Modernizing persistence-bioaccumulation-toxicity (PBT) assessment with high throughput animal-free methods.
Biodegradation
Hazard assessment
In vitro bioassay
Mobility
New approach methodologies (NAMs)
Persistence
Toxicity
Journal
Archives of toxicology
ISSN: 1432-0738
Titre abrégé: Arch Toxicol
Pays: Germany
ID NLM: 0417615
Informations de publication
Date de publication:
05 2023
05 2023
Historique:
received:
26
11
2022
accepted:
13
03
2023
medline:
19
4
2023
pubmed:
24
3
2023
entrez:
23
3
2023
Statut:
ppublish
Résumé
The assessment of persistence (P), bioaccumulation (B), and toxicity (T) of a chemical is a crucial first step at ensuring chemical safety and is a cornerstone of the European Union's chemicals regulation REACH (Registration, Evaluation, Authorization, and Restriction of Chemicals). Existing methods for PBT assessment are overly complex and cumbersome, have produced incorrect conclusions, and rely heavily on animal-intensive testing. We explore how new-approach methodologies (NAMs) can overcome the limitations of current PBT assessment. We propose two innovative hazard indicators, termed cumulative toxicity equivalents (CTE) and persistent toxicity equivalents (PTE). Together they are intended to replace existing PBT indicators and can also accommodate the emerging concept of PMT (where M stands for mobility). The proposed "toxicity equivalents" can be measured with high throughput in vitro bioassays. CTE refers to the toxic effects measured directly in any given sample, including single chemicals, substitution products, or mixtures. PTE is the equivalent measure of cumulative toxicity equivalents measured after simulated environmental degradation of the sample. With an appropriate panel of animal-free or alternative in vitro bioassays, CTE and PTE comprise key environmental and human health hazard indicators. CTE and PTE do not require analytical identification of transformation products and mixture components but instead prompt two key questions: is the chemical or mixture toxic, and is this toxicity persistent or can it be attenuated by environmental degradation? Taken together, the proposed hazard indicators CTE and PTE have the potential to integrate P, B/M and T assessment into one high-throughput experimental workflow that sidesteps the need for analytical measurements and will support the Chemicals Strategy for Sustainability of the European Union.
Identifiants
pubmed: 36952002
doi: 10.1007/s00204-023-03485-5
pii: 10.1007/s00204-023-03485-5
pmc: PMC10110678
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
1267-1283Subventions
Organisme : HORIZON EUROPE Reforming and enhancing the European Research and Innovation system
ID : 965406
Organisme : HORIZON EUROPE Framework Programme
ID : 101057014
Organisme : Helmholtz Association
ID : POF IV
Informations de copyright
© 2023. The Author(s).
Références
Abdelaziz A, Spahn-Langguth H, Schramm KW, Tetko IV (2016) Consensus modeling for HTS assays using in silico descriptors calculates the best balanced accuracy in Tox21 challenge. Front Environm Sci. https://doi.org/10.3389/fenvs.2016.00002
doi: 10.3389/fenvs.2016.00002
Arp HPH, Hale SE (2022) Assessing the persistence and mobility of organic substances to protect freshwater resources. ACS Environm Au. https://doi.org/10.1021/acsenvironau.2c00024
doi: 10.1021/acsenvironau.2c00024
Auerbach S, Filer D, Reif D, Walker V, Holloway Alison C, Schlezinger J, Srinivasan S, Svoboda D, Judson R, Bucher John R, Thayer Kristina A (2016) Prioritizing environmental chemicals for obesity and diabetes outcomes research: a screening approach using ToxCast™ High-throughput data. Environ Health Perspect 124(8):1141–1154. https://doi.org/10.1289/ehp.1510456
doi: 10.1289/ehp.1510456
pubmed: 26978842
pmcid: 4977057
Aven T (2011) On Some recent definitions and analysis frameworks for risk, vulnerability, and resilience. Risk Anal 31(4):515–522. https://doi.org/10.1111/j.1539-6924.2010.01528.x
doi: 10.1111/j.1539-6924.2010.01528.x
pubmed: 21077926
Ball N, Bars R, Botham PA, Cuciureanu A, Cronin MTD, Doe JE, Dudzina T, Gant TW, Leist M, van Ravenzwaay B (2022) A framework for chemical safety assessment incorporating new approach methodologies within REACH. Arch Toxicol 96(3):743–766. https://doi.org/10.1007/s00204-021-03215-9
doi: 10.1007/s00204-021-03215-9
pubmed: 35103819
pmcid: 8850243
Behl M, Ryan K, Hsieh JH, Parham F, Shapiro AJ, Collins BJ, Sipes NS, Birnbaum LS, Bucher JR, Foster PMD, Walker NJ, Paules RS, Tice RR (2019) Screening for developmental neurotoxicity at the national toxicology program: the future is here. Toxicol Sci 167(1):6–14. https://doi.org/10.1093/toxsci/kfy278
doi: 10.1093/toxsci/kfy278
pubmed: 30496580
pmcid: 6657567
Bell SM, Chang XQ, Wambaugh JF, Allen DG, Bartels M, Brouwer KLR, Casey WM, Choksi N, Ferguson SS, Fraczkiewicz G, Jarabek AM, Ke A, Lumen A, Lynn SG, Paini A, Price PS, Ring C, Simon TW, Sipes NS, Sprankle CS, Strickland J, Troutman J, Wetmore BA, Kleinstreuer NC (2018) In vitro to in vivo extrapolation for high throughput prioritization and decision making. Toxicol in Vitro 47:213–227. https://doi.org/10.1016/j.tiv.2017.11.016
doi: 10.1016/j.tiv.2017.11.016
pubmed: 29203341
Bennett D, Bellinger David C, Birnbaum Linda S, Null N, Bradman A, Chen A, Cory-Slechta Deborah A, Engel Stephanie M, Fallin MD, Halladay A, Hauser R, Hertz-Picciotto I, Kwiatkowski Carol F, Lanphear Bruce P, Marquez E, Marty M, McPartland J, Newschaffer Craig J, Payne-Sturges D, Patisaul Heather B, Perera Frederica P, Ritz B, Sass J, Schantz Susan L, Webster Thomas F, Whyatt Robin M, Woodruff Tracey J, Zoeller RT, Anderko L, Campbell C, Conry Jeanne A, DeNicola N, Gould Robert M, Hirtz D, Huffling K, Landrigan Philip J, Lavin A, Miller M, Mitchell Mark A, Rubin L, Schettler T, Tran Ho L, Acosta A, Brody C, Miller E, Miller P, Swanson M, Witherspoon Nsedu O (2016) Project TENDR: targeting environmental neuro-developmental risks The TENDR consensus statement. Environm Health Perspect 124(7):A118–A122. https://doi.org/10.1289/EHP358
doi: 10.1289/EHP358
Betts KS (2013) Tox21 to date steps toward modernizing human hazard characterization. Environ Health Perspect 121(7):A228–A228. https://doi.org/10.1289/ehp.121-a228
doi: 10.1289/ehp.121-a228
pubmed: 23816934
pmcid: 3702009
Birnbaum L, Burke T, Jones J (2016) Informing 21st-century risk assessments with 21st-century science. Environ Health Perspect 124(4):A60-63. https://doi.org/10.1289/ehp.1511135
doi: 10.1289/ehp.1511135
pubmed: 27035154
pmcid: 4829990
Blaauboer BJ (2015) The long and winding road of progress in the use of in vitro data for risk assessment purposes: From “carnation test” to integrated testing strategies. Toxicology 332:4–7. https://doi.org/10.1016/j.tox.2014.04.004
doi: 10.1016/j.tox.2014.04.004
pubmed: 24769060
Blum J, Masjosthusmann S, Bartmann K, Bendt F, Dolde X, Dönmez A, Förster N, Holzer A-K, Hübenthal U, Kebel HE, Kilic S, Klose J, Pahl M, Stürzl L-C, Mangas I, Terron A, Crofton KM, Scholze M, Mosig A, Leist M, Fritsche E (2023) Establishment of a human cell-based in vitro battery to assess developmental neurotoxicity hazard of chemicals. Chemosphere 311:137035. https://doi.org/10.1016/j.chemosphere.2022.137035
doi: 10.1016/j.chemosphere.2022.137035
Bopp SK, Barouki R, Brack W, Dalla Costa S, Dorne J, Drakvik PE, Faust M, Karjalainen TK, Kephalopoulos S, van Klaveren J, Kolossa-Gehring M, Kortenkamp A, Lebret E, Lettieri T, Norager S, Ruegg J, Tarazona JV, Trier X, van de Water B, van Gils J, Bergman A (2018) Current EU research activities on combined exposure to multiple chemicals. Environm Int 120:544–562. https://doi.org/10.1016/j.envint.2018.07.037
doi: 10.1016/j.envint.2018.07.037
Bopp SK, Kienzler A, Richarz AN, van der Linden SC, Paini A, Parissis N, Worth AP (2019) Regulatory assessment and risk management of chemical mixtures: challenges and ways forward. Crit Rev Toxicol 49(2):174–189. https://doi.org/10.1080/10408444.2019.1579169
doi: 10.1080/10408444.2019.1579169
pubmed: 30931677
Boxall ABA, Sinclair CJ, Fenner K, Kolpin D, Maud SJ (2004) When synthetic chemicals degrade in the environment. Environ Sci Technol 38(19):368A-375A
doi: 10.1021/es040624v
pubmed: 15506178
Brendel S, Fetter É, Staude C, Vierke L, Biegel-Engler A (2018) Short-chain perfluoroalkyl acids: environmental concerns and a regulatory strategy under REACH. Environ Sci Eur 30(1):9. https://doi.org/10.1186/s12302-018-0134-4
doi: 10.1186/s12302-018-0134-4
pubmed: 29527446
pmcid: 5834591
Brillet F, Maul A, Durand M-J, Thouand G (2016) From laboratory to environmental conditions: a new approach for chemical’s biodegradability assessment. Environ Sci Pollut Res 23(18):18684–18693. https://doi.org/10.1007/s11356-016-7062-x
doi: 10.1007/s11356-016-7062-x
Burden N, Sewell F, Andersen ME, Boobis A, Chipman JK, Cronin MTD, Hutchinson TH, Kimber I, Whelan M (2015) Adverse Outcome Pathways can drive non-animal approaches for safety assessment. J Appl Toxicol 35(9):971–975. https://doi.org/10.1002/jat.3165
doi: 10.1002/jat.3165
pubmed: 25943792
pmcid: 4682468
Carusi A, Davies M, De Grandis G, Escher B, Hodges G, Leung KMY, Whelan M, Willett C, Ankley G (2018) Harvesting the Promise of AOPs: an assessment and recommendations. Sci Total Environ 628–629:1542–1556
doi: 10.1016/j.scitotenv.2018.02.015
pubmed: 30045572
pmcid: 5888775
Castro M, Sobek A, Yuan B, Breitholtz M (2019) Bioaccumulation potential of CPs in aquatic organisms: uptake and depuration in daphnia magna. Environ Sci Technol 53(16):9533–9541. https://doi.org/10.1021/acs.est.9b01751
doi: 10.1021/acs.est.9b01751
pubmed: 31321968
Catron TR, Keely SP, Brinkman NE, Zurlinden TJ, Wood CE, Wright JR, Phelps D, Wheaton E, Kvasnicka A, Gaballah S, Lamendella R, Tal T (2019) Host developmental toxicity of BPA and BPA alternatives Is inversely RELATED to microbiota disruption in zebrafish. Toxicol Sci 167(2):468–483. https://doi.org/10.1093/toxsci/kfy261
doi: 10.1093/toxsci/kfy261
pubmed: 30321396
Celebi Sozener Z, Ozdel Ozturk B, Cerci P, Turk M, Gorgulu Akin B, Akdis M, Altiner S, Ozbey U, Ogulur I, Mitamura Y, Yilmaz I, Nadeau K, Ozdemir C, Mungan D, Akdis CA (2022) Epithelial barrier hypothesis: effect of the external exposome on the microbiome and epithelial barriers in allergic disease. Allergy 77(5):1418–1449. https://doi.org/10.1111/all.15240
doi: 10.1111/all.15240
pubmed: 35108405
Collins F, Gray GN, Bucher JR (2008) Transforming environmental health protection. Science 319:906–907
doi: 10.1126/science.1154619
pubmed: 18276874
pmcid: 2679521
European Commission (2013) European Commission, Directorate-General for Health and Consumers, Toxicity and assessment of chemical mixtures, European Commission, Doi: https://doi.org/10.2772/21444 .
European Commission (2020) Communication from the Commission to the European Parliament, the Council, the European Economic and Social Committee and the Committee of the Regions (COM (2020) 667 final). Chemicals Strategy for Sustainability towards a Toxic-free Environment. European Communities
den Braver-Sewradj SP, van Spronsen R, Hessel EVS (2020) Substitution of bisphenol A: a review of the carcinogenicity, reproductive toxicity, and endocrine disruption potential of alternative substances. Crit Rev Toxicol 50(2):128–147. https://doi.org/10.1080/10408444.2019.1701986
doi: 10.1080/10408444.2019.1701986
Drakvik E, Altenburger R, Aoki Y, Backhaus T, Bahadori T, Barouki R, Brack W, Cronin MTD, Demeneix B, Bennekou SH, van Klaveren J, Kneuer C, Kolossa-Gehring M, Lebret E, Posthuma L, Reiber L, Rider C, Ruegg J, Testa G, van der Burg B, van der Voet H, Warhurst AM, van de Water B, Yamazaki K, Oberg M, Bergman A (2020) Statement on advancing the assessment of chemical mixtures and their risks for human health and the environment. Environ Int 134:105267. https://doi.org/10.1016/j.envint.2019.105267
doi: 10.1016/j.envint.2019.105267
pubmed: 31704565
ECHA (2017a) Guidance on Information Requirements and Chemical Safety Assessment Chapter R.11: PBT/vPvB assessment. Version 3.0.European Chemicals Agency,
ECHA (2017b) Guidance on Information Requirements and Chemical Safety Assessment Part C: PBT/vPvB assessment. Version 3.0.European Chemicals Agency
ECHA (2017c) Read-Across Assessment Framework (RAAF)—considerations on multi-constituent substances and UVCBs. 102823/794394:European Chemicals Agency. Doi: https://doi.org/10.2823/794394
enHealth (2004) Environmental health risk assessment. Guidelines for assessing human health risks from environmental hazards. Department of Health and Aging and enHealth Council, Canberra, Australia
U.S. EPA (1976) Toxic substances control act. U.S. Environmental Protection Agency. Washington DC, USA
U.S. EPA (2021) New Approach Methods Work Plan (v2). U.S. Environmental Protection Agency, Washington, DC. EPA/600/X-21/209.
U.S. EPA (2022) EPA New Approach Methods Work Plan: Reducing Use of Vertebrate Animals in Chemical Testing. Accessed 30 July 2022
EP&EC (2006) Regulation (EC) No 1907/2006 of the European Parliament and of the Council of 18 December 2006 concerning the Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH), establishing a European Chemicals Agency, amending Directive 1999/45/EC and repealing Council Regulation (EEC) No 793/93 and Commission Regulation (EC) No 1488/94 as well as Council Directive 76/769/EEC and Commission Directives 91/155/EEC, 93/67/EEC, 93/105/EC and 2000/21/EC. European Parliament and European Council, Official Journal of the European Communities
EP&EC (2008) Regulation (EC) No 1272/2008 of the European Parliament and of the Council of 16 December 2008 on classification, labelling and packaging of substances and mixtures, amending and repealing Directives 67/548/EEC and 1999/45/EC, and amending Regulation (EC) No 1907/2006. Official Journal of the European Communities L 353/1 31.12.2008
EP&EC (2020) Regulation (EU) 2020/741 of the European parliament and of the Council of 25 May 2020 on minimum requirements for water reuse. European Parliament and European Council, Official Journal of the European Communities
Escher BI, Fenner K (2011) Recent advances in the environmental risk assessment of transformation products. Environ Sci Technol 45(9):3835–3847. https://doi.org/10.1021/es1030799
doi: 10.1021/es1030799
pubmed: 21473617
Escher BI, Glauch L, Konig M, Mayer P, Schlichting R (2019) Baseline toxicity and volatility cutoff in reporter gene assays used for high-throughput screening. Chem Res Toxicol 32(8):1646–1655. https://doi.org/10.1021/acs.chemrestox.9b00182
doi: 10.1021/acs.chemrestox.9b00182
pubmed: 31313575
Escher BI, Stapleton HM, Schymanski EL (2020) Tracking complex mixtures of chemicals in our changing environment. Sci 397:388–392. https://doi.org/10.1126/science.aay6636
doi: 10.1126/science.aay6636
Escher B, Neale P, Leusch F (2021) Bioanalytical tools in water quality assessment, second edition, www.iwapublishing.com/books/9781789061970/bioanalytical-tools-water-quality-assessment-2nd-edition . IWA Publishing, London, UK
Ezendam J, Braakhuis HM, Vandebriel RJ (2016) State of the art in non-animal approaches for skin sensitization testing: from individual test methods towards testing strategies. Arch Toxicol 90(12):2861–2883. https://doi.org/10.1007/s00204-016-1842-4
doi: 10.1007/s00204-016-1842-4
pubmed: 27629427
Fang WD, Peng Y, Yan L, Xia P, Zhang XW (2020) A tiered approach for screening and assessment of environmental mixtures by omics and in vitro assays. Environ Sci Technol 54(12):7430–7439. https://doi.org/10.1021/acs.est.0c00662
doi: 10.1021/acs.est.0c00662
pubmed: 32401503
Fantke P, Illner N (2019) Goods that are good enough: Introducing an absolute sustainability perspective for managing chemicals in consumer products. Curr Opinion Green Sustain Chem 15:91–97. https://doi.org/10.1016/j.cogsc.2018.12.001
doi: 10.1016/j.cogsc.2018.12.001
Fantke P, Weber R, Scheringer M (2015) From incremental to fundamental substitution in chemical alternatives assessment. Sustain Chem Pharm 1:1–8. https://doi.org/10.1016/j.scp.2015.08.001
doi: 10.1016/j.scp.2015.08.001
Fantke P, Cinquemani C, Yaseneva P, De Mello J, Schwabe H, Ebeling B, Lapkin AA (2021) Transition to sustainable chemistry through digitalization. Chem 7(11):2866–2882. https://doi.org/10.1016/j.chempr.2021.09.012
doi: 10.1016/j.chempr.2021.09.012
Fenner K, Scheringer M (2021) The need for chemical simplification as a logical consequence of ever-increasing chemical pollution. Environ Sci Technol 55(21):14470–14472. https://doi.org/10.1021/acs.est.1c04903
doi: 10.1021/acs.est.1c04903
pubmed: 34637288
Fischer F, Abele C, Droge STJ, Henneberger L, König M, Schlichting R, Scholz S, Escher B (2018) Cellular uptake kinetics of neutral and charged chemicals in In Vitro assays measured by fluorescence microscopy. Chem Res Toxicol 31:646–657. https://doi.org/10.1021/acs.chemrestox.8b00019
doi: 10.1021/acs.chemrestox.8b00019
pubmed: 29939727
Fischer M, Belanger SE, Berckmans P, Bernhard MJ, Blaha L, Schmid DEC, Dyer SD, Haupt T, Hermens JLM, Hultman MT, Laue H, Lillicrap A, Mlnarikova M, Natsch A, Novak J, Sinnige TL, Tollefsen KE, von Niederhausern V, Witters H, Zupanic A, Schirmer K (2019) Repeatability and reproducibility of the RTgill-W1 cell line assay for predicting fish acute toxicity. Toxicol Sci 169(2):353–364. https://doi.org/10.1093/toxsci/kfz057
doi: 10.1093/toxsci/kfz057
pubmed: 30825313
pmcid: 6542334
Fouyet S, Olivier E, Leproux P, Dutot M, Rat P (2021) Bisphenol A, Bisphenol F, and Bisphenol S: the bad and the ugly where is the good? Life-Basel. https://doi.org/10.3390/life11040314
doi: 10.3390/life11040314
pubmed: 33916708
pmcid: 8066465
Glauch L, Escher BI (2020) The combined algae test for the evaluation of mixture toxicity in environmental samples. Environ Toxicol Chem 39(12):2496–2508. https://doi.org/10.1002/etc.4873
doi: 10.1002/etc.4873
pubmed: 32926747
Glüge J, Escher B, Scheringer M (2022) How (flawed) bioaccumulation experiments impact the risk assessment of hydrophobic chemicals and what could be improved. Integr Environm Assess Manage. https://doi.org/10.1002/ieam.4714
doi: 10.1002/ieam.4714
Grandjean P, Landrigan PJ (2006) Developmental neurotoxicity of industrial chemicals. Lancet 368(9553):2167–2178. https://doi.org/10.1016/s0140-6736(06)69665-7
doi: 10.1016/s0140-6736(06)69665-7
pubmed: 17174709
Hale SE, Arp HPH, Schliebner I, Neumann M (2020) Persistent, mobile and toxic (PMT) and very persistent and very mobile (vPvM) substances pose an equivalent level of concern to persistent, bioaccumulative and toxic (PBT) and very persistent and very bioaccumulative (vPvB) substances under REACH. Environm Sci Euro. https://doi.org/10.1186/s12302-020-00440-4
doi: 10.1186/s12302-020-00440-4
Hallmann CA, Sorg M, Jongejans E, Siepel H, Hofland N, Schwan H, Stenmans W, Müller A, Sumser H, Hörren T, Goulson D, de Kroon H (2017) More than 75 percent decline over 27 years in total flying insect biomass in protected areas. PLoS ONE 12(10):0185809. https://doi.org/10.1371/journal.pone.0185809
doi: 10.1371/journal.pone.0185809
Hatherell S, Baltazar MT, Reynolds J, Carmichael PL, Dent M, Li HQ, Ryder S, White A, Walker P, Middleton AM (2020) Identifying and characterizing stress pathways of concern for consumer safety in next-generation risk assessment. Toxicol Sci 176(1):11–33. https://doi.org/10.1093/toxsci/kfaa054
doi: 10.1093/toxsci/kfaa054
pubmed: 32374857
pmcid: 7357173
Hennebert P (2021) The substitution of regulated brominated flame retardants in plastic products and waste and the declared properties of the substitutes in REACH. Detritus 16:16–25. https://doi.org/10.31025/2611-4135/2021.15122
doi: 10.31025/2611-4135/2021.15122
Hoffmann S, Kleinstreuer N, Alepee N, Allen D, Api AM, Ashikaga T, Clouet E, Cluzel M, Desprez B, Gellatly N, Goebel C, Kern PS, Klaric M, Kuhnl J, Lalko JF, Martinozzi-Teissier S, Mewes K, Miyazawa M, Parakhia R, van Vliet E, Zang QD, Petersohn D (2018) Non-animal methods to predict skin sensitization (I): the Cosmetics Europe database. Crit Rev Toxicol 48(5):344–358. https://doi.org/10.1080/10408444.2018.1429385
doi: 10.1080/10408444.2018.1429385
pubmed: 29474128
Honti M, Hahn S, Hennecke D, Junker T, Shrestha P, Fenner K (2016) Bridging across OECD 308 and 309 data in search of a robust biotransformation indicator. Environ Sci Technol 50(13):6865–6872. https://doi.org/10.1021/acs.est.6b01097
doi: 10.1021/acs.est.6b01097
pubmed: 27213716
Honti M, Bischoff F, Moser A, Stamm C, Baranya S, Fenner K (2018) Relating degradation of pharmaceutical active ingredients in a stream network to degradation in water-sediment simulation tests. Water Resour Res 54(11):9207–9223. https://doi.org/10.1029/2018wr023592
doi: 10.1029/2018wr023592
Huchthausen J, Henneberger L, Mälzer S, Nicol B, Sparham C, Escher BI (2022) High-throughput assessment of the abiotic stability of test chemicals in In Vitro bioassays. Chem Res Toxicol 35(5):867–879. https://doi.org/10.1021/acs.chemrestox.2c00030
doi: 10.1021/acs.chemrestox.2c00030
pubmed: 35394761
Hüesker F, Lepenies R (2022) Why does pesticide pollution in water persist? Environ Sci Policy 128:185–193
doi: 10.1016/j.envsci.2021.11.016
Ji ZW, Liu J, Sakkiah S, Guo WJ, Hong HX (2021) BPA replacement compounds: current status and perspectives. Acs Sustain Chem Eng 9(6):2433–2446. https://doi.org/10.1021/acssuschemeng.0c09276
doi: 10.1021/acssuschemeng.0c09276
Joerss H, Xie Z, Wagner CC, von Appen W-J, Sunderland EM, Ebinghaus R (2020) Transport of legacy perfluoroalkyl substances and the replacement compound hfpo-da through the atlantic gateway to the arctic ocean—Is the arctic a sink or a source? Environ Sci Technol 54(16):9958–9967. https://doi.org/10.1021/acs.est.0c00228
doi: 10.1021/acs.est.0c00228
pubmed: 32806910
pmcid: 7733389
Kassotis CD, Stapleton HM (2019) Endocrine-mediated mechanisms of metabolic disruption and new approaches to examine the public health threat. Front Endocrinol 10:39. https://doi.org/10.3389/fendo.2019.00039
doi: 10.3389/fendo.2019.00039
Kassotis C, Vandenberg L, Demeneix B, Porta M, Slama R, Trasande L (2020) Endocrine-disrupting chemicals: economic regulatory and policy. Implications. https://doi.org/10.1016/S2213-8587
doi: 10.1016/S2213-8587
Keminer O, Teigeler M, Kohler M, Wenzel A, Arning J, Kassner F, Windshugel B, Eilebrecht E (2020) A tiered high-throughput screening approach for evaluation of estrogen and androgen receptor modulation by environmentally relevant bisphenol A substitutes. Sci Total Environm. https://doi.org/10.1016/j.scitotenv.2019.134743
doi: 10.1016/j.scitotenv.2019.134743
Kleinstreuer NC, Allen D, Casey WM (2015) Using ToxCast/Tox21 HTS assays to assess endocrine disruption. Birth Defects Res Clin Mol Teratol 103(5):395–395
Klinke A, Renn O (2001) Precautionary principle and discursive strategies: Classifying and managing risks. J Risk Res 42(2):159–173. https://doi.org/10.1080/136698701750128105
doi: 10.1080/136698701750128105
Kortenkamp A, Faust M (2018) Regulate to reduce chemical mixture risk. Science 361(6399):224–226. https://doi.org/10.1126/science.aat9219
doi: 10.1126/science.aat9219
pubmed: 30026211
Kosnik MB, Hauschild MZ, Fantke P (2022) Toward assessing absolute environmental sustainability of chemical pollution. Environ Sci Technol 56(8):4776–4787. https://doi.org/10.1021/acs.est.1c06098
doi: 10.1021/acs.est.1c06098
pubmed: 35349278
pmcid: 9022439
Krewski D, Andersen ME, Tyshenko MG, Krishnan K, Hartung T, Boekelheide K, Wambaugh JF, Jones D, Whelan M, Thomas R, Yauk C, Barton-Maclaren T, Cote I (2020) Toxicity testing in the 21st century: progress in the past decade and future perspectives. Arch Toxicol 94(1):1–58. https://doi.org/10.1007/s00204-019-02613-4
doi: 10.1007/s00204-019-02613-4
pubmed: 31848664
Kümmerer K, Clark JH, Zuin VG (2020) Rethinking chemistry for a circular economy. Science 367(6476):369–370. https://doi.org/10.1126/science.aba4979
doi: 10.1126/science.aba4979
pubmed: 31974237
Lai A, Clark AM, Escher BI, Fernandez M, McEwen LR, Tian Z, Wang Z, Schymanski EL (2022) The next frontier of environmental unknowns: substances of unknown or variable composition, complex reaction products, or biological materials (UVCBs). Environ Sci Technol 56(12):7448–7466. https://doi.org/10.1021/acs.est.2c00321
doi: 10.1021/acs.est.2c00321
pubmed: 35533312
pmcid: 9228065
Landrigan PJ, Fuller R, Acosta NJR, Adeyi O, Arnold R, Basu N, Balde AB, Bertollini R, Bose-O’Reilly S, Boufford JI, Breysse PN, Chiles T, Mahidol C, Coll-Seck AM, Cropper ML, Fobil J, Fuster V, Greenstone M, Haines A, Hanrahan D, Hunter D, Khare M, Krupnick A, Lanphear B, Lohani B, Martin K, Mathiasen KV, McTeer MA, Murray CJL, Ndahimananjara JD, Perera F, Potocnik J, Preker AS, Ramesh J, Rockstrom J, Salinas C, Samson LD, Sandilya K, Sly PD, Smith KR, Steiner A, Stewart RB, Suk WA, van Schayck OCP, Yadama GN, Yumkella K, Zhong M (2018) The lancet commission on pollution and health. Lancet 391(10119):462–512. https://doi.org/10.1016/s0140-6736(17)32345-0
doi: 10.1016/s0140-6736(17)32345-0
pubmed: 29056410
Lee J, Braun G, Henneberger L, König M, Schlichting R, Scholz S, Escher BI (2021) Critical membrane concentration and mass-balance model to identify baseline cytotoxicity of hydrophobic and ionizable organic chemicals in mammalian cell lines. Chem Res Toxicol 34(9):2100–2109. https://doi.org/10.1021/acs.chemrestox.1c00182
doi: 10.1021/acs.chemrestox.1c00182
pubmed: 34357765
Leipold S (2021) Transforming ecological modernization ‘from within’or perpetuating it? The circular economy as EU environmental policy narrative. Environ Polit 30(6):1045–1067. https://doi.org/10.1080/09644016.2020.1868863
doi: 10.1080/09644016.2020.1868863
Liang XX, Yin NY, Liang SX, Yang RJ, Liu SY, Lu YP, Jiang LS, Zhou QF, Jiang GB, Faiola F (2020) Bisphenol A and several derivatives exert neural toxicity in human neuron-like cells by decreasing neurite length. Food Chem Toxicol. https://doi.org/10.1016/j.fct.2019.111015
doi: 10.1016/j.fct.2019.111015
pubmed: 33285210
Lofstedt R (2014) The precautionary principle in the EU: Why a formal review is long overdue. Risk Manag-an Int J 16(3):137–163. https://doi.org/10.1057/rm.2014.7
doi: 10.1057/rm.2014.7
Lombardo A, Roncaglioni A, Benfentati E, Nendza M, Segner H, Fernandez A, Kuhne R, Franco A, Patine E, Schuurmann G (2014) Integrated testing strategy (ITS) for bioaccumulation assessment under REACH. Environ Int 69:40–50. https://doi.org/10.1016/j.envint.2014.04.005
doi: 10.1016/j.envint.2014.04.005
pubmed: 24806447
Lowe CN, Phillips KA, Favela KA, Yau AY, Wambaugh JF, Sobus JR, Williams AJ, Pfirrman AJ, Isaacs KK (2021) Chemical characterization of recycled consumer products using suspect screening analysis. Environ Sci Technol 55(16):11375–11387. https://doi.org/10.1021/acs.est.1c01907
doi: 10.1021/acs.est.1c01907
pubmed: 34347456
pmcid: 8475772
Luijten M, Rorije E, Sprong RC, van der Ven LTM (2020) Practical application of next generation risk assessment of chemicals for human health. Chem Res Toxicol 33(3):693–694. https://doi.org/10.1021/acs.chemrestox.0c00074
doi: 10.1021/acs.chemrestox.0c00074
pubmed: 32133836
Maertens A, Golden E, Hartung T (2021) Avoiding regrettable substitutions: green toxicology for sustainable chemistry. Acs Sustain Chem Eng 9(23):7749–7758. https://doi.org/10.1021/acssuschemeng.0c09435
doi: 10.1021/acssuschemeng.0c09435
pubmed: 36051558
pmcid: 9432817
Malakar Y, Lacey J, Bertsch PM (2022) Towards responsible science and technology: How nanotechnology research and development is shaping risk governance practices in Australia. Human Social Sci Commun 9(1):17. https://doi.org/10.1057/s41599-021-01028-w
doi: 10.1057/s41599-021-01028-w
Martin TJ, Snape JR, Bartram A, Robson A, Acharya K, Davenport RJ (2017) Environmentally relevant inoculum concentrations improve the reliability of persistent assessments in biodegradation screening tests. Environ Sci Technol 51(5):3065–3073. https://doi.org/10.1021/acs.est.6b05717
doi: 10.1021/acs.est.6b05717
pubmed: 28125206
Mone MJ, Pallocca G, Escher SE, Exner T, Herzler M, Bennekou SH, Kamp H, Kroese ED, Leist M, Steger-Hartmann T, van de Water B (2020) Setting the stage for next-generation risk assessment with non-animal approaches: the EU-ToxRisk project experience. Archives Toxicol 94(10):3581–3592. https://doi.org/10.1007/s00204-020-02866-4
doi: 10.1007/s00204-020-02866-4
Muratov EN, Bajorath J, Sheridan RP, Tetko IV, Filimonov D, Poroikov V, Oprea TI, Baskin II, Varnek A, Roitberg A, Isayev O, Curtalolo S, Fourches D, Cohen Y, Aspuru-Guzik A, Winkler DA, Agrafiotis D, Cherkasov A, Tropsha A (2020) QSAR without Borders. Chem Soc Rev 49(11):3525–3564. https://doi.org/10.1039/d0cs00098a
doi: 10.1039/d0cs00098a
pubmed: 32356548
pmcid: 8008490
U.S. NAS (2017) National Academies of Sciences Engineering and Medicine. Using 21st Century Science to Improve Risk-Related Evaluations. Washington, DC: The National Academies Press. Doi: https://doi.org/10.17226/24635 .
Neale PA, Brack W, Ait-Aissa S, Busch W, Hollender J, Krauss M, Maillot-Maréchal E, Munz NA, Schlichting R, Schulze T, Vogler B, Escher B (2018) Solid-phase extraction as sample preparation of water samples for cell-based and other in vitro bioassays. Environ Sci Process Impacts 20:493–504. https://doi.org/10.1039/C7EM00555E
doi: 10.1039/C7EM00555E
pubmed: 29493668
Neale PA, Braun G, Brack W, Carmona E, Gunold R, Konig M, Krauss M, Liebmann L, Liess M, Link M, Schafer RB, Schlichting R, Schreiner VC, Schulze T, Vormeier P, Weisner O, Escher BI (2020) Assessing the mixture effects in in vitro bioassays of chemicals occurring in small agricultural streams during rain events. Environ Sci Technol 54(13):8280–8290. https://doi.org/10.1021/acs.est.0c02235
doi: 10.1021/acs.est.0c02235
pubmed: 32501680
Neel BA, Sargis RM (2011) The paradox of progress: environmental disruption of metabolism and the diabetes epidemic. Diabetes 60(7):1838–1848. https://doi.org/10.2337/db11-0153
doi: 10.2337/db11-0153
pubmed: 21709279
pmcid: 3121438
NRC (1983) Risk assessment in the federal government. National Research Council (NRC), National Academy Press, Washington DC, USA, Managing the process
NRC (2007) Toxicity testing in the 21st century: A vision and a strategy. National Academies Press, Washington DC
OECD (2002d) OECD guidelines for testing of chemicals; 309, Aerobic Mineralisation in Surface Water–Simulation Biodegradation Test. OECD, Paris, p 19
OECD (1996) OECD guidelines for testing of chemicals; 305. Bioaccumulation: Flow-through fish test OECD guidelines for testing of chemicals. Environmental Directorate, Organisation for Economic Co-operation and Development, Paris, France
OECD (2002a) OECD guidelines for testing of chemicals; 301, Ready biodegradability. OECD, Paris. 17
OECD (2002b) OECD guidelines for testing of chemicals; 307, Aerobic and anaerobic transformation in soil. OECD, Paris. 17
OECD (2002c) OECD guidelines for testing of chemicals; 308, Aerobic and anaerobic transformation in aquatic sediment systems. OECD, Paris. 19
OECD (2009) OECD guidelines for testing of chemicals; No. 302 A-D: Modified SCAS Test (TG 302 A), Zahn-Wellens/EMPA Test (TG 302 B), Modified MITI Test (II) (TG 302 C). OECD, Paris. 17
OECD (2012) OECD guidelines for testing of chemicals; 305. Bioaccumulation in fIsh: aqueous and dietary exposure OECD guidelines for testing of chemicals. Environmental Directorate, Organisation for Economic Co-operation and Development, Paris, France
Owen R, von Schomberg R, Macnaghten P (2021) An unfinished journey? Reflections on a decade of responsible research and innovation. J Resp Inno 8(2):217–233. https://doi.org/10.1080/23299460.2021.1948789
doi: 10.1080/23299460.2021.1948789
Pang QH, Li YR, Meng LX, Li GY, Luo ZW, Fan RF (2019) Neurotoxicity of BPA, BPS, and BPB for the hippocampal cell line (HT-22): An implication for the replacement of BPA in plastics. Chemosphere 226:545–552. https://doi.org/10.1016/j.chemosphere.2019.03.177
doi: 10.1016/j.chemosphere.2019.03.177
pubmed: 30953899
Persson L, Carney Almroth BM, Collins CD, Cornell S, de Wit CA, Diamond ML, Fantke P, Hassellöv M, MacLeod M, Ryberg MW, Søgaard Jørgensen P, Villarrubia-Gómez P, Wang Z, Hauschild MZ (2022) Outside the safe operating space of the planetary boundary for novel entities. Environ Sci Technol 56(3):1510–1521. https://doi.org/10.1021/acs.est.1c04158
doi: 10.1021/acs.est.1c04158
pubmed: 35038861
pmcid: 8811958
Proença S, Escher BI, Fischer FC, Fisher C, Gregoire S, Hewitt N, Nicol B, Paini A, Kramer NI (2021) Effective exposure of chemicals in in vitro cell systems: A review of chemical distribution models. Toxicol in Vitro 73:105133
doi: 10.1016/j.tiv.2021.105133
pubmed: 33662518
Reemtsma T, Berger U, Arp HPH, Gallard H, Knepper TP, Neumann M, Quintana JB, de Voogt P (2016) Mind the Gap: persistent and mobile organic compounds water contaminants that slip through. Environ Sci Technol 50(19):10308–10315. https://doi.org/10.1021/acs.est.6b03338
doi: 10.1021/acs.est.6b03338
pubmed: 27571393
Richard AM, Huang R, Waidyanatha S, Shinn P, Collins BJ, Thillainadarajah I, Grulke CM, Williams AJ, Lougee RR, Judson RS, Houck KA, Shobair M, Yang C, Rathman JF, Yasgar A, Fitzpatrick SC, Simeonov A, Thomas RS, Crofton KM, Paules RS, Bucher JR, Austin CP, Kavlock RJ, Tice RR (2021) The Tox21 10K compound library: collaborative chemistry advancing toxicology. Chem Res Toxicol 34(2):189–216. https://doi.org/10.1021/acs.chemrestox.0c00264
doi: 10.1021/acs.chemrestox.0c00264
pubmed: 33140634
Rossignol DA, Genuis SJ, Frye RE (2014) Environmental toxicants and autism spectrum disorders: a systematic review. Translat Psychiat. 4:360. https://doi.org/10.1038/tp.2014.4
doi: 10.1038/tp.2014.4
Rovida C, Alepee N, Api AM, Basketter DA, Bois FY, Caloni F, Corsini E, Daneshian M, Eskes C, Ezendam J, Fuchs H, Hayden P, Hegele-Hartung C, Hoffmann S, Hubesch B, Jacobs MN, Jaworska J, Kleensang A, Kleinstreuer N, Lalko J, Landsiedel R, Lebreux F, Luechtefeld T, Locatelli M, Mehling A, Natsch A, Pitchford JW, Prater D, Prieto P, Schepky A, Schuurmann G, Smirnova L, Toole C, van Vliet E, Weisensee D, Hartung T (2015) Integrated testing strategies (ITS) for safety assessment. Altex-Altern Animal Experim 32(1):25–40. https://doi.org/10.14573/altex.1411011
doi: 10.14573/altex.1411011
Sakamuru S, Zhu H, Xia M, Simeonov A, Huang R (2020) Profiling the Tox21 chemical library for environmental hazards: applications in prioritisation, predictive modelling, and mechanism of toxicity characterisation big data in predictive toxicology. Issues Toxicol. 41:242–263
Scherer LD, Maynard A, Dolinoy DC, Fagerlin A, Zikmund-Fisher BJ (2014) The psychology of “regrettable substitutions”: examining consumer judgements of Bisphenol A and its alternatives. Health Risk Soc 16(7–8):649–666. https://doi.org/10.1080/13698575.2014.969687
doi: 10.1080/13698575.2014.969687
pubmed: 29386966
pmcid: 5788195
Scholz S, Ortmann J, Kluever N, Leonard M (2014) Extensive review of fish embryo acute toxicities for the prediction of GHS acute systemic toxicity categories. Regul Toxicol Pharmacol 69(3):572–579. https://doi.org/10.1016/j.yrtph.2014.06.004
doi: 10.1016/j.yrtph.2014.06.004
pubmed: 24929227
Schug H, Maner J, Hulskamp M, Begnaud F, Debonneville C, Berthaud F, Gimeno S, Schirmer K (2020) Extending the concept of predicting fish acute toxicity In Vitro to the intestinal cell line RTgutGC. Altex-Alter Animal Exper 37(1):37–46. https://doi.org/10.14573/altex.1905032
doi: 10.14573/altex.1905032
Seibert H, Gulden M, Voss JU (1994) An in-vitro toxicity testing strategy for the classification and labeling of chemicals according to their potential acute lethal potency. Toxicol in Vitro 8(4):847–850. https://doi.org/10.1016/0887-2333(94)90084-1
doi: 10.1016/0887-2333(94)90084-1
pubmed: 20693028
Seller C, Özel Duygan BD, Honti M, Fenner K (2021) Biotransformation of Chemicals at the Water-Sediment Interface─Toward a Robust Simulation Study Setup. ACS Environmental Au 1(1):46–57. https://doi.org/10.1021/acsenvironau.1c00006
doi: 10.1021/acsenvironau.1c00006
Shah I, Houck K, Judson RS, Kavlock RJ, Martin MT, Reif DM, Wambaugh J, Dix DJ (2011) Using nuclear receptor activity to stratify hepatocarcinogens. PLoS ONE. https://doi.org/10.1371/journal.pone.0014584
doi: 10.1371/journal.pone.0014584
pubmed: 22220201
pmcid: 3248404
Silva E, Rajapakse N, Kortenkamp A (2002) Something from “nothing”– eight weak estrogenic chemicals combined at concentrations below NOECs produce significant mixture effects. Environ Sci Technol 36:1751–1756
doi: 10.1021/es0101227
pubmed: 11993873
Simmons SO, Fan CY, Ramabhadran R (2009) Cellular stress response pathway system as a sentinel ensemble in toxicological screening. Toxicol Sci 111(2):202–225. https://doi.org/10.1093/toxsci/kfp140
doi: 10.1093/toxsci/kfp140
pubmed: 19567883
Smith M, Guyton K, Gibbons C, Fritz J, Portier C, Rusyn I (2016) Key characteristics of carcinogens as a basis for organizing data on mechanisms of carcinogenesis. Environ Health Perspect 124:713–721. https://doi.org/10.1289/ehp.1509912
doi: 10.1289/ehp.1509912
pubmed: 26600562
Sobanska MA, Cesnaitis R, Sobanski T, Versonnen B, Bonnomet V, Tarazona JV, De Coen W (2014) Analysis of the ecotoxicity data submitted within the framework of the REACH Regulation. Part 1. General overview and data availability for the first registration deadline. Sci Total Environ 470:1225–1232. https://doi.org/10.1016/j.scitotenv.2013.10.074
doi: 10.1016/j.scitotenv.2013.10.074
pubmed: 24246945
Stalter D, Peters L, O’Malley E, Tang JYM, Revalor M, Farre MJ, Watson K, von Gunten U, Escher BI (2016) Sample enrichment for bioanalytical assessment of disinfected drinking water: concentrating the polar, the volatiles, and the unknowns. Environ Sci Technol 50:6495–6505
doi: 10.1021/acs.est.6b00712
pubmed: 27153244
Strempel S, Scheringer M, Ng CA, Hungerbuehler K (2012) Screening for PBT chemicals among the “existing” and “New” chemicals of the EU. Environ Sci Technol 46(11):5680–5687. https://doi.org/10.1021/es3002713
doi: 10.1021/es3002713
pubmed: 22494215
Tang S, Chen Y, Song G, Liu X, Shi Y, Xie Q, Chen D (2021) A cocktail of industrial chemicals in lipstick and nail polish: profiles and health implications. Environ Sci Technol Lett 8(9):760–765. https://doi.org/10.1021/acs.estlett.1c00512
doi: 10.1021/acs.estlett.1c00512
Tanneberger K, Knöbel M, Busser FJM, Sinnige TL, Hermens JLM, Schirmer K (2013) Predicting fish acute toxicity using a fish gill cell line-based toxicity assay. Environ Sci Technol 47(2):1110–1119. https://doi.org/10.1021/es303505z
doi: 10.1021/es303505z
pubmed: 23227966
Teixido E, Kiessling TR, Krupp E, Quevedo C, Muriana A, Scholz S (2019) Automated Morphological Feature Assessment for Zebrafish Embryo Developmental Toxicity Screens. Toxicol Sci 167(2):438–449. https://doi.org/10.1093/toxsci/kfy250
doi: 10.1093/toxsci/kfy250
pubmed: 30295906
Thoene M, Dzika E, Gonkowski S, Wojtkiewicz J (2020) Bisphenol S in food causes hormonal and obesogenic effects comparable to or worse than bisphenol a: a literature review. Nutrients 12(2):532. https://doi.org/10.3390/nu12020532
doi: 10.3390/nu12020532
pubmed: 32092919
pmcid: 7071457
Toporova L, Balaguer P (2020) Nuclear receptors are the major targets of endocrine disrupting chemicals. Mol Cell Endocrinol. https://doi.org/10.1016/j.mce.2019.110665
doi: 10.1016/j.mce.2019.110665
pubmed: 31760044
UNEP (2019) United Nations Environment Programme. Global Chemicals Outlook II – From Legacies to Innovative Solutions: Implementing the 2030 Agenda for Sustainable Development. https://www.unep.org/resources/report/global-chemicals-outlook-ii-legacies-innovative-solutions Accessed 18 Nov 2022.
United Nations (2019) Globally Harmonized System of Classification and Labelling of Chemicals (GHS), 8th revised edition. Geneva, Switzerland, and New York, NY, USA
van Dijk J, Gustavsson M, Dekker SC, van Wezel AP (2021) Towards ‘one substance – one assessment’: An analysis of EU chemical registration and aquatic risk assessment frameworks. J Environm Manag. 280:111692. https://doi.org/10.1016/j.jenvman.2020.111692
doi: 10.1016/j.jenvman.2020.111692
Von Schomberg R (2019) Why Responsible Innovation. In: Von Schomberg R, Hankins J (eds) The International Handbook on Responsible Innovation A Global Resource. Edward Elgar Publishing, Cheltenham and Northampton, pp 12–32
doi: 10.4337/9781784718862.00006
Walter H, Consolaro F, Gramatica P, Scholze M, Altenburger R (2002) Mixture toxicity of priority pollutants at no observed effect concentrations (NOECs). Ecotoxicology 11(5):299–310. https://doi.org/10.1023/a:1020592802989
doi: 10.1023/a:1020592802989
pubmed: 12463676
Wang Z, Hellweg S (2021) First Steps Toward Sustainable Circular Uses of Chemicals: Advancing the Assessment and Management Paradigm. Acs Sustain Chem Eng 9(20):6939–6951. https://doi.org/10.1021/acssuschemeng.1c00243
doi: 10.1021/acssuschemeng.1c00243
Wetmore BA (2015) Quantitative in vitro-to-in vivo extrapolation in a high-throughput environment. Toxicology 332:94–101. https://doi.org/10.1016/j.tox.2014.05.012
doi: 10.1016/j.tox.2014.05.012
pubmed: 24907440
Whale G, Parsons J, van Ginkel K, Davenport R, Vaiopoulou E, Fenner K, Schaeffer A (2021) Improving our understanding of the environmental persistence of chemicals. Integr Environ Assess Manag 17(6):1123–1135. https://doi.org/10.1002/ieam.4438
doi: 10.1002/ieam.4438
pubmed: 33913596
pmcid: 8596663
Wiesinger H, Wang Z, Hellweg S (2021) Deep dive into plastic monomers, additives, and processing aids. Environ Sci Technol 55(13):9339–9351. https://doi.org/10.1021/acs.est.1c00976
doi: 10.1021/acs.est.1c00976
pubmed: 34154322
Wu LH, Huang RL, Tetko IV, Xia ZH, Xu J, Tong WD (2021) Trade-off predictivity and explainability for machine-learning powered predictive toxicology: an in-depth investigation with Tox21 data sets. Chem Res Toxicol 34(2):541–549. https://doi.org/10.1021/acs.chemrestox.0c00373
doi: 10.1021/acs.chemrestox.0c00373
pubmed: 33513003
pmcid: 8867471
Zainzinger V (2022) Can Europe replace animal testing of chemicals? Chemistry & Engineering News: https://cen.acs.org/biological-chemistry/toxicology/Europe-replace-animal-testing-chemicals/100/i28
Zimmerman JB, Anastas PT, Erythropel HC, Leitner W (2020) Designing for a green chemistry future. Science 367(6476):397–400. https://doi.org/10.1126/science.aay3060
doi: 10.1126/science.aay3060
pubmed: 31974246