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MICHIGAN DIOXIN EXPOSURE STUDY APPARENT HALF-LIVES OF DIOXINS, FURANS, AND PCBS IN ADULTS AND CHILDREN Milbrath M O1, Wenger Y1, Gillespie B2, Jolliet O1 1Department of Environmental Health Sciences, University of Michigan School of Public Health, 109 S Observatory, Ann Arbor, MI 48109; 2Department of Biostatistics, University of Michigan School of Public Health, 109 S Observatory, Ann Arbor, MI 48109 Abstract It is necessary to know the half-life of each congener of polychlorinated dibenzodioxins (PCDDs), polychlorinated dibenzofurnans (PCDFs), and dioxin-like polychlorinated biphenyls (PCBs) in the body to estimate the contribution of past exposures on current serum concentrations. A literature search was conducted for measured and modeled kinetic values for 29 congeners. The mean or median age of each exposed cohort was recorded, and best available data and models were examined to determine a mean half-life for each congener. Sources that provide consistent data for numerous congeners and that are within the range of reported values are used to determine reference half-life values for an infant and for a middle age male. These values can serve as points of departure for determining individual variations of half-life with age and body fat1 and to adjust past intakes to present values2. Introduction A central goal of the University of Michigan Dioxin Exposure Study (UMDES) is to determine the factors that explain variation in serum congener levels of polychlorinated dibenzodioxins (PCDDs), polychlorinated dibenzofurans (PCDFs), and polychlorinated biphenyls (PCBs). To account for historical intake in current serum concentration levels of persistent congeners, it is necessary to decay past concentrations over time as a function of their half-lives. Different dioxin, furan, and dioxin-like PCB congeners have different persistence in the human body. This study examines the half-life data for 29 congeners from the literature. Based on the available information, a value for each congener is defined that approximatesthe half-life for an infant and for a hypothetical adult male nonsmoker with a normal body weight for an exposure to dioxins, furans, and dioxin-like PCBs, at a range relevant to the UMDES cohort (below 700 ppt TEQ). These values can be used as reference half-lives, and can be further adjusted for individual variation with known modifiers such as age, sex, percent body fat, and smoking status1. Materials and Methods An extensive literature search was conducted for studies with half-life or decay values for dioxins and furans (table 1) and dioxin-like PCBs (table 2) in humans. When information on age was not directly available, a mean age during the time of sampling was estimated. Secondly, a subset of data representative of a middle aged adult was selected (white cells in tables) based on the following criteria: a) the blood serum concentration at the time of sampling was below <700 ppt, b) the subjects were adults, and c) the measurements were not later refined or reported as inaccurate in later studies. Half-life values that were measured in assumed steady state conditions were only retained if they were less than 10 years, because of large historical changes in intake levels. Values for children were also excluded, as the effect of dilution due to rapid growth in the first years results in a much shorter apparent half-life3. The mean half-lives were calculated for the retained subset to define a typical level for a moderately exposed adult. In the final part, reference values for a male adult and for an infant were selected based on the best available data. Sources that provided consistent data across congeners within the range of all measured data were chosen. Values reported by Hon-Wing et al. for breastfed infants were used as a point of departure at young ages25. Results and Discussion The results of the literature search for dioxins and furans are presented in table 1. There is large variation in half-life values between congeners. For example, the mean half-lives for octa-chlorinated dibenzofuran (OCDF), tetra-chlorinated dibenzofuran (TCDF), and 1,2,3,7,8-pentachlorinated dibenzofuran are less than three years, whereas the mean half-lives for some of the hexa-chlorinated dibenzodioxins are over a decade. Organohalogen Compounds Vol 69 (2007) P-299 2248 MICHIGAN DIOXIN EXPOSURE STUDY OCDF 1234789 HpCDF 1234678 HpCDF 234678 HxCDF 123789 HxCDF 123678 HxCDF 123478 HxCDF 23478 PeCDF 12378 PeCDF 2378 TCDF OCDD 1234678 HpCDD 123789 HxCDD 123678 HxCDD 123478 HxCDD 12378 PeCDD 2378 TCDD Concentration Study Flesch-Janys19964 Flesch-Janys19964 Van der Molen 20005 Van der Molen 20005 Liem 19976 Ogura 2004 blood7 Ogura 2004 adipose7 Pirkle 19898 Wolfe 19949 Michalek 199610 Michalek 199911 Michalek 200212 Needham 199713 Michalek 200212 Geusau 2002a14 Geusau 2002b14 Poiger 198615 Schlatter 199116 Rohde199917 Schecter1990 b.18 Schecter1990 a.18 Schecter1990 comb.18 Iida 199519 Ryan 199120 Kashimoto 198321 Leung 200522 Ryan198920 Ryan199123 Gorski198424 HonWing 200625 N Age Range Cohort 7.2 11 8.4 9.9 4.9 3.7 6.7 6.2 6 5.8 3 3.2 43 48.7 15.6-300.2 Herbicide Plant Workers S median value 6.1 11.2 9.76 13.1 5.1 4.9 6.7 6.4 7.2 3.1 48.7 15.6-300.2 Herbicide Plant Workers S Regression 6.3 8.3 7.8 10 4.6 3.2 4.6 2.4 3.9 7.8 5.6 7.1 3.1 2.8 5.2 1.6 48.7 Regression of Flesh Janys 1996 (Ogura 2004) 7.8 11 12 12 6.8 8.8 5.7 1.4 2.9 10 7.7 24 3.6 5 10 0.7 48.7 Regression of Liem 1997 (Ogura 2004) 6.2 8.6 19 13 8.5 6.5 5.6 0.4 0.9 9.9 5.7 6.2 6.2 2.4 2.6 2.6 0.2 Population of Netherlands 6.7 42 5.8 22 4.9 9.9 17 4.8 42.5 General Japanese Population 6.7 6.6 24 9.2 1.4 5 0.2 0.4 5 3.7 5.8 2.1 1.4 2.1 54.5 General Japanese Population 7.1 36 44.7 16.9-423 Operation Ranch Hand 12 337 44.7 16.9-422 Operation Ranch Hand 8.7 213 47.1 11.5-422.7 Operation Ranch Hand 7.6 97 49.6 11.5-422.7 Operation Ranch Hand 7.5 97 49.6 Operation Ranch Hand 8.2 27 130-3830 Explosion in Seveso 6.9 54 Explosion in Seveso 1.5 1 30 144000-35900 Austrian Female TCDD poisoning 2.9 1 27 26000-9500 Austrian Female TCDD poisoning 5.8 1 42 Male Volunteer - one time 9.7 1 45 Male Volunteer - one time 7.9 13.0 13.9 11.6 7.7 3.5 9.2 13.9 9 6 10 4 7.9 13 6 57 84-505 Former chemical plant employees 4.7 2.9 3.5 6.5 1 60 Binghamton, NY Office building fire 7.2 4.4 4.3 4.1 1 60 Binghamton, NY Office building fire 4.5 4 4.9 6.8 1 60 Binghamton, NY Office building fire 9.1 8.6 17 Yu-Cheng 55 Yu-Cheng 1.5 1.5 30 Yu-Cheng 1.1 2.3 1.5 22 53 Yu-Cheng/Yusho 1.7 2.4 2.4 Yu-Cheng 2.5 2.5 2.5 3 Yusho 3.5 3.2 5.7 1.7 1.8 1 Child Exposed from Wood in Home 0.4 0.32 0.39 0.3 0.5 0.27 2 1 Breast Milk Fed Infants Mean Value 7.5 9.87 12.6 11.6 6.7 4.7 6.7 1.1 2 5.92 5.1 7.5 6.2 4.5 3.5 5.8 3.2 Adult Reference Value 7.2 11.2 9.82 13.1 5.1 4.9 6.7 2.1 3.5 7.03 6.4 7.2 6.2 2.7 3.1 4.6 1.4 Infant Reference Value 0.4 0.32 0.5 0.39 0.3 0.3 0.5 0.1 0.2 0.27 0.4 0.4 0.3 0.2 0.2 0.3 0.1 Reference Value Source 1 2 2 2 2 2 2 3 3 3 2 2 3 3 2 3 3 Table 1. Measured and modeled half-lives for dioxins and furans reported in the literature. N is the number of subjects in the study. Concentrations are expressed as ppt. Values in gray were excluded from this analysis. Underlined values are estimates based on similar chemical structure. Reference value sources: 1) Flesh-Janys reported median 2) Flesh-Janys Regression line 3) Van der Molen et al. model with Flesh-Janys data Organohalogen Compounds Vol 69 (2007) P-299 2249 MICHIGAN DIOXIN EXPOSURE STUDY The range and mean of reported values is for adults of both sexes with mixed smoking status and a range of percent body fat. The reference values were selected to represent a 48.7 year-old non-smoking male at a moderate level of exposure with a percent body fat of 21.86, the median age and percent body in the cohort studied by Flesh-Janys. The reference value was chosen to allow for adjustments based on known modifiers such as sex, smoking status, and percent body fat. The regression data of Flesch-Janys45was used preferentially because it examines a broad range of chemicals in a consistent way; contains information for percent body fat, sex, and smoking status; and the resulting value is within the range of the other studies. In the case of TCDD, the single median value given in the table of Flesh-Janys was used as the reference value, because it better fit with the reported data. For congeners not reported in the Flesch-Janys study, the model given by Van Der Molen et al. was used,56and a reference value was determined using the median age and percent body fat from Flesh-Janys (48.7, 21.9, respectively). There is a dearth of information in the literature regarding the kinetics of PCBs. Half-life values reported in the literature are shown in table 2. To determine the point of departure for ten of the twelve PCB congeners, values given by Ogura et al. for blood were used7. The value given by Ogura for adipose was used for PCB 77 and PCB 81, because there was no blood data available. These values correspond to the half-lives of the general Japanese population assuming steady state conditions. Because of the large decrease in dioxin, furan, and PCB concentrations in the environment in the last 30 years, the steady state assumption is only appropriate for congeners with very short half-lives, and congeners with longer half-lives could be over estimated. PCB 189 PCB 167 PCB 157 PCB 156 PCB 123 PCB 118 PCB 114 PCB 105 PCB 169 PCB 126 PCB 81 PCB 77 Study Liem 19976 Ogura 2004 blood7 Ogura 2004 adipose7 Ryan199123 Ryan 199326 Chen 198227 Chen 198227 Ryan 199326 Brown198928 Buhler198829 Wolff 199130 Wolff 199231 HonWing 2006 Mean Value Adult Reference Value Infant Reference Value Reference Value Source N Age cohort 0.1 0.1 2.7 13 2.7 2.7 2.7 2.7 13 13 13 13 Population of Netherlands 1.6 7.3 2.4 10 3.8 7.4 16 18 12 22 42.5 General Japanese Population 0.07 0.73 2.7 13 2.7 25 4.2 12 38 27 10 41 54.5 General Japanese Population 10.4 3 Yusho 10.4 1.1 1.62 3 Yusho 0.58 0.83 100 17 Yu-Cheng 0.51 0.77 100 17 Yu-Cheng 10.4 1.1 1.62 3 Yu-Cheng 3.9 5.8 39 42.5 Occupational Exposure 0.5 1 50 Male Volunteer 4.6 4 9.6 45 100 2 1 Breast Milk Fed Infants 0.085 0.42 2.33 11.1 6.5 7.12 3.6 4.18 22.3 9.0075 11.67 25.33 1.43 0.14 0.74 1.65 7.35 2.45 105 3.85 7.45 165 185 125 0.004 0.04 0.09 0.46 0.13 0.56 0.2 0.41 0.89 1 0.67 1.222 4 4 5 5 5 55 5 5 555 Table 2. Measured and modeled half-lives for PCBs reported in the literature. N is the number of subjects in the study. Values in gray were excluded from analysis. Reference values: 4) Ogura et al. blood (mean age = 49.5) 5) Ogura et al. adipose (mean age = 42.5) Full understanding of the half-lives of different congeners in the body requires continued study of the kinetics of these compounds in humans, especially for PCBs. The mean values and reference values provided above reflect well the current available data in the literature. These half-life values can be further adjusted to reflect individual characteristics that affect the persistence of the different congeners in the body, and can then be used to determine the effect of past intake on current body concentrations. Acknowledgements Financial support for this study comes from the Dow Chemical Company through an unrestricted grant to the University of Michigan. The authors acknowledge Ms. Sharyn Vantine for her continued assistance and Drs. Linda Birnbaum, Ron Hites, Paolo Boffetta and Marie Haring Sweeney for their guidance as members of our Scientific Advisory Board. Organohalogen Compounds Vol 69 (2007) P-299 2250 MICHIGAN DIOXIN EXPOSURE STUDY References 1. Milbrath, M.O., Wenger, Y., Garabrant, D., Franzblau, A., Gillespie, B., Chang C-W., Jolliet, O., Organohalogen Compounds 2007. 2. Jolliet, O., Wenger, Y., Milbrath, M.O., Towey, T., Adrians, P., Garabrant, D., Franzblau, A., Chang, C-W., Gillespie, B., Organohalogen Compounds 2007. 3. Clewell, H., Gentry, PR., Covington, TR., Sarangapani, R., Teeguarden, JG., Toxicological Sciences 79, 381 2004. 4. Flesch-Janys, D., Journal of Toxicology and Environmental Health Part A 47, 363 1996. 5. Van Der Molen, G. W.; Kooijman, B. A. L. M.; Wittsiepe, J.; Schrey, P.; Flesch-Janys, D.; Slob, W., Journal of Exposure Analysis and Environmental Epidemiology 10, 579 2000. 6. Liem, A. K. 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