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Combined Effect of Smoking Habits and Occupational Exposure to Hard Metal on Total IgE Antibodies
Combined Effect of Smoking Habits and Occupational Exposure to Hard Metal on Total IgE Antibodies·· Taro Shirakawa, M.D.;t Yukinori Kusaka, D.M.Sc.;+ and Kanekisa Morimoto, D.M.Sc.§ A survey was made within a population of workers (n = 706) exposed to hard metal dust (an alloy including cobalt), an agent Imown to cause occupational allergy. Twenty-seven (4 percent) of733 workers were eliminated from consideration in this study because of atopic status identi6ed prior to starting work in the plant. Using a Phadebas PRIST, the subjects' total 19E levels were determined and related to their smoking and exposure status. Nonexposed male smok~rs (n = 135) had a higher geometric mean 19E level (39.7 IU/ml) than did DOnexposed subjects who had never smoked (33.1 IU/ml; n=99); those with a higher Brinkman index (>300), a smoking index obtained by multiplying the number of cigarettes per day by the duration of smoking in years, had significantly (p
19E level (73.3 IU/ml) than did those who had never smoked, their serum 19E level declined with age since the time theY quit smoking, regardless of their hard metal exposure status. Hard metal (cobalt) exposure may play a significant role as an adjuvant in the production of total IgE. A multivariate analysis demonstrated that hard metal exp0sure and a smoking habit together arithmetically (p
High concentrations of total IgE occur primarily in atopic subjects who have an inherited predisposition to sensitization and to the development of specific IgE antibodies. 1.2 The precise mechanism for the atopy remains unknown, but skin or mucosal characteristics must play an important role in its development. 1-4 Cigarette smoking has been found to increase airway mucosal permeability, which then permits increased penetration of bronchospastic agents or allergens. 5 This finding has been supplemented by epidemiologic observations made in many populations6-16 demonstrating that smokers have higher total IgE values and eosinophil counts than ex-smokers and those who have never smoked. These findings suggest changes in immune responses as a possible mechanism by which smoking might be related to the etiology of bronchial asthma. Thus, in the workplace, the risk of sensitization depends upon the relationship between smoking status and the degree of exposure to occupational allergens,17 which include green coffee-bean dust, 1 ispaghula,1 TCPA (tetrachlorophthalic anhydride),4 laboratory animal agents,18 snow crab,19 and enzyme detergents. !In
Hard metal is an alloy Consisting primarily of tungsten carbide and cobalt. 21 .22 Our studies22 •23 has shown that cobalt in hard metal particles, acting as a hapten after conjugation with mucosal proteins, stimulates the production of specific IgE antibodies which can cause occupational asthma. Among grinders, atopy is strongly associated with the presence of IgE antibodies to cobalt-conjugatedhuman serum albumin (Co-HSA) or cobalt-conjugated exchange resin (Coresin) (or both) and with occupational asthma,23 bu~ is less strongly associated with the occurrence of skin symptoms unaccompanied by chest symp~oms.24 In our investigation of healthy volunteers and smoking workers,25 an acute drop in pulmonary function values was observed to occur immediately after inhalation of hard metal dust; however, no relationship has thus far been identified between smoking habits aDd hard metal exPosure in eliciting increased risk of allergy with elevated IgE. The purpose ofthe present study was to characterize further the dose-response relationships between smoking and hard metal (cobalt) exposure and total IgE levels. The former two factors were found to act together to elevate total IgE. The results of this stud~ when interpreted, provide additional strategies for the prevention of occupational allergy among hard metal workers.
*From the Department of Hygiene and Preventive Medicine, School of Medicine, Osaka University, Osaka, J~. tPresently with Asthma Genetics Group, Nuffield De~ment of Clinical Medicine, John Radcliffe Hospital, Oxford, England. *Presently Associate Professor of Environmental Health, Jichi Medical College, Japan. §Professor and Head, Department of Environmental Health and Preventive Medicine, Osaka University. Manuscript received August 6; revision accepted June 16.
BMRC=British Medical Research Council; Co-HSA=cobaItconjugated human senun albumin; Co-resin = cobaIt-conjugated exchange resin; RR relative risk; TCPA tetrachlorophthalic anhydride
=
=
MATERIALS AND METHODS
Criteria for Subjects
A sample population of 733 subjects was selected from among workers aged 18 yr and older at a hard metal plant. llo• Every worker CHEST I 101 I 6 I JUNE, 1992
1589
was interviewed regarding his work status, so that those engaged in handling hard metal were considered as having a positive history of exposure. Details of the environmental studies conducted within the plant have been described previously in our series of reports. 21.12 BrieRy, samples of total dust and mist in the workers' breathing zones were collected several times using a dust-sampling pump (DuPont F-6OOO) over a period of about 6 h, and cobalt levels in the samples were determined by atomic absorption spectrophotometry. Allergic diseases <:onsidered here include bronchial asthma, rhinitis, conjunctivitis, and dermatitis. As a first step, we designed a Japanese language version of a baseline questionnaire concerning age, sex, smoking habits, and respiratory symptoms translated from the BMRC· questionnaire and other allergic diseases translated from the questionnaire recommended by Bakke et a1. rr Those considered to have allergic diseases were referred to physicians of appropriate specialties at Osaka University Hospital. The remaining subjects, who were considered not to have an allergy, were checked by one of us (T.S.), and those judged susceptible to allergy were also referred to physicians. If a conDict arose in diagnosis between physicians, another physician participated in order to arrive at a final decision. Subjects were considered to have asthma if they had recurrent wheezing or dyspnea (or both) and if they had evidence ofobstructive disease on pulmonary function tests, with a good response to bronchodilators. is Seasonal or perennial rhinitis was defined according to the criteria of the World Organization of National Colleges and Academies and the Academic Association of General PractitionersIFamily Physicians, lIB which require the presence of three of the follOwing symptoms: sneezing; nasal obstruction; clear nasal discharge; or watering eyes. Seasonal rhinitis was diagnosed if the symptoms occurred in the pollen season, or perennial rhinitis if the symptoms were nonseasonal and associated with a known or strongly suspected allergen. Allergy testing (including skin testing), serum IgE level, or specific provocation tests were also required. Allergic dermatitis was diagnosed if three of the following four major criteria were fulfilled: pruritus; lichenification; a chronically
relapsing course; or a personal or family history of atop~ Skin biopsy was also required. 29 All of those considered to have allergic conjunctivitis had other allergic diseases. Allergic conjunctivitis was defined if they had tearing, injection, chemosis, itching, and lid edema following a provocation test with a suspected allergen. is Of lOB subjects (IS percent) diagnosed as having histories of allergic diseases, 27 subjects (4 percent) had been found to be atopic prior to beginning employment. They were excluded from consideration in the study in order to clarify the relationship between smoking, hard metal exposure, and total IgE level in workers occurring just after employment in a hard metal plant.
Peripheral Blood Analysis and Serologic Analysis Total and segmental white blood cell counts were determined in all subjects. Hypereosinophilia was defined as an eosinophil count of more than 200/cu mm. Serum samples were collected from all of the subjects and frozen at - SOOC until tests were conducted. Total serum IgE level was determined in duplicate by using Phadebas PRIST,&-16 a technique which yields more precise and speci6c measurements for low «10 IU/ml) IgE levels than do other commercial kits. After logarithmic conversion, normality of the set of resulting values was checked using Pearson's X2 test (p<0.05). Data Analysis
Subjects responded to this questionnaire during medical examinations, and response data were analyzed using the Osaka University ACOS-6 NEC computer system with the SPSSX (Statistic Package for Social Sciences extension, version 2.2) program30 including MANOVA, REGRESSION, and PROBIT. Incomplete answers received from seven subjects (six men and one woman) were eliminated from further analyses. Therefore, following these exclusions, a total of 550 male and 149 female workers remained as subjects for examination. Strong (>98 percent) reliability was demonstrated in a pilot study of 54 workers in a branch plant who filled out essentially the same questionnaire form 2 mo or 1 yr after
Table 1- Subject Profile' and Besults ofSerologic Studie,·
Sex and Group Male GI G2 G3 G4 G5 G6 Female GI G2 G3 G4 G5 G6
Allergy Cases (Asthma)
Exposure Doses, ...~eyr/m3
Normal Distribution ofIgE after Logarithmic Conversiont
33±6 38±7 54±7 65±7§1I 73±8, 119±8'tt
Yes Yes Yes Yes No No
Smokin~
No. of Cases
Mean Age, yr
No/never No/present Yes/never Yes/present No/former Yes/former
99 135 88 156 35 37
35±12 38±12 41± 12 38±12 37±12 44±15
10±8 12±8 11±8 13±8 11±8 13±7
12 (3) 10 12 13 (4) 8 IS (13)
0 381±278 0 348 ± 238 379±298* 340 ± 223*
0 0 1,222±2,413 766± 1,328 0 857±356
No/never No/present Yes/never Yes/present No/former Yeslformer
III 10 17 7 2 2
33±12 36±13 47±8 44±5 36 (37;34) 43 (44;42)
5±4 6±5 8±4 5±2 7±6 4±1
8 (2) 2 4 (2) 1 0 0
0 200± 179 0 334± 192 200* 300+
0 0 588±769 916±39 0 313 (320;305)
Exposure!
Mean Brinkman Index, pieceseyr
Geometric Mean IgE Level, IU/ml
Mean Length of Employment, yr
41±7 53±5 47±6 65±7 183
63
Yes Untested Untested Untested Untested Untested
*Data from seven subjects who did not respond to questionnaire were not used in this table. tBased on Pearson's X2 test (p<0.05). +Before quitting smoking. §p
1570
Smoking Habits and OCCupational Exposure to Hard Metal (Shirakawa, Kusaka, Morimoto)
the original. The validity of collected data was evaluated by comparing answers received in the self-administered questionnaire with those obtained following personal interviews made of all subjects by our staff. About 95 percent of the respondents gave identical answers on the two occasions.
(ft) 200
••
(I)
RESULTS
Subject profiles, by means ofwhich each respondent was categorized into one of six subgroups by smoking and hard metal exposure status, are summarized in Table 1. The female work force exposed to hard metal or with a positive smoking history was not large enough to make possible further analysis of the effect of hard metal exposure or smoking habits; analyses discussed henceforth refer therefore to results for men and nonexposed women only.
Distribution ofTotallgE Level, Allergy Prevalence, and Eosinophilia The distribution of log[IgE] in the male subjects was found to be gaussian follOwing logarithmic conversion (Fig lA), with a mean 10g[IgE] of 1.72 IU/ml and a geometric mean of52.5 IU/ml. A slight leftward skew is still apparent in the curve computed from female workers' IgE levels because of higher frequencies of younger individuals (Fig lA). Of 12 groups, male groups G 1 through G4 and female group G1 had normal distributions of log[IgE] (Table 1). The geometric means of the nonexposed male (33.5 IU/ml) and female (32.5 IU/ml) subjects were similar to those (25 to 35 IU/ml using PRIST kit) found in previous studies.6-16 Prevalences of allergy, including airway, eye, and skin symptoms identified by physicians, and eosinophilia are shown in Figure Ie. Abrupt increases of cumulative prevalences of allergy (from 5.2 to 11.2 percent) and eosinophilia (10.1 to 22.3 percent) in the subjects with IgE levels of more than 400 IU/ml were identified. The prevalence among male subjects exposed to hard metal (39/273 or 14 percent in combined group, G3 + G4 + G6, with eight missing cases) was similar to that among those men not exposed (301260 or 12 percent in combined group, G 1 + G2 + G5, with nine missing cases); however, it was striking that there were 20 cases of asthma, three (1 percent) among the 260 nonexposed male subjects and 17 (6 percent) from the 273 exposed male subjects (p
Effect of Hard Metal Exposure on TotallgE Level A history of hard metal (cobalt) exposure was significantly (p<0.05) associated with above normal log[IgE] (1.64 ± 0.83 in Gl + G2 vs 1.83 ± 0.80 in G3 + G4) in male subjects (Fig IB); however, there was no significant difference in mean log[IgE] between groups Gl and G3 (p = 0.07). Within group G3, those exposed to a cobalt concentration of more than 50JLg/m 3 in breathing zones had a significantly (p<0.05) higher geometric mean IgE level than did
~
MALE
FEMAlE
100
c.J IL
0
0 z
0
<1.0
1.0
1.5
2.0
2.5
LOG[IG E] (8)
3.0
••
25-
I
>3.0
I'O£>
15
5
o 30
1.5
2
2.5
3
3.5
LOG(lGE]
(C)
FIGURE 1. Frequency distribution of log[lgE) by sex (A, tQP) and by exposure status (B, middle) within groups of male subjects (Gl+G3+G5 vs G2+G4+G6; see also text and Table 1). C (bottom). Percentage ofcumulative prevalences ofallergy (bronchial asthma, dermatitis, rhinitis, and (."()njunctivitis) and eosinophilia in male subjects. Dia~oses were made using internationally established criteria."
those with exposure to lower concentrations. There was a significant (r=0.405; p400JLg'yr/m) dose group was significantly (p<0.05) higher than that of subjects exposed to lower doses. A similar result (r=0.445; p
1571
4 3
iii'
g
(;'
- .. , .--.. ..... - • - t ·. -r: -- ---- ..-.-. ---_i1t.,I:' - -• ~
2
0
...J
II
0
(A)
•
II
1
II
II
10
100
1000
EXPOSURE LEVEL
Relationship between cobalt exposure doses and log[IgE] levels in men of group G3. Cobalt level (in micrograms per cubic meter) in breathing zone was determined using previously described method.·...•
•• •
40
> u
30
Cl.RBlT SM.JI
Z
2IE
III
~
20 10
o
FIGURE 2.
<1.01.0
1.5
2.0
2.5
3.0
>3.0
LOG(lGE)
(8) 3
•
E>CPaiED
.~
Effect of Smoking on TotallgE Level
Male subjects smoking at the time of the study had a geometric mean serum IgE level of 53.1 IU/ml, not significantly different from that (93.9 IU/ml) of exsmokers (G5 + G6); however, each of these means was significantly (p<0.05) higher than that (46.7 IU/ml) of subjects who had never smoked (Fig 3A). Within group G2, there was a moderately significant inverse relationship between IgE level and duration of smoking (r = 0.32; p300) had a significantly (p=0.04) lower mean IgE level (26.7 IU/ml) than did those with lower index scores (52.9 IU/ml). A similar but nonsignificant (p=0.19) relationship was found for group G4. The mean Brinkman index (362.8± 289.5) ofex-smokers was similar to that (363.8 ± 308.5) of present smokers. This finding was due to the larger numbers (21.3 ± 8.4) of pieces per day smoked by exsmokers than by the present smokers (15.3 ± 8.8 pieces per day). The duration of time since quitting smoking among former smokers ranged from 1 yr to 41 yr, with a mean of 11.6±9.6 yr. As shown in Figure 3, there was among former smokers a definite trend for total IgE level to decrease with time since quitting smoking, regardless ofexposure status (groups G5 and G6). This was not explained by the mutual differences in mean time of employment. According to results of a multiregression analysis, the time since quitting (r = - 0.5467) was not significant but was a more important factor than age (- 0.1662). After a sufficient amount of time since quitting (>20 yr), total IgE levels in subjects of group G6 may sometimes approach those of nonsmokers (G3). 1572
2
o
·10
10·20 YEARS
20·
FIGURE 3. Frequency distribution of log[IgE] by smoking habits within group of male subjects (A) and relation between time since quitting smoking and log[IgE] levels in male subjects of groups GS and G6(B).
Combined Effect of Smoking and Dust Exposure on TotallgE Level
The geometric mean IgE level of subjects of group G4 (65.2 IU/ml) was significantly (p<0.05) higher than that of subjects of groups Gl (33.1 IU/ml), G2 (38.1 IU/ml), and G3 (53.6 IU/ml) among male subjects. The observed differences in IgE levels mentioned previously were probably not due to differences in age, Brinkman index, and exposure doses among subjects (Table 1). Hard metal exposure and smoking were found to have an arithmetically combining impact on 19E levels; as shown using MANOVA analysis, Z7 neither hard metal exposure (F: 1.78; df=2; p=O.068) nor smoking history (F: 1.48; df=2; p=O.097) made an independent contribution to the elevation of the total IgE level, while the combination of these factors (F: 3.28; p
Smoking HabIls and 0ccupali0naJ Exposure to H8Id Metal (Shifllk_. Kusake, Morimoto)
Table 2-HiBk ofE_ted 19E Related to Smoking Habita, Age, Sa, and Hard Metal Exposure·
Data Smoking pattern Present Past No. of cigarettes smoked per day 0-10 10-20 >20 Duration of smoking, yr 0-10 10-20 >20 Hard metal exposure Exposure concentration >50IJ.Wm3 Exposure doses >400lJ.g·yr/m3 Smoking and hard metal exposure Age, yr 30-39 40-49 >50 Male sex Male group GroupGl GroupG2 GroupG3 GroupG4 GroupG5 GroupG6
RRt
95 Percent Confidence Limits
1.6 1.6
0.5-2.5 0.8-2.9
1.5 1.8 1.3
0.4-2.2 0.6-2.6 0.3-1.9
1.1 1.2 1.2 1.9 2.0* 2.0+ 2.8*
0.4-1.9 0.4-1.9 0.4-1.9 0.9-3.3 1.0-3.8 1.0-3.9 1.3-4.5
1.1 1.0 1.0 1.1
0.4-2.2 0.2-1.6 0.2-1.6 0.4-2.2
1.0 1.1 1.4 2.4 1.8 2.4*
0.3-1.8 0.8-2.0 1.3-3.8 1.2-4.0 1.6-4.4
*Multiple logistic analysis. Cutoff point of elevated IgE level for high-risk status (>400 IU/ml) was determined as (1) 2 SDs above mean level of IgE in general population using Phadebas PRISp-15 and (2) significantly higher likelihood ofskin test reactivity, allergic diseases, or eosinophilia as previously reported8 •10 or in our subjects (Fig IC). tOdds ratio between low risk and high risk. +p
and hard metal exposure as well as two confounders (sex and age) were dichotomized and scored as 0 (low risk) or 1 (high risk). The risk of male groups (G1 to G6) was investigated using this method. As shown in Table 2, the resulting relative risk (RR) ranged from 1.1 to 2.8; two factors (smoking and hard metal exposure) had a substantial (RR= 1.4 and 1.8) but nonsignificant association with risk ofelevated IgE level; however, the combination ofhard metal exposure and smoking was found to contribute significantly (p
Furthermore, the existence of significant (p<0.05) RR (>2.0) for groups G4 and G6 confirms that smoking and hard metal exposure have a combined impact on IgE levels, while each alone may make no independent contribution to the determination of IgE levels (G2 and G3). Neither the duration of smoking nor the number ofcigarettes smoked per day plays a significant role in modulating total IgE level, while the Brinkman index showed a significant risk for decreasing IgE
level. A similar trend was observed for hard metal exposure. Age and sex may not exert effects independently (RR=0.7 and 1.1) on the development of risk status in the model used for the present stud)'; although there was a tendency for the IgE level to decrease with age. These results were quite similar to those obtained using univariate analyses. DISCUSSION
General population studies8-l6 have demonstrated an association between smoking and total IgE antibody level even when sex and age are controlled for; however, some researchers6.7 have not found that smoking is associated with elevated total IgE levels. The interaction between smoking and specific sensitizations (specific IgE) to some agents encountered in workplaces has been documented among workers exposed to various chemical 1,...l8,l9 and laboratory animal agents;l7 however, our knowledge of the distribution of total IgE levels in populations of workers remains extremely limited. 6The results of the present study were consistent with those obtained in general population studies;16 ex-smokers and those presently smoking have a higher geometric mean IgE level than do those who have never smoked (Table 1). The higher IgE level of ex-smokers compared to present smokers may be due to a higher prevalence (9n2) of allergic asthma22 with high IgE levels among the fonner than that (31291) among the latter. This finding supports the concept that asthmatic patients who at first had smoked became unable to continue to smoke due to recurrence of asthma attacks. The positive smoking-IgE relationship mentioned previously cannot be explained by differences due to confounders such as age, duration of smoking, length of employment, or cobalt exposure doses (Table 1). As has been reported,3,14 the duration of smoking and the number of cigarettes smoked per day do not seem to make independent contributions to the determination of total IgE levels, although a significant suppression of IgE level by heavy smoking has been reported by Bahna et al. 3 This finding is similar to our own finding that Brinkman index scores had a characteristic association with suppression of IgE production when age was controlled for. Such a relationship was not noted by Warren et al3l or O'Connor et al;2 however, interestingly, Zetterstroem et all have shown that IgE levels in smokers have a bimodal distribution that might be attributable to smoking intensity, although these investigators l did not explain this attribution. Heavy smoking has been associated with suppression of immunocompetent cell activity in airways;32-35 this finding may explain the lower IgE levels found among nonexposed heavy smokers. A further suggestion comes from the results of our series of studies that mean levels of specific IgE antibodies to Co-HSA have CHEST I 101 I 6 I JUNE, 1992
1573
been lowest among heavy smokers. 24 ,25 Animal experiments need to be conducted to study the doseresponse relationship between smoking and serum IgE levels.2,36 Although smoking and changes in total IgE levels have not been shown to be related in a cause-andeffect manner, the present findings on IgE levels in ex-smokers suggest that they probably are. As shown in Figure 3B, the increase in IgE associated with smoking might be reversible following cessation of smoking, although the extent of reversion toward normal levels was moderately correlated with the time since quitting. A similar relation has also been demonstrated in animal experiments;37 the IgE response in mice was first enhanced and then later suppressed during exposure to cigarette smoke. Recovery of normal response occurred after cessation of smoking. This finding may be useful in explaining the exacerbation of asthma and the increase in mecholyl sensitivity38 which occur in humans shortly after quitting smoking. These results support a policy of discouraging smoking for the purpose of prevention of aller~
Nevertheless, an alternative hypothesis is that this decline was due to an effect ofage on IgE. A significant decline of IgE levels identified among ex-smokers confined to the younger smokers 14 may lend support to this hypothesis; however, no significant age effect was identified in male groups G5 and G6 using multiregression analysis; moreover, the population (n = 72) examined was relatively small in size in the cross-sectional stud~ In addressing this question, further cohort studies among nonatopic ex-smokers need to be done. Laboratory investigations have reported that some environmental or occupational agents, such as ash fly19 and diesel-exhaust particles (DEP),40 can act as adjuvants increasing total production of IgE; however, no report has been published concerning the direct relationship between total IgE levels and exposure doses in human populations. Hard metal exposure can cause occupational allergic diseases, including bronchial asthma and dermatitis. 21 -24 It has not been reported whether eye or nasal symptoms are associated with hard metal exposure. Cobalt alone may also sensitize some workers;41 however, the prevalence of asthma among workers exposed to hard metal is much higher than that among workers with exposure to cobalt alone, even though 30 times more workers are exposed to cobalt alone than are exposed to hard metal dust. 42 Such a large difference in allergy prevalence has led us to suggest a new hypothesis that carbide metals alloyed to cobalt act as adjuvants to cobalt in eliciting allergic responses in vivo. The results of an animal experiment by Schepers43 demonstrating more damage to lung tissues induced by cobalt and tungsten 1574
carbide than by cobalt alone may be consistent with this hypothesis. A result of the present study that hard-metal-exposed workers had higher total IgE levels than did those without exposure (Table 1 or Fig IB) also supports this hypothesis. No strong relationship between these variables was found in group G3, although workers with higher exposure doses had higher levels of IgE than did those who had received lower doses (see also Table 2). A synergistic enhancement of the prevalence of specific IgE with smoking among workers has been well documented for exposure to TePA" and coffeebean dust;l however, it is not clear whether the same kind of enhancement occurs for total IgE level. The striking finding of our study was the combined effect of hard metal exposure and smoking habit in elevating total IgE levels. As has been demonstrated using MANOVA analysis,30 the combination of hard metal (Co) exposure and smoking results in a significant (F = 3.38; p
Smoking Habits and OCCupational Exposure to Hard Metal (Shlrakawa, Kusaka, Morimoto)
sion from employment requiring exposure to hard metal (or both) may be of benefit for improvement of asthma. This hypothesis received support from the result of a NOlWegian case-control study·that occupa-. tional exposure and smoking showed a relatively weak RR (0.9 to 1.6) for the development of hay fever and dennatitis. ~ It should be noted that this study's particular questionnaire items, its categorization of variables, its limitation of subjects to those aged 18 to 64 yr, and its fonn of analysis may have influenced its findings and the detennination of association between smoking, hard metal exposure, and IgE levels. Further work is therefore needed to corroborate and extend our findings. Further studies are needed also to determine the relationships between smoking, atopy, hard metal exposure, and specific IgE against Co-HSA. ACKNOWLEDGMENT: We thank Osaka University medical students, '[ Yamazaki, T. Kurumatani, H. Furuyama, M. Sasaki, Y. Horimoto, K. Mori, K. Maruo, and E. Hamada, for their assistance in the analysis of data. We also thank Drs. N. Fujimura, M. Kato, and M. Held (Takatsuki Red Cross Hospital) for their ence>uragement of our stud~ Supported in part by a grant-in-aid from the Ministry of Education, Culture and Science of Japan.
REFERENCES 1 Zetterstroem 0, Osterman K, Machado L, Johansson SGO. Another smoking hazard: raised serum IgE concentration and increased risk of occupational allergy. Br Med J 1981; 283:121517 2 O'Connor GT, Weiss ST, Speizer FE. In: Gershin ME, ed. Bronchial asthma. Orland, Calif: Grune and Stratton, Inc, 1986:3-18 3 Bahna SL, Heiner DC, Myher BA. Immunoglobulin E pattern in cigarette smoking. Allergy 1983; 38:57-64 4 Venables KM, Topping MD, Howe Lukzynska CM, Hawkins R, Taylor AJN. Interaction of smoking and atopy in producing specific IgE antibody against a hapten protein conjugate. Br Med J 1985; 290:201-04 5 JonesJG, Minty BD, Royston D, RoystonJf Carboxyhaemoglobin and pulmonary epithelial permeability in man. Thorax 1983; 38:129-33 6 FriedhofFLR, Meyers DA, Marsh DC. A genetie-epidemiologic study of human immune respo~siveness to allergens in an industrial population. J Allergy Clin Immunoll984; 73:490-99 7 Rawle MA, Burr ML, Platts-Mills TAE. Long-term falls in antibodies to dust mite and poUen allergens in patients with asthma or hay fever. Clin Allergy 1983; 13:409-17 8 Holford-Streven ~ Warren ~ Wong ~ Manfreda J. Serum total immunoglobulin E levels in Canadian adults. J Allergy Clin Immunoll981; 73:516-22 9 Barbee RA, Halonen M, Lewobitz M, Burrows M. Distribution of 19E in a community population sample. J Allergy Clio Immunoll981; 68:106-11 10 Wittig HJ, BeUoit J, FiUippi ID, Royal G. Age-related serum immunoglobulin E levels in healthy subjects and in patients with allergic diseases. J Allergy Clin Immunoll980; 66:305-13 11 Halonen M, Barbee AR, Lewobitz MD, Burrows B. An epidemiologic study of the interrelationships of total serum immunoglobulin E, allergy skin-test reactivity, and eosinophilia. J Allergy Clio Immunol 1982; 69:221-28 12 Grundbacher FJ, Massie FS. Levels of immunoglobulin G, A, M and E at various ages in allergic and non-allergic black and
w:
white individuals. J Allergy Clin Immunoll985; 75:651-55 13 Gerrard Jw: Heiner DC, Ko CG, et a1. Immunoglobulin levels in smokers and nonsmokers. Ann Allergy 1980; 44:261-62 14 Burrows B, Halonen M, Barbee RA, Lebowitz MD. The relationship of serum immunoglobulin E to cigarette smoking. Am Rev Respir Dis 1981; 24:523-25 Lebowitz M, Burrows 15 Barbee RA, Halonen M, Kaltenborn B. Longitudinal study of serum IgE in a community cohort. J Allergy Clin Immunoll987; 79:919-27 16 Cline MG, Burrows B. Distribution of allergy in a population sample residing in Tucson, Arizona. Thorax 1989; 44:425-31 17 Pepys J, Davies RJ. Occupational asthma. In: Middletton E Jr, Reed CE, Ellis E, eds. Allergy. St. Louis: CV Mosby Co, 1983 18 Venables KM, Upton JL, Hawkins EL, Tee R, Longbottom JL, Taylor AJN. Smoking, atopy and laboratory animal allergy. Br J Ind Med 1988; 45:667-71 19 Cartier A, Malo JL, Forest F, et a1. Occupational asthma in snow crab processing workers. J Allergy Clin Immunol 1984; 74:261-69 20 Mitchell CA, Gandevia B. Respiratory symptoms and skin reactivity in workers exposed to proteolytic enzymes in the detergent industry. Am Rev Respir Dis 1971; 104:1-12 21 Kusaka Y, Yokoyama K, Sera Y, Yamamoto S, Sone S, Kyono Y, et a1. Respiratory diseases in hard metal workers: an occupational hygienic study in a factory. Br J Ind Med 1986; 43:474-85 22 Kusaka Y, Ichikawa Y, Shirakawa T, Goto S. Effect of hard metal dust on ventilatory function. Br J Ind Med 1986; 43:486-89 23 Shirakawa T, Kusaka Y, Fujimura N, Coto S, Kato M, Heki S, et a1. Occupational asthma from cobalt sensitivity in workers exposed to hard metal dust. Chest 1989; 95:29-37 24 Shirakawa T, Kusaka Y, Fujimura N, Morimoto K. The existence of specific antibodies to cobalt in hard metal asthma. Clin Allergy 1988; 18:451-60 25 Shirakawa T, Kusalca Y, Fujimura N, Kato M, Heki S, Morimoto K. Hard metal asthma: cross immunological and respiratory reactivity between cobalt and nickel? Thorax 1990; 45:267-71 26 Questionnaire on respiratory symptoms: definition of chronic bronchitis recommended for epidemiologic studies. Read before the WHO meeting of investigators on epidemiology of chronic nonspecific respiratory diseases, Geneva, 1974 27 Bakke ~ Gulsvik A, Eide GE. Hay fever, eczema and urticaria in southern Norwa}'. Allergy 1990; 45:515-22 28 Middletton E Jr, Reed CE, Ellis EF, eds. Allerg}'. St. Louis: CV Mosby Co, 1983 29 World Organization of National Colleges, and Academies and the Academic Association of General PractitionersIFamily Physicians. International classification ofbealth problems in primary care. Oxford, England: Oxford University Press, 1983 30 SPSSX User's Guide. 2nd ed. Chicago: SPSS Inc, 1986 31 Warren CPW: Holford-Strevens ~ Wong C, Manfreda J. The relationship between smoking and total immunoglobulin E levels. J Allergy Clin Immunoll982; 69:370-75 32 Green G, Carolin D. The depressant effect of cigarette smoke on in vitro antibacterial activity of alveolar macrophage. N Engl J Med 1967; 276:421-27 33 Martin RR, Warr GA. Cigarette smoking and human pulmonary macrophages. Hosp Pract 1977; 9:97-104 34 Jacob ~ Stelzer GT, waUance JH. The influence of cigarette tobacco smoke products on the immune response: the ceUular basis of immunosuppression by a wate~soluble condensate of tobacco smoke. Immunology 1980; 40:621-27 35 Meyer 0, Cross CE, Ibrahim AM, Mustafa MG. Nicotine effects on alveolar macrophage respiration and adenosine triphosphate activity. Arch Environ Health 1971; 22:363-65 36 Burrows B. Bronchial responsiveness, atopy, smoking and chronic obstructive pulmonary disease. Am Rev Respir Dis 1989; 140:1515-17
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CHEST I 101 I 6 I JUNE, 1992
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37 Thomas ~ Holt PG, Keast D. Effect of cigarette smoking on primary and secondary immune response of mice. Nature 1973; 243:240-41 38 Bolin JF, Dahmus TE, Slavin RG. Effect of discontinuing smoking on mecholyl sensitivity in asthmatic smokers. J Allergy Clin Immunoll980; 65:207-08 39 Fujimaki H, Hawagoe A, Ozawa M, Yonemoto J, Watanabe N. Effects of instillation of 8y ash in the lung: physiochemical properties and immune responses. Am Rev Respir Dis 1989; 140:525-28 40 Muranaka M, Suzuki S, Koizumi K, et ale Adjuvant activity of diesel-exhausted particles for the production of IgE antibody in
mice. J Allergy Clin Immunoll986; 77:616-23 41 Gheysens B, Auwerxs J, Van den Eekhout, Demedts M. Cobalt induced bronchial asthma in diamond polishers. Chest 1986; 88:740-44 42 Demedts M, Ceuppens JL. Respiratory diseases from hard metal or cobalt exposure: solving the enigma. Chest 1989; 91: 2-3 43 Schepers GWH. The biological action of particular cobalt metal, tantalum oxide, cobalt oxide, particulate tungsten metal, tungsten carbide and carbon, tungsten carbide and cobalt. Arch Ind Health 1955; 12:127-46
7th World Congresses: Bronchology, Bronchoesophagology Sponsors of these congresses are the World Association for Broncholo~ International Bronchoesophagological Society, American .Broncho-EsophagologicaI Association, and the American College of Chest Physicians. The Congresses will be held at the Mayo Clinic and Mayo Medical Center, Rochester, Minnesota, September 28-0ctober 2. For information, contact Dr. Udaya B. S. Prakash, Mayo Clinic, Rochester, Minnesota 55905 (507:284-4162).
1576
SmokIng HabIts .., OccupatIonal Exposure to Hard Metal (ShiraIcaw8, Kusak8, Morimoto)
19E level (73.3 IU/ml) than did those who had never smoked, their serum 19E level declined with age since the time theY quit smoking, regardless of their hard metal exposure status. Hard metal (cobalt) exposure may play a significant role as an adjuvant in the production of total IgE. A multivariate analysis demonstrated that hard metal exp0sure and a smoking habit together arithmetically (p
High concentrations of total IgE occur primarily in atopic subjects who have an inherited predisposition to sensitization and to the development of specific IgE antibodies. 1.2 The precise mechanism for the atopy remains unknown, but skin or mucosal characteristics must play an important role in its development. 1-4 Cigarette smoking has been found to increase airway mucosal permeability, which then permits increased penetration of bronchospastic agents or allergens. 5 This finding has been supplemented by epidemiologic observations made in many populations6-16 demonstrating that smokers have higher total IgE values and eosinophil counts than ex-smokers and those who have never smoked. These findings suggest changes in immune responses as a possible mechanism by which smoking might be related to the etiology of bronchial asthma. Thus, in the workplace, the risk of sensitization depends upon the relationship between smoking status and the degree of exposure to occupational allergens,17 which include green coffee-bean dust, 1 ispaghula,1 TCPA (tetrachlorophthalic anhydride),4 laboratory animal agents,18 snow crab,19 and enzyme detergents. !In
Hard metal is an alloy Consisting primarily of tungsten carbide and cobalt. 21 .22 Our studies22 •23 has shown that cobalt in hard metal particles, acting as a hapten after conjugation with mucosal proteins, stimulates the production of specific IgE antibodies which can cause occupational asthma. Among grinders, atopy is strongly associated with the presence of IgE antibodies to cobalt-conjugatedhuman serum albumin (Co-HSA) or cobalt-conjugated exchange resin (Coresin) (or both) and with occupational asthma,23 bu~ is less strongly associated with the occurrence of skin symptoms unaccompanied by chest symp~oms.24 In our investigation of healthy volunteers and smoking workers,25 an acute drop in pulmonary function values was observed to occur immediately after inhalation of hard metal dust; however, no relationship has thus far been identified between smoking habits aDd hard metal exPosure in eliciting increased risk of allergy with elevated IgE. The purpose ofthe present study was to characterize further the dose-response relationships between smoking and hard metal (cobalt) exposure and total IgE levels. The former two factors were found to act together to elevate total IgE. The results of this stud~ when interpreted, provide additional strategies for the prevention of occupational allergy among hard metal workers.
*From the Department of Hygiene and Preventive Medicine, School of Medicine, Osaka University, Osaka, J~. tPresently with Asthma Genetics Group, Nuffield De~ment of Clinical Medicine, John Radcliffe Hospital, Oxford, England. *Presently Associate Professor of Environmental Health, Jichi Medical College, Japan. §Professor and Head, Department of Environmental Health and Preventive Medicine, Osaka University. Manuscript received August 6; revision accepted June 16.
BMRC=British Medical Research Council; Co-HSA=cobaItconjugated human senun albumin; Co-resin = cobaIt-conjugated exchange resin; RR relative risk; TCPA tetrachlorophthalic anhydride
=
=
MATERIALS AND METHODS
Criteria for Subjects
A sample population of 733 subjects was selected from among workers aged 18 yr and older at a hard metal plant. llo• Every worker CHEST I 101 I 6 I JUNE, 1992
1589
was interviewed regarding his work status, so that those engaged in handling hard metal were considered as having a positive history of exposure. Details of the environmental studies conducted within the plant have been described previously in our series of reports. 21.12 BrieRy, samples of total dust and mist in the workers' breathing zones were collected several times using a dust-sampling pump (DuPont F-6OOO) over a period of about 6 h, and cobalt levels in the samples were determined by atomic absorption spectrophotometry. Allergic diseases <:onsidered here include bronchial asthma, rhinitis, conjunctivitis, and dermatitis. As a first step, we designed a Japanese language version of a baseline questionnaire concerning age, sex, smoking habits, and respiratory symptoms translated from the BMRC· questionnaire and other allergic diseases translated from the questionnaire recommended by Bakke et a1. rr Those considered to have allergic diseases were referred to physicians of appropriate specialties at Osaka University Hospital. The remaining subjects, who were considered not to have an allergy, were checked by one of us (T.S.), and those judged susceptible to allergy were also referred to physicians. If a conDict arose in diagnosis between physicians, another physician participated in order to arrive at a final decision. Subjects were considered to have asthma if they had recurrent wheezing or dyspnea (or both) and if they had evidence ofobstructive disease on pulmonary function tests, with a good response to bronchodilators. is Seasonal or perennial rhinitis was defined according to the criteria of the World Organization of National Colleges and Academies and the Academic Association of General PractitionersIFamily Physicians, lIB which require the presence of three of the follOwing symptoms: sneezing; nasal obstruction; clear nasal discharge; or watering eyes. Seasonal rhinitis was diagnosed if the symptoms occurred in the pollen season, or perennial rhinitis if the symptoms were nonseasonal and associated with a known or strongly suspected allergen. Allergy testing (including skin testing), serum IgE level, or specific provocation tests were also required. Allergic dermatitis was diagnosed if three of the following four major criteria were fulfilled: pruritus; lichenification; a chronically
relapsing course; or a personal or family history of atop~ Skin biopsy was also required. 29 All of those considered to have allergic conjunctivitis had other allergic diseases. Allergic conjunctivitis was defined if they had tearing, injection, chemosis, itching, and lid edema following a provocation test with a suspected allergen. is Of lOB subjects (IS percent) diagnosed as having histories of allergic diseases, 27 subjects (4 percent) had been found to be atopic prior to beginning employment. They were excluded from consideration in the study in order to clarify the relationship between smoking, hard metal exposure, and total IgE level in workers occurring just after employment in a hard metal plant.
Peripheral Blood Analysis and Serologic Analysis Total and segmental white blood cell counts were determined in all subjects. Hypereosinophilia was defined as an eosinophil count of more than 200/cu mm. Serum samples were collected from all of the subjects and frozen at - SOOC until tests were conducted. Total serum IgE level was determined in duplicate by using Phadebas PRIST,&-16 a technique which yields more precise and speci6c measurements for low «10 IU/ml) IgE levels than do other commercial kits. After logarithmic conversion, normality of the set of resulting values was checked using Pearson's X2 test (p<0.05). Data Analysis
Subjects responded to this questionnaire during medical examinations, and response data were analyzed using the Osaka University ACOS-6 NEC computer system with the SPSSX (Statistic Package for Social Sciences extension, version 2.2) program30 including MANOVA, REGRESSION, and PROBIT. Incomplete answers received from seven subjects (six men and one woman) were eliminated from further analyses. Therefore, following these exclusions, a total of 550 male and 149 female workers remained as subjects for examination. Strong (>98 percent) reliability was demonstrated in a pilot study of 54 workers in a branch plant who filled out essentially the same questionnaire form 2 mo or 1 yr after
Table 1- Subject Profile' and Besults ofSerologic Studie,·
Sex and Group Male GI G2 G3 G4 G5 G6 Female GI G2 G3 G4 G5 G6
Allergy Cases (Asthma)
Exposure Doses, ...~eyr/m3
Normal Distribution ofIgE after Logarithmic Conversiont
33±6 38±7 54±7 65±7§1I 73±8, 119±8'tt
Yes Yes Yes Yes No No
Smokin~
No. of Cases
Mean Age, yr
No/never No/present Yes/never Yes/present No/former Yes/former
99 135 88 156 35 37
35±12 38±12 41± 12 38±12 37±12 44±15
10±8 12±8 11±8 13±8 11±8 13±7
12 (3) 10 12 13 (4) 8 IS (13)
0 381±278 0 348 ± 238 379±298* 340 ± 223*
0 0 1,222±2,413 766± 1,328 0 857±356
No/never No/present Yes/never Yes/present No/former Yeslformer
III 10 17 7 2 2
33±12 36±13 47±8 44±5 36 (37;34) 43 (44;42)
5±4 6±5 8±4 5±2 7±6 4±1
8 (2) 2 4 (2) 1 0 0
0 200± 179 0 334± 192 200* 300+
0 0 588±769 916±39 0 313 (320;305)
Exposure!
Mean Brinkman Index, pieceseyr
Geometric Mean IgE Level, IU/ml
Mean Length of Employment, yr
41±7 53±5 47±6 65±7 183
63
Yes Untested Untested Untested Untested Untested
*Data from seven subjects who did not respond to questionnaire were not used in this table. tBased on Pearson's X2 test (p<0.05). +Before quitting smoking. §p
1570
Smoking Habits and OCCupational Exposure to Hard Metal (Shirakawa, Kusaka, Morimoto)
the original. The validity of collected data was evaluated by comparing answers received in the self-administered questionnaire with those obtained following personal interviews made of all subjects by our staff. About 95 percent of the respondents gave identical answers on the two occasions.
(ft) 200
••
(I)
RESULTS
Subject profiles, by means ofwhich each respondent was categorized into one of six subgroups by smoking and hard metal exposure status, are summarized in Table 1. The female work force exposed to hard metal or with a positive smoking history was not large enough to make possible further analysis of the effect of hard metal exposure or smoking habits; analyses discussed henceforth refer therefore to results for men and nonexposed women only.
Distribution ofTotallgE Level, Allergy Prevalence, and Eosinophilia The distribution of log[IgE] in the male subjects was found to be gaussian follOwing logarithmic conversion (Fig lA), with a mean 10g[IgE] of 1.72 IU/ml and a geometric mean of52.5 IU/ml. A slight leftward skew is still apparent in the curve computed from female workers' IgE levels because of higher frequencies of younger individuals (Fig lA). Of 12 groups, male groups G 1 through G4 and female group G1 had normal distributions of log[IgE] (Table 1). The geometric means of the nonexposed male (33.5 IU/ml) and female (32.5 IU/ml) subjects were similar to those (25 to 35 IU/ml using PRIST kit) found in previous studies.6-16 Prevalences of allergy, including airway, eye, and skin symptoms identified by physicians, and eosinophilia are shown in Figure Ie. Abrupt increases of cumulative prevalences of allergy (from 5.2 to 11.2 percent) and eosinophilia (10.1 to 22.3 percent) in the subjects with IgE levels of more than 400 IU/ml were identified. The prevalence among male subjects exposed to hard metal (39/273 or 14 percent in combined group, G3 + G4 + G6, with eight missing cases) was similar to that among those men not exposed (301260 or 12 percent in combined group, G 1 + G2 + G5, with nine missing cases); however, it was striking that there were 20 cases of asthma, three (1 percent) among the 260 nonexposed male subjects and 17 (6 percent) from the 273 exposed male subjects (p
Effect of Hard Metal Exposure on TotallgE Level A history of hard metal (cobalt) exposure was significantly (p<0.05) associated with above normal log[IgE] (1.64 ± 0.83 in Gl + G2 vs 1.83 ± 0.80 in G3 + G4) in male subjects (Fig IB); however, there was no significant difference in mean log[IgE] between groups Gl and G3 (p = 0.07). Within group G3, those exposed to a cobalt concentration of more than 50JLg/m 3 in breathing zones had a significantly (p<0.05) higher geometric mean IgE level than did
~
MALE
FEMAlE
100
c.J IL
0
0 z
0
<1.0
1.0
1.5
2.0
2.5
LOG[IG E] (8)
3.0
••
25-
I
>3.0
I'O£>
15
5
o 30
1.5
2
2.5
3
3.5
LOG(lGE]
(C)
FIGURE 1. Frequency distribution of log[lgE) by sex (A, tQP) and by exposure status (B, middle) within groups of male subjects (Gl+G3+G5 vs G2+G4+G6; see also text and Table 1). C (bottom). Percentage ofcumulative prevalences ofallergy (bronchial asthma, dermatitis, rhinitis, and (."()njunctivitis) and eosinophilia in male subjects. Dia~oses were made using internationally established criteria."
those with exposure to lower concentrations. There was a significant (r=0.405; p
1571
4 3
iii'
g
(;'
- .. , .--.. ..... - • - t ·. -r: -- ---- ..-.-. ---_i1t.,I:' - -• ~
2
0
...J
II
0
(A)
•
II
1
II
II
10
100
1000
EXPOSURE LEVEL
Relationship between cobalt exposure doses and log[IgE] levels in men of group G3. Cobalt level (in micrograms per cubic meter) in breathing zone was determined using previously described method.·...•
•• •
40
> u
30
Cl.RBlT SM.JI
Z
2IE
III
~
20 10
o
FIGURE 2.
<1.01.0
1.5
2.0
2.5
3.0
>3.0
LOG(lGE)
(8) 3
•
E>CPaiED
.~
Effect of Smoking on TotallgE Level
Male subjects smoking at the time of the study had a geometric mean serum IgE level of 53.1 IU/ml, not significantly different from that (93.9 IU/ml) of exsmokers (G5 + G6); however, each of these means was significantly (p<0.05) higher than that (46.7 IU/ml) of subjects who had never smoked (Fig 3A). Within group G2, there was a moderately significant inverse relationship between IgE level and duration of smoking (r = 0.32; p
2
o
·10
10·20 YEARS
20·
FIGURE 3. Frequency distribution of log[IgE] by smoking habits within group of male subjects (A) and relation between time since quitting smoking and log[IgE] levels in male subjects of groups GS and G6(B).
Combined Effect of Smoking and Dust Exposure on TotallgE Level
The geometric mean IgE level of subjects of group G4 (65.2 IU/ml) was significantly (p<0.05) higher than that of subjects of groups Gl (33.1 IU/ml), G2 (38.1 IU/ml), and G3 (53.6 IU/ml) among male subjects. The observed differences in IgE levels mentioned previously were probably not due to differences in age, Brinkman index, and exposure doses among subjects (Table 1). Hard metal exposure and smoking were found to have an arithmetically combining impact on 19E levels; as shown using MANOVA analysis, Z7 neither hard metal exposure (F: 1.78; df=2; p=O.068) nor smoking history (F: 1.48; df=2; p=O.097) made an independent contribution to the elevation of the total IgE level, while the combination of these factors (F: 3.28; p
Smoking HabIls and 0ccupali0naJ Exposure to H8Id Metal (Shifllk_. Kusake, Morimoto)
Table 2-HiBk ofE_ted 19E Related to Smoking Habita, Age, Sa, and Hard Metal Exposure·
Data Smoking pattern Present Past No. of cigarettes smoked per day 0-10 10-20 >20 Duration of smoking, yr 0-10 10-20 >20 Hard metal exposure Exposure concentration >50IJ.Wm3 Exposure doses >400lJ.g·yr/m3 Smoking and hard metal exposure Age, yr 30-39 40-49 >50 Male sex Male group GroupGl GroupG2 GroupG3 GroupG4 GroupG5 GroupG6
RRt
95 Percent Confidence Limits
1.6 1.6
0.5-2.5 0.8-2.9
1.5 1.8 1.3
0.4-2.2 0.6-2.6 0.3-1.9
1.1 1.2 1.2 1.9 2.0* 2.0+ 2.8*
0.4-1.9 0.4-1.9 0.4-1.9 0.9-3.3 1.0-3.8 1.0-3.9 1.3-4.5
1.1 1.0 1.0 1.1
0.4-2.2 0.2-1.6 0.2-1.6 0.4-2.2
1.0 1.1 1.4 2.4 1.8 2.4*
0.3-1.8 0.8-2.0 1.3-3.8 1.2-4.0 1.6-4.4
*Multiple logistic analysis. Cutoff point of elevated IgE level for high-risk status (>400 IU/ml) was determined as (1) 2 SDs above mean level of IgE in general population using Phadebas PRISp-15 and (2) significantly higher likelihood ofskin test reactivity, allergic diseases, or eosinophilia as previously reported8 •10 or in our subjects (Fig IC). tOdds ratio between low risk and high risk. +p
and hard metal exposure as well as two confounders (sex and age) were dichotomized and scored as 0 (low risk) or 1 (high risk). The risk of male groups (G1 to G6) was investigated using this method. As shown in Table 2, the resulting relative risk (RR) ranged from 1.1 to 2.8; two factors (smoking and hard metal exposure) had a substantial (RR= 1.4 and 1.8) but nonsignificant association with risk ofelevated IgE level; however, the combination ofhard metal exposure and smoking was found to contribute significantly (p
Furthermore, the existence of significant (p<0.05) RR (>2.0) for groups G4 and G6 confirms that smoking and hard metal exposure have a combined impact on IgE levels, while each alone may make no independent contribution to the determination of IgE levels (G2 and G3). Neither the duration of smoking nor the number ofcigarettes smoked per day plays a significant role in modulating total IgE level, while the Brinkman index showed a significant risk for decreasing IgE
level. A similar trend was observed for hard metal exposure. Age and sex may not exert effects independently (RR=0.7 and 1.1) on the development of risk status in the model used for the present stud)'; although there was a tendency for the IgE level to decrease with age. These results were quite similar to those obtained using univariate analyses. DISCUSSION
General population studies8-l6 have demonstrated an association between smoking and total IgE antibody level even when sex and age are controlled for; however, some researchers6.7 have not found that smoking is associated with elevated total IgE levels. The interaction between smoking and specific sensitizations (specific IgE) to some agents encountered in workplaces has been documented among workers exposed to various chemical 1,...l8,l9 and laboratory animal agents;l7 however, our knowledge of the distribution of total IgE levels in populations of workers remains extremely limited. 6The results of the present study were consistent with those obtained in general population studies;16 ex-smokers and those presently smoking have a higher geometric mean IgE level than do those who have never smoked (Table 1). The higher IgE level of ex-smokers compared to present smokers may be due to a higher prevalence (9n2) of allergic asthma22 with high IgE levels among the fonner than that (31291) among the latter. This finding supports the concept that asthmatic patients who at first had smoked became unable to continue to smoke due to recurrence of asthma attacks. The positive smoking-IgE relationship mentioned previously cannot be explained by differences due to confounders such as age, duration of smoking, length of employment, or cobalt exposure doses (Table 1). As has been reported,3,14 the duration of smoking and the number of cigarettes smoked per day do not seem to make independent contributions to the determination of total IgE levels, although a significant suppression of IgE level by heavy smoking has been reported by Bahna et al. 3 This finding is similar to our own finding that Brinkman index scores had a characteristic association with suppression of IgE production when age was controlled for. Such a relationship was not noted by Warren et al3l or O'Connor et al;2 however, interestingly, Zetterstroem et all have shown that IgE levels in smokers have a bimodal distribution that might be attributable to smoking intensity, although these investigators l did not explain this attribution. Heavy smoking has been associated with suppression of immunocompetent cell activity in airways;32-35 this finding may explain the lower IgE levels found among nonexposed heavy smokers. A further suggestion comes from the results of our series of studies that mean levels of specific IgE antibodies to Co-HSA have CHEST I 101 I 6 I JUNE, 1992
1573
been lowest among heavy smokers. 24 ,25 Animal experiments need to be conducted to study the doseresponse relationship between smoking and serum IgE levels.2,36 Although smoking and changes in total IgE levels have not been shown to be related in a cause-andeffect manner, the present findings on IgE levels in ex-smokers suggest that they probably are. As shown in Figure 3B, the increase in IgE associated with smoking might be reversible following cessation of smoking, although the extent of reversion toward normal levels was moderately correlated with the time since quitting. A similar relation has also been demonstrated in animal experiments;37 the IgE response in mice was first enhanced and then later suppressed during exposure to cigarette smoke. Recovery of normal response occurred after cessation of smoking. This finding may be useful in explaining the exacerbation of asthma and the increase in mecholyl sensitivity38 which occur in humans shortly after quitting smoking. These results support a policy of discouraging smoking for the purpose of prevention of aller~
Nevertheless, an alternative hypothesis is that this decline was due to an effect ofage on IgE. A significant decline of IgE levels identified among ex-smokers confined to the younger smokers 14 may lend support to this hypothesis; however, no significant age effect was identified in male groups G5 and G6 using multiregression analysis; moreover, the population (n = 72) examined was relatively small in size in the cross-sectional stud~ In addressing this question, further cohort studies among nonatopic ex-smokers need to be done. Laboratory investigations have reported that some environmental or occupational agents, such as ash fly19 and diesel-exhaust particles (DEP),40 can act as adjuvants increasing total production of IgE; however, no report has been published concerning the direct relationship between total IgE levels and exposure doses in human populations. Hard metal exposure can cause occupational allergic diseases, including bronchial asthma and dermatitis. 21 -24 It has not been reported whether eye or nasal symptoms are associated with hard metal exposure. Cobalt alone may also sensitize some workers;41 however, the prevalence of asthma among workers exposed to hard metal is much higher than that among workers with exposure to cobalt alone, even though 30 times more workers are exposed to cobalt alone than are exposed to hard metal dust. 42 Such a large difference in allergy prevalence has led us to suggest a new hypothesis that carbide metals alloyed to cobalt act as adjuvants to cobalt in eliciting allergic responses in vivo. The results of an animal experiment by Schepers43 demonstrating more damage to lung tissues induced by cobalt and tungsten 1574
carbide than by cobalt alone may be consistent with this hypothesis. A result of the present study that hard-metal-exposed workers had higher total IgE levels than did those without exposure (Table 1 or Fig IB) also supports this hypothesis. No strong relationship between these variables was found in group G3, although workers with higher exposure doses had higher levels of IgE than did those who had received lower doses (see also Table 2). A synergistic enhancement of the prevalence of specific IgE with smoking among workers has been well documented for exposure to TePA" and coffeebean dust;l however, it is not clear whether the same kind of enhancement occurs for total IgE level. The striking finding of our study was the combined effect of hard metal exposure and smoking habit in elevating total IgE levels. As has been demonstrated using MANOVA analysis,30 the combination of hard metal (Co) exposure and smoking results in a significant (F = 3.38; p
Smoking Habits and OCCupational Exposure to Hard Metal (Shlrakawa, Kusaka, Morimoto)
sion from employment requiring exposure to hard metal (or both) may be of benefit for improvement of asthma. This hypothesis received support from the result of a NOlWegian case-control study·that occupa-. tional exposure and smoking showed a relatively weak RR (0.9 to 1.6) for the development of hay fever and dennatitis. ~ It should be noted that this study's particular questionnaire items, its categorization of variables, its limitation of subjects to those aged 18 to 64 yr, and its fonn of analysis may have influenced its findings and the detennination of association between smoking, hard metal exposure, and IgE levels. Further work is therefore needed to corroborate and extend our findings. Further studies are needed also to determine the relationships between smoking, atopy, hard metal exposure, and specific IgE against Co-HSA. ACKNOWLEDGMENT: We thank Osaka University medical students, '[ Yamazaki, T. Kurumatani, H. Furuyama, M. Sasaki, Y. Horimoto, K. Mori, K. Maruo, and E. Hamada, for their assistance in the analysis of data. We also thank Drs. N. Fujimura, M. Kato, and M. Held (Takatsuki Red Cross Hospital) for their ence>uragement of our stud~ Supported in part by a grant-in-aid from the Ministry of Education, Culture and Science of Japan.
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7th World Congresses: Bronchology, Bronchoesophagology Sponsors of these congresses are the World Association for Broncholo~ International Bronchoesophagological Society, American .Broncho-EsophagologicaI Association, and the American College of Chest Physicians. The Congresses will be held at the Mayo Clinic and Mayo Medical Center, Rochester, Minnesota, September 28-0ctober 2. For information, contact Dr. Udaya B. S. Prakash, Mayo Clinic, Rochester, Minnesota 55905 (507:284-4162).
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SmokIng HabIts .., OccupatIonal Exposure to Hard Metal (ShiraIcaw8, Kusak8, Morimoto)