Proposed reference dose for toxaphene carcinogenicity based on constitutive androstane receptor-mediated mode of action

References

• Aleksunes LM and Klaassen CD. 2012. Coordinated regulation of hepatic phase I and II drug-metabolizing genes and transporters using AhR-, CAR-, PXR-, PPARalpha-, and Nrf2-null mice. Drug Metab Dispos 40:1366–79. doi:10.1124/dmd.112.045112
   PubMed Web of Science ®Google Scholar
• Andersen ME, Preston RJ, Maier A, et al. 2014. Dose-response approaches for nuclear receptor-mediated modes of action for liver carcinogenicity: results of a workshop. Crit Rev Toxicol 44:50–63. doi:10.3109/10408444.2013.835785
   PubMed Web of Science ®Google Scholar
• Andrews P, Headrick K, Pilon JC, et al. 1996. Capillary GC-ECD and ECNI GCMS characterization of toxaphene residues in primate tissues during a feeding study. Chemosphere 32:1043–53. doi:10.1016/0045-6535(96)00024-0
   PubMed Web of Science ®Google Scholar
• Becker RA, Dellarco V, Seed J, et al. 2017. Quantitative weight of evidence to assess confidence in potential modes of action. Regul Toxicol Pharmacol 86:205–20. doi:10.1016/j.yrtph.2017.02.017
   PubMed Web of Science ®Google Scholar
• Besselink H, Nixon E, McHugh B, et al. 2008. Evaluation of tumour promoting potency of fish borne toxaphene residues, as compared to technical toxaphene and UV-irradiated toxaphene. Food Chem Toxicol 46:2629–38. doi:10.1016/j.fct.2008.04.039
   PubMed Web of Science ®Google Scholar
• Blanco-Bose WE, Murphy MJ, Ehninger A, et al. 2008. C-Myc and its target FoxM1 are critical downstream effectors of constitutive androstane receptor (CAR) mediated direct liver hyperplasia. Hepatol 48(4):1302–11. doi:10.1002/hep.22475
   PubMed Web of Science ®Google Scholar
• Bogen KT. 2017a. Biphasic hCAR inhibition-activation by two aminoazo liver carcinogens. Nulcear Receptor Res ( to be submitted)
   Google Scholar
• Bogen KT. 2017b. Low-dose dose-response for in vitro Nrf2-ARE activation in human HepG2 cells. Dose-Response (in press). doi:10.1177/1559325817699696
   Google Scholar
• Bogen KT. 2017c. Linear-no-threshold default assumptions are unwarranted for cytotoxic endpoints independently triggered by ultrasensitive molecular switches. Risk Anal ( in press). doi:10.1111/risa.12813
   Web of Science ®Google Scholar
• Boobis AR, Daston GP, Prestan RJ, et al. 2009. Application of key events analysis to chemical carcinogens and noncarcinogens. Crit Rev Food Sci Nutr 49:690–707. doi:10.1080/10408390903098673
   PubMed Web of Science ®Google Scholar
• Braeuning A, Gavrilov A, Brown S, et al. 2014. Phenobarbital-mediated tumor promotion in transgenic mice with humanized CAR and PXR. Toxicol Sci 140:259–70. doi:10.1093/toxsci/kfu099
   PubMed Web of Science ®Google Scholar
• Braeuning A. 2014. Liver cell proliferation and tumor promotion by phenobarbital: Relevance for humans? Arch Toxicol 88:1771–2. doi:10.1093/toxsci/kfn206
   PubMed Web of Science ®Google Scholar
• 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 Toxicol 44:83–119. doi:10.3109/10408444.2013.835787
   PubMed Web of Science ®Google Scholar
• Carrol RJ and Ruppert D. 1988. Transformation and Weighting in Regression. Chapman and Hall/CRC, New York, NY, USA. 9–62
   Google Scholar
• Chakraborty S, Kanakasabai S, and Bright JJ. 2011. Constitutive androstane receptor agonist CITCO inhibits growth and expansion of brain tumour stem cells. Br J Cancer 104:448–59. doi:10.1038/sj.bjc.6606064
   PubMed Web of Science ®Google Scholar
• Chen F, Zamule SM, Coslo DM, et al. 2013. The human constitutive androstane receptor promotes the differentiation and maturation of hepatic-like cells. Dev Biol 384:155–65. doi: 10.1016/j.ydbio.2013.10.012
   PubMed Web of Science ®Google Scholar
• Corton JC, Cunningham ML, Hummer BT, et al. 2014. Mode of action framework analysis for receptor-mediated toxicity: The peroxisome proliferator-activated receptor alpha (PPARα) as a case study. Crit Rev Toxicol 44:1–49. doi:10.3109/10408444.2013.835784
   PubMed Web of Science ®Google Scholar
• Costa RH, Kalichenko VV, Tan Y, et al. 2005. The CAR nuclear receptor and hepatocyte proliferation. Hepatol 42:1004–8. doi:10.1002/hep.20953
   PubMed Web of Science ®Google Scholar
• Dellarco VL and Baetcke K. 2005. A risk assessment perspective: Application of mode of action and human relevance frameworks to the analysis of rodent tumor date. Toxicol Sci 86:1–3. doi:10.1093/toxsci/kfi133
   PubMed Web of Science ®Google Scholar
• Dong B, Lee J-S, Park Y-Y, et al. 2015. Activating CAR and b-catenin induces uncontrolled liver growth and tumorigenesis. Nat Commun 6:5944. doi:10.1038/ncomms6944
   PubMed Web of Science ®Google Scholar
• Dong H, Gill S, Curran IH, et al. 2016. Toxicogenomic assessment of liver responses following subchronic exposure to furan in Fischer F344 rats. Arch Toxicol 90:1351–67. doi: 10.1007/s00204-015-1561-2
   PubMed Web of Science ®Google Scholar
• Dourson M, Higginbotham J, Crum J, et al. 2017. Update: Mode of action (MOA) for liver tumors induced by oral exposure to 1,4-dioxane. Regul Toxicol Pharmacol 88:45–55. doi: 10.1016/j.yrtph.2017.02.025
   PubMed Web of Science ®Google Scholar
• Dourson M, Reichard J, Nance P, et al. 2014. Mode of action analysis for liver tumors from oral 1,4-dioxane exposures and evidence-based dose response assessment. Regul Toxicol Pharmacol 68:387–401. doi: 10.1016/j.yrtph.2014.01.011
   PubMed Web of Science ®Google Scholar
• Elcombe CR, Peffer RC, Wolf DC, et al. 2014. Mode of action and human relevance analysis for nuclear receptor-mediated liver toxicity: A case study with phenobarbital as a model constitutive androstane receptor (CAR) activator. Crit Rev Toxicol 44:64–82. doi:10.3109/10408444.2013.835786
   PubMed Web of Science ®Google Scholar
• Gao J, Yan J, Xu M, et al. 2015. CAR suppresses hepatic gluconeogenesis by facilitating the Ubiquitination and degradation of PGC1. Mol Endocrinol 29(11):1558–70. doi: 10.1210/me.2015-1145
   PubMedGoogle Scholar
• Geter DR, Bhat VS, Gollapudi BB, et al. 2014. Dose-response modeling of early molecular and cellular key events in the CAR-mediated hepatocarcinogenesis pathway. Toxicol Sci 138:425–45. doi:10.1093/toxsci/kfu014
   PubMed Web of Science ®Google Scholar
• Goodman JI, Brusick DJ, Busey WM, et al. 2000. Reevaluation of the cancer potency factor of toxaphene: Recommendations from a peer review panel. Toxicol Sci 55:3–16. doi:10.1093/toxsci/55.1.3
   PubMed Web of Science ®Google Scholar
• Hao R, Su S, Wan Y, et al. 2016. Bioinformatic analysis of microRNA networks following the activation of the constitutive androstane receptor (CAR) in mouse liver. Biochim Biophysica Acta 1859(9):1228–37. doi:10.1016/j.bbagrm.04.002
   PubMedGoogle Scholar
• Hedli CC, Synder R, Kinoshita FK, et al. 1998. Investigation of hepatic cytochrome P-450 enzyme induction and DNA adduct formation in male CD/1 mice following oral administration of toxaphene. J Appl Toxicol 18:173–8. doi:10.1002/(SICI)1099-1263(199805/06)18:3%3c173::AID-JAT488%3e3.0.CO;2-2
   PubMed Web of Science ®Google Scholar
• Hernandez JR, Mota LC, and Baldwin WS. 2009. Activation of CAR and PXR by dietary, environmental and occupational chemicals alters drug metabolism, intermediary metabolism, and cell proliferation. Curr Pharmacogenomics Person Med 7(2):81–105. doi:10.2174/187569209788654005
   PubMedGoogle Scholar
• Holsapple MP, Pitot HC, Cohen SH, et al. 2006. Mode of action in relevant of rodent liver tumors to human cancer risk. Toxicol Sci 89:51–6. doi:10.1093/toxsci/kfj001
   PubMed Web of Science ®Google Scholar
• Huang R, Xia M, Cho MH, et al. 2011. Chemical genomics profiling of environmental chemical modulation of human nuclear receptors. Environ Health Perspect 119:1142–8. doi:10.1289/ehp.1002952
   PubMed Web of Science ®Google Scholar
• Huang R. 2016. A quantitative high-throughput screening data analysis pipeline for activity profiling. Methods Mol Biol1473, 111–122. doi:10.1007/978-1-4939-6346-1_12
   Google Scholar
• Huang W, Zhang J, Washington M, et al. 2005. Xenobiotic stress induces hepatomegaly and liver tumors via the nuclear receptor constitutive androstane receptor. Mol Endocrinol 19:1646–53. doi:10.1210/me.2004-0520
   PubMed Web of Science ®Google Scholar
• Jackson AF, Williams A, Recio L, et al. 2014. Case study on the utility of hepatic global gene expression profiling in the risk assessment of the carcinogen furan. Toxicol Appl. Pharmacol 274:63–77. doi:10.1016/j.taap.2013.10.019
   PubMed Web of Science ®Google Scholar
• Jones HB, Orton TC, and Lake BG. 2009. Effect of chronic phenobarbitone administration on liver tumour formation in the C57BL/10J mouse. Food Chem Toxicol 47(6):1333–40. doi:10.1016/j.fct.2009.03.014
   PubMed Web of Science ®Google Scholar
• Kang KS, Wilson MR, Hayashi T, et al. 1996. Inhibition of gap junctional intercellular communication in normal human breast epithelial cells after treatment with pesticides, PCBs, and PBBs, alone or in mixtures. Environ Health Perspect 104:192–200
   PubMed Web of Science ®Google Scholar
• Kazantseva YA, Pustylnyak YA, and Pustylnyak VO. 2016. Role of nuclear constitutive androstane receptor in regulation of hepatocyte proliferation and hepatocarcinogenesis. Biochem (Moscow) 81(4):338–47. doi:10.1134/S0006297916040040
   PubMed Web of Science ®Google Scholar
• Kerger BD, Bogen KT, Loccisano AE, et al. 2017. Liver tumor potency indicators for technical toxaphene and congeners simulating weathered toxaphene. Hum Ecol Risk Assess (in press). doi:10.1080/10807039.2017.1401450
   Web of Science ®Google Scholar
• Kobayashi K, Hashimoto M, Honkakoski P, et al. 2015. Regulation of gene expression by CAR: An update. Arch Toxicol 89:1045–55. doi:10.1007/s00204-015-1522–9
   PubMed Web of Science ®Google Scholar
• Lake BG, Price RJ, and Osimitz TG. 2015. Mode of action analysis for pesticide-induced rodent liver tumours involving activation of the constitutive androstane receptor: Relevance to human cancer risk. Pest Manage Sci 71(6):829–34. doi:10.1002/ps.3854
   PubMed Web of Science ®Google Scholar
• Lamb JC, Neal BH, and Goodman JI. 2008. Risk assessment of toxaphene and its breakdown products: Time for a change? Crit Rev Toxicol 38:805–15. doi:10.1080/10408440802237698
   PubMed Web of Science ®Google Scholar
• LeBaron MJ, Gollapudi BB, Terry C, et al. 2014. Human relevance framework for rodent liver tumors induced by the insecticide sulfoxaflor. Crit Rev Toxicol 44(Suppl 2):15–24. doi:10.3109/10408444.2014.910751
   PubMedGoogle Scholar
• Lehman-McKeenan LD, Rivera-Torres ML, Caudill D. 1990. Lysosomal degradation of alpha 2m-globulin and alpha 2m-globulin-xenobiotic conjugates. Toxicol Appl Pharmacol 103:539–548
   PubMed Web of Science ®Google Scholar
• Lempiäinen H, Müller A, Brasa S, et al. 2011. Phenobarbital mediates an epigenetic switch at the constitutive androstane receptor (CAR) target gene Cyp2b10 in the liver of B6C3F1 mice. PLoS One 6(3):e18216. doi:10.1371/journal.pone.0018216
   PubMed Web of Science ®Google Scholar
• Leonards PEG, Besselink H, Klungsoyr J, et al. 2012. Toxicological risks to humans of toxaphene residues in fish. Integr Environ Assess Manag 8:523–29. doi:10.1002/ieam.1275
   PubMed Web of Science ®Google Scholar
• Li D, Mackowiak B, Brayman TG, et al. 2015. Genome-wide analysis of human constitutive androstane receptor (CAR) transcriptome in wild-type and CAR-knockout HepaRG cells. Biochem. Pharmacol (Amsterdam, Neth.) 98:190–202. doi: 10.1016/j.bcp.2015.08.087
   PubMed Web of Science ®Google Scholar
• Li L, Bao X, Zhang Q-Y, et al. 2017. Role of CYP2B in phenobarbital-induced hepatocyte proliferation in mice. Drug Metab Disposit 45(8):977–981. doi: 10.1124/dmd.117.076406
   PubMed Web of Science ®Google Scholar
• Litton Bionetics. 1978. Carcinogenic Evaluation in Mice: Toxaphene Final Report. Prepared by Litton Bionetics, Inc. Kensington, MD, for Hercules, Inc., Wilmington, De LBI Project 20602
   Google Scholar
• Litton Bionetics. 1979. Evaluation of Carcinogenic Potential in Hamsters: Toxaphene, Final Report. Prepared by Litton Bionetics, Inc., Kensington, MD, for Hercules, Inc., Wilmington, DE. LBI Project 20601
   Google Scholar
• Luisier R, Unterberger EB, Goodman JI, et al. 2014a. Computational modeling identifies key gene regulatory interactions underlying phenobarbital-mediated tumor promotion. Nucleic Acids Res 42:4180–95. doi:10.1093/nar/gkt1415
   PubMed Web of Science ®Google Scholar
• Luisier R, Lempainen H, Scherbichler N, et al. 2014b. Phenobarbital induces cell cycle transcriptional responses in mouse liver humanized for constitutive androstane and pregnane X receptors. Toxicol Sci 139:501–11. doi:10.1093/toxsci/kfu038
   PubMed Web of Science ®Google Scholar
• Lynch C, Zhao J, Huang R, et al. 2015. Quantitative high-throughput identification of drugs as modulators of human constitutive androstane receptor. Sci Reports 5:10405. doi:10.1038/srep10405
   PubMed Web of Science ®Google Scholar
• MATT (Monitoring, Analysis and Toxicity of Toxaphene). 2000. Investigation into the Monitoring, Analysis and Toxicity of Toxaphene in Marine Foodstuffs. Final Report: FAIR CT PL.96.3131. European Union, Brussels
   Google Scholar
• Meek ME, Boobis A, Cote I, et al. 2014. New developments in the evolution and application of the WHO/IPCS framework on mode of action/species concordance analysis. J Appl Toxicol 34:1–18. doi:10.1002/jat.2949
   PubMed Web of Science ®Google Scholar
• Meek ME, Bucher JR, Cohen SM, et al. 2003. A framework for human relevance analysis of information on carcinogenic modes of action. Crit Rev Toxicol 33:591–653. doi:10.1080/713608373
   PubMed Web of Science ®Google Scholar
• Merrell MD, Jackson JP, Augustine LM, et al. 2008. The Nrf2 activator oltipraz also activates the constitutive androstane receptor. Drug Metab Dispos 36:1716–21. doi:10.1124/dmd.108.020867
   PubMed Web of Science ®Google Scholar
• Miousse IR, Murphy LA, Lin H, et al. 2017. Dose-response analysis of epigenetic, metabolic, and apical endpoints after short-term exposure to experimental hepatotoxicants. Food Chem Toxicol 109(Pt 1):690–702. doi: 10.1016/j.fct.2017.05.013
   PubMedGoogle Scholar
• NCBI (National Center for Biotechnology Information). 2017. Resources for Information on PubChem BioAssay Database; AID = 1224839. U.S. Library of Medicine, National Center for Biotechnology Information (NCBI), Bethesda, MD, USA. Available at https://pubchem.ncbi.nlm.nih.gov/bioassay/1224839
   Google Scholar
• NCI (National Cancer Institute). 1979. Bioassay of Toxaphene of Possible Carcinogenicity. Technical Report Series No. 37. National Cancer Institute, Washington, DC, USA
   Google Scholar
• Peffer R, Bailey K, Lichti-Kaiser K, et al. 2017. Constitutive Androstane Receptor Activation Leading to Hepatocellular Adenomas and Carcinomas in the Mouse and the Rat. OECD Working Paper AOP 107, June 19, 2017. Available at https://aopwiki.org/aops/107
   Google Scholar
• Phillips JM and Goodman JI. 2009. Multiple genes exhibit phenobarbital-induced constitutive active/androstane receptor-mediated DNA methylation changes during liver tumorigenesis and in liver tumors. Toxicol Sci 108:273–89. doi: 10.1093/toxsci/kfp031
   PubMed Web of Science ®Google Scholar
• Pitot HC, Goldsworthy TL, Moran S, et al. 1987. A method to quantitate the relative initiating and promoting potencies of hepatocarcinogenic agents in their dose-response relationships to altered hepatic foci. Carcinogenesis 8:1491–9. doi:10.1093/carcin/8.10.1491
   PubMed Web of Science ®Google Scholar
• Ross J, Plummer SM, Rode A, et al. 2010. Human constitutive androstane receptor (CAR) and pregnane X receptor (PXR) support the hypertrophic but not the hyperplastic response to the murine nongenotoxic hepatocarcinogens phenobarbital and chlordane in vivo. Toxicol Sci 116:452–66. doi:10.1093/toxsci/kfq118
   PubMed Web of Science ®Google Scholar
• Simon T and Manning R. 2006. Development of a reference dose for the persistent congeners of weathered toxaphene based on in vivo and in vitro effects related to tumor promotion. Regul Toxicol Pharmacol 44:268–81. doi:10.1016/j.yrtph.2006.01.001
   PubMed Web of Science ®Google Scholar
• Swenberg JA and Lehman-McKeenan LD. 1999. α2-Urinary globulin-associated nephropathy as a mechanism of renal tubule cell carcinogenesis in male rats. In: Capen CC, Dying E, Rice JM and Wilbourn JD (eds), Species Differences in Thyroid, Kidney, and Urinary Bladder Carcinogenesis, 95–118. IARC Scientific Publication No. 147. IARC, Lyon, France
   Google Scholar
• Timsit YE and Negishi M. 2014. Coordinated regulation of nuclear receptor CAR by CCRP/DNAJC7, HSP70 and the ubiquitin proteasome system. PLoS One 9:e96092. doi:10.1371/journal.pone.0096092
   PubMed Web of Science ®Google Scholar
• Trosko JR, Jone C, and Chang CC. 1987. Inhibition of gap junctional-mediated intercellular communication in vitro by aldrin, dieldrin and toxaphene: A possible cellular mechanism for their tumor-promoting and neurotoxic effects. Mol Toxicol 1:83–93
   PubMedGoogle Scholar
• USEPA (United States Environmental Protection Agency). 1988. Toxaphene – CASRN 8001-35-2 in Health Hazard Assessments for Effects Other than Cancer. U.S. Environmental Protection Agency, Washington, DC
   Google Scholar
• USEPA. 1990. Notice of Intent to Remove Certain Active Ingredients from Reregistration List B and to Cancel Pesticides Containing Those Ingredients. Federal Register. 55 FR 31164—31174. U.S. Environmental Protection Agency, Washington DC
   Google Scholar
• USEPA. 2005a. Guidelines for Carcinogen Risk Assessment. EPA/630/P-03/001F, March 2005. U.S. Environmental Protection Agency Risk Assessment Forum, Washington, DC, USA
   Google Scholar
• USEPA. 2005b. Implementation of the Cancer Guidelines and Accompanying Supplemental Guidance – Science Policy Council Cancer Guidelines Implementation Workgroup Communication I: Application of the Mode of Action Framework in Mutagenicity Determinations for Carcinogenicity. Memo from W Farland, Chair, USEPA Science Policy Council to Science Policy Council. October 4, 2005. U.S. Environmental Protection Agency, Washington, DC, USA
   Google Scholar
• USEPA. 2012a. Benchmark Dose Technical Guidance. EPA/100/R-12/001, June 2012. U.S. Environmental Protection Agency (USEPA), Risk Assessment Forum, Washington, DC, USA p. 37. Available at http://www.epa.gov/raf/publications/pdfs/benchmark_dose_guidance.pdf
   Google Scholar
• USEPA. 2012b. Benchmark Dose (BMD) Methodology. Updated July 31, 2012. U.S. Environmental Protection Agency, National Center for Environmental Assessment, Washington, DC, USA. Available at http://www.epa.gov/NCEA/bmds/bmds_training/methodology/intro.htm ( updated July 31, 2012)
   Google Scholar
• USEPA. 2014. Guidance for Applying Quantitative Data to Develop Data-Derived Extrapolation Factors for Interspecies and Intraspecies Extrapolation. U.S. Environmental Protection Agency, Washington, DC. EPA/R-14/002F
   Google Scholar
• USEPA. 2017. Integrated Risk Information System (IRIS) Database Profiles on Aldrin, Chlordane, Dieldrin, and Toxaphane. U.S. Environmental Protection Agency, Washington, DC. Available at https://cfpub.epa.gov/ncea/iris2/atoz.cfm
   Google Scholar
• Vardy A and Elcombe CR. 2014. Differential Dose-response Relationships for Hepatic Cyp2b10 Induction and Cell Proliferation in Wild Type Mice and Mice Humanized (huPXR/huCAR) for the Constitutive Androstane Receptor (CAR) and Pregnane X Receptor (PXR) Administered Phenobarbitone (PB). CXR Biosciences Ltd, Dundee, Scotland, UK. Available at https://www.conceptlifesciences.com/wp-content/uploads/2017/04/Differential-Dose-Response-Relationships-For-Hepatic-Cyp2b10-Induction-And-Cell-Proliferation-In-Wild-Type-Mice.pdf
   Google Scholar
• Wang Z, Li X, Wu Q, et al. 2017. Toxaphene-induced mouse liver tumorigenesis is mediated by the constitutive androstane receptor. J Appl Toxicol 37:967–75. doi:10.1002/jat.3445
   PubMed Web of Science ®Google Scholar
• Wang Z, Neal BH, Lamb JC, et al. 2015. Mechanistic investigation of toxaphene induced mouse liver tumors. Toxicol Sci 147:549–61. doi:10.1093/toxsci/kfv151
   PubMed Web of Science ®Google Scholar
• Waritz RS, Steinberg M, Kinoshita F, et al. 1996. Thyroid function an thyroid tumors in toxaphene-treated rats. Regul Toxicol Pharmacol 24:184–92. doi:10.1006/rtph.1996.0124
   PubMed Web of Science ®Google Scholar
• Wen YH and Chan HM. 2000. A pharmacokinetic model for predicting absorption, elimination, and tissue burden of toxaphene in rats. Toxicol Appl Pharmacol 168:235–43. doi:10.1006/taap.2000.9052
   PubMed Web of Science ®Google Scholar
• WHO (World Health Organization). 2007. World Health Organization Harmonization Project Document No. 4. Part 1: IPCS Frameworks for Analyzing the Relevant of a Cancer Mode of Action for Humans in Case-studies; Part 2: IPCS Framework for Analyzing the Relevant of a Non-Cancer Mode of Action for Humans. World Health Organization, Genevea, Switzerland
   Google Scholar
• Whysner J, Ross PM, and Williams GM. 1996. Phenobarbital mechanistic data and risk assessment: Enzyme induction, enhanced cell proliferation, and tumor promotion. Pharmacol Ther 71:153–91. doi:10.1016/0163-7258(96)00067-8
   PubMed Web of Science ®Google Scholar
• Wolfram Research (Wolfram Language and System Documentation Center). 2017. Resources for Information on Wolfram Research, Inc., Champaign, IL. Available at http://reference.wolfram.com/language/
   Google Scholar
• Wright PS. 1992. Adjusted p-values for simultaneous inference. Biometrics 48:1005–1013
   Web of Science ®Google Scholar
• Yamada T, Kikumoto H, Lake B, et al. 2015. Lack of effect of metofluthrin and sodium phenobarbital on replicative DNA synthesis on Ki-67 mRNA expression in cultured human hepatocytes. Toxicol Res 4:901–13. doi:10.1039/C4TX00217B
   Web of Science ®Google Scholar
• Yamamoto Y, Moore R, Goldsworthy TL, et al. 2004. The orphan nuclear receptor constitutive active/androstane receptor is essential for liver tumor promotion by phenobarbital in mice. Cancer Res 64:7197–200. doi:10.1158/0008-5472.CAN-04-1459
   PubMed Web of Science ®Google Scholar
• Yang H, Garzel B, Heyward S, et al. 2014. Metformin represses drug-induced expression of CYP2B6 by Modulating the constitutive androstane receptor signaling. Mol Pharmacol 85:249–60. doi:10.1124/mol.113.089763
   PubMed Web of Science ®Google Scholar
• Yang H and Wang H. 2014. Signaling control of the constitutive androstane receptor (CAR). Protein Cell 5(2):113–23. doi:10.1007/s13238-013-0013-0
   PubMed Web of Science ®Google Scholar
• Yoshida M. 1998. Exact probabilities associated with Tukey's and Dunnett's multiple comparisons procedures in imbalanced one-way ANOVA. J Japanese Soc Comp Statist 1:111–122
   Google Scholar