Transgenerational Implications of Age-Dependent Half-Life of Dioxins in Children
Main Article Content
Abstract
Transgenerational health risks of dioxin-like compounds (dioxins) have been a prominent concern due to environmental persistence and food chain bioaccumulation related to combustion processes and widespread historical usage of certain commercial compounds like 2,4,5-trichlorophenoxyacetate and polychlorinated biphenyls. Earlier research showed that human adults excreted dioxins extremely slowly, e.g., with a plasma clearance half-life of perhaps 7 to 11 years, which indicated potential transfer of elevated maternal body burden via breast-feeding. These concerns led to the development of regulatory strategies targeting the reduction of environmental releases of dioxins to help reduce childhood and maternal body burdens and associated health risks. Fortunately, these regulatory strategies resulted in substantially reduced dioxin body burdens and further research revealed that infants, adolescents, and young adults exhibit an age-dependent half-life, e.g., breast-fed infants showed dioxin half-life of ~0.4 years with only gradual increase with each subsequent year (e.g., 0.12 years per annum). These findings equate with reduced health concerns to children and mothers today and for future generations. Available research of highly exposed populations also demonstrates a concentration-dependent dioxin half-life reduction relating to liver enzyme induction triggered by aryl hydrocarbon receptor activation starting at relatively high blood dioxin concentrations. Epidemiological studies of the highest dioxin exposures demonstrate this liver enzyme induction and chloracne, but other potential effects were clinically subtle or not coherently linked to the aryl hydrocarbon receptor-driven toxicological impacts. These highly exposed populations have not demonstrated strong and consistent evidence of increased cause-specific cancer rates, and proposed epidemiology-based dose-response factors for total cancer and other specific diseases may be overstated due to the influences of age- and concentration-dependent dioxin half-lives on body burden estimates. Thus, while continued research of potential dioxin health hazards may be warranted, researchers must carefully consider influences of age- and concentration-dependent pharmacokinetics, diminishing background exposures, and aryl hydrocarbon receptor-based mechanism of action that likely limit transgenerational health impacts to young children and mothers going forward.
Keywords:
pharmacokinetics, human, exposure, internal dose modeling
Article Details
How to Cite
KERGER, Brent D.; LOCCISANO, Anne E..
Transgenerational Implications of Age-Dependent Half-Life of Dioxins in Children.
Medical Research Archives, [S.l.], v. 13, n. 8, aug. 2025.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/6902>. Date accessed: 12 jan. 2026.
doi: https://doi.org/10.18103/mra.v13i8.6902.
Section
Review Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
References
1. Greene JF, Hays S, Paustenbach D. Basis for a proposed reference dose (RfD) for dioxin of 1-10 pg/kg-day: a weight of evidence evaluation of the human and animal studies. J Toxicol Environ Health B Crit Rev. 2003 Mar-Apr;6(2):115-59. doi: 10.1080/10937400306470. PMID: 12554432
2. USEPA (United States Environmental Protection Agency). 2003. Exposure and Human Health Reassessment of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and Related Compounds. Office of Research and Development, National Center for Environmental Assessment. NAS Review Draft. December 2003
3. ATSDR (Agency for Toxic Substances and Disease Registry). 2024. Toxicological Profile for Chlorinated Dibenzo-p-Dioxins. Draft for Public Comment. October 2024. https://www.atsdr.cdc.gov/toxprofiles/tp104.pdf
4. Paustenbach DJ, Fehling K, Scott P, Harris M, Kerger BD. Identifying soil cleanup criteria for dioxins in urban residential soils: how have 20 years of research and risk assessment experience affected the analysis? J Toxicol Environ Health B Crit Rev. 2006 Mar-Apr;9(2):87-145. doi: 10.1080/10937400500538482. PMID: 16613806
5. USEPA (United States Environmental Protection Agency). 2002a. US Environmental Protection Agency Child-Specific Exposure Factor Handbook. Pp. 3-59. NCEA, Washington DC. EPA-600-P-00-002B
6. USEPA (United States Environmental Protection Agency). 1989. Risk Assessment Guidance for Superfund Vol 1. Human Health Evaluation Manual. Office of Emergency and Remedial Response. EPA/540/1-89/002
7. Williams, PRD; Holicky, KC; Paustenbach DJ 2003. Current methods for evaluating children’s exposures for use in health risk assessment. J Child Health 1, 41-98
8. USEPA (United States Environmental Protection Agency). 2002b. Short Sheet: Overview of the IEUBK Model for Lead in Children. EPA #PB 99-965-8, OSWER #9285-7-31. Office of Solid Waste and Emergency Response, USEPA, Washington DC
9. Kerger BD; Gerthoux PM; Mocarelli P. 2011. 1976 Trichlorophenol reactor explosion at Seveso, Italy. Encyclopedia of Environmental Health. Amsterdam; Elsevier. Editor-in-chief: Jerome O. Nriagu
10. ATSDR (Agency for Toxic Substances and Disease Registry). 2023. Toxicological Profile for Chlorodibenzofurans (CDFs). April 2023. https://www.atsdr.cdc.gov/toxprofiles/tp32.pdf
11. Aylward LL, Hays SM. Temporal trends in human TCDD body burden: decreases over three decades and implications for exposure levels. J Expo Anal Environ Epidemiol. 2002 Sep;12(5):319-28. doi: 10.1038/sj.jea.7500233. PMID: 12198580
12. Hays SM, Aylward LL. Dioxin risks in perspective: past, present, and future. Regul Toxicol Pharmacol. 2003 Apr;37(2):202-17. doi: 10.1016/s0273-2300(02)00044-2. PMID: 12726754
13. Lorber M. A pharmacokinetic model for estimating exposure of Americans to dioxin-like compounds in the past, present, and future. Sci Total Environ. 2002 Apr 8;288(1-2):81-95. doi: 10.1016/s0048-9697(01)01119-6. PMID: 12013550
14. Richter RO; Kerger BD; Leung HW; Paustenbach DJ. 2006. Implications of age-dependent half-lives of dioxins on assessment of breast milk dose and body burden. Toxicol Sci 89, 177 (Abstract 1561)
15. Lorber M, Patterson D, Huwe J, Kahn H. Evaluation of background exposures of Americans to dioxin-like compounds in the 1990s and the 2000s. Chemosphere. 2009 Oct;77(5):640-51. doi: 10.1016/j.chemosphere.2009.08.016. Epub 2009 Sep 4. PMID: 19733382
16. Arisawa K. Recent decreasing trends of exposure to PCDDs/PCDFs/dioxinlike PCBs in general populations, and associations with diabetes, metabolic syndrome, and gout/ hyperuricemia. J Med Invest. 2018;65(3.4):151-161. doi: 10.2152/jm i.65.151. PMID: 30282853
17. Bichteler A, Wikoff DS, Loko F, Harris MA. Estimating serum concentrations of dioxin-like compounds in the U.S. population effective 2005-2006 and 2007-2008: A multiple imputation and trending approach incorporating NHANES pooled sample data. Environ Int. 2017 Aug;105:112-125. doi: 10.1016/j.envint.2017.05.003. Epub 2017 May 18. PMID: 28527750
18. Kimbrough RD, Falk H, Stehr P, Fries G. Health implications of 2,3,7,8-tetrachlorodibenzodioxin (TCDD) contamination of residential soil. J Toxicol Environ Health. 1984;14(1):47-93. doi: 10.1080/15 287398409530562. PMID: 6389894
19. Kreuzer PE, Csanády GA, Baur C, Kessler W, Päpke O, Greim H, Filser JG. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) and congeners in infants. A toxicokinetic model of human lifetime body burden by TCDD with special emphasis on its uptake by nutrition. Arch Toxicol. 1997;71(6):383-400. doi: 10.1007/s002040050402. PMID: 9195020
20. Leung HW, Kerger BD, Paustenbach DJ. Elimination half-lives of selected polychlorinated dibenzodioxins and dibenzofurans in breast-fed human infants. J Toxicol Environ Health A. 2006 Mar;69(6):437-43. doi: 10.1080/152873905002468 86. PMID: 16574620
21. Lorber M, Phillips L. Infant exposure to dioxin-like compounds in breast milk. Environ Health Perspect. 2002 Jun;110(6):A325-32. doi: 10.1289/ ehp.021100325. PMID: 12055063; PMCID: PMC1240886
22. Kerger BD, Leung HW, Scott P, Paustenbach DJ, Needham LL, Patterson DG Jr, Gerthoux PM, Mocarelli P. Age- and concentration-dependent elimination half-life of 2,3,7,8-tetrachlorodibenzo-p-dioxin in Seveso children. Environ Health Perspect. 2006 Oct;114(10):1596-602. doi: 10.1289/ehp.888 4. PMID: 17035149; PMCID: PMC1626409
23. Kerger BD, Leung HW, Scott PK, Paustenbach DJ. An adaptable internal dose model for risk assessment of dietary and soil dioxin exposures in young children. Toxicol Sci. 2007 Nov;100(1):224-37. doi: 10.1093/toxsci/kfm199. Epub 2007 Aug 6. PMID: 17682006
24. Abraham K, Knoll A, Ende M, Päpke O, Helge H. Intake, fecal excretion, and body burden of polychlorinated dibenzo-p-dioxins and dibenzofurans in breast-fed and formula-fed infants. Pediatr Res. 1996 Nov;40(5):671-9. doi: 10.1203/00006450-199611000-00005. PMID: 8910931
25. Abraham K, Päpke O, Gross A, Kordonouri O, Wiegand S, Wahn U, Helge H. Time course of PCDD/PCDF/PCB concentrations in breast-feeding mothers and their infants. Chemosphere. 1998 Oct-Nov;37(9-12):1731-41. doi: 10.1016/s0045-6535(98)00238-0. PMID: 9828301
26. Leung, H-W, Loccisano, A.E., Kerger, B. 2017. “Toxicokinetic Model for Estimating Childhood Body Burdens of Polychlorinated Biphenyls.” Toxicological Sciences 2017; 156(1): 348. Abstract #2476
27. Milbrath MO, Wenger Y, Chang CW, Emond C, Garabrant D, Gillespie BW, Jolliet O. Apparent half-lives of dioxins, furans, and polychlorinated biphenyls as a function of age, body fat, smoking status, and breast-feeding. Environ Health Perspect. 2009 Mar;117(3):417-25. doi: 10.1289/ehp.11781. Epub 2008 Oct 3. PMID: 19337517; PMCID: PMC2661912
28. Grandjean P, Budtz-Jørgensen E, Barr DB, Needham LL, Weihe P, Heinzow B. Elimination half-lives of polychlorinated biphenyl congeners in children. Environ Sci Technol. 2008 Sep 15;42(18): 6991-6. doi: 10.1021/es800778q. PMID: 18853821 ; PMCID: PMC2600453
29. Paustenbach DJ, Kerger BD. The University of Michigan Dioxin Exposure Study: estimating residential soil and house dust exposures to young children. Chemosphere. 2013 Apr;91(2):200-4. doi: 10.1016/j.chemosphere.2012.12.047. Epub 2013 Jan 22. PMID: 23351485
30. Demond A, Adriaens P, Towey T, Chang SC, Hong B, Chen Q, Chang CW, Franzblau A, Garabrant D, Gillespie B, Hedgeman E, Knutson K, Lee CY, Lepkowski J, Olson K, Ward B, Zwica L, Luksemburg W, Maier M. Statistical comparison of residential soil concentrations of PCDDs, PCDFs, and PCBs from two communities in Michigan. Environ Sci Technol. 2008 Aug 1;42(15):5441-8. doi: 10.1021/es702554g. PMID: 18754458
31. Demond A, Franzblau A, Garabrant D, Jiang X, Adriaens P, Chen Q, Gillespie B, Hao W, Hong B, Jolliet O, Lepkowski J. Human exposure from dioxins in soil. Environ Sci Technol. 2012 Feb 7;46(3):1296-302. doi: 10.1021/es2022363. Epub 2011 Dec 22. PMID: 22136605
32. Garabrant DH, Franzblau A, Lepkowski J, Gillespie BW, Adriaens P, Demond A, Ward B, Ladronka K, Hedgeman E, Knutson K, Zwica L, Olson K, Towey T, Chen Q, Hong B. The University of Michigan Dioxin Exposure Study: methods for an environmental exposure study of polychlorinated dioxins, furans, and biphenyls. Environ Health Perspect. 2009 May;117(5):803-10. doi: 10.1289/ ehp.11777. Epub 2008 Dec 22. PMID: 19479025; PMCID: PMC2685845
33. Hedgeman E, Chen Q, Hong B, Chang CW, Olson K, Ladronka K, Ward B, Adriaens P, Demond A, Gillespie BW, Lepkowski J, Franzblau A, Garabrant DH. The University of Michigan Dioxin Exposure Study: population survey results and serum concentrations for polychlorinated dioxins, furans, and biphenyls. Environ Health Perspect. 2009 May ;117(5):811-7. doi: 10.1289/ehp.11780. Epub 2008 Dec 22. PMID: 19479026; PMCID: PMC2685846
34. Okey AB. 2007. An aryl hydrocarbon receptor odyssey to the shores of toxicology: the Deichmann Lecture, International Congress of Toxicology-XI. Toxicol Sci 98:5-38
35. Sorg O. 2014. AhR signalling and dioxin toxicity. Toxicol Lett 230:225-33
36. Kohle C, Bock KW. 2007. Coordinate regulation of Phase I and II xenobiotic metabolisms by the Ah receptor and Nrf2. Biochem Pharmacol 73:1853-62
37. Abel J, Haarmann-Stemmann T. 2010. An introduction to the molecular basics of aryl hydrocarbon receptor biology. Biol Chem 391:1235-48
38. Guyot E, Chevallier A, Barouki R, Coumoul X. 2013. The AhR twist: ligand-dependent AhR signaling and pharmaco-toxicological implications. Drug Discov Today 18:479-86
39. Hahn ME. 2002. Aryl hydrocarbon receptors: diversity and evolution. Chem Biol Interact 141:131-60
40. Poland A. 1997. Reflections on risk assessment of receptor-acting xenobiotics. Regul Toxicol Pharmacol 26:41-3
41. Chun OK, Chung SJ, Song WO. 2007. Estimated dietary flavonoid intake and major food sources of U.S. adults. J Nutr 137:1244-52
42. Quintana FJ, Sherr DH. 2013. Aryl hydrocarbon receptor control of adaptive immunity. Pharmacol Rev 65:1148-61
43. O'Donnell EF, Koch DC, Bisson WH, Jang HS, Kolluri SK. 2014. The aryl hydrocarbon receptor mediates raloxifene-induced apoptosis in estrogen receptor-negative hepatoma and breast cancer cells. Cell Death Dis 5:e1038
44. Wahlang B, Falkner KC, Clair HB et al. 2014. Human receptor activation by aroclor 1260, a polychlorinated biphenyl mixture. Toxicol Sci 140:283-97
45. Forgacs, A. L., Dere, E., Angrish, M. M., & Zacharewski, T. R. (2013). Comparative Analysis of Temporal and Dose-Dependent TCDD-Elicited Gene Expression in Human, Mouse, and Rat Primary Hepatocytes. Toxicol Sci, 133(1):54–66
46. Nault R, Forgacs AL, Dere E, Zacharewski TR. 2013. Comparisons of differential gene expression elicited by TCDD, PCB126, betaNF, or ICZ in mouse hepatoma Hepa1c1c7 cells and C57BL/6 mouse liver. Toxicol Lett 223:52-9
47. Black MB, Budinsky RA, Dombkowski A, Cukovic D, LeCluyse EL, et al. 2012. Cross-species comparisons of transcriptomic alterations in human and rat primary hepatocytes exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin. Toxicol Sci 127:199-215
48. Budinsky RA, LeCluyse EL, Ferguson SS, Rowlands JC, Simon T. 2010. Human and rat primary hepatocyte CYP1A1 and 1A2 induction with 2,3,7,8-tetrachlorodibenzo-p-dioxin, 2,3,7,8-tetrachlorodibenzofuran, and 2,3,4,7,8-pentachlor odibenzofuran. Toxicol Sci 118:224-35
49. Budinsky RA, Schrenk D, Simon T, et al. 2014. Mode of action and dose-response framework analysis for receptor-mediated toxicity: the aryl hydrocarbon receptor as a case study. Crit Rev Toxicology 44(1):83-119
50. Carlson EA, McCulloch C, Koganti A, Goodwin SB, Sutter TR, Silkworth JB. 2009. Divergent transcriptomic responses to aryl hydrocarbon receptor agonists between rat and human primary hepatocytes. Toxicol Sci 112:257-72
51. Connor KT, Aylward LL. 2006. Human response to dioxin: aryl hydrocarbon receptor (AhR) molecular structure, function, and dose-response data for enzyme induction indicate an impaired human AhR. J Toxicol Environ Health B 9:147-71
52. Peters AK, van Londen K, Bergman A et al. 2004. Effects of polybrominated diphenyl ethers on basal and TCDD-induced ethoxyresorufin activity and cytochrome P450-1A1 expression in MCF-7, HepG2, and H4IIE cells. Toxicol Sci 82:488-96
53. Zeiger M, Haag R, Hockel J, Schrenk D, Schmitz HJ. 2001. Inducing effects of dioxin-like polychlorinated biphenyls on CYP1A in the human hepatoblastoma cell line HepG2, the rat hepatoma cell line H4IIE, and rat primary hepatocytes: comparison of relative potencies. Toxicol Sci 63:65-73
54. Xu L, Li AP, Kaminski DL, Ruh MF. 2000. 2,3,7,8 Tetrachlorodibenzo-p-dioxin induction of cytochrome P4501A in cultured rat and human hepatocytes. Chem Biol Interact 124:173-89
55. Wiebel FJ, Wegenke M, Kiefer F. 1996. Bioassay for determining 2,3,7,8-tetrachlorodibenzo-p-dioxin equivalents (TEs) in human hepatoma HepG2 cells. Toxicol Lett 88:335-8
56. Vamvakas, A., Keller, J. and Dufresne, M. 1996. In vitro induction of CYP1A1-associated activities in human and rodent cell lines by commercial and tissue-extracted halogenated aromatic hydrocarbons. Environ Toxicol Chem 15: 814–823
57. Schrenk D, Stuven T, Gohl G, Viebahn R, Bock KW. 1995. Induction of CYP1A and glutathione S-transferase activities by 2,3,7,8-tetrachlorodibenzo-p-dioxin in human hepatocyte cultures. Carcinogenesis 16:943-6
58. Lipp HP, Schrenk D, Wiesmuller T, Hagenmaier H, Bock KW. 1992. Assessment of biological activities of mixtures of polychlorinated dibenzo-p-dioxins (PCDDs) and their constituents in human HepG2 cells. Arch Toxicol 66:220-3
59. Schrenk, D, Lipp, HP, Wiesmüller, T et al. 1991. Assessment of biological activities of mixtures of polychlorinated dibenzo-p-dioxins: Comparison between defined mixtures and their constituents. Arch Toxicol 65: 114. doi:10.1007/BF02034936
60. Silkworth JB, Koganti A, Illouz K et al. 2005. Comparison of TCDD and PCB CYP1A induction sensitivities in fresh hepatocytes from human donors, Sprague-Dawley rats, and rhesus monkeys and HepG2 cells. Toxicol Sci 87:508-19
61. Connor KT, Harris MA, Edwards MR, Budinsky RA, Clark GC, et al. 2008. AH receptor agonist activity in human blood measured with a cell-based bioassay: evidence for naturally occurring AH receptor ligands in vivo. J Expo Sci Environ Epidemiol 18:369-80
62. Haake JM, Safe S, Mayura K, Phillips TD. 1987. Aroclor 1254 as an antagonist of the teratogenicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin. Toxicol Lett 38:299-306
63. Bannister R, Davis D, Zacharewski T, Tizard I, Safe S. 1987. Aroclor 1254 as a 2,3,7,8-tetrachlorodibenzo-p-dioxin antagonist: effects on enzyme induction and immunotoxicity. Toxicology 46:29-42
64. Biegel L, Harris M, Davis D, Rosengren R, Safe L, Safe S. 1989. 2,2',4,4',5,5'-hexachlorobiphenyl as a 2,3,7,8-tetrachlorodibenzo-p-dioxin antagonist in C57BL/6J mice. Toxicol Appl Pharmacol 97:561-71
65. Davis D, Safe S. 1989. Dose-response immunotoxicities of commercial polychlorinated biphenyls (PCBs) and their interaction with 2,3,7,8-tetrachlorodibenzo-p-dioxin. Toxicol Lett 48:35-43
66. Emond C, Birnbaum LS, DeVito MJ. 2006. Use of a physiologically based pharmacokinetic model for rats to study the influence of body fat mass and induction of CYP1A2 on the pharmacokinetics of TCDD. Environ Health Perspect 114:1394-400
67. Young AL. 2009. The history, use, disposition and environmental fate of Agent Orange. New York: Springer Science+Business Media, LLC.
68. Abraham K, Geusau A, Tosun Y, Helge H, Bauer S, Brockmoller J. 2002. Severe 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) intoxication: insights into the measurement of hepatic cytochrome P450 1A2 induction. Clin Pharmacol Ther 72:163-74
69. Guzelian P, Quattrochi L, Karch N, Aylward L, Kaley R. 2006. Does dioxin exert toxic effects in humans at or near current background body levels?: An evidence-based conclusion. Hum Exp Toxicol 25:99-105
70. Landi MT, Bertazzi PA, Baccarelli A, Consonni D, Masten S, et al. 2003. TCDD-mediated alterations in the AhR-dependent pathway in Seveso, Italy, 20 years after the accident. Carcinogenesis 24:673-80
71. Masten SA, Grassman JA, Miller CR, et al. 1998.Population-based studies of dioxin responsiveness: Individual variation of CYP1A1 levels and relationship to dioxin body burden. Organohal Comp 38:13-16
72. Lambert GH, CC, L, JJ, DA.,. 1994 The dose response relationship between the serum levels of polychlorinated biphenyls (PCBs) and polychlorinated dibenzofurans (PCDFs) and cytochromes P4501A2 activity as determined by the caffeine breath test. Organohal Comp 21:485-488
73. Halperin W, Kalow W, Sweeney MH, Tang BK, Fingerhut M, et al. 1995. Induction of P-450 in workers exposed to dioxin. Occup Environ Med 52:86-91
74. Lucier GW, Sunahara GI, Wong TK. 1990. Placental markers of human exposure to polychlorinated dibenzofurans and polychlorinated biphenyls: implications for risk assessment. IARC Sci Publ 104:55-62
75. Buffler PA, Ginevan ME, Mandel JS, Watkins DK. 2011. The Air Force health study: an epidemiologic retrospective. Ann Epidemiol 21:673-87
76. Aylward LL, Brunet RC, Starr TB, Carrier G, Delzell E, Cheng H, Beall C. Exposure reconstruction for the TCDD-exposed NIOSH cohort using a concentration- and age-dependent model of elimination. Risk Anal. 2005 Aug;25(4):945-56. doi: 10.1111/j.1539-6924.2005.00645.x. PMID: 16268942
77. Aylward LL, Brunet RC, Carrier G, Hays SM, Cushing CA, Needham LL, Patterson DG Jr, Gerthoux PM, Brambilla P, Mocarelli P. Concentration-dependent TCDD elimination kinetics in humans: toxicokinetic modeling for moderately to highly exposed adults from Seveso, Italy, and Vienna, Austria, and impact on dose estimates for the NIOSH cohort. J Expo Anal Environ Epidemiol. 2005 Jan;15(1):51-65. doi: 10.1038/sj.jea.7500370. PMID: 15083163
78. Abel J, Haarmann-Stemmann T. 2010. An introduction to the molecular basics of aryl hydrocarbon receptor biology. Biol Chem 391:1235-48
79. Abraham et al. (1988) Pharmacokinetics and biological activity of 2,3,7,8 tetrachlorodibenzo-p-dioxin. Arch Toxicol 62:359-368
80. Air Force Health Study (AFHS) 2005. Air force health study: an epidemiologic investigation of health effects in air force personnel following exposure to herbicides. 2002 Follow-up Examination Results, May 2002 to March 2005. DTIC Document
81. Assennato G, Cervino D, Emmett EA, Longo G, Merlo F. 1989. Follow-up of subjects who developed chloracne following TCDD exposure at Seveso. Am J Ind Med 16:119-25
82. Baccarelli A, Pesatori AC, Consonni D, Mocarelli P, Patterson DG, Jr., et al. 2005. Health status and plasma dioxin levels in chloracne cases 20 years after the Seveso, Italy accident. Br J Dermatol 152:459-65
83. Black MB, Budinsky RA, Dombkowski A, Cukovic D, LeCluyse EL, et al. 2012. Cross-species comparisons of transcriptomic alterations in human and rat primary hepatocytes exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin. Toxicol Sci 127:199-215
84. Bradberry SM, Watt BE, Proudfoot AT, Vale JA. 2000. Mechanisms of toxicity, clinical features, and management of acute chlorophenoxy herbicide poisoning: a review. J Toxicol Clin Toxicol 38:111-22
85. Crosby DG, Wong AS. 1977. Environmental degradation of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Science 195:1337-8
86. Demond A, Adriaens P, Towey T, Chang SC, Hong B, Chen Q, Chang CW, Franzblau A, Garabrant D, Gillespie B, Hedgeman E, Knutson K, Lee CY, Lepkowski J, Olson K, Ward B, Zwica L, Luksemburg W, Maier M. Statistical comparison of residential soil concentrations of PCDDs, PCDFs, and PCBs from two communities in Michigan. Environ Sci Technol. 2008 Aug 1;42(15):5441-8. doi: 10.1021/es702554g. PMID: 18754458.
87. De Tata V. 2014. Association of dioxin and other persistent organic pollutants (POPs) with diabetes: epidemiological evidence and new mechanisms of beta cell dysfunction. Int J Mol Sci 15:7787-811
88. Ebner K, Brewster DW, Matsumura F. 1988. Effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin on serum insulin and glucose levels in the rabbit. J Environ Sci Health B 23:427-38
89. Ferriby LL, Knutsen JS, Harris M, Unice KM, Scott P, Nony P, Haws LC, Paustenbach D. Evaluation of PCDD/F and dioxin-like PCB serum concentration data from the 2001-2002 National Health and Nutrition Examination Survey of the United States population. J Expo Sci Environ Epidemiol. 2007 Jul;17(4):358-71. doi: 10.1038/sj.jes.7500498. Epu b 2006 Jul 5. PMID: 16823400.
90. Fingerhut MA, Halperin WE, Marlow DA, Piacitelli LA, Honchar PA, et al. 1991. Cancer mortality in workers exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin. N Engl J Med 324:212-8
91. Flesch-Janys D, Berger J, Gurn P, Manz A, Nagel S, et al. 1995. Exposure to polychlorinated dioxins and furans (PCDD/F) and mortality in a cohort of workers from a herbicide-producing plant in Hamburg, Federal Republic of Germany. Am J Epidemiol 142:1165-75
92. Fried KW, Guo GL, Esterly N, Kong B, Rozman KK. 2010. 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) reverses hyperglycemia in a type II diabetes mellitus rat model by a mechanism unrelated to PPAR gamma. Drug Chem Toxicol 33:261-8
93. Garabrant DH, Franzblau A, Lepkowski J, Gillespie BW, Adriaens P, Demond A, Hedgeman E, Knutson K, Zwica L, Olson K, Towey T, Chen Q, Hong B, Chang CW, Lee SY, Ward B, Ladronka K, Luksemburg W, Maier M. The University of Michigan Dioxin Exposure Study: predictors of human serum dioxin concentrations in Midland and Saginaw, Michigan. Environ Health Perspect. 2009 May;117(5):818-24. doi: 10.1289/ehp.11779. Epub 2008 Dec 22. PMID: 19479027; PMCID: PMC2685847.
94. Goodman, M., Narayan, K. M. V., Flanders, D., Chang, E. T., Adami, H.-O., Boffetta, P., & Mandel, J. S. (2015). Dose-Response Relationship Between Serum 2,3,7,8-Tetrachlorodibenzo-p-Dioxin and Diabetes Mellitus: A Meta-Analysis. Am J Epidemiol 181(6):374–384.
96. Gorski JR, Muzi G, Weber LW, Pereira DW, Arceo RJ, et al. 1988. Some endocrine and morphological aspects of the acute toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Toxicol Pathol 16:313-20
97. Gorski JR, Rozman K. 1987. Dose-response and time course of hypothyroxinemia and hypoinsulinemia and characterization of insulin hypersensitivity in 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-treated rats. Toxicology 44:297-307
98. Harden F; Mueller JF; Toms L-M; Gaus C; Moore M; Paepke O; Ryan JJ; Hobson P. 2004. Determination of the levels of dioxin in the Australian population by analysis of blood serum. Organohalogen Compounds 66: 2853-2858.
99. Henriksen, G.L.; Ketchum, N.S.; Michalek, J.E.; Swaby, J.A. 1997. Serum dioxin and diabetes mellitus in veterans of Operation Ranch Hand. Epidemiology 8, 252–258.
100. Hill AB. 1965. The Environment and Disease: Association or Causation? Proc R Soc Med 58:295-300
101. IARC (International Agency for Research on Cancer) 1997. Working Group on the Evaluation of Carcinogenic Risks to Humans: Polychlorinated Dibenzo-para-dioxins and Polychlorinated Dibenzofurans. Lyon, France, 4-11 February 1997, IARC Monogr Eval Carcinog Risks Hum 69:1-631.
101. IOM (Institute of Medicine) 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
102. Ishida T, Kan-OS, Mutoh J, Takeda S, Ishii Y, et al. 2005. 2,3,7,8-Tetrachlorodibenzo-p-dioxin-induced change in intestinal function and pathology: evidence for the involvement of arylhydrocarbon receptor-mediated alteration of glucose transportation. Toxicol Appl Pharmacol 205:89-97
103. Kahn SE, Hull RL, Utzschneider KM. 2006. Mechanisms linking obesity to insulin resistance and type 2 diabetes. Nature 444:840-6
104. Kerger BD, Scott PK, Pavuk M, Gough M, Paustenbach DJ. 2012. Re-analysis of Ranch Hand study supports reverse causation hypothesis between dioxin and diabetes. Crit Rev Toxicol 42:669-87
105 Kerkvliet NI, Steppan LB, Vorachek W, Oda S, Farrer D, et al. 2009. Activation of aryl hydrocarbon receptor by TCDD prevents diabetes in NOD mice and increases Foxp3+ T cells in pancreatic lymph nodes. Immunotherapy 1:539-47
106. Kreuzer PE, Csanády GA, Baur C, Kessler W, Päpke O, Greim H, Filser JG. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) and congeners in infants. A toxicokinetic model of human lifetime body burden by TCDD with special emphasis on its uptake by nutrition. Arch Toxicol. 1997;71(6):383-400. doi: 10.1007/s002040050402. PMID: 9195020.
107. Kurita H, Yoshioka W, Nishimura N, Kubota N, Kadowaki T, Tohyama C. 2009. Aryl hydrocarbon receptor-mediated effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin on glucose-stimulated insulin secretion in mice. J Appl Toxicol 29:689-94
108. Lee DH, Lee IK, Song K, Steffes M, Toscano W, et al. 2006. A strong dose-response relation between serum concentrations of persistent organic pollutants and diabetes: results from the National Health and Examination Survey 1999-2002. Diabetes Care 29:1638-44
109. Leung HW, Kerger BD, Paustenbach DJ, Ryan JJ, Masuda Y. Concentration and age-dependent elimination kinetics of polychlorinated dibenzofurans in Yucheng and Yusho patients. Toxicol Ind Health. 2007 Sep;23(8):493-501. doi: 10.1177/074823370 8089024. PMID: 18669171.
110. Linden J, Lensu S, Tuomisto J, Pohjanvirta R. 2010. Dioxins, the aryl hydrocarbon receptor and the central regulation of energy balance. Front Neuroendocrinol 31:452-78
111. Loccisano AE; Bernal A.; Kerger BD (2023). Polyhalogenated Biphenyls, In: Patty’s Toxicology, Seventh Edition (eds. Paustenbach DJ; Farland WH; Greim H; Klaunig JE; Levy L). Hoboken, NJ: Wiley. https://onlinelibrary.wiley.com/doi/10.1002/0471125474.tox066.pub3
112. Longnecker MP., and Michalek JE. 2000. Serum dioxin level in relation to diabetes mellitus among Air Force veterans with background levels of exposure. Epidemiology:11:44-8.
113. Matsumura F. 2009. The significance of the nongenomic pathway in mediating inflammatory signaling of the dioxin-activated Ah receptor to cause toxic effects. Biochem Pharmacol 77:608-26
114. Michalek JE, Pavuk M. 2008. Diabetes and cancer in veterans of Operation Ranch Hand after adjustment for calendar period, days of spraying, and time spent in Southeast Asia. J Occup Environ Med 50:330-40
115. Michalek JE, Tripathi RC. 1999. Pharmacokinetics of TCDD in veterans of Operation Ranch Hand: 15-year follow-up. J Toxicol Environ Health A 57:369-78
116. Mocarelli P. 2001. Seveso: a teaching story. Chemosphere 43:391-402
117. Nault R, Forgacs AL, Dere E, Zacharewski TR. 2013. Comparisons of differential gene expression elicited by TCDD, PCB126, betaNF, or ICZ in mouse hepatoma Hepa1c1c7 cells and C57BL/6 mouse liver. Toxicol Lett 223:52-9
118. Neuberger M, Rappe C, Bergek S, Cai H, Hansson M, et al. 1999. Persistent health effects of dioxin contamination in herbicide production. Environ Res 81:206-14
119. Novelli M, Piaggi S, De Tata V. 2005. 2,3,7,8-Tetrachlorodibenzo-p-dioxin-induced impairment of glucose-stimulated insulin secretion in isolated rat pancreatic islets. Toxicol Lett 156:307-14
120. Ott MG, Zober A. 1996. Cause specific mortality and cancer incidence among employees exposed to 2,3,7,8-TCDD after a 1953 reactor accident. Occup Environ Med 53:606-12
121. Pazderova-Vejlupkova J, Nemcova, M, Pickova, J. 1981. The Development and Prognosis of Chronic Intoxication by Tetrachlorodibenzo-p-dioxin in Men. Inst Hyg Epidemiol 36:1-11
122. Pesatori AC, Consonni D, Bachetti S et al. 2003. Short- and long-term morbidity and mortality in the population exposed to dioxin after the "Seveso accident". Ind Health 41:127-38
123. Porte D, Jr., Kahn SE. 2001. Beta-cell dysfunction and failure in type 2 diabetes: potential mechanisms. Diabetes 50 Suppl 1:S160-3
124. Remillard RB, Bunce NJ. 2002. Linking dioxins to diabetes: epidemiology and biologic plausibility. Environ Health Perspect 110:853-8
125. Ross JH, Hewitt A, Armitage J, Solomon K, Watkins DK, Ginevan ME. 2015. Exposure to TCDD from base perimeter application of Agent Orange in Vietnam. Sci Total Environ 511:82-90
126. Santostefano MJ, Ross DG, Savas U, Jefcoate CR, Birnbaum LS. 1997. Differential time-course and dose-response relationships of TCDD-induced CYP1B1, CYP1A1, and CYP1A2 proteins in rats. Biochem Biophys Res Commun 233:20-4
127. Saurat JH, Kaya G, Saxer-Sekulic N, Pardo B, Becker M, et al. 2012. The cutaneous lesions of dioxin exposure: lessons from the poisoning of Victor Yushchenko. Toxicol Sci 125:310-7
128. Sorg O, Zennegg M, Schmid P et al. 2009. 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) poisoning in Victor Yushchenko: identification and measurement of TCDD metabolites. Lancet 374:1179-85
129. Sugai E, Yoshioka W, Kakeyama M, Ohsako S, Tohyama C. 2014. In utero and lactational exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin modulates dysregulation of the lipid metabolism in mouse offspring fed a high-calorie diet. J Appl Toxicol 34:296-306
130. Thiess AM, Frentzel-Beyme R, Link R. 1982. Mortality study of persons exposed to dioxin in a trichlorophenol-process accident that occurred in the BASF AG on November 17, 1953. Am J Ind Med 3:179-89
131. Tritscher AM, Goldstein JA, Portier CJ et al. 1992 Dose-response relationships for chronic exposure to 2,3,7,8- etrachlorodibenzo-dioxin in a rat tumor promotion model- quantification and immunolocalization of CYP1A1 and CYP1A2 in the liver. Cancer Res 52(12):3436-42
132. Vamvakas, A., Keller, J. and Dufresne, M. 1996. In vitro induction of CYP1A1-associated activities in human and rodent cell lines by commercial and tissue-extracted halogenated aromatic hydrocarbons. Environ Toxicol Chem 15: 814–823.
133. Walker NJ, Portier CJ, Lax SF et al. 1999. Characterization of the dose-response of CYP1B1, CYP1A1, and CYP1A2 in the liver of female Sprague-Dawley rats following chronic exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin. Toxicol Appl Pharmacol 154:279-86
134. Warner M, Mocarelli P, Brambilla P et al. 2013. Diabetes, metabolic syndrome, and obesity in relation to serum dioxin concentrations: the Seveso women's health study. Environ Health Perspect 121:906-11
135. Weber LW, Lebofsky M, Stahl BU, Gorski JR, Muzi G, Rozman K. 1991. Reduced activities of key enzymes of gluconeogenesis as possible cause of acute toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in rats. Toxicology 66:133-44
136. Wong AS and Crosby DG. 1978. Decontamination of2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) by photochemical action. New York, NY: SP Medical & Scientific Books.
137. Yi SW, Hong JS, Ohrr H, Yi JJ. 2014. Agent Orange exposure and disease prevalence in Korean Vietnam veterans: the Korean veterans health study. Environ Res 133:56-65
2. USEPA (United States Environmental Protection Agency). 2003. Exposure and Human Health Reassessment of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and Related Compounds. Office of Research and Development, National Center for Environmental Assessment. NAS Review Draft. December 2003
3. ATSDR (Agency for Toxic Substances and Disease Registry). 2024. Toxicological Profile for Chlorinated Dibenzo-p-Dioxins. Draft for Public Comment. October 2024. https://www.atsdr.cdc.gov/toxprofiles/tp104.pdf
4. Paustenbach DJ, Fehling K, Scott P, Harris M, Kerger BD. Identifying soil cleanup criteria for dioxins in urban residential soils: how have 20 years of research and risk assessment experience affected the analysis? J Toxicol Environ Health B Crit Rev. 2006 Mar-Apr;9(2):87-145. doi: 10.1080/10937400500538482. PMID: 16613806
5. USEPA (United States Environmental Protection Agency). 2002a. US Environmental Protection Agency Child-Specific Exposure Factor Handbook. Pp. 3-59. NCEA, Washington DC. EPA-600-P-00-002B
6. USEPA (United States Environmental Protection Agency). 1989. Risk Assessment Guidance for Superfund Vol 1. Human Health Evaluation Manual. Office of Emergency and Remedial Response. EPA/540/1-89/002
7. Williams, PRD; Holicky, KC; Paustenbach DJ 2003. Current methods for evaluating children’s exposures for use in health risk assessment. J Child Health 1, 41-98
8. USEPA (United States Environmental Protection Agency). 2002b. Short Sheet: Overview of the IEUBK Model for Lead in Children. EPA #PB 99-965-8, OSWER #9285-7-31. Office of Solid Waste and Emergency Response, USEPA, Washington DC
9. Kerger BD; Gerthoux PM; Mocarelli P. 2011. 1976 Trichlorophenol reactor explosion at Seveso, Italy. Encyclopedia of Environmental Health. Amsterdam; Elsevier. Editor-in-chief: Jerome O. Nriagu
10. ATSDR (Agency for Toxic Substances and Disease Registry). 2023. Toxicological Profile for Chlorodibenzofurans (CDFs). April 2023. https://www.atsdr.cdc.gov/toxprofiles/tp32.pdf
11. Aylward LL, Hays SM. Temporal trends in human TCDD body burden: decreases over three decades and implications for exposure levels. J Expo Anal Environ Epidemiol. 2002 Sep;12(5):319-28. doi: 10.1038/sj.jea.7500233. PMID: 12198580
12. Hays SM, Aylward LL. Dioxin risks in perspective: past, present, and future. Regul Toxicol Pharmacol. 2003 Apr;37(2):202-17. doi: 10.1016/s0273-2300(02)00044-2. PMID: 12726754
13. Lorber M. A pharmacokinetic model for estimating exposure of Americans to dioxin-like compounds in the past, present, and future. Sci Total Environ. 2002 Apr 8;288(1-2):81-95. doi: 10.1016/s0048-9697(01)01119-6. PMID: 12013550
14. Richter RO; Kerger BD; Leung HW; Paustenbach DJ. 2006. Implications of age-dependent half-lives of dioxins on assessment of breast milk dose and body burden. Toxicol Sci 89, 177 (Abstract 1561)
15. Lorber M, Patterson D, Huwe J, Kahn H. Evaluation of background exposures of Americans to dioxin-like compounds in the 1990s and the 2000s. Chemosphere. 2009 Oct;77(5):640-51. doi: 10.1016/j.chemosphere.2009.08.016. Epub 2009 Sep 4. PMID: 19733382
16. Arisawa K. Recent decreasing trends of exposure to PCDDs/PCDFs/dioxinlike PCBs in general populations, and associations with diabetes, metabolic syndrome, and gout/ hyperuricemia. J Med Invest. 2018;65(3.4):151-161. doi: 10.2152/jm i.65.151. PMID: 30282853
17. Bichteler A, Wikoff DS, Loko F, Harris MA. Estimating serum concentrations of dioxin-like compounds in the U.S. population effective 2005-2006 and 2007-2008: A multiple imputation and trending approach incorporating NHANES pooled sample data. Environ Int. 2017 Aug;105:112-125. doi: 10.1016/j.envint.2017.05.003. Epub 2017 May 18. PMID: 28527750
18. Kimbrough RD, Falk H, Stehr P, Fries G. Health implications of 2,3,7,8-tetrachlorodibenzodioxin (TCDD) contamination of residential soil. J Toxicol Environ Health. 1984;14(1):47-93. doi: 10.1080/15 287398409530562. PMID: 6389894
19. Kreuzer PE, Csanády GA, Baur C, Kessler W, Päpke O, Greim H, Filser JG. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) and congeners in infants. A toxicokinetic model of human lifetime body burden by TCDD with special emphasis on its uptake by nutrition. Arch Toxicol. 1997;71(6):383-400. doi: 10.1007/s002040050402. PMID: 9195020
20. Leung HW, Kerger BD, Paustenbach DJ. Elimination half-lives of selected polychlorinated dibenzodioxins and dibenzofurans in breast-fed human infants. J Toxicol Environ Health A. 2006 Mar;69(6):437-43. doi: 10.1080/152873905002468 86. PMID: 16574620
21. Lorber M, Phillips L. Infant exposure to dioxin-like compounds in breast milk. Environ Health Perspect. 2002 Jun;110(6):A325-32. doi: 10.1289/ ehp.021100325. PMID: 12055063; PMCID: PMC1240886
22. Kerger BD, Leung HW, Scott P, Paustenbach DJ, Needham LL, Patterson DG Jr, Gerthoux PM, Mocarelli P. Age- and concentration-dependent elimination half-life of 2,3,7,8-tetrachlorodibenzo-p-dioxin in Seveso children. Environ Health Perspect. 2006 Oct;114(10):1596-602. doi: 10.1289/ehp.888 4. PMID: 17035149; PMCID: PMC1626409
23. Kerger BD, Leung HW, Scott PK, Paustenbach DJ. An adaptable internal dose model for risk assessment of dietary and soil dioxin exposures in young children. Toxicol Sci. 2007 Nov;100(1):224-37. doi: 10.1093/toxsci/kfm199. Epub 2007 Aug 6. PMID: 17682006
24. Abraham K, Knoll A, Ende M, Päpke O, Helge H. Intake, fecal excretion, and body burden of polychlorinated dibenzo-p-dioxins and dibenzofurans in breast-fed and formula-fed infants. Pediatr Res. 1996 Nov;40(5):671-9. doi: 10.1203/00006450-199611000-00005. PMID: 8910931
25. Abraham K, Päpke O, Gross A, Kordonouri O, Wiegand S, Wahn U, Helge H. Time course of PCDD/PCDF/PCB concentrations in breast-feeding mothers and their infants. Chemosphere. 1998 Oct-Nov;37(9-12):1731-41. doi: 10.1016/s0045-6535(98)00238-0. PMID: 9828301
26. Leung, H-W, Loccisano, A.E., Kerger, B. 2017. “Toxicokinetic Model for Estimating Childhood Body Burdens of Polychlorinated Biphenyls.” Toxicological Sciences 2017; 156(1): 348. Abstract #2476
27. Milbrath MO, Wenger Y, Chang CW, Emond C, Garabrant D, Gillespie BW, Jolliet O. Apparent half-lives of dioxins, furans, and polychlorinated biphenyls as a function of age, body fat, smoking status, and breast-feeding. Environ Health Perspect. 2009 Mar;117(3):417-25. doi: 10.1289/ehp.11781. Epub 2008 Oct 3. PMID: 19337517; PMCID: PMC2661912
28. Grandjean P, Budtz-Jørgensen E, Barr DB, Needham LL, Weihe P, Heinzow B. Elimination half-lives of polychlorinated biphenyl congeners in children. Environ Sci Technol. 2008 Sep 15;42(18): 6991-6. doi: 10.1021/es800778q. PMID: 18853821 ; PMCID: PMC2600453
29. Paustenbach DJ, Kerger BD. The University of Michigan Dioxin Exposure Study: estimating residential soil and house dust exposures to young children. Chemosphere. 2013 Apr;91(2):200-4. doi: 10.1016/j.chemosphere.2012.12.047. Epub 2013 Jan 22. PMID: 23351485
30. Demond A, Adriaens P, Towey T, Chang SC, Hong B, Chen Q, Chang CW, Franzblau A, Garabrant D, Gillespie B, Hedgeman E, Knutson K, Lee CY, Lepkowski J, Olson K, Ward B, Zwica L, Luksemburg W, Maier M. Statistical comparison of residential soil concentrations of PCDDs, PCDFs, and PCBs from two communities in Michigan. Environ Sci Technol. 2008 Aug 1;42(15):5441-8. doi: 10.1021/es702554g. PMID: 18754458
31. Demond A, Franzblau A, Garabrant D, Jiang X, Adriaens P, Chen Q, Gillespie B, Hao W, Hong B, Jolliet O, Lepkowski J. Human exposure from dioxins in soil. Environ Sci Technol. 2012 Feb 7;46(3):1296-302. doi: 10.1021/es2022363. Epub 2011 Dec 22. PMID: 22136605
32. Garabrant DH, Franzblau A, Lepkowski J, Gillespie BW, Adriaens P, Demond A, Ward B, Ladronka K, Hedgeman E, Knutson K, Zwica L, Olson K, Towey T, Chen Q, Hong B. The University of Michigan Dioxin Exposure Study: methods for an environmental exposure study of polychlorinated dioxins, furans, and biphenyls. Environ Health Perspect. 2009 May;117(5):803-10. doi: 10.1289/ ehp.11777. Epub 2008 Dec 22. PMID: 19479025; PMCID: PMC2685845
33. Hedgeman E, Chen Q, Hong B, Chang CW, Olson K, Ladronka K, Ward B, Adriaens P, Demond A, Gillespie BW, Lepkowski J, Franzblau A, Garabrant DH. The University of Michigan Dioxin Exposure Study: population survey results and serum concentrations for polychlorinated dioxins, furans, and biphenyls. Environ Health Perspect. 2009 May ;117(5):811-7. doi: 10.1289/ehp.11780. Epub 2008 Dec 22. PMID: 19479026; PMCID: PMC2685846
34. Okey AB. 2007. An aryl hydrocarbon receptor odyssey to the shores of toxicology: the Deichmann Lecture, International Congress of Toxicology-XI. Toxicol Sci 98:5-38
35. Sorg O. 2014. AhR signalling and dioxin toxicity. Toxicol Lett 230:225-33
36. Kohle C, Bock KW. 2007. Coordinate regulation of Phase I and II xenobiotic metabolisms by the Ah receptor and Nrf2. Biochem Pharmacol 73:1853-62
37. Abel J, Haarmann-Stemmann T. 2010. An introduction to the molecular basics of aryl hydrocarbon receptor biology. Biol Chem 391:1235-48
38. Guyot E, Chevallier A, Barouki R, Coumoul X. 2013. The AhR twist: ligand-dependent AhR signaling and pharmaco-toxicological implications. Drug Discov Today 18:479-86
39. Hahn ME. 2002. Aryl hydrocarbon receptors: diversity and evolution. Chem Biol Interact 141:131-60
40. Poland A. 1997. Reflections on risk assessment of receptor-acting xenobiotics. Regul Toxicol Pharmacol 26:41-3
41. Chun OK, Chung SJ, Song WO. 2007. Estimated dietary flavonoid intake and major food sources of U.S. adults. J Nutr 137:1244-52
42. Quintana FJ, Sherr DH. 2013. Aryl hydrocarbon receptor control of adaptive immunity. Pharmacol Rev 65:1148-61
43. O'Donnell EF, Koch DC, Bisson WH, Jang HS, Kolluri SK. 2014. The aryl hydrocarbon receptor mediates raloxifene-induced apoptosis in estrogen receptor-negative hepatoma and breast cancer cells. Cell Death Dis 5:e1038
44. Wahlang B, Falkner KC, Clair HB et al. 2014. Human receptor activation by aroclor 1260, a polychlorinated biphenyl mixture. Toxicol Sci 140:283-97
45. Forgacs, A. L., Dere, E., Angrish, M. M., & Zacharewski, T. R. (2013). Comparative Analysis of Temporal and Dose-Dependent TCDD-Elicited Gene Expression in Human, Mouse, and Rat Primary Hepatocytes. Toxicol Sci, 133(1):54–66
46. Nault R, Forgacs AL, Dere E, Zacharewski TR. 2013. Comparisons of differential gene expression elicited by TCDD, PCB126, betaNF, or ICZ in mouse hepatoma Hepa1c1c7 cells and C57BL/6 mouse liver. Toxicol Lett 223:52-9
47. Black MB, Budinsky RA, Dombkowski A, Cukovic D, LeCluyse EL, et al. 2012. Cross-species comparisons of transcriptomic alterations in human and rat primary hepatocytes exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin. Toxicol Sci 127:199-215
48. Budinsky RA, LeCluyse EL, Ferguson SS, Rowlands JC, Simon T. 2010. Human and rat primary hepatocyte CYP1A1 and 1A2 induction with 2,3,7,8-tetrachlorodibenzo-p-dioxin, 2,3,7,8-tetrachlorodibenzofuran, and 2,3,4,7,8-pentachlor odibenzofuran. Toxicol Sci 118:224-35
49. Budinsky RA, Schrenk D, Simon T, et al. 2014. Mode of action and dose-response framework analysis for receptor-mediated toxicity: the aryl hydrocarbon receptor as a case study. Crit Rev Toxicology 44(1):83-119
50. Carlson EA, McCulloch C, Koganti A, Goodwin SB, Sutter TR, Silkworth JB. 2009. Divergent transcriptomic responses to aryl hydrocarbon receptor agonists between rat and human primary hepatocytes. Toxicol Sci 112:257-72
51. Connor KT, Aylward LL. 2006. Human response to dioxin: aryl hydrocarbon receptor (AhR) molecular structure, function, and dose-response data for enzyme induction indicate an impaired human AhR. J Toxicol Environ Health B 9:147-71
52. Peters AK, van Londen K, Bergman A et al. 2004. Effects of polybrominated diphenyl ethers on basal and TCDD-induced ethoxyresorufin activity and cytochrome P450-1A1 expression in MCF-7, HepG2, and H4IIE cells. Toxicol Sci 82:488-96
53. Zeiger M, Haag R, Hockel J, Schrenk D, Schmitz HJ. 2001. Inducing effects of dioxin-like polychlorinated biphenyls on CYP1A in the human hepatoblastoma cell line HepG2, the rat hepatoma cell line H4IIE, and rat primary hepatocytes: comparison of relative potencies. Toxicol Sci 63:65-73
54. Xu L, Li AP, Kaminski DL, Ruh MF. 2000. 2,3,7,8 Tetrachlorodibenzo-p-dioxin induction of cytochrome P4501A in cultured rat and human hepatocytes. Chem Biol Interact 124:173-89
55. Wiebel FJ, Wegenke M, Kiefer F. 1996. Bioassay for determining 2,3,7,8-tetrachlorodibenzo-p-dioxin equivalents (TEs) in human hepatoma HepG2 cells. Toxicol Lett 88:335-8
56. Vamvakas, A., Keller, J. and Dufresne, M. 1996. In vitro induction of CYP1A1-associated activities in human and rodent cell lines by commercial and tissue-extracted halogenated aromatic hydrocarbons. Environ Toxicol Chem 15: 814–823
57. Schrenk D, Stuven T, Gohl G, Viebahn R, Bock KW. 1995. Induction of CYP1A and glutathione S-transferase activities by 2,3,7,8-tetrachlorodibenzo-p-dioxin in human hepatocyte cultures. Carcinogenesis 16:943-6
58. Lipp HP, Schrenk D, Wiesmuller T, Hagenmaier H, Bock KW. 1992. Assessment of biological activities of mixtures of polychlorinated dibenzo-p-dioxins (PCDDs) and their constituents in human HepG2 cells. Arch Toxicol 66:220-3
59. Schrenk, D, Lipp, HP, Wiesmüller, T et al. 1991. Assessment of biological activities of mixtures of polychlorinated dibenzo-p-dioxins: Comparison between defined mixtures and their constituents. Arch Toxicol 65: 114. doi:10.1007/BF02034936
60. Silkworth JB, Koganti A, Illouz K et al. 2005. Comparison of TCDD and PCB CYP1A induction sensitivities in fresh hepatocytes from human donors, Sprague-Dawley rats, and rhesus monkeys and HepG2 cells. Toxicol Sci 87:508-19
61. Connor KT, Harris MA, Edwards MR, Budinsky RA, Clark GC, et al. 2008. AH receptor agonist activity in human blood measured with a cell-based bioassay: evidence for naturally occurring AH receptor ligands in vivo. J Expo Sci Environ Epidemiol 18:369-80
62. Haake JM, Safe S, Mayura K, Phillips TD. 1987. Aroclor 1254 as an antagonist of the teratogenicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin. Toxicol Lett 38:299-306
63. Bannister R, Davis D, Zacharewski T, Tizard I, Safe S. 1987. Aroclor 1254 as a 2,3,7,8-tetrachlorodibenzo-p-dioxin antagonist: effects on enzyme induction and immunotoxicity. Toxicology 46:29-42
64. Biegel L, Harris M, Davis D, Rosengren R, Safe L, Safe S. 1989. 2,2',4,4',5,5'-hexachlorobiphenyl as a 2,3,7,8-tetrachlorodibenzo-p-dioxin antagonist in C57BL/6J mice. Toxicol Appl Pharmacol 97:561-71
65. Davis D, Safe S. 1989. Dose-response immunotoxicities of commercial polychlorinated biphenyls (PCBs) and their interaction with 2,3,7,8-tetrachlorodibenzo-p-dioxin. Toxicol Lett 48:35-43
66. Emond C, Birnbaum LS, DeVito MJ. 2006. Use of a physiologically based pharmacokinetic model for rats to study the influence of body fat mass and induction of CYP1A2 on the pharmacokinetics of TCDD. Environ Health Perspect 114:1394-400
67. Young AL. 2009. The history, use, disposition and environmental fate of Agent Orange. New York: Springer Science+Business Media, LLC.
68. Abraham K, Geusau A, Tosun Y, Helge H, Bauer S, Brockmoller J. 2002. Severe 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) intoxication: insights into the measurement of hepatic cytochrome P450 1A2 induction. Clin Pharmacol Ther 72:163-74
69. Guzelian P, Quattrochi L, Karch N, Aylward L, Kaley R. 2006. Does dioxin exert toxic effects in humans at or near current background body levels?: An evidence-based conclusion. Hum Exp Toxicol 25:99-105
70. Landi MT, Bertazzi PA, Baccarelli A, Consonni D, Masten S, et al. 2003. TCDD-mediated alterations in the AhR-dependent pathway in Seveso, Italy, 20 years after the accident. Carcinogenesis 24:673-80
71. Masten SA, Grassman JA, Miller CR, et al. 1998.Population-based studies of dioxin responsiveness: Individual variation of CYP1A1 levels and relationship to dioxin body burden. Organohal Comp 38:13-16
72. Lambert GH, CC, L, JJ, DA.,. 1994 The dose response relationship between the serum levels of polychlorinated biphenyls (PCBs) and polychlorinated dibenzofurans (PCDFs) and cytochromes P4501A2 activity as determined by the caffeine breath test. Organohal Comp 21:485-488
73. Halperin W, Kalow W, Sweeney MH, Tang BK, Fingerhut M, et al. 1995. Induction of P-450 in workers exposed to dioxin. Occup Environ Med 52:86-91
74. Lucier GW, Sunahara GI, Wong TK. 1990. Placental markers of human exposure to polychlorinated dibenzofurans and polychlorinated biphenyls: implications for risk assessment. IARC Sci Publ 104:55-62
75. Buffler PA, Ginevan ME, Mandel JS, Watkins DK. 2011. The Air Force health study: an epidemiologic retrospective. Ann Epidemiol 21:673-87
76. Aylward LL, Brunet RC, Starr TB, Carrier G, Delzell E, Cheng H, Beall C. Exposure reconstruction for the TCDD-exposed NIOSH cohort using a concentration- and age-dependent model of elimination. Risk Anal. 2005 Aug;25(4):945-56. doi: 10.1111/j.1539-6924.2005.00645.x. PMID: 16268942
77. Aylward LL, Brunet RC, Carrier G, Hays SM, Cushing CA, Needham LL, Patterson DG Jr, Gerthoux PM, Brambilla P, Mocarelli P. Concentration-dependent TCDD elimination kinetics in humans: toxicokinetic modeling for moderately to highly exposed adults from Seveso, Italy, and Vienna, Austria, and impact on dose estimates for the NIOSH cohort. J Expo Anal Environ Epidemiol. 2005 Jan;15(1):51-65. doi: 10.1038/sj.jea.7500370. PMID: 15083163
78. Abel J, Haarmann-Stemmann T. 2010. An introduction to the molecular basics of aryl hydrocarbon receptor biology. Biol Chem 391:1235-48
79. Abraham et al. (1988) Pharmacokinetics and biological activity of 2,3,7,8 tetrachlorodibenzo-p-dioxin. Arch Toxicol 62:359-368
80. Air Force Health Study (AFHS) 2005. Air force health study: an epidemiologic investigation of health effects in air force personnel following exposure to herbicides. 2002 Follow-up Examination Results, May 2002 to March 2005. DTIC Document
81. Assennato G, Cervino D, Emmett EA, Longo G, Merlo F. 1989. Follow-up of subjects who developed chloracne following TCDD exposure at Seveso. Am J Ind Med 16:119-25
82. Baccarelli A, Pesatori AC, Consonni D, Mocarelli P, Patterson DG, Jr., et al. 2005. Health status and plasma dioxin levels in chloracne cases 20 years after the Seveso, Italy accident. Br J Dermatol 152:459-65
83. Black MB, Budinsky RA, Dombkowski A, Cukovic D, LeCluyse EL, et al. 2012. Cross-species comparisons of transcriptomic alterations in human and rat primary hepatocytes exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin. Toxicol Sci 127:199-215
84. Bradberry SM, Watt BE, Proudfoot AT, Vale JA. 2000. Mechanisms of toxicity, clinical features, and management of acute chlorophenoxy herbicide poisoning: a review. J Toxicol Clin Toxicol 38:111-22
85. Crosby DG, Wong AS. 1977. Environmental degradation of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Science 195:1337-8
86. Demond A, Adriaens P, Towey T, Chang SC, Hong B, Chen Q, Chang CW, Franzblau A, Garabrant D, Gillespie B, Hedgeman E, Knutson K, Lee CY, Lepkowski J, Olson K, Ward B, Zwica L, Luksemburg W, Maier M. Statistical comparison of residential soil concentrations of PCDDs, PCDFs, and PCBs from two communities in Michigan. Environ Sci Technol. 2008 Aug 1;42(15):5441-8. doi: 10.1021/es702554g. PMID: 18754458.
87. De Tata V. 2014. Association of dioxin and other persistent organic pollutants (POPs) with diabetes: epidemiological evidence and new mechanisms of beta cell dysfunction. Int J Mol Sci 15:7787-811
88. Ebner K, Brewster DW, Matsumura F. 1988. Effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin on serum insulin and glucose levels in the rabbit. J Environ Sci Health B 23:427-38
89. Ferriby LL, Knutsen JS, Harris M, Unice KM, Scott P, Nony P, Haws LC, Paustenbach D. Evaluation of PCDD/F and dioxin-like PCB serum concentration data from the 2001-2002 National Health and Nutrition Examination Survey of the United States population. J Expo Sci Environ Epidemiol. 2007 Jul;17(4):358-71. doi: 10.1038/sj.jes.7500498. Epu b 2006 Jul 5. PMID: 16823400.
90. Fingerhut MA, Halperin WE, Marlow DA, Piacitelli LA, Honchar PA, et al. 1991. Cancer mortality in workers exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin. N Engl J Med 324:212-8
91. Flesch-Janys D, Berger J, Gurn P, Manz A, Nagel S, et al. 1995. Exposure to polychlorinated dioxins and furans (PCDD/F) and mortality in a cohort of workers from a herbicide-producing plant in Hamburg, Federal Republic of Germany. Am J Epidemiol 142:1165-75
92. Fried KW, Guo GL, Esterly N, Kong B, Rozman KK. 2010. 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) reverses hyperglycemia in a type II diabetes mellitus rat model by a mechanism unrelated to PPAR gamma. Drug Chem Toxicol 33:261-8
93. Garabrant DH, Franzblau A, Lepkowski J, Gillespie BW, Adriaens P, Demond A, Hedgeman E, Knutson K, Zwica L, Olson K, Towey T, Chen Q, Hong B, Chang CW, Lee SY, Ward B, Ladronka K, Luksemburg W, Maier M. The University of Michigan Dioxin Exposure Study: predictors of human serum dioxin concentrations in Midland and Saginaw, Michigan. Environ Health Perspect. 2009 May;117(5):818-24. doi: 10.1289/ehp.11779. Epub 2008 Dec 22. PMID: 19479027; PMCID: PMC2685847.
94. Goodman, M., Narayan, K. M. V., Flanders, D., Chang, E. T., Adami, H.-O., Boffetta, P., & Mandel, J. S. (2015). Dose-Response Relationship Between Serum 2,3,7,8-Tetrachlorodibenzo-p-Dioxin and Diabetes Mellitus: A Meta-Analysis. Am J Epidemiol 181(6):374–384.
96. Gorski JR, Muzi G, Weber LW, Pereira DW, Arceo RJ, et al. 1988. Some endocrine and morphological aspects of the acute toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Toxicol Pathol 16:313-20
97. Gorski JR, Rozman K. 1987. Dose-response and time course of hypothyroxinemia and hypoinsulinemia and characterization of insulin hypersensitivity in 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-treated rats. Toxicology 44:297-307
98. Harden F; Mueller JF; Toms L-M; Gaus C; Moore M; Paepke O; Ryan JJ; Hobson P. 2004. Determination of the levels of dioxin in the Australian population by analysis of blood serum. Organohalogen Compounds 66: 2853-2858.
99. Henriksen, G.L.; Ketchum, N.S.; Michalek, J.E.; Swaby, J.A. 1997. Serum dioxin and diabetes mellitus in veterans of Operation Ranch Hand. Epidemiology 8, 252–258.
100. Hill AB. 1965. The Environment and Disease: Association or Causation? Proc R Soc Med 58:295-300
101. IARC (International Agency for Research on Cancer) 1997. Working Group on the Evaluation of Carcinogenic Risks to Humans: Polychlorinated Dibenzo-para-dioxins and Polychlorinated Dibenzofurans. Lyon, France, 4-11 February 1997, IARC Monogr Eval Carcinog Risks Hum 69:1-631.
101. IOM (Institute of Medicine) 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
102. Ishida T, Kan-OS, Mutoh J, Takeda S, Ishii Y, et al. 2005. 2,3,7,8-Tetrachlorodibenzo-p-dioxin-induced change in intestinal function and pathology: evidence for the involvement of arylhydrocarbon receptor-mediated alteration of glucose transportation. Toxicol Appl Pharmacol 205:89-97
103. Kahn SE, Hull RL, Utzschneider KM. 2006. Mechanisms linking obesity to insulin resistance and type 2 diabetes. Nature 444:840-6
104. Kerger BD, Scott PK, Pavuk M, Gough M, Paustenbach DJ. 2012. Re-analysis of Ranch Hand study supports reverse causation hypothesis between dioxin and diabetes. Crit Rev Toxicol 42:669-87
105 Kerkvliet NI, Steppan LB, Vorachek W, Oda S, Farrer D, et al. 2009. Activation of aryl hydrocarbon receptor by TCDD prevents diabetes in NOD mice and increases Foxp3+ T cells in pancreatic lymph nodes. Immunotherapy 1:539-47
106. Kreuzer PE, Csanády GA, Baur C, Kessler W, Päpke O, Greim H, Filser JG. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) and congeners in infants. A toxicokinetic model of human lifetime body burden by TCDD with special emphasis on its uptake by nutrition. Arch Toxicol. 1997;71(6):383-400. doi: 10.1007/s002040050402. PMID: 9195020.
107. Kurita H, Yoshioka W, Nishimura N, Kubota N, Kadowaki T, Tohyama C. 2009. Aryl hydrocarbon receptor-mediated effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin on glucose-stimulated insulin secretion in mice. J Appl Toxicol 29:689-94
108. Lee DH, Lee IK, Song K, Steffes M, Toscano W, et al. 2006. A strong dose-response relation between serum concentrations of persistent organic pollutants and diabetes: results from the National Health and Examination Survey 1999-2002. Diabetes Care 29:1638-44
109. Leung HW, Kerger BD, Paustenbach DJ, Ryan JJ, Masuda Y. Concentration and age-dependent elimination kinetics of polychlorinated dibenzofurans in Yucheng and Yusho patients. Toxicol Ind Health. 2007 Sep;23(8):493-501. doi: 10.1177/074823370 8089024. PMID: 18669171.
110. Linden J, Lensu S, Tuomisto J, Pohjanvirta R. 2010. Dioxins, the aryl hydrocarbon receptor and the central regulation of energy balance. Front Neuroendocrinol 31:452-78
111. Loccisano AE; Bernal A.; Kerger BD (2023). Polyhalogenated Biphenyls, In: Patty’s Toxicology, Seventh Edition (eds. Paustenbach DJ; Farland WH; Greim H; Klaunig JE; Levy L). Hoboken, NJ: Wiley. https://onlinelibrary.wiley.com/doi/10.1002/0471125474.tox066.pub3
112. Longnecker MP., and Michalek JE. 2000. Serum dioxin level in relation to diabetes mellitus among Air Force veterans with background levels of exposure. Epidemiology:11:44-8.
113. Matsumura F. 2009. The significance of the nongenomic pathway in mediating inflammatory signaling of the dioxin-activated Ah receptor to cause toxic effects. Biochem Pharmacol 77:608-26
114. Michalek JE, Pavuk M. 2008. Diabetes and cancer in veterans of Operation Ranch Hand after adjustment for calendar period, days of spraying, and time spent in Southeast Asia. J Occup Environ Med 50:330-40
115. Michalek JE, Tripathi RC. 1999. Pharmacokinetics of TCDD in veterans of Operation Ranch Hand: 15-year follow-up. J Toxicol Environ Health A 57:369-78
116. Mocarelli P. 2001. Seveso: a teaching story. Chemosphere 43:391-402
117. Nault R, Forgacs AL, Dere E, Zacharewski TR. 2013. Comparisons of differential gene expression elicited by TCDD, PCB126, betaNF, or ICZ in mouse hepatoma Hepa1c1c7 cells and C57BL/6 mouse liver. Toxicol Lett 223:52-9
118. Neuberger M, Rappe C, Bergek S, Cai H, Hansson M, et al. 1999. Persistent health effects of dioxin contamination in herbicide production. Environ Res 81:206-14
119. Novelli M, Piaggi S, De Tata V. 2005. 2,3,7,8-Tetrachlorodibenzo-p-dioxin-induced impairment of glucose-stimulated insulin secretion in isolated rat pancreatic islets. Toxicol Lett 156:307-14
120. Ott MG, Zober A. 1996. Cause specific mortality and cancer incidence among employees exposed to 2,3,7,8-TCDD after a 1953 reactor accident. Occup Environ Med 53:606-12
121. Pazderova-Vejlupkova J, Nemcova, M, Pickova, J. 1981. The Development and Prognosis of Chronic Intoxication by Tetrachlorodibenzo-p-dioxin in Men. Inst Hyg Epidemiol 36:1-11
122. Pesatori AC, Consonni D, Bachetti S et al. 2003. Short- and long-term morbidity and mortality in the population exposed to dioxin after the "Seveso accident". Ind Health 41:127-38
123. Porte D, Jr., Kahn SE. 2001. Beta-cell dysfunction and failure in type 2 diabetes: potential mechanisms. Diabetes 50 Suppl 1:S160-3
124. Remillard RB, Bunce NJ. 2002. Linking dioxins to diabetes: epidemiology and biologic plausibility. Environ Health Perspect 110:853-8
125. Ross JH, Hewitt A, Armitage J, Solomon K, Watkins DK, Ginevan ME. 2015. Exposure to TCDD from base perimeter application of Agent Orange in Vietnam. Sci Total Environ 511:82-90
126. Santostefano MJ, Ross DG, Savas U, Jefcoate CR, Birnbaum LS. 1997. Differential time-course and dose-response relationships of TCDD-induced CYP1B1, CYP1A1, and CYP1A2 proteins in rats. Biochem Biophys Res Commun 233:20-4
127. Saurat JH, Kaya G, Saxer-Sekulic N, Pardo B, Becker M, et al. 2012. The cutaneous lesions of dioxin exposure: lessons from the poisoning of Victor Yushchenko. Toxicol Sci 125:310-7
128. Sorg O, Zennegg M, Schmid P et al. 2009. 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) poisoning in Victor Yushchenko: identification and measurement of TCDD metabolites. Lancet 374:1179-85
129. Sugai E, Yoshioka W, Kakeyama M, Ohsako S, Tohyama C. 2014. In utero and lactational exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin modulates dysregulation of the lipid metabolism in mouse offspring fed a high-calorie diet. J Appl Toxicol 34:296-306
130. Thiess AM, Frentzel-Beyme R, Link R. 1982. Mortality study of persons exposed to dioxin in a trichlorophenol-process accident that occurred in the BASF AG on November 17, 1953. Am J Ind Med 3:179-89
131. Tritscher AM, Goldstein JA, Portier CJ et al. 1992 Dose-response relationships for chronic exposure to 2,3,7,8- etrachlorodibenzo-dioxin in a rat tumor promotion model- quantification and immunolocalization of CYP1A1 and CYP1A2 in the liver. Cancer Res 52(12):3436-42
132. Vamvakas, A., Keller, J. and Dufresne, M. 1996. In vitro induction of CYP1A1-associated activities in human and rodent cell lines by commercial and tissue-extracted halogenated aromatic hydrocarbons. Environ Toxicol Chem 15: 814–823.
133. Walker NJ, Portier CJ, Lax SF et al. 1999. Characterization of the dose-response of CYP1B1, CYP1A1, and CYP1A2 in the liver of female Sprague-Dawley rats following chronic exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin. Toxicol Appl Pharmacol 154:279-86
134. Warner M, Mocarelli P, Brambilla P et al. 2013. Diabetes, metabolic syndrome, and obesity in relation to serum dioxin concentrations: the Seveso women's health study. Environ Health Perspect 121:906-11
135. Weber LW, Lebofsky M, Stahl BU, Gorski JR, Muzi G, Rozman K. 1991. Reduced activities of key enzymes of gluconeogenesis as possible cause of acute toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in rats. Toxicology 66:133-44
136. Wong AS and Crosby DG. 1978. Decontamination of2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) by photochemical action. New York, NY: SP Medical & Scientific Books.
137. Yi SW, Hong JS, Ohrr H, Yi JJ. 2014. Agent Orange exposure and disease prevalence in Korean Vietnam veterans: the Korean veterans health study. Environ Res 133:56-65