the estimated number of cigarettes smoked in the home. Four studies, however, reported risk ratios in relation to exposures assessed by measurement of salivary or urinary concentrations of cotinine as well as by parental reporting. In all four, the risk ratios associated with exposure to ETS were higher when exposure classification was based on cotinine levels rather than on parental reporting.

The results of this meta-analysis indicate a strong and consistent association between exposure to ETS and development of childhood asthma. This relationship persisted throughout various influence and sensitivity analyses. As anticipated, there was significant heterogeneity of results across studies. Our subset and meta-regression analyses revealed several important sources of heterogeneity related to elements of study design, particularly with respect to exposure assessment.

The U.S. EPA derived a quantitative estimate of risk of asthma induction associated with maternal ETS exposure (U.S. EPA, 1992, pp. 8-10 to 8-13). Using a threshold model, and assuming relative risks ranging from 1.75 to 2.25 for children of mothers smoking more than 10 cigarettes/day, U.S. EPA estimated that 7% to 9% of "all cases of asthma" (presumably pediatric cases only) could be attributable to maternal ETS exposure. This translated to an annual incidence of 8,000 to 26,000 cases attributable to ETS. U.S. EPA also calculated an annual incidence range of 13,000 to 60,000 using a nonthreshold model, noting, however, that a threshold model is more consistent with current epidemiologic data.

There are no California-specific data on asthma prevalence or incidence. Thus, an admittedly simplistic approach to estimating the attributable risk of ETS-induced pediatric asthma in California would be to multiply U.S. EPA's estimates by the percentage of the U.S. population living in this state, i.e., about 12%. This would lead to estimates of 960 to 3,120 new cases of childhood asthma each year using U.S. EPA's threshold model or 1,560 to 7,200 cases using the nonthreshold model.

Dozens of epidemiologic studies have linked chronic domestic ETS exposure with recurrent symptoms of cough, wheeze, and excess phlegm production in children. The NRC report (1986) concluded, based on a review of nine such studies involving approximately 25,000 subjects, "Children of parents who smoke compared with the children of parents who do not smoke show increased prevalences of respiratory symptoms, usually cough, sputum, and wheezing. The odds ratios from the larger studies, adjusted for the presence of parental symptoms, were 1.2 to 1.8, depending on the symptoms." This range may underestimate the effects of ETS, since adjustment for parental symptoms, which is intended to address possible biased parental reporting of symptoms because of greater somatic awareness, may actually overcorrect for children's symptoms in that it also corrects for parental smoking (Ferris et al., 1985). The Surgeon General's report (1986), reviewing 10 large epidemiologic studies that examined chronic symptoms in approximately 31,500 children, came to a similar conclusion: "[C]hildren whose parents smoke had a 30 to 80 percent excess prevalence of chronic cough or phlegm compared with children of nonsmoking parents. For wheezing, the increase in risk varied from none to over six-fold among the studies reviewed. Many studies showed an exposure-related increase in the percentage of children with reported chronic symptoms as the number of parental smokers in the home increased." (p. 48)

The U.S. EPA report (1992) reviewed an additional 14 studies published since 1986, which basically confirmed the findings of the previous major reviews. The U.S. EPA concluded:

The reports by the Surgeon General (U.S. DHHS, 1986), the National Research Council (1986), and the U.S. EPA (1992) concluded that a causal relationship is the most likely explanation of the consistently observed associations between ETS exposure and respiratory symptoms in children. Because this issue has been adequately addressed in these reports, a de novo analysis of the primary literature has not been undertaken. More recent published investigations tend to support the conclusions articulated in these reviews. In a study of 343 children, aged 7 - 12, Henderson et al. (1995) found odds ratios of 2.9 (95% C.I = 1.2 - 7.0) for ETS exposure in relation to risk of wheeze in nonallergic children and 4.4 (95% C.I = 1.2 - 16.1) in allergic girls but not allergic boys. Goren et al. (1995) found significantly increased prevalences of a variety of respiratory symptoms and conditions (cough and sputum, wheeze with and without respiratory infection, bronchitis, and others) associated with maternal or paternal smoking among 8,259 elementary school children in Israel. These and other studies support the conclusion, also stated in the reports by the NRC, the Surgeon General, and the U.S. EPA, that there is sufficient evidence that ETS exposure at home is causally associated with chronic respiratory symptoms (cough, phlegm, or wheezing) in children, particularly infants and young children.

Numerous cross-sectional and cohort studies have been published since the late 1970s examining the relationship of ETS exposure to various indices of lung function in children. A total of 29 studies, involving lung function measurements on approximately 77,000 subjects, were reviewed by the Surgeon General (1986), the National Research Council (1986), and the U.S. EPA (1992). While the results from all the studies reviewed were not wholly consistent, there was sufficient evidence for these three reviews to reach the conclusion that childhood exposure to ETS affects lung growth and development, as measured by pulmonary function tests (PFTs). Conclusions reported in these reviews are listed below, followed by a description of clinical implications of these findings, plus brief summaries of several more recent studies.

The three major ETS reviews found that:

(1) Some longitudinal (or cohort) studies report a small, but statistically significant, decrease in the rate of lung growth in children (as measured by multiple indices of lung function) exposed to ETS compared with nonexposed children. The magnitude of this decrement in naturally occurring growth, if projected through adolescence, appeared to be three to five percent or less (Surgeon General, NRC, U.S. EPA).

(2) In a majority of cross-sectional studies, ETS-exposed children had modestly lower PFT values, on average, than nonexposed children. These effects were greater in at least some susceptible subgroups (e.g., low birth weight, younger children) or in low SES families (e.g., in which the mothers had less than 12 years of education) (U.S. EPA).

(3) Maternal smoking had a more marked impact on children's PFTs than paternal smoking, though in a data set from China in which all the mothers were nonsmokers, there was an effect of paternal smoking, as well (Chen et al., 1986) (Surgeon General, NRC).

(4) In several studies, lower PFT values tended to be found with an increasing number of smokers in the child's household. In other words, in these investigations there appeared to be an exposure-response relationship (Surgeon General, NRC).

How ETS causes lung function decrements in otherwise healthy children is not known, but the observed effects may be related (at least in young children) to increased susceptibility to respiratory infection or to delayed developmental effects attributable to in utero exposure to maternal smoking. Several recent papers suggest that in utero or early childhood exposures to ETS may result in changes in lung development that may persist through childhood and adolescence (Cunningham et al. 1994, 1995; Hanrahan 1992; Brown 1995). The short-term clinical consequences of these apparent reductions in children's PFTs are likely to be of less importance, however, than their potential long-term implications. As was observed in the Surgeon General's report (U.S. DHHS, 1986), "The absolute magnitude of the difference in lung function is small on average. A small reduction of function, on the order of 1 to 5 percent of predicted value, would not be expected to have functional consequences." Nonetheless, reductions of lung function in childhood may persist into adulthood and increase the risk of developing chronic obstructive pulmonary disease (U.S. DHHS, 1986; NRC, 1986, U.S. EPA, 1992).The likelihood of such potential long-term consequences, however, has not yet been fully evaluated.

Several investigations of the relationship between childhood ETS exposure and lung function have been published since the U.S. EPA reviewed the data on this topic. As with previous studies, the evidence from these investigations is somewhat heterogeneous. The results from several large cross-sectional studies, in particular, tend to support the existence of a relationship between household ETS exposure and decreased lung function. Lebowitz et al. (1992) reported an analysis of ETS exposure on PFTs measured at least three times over a 13-year period in 138 Caucasian children (67 boys and 71 girls), aged 5 through 15 upon entrance into the study. ETS exposure was assessed by parental survey: there was no distinction made between light and heavy smoking. The analysis was stratified by gender and by level of lung function (normal or low) at the initiation of the study. This group of investigators had previously reported that, in comparison with children with normal lung function, children with lower initial PFTs experienced their peak lung growth at an earlier age and at a lower absolute value. In this report, there was no ETS effect detected in females who started with either normal or low lung function. Similarly, no effect was detected in males starting with normal lung function. In contrast, boys starting with low lung function who were ETS-exposed had a decreased FEV₁ (forced expiratory volume in one second) between ages 13 and 16, relative to unexposed boys with low initial lung function. Interestingly, growth of the forced vital capacity (FVC, which is a rough indicator of lung volume), in the ETS-exposed boys exceeded that in the nonexposed group between the ages of 17.5 and 23.5. Within this age interval the ratio of FEV₁/FVC (and another similar index of airway obstruction) decreased significantly in the exposed versus the unexposed low-function subjects (and versus the subjects with normal initial lung function). The clinical implications of these findings are unclear, since the apparent accelerated decline in the lung function ratios is at least partly attributable to the increase in the denominator (FVC). Furthermore, though there were a total of 142 lung function measurements made over the course of this study in the low-function males, there were only 28 in this group, including both smokers and nonsmokers. Thus, though it appears that the low-function ETS-exposed males began adult life with an accelerated decline from a lower-than-normal baseline, this type of analysis should be replicated with a larger sample size.

Sherrill et al. (1992) recently reported results from a longitudinal study of lung function in a cohort of 634 children (327 males, 307 females) in New Zealand. The children were part of a larger birth cohort whose health status was assessed by questionnaire every two years from 3 to 15 years of age. Questions regarding parental smoking were asked only at ages 7, 9, and 11. Spirometric measurements were performed at ages 9, 11, 13, and 15. There were no statistically significant ETS-related effects on FEV₁ or FVC in males, though females whose parents both smoked tended to have a slower rate of growth in FEV₁ and those exposed to maternal smoking tended to have a lower FVC than the nonexposed (p < 0.1 for both findings). The investigators indicated that because of a potential disjunction between somatic growth and lung function growth in adolescence, the ratio of FEV₁ to FVC might be a more accurate measure of lung function growth than either index alone. Using the FEV₁/FVC ratio, detrimental effects of ETS were identified; males, but not females, showed a nonprogressive decrease related to parental smoking. Moreover, in children with asthma or a history of wheezing, progressive decrements in FEV₁/FVC were observed in children of both sexes, compared with an increase in this ratio observed in nonexposed children with wheeze. The average reduction in FEV₁/FVC by age 15 was 3.9% in ETS-exposed boys with wheeze and 2.3% in girls. As noted by the authors of this report, there does appear to be an ETS-related effect on the subgroup of children with a history of wheezing, but the lack of an obvious separate effect on FEV₁ or FVC weakens this conclusion somewhat.

Wang and colleagues (1994) investigated the relationship between several measures of childhood ETS exposure and annual lung function measurements made in 8,706 nonsmoking white children between the ages of 6 and 18 who were participants in the Harvard Six Cities Study. ETS exposure metrics included: pre-school exposures (during the first 5 years of life), cumulative exposure from age six to the year before each annual examination, and current maternal and paternal smoking as reported each year. In this report, the investigators used regression splines to model pulmonary function growth as a function of ETS exposure, adjusting for age, height, city of residence, and parental education (a surrogate for socioeconomic status). Both current maternal smoking and pre-school exposure to maternal smoking were significant predictors of the children’s pulmonary function: there were no significant differences of effect observed in boys versus girls. Both of these measures were associated with small, but statistically significant reductions in FEV₁/FVC and FEF_25-75% (an indicator of flow rates in the smaller airways) through adolescence. Interestingly, early maternal smoking was also associated with a small increase in FVC, which was statistically significant only in children aged 11 to 18. In children aged 6 to 10, current maternal smoking was related to slower growth rates of both FVC and FEV₁, and in older children, with a reduction in the growth rate of FEF_25-75%. The findings of an increased FVC and reduced FEV₁ and FEF_25-75% is similar to the report of Lebowitz et al. (1992), and suggests that early childhood ETS exposure may induce an exaggerated disjunction in growth rates for airways (as measured by FEV₁ and FEF_25-75%) and lung parenchyma (lung volume as indicated by FVC), a process referred to as "dysanapsis". Moreover, after controlling statistically for current ETS exposure, this report suggests that early childhood exposures appear to exert long-lasting effects on lung maturation, as measured by pulmonary function tests.

Rona and Chinn (1993) studied lung function in relation to reported home ETS exposure in 2,756 children, aged 6 1/2 to 12, who took part in a cross-sectional national health survey in 1987 and 1988 in Great Britain. ETS exposure was assessed by parental questionnaire. A large number of potentially confounding variables were controlled for in the analysis, including age, height, ethnic group, weight, birth weight, percentage body fat (as measured by triceps skinfold thickness), reported parental heights, mother’s age at child’s birth, family size, father’s social class, "overcrowding", whether the child resided with one or both parents, mother’s educational level, father’s employment status, type of cooking fuel, study area, type of school meals, and a variety of the child’s respiratory symptoms. The investigators found significant associations of maternal smoking with reduced FEF_25-75% and FEF_75-85% in boys, but not girls. They also found similar gender-associated reductions of FEV₁ with maternal ETS exposure and of FEF_25-75% with total parental smoking, which were of borderline statistical significance. The results of this study are consistent with numerous others in showing an association between reduced childhood lung function and maternal but not paternal smoking. However, the differential effects on boys versus girls remains unexplained and, as the investigators noted, "illustrate the difficulties in making generalizations about the association between lung function and passive smoking in childhood."

Haby and colleagues (1994) assessed the relationship of several variables to spirometric indices (FVC, FEV₁, PEFR, and FEF_25-75%) in a cross-sectional study of Australian children in grades 3 to 5 (ages 7 - 12). ETS exposure was assessed by parental questionnaire, and was included as a continuous variable in stepwise multiple regression analyses of predictors of lung function in a group of 2,765 children. Other variables entered in the final models included height, weight, age, gender, current and past asthma, and the presence of a respiratory infection. The investigators reported a linear, dose-related reduction in FEV₁, PEFR, FEF_25-75%, but not FVC, where dose referred to the number of cigarettes smoked daily in the home. The magnitude of the reduction was small: a 10-year-old child would be expected to have a 2.4% reduction of FEF_25-75% if more than one pack of cigarettes were smoked in the home every day. The investigators did not report effects of prenatal or early childhood exposure to ETS, whether there were gender differences in the relationship of ETS exposure to spirometry, or the effects of maternal versus paternal smoking. As in several studies described above, Haby et al. speculated that the differential effects of ETS on FVC versus the flow-related measures of lung function may be due to dysanaptic growth of the lung.

Cook et al. (1993) examined the relationships between several lung function measures and ETS exposure in a population-based sample of 5.0 to 7.9-year old children randomly selected from elementary schools in 10 towns in England and Wales. ETS assessment was conducted by both parental questionnaire and by measurement of salivary cotinine obtained from the participants. Multiple regression models relating the spirometric indices to salivary cotinine were based on data from 2,511 children who had provided complete, acceptable data. The analysis relating lung function to questionnaire-based ETS assessment contained data from 2,500 children. In analyses adjusted for age, gender, height, body mass index, lung function technician, and the town of residence, every lung function index (FVC, FEV₁, FEF₂₅, FEF₅₀, FEF₇₅, and FEV₁/FVC) was negatively associated with salivary cotinine, and all but the FEV₁/FVC ratio were highly significant statistically. Additional adjustment for birth weight, presence or absence of a gas-burning stove, and the head of household’s social class (an indicator of SES) did not materially change the estimates. FEV₁ declined linearly with increasing salivary cotinine. The results from the questionnaire-based ETS exposure assessment were more ambiguous, reflecting the increased uncertainty and measurement error associated with such data. Though there was no clear exposure-response relationship between FEV₁ and the numbers of cigarettes reportedly smoked by the mother or the father, when ETS exposure was categorized by the number of smokers to which the child was exposed on a regular basis, all of the above indices except FVC declined with increasing numbers of smokers, though this negative association was significant only for FEF₂₅, FEF₅₀, FEF₇₅, and FEV₁/FVC. As was true of the cotinine analysis, the strongest association was with FEF₅₀. For a small subset of the children (n = 111), salivary cotinine was sampled twice (six months apart): though the mean levels were slightly different (1.59 vs 1.37 ng/ml), this difference was not significant, indicating the stability of ongoing exposure patterns. The cotinine-based analysis supports the existence of an exposure-response relationship between ETS and childhood lung function; however, these investigators could not distinguish between the effects of current versus early childhood exposures.

Two recent reports by Cunningham and colleagues (1994 and 1995) suggest that prenatal or very early post-natal exposures to tobacco smoke components may affect lung development, inducing persistent effects that may be detected throughout childhood. As part of the Harvard 24-Cities Study, Cunningham et al. presented results of an analysis of 8,863 nonsmoking white children, aged 8 -12, in which they examined the relationships of a variety of lung function measures to maternal smoking during pregnancy as well as to current maternal smoking. In regression models adjusted for sex, height, weight, age, parental education, city of residence, and interaction between sex and height, the investigators found decrements in FEV_0.75, FEV₁, FEV₁/FVC, PEFR, FEF_25-75%, and FEF_65-75% that were highly significantly related to both maternal smoking during pregnancy and to maternal ETS exposure in the year preceding the examination. However, when adjusted for current maternal smoking, the associations of these measures with maternal smoking during pregnancy were slightly reduced, but remained highly significant statistically. In contrast, when adjusted for maternal smoking during pregnancy, the effects of current smoking on the children’s lung function were markedly decreased and were no longer significant. Boys showed greater ETS-related deficits in all these measures of lung function than girls, but this was due to the greater effects in boys with a history of allergy, asthma, parental asthma, or severe respiratory illness. Among boys and girls with none of these risk factors for decreased lung function, the estimates of ETS-related effects were of similar magnitude. In general, mothers who smoked during pregnancy are likely to continue to smoke afterwards, so these two measures of ETS tend to be highly correlated. However, because of the large size of this study, the investigators were able to undertake a variety of subgroup analyses that highlighted the importance of in utero and possibly very early childhood exposure to maternal ETS. Paternal smoking was not a significant predictor of the participants’ lung function.

Cunningham et al. (1995) undertook a similar analysis with a sample of 493 white and 383 black children, aged 9 to 11, in Philadelphia. ETS exposure history was obtained through the children’s mothers’ answers to questionnaires. In the statistical analysis, exposures were modeled as dichotomous variables for maternal smoking and for current smoking, and as a continuous variable for the number of cigarettes smoked per day. Pulmonary function testing was conducted at school. Multiple regression techniques were employed to model several lung function measurements as a function of ETS exposure, adjusting for height, weight, age, area of residence, parental education, mother’s primary language, and single-parent family status. Models that included boys and girls, or members of both races, required additional adjustments for gender, race, interaction of gender and height, race and gender, race and height, race and weight, and race and age. In regression models for the whole study population, maternal smoking during pregnancy was associated with statistically significant decrements of - 8.1% FEF_25-75% (95% CI = - 12.9 to - 3.1%) and - 2.0 % in FEV₁/FVC (95% CI = - 3.0 to - 0.9%), while a decrease in FEV₁ was not significant. No decrease in FVC was observed. Larger deficits were observed in black than in white children, with the greatest decreases detected in African-American boys (- 19.6% FEF_25-75% (95% CI = - 31.1 to - 6.1%), - 5.9% in FEV₁/FVC _% (95% CI = - 8.7 to - 2.9%);
FEV₁ = - 6.0; (95% CI = - 10.4 to - 1.4%)). These differences could not be explained by potential confounding by SES, prior respiratory illness, or housing characteristics. Current ETS exposure to ETS was not associated with lung function deficits after adjustment for maternal smoking during pregnancy.

In their ensemble, these studies, especially the cross-sectional investigations, tend to support the conclusions reached in the earlier reviews by the NRC, the Surgeon General, and the U.S. EPA regarding the relationships between ETS exposure and lung function in children. However, as noted above, the data are not entirely consistent. Some of the differences may be explicable by the crudeness of questionnaire-based exposure assessment, which is likely to result in nondifferential misclassification of exposure and a consequent bias towards the null hypothesis of no relationship. Some inter-study discrepancies may also be attributable to the different age ranges of the study populations, especially since early childhood or in utero exposures appear to exert long-lasting effects, which may diminish over time. Finally, although the mean changes observed have generally been of small magnitude and uncertain clinical significance, the potential long-term implications of these lung function decrements warrant additional investigation.

Several investigators have examined the question of chronic chest symptoms and/or pulmonary function changes in adults exposed to ETS. It is well established that active smoking leads to increased age-related decrements in pulmonary function. For example, in a large multi-center longitudinal study, the yearly decline in FEV1 was 30-40% greater in smokers than in nonsmokers (Xu, 1992). Smoking also can lead to chronic obstructive pulmonary disease (COPD). COPD is characterized by mucus hypersecretion/infection (chronic bronchitis) and loss of elastic recoil and alveolar integrity (emphysema), resulting in varying degrees of airway obstruction (particularly during expiration) and sputum production. Mechanisms underlying these changes include cigarette smoke-induced bronchopulmonary inflammation, induction of airway hyperresponsiveness, inhibition of mucociliary clearance (and other antimicrobial defenses), goblet cell hyperplasia, release of proteolytic enzymes from inflammatory cells, and possibly inhibition of antiproteases (Snider, 1989, 1991; Wagner, 1992). This section reviews the epidemiologic evidence bearing on the question of chronic exposure to ETS, lung function, and chronic respiratory symptoms in adults.

The Surgeon General's Office (U.S. DHHS, 1986) and NRC (1986) reviewed five, and the U.S. EPA (1992) an additional six, studies of chronic respiratory symptoms and/or pulmonary function among adults exposed to environmental tobacco smoke in the home or workplace; these are summarized below. Several additional studies were found which were not summarized in any of the above reviews.

White and Froeb (1980) surveyed 2100 middle-aged subjects who enrolled in a physical fitness course sponsored by the University of California, San Diego over a ten-year period. Roughly seven-eighths of the registrants were white collar workers. For both sexes, nonsmokers who reported chronic workplace exposure to ETS had, as a group, significantly lower FEF_25-75 (forced expiratory flow during the middle half of the forced vital capacity maneuver) and FEF_75-85 values than did non-ETS exposed nonsmokers; comparable decrements were found in the above parameters among light smokers and smokers who did not inhale. By comparison, persons actively smoking at least one pack-per-day for 20 years or more had decrements in the forced expiratory volume in one second (FEV₁) and the forced vital capacity (FVC), which were not seen in passive smokers or light smokers.

Comstock (1981) analyzed cross-sectional data on 1,724 adult participants in two different studies of respiratory symptoms. Non-significant excesses of subjects with an FEV₁ <80% of predicted or an FEV₁/FVC <70% were observed among males exposed to ETS; no such excesses were seen among women. Most respiratory tract symptoms were equally prevalent among those exposed and not exposed.

Kauffman (1983 and 1989) analyzed questionnaire and pulmonary function data in two cross-sectional studies that included 3,855 French women (aged 25 to 59 years) and 2,220 American women (aged 25 to 74). For most lower respiratory symptoms, odds ratios comparing passive smokers with nonsmokers were elevated, but not to a statistically significant degree. Among French women over age 40, both FEV₁ and FVC were significantly lower among the passive smokers. In the U.S. sample, there was a significantly elevated rate of self-reported wheezing among passive smokers compared to the unexposed group.

Kentner et al. (1984) conducted a cross-sectional study of 1,351 office workers, including both a questionnaire and pulmonary function testing. Smokers, ex-smokers, and passive smokers were compared to lifetime non-smokers. Whereas active and prior smokers had significantly lower age- and sex-standardized ventilatory parameters, no such changes were evident among persons whose sole lifetime exposure was passive smoking.

Brunekreef et al. (1985) followed 97 nonsmoking rural Dutch females for approximately 15 years with serial measures of pulmonary function. Analyzed cross-sectionally, those women 40 to 60 years of age at the time of the latest measurement who were passively exposed to cigarette smoke in the home had significantly lower peak expiratory flow (PEF) than did the unexposed group. Among those with passive smoke exposure throughout the period of the study, forced expiratory flow at 75% of total lung volume (FEF₇₅) was also significantly lower. Other lung function parameters, while generally lower among passive smokers, were not significantly so. Analyzed longitudinally, however, there was no significant difference in yearly age-related pulmonary function loss between the two groups.

Svendsen (1987) analyzed data from the Multiple Risk Factor Intervention Trial on 1,245 married men aged 35-57 years who had never smoked, roughly a quarter of whom had wives who smoked. Upon entry into the study, the latter had FEV₁ values, on average, 99 ml (2.8%) lower than those with nonsmoking wives (95% CI, 5-192 ml lower). Separating subjects whose wives smoked less than versus greater than one pack per day did not provide evidence of a dose-response relationship, however. Passive smoking histories were validated with serum thiocyanate levels (no difference observed by spousal smoking) and expired air carbon monoxide (significant trend with increasing spousal smoking).

Kalandidi (1987 and 1990) conducted a case-control study, comparing 103 nonsmoking Greek women aged 40-79 who were admitted to the hospital for an initial diagnosis of COPD with 179 similarly aged nonsmoking visitors (i.e., friends and family of patients). A significant trend was observed in the odds ratio for COPD and spousal smoking as the husband's estimated (during-marriage) total cigarette consumption increased, with the OR equaling 1.3 for fewer than 3x105 cigarettes and 1.8 for greater than 3x105 (i.e., greater than approximately 40 pack-years of spousal cigarette smoking; p=0.01 crude, p=0.03 adjusted). Factors adjusted for in the analysis included age, education, rural vs. urban residence, and employment status.

Euler et al. (1988) performed a multivariate logistic regression analysis of questionnaire data from 7,445 nonsmoking Seventh Day Adventists in California. The study, which focused mainly on the effects of air pollution, looked at passive smoking as a covariate. Among other variables, self-reported ETS exposure, both in the workplace and in the home, was significantly related to self-reported symptoms of COPD (i.e., breathlessness, sputum production, and wheezing).

Masi et al. (1988) did a cross-sectional analysis of 293 nonsmoking men and women, 15-35 years of age, who had previously been recruited for a study of lung function in adolescence and young adulthood. There was a significant decrement in FEF_25-75, FEF₅₀, and residual volume as a function of cumulative lifetime exposure to ETS at home (but not at work) among males only. Females showed a significant trend toward lower carbon monoxide diffusion capacity (DLco) with increasing cumulative ETS exposure at work (but not at home). The analysis involved a total of 40 test statistics. Of note, the observation of a significantly lower residual volume (RV) in males exposed to ETS at home runs counter to the hypothesis that ETS exposure produces clinically significant COPD, since an elevated RV is normally observed in COPD.

Hole et al. (1989) interviewed and examined 671 lifetime nonsmoking Scottish men and women, 243 of whom lived with one or more smokers. Age-, height-, and sex-adjusted FEV1 values were significantly lower among those exposed to ETS compared to those not exposed (difference = 3.5%). A variety of respiratory symptoms (e.g., shortness of breath, sputum production) were elevated to a nonsignificant degree among the ETS-exposed group.

Schwartz and Zeger (1990) reanalyzed data from a diary study of acute respiratory symptoms among 100 student nurses. Subjects completed daily entries for as long as three years. Variables used in the analysis included smoking and ETS exposure history, allergy status, and various measures of outdoor air quality. Controlling for personal smoking, self-reported phlegm production was significantly more common among students with smoking, as opposed to nonsmoking, roommates (OR = 1.41; p <0.001).

The studies described below were not included in the Surgeon General's, NRC, or U.S. EPA reports.

Schilling et al. (1977) conducted a cross-sectional analysis of questionnaire and pulmonary function data from 376 families in Connecticut and South Carolina. They found no significant differences in adult symptom reporting rates or, controlling for prior smoking history, in pulmonary function measures as a function of spousal smoking habit.

Masjedi et al. (1990) administered a questionnaire to (and performed pulmonary function tests on) 275 lifetime nonsmoking hospital employees and physicians. Among male subjects (n=167), significantly lower spirometric values (FEV₁, FVC, and FEF_25-75) were observed for those who reported ETS exposure at work (not home) versus those who did not. Among females, no systematic differences were found with ETS exposure at either work or home. A potential confounder in the study was the high level of ambient air pollution in the area surrounding the recruiting hospital (Teheran, Iran).

More recently, Jaakkola et al. (1995) reported the results of a longitudinal study of lung function in 117 nonsmoking young adults (aged 15 to 35) in Montreal, Canada who were tested in 1981-83 and again in 1988-89. ETS exposures at home and at work during and prior to the study were assessed by questionnaire. In multiple linear regression analyses controlling for age, gender, height, Quetelet index (wt/ht²), baseline FEV₁, baseline FEF_25-75, atopic status, and the presence of wheeze at baseline, these investigators did not find a significant relationship between either current or past home or work exposure to ETS and the change in FEV₁ or in FEF_25-75 during the study period In a subanalysis of the subjects who were 25 years of age or younger at baseline
(n = 62), Jaakkola and colleagues found that work-related ETS exposure during the study period was associated with a slight, but significant increase in the rate of decline of FEV₁. They also calculated 95% confidence intervals on their estimates, indicating that, given the exposure conditions and baseline health of their study population, the changes in lung function during young adulthood potentially attributable to ETS would be approximately - 1.0 ml/yr per pack-year, which would be of little clinical importance. It should be noted, however, that 80% of the men (total n = 60) in this study had no ETS exposure at home during the study period, while another 8% were exposed to fewer than 10 cigarettes/day; only one man was exposed to a pack or more on a daily basis. For women (n = 57), the corresponding numbers were 45% with no ETS exposure at home, 33% with exposure to less than half a pack, and six who were exposed to a pack or more. The frequencies of work-related exposures were greater, but still reflected light to moderate exposure at most. Thus, as the investigators acknowledged, their findings would not necessarily be representative of what might occur with more frequent exposure in smaller indoor spaces with poorer ventilation. Also, the authors of this small study focused only on changes during the study period and did not report whether baseline lung function was related to prior ETS exposure.

Dayal and co-workers (1994) undertook a case-control study of the relationship between self-reported, previously diagnosed obstructive lung disease (including asthma, chronic bronchitis, and emphysema), where cases and controls were selected from a probability sample of 4,200 individuals residing in nine Philadelphia neighborhoods in 1985-86. In an analysis restricted to never-smokers, the cases (n = 219) were matched on age, gender, and neighborhood with three randomly selected controls. The matching on neighborhood was intended to control both for SES and local environmental conditions, such as air pollution. In conditional logistic regression analysis that also controlled for type of heating and whether a gas stove was present (and possibly other variables), Dayal et al. found a significant relationship between reported obstructive lung disease and household ETS exposure involving one or more packs a day, corresponding to an odds ratio of 1.86 (95% CI = 1.21 - 2.86). While this result suggests that household ETS exposure increases the risk of obstructive lung disease, the interpretation of this study is limited by a lack of information about the study populations (e.g., basic demographics) and about the temporal character of the disease outcomes in relation to the study date -- in other words, whether the disease(s) reported by the participants were "ever-diagnosed" or still present (i.e., asthma and chronic bronchitis).

Xu and Li (1995) analyzed relationships of household and occupational ETS exposure on pulmonary function in 1,033 adults (including 502 never-smokers), aged 40 to 69, in a residential area of Beijing. Current ETS exposure was assessed by questionnaire. In stratified multiple regression analyses controlling for age, income, educational level, personal smoking status, indoor use of coal stoves for heating or cooking, and occupational exposures to dusts, gases, or fumes, Xu and Li reported reduced levels of FEV₁ and FVC associated with ETS exposure, which were statistically significant in never-smoking men, but not women. While almost all of the estimates of effect of ETS exposure on lung function in ever-smokers were also negative, these were significant only for the pooled group (men and women) exposed both at home and at work. Also, when the exposures were categorized as low (1 - 5 cigarettes/day) versus high (>6/day), Xu and Li found evidence of linear exposure-response relationships, which were statistically significant for FEV₁ and FVC in never-smoking men and for ever-smoking women. In this study, the magnitudes of the lung function decrements reported to be associated with ETS exposure were substantial (4.2 ± 1.8 ml/cigarette smoked in the household for FEV₁ and 5.2 ± 1.9 ml/cigarette for FVC). However, the exposure conditions in Beijing are clearly different from those obtaining in California or the U.S., potentially limiting the generalizability of these findings.

Robbins and co-workers (1993) reported that several measures of childhood and adult ETS exposure were associated with onset of airway obstructive disease (AOD, comprised of asthma, chronic bronchitis, and emphysema) in 3,914 nonsmoking Seventh Day Adventist adults in a prospective investigation. Questionnaires about both symptoms and historical ETS exposure were administered to study participants in California in 1977 and again in 1987. Though all three disease entities constituting AOD were self-reported, the questions about both asthma and emphysema were structured to require a physician’s diagnosis. Statistical analysis relied on multiple logistic regression modeling of AOD onset over the 10-year period, controlling for age, education level (an indicator of SES), gender, years of past smoking (15% of the study population), and an indicator of chronic exposure to particulate air pollution. Robbins et al. reported that several, but not all, qualitative measures of ETS exposure were associated with an increased relative risk of developing AOD during this interval, including adult plus childhood exposure (RR = 1.72, 95% CI = 1.31 - 2.23), but not childhood or adult exposure alone (RR = 1.09, 95% CI = 0.69 -1.79 and RR = 1.28, 95% CI = 0.90 - 1.79, respectively). Similarly, examining the outcomes of chronic bronchitis and asthma separately, they reported increased RRs for both outcomes in relation to combined adult and childhood ETS exposures: RR = 1.71 (95% CI = 1.27 - 2.27) for chronic bronchitis and RR = 1.89 (95% CI = 1.13 - 3.15) for asthma. Several sensitivity analyses indicated that these findings were robust: specifically, the ETS risk estimates changed little when the analysis was restricted to never-smokers, and when terms were included in these regressions for childhood respiratory illness and frequency of childhood colds. One unexpected finding in this report, however, was that the RR for AOD corresponding to having actively smoked for 10 years was lower (RR = 1.27, 95% CI = 1.10 - 1.47) than those estimated for the combined adult and childhood ETS exposures. The authors explained this unusual result as a combination of factors: the low prevalence of ever-smoking adults in the study population (15%), the long time that had elapsed since the active smokers had quit (mean = 21.4 year), and the "short" period of time during which active smoking had taken place (mean = 14.8 year).

In a separate analysis of virtually the same data set, Greer et al. (1993) examined the incidence of new cases of asthma as a function of adult ETS exposure ("years lived with a smoker" and "years worked with a smoker"), controlling for years of active smoking, ozone and particulate air pollution, occupational dust and vapor exposures, childhood history of AOD, age, gender, and education. In the final models that Greer et al. reported, the incidence of "definite asthma" by reported symptoms or reported physician diagnosis during the 10-year interval was significantly related to occupational ETS exposure, with a relative risk of 1.45 (95% CI = 1.21 - 1.80). Separate subanalyses for men and women produced similar results. Greer et al. (1993) also obtained medical records for 49 of the self-reported cases of asthma, and validated the diagnosis in 30 (61%), suggesting a reason for caution in interpreting the results of these investigations. Although these investigators indicated that the relative risks for occupational ETS exposure remained significant when only the validated asthma cases were used in the regression models, the magnitudes of the risks were not specified. Based on the results of these two studies, it seems likely that ETS exposure is significantly related to self-reported symptoms of AOD, but the extent to which this relationship holds true for each of the subsets of AOD (i.e., asthma and chronic bronchitis) would require additional research.

In a cross-sectional study of nonsmoking women in Singapore, Ng et al. (1993) reported increased risks of chronic respiratory symptoms and reduced FEV₁ associated with household ETS exposure. Symptom and ETS exposure data were collected from 1,438 women, 1,282 of whom were life-long nonsmokers. Of the latter, 1,008 provided acceptable FEV₁ tracings for analysis. In multiple logistic regressions that adjusted for age, race, area and size of residence (indicators of SES), and employment status, (and for chronic rhinitis and eczema, when examining odds ratios for wheeze and physician-diagnosed asthma), Ng and co-workers found elevated odds ratios for all respiratory symptoms where the women were exposed to one or more heavy smokers (defined as those who smoked ³ 20 cigarettes/day). ORs were significantly elevated for chronic or usual cough (OR = 3.79, 95% CI = 1.76 - 8.14), cough at least 3 months out of the year (OR = 3.01, 95% CI = 1.13 - 8.03), breathlessness on exertion (OR = 1.83, 95% CI = 1.30 - 2.58), and wheeze (OR = 2.69, 95% CI = 1.23 - 5.88). For women exposed to one or more light smokers (i.e., those consuming < 20 cigarettes/day), the only significantly increased OR was for usual or chronic cough (OR = 2.84, 95% CI = 1.29 - 6.24). Restricting the analysis to housewives (n = 548), who would be expected to be exposed to ETS only at home, resulted in elevated ORs for all symptoms examined except physician-diagnosed asthma, though these increases were statistically significant only for chronic cough and breathlessness on exertion. Analysis of FEV₁ in relation to ETS, controlling for the same potentially confounding factors and effect modifiers, with the addition of the variable height, indicated that small, but statistically reductions in lung function were associated with the presence of one or more light or heavy smokers in the home, whether the analysis included all women or only housewives. In this study population, frequency of gas cooking was not associated with increased risks of respiratory symptoms (except breathlessness on exertion), but was associated with small reductions in lung function. The investigators’ conclusions would have been strengthened had they also controlled for this potential confounder in the ETS analyses.

In a cross-sectional study of 4,197 never-smoking adults, aged 18 to 60, Leuenberger et al. (1994) examined the relationships between ETS exposure and a variety of symptoms. Information on both exposure and symptoms were obtained though structured interviews. Analysis involved multiple logistic regression that controlled for age, gender, body mass index (weight/height²), area of residence, parental and sibling history of asthma, and atopy (determined by a serum immunofluorescence assay for specific IgE against common inhalant allergens). Leuenberger and co-workers found elevated odds ratios for all respiratory symptoms examined except allergic rhinitis, as follows: wheezing apart from colds (OR = 1.94, 95% CI = 1.39 - 2.70), physician diagnosed asthma (OR = 1.39, 95% CI = 1.04 - 1.86), dyspnea on exertion (OR = 1.45, 95% CI = 1.20 - 1.76), symptoms of bronchitis (OR = 1.59, 95% CI = 1.17 - 2.15), and symptoms of chronic bronchitis (OR = 1.65, 95% CI = 1.28 - 2.16). These estimates of elevated risk did not change significantly when a variety of sensitivity analyses were undertaken, such as excluding subjects whose mothers had ever smoked, excluding subjects who were likely to have been active smokers (determined by measuring the concentration of exhaled carbon monoxide in their breath) and controlling statistically for low educational level (an indicator of SES), and for occupational exposures. Moreover, these investigators found evidence of a dose-related increase in risk for all these symptoms where dose was represented as either reported hours per day or years of passive smoke exposure. This study addressed most concerns usually raised about potential confounders in epidemiological studies of ETS-related health effects, notably differential symptom reporting by those whose mothers smoked during pregnancy or during the subjects’ early childhood, by active smokers claiming to be nonsmokers, by factors related to SES, and by occupational exposures. On the basis of the studies reviewed prior to 1987, the Surgeon General's Office (U.S. DHHS, 1986) concluded that "The small magnitude of effect implies that a previously healthy individual would not develop chronic lung disease solely on the basis of involuntary tobacco smoke exposure in adult life." On the basis of more recent studies (particularly Hole et al., 1989 and Svendsen et al., 1987) the U.S. EPA (1992) estimated a 2.5% lower FEV₁ and a 30-60% increase in respiratory symptoms among passive smokers as compared to unexposed individuals. U.S. EPA further concluded that the "...effects of passive smoking on lung function are approximately comparable to those reported for light (<10 cigarettes/day), male active smokers." The report did point out that several of the studies reviewed were problematic with respect to control for potential confounding variables.

Prior to the publication of relevant recent studies, we concurred with the Surgeon General's Office and the U.S. EPA that the effect of chronic ETS exposure upon pulmonary function in otherwise healthy adults is likely to be small in comparison to active smoking, and is unlikely, by itself, to result in clinically significant chronic disease. The results of Leuenberger et al. (1994), Robbins et al. (1993) and other recent papers, however, suggest that ETS exposure may make a significant contribution to chronic respiratory symptoms in adults. In conjunction with reports of acute lower respiratory tract symptoms among individuals with pre-existing asthma (see Section 6.1.1), the small differences in lung function found in epidemiological studies are a basis for concern and further study.

Evidence for effects of mainstream smoke (MS) exposure of pregnant rodents on fetal lung development has been provided over the past ten years. More recently, effects of sidestream smoke (SS) on both prenatal and postnatal lung development, function and airway reactivity have been studied in rats. In animal studies, MS and SS are distinguished by the mode of generating the smoke, but all exposures have been passive or environmental (i.e., smoke has been inhaled from ambient air). SS differs from ETS in that it does not contain exhaled mainstream components.

Studies of lung development were undertaken after data indicated a proportionally greater growth retardation in fetal lung than in other organs as a result of MS exposure of pregnant rats (Bassi et al., 1984). Histopathology and morphometry studies of the growth-retarded lungs demonstrated increased sizes and reduced numbers of primitive alveoli (saccules) leading to a reduced surface area available for gas exchange in the term fetus (Collins et al., 1985). When fifteen-day-old rats were examined after in utero smoke exposure, gas diffusion capacity of the lung as determined from histomorphometry was similar to that of controls (Lichtenbeld and Vidic, 1989). Nonetheless, biochemical measures suggested delayed septal growth and development of lung interstitial cells (Vidic et al., 1985). Since septa subdivide existing alveoli to produce new alveoli, these findings are consistent with the lower number of alveoli seen in fetuses at term (Collins et al., 1985). However, functional lung parameters (respiratory capacity, reactivity, immune defense) were not evaluated in these studies.

Developmental studies of lung function and reactivity have recently been undertaken in rats using methodologies specifically designed for producing SS exposure (Teague et al, 1994).

Joad and colleagues (1993; 1995a) studied functional lung parameters (compliance, resistance, reactivity) in adult rats exposed to SS prenatally and/or postnatally. The rats were 7-10 weeks of age (sexual maturation in rats occurs at 5-6 weeks of age) at the time of the lung function tests. As measured in isolated perfused lungs, compliance was decreased 24%, and reactivity (to methacholine challenge) was 200% greater in rats exposed to SS both prenatally and postnatally. Furthermore, the number of neuroendocrine cells, an immature cell type in the lung, was 22-fold greater after the combined gestation/lactation exposure. Hyperplasia and persistence of neuroendocrine cells, which contain mediators of bronchoconstriction, were considered the basis for reduced compliance and increased reactivity. The SS air concentration in this study was 1 mg/m³, which is at the top of the range of ETS exposures recorded in any environment (U.S. EPA, 1993).

These effects were not seen when exposures occurred only prenatally or only postnatally (Joad et al., 1993). The postnatal exposures were given from day 2 through 7-15 weeks of age, or only at 15 weeks of age, and thus covered the entire period of postnatal lung development. The lack of effect emphasizes the importance of exposure during fetal as well as postnatal stages of lung development. In rats exposed only postnatally to SS, cell division in epithelial cells of terminal but not proximal bronchi was lower than in controls at 7 and 14 days of age. Since cell division is an immature property of the bronchiolar epithelium, this indicated stimulation of lung maturation, as also suggested by studies of enzyme induction.

Induction of metabolic enzymes by SS in the immature lung has been studied in the postnatal period. The establishment of metabolic competence of the lung is delayed well into the postnatal period in laboratory animals as well as in humans. Aryl-hydrocarbon hydroxylase (AHH), also known as cytochrome P450 1A1, was induced in lungs of rat offspring who were exposed to MS constituents in utero, by nursing or directly through inhalation after birth (Bilimoria and Ecobichon, 1989). This enzyme is know to be induced by polycyclic aromatic hydrocarbons (PAHs) present in cigarette smoke (Bilimoria and Ecobichon, 1980). Little or no induction was seen in hamster or guinea pig offspring. The results seen in rats demonstrate that tobacco smoke components can reach the fetal lung of rats and produce a biochemical response. Other studies demonstrated that SS exposure can alter the ontogenetic time course of appearance of lung enzymes (Ji et al., 1994). In rat pups exposed to SS from birth at a concentration of one mg/m³, cytochrome P450 1A1 was seen earlier, and persisted at high levels longer after the normal developmental peak. Clara cells, an epithelial cell type that contains P450, also demonstrated reduced cell proliferation in late maturing areas and increased NADPH reductase expression, two indicators of early maturation. Two other Clara cell enzymes, cytochrome P450 2B and Clara cell secretory protein, were not affected. Premature induction of metabolic pathways could be seen to serve a protective function in the immature lung; however, production of reactive intermediates that induce oxidative damage and genotoxicity is also possible.

Postnatal SS exposure has also been studied in connection with lung responsiveness associated with the C-fiber system. C-fibers in the lung mediate an airway defense response which includes mucus secretion, bronchoconstriction, and coughing in response to irritants. Compliance, resistance and lung morphology were measured in the isolated, perfused lungs of 43-day-old guinea pigs that had been exposed to SS at a concentration of one mg/m³ from eight days of age (Joad et al., 1995). Baseline compliance was increased modestly (17%) by SS exposure, but lung morphology and baseline resistance were not altered. The response of the lung to capsaicin, a specific C-fiber agonist, was reduced by SS exposure but the response to substance P, which is released by the C-fiber, was not affected; this suggests a down-regulation of C-fiber responsiveness (i.e., the lung is still able to respond to directly to substance P, but doesn’t respond to capsaicin, indicating that decreased responsiveness to capsaicin involves the C-fibers). Reduced C-fiber responsiveness indicates a depressed defense response that could result in greater penetration of toxicants and infectious agents into the lung and be responsible for higher incidence of respiratory problems.

Atopy refers to an inherited predisposition to develop IgE antibodies against common environmental and dietary allergens. This predisposition is manifested in several chronic conditions: allergic asthma, atopic dermatitis, allergic rhinitis, and allergic gastroenteropathy. Allergy (atopy with or without high serum levels of IgE) can be documented in most cases of asthma (Burrows et al., 1989, as cited in U.S. EPA, 1992), although exercise-induced bronchospasm, reactive airways dysfunction syndrome, and many types of occupational asthma can occur in nonatopic individuals.

The evidence relating ETS exposure to the development of atopy is mixed. Several studies have shown that exposure to passive smoke is significantly associated with total serum IgE concentration and may therefore affect the development of allergic disease. Studies that showed a relationship between active smoking and IgE levels, such as those reviewed in U.S. EPA (1992) (Gerrard et al., 1980; Burrows et al., 1981; Zetterstrom et al., 1981; Taylor et al., 1985), prompted researchers to investigate the relationship of passive smoke exposure and allergic sensitization in children. Several studies have shown up to a 2.2-fold increased risk of atopy in children of smoking mothers (Weiss et al., 1985; Martinez et al., 1988). Ronchetti et al. (1990) analyzed the same population used by Martinez et al. (1985) and found that total serum IgE levels and eosinophil counts were significantly greater in children of smoking parents.

In contrast, two studies of maternal active and passive smoking during pregnancy showed no association of in utero ETS exposure and umbilical cord blood IgE (Oryszczyn et al., 1991; Ownby et al., 1991). High levels of cord blood IgE are predictive of the development of childhood allergy. A group of 99 singleton births in a hospital in Paris, France were used to validate use of cord blood cotinine and maternal urinary cotinine concentrations in a study of in utero exposure to parental smoking (Oryszczyn et al., 1991). Twenty percent of the mothers smoked at least one cigarette per day during one of three trimesters. Infants whose mothers smoked or had been passively exposed to ETS had significantly higher cord blood cotinine levels than infants whose mothers neither smoked nor been exposed to ETS. However, no association was observed between cord blood IgE and maternal smoking as assessed by either questionnaire or cord blood cotinine. This study did not examine post-natal ETS exposure.

Ownby et al. (1991) followed 114 infants born to subscribers of a health maintenance organization in Michigan. The infants were selected from a stratified sample chosen to assure nearly equal proportions of infants from nonsmoking, light and heavy smoking households, although the definitions for each category are not stated in the report. As in the previous study, cord cotinine concentrations were measured to assess the validity of self-reported maternal smoking. Neither univariate analyses nor analyses that adjusted for the children’s gender, birth weight, birth length, paternal history of allergies, maternal history of allergies or asthma, maternal visit to an allergist, history of skin testing or immunotherapy were significantly related to cord blood IgE. The authors speculated that if passive smoking induces atopy only in those with a familial tendency, such a study design might mask an association if atopics are less likely to smoke. Therefore, regression models were run both with and without adjustment for parental history of allergic disease. The association was also nonsignificant for a subgroup of infants whose parents were not atopic. When multiple regression models were used, the authors detected an association of immunoglobulin D (IgD) and paternal, but not maternal, smoking. However, the function of IgD and its relationship, if any, to the development of atopy and allergy, have not yet been elucidated.

Recently, Søyseth et al. (1995) investigated the relationship of prenatal and postnatal household smoking to the prevalence of atopy, defined as at least one positive skin prick test, in a cross-sectional study of 556 Norwegian school children, aged 7 to 13 years. Questionnaire assessment of ETS exposure addressed smoking by either parent during the mother’s pregnancy, as well as several indices of parental postnatal smoking. In multivariate analyses that initially included age, gender, reported bronchitis before two years of age, and parental history of asthma or hay fever, Søyseth et al. reported that pre-natal maternal smoking was negatively associated with atopy
(OR = 0.6, 95% CI = 0.4 - 0.9), while postnatal ETS exposure was not associated with this condition (OR = 1.2, 95% CI = 0.7 - 2.1). No index of paternal smoking was associated with atopy. The authors did not believe that this negative association of prenatal smoking with atopy was causal, but hypothesized rather that it may have been due to selective avoidance of smoking during pregnancy by women whose offspring might have been at higher risk of developing atopy (e.g., because of a family history of allergy). Regardless of the validity of this hypothesis, these results do not indicate an increased risk of allergic sensitization due to parental smoking, either prenatally or postnatally.

Investigators have also examined both the interactive effect of passive smoke exposure in children with atopic dermatitis (AD) and subsequent development of asthma. AD is characterized by a chronic or relapsing pruritic (itchy) rash. Murray et al. (1990) studied 240 asthmatic children aged 6 to 17 years. They found a relationship between AD and subsequent development of asthma in children with mothers who smoked. In a reanalysis of the data (Murray et al., 1992), asthmatic children with smoking mothers were found to have significantly greater asthma severity than those with non-smoking mothers. The authors concluded that passive smoking may cause asthma only in children who have a history of atopic dermatitis, while exacerbating severity in those who are already symptomatic.

In summary, whether there is a relationship between the development of atopy and pre-natal or post-natal exposure to ETS has not been as thoroughly researched as have other outcomes discussed in this report. Published investigations of this issue have produced mixed results.

Cystic fibrosis (CF) is an autosomal recessive disease characterized by thickened mucus, a nonfunctional mucociliary clearance pathway, and recurrent and chronic pulmonary infections. Among whites in the United States, it is the most common life-threatening genetic disease, occurring in 1 in 2,500 live births. Incidence of CF is much lower in U.S. black populations, affecting only 1 in 17,000 live births. Certain patients with CF have severe pancreatic insufficiency with intestinal malabsorption and growth retardation. Life expectancy for patients with CF has improved dramatically over the past two decades. In 1978, only 18 percent of CF patients were aged 18 and older. By 1991, this had risen to 33 percent. Patients with CF are now living into the sixth and seventh decades of life (Boat and Boucher, 1994). Only a few studies have examined potential effects of ETS on patients with CF: these are summarized in Table 6.5

In a cross-sectional study, Gilljam et al. (1990) studied 32 Swedish children with CF, aged 1 to 20 years, 22 of whom had at least one parent who smoked one or more cigarettes per day in the home. A clinical index was computed for each child using the Shwachman score (the lower the score, the more severe the disease). The number of severe respiratory infections was assessed by the number of days of antibiotic treatment in a hospital during a one-year interval. Pulmonary function tests were administered and the number of weekly scheduled physical activities per week were counted. Gilljam et al. found that there was no significant association between passive smoking and clinical score; however six of seven children with low scores came from smoking families. There was a significant difference between days of antibiotic treatment in a hospital if the mother was a smoker compared to if only the father smoked (p<0.05). High physical activity level appeared to dampen the negative effects of ETS. Lung function was not associated with passive smoking.

In another cross-sectional study, Rubin (1990) studied 43 Canadian children (18 girls and 25 boys) aged 6 to 11 years at a CF summer camp to assess the relationship of passive smoke exposure to growth, nutritional status, lung function, clinical condition and number of hospital admissions. Over half (24) of the children came from homes with smokers and nearly 40% from families in which the mother smoked. None of the children smoked. Although statistical analyses were normalized for age, no further adjustments were made.

Hospital admission rates (defined as the total number of admissions adjusted for the child's age) were strongly correlated with number of cigarettes smoked in the home (r = 0.58, p<0.0001) for the group as a whole and for the subset of children with smoke exposure in the home. When analyses were stratified by gender, this relationship was apparent for female subjects only. A significant correlation of ETS exposure and clinical score was apparently confounded by nutritional status, attributed largely to the strong correlation between nutritional subscore and ETS exposure. In addition, those children assessed as having poor nutritional status who were exposed to passive smoke had higher admission rates than those with poor nutrition from non-smoking homes (p=0.10).

Rubin also found a significant interaction between lung function and ETS in relation to hospital admission rates (p=0.05); among children with lower lung function, smoking in the home was associated with significantly more hospitalizations. There was also a significant association between percent of predicted peak expiratory flow rate (PEFR) and smoke exposure, but no significant associations were found for other pulmonary function measures. For girls, there was a significant inverse correlation between number of cigarettes smoked per day in the home and height and weight (p<0.05); for boys, a near-significant correlation with height (p=0.067). There was no association of coughing, sputum production or nasal polyps with passive smoke exposure.

This study did not adjust for socioeconomic status (SES). However, changes in clinical status that could be related to economic barriers to health access are unlikely to have affected the results because Canada has national health insurance. Moreover, this CF population was in fairly good health, with participants scoring an average of 22 points on the 25-point Shwachman score. Although the camp population might not be representative of all children with CF, the camp was free and open to anyone with the disease. On the other hand, in epidemiological studies of ETS, SES may be a confounder, not only because people in lower SES brackets tend to have a greater prevalence of smoking, but also because their residences tend to be smaller, increasing the probability of exposure to more concentrated ETS and other household respiratory irritants that could exacerbate CF.

Campbell et al. (1992) studied 44 CF patients aged 1 to 22 years, who were homozygous for the F508 deletion (the most prevalent CF mutation) to examine the effect of ETS exposure on clinical status after controlling for age and SES. All patients had pancreatic insufficiency, a condition associated with more severe disease. Of the 44 patients, 22 lived in homes with light smoke exposure (1 to 2 packs per day) and 6 lived in homes with heavy exposure (3-4 packs per day). The data were analyzed using a generalized linear model. There were no significant differences between the light-exposure and no-exposure groups, so these two groups were combined in later analyses and compared to the heavy smoking group. Heavy exposure was significantly associated with disease severity as measured by the Shwachman score, FEV₁ (p=0.007), forced vital capacity (p<0.0001) and a five-fold increase in the number of pulmonary related hospital admissions (p<10-6). Models were adjusted for age and SES. Since the heavy-exposure group contained only six people, other investigators have cautioned that the results of this study may have been due to a chance clustering of high ETS exposure and poor nutritional status. The authors did conduct a "sensitivity analysis" in which two of six people were given normal pulmonary function levels and severity scores; however this did not reduce the results to nonsignificance.

More recently, Smyth and co-workers (1994) assessed the relationship of ETS exposure as measured by questionnaire and urinary cotinine in 57 children with CF and 51 controls. The age range of both groups was 5 to 16 years. The investigators examined the relationship of ETS to pulmonary function (FEV₁ and FVC) in the CF patients. Urinary cotinine levels and ETS exposure assessed by questionnaire ("smoking index") were both significantly greater in the homes of control children. FEV₁ and FVC (both expressed as a percentage of predicted for height) were regressed on cotinine concentration, smoking index, parental occupations, and patient’s age and sex. Smoking index was a significant predictor of decreased FEV₁ (p=0.022) and FVC (p=0.047): for each 10-cigarette increment in the smoking index, the investigators predicted a 4% decrement in FEV₁ and a 3% decline in FVC. However, urinary cotinine was not predictive of either measure of lung function, which Smyth et al. speculated might have been due to the flatness of the cotinine - lung function curve in the lowest three-fifths of the cotinine distribution. The geometric mean urinary cotinine concentration was 5.12 ng/ml, which lends credibility to the investigators’ hypothesis; however, not enough detail is provided in this brief report to evaluate adequately the discrepancy between the results of the smoking index and cotinine analyses. Smyth et al. did not examine the relationship of ETS to either disease severity or hospitalizations in these CF patients.

Kovesi and co-workers (1993) examined relationships between household ETS exposure and several clinical parameters in 325 patients attending the Cystic Fibrosis Clinic at the Hospital for Sick Children in Toronto in 1990 to 1991. Data on household smoking were routinely obtained by clinic nurses on standardized forms, and included whether anyone in the household (including the patient) smoked cigarettes and, if so, the total number of cigarettes consumed in the home by all smokers. The age range of 1 to 42 years was considerably larger than in any of the other studies (Kovesi, personal communication), but separate analyses were done on children aged 6 to 11 for comparison to the study by Rubin (1990). The percentage of participants exposed only to maternal smoking was not identified. Given the reported mean age in both exposed and nonexposed groups, some of these patients were probably not living with their parents, which might distinguish this study population from the others described above. Comparing patients from smoking versus nonsmoking households, there were no significant differences in Shwachman scores, spirometry (FVC, FEV₁, FEF_25-75), height and weight percentiles, colonization by Pseudomonas species, and other variables. However, patients with ETS exposure were younger, with a mean age of 14.4 years versus 17.0 years for the unexposed. Linear regression analysis showed no relationship between the number of cigarettes smoked in the household and the children’s weight or weight percentiles, weight for height, Shwachman or Brasfield scores (different measures of clinical status), spirometric indices, number of hospital admissions or number of days spent in the hospital. When households with smokers (n=97) were analyzed separately, similar results were obtained. When the subset of children aged 6 to 11 were analyzed, the results were similar to those obtained for the entire study population except that there was a significant inverse correlation between the number of cigarettes smoked in the household and the patients’ height percentile (r = -0.27, p = 0.04).

The authors also conducted separate longitudinal analyses of spirometry, weight and height percentiles for 182 patients who had had smoking and spirometric data collected between 1977 and 1985. ANOVA was used to compare various clinical parameters among three groups: those who reported no smoke exposure in either data collection period ("NEVER"), those reporting ETS exposure both times ("ALWAYS"), and those reporting such exposure between 1977 and 1985, but not in 1990 or 1991 ("QUIT"). A fourth "STARTED" group was too small and heterogeneous to be used in analysis. The NEVER group’s height percentile increased, while this index decreased for the ALWAYS group; and even more so for the QUIT group. This same relative order was observed for changes in weight percentile and weight for height percentile. Though all groups experienced a decline in their percent predicted spirometric indices (FVC, FEV₁, FEF_25-75), the decrease was greatest in the QUIT group and least in the NEVER group. When the analysis was restricted to the subgroup of CF patients homozygous for the D F₅₀₈ mutation, similar results were found, after an "outlying" patient with "extremely heavy smoking exposure" was excluded from the analysis.

In this large study, Kovesi et al. confirmed the existence of a negative dose-response relationship between household ETS exposure and linear growth in children with CF aged 6 to 11, reported previously by Rubin (1990). In the longitudinal component of the investigation, they found that exposure to household ETS was associated with growth suppression. In contrast to the findings of Campbell et al. (1992) and Smyth et al. (1994), but similar to Rubin (1990), those investigators did not find a relation between ETS exposure and lung function. In the Campbell study, which examined patients homozygous for the D F₅₀₈ deletion, effects were found only in six patients with relatively high reported ETS exposure. Moreover, the distribution of reported smoking levels in the investigation by Kovesi and co-workers was such that all patients would have been classified in the "light-exposure" group in the Campbell study, thus the results of these two reports are not inconsistent.

In the Kovesi study population there was considerable inter-child variability in spirometry, which is characteristic of CF patients, making small mean lung function differences difficult to detect. Kovesi and colleagues also could not confirm the relationship between ETS and hospital admissions reported by both Rubin and Campbell et al. However, whereas Rubin examined age-adjusted hospitalizations over the children’s lifetimes, Kovesi et al. appear to have examined only hospitalizations (and days in hospital) over the year preceding the children’s clinic visit. Furthermore, although the initial analysis comprised a much larger study population than previous studies, the subsample of children aged 6 to 11 was not much larger than that of Rubin. In addition, the study by Kovesi et al. included older patients than the other five studies, although the investigators were not able to detect an interaction of age and smoking exposure on any of the outcomes. As noted above, the reported exposure distribution of ETS-exposed children in the Kovesi study was comparable to Campbell and co-workers’ "light-exposure" group, for which the latter investigators found no effect of ETS exposure on hospitalizations. Thus, the results of the Kovesi study with respect to hospital admissions are not necessarily inconsistent with those reported by others. In addition, the identities of household smokers (other than the few actively smoking study participants) were not obtained: in other settings (e.g., induction of childhood asthma), maternal smoking appears to be more strongly related to young children’s actual ETS exposure than paternal smoking. Thus, here, as elsewhere, misclassification of exposure may have produced a bias towards the null hypothesis of no effect. Finally, in the regression analysis conducted by Kovesi et al, it appears that they did not adjust for SES, which could also have confounded the results (see above).

In part because CF is such an uncommon disease, four of these five studies have small sample sizes and low statistical power. Given this limitation, the finding that ETS is associated with hospitalizations for respiratory infection in three of four studies is striking. This relationship was observed in Rubin's (1990) study, which included relatively healthy children, and Campbell's study in which the children presumably had more severe disease. Rubin (1990) also detected interactions of ETS with the number of hospitalizations in those with lower pulmonary function and poor nutrition. While Gilljam et al. (1989) did not observe a direct effect of ETS on hospitalizations, they did find effects in those exposed to maternal smoking. In contrast, Kovesi et al. did not find any relationship between ETS exposure and hospitalizations.

The relationship between ETS exposure and pulmonary function in CF patients is less clear. Campbell et al. (1992) observed an association between ETS exposure and pulmonary function, whereas Gilljam et al. (1990), and Kovesi et al. (1993) in a much larger study, did not. Smyth et al. (1994) observed a relationship between ETS and lung function, as measured by FEV₁ and FVC, when questionnaire data were used but not when ETS was assessed using salivary cotinine levels. Rubin (1990) found an association with PEFR but not with other spirometric measures. People with CF demonstrate greater variability on pulmonary function tests than healthy subjects. This variability combined with the rarity of the disease make it difficult to demonstrate effects on pulmonary function.

Disease severity was investigated in four of the five studies. Only one study, that of Campbell et al. (1992) found a relationship with ETS exposure. Gilljam et al. (1989) found a positive but nonsignificant relationship with disease severity, Rubin’s analysis was confounded by nutritional status, and Kovesi et al. found no effect of ETS on disease severity in their large study population. Finally, in the two studies that looked at effects on growth, both found effects in the 6- to 11- year old age group. Rubin observed age-adjusted relationships with height and weight in girls and with height in boys. Kovesi et al. also found a significant relationship with height by household smoking group in their longitudinal analysis.

In reviewing these five studies, it is important to note that the age ranges of the study populations were different. Two studies included children only (Smyth et al., 1994; Rubin, 1990), two study populations were comprised of infants, children and young adults (Campbell, 1992; Gilljam et al., 1989) and one included infants, children and young and older adults (Kovesi et al., 1993). Some of the differences in study findings are potentially attributable to this variation in composition. In particular, if young children with CF are most sensitive to ETS or are likely to experience the greatest intensity of exposure, the study population of Kovesi et al. would have had any ETS-related effects diluted by the inclusion of relatively older participants.

In summary, although several reports suggest that passive smoke exposure can affect patients with CF, the extent and magnitude of such effects are still uncertain. The evidence for an effect on hospitalizations is compelling, while the studies are less conclusive in showing an effect on pulmonary function or disease severity. The two studies that have looked at growth have both found an inverse relationship between ETS exposure and linear growth. Because of the rarity of CF, relatively few children with CF in California are likely to be affected by ETS exposure. In all five studies, however, the proportion of CF patients with ETS exposure was quite high, ranging from 42% in the study by Kovesi et al. (1993) to 69% in the study by Gilljam et al. (1989).

ETS exposure produces a variety of acute effects involving the upper and lower respiratory tract. ETS exposure can exacerbate asthma in children, perhaps affecting 48,000 to 120,000 children annually in California; adults may also be affected. Parental smoking is associated with an increased risk of acute lower respiratory tract illnesses in children, as well as acute and chronic otitis media with middle ear effusions. In California, ETS-related otitis media cases may result in an estimated 78,000 to 188,000 office visits per year among children under three years of age. From 18,000 to 36,000 cases of ETS-related bronchitis or pneumonia can be predicted to occur in children 18 months of age and under, based on national statistics. Eye and nasal irritation are the most commonly reported symptoms among adult nonsmokers exposed to ETS; in addition, odor annoyance from indoor exposure to ETS has been shown in several studies. Experimental studies conducted by investigators familiar with building ventilation practice suggest that, short of prohibiting indoor smoking, protection of nonsmokers against both sensory irritation and odor annoyance can only be achieved through extensive engineering measures.

There is consistent and compelling evidence that ETS is a risk factor for induction of new cases of asthma; in California, between 960 and 3,120 new cases per year may be ETS-related. In addition, chronic respiratory symptoms in children, such as cough, phlegm, or wheezing, are associated with parental smoking. While the results from all studies are not wholly consistent, there is substantial evidence that childhood exposure to ETS affects lung growth and development, as measured by small, but statistically significant decrements in pulmonary function tests; associated reductions of lung function may persist into adulthood. The effect of chronic ETS exposure upon pulmonary function in otherwise healthy adults is likely to be small, and unlikely by itself to result in clinically significant chronic disease. However, in combination with other insults (e.g., prior smoking history, exposure to occupational irritants or ambient air pollutants), ETS exposure could contribute to chronic respiratory impairment in adults. In addition, regular ETS exposure in adults has been reported to increase the risk of occurrence of a variety of lower respiratory symptoms.

Children are especially sensitive to the respiratory effects of ETS exposure. Children with cystic fibrosis are likely to be more sensitive than healthy individuals. Several studies of patients with cystic fibrosis, a disease characterized by recurrent and chronic pulmonary infections, suggest that ETS can exacerbate the condition. Several studies have shown an increased risk of atopy (a predisposition to develop IgE antibodies against common allergens, which can then be manifested as a variety of allergic conditions) in children of smoking mothers, though the evidence regarding this issue is mixed.

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