[1] Kaufman DW, Kelly JP, Rosenberg L, Anderson TE, Mitchell  AA. Recent patterns of medication use in the ambulatory adult  population of the United States: the Slone survey. JAMA.  2002; 287: 337-344.

[2] Lee WM. Etiologies of acute liver failure. Semin Liver Dis.  2008; 28: 142-52.

[3] Davidson DG, Eastham WN. Acute liver necrosis following  overdose of paracetamol. Br Med J. 1966; 2: 497-499.

[4] Boyd EM, Bereczky GM. Liver necrosis from paracetamol. Br  J Pharmacol Chemother. 1966; 26: 606-614.

[5] Proudfoot AT, Wright N. Acute paracetamol poisoning. Br  Med J. 1970; 3: 557-558.

[6] Torres AR. Is fever suppression involved in the etiology of  autism and neurodevelopmental disorders? BMC Pediatr.  2003; 3: 9.

[7] Schultz ST, Klonoff-Cohen HS, Wingard DL, Akshoomoff  NA, Macera CA, Ji M. Acetaminophen (paracetamol) use,  measles-mumps-rubella vaccination, and autistic disorder: the  results of a parent survey. Autism. 2008; 12: 293-307.

[8] Yorgason JG, Kalinec GM, Luxford WM, Warren FM,  Kalinec F. Acetaminophen ototoxicity after acetaminophen / hydrocodone abuse: evidence from two parallel in vitro mouse  models. Otolaryngol Head Neck Surg. 2010; 142: 814-9,  819.e1-2.

[9] Posadas I, Santos P, Blanco A, Munoz-Fernández M, Cena V.  Acetaminophen induces apoptosis in rat cortical neurons.  PLoS One. 2010; 5: e15360.

[10] da Silva MH, da Rosa EJ, de Carvalho NR, Dobrachinski F,  da Rocha JB, Mauriz JL, González-Gallego J, Soares FA.  Acute brain damage induced by acetaminophen in mice:  effect of diphenyl diselenide on oxidative stress and  mitochondrial dysfunction. Neurotox Res. 2012; 21: 334-344.

[11] Bauer AZ, Kriebel D. Prenatal and perinatal analgesic  exposure and autism: an ecological link. Environ Health.  2013; 12: 41.

[12] Viberg H, Eriksson P, Gordh T, Fredriksson A. Paracetamol  (acetaminophen) administration during neonatal brain  development affects cognitive function and alters its analgesic and anxiolytic response in adult male mice. Toxicol  Sci. 2014; 138: 139-47.

[13] Kalinec GM, Thein P, Parsa A, Yorgason J, Luxford W,  Urrutia R, Kalinec F. Acetaminophen and NAPQI are toxic to  auditory cells via oxidative and endoplasmic reticulum stressdependent pathways. Hear Res. 2014; 313: 26-37.

[14] Liew Z, Ritz B, Rebordosa C, Lee PC, Olsen J. Acetaminophen  use during pregnancy, behavioral problems, and hyperkinetic  disorders. JAMA Pediatr. 2014; 168: 313-20.

[15] Placke ME, Wyand DS, Cohen SD. Extrahepatic lesions  induced by acetaminophen in the mouse. Toxicol Pathol.  1987; 15: 381-387.

[16] Bartolone JB, Beierschmitt WP, Birge RB, Hart SG, Wyand  S, Cohen SD, Khairallah EA. Selective acetaminophen metabolite binding to hepatic and extrahepatic proteins: an in  vivo and in vitro analysis. Toxicol Appl Pharmacol. 1989; 99:  240-9.

[17] Nassini R, Materazzi S, André E, Sartiani L, Aldini G,  Trevisani M, Carnini C, Massi D, Pedretti P, Carini M,  Cerbai E, Preti D, Villetti G, Civelli M, Trevisan G, Azzari C,  Stokesberry S, Sadofsky L, McGarvey L, Patacchini R,  Geppetti P. Acetaminophen, via its reactive metabolite Nacetyl-p-benzo-quinoneimine and transient receptor potential  ankyrin-1 stimulation, causes neurogenic inflammation in the  airways and other tissues in rodents. FASEB J. 2010; 24:  4904-4916

[18] Karimi K, Kebler T, Thiele K, Ramisch K, Erhardt A,  Huebener P, Barikbin R, Arck P, Tiegs G. Prenatal  acetaminophen induces liver toxicity in dams, reduces fetal  liver stem cells, and increases airway inflammation in adult  offspring. J Hepatol. 2015; 62: 1085-1091.

[19] Shaheen SO, Newson RB, Sherriff A, Henderson AJ, Heron  JE, Burney PG, Golding J; ALSPAC Study Team. Paracetamol use in pregnancy and wheezing in early childhood. Thorax.  2002; 57: 958-963.

[20] Shaheen SO, Sterne JA, Songhurst CE, Burney PG. Frequent  paracetamol use and asthma in adults. Thorax. 2000; 55: 266- 270.

[21] Shaheen S, Potts J, Gnatiuc L, Makowska J, Kowalski ML,  Joos G, van Zele T, van Durme Y, De Rudder I, Wӧhrl S,  Godnic-Cvar J, Skadhauge L, Thomsen G, Zuberbier T,  Bergmann KC, Heinzerling L, Gjomarkaj M, Bruno A, Pace E,  Bonini S, Fokkens W, Weersink EJ, et al. The relation between  paracetamol use and asthma: a GA2LEN European casecontrol study. EurRespir J. 2008; 32: 1231-1236.

[22] Thiele K, Solano ME, Huber S, Flavell RA, Kessler T,  Barikbin R, Jung R, Karimi K, Tiegs G, Arck PC. Prenatal  acetaminophen affects maternal immune and endocrine  adaptation to pregnancy, induces placental damage, and  impairs fetal development in mice. Am J Pathol. 2015; 185:  2805-2818.

[23] Lee WM. Acetaminophen (APAP) hepatotoxicity – isn’t it time  for APAP to go away? J Hepatol. 2017. [Epub ahead of print]  doi: 10.1016/j.jhep.2017.07.005.

[24] Black RA, Hill DA. Over-the-counter medications in pregnancy. Am Fam Physician. 2003; 67: 2517-2524.

[25] Thiele K, Kessler T, Arck P, Erhardt A, Tiegs G. Acetaminophen  and pregnancy: short-and long-term consequences for mother and  child. J Reprod Immunol. 2013; 97: 128-139.

[26] McGill MR, Jaeschke H. Metabolism and disposition of  acetaminophen: recent advances in relation to hepatotoxicity  and diagnosis. Pharm Res. 2013; 30: 2174-2187.

[27] Xie Y, McGill MR, Cook SF, Sharpe MR, Winefield RD,  Wilkins DG, Rollins DE, Jaeschke H. Time course of  acetaminophen-protein adducts and acetaminophen metabolites in  circulation of overdose patients and in HepaRG cells.  Xenobiotica. 2015; 45: 921-929.

[28] Dahlin DC, Miwa GT, Lu AY, Nelson SD. N-acetyl-pbenzoquinone imine: a cytochrome P-450-mediated oxidation  product of acetaminophen. Proc Natl Acad Sci U S A. 1984;  81: 132713-31.

[29] Potter WZ, Davis DC, Mitchell JR, Jollow DJ, Gillette JR,  Brodie BB. Acetaminophen-induced hepatic necrosis. 3.  Cytochrome P-450-mediated covalent binding in vitro. J  Pharmacol Exp Ther. 1973 Oct; 187: 203-210.

[30] Jollow DJ, Mitchell JR, Potter WZ, Davis DC, Gillette JR,  Brodie BB. Acetaminophen-induced hepatic necrosis. II. Role  of covalent binding in vivo. J Pharmacol Exp Ther. 1973; 187:  195-202.

[31] Mitchell JR, Jollow DJ, Potter WZ, Davis DC, Gillette JR,  Brodie BB. Acetaminophen-induced hepatic necrosis. I. Role  of drug metabolism. J Pharmacol Exp Ther. 1973; 187: 185- 194.

[32] Mitchell JR, Jollow DJ, Potter WZ, Gillette JR, Brodie BB.  Acetaminophen-induced hepatic necrosis. IV. Protective role of  glutathione. J Pharmacol Exp Ther. 1973; 187: 211-217.

[33] Meyers LL, Beierschmitt WP, Khairallah EA, Cohen SD.  Acetaminophen-induced inhibition of hepatic mitochondrial  respiration in mice. Toxicol Appl Pharmacol. 1988; 93: 378- 387.

[34] Kon K, Kim JS, Jaeschke H, Lemasters JJ. Mitochondrial  permeability transition in acetaminophen-induced necrosis and  apoptosis of cultured mouse hepatocytes. Hepatology. 2004;  40: 1170-1179.

[35] McGill MR, Sharpe MR, Williams CD, Taha M, Curry SC,  Jaeschke H. The mechanism underlying acetaminophen-induced hepatotoxicity in humans and mice involves mitochondrial  damage and nuclear DNA fragmentation. J Clin Invest. 2012;  122: 1574-1583.

[36] McGill MR, Staggs VS, Sharpe MR, Lee WM, Jaeschke H. Acute Liver Failure Study Group. Serum mitochondrial  biomarkers and damage-associated molecular patterns are  higher in acetaminophen overdose patients with poor  outcome. Hepatology. 2014; 60: 1336-1345.

[37] Xie Y, McGill MR, Du K, Dorko K, Kumer SC, Schmitt TM,  Ding WX, Jaeschke H. Mitochondrial protein adducts  formation and mitochondrial dysfunction during N-acetyl-maminophenol (AMAP)-induced hepatotoxicity in primary  human hepatocytes. Toxicol Appl Pharmacol. 2015; 289: 213- 222.

[38] Hadi M, Dragovic S, van Swelm R, Herpers B, van de Water  B, Russel FG, Commandeur JN, Groothuis GM. AMAP, the  alleged non-toxic isomer of acetaminophen, is toxic in rat and  human liver. Arch Toxicol. 2013; 87: 155-165.

[39] McGill MR, Williams CD, Xie Y, Ramachandran A,  Jaeschke H. Acetaminophen-induced liver injury in rats and  mice: comparison of protein adducts, mitochondrial  dysfunction, and oxidative stress in the mechanism of  toxicity. Toxicol Appl Pharmacol. 2012; 264: 387-394.

[40] Cover C, Mansouri A, Knight TR, Bajt ML, Lemasters JJ,  Pessayre D, Jaeschke H. Peroxynitrite - induced mitochondrial and endonuclease - mediated nuclear DNA damage in acetaminophen hepatotoxicity. J Pharmacol Exp Ther. 2005;  315: 879-887.

[41] Jaeschke H. Glutathione disulfide formation and oxidant  stress during acetaminophen-induced hepatotoxicity in mice  in vivo: the protective effect of allopurinol. J Pharmacol Exp Ther. 1990; 255: 935-941.

[42] Fujimoto K, Kumagai K, Ito K, Arakawa S, Ando Y, Oda S,  Yamoto T, Manabe S. Sensitivity of liver injury in heterozygous Sod2 knockout mice treated with troglitazone or acetaminophen. ToxicolPathol. 2009; 37: 193-200.

[43] Yoshikawa Y, Morita M, Hosomi H, Tsuneyama K, Fukami  T, Nakajima M, Yokoi T. Knockdown of superoxide dismutase 2 enhances acetaminophen-induced hepatotoxicity in rat. Toxicology. 2009; 264: 89-95.

[44] Ramachandran A, Lebofsky M, Weinman SA, Jaeschke H.  The impact of partial manganese superoxide dismutase  (SOD2)-deficiency on mitochondrial oxidant stress, DNA  fragmentation and liver injury during acetaminophen hepatotoxicity. Toxicol Appl Pharmacol. 2011; 251: 226-233.

[45] Du K, McGill MR, Xie Y, Bajt ML, Jaeschke H. Resveratrol  prevents protein nitration and release of endonucleases from  mitochondria during acetaminophen hepatotoxicity. Food  Chem Toxicol. 2015; 81: 62-70.

[46] McGill MR, Du K, Weemhoff JL, Jaeschke H. Critical  review of resveratrol in xenobiotic-induced hepatotoxicity.  Food ChemToxicol. 2015; 86: 309-318.

[47] Knight TR, Ho YS, Farhood A, Jaeschke H. Peroxynitrite is a  critical mediator of acetaminophen hepatotoxicity in murine  livers: protection by glutathione. J Pharmacol Exp Ther.  2002; 303: 468-475.

[48] Bajt ML, Knight TR, Lemasters JJ, Jaeschke H. Acetaminophen - induced oxidant stress and cell injury in cultured mouse  hepatocytes: protection by N-acetyl cysteine. Toxicol Sci.  2004; 80: 343-349.

[49] Nakagawa H, Maeda S, Hikiba Y, Ohmae T, Shibata W,  Yanai A, Sakamoto K, Ogura K, Noguchi T, Karin M, Ichijo  H, Omata M. Deletion of apoptosis signal-regulating kinase 1  attenuates acetaminophen-induced liver injury by inhibiting  c-Jun N-terminal kinase activation. Gastroenterology. 2008;  135: 1311-1321.

[50] Xie Y, McGill MR, Dorko K, Kumer SC, Schmitt TM,  Forster J, Jaeschke H. Mechanisms of acetaminophen-induced cell death in primary human hepatocytes. Toxicol ApplPharmacol. 2014; 279: 266-274

[51] Gunawan BK, Liu ZX, Han D, Hanawa N, Gaarde WA,  Kaplowitz N. c-Jun N-terminal kinase plays a major role in  murine acetaminophen hepatotoxicity. Gastroenterology. 2006;  131: 165-178.

[52] Saito C, Lemasters JJ, Jaeschke H. c-Jun N-terminal kinase  modulates oxidant stress and peroxynitrite formation independent of inducible nitric oxide synthase in acetaminophen  hepatotoxicity. Toxicol Appl Pharmacol. 2010; 246: 8-17.

[53] Henderson NC, Pollock KJ, Frew J, Mackinnon AC, Flavell  RA, Davis RJ, Sethi T, Simpson KJ. Critical role of c-jun  (NH2) terminal kinase in paracetamol- induced acute liver  failure. Gut. 2007; 56: 982-990.

[54] Bourdi M, Korrapati MC, Chakraborty M, Yee SB, Pohl LR.  Protective role of c-Jun N-terminal kinase 2 in acetaminopheninduced liver injury. Biochem Biophys Res Commun. 2008;  374: 6-10.

[55] Cubero FJ, Zoubek ME, Hu W, Peng J, Zhao G, Nevzorova  YA, Al Masaoudi M, Bechmann LP, Boekschoten MV, Muller  M, Preisinger C, Gassler N, Canbay AE, Luedde T, Davis RJ,  Liedtke C, Trautwein C. Combined activities of JNK1 and  JNK2 in hepatocytes protect against toxic liver injury.  Gastroenterol. 2016 Apr; 150: 968-981.

[56] Bourdi M, Davies JS, Pohl LR. Mispairing C57BL/6 substrains of genetically engineered mice and wild-type controls can lead  to confounding results as it did in studies of JNK2 in  acetaminophen and concanavalin A liver injury. Chem Res  Toxicol. 2011; 24: 794-796.

[57] Latchoumycandane C, Goh CW, Ong MM, Boelsterli UA.  Mitochondrial protection by the JNK inhibitor leflunomide  rescues mice from acetaminophen-induced liver injury.  Hepatology. 2007; 45: 412-421.

[58] Du K, Xie Y, McGill MR, Jaeschke H. Pathophysiological  significance of c-jun N-terminal kinase in acetaminophen  hepatotoxicity. Expert Opin Drug Metab Toxicol. 2015; 11:  1769-1779.

[59] Hanawa N, Shinohara M, Saberi B, Gaarde WA, Han D,  Kaplowitz N. Role of JNK translocation to mitochondria  leading to inhibition of mitochondria bioenergetics in  acetaminophen-induced liver injury. J Biol Chem. 2008; 283:  13565-13577.

[60] Jaeschke H, McGill MR, Ramachandran A. Oxidant stress,  mitochondria, and cell death mechanisms in drug-induced liver  injury: lessons learned from acetaminophen hepatotoxicity.  Drug Metab Rev. 2012; 44: 88-106.

[61] Sharma M, Gadang V, Jaeschke A. Critical role for mixedlineage kinase 3 in acetaminophen-induced hepatotoxicity.  MolPharmacol. 2012; 82: 1001-1007.

[62] Ramachandran A, McGill MR, Xie Y, Ni HM, Ding WX,  Jaeschke H. Receptor interacting protein kinase 3 is a critical  early mediator of acetaminophen-induced hepatocyte necrosis  in mice. Hepatology. 2013; 58: 2099-2108.

[63] Zhang YF, He W, Zhang C, Liu XJ, Lu Y, Wang H, Zhang ZH,  Chen X, Xu DX. Role of receptor interacting protein (RIP)1 on apoptosis-inducing factor-mediated necroptosis during  acetaminophen-evoked acute liver failure in mice. Toxicol Lett.  2014; 225: 445-453

[64] Deutsch M, Graffeo CS, Rokosh R, Pansari M, Ochi A, Levie  EM, Van Heerden E, Tippens DM, Greco S, Barilla R,  Tomkӧtter L, Zambirinis CP, Avanzi N, Gulati R, Pachter HL,  Torres-Hernandez A, Eisenthal A, Daley D, Miller G.  Divergent effects of RIP1 or RIP3 blockade in murine models  of acute liver injury. Cell Death Dis. 2015; 6: e1759.

[65] Reid AB, Kurten RC, McCullough SS, Brock RW, Hinson  JA. Mechanisms of acetaminophen-induced hepatotoxicity:  role of oxidative stress and mitochondrial permeability  transition in freshly isolated mouse hepatocytes. J Pharmacol Exp Ther. 2005; 312: 509-516.

[66] Ramachandran A, Lebofsky M, Baines CP, Lemasters JJ,  Jaeschke H. Cyclophilin D deficiency protects  against acetaminophen-induced oxidant stress and liver  injury. Free Radic Res. 2011; 45: 156-164.

[67] Hu J, Ramshesh VK, McGill MR, Jaeschke H, Lemasters JJ.  Low dose acetaminophen induces reversible mitochondrial  dysfunction associated with transient c-Jun N-terminal kinase  activation in mouse liver. Toxiol Sci. 2016; 150: 204-215.

[68] Placke ME, Ginsberg GL, Wyand DS, Cohen SD.  Ultrastructural changes during acute acetaminophen-induced  hepatotoxicity in the mouse: a time and dose study. Toxicol Pathol. 1987; 15: 431-438.

[69] Bajt ML, Cover C, Lemasters JJ, Jaeschke H. Nuclear  translocation of endonuclease G and apoptosis-inducing  factor during acetaminophen-induced liver cell injury.  Toxicol Sci. 2006; 94: 217-225.

[70] Gujral JS, Knight TR, Farhood A, Bajt ML, Jaeschke H.  Mode of cell death after acetaminophen overdose in mice:  apoptosis or oncotic necrosis? Toxicol Sci. 2002; 67: 322- 328.

[71] Williams CD, Koerner MR, Lampe JN, Farhood A, Jaeschke  H. Mouse strain-dependent caspase activation during  acetaminophen hepatotoxicity does not result in apoptosis or  modulation of inflammation. Toxicol Appl Pharmacol. 2011;  257: 449-458.

[72] Jaeschke H, Williams CD, Farhood A. No evidence for  caspase-dependent apoptosis in acetaminophen hepatotoxicity. Hepatology. 2011; 53: 718-719.

[73] McGill MR, Yan HM, Ramachandran A, Murray GJ, Rollins  DE, Jaeschke H. HepaRG cells: a human model to study  mechanisms of acetaminophen hepatotoxicity. Hepatology.  2011; 53: 974-82.

[74] Woolbright BL, Jaeschke H. The impact of sterile inflammation in acute liver injury. J Clin Transl Res. 2017; 3: 170-188.

[75] Woolbright BL, Jaeschke H. Role of the inflammasome in  acetaminophen-induced liver injury and acute liver failure. J  Hepatol. 2017; 66(4): 836-848.

[76] Laskin DL, Pilaro AM. Potential role of activated  macrophages in acetaminophen hepatotoxicity. I. Isolation  and characterization of activated macrophages from rat liver.  Toxicol Appl Pharmacol. 1986; 86: 204-215.

[77] Laskin DL, Gardner CR, Price VF, Jollow DJ. Modulation of  macrophage functioning abrogates the acute hepatotoxicity of  acetaminophen. Hepatology. 1995; 21: 1045-1050.

[78] Michael SL, Pumford NR, Mayeux PR, Niesman MR, Hinson  JA. Pretreatment of mice with macrophage inactivators  decreases acetaminophen hepatotoxicity and the formation of  reactive oxygen and nitrogen species. 1999; 30(1): 186-195.

[79] Smith GS, Nadiw DE, Kokoska ER, Solomon H, Tiniakos  DG, Miller TA. Role of neutrophils in hepatotoxicity induced  by oral acetaminophen administration in rats. J Surg Res.  1998; 80(2): 252-258.

[80] Liu ZX, Han D, Gunawan B, Kaplowitz N. Neutrophil  depletion protects against murine acetaminophen hepatotoxicity. Hepatology. 2006; 43(6): 1220-1230.

[81] Imaeda AB, Watanabe A, Sohail MA, Mahmood S,  Mohamadnejad M, Sutterwala FS, Flavell RA, Mehal WZ.  Acetaminophen-induced hepatotoxicity in mice is dependent  on Tlr9 and the Nalp3 inflammasome. J Clin Invest. 2009;  119(2): 305-314

[82] Kono H, Chen CJ, Ontiveros F, Rock KL. Uric acid promotes  an acute inflammatory response to sterile cell death in mice. J  Clin Invest. 2010; 120: 1939-1949.

[83] Dear JW, Simpson KJ, Nicolai MP, Catterson JH, Street J,  Huizinga T, Craig DG, Dhaliwal K, Webb S, Bateman DN,  Webb DJ. Cycophilin A is a damage-associated molecular  pattern molecule that mediates acetaminophen-induced liver  injury. J Immunol. 2011; 187: 3347-3352.

[84] Marques PE, Amaral SS, Pires DA, Nogueira LL, Soriani FM,  Lima BH, Lopes GA, Russo RC, Avila TV, Megaco JG,  Oliveira AG, Pinto MA, Lima CX, De Paula AM, Cara DC,  Leite MF, Teixeira MM, Menezes GB. Chemokines and  mitochondrial products activate neutrophils to amplify organ  injury during mouse acute liver failure. Hepatology. 2012; 56:  1971-1982.

[85] Ju C, Reilly TP, Bourdi M, Radonovich MF, Brady JN, George  JW, Pohl LR. Protective role of Kupffer cells in  acetaminophen-induced hepatic injury in mice. Chem Res  Toxicol. 2002; 15: 1504-1513.

[86] Williams CD, Antoine DJ, Shaw PJ, Benson C, Farhood A,  Williams DP, Kanneganti TD, Park BK, Jaeschke H. Role of  the Nalp3 inflammasome in acetaminophen-induced sterile  inflammation and liver injury. Toxicol Appl Pharmacol. 2011;  252(3): 289-297.

[87] Williams CD, Farhood A, Jaeschke H. Role of caspase-1 and  interleukin-1beta in acetaminophen-induced hepatic inflammation and liver injury. Toxicol Appl Pharmacol. 2010; 247: 169-178.

[88] Davis M, Ideo G, Harrison NG, Williams R. Hepatic  glutathione depletion and impaired bromosulphthalein clearance early after paracetamol overdose in man and the rat.  Clin Sci Mol Med. 1975; 49: 495-502.

[89] Lauterburg BH, Mitchell JR. Therapeutic doses of  acetaminophen stimulate the turnover of cysteine and  glutathione in man. J Hepatol. 1987; 4: 206-211.

[90] Muldrew KL, James LP, Coop L, McCullough SS,  Hendrickson HP, Hinson JA, Mayeux PR. Determination of  acetaminophen-protein adducts in mouse liver and serum and  human serum after hepatotoxic doses of acetaminophen using  high-performance liquid chromatography with electrochemical detection. Drug Metab Dispos. 2002; 30: 446-451.

[91] Bhattacharyya S, Yan K, Pence L, Simpson PM, Gill P, Letzig  LG, Beger RD, Sullivan JE, Kearns GL, Reed MD, Marshall  JD, Van Den Anker JN, James LP. Targeted liquid  chromatography-mass spectrometry analysis of serum  acylcarnitines in acetaminophen toxicity in children. Biomark  Med. 2014; 8: 147-159.

[92] Mitchell JR, McMurtry RJ, Statham CN, Nelson SD.  Molecular basis for several drug-induced nephropathies. Am J  Med. 1977; 62: 518-526.

[93] Trumper L, Girardi G, Elías MM. Acetaminophen nephrotoxicity in male Wistar rats. Arch Toxicol. 1992; 66: 107-111.

[94] Lucas AM, Hennig G, Dominick PK, Whiteley HE, Roberts  JC, Cohen SD. Ribose cysteine protects against acetaminopheninduced hepatic and renal toxicity. Toxicol Pathol. 2000; 28:  697-704.

[95] Stern ST, Bruno MK, Hennig GE, Horton RA, Roberts JC,  Cohen SD. Contribution of acetaminophen-cysteine to  acetaminophen nephrotoxicity in CD-1 mice: I. Enhancement  of acetaminophen nephrotoxicity by acetaminophen-cysteine.  Toxicol Appl Pharmacol. 2005; 202: 151-159.

[96] Stern ST, Bruno MK, Horton RA, Hill DW, Roberts JC, Cohen  SD. Contribution of acetaminophen-cysteine to acetaminophen  nephrotoxicity II. Possible involvement of the gamma-glutamyl  cycle. Toxicol Appl Pharmacol. 2005; 202: 160-171.

[97] Boyer TD, Rouff SL. Acetaminophen-induced hepatic necrosis  and renal failure. JAMA. 1971; 218(3): 440-1.

[98] Mour G, Feinfeld DA, Caraccio T, McGuigan M. Acute renal  dysfunction in acetaminophen poisoning. Ren Fail. 2005; 27:  381-383.

[99] Pakravan N, Simpson KJ, Waring WS, Bates CM, Bateman  DN. Renal injury at first presentation as a predictor for poor  outcome in severe paracetamol poisoning referred to a liver  transplant unit. Eur J Clin Pharmacol. 2009; 65: 163-168.

[100] O'Riordan A, Brummell Z, Sizer E, Auzinger G, Heaton N,  O'Grady JG, Bernal W, Hendry BM, Wendon JA. Acute  kidney injury in patients admitted to a liver intensive therapy  unit with paracetamol-induced hepatotoxicity. Nephrol Dial  Transplant. 2011; 26: 3501-3508.

[101] Chen YG, Lin CL, Dai MS, Chang PY, Chen JH, Huang TC,  Wu YY, Kao CH. Risk of acute kidney Injury and LongTerm Outcome in Patients With Acetaminophen Intoxication:  A Nationwide Population-Based Retrospective Cohort Study.  Medicine (Baltimore). 2015; 94: e2040.

[102] Curry SC, Padilla-Jones A, O'Connor AD, Ruha AM, Bikin  DS, Wilkins DG, Rollins DE, Slawson MH, Gerkin RD. Acetaminophen adduct study group. Prolonged  acetaminophen-protein adduct elimination during renal failure, lack of adduct removal by hemodiafiltration, and  urinary adduct concentrations after acetaminophen  overdose. J Med Toxicol. 2015; 11: 169-178.

[103] Prescott LF, Critchley JA. The treatment of acetaminophen  poisoning. Annu Rev Pharmacol Toxicol. 1983; 23: 87-101.

[104] Wilkinson SP, Moodie H, Arroyo VA, Williams R.  Frequency of renal impairment in paracetamol overdose  compared with other causes of acute liver damage. J Clin Pathol. 1977; 30: 141-143.

[105] Larson AM, Polson J, Fontana RJ, Davern TJ, Lalani E,  Hynan LS, Reisch JS, Schiødt FV, Ostapowicz G, Shakil AO,  Lee WM; Acute Liver Failure Study Group. Acetaminopheninduced acute liver failure: results of a United States  multicenter, prospective study. Hepatology. 2005; 42: 1364- 1372.

[106] Antoine DJ, Sabbisetti VS, Francis B, Jorgenson AL, Craig  DG, Simpson KJ, Bonventre JV, Park BK, Dear JW.  Circulating kidney injury molecule 1 predicts prognosis and  poor outcome in patients with acetaminophen-induced liver  injury. Hepatology. 2015; 62: 591-599.

[107] Perneger TV, Whelton PK, Klag MJ. Risk of kidney failure  associated with the use of acetaminophen, aspirin, and  nonsteroidal antiinflammatory drugs. N Eng J Med. 1994;  331: 1675-1679.

[108] Blantz RC. Acetaminophen: acute and chronic effects on  renal function. Am J Kidney Dis. 1996; 28: S3-6.

[109] Mudge GH, Gemborys MW, Duggin GG. Covalent binding  of metabolites of acetaminophen to kidney protein and  depletion of renal glutathione. J Pharmacol Exp Ther. 1978;  206: 218-226

[110] Bessems JG, Vermeulen NP. Paracetamol (acetaminophen)- induced toxicity: molecular and biochemical mechanisms,  analogues and protective approaches. Crit Rev Toxicol. 2001;  31: 55-138.

[111] Carpenter HM, Mudge GH. Acetaminophen nephrotoxicity:  studies on renal acetylation and deacetylation. J Pharmacol Exp Ther. 1981; 218: 161-167.

[112] Newton JF, Braselton WE Jr, Kuo CH, Kluwe WM,  Gemborys MW, Mudge GH, Mudge GH, Hook JB.  Metabolism of acetaminophen by the isolated perfused  kidney. J Pharmacol Exp Ther. 1982; 221: 76-79.

[113] Newton JF, Kuo CH, DeShone GM, Hoefle D, Bernstein J,  Hook JB. The role of p-aminophenol in acetaminopheninduced nephrotoxicity: effect of bis(p-nitrophenyl) phosphate on acetaminophen and p-aminophenol nephrotoxicity and metabolism in Fischer 344 rats. Toxicol Appl Pharmacol. 1985; 81: 416-430.

[114] Newton JF, Pasino DA, Hook JB. Acetaminophen  nephrotoxicity in the rat: quantitation of renal metabolic  activation in vivo. Toxicol Appl Pharmacol. 1985; 78: 39-46.

[115] Ściskalska M, Śliwinska-Mosson M, Podawacz M, Sajewicz  W, Milnerowicz H. Mechanisms of interaction of the N-acetylp-aminophenol metabolites in terms of nephrotoxicity. Drug  Chem Toxicol. 2015; 38: 121-125.

[116] Mugford CA, Tarloff JB. Contribution of oxidation and  deacetylation to the bioactivation of acetaminophen in vitro in  liver and kidney from male and female Sprague-Dawley rats.  Drug Metab Dispos. 1995; 23: 290-294.

[117] Emeigh Hart SG, Beierschmitt WP, Bartolone JB, Wyand DS,  Khairallah EA, Cohen SD. Evidence against deacetylation and  for cytochrome P450-mediated activation in acetaminopheninduced nephrotoxicity in the CD-1 mouse. Toxicol Appl Pharmacol. 1991; 107: 1-15.

[118] Hart SG, Beierschmitt WP, Wyand DS, Khairallah EA, Cohen  SD. Acetaminophen nephrotoxicity in CD-1 mice. I. Evidence  of a role for in situ activation in selective covalent binding and  toxicity. Toxicol Appl Pharmacol. 1994; 126: 267-275.

[119] Hoivik DJ, Manatou JE, Tviet A, Hart SG, Khairallah EA,  Cohen SD. Gender-related differences in susceptibility to  acetaminophen-induced protein arylation and nephrotoxicity in  the CD-1 mouse. Toxicol Appl Pharmacol. 1995; 130: 257- 271.

[120] Clark PM, Clark JD, Wheatley T. Urine discoloration after  acetaminophen overdose. Clin Chem. 1986; 32: 1777-1778.

[121] Chen CF, Tseng TY, Tseng HK, Liu TZ. Automated  spectrophotometric assay for urine p-aminophenol by oxidative  coupling reaction. Ann Clin Lab Sci. 2004; 34: 336-340.

[122] Larsson R, Ross D, Berlin T, Olsson LI, Moldeus P.  Prostaglandin synthase catalyzed metabolic activation of pphenetidine and acetaminophen by microsomesisoalted from  rabbit and human kidney. J Pharmacol Exp Ther. 1985; 235:  475-480.

[123] Porter KE, Dawson AG. Inhibition of respiration and  gluconeogenesis by paracetamol in rat kidney preparations.  Biochem Pharmacol. 1979; 28: 3057-3062.

[124] Satav JG, Bhattacharya RK. Respiratory functions in kidney  mitochondria following paracetamol administration to youngadult & old rats. Indian J Med Res. 1997; 105: 131-135.

[125] Stallons LJ, Funk JA, Schnellmann RG. Mitochondrial  homeostasis in acute organ failure. Curr Pathobiol Rep. 2013; 1.

[126] Newson RB, Shaheen SO, Chinn S, Burney PG. Paracetamol  sales and atopic disease in children and adults: an ecological  analysis. Eur Respir J. 2000; 16: 817-823.

[127] Shaheen SO, Newson RB, Henderson AJ, Headley JE, Stratton  FD, Jones RW, Strachan DP; ALSPAC Study Team. Prenatal  paracetamol exposure and risk of asthma and elevated  immunoglobulin E in childhood. Clin Exp Allergy. 2005; 35:  18-25.

[128] Beasley R, Clayton T, Crane J, von Mutius E, Lai CK,  Montefort S, Stewart A; ISAAC Phase Three Study Group.  Association between paracetamol use in infancy and childhood,  and risk of asthma, rhinoconjunctivitis, and eczema in children  aged 6-7 years: analysis from Phase Three of the ISAAC  programme. Lancet. 2008; 372: 1039-1048.

[129] Perzanowski MS, Miller RL, Tang D, Ali D, Garfinkel RS,  Chew GL, Goldstein IF, Perera FP, Barr RG. Prenatal  acetaminophen exposure and risk of wheeze at age 5 years in  an urban low-income cohort. Thorax. 2010; 65: 118-123.

[130] Kelkar M, Cleves MA, Foster HR, Hogan WR, James LP,  Martin BC. Prescription-acquired acetaminophen use and the  risk of asthma in adults: a case-control study. Ann  Pharmacother. 2012; 46: 1598-1608.

[131] McKeever TM, Lewis SA, Smit HA, Burney P, Britton JR,  Cassano PA. The association of acetaminophen, aspirin, and  ibuprofen with respiratory disease and lung function. Am J  Respir Crit Care Med. 2005; 171: 966-971.

[132] Singh A. Acetaminophen and asthma. CMAJ. 2009; 181: 616.

[133] Henderson AJ, Shaheen SO. Acetaminophen and asthma.  Paediatr Respir Rev. 2013; 14: 9-15.

[134] Weatherall M, Ioannides S, Braithwaite I, Beasley R. The  association between paracetamol use and asthma: causation  or coincidence? Clin Exp Allergy. 2015; 45: 108-113.

[135] Rusconi F, Gagliardi L, Galassi C, Forastiere F, Brunetti L,  La Grutta S, Piffer S, Talassi F; SIDRIA-2 Collaborative  Group. Paracetamol and antibiotics in childhood and  subsequent development of wheezing/asthma: association or  causation? Int J Epidemiol. 2011; 40: 662-667.

[136] Gu J, Cui H, Behr M, Zhang L, Zhang QY, Yang W, Hinson  JA, Ding X. In vivo mechanisms of tissue-selective drug  toxicity: effects of liver-specific knockout of the NADPHcytochrome P450 reductase gene on acetaminophen toxicity  in kidney, lung, and nasal mucosa. Mol Pharmacol. 2005; 67:  623-630.

[137] Chen TS, Richie JP Jr, Lang CA. Life span profiles of  glutathione and acetaminophen detoxification. Drug Metab Dispos. 1990; 18: 882-887.

[138] Smith GJ, Cichocki JA, Doughty BJ, Manautou JE, Jordt SE,  Morris JB. Effects of acetaminophen on oxidant and irritant  respiratory tract responses to environmental tobacco smoke in  female mice. Environ Health Perspect. 2016; 124: 642-650.

[139] Shaheen SO, Newson RB, Ring SM, Rose-Zerilli MJ, Holloway JW, Henderson AJ. Prenatal and infant  acetaminophen exposure, antioxidant gene polymorphisms,  and childhood asthma. J Allergy Clin Immunol. 2010; 126:  1141-8.e7.

[140] Breen K, Wandscheer JC, Peignoux M, Pessayre D. In situ  formation of the acetaminophen metabolite covalently bound  in kidney and lung. Supportive evidence provided by total  hepatectomy. BiochemPharmacol. 1982; 31: 115-116.

[141] Bartolone JB, Beierschmitt WP, Birge RB, Hart SG, Wyand  S, Cohen SD, Khairallah EA. Selective acetaminophen  metabolite binding to hepatic and extrahepatic proteins: an in  vivo and in vitro analysis. Toxicol Appl Pharmacol. 1989; 99:  240-249.

[142] Bulera SJ, Cohen SD, Khairallah EA. Acetaminophenarylated proteins are detected in hepatic subcellular fractions  and numerous extra-hepatic tissues in CD-1 and C57B1/6J  mice. Toxicology. 1996; 109: 85-99.

[143] Berkowitz GS, Lapinski RH. Risk factors for cryptorchidism:  a nested case-control study. Paediatr Perinat Epidemiol. 1996;  10: 39-51.

[144] Jensen MS, Rebordosa C, Thulstrup AM, Toft G, Sørensen  HT, Bonde JP, Henriksen TB, Olsen J. Maternal use of  acetaminophen, ibuprofen, and acetylsalicylic acid during  pregnancy and risk of cryptorchidism. Epidemiology. 2010;  21: 779-785.

[145] Kristensen DM, Hass U, Lesné L, Lottrup G, Jacobsen PR,  Desdoits-Lethimonier C, Boberg J, Petersen JH, Toppari J,  Jensen TK, Brunak S, Skakkebaek NE, Nellemann C, Main  KM, Jacgou B, Leffers H. Intrauterine exposure to mild  analgesics is a risk factor for development of male  reproductive disorders in human and rat. Hum Reprod. 2011;  26: 235-244.

[146] Lind DV, Main KM, Kyhl HB, Kristensen DM, Toppari J,  Andersen HR, Andersen MS, Skakkebæk NE, Jensen TK.  Maternal use of mild analgesics during pregnancy associated  with reduced anogenital distance in sons: a cohort study of  1027 mother-child pairs. Hum Reprod. 2017; 32: 223-231.

[147] Holm JB, Chalmey C, Modick H, Jensen LS, Dierkes G, Weiss  T, Jensen BA, Nørregård MM, Borkowski K, Styrishave B,  Martin Koch H, Mazaud-Guittot S, Jegou B, Kristiansen K,  Kristensen DM. Aniline is rapidly converted into paracetamol  impairing male reproductive development. Toxicol Sci. 2015;  148: 288-298.

[148] Holm JB, Mazaud-Guittot S, Danneskiold-Samsøe NB,  Chalmey C, Jensen B, Nørregård MM, Hansen CH, Styrishave  B, Svingen T, Vinggaard AM, Koch HM, Bowles J, Koopman  P, Jegou B, Kristiansen K, Kristensen DM. Intrauterine  exposure to paracetamol and aniline impairs female  reproductive development by reducing follicle reserves and  fertility. Toxicol Sci. 2016; 150: 178-189.

[149] McGill MR, Lebofsky M, Norris HR, Slawson MH, Bajt ML,  Xie Y, Williams CD, Wilkins DG, Rollins DE, Jaeschke H.  Plasma and liver acetaminophen-protein adduct levels in mice  after acetaminophen treatment: dose-response, mechanisms,  and clinical implications. Toxicol Appl Pharmacol. 2013; 269:  240-249.

[150] Hay-Schmidt A, Finkielman OTE, Jensen BAH, Hogsbro CF,  Bak Holm J, Johansen KH, Jensen TK, Andrade AM, Swan  SH, Bornehag CG, Brunak S, Jeqou B, Kristiansen K,  Kristensen DM. Prenatal exposure to paracetamol/ acetaminophen and precursor aniline impairs masculinisation of male brain and  behavior. Reproduction. 2017; 154: 145-152.

[151] Patel R, Rosengren RJ. Acetaminophen elicits anti-estrogenic  but not estrogenic responses in the immature mouse. Toxicol  Lett. 2001; 122: 89-96.

[152] Fortner RT, Oh H, Daugherty SE, Xu X, Hankinson SE,  Ziegler RG, Eliassen AH. Analgesic use and patterns of  estrogen metabolism in premenopausal women. Horm Cancer.  2014; 5: 104-112.

[153] van den Driesche S, Macdonald J, Anderson RA, Johnston ZC,  Chetty T, Smith LB, McKinnell C, Dean A, Homer NZ,  Jorgensen A, Camacho-Moll ME, Sharpe RM, Mitchell RT.  Prolonged exposure to acetaminophen reduces testosterone  production by the human fetal testis in a xenograft model.  SciTransl Med. 2015; 7: 288ra80.

[154] Kristensen DM, Lesné L, Le Fol V, Desdoits-Lethimonier C,  Dejucq-Rainsford N, Leffers H, Jégou B. Paracetamol  (acetaminophen), aspirin (acetylsalicylic acid) and  indomethacin are anti-androgenic in the rat foetal testis. Int J  Androl. 2012; 35: 377-384.

[155] Albert O, Desdoits-Lethimonier C, Lesné L, Legrand A, Guillé  F, Bensalah K, Dejucq-Rainsford N, Jégou B. Paracetamol,  aspirin and indomethacin display endocrine disrupting  properties in the adult human testis in vitro. Hum Reprod.  2013; 28: 1890-1898.

[156] Mazaud-Guittot S, Nicolas Nicolaz C, Desdoits-Lethimonier C,  Coiffec I, Ben Maamar M, Balaguer P, Kristensen DM,  Chevrier C, Lavoué V, Poulain P, Dejucq-Rainsford N, Jégou  B. Paracetamol, aspirin, and indomethacin induce endocrine  disturbances in the human fetal testis capable of interfering  with testicular descent. J Clin Endocrinol Metab. 2013; 98:  1757-1767. 4

[157] Nohynek GJ, Borgert CJ, Dietrich D, Rozman KK. Endocrine  disruption: fact or urban legend? Tox

[158] Friedman RA, House JW, Luxford WM, Gherini S, Mills D.  Profound hearing loss associated with hydrocodone/ acetaminophen abuse. Am J Otol. 2000; 21: 188-191.

[159] Oh AK, Ishiyama A, Baloh RW. Deafness associated with  abuse of hydrocodone/acetaminophen. Neurology. 2000; 54:  2345.

[160] Ho T, Vrabec JT, Burton AW. Hydrocodone use and  sensorineural hearing loss. Pain Physician. 2007; 10: 467- 472.

[161] Kalinec GM, Webster P, Lim DJ, Kalinec F. A cochlear cell  line as an in vitro system for drug ototoxicity screening.  Audiol Neurootol. 2003; 8: 177-189.

[162] Kalinec G, Thein P, Park C, Kalinec F. HEI-OC1 cells as  a model for investigating drug cytotoxicity. Hear Res. 2016;  335: 105-17.

[163] McGill MR, Kennon-McGill S, Durham D, Jaeschke H.  Hearing, reactive metabolite formation, and oxidative stress  in cochleae after a single acute overdose of acetaminophen:  an in vivo study. Toxicol Mech Methods. 2016; 26: 104-111.

[164] Boulares HA, Giardina C, Navarro CL, Khairallah EA, Cohen  SD. Modulation of serum growth factor signal transduction in  Hepa 1-6 cells by acetaminophen: an inhibition of c-myc  expression, NF-kappaB activation, and Raf-1 kinase activity.  Toxicol Sci. 1999; 48: 264-274.

[165] Boulares AH, Zoltoski AJ, Stoica BA, Cuvillier O, Smulson  ME. Acetaminophen induces a caspase-dependent and BclXL sensitive apoptosis in human hepatoma cells and  lymphocytes. Pharmacol Toxicol. 2002; 90: 38-50.

[166] Antoine DJ, Jenkins RE, Dear JW, Williams DP, McGill MR,  Sharpe MR, Craig DG, Simpson KJ, Jaeschke H, Park BK.  Molecular forms of HMGB1 and keratin-18 as mechanistic  biomarkers for mode of cell death and prognosis during  clinical acetaminophen hepatotoxicity. J Hepatol. 2012; 56:  1070-1079.

[167] Alberti A, Pirrone P, Elia M, Waring RH, Romano C.  Sulphation deficit in "low-functioning" autistic children: a  pilot study. Biol Psychiatry. 1999; 46: 420-424.

[168] Good P. Did acetaminophen provoke the autism epidemic?  Altern Med Rev. 2009; 14: 364-372.

[169] Prescott LF. Kinetics and metabolism of paracetamol and  phenacetin. Br J Clin Pharmacol. 1980; 10 Suppl 2: 291S- 298S.

[170] Liew Z, Ritz B, Virk J, Olsen J. Maternal use of acetaminophen during pregnancy and risk of autism spectrum disorders in  childhood: A Danish national birth cohort study. Autism Res.  2016; 9: 951-958.

[171] Cox AR, McDowell S. A response to the article on the  association between paracetamol/acetaminophen: use and  autism by Stephen T. Schultz. Autism. 2009; 13: 123-4.

[172] Olson J, Liew Z. Commentary: acetaminophen use in  pregnancy and neurodevelopment: attention function and autism spectrum symptoms. Int J Epidemiol. 2016; 45: 1996- 1997.

[173] Brandlistuen RE, Ystrom E, Nulman I, Koren G, Nordeng H.  Prenatal paracetamol exposure and child neurodevelopment: a  sibling-controlled cohort study. Int J Epidemiol. 2013; 42:  1702-1713.

[174] Thompson JM, Waldie KE, Wall CR, Murphy R, Mitchell EA;  ABC study group. Associations between acetaminophen use  during pregnancy and ADD/ADHD symptoms measured at  ages 7 and 11 years. PLoS One. 2014; 9: e108210.

[175] Avella-Garcia CB, Julvez J, Fortuny J, Rebordosa C, GarciaEsteban R, Galan IR, Tardon A, Rodriguez-Bernal CL,   Iniguez C, Andiarena A, Santa-Marina L, Sunyer J.  Acetaminophen use in pregnancy and neurodevelopment:  attention function and autism spectrum symptoms. Int J  Epidemiol. 2016; 45: 1987-1996.

[176] Stergiakouli E, Thapar A, Davey Smith G. Association of  acetaminophen use during pregnancy with behavioral  problems in childhood: evidence against confounding. JAMA  Pediatr. 2016; 170: 964-970.

[177] Hoover RM, Hayes VA, Erramouspe J. Association between prenatal acetaminophen exposure and future risk of attention  deficit/hyperactivity disorder in children. Ann Pharmacother.  2015; 49: 1357-1361.

[178] Streissguth AP, Treder RP, Barr HM, Shepard TH, Bleyer WA,  Sampson PD, Martin DC. Aspirin and acetaminophen use by  pregnant women and subsequent child IQ and attention  decrements. Teratology. 1987; 35: 211-219.

[179] Saad A, Hegde S, Kechichian T, Gamble P, Rahman M, Stutz  SJ, Anastasio NC, Alshehri W, Lei J, Mori S, Kajs B,  Cunningham KA, Saade G, Burd I, Costantine M. Is There a  Causal Relation between Maternal Acetaminophen Administration and ADD/ADHD? PLoS One. 2016; 11: e0157380.

[180] Philippot G, Gordh T, Fredriksson A, Viberg H. Adult  neurobehavioral alterations in male and female mice following  developmental exposure to paracetamol (acetaminophen):  characterization of a critical period. J Appl Toxicol. 2017. doi:  10.1002/jat.3473. [Epub ahead of print]

[181] Schultz ST. Can autism be triggered by acetaminophen  activation of the endocannabinoid system? Acta Neurobiol Exp  (Wars). 2010; 70: 227-231.

[182] Parker W, Hornik CD, Bilbo S, Holzknecht ZE, Gentry L, Rao  R, Lin SS, Herbert MR, Nevison CD. The role of oxidative  stress, inflammation and acetaminophen exposure from birth to  early childhood in the induction of autism. J Int Med Res.  2017; 45: 407-438.

[183] Constantino JN, Marrus N. The early origins of autism. Child  Adolesc Psychiatr Clin N Am. 2017; 26: 555-570.

[184] Constantino JN, Kennon-McGill S, Weichselbaum C, Marrus  N, Haider A, Glowinski AL, Gillespie S, Klaiman C, Klin A,  Jones W. Infant viewing of social scenes is under genetic  control and is atypical in autism. Nature. 2017; 547: 340-344.

[185] Zhao C, Shichi H. Histocytological study on the possible  mechanism of acetaminophen cataractogenesis in mouse eye.  Exp Mol Pathol. 1995; 63: 118-128.

[186] Qian W, Amin RH, Shichi H. Cytotoxic metabolite of  acetaminophen, N-acetyl-p-benzoquinone imine, produces  cataract in DBA2 mice. J Ocul Pharmacol Ther. 1999; 15: 537- 545.

[187] ArmourA, Slater SD. Paracetamol cardiotoxicity. Postgrad  Med J. 1993; 69: 52-54.