to 2,3,7,8-tetrachlorodibenzo-pdioxin

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1 270 Divisio of Surveillace, Hazard Evaluatios ad Field Studies, Natioal Istitute for Occupatioal Safety ad Health, Ceters for Disease Cotrol ad Prevetio, Ciciati, Ohio, USA G M Calvert M H Sweeey J Deddes DKWall Correspodece to: Dr GeoVrey M Calvert, Natioal Istitute for Occupatioal Safety ad Health, 4676 Columbia Parkway, R-21, Ciciati, OH 45226, USA. Telephoe ; fax ; JAC6@CDC.GOV Accepted 12 November 1998 Evaluatio of diabetes mellitus, serum glucose, ad thyroid fuctio amog Uited States workers exposed to 2,3,7,8-tetrachlorodibezo-p-dioxi GeoVrey M Calvert, Marie Harig Sweeey, James Deddes, David K Wall Abstract Objective Some studies suggest that exposure to 2,3,7,8-tetrachlorodibezo-pdioxi (TCDD) may avect glucose metabolism ad thyroid fuctio. To further assess the relatio betwee exposure to TCDD ad edocrie fuctio, data from the largest morbidity study of idustrial workers exposed to TCDD were examied. Methods A cross sectioal study of workers employed >15 years earlier i the maufacture of 2,4,5-trichloropheol or oe of its derivatives at two Uited States chemical plats was coducted. The referet group cosisted of people with o occupatioal exposure to pheoxy herbicides ad were recruited from the eighbourhoods where the workers lived. Results A total of 281 workers ad 260 uexposed referets participated. The mea curret serum lipid adjusted TCDD cocetratio amog workers was 220 pg/g lipid, ad amog referets was 7 pg/g lipid (p<0.05). The half life extrapolated TCDD cocetratios (the estimated TCDD cocetratio whe occupatioal exposure to TCDD stopped) amog workers averaged 1900 pg/g lipid (rage: ot detected pg/g lipid). Overall, the prevalece of diabetes mellitus was ot sigificatly diveret betwee the workers ad referets. Also, there was ot a sigificat positive tred betwee prevalece of diabetes ad icreasig serum TCDD cocetratio. However, diabetes was foud i six of 10 (60%) workers with curret serum TCDD cocetratios >1500 pg/g lipid. After excludig subjects beig treated for diabetes, workers i the group with the highest half life extrapolated TCDD cocetratios had a sigificatly icreased adjusted mea serum glucose cocetratio compared with referets (p=0.03). Workers were also foud to have a sigificatly higher adjusted mea free thyroxie idex compared with referets (p=0.02), especially amog workers i the group with the highest half life extrapolated TCDD cocetratios. However, o evidece was foud that workers exposed to TCDD were at icreased risk of thyroid disease. Coclusios These fidigs provide modest evidece that exposure to TCDD Occup Eviro Med 1999;56: may avect thyroid fuctio ad glucose metabolism. (Occup Eviro Med 1999;56: ) Keywords: dioxi; diabetes mellitus; thyroid fuctio tests; cross sectioal study Small quatities of dioxis ca be foud throughout the developed world. As such, cocer about the toxicity of these dioxis cotiues to be widespread. 2,3,7,8-Tetrachlorodibezo-p-dioxi (TCDD) is the best studied ad is amog the most toxic dioxi cogeers. Amog the cocers are evects o edocrie fuctio. Some huma evidece idicates that TCDD may avect glucose metabolism, maifestig as hyperglycaemia. Amog the previous studies that examied the associatio betwee exposure to TCDD ad serum glucose cocetratio, 1 4 both of the studies that used serum TCDD cocetratio as the exposure measure foud positive associatios. 1 3 Amog three studies of cohorts exposed to TCDD that reported mortality risk for diabetes mellitus, 5 7 oly the study of Pesatori et al foud a sigificat icrease i risk. 5 Although there is also huma evidece for a TCDD evect o thyroid fuctio, it is icosistet. Amog the four studies that examied the associatio betwee exposure to TCDD ad evects o the thyroid glad, exposure to TCDD was sigificatly associated with icreases i serum thyroxie (total T 4 ) cocetratio i oe study, 3 ad with decreases i total T 4 cocetratio i aother. 8 Oly oe study foud a icreased prevalece of thyroid disease. 2 Noe of the studies reported a sigificat associatio betwee TCDD ad cocetratios of thyroid stimulatig hormoe (TSH). To further assess the relatio betwee exposure to TCDD ad edocrie fuctio, we examied data from the largest cross sectioal morbidity study of idustrial workers exposed to TCDD. Materials ad methods The details of the study desig were previously described. 9 I summary, this study compared a uexposed compariso group with livig workers employed >15 years earlier i the productio of 2,4,5-trichloropheol or oe of its derivatives, which were substaces cotamiated with TCDD. The workers were employed i oe of two plats located i Newark,

2 Edocrie outcomes amog workers exposed to TCDD 271 New Jersey, ad Veroa, Missouri. Four hudred ad iety eligible workers were employed at the New Jersey factory from 1951 to the ed of 1969 i the productio of 2,4,5- trichloropheol or oe of its derivatives. At the facility i Veroa, Missouri, 96 eligible workers were ivolved i the productio of 2,4,5- trichloropheol or oe of its derivatives. Productio occurred for about four moths i 1968 ad from April 1970 to Jauary Both plats produced various other chemicals, oe of which are kow or suspected to avect thyroid fuctio or glucose metabolism. To costitute the referet group, oe perso with o self reported occupatioal exposure to substaces cotamiated with TCDD was sought from withi the residetial eighbourhood of each worker, who matched the worker by age (withi 5 years), race, ad sex. The study protocol was approved by the Natioal Istitute for Occupatioal Safety ad Health (NIOSH) Huma Subjects Review Board ad iformed coset was obtaied from each of the participats. Iformatio o worker ad referet health status was collected through a comprehesive set of stadardised iterviews ad medical examiatios betwee 1987 ad A lifetime medical history was elicited from each participat with iterviewer admiistered questioaires. To reduce observer bias, all people coductig the medical histories, examiatios, ad tests were blid to the exposure (worker or referet) of the participat. Blood was obtaied from the participats after a 12 hour fast. The serum was aalysed for TCDD, 10 glucose, TSH, total T 4, ad thyroid hormoe bidig resi (THBR[T 3 ]). If the iitial fastig serum glucose cocetratio was >7.8 mmol/l, additioal blood was obtaied the ext morig after aother 12 hour fast to remeasure serum glucose. Diabetic subjects takig hypoglycaemic medicatios were permitted to take their prescribed dose. Glucose was measured with a stadard adaptatio (Ektachem, Kodak) of the glucose oxidase peroxidase chromoge coupled system for glucose determiatio i biological fluids. 11 Total T 4 was measured with a atibody radioimmuoassay system (Becto Dickiso), ad TSH was measured with a stadard double atibody radioimmuoassay system (the lower detectio limit was 0.5 mu/l)(becto Dickiso). Thyroid hormoe bidig resi was measured with the automated Aria HT T 3 uptake assay (Becto Dickiso). The free T 4 idex was calculated because it is cosidered to be a useful screeig test for thyroid dysfuctio. 12 For each participat, the free T 4 idex was calculated as the product of the THBR[T 3 ] ad serum T 4 cocetratio. Two participats (oe worker, oe referet) did ot have their blood sampled. CASE DEFINITIONS A participat was defied as havig diabetes mellitus if the fastig serum glucose cocetratio was >7.8 mmol/l o both days, 13 or if the participat reported a history of diabetes diagosed by a physicia. Medical records were ot obtaied to cofirm self reported diabetes. Thyroid disease was defied as a self reported history of a thyroid disorder diagosed by a physicia (giotre, thyroid problems, or Graves disease). Thyroid stimulatig hormoe was icreased if >6.5 mu/l (the TSH assay lacked sesitivity to detect cliically low TSH cocetratios), T 4 was icreased if >154.4 mol/l, ad T 4 was low if <57.9 mol/l. 14 The free T 4 idex was cosidered to be outside the referece rage if it was above the 95th percetile (34.25 mol/l) or below the 5th percetile (20.07 mol/l) of the referet group. ANALYSIS OF DATA Studet s t tests were used i the aalysis of cotiuous demographic characteristics. χ 2 Statistics were used to compare categorical demographic characteristics ad to evaluate for the presece of participatio bias. To evaluate the associatio betwee exposure to TCDD ad categorical outcome measures, logistic regressio aalyses were performed. Multiple liear regressio aalyses were used to examie cotiuous outcome measures. A log trasformatio was applied to glucose to ormalise the residuals. Cofouders for each outcome were idetified before the start of the aalysis by a review of the literature. The regressio model for diabetes mellitus icluded age, race, sex, body mass idex (BMI, weight i kg divided by height squared i m), history of diabetes amog parets or sibligs, ad curret use of medicatios that ca icrease serum glucose. The model for glucose icluded age, race, sex, body mass idex, ad curret use of medicatios that ca icrease serum glucose. The regressio models for TSH, T 4, ad free T 4 idex icluded age, race, sex, ad curret use of medicatios that ca alter the particular thyroid test. For each of the aalyses, some participats were excluded iitially. The two participats (oe worker, oe referet) who did ot have their blood sampled were excluded from all of the aalyses. Those diagosed with diabetes before the date of first hire ito processes cotamiated with TCDD were excluded from aalysis of diabetes mellitus (oe worker, oe referet). Those uder treatmet for diabetes mellitus were excluded from the aalyses of glucose cocetratio (18 workers, 15 referets). Four participats (two workers, two referets) o thyroid replacemet medicatios were excluded from the aalyses of TSH, T 4, ad free T 4 idex cocetratios. I each model, the liearity assumptio was checked for all cotiuous idepedet variables. Variables determied to be o-liear i oe or more models icluded BMI, curret serum TCDD, ad half life extrapolated lipid adjusted TCDD (the estimated TCDD cocetratio whe occupatioal exposure to TCDD stopped, which was calculated to reflect the 7 year estimated half life of the serum TCDD cocetratio 15 ). Variables foud to be o-liear were stratified based o the origial cut ov poits. Separate regressio aalyses were coducted with each of three exposure idices i separate models: status as a worker or a referet (a

3 272 Calvert, Sweeey, Deddes, et al Table 1 Characteristics of the study populatio by lipid adjusted TCDD i serum samples (pg/g lipid) dichotomous exposure variable), curret serum TCDD cocetratios measured at the time of examiatio ad adjusted for serum lipid cocetratio, ad half life extrapolated lipid adjusted serum TCDD cocetratios separately calculated for each worker. The workers were stratified before the start of the aalyses ito four groups of about equal size based o serum TCDD cocetratios. Serum TCDD cocetratios were ot obtaied for eight workers ad these workers were excluded from aalyses ivolvig serum TCDD cocetratios ad half life extrapolated serum TCDD cocetratios. Each group of exposed workers was compared with the uexposed referet group, ad either odds ratios (ORs) (with 95% cofidece itervals (95% CIs)) or p values are provided. Mea (SD) age (y) White (%) Me (%) BMI >29 (%) Mea (SD) TCDD cocetratio (pg/gm lipid) Referets (<20) (10.5) (2) All workers (10.3) (434)* TCDD< (9.0) * (5) 20<TCDD< (10.4) (16) 75<TCDD< (9.6) (45)* 238<TCDD< (10.0)* * (674)* *p<0.05 v the uexposed referet group. TCDD=2,3,7,8-tetrachlorodibezo-p-dioxi. The umber of all workers is greater tha the sum of the four subcategories of workers. This is because the group of all workers icludes eight workers for whom serum TCDD was ot measured. Table 2 Cases of diabetes ( (%)) by diagostic criteria Physicia diagosed* Fastig serum glucose >7.8 (mmol/l) Total Workers (=279) 17 (6.1) 9 (3.2) 26 (9.3) Referets (=258) 15 (5.8) 3 (1.2) 18 (7.0) Oe worker ad oe referet were excluded because the date of diagosis preceded the date of first hire ito TCDD cotamiated processes (i the case of the referet the diagosis date preceded the matched worker s date of first hire ito TCDD cotamiated processes). Also, two participats (oe worker ad oe referet) did ot have their blood sampled ad were excluded. *Self reported history of physicia diagosed diabetes mellitus. These participats did ot self report a history of physicia diagosed diabetes mellitus. Table 3 Adjusted OR for diabetes mellitus by TCDD i serum samples (pg/g lipid) Proportio with diabetes mellitus (%) Adjusted OR* (95% CI) Referets (<20) All workers (0.77 to 2.91) TCDD< (0.77 to 5.75) 20<TCDD< (0.53 to 4.27) 75<TCDD< (0.17 to 2.57) 238<TCDD< (0.79 to 4.90) TCDD=2,3,7,8-tetrachlorodibezo-p-dioxi. *Adjusted for race, sex, age, BMI, family history of diabetes mellitus, ad curret use of medicatios that ca icrease serum glucose cocetratio. Two referets were excluded (oe because blood was ot draw ad aother because the referet s date of diagosis preceded the matched worker s date of first hire ito TCDD cotamiated processes). The umber of all workers is greater tha the sum of the four subcategories of workers. This is because the group of all workers icludes seve workers for whom serum TCDD was ot measured. Two workers were excluded from the all worker category (oe because blood was ot sampled ad aother because the date of diagosis preceded the worker s date of first hire ito TCDD cotamiated processes). No importat iteractios betwee other covariates ad exposure to TCDD were idetified. All logistic models seemed to have adequate fit. 16 All aalyses were carried out with SAS procedures (SAS Istitute, Cary, North Carolia, USA). Results Of the 586 workers at the two plats who were eligible for the study, 400 (68.3%) were foud to be alive ad could be located. A total of 142 (24.2%) workers were dead, ad 44 (7.5%) could ot be located. From the two plats, all 400 workers who were livig ad could be located were ivited to participate i the study; 281 (70%) were examied. A total of 938 referets were ivited to participate i the study, of whom 260 (28%) were examied. Descriptive iformatio o the study cohort is provided i table 1. Workers were foud to have a sigificatly icreased mea curret serum lipid adjusted TCDD cocetratio (workers=220 pg/g lipid (rage=ot detected 3400 pg/g lipid, media=68 pg/g lipid), referets=7 pg/g lipid (rage=ot detected 20 pg/g lipid), p<0.001). Half life extrapolated lipid adjusted serum TCDD cocetratio were also icreased amog workers (mea=1900 pg/g lipid, media=476 pg/g lipid). Overall, there were o sigificat divereces or cosistet patters of divereces betwee workers ad referets for ay demographic characteris- Table 4 Adjusted geometric mea serum glucose cocetratio by TCDD i serum samples (pg/g lipid) Adjusted geometric mea glucose cocetratio* (mmol/l) (GSE) * Referets (<20) (1.01) All workers (1.01) 0.16 TCDD< (1.02) <TCDD< (1.02) <TCDD< (1.02) <TCDD< (1.02) 0.12 TCDD=2,3,7,8-tetrachlorodibezo-p-dioxi, GSE=geometric stadard error of the adjusted geometric mea. *Adjusted for race, sex, age, BMI, ad curret use of medicatios that ca icrease serum glucose cocetratio. The p values are for the compariso betwee the worker group ad the referets. To calculate the 95% CI, the upper boud=geometric mea*(gse) 1.96, ad the lower boud=geometric mea* (1/ GSE 1.96 ). 16 Referets were excluded (15 were receivig treatmet for diabetes mellitus, ad oe did ot have blood sampled). The umber of all workers is greater tha the sum of the four subcategories of workers. This is because the group of all workers icludes seve workers o whom serum TCDD was ot measured. 19 Workers were excluded from the all worker category (18 were receivig treatmet for diabetes mellitus, ad oe did ot have blood sampled).

4 Edocrie outcomes amog workers exposed to TCDD 273 Table 5 Adjusted geometric mea serum glucose cocetratio by half life extrapolated TCDD i serum samples Half life extrapolated (pg/g lipid) Adjusted geometric mea glucose cocetratio* (mmol/l)(gse) * Referets (<20) (1.01) Workers-all (1.01) 0.16 TCDD< (1.02) <TCDD< (1.02) <TCDD< (1.02) <TCDD< (1.02) 0.03 TCDD=2,3,7,8-tetrachlorodibezo-p-dioxi, GSE=geometric stadard error of the adjusted geometric mea. *,, See foototes for table 4. Table 6 (pg/gm lipid) tics (age, race, sex) idetified as cofouders. Workers i the group with the highest serum TCDD cocetratios were older ad a higher proportio were me compared with the referet group. Amog the examied participats, 26 (9.3%) workers ad 18 (7.0%) referets met the case defiitio for diabetes (table 2). Table 3 provides the logistic regressio aalysis fidigs for diabetes mellitus. The risk for diabetes mellitus amog exposed workers was ot foud to be sigificatly icreased (adjusted OR 1.49, 95% CI 0.77 to 2.91). No dose respose tred with serum TCDD was foud. The fidigs were similar for the half life extrapolated serum TCDD cocetratios (data ot show). However, it should be oted that amog the 10 workers with serum TCDD cocetratios >1500 pg/g lipid (ad amog the 10 workers with half life extrapolated serum TCDD cocetratios over pg/g lipid), six (60%) had diabetes mellitus. Recetly, the Expert Committee of the America Diabetes Associatio lowered the diagostic criterio for diabetes from 7.8 to 7.0 mmol/l. 17 We reaalysed our data with these ew criteria. Whe we classified as diabetic all participats with iitial serum glucose cocetratios of >7.0 mmol/l, the fidigs were essetially uchaged from those usig the iitial defiitio for diabetes. Tables 4 ad 5 provide the results of the liear regressio aalyses for serum glucose cocetratio. Serum glucose cocetratios were ot sigificatly diveret betwee exposed workers ad referets (p=0.16). Also, o doserespose tred with serum TCDD was foud. However, workers i the group with the highest half life extrapolated serum TCDD cocetratios had a sigificatly icreased adjusted mea serum glucose cocetratio compared with referets (p=0.03, table 5). Whe the three participats (two workers ad oe referet) with glucose cocetratios >10 mmol/l were removed, this icrease was o loger sigificat (p=0.29). Oly three participats (two workers ad oe referet) self reported a history of thyroid disorder that was diagosed after the start of employmet i a process cotamiated with TCDD. The specific type of thyroid disorder experieced by these participats is ukow; however, two were curretly receivig thyroid replacemet medicatio, ad the third reported admissio to hospital for the thyroid coditio that required uclear medicie. Tables 6 ad 7 provide the liear regressio fidigs for the thyroid fuctio measures. Workers were foud to have a sigificatly higher adjusted mea free T 4 idex tha referets (p=0.02). Although there was ot a clear dose-respose tred with either serum measure of exposure to TCDD, workers i the group with the highest half life extrapolated serum TCDD cocetratios had the highest adjusted mea free T 4 idex, which was sigificat whe compared with the referet mea (p=0.004, table 7). With curret serum TCDD cocetratios, workers i the group with the third highest TCDD cocetratios ( pg/g lipid) had the highest adjusted mea free T 4 idex (table 6). However, a higher proportio of referets tha workers had a free T 4 idex cocetratio above the referece rage (workers 3.0%, referets 5.1%, adjusted OR 0.58, 95% CI 0.24 to 1.43), ad below the referece rage (workers 2.2%, referets 5.1%, adjusted OR 0.41, 95% CI 0.15 to 1.11). Also, each of the worker groups had a lower proportio with out of rage free T 4 idex cocetratios tha the referet group (data ot show); however, oe of the divereces were sigificat. Workers also had a higher adjusted mea total T 4 cocetratio tha referets (p=0.07, tables 6 ad 7). Although each of the worker Adjusted mea TSH, T 4, ad free T 4 idex (FTI) by i serum samples TSH (mu/l) T 4 (mol/l) FTI (mol/l) Adjusted mea* (SE) Adjusted mea (SE) Adjusted mea (SE) Referets (<20) (0.13) 98.8 (1.05) 26.8 (0.28) All workers (0.13) (1.01) (0.27) 0.02 TCDD< (0.25) (1.99) (0.54) <TCDD< (0.26) (2.09) (0.56) <TCDD< (0.26) (2.09) (0.56) <TCDD< (0.27) (2.16) (0.58) 0.19 TCDD=2,3,7,8-tetrachlorodibezo-p-dioxi, SE=stadard error of the adjusted mea. *Adjusted for race, sex, age, ad curret use of medicatios that ca alter TSH. The p values are for the compariso betwee the worker group ad the referets. Adjusted for race, sex, age, ad curret use of medicatios that ca alter T 4. The p values are for the compariso betwee the worker group ad the referets. Three referets were excluded (oe because blood was ot sampled ad two because they were takig thyroid replacemet medicatio). The umber of all workers is greater tha the sum of the four subcategories of workers. This is because the group of all workers icludes seve workers o whom serum TCDD was ot measured. Three workers were excluded from the all worker category (oe because blood was ot sampled ad two because they were takig thyroid replacemet medicatio).

5 274 Calvert, Sweeey, Deddes, et al Table 7 Halflife extrapolated (pg/g lipid) Adjusted mea TSH, T 4, ad free T 4 idex (FTI) by half life extrapolated i serum samples groups had a higher adjusted mea total T 4 tha the referet group, oe of the differeces was sigificat, ad a dose-respose tred was ot foud with either measure of exposure to TCDD. Oly two participats (both referets) had low T 4 cocetratios, ad oly two participats (both workers) had icreased T 4 cocetratios. For TSH cocetratio, little diverece was foud betwee workers ad referets (tables 6 ad 7). Oly seve participats had icreased TSH cocetratios (three workers ad four referets). Discussio Our study does ot provide strog evidece that exposure to TCDD is associated with a icreased risk of diabetes mellitus. However, diabetes was foud i a high proportio (60%) of workers with curret serum TCDD cocetratios >1500 pg/g lipid. This fidig suggests that workers with very high TCDD body burdes may have a icreased risk of diabetes mellitus. It should be oted that data collected from 211 workers while still workig at the two study plats showed that the mea BMI was sigificatly higher amog the six diabetic workers with TCDD cocetratio >1500 pg/g lipid compared with all other workers (p=0.002) ad the other diabetic workers (p=0.03). However, with data from our study, o divereces were foud i BMI betwee these three groups of workers. Although atecedet obesity is a kow risk factor for diabetes, 18 it is ulikely that the higher BMIs completely explai the high proportio of heavily exposed workers with diabetes. The iitial criteria used i this study to idetify udiagosed diabetic patiets (fastig glucose >7.8 mmol/l) have bee show to produce a uderestimate of the umbers. 19 New diagostic criteria for diabetes, based o a fastig plasma glucose of 7.0 mmol/l, improves the ability to idetify udiagosed diabetic TSH (mu/l) T 4 (mol/l) FTI (mol/l) Adjusted mea* (SE) Adjusted mea (SE) Adjusted mea (SE) Referets (<20) (0.13) 98.8 (1.05) 26.8 (0.28) Workers-all (0.13) (1.01) (0.27) 0.02 TCDD< (0.26) (2.03) (0.55) <TCDD< (0.27) (2.11) (0.57) <TCDD< (0.26) (2.09) (0.56) <TCDD< (0.27) (2.16) (0.58) TCDD=2,3,7,8-tetrachlorodibezo-p-dioxi, SE=stadard error of the adjusted mea. *,,, See foototes to table 6. Table 8 Compariso of self reported history of physicia diagosed diabetes mellitus betwee examied ad refusig subjects ad betwee examied ad refusig referets Outcome Examied workers Refusat workers Yes No Excluded Yes No Excluded Uadjusted OR (95% CI) Compariso betwee examied ad refusig workers: Total umber Diabetes mellitus: self reported 17 (6.1%) 263 1* 8 (11.8%) (0.20 to 1.16) Compariso betwee examied ad refusig referets: Total umber Diabetes mellitus: self reported 15 (5.8%) (9.3%) (0.26 to 1.41) *The participat was excluded because the date of diagosis preceded the date of first hire ito TCDD cotamiated processes. Participats were excluded from the aalysis if they could ot recall whether they had the disease of iterest, or because the date of diagosis preceded the matched worker s date of first hire ito TCDD cotamiated processes. subjects. 17 Whe we re-examied our data with this ew cut ov poit, the fidigs were essetially uchaged from those with the iitial defiitio for diabetes. Therefore, the fidigs from this study do ot seem to be limited by the diabetes case defiitio. However, a possible limitatio i this study is the low statistical power for examiig diabetes mellitus. Our study had about 50% power to detect a twofold icrease i risk of this coditio. Other studies have examied the associatio betwee exposure to TCDD ad the risk of diabetes mellitus However, the fidigs from these studies are mixed. A study of Uited States Air Force persoel (Rach Hads) resposible for sprayig aget orage, a herbicide mixture cotamiated with TCDD, i Vietam from foud that the proportio of rach hads ad uexposed people with diabetes were similar. 8 However, Rach Hads with half life extrapolated TCDD cocetratios of >94 pg/g lipid had a icreased relative risk (RR) of diabetes (RR 1.5, 95% CI 1.2 to 2.0). 1 Aother morbidity study of workers occupatioally exposed to TCDD foud that the uexposed referet group had a higher lifetime prevalece of diabetes tha the group exposed to TCDD. 2 This study did ot use serum TCDD cocetratio as the exposure measure i the diabetes aalyses. Three mortality studies of populatios exposed to TCDD reported risk of mortality from diabetes mellitus. 5 7 Pesatori et al 5 studied those i the Seveso regio of Italy who were exposed to TCDD after a explosio at a trichloropheol plat. The Seveso regio was divided ito zoes A, B, ad R (zoe A had the highest TCDD cotamiatio, ad zoe R the lowest). The referece group cosisted of residets i the surroudig o-cotamiated territory. Fiftee years after the Seveso explosio, risk of mortality from diabetes mellitus

6 Edocrie outcomes amog workers exposed to TCDD 275 was icreased amog female residets of zoe B (RR 1.9, 95% CI 1.1 to 3.2) ad zoe R (RR 1.2, 95% CI 1.0 to 1.6). Male residets i these zoes had o-sigificatly icreased risks. Risk of diabetes mellitus was ot sigificatly icreased amog residets i Zoe A. The two other mortality studies of populatios exposed to TCDD ivolved workers employed at pesticide producig chemical plats Neither foud a sigificatly icreased risk of mortality from diabetes mellitus. The two plats that we studied were icluded i a large cohort mortality study that foud a stadardised mortality ratio (SMR) of 1.08 (95% CI 0.61 to 1.74) for mortality from diabetes mellitus Our fidig that workers with the highest half life extrapolated serum TCDD cocetratios had sigificatly icreased mea serum glucose cocetratios suggests that high exposure to TCDD may have a evect o glucose metabolism. Amog the three previous studies that examied the associatio betwee exposure to TCDD ad serum glucose cocetratio, both of the studies that used serum TCDD cocetratio as the exposure measure foud positive associatios. 1 3 As for evects o thyroid hormoe homeostasis, our study foud that workers exposed to TCDD had a modestly higher mea free T 4 idex tha the referets. However, the proportio of workers with free T 4 idex cocetratios above the referece rage was osigificatly lower tha referets. It should also be oted that this study had limited statistical power to detect a diverece i out of rage free T 4 idex cocetratios (50% power to detect a twofold rise i risk). These fidigs suggest that exposure to TCDD may have a modest, subcliical evect o thyroid fuctio. Although the free T 4 cocetratio is a useful screeig test for thyroid dysfuctio, oly oe other study has evaluated this outcome. 21 The 1982 Rach Had baselie study foud o sigificat divereces i free T 4 idex betwee Rach Hads ad the uexposed compariso group; however, aalyses with serum TCDD cocetratios were ot performed. 21 We also examied the total T 4 (protei boud T 4 plus free T 4 ) cocetratio which is less specific for thyroid dysfuctio ad more diycult to iterpret tha the free T 4 idex. Our study foud that exposed workers had modest subcliical icreases i serum total T 4 cocetratio, which is cosistet with the fidigs amog aother group of chemical workers. 3 That study foud positive associatios betwee curret serum TCDD cocetratio ad both total T 4 (p=0.02) ad thyroid bidig globuli (p=0.001), but ot TSH. 3 Those workers also had a icreased prevalece of pooled thyroid disorders (giotre, thyrotoxicosis, hypothyroidism, ad thyroid adeoma) tha a uexposed referet group (p<0.05). 2 Two other cross sectioal studies examied the associatio betwee exposure to TCDD ad evects o the thyroid glad. 4 8 I oe study, 8 a associatio was foud betwee curret lipid adjusted TCDD cocetratio ad a abormally low total T 4 (p=0.03). Several other thyroid outcomes examied i that study were foud ot to be associated with serum lipid adjusted TCDD cocetratio (history of thyroid disease, ad serum cocetratios of TSH, atithyroid atibodies, ad total T 4 (whe examied cotiuously)). 8 Fially, aother cross sectioal study foud o sigificat divereces i either serum total T 4 or thyroid bidig globuli betwee the workers exposed to TCDD ad the uexposed cotrol group. 4 Serum TCDD cocetratios were ot measured i that study. To assess the potetial magitude of participatio bias i our study, a telephoe iterview was attempted with all of the workers who refused to be examied, a 10% radom sample of the referets who refused all participatio, ad all of the referets who provided lifetime occupatioal histories but refused to be examied. Of the 115 refusig workers ad 129 refusig referets who were cotacted, 68 (57%) ad 100 (78%), respectively, agreed to be iterviewed by phoe. These people were asked questios about diabetes similar to those asked i our medical study. A lower proportio of workers examied reported a history of diabetes tha did the refusig workers; however, the diverece was ot sigificat (table 8). Also, o sigificat divereces i age or sex were foud betwee the two groups of workers. Similar results were foud for the referets (table 8). These results suggest that participatio bias is ulikely to be resposible for our study fidigs. I coclusio, this study of workers with high occupatioal exposure to TCDD >15 years earlier, may of whom cotiued to have persistetly icreased TCDD body burdes, foud evidece for modest evects o glucose metabolism ad thyroid fuctio. Our fidigs are cosistet with some but ot all other cross sectioal medical studies of people exposed to TCDD. We are grateful for the assistace provided by Marily Figerhut, David Dakovic, Barbara Coally, ad may other NIOSH persoel. The study was partially fuded by the Agecy for Toxic Substaces ad Disease Registry. 1 Herikse GL, Ketchum NS, Michalek JE, et al. Serum dioxi ad diabetes mellitus i veteras of Operatio Rach Had. Epidemiology 1997;8: Zober A, Ott MG, Messerer P. Morbidity follow up study of BASF employees exposed to 2,3,7,8-tetrachlorodibezo-pdioxi (TCDD) after a 1953 chemical reactor icidet. Occup Eviro Med 1994;51: Ott MG, Zober A, Germa C. Laboratory results for selected target orgas i 138 idividuals occupatioally exposed to TCDD. Chemosphere 1994;29: Suskid RR, Hertzberg VS. Huma health evects of 2,4,5-T ad its toxic cotamiats. JAMA 1984;251: Pesatori AC, Zocchetti C, Guercilea S, et al. Dioxi exposure ad o-maligat health evects: a mortality study. Occup Eviro Med 1998;55: Figerhut MA, Halperi WE, Marlow DA, et al. 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