Document 1grNwdbJq7Qnwq90939M5dDDE

Acute and Chronic Respiratory Effects of Sodium Borate Particulate Exposures David H. Wegman7, Ellen A. Eisen7, Xiaohan Hu2, Susan R. Woskie7, Ralph G. Smith3, and David H. Garabrant3 'Department of Work Environment, University of Massachusetts, Lowell, Massachusetts; department of Epidemiology and Biostatistics, University of Massachusetts, Amherst, Massachusetts; department of Environmental and Industrial Health, University of Michigan, Ann Arbor, Michigan; Emeritus This study examined work-related chronic abnormality in pulmonary function and work-related acute irritant symptoms associated with exposure to borate dust in mining and processing operations. Chronic effects were examined by pulmonary function at the beginning and end of a 7-year inter val. Time-specific estimates of sodium borate particulate exposures were used to estimate cumulative exposure during the study interval. Change in pulmonary function over the 7 years was found unrelated to the estimate of cumulative exposure during that interval. Exposure-response associ ations also were examined with respect to short-term peak exposures and incidence of five symptoms of acute respiratory irritation. Hourly mea sures of health outcome and continuous measures of particulate exposure were made on each subject throughout the day. Whenever a subject reported one of the irritant symptoms, a symptom intensity score was also recorded along with the approximate time of onset. The findings indicat ed that exposure-response relationships were present for each of the specific symptoms at several symptom intensity levels. The associations were present when exposure was estimated by both day-long and short-term (15-min) time-weighted average exposures. Associations persisted after taking account of smoking, age, and the presence of a common cold. No significant difference in response rate was found between workers exposed to different types of sodium borate dusts. -- Environ Health Perspect 102(Suppl 7): 119-128 (1994) Key words: irritation, acute effects, pulmonary function, sodium borates, real-time exposures Introduction In the early 1980s, the California Occupa tional Safety and Health Administration (CalOSHA) adopted the American Conference of Governmental Industrial Hygienists' (ACGIH) list of threshold limit values (TLVs), thereby converting these from guidelines into legal standards applic able in California. Included on the list were the commercially important forms of sodi um tetraborate (Na2B4Oy), the anhydrous salt, and the pentahydrate and decahydrate containing 5 and 10 moles of water of hydration, respectively. The 10-mole salt is most widely encountered in industry and in the home, and is generally known as borax. Prior to the legislation, the borate TLVs had been established rather recently by the ACGIH, and were based upon predicted irritant effects of boron dust present in workplace air. In the judgment of the ACGIH, the anhydrous and 5-mole com pounds were most irritating. As a result, a This paper was presented at the International Symposium on Health Effects of Boron and Its Compounds held 16-17 September 1992 at the University of California, Irvine, California. Address correspondence to Dr. D.H. Wegman, Department of Work Environment, University of Massachusetts, 1 University Ave., Lowell, MA 01854. Telephone (508) 934-3265. Fax (508) 452-5711. TLV of 1 mg/m3 was established for these, while the TLV for exposures to the 10mole compound was set at 5 mg/m3. Prior to the adoption of the TLVs, expo sures to all forms of borates in California were controlled by the same total-dust per missible-exposure-limit (PEL) that OSHA uses elsewhere (10 mg/m3). Since the newly adopted CalOSHA PELs did not appear to be consistent with the experience of U.S. Borax in their production of these compounds, the company decided to con duct the study reported here. Today, sodium borates are used primarily in the manufacture of specialized glass, enamels, and glazes; as soldering and weld ing fluxes; as fat solvents; as fixatives for mordants on textiles; in silk spinning; and in the soap, leather, and cosmetic indus tries. There are an estimated 420,000 U.S. workers with potential occupational expo sure to sodium borates (7). Prior to the study reported here, there had been an earlier study that suggested borate exposure was associated with symp toms of acute respiratory irritation, such as dryness of the mouth, nose, or throat; dry cough; nose bleeds; sore throat; productive cough; shortness of breath; and chest tight ness (2). Excessive symptoms were reported at levels estimated between 4 and 14.6 mg/m3. Symptoms were infrequent at expo sures of 1.1 mg/m3. The cross-sectional design of that earlier study had available only sparse information on actual exposure, and had to rely on subjects' recollections of past irritation. The earlier study also report ed a reduction of forced expiratory volume in 1 sec (FEVj) among smokers who had heavy cumulative sodium borate exposure (>80 mg/m3-years), but not among lessexposed smokers or among nonsmokers. The present study was designed with the objective of refining measures of both acute irritation and current exposure in an effort to characterize better the acute exposure-response relationships for sodium borate particulates. In addition, a longitudi nal analysis of pulmonary function related to chronic exposure was performed. The study was carried out among U.S. Borax employees exposed to the various forms of borate ore and processed materials present at the Mojave Desert plant site. At this plant, sodium borate minerals, such as tincal and kernite, are mined from an open pit. The resulting ores are processed into refined borate products and packed for shipment in bags or railcars. Three major forms of fin ished sodium borates are handled in this environment: disodium tetraborate decahy drate--Na2B407 + 10H2O, (10 mole); disodium tetraborate pentahydrate-- Environmental Health Perspectives 119 WEGMANETAL. Na2B407 + 5H20 (5 mole); and disodium tetraborate--Na2 B 4 07, (anhydrous). The Irritant Response Many of the irritant symptoms of sodium borate exposure (sensory irritation of the nose and throat, cough, phlegm produc tion, and bronchoconstriction, as evi denced by a decrease in FEVj) are part of the respiratory defense reflex, which func tions to protect the body from inhaled irri tants (3). This reflex can be triggered by agents that stimulate receptors in the respi ratory tract (4). However, little is known about the mechanism by which the irritant receptors are stimulated. There is evidence that stimulation of the irritant reflex response can occur both as a direct and an indirect response to changes in the osmolarity of the lung-lining fluid (5-17) and may be mediated through hist amine (18y19). Thus, if hyperosmolarity triggers defensive reflex responses, the irri tant symptoms reported by sodium borateexposed workers may be either a direct function of osmolarity or an indirect func tion of histamine. Methods Study Design for Chronic Effects of Exposure Population and Pulmonary Function Measures. A prospective (follow-up) cohort design was used to examine the associations between change in respiratory health status during the period 1981 to 1988 and expo sure during that same period. This design relied on the availability of the 1981 survey results (2). The spirometry instrument used in 1988 was the Eagle IIS spirometry system (Warren E. Collins), while that used in 1981 was an Ohio 840 rolling seal spirometer. Both meet the American Thoracic Society/ Division of Lung Disease performance criteria and were found in side-by-side evaluations to provide the same results within acceptable spirometer error. Spirometry results were standardized using the prediction equations of Knudson et al. (20). A minimum of five (maximum of seven) technically acceptable forced expi ratory maneuvers were obtained in 1988, and a minimum of three (maximum of five) were similarly obtained in 1981. In both surveys, repeatability was assessed from the two largest values for each para meter. Subjects were tested without regard to the time of day or day of the work week. Historical Exposures. Estimates of levels of dust exposure and the definition of sepa rate, homogeneous exposure categories over time were based on examination of current exposure measurements, historical records of exposure, and information on dates of changes in the introduction of exposure controls. Since very litde exposure informa tion existed for the years prior to 1978, only interim exposures covering the years between the two surveys were estimated. This information was then organized in a matrix that permitted computation of esti mates of interim exposure for each subject. Estimates of cumulative, interim dust exposure during the 7-year period between the two surveys were computed as a sum of the exposure in each job held in the period, weighted by the number of years between 1981 and 1988 during which the subject worked in that job. Study Design for Acute Effects of Exposure In studying the association between sodi um borates and acute respiratory irritation, a primary objective was to describe in detail the exposure-response relationships observed when both exposure and response were measured frequently throughout the course of daily work activities. A related question was whether the relationships dis covered differed according to the type of sodium borate exposure. As can be seen, the borate types varied only by the moles of waters of hydration in the three chemical forms. Population and Health Effects. All employees were eligible for the acute study if their exposures to dust could be ade quately characterized with respect to borate type. Subjects eligible for the comparison group were identified as current nonoffice, hourly employees who had no routine exposure to borate particulate (other than background). A total of 115 exposed and comparison workers were eligible. All eligibles were invited to participate, and 106 accepted. At the pre-shift survey, subjects were queried about the presence of a common cold on that survey day or within the past two weeks, about the presence of allergic symptoms or asthma on the survey day, and the time of day they last smoked a cig arette (see Appendix). To provide close supervision of the study protocol, a technician was assigned to each study subject (2 to 4 subjects were studied per day) and was instructed to stay with that subject throughout the day. The tech nician was responsible for monitoring the use of the continuous-exposure monitor, and for administering the hourly symptom surveys. Acute irritant effects were studied in detail through administration of symptom questionnaires before work, and at hourly intervals throughout each of 4 consecutive workdays (see appendix). The closed-ended questionnaires were pilot tested on a sepa rate group of workers who did not partici pate in the full-scale irritant study. Questionnaires were revised as needed to confirm that symptom queries were under standable. The questionnaire inquired about symptoms of eye, nose, and throat irritation; sneezing; nose bleeds; coughing; and breathlessness. Whenever a subject reported one of these symptoms, the inter viewer requested an intensity score and approximate time of onset to the nearest quarter hour. The outcomes were measures of acute irritant symptoms of the respirato ry tract and mucous membranes. Symptom intensity was scored using a category-ratio scale based on Borg's studies of pain or exertion (21-24). A score on a scale between 0 and 10 was requested (Figure 1). Subjects were asked to indicate the time of onset to the nearest 15 min within the previous hour (or to indicate when the symptom had persisted from the previous survey). When the analyses were restricted to symptoms of a minimum sever ity, reports of less severe symptoms were ignored (i.e., considered nonsymptoms). Only incident symptoms that arose dur ing the workshift were included in the exposure-response analysis. A symptom reported at an hourly survey was defined as an incident symptom if the same type of symptom was not reported in the preced ing hour, or the same type of symptom had been reported in the preceding interval but Numerical value 0 0.5 1 2 3 4 5 6 7 8 9 10 Severity Not at all Very, very little (just noticeable) Very little Fairly little Moderate Pretty much A lot (strong) Very much Very, very much (almost maximal) Maximal Figure 1. The category ratio severity scale presented to each study participant at preshift and hourly sur veys. When an irritant symptom was reported, the par ticipant selected a numerical score to characterize the severity of the symptom. 120 Environmental Health Perspectives ACUTE AND CHRONIC RESPIRATORY EFFECTS OF BORATES it could be determined that the symptom had not persisted from one interval to the next. If no second onset time was reported, the symptom was regarded as persistent rather than incident. In addition to the hourly survey, subjects were provided a means of adding a mark to the exposure monitor each time they expe rienced an acute irritant symptom (see "Measurements of Acute Exposures"). This device permitted each subject to record the actual time of symptom onset without technician prompting. However, at the hourly survey, the technician would ask whether the marker had been used, and if so, for what symptom. Measurements ofAcute Exposures. A per sonal direct-reading aerosol monitor (the MINIRAM, Miniature Real-time Aerosol Monitor; MIE Inc., formerly GCA, Bedford, MA) was used in conjunction with a datalogger system, (the RangerRustrak; E. Greenwich, RI). This system provided for the recording of short-inter val, real-time exposures. The MINIRAM aerosol monitor is most sensitive to aerosols in the respirable size range, and like all photometers, is sensitive to high humidity and changes in the parti cle-size distribution and composition. Since irritation of the eyes, nose, and throat may be caused by particles in the nonrespirable size range, the MINIRAM's use in the study had to be calibrated sepa rately for the three dust types, as well as for different particle sizes. Throughout the study, the MINIRAM was used in the active mode as a total-dust monitor, with a flow adapter that enabled pumps calibrated at 2 1/min to pull the aerosol through the MINIRAM chamber and onto a closed-faced filter that was sub sequently gravimetrically analyzed. To account for the fact that both borates and nonspecific dust may have irritant proper ties, it was hypothesized that the boron content of dust samples might better repre sent exposure to borates. Consequently, each filter was also analyzed for total boron content. A Marple Personal Cascade Impactor with four stages (Anderson Samplers; Atlanta, GA) was used to determine parti cle-size distributions with cut points for the impactor stages at 21.3, 14.8, 9.8, and 3.3 microns (25). A Cahn model 29 elec trobalance was used to weigh the filters for gravimetric determinations. All filters were desiccated for 18 hr prior to weighing. Continuous MINIRAM readings were recorded on a datalogger data tape outfitted with an event-marker button, so that each Table 1. Pulmonary function characteristics of follow-up cohort (n = 303). Category Mean SD Range FEV, (1981)a FEV, (1988) % Predicted FEV, (1988) FVC (1981) FVC (1988) % Predicted FVC (1988) FEV, Decline + b FVC Decline-i- 3.95 3.75 96% 5.14 4.95 104% 0.20 0.20 0.78 1.49-6.02 0.75 1.23-5.91 14% 46-137% 0.96 2.23-7.91 0.91 2.12-7.92 13% 67-148% 0.31 -2.02-1.84 0.38 -2.30-2.39 Abbreviations: FEV,, forced expiratory volume in 1 sec; FVC, forced vital capacity. 3 Pulmonary function values reported in liters.b + decline = test value in 1981-test value in 1988. subject could mark the time(s) an irritant symptom occurred. With this sampling method, it was possible to estimate real time, total particulate exposure for each subject during each survey day. The instru ment, however, cannot distinguish the type of particulate measured. Therefore, sodium borate type was assigned to each daily exposure record based on the type of borate being processed in the area surrounding the individual's work station. Data Analysis for Acute Effects. The exposure-response analysis of symptoms included detailed examination of exposure as measured by the MINIRAM-integrated estimates of daily (6-hr) and short-term (15-min) exposures. Incidence rates for each symptom were computed as the ratio of the number of episodes to the number of person-hours for which the individual was at risk. Risk ratios, defined as the ratio of the probability in the exposed to the probability in the comparison group, were estimated for each symptom. Categories of increasing exposure levels were then defined, and the incidence was estimated within each category. To adjust for confounding due to smok ing, age, and recent cold, the associations were then estimated in a series of logistic regression models. A separate model was fitted to the data for each of the five most common symptom outcomes. The exposure-response analyses were based first on daily exposures and then on exposure measured in 15-min intervals. The unit of analysis for the daily exposures was the person-day; and the presence or absence of a particular symptom over the course of the day was paired with the daily, measured exposure. Thus, each person contributed four observations to these analyses, one for each person-day of observation. In the final phase of the symptom analy sis, contiguous 15-min intervals were defined from the start to the end of each observation day. The presence or absence of a symptom was then determined for each interval and paired with the 15-min exposure for that interval. Probabilities of response were estimated across categories of increasing levels. In these stratified analy ses, subjects were included up to 96 times, one for each of the 15-min exposure inter vals during which they were at risk over their 4 days of monitoring. These analyses did not satisfy the assumption of independent observations, because multiple observations were made for each subject. Therefore, methods recently developed to account for correlat ed outcomes in the analysis of repeated measures were also used. Logistic models were fit to the data for each individual with at least three positive symptom reports in the first stage of a two-stage model. Thus, each exposure-response model was based on up to 96 observations. In stage two, the individual odds ratios were summarized using a maximum likelihood estimate of the mean, within strata defined by smok ing, cold status, age, and duration of employment. These results have been pre sented in more detail elsewhere (26). Results Chronic Pulmonary Function Effects Loss to Follow-up. Of the 631 workers who participated in 1981, 371 were available for the pulmonary-function retesting in 1988. Of these, 336 performed pulmonary func tion tests; 303 of the 336 subjects had acceptable tests for both years. Those who were not resurveyed were, on average, 5 years older than those who did participate in the second survey; they also had smoked longer than the second survey participants. FEV, differences between the two groups appeared to be accounted for by the differ ences in smoking. Follow-up Population. On average, sub jects were 44 ( 9.0) years old and had worked for 19 years; the group included 42% current smokers, 28% ex-smokers, and 30% never-smokers. The average 1988 Volume 102, Supplement 7, November 1994 121 WEGMANETAL. Table 2. FEV, decline by smoking status and years employed. Years employed Smoking status 0-10 10-20 >20 Never smoker FEV, decline3 % pred FEV, (1981) % pred FEV, (1988) >0-10 FEV, decline % pred FEV, (1981) % pred FEV, (1988) >10-20 FEV, decline % pred FEV, (1981) % pred FEV, (1988) >20 FEV, decline % pred FEV, (1981) % pred FEV, (1988) n=9 0.24 (0.08)b 103 (3)c 103 (2) n=4 0.38 (.14) 104(2) 100 (4) n= 12 10(0.08) 92 (3) 94(3) n=8 0.16(0.06) 104(5) 105 (4) /7 = 60 0.21 (0.06) 98 (2) 97(1) n- 12 0.25 (0.06) 99 (3) 97(2) n = 28 14(0.05) 104(2) 106 (2) /?= 83 0.23 (0.04) 93 (2) 91 (2) n = 23 0.17(0.05) 102 (3) 102 (2) n=4 0.24 0(.14) 93 (6) 91 (8) /? = 9 0.18(0.13) 93(4) 93 (3) /? = 40 0.20(0.04) 92 (2) 91 (2) Abbreviations: FEV,, forced expiratory volume in 1 sec; FVC, forced vital capacity. 3 Decline = FEV, (1981) - FEV, (1988).b numbers in parentheses indicate standard error.c Percent predicted based on Knudson (75). Table 3. Dose-response model for FEV, and exposure with adjustments. Variable Intercept Cumulative exposure, 1981-1988 Years employed to 1981 Pack-years, cigarettes Age Height p -202 -0.000 0.45 -0.66 -3.61 4.25 SE 83.7 0.001 1.23 0.149 0.373 0.448 P>T 0.017 0.999 0.717 0.001 0.001 0.001 Table 4. Regression equation relating FVC decline to 1981 to 1988 cumulative exposure with adjustments. Variable Intercept FVC, 1981 Exposure, 1981-88 Ever smoked Age, 1981 Height, cm p -32.29 0.78 -0.11 1.45 -1.07 0.96 /?2 = .83 SE, 58.73 0.03 0.24 4.46 0.25 0.39 P> T 0.5597 0.0001 0.6216 0.7439 0.0001 0.0146 Abbreviations: FVC, forced vital capacity; FEV,, forced expiratory volume in 1 sec. Table 5. Regression equation relating FEV, decline to 1981 to 1988 cumulative exposure with adjustments. Variable Intercept FEV,, 1981 Exposure, 1981-88 Ever smoked Age, 1981 Height, cm p 0.62 0.79 -0.07 -2.50 -0.91 0.56 R2 = 0.84 SE, 43.85 0.03 0.19 3.59 0.22 0.28 P> T 0.9986 0.0001 0.7122 0.4860 0.0001 0.0450 Abbreviations: FVC, forced vital capacity; FEV,, forced expiratory volume in 1 sec. FEV, and forced vital capacity (FVC) val ues were 96 and 104% of predicted values, respectively (Table 1). The average annual loss in both FEV, and FVC was close to 30 ml/year, the rate of loss expected on the basis of cross-sectional studies in most stan dard population studies. Exposure--Response Associations. FEV, decline and percentage of loss predicted were examined via duration of work, con trolled for smoking status (Table 2). Although years worked was not associated with pulmonary status among never-smokers, evidence for an exposure-related decrease was seen in FEV, percent among those who had smoked the longest. To examine these findings further, FEV, was regressed on age, height, pack-years of ciga rette smoking, and duration of employ ment (Table 3). These results suggest that once cigarette smoking is accounted for, the effect of exposure duration is not sig nificant. Since exposure measures were not avail able prior to the late 1970s, exposure between 1981 and 1988 was estimated for each subject. The method and results for estimating historical exposures are reported elsewhere (27). These estimates were com pared with rates of loss in function over the study interval. An autoregressive model was used to examine the exposure-response rela tionship, adjusting for the 1981 pulmonary function level, age, height, and cigarette smoking status. The models explained 83 and 84% of the variability in the 7-year decline in FVC and FEV,, respectively (Tables 4, 3). After taking 1981 FEV, into account, current cigarette smoking status and interim exposure were not statistically significant factors in predicting FEV, decline. Nor was duration of employment prior to 1981 a significant factor. Acute Irritant Effects Population. A total of 106 subjects partici pated in the survey of acute health effects of sodium borate exposure. Among the 106, the comparison group was, on aver age, 7 years older and included more cur rent smokers and workers with longer employment tenure than the exposed group (Table 6). Exposure: Calibration Study. As noted above, since the MINIRAM cannot sepa rately monitor the different sodium borate aerosols (10 mole borax, 3 mole borax, and anhydrous borax), the calibration study had to be carried out in areas where each of the types was exclusively processed. Over 450 samples were collected in the three dust-type environments. The 122 Environmental Health Perspectives ACUTE AND CHRONIC RESPIRATORY EFFECTS OF BORATES Table 6. Demographic characteristics of 106 borax employees in acute study cohort. Characteristic3 Exposed (79) Comparison (27) those exposed, nonsmokers had higher rate ratios than smokers for nasal (1.3) and eye (16.8) irritation, and lower rate ratios for Age Height Sex (male) Race (white) Current smokers Packyears smokingb Duration of employment Physical exertion 34.0 (7.8) 69.5 (2.6) 78 98.7% 75 94.9% 29 36.7% 9.2 (13.8) 8.7 (6.3) 10.4 (2.5) 40.9 (11.1) 70.3 (3.1) 25 92.6% 26 96.3% 14 50.0% 14.0 (20.4) 11.9 (7.5) 8.5 (2.3) 3 Values are expressed as mean SD, or as number and percent.b Results are based on 96 subjects (70 exposed and 26 comparison) whose smoking information was complete from the baseline survey. throat irritation (0.9), cough (0.5), and breathlessness (0.4). Because dust was measured continuously over the day, paralleling the collection of health data, short-term 15-min and daily exposure levels could be examined in rela tion to health outcomes. For these analyses, risk was expressed as a probability of response, equal to the proportion of expo sure intervals in which a symptom was reported. samples represented dust concentrations reported approximately equally by mem Respiratory Irritation: Exposure- ranging from 0.1 to 205 mg/m3. The types bers of the comparison and exposed Responsefor Daily Exposures. When exam of sodium borate dust do not vary greatly in groups. Only nasal irritation was notably ined by daily exposure (Table 8), the prob refractive index or particle size. more prevalent in the comparison group ability of nasal irritation increased from Nevertheless, the calibration curves were (11 of 27 vs 25 of 76). Approximately 0.01 on days when the daily exposure was examined for each of the dust types and one-quarter of both groups reported having less than 1 mg/m3, to 0.27 when daily combinations of dust types to which work a cold on the survey day, and more than exposures exceeded 15 mg/m3, almost a ers were exposed, to verify that the calibra one-third reported having had a cold in the 30-fold increase. For all five symptoms, the tion did not change across dust types. previous 2 weeks. Although this frequency probability of response increased with Details of the calibration study are reported of colds appears high, the prevalence was increasing levels of exposure. These expo elsewhere (28). Gravimetric results predict the same in the two exposure groups. sure-response trends were statistically sig ed from the calibration curves were com Respiratory Irritation: Incident nificant (/><0.05) for all but eye irritation. pared with those actually measured in areas Symptoms. Previous studies of employees When these same relationships were exam not used to generate the curves and were exposed to borate dusts included reports of ined using estimates of daily exposures to found not to be significantly different. This nosebleeds as an important finding. In this boron in place of total dust the same find suggested that the calibration curves could study, although subjects were interviewed ings were observed (data not shown). be generalized to all areas in the study. regularly about them, no nosebleeds were To adjust for confounding, we included Personal Exposure Estimates. The envi reported. Therefore, nosebleeds are not age, current colds, cigarette smoking, and ronmental sampling activity was undertak referred to in any of the tables describing dust level as independent variables in logis en on 432 sample-days (each person sam symptoms. Sneezing is represented only in tic models. The results for each symptom pled for 1 day contributed 1 sample-day). the collapsed category, any symptom, were modeled with subjects included once There were only 13 (3.0%) sample-days because it was not reported frequently for each day of observation (generally four without complete daily measures and only enough to be evaluated separately. times). The exposure-response relation 2 sample-days without even partial data In contrast to the preshift symptom pat ships remained present for all five irritant (0.5%). tern, the frequency of incident reports was symptoms (data not shown) with the mag Daily versus Short-Term Exposure. The uniformly higher among the borate- nitude of the adjusted risk estimates very arithmetic mean of daily exposures in the exposed. The most striking difference was close to the unadjusted risk estimates (29). comparison group was 0.45 mg/m3 total for nasal irritation, where 23% of the To assess the importance of dust type as dust (0.02 mg/m3 total boron), with virtu exposed group reported at least three inci well as dust level, a variable for dust type ally 100% of the daily levels below 1.0 dent symptoms, in contrast to none among was added to the model. Due to limitations mg/m3 total dust and almost 90% below the comparison group. When incidence in the distribution of type-specific data, 0.5 mg/m3. Less than 10% of the 15-min rates were calculated for each symptom, the this variable was defined as anhydrous levels were greater than 1.0 mg/m3. In exposed group was almost nine times as borax versus other. When this type variable contrast, average daily exposure for the likely to report nasal irritation as the com was included, it was found not to be a sig exposed group was 5.72 mg/m3 of total parison group, and seven times as likely to nificant risk factor in any of the models. dust (0.44 mg/m3 total boron), with only report breathlessness (Table 7). Among 21% of the group showing daily exposures of less than 1.0 mg/m3 total dust, while the majority of exposures were between 1.0 and 10.0 mg/m3. A total of 68% of the Table 7. Acute symptom rate ratios. Exposed Comparison exposed subject-days included at least one Symptom Event Rate Event Rate Rate ratio6 15-min interval when exposure exceeded 10.0 mg/m3. Respiratory Irritation: Preshift Symptoms. Preshift symptoms reported by workers surveyed before entry to the work Nasal irritation Eye irritation Throat irritation Cough Breathlessness 152 (1624)3 31 (1792) 56(1689) 89(1697) 20(1771) 0.09 0.02 0.03 0.05 0.01 6(562) 2(615) 7(609) 18(594) 1 (630) 0.01 0.00 0.01 0.03 0.00 8.8 5.2 2.9 1.7 7.1 place were presumed to be unrelated to 3 Parentheses contain number of 15 min intervals at risk.b for all rate ratios, p<0.001 based on binomial distribu work. Four of the five symptoms were tion (one-sided test). Volume 102, Supplement 7, November 1994 123 WEGMANETAL. Table 8. Probability of response by TWA-6 dust levels.3 Dust concentration, mg/m3 Symptoms <1 1-4 5-9 10-14 >15c Correlation coefficient Nasal irritation Events Probability Eye irritation Events Probability Throat irritation Events Probability Cough Events Probability Breathlessness Events Probability 7(877)b 29 (765) 44(266) 36(120) 42(158) 0.01 0.04 0.17 0.30 0.27 1 (958) 0.00 4(858) 7(275) 11 (126) 10(190) 0.01 0.03 0.09 0.05 8 (942) 16(795) 10(273) 0.01 0.02 0.04 1 (122) 19(166) 0.08 0.11 30 (920) 32 (792) 14(278) 0.03 0.04 0.05 8(120) 23(181) 0.07 0.13 1 (983) 0.01 3(822) 3(280) 0.00 0.01 3(132) 11(184) 0.02 0.06 0.964" 0.894" 0.980" 0.929d 0.9833 3 Dose-response evaluated by weighted least squares method using the midpoint of the dust range for each group. b Parentheses contain person-hours at risk. c Median (mean) dust level for this category is 23.8 (34.5) mg/m3. dp<0.05 based on binomial distribution (one-sided test). ep<0.01 based on binomial distribution (one sided test). Table 9. Probability of symptoms of severity >3 by TWA-6 dust levels.3 Dust concentration, mg / m3 Symptoms <1 1-4 5-9 10-14 15 Correlation coefficient Nasal irritation Events Probability Eye irritation Events Probability Throat irritation Events Probability Cough Events Probability Breathlessness Events Probability 5 (877) * 10(765) 21 (266) 24(120) 18(158) 0.01 0.01 0.08 0.20 0.11 0 (958) 0.00 3 (858) 6(275) 0.00 0.02 9(126) 3(190) 0.07 0.02 0(942) 0.00 6 (795) 7 (273) 0.00 0.02 4(122) 0.03 6(166) 0.04 4(920) 0.00 7 (792) 4(278) 0.01 0.01 3(120) 0.03 5(181) 0.03 0(983) 0.00 0 (822) 2 (280) 0.00 0.01 0(132) 2(184) 0.00 0.01 0.859 0.783 0.940c 0.989" 0.018 3 Dose response evaluated by weighted least squares method using the midpoint of the dust range for each group. b () Parentheses contain person-hours at risk.c p<0.05 based on binomial distribution (one-sided test).d p<0.01 based on binomial distribution (one-sided test). Respiratory Irritation: ExposureResponse for 15-min Exposures. To exam ine how symptoms relate to changes in short-term exposure levels, each full day was divided into 15-min intervals. Fifteenminute, time-weighted average and symp tom status were determined within each short-term interval. Symptom presence within an interval was defined by the onset of an incident symptom. All other at-risk intervals were associated with the absence of a symptom. For convenience, a summa ry variable (any symptom) representing the presence of any of the irritant symptoms was used in these analyses. Examined by deciles, the probability of an irritant response in a 15-min interval increased sig nificantly from 0.01 in the lowest exposure category (<0.084 mg/m3) to 0.11 when the exposure exceeded approximately 10 mg/m3. Exposure-response associations having been demonstrated using both daily and 15-min exposure measures, both daily and short-term exposure were included in the same logistic regression model. When this was done, a strong, linear, exposure-response trend remained, while the trend for the daily exposures was rela tively flat (29). Respiratory Irritation: Short-term Exposure Models. To address the problem of correlated outcomes when examining 15-min exposures within study subjects, separate logistic models were estimated for individual subjects where possible. The 29 subjects who reported a minimum of three incidents of a symptom during the four survey days were identified. Doseresponse models were fit to the data for the 25 of these individuals who had complete exposure data. The exposure-response parameters estimated in these logistic mod els are estimated-odds ratios, (EOR), inter preted as an individual's odds of reporting a symptom given an increase of 1 mg/m3 in 15-min exposure interval. Ninety percent of the 25 EORs exceed ed 1.0. The maximum-likelihood estimate of the EOR among the subjects with multi ple positive responses was 1.02 (95% Cl: 1.01-1.04) per unit dust. When these odds ratios were stratified by smoking, dust type, duration of employment, recent cold, or age, none of the effect modifiers signifi cantly changed the estimates. All of the above relationships, using either daily or 15-min estimates of total dust exposures were also examined using estimates of total boron exposures. In every instance, the results were similar (data not shown). Respiratory Irritation: Multiple Responders. Finally, there was a question as to whether individuals with multiple-symp tom reports were more sensitive or more highly exposed. The group of subjects with multiple-symptom reports were younger, smoked less, and were more likely to have a current cold or allergy. However, the mul tiple responders had substantially higher average exposures (11.2 vs 3.7 mg/m3). Respiratory Irritation: Acute Symptom Severity. The evidence presented suggests that frequency of irritant events is increased in a sodium borate-exposed work environ ment. The possibility that intensity of the symptoms reported also increased over background was also examined. This effort took advantage of the fact that, for each symptom reported, the subject was asked to rate its severity. Subjects responded without difficulty to this query; and, as expected, reports of more severe responses were less frequent. The severity of symptoms reported by comparison-group subjects before they entered the workplace was examined to suggest background severity levels. The results showed that background irritant symptoms were uncommon, and the sever ity level was lower than that reported for symptoms that occurred at work. Among all comparison subjects without current colds, the average preshift symptom severi- 124 Environmental Health Perspectives ACUTE AND CHRONIC RESPIRATORY EFFECTS OF BORATES Table 10. Probability of nasal irritation in an hour by TWA-6 dust levels for different severity levels.3 Dust concentration, mg/m3 Symptoms <1 1-4 5-9 10-14 15c Correlation coefficient Any severity Events Probability > Severity 3 Events Probability >Severity 4 Events Probability > Severity 5 Events Probability 7(877)* 29 (765) 44(266) 36(120) 42(158) 0.01 0.04 0.17 0.30 .27 5 (877) 10(765) 21 (266) 24(120) 18(158) 0.01 0.01 0.08 0.20 .11 2 (877) 0.00 3 (765) 3(266) 0.00 0.01 4(120) 7(158) 0.03 .04 1 (877) 0.00 2 (765) 1 (266) 0.00 0.00 0(120) 3(158) 0.00 .02 0.964d 0.859 0.913 -0.308 3 Dose response evaluated by weighted least squares method using the midpoint of the dust range for each group. b Parentheses contain person-hours at risk.c p<0.05 based on binomial distribution (one-sided test).d p<0.01 based on binomial distribution (one-sided test). ty across all symptoms was 1.9, and the average severity for nasal irritation, the most common symptom, was 2.2. Those with current colds reported slightly lower average severity (2.0) for nasal irritation, but higher severity for throat irritation (2.0 vs 0.9) and cough (2.3 vs 1.4). When the frequency distribution of the severity of responses during the workshift was described, it was found that, among all symptoms, 91% were <3 and 96% were <4. Thus, there was a virtual cap on the degree of irritation reported in association with current exposures to sodium borate in this setting. Approximately one-third of the total study time was spent in the lowest exposure category, <1 mg/m3. Among symptoms reported in this exposure category there were virtually none with severity greater than 2, "very little" (Table 9). At exposures greater than 1 mg/m3, however, expo sure-response associations were seen for each specific type of symptom of severity >3. The trends were similar to those seen when symptom severity was ignored. When examined in logistic models, it again was found that confounders did not alter the significant exposure--response relation ships. Exposure relationships were further reviewed using a stricter severity criterion. Severity levels of >4 and >5 were examined for nasal irritation; the only specific symp tom that occurred with sufficient frequency for such refinement (Table 10). Using either severity criterion, an increasing risk with increasing exposure was observed. The trend for the >4 symptom group was statis tically significant. Discussion The analysis of the relationship of sodium borate exposures in the workplace to chronic effects on pulmonary function could be examined only by evaluating annual, functional decline in relation to exposure between 1981 and 1988. In this analysis, no association was found between FEV, and exposure accumulated between surveys. The expected smoking-related abnormalities were observed. Thus, it appears that the 7-year exposure to dust in the work environment examined is not associated with long-term health effects. An effect associated with exposure cumulated prior to the 1981 survey, although unlike ly, has not been ruled out. Having estimated the likelihood of response at different exposure levels, it is possible to consider targets for exposure control. There are no normative data (inci dence or prevalence) on the distribution of acute irritant symptoms to use as a guide. The absence of general population rates makes it necessary to make a judgment about an acceptable frequency of irritant symptoms based only on data from this study. Were the irritant symptoms considered to serve as sentinels of chronic, irreversible changes, it might be required that all symp toms of 3+ severity be prevented. The analysis of the chronic pulmonary function data, however, suggests that this population is not developing chronic pulmonary func tion decrement attributable to the current work exposures. Although the analysis does not provide a definitive answer to whether the irritant symptoms can be treated only as short-term reversible events, it is suffi ciently convincing to suggest that some fre quency of moderate irritation (severity level 3) can be tolerated without undue chronic sequelae. The focus on moderate irritation should be seen in the context of this study's use of a new symptom severity scale. This scale has been adapted following extensive use of similar scales in the evaluation of mus culoskeletal and anginal pain. In the results presented above, the severity scale has been shown to provide reproducible and reliable results. In particular, the reported symptoms occurred with less fre quency in the higher severity categories, but the exposure response relationships were consistent regardless of severity level selected as a minimum. It is important to note, however, that the severity scale has not yet been used in other irritant-exposure environments. Thus, although it has been shown to provide internally consistent data within this study, there is limited information on how to interpret the absolute level of irritation associated with a moderate response to sodium borate. Ideally, this scale would have been applied in the field to study other known irritants such as sulfuric acid mist (in a battery plant) or ammonia (in a chemical manufacturing environment). In the absence of such data, one is forced to make the necessary judgments about the absolute level of severity on the basis of data collected with a different severity scale in an experimental, rather than in a field study. The totality of the evidence suggests that the current levels of sodium borate exposures in this plant are generally associ ated with no more than moderate irritant responses. The definition of an acceptable level of risk is a difficult and arbitrary one. The exposure limits necessary for control will depend on the health risk of interest. For sensory irritation, in the absence of a chronic effect, some risk is probably acceptable. In this circumstance, then, the selection of an appropriate goal for limits of exposure to borates is likely to depend in part on considerations of technical feasibili ty and cost. Lower exposure limits would be required to achieve longer work-related symptomfree periods. Using the data available, an effort was made to estimate the number of hours or days at different daily exposure levels during which an irritant symptom was not probable. The results suggested that a daily exposure level of 1.0 mg/m3 would permit an exposed worker to experi ence one incident symptom per week, while a daily level of 10.0 mg/m3 would Volume 102, Supplement 7, November 1994 125 WEGMAN ETAL. make more than one moderate symptom per day improbable. Examination of the analogous results for total boron suggested that the same goal would be accomplished if daily levels were kept below 1.0 mg/m3 of boron. Differences in the potency of the three dust types were suggested in some of the analyses. These differ ences, however, were no longer pre sent when confounding was taken into account. In the absence of a specific analytical method to distinguish dust type in environmental samples from the field, type differences cannot be directly evaluated in field samples. REFERENCES 1. US Department of Health and Human Services. National Occupational Hazard Survey. Estimate of Occupational Exposure to Sodium Borate. Cincinnati, Ohio: Centers for Disease Control, National Institute for Occupational Safety and Health, Hazard Section, Surveillance Branch, 1982. 2. Garabrant DH, Bernstein L, Peters JM, Smith TJ, Wright WE. Respiratory effects of borax dust. Br J Ind Med 42:831-837 (1985). 3. Widdicombe JG. Respiratory reflexes and defense In: Respiratory Defense Mechanisms (Brain JD). New York:Marcel Dekker, 1977;593--630. ... < 4. Alarie Y. Sensory irritation by airborne chemicals. CRC Crit Rev Toxicol 2:199-263 (1973). 5. Anderson SD, Schoeffel RE, Finney M. Evaluation of ultrasonically nebulized solutions for provocation testing in patients with asthma. Thorax 38:284-291 (1983). 6. Boulet LP, Legris C, Thibault L, Turcotte H. Comparative bronchial responses to hyperosmolar saline and methacholine in asthma. Thorax 42:953-938 (1987). 7. Eschenbacher WL, Boushey HA, Sheppard D. Iteration in osmolar- ity of inhaled aerosols causes bronchoconstriction and cough, but absence of a permeant anion causes cough alone. Am Rev Respir Dis 129:211-215 (1984). 8. Belcher NG, Rees PJ, Clark TJH, Lee TH. A comparison of the refractory periods induced by hypertonic airway challenge and exer cise in bronchial asthma. Am Rev Respir Dis 135:822-825 (1987). 9. Kivity S, Greif J, Reisner B, Fireman E, Topilsky M. Bronchial inhalation challenge with ultrasonically nebulized saline: compari son to exercise-induced asthma. Ann Allergy 57:355-358 (1986). 10. Godden DJ, Borland C, Lowry R, Higenbottam TW. Chemical specificity of coughing in man. Clin Sci 70:301-306 (1986). 11. Finney, MJB, Anderson, SD, Black, JL. The effect of non-isotonic solutions on human isolated airway smooth muscle. Respir Physiol 69:277-286 (1987). 12. Sheppard D, Rizk NW, Boushey HA, Bethel RA. Mechanism of cough and bronchoconstriction induced by distilled water aerosol. Am Rev Respir Dis 127:691-694 (1983). 13. Patterson R, Tomita Y, Oh SH, Suszko IM, Pruzansky JJ. Respiratory mast cells and basophiloid cells I. Evidence that they are secreted into the bronchial lumen, morphology, degranulation and histamine release. Clin Exp Immunol 16:223-234 (1974). 14. Silber G, Naclerio R, Eggleston P, Proud D, Togias A, Lichtenstein L, Norman P. In vivo release of histamine by hyperosmolar stimuli. J Allergy Clin Immunol 75:176 (1985). 15. Findlay SR, Dvorak AM, Kagey-Sobotka A, Lichtenstein LM. Hyperosmolar triggering of histamine release from human basophils. J Clin Invest 67:1604-1613 (1981). 16. Eggleston PA, Kagey-Sobotka A, Lichtenstein LM. A comparison of the osmotic activation of basophils and human lung mast cells. Am Rev Respir Dis 135:1043-1048 (1987). 17. Iggo A. Non-myelinated afferent fibers from mammalian skeletal muscle. J Physiol 155:52-53 (1961). 18. Juniper EF, Frith PA, Dunnett C, Cockcroft DW, Hargreave FE. Reproducibility and comparison of responses to inhaled histamine and methacholine. Thorax 33: 705-710 (1978). 19. Mygind N, Berum P, Secher C, Kirkegaard J. Nasal challenge. Eur J Respir Dis 68(suppl 143):31--34 (1986). 20. Knudson RJ, Slatin RC, Lebowitz MD, Burrows B. The maximal expiratory flow-volume curve. Am Rev Respir Dis 113:587-600 (1976). ......................................................... 21. Borg G. Psychophysical scaling with applications in physical work and the perception of exertion. Scand J Work Environ Health 16 (suppl 1): 55-58 (1990). 22. Borg G. A category scale with ratio properties for intermodal and interindividual comparisons. In: Psychophysical Judgement and the Process of Perception (Geisler H-G, Petzold P, eds). Berlin: VEB Deutscher Verlag der Wissenchaften, 1982;25--34. 23. Harms-RingdahlK, Carlsson AM, Ekholm J, Raustorp A, Svensson T, Torresson H-G. Pain assessment with different intensity scales in response to loading ofjoint structures. Pain 27:401-411 (1986). 24. Borg G. Psychophysical bases of perceived exertion. Med Sci Sports Exer 4:377-381 (1982). 25. Rubow, KL, Marple, VA, Olin J, McCawley MA. A personal cas cade impactor: design, evaluation and calibration. Am Ind Hyg Assoc J 48(6):532--538 (1987). 26. Eisen EA, Wegman DH, Kriebel D, Woskie SR, Hu X. An epi demiologic approach to the study of acute reversible health effects in the workplace. Epidemiology 2:263-270 (1991). 27. Wegman, DH, Eisen EA, Smith RG. Acute and chronic respiratory effects of sodium borate particulate exposures. Final Report to the U.S. Borax Corporation (1991). 28. Woskie SR, Shen P, Finkel M, Eisen EA, Smith TJ, Smith R, Wegman, DH. Calibration of a continuous reading aerosol moni tor (Miniram) to measure borate dust exposure. Appl Ind Hyg 8:38-45 (1993). 29. Hu X, Wegman DH, Eisen EA, Woskie SR, Smith RG. Dose relat ed acute irritant symptom responses to occupational exposure to sodium borate dusts. Brit J Indust Med 49:706-713 (1992). 126 Environmental Health Perspectives ACUTE AND CHRONIC RESPIRATORY EFFECTS OF BORATES APPENDIX U.S. BORAX HEALTH STUDY QUESTIONNAIRE ID________ Date_________ Shift______ Day of Subject's Work Week 1 2 3 4 5 Name Technician 1. Do you have a cold today? No___ Yes___ 2. Do you have allergic symptoms or asthma today? No___ Yes___ 3. Have you had a cold in the last two weeks? No___ Yes___ If yes, when? ___ 4. When did you smoke your last cigarette? _______ 5. Do you usually breath through your: Nose______ or Mouth ______ 6. Time 7. PK Flow Meter Number_______ Readings_______ _______ _______ Score Onset 8. Are your eyes irritated today? (This includes burning painful, tearing or in any other way irritated.) _______ How recently did this begin? _______ 9. Is your nose irritated today? (This includes runny, stuffy, dry or in any other way irritated.) _______ How recently did this begin? _______ 10. Have you had a sneezing bout today? (A bout is considered to be 3 or more sneezes in a row) _______ How recently did this occur? _______ 11. Have you had a recent nosebleed _______ How recently did this begin? _______ 12. Is your throat irritated today? (This includes sore, dry, scratchy or in any other way irritated.) _______ How recently did this begin? _______ 13. Are you bothered by coughing today? _______ Is it dry (D) or with phlegm (P) D/P How recently did this begin? _______ 14. Is your breathing bothering you today? _______ Is it due to Chest Tightness (CT), Wheezing (W), Shortness of Breath (SOB), or Other (Other) CT / W / SOB / Other How recently did this begin? _______ REMIND SUBJECT TO PUSH BUTTON WHEN EXPERIENCING SYMPTOMS AND THAT WE WILL ASK THESE QUESTIONS EVERY HOUR 1 ID Time Time Date Pk Flow Pk Flow Pk Flow Pk Flow Pk Flow Pk Flow Pk Flow Pk Flow 1. Score the level of physical exertion felt by your total body during the last hour of work 2. How many cigarettes have you smoked in the last hour 3. When did you smoke your last cigarette? SINCE THE LAST INTERVIEW Score Onset Score 4. Have your eyes been irritated? ______ ______ (This includes burning, painful, tearing, or in any other way irritated.) How recently did this begin? ______ 5. Has your nose been irritated? ______ ______ (This includes runny, stuffy, dry, or in any other way irritated.) How recently did this begin? ______ 2 Onset Time Pk Flow Pk Flow Pk Flow Pk Flow 3 Score Onset Volume 102, Supplement 7, November 1994 127 WEGMANETAL. 6. Have you had a bout of sneezing?______ (3 or more sneezes in a row) _ How recently did this begin? ______ 7. Have you had a nosebleed? ______ _ How recently did this begin? ______ 8. Has your throat been irritated? ______ _ (This includes sore, dry, scratchy or in any other way irritated.) How recently did this begin? ______ 9. Have you been bothered by coughing?______ _ Is it dry or with phlegm? D/P D/P How recently did this begin? 10. Has your breathing bothered you?______ Is it due to chest tighhttness (CT) CT / W /S OB wheezing (W), or shortness Other of breath (SOB) CT/W/S OB Other How recently did this begin? _ 11. Did you press the marker? No___ Yes No Yes How many times? ____ For what symptom (s)? ______ RESET TIMER 55 MINUTES D/P CT/W/S OB Other No Yes 128 Environmental Health Perspectives