UNIVERSITY OF CALIFORNIA RIVERSIDE A Screening-Level Hazard Assessment of Human and Environmental Health Endpoints of Halogenated and Organophosphate Flame Retardants A Thesis submitted in partial satisfaction of the requirements for the degree of Master of Science in Environmental Toxicology by Seth Rojello Fernández March 2019 Thesis Committee: Dr. David Eastmond, Chairperson Dr. Carl Cranor Dr. David Volz Copyright by Seth Rojello Fernández 2019 The Thesis of Seth Rojello Fernández is approved: Committee Chairperson University of California, Riverside Acknowledgments I would like to thank Dr. David Eastmond for his unwavering support and guidance during my progress towards this degree and as my major adviser. His expertise and know-how made this thesis possible. Even before I entered his research group he has been a genuine champion on my behalf. His door is always open for my ceaseless questions and wonderings. In his research group, I have grown as a scientist, a writer, a thinker, and as a person. For this, I cannot give enough thanks. I would like to thank the members of my thesis committee, Dr. Carl Cranor and Dr. David Volz for their commitment and flexibility as I have undergone this process. Also, for their unique viewpoints and expertise on the subject matter. I would like to thank my parents, Ivan and Melissa Fernández for their thoughts and prayers as I have gone through my educational career. They have been vital for my success and a place of comfort. They have supported me as I moved across the country and to other countries in the pursuit of knowledge. Furthermore, I would also like to thank Hector Godoy for always listening to me and making sure that I did not become too wrapped up in my work. He was always there when I wanted to quit and made sure that I kept my priorities straight. From the trips to the beach and to see snow his friendship has made all the difference. Because of you, I will always keep swimming. I would like to acknowledge the Lord my God for always seeing me through. iv Dedication I dedicate this thesis to Dr. Deirdre Hill. You believed in me before I knew what to believe in. v ABSTRACT OF THE THESIS A Screening-Level Hazard Assessment of Human and Environmental Health Endpoints of Halogenated and Organophosphate Flame Retardants by Seth Rojello Fernández Master of Science, Graduate Program in Environmental Toxicology University of California, Riverside, March 2019 Dr. David Eastmond, Chairperson ABSTRACT Organohalogen flame retardants are extensively used in both industrial and consumer products but now are being phased out of circulation by both state governments and the United States Federal government. Organophosphate flame retardants have been chosen as the replacement for the halogenated flame retardants. However, relatively little is known about the potential hazard of these class of chemicals to cause adverse health and environmental effects. To address this, we conducted a health and environmental hazard screening of 90 halogenated and 97 organophosphate flame retardants based on the GreenScreen® or Quick Chemical Assessment Tool (QCAT©) methodologies. Priority consideration was given to human health hazards including carcinogenicity (including mutagenicity and genetic toxicity), reproductive or developmental toxicity, endocrine disruption, and acute mammalian toxicity. Environmental hazards given priority consideration included acute aquatic toxicity, persistence, and bioaccumulation. Using publicly available information, each hazard category was assigned a concern level (very-low, low, moderate, high, or very high) based on pre-defined numerical ranges, vi such as no-observed adverse effect levels and hazard classification schemes from authoritative sources, when available. Where empirical data were not identified, quantitative structure-activity relationship (QSAR) models were relied upon to predict hazard potential. After assigning concern levels for each priority health effect, each chemical received a score, similar to a report card (A, B, C, or F). The majority of the screened chemicals received an F grade due to empirical data suggesting high hazard, QSAR model predictions, and/or excessive data gaps. Acute Mammalian Toxicity was the most prominent potential health hazard identified based on empirical data. The most prevalent data gap was found in both reproductive toxicity and endocrine disruption endpoints due to the lack of identified empirical data or computer models able to predict this hazard. This study highlights the limited toxicity information available for these widely used chemical classes and indicates that more testing and oversight is critically needed to identify safer alternatives for fire prevention. vii Table of Contents General Introduction 1 Chapter 1 5 Introduction 6 Hazard Screening Method 9 Materials and Methods 11 QCAT© Method 11 Flame Retardant / Compounds of Interest List 13 Hazard Categories 13 Public Database Searches for Toxicity Data 14 Modeling Software 15 Assigning Initial Grades 16 Assigning Final Grades / Benchmark Scores 17 Results 20 Acute Mammalian Toxicity 22 Carcinogenicity 24 Mutagenicity 26 Reproductive / Developmental Toxicity 28 Endocrine Disruption 31 Acute Aquatic Toxicity 33 Persistence 35 Bioaccumulation 37 Overall Assessment 39 Discussion 40 Environmental Quality Endpoints 41 Endocrine Disruption 42 Chemical Class Assessment 43 Limitations of QCAT© 46 Conclusion 47 References 48 Appendix 53 viii Chapter 2 54 Introduction 55 Materials and Methods 58 Hazard Screening Methodology 58 Flame Retardant List 58 Public Database Searches for Toxicity Data 59 Initial Grade 60 Significance Testing 62 Results 63 Acute Mammalian Toxicity 66 Carcinogenicity 69 Reproductive and Developmental Toxicity 71 Mutagenicity and Genetic Toxicity 73 Endocrine Disruption 75 Acute Aquatic Toxicity 77 Persistence 79 Bioaccumulation 81 GreenScreen® 83 Overall Assessment 84 Discussion 85 Notable Organophosphates and Impacts 87 Organophosphates as Replacements 89 References – Chapter 2 91 General Conclusion 96 General Introduction & Conclusion References 99 Appendixes 101 Chapter 1 Appendixes 101 Appendix 1: OHFR of Interest 101 Appendix 2: OHFR Full Data Tables 106 Appendix 3: Systematic Process Chart 107 Appendix 4: OHFR Qualitative Data 108 Chapter 2 Appendixes 109 Appendix 1: QCAT© Process Flow Chart 109 Appendix 2: OPFR of Interest 110 Appendix 3: List of Databases Used 114 ix Appendix 4: OPFR Full Data Tables 117 Appendix 5: Wilcox Test and Bonferroni’s Test 118 Appendix 6: OPFR Qualitative Data 119 x List of Figures Chapter 1 Figure 1: QCAT© Process 12 Figure 2: Halogen Flame Retardants Heat Map 21 Figure 3: Acute Mammalian Toxicity 23 Figure 4: Carcinogenicity Data 25 Figure 5: Mutagenicity/Genetic Toxicity Data 27 Figure 6: Reproductive Toxicity Data 30 Figure 7: Developmental Toxicity Data 30 Figure 8: Endocrine Disruption Data 32 Figure 9: Acute Aquatic Toxicity Data 34 Figure 10: Persistence Data 36 Figure 11: Bioaccumulation Data 38 Chapter 2 Figure 12: QCAT© Grading Rubric 60 Figure 13: OPFR Heat Map 64 Figure 14: Acute Mammalian Toxicity Data 68 Figure 15: Carcinogenicity Data 70 Figure 16: Reproductive Toxicity Data 72 Figure 17: Developmental Toxicity Data 72 Figure 18: Mutagenicity Data 74 Figure 19: Endocrine Disruption Data 76 Figure 20: Acute Aquatic Toxicity Data 78 Figure 21: Persistence Data 80 Figure 22: Bioaccumulation 81 xi List of Tables Chapter 1 Table 1: QCAT© Endpoints 13 Table 2: Acute Mammalian Toxicity Data 22 Table 3: Carcinogenicity Data 24 Table 4: Mutagenicity/Genetic Toxicity Data 26 Table 5: Reproductive Toxicity Data 28 Table 6: Developmental Toxicity Data 28 Table 7: Endocrine Disruption Data 31 Table 8: Acute Toxicity Data 33 Table 9: Persistence Data 35 Table 10: Bioaccumulation Data 37 Table 11: OHFR Final Grade 39 Chapter 2 Table 12: Tris-Family 56 Table 13: Acute Mammalian Toxicity Data 66 Table 14: Carcinogenicity Data 69 Table 15: Reproductive Toxicity Data 71 Table 16: Developmental Toxicity Data 71 Table 17: Mutagenicity Data 73 Table 18: Endocrine Disruption Data 75 Table 19: Acute Aquatic Toxicity Data 77 Table 20: Persistence Data 79 Table 21: Bioaccumulation Data 81 Table 22: OPFR Hazard Scores 84 Table 23: GreenScreen® and DfE Scores 87 Table 24: OHFR and OPFR Average Scores 89 xii General Introduction The Federal Drug and Food Administration regulates food products and medical drugs. In this way, the United States government is proactive in regulating chemical compounds that are allowed into circulation. In regards to consumer products such as sofas, electronics, and baby products, the regulatory system is much more passive or reactive. Commonly, the way a chemical is phased out or limited in its use is after public health has been, or perceived to have been, negatively impacted, which is typically associated with a lack of adequate toxicological testing prior to its use. A notable example of this is the introduction of tris-(2, 3-dibromopropyl) phosphate (tris-BP) into children’s pajamas during the 1970s. Tris-BP was thought to be a totally safe and effective flame retardant in these pajamas but was discovered to have mutagenic and potentially carcinogenic effects on children (Blum & Ames, 1977). A year later another member of the tris-family was discovered by the same research group to have potential cancer-causing effects (Gold, Blum, & Ames, 1978). These toxic chemicals were phased out but were replaced with other compounds with unknown toxicities. This trend has continued to this day with