British Journal of Industrial Medicine 1991;48:830-837

Quantitative skin prick and bronchial provocationtests with platinum salt

Rolf Merget, Gerhard Schultze-Werninghaus, Florian Bode, Eva-Maria Bergmann,Wolfgang Zachgo, Jurgen Meier-Sydow

AbstractOccupational asthma due to platinum salts is afrequent disease in platinum refineries. Thediagnosis is based upon a history of workrelated symptoms and a positive skin prick testwith platinum salts. Bronchial provocationtests have not been performed in epidemi-ological studies because the skin test is believedto be highly specific and sensitive. Asno reliabledata about this issue currently exist, this studyassesses the use of skin prick and bronchialprovocation tests with methacholine andplatinum salt in platinum refinery workers.Twenty seven of 35 workers, who were referredto our clinic with work related symptoms andnine control subjects with bronchial hyper-reactivity underwent a skin prick test andbronchial provocation with methacholine andplatinum salt. For skin prick and bronchialprovocation tests with platinum salt a 102-10' mol/l hexachloroplatinic acid solution, in10-fold dilutions was used. Four of the 27subjects and all controls showed neither abronchial reaction nor a skin reaction. Twentythree subjects were considered allergic toplatinum salt; 22 of these showed a fall of 50%or more in specific airway conductance afterinhalation of the platinum salt solution. Fourworkers experienced a positive bronchial reac-tion despite a negative skin prick test. Nocorrelation of responsiveness to methacholinewith responsiveness to platinum salt wasfound, but the skin prick test correlated withthe bronchial reaction to platinum salt (r, =

0 50, p < 0-023, n = 22). One dual reaction wasseen in bronchial provocation tests. Side effectsof both skin tests and bronchial provocationtests with platinum salt were rare and were notencountered in workers without a skin reaction

to platinum salt. It is concluded that bronchialprovocation tests with platinum salts should beperformed on workers with work related sym-ptoms but negative skin tests with platinumsalts.

Occupational asthma, rhinitis, conjunctivitis, andeczema are common diseases in platinum refineries'"and catalyst production plants.7 The prevalence ofthese symptoms in cross sectional studies is con-siderably higher than the prevalence ofa positive skinprick test with platinum salt (table 1). Thus reliablediagnostic measures are necessary to establish thecausal relation between symptoms and exposure toplatinum salts. For longitudinal studies quantitativeassessment of sensitisation is of interest.

In platinum salt allergy in vitro data such as theradioallergosorbent test (RAST)69 13 14 and histaminerelease from basophils' lack specificity. Binding ratesin RAST showed some correlation with total serumIgE activity59 and although some authors found

Table 1 Prevalence ofplatinum salt allergy in crosssectional studies according to a positive skin test withplatinum salt (upper part) or work related symptoms (lowerpart)

Country and Prevalence Air concentration ofNo reference (%) platinum (g/rm3)

Prevalence of positive skin test:16 Great Britain' 25 0-9-1700 ,ug/m319* United States3 42 nd86t Great Britain2 30 nd107 United States68 14 > 2 pg/m3 in 50-75%306 South Africa' 28 nd20 Germany5 20 <0-08 pg/m364 Germany'2 19 <0 1 pg/m3

Prevalence of symptoms:91 Great Britain' 57 0 9-1700 pg/M320 United States3 60 nd11 Germany"o 73 nd51 France" 69 nd86 Great Britain2 41 nd107 United States68 29-44+ >2 p,g/m3 in 50-75%24 Germany5 8 < 0-08 pg/m365 Germany'2 23 <0 1 pug/mr

*Findings made within five years.tRetrospective cohort analysis.:Prevalence of upper and lower respiratory tract symptoms.nd = Not done.

Department of Pneumology, University Hospital,Johann Wolfgang Goethe-University, Frankfurt/Main, GermanyR Merget, G Schultze-Werninghaus, F Bode,E-M Bergmann, W Zachgo, J Meier-Sydow

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significant differences inRAST binding rates betweenskin test positive subjects and controls, this test haspoor sensitivity and specificity. An individual diag-nosis cannot be made by means ofRAST and this isalso the case for histamine release from basophilswith free platinum salts.5 Little information is avail-able about histamine release with platinum salt/protein conjugates. Pepys et al'5 found significanthistamine release with various conjugates in only oneof six workers with suspected allergy to platinumsalts, but not in two controls. Passive transfer ofantibodies also gave conflicting results, althoughspecificity seems high as no positive reactions werefound in controls.61415Thus the diagnosis of allergy to platinum salts is

based on work related respiratory or cutaneoussymptoms and a positive skin test. A skin prick testwith platinum salt is believed to be highly specific.6 14Little information is available about bronchialprovocation tests with platinum salts. Powder inhala-tion without any information about the inhaledquantity was described in two early case reports.'6 17Pepys et al 8 performed bronchial provocation testswith 40 mg platinum salt (ammonium hexachloro-platinate, ammonium tetrachloroplatinate, andsodium hexachloroplatinate) per kg lactose powderin 16 refinery workers. Subjects inhaled the dustwhile shaking 250 g of this mixture. The authorsdescribed eight immediate type reactions with onedual reaction. Two subjects showed positive skintests but negative bronchial tests. In two furthercases showing negative skin prick tests with platinumsalt isolated late asthmatic reactions were reported.No data about non-specific bronchial hyperreactivitywere given in these studies. A control group was notincluded.

It was the aim of the present study to evaluate thedose response relation for a platinum salt (sodiumhexachloroplatinate) in bronchial provocation testsand to define the value of skin prick and bronchialprovocation tests in the diagnosis of platinum saltasthma to establish diagnostic tools for epidemi-ological investigations.

Materials and methodsSUBJECTSA total of 35 workers from two platinum refinerieswith work related symptoms were referred to ourpulmonary department for a medical opinion bet-ween February 1983 and February 1990 by theMinistry of Social Welfare. Tests were performed onaverage 15 (range 0-132) months after the workershad been removed from the refinery workshop.Although most workers were no longer in the refiningarea, 19 still had occasional contact with platinumsalts, mainly via personal contact with refinery work-ers or contaminated materials. Twenty seven of the

35 subjects were submitted to bronchial provocationtests with both methacholine and platinum salt. Nobronchial provocation tests were performed in eightsubjects (one had severe airways obstruction (forcedexpiratory volume in one second (FEV,)% inspira-tory vital capacity (IVC) 41%), three showed a mildasthmatic reaction during skin prick tests (amongthem another subject with severe airway obstruc-tion), and four were not challenged for technicalreasons). For controls, we investigated nine subjectswith episodic asthma, bronchial hyperreactivity, andno exposure to platinum salts. Thirty three of the 35workers (including the 27 subjects who were submit-ted to bronchial provocation tests) and none of thecontrols had any medication for at least 48 hoursbefore the tests and neither steroids nor antihis-tamines for at least four weeks. Skin prick tests withplatinum salt were performed on a further 100controls with respiratory symptoms. Medicationtaken by these controls was not recorded. Workersand control subjects signed informed consent formsfor all tests.

CLINICAL DATAData on occupational exposure time, smoking his-tory, symptoms, and time between the onset ofoccupational exposure to platinum salt and theoccurrence of symptoms (sensitisation period) wererecorded, together with personal or family history ofbronchitis, asthma, or any type of allergic disease.

SKIN PRICK TESTModified skin prick tests were performed on the volarpart of the forearm with 18 common allergens (grassand tree pollens, animal dander, house dust mites,moulds (Allergopharma, Reinbek, Germany). Skinprick tests with platinum salt were performed with astock solution of 102 mol/l hexachloroplatinic acid(PtCl62; Sigma, Munich, Germany) adjusted to pH7-4 with 0-1 N NaOH and freshly diluted in 0 9%NaCl to 10' mol/l. The stock solution was stored at4°C for not longer than four weeks. Tests wereperformed in duplicate. Control tests were done withNaCl (0 9%) and histamine (1 mg/ml). The hista-mine equivalent (the concentration of platinum saltcausing a weal of the size of the histamine control orgreater) was calculated with a Hewlett Packard 41Ccalculator from individual log dose-response curves.A positive skin prick test was defined as one with aweal diameter greater or equal to the histaminecontrol.

LUNG FUNCTION AND BRONCHIAL PROVOCATION TESTS

Lung function tests (FEV,%IVC, specific airwayresistance (sRaw), specific airway conductance(sGaw)) were performed using a volume constantbody plethysmograph (Jaeger, Wurzburg, Ger-many). Measuring conditions were chosen as rec-

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ommended by Quanjer.'9 Bronchial hyperreactivitywas assessed by bronchial provocation tests withmethacholine (Aldrich, Steinheim, Germany). Amethacholine stock solution of 50 mg/ml in 0 9%NaCl was used. The stock solution was stored at 4°Cfor not longer than two weeks and dilutions were

freshly made before tests. Bronchial provocationtests were performed between 9.00 and 12.00 am.

Specific airway conductance was recordedoneminuteafter 10 breaths of each methacholine concentration(0-5, 1, 5, 25, and 50 mg/ml). Inhalation of metha-choline was from a jet nebuliser (Heyer, Bad Ems,Germany). An estimate of the amount of aerosolreleased from the nebuliser was made by weighingthe aerosol reservoir. These measurements were usedfor calculation ofprovocation doses. The method wasdescribed by Gonsior and coworkers.20 The provoca-tion doses causing a 50 and 35% fall in sGaw(PD,0sGaw and PD,5sGaw) were calculated from theregression line between the two data points of thecumulative log dose-response curve adjacent to the50% or 35% fall in sGaw by interpolation with aHewlett Packard 41C calculator. For statisticalanalysis the threshold methacholine concentrationsfor a 50% fall in sGaw were considered. Bronchialhyperreactivity was defined as a fall in sGaw of 50%or more with a methacholine provocation dose of1 mg or less.

In bronchial provocation tests with platinum, theplatinum salt solution was that used in skin pricktests. The inhalation procedure was the same as formethacholine. Inhalation of platinum salt was per-formed with 10 breaths of 10-fold dilutions ofplatinum salt solutions at intervals of 15 minutes.According to non-specific reactivity and anamnesticdata, bronchial provocation tests started with a

platinum salt solution of 107 to 10-5 mol/l. Individualdose-response curves were obtained and PD50 andPD,5sGaw (platinum salt) were calculated as formethacholine. A positive reaction was defined as a fallin sGaw of 50% or more with a platinum saltconcentration equal to or less than 102 mol/l. Time-

response studies were performed by measuringspecific airway resistance at 0, 10, 20, 30, and 60minutes after the inhalation of the highest platinumsalt concentration. Peak flow measurements were

recorded for six hours with a Mini-Wright peak flowmeter (Airmed, London, England).

TOTAL SERUM IgE CONCENTRATIONIgE concentration in serum was measured withan enzyme immunoassay using anti-IgE covalentlybound to paper discs (Phadezym PRIST, Pharmacia,Freiburg, Germany).

STATISTICAL ANALYSISMeans are medians. The dose-response curve of skinprick tests and the time-response curve for bronchialprovocation tests were drawn as a Box and Whiskerplot with medians, maximum, and minimum valuesas well as upper and lower quartiles. The correlationof the parameters was determined by Spearman rankcorrelation analysis. Differences between the tworefineries and between workers with and withoutactual contact with platinum salts were comparedusing two tailed U tests (Wilcoxon, Mann-Whitney).For both tests a 5% level ofsignificance was assumed.

ResultsThirty one ofthe 35 workers were considered allergicto platinum salt-that is, they showed either a

positive skin reaction or a positive bronchial provoca-tion test with platinum salt. Three workers had no

signs of allergy to platinum salt and one was doubt-ful. Table 2 gives the anamnestic data. A personalhistory of previous respiratory symptoms or allergicdiseases was found in 13% of subjects allergic toplatinum salt. A wide variability of occupationalexposure time and of the sensitisation periodoccurred (mean 24; range 1-264 months) without a

significant difference in both refineries. Main symp-

toms were rhinitis and asthma and symptoms did notdiffer between the refineries; 71% of workers allergic

Table 2 Anamnestic data. Platinum salt allergy was defined by work related symptoms, positive skin prick tests, and/orbronchial provocation tests with platinum. Personal history of the exposed group refers to those with allergic symptomsunrelated to work. Symptoms of skin(S), conjunctivitis (C), rhinitis (R), and asthma (A) are given as % of the groupmembers. NoS = Non-smoker; ExS = ex-smoker; Smo = smoker; OET = occupational exposure time. Ranges are given inparentheses

Family Personal Sensitisationhistory history OET period Symptoms Smoking

No Age (y) (%) (%) (months) (months) (%) (pack-years)

Exposed group:Platinum salt allergy 31 36 (19-55) 13 13 57 (1-298) 24 (1-264) S: 48 C:68 10 (0-31)

R: 90 A: 100 9 NoS/6 ExS/16 SmoNo platinum salt allergy 4 40 (24-54) 0 25 219 (7-240) - S: 25 C: 75 10 (6-15)

R: 100 A: 100 4 SmoControls 9 34 (20-58) 22 100 - - Smo: 44 C: 33 7(0-30)

R: 56 A: 100 2 NoS/3 ExS/4 Smo

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Table 3 Skin prick test with standard allergens, total serumIgE, and lungfunction

Skin test withstandardallergens Total serum FEV, °/VC

No positive (0) IgE (U/ml) (%°

Exposed group:Platinum salt 31 48 132 (11-1200) 75(41-87)

allergyNo platinum 4 75 84 (12-99) 84 (71-93)

salt allergyControls 9 22 89 (17-550) 69 (51-81)

Ranges are given in parentheses.

to platinum salt were smokers or ex-smokers; 48% ofsubjects allergic to platinum salt showed positive skinprick tests with standard allergens (table 3); and IgEconcentration was raised (> 100 U/ml) in 50% ofsuch workers. Only five workers had FEV,%IVC of< 65%. Thus severe airway disease was a rare findingin these platinum salt allergic workers. Allergicworkers with obstructive airway disease were older(mean 49, range 41-55 years) than allergic workerswith normal spirometric values (mean 32, range 19-55 years).

All workers who were not submitted to bronchialprovocation tests showed a positive skin prick testwith platinum salt. Four workers with severe diseaseor with an asthmatic reaction after skin prick testswere older (mean 54-5, range 45-55 years) than thosewho were challenged (mean 40, range 19-55 years).Skin reactivity to platinum salt was higher in thesefour workers (mean histamine equivalent reaction atmean 5 5 x 10' (range 1-0 x 10' - 7-2 x 10-') mol/1) than in skin test positive subjects who inhaledplatinum salt (mean 4-2 x 10-' (range 1-0 x 10' -2-6 x 10-3) mol/l). This subgroup of highly sensit-ised workers had been removed from the refinerybecause of severe disease but still had occasionalcontact with platinum salts.Three workers showed a mild systemic reaction

during skin prick tests. These subjects experienceddyspnoea, coughing, and rhinitis. Symptomsresolved without treatment. They were not submit-ted to bronchial provocation tests with platinum salt.Two of them had obstructive airways disease(FEV,%IVC 37% and 41%); the third subject washighly hyperreactive (PDOsGaw (methacholine)0 39 mg).

Thirteen of the 27 subjects who underwent a skintest and bronchial provocation with methacholineand platinum salt still had occasional contact and sixhad regular contact with platinum salts. No differ-ences were found in skin prick tests, bronchialprovocation tests with methacholine and platinumsalt, IgE concentration, or FEV,%IVC betweenworkers with and without contact with platinum

salts. The period since the end of exposure did notcorrelate with lung function, IgE concentration, andreactivity to methacholine. The time since leavingthe refinery workshop had a negative correlation withskin prick (r, -0-48, p < 0-014, n = 27) andbronchial provocation tests with platinum salt (r. forPD,0sGaw -0-53, p < 0 007, n = 27), suggestingthat sensitivity to platinum salts decreases after theend ofexposure. Age and occupational exposure timeshowed no correlation with skin reactivity and bron-chial reactivity to platinum salt.Nineteen of the 27 workers (but none of the

controls (n = 109)) showed a positive skin prick testwith platinum salt. One worker was doubtful; he hada weal diameter of 4 mm with the 102 mol/l solutionand no reactions with lower concentrations. The wealdiameter of the histamine control was 7-75 mm. Heexperienced no 50% fall in sGaw but coughed andsneezed after inhalation of the platinum salt. Themean platinum salt concentration of subjects withpositive skin tests for a histamine equivalent reactionwas 4-2 x 10' (1-0 x 10' - 2-6 x 10-3) mol/l.Figure 1 gives the dose-response curve for the 19subjects with positive skin prick tests with platinumsalt.With a threshold value of 1 mg methacholine,

three subjects were not hyperreactive; among themwere two workers considered allergic to platinumsalt. These workers experienced first symptoms 28and 38 months previously. One of them was stillworking in the refining area and the others had left therefinery workshop 27 months previously. Thus thelack of hyperreactivity could not be attributed to ashorter exposure period. Mean PD5, sGaw (metha-choline) was 03 (range 0-014-15) mg (n = 27).Figure 2 gives the methacholine concentrations caus-ing a 50% fall in sGaw. No correlation of PD,0sGaw(methacholine) with PD50sGaw (platinum salt) was

20-

E 15-

E.~10-

5-

10-81-7 1o6 10-5 104 10-3 1o-2Platinum salt concentration (mol/l)

Figure 1 Box and Whisker plot of the dose-responserelation for skin prick tests with platinum salt in workerswith positive skin prick tests (n = 19). The dotted linerepresents the median of the histamine control.

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20-

16-

12-

8-

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0-01,

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0

(2

0LO

0~0-

0-5 1.0 5.0 25,0 50-0

Methacholine concentration (mg/mi)

10

PtCI62-concentration (mol/l)

Figure 2 Threshold methacholine and platinum saltconcentrations causing a fall in sGaw of 5000 or more inworkers with positive bronchial provocation tests withplatinum salt (n = 22).

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found (fig 3). This was also the case with PD3,5 with thethreshold concentration for a 50% fall in sGaw. Also,methacholine responsiveness did not show any

correlation with skin reactivity to platinum salt. Lackof correlation was also found when considering onlysubjects with a positive bronchial provocation test (n= 22).Twenty two of the 27 workers had a positive

bronchial provocation test with platinum salt. Noneof the nine controls were positive although theyshowed a more pronounced non-specific hyper-reactivity with a mean PD50sGaw (methacholine) of0-04 (range 0-02-1 09) mg. Figure 4 gives the timecourse of sRaw after a positive bronchial provocationtest with platinum salt. Most workers experienced a

fall in sGaw of 50% or more during bronchialprovocation tests with platinum salt at a concentra-tion of 10' mol/l (fig 2). Mean PD,5,sGaw (platinumsalt) was 8-3 x 10'- (range 4-3 x 10-10 - 6-2 x

10') M. Four workers with positive bronchialprovocation tests but negative skin prick tests withplatinum salt showed a higher PD,0sGaw (platinumsalt) with a mean of2-3 x 104 (range 8-9 x 10 - 6-2x 10') M. Mean occupational exposure time inthese workers was 41 (range 1-161) months and themean time since leaving the refinery workshop was9 5 (range 0-60) months. The time between theinvestigation and first symptoms also showed a widerange (mean 54, range 2-101 months).

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Figure 3 Correlation of skin prick tests and bronchialprovocation tests with methacholine (MCH) and platinumsalt (Pt). "-PD50" and "-His" means that no 50% fall insGaw or no histamine equivalent reaction in skin prick testwas achieved. Dots represent refinery workers (n = 27);stars are controls (n = 9). Correlation coefficients do notinclude control subjects.

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u

c

.CA

>- 4-

.i_

2-cn

Ptl2-PtCI6r-iII

-30 -20 -10 0 10 20 30 40 50 60Time (min)

Figure 4 Box and Whisker plot of the time-responserelation of bronchial provocation tests with platinum salt inworkers with a fall in sGaw of50% or more (n = 22).

The PD50sGaw (platinum salt) showed a corre-lation with skin reactivity (r, 0-66, p < 0-0008, n =27). Again, this was also the case with PD3, and thethreshold value for a 50% fall in sGaw (r. 0-60 and0-68). Correlation coefficients were lower but stillsignificant when only subjects with a positive bron-chial provocation with platinum salt were considered(r, 0 50, p < 0-023 for PD50sGaw, n = 22).One worker (histamine equivalent in skin prick test

with platinum salt 2-8 x 10' mol/l, PD50sGaw(platinum salt) of immediate reaction 4-3 x 10-' M)showed a dual reaction with a clear late reactionrequiring parenteral steroid therapy (fig 5). No severeimmediate asthmatic responses were seen (maximumsRaw7-5kPa x s).

Figure 6 gives the patterns of positive reactions inskin tests and bronchial provocation tests with meth-acholine and platinum salt. Sixteen of27 workers hadpositive reactions in all three tests. Two subjects withpositive skin prick tests showed a fall in sGaw of50%or more after inhaling the platinum salt despite a lackof hyperreactivity (PD,0sGaw (methacholine) 4-2and 2-3 mg). Four subjects with negative skin pricktests with platinum salt had a positive bronchialprovocation test with platinum salt and all of themwere hyperreactive. One worker showed weakhyperreactivity to methacholine (PD50sGaw0 97 mg) and a positive skin prick test with platinumsalt but no reaction in a bronchial provocation testwith platinum salt. One worker had negative testsand was not considered allergic to platinum salts, aswere three workers with bronchial hyperreactivitybut negative skin tests and bronchial provocationtests with platinum salt.

DiscussionHexachloroplatinate is the main platinum salt com-plex encountered in refineries and catalyst productionplants. As other complexes offer no advantage,'4 we

chose the hexachloroplatinate complex for our inves-tigation.

Thirty one of a total of 35 workers with workrelated respiratory symptoms were considered aller-gic to platinum salt-that is, they had either apositive bronchial or positive skin test reaction. Oneworker showed a doubtful skin reaction without abronchial reaction. Thus workers of platinum refin-eries with work related symptoms have a highprobability of having platinum salt allergy. As ourstudy is not an epidemiological one, further inter-pretation of results is not possible.

Subjects were examined at a mean of 15 (range 0-132) months after they had left the refining area.Although reactions in skin prick and bronchialprovocation tests with platinum salts decreased withincreasing time since end of exposure, allergy toplatinum salt could be diagnosed in 23 of 27 subjectswho underwent bronchial provocation tests.Longitudinal studies are needed to determine thetime course of platinum salt sensitisation after end ofexposure.The skin prick test with platinum salt is not as

sensitive as it is specific. Four workers with workrelated respiratory symptoms and a positive bron-chial provocation test with platinum salt showed noskin reactions to platinum salt. False negative skinprick tests with platinum salt were excluded becausetests were performed with freshly prepared platinumsalt solutions in duplicate. Negative skin tests withplatinum salts and positive isolated bronchial reac-tions were described by Pepys and coworkers.'8 Wecould not find any isolated late reaction (and only onedual reaction in a highly sensitive worker) in oursubjects. This subgroup of workers with negativeskin prick tests and positive bronchial provocationtests could not be identified by anamnestic data. It isnot likely that the lack of skin reaction in theseworkers was due to a shorter period of exposure orlonger absence of exposure to platinum salt. Totalserum IgE concentration showed a wide variation in

600-C

500-

a 400-0.,.

" 300-

.- 200

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0

Methacholine

Ptc62-

Severeasthmaticreaction

o 2 4 18 1o 12 14 16 18Time (h)

Figure 5 Peakflow protocolfor one worker showing animmediate and clear late asthmatic reaction in bronchialprovocation tests with platinum salt.

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All testsnegative(n=1)

Provocation Mch +(n=3) A

Provocation Pt +provocation Mch +

(n=4)

Skin test + Nprovocation Pt +

(n=2)

[Pt = Platinum salt||Mch= Methacholine

Figure 6 Number ofpositive reactions in skin prick testsand bronchial provocation tests with platinum salt andmethacholine of workers submitted to bronchial provocationtests (n = 27). Bronchial hyperreactivity was assumed at athreshold value of 1 mg methacholine or less.

these four workers; two subjects with positive skintests to standard allergens had raised IgE concentra-tions (115 and 161 U/ml); the rest, without skinreactions to standard allergens, showed normal IgEconcentrations (5 and 45 U/ml). It is tempting tospeculate that these subjects with negative skinreactions and positive bronchial reactions toplatinum salts might show a different reaction mode,probably not mediated by IgE.

Skin prick tests with platinum salt caused mildsystemic reactions not requiring treatment in threeworkers. As we applied a rather high quantity ofplatinum salt to the skin (complete dose-responsecurve in duplicate from 10-8 up to 10-2 mol/l), sideeffects might be reduced by using only one concentra-tion or stepwise testing. For practical purposes, we

recommend performing skin prick tests with a

platinum salt concentration of 10-' mol/l(4 1 x 10-3 g/ml). This concentration is in the rangeof the recommendation of Roberts3 who foundspecific skin reactions with concentrations of 10-3 to10-8 g/ml. With the concentration of 102 mol/l, themaximum weal diameter was 19-5 mm and with theI0-3 mol/l solution, 12 5 mm; the doubtful reactionwas not recognised and four further reactionsdecreased to the size of the histamine control.Most subjects showed clear bronchial hyperreac-

tivity. Hyperreactivity to methacholine is not aconstant finding, however, in platinum salt inducedasthma and is quantitatively not correlated with skinand bronchial reactivity to platinum salt. Thusquantitative assessment of bronchial hyperreactivity

to methacholine is of little value for a prediction ofthe reaction in bronchial provocation tests.

Bronchial provocation tests with platinum saltappear to be specific as none of the controls showedany reaction. Sensitivity of bronchial provocationtests was higher than that of skin prick tests. Only oneof the 23 workers who were considered allergic toplatinum salt had a negative bronchial provocation.This worker with borderline hyperreactivity(PD5,sGaw (methacholine) 0 97 mg) showed no 50%fall in sGaw during a bronchial provocation test withplatinum salt, but a clear clinical reaction withsneezing and coughing.

Bronchial provocation tests with platinum salt asperformed in this study are not hazardous. Usingstepwise increasing platinum salt concentrations,maximum airway obstruction can be kept at amoderate level. The maximum sRaw was 7-5 kPa x swith a mean maximum sRaw of 3-6 kPa x s in thegroup ofworkers with a positive bronchial reaction toplatinum salts. Only one immediate reaction had tobe treated by a fi agonist because of severe coughing.As one highly sensitised worker experienced a lateasthmatic reaction, we suggest performing bronchialprovocation tests in a clinical setting where emergen-cies can be treated adequately. We recommend aprovocation dose of about 10" M platinum salt asthe first inhalation step in highly sensitised workers,which corresponds to a concentration of lo- mol/lwith our inhaler device. In our study only one of the27 subjects reacted to a concentration of 10-6 mol/l;however, workers with a systemic reaction in skintests and with obstructive airway disease were notsubmitted to bronchial provocation tests. Bronchialsensitivity in these subjects might be even higher. Inpersons with negative skin prick tests with platinumsalt, a 10-fold higher platinum salt dose or concentra-tion seems appropriate as a first step.We have shown that work related respiratory

symptoms are not predictive ofplatinum salt asthma.Negative skin prick tests with hexachloroplatinicacid do not exclude the disease. This has to beconsidered when interpreting or performingepidemiological studies concerning platinum saltasthma.Our investigations further show that in a number

of countries legal threshold values for occupationalplatinum salt exposure bear risks for those workerswho are sensitised to platinum salt. At the thresholdexposure of2 ug/m3 workers inhale about 2-0 x 10 8g/minute or 0-5 x 1010 mol/minute. This corre-sponds to the PD50sGaw in bronchial provocationtests with platinum salt.

We acknowledge the technical assistance of MrsBarbel Aulbach and Mr Steve Collins for reading theproofs. We thank Allergopharma, Reinbek, Ger-many, for technical support.

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Quantitative skin prick and bronchial provocation tests with platinum salt

Requests for reprints to: Dr Rolf Merget, Klinikumder Johann Wolfgang Goethe-Universtat, Zentrumder Inneren Medizin, Abteilung fur Pneumologie,Theodor-Stern-Kai 7, D-6000 Frankfurt/Main 70,Germany.

1 Hunter D, Milton R, Perry KMA. Asthma caused by thecomplex salts of platinum. Br J Ind Med 1945;2:92-8.

2 Dally MB, Hunter JV, Hughes EG, Stewart M, Newman-Taylor AJ. Hypersensitivity to platinum salts: a populationstudy. Am Rev Respir Dis 1980;121(suppl):230 [abstract].

3 Roberts AE. Platinosis. Archives of Industrial Health andOccupational Hygiene 195 1;4:549-59.

4 Venables KM, Dally MB, Nunn AJ, Stevens JV, Stephens R,Farrer N, et al. Smoking and occupational allergy in workersin a platinum refinery. BMJ 1989;299:939-42.

5 Merget R, Schultze-Werninghaus G, Muthorst T, Friedrich W,Meier-Sydow J. Asthma due to the complex salts ofplatinum-a cross sectional survey of workers in a platinumrefinery. Clin Allergy 1988;18:569-80.

6 Biagini RE, Bernstein IL, Gallagher JS, Moorman WJ, BrecksS, Gann PH. The diversity of reaginic immune responses toplatinum and palladium metallic salts. J Allergy Clin Immunol1985;76:794-802.

7 Gladkova EV, Odintsova FP, Volkova ID, Vinogradova VK.The health status of workers in the production of platinumcatalysts. Gig Tr Prof Zabol 1974;18:10-13. [In Russian.]

8 Brooks SM, Baker DB, Gann PH, Jarabek AM, Hertzberg V,Gallagher J, et al. Cold air challenge and platinum skinreactivity in platinum refinery workers. Chest 1990;7:1401-7.

9 Murdoch RD, Pepys J, Hughes EG. IgE antibody responses to

platinum group metals: a large scale refinery survey. Br J IndMed 1986;43:37-43.

10 Massmann W, Opitz H. About platinum allergy. ZentralblArbeitsmed Arbeitsschutz 1954;4:1-4. [In German].

11 HebertR. Affections caused by compounds ofplatinum. Archivesdes Maladies Professionelles de Midecine du Travail et deSicuriti Sociale (Paris) 1966;27:877-86. [In French].

12 Bolm-AudorffU, Bienfait HG, Burkhard J, Bury AH, Merget R,Pressel G, et al. Respiratory allergy in chemical workersexposed to platinum salts. In: Sakurai H, et al eds.Occupational Epidemiology. Amsterdam: Elsevier Sci Publ1990:157-60.

13 Cromwell 0, Pepys J, Parish WE, Hughes EG. Specific IgEantibodies to platinum salts in sensitised workers. Clin Allergy1979;9:109-17.

14 Cleare MJ, Hughes EG, Jacoby B, Pepys J. Immediate (type I)allergic responses to platinum compounds. Clin Allergy1976;6: 183-95.

15 Pepys J, Parish WE, Cromwell 0, Hughes EG. Passive transferin man and the monkey of type I allergy due to heat labile andheat stable antibody to complex salts of platinum. Clin Allergy1979;9:99-108.

16 Bijl WJF. Asthma as occupational disease: Allergy againstplatinum ammonium chloride. Allergie und Asthma1963;9:155-7. [In German.]

17 Pasteur Vallery-Radot L, Blamoutier P. Sensitisation againstpotassium chloroplatinate-Anaphylactic shock after a skintest with this salt. Bulletins et Memoires de la Societi Midicaledes Hopitaux (de Paris) 1928;45:222-30. [In French.]

18 Pepys J, Pickering CAC, Hughes EG. Asthma due to inhaledchemical agents-complex salts of platinum. Clin Allergy1972;2:391-6.

19 Quanjer PH, ed. Standardised lung function testing. Bull EurPhysiopathol Respir 1983;19:1-95.

20 Gonsior E, Kruger M, Meier-Sydow J. How to performbronchial provocation tests with antigen by body plethys-mography. Acta Allergologica 1976;31:283-96. [In German.]

Accepted 8 April 1991.

Vancouver style

All manuscripts submitted to the Br J Ind Medshould conform to the uniform requirements formanuscripts submitted to biomedical journals(known as the Vancouver style).The Br J Ind Med, together with many other

international biomedical joumals, has agreed toaccept articles prepared in accordance with theVancouver style. The style (described in full in BrMed J, 24 February 1979, p 532) is intended tostandardise requirements for authors.

References should be numbered consecutivelyin the order in which they are first mentioned inthe text by Arabic numerals above the line on eachoccasion the reference is cited (Manson' confirmedother reports2-5 .. .). In future references to paperssubmitted to the Br J IndMed should include: the

names of all authors if there are six or less or, ifthere are more, the first three followed by et al; thetitle of journal articles or book chapters; the titlesof journals abbreviated according to the style ofIndex Medicus; and the first and final pagenumbersof the article or chapter.Examples of common forms of references are:

1 International Steering Committee of Medical Editors.Uniform requirements for manuscripts submitted tobiomedical journals. Br Med J 1979;1:532-5.

2 Soter NA, Wasserman SI, Austen KF. Cold urticaria:release into the circulation of histamine and eosino-philchemotactic factor of anaphylaxis during cold challenge.N Engl J Med 1976;294:687-90.

3 Weinstein L, Swartz MN. Pathogenic properties ofinvadingmicro-organisms. In: Sodeman WA Jr, Sodeman WA,eds. Pathologic physiology: mechanisms ofdisease. Philadel-phia: W B Saunders, 1974:457-72.

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