Regulatory assessment and risk management of chemical mixtures: challenges and ways forward

References

• Altenburger R, Backhaus T, Boedeker W, Faust M, Scholze M. 2013. Simplifying complexity: mixture toxicity assessment in the last 20 years. Environ Toxicol Chem. 32:1685–1687.
   PubMed Web of Science ®Google Scholar
• Altenburger R, Nendza M, Schüürmann G. 2003. Mixture toxicity and its modeling by quantitative structure-activity relationships. Environ Toxicol Chem. 22:1900–1915.
   PubMed Web of Science ®Google Scholar
• Altenburger R, Scholz S, Schmitt-Jansen M, Busch W, Escher BI. 2012. Mixture toxicity revisited from a toxicogenomic perspective. Environ Sci Technol. 46:2508–2522.
   PubMed Web of Science ®Google Scholar
• Andrianou XD, Makris KC. 2018. The framework of urban exposome: application of the exposome concept in urban health studies. Sci Tot Environ. 636:963–967.
   PubMed Web of Science ®Google Scholar
• Ankley GT, Bennett RS, Erickson RJ, Hoff DJ, Hornung MW, Johnson RD, Mount DR, Nichols JW, Russom CL, Schmieder PK, et al. 2010. Adverse outcome pathways: a conceptual framework to support ecotoxicology research and risk assessment. Environ Toxicol Chem. 29:730–741.
   PubMed Web of Science ®Google Scholar
• Ashauer R, O’Connor I, Escher BI. 2017. Toxic mixtures in time - the sequence makes the poison. Environ Sci Technol. 51:3084–3092.
   PubMed Web of Science ®Google Scholar
• ATSDR (Agency for Toxic Substances and Disease Registry). 2018 Framework for Assessing Health Impacts of Multiple Chemicals and Other Stressors. Atlanta, GA: U.S. Department of Health and Human Services, Public Health Service. https://www.atsdr.cdc.gov/interactionprofiles/ipga.html.
   Google Scholar
• Backhaus T, Blanck H, Faust M. 2010. Hazard and risk assessment of chemical mixtures under REACH - state of the art, gaps and options for improvement. Swedish Chemicals Agency Report PM 3/10 1–91. Order No. 510968.
   Google Scholar
• Backhaus T, Faust M. 2012. Predictive environmental risk assessment of chemical mixtures: a conceptual framework. Environ Sci Technol. 46:2564–2573.
   PubMed Web of Science ®Google Scholar
• Backhaus T, Karlsson M. 2014. Screening level mixture risk assessment ofpharmaceuticals in STP effluents. Water Res. 49:157–165.
   PubMed Web of Science ®Google Scholar
• Binderup ML, Dalgaard M, Dragsted LO, Hossaini A, Ladefoged O, Lam HR, Larsen JC, Madsen C, Meyer O, Selzer Rasmussen E, et al. 2003. Combined Actions and Interactions of Chemicals in Mixtures-The Toxicological Effects of Exposure to Mixtures of Industrial and Environmental Chemicals, Fødevare Rapport 2003:12, 1st Edition, 1st Circulation, August 2003, Danish Veterinary and Food Administration, Søborg, Denmark.
   Google Scholar
• Boobis A, Budinsky R, Collie S, Crofton K, Embry M, Felter S, Hertzberg R, Kopp D, Mihlan G, Mumtaz M, et al. 2011. Critical analysis of literature on low-dose synergy for use in screening chemical mixtures for risk assessment. Crit Rev. Toxicol. 41(5):369–383.
   PubMed Web of Science ®Google Scholar
• Bopp S, Berggren E, Kienzler A, van der Linden S, Worth A. 2015. Scientific methodologies for the assessment of combined effects of chemicals – a survey and literature review. JRC Technical Report. EUR 27471 EN, 64 pp. Publications Office of the European Union, Luxembourg. https://doi.org/10.2788/093511.
   Google Scholar
• Bopp SK, Kienzler A, van der Linden S, Lamon L, Paini A, Parissis N, Richarz A-N, Triebe J, Worth A. 2016. Review of case studies on the human and environmental risk assessment of chemical mixtures future needs. JRC Technical Report. EUR 27968 EN; 89 pp. Publications Office of the European Union, Luxembourg.
   Google Scholar
• Bopp SK, Barouki R, Brack W, Dalla Costa S, Dorne JLCM, Drakvik PE, Faust M, Karjalainen TK, Kephalopoulos S, van Klaveren J, et al. 2018a. Current EU research activities on combined exposure to multiple chemicals. Env Int. 120:544–562.
   Google Scholar
• Bopp S, Richarz A, Worth A, Berggren E, Whelan M. 2018b. Something from nothing? Ensuring the safety of chemical mixtures. Policy Brief. JRC Science for Policy Brief. 2pp. doi: 10.2760/618648 ISBN 978-92-79-86747-7.
   Google Scholar
• Brack W, Ait-Aissa S, Burgess RM, Busch W, Creusot N, Di Paolo C, Escher BI, Mark Hewitt L, Hilscherova K, Hollender J, et al. 2016. Effect-directed analysis supporting monitoring of aquatic environments — an in-depth overview. Sci Tot Environ. 544:1073–1118.
   PubMed Web of Science ®Google Scholar
• Brack W, Dulio V, Ågerstrand M, Allan I, Altenburger R, Brinkmann M, Bunke D, Burgess RM, Cousins I, Escher BI, et al. 2017. Towards the review of the European Union Water Framework management of chemical contamination in European surface water resources. Sci Tot Environ.576:720–737.
   PubMed Web of Science ®Google Scholar
• Braun JM, Gennings C, Hauser R, Webster TF. 2016. What can epidemiological studies tell us about the impact of chemical mixtures on human health? Environ Health Perspect. 124:A6–A9.
   PubMed Web of Science ®Google Scholar
• Brown AR, Whale G, Jackson M, Marshall S, Hamer M, Solga A, Kabouw P, Galay-Burgos M, Woods R, Nadzialek S, et al. 2017. Toward the definition of specific protection goals for the environmental risk assessment of chemicals: a perspective on environmental regulation in Europe. Integr Environ Assess Manag. 13:17–37.
   PubMed Web of Science ®Google Scholar
• Burgess RM, Ho KT, Brack W, Lamoree M. 2013. Effects-directed analysis (EDA) and toxicity identification evaluation (TIE): complementary but different approaches for diagnosing causes of environmental toxicity. Environ Toxicol Chem. 32:1935–1945.
   PubMed Web of Science ®Google Scholar
• Burkhardt-Holm P, Giger W, Guttinger H, Ochsenbein U, Peter A, Scheurer A, Segner H, Staub E, Suter MJF. 2005. Where have all the fish gone? Environ Sci Technol. 39:441A–447A.
   PubMed Web of Science ®Google Scholar
• Burton GA. 2017. The focus on chemicals alone in human-dominated ecosystems is inappropriate. Integr Environ Assess Manag. 13:568–572.
   PubMed Web of Science ®Google Scholar
• Carpenter DO, Arcaro K, Spink DC. 2002. Understanding the human health effects of chemical mixtures. Environ Health Perspect.110:25–42.
   PubMed Web of Science ®Google Scholar
• Cedergreen N. 2014. Quantifying synergy: a systematic review of mixture toxicity studies within environmental toxicology. PLoS ONE. 9(5): e96580. doi:10.1371/journal.pone.0096580.
   PubMed Web of Science ®Google Scholar
• Dalla Costa S, Kephalopoulos S, Bopp S, Kienzler A, Richarz A, Van der Linden S, Korytar P, Backhaus T, Lebret E, Van Klaveren J, et al. 2018. JRC workshop on IPCHEM supporting the assessment of chemical mixtures. Final report. JRC workshop report, Joint Research Centre, Ispra, Italy. 52 pp. JRC112027.
   Google Scholar
• De Brouwere K, Cornelis C, Arvanitis A, Brown T, Crump D, Harrison P, Jantunen M, Price P, Torfs R. 2014. Application of the maximum cumulative ratio (MCR) as a screening tool for the evaluation of mixtures in residential indoor air. Sci Tot Environ. 479–480:267–276.
   PubMed Web of Science ®Google Scholar
• Dewalque L, Charlier C, Pirard C. 2014. Estimated daily intake and cumulative risk assessment of phthalate diesters in a Belgian general population. Toxicol Lett. 231:161–168.
   PubMed Web of Science ®Google Scholar
• Desalegn A, Bopp S, Asturiol D, Lamon L, Worth A, Paini A 2019. Role of Physiologically Based Kinetic modelling in addressing environmental chemical mixtures - A review. Comp Tox. In press. doi:10.1016/j.comtox.2018.09.001.
   PubMedGoogle Scholar
• EC (European Commission). 2012. Communication from the commission to the council - the combination effects of chemicals. Chemical mixtures. Brussels, 31.5.2012, COM(2012) 252 final.
   Google Scholar
• ECHA. (European Chemicals Agency) and EFSA (European Food Safety Authority) with the technical support of the Joint Research Centre (JRC); Andersson N, Arena M, Auteri D, Barmaz S, Grignard E, Kienzler A, Lepper P, Lostia AM, Munn S, Parra Morte JM, et al. 2018. Guidance for the identification of endocrine disruptors in the context of regulations (EU) No 528/2012 and (EC) No 1107/2009. EFSA J. 16:5311. ECHA-18-G-01-EN
   Web of Science ®Google Scholar
• ECHA (European Chemicals Agency). 2017a. Guidance on the biocidal products regulation, Volume III Human health - assessment & evaluation, Helsinki, Finland: European Chemicals Agency. (Parts B + C), Version 3.0, November 2017. Reference: ECHA-17-G-25-EN.
   Google Scholar
• ECHA (European Chemicals Agency). 2017b. Guidance on the biocidal products regulation - Volume IV Environment - assessment & evaluation, European Chemicals Agency, Helsinki, Finland. (Parts B + C) (Vol. II).
   Google Scholar
• ECHA (European Chemicals Agency). 2017c. Read-Across Assessment Framework (RAAF) — considerations on multi-constituent substances and UVCBs. Helsinki, Finland: European Chemicals Agency.
   Google Scholar
• EEA (European Environment Agency). 2017. Air quality in Europe — 2017. European Environment Agency, Copenhagen, Denmark. Report No 13/2017.
   Google Scholar
• EFSA Panel on Plant Protection Products and their residues (PPR). 2013. Scientific opinion on the relevance of dissimilar mode of action and its appropriate application for cumulative risk assessment of pesticides. EFSA Journal. 2013;11(12):3472, 40 pp.
   Google Scholar
• EFSA Panel on Plant Protection Products and their Residues (PPR). 2013. Scientific Opinion on the identification of pesticides to be included in cumulative assessment groups on the basis of their toxicological profile (2014 update).. EFSA Journal 2013;11(7):3293, 131:3293.
   Google Scholar
• EFSA (European Food Safety Authority) Scientific Committee. 2018a. Guidance on uncertainty analysis in scientific assessments. EFSA J. 16:5123.
   Web of Science ®Google Scholar
• EFSA (European Food Safety Authority) Scientific Committee 2018b. The principles and methods behind EFSA’s Guidance on Uncertainty Analysis in Scientific Assessment. EFSA J. 16:5122.
   Web of Science ®Google Scholar
• EFSA (European Food Safety Authority) Scientific Committee. 2018c. Draft guidance on harmonised methodologies for human health, animal health and ecological risk assessment of combined exposure to multiple chemicals. Published for public consultation 26 June–15 September 2018. http://www.efsa.europa.eu/sites/default/files/consultation/consultation/180626-1-ax1.pdf
   Google Scholar
• EFSA (European Food Safety Authority); Hart A, Maxim L, Siegrist M, Von Goetz N, da Cruz C, Merten C, Mosbach-Schulz O, Lahaniatis M, Smith A, Hardy A. 2019. Guidance on communication of uncertainty in scientific assessments. EFSA J. 17:5520.
   Web of Science ®Google Scholar
• Escher BI, Neale PA, Leusch FDL. 2015. Effect-based trigger values for in vitro bioassays: reading across from existing water quality guideline values. Water Res. 81:137–148.
   PubMed Web of Science ®Google Scholar
• Escher BI, Hackermüller J, Polte T, Scholz S, Aigner A, Altenburger R, Böhme A, Bopp SK, Brack W, Busch W, et al. 2017. From the exposome to mechanistic understanding of chemical-induced adverse effects. Environ Int. 99:97–106.
   PubMed Web of Science ®Google Scholar
• Escher BI, Aït-Aïssa S, Behnisch PA, Brack W, Brion F, Brouwer A, Buchinger S, Crawford SE, Du Pasquier D, Hamers T, et al. 2018. Effect-based trigger values for in vitro and in vivo bioassays performed on surface water extracts supporting the environmental quality standards (EQS) of the European Water Framework Directive. Sci Tot Environ. 628–629:748–765.
   PubMed Web of Science ®Google Scholar
• Evans RM, Scholze M, Kortenkamp A. 2015. Examining the feasibility of mixture risk assessment: a case study using a tiered approach with data of 67 pesticides from the Joint FAO/WHO Meeting on Pesticide Residues (JMPR). Food Chem Toxicol. 84:260–269.
   PubMed Web of Science ®Google Scholar
• Evans RM, Martin OV, Faust M, Kortenkamp A. 2016. Should the scope of human mixture risk assessment span legislative/regulatory silos for chemicals? Sci Total Environ. 543:757–764.
   PubMed Web of Science ®Google Scholar
• Ferguson KK, Peterson KE, Lee JM, Mercado-García A, Blank-Goldenberg C, Téllez-Rojo MM, Meeker JD. 2014. Prenatal and peripubertal phthalates and bisphenol A in relation to sex hormones and puberty in boys. Reprod Toxicol. 47:70–76.
   PubMed Web of Science ®Google Scholar
• Goodson WH, Lowe L, Carpenter DO, Gilbertson M, Manaf Ali A, Lopez de Cerain Salsamendi A, Lasfar A, Carnero A, Azqueta A, Amedei A, et al. 2015. Assessing the carcinogenic potential of low-dose exposures to chemical mixtures in the environment: the challenge ahead. Carcinogenesis. 36:S254–S296.
   PubMed Web of Science ®Google Scholar
• Gustavsson M, Kreuger J, Bundschuh M, Backhaus T. 2017. Pesticide mixtures in the Swedish streams: environmental risks, contributions of individual compounds and consequences of single-substance oriented risk mitigation. Sci Tot Environ. 598:973–983.
   PubMed Web of Science ®Google Scholar
• Hadrup N, Svingen T, Mandrup K, Skov K, Pedersen M, Frederiksen H, Frandsen HL, Vinggaard AM. 2016. Juvenile male rats exposed to a low-dose mixture of twenty-seven environmental chemicals display adverse health effects. PLoS One. 11:e0162027.
   PubMed Web of Science ®Google Scholar
• Han X, Price PS. 2011. Determining the maximum cumulative ratios for mixtures observed in ground water wells used as drinking water supplies in the United States. Int J Environ Res Public Health. 8:4729–4745.
   PubMed Web of Science ®Google Scholar
• Han X, Price PS. 2013. Applying the maximum cumulative ratio methodology to biomonitoring data on dioxin-like compounds in the general public and two occupationally exposed populations. J Expo Sci Environ Epidemiol. 23:343–349.
   PubMed Web of Science ®Google Scholar
• Hanahan D, Weinberg RA. 2000. The hallmarks of cancer. Cell. 100:57–70.
   PubMed Web of Science ®Google Scholar
• Hanahan D, Weinberg RA. 2011. Hallmarks of cancer: the next generation. Cell. 144:646–674.
   PubMed Web of Science ®Google Scholar
• Hernández AF, Gil F, Lacasaña M. 2017. Toxicological interactions of pesticide mixtures: an update. Arch Toxicol. 91:3211–3223.
   PubMed Web of Science ®Google Scholar
• Heys KA, Shore RF, Pereira MG, Jones KC, Martin FL. 2016. Risk assessment of environmental mixture effects. RSC Adv. 6:47844–47857.
   Web of Science ®Google Scholar
• Hines DE, Edwards SW, Conolly RB, Jarabek AM. 2018. A case study application of the aggregate exposure pathway (AEP) and adverse outcome pathway (AOP) frameworks to facilitate the integration of human health and ecological end points for cumulative risk assessment (CRA). Environ Sci Technol. 52:839–849.
   PubMed Web of Science ®Google Scholar
• IGHRC. 2009. Chemical Mixtures: A Framework for Assessing Risk to Human Health (CR14). Cranfield University, UK: Institute of Environment and Health. http://www.iehconsulting.co.uk/IEH_Consulting/IEHCPubs/IGHRC/cr14.pdf
   Google Scholar
• Johnson AC, Sumpter JP. 2016. Are we going about chemical risk assessment for the aquatic environment the wrong way? Environ Toxicol Chem. 35:1609–1616.
   PubMed Web of Science ®Google Scholar
• Kapraun DF, Wambaugh JF, Ring CL, Tornero-Velez R, Woodrow Setzer R. 2017. A method for identifying prevalent chemical combinations in the U.S. population. Environ Health Perspect 125:1–16.
   PubMed Web of Science ®Google Scholar
• Kemi. 2015. An additional assessment factor (MAF) – a suitable approach for improving the regulatory risk assessment of chemical mixtures? Stockholm. Report 5/15. Swedish Chemicals Agency, Stockholm, Sweden.
   Google Scholar
• Kienzler A, Berggren E, Bessems J, Bopp S, van der Linden S, Worth A. 2014. Assessment of mixtures - review of regulatory requirements and guidance. JRC Science for Policy Report, EUR 26675EN. Luxembourg: Publications Office of the European Union.
   Google Scholar
• Kienzler A, Bopp SK, van der Linden S, Berggren E, Worth A. 2016. Regulatory assessment of chemical mixtures: Requirements, current approaches and future perspectives. Regul Toxicol Pharmacol 80:321–334.
   PubMed Web of Science ®Google Scholar
• Kienzler A, Bopp SK, Halder M, Embry M, Worth A. 2019. Application of new statistical distribution approaches for environmental mixture risk assessment: a case study. Submitted to Sci Tot Env.
   Google Scholar
• Kim J, Kim S. 2015. State of the art in the application of QSAR techniques for predicting mixture toxicity in environmental risk assessment. SAR QSAR Environ Res. 26:41–59.
   PubMed Web of Science ®Google Scholar
• Kortenkamp A, Backhaus T, Faust M. 2009. State of the Art Report on Mixture Toxicity. Final Report. 22 December 2009. Study Contract Number 070307/2007/485103/ETU/D.1
   Google Scholar
• Kortenkamp A, Faust M. 2010. Combined exposures to anti-androgenic chemicals: steps towards cumulative risk assessment. Int J Androl. 33:463–472.
   PubMed Web of Science ®Google Scholar
• Kortenkamp A, Faust M. 2018. Regulate to reduce chemical mixture risk. Science. 361:224–225.
   PubMed Web of Science ®Google Scholar
• Kristensen SL, Ramlau-Hansen CH, Ernst E, Olsen SF, Bonde JP, Vested A, Halldorsson TI, Rantakokko P, Kiviranta H, Toft G. 2016. Prenatal exposure to persistent organochlorine pollutants and female reproductive function in young adulthood. Environ Int. 92–93:366–372.
   PubMed Web of Science ®Google Scholar
• Lindim C, van Gils J, Cousing IT. 2016. A large scale model for simulating the fate & transport of organic contaminants in river basins. Chemosphere. 144:803–810.
   PubMed Web of Science ®Google Scholar
• Malaj E, von der Ohe PC, Grote M, Kühne R, Mondy CP, Usseglio-Polatera P, Brack W, Schäfer RB. 2014. Organic chemicals jeopardize the health of freshwater ecosystems on the continental scale. Proc Natl Acad Sci U S A. 111:9549–9554.
   PubMed Web of Science ®Google Scholar
• Martin OV, Bopp S, Ermler S, Kienzler A, McPhie J, Paini A, Parrisis N, Richarz AN, Scholze M, van der Linden S, et al. 2018. Protocol for a systematic review of ten years of research on interactions in chemical mixtures of environmental pollutants. doi:10.5281/zenodo.1319759.
   Google Scholar
• Martino-Andrade AJ, Liu F, Sathyanarayana S, Barrett ES, Redmon JB, Nguyen RHN, Levine H, Swan SH. 2016. Timing of prenatal phthalate exposure in relation to genital endpoints in male newborns. Andrology. 4:585–593.
   PubMed Web of Science ®Google Scholar
• Marx C, Mühlbauer V, Krebs P, Kuehn V. 2015. Environmental risk assessment of antibiotics including synergistic and antagonistic combination effects. Sci Tot Environ. 524–525:269–279.
   PubMed Web of Science ®Google Scholar
• McCarty LS, Borgert CJ. 2006. Review of the toxicity of chemical mixtures: theory, policy, and regulatory practice. Regul Toxicol Pharmacol. 45:119–143.
   PubMed Web of Science ®Google Scholar
• Meek ME, Boobis AR, Crofton KM, Heinemeyer G, Raaij MV, Vickers C. 2011. Risk assessment of combined exposure to multiple chemicals: A WHO/IPCS framework. Regul Toxicol Pharmacol. 60:S1–S14.
   PubMed Web of Science ®Google Scholar
• Mons MN, Heringa MB, van Genderen J, Puijker LM, Brand W, van Leeuwen CJ, Stoks P, van der Hoek JP, van der Kooij D. 2013. Use of the Threshold of Toxicological Concern (TTC) approach for deriving target values for drinking water contaminants. Water Res. 47:1666–1678.
   PubMed Web of Science ®Google Scholar
• Moretto A, Bachman A, Boobis A, Solomon KR, Pastoor TP, Wilks MF, Embry MR. 2017. A framework for cumulative risk assessment in the 21st century. Crit Rev Toxicol. 47:85–97.
   PubMed Web of Science ®Google Scholar
• Napierska D, Sanseverino I, Loos R, Cortés LG, Niegowska M, Lettieri T. 2018. Modes of action of the current priority substances list under the water framework directive and other substances of interest review of the relevant modes of action. EUR29008 EN, Publications Office of the European Union, Luxembourg, ISBN 978-92-79-77301-3, doi:10.2760/226911.
   Google Scholar
• Neale PE, Ait-Aissa S, Brack W, Creusot N, Denison MS, Deutschmann B, Hilscherova K, Hollert H, Krauss M, Novak J, et al. 2015. Linking in vitro effects and detected organic micropollutants in surface water using mixture-toxicity modeling. Environ Sci Technol. 49:14614–14624.
   PubMed Web of Science ®Google Scholar
• Nienstedt KM, Brock TC, van Wensem J, Montforts M, Hart A, Aagaard A, Alix A, Boesten J, Bopp SK, Brown C, et al. 2012. Development of a framework based on an ecosystem services approach for deriving specific protection goals for environmental risk assessment of pesticides. Sci Total Environ. 415:31–38.
   PubMed Web of Science ®Google Scholar
• OECD. 2013. Guidance document on developing and assessing adverse outcome pathways. Series on testing and assessment no. 184. Organisation for Economic Co-operation and Development, Paris, France. http://www.oecd.org/officialdocuments/publicdisplaydocumentpdf/?cote=env/jm/mono(2013)6&doclanguage=en.
   Google Scholar
• OECD. 2018. Considerations for assessing the risks of combined exposure to multiple chemicals. Series on testing and assessment no. 296. Environment, Health and Safety Division, Environment Directorate. Paris, France: Organisation for Economic Co-operation and Development.
   Google Scholar
• Oldenkamp R, Hoeks S, Čengić M, Barbarossa V, Burns EE, Boxall ABA, Ragas AMJ. 2018. A high-resolution spatial model to predict exposuire to pharmaceuticals in european surface waters: ePiE. Environ Sci Technol. 52:12494–12503.
   PubMed Web of Science ®Google Scholar
• Posthuma L, De Zwart D, Keijzers R, Postma J. 2016. Watersysteemanalyse met de Ecologische Sleutelfactor Toxiciteit Deel 2. Kalibratie: toxische druk en ecologische effecten op macrofauna. STOWA rapport number: 2016-15 B. Stichting toegepast Onderzoek Waterbeheer, Amersfoort, The Netherlands. ISBN 978.90.5773.727.5
   Google Scholar
• Posthuma L, Brown CD, de Zwart D, Diamond J, Dyer SD, Holmes CM, Marshall S, Burton Jr. GA. 2018. Prospective mixture risk sssessment and management prioritizations for river catchments with diverse land uses. Env Tox Chem. 37:715–728.
   PubMed Web of Science ®Google Scholar
• Price PS, Hollnagel HM, Zabik JM. 2009. Characterizing the noncancer toxicity of mixtures using concepts from the TTC and quantitative models of uncertainty in mixture toxicity. Risk Anal. 29:1534–1548.
   PubMed Web of Science ®Google Scholar
• Price PS, Han X. 2011. Maximum cumulative ratio (MCR) as a tool for assessing the value of performing a cumulative risk assessment. Int J Environ Res Public Health. 8:2212–2225.
   PubMed Web of Science ®Google Scholar
• Price P, Dhein E, Hamer M, Han X, Heneweer M, Junghans M, Kunz P, Magyar C, Penning H, Rodriguez C. 2012a. A decision tree for assessing effects from exposures to multiple substances. Environ Sci Eur. 24:26.
   Google Scholar
• Price P, Han X, Junghans M, Kunz P, Watts C, Leverett D. 2012b. An application of a decision tree for assessing effects from exposures to multiple substances to the assessment of human and ecological effects from combined exposures to chemicals observed in surface waters and waste water effluents. Environ Sci Eur. 24:36.
   Google Scholar
• Price P, Zaleski R, Hollnagel H, Ketelslegers H, Han X. 2014. Assessing the safety of co-exposure to food packaging migrants in food and water using the maximum cumulative ratio and an established decision tree. Food Addit Contam Part A Chem Anal Control Expo Risk Assess. 31:414–421.
   PubMed Web of Science ®Google Scholar
• Reyes JM, Price PS. 2018. An analysis of cumulative risks based on biomonitoring data for six phthalates using the Maximum Cumulative Ratio. Environ Int. 112:77–84.
   PubMed Web of Science ®Google Scholar
• Rider CV, Boekelheide K, Catlin N, Gordon CG, Morata T, Selgrade MJK, Sexton K, Simmons JE. 2014. Cumulative risk: toxicity and interactions of physical and chemical stressors. Toxicol Sci.137:3–11.
   PubMed Web of Science ®Google Scholar
• Rodea-Palomares I, Gonzalez-Pleiter M, Martin-Betancor K, Rosal R, Fernandez-Pinas F. 2015. Additivity and interactions in ecotoxicity of pollutant mixtures: some patterns, conclusions, and open questions. Toxics. 3:342–369.
   PubMed Web of Science ®Google Scholar
• Rotter S, Beronius A, Boobis AR, Hanberg A, van Klaveren J, Luijten M, Machera K, Nikolopoulou D, van der Voet H, Zilliacus J, et al. 2018. Overview on legislation and scientific approaches for risk assessment of combined exposure to multiple chemicals: the potential EuroMix contribution. Crit Rev Toxicol. 48:796–781. doi:10.1080/10408444.2018.1541964
   PubMed Web of Science ®Google Scholar
• Sarigiannis DA, Hansen U. 2012. Considering the cumulative risk of mixtures of chemicals - a challenge for policy makers. Environ Health. 11(Suppl 1):S18.
   PubMedGoogle Scholar
• SCHER, SCENIHR, SCCS. 2012. Toxicity and assessment of chemical mixtures. European Union. doi:10.2772/21444
   Google Scholar
• 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.
   PubMed Web of Science ®Google Scholar
• Swan SH, Sathyanarayana S, Barrett ES, Janssen S, Liu F, Nguyen RH, Redmon JB. 2015. First trimester phthalate exposure and anogenital distance in newborns. Hum Reprod. 30:963–972.
   PubMed Web of Science ®Google Scholar
• Tang JYM, Busetti F, Charrois JWA, Escher BI. 2014. Which chemicals drive biological effects in waste water and recycled water? Water Res. 60:289–299.
   PubMed Web of Science ®Google Scholar
• Teeguarden JG, Tan YM, Edwards SW, Leonard JA, Anderson KA, Corley RA, Kile ML, Simonich SM, Stone D, Tanguay RL, et al. 2016. Completing the link between exposure science and toxicology for improved environmental health decision making: the aggregate exposure pathway framework. Environ Sci Technol. 50:4579–4586.
   PubMed Web of Science ®Google Scholar
• US EPA (Environmental Protection Agency). 2014 Apr. Framework for human health risk assessment to inform decision making. U.S. Environmental Protection Agency, Risk Assessment Forum. EPA/100/R-14/001. http://www.epa.gov/sites/production/files/2014-12/documents/hhra-framework-final-2014.pdf
   Google Scholar
• van Broekhuizen FA, Posthuma L, Traas TP. 2016. Addressing combined effects of chemicals in environmental safety assessment under REACH - a thought starter. RIVM Letter report 2016-0162, National Institute for Public Health and the Environment, Bilthoven, The Netherlands.
   Google Scholar
• WHO International Programme on Chemical Safety (IPCS). 2017. Guidance document on evaluating and expressing uncertainty in hazard characterization. 2nd ed. Geneva, Switzerland: World Health Organization. Harmonization Project Document No. 11.
   Google Scholar