Oral Argument: Sublingual Findings Challenge Key Assumptions about BPA Exposure

Abstract

Vol. 121, No. 8 News | Science SelectionsOpen AccessOral Argument: Sublingual Findings Challenge Key Assumptions about BPA Exposure Julia R. Barrett Julia R. Barrett Search for more papers by this author Published:1 August 2013https://doi.org/10.1289/ehp.121-a257Cited by:34View Article in:中文版AboutSectionsPDF ToolsDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InReddit Key assumptions about bisphenol A (BPA) exposure and bioavailability may be off base, according to a new report in EHP that questions the traditional interpretation of biomonitoring data underlying current risk assessments of the chemical.1 Laboratory research suggests that BPA, a widely used chemical for polycarbonate plastics and other products, is an endocrine disruptor with potential adverse health effects involving reproduction, metabolism, and cancer.2,3Median daily intake of the chemical through the diet is estimated to be 0.01–0.12 µg/kg body weight, based on urinary concentrations of BPA metabolites.4 These metabolites, particularly BPA glucuronide (BPAG), are not biologically active like the parent compound. Nearly all ingested BPA has been thought to be absorbed in the small intestine and rapidly converted to BPAG in the liver prior to bodywide distribution.5,6Given the estimated daily intake and assumption of rapid conversion, the European Food Safety Authority set a tolerable daily intake of BPA at 0.05 mg/kg.1 However, the current study indicates that BPA can be completely absorbed directly into the bloodstream from the mouth, thus bypassing early rapid metabolism and remaining biologically active for an extended period of time.“Most previous studies have relied on the gavage method, where BPA is distributed directly into the gut,” says Laura Vandenberg, a postdoctoral fellow at the Tufts University Center for Regenerative and Developmental Biology, who was not involved in the study. “This isn’t how food actually enters our bodies. We chew it, move it around in our mouths, and it interacts with numerous surfaces—our tongue, cheeks, etc.—before it enters the stomach.” Gavage studies suggest there should not be detectable levels of unmetabolized BPA in the blood after exposure, yet dozens of other studies report otherwise, she says.The researchers compared the bioavailability of BPA given sublingually (under the tongue) versus intravenously or by gavage. In one experiment 6 dogs received a dose of 5 mg/kg first intravenously, then a week later sublingually either all at once or one drop at a time. In another experiment, conducted in three parts, the same dogs received a dose of 0.05 mg/kg first intravenously, then sublingually, and finally a 20-mg/kg dose delivered by gavage. After each administration, blood samples were collected to measure BPA and BPAG and calculate various parameters such as maximum concentration, time to maximum concentration, and mean residence time.1BPA was readily absorbed from both the mouth and the gut, but bioavailability throughout the body differed significantly depending on the absorption site. Over the 2 hours following dosing, 5 mg/g and 0.05 mg/kg sublingual BPA yielded ratios of biologically inactive BPAG to biologically active BPA of 1:1–13:1 and 1:1–6:1, respectively, compared with 237:1–634:1 for the dose placed directly in the stomach.1If confirmed, new findings on sublingual BPA dosing could have important implications for human exposures to BPA.© Shutterstock.com“The sublingual route is a rather well-known route of absorption for those who are involved in the development of drugs but not for those working with contaminants in general and BPA in particular,” says study coauthor Pierre-Louis Toutain, a professor of physiology and therapeutics at the National Veterinary School of Toulouse, France. He says dogs were chosen as the study animals because their oral tissue closely resembles that of humans.The sublingual dosing used in the study may present different conditions from the exposure that occurs while eating or drinking. It also does not reflect potential nonfood exposures from sources such as dust, cigarette filters, thermal papers, and dental sealants that previous research has suggested occur.7 However, “the authors have shown very clearly that when BPA comes into contact with the mucosa under the tongue, it can be rapidly absorbed into the bloodstream. When this happens, it enters the bloodstream without being metabolized,” says Vandenberg. Additionally, this study may explain previous biomonitoring reports of plasma BPA levels deemed impossible or incorrect based on assumptions about gut-only absorption. This is important because plasma levels found in biomonitoring studies are similar to those found to cause adverse health effects in animal studies.7Urinary BPAG serves as an index of external BPA exposure in biomonitoring studies, but it tells us nothing about the route of absorption, says Toutain. Given the researchers’ findings, he says it would be unacceptable to assume that only a negligible fraction of BPAG circulated as active BPA before it was converted to the inactive form measured in urine. He says, “It is clear that our data suggesting that BPA bioavailability can be high should raise some questions and possibly lead some agencies to reconsider their risk analysis on BPA.”References1 Gayrard Vet al.High bioavailability of bisphenol A from sublingual exposure.Environ Health Perspect 121(8):951-9562013.; http//dx..org/doi:10.1289/ehp.120633923761051. Link, Google Scholar2 Vandenberg LNet al.Urinary, circulating, and tissue biomonitoring studies indicate widespread exposure to bisphenol A.Environ Health Perspect 118(8):1055-10702010.; http//dx..org/doi:10.1289/ehp.090171620338858. Link, Google Scholar3 Calafat AMet al.Exposure of the U.S. population to bisphenol A and 4-tertiary-octylphenol: 2003–2004.Environ Health Perspect 116(1):39-442008.; http//dx..org/doi:10.1289/ehp.1075318197297. Link, Google Scholar4 FAO/WHO. Joint FAO/WHO Expert Meeting to Review Toxicological and Health Aspects of Bisphenol A: Summary Report Including Report of Stakeholder Meeting on Bisphenol A. Food and Agriculture Organization of the United Nations/World Health Organization (2010). Available: http://www.who.int/foodsafety/chem/chemicals/BPA_Summary2010.pdf [accessed 15 July 2013]. Google Scholar5 Völkel Wet al.. 2002. Metabolism and kinetics of bisphenol A in humans at low doses following oral administration.Chem Res Toxicol 15(10):1281-12872002.; http//dx..org/.doi:10.1021/tx025548t12387626. Crossref, Medline, Google Scholar6 Stahlhut RWet al.Bisphenol A data in NHANES suggest longer than expected half-life, substantial nonfood exposure, or both.Environ Health Perspect 117(5):784-7892009. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2685842/19479022. Link, Google Scholar7 Vandenberg LNet al.Human exposures to bisphenol A: mismatches between data and assumptions.Rev Environ Health 28(1):37-582013.; http//dx..org/doi:10.1515/reveh-2012-003423612528. Crossref, Medline, Google ScholarFiguresReferencesRelatedDetailsCited by Chen L, Wang C, Zhang Y, Zhou Y, Shi R, Cui C, Gao Y and Tian Y (2018) Polybrominated diphenyl ethers in cord blood and perinatal outcomes from Laizhou Wan Birth Cohort, China, Environmental Science and Pollution Research, 10.1007/s11356-018-2158-0, 25:21, (20802-20808), Online publication date: 1-Jul-2018. Lucas D, Petty S, Keen O, Luedeka B, Schlummer M, Weber R, Barlaz M, Yazdani R, Riise B, Rhodes J, Nightingale D, Diamond M, Vijgen J, Lindeman A, Blum A and Koshland C (2018) Methods of Responsibly Managing End-of-Life Foams and Plastics Containing Flame Retardants: Part I, Environmental Engineering Science, 10.1089/ees.2017.0147, 35:6, (573-587), Online publication date: 1-Jun-2018. Grandjean P and Bellanger M (2017) Calculation of the disease burden associated with environmental chemical exposures: application of toxicological information in health economic estimation, Environmental Health, 10.1186/s12940-017-0340-3, 16:1, Online publication date: 1-Dec-2017. Muenhor D, Moon H, Lee S and Goosey E (2017) Polybrominated diphenyl ethers (PBDEs) in floor and road dust from a manual e-waste dismantling facility and adjacent communities in Thailand, Journal of Environmental Science and Health, Part A, 10.1080/10934529.2017.1357405, 52:14, (1284-1294), Online publication date: 6-Dec-2017. Bond G and Dietrich D (2017) Human cost burden of exposure to endocrine disrupting chemicals. A critical review, Archives of Toxicology, 10.1007/s00204-017-1985-y, 91:8, (2745-2762), Online publication date: 1-Aug-2017. Diamond M (2017) Toxic chemicals as enablers and poisoners of the technosphere, The Anthropocene Review, 10.1177/2053019617726308, 4:2, (72-80), Online publication date: 1-Aug-2017. Lei E, Yau M, Yeung C, Murphy M, Wong K and Lam M (2016) Profiling of Selected Functional Metabolites in the Central Nervous System of Marine Medaka (Oryzias melastigma) for Environmental Neurotoxicological Assessments, Archives of Environmental Contamination and Toxicology, 10.1007/s00244-016-0342-0, 72:2, (269-280), Online publication date: 1-Feb-2017. Pereira L, Souza A, Tasso M, Oliveira A, Duarte F, Palmeira C and Dorta D (2017) Exposure to decabromodiphenyl ether (BDE-209) produces mitochondrial dysfunction in rat liver and cell death, Journal of Toxicology and Environmental Health, Part A, 10.1080/15287394.2017.1357370, 80:19-21, (1129-1144), Online publication date: 2-Nov-2017. Dach K, Bendt F, Huebenthal U, Giersiefer S, Lein P, Heuer H and Fritsche E (2017) BDE-99 impairs differentiation of human and mouse NPCs into the oligodendroglial lineage by species-specific modes of action, Scientific Reports, 10.1038/srep44861, 7:1, Online publication date: 1-Dec-2017. Chang S, Wang W, Chen Y, Chen T, Chiang P and Lo Y (2016) Emulsion-enhanced recovery and biodegradation of decabrominated diphenyl ether in river sediments, Journal of Soils and Sediments, 10.1007/s11368-016-1590-3, 17:4, (1197-1207), Online publication date: 1-Apr-2017. Terry P, Towers C, Liu L, Peverly A, Chen J and Salamova A (2017) Polybrominated diphenyl ethers (flame retardants) in mother-infant pairs in the Southeastern U.S., International Journal of Environmental Health Research, 10.1080/09603123.2017.1332344, 27:3, (205-214), Online publication date: 4-May-2017. Gomes G, Ward P, Lorenzo A, Hoffman K and Stapleton H (2016) Characterizing Flame Retardant Applications and Potential Human Exposure in Backpacking Tents, Environmental Science & Technology, 10.1021/acs.est.6b00923, 50:10, (5338-5345), Online publication date: 17-May-2016. Ochoa-Martinez A, Orta-Garcia S, Rico-Escobar E, Carrizales-Yañez L, Del Campo J, Pruneda-Alvarez L, Ruiz-Vera T, Gonzalez-Palomo A, Piña-Lopez I, Torres-Dosal A and Pérez-Maldonado I (2016) Exposure Assessment to Environmental Chemicals in Children from Ciudad Juarez, Chihuahua, Mexico, Archives of Environmental Contamination and Toxicology, 10.1007/s00244-016-0273-9, 70:4, (657-670), Online publication date: 1-May-2016. Lv Y, Cao X, Jiang H, Song W, Chen C and Zhao J (2016) Rapid photocatalytic debromination on TiO 2 with in-situ formed copper co-catalyst: Enhanced adsorption and visible light activity, Applied Catalysis B: Environmental, 10.1016/j.apcatb.2016.04.053, 194, (150-156), Online publication date: 1-Oct-2016. Gross M, Butryn D, McGarrigle B, Aga D and Olson J (2015) Primary Role of Cytochrome P450 2B6 in the Oxidative Metabolism of 2,2′,4,4′,6-Pentabromodiphenyl Ether (BDE-100) to Hydroxylated BDEs, Chemical Research in Toxicology, 10.1021/tx500446c, 28:4, (672-681), Online publication date: 20-Apr-2015. Li Q, Kappil M, Li A, Dassanayake P, Darrah T, Friedman A, Friedman M, Lambertini L, Landrigan P, Stodgell C, Xia Y, Nanes J, Aagaard K, Schadt E, Murray J, Clark E, Dole N, Culhane J, Swanson J, Varner M, Moye J, Kasten C, Miller R and Chen J (2015) Exploring the associations between microRNA expression profiles and environmental pollutants in human placenta from the National Children's Study (NCS), Epigenetics, 10.1080/15592294.2015.1066960, 10:9, (793-802), Online publication date: 2-Sep-2015. Berghuis S, Bos A, Sauer P and Roze E (2015) Developmental neurotoxicity of persistent organic pollutants: an update on childhood outcome, Archives of Toxicology, 10.1007/s00204-015-1463-3, 89:5, (687-709), Online publication date: 1-May-2015. Wang Q, Lai N, Wang X, Guo Y, Lam P, Lam J and Zhou B (2015) Bioconcentration and Transfer of the Organophorous Flame Retardant 1,3-Dichloro-2-propyl Phosphate Causes Thyroid Endocrine Disruption and Developmental Neurotoxicity in Zebrafish Larvae, Environmental Science & Technology, 10.1021/acs.est.5b00558, 49:8, (5123-5132), Online publication date: 21-Apr-2015. Abbasi G, Buser A, Soehl A, Murray M and Diamond M (2015) Stocks and Flows of PBDEs in Products from Use to Waste in the U.S. and Canada from 1970 to 2020, Environmental Science & Technology, 10.1021/es504007v, 49:3, (1521-1528), Online publication date: 3-Feb-2015. Wu X, Bennett D, Moran R, Sjödin A, Jones R, Tancredi D, Tulve N, Clifton M, Colón M, Weathers W and Hertz-Picciotto I (2015) Polybrominated diphenyl ether serum concentrations in a Californian population of children, their parents, and older adults: an exposure assessment study, Environmental Health, 10.1186/s12940-015-0002-2, 14:1, Online publication date: 1-Dec-2015. Poon S, Aleksa K, Carnevale A, Kapur B, Goodyer C and Koren G (2015) Evaluating External Contamination of Polybrominated Diphenyl Ethers in Human Hair, Therapeutic Drug Monitoring, 10.1097/FTD.0000000000000137, 37:2, (270-274), Online publication date: 1-Apr-2015. Lanphear B (2015) The Impact of Toxins on the Developing Brain, Annual Review of Public Health, 10.1146/annurev-publhealth-031912-114413, 36:1, (211-230), Online publication date: 18-Mar-2015. Noyes P and Stapleton H (2014) PBDE flame retardants, Endocrine Disruptors, 10.4161/endo.29430, 2:1, (e29430), Online publication date: 1-Jan-2014. Gassmann K, Schreiber T, Dingemans M, Krause G, Roderigo C, Giersiefer S, Schuwald J, Moors M, Unfried K, Bergman Å, Westerink R, Rose C and Fritsche E (2014) BDE-47 and 6-OH-BDE-47 modulate calcium homeostasis in primary fetal human neural progenitor cells via ryanodine receptor-independent mechanisms, Archives of Toxicology, 10.1007/s00204-014-1217-7, 88:8, (1537-1548), Online publication date: 1-Aug-2014. Persico A and Merelli S (2014) Environmental Factors in the Onset of Autism Spectrum Disorder, Current Developmental Disorders Reports, 10.1007/s40474-013-0002-2, 1:1, (8-19), Online publication date: 1-Mar-2014. Herbstman J and Mall J (2014) Developmental Exposure to Polybrominated Diphenyl Ethers and Neurodevelopment, Current Environmental Health Reports, 10.1007/s40572-014-0010-3, 1:2, (101-112), Online publication date: 1-Jun-2014. Betts K (2014) More Evidence for PBDEs as Neurotoxicants: Cohort Study Corroborates Earlier Findings, Environmental Health Perspectives, 122:8, (A221-A221), Online publication date: 1-Aug-2014.Chen A, Yolton K, Rauch S, Webster G, Hornung R, Sjödin A, Dietrich K and Lanphear B (2014) Prenatal Polybrominated Diphenyl Ether Exposures and Neurodevelopment in U.S. Children through 5 Years of Age: The HOME Study, Environmental Health Perspectives, 122:8, (856-862), Online publication date: 1-Aug-2014.Ward M, Colt J, Deziel N, Whitehead T, Reynolds P, Gunier R, Nishioka M, Dahl G, Rappaport S, Buffler P and Metayer C (2014) Residential Levels of Polybrominated Diphenyl Ethers and Risk of Childhood Acute Lymphoblastic Leukemia in California, Environmental Health Perspectives, 122:10, (1110-1116), Online publication date: 1-Oct-2014. Bellinger D (2013) Prenatal Exposures to Environmental Chemicals and Children’s Neurodevelopment: An Update, Safety and Health at Work, 10.5491/SHAW.2013.4.1.1, 4:1, (1-11), Online publication date: 1-Mar-2013. Makris K, Andra S, Jia A, Herrick L, Christophi C, Snyder S and Hauser R (2013) Association between Water Consumption from Polycarbonate Containers and Bisphenol A Intake during Harsh Environmental Conditions in Summer, Environmental Science & Technology, 10.1021/es304038k, 47:7, (3333-3343), Online publication date: 2-Apr-2013. Chevrier J (2013) Invited Commentary: Maternal Plasma Polybrominated Diphenyl Ethers and Thyroid Hormones--Challenges and Opportunities, American Journal of Epidemiology, 10.1093/aje/kwt138, 178:5, (714-719), Online publication date: 1-Sep-2013. Cowell W, Sjödin A, Jones R, Wang Y, Wang S and Herbstman J (2018) Temporal trends and developmental patterns of plasma polybrominated diphenyl ether concentrations over a 15-year period between 1998 and 2013, Journal of Exposure Science & Environmental Epidemiology, 10.1038/s41370-018-0031-3 Lau G, Walter K, Kass P and Puschner B (2017) Comparison of polybrominated diphenyl ethers (PBDEs) and polychlorinated biphenyls (PCBs) in the serum of hypothyroxinemic and euthyroid dogs, PeerJ, 10.7717/peerj.3780, 5, (e3780) Vol. 121, No. 8 August 2013Metrics About Article Metrics Publication History Originally published1 August 2013Published in print1 August 2013 Financial disclosuresPDF download License information EHP is an open-access journal published with support from the National Institute of Environmental Health Sciences, National Institutes of Health. All content is public domain unless otherwise noted. 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