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Reprinted from British Journal of Industrial Medicine 1982:39:361-369 Copyright 1982 British Journal of Industrial Medicine All rights of reproduction of this reprint are reserved in all countries of the world Metabolic and health consequences of occupational exposure to polychlorinated biphenyls A B SMITH. JOANNE SCHLOEMER. L K LOWRY. A W SMALLWOOD, R N LIGO, STANAKA. W STRINGER. M JONES. R HERVIN, AND C J GLUECK EXHIBIT NO.___ R.G. /-//*> British Medical Association, Tavistock Square, London WC1H 9JR HARTOLDMONOO11721 Jones, Hervin, and Glueck a maintenance facility. Data employees of the private util0 worked in transformer .sformer overhaul, and 21 in ipational exposure to PCBs, EVALUATIONS istrial hygiene evaluations at ole from ABS on request, me PCB and levels of skin 1 were measured during surnene conducted at times the medical surveys. Perollected on florosil. a magnt. by using a Sipin SP1 v rate of about 200 cc/min The PCBs were desorbed zene and analysed by using i an electron capture detecm was 0-01 pg per tube, i on Whatman smear tabs lead, nose, and cheek area wipe samples were anaced>'~' to determine the .rfi "itamination with undertaken to determine ted clinical and biochemiPCB concentration as an xposure to PCB. A ques: to each participant by a in demographic data, and d tobacco consumption, les (a copy is available esent and previous occuitained from plant eraphysical examination was physicians. Neither the ^erc blinded with respect tcipants. itions were performed i blood drawn after a ology (haemoglobin, id differential count), inorganic phosphorous, acid, cholesterol, total tbin, alkaline phosphaind glutamic-oxalacetic rum glutamic-pyruvic rum gamma-glutamyl ~um creatinine, serum serum protein decidr -v creatinine and i, 'Vphyrin, and Metabolic and health consequences of occupational exposure to polychlorinated biphenyls 363 porphobilinogen were measured on spot urine specimens. Urinary glucose and protein determina tions were performed at the study site by dipstick method. Plasma total cholesterol, triglycerides (TG), and high density lipoprotein cholesterol (HDL-C) determinations were performed bv the Lipid Research Centre. University of Cincinnati, follow ing standardised Lipid Research Centre methods.7 slightly modified for HDL-cholesterol determina tions. Low density lipoprotein cholesterol (LDL-C) levels were calculated'1 in all sublets except three with triglyceride levels greater than 400 mg/dl. The clinical evaluations at the public and private utilities were identical with those described above, except that, m addition, urinary 17-ketosteroid and 17-hvdroxysteroid concentrations were measured and standardised for urinary' creatinine excretion on spot urines. Serum PCB determinations were performed by Environmental Science and Engineering, Inc. in Gainesville. Florida, using a slightly modified ver sion of an electron capture gas chromatographic procedure developed for the Office of Toxic Sub stances. United States Environmental Protection Agency.10" PCB components were quantitated as lower chlorinated biphenyls (L-PCBs) and higher chlorinated biphenyls (H-PCBs) by comparing retention times on the gas chromatogram with those of standard samples of Aroclor 1242 and Aroclor 1254. Peaks eluting before DDE (injected in the column in a pesticide mixture control) were included in the serum L-PCB determination, and those after DDE in the serum H-PCB determination. The L-PCBs so quantitated were predominantly biphenyl molecules with four or fewer chlorine atoms per molecule, and the H-PCBs were pre dominantly biphenyl molecules with five or more chlorine atoms per molecule.12 Major peaks that appeared in both Aroclor 1242 and 1254 standards with equivalent retention times were quantitated only once, as either serum L-PCB or serum H-PCB. Because of the similarity in composition of Aroclor 1016 and Aroclor 1242, no specific quantitation was attempted for Aroclor 1016, and instead the serum L-PCB quantitation was taken to be representative of the distribution of PCB isomers found in both these products. Because of the low concentrations of PCB, mass spectral confirmation of individual peak identity was not attempted. Quality control proce dures included the analysis of two in-vitro spiked pool specimens and of one blind split duplicate in each analytical run. STATISTICAL METHODS Inspection of histograms and normal probability plots of the various blood tests showed that logarithmic transformation (base 10) was required to "normalise" the following data: serum L-PCB and H-PCB concentrations, SGOT, SGPT, GGTP, AK, total and direct bilirubin, glucose, BUN, creatinine. T-4, TG, HDL-C, and LDL-C. Para metric statistical analyses were performed with the log-transformed data, using standard packaged statistical programs.1>~'5 Deficits in tabulations from specified total numbers of participants are attribu table to missing values for data, which required elimination of the individuals with the missing values from the particular analysis. Results ENVIRONMENTAL PCB LEVELS Electrical equipment manufacturing plant--The time-weighted average (TWA) personal air sample concentrations of PCBs, all obtained for workers in F-30, G-44. or an area ("miscellaneous assembly") adjacent to the impregnation ovens (located in F-30), ranged from non-detectable to 264 pgjm3, with a median of 81 pgjm3. The current OSHA standard and ACGIH threshold limit value for 42% chlorinated biphenyls are both 1000 pg/m3. Skin smear wipes of selected workers, all from F-30 or the area adjacent to F-30, ranged from 10 /tg/100 cm2 to 668 pg) 100 cm2 of PCB accumulated over the course of a shift. These findings indicated workrelated skin contamination by PCBs that would not be quantified under present sampling methods, which are limited to air sampling for PCBs. Public utility company--Two industrial hygiene surveys were conducted, one in November 1976 and the other in August 1977. During the November survey, all personal air samples for PCBs (analysed as Aroclor 1254) were under the limit of detection, --that is, under 1 /ig/tube, corresponding to a con centration of under 19 pg/m3. During the August 1977 survey, personal air samples for PCBs (analysed as Aroclor 1260) ranged from 37 to 215 /ig/m2. The current OSHA standard and ACGIH threshold limit value for 54% chlorinated biphenyl are both 500 pg/m3. Private utility company--Samples obtained during yearly inspection of transformers in underground vaults showed personal air exposures varying from 0-4 to 8-8 pg/m3. Wipe samples from the hands and face of two employees varied from 5 pg/100 cm2 to 487 /ig/100 cm2. A wipe of the table top containing test equipment and the floor of the test area showed about 800 M8/100 cm2 for PCBs, showing localised or general smearable contamination. Personal air samples obtained during overhaul of transformers varied from 3-1 to 82-3 pg/m3. Wipe samples from HARTOLDMONOO11722 Jones, Hervin, and Glueek ted. without occupational or e to PCBs. were 116 ng/ml ively. concentrations among workipment manufacturing plant to 50 times the community lean serum H-PCB concen>out two to four times the level. Mean serum L-PCB inv times greater among equipment manufacturing isformer maintenance and Inee Ranee 'ie mh -if)-.1.1.111 .14-2.4(1(1 X-1500 1-370 1-54 4-48 I 5: Ran^e fne'mh -'0-250 10-250 7-130 1-110 Metabolic and health consequences of occupational exposure to polychlorinated biphenyls 365 repair workers, while mean serum H-PCB concen trations among workers at the electrical equipment manufacturing plant more closely resembled con centrations among the transformer maintenance and repair workers. The relation of serum log(L-PCB) and log(H- PCB) concentrations, and personal air levels of PCBs. was examined among workers at the electri cal equipment manufacturing plant. Time-weighted average personal air level exposure measurements were available for 10 job descriptions, to which 20 participants in the survey were assigned. The corre lation of personal PCB air levels with serum log(LPCB) concentration was significant ir = 0-66. p = 0-0013); but the correlation of personal PCB air levels with serum logiH-PCB) concentration was not (r = 0-37. p = (Ml). The lack of statistical significance of the latter correlation may well have been a function of the size of the data set available for the analysis. Data were noi available to permit similar analyses for the transformer maintenance and repair workers. The use of protective equipment (protective clothes, gloves, and respirators) increased with per sonal air level exposure. Thus, while a significant positive correlation between the use of protective equipment and serum log(L-PCB) and log(H-PCB) concentrations could be shown (data not given), the primary association was likely between personal air level exposure and the use of protective equipment rather than the use of protective equipment and serum log(PCB) concentration. QUESTIONNAIRE DATA The relationships between serum PCB concentra tion and response to questions concerning symptoms and past illnesses were examined. Age and study site were potential confounding variables that had to be taken into account in the analysis, so that it might reasonably be inferred that any observed associa tions had not resulted from the effect of the con founding variables alone. The questionnaire response data were analysed by a logistic regression in which the logarithm of the odds for a positive ("Yes") response for the dichotomous variable (questionnaire response) was modelled as a linear function of independent predictor variables, such as serum log(L-PCB) and log(H-PCB) concentrations, as well as the confounders' age and study site. The following histories of symptom were significantly associated with either serum log( L-PCB) or log(HPCB) concentration, or both, in the presence of the confounders (see table below). PHYSICAL EXAMINATIONS No consistent patterns of abnormalities were noted on physical examination at any study site. None of the participants was found to have acneform lesions suggestive of chloracne. Although a correlation was noted between serum log( H-PCB) concentration and diastolic blood pressure at the electrical equip ment manufacturing plant (r = 0-1395. Fl2,, = 4-61). multiple linear regression including the addi tional confounding variables age and sex showed the apparent association of diastolic blood pressure with increasing serum Iog(H-PCB) concentration to have been attributable to an association primarily with age (partial r = 0-2742. F, 2I7 = 17-64) as well as with sex (partial r = 0-1381, F, 2I7 = 4-27). LABORATORY DATA--BLOOD TESTS Simple correlations between serum Iog(L-PCB) and log(H-PCB) concentrations and the results of clini cal biochemistry and haematological tests were computed for participants at each study site separ ately. Statistically significant correlations are sum marised in table 3. To control for confounding by age (and sex, at the electrical equipment manufac turing plant), multiple linear regression equations were computed for each statistically significant cor relation, with serum log(PCB) concentration, age, and (at the electrical equipment manufacturing plant only) sex as independent variables. Because of the collinearity of serum log(L-PCB) and log(HPCB) concentrations, separate regressions were computed, with serum Iog(L-PCB) and the confounder(s) as predictors, and serum Iog(H-PCB) and the confounder(s) as predictors. The squared partial correlations, "partial R1," were computed. This is a measure of the variance of the outcome variable still to be accounted for by serum log(PCB) concentration, relative to the variance already Symptom Coughing on the job or soon after work Irritated or burning eyes Unexplained losa of appetite Unexplained tingling in the hands Rash or dermatitis PrixM) 3-84) - 0-05. Associated with log(L-PCB) level in presence of confounders ~ y-(1)' 5-05 7-66 5-70 5-16 0-04 Associated with log(H-PCB) level in presence of confounders ~ xJ(l)' 3-87 It-29 3-40 3-51 4-51 HARTOLDMONOO11723 366 Smith, Schloemer, Lowry, Smallwood, Ligo, Tanaka, Stringer, Jones, Hervin, and Glueck B -iitu Table 3 Product-moment correlations between selected clinical biochemistries and haematologies and serum log(L-PCB) I and logtH-PCB) concentranons. bv studv site K Clinical biochemistry Electrical equipment manufacturing ptant Log(SGOT) Log(GGTP) Uric acid Cholesterol Log((nglyccnde) Log(HDL-cholesierol I Loe( LDL-cholesterol I Befa-elobulin Haemoglobin Public utility compan\ Log( mglvcende I Log(HDL-cholesieroi I Pnvate utility compun\ LoelSGOT) ( holesierol ' Statistically significant Ip *- imjS) correlation. Vo of observations 220 217 220 221 221 221 218 217 221 46 46 46 46 Correlation with serum logiL-PCB) 0-1308* 0* 1936* 01151 0-1308 0-1621* -0-0837 0-0575 0-1 163 0-0617 0-0222 0-0528 0-3173* 0-2872* Correlation with serum log(H'PCB) $ 0-1894* 0-2651* 0-1955* 0-2615* 0-3212* -01473* 0-1473* 0-1526* 0-1492* 0-4292* -04148* -0-0927 0-0471 accounted for by the regression on the confounders alone.16 The results are summarised in table 4. Neither serum log(L-PCB) nor log(H-PCB) con centrations were significant predictors of serum uric acid, beta-globulin, LDL-cholesterol, or haemoglo bin when confounding variables age and sex were taken into consideration. Significant partial correla tions. however, in the presence of the confounding variables, between log(SGOT), log(GGTP), choles terol. log(triglycende), and log(HDL-cholesterol); and either serum log(L-PCB) or log(H-PCB) con centrations, were still shown at at least one site. Given the same data available at three sites, it would be reasonable to expect meaningful correlations/associations to be found at more than one site. Accordingly, homogeneity of trend was investigated across all three sites by an analysis of covariance. The results are summarised in table 5. It is apparent that log(SGOT), log(GGTP), log(triglyceride), and log(HDL-cholesterol) were mbi lot CUtu bioci Lor Log1 Clio Log sigi PC all lot re re Jv It sl L * e 1 Table 4 Partial correlations between clinical biochemistries and serum log(L-PCB) and log(H-PCB) concentrations, by studv site Clinical biochemistry Electrical equipment manufacturing plant Log(SGOT) Log(GGTP) Uric acid Cholesterol Log(lriglyceride) Log(HDL-cholesterol) log(LDL-cholesterol) Beta-globulin Haemoglobin Public utility company Log(SGOT) Log(GGTP) Cholesterol Log(trialyceride) LojnHuL-cholesterol) Log(LD L-cholesterol) Private urilitv company Log(SGOT) Log GGTP) Cholesterol Log(triglyceride) Log(HDL-cholesterol) Log(LDL-cholesterol) * Statistically significant (p < 0-05) correlation. Correlation with serum logtL-PCB) 0-1085 0-1618* 0-0037 0-0899 0-1234 -0-0449 0-0001 0-0086 0-0000 0-1436 0-0724 -0-0827 0-0819 0-0242 -0-0111 0-3182* 0-0859 0-3227* 0-2661 0-0929 0-0421 Correlation with serum loglH-PCB) 0-1579* 0-2017* 0-0101 0-1822* 0-2526* -0-0887 0-0027 0-0128 0-0028 -0-1753 -0-0777 -0-2020 0-5182* -0-4403* 0-0474 -0-1242 -0-2115 -0-0357 -0-0494 -0-1425 0-0007 I HARTOLDMONOO11724 nnger. Jones. Hervin. and Gluerk aematologtes and serum loglL-PCBt with PCB) torrelation with serum logfH-PCB) 0-1894' 0-2651' U-1955* 0-2615* 0-321 2 * -0-1473' 0-1473' 0-1526' u- f 492* 0-4292' -"4USH-IIV27 IHI47| L-PCB) or log(H-PCB) conshown at at least one site, ta available at three sites, it 'le to expect meaningful ns r%found at more than I. .-neity of trend was threeNites by an analysis of are summarised in table 5. It GOT). log(GGTP). log(trig(HDL-cholesterol) were 'og(H-PCB) concentrations, bv Cnrretannn with serum logtH-PCB) 0-1579' 02017' OOIOI 0-1822' 0-2526' -0-0887 0-0027 0-0128 0-0028 -0-1753 -00777 -0-2020 0-5182' -0-4403* 0-0474 -0-1242 -0-2115 -0-0357 -00494 -01425 0-0007 Metabolic and health consequences of occupational exposure to polychlorinated biphenyls 367 Clinical biochemistry Log(SGOT) Log(GGTP) Cholesterol Logtmglyeendel Log(HDL-cholesieroll Regression on serum loglL-PCB) plus confounders Homogenous trend? Significant trend? Yes Yes Yes Yes Yes No Yes Yes V os No Regression on serum tog(H-PCB) plus confounders Homogenous trend? Significant trend? Yes No No No No No No Yes Yes Yes significantly associated with either serum log(LPCB) or log(H-PCB) concentrations, or both across all three sites. The trend was homogeneous for log(SGOT) regressed on log(L-PCB), iog(GGTP) regressed on log(L-PCB), log(triglyceride) regres sed on log(L-PCB). and log(HDL-cholesterol) regressed on log(H-PCB). The trend was not homogeneous for log(triglyceride) regressed on log(H-PCB). Biochemistries for which non homogeneity of trend was noted in the absence of significant trend were of no practical interest. LABORATORY DATA--URINE TESTS Urinary glucose, protein, porphyrin, and steroid excretion were not correlated with either serum L-PCB or H-PCB concentrations. Discussion Serum log(PCB) correlated significantly with symp toms suggestive of mucous membrane and skin irri tation. of systemic malaise, and of altered peripheral sensation; and with serum log(SGOT), log(GGTP), plasma log(trigiyceride), and log(HDL-cholesterol). These correlations occur in the absence of overt clinical dysfunction identifiable on physical exami nations. The simultaneous changes in SGOT, GGTP, plasma triglyceride, and HDL-choiesteroi are evidence of an effect on the liver of exposure to PCB, the biological significance of which is not clear. A positive correlation between serum GGTP and triglyceride has been described,17 as has the rise of serum GGTP in the presence of drugs known to induce liver microsomal enzymes." It has been sug gested that the positive association of GGTP and triglyceride may reflect hepatic microsomal enzyme induction, with an increase in the hepatic content of enzymes related to triglyceride synthesis." In sup port of this conjecture, PCBs are well known to induce hepatic microsomal (mixed function oxidase) enzymes both in laboratory animals10 and in man.11 Therefore, alterations in liver enzyme tests in association with increasing serum PCB concentra tion may not themselves be predictive of future chronic liver disease but may reflect liver micro somal enzyme induction. It should be emphasised, however, that the consistent inverse associations of log(H-PCB) with log(HDL-cholesterol) at all three worksites may have long-term cardiovascular significance, given the significant inverse, indepen dent associations of HDL-cholesterol with coronary artery disease.11 In general, a lack of clinically apparent illness among workers with high levels of exposure to PCB and high serum PCB concentrations seems to have been the rule.21"17 None the less, correlations of exposure to PCB or serum PCB concentrations have been reported with various clinical biochemical tests in the absence of clinically detectable disease, including positive correlations with SGOT14 26 and GGTP1* (Avitto V N. 15th annual meeting of US Public Health Service Professional Association, Houston. 26-29 May 1980), negative correlation with serum bilirubin,2' and positive correlations with plasma cholesterol2* and triglyceride.5 20 21 More recently, however, findings of "dermatotoxicity" in association with increasing plasma PCB concentra tions, and of increasing serum triglyceride concen trations in association with increasing plasma PCB concentrations, have been reported,22 Two reports22 24 from Italy have documented, among workers exposed to 54% chlorinated biphenyl in the manufacture of electrical capacitors, signs of "hepatotoxicity" (primarily hepatomegaly) along with rises of liver enzyme tests and four cases of chloracne (among 80 workers). No "definite associ ation" was found between chloracne and blood PCB concentration. By contrast, abnormal liver enzyme tests and blood PCB concentrations, particularly trichlorobiphenyl blood concentrations, were posi tively associated. One would expect that adverse human health effects from exposure to PCB, if they exist, would most readily be identified in groups with the greatest exposures (excluding poisoning attributable to acci dental contamination of food). None of the pub lished occupational or epidemiological studies (including ours), however, have shown that occupa tional exposure to PCBs is associated with any adverse health outcome, to be distinguished from HARTOLDMONOO11725 myer, Jones. Herein, and Glucck xposures that prevailed at times nd the data in themselves do not > suggest a specific permissible Woolf 8S Stern HP. Polychlorinated 18: f 1)9- f 3 natsontne and pollution New York: { Occurrence and sources of PCBs tn enial task force on PCBs. Pnl\chlor\he environment Springfield. Va: US rce. 1972 \S Distribution o| polvchlonnated t wastewater treatment plant and envi* il Environment 1977:8:197-204. ! Glueck ( i.etal. Metabolic consequ\chlorinated hiphenvls (PCB) in sewmini |9HU:U2:553-63. Aeencv PoKchlorinated biphenyls jnces control Federai Register :ram. Manual of laboratory operations .075. (DHEW Publication No (NtH) teiner Stewart LE, Gartside PS. (, ann-manganese chlonde i ,, alpha-hpoprotein cholesr 1976;11:628-33. Fredrickson DS. Estimation of the iensity lipoprotein cholesterol in ie preparative ultracentnfuge. Clin id Enemeenng. Inc. Analysts of PCBf in human blood serum ramlle. Florida: ECEI. 1977 (Research et 68-01*3248.) iuai of anaivucal methods. Cinctn<) 1980 (DHHS(MOSH) pubhea- Ihe chemistry of PCBs. Cleveland: 1974. ' .nude. 1979 ed. Raleigh. Nonh -9. * i/a/ library u.ser s guide. 1980 ed. Institute. 1980 cal computer programs. Berkeley: 1977. ' mate data. Chap 2. Hinsdale. rg DM. Gamma-glutamyl trans : enzyme induction. Br Med J 4e G. Moss DW Serum gamma- er disease. Gut 1972;13:702-8. A, Frezzau S. Bertazzom A. erum alkaline phosphatase and se activities bv short-term clofi* v449. ' 11 v relationships of halogenated ucerc. Ann NY Acad Sci son KE, Kappas A. Alterations rs exposed to polychlorinated r 1 140-6. `1 pL-cholesterol and Metabolic and health consequences of occupational exposure to polychlorinated biphenyls v r. sacA/tw - - .------ r-n.onerattve lipo- other lipids in coronars heart disease. The co-operative lipo protein phenolyping studs. Cinitiation 1977:55:767-72. u Hasagawa H. Sato M. fsuruta H. Report of survey of work area JJoonneess BBTT.. AAssssoocciiaattiioonn ooff bblloooodd pprreessssuunre and polychlorinated biphenyl levels. J'A"MaA 1o9a81t-;24455-:2550055--9. Hirayama C Okumura M, Hagai J. Masuda Y. Hypobiltrubmemia in patients with polychlorinated biphenyls environment while PCB is handled and of the health of work- era handling PCB. In: Special report on prevention of environ* menial pollution bv PCB-ltke subsiances. Japan: Research Coordination 1972:141-99 Bureau. Science and Pechnoioev Agencv. "' Karppanen . Kulho L I he concentration of PCB in human blood and adipose tissue m three different research groups. In: poisoning. Clin Chem Acta 1974;55:97-100. Nagai J. Furukawa M, Yae Y, er al. CUntco-chemical investiga tion of chlorobiphenyls poisoning, especially in the serum lipid analysts of the patients. FuAuoAa Ac/o Medial 1969;60:475-9. L'zawa H. Noton A. Nakamuta S. Ikeura Y. Consecutive threeyear follow-up study of serum triglyceride concentrattonsof 82 subjects with PCB poisoning. Fukuoka Acia Medica PCB conference il. Snukbolm. /973. Stockholm: National Swedish Environmental Protection Board, 1973:124-8. Ouw KH. Simpson UR. Si\i1i OS I he use and health effects of Arocior 1242. j pol\chlorinated hiphcnvl in the electrical industry. Arch hnunm Heufih 197^:31:189-94. Crow KD. Chloracne A critical review including a comparison of two senes ot cases oi .icnc from chioronaphthalene and pitch fumes, irusavnnns at the Si John v Hospital Dermatological ; Ch{a9s7e3K:6H3.:4C0l1in-i4c.al and metabolic abnormalities in occupational exposure to polvchlonnated hiphenvls (PCBs). JOM 1981:23:305. " " Maront M. Colombi A. Canioni S. Ferioli E. Foa V. Occupa tional exposure to polvchlonnated biphenyls in electrical workers. I Environmental and blood polychlorinated biphenyls concentrations. 8r J Ind Med 198) ;38;49-54. '* Viaroni M. Colombi A. Cantoni S. Ferioli E. Foa V. Occupa ' FisScohcbietmy A1 9,NAi.o5o6l`l"Mu-Sw.uLitis R. I hormon J. Seiikoff IJ. Clinical findings umnrttr Pc 8*cxpo*eU capacitor manufacturing work tional exposure so polychlonnaied biphenyls in electrical workers, 11 Health effects. Br J (nd Med 1981;38:55-60. ers. Ann \) AuUtSll I 9**U;32U. 70.U I 5. ' Kreiss K. Zac*. MM, Kirnbrouuh RD. Needham LL. Smrck AL. HARTOLDMONOOI ORIGINAL IN THE COURT OF COMMON PLEAS PHILADELPHIA COUNTY IN RE: PAOLI RAILROAD YARD ) PCB LITIGATION, ) ) ) ) MASTER FILE ) NO, 90-0609-C-6 EXHIBITS TO THE DEPOSITION OF R. EMMET KELLY, DECEMBER 11-12, 1990 M.D. GORE REPORTING COMPANY 408 OLIVE STREET ST. LOUIS, MISSOURI 241-6750 HARTOLDMONOO11727