morbidityfollow studyof basf employees exposed 2,3,7,8 ... · morbidityfollow...

Occupational and Environmental Medicine 1994;51:479-486

Morbidity follow up study of BASF employeesexposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin(TCDD) after a 1953 chemical reactor incident

Andreas Zober, M Gerald Ott, Peter Messerer

AbstractObjective-The aim was to examine thelong term morbidity experience of menexposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD).Methods-A retrospective cohort mor-bidity study of 158 men first exposed toTCDD between 17 November 1953 and 16November 1954 subdivided by chloracnestate and back calculated TCDD bloodlipid concentration, and 161 referents.Cause specific illness absence and admis-sions to hospital were examined between1953 and 1989.Results-On an ever or never basis,thyroid disease and appendicitis werediagnosed more often in the study group;these diseases were not differentially dis-tributed by chloracne state, but wereincreased in the high TCDD subgroup.An 18% increase in total illness episodeswas also seen (p = 0.002); illness ratesincreased with severity of chloracne andhigher TCDD concentration within thechloracne subgroup. There wereincreases in infectious and parasitic dis-eases (primarily ill defined intestinalinfections), disorders of the peripheralnervous system and sense organs, upperrespiratory tract infections, and otherskin diseases. Several of these increasescorrelated with chloracne state and infec-tious disease episodes increased withhigher TCDD concentration as well.Occurrences of mental disorders corre-lated with severity of chloracne, but notTCDD concentration. Benign andunspecified neoplasms were marginallyincreased in the severe chloracne andhigh TCDD subgroups. Chronic liverdisease was marginally increased in thehigh TCDD subgroup. Findings relativeto occurrence of ulcers, chronic lung dis-ease, and kidney and metabolic disorderswere unremarkable.Discussion-For various conditions,increased illness episodes were seenamong TCDD exposed employees com-pared with referents and were associatedwith either or both chloracne severity andback calculated TCDD concentration.The results are derived from insurancedata; hence, it is possible that heightenedawareness and personal health concernsled to greater utilisation of medical ser-vices in the exposed group. The findings

based on TCDD concentration should beless subject to this potential bias.

(Occup Environ Med 1994;51:479-486)

Key words: TCCD, thyroid disease, infectious disease

On 17 November 1953, within a few monthsof its start up, a BASF trichlorophenol unitexperienced an uncontrolled decompositionreaction. Fumes escaping from the affectedautoclave condensed on surfaces in the imme-diate work area of the enclosed facility. In amatter of days, workmen engaged in clean upefforts began to experience acnegenicresponses as well as other signs and symptomsof toxicity.'-3 The agent most likely to havecaused these responses was not determineduntil 1957 when 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) was chemically identified asa byproduct of trichlorophenol production andwas shown to be a potent inducer of chloracne.4As well as the clinical reports, follow up

studies were conducted to evaluate the mor-tality experience of exposed employees.56 Theeventual study population included personswho assisted in demolishing the autoclaveportion of the unit in 1968-9 as well as thoseassigned to prior assessment and clean upactivities. Although other materials were pro-duced by the unit after the accident,trichlorophenol production was not resumed.

Beginning in 1988, TCDD concentrationswere determined in blood lipids for 138 sur-viving members of the accident cohort. Fromthese data and detailed exposure descriptions,a regression model was developed to assessthe contribution of various exposure factors toeach employee's overall TCDD burden.'Cumulative TCDD concentrations, back cal-culated to the time of exposure, have nowbeen estimated for all cohort members fromthese model results.78 Concentrations ofhigher chlorinated dioxins were not increasedbeyond background values.7

Prior studies indicate that TCDD exposedpeople may experience a wide range of symp-toms shortly after exposure and that the liver,kidneys, peripheral, and central nervous sys-tem, immune system, and skin may all be tar-gets of injury.9 Complaints have includedheadache, dizziness, nausea, severe musclepain, fatigue, nervousness and irritability, dys-pnoea, decreased libido, and intolerance tocold.9 Other than a persistent acne, there has

Occupational Medicaland Health ProtectionDepartment, BASFAktiengesellschaft,D67056 Ludwigshafen,GermanyA ZoberP MessererMedical Department,BASF Corporation,Parsippany NJ, USAM Gerald OttCorrespondence to:Professor A ZoberAccepted for publication18 March 1994

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been little evidence of lasting or progressivenon-carcinogenic effects.New health legislation enacted in Germany

during 1990 has enabled insurers to shareanonymous medical diagnosis data with occu-pational medical departments as long as thesedata cannot be linked back to specific sub-jects. From an epidemiological perspective,use of this data resource offers several advan-tages. Firstly, it can provide morbidity infor-mation over a long period. Secondly, thediagnoses are generally based on independentexternal evaluations without detailed knowl-edge of exposure, thus minimising the poten-tial for observation bias. There are inherentdisadvantages as well. Because of considera-tions of confidentiality, it is not possible toconfirm diagnoses independently and poten-tial confounding factors such as age can onlybe considered through prior selection of com-parable referents. Secondly, the availability ofdata is restricted to those insured through thehealth insurance fund, the Betriebskranken-kasse (BKK). Data are accessible for retirees,but not for contract workers or workers wholeft the company for other jobs. Finally,claims data are provided for admissions tohospital and absences from work due to illnessbut these may not be available for less debili-tating conditions.The current study objectives were to

describe the long term morbidity experienceof TCDD exposed workers and to determineif exposed employees experienced highercause specific morbidity than comparablenon-exposed employees. A corollary objectivewas to evaluate the usefulness of medicalinsurance data as a means of assessing pos-sible work related health effects. The observa-tion period was from 17 November 1953 to31 December, 1989 and the indices of mor-bidity were the coded diagnoses and condi-tions reported in the medical insurance claimsof employees.

Population and methodsSTUDY GROUPStudy participants were chosen from the 247TCDD exposed workers reported in the latestcohort mortality study6 plus seven employeessubsequently identified as belonging to theaccident cohort.7 To permit analysis of mor-bidity by time since exposure and, at the sametime, protect participant anonymity, the tar-get population was restricted to the 175cohort members whose first TCDD contactoccurred within one year of the accident. Thehighest potential for exposure to TCDDundoubtedly occurred during this time asconfirmed later by biomonitoring data.7 Thefinal study group consisted of 158 men afterexclusion of four women employees becauseof anonymity considerations and 13 maleemployees who were never BKK members.Most of the excluded employees held man-agerial or professional positions.The study group was divided into three

subgroups based on chloracne state as deter-mined from a prior review of occupational

medical records.6 Subgroup I consisted of 52workers whose chloracne was classified asextensive or severe. Subgroup II consisted of61 workers, 50 with moderate chloracne and11 with a diagnosis of "erythema" at the timeof exposure but no chloracne. Finally, sub-group III comprised 45 men with no evidenceof chloracne or "erythema". These groupswere similar in size and large enough to pro-tect the anonymity of subjects. The exposureassessment, referred to previously, enabled afurther subdivision of the study group accord-ing to model based TCDD blood lipid con-centrations back calculated to the time ofexposure.7 Thus each of the chloracne sub-groups was also subdivided with 1000 partsper trillion (ppt) as a cut offpoint. In total, 73members of the study group had back calcu-lated TCDD values of >1000 ppt, 33 in thesevere, 29 in the moderate, and 11 in the nochloracne subgroups.

REFERENTSThe referent group was selected from a com-puterised data base of all persons who eitherworked at this large manufacturing complexafter 1969 or who retired before 1970. In1989, the complex employed more than50 000 workers. General site employees werepresumed not to have experienced TCDDexposures above background. Limited sam-pling of six workers gave TCDD blood lipidconcentrations averaging 3-3 ppt. Also, 42samples from long term employees notincluded in the study, but who were assignedduties in and around the affected buildingbetween 1960 and 1968, averaged only 5-1ppt. The referent pool was restricted to menhired before November 1953 and to peoplewith German or German-French surnames asthis was the case for all study group members.Finally, managerial and professional employ-ees were excluded because less than 10% ofthe exposed employees came from these posi-tions and BKK membership is less commonin high income groups. Among hourlyemployees, BKK membership is over 95%.The referent selection process was carried

out by computer with random selection with-out replacement based on birth year distribu-tion frequencies after selecting a pool ofeligible candidates. The process was per-formed separately for each of the three chlo-racne subgroups, but not separately for theTCDD concentration subgroups. This led toreferents that were frequency but not individu-ally matched on age within each chloracnesubgroup. Referents who were not BKKmembers were replaced. Three workers in thestudy group were shown not to have beenBKK members only after referent selectionhad been completed. Hence, in the "no chlo-racne" subgroup, there were three more refer-ents than study group members.

Several notable factors could not be con-trolled through the selection procedure.Firstly, there were 43 study group memberswho left active employment before 1970including 13 who died before 1970. The cor-responding referent group included only 27

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Morbidity follow up study ofBASF employees exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) after a 1953 chemical reactor incident

people who left employment before 1970, allpresumably due to retirement. Six of thesemen had died before 1970. Secondly, a num-ber of study group members were contractworkers in 1953 and only later became com-pany employees. Thus these workers wouldnot have been BKK members until 1954 orlater, whereas all referents were companyemployees as of November 1953.

DATA COLLECTIONSeparate lists containing the names, employeeID numbers, and birth dates were provided toinsurance personnel for each study and refer-ent subgroup. Insurance folders were thenreviewed and the following information wasprovided back to the medical department bysubgroup: (a) a numerical personal identifierassigned by the Insurance Department, (b) foreach reported illness absence or admission tohospital, from one to five diagnoses abstractedfrom the physician's report and coded accord-ing to the International Classification ofDiseases, 9th revision, (ICD-9), and (c) anindication of retirement state and period(1953-9, 1960-9, 1970-89) in which the ill-ness episode occurred.The BKK separately provided an annual

frequency tabulation of the number of BKKmembers within each study and referent sub-group and also provided an annual tabulationof the number of retirees in each group. Thisinformation was used for calculation of person-years of observation by group and timeperiod. As retiree episodes were limited toadmissions to hospital, it was expected thatfewer episodes would be reported after retire-ment.

STATISTICAL APPROACHIn general, the outcome measure for acuteand non-specific conditions was the numberof illness episodes per time period peremployee, whereas chronic disease conditionswere classified on an ever or never basis.When multiple diagnoses were reported, eachwas associated with the specific episode in theanalyses. The selection of ICD categories wasmade a priori and was based largely on diseaseentities postulated to be related to TCDDexposure in the medical literature.Appendicitis is an exception in that this cate-gory was included on the basis of ICD fre-quency tabulations suggesting an unusualdistribution with respect to exposure state. Asecond exception was made for the categorypoisonings by non-medicinals. Based onreview of the text and time of the diagnoses, itwas realised that most of these episodesrelated to the immediate consequences ofoverexposure to TCDD after the accident.

Comparisons of disease conditions codedon an ever or never basis were made withFisher's exact test. An approximate statisticaltest for detecting differences in illness ratesbetween the exposed and referent groups wasbased on a comparison of directly standard-ised rates. Rates were standardised by periodbut not by employment state as the percent-age of person-years among retirees was rela-

tively constant across employee subgroups.The standard population was chosen to be thecombined study and referent groups. For agiven employee subgroup, the standardizedillness episode rate can be expressed asY i(Pi(T in j)/py ) where Pi represents the pro-portion of total person-years assigned to the illstratum within the standard population andwhere nij and pyi represent the number ofepisodes reported for the jil person in the illstratum and the observed person-years in theill stratum, respectively. The variance of nij isestimated as the variance of episode countsamong subjects within the ii stratum. Thecomparison of two rates was based on normaldistribution assumptions by a z score statisticformed as the difference in rates over thesquare root of the sum of the rate variances.

ResultsThe mean ages of the TCDD exposed andreferent groups in 1954 were 33-0 (SD 10.9)and 33 1 (11-0) years respectively. The agedistributions across chloracne subgroups werealso similar with the average age differing byno more than 1 9 years. The mean duration ofinsurance coverage varied from 25-2 to 31-8years across subgroups. The shorter meancoverage among exposed workers (27-8 years)compared with referents (30 7 years) resultedfrom greater membership of referents in theBKK as of late 1953 and fewer exposed work-ers remaining covered near the end of theobservation period. For the moderate chlo-racne subgroup, 12 fewer exposed than refer-ent workers were BKK members in 1989.

Geometric mean TCDD blood lipid con-centrations back calculated to date of expo-sure were lowest for the no chloracne (148ppt) and highest for the severe chloracne sub-group (1118 ppt). The broad range in the20th to 80th percentile concentrations(20-1279 ppt for the no chloracne group and493-2955 ppt for the severe chloracne sub-group) shows considerable overlap in TCDDexposures across subgroups. The geometricmean TCDD concentration among the 96people from the total cohort who wereexcluded from the present morbidity studywas 7-3 ppt, considerably less than that ofeven the no chloracne subgroup exposed toTCDD within one year of the accident.

ANALYSES BY EXPOSURE AND CHLORACNESTATETable 1 shows the percentage of exposed andreferent group members ever diagnosed withselected conditions. Higher percentages ofexposed workers were diagnosed with diseasesof the thyroid and appendicitis. For these dis-ease categories the differences between theexposed and referent groups were relativelyconstant across chloracne subgroups. Onlyone condition, diabetes mellitus, was foundsignificantly less often in the exposed groupthan among referents. This finding was largelydue to low percentages of workers with dia-betic conditions in the no chloracne andmoderate chloracne subgroups. A significantly

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Table I % ofTCDD and referent group members ever with selected morbidity diagnoses by chloracne state of TCDDgroup (1953-89)

People ever with diagnosis (%)

Total group No chloracne Moderate chloracne Severe chloracne

TCDD Referents TCDD Referents TCDD Referents TCDD ReferentsDisease category (ICD-9) (n=158) (n=161) (n=45) (n=48) (n=61) (n=61) (n=52) (n=52)

Malignant neoplasms(140-208) 14-6 11-2 8-9 8-3 19-7 13-1 13-5 11-5

Benign and unspecifiedneoplasms (210-229,235-239) 19-6 16 8 15-6 18-8 18-0 19 7 25-0 11 5

Diseases of the thyroid(240-246) 7.0* 1-2 6-7 0 0 8-2 1-6 5-8 1.9

Diabetes mellitus (250) 6-3 14-3* 2-2 18-8* 4 9 11-5 11-5 13-5Disorders of lipid metabolism

(272) 2-5 0-6 0.0 0.0 1-6 1-6 5-8 0.0Ischaemic heart disease

(410-414) 43 0 41-0 51-1 60-4 39-3 29-5 40 4 36-5Ulcer (531-534) 15-8 23-0 2-2 18-8* 26-2 21-3 15-4 28-9Appendicitis (540-543) 16-5** 5-6 20-0 6-3 14-8 4 9 15-4 5-8Chronic liver disease

(570-573) 26-0 23-0 15-6 20-8 29-5 24-6 30-8 23-1Nephritis and nephrosis

(580-589) 5-1 5-0 4-4 8-3 6-6 3-3 3.9 3.9Calculus of kidney and ureter

(592) 11-4 99 11*1 6-3 4-9 11-5 19-2 11-5Diseases of the sebaceous

glands (706) 10 1 8-7 0.0 8-3 6-6 13-1 23l1** 3.9

*p < 0 05; **p < 0-01 by Fishers two sided exact test.

lower frequency of ulcers was reported in sistent pattern was found for the no chloracnethe no chloracne subgroup compared with and moderate chloracne subgroups.referents and a marginally lower frequency of Table 3 shows cause specific illness rates.ulcers was reported in the severe chloracne The directly standardised rates were 18%subgroup. There was higher disability due to higher in the TCDD group for total episodesdiseases of the sebaceous glands in the severe (p = 0-002) and were also statisticallychloracne group, as expected. Benign and increased for the following categories: disor-unspecified neoplasms were marginally ders of peripheral nervous system and senseincreased in the severe chloracne subgroup organs, upper respiratory tract infections,with a positive diagnosis made for 25% of all other skin diseases, injury, and poisonings bysubgroup members. non-medicinals. The illness rate was also mar-

Table 2 summarises illness rates by expo- ginally increased for infectious and parasiticsure subgroup, time period, and employment diseases (p = 0-067). A single diagnosis entry(active v retired). There was a total of 10 335 was reported for 78-0% of the referent andillness absences or admissions to hospital 81-2% of the TCDD group episodes. Threeamong the 319 men studied. Illness rates were or more diagnoses were provided for 3-7% ofmuch lower among retired employees as only the referent and 2-9% of the TCDD groupadmissions to hospital have been reported. episodes. Multiple diagnoses were more likelyLess than 13% of the person-years of observa- to be reported in later years of the study.tion occurred, however, among retirees. Table 4 summarises subgroup compar-During active employment, illness rates isons. Only disease categories with one ordeclined over time in both the exposed and more statistically significant findings are pre-referent groups. Rates were highest in the sented. All but one of the findings pertain tosevere chloracne subgroup for each time the severe chloracne subgroup. Overall illnessperiod and after retirement as well. An incon- rates were 46% higher in this subgroup

Table 2 Illness episodes per 100 person-years by employment state, time period, and exposure group

Active employment Retired

Total period 1953-9 1960-9 1970-89 Total

Exposure group Rate (TE) Rate (TE) Rate (TE) Rate (TE) Rate (TE)

Total cohort:TCDD (n=158) 132-9 (5057) 156-2 (1338) 145-1 (1827) 111-9 (1892) 42-1 (244)Referents (n=161) 111-7 (4848) 133-5 (1258) 112-1 (1634) 100-8 (1956) 30-8 (186)

No chloracne:TCDD (n=45) 104-5 (1206) 120-9 (286) 115-1 (405) 91 0 (515) 19.1 (31)Referents (n=48) 109-6 (1455) 102-9 (300) 105-9 (483) 115-8 (672) 19.0 (38)

Moderate chloracne:TCDD (n=61) 138-1 (1756) 155-7 (520) 151-6 (705) 112-3 (531) 40-8 (108)Referents (n=61) 120-0 (1873) 163-1 (552) 128-5 (674) 92-8 (647) 34-2 (81)

Severe chloracne:TCDD (n=52) 151-9 (2095) 186-0 (532) 162-2 (717) 129-9 (846) 68 9 (105)Referents (n=52) 104-8 (1520) 130-1 (406) 100 1 (477) 96-2 (637) 39-9 (67)

TE=total episodes

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Table 3 Illness episodes per 100 person-years for selected disease categories (1953-89)

Episodes per 100 person years

TCDD ReferentsDisease category (ICD-9) * (n=158) (n=161) p Value

Total episodes 120-7 101-9 0-002Infectious and parasitic diseases (001-139) 3-0 2-2 0-067Mental disorders (290-317) 2-6 2-4 0-704Disorders of the central nervous system (320-349) 0-6 0-5 0-912Disorders of peripheral nervous system and sense organs

(350-389,781) 3-2 1-8 0-018Disorders of circulatory system except ischaemic heart

disease (392-404, 415-459) 10-3 9-4 0-488Total respiratory disease (460-519) 33-7 31-0 0-215Upper respiratory tract infections (460-478) 12-0 9-0 0-003Pneumonia and influenza (480-487) 17-4 18-8 0-078Chronic obstructive pulmonary disease (490-496) 8-0 7-5 0-306

Disorders of stomach and duodenum (535-537) 5-5 4-8 0-395Diseases of intestine and peritoneum (555-569) 3-8 3-1 0-202Other skin diseases (680-705, 707-709, 782) 6-7 3-7 0-001Arthropathies (710-719) 4-7 3-6 0-180Disorders of soft tissue (728-729) 2-1 1-9 0-608Symptoms and ill defined conditions (780-799) 5-8 5-5 0-624Injury (800-959) 19-5 15-7 0-008Poisonings by non-medicinals (980-989) 0-8 0-3 0-003

*When multiple diagnoses are reported for an episode, each represented disease category iscounted for the episode.tRates directly standardized to the overall distribution of person years by time period.

compared with referents. More than twofoldincreases were seen for several diseasecategories including infectious and parasiticdiseases. Total respiratory disease was

increased by 35%.

ANALYSES BY BACK CALCULATED TCDDCONCENTRATIONSecondary analyses were performed to exam-

ine the possible impact of high TCDD con-

centration ( 1000 ppt) on illness rates basedon comparisons with both the low TCDDsubgroup and referents. Frequency matchingby age was not possible in these analyses andthere were age differences among the groups.By contrast with a mean age of 33-1 yearsamong all referents in 1954, the average ageof the high TCDD subgroup was 35-5 yearsand that of the low TCDD subgroup was 30-8years. The highest mean age (37-4 years) was

for the 29 men in the subgroup with moderate

Table 4 Illness episodes per 100 person-years by exposure subgroup for disease categories with one or more statisticalfindings (p < 0-05)

Episodes per 100 person-yearst

No chloracne Moderate chloracne Severe chloracne

Disease category (ICD-9)t TCDD Referents TCDD Referents TCDD Referents

Total episodes 95 5 97-7 118-4 109-4 143-7** 98-0Infectious and parasitic diseases (001-139) 2-0 2-8 2-8 2-2 4-1** 1-7Mental disorders (290-317) 1-6 2-6 2-8 2-9 3-2* 1-5Disorders of peripheral nervous system and sense

organs (350-389, 781) 1-9 2-1 3-0 1-8 4-4* 1-6Total respiratory disease (460-519) 28-8 32-4 30-5 30-7 40-8* 30-2Upper respiratory tract infections (460-478) 8-4 9-1 11-1 95 15-8** 8-2Chronic obstructive pulmonary disease (490-496) 6-7 9 1 6-5 6-9 10-8* 6-7

Other skin disease (680-705, 707-709, 782) 4-5 4-1 4-6** 2-5 10-5** 4-7Poisonings by non-medicinals (980-989) 0 4 0-1 0-8 0-4 1-3** 0-2

*p<0-05; **p<0-01.tWhen multiple diagnoses are reported for an episode, each represented disease category is counted for the episode.$Rates directly standardized to the overall distribution of person-years by time period.

Table 5 Illness episodes per 100 person-years for selected disease categories (1 953-89)Episodes per 100 person-yearst

Back calculatedTCDD Severe chloracne Moderate chloracne No chloracne

Referentsp Cp1000ppt<1000ppt pt 1000ppt <1000ppt ]100pt <1000ppt

Disease category (ICD-9) * (n=73) (n=85) (n=161) (n=33) (n=19) (n=29) (n=32) (n=11) (n=34)

Total episodes 134-8 108-6 101-9 148-9 134-8 125-9 111-7 108-3 91 3Infectious and parasitic diseases (001-139) 4-2 2-0 2-2 4-8 3-0 3-5 2-1 3-9 1-4Mental disorders (290-317) 2-2 2-9 2-4 2-6 4-3 2-7 2-9 0-3 2-0Disorders of peripheral nervous system and

sense organs (350-389, 781) 3-3 3-0 1-8 49 3-6 1-6 4-3 2-3 1.7Disorders of circulatory system except

ischaemic heart disease (392-404,415-459) 10-4 10-2 9-4 11-2 9-8 10-9 11-2 6-7 9-3

Total respiratory disease (460-519) 35.9 31-7 31-0 38-3 45-2 34-9 26-5 29-2 28-6Upper respiratory tract infections

(460-478) 13-3 10-8 9 0 14-0 18-8 13-8 8-6 9-2 8-1Pneumonia and influenza (480-487) 18-0 16-9 18-8 19-0 18 6 17-2 14-2 15-7 18-3Chronic obstructive pulmonary disease

(490-496) 8-5 7 6 7-5 9-8 12-5 6-3 6-6 94 5-8Disorders of stomach and duodenum

(535-537) 7-8 3-6 4-8 7-6 7-0 7-9 40 7-3 1-3Diseases of intestine and peritoneum

(555-569) 4-3 3-4 3-1 3-3 4-6 5.1 2-0 5-4 3 8Other skin diseases (680-705, 707-709,

782) 7-9 5-6 3-7 11-0 9-6 4-7 4-5 5-5 4-2Arthropathies (710-719) 6-2 3-4 3-6 7-3 3-2 3.9 4-6 8-4 2-7Disorders of soft tissue (728-729) 2-3 1-9 1-9 2-9 2-5 1-3 2-9 2-5 0-8Symptoms and ill defined conditions

(780-799) 8-0 39 5-5 8-5 6-3 8-6 5.0 4-8 1-8Injury (800-959) 19-2 19-8 15-7 17-5 18-7 23-3 23-1 14-1 18-3Poisonings by non-medicinals (980-989) 1-0 0-6 0 3 1-4 1-1 1-0 0-5 0-0 0-5

*When multiple diagnoses are reported for an episode, each represented disease category is counted for the episode.tRates directly standardised to the overall distribution of person years by time period (no age standardisation was possible).

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chloracne and high TCDD concentrations.These age differences indirectly reflect ourprior finding that occurrence and severity ofchloracne is greater among younger employ-ees after controlling for TCDD concentra-tion.7 Bond et al (1989) had previously shownthat risk of chloracne was highest among menunder age 25.10The percentage of those ever diagnosed

with diseases of the thyroid was 8-2% (sixcases) in the high TCDD subgroup, v 5 9% inthe low TCDD subgroup and 1 2% amongreferents. A single case of thyroid adenomaalso occurred in a person with high TCDDexposure and severe chloracne. There were 14cases of appendicitis in the high TCDD(19-2%) group v 12 cases in the low TCDDgroup (14-1%) and nine cases among allreferents (5 6%). The percentages of diabeteswere 11 0% in the high TCDD group, 2-4%in the low TCDD group, and 14-3% amongreferents. The corresponding percentages forbenign and unspecified neoplasms were:24-7%, 15-3%, and 16-8% respectively.Chronic liver disease was marginally higher inthe high TCDD group: 31-5% v 21-2% in thelow TCDD group and 23-0% among refer-ents. Ischaemic heart disease percentageswere unrelated to TCDD concentration.

Table 5 summarises illness rates accordingto TCDD concentration across and withinchloracne subgroups. Overall rates increasedwith higher TCDD concentration in total andwithin each of the chloracne subgroups. Thepattern was similar for infectious and parasiticdiseases, disorders of the stomach and duode-num, and several other categories, but not forthe respiratory disease categories and mentaldisorders. These last categories were raised inassociation with chloracne state but not con-sistently with high TCDD concentration.

DiscussionIn this study, overall illness rates were posi-tively correlated with prior chloracne stateand were increased with higher TCDD con-centration within the chloracne subgroup.Increased rates were found throughout theobservation period and not just in the earlyyears after exposure. Rates were notablyhigher in the severe chloracne group overalland for infectious and parasitic diseases, sev-eral respiratory disease categories, disorders ofthe peripheral nervous system and senseorgans, mental disorders, and for other skindiseases. Consistency was shown for somedisease categories but not for others when thedata were subcategorised by back calculatedTCDD concentration. For example, episodesdue to mental disorders were associated withchloracne state but not high TCDD concen-tration.

Findings were positive for the skin, thyroid,immune system, and the central as well as theperipheral nervous system. Increased morbid-ity due to dermatological conditions occurredmainly in the severe chloracne subgroup. Theabsence of any insurance diagnoses attribut-able to diseases of the sebaceous glands in the

no chloracne group indicates that either thissubgroup was resistant to acne or that anyexisting acne among exposed workers hadbeen classified as chloracne in the occupa-tional medical records.

Eleven subjects were diagnosed with thy-roid disease in the TCDD cohort and onlytwo in the referent group. Unspecific goitrewas reported in four exposed and the two ref-erent cases. Four cases of thyrotoxicosis, twocases of hypothyroidism, and one case ofanother thyroid disorder were found amongTCDD exposed workers. These cases wereevenly distributed across chloracne sub-groups, but were somewhat more likely tooccur in the high TCDD group. Both cases ofhypothyroidism occurred in workers with ahigh TCDD concentration and moderate tosevere chloracne. A single case of thyroid ade-noma was also reported in the severe chlo-racne, high TCDD, subgroup. Concernsabout possible TCDD effects on thyroid func-tion have been raised based on mechanisticarguments and experimental studies."-'3 Aclear understanding of the mechanismsthrough which TCDD could influence thecomplex thyroid regulatory system and howthese effects might be expressed as humandisease is presently lacking. McKinney andPedersen have modelled the effect ofTCDD-like materials competing for thyroid hormonebinding sites and have suggested that thiscould lead to varying degrees of hypothy-roidism.'4 Thyroid hormone economy couldalso be disrupted by increased metabolismdue to hepatic microsomal enzyme induc-tion.'5 Capen also discussed how loss of thy-roid hormone economy could lead to chronichypersecretion of thyroid stimulating hor-mone (TSH) and an increased incidence offollicular cell tumours.'5 The Ah-receptormediated toxicity ofTCDD could also play apart, for instance, through induction of thy-roxin binding globulin (TBG) synthesis in theliver. We have shown TBG to be positivelyassociated with internal TCDD dose in thissame population.'6 Serum thyroxine was alsoincreased and marginal increases in both TSHand serum thyroxine were found among olderworkers with back calculated TCDD concen-trations above 1000 ppt.Our findings of increased morbidity due to

infectious and parasitic diseases in the severechloracne subgroup and in the high TCDDgroup are consistent with reduced host resis-tance, but may also reflect differences ininsurance utilisation. Within the severe chlo-racne subgroup, much of the overall differ-ence was accounted for by one diseasesubcategory, ill defined intestinal infections.Within this subcategory there were 37episodes among 15 different people in thesevere chloracne subgroup and only 13episodes among 10 different people in thereferent group. More episodes involvingmycoses, particularly tinea pedis (athlete'sfoot) were also reported among those exposedto TCDD. For most other infectious diseasesthere were no notable differences in the fre-quency of diagnosis. There were five workers

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in the high TCDD group diagnosed withtuberculosis or late effects of tuberculosiscompared with no cases among employees inthe low TCDD group and three cases amongall referents. There were no specific diagnosesof disorders involving the immune mechanism(ICD-9 279) among either exposed employ-ees or referents.

There was nearly a twofold differential inrates of upper respiratory tract infectionsbetween employees with severe chloracne andtheir referents. The relative rate differentialheld throughout the observation period,although absolute rates in both groupsdeclined steadily over time. Upper respiratorytract infection rates were not consistentlyincreased in the high TCDD subgroups, how-ever. Again there is a possibility that differ-ences in medical care utilisation rates betweenthe exposed and referent groups could biasthe findings. For example, those in theexposed group and, in particular, in the severechloracne subgroup, may have been moreprone than referents to seek medical attentioneither because of their concerns about longterm sequelae from exposure or because ofmedical counselling.By contrast with the findings for these two

categories, the percentage of employees everdiagnosed with appendicitis was increasedacross all chloracne subgroups. The 26 caseswere nearly equally distributed by subgroup,but tended to occur in the earlier time peri-ods. There were 23 exposed v five referentcases before 1970 and three exposed v fourreferent cases after that date. Within eachchloracne subgroup, cases were more likelyamong men with estimated TCDD concen-trations above 1000 ppt. The relevance ofthese findings to exposure to TCDD isunclear. Generally, the diagnosis of appen-dicitis should be verified histologically andthis was not possible here. The intestine playsa part both in metabolising xenobiotics andin immunological protection of the host.Because faeces possibly containing lipid solu-ble compounds may remain much longer inthe appendix than in the intestinal lumen andthe concentration of immunocompetent tissueis very high in the appendix, these unantici-pated findings would be plausible if TCDDwas specifically toxic to this tissue. Othermechanisms of action may also explain ourfindings. More important is the need to con-firm the findings in other TCDD exposedpopulations.

In all exposure subgroups and among thereferents, there was no indication of an inter-action between the occurrence of appendicitisand that of either upper respiratory tractinfections or other infectious diseases. Inother words, the occurrence of upper respira-tory tract infections was independent ofwhether or not the same person had beendiagnosed with appendicitis. There were alsono differences in rates of influenza among theexposure subgroups. A somewhat higherpneumonia rate based on 17 cases was seen inthe severe chloracne group: 1 1 v 0-6 episodesper 100 person-years among referents. The

corresponding rate for the high TCDD groupwas 1 0 episodes per 100 person-years.

Although there have been several clinicalinvestigations of immune system indices (forexample, lymphocyte subset populations,immunoglobulins, and delayed hypersensitiv-ity tests), we are unaware of human studiesthat have specifically examined infectious dis-ease rates in exposed populations. There havebeen some reports correlating respiratorysymptoms and the concentration of polychlo-rinated biphenyls in blood.'7 18 It is generallydifficult to show immunotoxic effects of xeno-biotics on occurrence of infectious diseasebecause of a remarkable functional reservecapacity in immune response.'9 Although ourfindings are not consistent across a range ofinfectious diseases, it is also difficult toattribute all the positive findings to confound-ing or observation bias.

Regarding mental diseases and peripheralnervous system diseases, increased episodes ofillness for the total exposed cohort were seenonly for disorders of the peripheral nervoussystem and sense organs. Review of diagnosesin this category showed that 13% of theexposed group episodes were for repeat occur-rences of trigeminal nerve disorder in oneworker from the severe chloracne subgroup.Eye and ear disorders accounted for about50% of the total episodes. There was only onediagnosis of peripheral neuropathy (ICD-9356) in the severe chloracne subgroup andthis person was also diagnosed as diabetic.Our findings are thus consistent with theresults of cross sectional studies of TCDDexposed workers, which found no evidence ofincreased occurrence of peripheral neuro-pathy.20 21

Within the severe chloracne subgroup therewas a statistical increase in episodes due tomental disorders. More than 50% of theepisodes related to ICD-9 306, a categoryincluding physiological malfunction arisingfrom mental factors but not secondary to psy-chiatric disorders. The individual episodeswere spread across subjects rather than beingconcentrated in only a few people. Someemployees with severe chloracne have beensubject to both persistent and disfiguringlesions. This could explain the associationwith severity of chloracne but not with highTCDD concentration itself. Taken as awhole, the pattern of mental and peripheralnervous system disorders seen in this studyprovides no concrete evidence linking specificpathological entities to TCDD exposure butsuggests that more frequent episodes of abroad range of mental or nervous system dis-orders may be linked to high TCDD expo-sure.Among other disease categories the most

noteworthy finding was a marginal increase inbenign and unspecified neoplasms within thesevere chloracne subgroup. The 13 casesincluded one adenoma of the thyroid, oneangioma, four neoplasms of the digestive sys-tem (three benign and one of uncertainbehaviour), and seven neoplasms of unspeci-fied sites (one benign and six of unspecified

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nature). Only one of these 13 employees was

later diagnosed with a malignant neoplasm (aleukaemia). There was no significant increasein the number of malignant neoplasms in thetotal population or in any of the subgroups. Inthe earlier mortality study, an increase ofmalignancy related deaths was seen amongthose with chloracne allowing for a 20 yearlatency.6

Questions have been raised about TCDDcausing liver disease, ulcer, ischaemic heartdisease, and disorders of lipid metabolism as

well as diabetes. For ulcer and diabetes we

found no increased frequency of occurrence

within the total exposed population, no

increasing frequency with chloracne severity,and the high TCDD group had no increasesrelative to controls. For ischaemic heart dis-ease there were no differences based on expo-sure state, severity of chloracne, or

concentration of TCDD. Three of the fivecases of disorders of lipid metabolism in thecombined study and referent groups did occur

among men in the high TCDD group. Forchronic liver disease there were marginalincreases in the percentage of cases in thetotal exposed group, in the moderate andsevere chloracne subgroups, and in the highTCDD group. It is not possible, however, todraw firm conclusions from these limitedfindings. A proper interpretation of this studycan only be made in the light of findings fromthe mortality study, which is currently beingupdated, and clinical laboratory studies,which are also being completed among surviv-ing members of the study population.

We thank Professor Sir Richard Doll, Oxford, England andProfessor Harvey Checkoway, Seattle, Washington USA, fortheir comments and suggestions regarding our draft manu-script and Mr Schimbeno and his staff with the BASF HealthInsurance Fund for abstraction and coding of the medicalinsurance data.

1 NN. Hautschadigungen durch unbekannte Zersetzungs-produkte. BASF, Ludwigshafen. Arbeitsschutz im Werk1954;3:11-2.

2 Hoffmann H. Neue Erfahrungen mit hochtoxischenChlorkohlenwasserstoffen. Archiv fur experimentellePathologie und Pharmakologie 1957;232:228-30.

3 Goldmann P. Schwerste akute Chlorakne durch Trichlor-phenol-Zersetzungsprodukte. Arbeitsmedizin, Sozial-medizin, Arbeitshygiene 1972;7:12-8.

4 Kimmig J, Schulz KH. Chlorierte aromatische zyklischeAther als Ursache der sogenannten Chlorakne. Natur-wissenschaften 1957;44:337-8.

5 Thiess AM, Frentzel-Beyme R, Link R. Mortality study ofpersons exposed to dioxin in a trichlorphenol-processaccident that occurred in the BASF AG on November17, 1953. AmJ'Ind Med 1982;3:179-89.

6 Zober A, Messerer P, Huber P. Thirty-four-year mortalityfollow-up of BASF employees exposed to 2,3,7,8-TCDD after the 1953 accident. Int Arch Occup EnvironHealth 1990;62:139-57.

7 Ott MG, Messerer P, Zober A. Assessment of past occupa-tional exposure to 2,3,7,8-TCDD using blood lipidanalysis. Int Arch Occup Environ Health 1993;65:1-8.

8 Pirkle JL, Wolfe WH, Patterson DG, Needham LL,Michalek JE, Miner JC, et al. Estimates of the half-life of2,3,7,8-tetrachlorodibenzo-p-dioxin in Vietnam veteransof Operation Ranch Hand. 7 Toxicol Environ Health1989;27:165-71.

9 Suskind RR. Chloracne, "The hallmark of dioxin intoxica-tion". ScandJI Work Entvron Health 1985;11:165-71.

10 Bond GG, McLaren EA, Brenner FE, Cook RR.Incidence of chloracne among chemical workers poten-tially exposed to chlorinated dioxins. J Occup Med 1989;31:771-4.

11 Potter CL, Moore RW, Inhorn SL, Hagen TC, PetersonRE. Thyroid status and thermogenesis in rats treatedwith 2,3,7,8-tetrachlorodibenzo-p-dioxin. Toxicol ApplPharmacol 1986;84:45-55.

12 McKinney JD, Chae K, Oatley SJ, Blake CCF. Molecularinteractions of toxic chlorinated dibenzo-p-dioxins anddibenzofurans with thyroxine binding prealbumin. JMed Chem 1985;28:375-81.

13 Gorski JR, Muzi G, Wever LWD, Pereira DW, Arceo RJ,Iatropoulos MJ, Rozman K. Some endocrine and mor-phological aspects of the acute toxicity of 2,3,7,8-tetra-chlorodibenzo-p-dioxin (TCDD). Toxicol Pathol 1988;16:313-20.

14 McKinney JD, Pedersen LG. Do residue levels of poly-chlorinated biphenyls (PCBs) in human blood producemild hypothyroidism? J Theor Biol 1987;129:231-41.

15 Capen CC. Pathophysiology of chemical injury of the thy-roid gland. Toxicol Lett 1992;64-65:381-8.

16 Zober A, Ott MG, Messerer P, Germann C. Laboratoryresults for selected target organs in 138 individuals occu-pationally exposed to TCDD. presented to: Dioxin '9313th international symposium on chlorinated dioxins andrelated compounds, 20-24 September, Vienna, 1993.

17 Kuratsume M. Yusho, with reference to Yu-Cheng. In:Kimbrough RD, Jensen AA, eds. Halogenated biphenyls,terphenyls, naphthalenes, dibenzodioxins and related prod-ucts. Amsterdam: Elsevier Sci Publ, 1989:381-400.

18 Shigematsu N, Ishimura S, Saito R, Ikeda T, Matsuba K,Sugiyama K, Masuda Y. Respiratory involvement inpolychlorinated biphenyls poisoning. Entiron Res 1978;16:92-100.

19 Fischbein A, Tarcher AB. Disorders of the immune sys-tem. In: Tarcher AB ed. Principles and practice of environ-mental medicine. New York: Plenum Medical, 1992:389-411.

20 Sweeney MH, Fingerhut MA, Arezzo JC, Hornung RW,Conally LB. Peripheral neuropathy after occupationalexposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD).AmJ Ind Med 1993;23:845-58.

21 Alderfer R, Sweeney MH, Fingerhut MA, Patterson JrDG, Turner WE, Conally LB, et al. Serum levels ofPCDDs and PCDFs among workers exposed to 2,3,7,8-TCDD contaminated chemicals. Chemosphere 1992;25:247-50.

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