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Sciences","doi-asserted-by":"publisher","award":["UL1TR004419"],"award-info":[{"award-number":["UL1TR004419"]}],"id":[{"id":"10.13039\/100006108","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000024","name":"Canadian Institutes of Health Research","doi-asserted-by":"publisher","award":["187861"],"award-info":[{"award-number":["187861"]}],"id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,9,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>BACKGROUND: Per- and polyfluoroalkyl substances (PFAS) have been associated with numerous deleterious health outcomes, including liver damage. However, whether exposure to PFAS is associated with liver cancer risk remains unclear. METHODS: We conducted a matched nested case-control study among 12 prospective cohort studies located in the United States. Prediagnostic PFAS, namely, perfluorooctanesulfonate (PFOS), perfluorooctanoate (PFOA), and perfluorohexanesulfonate (PFHxS), were measured from blood samples among 853 individuals who developed liver cancer and 853 matched control participants. Odds ratios (OR) and 95% confidence intervals (CI) were estimated using multivariable-adjusted conditional logistic regression for liver cancer risk by study-specific quartiles of concentrations and per 90th vs 10th percentile incremental increase. RESULTS: In the main multivariable-adjusted model, circulating PFOS, PFOA, and PFHxS levels were not associated with liver cancer risk (OR per 90th vs 10th percentile increase: 1.00, 95% CI: 0.79\u20131.28; 0.92, 0.73\u20131.15; and 0.95, 0.75\u20131.21, respectively). However, when analyses were stratified by sex, PFOA concentrations were positively associated with liver cancer risk in males (OR per 90th vs 10th percentile increase: 1.62 95% CI: 1.07\u20132.45), whereas an inverse association was observed among females (OR per 90th vs 10th percentile increase: 0.68, 0.50\u20130.92; p-interaction = 0.005). Analyses separating liver cancer subtypes, hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma, showed no evidence of heterogeneity, although associations were stronger but not significant for HCC. No evidence of interaction was observed by time to diagnosis, time period of blood draw, body mass index, alcohol intake, ethnicity, or diabetes status. CONCLUSIONS: In the largest study to date, none of the measured circulating PFAS were associated with liver cancer risk; however, PFOA associations appeared to differ by sex, and further research is needed to explore these apparent differences by sex.<\/jats:p>","DOI":"10.1021\/ehp.6c00400","type":"journal-article","created":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T14:01:34Z","timestamp":1786111294000},"page":"502-511","source":"Crossref","is-referenced-by-count":16,"title":["Circulating per- and\npolyfluoroalkyl substances and\nliver cancer risk: a nested case-control analysis of individual participant\ndata from 12 prospective cohorts"],"prefix":"10.1021","volume":"134","author":[{"given":"Cody Z.","family":"Watling","sequence":"first","affiliation":[{"name":"National Cancer Institute , , , ,","place":["Rockville, Maryland, United States, 20850"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jessica L.","family":"Petrick","sequence":"additional","affiliation":[{"name":"Slone Epidemiology Center at Boston University , , ,","place":["Boston, Massachusetts, United States, 02215"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barry I.","family":"Graubard","sequence":"additional","affiliation":[{"name":"National Cancer Institute , , , ,","place":["Rockville, Maryland, United States, 20850"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuehong","family":"Zhang","sequence":"additional","affiliation":[{"name":"Yale University , , , ,","place":["New Haven, Connecticut, United States, 06520"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew J.","family":"Barnett","sequence":"additional","affiliation":[{"name":"Fred Hutchinson Cancer Center , , , ,","place":["Seattle, Washington, United States, 98109"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julie E.","family":"Buring","sequence":"additional","affiliation":[{"name":"Brigham and Women\u2019s Hospital, Harvard Medical School , , ,","place":["Boston, Massachusetts, United States, 02115"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Chen","sequence":"additional","affiliation":[{"name":"NYU Grossman School of Medicine , , , ,","place":["New York, New York, United States, 10016"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A. Heather","family":"Eliassen","sequence":"additional","affiliation":[{"name":"Harvard T.H. 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98109"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caroline Y.","family":"Um","sequence":"additional","affiliation":[{"name":"American Cancer Society , , , ,","place":["Atlanta, Georgia, United States, 30303"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kala","family":"Visvanathan","sequence":"additional","affiliation":[{"name":"Johns Hopkins School of Medicine and Bloomberg School of Public Health , , ,","place":["Baltimore, Maryland, United States, 21205"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean","family":"Wactawski-Wende","sequence":"additional","affiliation":[{"name":"University at Buffalo , , , ,","place":["Getzville, New York, United States, 14068"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Walter","family":"Willett","sequence":"additional","affiliation":[{"name":"NYU Grossman School of Medicine , , , ,","place":["New York, New York, United States, 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20850"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter T.","family":"Campbell","sequence":"additional","affiliation":[{"name":"Albert Einstein College of Medicine , , , ,","place":["New York, New York, United States, 10461"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dinesh","family":"Barupal","sequence":"additional","affiliation":[{"name":"Icahn School of Medicine at Mount Sinai , , , ,","place":["New York, New York, United States, 10029"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katherine A.","family":"McGlynn","sequence":"additional","affiliation":[{"name":"National Cancer Institute , , , ,","place":["Rockville, Maryland, United States, 20850"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,8,7]]},"reference":[{"key":"2026090306405076900_cit1","doi-asserted-by":"publisher","first-page":"229","DOI":"10.3322\/caac.21834","article-title":"Global cancer 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J. Cancer"},{"key":"2026090306405076900_cit4","doi-asserted-by":"publisher","first-page":"205","DOI":"10.1097\/CEJ.0000000000000428","article-title":"Worldwide incidence of hepatocellular\ncarcinoma cases attributable to major risk factors","volume":"27","author":"Baecker","year":"2018","journal-title":"Eur J Cancer Prev"},{"key":"2026090306405076900_cit5","doi-asserted-by":"publisher","first-page":"1757","DOI":"10.1002\/cncr.29971","article-title":"Population\nattributable fractions of risk factors for hepatocellular carcinoma\nin the United States","volume":"122","author":"Makarova-Rusher","year":"2016","journal-title":"Cancer"},{"key":"2026090306405076900_cit6","doi-asserted-by":"publisher","first-page":"1828","DOI":"10.1053\/j.gastro.2018.08.024","article-title":"Risk of\nHepatocellular Cancer in Patients With Non-Alcoholic Fatty Liver Disease","volume":"155","author":"Kanwal","year":"2018","journal-title":"Gastroenterology"},{"key":"2026090306405076900_cit7","doi-asserted-by":"publisher","first-page":"6076","DOI":"10.1158\/0008-5472.CAN-16-0787","article-title":"Body Mass Index, Waist Circumference,\nDiabetes, and Risk of Liver Cancer for U.S","volume":"76","author":"Campbell","year":"2016","journal-title":"Adults. Cancer Res"},{"key":"2026090306405076900_cit8","doi-asserted-by":"publisher","first-page":"1494","DOI":"10.1038\/s41395-018-0207-4","article-title":"Body Mass Index,\nDiabetes and Intrahepatic Cholangiocarcinoma\nRisk: The Liver Cancer Pooling Project and Meta-analysis","volume":"113","author":"Petrick","year":"2018","journal-title":"Am J Gastroenterol"},{"key":"2026090306405076900_cit9","doi-asserted-by":"publisher","first-page":"1476","DOI":"10.1016\/j.jhep.2021.08.012","article-title":"Epidemiology\nand risk-stratification of NAFLD-associated HCC","volume":"75","author":"Ioannou","year":"2021","journal-title":"Journal of Hepatology"},{"key":"2026090306405076900_cit10","doi-asserted-by":"publisher","first-page":"100550","DOI":"10.1016\/j.jhepr.2022.100550","article-title":"Exposure\nto perfluoroalkyl substances and risk of hepatocellular carcinoma\nin a multiethnic cohort","volume":"4","author":"Goodrich","year":"2022","journal-title":"JHEP 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Cell Tumors among U.S. Air Force Servicemen","volume":"131","author":"Purdue","year":"2023","journal-title":"Environ Health Perspect"},{"key":"2026090306405076900_cit17","doi-asserted-by":"publisher","first-page":"37","DOI":"10.1016\/j.envint.2018.05.051","article-title":"Serum polyfluoroalkyl\nchemicals are associated with risk of cardiovascular diseases in national\nUS population","volume":"119","author":"Huang","year":"2018","journal-title":"Environ Int"},{"key":"2026090306405076900_cit18","doi-asserted-by":"publisher","first-page":"724","DOI":"10.1093\/humupd\/dmaa018","article-title":"Perfluoroalkyl and\npolyfluoroalkyl substances (PFAS)\nand their effects on the ovary","volume":"26","author":"Ding","year":"2020","journal-title":"Hum Reprod Update"},{"key":"2026090306405076900_cit19","doi-asserted-by":"publisher","first-page":"1100","DOI":"10.1289\/ehp.0901827","article-title":"Epidemiologic\nevidence on the health\neffects of perfluorooctanoic acid (PFOA)","volume":"118","author":"Steenland","year":"2010","journal-title":"Environ\nHealth Perspect"},{"key":"2026090306405076900_cit20","doi-asserted-by":"publisher","first-page":"354","DOI":"10.1016\/j.envint.2013.06.004","article-title":"Accumulation\nof perfluoroalkyl substances in human tissues","volume":"59","author":"Pe\u0301rez","year":"2013","journal-title":"Environment International"},{"key":"2026090306405076900_cit21","doi-asserted-by":"publisher","first-page":"46001","DOI":"10.1289\/EHP10092","article-title":"Exposure to per- and Polyfluoroalkyl\nSubstances and Markers of Liver\nInjury: A Systematic Review and Meta-Analysis","volume":"130","author":"Costello","year":"2022","journal-title":"Environ Health Perspect"},{"key":"2026090306405076900_cit22","doi-asserted-by":"publisher","first-page":"100694","DOI":"10.1016\/j.jhepr.2023.100694","article-title":"Association\nof per- and polyfluoroalkyl\nsubstance exposure with fatty liver disease risk in US adults","volume":"5","author":"Zhang","year":"2023","journal-title":"JHEP Rep"},{"key":"2026090306405076900_cit23","doi-asserted-by":"publisher","first-page":"101602","DOI":"10.1016\/j.molmet.2022.101602","article-title":"Exposure to low-dose perfluorooctanoic\nacid promotes hepatic steatosis and disrupts the hepatic transcriptome\nin mice","volume":"66","author":"Attema","year":"2022","journal-title":"Mol Metab"},{"key":"2026090306405076900_cit24","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.tox.2012.01.003","article-title":"Chronic\ndietary\ntoxicity and carcinogenicity study with potassium perfluorooctanesulfonate\nin Sprague Dawley rats","volume":"293","author":"Butenhoff","year":"2012","journal-title":"Toxicology"},{"key":"2026090306405076900_cit25","doi-asserted-by":"publisher","first-page":"605","DOI":"10.1093\/jnci\/djp041","article-title":"Perfluorooctanoate and perfluorooctanesulfonate\nplasma levels and risk of cancer in the general Danish population","volume":"101","author":"Eriksen","year":"2009","journal-title":"J Natl Cancer Inst"},{"key":"2026090306405076900_cit26","doi-asserted-by":"publisher","first-page":"1313","DOI":"10.1289\/ehp.1306615","article-title":"Perfluorooctanoic acid (PFOA) exposures\nand incident cancers among adults living near a chemical plant","volume":"121","author":"Barry","year":"2013","journal-title":"Environ Health Perspect"},{"key":"2026090306405076900_cit27","doi-asserted-by":"publisher","first-page":"318","DOI":"10.1289\/ehp.1205829","article-title":"Perfluorooctanoic acid exposure and cancer outcomes\nin a contaminated community: a geographic analysis","volume":"121","author":"Vieira","year":"2013","journal-title":"Environ Health Perspect"},{"key":"2026090306405076900_cit28","doi-asserted-by":"publisher","first-page":"909","DOI":"10.1093\/aje\/kws171","article-title":"Cohort Mortality Study of Workers Exposed to Perfluorooctanoic 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