Document BvDMqm2JQMRndY7ML1BzqG9eJ

'742 Letters to the Editor itor workers exposed to polychlorinated biphenyls. J Occup Environ Med. 1999; 41:161-171. 2. Carpenter DO. Polychlorinated biphenyls and human health. Int J Occup Med Environ Health. 1998;11:291-303. 3. Patandin S, Koopman-Esseboom C, de Ridder MA, Weisglas-Kuperus N, Sauer PJ. Effects of environmental exposure to polychlorinated biphenyls and dioxins on birth size and growth in Dutch children. Pediatr Res. 1998;44:538-545. 4. Rylander L, Stromberg U, Dyremark E, Ostman C, Nilsson-Ehle P, Hagmar L. Polychlorinated biphenyls in blood plasma among Swedish female fish con sumers in relation to low birth weight. Am J Epidemiol. 1998;147:493-502. 5. Winneke G, Bucholski A, Heinzow B, et al. Developmental neurotoxicity of poly chlorinated biphenyls (PCBS): cognitive and psychomotor functions in 7-month old children. Toxicol Lett. 1998;102--103: 423-428. 6. Patandin S, Lanting Cl, Mulder PG, et al. Effects of environmental exposure to polychlorinated biphenyls and dioxins on cognitive abilities in Dutch children at 42 months of age. J Pediatr. 1999;134:3341. 7. Tilson HA; Kodavanti PR. The neurotox icity of polychlorinated biphenyls. Neu rotoxicology. 1998;19:517-525. 8. Jacobson JL, Jacobson SW. Evidence for PCBs as neurodevelopmental toxicants in humans. Neurotoxicology. 1997; 18:415-- 424. 9. Connor K, Ramamoorthy K, Moore M, et al. Hydroxylated polychlorinated biphe nyls (PCBs) as estrogens and antiestro gens: structure-activity relationships. Toxicol Appl Pharmacol. 1997; 145:111 123. 10. Porterfield SP, Hendry LB. Impact of PCBs on thyroid hormone directed brain development. Toxicol Jnd Health. 1998; 14:103-120. 11. Cushman JH. Study finds little risks from PCB's. New York Times. March 10, 1999. The Authors Reply: Thank you for giving us the opportunity to reply to the letters by Bove et al and Frumkin and Oris commenting on our mortality study of PCB-exposed capacitor workers.1 We disagree with the statement by Bove et al that "... limitations in the study ap proach tend to dilute any excesses in cancer mortality resulting from PCB exposure...." These assertions are speculative and not supported by the data. Although some degree of misclassification in observational stud ies is unavoidable, it is usually not possible to determine whether this misclassification is differential or non-differential. Furthermore, non differential misclassification does not always result in bias toward the null hypothesis. Neither the type nor the effect of the misclassification can be determined by Bove et al. In our article, we do, however, discuss at length the measures taken to limit misclassification, and we feel strongly that we were successful in doing so. Bove et al assert that the healthy worker effect (HWE) results are an underestimate of the SMRs for all causes mortality and cancer mortal ity. This is partially true. The HWE is most pronounced for cardiovascu lar deaths and thus affects all-causes mortality.2 It has much less of an effect on cancer deaths.3 The presentation by Bove et al of the all-cancers SMRs and selected cancer-specific SMRs without confi dence intervals (CIs) gives incom plete information and is misleading. Had the confidence intervals been reported, the lack of significance for these SMRs would have been imme diately obvious to the reader. Bove et al selected the female hourly em ployees' all-cancers SMR of 110 (95% Cl, 93 to 129), intestinal can cer (SMR = 157; 95% Cl, 96 to 242), rectal cancer (SMR = 169; 95% Cl, 46 to 434), melanomas (SMR = 144; 95% Cl, 30 to 421), and melanomas in male hourly em ployees (SMR = 130; 95% Cl, 42 to 303). Notably absent from this list of SMRs considered by Bove et al are the male hourly SMRs for intestinal and rectal cancer (SMR = 57; 95% Cl, 25 to 112; and SMR = 87; 95% Cl, 18 to 255, respectively). Bove et al suggest that the male all-cancers SMRs of 81 (hourly em ployees; 95% Cl, 68 to 97) and 69 (salaried employees, 95% Cl, 52 to 90) are largely due to the HWE. A careful examination of Table 4 in our article suggests that the statistically significantly low all-cancers SMRs in both the hourly and salaried males result primarily from the lower than expected lung cancer SMR (for hourly workers: 42 observed/54.5 expected; SMR = 77; 95% Cl, 56 to 104; and for salaried workers: 12 observed/29.6 expected; SMR = 41; 95% Cl, 21 to 71). The statement by Bove et al that these elevations were consistent with elevations found in other studies of PCB-exposed workers is not cor rect.4-6 In addition to the three stud ies cited by Bove et al, there is the Bertazzi cohort and its update by Bertazzi et al7 and Tironi et al.8 The results of the Brown4 and Sinks et al5 studies are inconsistent with each other. The Loomis et al6 study of utility workers, not capacitor work ers, did report an elevation in mela nomas in some subsets of the cohort that were presumed to have had ex posure to PCBs while working out doors. Exposure to sunlight was not adequately accounted for by Loomis et al.6 Brown and Jones9 and Brown4 found an excess of liver and rectal cancers. Neither Sinks et al5 nor Loomis et al6 reported such in creases. Sinks et al5 reported a non significant elevation in brain and nervous system cancers. Neither Brown and Jones,9 Brown,4 Bertazzi et al,7 or Tironi et al8 found an elevation in brain cancer. These in consistencies were discussed in our article. Bove et al state that we only in cluded a latency-period analysis for all cancers and for intestinal cancer. This was done primarily because of space limitations. Cumulative expo sure and latency tables were com puted and evaluated for many other causes of death, including all of the cancers of interest. The interpretation by Bove et al that the intestinal cancer SMR increases to a signifi cant level for women with >20 years of latency ignores the importance of examining the trend associated with latency and length of employment. Furthermore, it might be worth not ing that for women employed for 10 DSW 148281 STLCOPCB4039766 JOEM Volume 41, Number 9, September 1999 743 years or longer with a latency period >20 years, the SMR was 100. The individual category-specific SMRs cannot be interpreted as meaningful without examination of the trend across cumulative exposure catego ries. Although the intestinal cancer SMR for latency ^20 years was significantly elevated, there was no significant trend indicating an in crease in risk with cumulative expo sure or latency, as discussed in our article. Furthermore, comparison with the regional population resulted in a much-reduced SMR (SMR = 120; 95% Cl, 74 to 186) for intestinal cancer in female hourly workers. The regional comparison is more repre sentative because higher rates of in testinal cancer are observed among the white population of the north eastern part of the United States. Bove et al raise concerns about our exposure assessment. Several factors need to be recognized when assess ing the propriety of our exposure assessment and our use of length of employment as a surrogate of expo sure. Workers accumulate PCB body burdens over time, which persist for many years even after their occupa tional PCB exposure is discontinued. To suggest that PCB body burdens among capacitor workers were com parable to those found in the general population is unjustified and is not supported by previously published data.10-13 The fact that workers in capacitor plants had significantly higher body burdens than the general population has been demonstrated in other capacitor plants.14 As reported in our article, average serum PCB levels in the general population be tween 1976 and 1979 were 5 to 7 parts per billion (ppb; p,g/L).14 Geo metric mean serum PCB levels in GE workers in 1979 (2 years after PCBs were no longer used) were 277 ppb (p,g/L) reported as Aroclor 1242 and 55 ppb (|xg/L) reported as Aroclor 1254. In 1983, 5 years after termina tion of the use of PCBs, geometric mean serum levels were 116 ppb (p,g/L) for Aroclor 1242 and 34 ppb (p,g/L) for Aroclor 1254. In 1988, the geometric mean serum PCB lev els were 90 ppb (|xg/L) quantitated as Aroclor 1242 and 32 ppb (pg/L) quantitated as Aroclor 1254.15 Workers preferentially retained the more persistent congeners so that the gas chromatographic pattern of their body burden gradually approached that observed in the general popula tion, with primary retention of the more highly chlorinated, poorly me tabolized congeners.12 The half-lives of the major PCB congeners retained in these workers were as follows: for 2,4,4' trichlorobiphenyl, 1.4 years; for 2,4,4'5 tetrachlorobiphenyl, 3.2 years; for 2,3',4,4',5 pentachlorobiphenyl, 5.8 years; and for 2,2',4,4',5,5' hexachlorobiphenyl, 12.4 years.16 Even though different commercial mixtures of PCBs were used in the capacitor plants, the con generic composition on a qualitative basis is similar.17 Production began in 1946 with the highly chlorinated Aroclor 1254, and small amounts of Aroclor 1254 were used in the plant at least through 1971. The statement that length of em ployment alone was an inadequate surrogate for exposure and a likely source of exposure misclassification bias leading to an underestimation of the effect and a distortion of the exposure-response relationship is not supported by the toxicokinetics of PCBs, nor is it an accurate represen tation of the data analyses conducted on our cohort and reported in the article. Bove et al report that the majority of hourly workers never worked in a high-exposure job, when in fact 1268 of the 2984 male hourly employees (42.4%) did work in a high-exposure job. Only 13.8% of the female hourly employees worked in a high-expo sure job, not an uncommon occur rence in an industrial setting. To suggest that the remaining portion of the cohort experienced PCB expo sure similar to that of the general population is not an accurate repre sentation of the facts. This is pre sented in the exposure-assessment section of our article. Bove et al state in the opening sentence that although the goal of the study was to evaluate six specific cancers, we focused almost entirely on all-cancers mortality. Table 4 in the article presents SMRs and 95% CIs not only for the six cancers of interest but for 32 other causes of death, including 15 additional can cers. The issue of statistical power is raised by Bove et al and two tables were provided. These tables were not properly referenced nor was the methodology used to generate these calculations explained. It is unclear why an SMR of 150 should be con sidered the "highest expected" for these cancers, when previous publi cations on smaller cohorts reported statistically significant SMRs well above 150. Our study was an attempt to evaluate these earlier observations in a larger study with a longer fol low-up period. Bove et al question the decision to limit the latency by length of em ployment calculations to cancers with more than two observed cases and a lower boundary of the 95% Cl of 90 or above. This decision was made by the investigators to limit the multiple comparison problem and to provide more meaningful data, rather than to obscure data. Additionally, the lack of presentation of data should not be interpreted as the data not having been analyzed. All six a priori cancers of concern were exam ined carefully; however, publication space is limited and presenting a table of latency by cumulative expo sure for liver cancer, for instance, with two deaths was deemed unwar ranted. In their summary statement, Bove et al dismiss our study findings be cause of the HWE effect, failure to account for latency, exposure mis classification, potentially insufficient dosage differences between exposed and comparison groups, and poor statistical power, yet they still insist that we did find excess cancer risk for three of the six a priori cancers of interest and give credence to those findings. It is inconceivable to the DSW 148282 STLCOPCB4039767 ! 744 Letters to the Editor investigators of this study how Bove rum levels reported by Lawton et tions. We conclude that overt abnor et al, given this litany of problems, al,n Brown et al15,16 and Brown.18 malities found in the neonatal period were able to differentiate the impact The PCB blood levels (from 194 are not caused by either direct effects and direction of these biases with and 290 workers) mentioned by of PCB or dioxin exposure or low such certainty and specificity. Frumkin and Orris were of limited ered thyroid hormone levels." Ac The authors take exception to the value in validating an exposure job cording to the National Center for tone of the letter by Frumkin and matrix for 7075 workers. Although Health Statistics,28 birth weight is Orris and find statements such as the job histories and the exposure affected by education of the mother, "conspicuously silent" and "willful assignment did confirm that workers mother's age, birth order, interval effort to avoid a positive finding" in high-exposure jobs had high PCB between births, gender, inadequate inflammatory and suggest that such blood levels, these workers were se prenatal nutrition, alcohol consump statements do little to advance the understanding of PCBs and cancer risk. Most of the issues raised by Frumkin and Orris have been ad dressed earlier. Their suggestion to include more capacitor plants to in crease power has merit, however. The General Electric Company had only the two facilities in upstate New York (Hudson Falls and Fort Ed ward) where capacitors were made using PCBs. Frumkin and Orris question whether high-exposure jobs actually entailed high exposure and raise con cerns about misclassification. The exposure misclassification suggested by Frumkin and Orris is highly im probable, given the distinction be tween jobs with direct dermal and inhalation exposure and those with only inhalation exposure to PCB air levels in the plant, as explained and referenced in our article. Addition ally, the characterization of this bias as substantial is unwarranted and is an overstatement of the potential ef fect. Assignment of exposure for specific job categories was done be fore determination of vital status. At both plants, workers were located in the same building, and the same air-ventilating system served the en tire building. We verified the physi cal layout by conducting a walk through the building and by talking to present and former employees. lected either because of their known high-exposure job11 or they were self-selected.10 The high-exposure jobs were readily identified by plant personnel and were confirmed by PCB air-level readings and PCB blood levels. Misclassification of jobs into the high-exposure category or misclassifying high-exposure jobs as lower-level exposure jobs was ex tremely unlikely. Frumkin and Orris suggested that PCBs are serious health hazards, ir respective of carcinogenicity, with effects that include decreased birth weight, neurodevelopmental effects, and interference with thyroid and estrogen hormone function. It has not been shown that PCBs interfere with estrogen-hormone function in hu mans. Studies conducted to examine the effects of PCBs in infants and children have been critically re viewed19-25 or could not be support ed.26 Results from thyroid function tests performed in infants were within the normal range. Further more, Koopman-Esseboom et al27 stated, "The mean dioxin-like PCB toxic equivalent levels and the mean total PCB and dioxin toxic equiva lent levels of the neurological normal infants were significantly higher (p = 0.04 for both) compared with the levels of the neurologically (mildly or definitely) abnormal in fants. There was no relationship be tween the TT3 (serum total triiodo tion, smoking, lack of prenatal care, incidence of elective induction, con traceptive utilization, out-of-wedlock births, metropolitan areas (lower), and race. The body size of the par ents and maternal illnesses such as diabetes also play a role. These many variables exemplify the difficulties of appropriately designing studies to examine a single factor affecting birth weight. Given these uncertain ties and the published criticisms of studies reporting "other health ef fects of PCBs," it has not been con clusively shown that PCBs cause other "serious" health problems in humans. We disagree with the final com ment by Frumkin and Orris that this study was a great leap sideways on the path to a more complete under standing of the health effects of PCBs. The issue of PCBs and poten tial health effects has been a signifi cant public health concern for more than 30 years. The lack of consistent findings in the previous cohort stud ies was assumed to have resulted from small cohort sizes and short follow-up periods. Given the dispar ate findings in these smaller capaci tor cohorts, the appropriate next step was to assemble a larger cohort of PCB-exposed workers and examine them throughout a longer follow-up period. The fact that we were unable to confirm any of the previously Many workers had different jobs in thyronine), TT4 (serum total reported findings is important and the different exposure categories thyroxine), FT4 (free thyroxine), and adds to the knowledge about PCBs (high, undefinable, and low). All TSH (thyroid stimulating hormone) and health effects. The assumption- workers, including those in low- levels in maternal, umbilical, or in that a negative study does not pro exposure jobs, had significantly fant plasma (collected in the second vide valuable information imposes higher exposures than the general week after birth) and the results of significant restrictions on the scien population, on the basis of PCB se the neonatal neurological examina- tific process and the ability to ade- * i DSW 146283 STLCOPCB4039768 JOEM Volume 41, Number 9, September 1999 745 quately and objectively assess all data. Errata: The correct number of fe male salaried workers with a length of employment of 10 to <15 years in Table 2 is 27; 5.8% is the correct percentage. In Table 6, line 2, last column, total SMR for S:20 years of latency should be 117. The total number of workers in the upper panel of Table 2 should be 7075. Renate D. Kimbrough, MD Martha L. Doemland, PhD Maurice E. LeVois, PhD Institute for Evaluating Health Risks Washington, DC References 1. Kimbrough RD, Doemland ML, LeVois ME. Mortality in male and female capac itor workers exposed to polychlorinated biphenyls. J Occup Environ Med. 1999; 41:161-171. 2. McMichael AJ. Standardized mortality ratios and the "healthy worker effect': scratching beneath the surface. J Occup Med. 1976;18:165-168. 3. Checkoway H, Pearce NE, CrawfordBrown DJ. Issues of study design and analysis. In: Research Methods in Occu pational Epidemiology. New York: Ox ford University Press; 1989:78-79. 4. Brown DP. Mortality of workers exposed to poylchlorinated biphenyls: an update. Arch Environ Health. 1987;42:333-339. 5. Sinks T, Steele G, Smith AB, et al. Mortality among workers exposed to polychlorinated biphenyls. Am J Epide miol. 1992;136:389-398. 6. Loomis D, Browning SR, Schenk AP, et al. Cancer mortality among electrical workers exposed to polychlorinated bi phenyls. Occup Environ Med. 1997;54: 720-728. 7. Bertazzi PA, Riboldi L Pesatori A, et al. Cancer mortality of capacitor manufac turing workers. Am J Ind Med. 1987; 11: 165-176. 8. Tironi A, Presatori A, Consonei D, et al. The mortality of female workers exposed to PCBs. Epidemiol Prev. 1996;20:200- 202. 9. Brown DP, Jones J. Mortality and indus trial hygiene study of workers exposed to polychlorinated biphenyls. Arch Environ Health. 1981;36:120-129. 10.Wolff MS, Fischbein A, Thornton J, Rise C, Lilis R, Selikoff IJ. Body burden of polychlorinated biphenyls among persons employed in capacitor manufacturing. Int Arch Occup Environ Health. 1982;49: 199-208. 11. Lawton RW, Ross MR, Feingold J, Brown JF Jr. Effects of PCB exposure on biochemical and hematological findings in capacitor workers. Environ Health Perspect. 1985;60:165-184. 12. Lawton RW, Brown JF, Ross MR, Fein gold J. Comparability and precision of serum PCB measurements. Arch Environ Health. 1985;40:29-37. 13. Taylor PR, Reilly AA, Stelma J, Law rence CE. Estimating serum polychlori nated biphenyl levels in highly exposed workers: an empirical model. J Toxicol Environ Health. 1991 ;34:413-422. 14. Kimbrough RD. Polychlorinated biphe nyls (PCBs) and human health: an up date. Crit Rev Toxicol. 1995;25:133-163. 15. Brown JF Jr, Lawton RW, Ross MR, Feingold J. Assessing the human health effects of PCBs. Chemosphere. 1991 ;23: 1811-1815. 16. Brown JF Jr, Lawton RW, Ross MR, et al. Persistence of PCB congeners in ca pacitor workers and Yusho patients. Che mosphere. 1989;19:829-834. 17. Mayes BA, McConnell EE, Neal BH. Comparative carcinogenicity in SpragueDawley rats of the polychlorinated biphe nyl mixtures Aroclors 1016, 1242, 1254, and 1260. Toxicol Sci. 1998;41:62-76. 18. Brown JF Jr. Determination of PCB met abolic, excretion, and accumulation rates for use as indicators of biological re sponse and relative risk. Environ Sci Technol. 1994;28:2295-2305. 19. Paneth N. Human reproduction after eat ing PCB-contaminated fish. Health Envi ron Digest. 1991;5:4-8. 20. Paneth N. Adopting a public health ap proach to developmental neurotoxicity. Neurotoxicol Teratol. 1996;18:233-234. 21. Buck GM. Epidemiologic perspective of the developmental neurotoxicity in PCBs in humans. Neurotoxicol Teratol. 1996; 18:239-241. 22. Guo YL, Yu M-LM, Ryan JJ. Different congeners of PCBs/PCDFs may have contributed to different health outcomes in the Yu-Cheng cohort. Neurotoxicol Teratol. 1996;18:255-256. 23. Schantz SL. Developmental neurotoxic ity of PCBs in humans: what do we know and where do we go from here? Neuro toxicol Teratol. 1996;18:217-227. 24. Schantz SL. Response to commentaries. Neurotoxicol Teratol. 1996;18:271-276. 25. Borak J, Israel L. Does in utero exposure to PCBs cause developmental toxicity? The occupational and environmental medicine report. J Occup Environ Med. 1997;11:13-18. 26. Grandjean P, Weihe P, White RF, et al. Cognitive deficit in 7-year-old children with prenatal exposure to methylmercury. Neurotoxicol Teratol. 1997;19: 417-428. 27. Koopman-Esseboom C, Huisman M, Touwen BC, et al. Newborn infants diag nosed as neurologically abnormal with relation to PCB and dioxin exposure and their thyroid hormone status. Dev Med Child Neurol. 1997;39:785. 28. NCHS. Trends in Low Birth Weight in the United States 1975-1985. Washing ton, DC: Department of Health and Hu man Services, CDC National Center for Health Statistics; October 1989. National Center for Health Statistics Series 21, No. 48. Investigation ot Elevated Urine Beta2-Microglobulin in a Cohort of Cadmium Workers To the Editor: Prior to the issuance of the 1993 Occupational Safety and Health Administration Cadmium Standard, urine testing for beta-2microglobulin ((32m) was not fre quently performed. Testing for (32m was an esoteric laboratory test per formed only on workers whose cad mium levels had been found to be elevated. The Cadmium Standard mandated that all employees exposed to greater than 2.5 p,g/m3 cadmium dust or fumes be tested at least an nually for urine (32m, as well as for blood cadmium (CdB) and urine cad mium (CdU). At a nickel-cadmium battery manufacturing facility, ap proximately 1000 employees, some of whom had been exposed to cad mium and some of whom had not, were evaluated for |32m levels, most for the first time. Elevated (32m was defined as a p2m level higher than 300 |xg/g cre atinine1; expectations were that ap proximately 10% of workers with cadmium levels higher than 10 (xg/L blood or 10 [xg/g creatinine would also show an elevated (32m level.2'3 Because 54 employees had such ele vated cadmium levels in 1993, it was expected that approximately five or six would also show elevated (32m levels. It was not known how many employees with other conditions OSW 148284 STLCOPCB4039769