British Journal of Industrial Medicine 1986;43:192-198

Allergy to laboratory animals in laboratorytechnicians and animal keepersG AGRUP,'2 L BELIN,3 L SJOSTEDT,' AND S SKERFVING'

From the Department ofOccupational Medicine,' University ofLund, S-221 85 Lund, Department ofOccupational Dermatology,2 National Board ofOccupational Safety and Health, S-171 84 Solna, OccupationalAllergy Unit,3 Department ofMedicine I, Sahlgren's Hospital, S-413 45 Goteborg, and Swedish FoundationforOccupational Health and Safetyfor State Employees,4 Statshalsan, S-2210O Lund, Sweden

ABSTRACT The prevalence of allergy to laboratory animals (LAA) was investigated in laboratorytechnicians and animal keepers. In a questionnaire 41 of 101 technicians reported symptoms pro-voked by work with laboratory animals. On clinical investigation 30 were found to have symptomsand signs related to contact with animals, and allergy was confirmed by radioallergosorbent tests(RAST) and skin tests in 19. All had rhinitis and 10 also had bronchial asthma. Forty seven othertechnicians who had stopped working with laboratory animals showed the same relative numbersof respiratory tract symptoms and of confirmed allergy to laboratory animals as did those currentlyhandling animals. Seven of 23 animal keepers had work related symptoms. LAA symptoms werefound in four and confirmed animal allergy in two. All four animal keepers with animal relatedsymptoms had rhinitis, none had bronchial asthma. Positive animal RAST and skin tests werefound only among people with animal related symptoms. A history of atopic disease was commoneramong those with positive animal test results than among those with negative test results. Norelation between smoking and the development of allergy to laboratory animals emerged. Simpleprophylactic measures often sufficed to help technicians with animal related symptoms to remain atwork.

In 1957 Sorrell and Gottesman described allergy tomice in a laboratory worker1 and in 1961 Rajkareported a series of 10 patients with allergy to guineapig, rat, rabbit, and mouse.2 During the past decadeallergy to laboratory animals has become a matter ofincreasing interest, and a clinical entity called labora-tory animal allergy syndrome (LAA syndrome) hasbeen defined. The occurrence of these allergies hasbeen studied, and major investigations on differentand often mixed occupational groups have also beenperformed3- 12; prevalence rates varying between11% and 30% have been reported.The aim of the present study was to define the prev-

alence of allergy to laboratory animals in two welldefined occupational groups, laboratory technicianshandling animals and animal keepers at the Univer-sity of Lund, Sweden. The study also included tech-nicians and animal keepers who had stopped workingwith animals during the past decade. These formerAccepted 15 July 1985

employees were investigated to establish whether a"healthy worker selection" existed. The clinical mani-festations (rhinitis, rhinoconjuctivitis, asthma, andurticaria) were studied. Allergies to the following sixspecies were investigated; rat, mouse, rabbit, guineapig, hamster, and cat.The effect of the allergies on working routines and

on the ability of the sufferers to continue their workwas also investigated. Work practices were studiedand hygienic improvements and prophylactic mea-sures taken by the staff are reported.The currently employed laboratory technicians in

whom symptoms related to laboratory animals werefound were compared with the same number of tech-nicians with no symptoms. This control group waschosen from among the currently employed tech-nicians who reported no symptoms when handlinganimals and who had the same age and sex distribu-tion as the LAA technicians; exposure to animals wascomparable in the two groups.

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Allergy to laboratory animals in laboratory technicians and animal keepersMaterial and methods

All technicians working with laboratory animals andemployed at the 25 research laboratories at the Uni-versity of Lund and all animal keepers working atthese laboratories were included. They were invited tocomplete a questionnaire designed to disclose symp-toms related to handling animals. Information onprevious and current exposure to six species (rat,mouse, guinea pig, cat, rabbit, and hamster) wassought and also details of domestic pets. Questionsabout rhinitis, conjunctivitis, asthma, and urticariarelated to animal work, and personal or family his-tory, or both, of atopic disease (asthma, allergic rhi-nitis, and atopic dermatitis) were included. Smokinghabits were also noted.

Questionnaires were sent to 155 laboratory tech-nicians, 101 currently employed and 54 who had dis-continued their work in the preceding 10 years. The54 who had stopped work had been employed at thefive largest laboratories. The same questionnaire wasdistributed to all 24 currently employed animal keep-ers and to all 25 previously employed animal keeperswho had stopped work during the past decade.

All those who reported animal related symptomswere invited to the department of occupational medi-cine, Lund, for clinical examination. All clinicalexaminations were performed by one of us (GA). Ahistory with special attention to routines in animalhandling was taken. The latent period (the periodbetween starting work with animals and the firstappearance of symptoms of allergy) was noted. Thishistory was taken "blind," before the physical exam-ination. As part of the examination alphal-antitrypsin was measured by serum electrophoresis,and the total serum IgE was determined by paperradio immunosorbent tests (PRIST) using reagentsfrom Pharmacia AB, Uppsala. Lung function testswere performed on a Vitalograph spirometer withrecording of the forced expiratory volume in one sec-ond (FEVy) and the forced vital capacity (FVC). Allthose with pulmonary symptoms indicating bronchialobstruction or hyperreactivity were examined with amethacholine test using concentrations of 0 001, 0 01,and 0-1% of methacholine solutions and a Bernsteinspirometer. A fall in the FEV, of at least 15% afterexposure to a solution of 0-1% methacholine wasregarded as pathological.

Skin prick tests were performed on the volar aspectof the forearm with the following animal allergens:urine extracts from white rat and white mouse, andhair skin extracts from guinea pig, hamster, cat, andrabbit. The rat and mouse antigens are low molecularweight urinary proteins, mainly an alpha2-globulin inrat urine and a prealbumin in mouse urine.6 13 Theywere separated from tenfold concentrated urine by

gel-filtration on a Sephadex G 100 column. Pooledfractions eluted as protein markers with molecularweights of ca 20000, and concentrations of 0 5 and1 mg/ml were used. The cat extract also contained asaliva preparation, because it has been suggested thatsaliva may be the best source of cat allergen. 141 S Theskin tests also included a standard battery ofcommonenvironmental allergens-namely, four different pol-len extracts (Betula pubescens, Phleum pratense, Arte-misia vulgaris, and Dactylis glomerata), allergensfrom fish, dog, and horse, two mite species (Der-matophagoides pteronyssinus and Dermatophagoidesfarine), and four moulds (Alternaria iridis, Cladospo-riwn herbarwn, Penicillium notatun, and Aspergillusfumigatus). The allergens were prepared by theoccupational allergy unit, Sahlgren's Hospital, Goth-enburg, Pharmacia AB, Uppsala, and the Aller-gological Laboratory, Copenhagen.

Histamine hydrochloride, 1Omg/ml, was used as areference for prick tests, and the weal size producedwas defined as + + +. Skin reactions to the allergenswere compared with the histamine weal area and wereclassified as follows.

0 = no reaction or less then 1/4 of the histamine wealsize,+ = 1/4 of histamine weal,+ + = 1/2 of histamine weal,+ + + = histamine weal,+ + + + = 2 x histamine weal, and+ + + + + = 4 x histamine weal.

All plus reactions were regarded as positive.Specific serum IgE antibodies to the laboratory ani-

mal allergens were measured with radio-allergosorbent tests (RAST). Bromocyanide activatedcellular discs were coupled with guinea pig, rat, andmouse allergens using standard procedures. Theguinea pig extract was prepared from superficial skinscrapes, the others from urine as described above.Rabbit, cat, and hamster discs and radioactive anti-IgE tracer were prepared by Pharmacia AB, Uppsala.RAST results were calculated according to the manu-facturer's recommendation using a highly positivesera from a birch pollen allergen individual as aninternal standard. Positive results were accordinglygraded from classes 1 to 4. In terms of radioactivityRAST class 1 corresponds to a binding to the RASTdisc at about 2% of total added amount of tracer(40 000 counts per 90 sec).The 30 people in the control group of technicians

working with laboratory animals and with no symp-toms or signs associated with the animals wereinvestigated in the same way as those with symptoms.

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194Table 1 Results ofRAST and skin tests to laboratoryanimals in 101 currently employed technicians

No of subjects Animal tests

Positive Negative

Animal related symptoms 30 19 11Other work relatedsymptoms 11 0 11Control group 30 0 30

Results

CURRENTLY EMPLOYED TECHNICIANSAll 101 technicians (4 men and 97 women, mean age36, range 22-58) working with laboratory animalscompleted the questionnaires. Forty one (two menand 39 women) reported symptoms that they relatedto their work and possibly to the animals. A detailedhistory suggested that the symptoms were related toexposure to animals in 30 people (two men and 28women, mean age 37, range 26-58); the remaining 11had nasal or ocular symptoms related to for-maldehyde, solvents, dust, or dry air.The symptoms varied from slight discomfort from

rhinorrhoea, nasal congestion, sneezing, and conjunc-tival itching to severe respiratory symptoms such ascough, dyspnoea, and wheezing. The first symptomsappeared within 12 months of starting animal hand-ling in seven people; the mean latent period was 2-3years, range one month-seven years.

Nasal or conjunctival symptoms, or both, were thefirst in all those with animal related symptoms. Daysor weeks after the appearance of the nasal or conjunc-tival symptoms many noted itching and wealing ofskin at sites of animal contact. Asthma developedafter several months and in two cases more than oneyear after the initial symptoms.The 41 technicians with work related symptoms

included 30 (28 women and two men) with symptomssuggestive ofLAA when the clinical history was takenbefore the physical examination and testing. Of these,19 (18 women and one man) showed positive RASTand skin test results to one or more laboratory animalallergens and 11 were test negative. The remaining 11

Table 2 Number oflaboratory technicians exposed to thesix animal species, and eorresponding animal test results

Species No exposed No with positive tests

All species 101 19Rat 83 15Mouse 55 10Rabbit 55 6Guinea pig 35 9Cat 26 8Hamster 1 9

Agrup, Belin, Sjostedt, and SkerfvingTable 3 Results ofRASTand skin tests to one or more ofthe six species oflaboratory animals in 30 laboratorytechnicians with respiratory symptoms. In the group withpositive results one or more tests were positive

Aninal test results

Positive Negative

Rhinitis 10 10Asthma and rhinitis 9 1

who had work related symptoms not connected withanimal handling showed negative animals tests. Ofthe control group of 30 technicians working with ani-mals but with no symptoms, all showed negativeRAST and skin test reactions to laboratory animals(table 1).

Table 2 shows the number of technicians workingwith the different animals and the number of peoplewith positive RAST and skin tests: 15 reacted to ratand 10 to mouse. Many reported that they had firstnoticed sensitivity to rat and later also to mouse. Ofthe 15 allergic to rats, 14 had been working with maleanimals and one worked only with mice and neverwith rats, but was strongly positive to both rat andmouse urine. Among the 10 people who reacted tomouse allergen, nine also reacted to rat allergen. Nineshowed positive reactions to guinea pig, and all hadbeen exposed to this animal; they were also positive tohamster allergen, although only one had been work-ing with a hamster. Another worker had had a ham-ster as a domestic pet and had noticed some sensi-tivity before starting to work with guinea pigs. Eightwere positive to cat, of whom five were working withcats. Six were positive to rabbit allergen and were

3.RAST

21

00

* 0:

00

o

o~~~O Rhinitis oo Asthma *

4000

+ ++ +++ ++++Prick test

RASTand skin prick test results (9 negative) to rat urinaryproteins in 24 laboratory technicians with respiratorysymptoms caused by handling rats. Correlation coefficient(r = 0 82).

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Allergy to laboratory animals in laboratory technicians and animal keepers

Table 4 Past symptoms in 47 laboratory technicianspreviously working with laboratory animals

No of subjects %

Animal related symptoms 18 38Stopped work owing to animalrelated symptoms 8 17Other work related symptoms 9 19

working with rabbits. The highest relative frequencyof allergy was to cat (31%) and the lowest to rabbit(11%); this difference is significant (x2 = 4-87, p <

0-05). The relative frequencies of allergies to otheranimals did not differ significantly.

Table 3 presents the results of the skin tests andRAST in 20 laboratory technicians with rhinitis onlyand in 10 with both rhinitis and asthma. Of the 10with asthma, nine had positive test results to the rele-vant animals; but only 10 of the 20 technicians withrhinitis but not asthma had positive RAST and skintests. There was a positive correlation between theresults of the skin prick tests and RAST. The peoplewith bronchial asthma had the strongest test results.Twenty four technicians had respiratory symptomscaused by handling rats. The RAST and skin pricktests and the positive correlation between the twotypes of test results are illustrated in the figure. Onewoman with bronchial asthma, however, had nega-

tive skin and RAST tests, and was investigated forprecipitating specific antibodies with negative result;she had been working exclusively with female rats.Of the 19 people with LAA symptoms and positive

animal tests, 13(68%) had a history of atopic der-matitis, rhinitis, or asthma before they started workat the laboratory or reacted to one or more allergensin the standard battery, or both. Among the 13 indi-viduals regarded as atopic, six had a history of atopyand 12 had one or more positive skin prick tests to thestandard battery, animal test excluded. Such atopicfeatures were present in three of the 11 people withanimal related symptoms but with negative animalRAST and skin tests (27%). Of the 30 with no animalrelated symptoms, six (20%) had a history of atopicdisease or a positive reaction to a standard test, or

both. Thus atopy was commoner among those withpositive tests to laboratory animal allergens (X2 =

12-07, p < 0-001).Smoking habits did not differ significantly between

those with and those without sensitivity to laboratoryanimals. The proportion of smokers was roughly thesame in both groups (47% and 60% respectively), theaverage duration of history of smoking was similar(15 and 16 years), and almost the same number hadgiven up smoking in each group.

Alpha,-antitrypsin was normal in every personinvestigated. The total serum IgE (PRIST) was raisedin one of the 20 people with rhinitis, and in four of the10 with asthma. All showing negative animal testshad normal total serum IgE values.FEV1 and FVC were normal in all those with rhi-

nitis only and in nine of the 10 people with bronchialasthma. All those with symptoms and signs of bron-chial asthma had positive methacholine test results,however.

All 30 currently employed technicians with LAAsymptoms had modified their working conditions inorder to carry on with their work. Many alleviatedtheir discomfort by using masks, gloves, and longsleeves, avoided fetching the animals, and did notshave them. Fume cupboards were often used. Fourconfined themselves to surgical work only and usedgloves and mask.

Seventeen technicians had sought medical advicebecause of their symptoms. Only one had beeninvestigated for allergy, and none had claimed work-ers' compensation. Six had had sick leave owing totheir allergy, but never for longer than two months.Most had received informal medical advice from theirmedical collaborators, and many took an anti-histamine before handling animals.

PREVIOUSLY EMPLOYED TECHNICIANSAt five laboratories 54 technicians, all women, haddiscontinued working with animals during the pre-

ceding 10 years; 47 of them (87%) completed thequestionnaire and 28 of these reported symptomsrelated to their former work. Eight had given up theirjobs because of symptoms related to animal handling(table 4).

All those who reported work related symptomswere interviewed by telephone, and 18 gave a historyhighly suggestive of allergy to laboratory animals.

Table 5 Comparison ofthe occurrence ofwork related symptom, animal related symptoms, and test confirmed allergies tolaboratory animals in technicians currently working with aninals and in those who had discontinued animal handling

No exposed No with work related No with animal related No with positive animalsymptoms symptoms tests

Currently employed 101 41 30 19Previously employed 47 28 18 6

Total 148 69 48 25

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196

Fifteen were examined clinically; five had symptomsand signs of bronchial asthma and 10 of rhinitis only;six showed positive RAST and skin test reactions tolaboratory animals, four of the five with bronchialasthma and two who had had only nasal symptoms.In all four with bronchial asthma caused by allergy tolaboratory animals the asthma persisted after stop-ping work, and another with negative test results whohad reported asthmatic symptoms when handling theanimals also had persistent asthma. Methacholinetests were positive in all those with asthma.

Table 5 shows the symptoms of asthma and rhinitisand the results of animal skin and RAST tests in tech-nicians with current symptoms resulting from hand-ling animals and in technicians in whom previouswork with animals produced symptoms. Symptomswere equally common in the two groups, and there isno significant difference in the number of provedallergies.

ANIMAL KEEPERSTwenty three (14 men and 9 women, mean age 36,range 20-65) of the 24 currently employed animalkeepers responded to the questionnaire. Seven (fourmen and three women) reported symptoms that theysuspected to be caused by allergy to laboratory ani-mals. Detailed histories showed that four (one manand three women) of the seven suffered from sneezing,rhinorrhoea, and nasal congestion or conjunctivalitching or both, when handling animals. None hadsymptoms of bronchial asthma. Two women had con-tact urticaria caused by rats. The animal speciesreported to produce symptoms were in all four casesrat, in two cases rat and mouse, and in one case ratand guinea pig.

Positive RAST and skin test reactions occurred intwo women, in one to rat only and in the other to allsix species. Skin tests and RAST tests parallelled eachother. The first symptoms appeared within two yearsof starting animal handling (1-5 and 2 yearsrespectively). The two women with positive tests werethose with a history of contact urticaria.The remaining three people had symptoms not

related to animal handling, and gave a history ofnasal or conjunctival symptoms, or both, caused by

Agrup, Belin, Sjostedt, and Skerfvingwoodshavings, dust, detergents, and organic solvents.Thus seven of the 23 currently employed animal

keepers had work related symptoms. Four had symp-

toms caused by handling animals, two with positiveand two with negative animal test reactions. All fourhad rhinitis or rhinoconjunctivitis but none had bron-chial asthma. Of the 101 laboratory technicians, 10had bronchial asthma, however. It has been suggestedthat a "healthy worker effect" exists. To investigatewhether such an effect could be more pronounced inanimal keepers than in laboratory technicians we sentthe same questionnaire to all 25 previously employedanimal keepers who had stopped working with ani-mals during the preceding 10 years. Answers werereturned by 18 (13 women and 5 men). Eight withsuspect histories were interviewed, investigated, andtested. Five (four women and one man) had animalrelated symptoms, and two women had positive testreactions (table 6). One man with a characteristic his-tory of rhinitis while working with animals hadretired at 65 and later developed bronchial asthma;on investigation he had a negative response to animalallergens.The four animal keepers (two currently and two

previously employed) with positive tests to laboratoryanimals were all young women, mean age 29. The sexdifference is not statistically significant, however (X2= 3-83, p > 0-05).Atopy was commoner among animal keepers with

positive animal tests (50%, two of four) than amongthose with negative tests (17%, five of 30). Thedifference is not significant, possibly owing to thesmall numbers.

Discussion

In the questionnaires 41% of the 101 currentlyemployed laboratory technicians reported symptomsrelated to work with animals. This figure, however,was reduced to 30% when the symptoms were evalu-ated at clinical examination. The difference is ex-plained mainly by the fact that the clinical history atthe time of examination was able more critically todefine the time relation between working with animalsand the appearance of symptoms. Among the 30 con-

Table 6 Comparison ofthe occurrence ofwork related symptoms, animal related symptoms, and test confirmed allergies inanimal keepers currently working with animals and in people who had stopped handling animals

No exposed No with work related No with animal related No with positive animalsymptoms symptoms tests

Currently employed 23 7 4 2Previously employed 18 8 5 2

Total 41 15 9 4

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Allergy to laboratory animals in laboratory technicians and animal keeperssidered to have symptoms from the respiratory tractdefinitely related to handling animals 19 showed posi-tive RAST and skin test reactions to one or morelaboratory animals and nine had bronchial asthma.Only one with bronchial asthma showed negative testreactions. All the others with negative test reactionshad rhinitis or rhinoconjunctivitis only. There was adefinite tendency to bronchial symptoms among peo-ple with strongly positive test results.Among the 23 animal keepers 30% reported symp-

toms related to animal keeping, but this figure wasreduced to 17% at clinical examination; 9% of theanimal keepers showed positive animal RAST andskin tests. All four with symptoms of LAA had rhi-nitis only and none of the currently employed animalkeepers had bronchial asthma.The prevalence of confirmed animal allergy in ani-

mal keepers (2/23) was similar to that encountered inthe laboratory technicians (19/101). This was sur-prising since the animal keepers probably have agreater exposure to allergens than the technicians.Primary selection could occur, because people with ahistory of allergic symptoms may be less eager to takesuch employment. In fact none of the currentlyemployed animal keepers had had asthma in child-hood, whereas among the technicians studied threehad had asthma in childhood and two later developedbronchial asthma on handling laboratory animals.The nasal and conjunctival symptoms among those

showing negative animal RAST and skin test reac-tions and the bronchial asthma in the woman show-ing negative animal tests could have been non-allergic. The history of acquired reactivity tolaboratory animals similar to that reported amongthe test positive subjects, however, strongly suggeststhat the symptoms were of allergic nature. Quite pos-sibly, the allergen preparations used in the skin testingand RAST may have been inadequate for demonstra-ting certain allergies.

Figures for the prevalence of allergy to laboratoryanimals have been reported in other investigations.Cockcroft et al, in a study on 179 workers at threemedical research establishments, found a prevalenceof 27% among people working with laboratory ani-mals and who had symptoms related to this work.9The group also included some who had previouslyworked with laboratory animals but were not cur-rently exposed: 16% showed positive test reactions toone or more of five different species of laboratory ani-mals. Slovak and Hill reported that 30% of 146 menand women in different work categories exposed tolaboratory animals in a pharmaceutical company hadsymptoms related to this work.'0 Only 46% of thosewith symptoms showed positive skin reactions toallergens from the relevant species.

The present investigation reports prevalence figuresin two well defined occupational groups, and ourfigures are similar to those in the two earlier studies.We looked for healthy worker effect but found thatthe proportions of allergic symptoms and positivetests in the group currently working with animalswere the same as in those who had abandoned animalhandling.

All those who were allergic to rat allergens hadbeen working with mature male animals, which pro-duce the most potent allergen.6 13 Some technicianswith mouse allergy had not been working with thisspecies but with rats, indicating some cross sensi-tisation between rat and mouse urine.6 1113 A crosssensitivity also seems to exist between guinea pig andhamster, because all nine people allergic to guinea pigalso reacted to hamster, although only one had hadoccupational contact with hamster and only one hada hamster as a domestic pet. The number of positivetests to rabbit and cat might suggest that cat was themore allergenic of the two. Four technicians, how-ever, had had a cat as a domestic pet but nobody hadowned a rabbit. The higher figure for cat hyper-sensitivity was therefore probably related to closercontact, which is more usual with this species.The average latent period before appearance of the

symptoms and signs was about two years and, as inother studies on laboratory animal allergy, nasalsymptoms consistently appeared before bronchialasthma.67911The effect of smoking may be disregarded because

smoking habits were roughly the same in people withand without sensitivity to laboratory animals.Atopy (a history of atopic disease or positive test

reactions, or both, to allergens in the standard bat-tery) was significantly commoner in technicians withpositive RAST and skin test reactions to the animalallergens.

Detailed interviews and inspection ofmany labora-tories resulted in simple prophylactic measures thathelped many technicians to keep on working with ani-mals, but comprehensive changes in working condi-tions were sometimes necessary. Among those whohad given up animal handling most could make use oftheir training in other laboratory fields.From the interviews with the currently and pre-

viously employed animal keepers with allergies to lab-oratory animals we gained the impression that animalkeepers have more difficulties than technicians inmanaging and modifying their occupational situationin order to prevent symptoms. The two previouslyemployed animal keepers with positive animal testresults had left their employment because of their ani-mal induced symptoms.The advisability of animal handling by allergic peo-

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198ple may be questioned, however, because continuedcontact with animals may raise the level of sensitivity;slight symptoms to animal allergy could contribute awarning for the risk of developing bronchial symp-toms.

This study was supported by a grant from the Walter,Ellen, and Lennart Hesselman Foundation forScientific Research.

Requests for reprints to: Gun Agrup, MD,Department of Occupational Medicine, University ofLund, S-221 85 Lund, Sweden.

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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 journals, 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 oneach occasion the reference is cited (Manson'confirmed other reports2-5 ...). In future refer-ences to papers submitted to the Br J Ind Medshould include: the names of all authors if there

are six or less or, if there are more, the first threefollowed by et al; the title of journal articles orbook chapters; the titles of journals abbreviatedaccording to the style of Index Medicus; and thefirst and final page numbers of the article orchapter.Examples of common forms of references are:

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

Soter NA, Wasserman SI, Austen KF. Cold urticaria: releaseinto the circulation of histamine and eosinophil chemotac-tic factor of anaphylaxis during cold challenge. N Engl JMed 1976; 294:687-90.

3 Weinstein L, Swartz MN. Pathogenic properties of invadingmicro-organisms. In: Sodeman WA Jr, Sodeman WA, eds.Pathologic physiology: mechanisms of disease. Philadel-phia: W B Saunders, 1914:457-72.

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