Analytical methodology for unveiling human exposure to (micro)plastic additives

1 Electronic Supplementary Material Analytical methodology for unveiling human exposure to (micro)plastic additives Andrea Estévez-Danta a, Juan F. Ayala-Cabrera b,c,*, Javier López-Vázquez a, Mikel Musatadi b,c, Rosa Montes a,*, Nestor Etxebarria b,c, José Benito Quintana a, Maitane Olivares b,c, Ailette Prieto b,c, Rosario Rodil a, Manuel Miró d,*and Olatz Zuloaga b,c a Department of Analytical Chemistry, Nutrition and Food Science, Institute for Research on Chemical and Biological Analysis (IAQBUS), Universidade de Santiago de Compostela (USC), Santiago de Compostela, Spain b Department of Analytical Chemistry, University of the Basque Country (UPV/EHU), Leioa, Spain c Research Centre for Experimental Marine Biology and Biotechnology, University of the Basque Country (PiEUPV/EHU), Plentzia, Spain d FI-TRACE Group, Department of Chemistry, University of the Balearic Islands (UIB), Palma de Mallorca, Spain Corresponding authors: Dr. Juan F. Ayala Cabrera ([email protected]) Dr. Rosa María Montes Goyanes ([email protected]) Dr. Manuel Miró Lladó (manuel.[email protected]) Table of Contents Supporting Tables ...................................................................................................................................... 2 Table S1. List of plastic additives and plastic constituents, including conventional and alternative plasticizers, flame-retardants antioxidants and bisphenol compounds, along with their main phase-I metabolites included in this review (* refers to metabolites not discussed in this review). ...................................................................................................................... 2 Table S2. Human oral bioaccessibility data of plastic additives using different in-vitro physiologically based extraction tests. (See Table S1 for the full names of the compounds). ..................................................................................................................... 6 Table S3. Overview of the main metabolites of plastic-related chemicals and their respective 24hour excretion rates. ......................................................................................................... 7 Table S4. Concentration levels of plasticizers, bisphenols, flame retardants and antioxidants in human biomonitoring approaches as applied to urine, breast milk and plasma (20192023). (See Table S1 for the full names of compounds, the “m” refers to “metabolite of”) ....................................................................................................................................... 8 Supporting Figures ................................................................................................................................... 17 Figure S1. Overview of physiologically-based extraction tests for the investigation of the gastrointestinal, dermal and lung bioaccessibility of plastic-related chemicals. In oral bioaccessibility, underlined chemicals and experimental conditions are those recommended by Ruby et al. (2002). The remaining conditions are both applied to UBM and RIVM. ..................................................................................................................... 17 Figure S2. Top phase I metabolites monitored in human biomonitoring papers (2019-2023) included in this review and given as the number of times they have been analyzed in biological samples: a) primary and secondary phthalate ester metabolites, b) primary and secondary phase-I metabolites of alternative plasticizers, and c) primary phase-I metabolites of organophosphate flame-retardants. (See Table S1 for the full names of compounds as well as the information related to the parent compound). ..................................................... 18 References ................................................................................................................................................. 19 2 Supporting Tables Table S1. List of plastic additives and plastic constituents, including conventional and alternative plasticizers, flame-retardants antioxidants and bisphenol compounds, along with their main phaseI metabolites included in this review (* refers to metabolites not discussed in this review). Phthalate Esters (PAEs) Parent Primary Phase I metabolite Secondary Phase I metabolite DMP dimethyl phthalate MMP monomethyl phthalate n.r.a DEP diethyl phthalate MEP monoethyl phthalate n.r.a DPrP dipropyl phthalate MnPrP mono-n-propyl phthalate MCPP (cx-MPrP) mono(3-carboxypropyl) phthalate DiPrP di-isopropyl phthalate MiPP mono-isopropyl phthalate n.r.a DAP diallyl phthalate MAP* monoallyl phthalate* n.r.a DMEP di(2-methoxyethyl) phthalate MMEP* monomethoxyethyl phthalate* MAA* methoxyacetic acid DEEP di(ethoxyethyl) phthalate MEEP* monoethoxyethyl phthalate* n.r.a DnBP di-n-butyl phthalate MnBP mono-n-butyl phthalate 3OH-MnBP mono(3-hydroxybutyl) phthalate MCPP mono (3-carboxypropyl) phthalate DiBP di-isobutyl phthalate MiBP mono-isobutyl phthalate 2OH-MiBP mono(2-hydroxy-isobutyl) phthalate DnPeP dipentyl phthalate MnPeP (MPP) mono-n-pentyl phthalate cx-MPeP mono(5-carboxypentyl) phthalate OH-MPeP mono(4-hydroxypentyl) phthalate DiPeP di-isopentyl phthalate MiPeP mono-isopentyl phthalate 4OH-MiPeP mono(4-hydroxy-isopentyl) phthalate DBEP di(2-butoxyethyl) phthalate n.r.a n.r.a BBzP butyl benzyl phthalate MBzP monobenzyl phthalate n.r.a DnHP di-n-hexyl phthalate MHxP monohexyl phthalate 5OH-MHxP mono(5-hydroxyhexyl) phthalate DMPP di(4-methyl-2-pentyl) phthalate n.r.a n.r.a DCHP dicyclohexyl phthalate MCHP monocyclohexyl phthalate n.r.a DEHP di(2-ethylhexyl) phthalate MEHP mono(2-ethylhexyl) phthalate cx-MEPP mono(2-ethyl-5-carboxypentyl) phthalate MEHHP mono(2-ethyl-5-hydroxyhexyl) phthalate MEOHP mono(2-ethyl-5-oxohexyl) phthalate cx-MMHP mono[(2-carboxymethyl)hexyl] phthalate DPrHP di(2-propylheptyl) phthalate cx-MPHxP mono(2-propyl-6carboxyhexyl) phthalate n.r.a DHpP di-n-heptyl phthalate MnHpP mono-n-heptyl phthalate 6OH-MnHpP mono(6-hydroxyheptyl) phthalate DnOP di-n-octyl phthalate MnOP mono-n-octyl phthalate cx-MiOP mono(carboxy-iso-octyl) phthalate MCPP mono(3-carboxypropyl) phthalate DnNP di-nonyl phthalate MnNP Mono-n-nonylphthalate n.r.a DiNP di-isononyl phthalate MiNP mono-isononyl phthalate cx-MiNP mono(carboxy-isononyl) phthalate OH-MiNP mono(hydroxy-isononyl) phthalate oxo-MiNP mono(oxo-isononyl) phthalate nPiPP n-pentyl-isopentyl phthalate n.r.a n.r.a DiDP di-isodecyl phthalate MiDP (MPHP) mono-isodecyl phthalate cx-MiDP mono(carboxy-isodecyl) phthalate OH-MiDP mono(hydroxy-isodecyl) phthalate oxo-MiDP mono(oxo-isodecyl) phthalate a Not reported. 3 Table S1 (cont). List of plastic additives and plastic constituents, including conventional and alternative plasticizers, flame-retardants antioxidants and bisphenol compounds, along with their main phase-I metabolites included in this review (* refers to metabolites not discussed in this review). Alternative plasticizers (APs) Parent Primary Phase I metabolite Secondary Phase I metabolite DMTP dimethyl terephthalate MMTP monomethyl terephthalate n.r.a DETP diethyl terephthalate METP monoethyl terephthalate n.r.a DTBTP di-tert-butyl terephthalate MTBTP mono-tert-butyl terephthalate n.r.a BBzTP butyl benzyl terephthalate MBzTP monobenzyl terephthalate n.r.a DEHTP di(ethylhexyl) terephthalate TPA terephthalic acid n.r.a MEHTP mono(2-ethylhexyl) terephthalate 2cx-MMHTP mono-(2-carboxyl-methyl-hexyl) benzene-1,4-dicarboxylate 5cx-MEPTP mono(2-ethyl-5-carboxypentyl) terephthalate MEHHTP mono(2-ethyl-5-hydroxyhexyl) terephthalate MEOHTP mono(2-ethyl-5-oxo-hexyl) terephthalate DINCH di(isononyl)cyclohexane1,2dicarboxylate MCOCH cyclohexane-1,2-dicarboxylic acid monocarboxyisooctyl ester n.r.a MINCH mono-isononyl-cyclohexane-1,2dicarboxylate cx-MINCH Mono-(7-carboxy-4-methyloctyl) cyclohexane-1,2dicarboxylate OH-MINCH Mono-(4-methyl-7-hydroxyoctyl) cyclohexane-1,2dicarboxylate oxo-MINCH Mono-(4-methyl-7-oxo-octyl) cyclohexane-1,2-dicarboxylate DEHA di(2-ethylhexyl) adipate MEPA mono(2-ethylpexyl) adipate 5cx-MEPA mono(5-carboxy-2-ethylpentyl) adipate MEHA mono(2-ethylhexyl) adipate 5OH-MEHA mono(2-ethyl-5-hydroxyhexyl) adipate 5oxo-MEHA mono(2-ethyl-5-oxohexyl) adipate TOTM (TEHTM) tri(2-ethylhexyl) trimellitate 1-MEHTM 1-mono-(2-ethylhexyl) trimellitate 5cx-1-MEPTM 1-mono(2-ethyl-5carboxypentyl) trimellitate 5OH-1-MEHTM 1-mono(2-ethyl-5-hydroxyhexyl) trimellitate 5oxo-1-MEHTM 1-mono(2-ethyl-5-oxohexyl) trimellitate 2-MEHTM 2-mono-(2-ethylhexyl) trimellitate 5cx-2-MEPTM 2-mono(2-ethyl-5carboxypentyl) trimellitate 5OH-2-MEHTM 2-mono(2-ethyl-5-hydroxyhexyl) trimellitate 5oxo-2-MEHTM 2-mono(2-ethyl-5-oxohexyl) trimellitate 4-MEHTM 4-mono-(2-ethylhexyl) trimellitate n.r.a DiPGDB dipropylene glycol dibenzoate DiPGDBM194 3-(3-hydroxypropoxy)propyl benzoate n.r.a ATBC Acetyl tributyl citrate ADBC* acetyl dibutyl citrate* AMBC* acetyl monobutyl citrate* DBC* dibutyl citrate* a Not reported. 4 Table S1 (cont). List of plastic additives and plastic constituents, including conventional and alternative plasticizers, flame-retardants antioxidants and bisphenol compounds, along with their main phase-I metabolites included in this review (* refers to metabolites not discussed in this review). Organophosphate Flame Retardants (OPFRs) Parent Primary Phase I metabolite Secondary Phase I metabolite TMP trimethyl phosphate DMP dimethyl phosphate n.r.a TEP triethyl phosphate DEP diethyl phosphate n.r.a TPrP tripropyl phosphate DPrP dipropyl phosphate n.r.a TnBP tri-n-butyl phosphate DBP di-n-butyl phosphate n.r.a 3OH-TNBP di-n-butyl-3-hydroxybutyl phosphate n.r.a TiBP tri-iso-butyl phosphate DIBP diisobutyl phosphate n.r.a TBzP tribenzyl phosphate DBzP dibenzyl phosphate n.r.a TCP tricresyl phosphate DoCP di-o-cresyl phosphate n.r.a BMPP di(2-methylhexyl) phosphate n.r.a DpCP di-p-cresyl phosphate n.r.a TPHP triphenyl phosphate MPHP Monophenyl phosphate n.r.a DPHP diphenyl phosphate 3OH-DPHP 3-hydroxyphenyl phenyl phosphate 4OH-DPHP 4-hydroxyphenyl phenyl phosphate 3OH-TPHP 3-hydroxyphenyl diphenyl phosphate n.r.a 4OH-TPHP 4-hydroxyphenyl diphenyl phosphate n.r.a TPPO triphenylphosphine oxide n.r.a n.r.a TMPP trimethylpropane phospahte n.r.a n.r.a TEHP tri(2-ethylhexyl) phosphate BEHP di(2-ethylhexyl) phosphate n.r.a TBOEP tri(2-butoxyethyl) phosphate BBOEP di(2-butoxyethyl) phosphate n.r.a BBOEHEP di(2-butoxyethyl) 2-hydroxyethyl phosphate n.r.a 3OH-TBOEP di(2-butoxyethyl) 3-hydroxyl-2butoxyethyl phosphate n.r.a TIPPP tri(isopropylphenyl) phosphate IPPPP isopropylphenyl phenyl phosphate n.r.a EHDPHP 2-ehylhexyldiphenyl phosphate EHPHP 2-ethylhexyl phenyl phosphate n.r.a 5OH-EHDPHP 2-ethyl-5-hydroxyhexyl diphenyl phosphate n.r.a TClEP tri(2-chloroethyl) phosphate BClEP di(2-chloroethyl) phosphate n.r.a TClPP tri(1-chloro-2-propyl) phosphate BClPP di(1-chloro-2-propyl) phosphate n.r.a TDCIPP tri(1,3-dichloro-2-propyl) phosphate BDCIPP di(1,3-dichloro-2-propyl) phosphate n.r.a TCIPP tri(2-chloroisopropyl) phosphate BCIPP di(2-chloropropyl) hydrogen phosphate n.r.a BCIPHIPP di(1-chloro-2-propyl) 1-hydroxy-2propyl phosphate n.r.a TBP tri(2,3-dibromopropyl) phosphate BDBPP di(2,3-dibromopropyl) phosphate n.r.a TBB 2-ethylhexyl-2,3,4,5tetrabromobenzoate TBBA 2,3,4,5-tetrabromobenzoic acid n.r.a BDMEPPP bis(tert-butyphenyl) phenylphosphate tBPPP tert-butylphenyl phenyl phosphate n.r.a Other Flame Retardants (FRs) n.r.a n.r.a TBBPA tetrabromobisphenol 2,4-DBP 2,4-dibromophenol n.r.a HBCD hexabromocyclodecane OH-HBCD* monohydroxyhexabromocyclodecane* n.r.a a Not reported. 5 Table S1 (cont). List of plastic additives and plastic constituents, including conventional and alternative plasticizers, flame-retardants antioxidants and bisphenol compounds, along with their main phase-I metabolites included in this review (* refers to metabolites not discussed in this review). Synthetic antioxidants compounds (SAs) Parent Primary Phase I metabolite BHT 2,6-di-tert-butyl-4-methylphenol BHT-OH 2,6-di-tert-butyl-4-(hydroxymethyl)phenol BHT-CHO 3,5-di-tert-butyl-4-hydroxybenzaldehyde BHT-COOH 3,5-di-tert-butyl-4-hydroxybenzoic acid BHT-Q 2,6-di-tert-butylcyclohexa-2,5-diene-1,4-dione BHT-quinol 3,5-di-tert-butyl-4-hydroxy-4-hydroxy-4-methyl-2,5cyclohexadione 2-BHAa 2-tert-butyl-4-hydroxyanisole 2-BHAa 2-tert-butyl-4-hydroxyanisole 3-BHAa 3-tert-butyl-4-hydroxyanisole 3-BHAa 3-tert-butyl-4-hydroxyanisole 6PDD N-(1,3-Dimethylbutyl)-N′-phenyl-p-phenylenediamine 6PDD-Q 6PDD-Quinone Bisphenols BPA Bisphenol A n.r.b BPC Bisphenol C n.r.b BPF Bisphenol F n.r.b BPG Bisphenol G n.r.b BPS Bisphenol S n.r.b BPAF Bisphenol AF n.r.b a Isomers. b Not reported. 6 Table S2. Human oral bioaccessibility data of plastic additives using different in-vitro physiologically based extraction tests. (See Table S1 for the full names of the compounds). Oral bioaccessibility References [1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] PBET methods Fasted (mod. Ruby, 1996)b Fasted (mod. Ruby, 1996)b Fasted (CE-mod. Ruby, 1996)b Fasted (Ruby, 1996)b Fasted (Ruby, 1996)b Fasted (Ruby, 1996)b Fasted (UBM) Fasted (UBM) Fed (RIVM method) Fasted (UBM) and fed (RIVM) methods Fasted (UBM) and fed (RIVM) methods Fasted (UBM) and fed (FOREhST) methods Plastic additives % Bioaccessibility DMP 32 17-27 73-94 60-80 70-72 81-87 55-83 DEP 25 17-27 50-75 56-74 84-87 40-68 DnBP 15 1-5 45-50 18-27 80-100 12-32 BzBP 13 2-13 2-10 40-55 12-16 60-80 5-28 DEHP 10 2-13 1-5 20-40 <LOQa 30-40 5-32 DnOP 14 2-13 30-50 <LOQa 20-30 6-25 DiNP 2-13 30-50 2-22 BPA 30-43 80-99 48-51 37-67 TCEP 53-57 50-80 71-98 TClPP 53-94 50-57 41-82 16-52 TDClPP 48-99 15-27 9-57 <LOQa TPP 7-8 5-24 TPhP 61-95 a Limit of quantification. b Ruby, M. V., Davis, A., Schoof, R., Eberle, S., and Sellstone, C. M. 1996. Estimation of lead and arsenic bioavailability using a physiologically based extraction test. Environ. Sci. Technol. 30:422–430. 7 Table S3. Overview of the main metabolites of plastic-related chemicals and their respective 24-hour excretion rates. Parent Metabolite Average percentage of excretion (24 h) a,b References Dimethyl phthalate (DMP) Monomethyl phthalate (MMP) 69 [13]a Diethyl phthalate (DEP) Monoethyl phthalate (MEP) 69 Di-isobutyl phthalate (DiBP) Mono-isobutyl phthalate (MiBP) 71 Di-n-butyl phthalate (DnBP) Mono-n-butyl phthalate (MnBP) 63 Butyl benzyl phthalate (BBzP) Monobenzyl phthalate (MBzP) 73 Di(2-ethylhexyl) phthalate (DEHP) Mono(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP) 16 Mono(2-ethyl-oxohexyl) phthalate (MEOHP) 11 Mono(2-ethyl-5-carboxypentyl) phthalate (cx-MEPTP) 14 Di-isononyl phthalate (DiNP) Mono(hydroxy-isononyl) phthalate (MHINP) 20.2 [14] Mono(oxo-isononyl) phthalate (oxo-MiNP) 10.6 Mono(carboxy-isononyl) phthalate (cx-MiNP) 10.7 Di-isodecyl phthalate (DiDP) Mono(carboxy-isodecyl) phthalate (cx-MiDP) 10.7 Di(2-ethylhexyl) terephthalate (DEHTP) Mono(2-ethyl-5-hydroxyhexyl) terephthalate (MEHHTP) 1.8 [15] Mono(2-ethyl-5-oxohexyl) terephthalate (MEOHTP) 1.0 Mono(2-ethyl-5-carboxypentyl) terephthalate (cx-MEPTP) 13 Di(isononyl)cyclohexane-1,2dicarboxylate (DINCH) Mono-isononyl-cyclohexane-1,2-dicarboxylate (MINCH) 0.65 [15] Mono-(7-carboxy-4-methyl-octyl) cyclohexane1,2-dicarboxylate (cx-MINCH) 1.67 Mono-(4-methyl-7-hydroxy-octyl) cyclohexane1,2-dicarboxylate (OH-MINCH) 9.55 Mono-(4-methyl-7-oxo-octyl) cyclohexane-1,2dicarboxylate (oxo-MINCH) 1.85 Bisphenol A (BPA) Bisphenol A Monosulfate (BPA-S) 3 / 12 [16,17] Bisphenol A β-D-Glucuronide (BPA-G) 87 / 64 Bisphenol S (BPS) Bisphenol S β-D-Glucuronide (BPS-G) 54 [18] Tri(2-butoxyethyl) phosphate (TBOEP) Di(2-butoxyethyl) phosphate (BBOEP) 0.75 [18] Di(2-butoxyethyl) 3-hydroxyl-2-butoxyethyl phosphate (OH-TBOEP) 0.02 Di(2-butoxyethyl) 2-hydroxyethyl phosphate (BBOEHEP) 5.77 a Obtained from curated metastudies, whenever possible. b Average corresponding to the sum of the excretion of the phase I metabolite and its phase II conjugate after being enzymatically deconjugated, except for BPA and BPS, which correspond to phase-II metabolites. 8 Table S4. Concentration levels of plasticizers, bisphenols, flame retardants and antioxidants in human biomonitoring approaches as applied to urine, breast milk and plasma (2019-2023). (See Table S1 for the full names of compounds, the “m” refers to “metabolite of”) Compound Family Nº compounds Region/ Country Matrix Nº Samples Studied population Concentration range per family (ng/mL) Analyte found at highest concentration Ref. Plasticizers PAEs, mPAEs, APs and mAPs 50 Guangzhou, China Breast milk 64 Breast-feeding women PAEs: 2.12-34.1 (range) DEHP [19] mPAEs: 4.41-138 (range) MnBP APs 0.252-16.1 (range) DEHTP mAPs: 0.02-5.52 (range) MEHTP mPAEs and mAPs 40 Copenhagen , Denmark Urine 300 Young Danish men (18-30 years, 20092017) mPAEs: <LOD-6255 (max) or <LOD-85 (median) or <LOD-233 (75% P.) or <LOD-1565 (95% P.) (osmolality adjusted) MEP [20] mAPs: 0.8-908 (max) or <LOD-3.79 (median) or <LOD-9.53 (75% P.) or <LOD-42.5 (95% P.) (osmolality adjusted) 5cx-MEPTP and OH-MINCH mPAEs and mAPs 17 Copenhagen , Denmark Urine 349 Danish newborns and their parents (Infants, n = 144; mothers n = 127; fathers n = 118) Infants: mPAEs: <LOD-381; mAPs: <LOD-583 (ranges, osmolality adjusted) MEP and ∑mDINCH (molar sum of OH-MiNCH and cxMiNCH expressed as DINCH) [21] Mothers: mPAEs: <LOD-1022; mAPs: <LOD440 (ranges, osmolality adjusted) ∑mDiNP (molar sum of MiNP, OH-MiNP, oxo-MiNP and cxMiOP expressed as DiNP) and ∑mDEHTP (molar sum of MEHHTP, MEOHTP, 5cxMEPTP and 2cx-MMHTP expressed as DEHTP) Fathers: mPAEs: <LOD-1162(Range); mAPs: 0.19-334 (ranges, osmolality adjusted) mPAEs 11 Norway Urine 254 General population (2016-2017) n.r.a Dibutyl phthalate metabolites (mDBPs) [22] mAPs (mDINCH) 3 Germany Urine 300 Young adults (2000-2017) <0.05-72.4 (range, creatinine adjusted, ng/mL) OH-MINCH [23] mPAEs 6 Crete, Greece Urine 100 Pregnant women (22-44 years) 4.9-2256.6 (range, unadjusted) MiBP [24] mPAEs and mAPs (mDINCH) 23 Korea and Thailand Urine 183 Pregnant women (<14 weeks of gestation) Korea: mPAEs (2.0-18.3); mDINCH (0.3-0.6) (GMb for mPAEs and 75% P. for mDINCH, SG adjustedc) cx-MEPP, MEP and OHMINCH [25] Thailand: mPAEs (1.2-33); mDINCH (0.5) (GM for mPAEs and 75% P. for mDINCH, SG adjustedc) mPAEs 19 Riyadh, Saudi Arabia Urine 109 Children (3-9 years) 0.8-277.5 (GMb, unadjusted) MEP [26] a Not reported; b Geometric mean; c Specific gravity adjusted. 9 Table S4 (cont.). Concentration levels of plasticizers, bisphenols, flame retardants and antioxidants in human biomonitoring approaches as applied to urine, breast milk and plasma (2019-2023). (See Table S1 for the full names of compounds, the “m” refers to “metabolite of”) Compound Family Nº compounds Region/ Country Matrix Nº Samples Studied population Concentration range per family (ng/mL) Analyte found at highest concentration References Plasticizers mPAEs and mAPs 32 Indonesia, Saudi Arabia and Thaliand Urine 302 Children (3-11 years) Indonesia: mPAEs (<LOQ-77.8); mAPs (<LOQ-3.6) (GMb, unadjusted) 5cx-MEPP and 5cx-MEPTP [27] Saudi Arabia: mPAEs (1.2-270.5); mAPs (<LOQ-139.6) (GMb, unadjusted) MEP and 5cx-MEPTP Thailand: mPAEs (<LOQ-43.6); mAPs (<LOQ-8) (GMb, unadjusted) MnBP and 5cx-MEPTP mPAEs 11 Senzhen, China Urine 309 Waste incineration plant workers (cases, n = 104) and general population 8 km away from the incinerator plant (controls, n = 205) Cases: 217-3480 (range, unadjusted) MEP and MnBP [28] Controls: n.d.-1850 (range, unadjusted) MnBP mPAEs 18 Kyoto, Japan Urine 132 General population (1993-2016) <LOD-2508 (range, creatinine adjusted, µg/g) MEP [29] mPAEs 16 Aichi Region, Japan Urine 1023 Toddlers (1.5-year-old) 41-34696 nmol/L (range) or 496 nmol/L (GMb) (unadjusted) cx-MEPP [30] mPAEs and mAPs 19 Illinois, USA Urine 482 Pregnant women (18-40 years, 20132018) mPAEs: 0.7-25 (median) or 0.4-12.6 (25% P.) or 1.5-46.5 (75% P.) (unadjusted) MEP [31] mAPs: 9.2-69.2 (median) or 4.0-24.7 (25% P.) or 20.7-146 (75% P.) (unadjusted) cx-MEPTP mPAEs and mAPs (mDINCH) 10 Liege, Belgium Urine 251 General population (2015 and 2018) mPAEs: <LOQ-21.25 (median) or 1.1062.85 (75% P.) or 2.4-689.67 (95% P.) (unadjusted) MEP [32] mAPs: <LOQ (median) or <LOQ-4.76 (75% P.) or 9.13-35.99 (95% P.) (unadjusted) OH-MINCH mPAEs 16 Jalisco, Mexico Urine 90 Pregnant women (< 20 weeks of gestation) <LOD1830 (range, unadjusted) or 0.3 - 55.8 (GMb, unadjusted) or 2.1 - 48.6 (median, unadjusted) or 1.7-55.8 (GMb, creatinine adjusted, µg/g) MEP [33] mPAEs 21 Germany Urine 2256 Children and teenagers (2014-2017) 0.6 - 27.0 (range) or 0.6 - 26.1 (GMb) (Unadjusted) MiBP [34] b Geometric mean; c Specific gravity adjusted. 16 Table S5. (cont.). Survey of Correction Factors (CFs) and estimated exposure of several plastic-related chemicals by WBE. (See Table S1 for the full names of compounds). Class Compound Biomarker CF Estimated exposure (µg inh-1 day-1) Location Ref. Bisphenols BPA BPA-S 24.7 43 ± 9 - 407 ± 183 2 cities Belgium, 1 city Spain, 1 city Croatia [61] Bisphenols BPA BPA-S 0.45 4 – 6 1 city, USA [62] BPS Free BPS (1) 91 ± 59 Bisphenols BPA BPA-S 0.45 0.16 0.97±0.1 - 157±16 (4) 0.35 ±0.03 - 46.2 ±5.6 (4) 5 WWTP, UK [63] Flame retardants TBOEP BBOEHEP 13.9 395 ± 60 - 1783 ± 830 2 cities Belgium, 1 city Spain, 1 city Croatia [61] Flame retardants TBOEP BBOEP OH-TBOEP BBOEHEP (1) (3) 5 cities, Europe [64] TPHP DPHP (2) OH-DPHP (1) (3) TDCIPP BDCIPP (1) (3) EHDPHP DPHP (2) OH-EHDPHP EHPHP (1) (3) TCIPP BCIPP BCIPHIPP (1) (3) TClEP Free TClEP (1) (3) Flame retardants TClPP BClPP 45-47 1 city, Spain [65] Flame retardants TCIPP BCIPHIPP 1.8-3.3 4 cities, Belgium [66] TCEP Free TClEP 18-108 EHDPHP DPHP (2) EHPHP 5OH-EHDPHP 18-175 38-393 0.6-2.7 TBOEP BBOEHEP 3OH-TBOEP 6.9-35 12-61 TPHP DPHP (2) 18-175 (1) No correction factor was applied. (2) biomarker of exposure for more than 1 parent compound (3) Data reported in figures (4) Loads reported as µg day-1 kg-1. 17 Supporting Figures Figure S1. Overview of physiologically-based extraction tests for the investigation of the gastrointestinal, dermal and lung bioaccessibility of plastic-related chemicals. In oral bioaccessibility, underlined chemicals and experimental conditions are those recommended by Ruby et al. (2002). The remaining conditions are both applied to UBM (Unified Bioaccessibility Method) and RIVM (Dutch Institute for Public Health and the Environment Method). ALF: Artificial Lysosomal Fluid, SSSM: Synthetic Sweat and Sebum Mixture. ConditionsInorg. salts ConditionsInorg. salts Org. species Biomolecules KCl KSCN NaH2PO4 Na2SO4 NaCl NaHCO3(RIVM) NaOH (UBM) Urea Uric acid α-Amylase Mucin pH = 6.8 ± 0.2 10 s 37°C KCl NaH2PO4 Na2SO4 NaCl CaCl2 NH4Cl HCl Urea D+ Glucose DGlucuronic acid DGlucosamine Mucin BSA Pepsin pH = 1.30 ± 0.02 1 h (UBM) 2 h (RIVM) pH = 2.0 1 h (Ruby et al) 37°C Mouth KCl NaCl NaHCO3 KH2PO4 MgCl2 CaCl2 HCl Urea BSA Pancreatin Lipase Bile salts pH = 8.1 ± 0.2 4 h (UBM) 2 h (RIVM) pH = 7.5 3 h (Ruby et al.) 37°C Stomach Small intestine Colon (Tilston, 2011) KCl NaCl NaHCO3 MgSO4 KH2PO4 K2HPO4 CaCl2 L-Cysteine Haemin Mucin Bile salts pH = 6.5 8 h 37°C MgCl2 NaCl Na2HPO4 Na2SO4 CaCl2 NaOH (ALF) NaHCO3 (Gamble) KCl (Gamble) Sodium citrate Citric acid (ALF) Glycine (ALF) Na2Tartrate (ALF) NaLactate (ALF) NaPyruvate (ALF) Sodium acetate (Gamble) pH = 4.5 (ALF) 7.4 (Gamble) 96 h 37°C Na2SO4 NaCl NH4OH NH4Cl NaHCO3 Na2HPO4 KCl MgCl2 CaCl2 CuCl2 FeSO4 Acetic acid Butyric acid D+ Glucose Lactic acid Urea Creatinine Squalene Palmityl Palmitate Triolein Cholesteryl Oleate pH = 5.3 ± 0.1 1 h 32°C Lung (Gamble and ALF methods) Dermal (SSSM method) Oral (UBM, RIVM, Ruby and Tilston methods) Org. species Gastrointestinal 18 Figure S2. Top phase I metabolites monitored in human biomonitoring papers (2019-2023) included in this review and given as the number of times they have been analyzed in biological samples: a) primary and secondary phthalate ester metabolites, b) primary and secondary phase-I metabolites of alternative plasticizers, and c) primary phase-I metabolites of organophosphate flame-retardants. (See Table S1 for the full names of compounds as well as the information related to the parent compound). 19 References [1] M.V. Ruby, K.A. Fehling, D.J. Paustenbach, B.D. Landenberger, M.P. Holsapple, Oral Bioaccessibility of Dioxins/Furans at Low Concentrations (50−350 ppt Toxicity Equivalent) in Soil, Environ. Sci. Technol. 36 (2002) 4905–4911. https://doi.org/10.1021/es020636l. [2] W. Wang, F.-Y. Wu, M.-J. Huang, Y. Kang, K.C. Cheung, M.H. Wong, Size fraction effect on phthalate esters accumulation, bioaccessibility and in vitro cytotoxicity of indoor/outdoor dust, and risk assessment of human exposure, J. Hazard. Mater. 261 (2013) 753–762. https://doi.org/10.1016/j.jhazmat.2013.04.039. [3] M. Fang, H.M. Stapleton, Evaluating the Bioaccessibility of Flame Retardants in House Dust Using an In Vitro Tenax Bead-Assisted Sorptive Physiologically Based Method, Environ. Sci. Technol. 48 (2014) 13323–13330. https://doi.org/10.1021/es503918m. [4] R. He, Y. Li, P. Xiang, C. Li, C. Zhou, S. Zhang, X. Cui, L.Q. Ma, Organophosphorus flame retardants and phthalate esters in indoor dust from different microenvironments: Bioaccessibility and risk assessment, Chemosphere 150 (2016) 528–535. https://doi.org/10.1016/j.chemosphere.2015.10.087. [5] R.-W. He, Y.-Z. Li, P. Xiang, C. Li, X.-Y. Cui, L.Q. Ma, Impact of particle size on distribution and human exposure of flame retardants in indoor dust, Environ. Res. 162 (2018) 166–172. https://doi.org/10.1016/j.envres.2017.12.014. [6] T. Zhang, B. Ma, L. Wang, Phthalic acid esters in grains, vegetables, and fruits: concentration, distribution, composition, bio-accessibility, and dietary exposure, Environ. Sci. Pollut. Res. Int. 30 (2023) 2787–2799. https://doi.org/10.1007/s11356-022-22415-z. [7] M.J. Trujillo-Rodríguez, R.M. Gomila, G. Martorell, M. Miró, Microscale extraction versus conventional approaches for handling gastrointestinal extracts in oral bioaccessibility assays of endocrine disrupting compounds from microplastic contaminated beach sand, Environ. Pollut. 272 (2021) 115992. https://doi.org/10.1016/j.envpol.2020.115992. [8] D.F.M.S. Mohamed, D.Y. Kim, J. An, M. Kim, S.-H. Chun, J.-H. Kwon, Simplified Unified BARGE Method to Assess Migration of Phthalate Esters in Ingested PVC Consumer Products, Int. J. Environ. Res. Public. Health 20 (2023) 1907. https://doi.org/10.3390/ijerph20031907. [9] S.C. Cunha, R.N. Alves, J.O. Fernandes, S. Casal, A. Marques, First approach to assess the bioaccessibility of bisphenol A in canned seafood, Food Chem. 232 (2017) 501–507. https://doi.org/10.1016/j.foodchem.2017.04.006. [10] A. Sixto, B. El-Morabit, M.J. Trujillo-Rodríguez, E.J. Carrasco-Correa, M. Miró, An automatic flow-through system for exploration of the human bioaccessibility of endocrine disrupting compounds from microplastics, Analyst 146 (2021) 3858–3870. https://doi.org/10.1039/D1AN00446H. [11] J. López-Vázquez, R. Rodil, M.J. Trujillo-Rodríguez, J.B. Quintana, R. Cela, M. Miró, Mimicking human ingestion of microplastics: Oral bioaccessibility tests of bisphenol A and phthalate esters under fed and fasted states, Sci. Total Environ. 826 (2022) 154027. https://doi.org/10.1016/j.scitotenv.2022.154027. [12] J.B. Quintana, M. Rosende, R. Montes, T. Rodríguez-Álvarez, R. Rodil, R. Cela, M. Miró, In-vitro estimation of bioaccessibility of chlorinated organophosphate flame retardants in indoor dust by fasting and fed physiologically relevant extraction tests, Sci. Total Environ. 580 (2017) 540–549. https://doi.org/10.1016/j.scitotenv.2016.11.210. [13] I. González-Mariño, R. Rodil, I. Barrio, R. Cela, J.B. Quintana, Wastewater-Based Epidemiology as a New Tool for Estimating Population Exposure to Phthalate Plasticizers, Environ. Sci. Technol. 51 (2017) 3902–3910. https://doi.org/10.1021/acs.est.6b05612. [14] S.M. Hays, L.L. Aylward, C.R. Kirman, K. Krishnan, A. Nong, Biomonitoring Equivalents for di-isononyl phthalate (DINP), Regul. Toxicol. Pharmacol. 60 (2011) 181–188. https://doi.org/10.1016/j.yrtph.2011.03.013. [15] F. Lessmann, A. Schütze, T. Weiss, A. Langsch, R. Otter, T. Brüning, H.M. Koch, Metabolism and urinary excretion kinetics of di(2-ethylhexyl) terephthalate (DEHTP) in three male volunteers after oral dosage, Arch. Toxicol. 90 (2016) 1659–1667. https://doi.org/10.1007/s00204-016-1715-x. [16] K.A. Thayer, D.R. Doerge, D. Hunt, S.H. Schurman, N.C. Twaddle, M.I. Churchwell, S. Garantziotis, G.E. Kissling, M.R. Easterling, J.R. Bucher, L.S. Birnbaum, Pharmacokinetics of bisphenol A in humans following a single oral administration, Environ. Int. 83 (2015) 107–115. https://doi.org/10.1016/j.envint.2015.06.008. [17] J.G. Teeguarden, N.C. Twaddle, M.I. Churchwell, X. Yang, J.W. Fisher, L.M. Seryak, D.R. Doerge, 24-hour human urine and serum profiles of bisphenol A: Evidence against sublingual absorption following ingestion in soup, Toxicol. Appl. Pharmacol. 288 (2015) 131–142. https://doi.org/10.1016/j.taap.2015.01.009. [18] W. Völkel, V. Fuchs, M. Wöckner, H. Fromme, Toxicokinetic of tris(2-butoxyethyl) phosphate (TBOEP) in humans following single oral administration, Arch. Toxicol. 92 (2018) 651–660. https://doi.org/10.1007/s00204017-2078-7. [19] M. Deng, X. Liang, B. Du, D. Luo, H. Chen, C. Zhu, L. Zeng, Beyond Classic Phthalates: Occurrence of Multiple Emerging Phthalate Alternatives and Their Metabolites in Human Milk and Implications for Combined Exposure in Infants, Environ. Sci. Technol. Lett. 8 (2021) 705–712. https://doi.org/10.1021/acs.estlett.1c00476. 20 [20] H. Frederiksen, O. Nielsen, H.M. Koch, N.E. Skakkebaek, A. Juul, N. Jørgensen, A.-M. Andersson, Changes in urinary excretion of phthalates, phthalate substitutes, bisphenols and other polychlorinated and phenolic substances in young Danish men; 2009-2017, Int. J. Hyg. Environ. Health 223 (2020) 93–105. https://doi.org/10.1016/j.ijheh.2019.10.002. [21] H. Frederiksen, E.N. Upners, M.L. Ljubicic, M.B. Fischer, A.S. Busch, C.P. Hagen, A. Juul, A.-M. Andersson, Exposure to 15 phthalates and two substitutes (DEHTP and DINCH) assessed in trios of infants and their parents as well as longitudinally in infants exclusively breastfed and after the introduction of a mixed diet, Environ. Int. 161 (2022) 107107. https://doi.org/10.1016/j.envint.2022.107107. [22] A. Gkrillas, H. Dirven, E. Papadopoulou, M. Andreassen, H. Hjertholm, T. Husøy, Exposure estimates of phthalates and DINCH from foods and personal care products in comparison with biomonitoring data in 24-hour urine from the Norwegian EuroMix biomonitoring study, Environ. Int. 155 (2021) 106598. https://doi.org/10.1016/j.envint.2021.106598. [23] M. Kasper-Sonnenberg, H.M. Koch, P. Apel, M. Rüther, C. Pälmke, T. Brüning, M. Kolossa-Gehring, Time trend of exposure to the phthalate plasticizer substitute DINCH in Germany from 1999 to 2017: Biomonitoring data on young adults from the Environmental Specimen Bank (ESB), Int. J. Hyg. Environ. Health 222 (2019) 1084–1092. https://doi.org/10.1016/j.ijheh.2019.07.011. [24] I. Katsikantami, M.N. Tzatzarakis, A.K. Alegakis, V. Karzi, E. Hatzidaki, A. Stavroulaki, E. Vakonaki, P. Xezonaki, S. Sifakis, A.K. Rizos, A.M. Tsatsakis, Phthalate metabolites concentrations in amniotic fluid and maternal urine: Cumulative exposure and risk assessment, Toxicol. Rep. 7 (2020) 529–538. https://doi.org/10.1016/j.toxrep.2020.04.008. [25] G. Lee, S. Kim, Y. Kho, S. Kim, S. Lee, G. Choi, J. Park, S. Worakhunpiset, H.-B. Moon, K. Okanurak, M. Geounuppakul, J. Tangtitawong, K. Wetsutthanon, D. Trisurat, K. Choi, Urinary levels of phthalates and DINCH metabolites in Korean and Thai pregnant women across three trimesters, Sci. Total Environ. 711 (2020) 134822. https://doi.org/10.1016/j.scitotenv.2019.134822. [26] I. Lee, R. Alakeel, S. Kim, Y.A. Al-Sheikh, H. Al-Mandeel, A.A. Alyousef, Y. Kho, K. Choi, Urinary phthalate metabolites among children in Saudi Arabia: Occurrences, risks, and their association with oxidative stress markers, Sci. Total Environ. 654 (2019) 1350–1357. https://doi.org/10.1016/j.scitotenv.2018.11.025. [27] I. Lee, C. Pälmke, B. Ringbeck, Y. Ihn, A. Gotthardt, G. Lee, R. Alakeel, M. Alrashed, R. Tosepu, E.A. Jayadipraja, K. Tantrakarnapa, W. Kliengchuay, Y. Kho, H.M. Koch, K. Choi, Urinary Concentrations of Major Phthalate and Alternative Plasticizer Metabolites in Children of Thailand, Indonesia, and Saudi Arabia, and Associated Risks, Environ. Sci. Technol. 55 (2021) 16526–16537. https://doi.org/10.1021/acs.est.1c04716. [28] S. Lu, D. Yang, X. Ge, L. Li, Y. Zhao, C. Li, S. Ma, Y. Yu, The internal exposure of phthalate metabolites and bisphenols in waste incineration plant workers and the associated health risks, Environ. Int. 145 (2020) 106101. https://doi.org/10.1016/j.envint.2020.106101. [29] Z. Lyu, K.H. Harada, S. Kim, T. Fujitani, Y. Cao, T. Hitomi, Y. Fujii, Y. Kho, K. Choi, Exposure to phthalate esters in Japanese females in Kyoto, Japan from 1993 to 2016: Temporal trends and associated health risks, Environ. Int. 165 (2022) 107288. https://doi.org/10.1016/j.envint.2022.107288. [30] N.C. Mohanto, Y. Ito, S. Kato, T. Ebara, K. Kaneko, T. Tsuchiyama, M. Sugiura-Ogasawara, S. Saitoh, M. Kamijima, Quantitative Measurement of Phthalate Exposure Biomarker Levels in Diaper-Extracted Urine of Japanese Toddlers and Cumulative Risk Assessment: An Adjunct Study of JECS Birth Cohort, Environ. Sci. Technol. 57 (2023) 395–404. https://doi.org/10.1021/acs.est.2c04816. [31] D.C. Pacyga, D.K. Haggerty, M. Nicol, M. Henning, A.M. Calafat, J.M. Braun, S.L. Schantz, R.S. Strakovsky, Identification of profiles and determinants of maternal pregnancy urinary biomarkers of phthalates and replacements in the Illinois Kids Development Study, Environ. Int. 162 (2022) 107150. https://doi.org/10.1016/j.envint.2022.107150. [32] C. Pirard, C. Charlier, Urinary levels of parabens, phthalate metabolites, bisphenol A and plasticizer alternatives in a Belgian population: Time trend or impact of an awareness campaign?, Environ. Res. 214 (2022) 113852. https://doi.org/10.1016/j.envres.2022.113852. [33] A. Rodríguez Arreola, A.A. Peregrina-Lucano, Urinary concentrations of phthalate metabolites in pregnant women living near Chapala Lake, Jalisco, Mexico, Arch. Environ. Occup. Health 76 (2021) 450–454. https://doi.org/10.1080/19338244.2020.1861423. [34] G. Schwedler, E. Rucic, R. Lange, A. Conrad, H.M. Koch, C. Pälmke, T. Brüning, C. Schulz, M.I.H. SchmiedTobies, A. Daniels, M. Kolossa-Gehring, Phthalate metabolites in urine of children and adolescents in Germany. Human biomonitoring results of the German Environmental Survey GerES V, 2014–2017, Int. J. Hyg. Environ. Health 225 (2020) 113444. https://doi.org/10.1016/j.ijheh.2019.113444. [35] Y. Sjöström, K. Hagström, C. Lindh, I.-L. Bryngelsson, M. Larsson, J. Hagberg, Exposure to phthalates and DiNCH among preschool children in Sweden: Urinary metabolite concentrations and predictors of exposure, Int. J. Hyg. Environ. Health 250 (2023) 114161. https://doi.org/10.1016/j.ijheh.2023.114161. 21 [36] P. Stuchlík Fišerová, L. Melymuk, K. Komprdová, E. Domínguez-Romero, M. Scheringer, J. Kohoutek, P. Přibylová, L. Andrýsková, P. Piler, H.M. Koch, M. Zvonař, M. Esteban-López, A. Castaño, J. Klánová, Personal care product use and lifestyle affect phthalate and DINCH metabolite levels in teenagers and young adults, Environ. Res. 213 (2022) 113675. https://doi.org/10.1016/j.envres.2022.113675. [37] K. Urbancova, R.J. Sram, J. Hajslova, J. Pulkrabova, Concentrations of Phthalate and DINCH Metabolites in Urine Samples from Czech Mothers and Newborns, Expo. Health 14 (2022) 17–27. https://doi.org/10.1007/s12403-02100415-7. [38] J.P. Buckley, J.R. Kuiper, D.H. Bennett, E.S. Barrett, T. Bastain, C.V. Breton, S. Chinthakindi, A.L. Dunlop, S.F. Farzan, J.B. Herbstman, M.R. Karagas, C.J. Marsit, J.D. Meeker, R. Morello-Frosch, T.G. O’Connor, M.E. Romano, S. Schantz, R.J. Schmidt, D.J. Watkins, H. Zhu, E.D. Pellizzari, K. Kannan, T.J. Woodruff, Exposure to Contemporary and Emerging Chemicals in Commerce among Pregnant Women in the United States: The Environmental influences on Child Health Outcome (ECHO) Program, Environ. Sci. Technol. 56 (2022) 6560– 6573. https://doi.org/10.1021/acs.est.1c08942. [39] T. Husøy, M. Andreassen, H. Hjertholm, M.H. Carlsen, N. Norberg, C. Sprong, E. Papadopoulou, A.K. Sakhi, A. Sabaredzovic, H. a. a. M. Dirven, The Norwegian biomonitoring study from the EU project EuroMix: Levels of phenols and phthalates in 24-hour urine samples and exposure sources from food and personal care products, Environ. Int. 132 (2019) 105103. https://doi.org/10.1016/j.envint.2019.105103. [40] T. Jamnik, M. Flasch, D. Braun, Y. Fareed, D. Wasinger, D. Seki, D. Berry, A. Berger, L. Wisgrill, B. Warth, Next-generation biomonitoring of the early-life chemical exposome in neonatal and infant development, Nat. Commun. 13 (2022) 2653. https://doi.org/10.1038/s41467-022-30204-y. [41] A. Murawski, M.I.H. Schmied-Tobies, E. Rucic, C. Schmidtkunz, K. Küpper, G. Leng, E. Eckert, L. Kuhlmann, T. Göen, A. Daniels, G. Schwedler, M. Kolossa-Gehring, Metabolites of 4-methylbenzylidene camphor (4-MBC), butylated hydroxytoluene (BHT), and tris(2-ethylhexyl) trimellitate (TOTM) in urine of children and adolescents in Germany - human biomonitoring results of the German Environmental Survey GerES V (2014-2017), Environ. Res. 192 (2021) 110345. https://doi.org/10.1016/j.envres.2020.110345. [42] L. Xu, Y. Hu, Q. Zhu, C. Liao, G. Jiang, Several typical endocrine-disrupting chemicals in human urine from general population in China: Regional and demographic-related differences in exposure risk, J. Hazard. Mater. 424 (2022) 127489. https://doi.org/10.1016/j.jhazmat.2021.127489. [43] M. Bastiaensen, C. Gys, A. Colles, V. Verheyen, G. Koppen, E. Govarts, L. Bruckers, B. Morrens, I. Loots, A. De Decker, V. Nelen, T. Nawrot, S. De Henauw, N. Van Larebeke, G. Schoeters, A. Covaci, Exposure levels, determinants and risk assessment of organophosphate flame retardants and plasticizers in adolescents (14– 15 years) from the Flemish Environment and Health Study, Environ. Int. 147 (2021) 106368. https://doi.org/10.1016/j.envint.2020.106368. [44] P.A. Bommarito, A. Friedman, B.M. Welch, D.E. Cantonwine, M. Ospina, A.M. Calafat, J.D. Meeker, T.F. McElrath, K.K. Ferguson, Temporal trends and predictors of gestational exposure to organophosphate ester flame retardants and plasticizers, Environ. Int. 180 (2023) 108194. https://doi.org/10.1016/j.envint.2023.108194. [45] S.C. Hammel, S. Zhang, A.M. Lorenzo, B. Eichner, H.M. Stapleton, K. Hoffman, Young infants’ exposure to organophosphate esters: Breast milk as a potential source of exposure, Environ. Int. 143 (2020) 106009. https://doi.org/10.1016/j.envint.2020.106009. [46] M.E. Ingle, D. Watkins, Z. Rosario, C.M. VélezVega, A.M. Calafat, M. Ospina, K.K. Ferguson, J.F. Cordero, A. Alshawabkeh, J.D. Meeker, An exploratory analysis of urinary organophosphate ester metabolites and oxidative stress among pregnant women in Puerto Rico, Sci. Total Environ. 703 (2020) 134798. https://doi.org/10.1016/j.scitotenv.2019.134798. [47] M. Li, Y. Yao, Y. Wang, M. Bastiaensen, A. Covaci, H. Sun, Organophosphate ester flame retardants and plasticizers in a Chinese population: Significance of hydroxylated metabolites and implication for human exposure, Environ. Pollut. Barking Essex 1987 257 (2020) 113633. https://doi.org/10.1016/j.envpol.2019.113633. [48] D. Luo, W. Liu, Y. Tao, L. Wang, M. Yu, L. Hu, A. Zhou, A. Covaci, W. Xia, Y. Li, S. Xu, S. Mei, Prenatal Exposure to Organophosphate Flame Retardants and the Risk of Low Birth Weight: A Nested Case-Control Study in China, Environ. Sci. Technol. 54 (2020) 3375–3385. https://doi.org/10.1021/acs.est.9b06026. [49] Z. Percy, A.M. Vuong, M. Ospina, A.M. Calafat, M.J. La Guardia, Y. Xu, R.C. Hale, K.N. Dietrich, C. Xie, B.P. Lanphear, J.M. Braun, K.M. Cecil, K. Yolton, A. Chen, Organophosphate esters in a cohort of pregnant women: Variability and predictors of exposure, Environ. Res. 184 (2020) 109255. https://doi.org/10.1016/j.envres.2020.109255. [50] X. Wu, D. Zhang, Y. Chen, J. Shen, X. Li, Q. Zheng, J. Ma, J. Xu, M. Rao, X. Liu, S. Lu, Organophosphate ester exposure among Chinese waste incinerator workers: Urinary levels, risk assessment and associations with oxidative stress, Sci. Total Environ. 854 (2023) 158808. https://doi.org/10.1016/j.scitotenv.2022.158808. [51] Y. Wang, W. Li, M.P. Martínez-Moral, H. Sun, K. Kannan, Metabolites of organophosphate esters in urine from the United States: Concentrations, temporal variability, and exposure assessment, Environ. Int. 122 (2019) 213– 221. https://doi.org/10.1016/j.envint.2018.11.007. 22 [52] J. Ma, H. Zhu, K. Kannan, Organophosphorus Flame Retardants and Plasticizers in Breast Milk from the United States, Environ. Sci. Technol. Lett. 6 (2019) 525–531. https://doi.org/10.1021/acs.estlett.9b00394. [53] M. Huang, J. Li, Z. Xiao, Z. Shi, Tetrabromobisphenol A and hexabromocyclododecane isomers in breast milk from the general population in Beijing, China: Contamination levels, temporal trends, nursing infant’s daily intake, and risk assessment, Chemosphere 244 (2020) 125524. https://doi.org/10.1016/j.chemosphere.2019.125524. [54] J. Rovira, M.Á. Martínez, M. Mari, S.C. Cunha, J.O. Fernandes, I. Marmelo, A. Marques, L.S. Haug, C. Thomsen, M. Nadal, J.L. Domingo, M. Schuhmacher, Mixture of environmental pollutants in breast milk from a Spanish cohort of nursing mothers, Environ. Int. 166 (2022) 107375. https://doi.org/10.1016/j.envint.2022.107375. [55] W. Wang, K. Kannan, Quantitative identification of and exposure to synthetic phenolic antioxidants, including butylated hydroxytoluene, in urine, Environ. Int. 128 (2019) 24–29. https://doi.org/10.1016/j.envint.2019.04.028. [56] B. Du, B. Liang, Y. Li, M. Shen, L.-Y. Liu, L. Zeng, First Report on the Occurrence of N-(1,3-Dimethylbutyl)- N′-phenyl-p-phenylenediamine (6PPD) and 6PPD-Quinone as Pervasive Pollutants in Human Urine from South China, Environ. Sci. Technol. Lett. 9 (2022) 1056–1062. https://doi.org/10.1021/acs.estlett.2c00821. [57] C. Schmidtkunz, K. Küpper, T. Weber, G. Leng, M. Kolossa-Gehring, A biomonitoring study assessing the exposure of young German adults to butylated hydroxytoluene (BHT), Int. J. Hyg. Environ. Health 228 (2020) 113541. https://doi.org/10.1016/j.ijheh.2020.113541. [58] P. Du, Z. Zhou, H. Huang, S. Han, Z. Xu, Y. Bai, X. Li, Estimating population exposure to phthalate esters in major Chinese cities through wastewater-based epidemiology, Sci. Total Environ. 643 (2018) 1602–1609. https://doi.org/10.1016/j.scitotenv.2018.06.325. [59] I. González-Mariño, L. Ares, R. Montes, R. Rodil, R. Cela, E. López-García, C. Postigo, M. López de Alda, E. Pocurull, R.M. Marcé, L. Bijlsma, F. Hernández, Y. Picó, V. Andreu, A. Rico, Y. Valcárcel, M. Miró, N. Etxebarria, J.B. Quintana, Assessing population exposure to phthalate plasticizers in thirteen Spanish cities through the analysis of wastewater, J. Hazard. Mater. 401 (2021) 123272. https://doi.org/10.1016/j.jhazmat.2020.123272. [60] A. Estévez-Danta, R. Rodil, B. Pérez-Castaño, R. Cela, J.B. Quintana, I. González-Mariño, Comprehensive determination of phthalate, terephthalate and di-iso-nonyl cyclohexane-1,2-dicarboxylate metabolites in wastewater by solid-phase extraction and ultra(high)-performance liquid chromatography-tandem mass spectrometry, Talanta 224 (2021) 121912. https://doi.org/10.1016/j.talanta.2020.121912. [61] I. Senta, S. Rodríguez-Mozaz, L. Corominas, A. Covaci, M. Petrovic, Applicability of an on-line solid-phase extraction liquid chromatography – tandem mass spectrometry for the wastewater-based assessment of human exposure to chemicals from personal care and household products, Sci. Total Environ. 845 (2022) 157309. https://doi.org/10.1016/j.scitotenv.2022.157309. [62] R. Kumar, S. Adhikari, E. Driver, J. Zevitz, R.U. Halden, Application of wastewater-based epidemiology for estimating population-wide human exposure to phthalate esters, bisphenols, and terephthalic acid, Sci. Total Environ. 847 (2022) 157616. https://doi.org/10.1016/j.scitotenv.2022.157616. [63] L. Lopardo, B. Petrie, K. Proctor, J. Youdan, R. Barden, B. Kasprzyk-Hordern, Estimation of community-wide exposure to bisphenol A via water fingerprinting, Environ. Int. 125 (2019) 1–8. https://doi.org/10.1016/j.envint.2018.12.048. [64] F. Been, M. Bastiaensen, F.Y. Lai, K. Libousi, N.S. Thomaidis, L. Benaglia, P. Esseiva, O. Delémont, A.L.N. van Nuijs, A. Covaci, Mining the Chemical Information on Urban Wastewater: Monitoring Human Exposure to Phosphorus Flame Retardants and Plasticizers, Environ. Sci. Technol. 52 (2018) 6996–7005. https://doi.org/10.1021/acs.est.8b01279. [65] V. Castro, R. Rodil, J.B. Quintana, R. Cela, L. Sánchez-Fernández, I. González-Mariño, Determination of human metabolites of chlorinated phosphorous flame retardants in wastewater by N-tert-butyldimethylsilyl-Nmethyltrifluoroacetamide-derivatization and gas chromatography-high resolution mass spectrometry, J. Chromatogr. A 1602 (2019) 450–457. https://doi.org/10.1016/j.chroma.2019.06.015. [66] F. Been, M. Bastiaensen, F.Y. Lai, A.L.N. van Nuijs, A. Covaci, Liquid Chromatography–Tandem Mass Spectrometry Analysis of Biomarkers of Exposure to Phosphorus Flame Retardants in Wastewater to Monitor Community-Wide Exposure, Anal. Chem. 89 (2017) 10045–10053. https://doi.org/10.1021/acs.analchem.7b02705.