A Comprehensive Overview of Edcs and Ppcps in Water

A Comprehensive Overview of EDCs and PPCPs in Water

Web Report #4387b

Subject Area: Management and Customer Relations A Comprehensive Overview of EDCs and PPCPs in Water

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Prepared by: Gretchen M. Bruce and Richard C. Pleus Intertox, Inc., 600 Stewart Street, Seattle, WA 98101

Sponsored by: Water Research Foundation 6666 West Quincy Avenue, Denver, CO 80235-3098

Published by:

This study was funded by the Water Research Foundation (WRF). WRF assumes no responsibility for the content of the research study reported in this publication or for the opinions or statements of fact expressed in the report. The mention of trade names for commercial products does not represent or imply the approval or endorsement of WRF. This report is presented solely for informational purposes.

Printed in the U.S.A.

LIST OF TABLES ...... ix

LIST OF FIGURES ...... xiii

FOREWORD ...... xv

ACKNOWLEDGMENTS ...... xvii

EXECUTIVE SUMMARY ...... xix

CHAPTER 1: INTRODUCTION ...... 1 Overview ...... 1 Background ...... 1 Project Goals ...... 1 Organization of This Report ...... 2

CHAPTER 2: METHODS AND MATERIALS ...... 5 Literature Review of Sources and Occurrence of PPCPs and EDCs in Water ...... 5 Literature Review of Potential Toxicological Significance and Human Health Effects of Detected PPCPs and EDCs ...... 6 Identification of Acceptable Daily Intakes (ADIs) and Drinking Water Equivalent Levels (DWELs) ...... 7 Summarize Status of Federal and State Legislation, Regulations, and Programs Addressing PPCPs and EDCs in Water ...... 7 Summarize Treatment Options and Source Water Protection Approaches ...... 8 Characterize Monitoring and Communication Approaches Applied by Drinking Water Utilities ...... 8

CHAPTER 3: SOURCES AND OCCURRENCE OF PPCPS AND EDCS IN WATER ...... 11 What are PPCPs and EDCs? ...... 11 Sources and Increasing Detection of PPCPs and EDCs in Water ...... 12 Compilation and Statistical Treatment of Data ...... 14 Additional Sources of Information on Sources and Occurrence ...... 39

CHAPTER 4: POTENTIAL TOXICOLOGICAL SIGNIFICANCE AND HUMAN HEALTH EFFECTS OF PPCPS AND EDCS IN DRINKING WATER ...... 41 Evidence for Adverse Effects of PPCPs or EDCs in Drinking Water or the Environment on Human Health ...... 41 The Dose-Response Concept ...... 44 Identification of Existing MCLs or ADIs ...... 46 Methods for Deriving Screening Levels ...... 46 Derivation of Comparison Levels Using NOAELs or LOAELs from Toxicity Studies ...... 49

©2015 Water Research Foundation. ALL RIGHTS RESERVED. Derivation of Comparison Levels Based on the Lowest Therapeutic Doxe of Pharmaceuticals ...... 50 Derivation of Comparison Levels for Antibiotics Based on Minimum Inhibitory Concentrations ...... 50 Derivation of Comparison Levels for Carcinogenicity Based on Tumor Incidence Data ...... 51 Derivation of a Virtually Safe Dose for Carcinogens ...... 52 Derivation of Comparison Levels Based on Thresholds of Toxicologic Concern ...... 52 Conversion of the Lowest Comparison Level to a DWEL ...... 54 Summary of Identified ADIs and DWELs ...... 54 Comparison of Drinking Water Concentrations to DWELs ...... 68 Characterization of “Highest Risk” Compounds ...... 76 17α-Ethynylestradiol ...... 76 Atrazine ...... 77 Estrone ...... 78 Assessing Total Exposure from Water, Diet, and Other Sources ...... 80 Studies that Evaluate Exposures to Multiple Sources of PPCPs or EDCs ...... 80 Studies that Evaluate Exposure to Mixtures of PPCPs and EDCs...... 89 Risk Assessment Approaches to Predict Potential Effects of Mixtures or Multiple Source Exposure ...... 91 Other Effects: Antimicrobial Resistance ...... 93 Relevant Water Research Foundation Projects ...... 94 Additional Sources of Information on Health-Based Exposure Limits and Potential Health Effects ...... 95

CHAPTER 5: STATUS OF FEDERAL AND STATE LEGISLATION, REGULATIONS, AND PROGRAMS ...... 97 Federal Legislation and Regulation Addressing PPCPs and EDCs in Water ...... 97 EPA Water Legislation and Regulations ...... 97 Federal Waste Legislation and Regulations ...... 108 Drug Enforcement Agency (DEA) Legislation and Regulations ...... 111 Federal Guidance and Other Resources ...... 111 EPA ...... 111 Food and Drug Administration (FDA) ...... 112 State-Specific Programs Addressing PPCPs and EDCs in Drinking Water ...... 113 California ...... 113 Massachusetts ...... 114 Minnesota ...... 114 New Jersey ...... 120 State Legislation and Regulations Addressing Prescription Drug Return, Recycling, or Disposal ...... 120 Other State Programs Addressing Exposures to Contaminants of Emerging Concern ...... 126 PPCP and EDC Research ...... 126

CHAPTER 6: TREATMENT APPROACHES AND SOURCE WATER PROTECTION ...... 139 Summary of Effectiveness of Treatment Technologies ...... 139 Relevant Water Research Foundation Projects ...... 139 Summary of Literature Review of Treatment Technologies ...... 143 Source Water Protection Programs ...... 166 The Multibarrier Approach to Source Water Protection ...... 167 Examples of Options for Source Water Protection Programs ...... 167 Relevant Water Research Foundation Projects ...... 175 Water Protection Practices for the Public ...... 176 Animal Wastes ...... 176 Boating ...... 176 Disposal of Household Hazard Wastes ...... 176 Disposal of Medications ...... 177 Erosion Control ...... 177 Fertilizers and Pesticides...... 177 Household Cleaning Products ...... 177 Septic Systems ...... 178 Vehicle Washing ...... 178 Water Use and Gardening ...... 178 Additional Sources of Information on Treatment Technologies and Source Water Protection ...... 179

CHAPTER 7: MONITORING AND COMMUNICATION APPROACHES APPLIED BY DRINKING WATER UTILITIES ...... 181 Monitoring Approaches Implemented by Utilities ...... 181 Design of Monitoring Programs for PPCPs and EDCs in Water...... 193 Selection of Compounds to Monitor ...... 194 Determination of Sufficient Analytical Method Reporting Limits ...... 202 Motivation for Monitoring and Risk Communications ...... 202 Relevant Water Research Foundation Projects ...... 202 Approaches to Communicating PPCP and EDC Water Monitoring Results ...... 204 Examples of Utility Risk Communication on PPCPs and EDCs in Water ...... 204 Recommendations for Communication of Information about PPCPs and EDCs in Water ...... 208 Relevant Water Research Foundation Projects ...... 218 Additional Sources of Information on Monitoring and Communication for PPCPs and EDCs in Water ...... 221

CHAPTER 8: SUMMARY AND CONCLUSIONS ...... 223 Sources and Occurrence ...... 223 Toxicological Significance ...... 223 Federal and State Legislation and Regulations ...... 224 Treatment Approaches and Source Water Protection ...... 225

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CHAPTER 9: RECOMMENDATIONS FOR UTILITIES ...... 227

REFERENCES ...... 229

ABBREVIATIONS ...... 267

APPENDIX A: SUPPORTING DOCUMENTATION ON RELATIVE OCCURANCE OF SUBSTANCES IN WATER...... 273

APPENDIX B: SUPPORTING DOCUMENTATION FOR CHARACTERIZING POTENTIAL TOXICOLOGICAL SIGNIFICANCE AND HUMAN HEALTH EFFECTS ...... 281

APPENDIX C: INFORMATION FROM UTILITIES ON RATIONALE FOR MONITORING AND RISK COMMUNICATION OF CECS ...... 363

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3.1 Hormone-producing organs of the human endocrine system ...... 12

3.2 Summary of sources of compiled occurrence data ...... 15

3.3 Numbers of distinct PPCPs detected vs. analyzed, by compound group and water type (based on compiled data from sources identified in Table 3.2) ...... 18

3.4 Numbers of distinct EDCs and non-PPCPs detected vs. analyzed, by compound group and water type (based on compiled data from sources identified in Table 3.2) ... 19

3.5 Summary of PPCPs identified as detected in drinking water (based on compiled data from sources identified in Table 3.2) ...... 20

3.6 Summary of PPCPs detected in DWTP influent (based on compiled data from sources identified in Table 3.2) ...... 21

3.7 Summary of PPCPs detected in surface water (based on compiled data from sources identified in Table 3.2) ...... 22

3.8 Summary of EDCs detected in drinking water (based on compiled data from sources identified in Table 3.2) ...... 25

3.9 Summary of occurrence data for the most frequently detected EDCs and other nonPPCPs in surface water and DWTP influent (average frequency of detection of 25% or more, based on compiled data from sources identified in Table 3.2) ...... 28

3.10 Detection frequencies of PPCPs detected in drinking water compared to DWTP influent and surface water (based on compiled data from sources identified in Table 3.2) ...... 30

3.11 Detection frequencies of PPCPs detected in DWTP influent or surface water but not drinking water (based on compiled data from sources identified in Table 3.2) ... 31

4.1 Summary of suspected endocrine modes of action for selected EDCs, based on studies in animals or humans ...... 43

4.2 Approximate acute LD50s of representative chemical agents ...... 45

4.3 DWELs for PPCPs derived using the decision tree approach ...... 55

4.4 DWELs for EDCs derived using the decision tree approach ...... 61

4.6 Comparison of Drinking Water Equivalent Levels (DWELs) and highest level detected in drinking water for EDCs ...... 70

4.7 Amount of water required to consume to equal amount in one typical pill or exposure unit, at maximum concentration of PPCPs or EDCs detected in drinking water ...... 74

4.8 Number of years of exposure to equal dose in one typical pill or exposure unit, at maximum concentration of PPCPs or EDCs detected in drinking water (assuming 2 L water/d) ...... 75

4.9 Selected studies on PPCP ingredients and EDCs in fish ...... 81

4.10 PPCPs detected in fish tissues...... 82

4.11 Margin of safety compared to Schwab et al. (2005) ADIs for exposure to PCPPs in drinking water, fish, and drinking water and fish combined for children ...... 83

4.12 Margin of safety for children exposed to neuropharmaceuticals ...... 84

4.13 Bioaccumulation of PPCPs in fish ...... 85

4.14 Bioaccumulation of PPCPs in cabbage leaves and roots ...... 86

4.15 Contribution of drinking water and foods to human daily dose ...... 86

4.16 Estimated geometric mean dermal intakes of EDCs from personal care products by U.S. women (ng/d) ...... 88

4.17 Selected studies of toxicological effects from mixtures of PPCP ingredients and EDCs ...... 90

4.18 Estimated relative estrogenic potencies of four estrogenic compounds in wastewater, based on the rYES in vitro assay ...... 91

4.19 Published relative source contribution (RSC) factors for EDCs and PPCPs in drinking water ...... 93

5.1 Summary of federal current or proposed legislation, regulations, and guidance impacting PPCPs and EDCs in source or drinking water or their disposal ...... 99

5.2 Potential EDCs regulated by the National Primary Drinking Water Standards ...... 104

5.4 Contaminant Candidate List (CCL)3 EDCs and PPCPs ...... 106

5.5 2013-2015 UCMR3 compounds ...... 108

5.6 Pharmaceuticals considered hazardous waste by RCRA ...... 109

5.7 EDCs regulated under RCRA ...... 110

5.8 Drugs recommended for disposal by flushing by the FDA because they can be especially harmful to children or pets ...... 112

5.9 Selected state-specific programs specifically addressing PPCPs and EDCs in water .... 115

5.10 California Department of Public Health (CDPH) Public Health Goals (PHGs) and Maximum Contaminant Levels (MCLs) for EDCs in water ...... 118

5.11 Minnesota Department of Health (MDH) Contaminants of Emerging Concern (CEC) Program guidance values for PPCPs or EDCs in water ...... 119

5.12 Summary of state regulations regarding prescription drug return, recycling, or disposal ...... 121

5.13 International, federal, and state research programs on PPCPs and EDCs in the environment ...... 128

5.14 Other federal and state information sources on PPCPs and EDCs in the environment ...... 135

6.1 Key findings from Water Research Foundation projects on effectiveness of treatment technologies for removal of PPCPs and EDCs from drinking and source water ...... 142

6.2 PPCP and EDC removal using membrane bioreactors (MBR) alone or in combination with other treatment technologies ...... 144

6.3 PPCP and EDC removal using advanced oxidation processes (AOP) alone or in combination with other treatment technologies ...... 150

6.4 PPCP and EDC removal using reverse osmosis (RO) alone or in combination with other treatment technologies ...... 153

6.5 PPCP and EDC removal using activated carbon (AC) processes alone or in combination with other treatment technologies ...... 157

6.7 Examples of source water protection strategies/programs ...... 168

6.8 Measures of effectiveness of source water protection approaches on improving water quality ...... 174

7.1 Examples of utilities that have conducted water monitoring for PPCPs and unregulated EDCs ...... 183

7.2 Comparison of maximum detected concentrations of PPCPs that were detected in DWTP influent or surface water, but not in drinking water, to DWELs (based on data gathered in this evaluation) ...... 196

7.3 PPCPs and natural and synthetic EDCs identified as typically detected in reclaimed water ...... 197

7.4 EPA analytical methods for Contaminants of Emerging Concern in drinking water ..... 198

7.5 PPCPs analyzed by EPA Method 1694 ...... 199

7.6 Steroids and hormones analyzed by EPA Method 1698 ...... 201

7.7 Key recommendations from Water Research Foundation Projects for communications regarding CECs in source and drinking water ...... 209

7.8 Questions to establish the need and utility’s preparedness to respond to an emerging contaminant issue ...... 212

7.9 Main conclusions and recommendations regarding consumer perceptions and attitudes toward EDCs and PPCPs in drinking water (Water Research Foundation Project # 4323) ...... 213

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3.1 Number of published articles by year, containing terms “endocrine disruptor”, “endocrine disruption”, or “endocrine disrupting” ...... 14

3.2 Ranges of detected concentrations of PPCPs in drinking water...... 32

3.3 Ranges of detected concentrations of PPCPs in DWTP influent...... 33

3.4 Ranges of detected concentrations of PPCPs in surface water...... 35

3.5 Ranges of detected concentrations of EDCs in drinking water...... 37

3.6 Maximum detected concentrations of selected PPCPs in water from different sources...... 38

4.1 Decision tree for determining ADIs for substances of interest without existing criteria……………………………………………………………………….…...47

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The Water Research Foundation (WRF) is a nonprofit corporation that is dedicated to the implementation of a research effort to help utilities respond to regulatory requirements and traditional high-priority concerns of the industry. The research agenda is developed through a process of consultation with subscribers and drinking water professionals. Under the umbrella of a Strategic Research Plan, the Research Advisory Council prioritizes the suggested projects based upon current and future needs, applicability, and past work; the recommendations are forwarded to the Board of Trustees for final selection. WRF also sponsors research projects through the unsolicited proposal process; the Collaborative Research, Research Applications, and Tailored Collaboration programs; and various joint research efforts with organizations such as the U.S. Environmental Protection Agency, the U.S. Bureau of Reclamation, and the Association of California Water Agencies. This publication is a result of one of these sponsored studies, and it is hoped that its findings will be applied in communities throughout the world. The following report serves not only as a means of communicating the results of the water industry’s centralized research program but also as a tool to enlist the further support of the nonmember utilities and individuals. Projects are managed closely from their inception to the final report by WRF’s staff and large cadre of volunteers who willingly contribute their time and expertise. The Foundation serves a planning and management function and awards contracts to other institutions such as water utilities, universities, and engineering firms. The funding for this research effort comes primarily from the Subscription Program, through which water utilities subscribe to the research program and make an annual payment proportionate to the volume of water they deliver and consultants and manufacturers subscribe based on their annual billings. The program offers a cost-effective and fair method for funding research in the public interest. A broad spectrum of water supply issues is addressed by WRF’s research agenda: resources, treatment and operations, distribution and storage, water quality and analysis, toxicology, economics, and management. The ultimate purpose of the coordinated effort is to assist water suppliers to provide the highest possible quality of water economically and reliably. The true benefits are realized when the results are implemented at the utility level. WRF’s trustees are pleased to offer this publication as a contribution toward that end.

Denise Kruger Robert C. Renner, P.E. Chair, Board of Trustees Executive Director Water Research Foundation Water Research Foundation

This study would not have been possible without the insights, efforts, and dedication of a number of individuals and organizations. In particular, the research team would like to thank the Water Research Foundation project manager, Linda Reekie, who guided the project and provided key perspectives on how best to organize and present the information, and the project coordinator Valerie Roundy. We express sincere gratitude to the Project Advisory Committee members, who provided expert insights into the information that would be most valuable to water professionals, specifically Julia Battocchi of the U.S. Army Corps of Engineers, Baltimore District, Jennifer Calles of the City of Phoenix Water Services Laboratory, and Steve Schindler of the New York City Department of Environmental Protection. In addition, the authors appreciate the contributions of our utility partners, specifically Orange County Water District, Fountain Valley, California; Fairfax Water, Herndon, Virginia; and LOTT Clean Water Alliance, Olympia, Washington, for their insights on factors influencing monitoring practices, and characterization of effective communication practices. The authors would also like to thank our project team members, including Paul Chang and Stephanie Tang of Greenlind, for their assistance with preparing graphical materials for the documents. At Intertox, the project team acknowledges Heather Klintworth for her efforts in compiling and interpreting occurrence and toxicology data, and conducting quality assurance/ quality control, and Gavin Bell of Intertox, for his contributions to data entry, quality assurance and control, and formatting and proofing the documents.

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OBJECTIVES

The objective of this project was to distill and synthesize current information on pharmaceutical and personal care product (PPCPs) ingredients and endocrine disrupting compounds (EDCs) in source and drinking water. The project resulted in three deliverables: a primer, a technical summary report, and a slide deck. Drinking water utilities can use these deliverables to further their understanding of these issues and support decision-making and communication efforts. It is anticipated that these materials will serve as a benchmark for future investigations of PPCPs and EDCs in water.

BACKGROUND

As the public’s concern about the presence of PPCPs and EDCs in source and drinking water increases, utilities must design monitoring and treatment programs to address these concerns and communicate effectively with the public regarding these issues. However, the sheer volume of information on PPCPs and EDCs makes understanding the issues difficult. Hundreds of papers addressing PPCPs and EDCs in the environment and source/drinking water have been published, and increasing numbers of new industrial compounds and drugs means that the occurrence of unique PPCPs and EDCs in waste streams will likely continue. Furthermore, it is challenging to remove many of these compounds using traditional municipal wastewater treatment approaches. Increasingly sophisticated analytical methods now allow the detection of contaminants at sub-part per trillion (ppt) levels, such that even the tiniest amounts of contaminants can be detected, which leads to questions about their significance.

APPROACH

This project addressed several key questions:

 What compounds have been detected in source and drinking water, and which are likely to be detected in the future?  What are the relative potential health risks of exposure to these compounds, particularly to sensitive populations such as infants and children, pregnant women, and the immunocompromised?  How does exposure to these compounds from drinking water compare to other types of exposure?  What state and federal regulations address the presence of these compounds in the environment and in source and drinking water?  What treatment and risk reduction options are available?  How are utilities addressing these concerns, including monitoring and communication approaches?

To address these questions, the project was comprised of seven primary tasks:

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©2015 Water Research Foundation. ALL RIGHTS RESERVED. 1. Characterize the state-of-knowledge on sources and occurrence of PPCPs and EDCs in water 2. Characterize the potential toxicological significance and human health effects of these PPCPs and EDCs 3. Summarize the status of federal and state regulations related to PPCPs and EDCs in the environment and in source and drinking water 4. Summarize available treatment options and source water protection approaches 5. Characterize monitoring and communication approaches that have been taken by drinking water utilities to address PPCPs and EDCs in water, and provide guidelines for communication of these issues 6. Generate a primer summarizing this information 7. Prepare materials that utilities can use to communicate with the public about PPCPs and EDCs in drinking and source water

A detailed literature review was conducted to synthesize current knowledge on PPCPs and EDCs in source and drinking water. Hundreds of relevant literature citations were available for some topics. While the budget limitations and schedule of this project made acquiring and summarizing all of this information impossible, every effort was made to capture a breadth of data. In general, efforts focused on recent literature (published within the last 10 years). This literature review can be found in the technical report. For substances detected in drinking water, compiled toxicity information was used to determine acceptable daily intakes (ADIs) and corresponding drinking water equivalent levels (DWELs), according to a conservative scheme designed to allow rapid assignment of health- protective values. The DWELs were compared to maximum-detected drinking water concentrations that were identified in the studies compiled in this project, and then ranked in terms of potential human health risk. The reader should note that the ADIs and DWELs derived in this project are not equivalent to regulatory levels, as additional considerations are often incorporated when establishing regulatory criteria for drinking water (including feasibility and cost). Before applying these ADIs and DWELs to individual projects and circumstances, utilities should note that if water concentrations or exposure levels exceed these values, it does not mean that adverse health effects are likely or expected. More careful examination and possible refinement of these conservative ADIs and DWELs is recommended, as is closer examination of the source and occurrence of the compounds. Information on assessing health hazards from exposure to PPCPs and EDCs was also summarized, including:

 Knowledge of human and ecological effects from exposure to PPCPs or EDCs in the environment  Uptake of PPCPs and EDCs into potential food sources (e.g., fish or produce)  The relative magnitude of potential exposures from drinking water compared to other sources  Approaches for characterizing the effects of exposure to mixtures of PPCPs and EDCs  Information about the potential for antibiotic resistance

This project summarized data on the occurrence of PPCPs and EDCs in source and drinking water from over 65 sources published through 2013, on more than 440 different PPCP ingredients and putative EDCs. Data included samples collected from streams, rivers, lakes, influent and effluent from wastewater treatment plants (WWTPs), influent to drinking water treatment plants (DWTPs), finished drinking water (that has undergone treatment), and distribution drinking water (collected somewhere in the distribution system between water utility and at the tap). Data on potential health effects were compiled for each PPCP or EDC. Screening-level health-protective ADIs and DWELs were derived by applying a decision tree approach taking into account a range of possible available data types. Overall, conservative ADIs and DWELs were identified or derived for 159 non-EDC pharmaceuticals, 11 hormones, and 210 EDCs and non-pharmaceutical compounds. The assessment of potential effects of exposure to multiple sources of individual substances and to mixtures of different substances was also reviewed. To account for multiple sources of exposure, application of a relative source contribution (RSC) factor to adjust water quality criteria is recommended, with a default of 20% of the total exposure assumed to be from water when data on potential exposure sources is limited. In general, data suggest that uptake of pharmaceuticals into fish and produce is limited, but uptake of EDCs into fish or produce can be significant and result in exposures that exceed those from drinking water. Some EDCs such as surfactants and plasticizers can also leach from packaging materials into foods and beverages, potentially leading to significant exposures. Exposure to some ingredients of personal care products, such as soaps and lotions, by absorption through the skin can also occur. Under the Safe Drinking Water Act (SDWA), the U.S. Environmental Protection Agency (EPA) has set drinking water MCLs for some EDCs (primarily pesticides), but no pharmaceuticals. Two states—California and Minnesota—have drinking water regulations for some EDCs and pharmaceuticals that may be stricter than federal guidelines, and utility managers should be familiar with the regulations in their specific state. Some additional legislation to manage potential sources of PPCPs and EDCs in water has been proposed at the federal and state level, and additional regulations are possible in the future. In addition, research programs sponsored by government and state agencies continue to increase understanding of how PPCPs and EDCs behave in the environment, their potential ecological and human health risks, and treatment approaches. Water managers are advised to track ongoing legislative and regulatory activities, as well as research programs that can impact management of PPCPs and EDCs in source and drinking water. A number of treatment options have been shown to be effective in reducing or eliminating PPCPs and EDCs in waste and drinking water, with effectiveness varying according to compound type and treatment parameters. However, treatment technologies currently in place at most WWTPs and DWTPs were not designed or intended to remove PPCPs or most EDCs. Research on the relative costs and benefits of these treatment approaches is limited. Source water protection programs offer an alternative to costly treatment methodologies by preventing contamination from reaching source water supplies. Utilities can benefit from increasing public awareness on how to properly dispose of household hazardous wastes and medications, and how to implement best management practices to prevent contamination of source waters. Some major water utilities monitor source and/or treated water for emerging contaminants such as PPCPs and unregulated EDCs. Testing for these contaminants is not

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©2015 Water Research Foundation. ALL RIGHTS RESERVED. required under the SDWA, but has been motivated by the opportunity to participate in national and regional studies, the desire to improve understanding of the effectiveness of treatment technologies and methodologies, and the need to proactively respond to concerns of the public and others. When selecting compounds to monitor, criteria to consider include occurrence, use, potential health effects, and potential for persistence. Communicating about contaminants of emerging concern (CECs) in water is a challenge due to the lack of existing regulatory criteria and uncertainties regarding the potential health effects of exposure to these compounds. Numerous Water Research Foundation projects have provided recommendations for communicating about CECs in water. If a monitoring program is initiated, utilities should ensure that resources are available to appropriately respond to questions regarding CECs. Utilities should strive to build positive relationships with the community before a crisis occurs. Messages for target audiences should be delivered by spokespeople that are recognized as credible by the community. In addition, such messages should avoid alarmist language and provide sufficient but not overly technical content. With regard to CECs in water, risk communication approaches applied by participating utilities include presenting monitoring results at public meetings and to community groups, preparing fact sheets and posting short videos on the utility website, and developing messages that use neutral language. Some utilities have convened focus groups to obtain information about community members’ response to specific language on CECs. This research found that the public responds well to dose equivalency measures, which show that the amounts of CECs in water are typically much lower than the amount in a typical medication tablet, and lower than ADIs.

APPLICATIONS/ RECOMMENDATIONS

Public concern about health risks associated with EDCs and PPCPs in source and drinking water has left many water industry professionals struggling to provide a clear, positive response on how they are addressing these issues. The primer provides water utilities with accurate, comprehensive, and up-to-date information about the occurrence and potential human health effects associated with these compounds in source and drinking water. It also summarizes information on treatment options, the status of state and federal regulations, and monitoring and communication approaches that have been applied. The technical report provides a complete and detailed reference guide with citations and sources of additional information. The slide deck provides visual media to support communication efforts. These deliverables were written either for an audience of water industry professionals or lay individuals. These deliverables together provide a comprehensive resource that water industry professionals can consult as they make decisions about how to address current or future concerns regarding EDCs and PPCPs in water. These deliverables will also provide direction for future research. This project resulted in several recommendations for utilities:

 Utilities should continually monitor new scientific developments regarding the occurrence and health significance of PPCPs and EDCs in the environment, and incorporate new information using sound science.  Utilities should monitor federal and state regulatory developments that affect PPCPs and EDCs in water.

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©2015 Water Research Foundation. ALL RIGHTS RESERVED.  Because of the public’s role in the use of pharmaceuticals and chemical agents, utilities should work with the public to develop strategies for source water protection programs.  Utilities should tailor risk communication messages to reach target audiences and deliver them using appropriate mechanisms. Effective communications can improve customer and stakeholder trust of and support for a water utility.  Utilities should strive to communicate the results of monitoring promptly, but take sufficient time to provide scientifically accurate context regarding what the data mean in terms of potential health risks.

MULTIMEDIA

A slide deck, which is posted on the #4387 project page under Project Resources/Presentations, is provided to help utilities communicate about PPCPs and EDCs in water. It provides examples of risk metrics and approaches that can put monitoring results in perspective. It is assumed that information provided in this deliverable will be communicated to the public.

PARTICIPANTS

Three utilities, Orange County Water District, Fairfax Water, and Lott Clean Water Alliance, participated in this project by providing information regarding their strategies and rationale for conducting source and drinking water monitoring programs for PPCPs and EDCs, as well as insights into their risk communication approaches and the effectiveness of these approaches. Their contributions were invaluable in developing recommendations targeted to the needs of water industry professionals.

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OVERVIEW

As the public’s concern about the potential presence of pharmaceutical and personal care product (PPCP) ingredients and endocrine disrupting compounds (EDCs) in source and drinking water increases, utilities are faced with the challenge of designing monitoring and treatment programs to address these concerns, and communicating this information to the public. However, acquiring and interpreting the growing volume of data on PPCPs and EDCs in water is difficult and time consuming. The goal of Water Research Foundation (WRF) Project #4387, Development of a Water Utility Primer on EDCs/PPCPs for Public Outreach, is to distill and synthesize current information on PPCPs and EDCs in source and drinking water into a primer, with supporting documentation, citations, and communication materials, that drinking water utilities can use to develop an understanding of the issues and to support decision making and communication efforts. This centralized up-to-date resource provides a benchmark for future investigations of PPCPs and EDCs presence in water, as well as a reference source for further information.

BACKGROUND

Examination of the sheer volume of information on PPCPs and EDCs in the environment makes evident the challenges to the water industry. In the past several decades, hundreds of papers addressing PPCPs and EDCs in the environment and source or drinking water have been published, and the increasing production and use of new compounds means the contribution of unique PPCPs and EDCs to waste streams is expected to continue. Further, challenges exist in the removal of many of these compounds using traditional municipal wastewater treatment approaches, and increasingly sophisticated analytical methods now allow the detection of contaminants at sub-part per trillion (ppt) levels (Al-Odaini et al. 2010, Baker and Kasprzyk- Hordern 2011). As such, even the tiniest amounts of contaminants can be detected and raise concerns about their significance. Scientific questions about the significance of these compounds are increasing. A recent article (Boxall et al. 2012) ranked 20 priority questions about PPCPs in the environment, as identified during an international expert workshop. These questions included how to prioritize PPCPs for research on environmental and human health exposure and effects, how PPCP risks rank relative to other chemicals and non-chemical stressors, what can be done to manage and mitigate the risks, and how the efficacy of risk management approaches can be assessed. EDCs, in turn, have also been the subject of significant controversy. Topics of ongoing debate include the definition of an EDC, what types of effects reflect endocrine disruption, and the potential for low-dose toxicity and non-linear (non-monotonic) dose-response (Zoeller et al. 2012). Clearly, utilities face significant challenges as they attempt to understand and respond to these issues.

PROJECT GOALS

The primary research goals of this project were to: (1) characterize the state-of- knowledge on sources and occurrence of PPCPs and EDCs in water and their potential

©2015 Water Research Foundation. ALL RIGHTS RESERVED. toxicological significance and human health effects; (2) summarize the status of federal and state legislation and regulations related to PPCPs and EDCs in the environment, particularly in source and drinking water; (3) summarize available treatment options and source water protection approaches; (4) characterize monitoring and communication approaches that have been taken by drinking water utilities to address issues associated with PPCPs and EDCs in water, and provide guidelines for communication of issues related to PPCPs and EDCs in source and drinking water; (5) generate a primer summarizing this information; and (6) prepare materials that utilities can use to communicate with the public about PPCPs and EDCs in drinking and source water. Specific questions this research focused on include:

 What compounds have been detected in source and drinking water around the country, and which additional compounds might be detected in the future?  Where do these compounds come from?  What levels have been detected?  What are the relative potential health risks of exposure to these substances at detected concentrations, particularly to sensitive populations such as infants and children, pregnant women, and the immune compromised? Which compounds may pose the greatest risks?  How were these acceptable levels developed and what are the uncertainties associated with them?  How do exposures to these compounds from drinking water compare to exposures from other sources, such as medicine or food?  What federal and state legislation and regulations address the presence of these compounds in the environment and in source and drinking water? What additional research is ongoing to address uncertainties?  What treatment options or other means of reducing levels of these substances in drinking water are available, and how effective are they?  What are utilities doing to address these concerns, including monitoring and communication approaches, and how effective have these approaches been?  How can utilities communicate the information contained in this report to the public?

Many hundreds of relevant literature citations were available for some project topics. While the limitations of budget and schedule within this project made acquiring and summarizing all of this information impossible, every effort was made to capture the breadth of available data and characterize information that allows drinking water utilities to attain an understanding of the state-of-knowledge of these issues. In general, we focused our efforts on recent literature (published within the last 10 years).

ORGANIZATION OF THIS REPORT

This Technical Report describes the methodologies used to complete this project and provides more detailed information to support the summary presented in the Primer. This report is organized into the following sections:

Chapter 2: Methods and Materials Chapter 3: Sources and Occurrence of PPCPs and EDCs in Water

©2015 Water Research Foundation. ALL RIGHTS RESERVED. Chapter 4: Potential Toxicological Significance and Human Health Effects of PPCPs and EDCs in Drinking Water Chapter 5: Status of Federal and State, Legislation, Regulations, and Programs Chapter 6: Treatment Approaches and Source Water Protection Chapter 7: Monitoring and Communication Approaches Applied by Drinking Water Utilities Chapter 8: Summary and Conclusions Chapter 9: Recommendations for Utilities

Two additional deliverables accompany this report:

 A Primer summarizing the information that is presented in this Technical Report in a clear concise manner, for an assumed audience of drinking water utility, water district, and water provider professionals. The Primer provides information to allow water industry professionals to respond to concerns about PPCPs and EDCs in water posed by nontechnical audiences and to support decisions about monitoring, source water protection, and treatment approaches with regard to PPCPs and EDCs.  Visual media to assist utilities in communicating about PPCPs and EDCs in water, providing examples of risk metrics and approaches that can be used to put monitoring results in perspective. It is assumed that information provided in this deliverable will be communicated to the public.

For water utilities that have committed to understanding and addressing emerging contaminant issues, determining the most effective means to address them is critical. Doing so demands collection, analysis, and interpretation of the growing volume of information available, so that utilities can proceed with a sound foundation of knowledge. The approach used to identify, gather, and summarize the information presented in this Technical Summary Report and in the Primer is described below.

LITERATURE REVIEW OF SOURCES AND OCCURRENCE OF PPCPS AND EDCS IN WATER

We conducted a detailed literature review to identify and characterize current knowledge on the sources and occurrence of PPCPs and EDCs in source and drinking water. Information gathered was limited to data collected at locations in the United States. The literature search and review emphasized peer-reviewed research reports and publications; data and information provided by federal and state regulatory agencies (e.g., U.S. Environmental Protection Agency (EPA), the United States Geological Survey (USGS), the U.S. Food and Drug Agency (FDA), state departments of environmental protection or health, and other agencies); and information from utilities and research organizations. Types of compounds considered included:

 Human pharmaceuticals, including prescription and over-the-counter (OTC) drugs and medical imaging media, focusing on those approved for use in the United States.  Veterinary pharmaceuticals, including antibiotics and other drugs (e.g., growth hormones) used in the treatment of animals, particularly livestock.  Drugs of abuse, including psychoactive or performance enhancing drugs generally used illegally for nonmedical purposes (e.g., cocaine, amphetamines).  Personal care product ingredients, including ingredients of hair, skin, and dental care products such as soaps, lotions, perfumes, deodorants, toothpaste, and sunscreen. Ingredients may include preservatives or excipients.  EDCs known or suspected to act through the estrogenic/ antiestrogenic, androgenic/ antiandrogenic, neuroendocrine, or thyroid-related modes of action, including certain PPCPs, biocides (pesticides, herbicides), industrial chemicals and byproducts of industrial activities, hormones excreted by humans and animals, and phytoestrogens/ mycoestrogens. Putative EDCs were identified from such sources as EPA’s Endocrine Disruptor Screening Program (EDSP) (EPA 2011a) and the European Union-Strategy for Endocrine Disruptors (European Commission 2012), as well as earlier references (Van der Putte and Groshart 2000, WHO 2002, IEH 2005).  Metabolites or degradation products of the above compounds.

©2015 Water Research Foundation. ALL RIGHTS RESERVED. brand/trade name, use or drug category, type of water in which the sample was collected (e.g., treatment plant influent/ effluent, surface water, drinking water including finished drinking water that has undergone treatment or water collected in the distribution system between the water utility and tap), utility or geographical location of detection, limit of detection, number of samples collected and frequency of detection, and statistics on detected concentrations (e.g., mean, median, standard deviation, minimum, and/or maximum), as available. Gathered information was tabulated in Microsoft Excel spreadsheets. Compiled information was used to rank or sort PPCPs and EDCs based on frequency of detection, concentration, location, chemical type, water type, and other criteria. Estimates of frequency of detection and ranges of detected concentrations tabulated based on these data reflect the publications summarized in this project and as such do not represent national occurrence statistics; however, these summaries do provide a snapshot of the relative detection frequency and concentrations that have been detected. The results of the literature review on sources and occurrence of PPCPs and EDCs in water are provided in Chapter 3.

LITERATURE REVIEW OF POTENTIAL TOXICOLOGICAL SIGNIFICANCE AND HUMAN HEALTH EFFECTS OF DETECTED PPCPS AND EDCS

For the PPCPs or EDCs that were identified as analyzed in source or drinking water, a literature search was conducted for information on their potential toxicity to humans, that could be used to determine acceptable daily intakes (ADIs) assuming repeated exposures. In general, a common characteristic of contaminants of emerging concern (CECs) is that toxicity criteria that can be used to establish the potential significance of exposures have not been established by regulatory agencies or other authoritative entities. However, for pharmaceuticals, substantial toxicological data generated during the drug development and approval process or compiled during the use of the drug are available. Further, toxicological criteria are available for many of the EDCs because of their long industrial or agricultural use. The availability of data of this type was assessed for the compounds of interest. Sources of toxicity information considered included peer-reviewed articles published in scientific journals, online drug references (e.g., www.RxList.com, www.drugs.com), U.S. FDA’s Drugs@FDA online catalog of approved drug products including drug labels and data submitted in support of regulatory approval, and other regulatory and government agency documents (e.g., from the EPA, European Union, and the World Health Organization (WHO)). The search included multiple databases, including the Registry of Toxic Effects of Chemical Substances (RTECS), Toxline, the Hazardous Substances Data Bank (HSDB), PubMed, PubChem, U.S. FDA, EPA, and other sources. Emphasis was placed on determining the potential for toxicity associated with low dose, longer term exposures and on toxicity to sensitive populations (e.g., infants, children, pregnant women). Information on other topics potentially important to assessing health hazards from exposure to PPCPs and EDCs in source and drinking water was also summarized, including general knowledge of human and ecological effects from exposure to PPCPs or EDCs in the environment, uptake of PPCPs and EDCs into other potential food sources (e.g., fish or produce), the relative magnitude of potential exposures from drinking water compared to other sources, approaches to characterizing the effects of exposure to mixtures, and information about the potential for antibiotic resistance.

©2015 Water Research Foundation. ALL RIGHTS RESERVED. The results of the literature review on potential toxicological significance and human health effects of PPCPs and EDCs in drinking water are provided in Chapter 4.

IDENTIFICATION OF ACCEPTABLE DAILY INTAKES (ADIS) AND DRINKING WATER EQUIVALENT LEVELS (DWELS)

We used the compiled toxicity information to determine screening-level (i.e., conservative) ADIs for each substance and calculate corresponding drinking water equivalent levels (DWELs). The DWELs were compared to detected drinking water concentrations to support ranking of the relative importance of detected compounds in terms of potential human health risk. Where ADIs did not already exist for compounds, they were derived by applying a modification of the decision tree approach that was developed as part of WateReuse Foundation Project #05-005, Identifying Hormonally Active Compounds, Pharmaceuticals, and Personal Care Product Ingredients of Health Concern from Potential Presence in Water Intended for Indirect Potable Reuse (Snyder et al. 2010). In that project, methodologies for developing screening-level human health risk-based criteria for PPCPs and EDCs potentially present in water intended for potable reuse were reviewed, and with input gathered during an expert workshop, a decision tree was proposed for efficiently developing screening levels based on compound type and available information. Briefly, for each detected compound, several “comparison levels” were derived that reflect acceptable concentrations in drinking water, using a range of different approaches and data. Then, based on the decision tree, a screening-level ADI was selected from among these comparison levels for each compound. Estimated ADIs/DWELs were then compared to detected concentrations identified in drinking water based on the data compiled in the occurrence survey, and the relative importance of specific PPCPs and EDCs, and PPCP/EDC classes was assessed based on detected concentrations and toxicity potential. Gathered data were summarized in tables, included in Chapter 4. Tabulated information includes doses at which effects were reported in toxicity studies, comparison levels, the screening level ADIs/DWELs determined using the decision tree approach, and comparisons of maximum detected drinking water concentrations to DWELs. In addition, to put the detected concentrations and risk estimates in perspective, several different types of risk metrics ware developed including the number of glasses of water one would have to drink per day to get a dose equal to the ADI or the amount in one pill or other typical exposure unit. Examples were also presented of how estimated daily exposure levels from drinking water compare to other sources of exposure.

SUMMARIZE STATUS OF FEDERAL AND STATE LEGISLATION, REGULATIONS, AND PROGRAMS ADDRESSING PPCPS AND EDCS IN WATER

We conducted research to characterize the status of federal and state legislation, regulations, guidance, and other programs addressing PPCPs and EDCs in source and drinking water, to identify regulatory drivers or other programs that could impact utilities’ decisions regarding monitoring and treatment. Specifically, we:

©2015 Water Research Foundation. ALL RIGHTS RESERVED.  Identified U.S. federal and state regulations and guidance that address PPCPs and EDCs in the environment and in source and drinking water, including existing and pending legislation that may impact how utilities address PPCPs and EDCs.  Compiled a summary of ongoing international, federal, and state agency research efforts to understand the behavior and significance of PPCPs and EDCs in water.  Provided links or citations for other federal, state, and local agency resources on PPCPs and EDCs in the environment. Findings from the research are summarized in Chapter 5.

SUMMARIZE TREATMENT OPTIONS AND SOURCE WATER PROTECTION APPROACHES

We conducted a literature search to summarize available treatment options for PPCPs and EDCs in water, including wastewater, source, and drinking water. Because of the numerous treatment options available and the extensive literature on treatment options, the information presented is an overview of available methods and their relative efficiency at removing PPCPs and EDCs from water. It is expected that utility managers considering treatment options will conduct additional detailed evaluations of treatment options to address their treatment requirements. In addition, we summarized source water protection program management strategies that can be taken to reduce consumer contributions to PPCPs and EDCs in source water, and summarized resources for more information. We also summarized information on the relative effectiveness of different source water protection approaches on improving water quality. Findings from the research are summarized in Chapter 6.

CHARACTERIZE MONITORING AND COMMUNICATION APPROACHES APPLIED BY DRINKING WATER UTILITIES

We conducted research to identify and describe monitoring efforts applied by drinking water utilities for PPCPs and EDCs in source and drinking water, and to characterize public communication efforts used by utilities to address emerging contaminant issues. The objective was to present alternatives utilities may consider when choosing to implement monitoring and communication programs. Specifically, we:

 Identified public drinking water utilities that have conducted water quality monitoring for PPCPs or EDCs and summarized, as available, the analytical methods used, compounds included, time period, locations, and general findings.  Determined as possible the drivers for monitoring and the approaches used to communicate monitoring results and health risk findings to stakeholders. Where such information was available, characterized challenges and advantages/ disadvantages to taking a proactive approach.  Presented an overview of communication strategies and tactics that have been used by drinking water utilities and regulatory agencies to communicate about PPCPs and EDCs or other trace contaminants. Where such information was available, characterized the effectiveness and outcomes of these approaches.

Based on these findings, we proposed some risk communication approaches that utilities could consider to increase understanding of the relative significance of PPCPs and EDCs in source and drinking water in terms of potential health impacts. To support this, we generated graphical materials to assist utilities in communicating this information, and provided examples of risk metrics that can be used to put technical information in perspective. Findings from this research are presented in Chapter 7.

CHAPTER 3: SOURCES AND OCCURRENCE OF PPCPS AND EDCS IN WATER

The ubiquitous use of pharmaceuticals and the domestic, agricultural, and industrial use of substances with suspected endocrine disrupting properties has resulted in the widespread presence of these substances in the environment. In addition to detection in source and drinking water, some of these substances have been detected throughout the food chain. This chapter addresses the following questions:

 What are PPCPs and EDCs?  How do PPCPs and EDCs get in water?  Why are more pharmaceuticals and other compounds being detected in water?  Have PPCPs and EDCs been detected in the water we drink? At what levels?  What is a part per billion (ppb) and part per trillion (ppt)?  Which compounds are detected the most?

In addition, links to sources of additional information on these topics are provided.

WHAT ARE PPCPS AND EDCS?

PPCPs include ingredients of prescription drugs, over-the-counter (OTC) medications, illicit drugs, veterinary drugs, and products used for personal health or cosmetic reasons (for example, fragrances, soaps, lotions, sunscreens). In addition to active pharmaceutical agents and their metabolites, PPCP ingredients may include solvents, surfactants, and other agents used in the formulation of these products. The EPA has defined an EDC as “an exogenous agent that interferes with synthesis, secretion, transport, metabolism, binding action, or elimination of natural blood-borne hormones that are present in the body and are responsible for homeostasis, reproduction, and developmental process” (Diamanti-Kandarakis et al. 2009). The human endocrine system consists of a number of organs that release hormones into the blood to regulate a variety of body functions (Table 3.1). Typically, EDCs are classified as acting through estrogenic (or antiestrogenic), androgenic (or antiandrogenic), neuroendocrine, or thyroid-related modes of action. A wide range of natural and man-made substances are thought to cause endocrine disruption, including pharmaceuticals, flame retardants, pesticides, plasticizers, and hormones excreted by humans and animals. They can be found in everyday products including plastic bottles, detergents, furniture, food, toys, and cosmetics. PPCP ingredients that have endocrine action (such as phthalates and phenol-containing compounds) are typically classified as EDCs.

Table 3.1 Hormone-producing organs of the human endocrine system Organ Hormones produced Primary action Adrenal glands corticosteroids, epinephrine, norepinephrine, immune and stress response androgens Hypothalamus neurohormones nervous system function, metabolism Ovaries estrogen, progesterone, testosterone growth, reproduction Pancreas insulin, glucagon metabolism, digestion Pineal glands melatonin growth, sleep, mood Pituitary gland growth hormone, thyroid stimulating hormone growth, reproduction, thyroid (TSH), corticotrophin, gonadotropin, function, metabolism lactotrophin Placenta estrogen, gonadotropin pregnancy support, fetal development Testes androgens (testosterone) growth, reproduction Thyroid gland thyroid hormones growth, sleep, mood, metabolism

SOURCES AND INCREASING DETECTION OF PPCPS AND EDCS IN WATER

PPCPs and EDCs can enter source water in a number of ways, from both point and nonpoint source discharges. Point source discharges reflect incomplete removal of compounds from municipal wastewater, individual sewage disposal systems, agricultural wastewater, and industrial wastewater. Non-point source discharges include water runoff that contains PPCP ingredients and EDCs from such sources as confined animal feeding operations containing animal waste and its constituents, other agricultural land, industrial land, and urban land. Most administered drugs are not completely absorbed and metabolized in the body and can enter source water from human wastes, either as the parent compound or as a metabolite, if they are incompletely removed in conventional wastewater treatment systems that then discharge to surface water, or if they leach from septic systems. Improper disposal of unused medications, such as flushing them down the toilet or drain, at homes or healthcare facilities can also result in these substances entering source water if they are incompletely removed from municipal wastewater. Veterinary drugs can enter water from animal wastes, especially in runoff from large scale farms where drugs are used to prevent disease or enhance growth (e.g., antibiotics and growth hormones) or from agricultural land treated with land application of manure. In addition, PPCP ingredients can enter municipal wastewater through such routes as bathing or washing dishes and clothing. EDCs can enter source water from point and non-point sources in many of the same ways as PPCPs, initiating from human or animal wastes, improper disposal of unused medications, and bathing or washing, as well as use of household products, land application of pesticides, and other industrial and agriculture sources.

PPCPs and EDCs have probably been present in water and the environment for as long as humans have been using them. However, several factors have driven the increased interest in and detection of these substances in the environment, including:

 Increases in the number of chemicals being manufactured or used in commerce  Increases in the volume and types of PPCPs and EDCs used by people  Improved methods for detecting chemicals in the environment  Greater interest in the potential biological effects of these substances  New testing of older chemicals for different types of toxicity including endocrine effects

The increase in number of chemicals that are manufactured or used in commerce is evident in the increasing number of chemicals registered by the EPA. Under the Toxic Substances Control Act (TSCA), EPA is required to compile, keep current, and publish a list of each chemical substance that is manufactured or processed in the United States (EPA 2014a). In 1982, 62,000 chemicals were on the TSCA inventory; currently, more than 84,000 chemicals are on the list. In addition, between 1996 and 2010, FDA approved 443 “new molecular entities” (drugs that contain an active moiety that has never been approved by the FDA or marketed in the United States) (FDA 2013b). Before the 1990s, the technology needed to detect chemicals in the environment at low levels was not available. Today, state-of-the-art equipment can detect these substances in water at much lower levels than just 5-6 years ago. For example, the method detection limits for fluoxetine, triclocarban, carbamazepine, and trimethoprim under EPA Method 1694— which was published in 2007 for analysis of PPCPs in water, soil, sediment, and biosolids by high performance liquid chromatography with tandem mass spectrometry (HPLC/MS/MS)—were 3.7, 2.1, 1.4, and 1.1 ng/L, respectively (EPA 2007). Using a newer method for the analysis of 36 trace organic contaminants including PPCPs and PFCs by ultra-high performance liquid chromatography coupled to tandem mass spectrometry (UHPLC-MS/MS), practical method reporting limits (MRLs) for the same compounds were reported to be 0.5, 1, 0.25, and 0.1 ng/L respectively (Anumol et al. 2013), or as much as about 10 times lower. The majority of data on the occurrence of PPCPs and EDCs in the environment have been published in the last 15 years. These studies, conducted by a variety of agencies and research groups, have been published in journal articles and technical reports. For example, Figure 3.1 shows the number of studies addressing EDCs published per year since 1970.

Source: Based on NLM PubMed data, 2014

Figure 3.1 Number of published articles by year, containing terms “endocrine disruptor”, “endocrine disruption”, or “endocrine disrupting”

Another factor that has driven the increase in reported detection of EDCs is that advances in toxicology have contributed to an increase in the number of suspected EDCs. When older chemicals used in industry or agriculture were first tested for toxicity, scientists rarely tested for effects on the endocrine system. Now, testing for endocrine effects is more common. As a result, many substances that were not initially considered EDCs are now thought to potentially affect the endocrine system. Currently, nearly 800 chemicals are known or suspected to be capable of interfering with hormone receptors, synthesis, or conversion (WHO/UNEP 2013).

COMPILATION AND STATISTICAL TREATMENT OF DATA

To characterize which PPCPs and EDCs have been detected in source and drinking water and at what concentrations, data on PPCP and EDC concentrations measured in source and drinking water were collected from 61 published reports or scientific articles (Table 3.2). Data were gathered for 440 compounds, of which 162 were characterized as PPCPs and 278 were characterized as putative EDCs. For each of the studies, the following data (if available) were extracted from the published document or support information, and summarized by compound in MS Excel spreadsheets:

 Compound(s) detected  Type of water (drinking water, source water, drinking water treatment plant influent, wastewater treatment plant influent, or wastewater treatment plant effluent)  Location (e.g., municipality, state, source water body, as reported in the source study)  Utility (drinking water or wastewater utility name if provided)

Table 3.2 Summary of sources of compiled occurrence data Compound Type Source DWTP WWTP WWTP Citation Location PPCPs EDCs DW SW influent influent effluent Arnold et al. 2013 US- Multiple    Barber et al. 2003 IA    Barnes et al. 2002 US- Multiple   Bartelt-Hunt et al. 2009 NE     Batt et al. 2008 OH    Batt et al. 2008 NM    Benotti et al. 2009 US- Multiple      Boyd and Furlong 2002 AZ, NV    Boyd and Grimm 2001 LA    Boyd et al. 2003 LA       Boyd et al. 2003 CA    Boyd et al. 2004 LA   Cedar Rapids 2011 IA   Chiaia et al. 2008 US- Multiple   CDWM 2011 IL     Dougherty et al. 2010 WA   Drewes et al. 2007 US- Unspecified   Drewes et al. 2008 US- Unspecified     Fairfax Water 2008-2013 VA    Focazio et al. 2008 US- Multiple    Fono and Sedlak 2005 MD, NY   Galloway et al. 2005 AR     Gao et al. 2012 MI    Glassmeyer et al. 2005 US- Multiple      Graziano et al. 2006 US- Multiple   Gross et al. 2004 CA     Hedgespeth et al. 2012 SC      Hemming et al. 2004 TX    Hopenhayn-Rich et al. 2002 KY   Huang and Sedlak 2001 CA    Huntsville Utilities 2012 AL    Kingsbury et al. 2008 US- Multiple      Great Lakes Klecka et al. 2010 Basin      Kolodziej et al. 2003 CA   Kolpin et al. 2002 US- Multiple      Kolpin et al. 2004 IA     Lee et al. 2004 MN    Loganathan et al. 2009 KY     Loraine and Pettigrove 2006 CA      Nakayama et al. 2010 IL, MN, WI   NYC DEP 2010 NY    (continued)

Table 3.2 (continued) Compound Type Source DWTP WWTP WWTP Citation Location PPCPs EDCs DW SW influent influent effluent NYC DEP 2011 NY Palmer et al. 2008 NY    Phillips et al. 2010 NY   Phillips et al. 2010 US- Multiple   Rosario Ortiz et al. 2010 CO, FL, NV   Sando et al. 2005 SD      Schultz and Furlong 2008 TX   Schultz and Furlong 2008 MN   Schultz et al. 2010 IA    Sedlak et al. 2005 AZ, CA, GA   Skadsen et al. 2004 MI      Skadsen et al. 2006 MI    Snyder et al. 2001 NV     Snyder et al. 2006 US- Unspecified    Snyder et al. 2006 CO    Snyder et al. 2006 NV    Snyder et al. 2007b US- Multiple   Spongberg and Witter 2008 OH     Stackelberg et al. 2004 US- Unspecified     Stackelberg et al. 2007 US- Unspecified     Standley et al. 2008 MA   Thomas and Foster 2005 VA     US EPA 2009d US- Multiple    Vanderford et al. 2003 NV     WSSC 2008 VA     Ying et al. 2002 US- Multiple   Ying et al. 2002 NJ, NY   Ying et al. 2002 MA   Yu et al. 2012 MD     Yu et al. 2013 CA     DW − drinking water; SW – source water (including surface water); DWTP influent − drinking water treatment plant influent; WWTP influent – wastewater treatment plant influent; WWTP effluent – wastewater treatment plant effluent

 Date of sampling collection (range of sample months, quarters, or years, or specific dates if provided and sample collection period was limited)  Limit of detection (in ng/L)  Mean, median, standard deviation, minimum detected concentration, and maximum detected concentration (in ng/L)  Number of samples  Number of detections  Frequency of detection  Citation  Other relevant information (e.g., any assumptions made in transcribing data from the original source)

Median, mean, minimum, and maximum concentration(s) were recorded if explicitly stated by the study authors. All concentrations were recorded in units of nanograms per liter (ng/L). The frequency of detection was recorded as given by the study authors, or was calculated using the number of positive detections divided by the number of samples analyzed for that particular compound. Where given by the study authors, the limit of detection was also reported. Compiled occurrence data were separated into drinking water (which included “finished” drinking water that has undergone treatment and was sampled at the water utility, and “distribution” water collected from somewhere within the distribution system or at the tap) and other water. Other water included source water samples collected from surface water sources such as rivers, streams, lakes, and reservoirs, as well as samples collected from drinking water treatment plant (DWTP) influent and wastewater treatment plant (WWTP) influent and effluent. Samples included those collected by research entities or water utilities, at water treatment plants and wastewater treatment facilities. For each water type, summary statistics for specific compounds were developed including the number of samples analyzed, overall frequency of detection, and range of detected concentrations. Tables 3.3 through 3.11 summarize this information. Figures 3.2 through 3.5 illustrate the ranges of concentrations identified as detected based on the compiled occurrence data, for PPCPs in drinking water, DWTP influent, and surface water, and EDCs in drinking water. Note that the identification of the most detected compounds and the estimates of frequency of detection and ranges of detected concentrations shown in these tables and discussed below are based on the publications summarized in this project and as such do not represent national occurrence statistics; however, these summaries do provide a snapshot of the relative detection frequency and concentrations that have been detected. For each water type, Tables 3.3 and 3.4 list the numbers of distinct compounds analyzed for and detected within different compound groups, for PPCPs and EDCs and non- pharmaceutical compounds, respectively, based on the data that were compiled in this evaluation. Table 3.5 lists the PPCPs that were identified as detected in drinking water in decreasing order of frequency of detection, with the range of detected concentrations and the range of limits of detection. Table 3.6 lists the PPCPs that were identified as detected in DWTP influent, and Table 3.7 lists the PPCPs that were identified as detected in surface water. Table A.2 in Appendix A summarizes compounds that were analyzed for in the various media but were never detected.

Table 3.3 Numbers of distinct PPCPs detected vs. analyzed, by compound group and water type (based on compiled data from sources identified in Table 3.2)* Water Type Drinking DWTP Surface WWTP WWTP Group water influent water influent effluent Analgesic/ anti-inflammatory 7/14 5/7 13/20 11/12 17/17 Anesthetic/ anti-infective 0/1 ---† 0/1 1/1 --- Antacid 0/2 0/2 2/2 2/2 2/2 Antibiotic/antibacterial 4/39 9/50 28/66 26/30 26/46 Anticholinergic ------0/1 --- 1/1 Anticoagulant 0/1 0/1 0/1 1/1 1/1 Anticonvulsant 2/3 2/3 4/5 6/6 2/5 Antidiabetic ------1/3 1/1 3/3 Antifungal 0/1 0/1 0/1 1/1 0/1 Antihistamine 0/1 1/1 1/2 1/1 2/2 Antihypertensive 3/8 2/4 9/13 3/3 10/10 Antilipidemic 1/9 5/7 4/5 2/3 4/4 Antiparasitic (anthelmintic) 0/1 0/1 1/1 1/1 1/1 Appetite suppressant ------1/1 Arthritis drug ------0/1 ------Barbiturate ------0/1 0/1 0/1 Bronchodilator 0/2 1/1 1/2 1/1 1/1 Caffeine and metabolites 2/3 2/4 4/4 2/2 2/2 Cancer drug 0/1 --- 1/2 0/1 1/2 Cardiac glycoside ------1/2 ------Diuretic 1/2 0/1 3/4 --- 3/3 Expectorant ------1/1 ------Fragrance/flavoring agent 1/1 1/1 2/3 --- 4/5 Glucocorticoid/steroid 0/2 --- 0/2 ------Illicit drug ------1/3 10/15 2/3 Keratolytic agent 0/1 0/1 1/1 1/1 1/1 Muscle relaxant 0/1 --- 0/1 --- 2/2 Nicotine and metabolites 2/2 1/2 2/2 1/1 1/1 Psychotropic‡ 5/5 3/5 12/16 3/4 14/14 Sunscreen component ------1/1 ------Sweetener 1/2 --- 0/2 ------X-ray contrast agent 1/2 1/1 1/2 ------Totals 30/104 33/93 94/171 74/88 101/129 (29%) (35%) (55%) (84%) (78%) * Presentation of detected compounds is based on the publications summarized in this project and as such does not represent national occurrence statistics. For each compound group, values indicate the number of distinct compounds detected at least once compared to the number of distinct compounds analyzed for at least once in that water type. † --- = No compounds in this group were analyzed in this water type ‡ Includes antidepressants, antianxiety agents, and antipsychotics

Table 3.4 Numbers of distinct EDCs and non-PPCPs detected vs. analyzed, by compound group and water type (based on compiled data from sources identified in Table 3.2)* Water Type Drinking DWTP Surface WWTP WWTP Group water influent water influent effluent Alkylphenol† 4/4 2/3 4/4 3/3 3/3 Anticorrosive/antioxidant 0/1 ---‡ 1/1 ------Antimicrobial/disinfectant 1/3 1/2 3/3 4/4 4/4 Chlorinated paraffin ------1/1 ------Explosives ingredient 1/1 ------Fertilizer 0/1 ------1/1 --- Flame retardant 5/6 1/1 6/7 10/10 10/10 Fragrance/flavoring agent 3/5 --- 7/8 1/1 8/8 Fungicide 3/4 ------1/1 1/1 Gasoline additive 1/1 ------Herbicide or degradate 44/59 2/2 12/22 25/27 12/23 Hormone 6/17 0/6 13/19 13/13 12/15 Insect repellant 1/1 1/1 1/1 1/1 1/1 Insecticide 13/17 --- 2/4 9/9 3/9 Isoflavone ------7/7 ------Misc industrial compound 1/1 --- 1/1 ------Nitrosamine 1/1 ------PAH 2/2 --- 3/3 1/1 --- Personal-care and domestic-use 1/1 --- 2/2 --- 1/1 product ingredient, misc. PFC (perfluorinated compound) 0/1 0/1 22/22 ------Plasticizer 6/9 1/1 7/9 4/4 1/1 Preservative 2/8 --- 2/7 3/3 2/2 Refrigerant 0/1 ------Sterol 4/5 1/2 5/5 10/10 10/10 Sunscreen ingredient 2/3 2/2 1/2 2/2 1/1 100/152 11/21 100/102 88/90 69/88 Totals (66%) (52%) (98%) (97%) (78%) * Presentation of detected compounds is based on the publications summarized in this project and as such does not represent national occurrence statistics. For each compound group, values indicate the number of distinct compounds detected at least once compared to the number of distinct compounds analyzed for at least once in that water type. †The alkylphenols nonylphenol and octylphenol and their derivatives are assigned a number of different names in different programs. For simplicity, for purposes of counting, these compounds were grouped as follows: nonylphenol (including nonylphenol, nonylphenols, para-nonylphenol); nonylphenol ethoxylates (including nonylphenol monoethoxylates, nonylphenol diethoxylates, nonylphenol ether carboxylates, nonylphenol ethoxylates, and nonylphenol triethyoxylate); octylphenol (including octylphenol and 4-tert- octylphenol); and octylphenol ethoxylates (including 4-octylphenol diethoxylate and 4-octylphenol monoethoxylate). ‡--- = No compounds in this group were analyzed in this water type

Table 3.5 Summary of PPCPs identified as detected in drinking water (based on compiled data from sources identified in Table 3.2)* Freq det Min det Max det LOD PPCP Group #† (%)‡ (ng/L) (ng/L) (ng/L) Acesulfame (Sweet One) Sweetener 2 50% 22 22 20 Meprobamate Psychotropic 77 36% 1 42 0.25-1 Propranolol Antihypertensive 3 33% NA 0.8 NA Atenolol Antihypertensive 63 32% 3 18 0.25-1 Caffeine Caffeine 191 31% 2.9 220 3-500 Carbamazepine Anticonvulsant 122 29% NA 258 0.5-11 Phenytoin Anticonvulsant 74 28% 2 19 1-2 Cotinine Nicotine 158 24% NA 77 1-40 Gemfibrozil Antilipidemic 90 22% NA 2.1 0.25-0.5 Nicotine Nicotine 12 17% 5 5 5 Furosemide Diuretic 14 14% 45 53 10 Theobromine Caffeine 25 12% 13 60 5 Camphor Fragrance/ flavor 108 11% NA 21 500 Methadone Analgesic 9 11% 16 16 4.8 Ketoprofen Analgesic 12 8% 26 26 5 Ibuprofen Analgesic 106 8% 1.3 1,350 1-280 Acetaminophen Analgesic 56 7% 2 2 NA Ibuprofen methyl ester Analgesic 15 7% NA 330 110 Sulfamethoxazole Antibiotic 133 6% 1 6 0.25-10 Codeine Analgesic 19 5% 0 30 15 Dehydronifedipine Antihypertensive 20 5% 70 70 5-10 Fluoxetine Psychotropic 108 5% NA 0.82 0.5-25.4 Tylosin Antibiotic 27 4% NA 1 1 Norfluoxetine Psychotropic 33 3% NA 0.77 0.5 Risperidone Psychotropic 33 3% NA 2.9 2.5 Iopromide X-ray contrast 43 2% 11 11 5 Sulfathiazole Antibiotic 47 2% NA 10 1-10 Monensin Antibiotic 50 2% 4 4 1 Diazepam Psychotropic 76 1% NA 0.33 0.25 Naproxen Analgesic 108 1% 3 3 0.4-2 *NOTE: Estimates of frequency of detection and ranges of detected concentrations shown in these tables are based on the publications summarized in this project and as such do not represent national occurrence statistics. † Total number of individual sample results identified in the publications summarized in this project ‡Number of detections/Number of individual sample results in drinking water. LOD − limit of detection; NA − not available

Table 3.6 Summary of PPCPs detected in DWTP influent (based on compiled data from sources identified in Table 3.2)* Freq det Min det Max det LOD PPCP Group #† (%)‡ (ng/L) (ng/L) (ng/L) Carbamazepine Anticonvulsant 63 86% 3.4 600 0.5-11 Meprobamate Psychotropic 27 74% 4 73 0.25-1 Phenytoin Anticonvulsant 27 67% 3.1 29 1-2 Erythromycin-H2O Antibiotic 24 63% NA 10 10-50 Flumequine Antibiotic 12 58% NA 10 50 Acetaminophen Analgesic 36 56% 1.4 120 1-36 Naproxen Analgesic 31 55% 1 68 0.4-2 Sulfamethoxazole Antibiotic 63 52% 4 110 0.25-50 Atenolol Antihypertensive 23 52% NA 36 0.25 Cotinine Nicotine 40 43% NA 10 1-1,000 1,7-Dimethylxanthine Caffeine 24 38% NA NA 18-144 0.25- Trimethoprim Antibiotic 59 36% 0.5 11 1470 Iopromide X-ray contrast 7 29% 2.2 48 1-10 Gemfibrozil Antilipidemic 51 27% 2 24 0.25-15 Caffeine Caffeine 121 27% 3.2 580 10-500 Dehydronifedipine Antihypertensive 36 25% NA NA 10-15 Diphenhydramine Antihistamine 12 25% NA NA 14.8 Diclofenac Analgesic 23 17% NA 1.2 0.25-0.5 Codeine Analgesic 24 17% NA 10 15-240 Atorvastatin Antilipidemic 19 16% NA 1.4 0.25 o-hydroxy atorvastatin Antilipidemic 19 16% NA 1.2 0.5 p-hydroxy atorvastatin Antilipidemic 19 16% NA 2 0.5 Clofibric acid Antilipidemic 7 14% NA 103 0.5-0.8 Ibuprofen Analgesic 23 13% 1.4 11 1-42 Erythromycin Antibiotic 27 11% NA 40 1-100 Lincomycin Antibiotic 28 11% NA 60 0.1-50 Diazepam Psychotropic 23 9% NA 0.47 0.25-1 Sulfamethazine Antibiotic 28 7% NA 40 1-50 Fluoxetine Psychotropic 53 6% NA 3 0.5-25.4 Albuterol Bronchodilator 24 4% NA NA 23-29 Camphor Fragrance/ flavor 108 4% NA 21 500 Sulfadimethoxine Antibiotic 28 4% NA 10 0.1-50 Sulfathiazole Antibiotic 28 4% NA 80 1-50 * Estimates of frequency of detection and ranges of detected concentrations are based on the publications summarized in this project and as such do not represent national occurrence statistics. †Total number of individual sample results identified in the publications summarized in this project. ‡Number of detections/Number of individual sample results in drinking water. LOD − limit of detection; NA − not available

Table 3.7 Summary of PPCPs detected in surface water (based on compiled data from sources identified in Table 3.2)* Freq det Min det Max det LOD PPCP Group #† (%)‡ (ng/L) (ng/L) (ng/L) Clindamycin Antibiotic 3 100% 1 1.3 0.17 Desmethyldiltiazem Antihypertensive 1 100% NA 12 0.1 Hydrochlorothiazide Diuretic 1 100% NA 75 11 Oxycodone Analgesic 1 100% NA NA 4.1 Triamterene Diuretic 1 100% 12 12 2.4 Valsartan Antihypertensive 1 100% NA NA 1.6 Methamphetamine Illicit drug 9 67% 1.3 62.6 0.43-10 Monensin Antibiotic 260 65% NA 1,172 1-20 Propranolol Antihypertensive 6 50% 2 32 0.1-0.6 Atorvastatin Antilipidemic 13 46% 3.7 15 0.7-5 Carbamazepine Anticonvulsant 660 39% NA 660 NA-11 Fenoprofen Analgesic 78 36% NA 142 0.2 Lincomycin Antibiotic 600 36% NA 730 0.1-50 Nicotine Nicotine 50 34% 5 23 5 Butalbital Analgesic 24 33% 8.6 24 5 Cotinine Nicotine 653 33% 0.4 900 0.1-1,000 Caffeine Caffeine 911 33% 3.1 6,000 0.33-500 Indole Fragrance/ flavoring 19 32% 24 83 15 1,7-Dimethylxanthine Caffeine 359 24% 1.9 3,100 0.61-140 Anhydro-erythromycin Antibiotic 22 23% 50 1,210 50 Erythromycin Antibiotic 348 21% 81 280 0.1-100 Ketoprofen Analgesic 130 21% NA 50 0.1-5 Naproxen Analgesic 437 20% 4.2 551 0.4-5 Cyclophosphamide Cancer drug 15 20% NA 5 0.2-0.2 Clarithromycin Antibiotic 22 18% 4.9 9 0.42-1 Sulfamethoxazole Antibiotic 804 18% 1 1,900 0.2-64 Trimethoprim Antibiotic 1089 17% 1.1 710 0.2-50 Sulfamethazine Antibiotic 715 16% 2.4 472 0.43-50 Clofibric acid Antilipidemic 266 16% 5 175 0.2-5 Indomethacin Analgesic 159 16% NA 18 0.2 Ofloxacin Antibiotic 41 15% 67 270 30-50 Meprobamate Psychotropic 89 15% 1 220 1 Gemfibrozil Antilipidemic 786 14% 0.5 790 0.8-28 Acetaminophen Analgesic 457 13% 2.6 10,000 1-36 Erythromycin-H2O Antibiotic 275 12% 48 1,700 1-50 Diclofenac Analgesic 317 12% NA 194 0.2-1.49 Bezafibrate Antilipidemic 260 10% NA 200 0.5-1 (continued)

Table 3.7 (continued) Freq det Min det Max det LOD PPCP Group #† (%) (ng/L) (ng/L) (ng/L) Pentoxifylline Antihypertensive 74 9% 2.2 50 0.1-1 Diltiazem Antihypertensive 358 9% 0.1 106 0.1-24 Hydrocodone Analgesic 36 8% 6 19 1-1.4 Paraxanthine Caffeine 24 8% 5 10 5 Cimetidine Antacid 309 8% 11 580 0.4-13 Dehydronifedipine Antihypertensive 318 8% 0.4 130 3.5-19 Codeine Analgesic 344 7% 10 1,000 12-240 Sulfachloropyridazine Antibiotic 516 7% NA 70 0.6-50 Ibuprofen Analgesic 411 7% 1.1 1,000 1-18 Theobromine Caffeine 71 7% 7.3 90 5-50 Diphenhydramine Antihistamine 201 6% 7.7 616.2 0.35-36 Furosemide Diuretic 67 6% 49 100 10-12 Primidone Anticonvulsant 54 6% 8 130 5 Phenytoin Anticonvulsant 109 5% 2.6 261 1-50 Metoprolol Antihypertensive 24 4% 12 12 1.1-5 Tylosin Antibiotic 496 4% 8 280 1-70 Metformin Antidiabetic 145 3% NA 140 1.5-3 Sulfadimethoxine Antibiotic 626 3% 1.4 2,062.8 0.1-50 Roxithromycin Antibiotic 484 3% NA 180 1-100 Azithromycin Antibiotic 182 3% NA 1,546.7 0.5-23 Thiabendazole Antiparasitic 119 3% 3.9 27.3 0.17-10.8 Diazepam Psychotropic 121 2% 1.5 62 0.95-1 Atenolol Antihypertensive 358 2% 1 35 1-9 Lasalocid Antibiotic 47 2% 3 3 1 Salicylic acid Keratolytic agent 52 2% 4.7 4.7 10-50 Ciprofloxacin Antibiotic 370 2% 27 39 10-50 Ranitidine Antacid 296 2% 9.6 27 5-10 Sulfadiazine Antibiotic 120 2% 6.4 44 1-50 Fluoxetine Psychotropic 436 2% NA 46 0.25-36 Sulfathiazole Antibiotic 627 1% 0.7 50 0.46-100 Iopromide X-ray contrast agent 97 1% 11 11 5-10 Chlortetracycline Antibiotic 583 1% NA 690 20-100 Doxycycline Antibiotic 495 1% NA 73 25-100 Enalaprilat Antihypertensive 126 1% NA 46 76-600 Albuterol Bronchodilator 326 1% 1.3 9 0.8-58 Norfloxacin Antibiotic 370 1% NA 120 10-500 Camphor Fragrance/ flavoring 190 1% NA 84 500-700 Tetracycline Antibiotic 575 1% NA 300 20-500 (continued)

Table 3.7 (continued) Freq det Min det Max det LOD PPCP Group #† (%) (ng/L) (ng/L) (ng/L) Oxytetracycline Antibiotic 595 NA NA 340 30-500 Sulfamethizole Antibiotic 357 NA NA 130 0.17-50 Enrofloxacin Antibiotic 329 NA NA 40 10-500 Sarafloxacin Antibiotic 301 NA NA 20 10-30 Digoxin Cardiac glycoside 83 NA NA NA 50-260 Norfluoxetine Psychotropic 47 NA 0.93 1.4 0.28-4.5 Paroxetine Psychotropic 32 NA 1.12 2.87 0.32-0.8 Sertraline Psychotropic 32 NA 0.84 5.92 0.21-1.5 Bupropion Psychotropic 31 NA 9.1 56.7 0.33-0.33 Citalopram Psychotropic 31 NA 4.58 86.4 0.45-0.45 Duloxetine Psychotropic 31 NA NA NA 0.24-0.24 Norsertraline Psychotropic 31 NA 1.65 6.63 0.32-0.32 Venlafaxine Psychotropic 31 NA 73.3 158 0.29-0.29 6-O-des-methyl-naproxen Analgesic 24 NA NA 8 1-1 COOH-ibuprofen Analgesic 24 NA 4 24 1-1 Fluvoxamine Psychotropic 16 NA 0.61 0.83 NA-NA Guaifenesin Expectorant NA NA 21 52 NA-NA Sunscreen Homomenthyl salicylate component NA NA NA NA NA-NA Phenobarbital Anticonvulsant NA NA 11 39 NA-NA * Estimates of frequency of detection and ranges of detected concentrations are based on the publications summarized in this project and as such do not represent national occurrence statistics. †Total number of individual sample results identified in the publications summarized in this project. ‡Number of detections/Number of individual sample results in drinking water. LOD − limit of detection; NA − Not available

Table 3.8 Summary of EDCs detected in drinking water (based on compiled data from sources identified in Table 3.2)* Freq det Min det Max det LOD EDC Group #† (%)‡ (ng/L) (ng/L) (ng/L) PFOS PFC 12 100% 0.52 2.8 0.2 DACT Herbicide 12 83% 46 100 5 Stigmasterol Sterol 4 50% 100 160 0 cis-Testosterone Hormone 12 33% 0.2 0.2 0.1 TCPP Flame retardant 35 31% 50 510 5-50 DEET Insect repellant 143 29% 0.52 97 2-500 Coprostanol Sterol 7 29% NA 2 100 Atrazine Herbicide 179 28% NA 3,400 7-100 Metolachlor Herbicide 33 27% 10 470 6-10 Cyanazine Herbicide 12 17% 23 23 5 TBEP Flame retardant 12 17% 280 320 200 Perchlorate Explosives ingredient 16 13% 600 2,200 500 Butylbenzyl phthalate Plasticizer 85 12% 50 911 33-1,000 TCEP Flame retardant 183 11% 10 470 5-500 Estriol Hormone 30 10% 1.4 2.8 0.3 4-n-nonylphenol Alkylphenol 45 9% 80 1,100 80-5,000 Deisopropyl atrazine Herbicide 117 9% 5.5 120 5-1,000 17α-Ethynylestradiol Hormone 36 8% 1.4 3.9 1 DEHP Plasticizer 48 8% 2430 2,680 3,530 Simazine Herbicide 115 8% 6.4 730 5-70 2,4-D Methyl ester Herbicide 117 8% 5.8 460 5-38 BHA Preservative 15 7% 70 230 70 Diethyl phthalate Plasticizer 15 7% NA 160 490 Dimethyl phthalate Plasticizer 15 7% NA 40 39 Octyl methoxy cinnamate Sunscreen ingredient 15 7% NA 30 280 Desethyl atrazine Herbicide 201 5% 7.7 130 5-1,000 Progesterone Hormone 122 4% 0.4 0.6 0.1-200 17 β-Estradiol Hormone 91 3% 0.3 3.5 0.1-0.5 Benzophenone Sunscreen ingredient 31 3% 500 130 44-500 BHT Preservative 33 3% 25 26 25 Sitosterol, beta- Sterol 100 3% 250 1,400 2,000 Linuron Herbicide 69 3% 0.5 6.2 0.5-500 Bisphenol A Plasticizer 237 3% 5 440 0.1-1,000 Estrone Hormone 82 2% NA 4.5 0.2-0.3 1,350- Dibutyl phthalate Plasticizer 53 2% NA 180 2,000 Triclosan Antimicrobial 202 1% 1 734 0.2-500 HHCB Fragrance/ flavor 229 1% 25 300 25-500 2,4-D Methyl ester Herbicide 87 NR NA 63 190 2-Hydroxy atrazine Herbicide 88 NR NA 300 32 3,4-Dichloroaniline Misc ingredient 83 NR NA 9 4.5 4-n-Octylphenol Alkylphenol 108 NR NA 250 500-1,000 Acetochlor Herbicide 87 NR NA 140 6 Acetochlor ESA Herbicide 48 NR NA 310 20 (continued)

Table 3.8 (continued) Freq Min det Max det LOD EDC Group #† det (%) (ng/L) (ng/L) (ng/L) Acetochlor ESA 2nd amide Herbicide 48 NR NA 80 20 Acetochlor oxanilic acid Herbicide 48 NR NA 400 20 Acetochlor sulfynilacetic acid Herbicide 48 NR NA 170 20 AHTN Fragrance/ flavor 96 NR NA 300 500 Alachlor Herbicide 87 NR NA 17 5 Alachlor ESA Herbicide 48 NR NA 370 20 Alachlor ESA 2nd amide Herbicide 48 NR NA 70 20 Alachlor oxanilic acid Herbicide 48 NR NA 120 20 Alachlor sulfynilacetic acid Herbicide 48 NR NA 50 20 Bendiocarb Insecticide 87 NR NA 19 80 Benomyl Fungicide 89 NR NA 8 22 Bentazon Herbicide 87 NR NA 20 24 Carbaryl Insecticide 93 NR NA 35 18-50 Chlorimuron ethyl Herbicide 89 NR NA 6 32 Chlorothalonil Herbicide 82 NR NA 710 35 Dacthal Herbicide 87 NR NA 5 14 Deethyldeiso propyl atrazine Herbicide 89 NR NA 71 40 Desulfinyl fipronil Insecticide 87 NR NA 8 12 Desulfinyl fipronil amide Insecticide 87 NR NA 6 29 Diazinon Insecticide 103 NR NA 6 5-25 Diazinon, oxygen analog Insecticide 87 NR NA 1.1 6 Dicamba Herbicide 87 NR NA 71 36 Dichlorvos Insecticide 87 NR NA 5 6 Dimethenamid Herbicide 48 NR NA 120 20 Dinoseb Herbicide 89 NR NA 6 38 Diuron Herbicide 117 NR NA 180 1-16 Fipronil Insecticide 87 NR NA 9 16 Fipronil sulfide Insecticide 87 NR NA 8 13 Fipronil sulfone Insecticide 87 NR NA 7 24 Flumetsulam Herbicide 88 NR NA 49 40 Hexazinone Herbicide 87 NR NA 21 26 Imazaquin Herbicide 89 NR NA 25 36 Imazethapyr Herbicide 89 NR NA 26 38 Imidacloprid Insecticide 87 NR NA 21 23 Indole Fragrance/ flavor 96 NR NA 3 0 Iprodione Fungicide 87 NR NA 18 26 Malaoxon Insecticide 87 NR NA 10 39 Malathion Insecticide 87 NR NA 9 27 MCPA Herbicide 87 NR NA 390 70 Metolachlor ESA Herbicide 48 NR NA 1,900 20 Metolachlor OA Herbicide 48 NR NA 460 20 Metribuzin Herbicide 87 NR NA 16 28 (continued)

Table 3.8 (continued) Freq det Min det Max det LOD EDC Group #† (%) (ng/L) (ng/L) (ng/L) Metsulfuron methyl Herbicide 89 NR NA 58 67 MTBE Gasoline additive 94 NR NA 560 100 Myclobutanil Fungicide 87 NR NA 18 33 NDMA Nitrosamine 0 NR NA 27 0 Nonylphenol diethoxylate Alkylphenol 96 NR NA 5,900 5,000 Octylphenol monoethoxylate Alkylphenol 96 NR NA 700 1,000 Octylphenol, 4-tert- Alkylphenol 115 NR NA 16 10-1,000 OP2EO Alkylphenol 108 NR NA 240 1,000 p-Cresol Misc ingredient 96 NR NA 100 1,000 Pendimethalin Herbicide 87 NR NA 25 22 Prometon Herbicide 91 NR NA 200 10-500 Propyzamide Herbicide 87 NR NA 7 4 Stigmastanol, beta- Sterol 100 NR NA 1,600 200-2,000 Triclopyr Herbicide 89 NR NA 35 26 Trifluralin Herbicide 87 NR NA 6 9 Triphenyl phosphate Flame retardant 108 NR NA 160 25-500 Tris (dichlorisopropyl phosphate) (TDCPP) Flame retardant 112 NR NA 5,500 500 * Estimates of frequency of detection and ranges of detected concentrations are based on the publications summarized in this project and as such do not represent national occurrence statistics. †Total number of individual sample results identified in the publications summarized in this project. ‡Number of detections/Number of individual sample results in drinking water. 2,4-D − 2,4-dichlorophenoxyacetic acid; AHTN − acetyl hexamethyl tetrahydro naphthalene; BHA − butylated hydroxyanisole; BHT − butylated hydroxyl toluene; DACT − atrazine-desethyl-desisopropyl; DEET − N,N-diethyltoluamide; DEHP − di(ethylhexyl) phthalate; DIA deisopropyl atrazine; ESA − ethanesulfonic acid; HHCB − 1,3,4,6,7,8-hexahydro-4,6,6,7,8,8,-hexamethylcyclopenta[γ]-2-benzopyran; LOD − limit of detection; MCPA − 2-methyl-4-chlorophenoxyacetic acid; MTBE − methyl tert-butyl ether; NA – not available; NDMA − N-nitrosodimethylamine; OA − oxanilic acid; OP2EO – octylphenol diethoxylate; PFC − perfluorinated compound; PFOS − perfluorooctane sulfonic acid; TBEP − tris (2- butoxyethyl) phosphate; TCEP − tris (2-chloroethyl) phosphate; TCPP − tris(1,3-dichloro-2-propyl) phosphate

Table 3.9 Summary of occurrence data for the most frequently detected EDCs and other non-PPCPs in surface water and DWTP influent (average frequency of detection of 25% or more, based on compiled data from sources identified in Table 3.2)* Number of Max conc. studies or Compound Typical use or group Freq det %† (ng/L) sources Oxybenzone Sunscreen ingredient 100% 364 1 Perfluoropropionic acid PFC 100% 8.9 1 Perflurobutyric acid PFC 100% 9.1 1 Total SCCP Chlorinated paraffin 100% 38.4 1 Tri (dichloro-propyl) phosphate Flame retardant 100% 35 1 Trifluoroacetic acid PFC 100% 200 1 N-EtFOSAA PFC 94% 11 1 Total PFA PFC 90% 200 1 Perfluorohexanoic acid (C6) PFC 85% 53.4 2 Perfluorooctanoic acid (C8) PFC 83% 125 2 Perfluorohexane sulfonic acid PFC 82% 7.4 1 Perfluorooctane sulfonamide PFC 78% 5 1 Perfluorobutanoic acid (C4) PFC 77% 458 1 5-methyl-1H-benzotriazole Anti-corrosive/antioxidant 75% 550 1 Nonylphenols Alkylphenol 74% 37,000 1 Perfluoroheptanoic acid (C7) PFC 74% 90.2 2 Perfluoropentanoic acid (C5) PFC 71% 31.5 2 Nonylphenol monoethoxylate Alkylphenol 70% 332,000 11 Perfluorooctane sulfinate PFC 69% 18 1 PFOS PFC 68% 756 3 Atrazine Herbicide or degradate 68% 2,600 5 Total perfluorinated sulfonyls PFC 65% 756 1 Octylphenol Alkylphenol 64% 68 2 TCPP Flame retardant 63% 1,600 2 TDCPP Flame retardant 62% 110 1 AHTN Fragrance/flavoring agent 60% 2,100 5 Pyrene PAH 57% 270 1 Di-n-butyl phathalate Plasticizer 55% 8,340 2 Cholesterol Sterol 54% 2,380 2 DACT Herbicide or degradate 54% 70 1 Nonylphenol diethoxylates Alkylphenol 52% 18,000 11 4-Octylphenol monoethoxylate Alkylphenol 52% 2,000 1 Atrazine-desisopropyl (DIA) Herbicide or degradate 51% 24 1 Desethyl atrazine Herbicide or degradate 51% 67 1 (continued)

Table 3.9 (continued) Number of Max Conc. studies or Compound Typical use or group Freq det %† (ng/L) sources Nonylphenol Alkylphenol 48% 5,000 18 DEET Insect repellant 47% 1,616.5 21 Diethyl phthalate Plasticizer 46% 420 3 Galaxolide (HHCB) Fragrance/flavoring agent 45% 990 5 TCEP Flame retardant 45% 1,800 6 Glycitein Isoflavone 44% 25 1 Bisphenol A Plasticizer 44% 12,000 14 Perfluorobutane-sulfonate PFC 43% 84.1 1 4-Methylphenol Antimicrobial/disinfectant 43% 70 1 Ethanol, 2-butoxy phosphate Plasticizer 43% 820 1 Fluoranthene PAH 43% 200 1 Phthalic anhydride Plasticizer 43% 900 1 Phenanthrene PAH 43% 60 1 Triclosan Antimicrobial/disinfectant 41% 2,300 14 Perfluorohexane-sulfonate PFC 40% 169 1 Simazine Herbicide or degradate 40% 15 1 PFOSA PFC 38% 6.5 1 Coprostanol Sterol 34% 2,000 2 Perfluorononanoic acid (C9) PFC 34% 72.9 2 Benzophenone Sunscreen ingredient 33% 510 1 Genistein Isoflavone 33% 9.5 1 4-Octylphenol diethoxylate Alkylphenol 29% 1,000 1 1,4-Dichlorobenzene Fragrance/flavoring agent 29% 170 1 Butylbenzyl phthalate Plasticizer 29% 200 2 Daidzein Isoflavone 28% 9.2 1 Formononetin Isoflavone 28% 22 1 Prometon Herbicide or degradate 26% 500 1 Nonylphenol, para- Alkylphenol 25% 40,000 3 Tris(2,3-dichloro-propyl) phosphate Flame retardant 25% 500 2 * Estimates of frequency of detection and ranges of detected concentrations are based on the publications summarized in this project and as such do not represent national occurrence statistics. †Average of average frequencies of detection reported in individual studies. AHTN − acetyl hexamethyl tetrahydro naphthalene; DACT − atrazine-desethyl-desisopropyl; DEET − N,N-diethyltoluamide; DIA − atrazine-deisopropyl; DWTP − drinking water treatment plant; HHCB − 1,3,4,6,7,8-hexahydro-4,6,6,7,8,8,-hexamethylcyclopenta[γ]-2-benzopyran; N-EtFOSAA − N-ethyl perfluorooctane sulfonamido acetic acid; PAH − polycyclic aromatic hydrocarbon; PFA − perfluoroalkoxy polymer; PFC − perflourinated compound; PFOS − perfluorooctane sulfonic acid; PFOSA − perfluorooctane sulfonamide acetic acid; SCCP − short chain chlorinated paraffin; TCEP − tris (2-chloroethyl) phosphate;TCPP − tris(1,3-dichloro-2-propyl) phosphate; TDCPP − tris (dichlorisopropyl) phosphate

Table 3.10 Detection frequencies of PPCPs detected in drinking water compared to DWTP influent and surface water (based on compiled data from sources identified in Table 3.2)* Drinking water DWTP influent Surface water Name† Drug group % det Freq % det Freq % det Freq Acesulfame Sweetener 50% 1/2 NA NA 0% 0/3 1) Meprobamate Psychotropic F 28/77 74% 20/27 15% 13/89 Propranolol Antihypertensive 33% 1/3 NA NA 50% 3/6 2) Atenolol Antihypertensive 32% 20/63 52% 12/23 2% 8/358 3) Caffeine Caffeine 31% 60/191 27% 33/121 33% 299/911 4) Carbamazepine Anticonvulsant 29% 35/122 86% 54/63 39% 257/660 5) Phenytoin Anticonvulsant 28% 21/74 67% 18/27 5% 5/109 6) Cotinine Nicotine 24% 38/158 43% 17/40 33% 215/653 7) Gemfibrozil Antilipidemic 22% 20/90 27% 14/51 14% 110/786 8) Nicotine Nicotine 17% 2/12 0% 0/4 34% 17/50 9) Furosemide Diuretic 14% 2/14 0% 0/12 6% 4/67 10) Theobromine Caffeine 12% 3/25 0% 0/4 4% 3/68 Camphor Fragrance/ flavor 11% 12/108 4% 4/108 1% 1/190 Methadone Analgesic 11% 1/9 NA NA 0% 0/18 Ketoprofen Analgesic 8% 1/12 NA NA 21% 27/130 Ibuprofen Analgesic 8% 8/106 13% 3/23 7% 27/411 Acetaminophen Analgesic 7% 4/56 56% 20/36 13% 58/457 Ibuprofen methyl ester Analgesic 7% 1/15 NA NA NA NA Sulfamethoxazole Antibiotic 6% 8/133 52% 33/63 18% 145/804 Codeine Analgesic 5% 1/19 17% 4/24 7% 24/344 Dehydronifedipine Antihypertensive 5% 1/20 25% 9/36 8% 25/318 Fluoxetine Psychotropic 5% 5/108 6% 3/53 2% 7/436 Tylosin Antibiotic 4% 1/27 0% 0/16 4% 20/496 Norfluoxetine Psychotropic 3% 1/33 0% 0/19 NA NA/47 Risperidone Psychotropic 3% 1/33 0% 0/19 NA NA Iopromide X-ray contrast 2% 1/43 29% 2/7 1% 1/97 Sulfathiazole Antibiotic 2% 1/47 4% 1/28 1% 8/627 Monensin Antibiotic 2% 1/50 0% 0/4 65% 170/260 Diazepam Psychotropic 1% 1/76 9% 2/23 2% 3/121 Naproxen Analgesic 1% 1/108 55% 17/31 20% 88/437 * Estimates of frequency of detection and ranges of detected concentrations are based on the publications summarized in this project and as such do not represent national occurrence statistics. †For compounds analyzed in at least 10 samples, the top 10 substances detected in drinking water are ranked by detection frequency

Table 3.11 Detection frequencies of PPCPs detected in DWTP influent or surface water but not drinking water (based on compiled data from sources identified in Table 3.2)* Drinking Water DWTP Influent Surface Water Name† Drug group % det Freq % det Freq % det Freq Erythromycin-H2O Antibiotic 0% 0/16 63% 15/24 12% 34/275 Flumequine Antibiotic 0% 0/12 58% 7/12 0% 0/64 1,7-Dimethylxanthine Caffeine 0% 0/10 38% 9/24 24% 86/359 Trimethoprim Antibiotic 0% 0/90 36% 21/59 17% 181/1089 Diphenhydramine Antihistamine 0% 0/4 25% 3/12 6% 12/201 Diclofenac Analgesic 0% 0/68 17% 4/23 12% 37/317 Atorvastatin Antilipidemic 0% 0/33 16% 3/19 46% 6/13 o-hydroxy atorvastatin Antilipidemic 0% 0/33 16% 3/19 NA NA p-hydroxy atorvastatin Antilipidemic 0% 0/33 16% 3/19 NA NA Clofibric acid Antilipidemic 0% 0/30 14% 1/7 16% 43/266 Erythromycin Antibiotic 0% 0/31 11% 3/27 21% 74/348 Lincomycin Antibiotic 0% 0/46 11% 3/28 36% 215/600 Sulfamethazine Antibiotic 0% 0/47 7% 2/28 16% 117/715 Clindamycin Antibiotic NA NA NA NA 100% 3/3 Desmethyldiltiazem Antihypertensive NA NA NA NA 100% 1/1 Hydrochlorothiazide Diuretic NA NA NA NA 100% 1/1 Oxycodone Analgesic NA NA NA NA 100% 1/1 Triamterene Diuretic NA NA NA NA 100% 1/1 Valsartan Antihypertensive NA NA NA NA 100% 1/1 Methamphetamine Illicit drug NA NA NA NA 67% 6/9 Fenoprofen Analgesic NA NA NA NA 36% 28/78 Butalbital Analgesic 0% 0/23 0% 0/4 33% 8/24 Indole Fragrance/ flavoring NA NA NA NA 32% 6/19 Anhydro-erythromycin Antibiotic NA NA NA NA 23% 5/22 Cyclophosphamide Cancer drug NA NA NA NA 20% 3/15 Clarithromycin Antibiotic NA NA NA NA 18% 4/22 Indomethacin Analgesic NA NA NA NA 16% 25/159 Ofloxacin Antibiotic NA NA 0% 0/12 15% 6/41 Bezafibrate Antilipidemic 0% 0/23 0% 0/4 10% 25/260 * Estimates of frequency of detection and ranges of detected concentrations are based on the publications summarized in this project and as such do not represent national occurrence statistics. †Substances not detected in drinking water but detected with frequency of 10% or more in DWTP influent or surface water NA − Not analyzed

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Water Concentration (ng/L) 1

0.1 Tylosin (1/27) Codeine (1/19) Nicotine (2/12) Methadone (1/9) Methadone Atenolol (20/64) (1/50) Monensin Diazepam (1/76) Primidone (2/22) Primidone Iopromide (1/43) Iopromide Propranolol (1/3) Propranolol Naproxen (1/108) Naproxen Cotinine (38/158) Caffeine (60/191) Caffeine (8/106) Ibuprofen Ketoprofen (1/12) Ketoprofen Phenytoin (21/74) Camphor (12/108) Camphor Furosemide (2/14) Furosemide Fluoxetine (5/108) Risperidone (1/33) Risperidone Sulfathiazole (1/47) Theobromine (3/25) Theobromine Gemfibrozil (20/90) Gemfibrozil Norfluoxetine (1/33) Norfluoxetine Meprobamate (28/77) Meprobamate Acetaminophen (4/56) Carbamazepine (35/122) Dehydronifedipine (1/20) Dehydronifedipine Sulfamethoxazole (8/133) Sulfamethoxazole Ibuprofen methyl ester (1/15) methyl ester Ibuprofen

Sweet One (Ace K, Sunnet) (1/2) K, Sunnet) Sweet One (Ace Figure 3.2 Ranges of detected concentrations of PPCPs in drinking water. Based on compiled data from sources identified in Table 3.2. Number detected and total number of compounds analyzed are given in parentheses.

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0.1 Codeine (4/24) Iopromide (2/7) Cotinine (17/40) Atenolol (12/23) Ibuprofen (3/23) Diazepam (2/23) Camphor (4/108) Fluoxetine (3/53) Naproxen (17/31) Diclofenac (4/23) Caffeine (33/121) Phenytoin (18/27) Flumequine (7/12) Lincomycin (3/28) Atorvastatin (3/19) Clofibric acid (1/7) Sulfathiazole (1/28) Gemfibrozil (14/51) Erythromycin (3/27) Meprobamate (20/27) Trimethoprim (21/59) Sulfamethazine (2/28) Carbamazepine (54/63) Acetaminophen (20/36) Sulfadimethoxine (1/28) Sulfamethoxazole (33/63) Erythromycin-H2O (15/24) o-hydroxy atorvastatin (3/19) p-hydroxy atorvastatin (3/19)

Figure 3.3 Ranges of detected concentrations of PPCPs in DWTP influent. Based on compiled data from sources identified in Table 3.2. Number detected and total number of compounds analyzed are given in parentheses.

a) 10000

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10 Water Concentration (ng/L)

0.1 Butalbital (8/24) Atenolol (8/358) Camphor (1/190) Codeine (24/344) Albuterol (2/326) Diazepam (3/121) Clindamycin (3/3) Diltiazem (31/358) Atorvastatin (6/13) Cotinine (216/650) Caffeine (299/911) Bupropion (NA/31) Diclofenac (37/317) Cimetidine (25/309) Citalopram (NA/31) Bezafibrate (25/260) Azithromycin (5/182) Ciprofloxacin (7/370) Clarithromycin (4/22) Clofibric acid (43/266) Acetaminophen (58/457) Chlortetracycline (6/583) Desmethyldiltiazem (1/1) Carbamazepine (250/655) Cyclophosphamide (3/15) COOH-ibuprofen (NA/24) Diphenhydramine (12/201) Dehydronifedipine (25/318) Anhydro-erythromycin (5/22) 1,7-Dimethylxanthine (86/359)

b) 10000

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0.1 Indole (6/19) Lasalocid (1/47) Nicotine (16/47) Iopromide (1/97) Metoprolol (1/24) Furosemide (4/67) Fluoxetine (7/436) Metformin (5/145) Enalaprilat (1/126) Ibuprofen (27/411) Naproxen (88/437) Fenoprofen (28/78) Norfloxacin (2/370) Hydrocodone (3/36) Monensin (170/260) Ketoprofen (27/130) Doxycycline (4/495) Meprobamate (11/86) Fluvoxamine (NA/16) Guaifenesin (NA/NA) Guaifenesin Norsertraline (NA/31) Lincomycin (215/600) Gemfibrozil (108/783) Indomethacin (25/159) Erythromycin (74/348) Norfluoxetine (NA/47) Enrofloxacin (NA/329) Methamphetamine (6/9) Hydrochlorothiazide (1/1) Erythromycin-H2O (34/275) (continued)

Figure 3.4 a, b, c Ranges of detected concentrations of PPCPs in surface water. Based on compiled data from sources identified in Table 3.2. Number detected and total number of compounds analyzed are given in parentheses.

c) 10000

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0.1 Valsartan (1/1) Ofloxacin (6/41) Tylosin (20/496) Oxycodone (1/1) Primidone (1/51) Propranolol (3/6) Triamterene (1/1) Phenytoin (5/109) Ranitidine (5/296) Sertraline (NA/32) Paroxetine (NA/32) Paraxanthine (2/24) Salicylic acid (1/52) Theobromine (3/68) Sulfadiazine (2/120) Tetracycline (3/575) Pentoxifylline (7/74) Venlafaxine (NA/31) Sulfathiazole (8/627) Thiabendazole (3/119) Sarafloxacin (NA/301) Phenobarbital (NA/NA) Roxithromycin (14/484) Sulfamethizole (NA/357) Trimethoprim (181/1089) Sulfamethazine (117/715) Oxytetracycline (NA/595) Sulfadimethoxine (21/626) Sulfamethoxazole (141/799) Sulfachloropyridazine (34/516)

Figure 3.4 a, b, c (Continued) Ranges of detected concentrations of PPCPs in surface water. Based on compiled data from sources identified in Table 3.2. Number detected and total number of compounds analyzed are given in parentheses.

a) 10000

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Water Concentration (ng/L) 0.1

0.01 BHT (1/33) BHA (1/15) 2,4-D (9/117) AHTN (NR/96) Dacthal (NR/87) Coprostanol (2/7) Alachlor (NR/87) Carbaryl (NR/93) Atrazine (31/158) Benomyl (NR/89) Bentazone (NR/87) Acetochlor (NR/87) Bisphenol A (2/188) Bendiocarb (NR/87) Benzophenone (1/31) Alachlor OA (NR/48) Alachlor ESA (NR/48) 4-n-nonylphenol (4/45) Chlorothalonil (NR/82) 17 beta-Estradiol (3/91) Acetochlor OA (NR/48) Acetochlor ESA (NR/48) 4-n-Octylphenol (NR/108) Chlorimuron ethyl (NR/89) 2,4-D Methyl ester (NR/87) 2-Hydroxy atrazine (NR/88) 3,4-Dichloroaniline (NR/83) Butylbenzyl phthalate (10/85) 17 alpha-Ethynylestradiol (3/36) Alachlor ESA 2nd amide (NR/48) Acetochlor ESA 2nd amide (NR/48) Alachlor sulfynilacetic acid (NR/48)

acetochlor sulfynilacetic acid (NR/48)

b) 10000

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1 Water Concentration (ng/L) 0.1

0.01 DEHP (4/48) Estriol (3/36) Estrone (2/82) Linuron (2/75) HHCB (2/229) Indole (NR/96) DEET (41/143) Fipronil (NR/87) Dinoseb (NR/89) Diuron (NR/123) Dicamba (NR/87) Iprodione (NR/87) Malaoxon (NR/87) Malathion (NR/87) Diazinon (NR/103) Imazaquin (NR/89) Dichlorvos (NR/87) Hexazinone (NR/87) Imazethapyr (NR/89) Imidacloprid (NR/87) Flumetsulam (NR/88) Dimethenamid (NR/48) Diethyl phthalate (1/15) Dibutyl phthalate (1/53) Fipronil sulfide (NR/87) Fipronil sulfone (NR/87) Dimethyl phthalate (1/15) Desethyl atrazine (NR/103) Desulfinyl fipronil (NR/87) Deisopropyl atrazine (NR/105) Diazinon, oxygen analog (NR/87) Desulfinyl fipronil amide (NR/87)

Deethyldeiso propyl atrazine (NR/89) (continued) Figure 3.5 a, b, c Ranges of detected concentrations of EDCs in drinking water. Based on compiled data from sources identified in Table 3.2. Number detected and total number of compounds analyzed are given in parentheses.

c) 10000

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1 Water Concentration (ng/L) 0.1

0.01 TBEP (2/12) TCPP (11/35) NDMA (10/0) TCEP (21/183) TCEP MTBE (NR/94) MCPA (NR/87) Simazine (1/103) Triclosan (2/208) Triclosan OP2EO (NR/108) OP2EO Perchlorate (2/16) Perchlorate Stigmasterol (2/4) Triclopyr (NR/89) Prometon (NR/91) Prometon Metolachlor (9/33) Trifluralin (NR/87) Progesterone (1/75) Progesterone Metribuzin (NR/87) Propyzamide (NR/87) Propyzamide Myclobutanil (NR/87) Myclobutanil Pendimethalin (NR/87) Sitosterol, beta- (3/100) beta- Sitosterol, Metolachlor OA (NR/48) Metolachlor ESA (NR/48) Metsulfuron methyl (NR/89) Metsulfuron Stigmastanol, beta- (NR/100) beta- Stigmastanol, Octylphenol, 4-tert- (NR/115) 4-tert- Octylphenol, Triphenyl phosphate (NR/114) Triphenyl Octyl methoxy cinnamate (1/15) Nonylphenol diethoxylate (NR/96) Octylphenol monoethoxylate (NR/96)

Tris (dichlorisopropyl phosphate) (NR/112) phosphate) (dichlorisopropyl Tris

Figure 3.5 a, b, c (Continued) Ranges of detected concentrations of EDCs in drinking water. Based on compiled data from sources identified in Table 3.2. Number detected and total number of compounds analyzed are given in parentheses.

A total of 30 unique PPCPs were identified as detected in at least one drinking water sample from sites in the United States. As shown in Table 3.3, the classes with the most detected compounds, based on the data that were compiled, were analgesics and anti-inflammatories (7 compounds), antibiotics/antibacterials (4 compounds), and psychotropic compounds (i.e., antidepressants/antianxiety agents/ antipsychotics (5 compounds). The most frequently detected PPCPs in drinking water (Table 3.5), with detection frequencies ≥25% based on the data that were compiled were (in decreasing order): acesulfame (50%), meprobamate (36%), propranolol (33%), atenolol (32%), caffeine (31%), carbamazepine (29%), and phenytoin (28%), although acesulfame was only analyzed in two samples and propranolol only in three. A total of 100 unique EDCs and nonPPCPs were identified as detected in at least one drinking water sample from sites in the United States. As shown in Table 3.4, the classes with the most detected compounds, based on the data that were compiled, were alkylphenols (4 compounds), flame retardants (5 compounds), herbicides and herbicide degradates (44 compounds), hormones (6 compounds), insecticides (13 compounds), and plasticizers (6

compounds). The most frequently detected individual EDCs and nonPPCPs in drinking water (Table 3.8), with detection frequencies ≥25% and analysis in at least three samples based on the data that were compiled, were perfluorooctane sulfonic acid (PFOS) (100%), atrazine-desethyl- desisopropyl (DACT) (83%), stigmasterol (50%), cis-testosterone (33%), tris (1,3-dichloro-2- propyl) phosphate (TCPP) (31%), N,N-diethyltoluamide (DEET) (29%), coprostanol (29%), atrazine (28%), and metolachlor (27%). Table 3.10 lists the relative detection frequencies of PPCPs in drinking water compared to DWTP influent and surface water. More detailed data for all compounds is presented in Appendix A. The 10 most frequently detected compounds in drinking water (for substances analyzed in at least 10 samples) in decreasing order, based on the data that were compiled, were: meprobamate, atenolol, caffeine, carbamazepine, phenytoin, cotinine, gemfibrozil, nicotine, furosemide, and theobromine. All of these compounds with the exception of nicotine, furosemide, and theobromine were also detected in DWTP influent and surface water. Nicotine, furosemide, and theobromine were not detected in DWTP influent (they were analyzed infrequently there) but were detected in surface water. Many other compounds were detected in DWTP influent or in surface water, but were infrequently detected or not detected in drinking water (Table 3.11). In general, concentrations of emerging contaminants decreased with increasing treatment, from WWTP influent to WWTP effluent, surface water, DWTP influent, and drinking water (Figure 3.6).

1000000 Legend WWTP Influent WWTP Effluent 100000 Surface Water DWTP Influent Drinking Water

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l r e e l n e e i n e n e t l e o o n d i l n n z e i i i i a o h h f o o o e p t z p n o p m r m n f e i r y a f t b o e e a m z i p n x t a o s n f b a a u e o i o A C C o r b h C m m r t m I Ph a e p a e t b Fu e G e r m c a M a f A C l Su

Figure 3.6 Maximum detected concentrations of selected PPCPs in water from different sources.

Results shown for the 12 most frequently detected compounds in drinking water that have 10 or more sample analyses in drinking water and in DWTP influent or surface water.

ADDITIONAL SOURCES OF INFORMATION ON SOURCES AND OCCURRENCE

Sources of additional information on sources and occurrence of PPCPs and EDCs in the environment include the following:

 EPA bibliographic list of published documents on PPCPs as environmental contaminants http://www.epa.gov/ppcp/lit.html  EPA general information on PPCPs in the environment, including basic information, frequent questions, and research areas http://www.epa.gov/ppcp/  EPA illustration of the Origins and Fate of PPCPs in the Environment: http://www.epa.gov/ppcp/pdf/drawing.pdf  EPA general information on Endocrine Disruptors http://www.epa.gov/endo/pubs/edspoverview/whatare.htm, including a Primer  EPA information on EDC research http://www.epa.gov/research/endocrinedisruption  USGS summary of research on Emerging Contaminants in the Environment http://toxics.usgs.gov/regional/emc/index.html  WHO/ United Nations Environment Programme (UNEP) publication (2013) on the State of the Science of Endocrine Disrupting Chemicals http://www.unep.org/chemicalsandwaste/UNEPsWork/EndocrineDisruptingChemicalsE DCs/tabid/79616/Default.aspx  Workshop report sponsored by the California Ocean Protection Council, the National Water Research Institute, and others on Managing Contaminants of Emerging Concern http://www.sfei.org/sites/default/files/CA%20CEC%20Workshop%20Final%20Report% 20Sept%202009.pdf  World Health Organization (WHO) publication (2012) on Pharmaceuticals in Drinking Water http://www.who.int/water_sanitation_health/publications/2011/pharmaceuticals/en/

CHAPTER 4: POTENTIAL TOXICOLOGICAL SIGNIFICANCE AND HUMAN HEALTH EFFECTS OF PPCPS AND EDCS IN DRINKING WATER

In general, for most PPCPs and many EDCs, regulatory criteria for source or drinking water have not been established. However, for most of these substances, data from scientific studies that assess the potential for adverse health effects are available. This chapter addresses the following questions:

 What is the evidence that PPCPs or EDCs in drinking water or other environmental media are affecting human health?  How much exposure does it take to cause an adverse effect?  Are the levels in water high enough to cause a concern?  How can the potential health risks of detected ppb or ppt levels of substances in water be evaluated?  What is the source of this information? Is it credible?  Do these assumptions consider sensitive populations?  What about exposures to multiple substances?  How does exposure from drinking water compare to exposure in food or other sources?

In addition, links to sources of additional information on these topics are provided.

EVIDENCE FOR ADVERSE EFFECTS OF PPCPS OR EDCS IN DRINKING WATER OR THE ENVIRONMENT ON HUMAN HEALTH

While research in this area is new, scientific studies have not demonstrated a link between low levels of pharmaceuticals detected in drinking water and adverse effects in human. Regarding pharmaceuticals in drinking water, the World Health Organization (WHO), in their technical report on Pharmaceuticals in Drinking Water (WHO 2012) concluded that

Current observations suggest that it is very unlikely that exposure to very low levels of pharmaceuticals in drinking-water would result in appreciable adverse risks to human health, as concentrations of pharmaceuticals detected in drinking-water (typically in the nanogram per liter range) are several orders of magnitude (typically more, and often much more, than 1000-fold) lower than the minimum therapeutic dose.

Also regarding pharmaceuticals in drinking water, the Global Water Research Coalition in their Science Brief entitled Occurrence and Potential For Human Health Impacts of Pharmaceuticals in the Water System (GWRC 2009), concluded based on a review of nine reports that:

It can be concluded from these reports that, to date, no definitive link has been reported or established between human exposure to pharmaceutical exposure in drinking water and human health risk. Put another way, there is no known impact on human health.

Regarding EDCs, authoritative bodies have expressed greater uncertainty about the potential for adverse effects in humans from exposure in drinking water or through other media (including food). For example, the World Health Organization and UNEP (WHO/UNEP 2013) in their State of the Science of Endocrine Disrupting Chemicals—2012 stated:

Three strands of evidence fuel concerns over endocrine disruptors:

 the high incidence and increasing trends of many endocrine-related disorders in humans  observations of endocrine-related effects in wildlife populations;  the identification of chemicals with endocrine disrupting properties linked to disease outcomes in laboratory studies.

Further, they note that only a small fraction of the suspected hundreds of compounds thought capable of interfering with hormone receptors have undergone adequate testing for these effects. The European Commission, in their State of the Art Assessment of Endocrine Disruptors (Kortenkamp 2011), described similar uncertainties, stating:

During the last two decades evidence of increasing trends of many endocrine-related disorders in humans has strengthened. Although the correct description of disease time trends is often complicated by a lack of uniform diagnostic criteria, unfavourable disease trends have become apparent where these difficulties could be overcome. There are negative impacts on the ability to reproduce and develop properly. There is good evidence that wildlife populations have been affected, with sometimes widespread effects. Multiple causes underlie these trends, and evidence is strengthening that chemical exposures are involved. Nevertheless, there are significant difficulties in identifying specific chemicals as contributing to risks.

Overall, the potential for endocrine disrupting effects in humans from exposure to EDCs at environmental levels is controversial. For example, some studies have suggested that exposure to bisphenol A, a plasticizer, is associated with weak estrogenic effects in females and males (Takeuchi 2002, Takeuchi et al. 2004); however, a cause-and-effect relationship has not been demonstrated definitively and some studies report negative findings. In other studies, high levels of a DDT metabolite, p,p’-DDE, in the blood of girls in Belgium and high levels of phthalate in blood of girls in Puerto Rico were associated with early puberty (Colón et al. 2000, Krstevska- Konstantinova et al. 2001), and some associations have been suggested between high levels of phthalates in blood and reproductive effects in males, including lower sperm count and reduced semen quality (Duty et al. 2003). In addition, the incidence of many endocrine-related diseases and disorders in humans, including reduced fertility, early puberty, and global rates of endocrine-related cancers (breast, endometrial, ovarian, prostate, testicular, thyroid) is thought to be on the rise. However, there is very little scientific and medical evidence to link these effects to any specific exposure. Some effects thought to be associated with environmental exposure to EDCs have been observed in wildlife, including developmental effects in fish and wildlife and declines in population sizes. For example, declines in bird populations have been associated with reduced eggshell thickness from DDT exposure (Struger and Weseloh 1985, Struger et al. 1985, Elliott et

al. 1988) and a group of coolant and insulating fluid chemicals known as polychlorinated biphenyls (PCBs) has been associated with disruption in thyroid function in sea lions and other aquatic mammals (Debier et al. 2005, Tabuchi et al. 2006). Feminization of male fish living near sewage treatment plant outfalls has been reported in a number of studies, thought to be due to exposure to estrogenic compounds (Barber et al. 2007, Blazer et al. 2007, Writer et al. 2010). In the laboratory, many chemicals have been shown to adversely affect animal endocrine systems and ongoing research is investigating the potential hazards of EDCs in the environment. WHO and the United National Environment Programme (UNEP) recently published a comprehensive review of studies examining the potential effects of EDCs in the environment on humans and ecological receptors (WHO/UNEP 2013). In general, the most sensitive window of exposure to EDCs is thought to be critical periods of development, such as fetal development and puberty. Table 4.1 summarizes the suspected endocrine modes of action for selected EDCs, based on studies in animals or humans.

Table 4.1 Summary of suspected endocrine modes of action for selected EDCs, based on studies in animals or humans Substance Group/ Use Mode of action* 4-Nonylphenol Surfactant Estrogenic; effects on male reproductive organs in rodents 4-tert-Octylphenol Surfactant Estrogenic; effects on male reproductive organs in rodents BHA (butylated Antioxidant Anti-estrogenic; delayed sexual maturation hydroxyanisole) and effects on thyroid gland in rodents (Jeong et al. 2005, EFSA 2011) Bisphenol A Plasticizer used in polycarbonate Estrogenic; limited evidence of disruption bottles and epoxy resins of estrus in rodents; affects adipose tissue deposition and food intake in rodents; early exposure affects development of mammary gland in rodents Chlordane Insecticide (organochlorine) Estrogenic; linked with increased prostate cancer DDT (dichlorodiphenyl- Insecticide (organochlorine) Estrogenic and antiandrogenic; possible trichloroethane) cause of endometriosis and disruption of ovarian cyclicity in humans; eggshell thinning and population declines in birds DEET (N,N-Diethyl- Insect repellant Combined exposure with permethrin and meta-toluamide) pyridostigmine bromide (PB) implicated in genitourinary disorders in Gulf War veterans; combined exposure suppressed spermatogenesis in rodents (Abou-Donia et al. 2003) Dieldrin Insecticide (organochlorine) Estrogenic Heptochlor Insecticide (organochlorine) Estrogenic; decreased circulating estradiol concentrations in rodents (continued)

Table 4.1 (Continued) Substance Group/ Use Mode of action* HHCB (galaxolide) Musk fragrance No clear evidence from in vivo studies; in vitro studies suggest weak estrogenic and anti-estrogenic activity Lindane (gamma-BHC) Insecticide (organochlorine) Estrogenic; decreased circulating estradiol concentrations in rodents Methoxychlor Insecticide (organochlorine) Estrogenic; affects estrous cycle; decreased progesterone concentrations in rodents Organophosphate flame Flame retardants Some evidence of thyroid hormone retardants (TCPP, TCEP, disruption and reduced fertility (Betts TDCPP) 2010) PBDEs (Polybrominated Flame retardants; used in textiles, Limited evidence for earlier age at diphenyl ethers) electronics, building materials menarche in humans; eggshell thinning and delayed hatching in birds; suppression of thyroid hormones in humans and wildlife PFOA Fluoropolymers (e.g., Teflon); Some association with adverse pregnancy (Perfluorooctanoic acid) surfactant outcomes in humans and with obesity; adrenal glands a potential target PFOS (Perfluorooctane- Fluoropolymers (e.g., Teflon); Lowered female fecundity and altered sulfonate) surfactant menstrual cycle through occupational exposure; reduced fetal growth Phthalate esters (DEHP, Plasticizer, finish, nail care Estrogenic; in animals, developmental butylbenzyl phthalate, effects on reproductive organs and reduced di-n-butyl phthalate) semen quality in males and reduced fertility in females Triazine herbicides Herbicide Neuroendocrine with effects primarily on (atrazine, simazine) female reproductive system (EPA 2006a); interrupted estrous cycle in rodents Triclosan Broad-spectrum antimicrobial; Disrupts steroidogogenic enzymes used in personal care products involved in the production of testosterone (mouth wash, toothpaste) and and estrogen consumer products Vinclozolin Fungicide Anti-androgenic; effects on male reproductive organs and sperm in rodents; decreased fertility and serum testosterone levels Source: WHO and UNEP 2013 unless otherwise stated

THE DOSE-RESPONSE CONCEPT

Detection of a compound in water does not mean that adverse health effects will occur or are likely. While all chemicals are potentially toxic at some dose, many factors play a role in whether or not a compound is toxic or harmful to humans or animals. In particular, the dose, or

amount, of chemical a person or animal receives is important in determining the likelihood that a chemical will cause an adverse effect. Even seemingly innocuous compounds such as sugar or water have the potential to be toxic at some level of exposure. For example, Table 4.2 summarizes the dosage of a variety of agents, ranging from sugar to botulinum toxin, that produces death after a single (acute) oral exposure (in milligrams per kilogram of body weight) based on exposures in laboratory rodents (mice or rats).

Table 4.2 Approximate acute LD50s of representative chemical agents Agent LD50 (mg/kg of body weight) Sucrose (table sugar) 30,000 Ethanol 10,000 Sodium chloride (table salt) 4,000 Benzene 3,300 Water 400 Caffeine 200 Nicotine 1 Tetrodotoxin (puffer fish toxin) 0.10 Dioxin 0.001 Botulinum toxin 0.00001 Source: data from Klaassen 2013 and Lewis 2004 LD50: The dose that is lethal to 50% of a study population, usually rodents. The lower the LD50, the more acutely toxic is the compound.

Clearly, while some chemicals are toxic in very small amounts, others are only toxic when the exposure is very large. The duration, or how long, a person is exposed is also important: exposure to some substances over a short period of time (known as acute exposure) may not be harmful while exposure over many years (known as chronic exposure) can cause adverse health effects. The nature of toxicological effects from exposure to different substances also varies depending on how they act in the body, with effects ranging from cancer to noncarcinogenic effects such as effects on reproductive capacity, growth and development, immune parameters, and organ systems. To predict the potential for a given substance to cause toxicity, scientists conduct tests in animals or evaluate humans that have been unintentionally or intentionally exposed (e.g., to medications). Newer methods using computer models can also predict toxicity. With this information, scientists can determine the dose at which adverse effects can occur and the nature of the response (i.e., the “dose-response”). They can also estimate the likelihood that exposure at a given dose will have a harmful effect in humans. This process is referred to as “risk assessment.” To determine whether detected concentrations of PPCPs or EDCs in drinking water present a significant health risk to people who consume the water, the availability of existing acceptable daily intakes (ADIs) or corresponding drinking water equivalent levels (DWELs), such as EPA MCLs, was determined. If an existing value was not available, screening-level human health risk-based ADIs and DWELs were derived from published toxicity information, following a decision tree approach. Detected concentrations in water were then compared to DWELs. The process is described below.

IDENTIFICATION OF EXISTING MCLS OR ADIS

For each of the compounds, the availability of existing MCLs or ADIs published by authoritative bodies and other entities was determined. Sources of values considered include the following:

 EPA MCLs  California MCLs  EPA reference doses (RfDs) for noncancer effects  EPA oral slope factors (SFs) for cancer  ATSDR minimal risk levels (MRLs) for noncancer effects, for intermediate and chronic duration exposures  California EPA Public Health Goals (PHGs) for drinking water  California EPA No Significant Risk Levels (NSRLs) for cancer and reproductive/ developmental toxicity developed as part of the Proposition 65 program  California EPA oral SFs for cancer  Joint FAO/WHO Expert Committee on Food Additives (JEFCA) ADIs  Joint FAO/WHO Meeting on Pesticide Residues (JMPR) ADIs  Other sources of values as appropriate

ADIs for noncancer endpoints were presented in units of milligrams per kilogram of body weight per day (mg/kg-d). For cancer endpoints, published SFs (presented in units of the proportion of a population affected per milligram of exposure per kilogram of body weight per day ((mg/kg-d)-1)) were converted to ADIs in units of mg/kg-d by assuming an acceptable lifetime excess cancer risk (de minimis risk) of 1 in one million (10-6) and that a person is exposed to the chemical at this dose daily over a lifetime (EPA 2005a). Specifically, for cancer ADIs were derived from published SFs as follows:

(4.1)

If a compound had a published EPA MCL, that value was selected for use in this evaluation regardless of other available values, since it has a regulatory basis. Otherwise, the lowest identified value was selected.

METHODS FOR DERIVING SCREENING LEVELS

For compounds detected in drinking water without identified published screening levels, “comparison levels” were derived from published toxicity data and other information using several methodologies per a decision tree approach. Then, the lowest of these comparison levels was selected as the ADI (Figure 4.1). This decision tree is based on an approach developed in WateReuse Foundation Project #05-005 (Snyder et al. 2010). In that project, methodologies for developing screening level human health risk-based criteria for PPCPs and EDCs potentially

Chemical X

Available MCL or published Yes ADI(s)?

If NOAEL available, divide by 1,000 or if LOAEL available, No divide by 3,000; if nongenotoxic carcinogen or EDC, divide by 10

Divide therapeutic dose by 3,000; if nongenotoxic carcinogen or EDC, Yes divide by 10 Pharmaceutical?

If antibiotic, use MIC to calculate comparison level

Select MCL or No lowest DWEL If genotoxic carcinogen and based on ADIs tumor data are available, -6 derive SF and SL using 10 risk; if no tumor data, use lower of VSD or TTC

If NOAEL available, divide by Available NOAELs Yes 1,000 or if LOAEL available, or LOAELs, or divide by 3,000; if genotoxic nongenotoxic carcinogen or carcinogen? EDC, divide by 10

No If genotoxic carcinogen and tumor data are available, -6 derive SF and SL using 10 Apply TTC risk; if no tumor data, use approach lower of VSD or TTC

Source: Adapted from Snyder et al. 2010

Figure 4.1 Decision tree for determining ADIs for substances of interest without existing criteria

present in water intended for indirect potable reuse were reviewed by a panel of experts comprised of regulators, scientists, water professionals, and other interested parties. Decision criteria were then developed to help in the selection of an appropriate screening methodology that can be used to rapidly develop a screening level for water in the event that a “new” chemical is detected. Note that ADIs and DWELs for PPCPs and EDCs published in previous WRF work (i.e., Project #3085, Snyder et al. 2008) may differ somewhat from those presented here since somewhat differing methodologies were applied (i.e., the screening methodology presented here incorporates additional sources of information or published ADIs, and includes in some cases an additional uncertainty factor of 10 when screening levels were derived from toxicological data or therapeutic doses and the compound shows evidence of non-genotoxic carcinogenicity or endocrine disrupting effects). As discussed by the expert panel in WRF-05-005, making chemical-specific uncertainty factor decisions for a large number of compounds is a major endeavor, requiring careful resource-intensive weighing of the database and its various uncertainties, and can engender disagreement. Consistent with the approach applied in WRF-05- 005, to simplify the process of developing screening values for this project, a more generic screening protocol, as presented in Figure 4.1, was applied. Alternative levels may be appropriate if the assumptions used to derive the levels are provided and justified. As was noted, if the concentration of the chemical is at or above the screening level determined with this methodology, then more detailed evaluation of the toxicity and occurrence of the compound is recommended; if the concentration of that compound is below the screening level, then the risk to public health is predicted to be well below levels of concern and the presence of the compound does not alone warrant further toxicological studies. Per the decision tree, the following decision criteria were applied:

1. If the compound is a pharmaceutical, derive comparison levels following several approaches depending on data availability: based on the therapeutic dose, based on the minimum inhibitory concentration (MIC) if the compound is an antibiotic, based on threshold doses for noncancer effects, or based on cancer toxicity data. Then, select the lowest value as the ADI.

If the compound is not a pharmaceutical, the availability of noncancer and/or cancer toxicity data was determined. If such data were available, comparison levels were derived using these data and the lowest of these values was selected as the ADI.

2. If the compound is not a pharmaceutical and no suitable noncancer or cancer toxicity data from toxicological studies were identified, an ADI was identified using the Threshold of Toxicologic Concern (TTC) approach.

Each method used to derive comparison levels per the decision tree approach is described in more detail below.

Derivation of Comparison Levels Using NOAELs or LOAELs from Toxicity Studies

Comparison levels for noncancer endpoints were derived from data on no observed adverse effect levels (NOAELs) or lowest observed adverse effect levels (LOAELs) for noncancer effects reported in animal toxicity studies or studies in humans (e.g., clinical trials). When establishing guidelines or standards for noncarcinogenic effects, including RfDs (EPA 2002b), MRLs (ATSDR 2007), and tolerable daily intakes (TDIs) (WHO 1994), agencies charged with developing guidance values typically assume that there is some threshold level of exposure below which adverse health effects do not occur and, based on review of toxicity data, identify a point of departure upon which to base the guidance level. This is typically the highest dose at which an effect is not seen (the NOAEL) or the lowest dose at which an effect is seen (the LOAEL). Below this dose, there is no evidence in animals or humans of a statistically or biologically significant increase in adverse effects, although some changes may occur that are not considered adverse (e.g., changes in certain enzyme levels). This “point of departure” is then divided by uncertainty factors (UFs) to derive a screening value considered protective to broader population groups, including sensitive populations such as children or people with immune compromised systems, as follows:

(4.2) Generally, several multiplicative UFs are applied, individually ranging in value from 3 to 10 with each factor representing a specific area of uncertainty in the available data (e.g., intraspecies uncertainty/variability, interspecies uncertainty/ variability, extrapolation from a LOAEL to a NOAEL, extrapolation from less-than-lifetime exposure to lifetime exposure, and database uncertainties). When high quality toxicity data are available, combined uncertainty in Schfactors typically range from 30 to 1,000. Per EPA risk assessment guidance (EPA 2008), a factor of 3 represents a “partial” uncertainty factor, equal to the half-log (square root) of 10 (i.e., 101/2), usually rounded to 3 for use in risk assessment. As such, by convention, when two UFs with a value of 3 are multiplied together, the resulting combined UF is 10 (not 3 × 3 =9). However, making chemical-specific UF decisions for a large number of compounds is a major endeavor, requiring careful resource-intensive weighing of the database and its various uncertainties, and can engender disagreement. Consistent with the approach applied in WRF-05- 005, to simplify the process of developing screening values for this project, we utilized a more generic screening protocol: applying a statistically-derived default cumulative UF of 1,000 when the point of departure is a NOAEL and a UF of 3,000 when the point of departure is a LOAEL, rather than deriving UFs on a study-specific basis. Application of default UFs of 1,000 and 3,000 is supported by a statistical analysis of a set of 216 “learning compounds” with EPA RfDs, NOAELs, and LOAELs conducted by EPA as part of the Contaminant Candidate List (CCL) Classification Process (EPA 2012f). In the WRF-05-005 process that we applied here, an additional UF of 10 was also applied if the substance was determined to be either a nongenotoxic carcinogen or an EDC. In a manner analogous to EPA RfDs, screening levels derived using this approach are assumed to correspond to the amount of a chemical to which a person, including members of sensitive subpopulations, can be exposed on a daily basis over an extended period of time (usually a lifetime) without suffering a deleterious effect (EPA 1993). Study types of most relevance for evaluating long-term low level exposures to compounds in water are assumed to be

subchronic, chronic, reproduction, and developmental toxicity (teratology) studies with exposure primarily via the oral route. Animal species of interest primarily included mice and rats, but could also include rabbits, dogs, primates, and other animals.

Derivation of Comparison Levels Based on the Lowest Therapeutic Dose of Pharmaceuticals

The lower end of a drug’s therapeutic range can be considered an estimate of the threshold for appreciable biological activity in target populations, and therefore may be considered a threshold for potential adverse effects. Following an approach analogous to the NOAEL/ LOAEL approach, for pharmaceutical compounds a comparison level was derived by dividing the lowest therapeutic dose by UFs to account for extrapolation from the LOAEL to a NOAEL, variations in susceptibility between different members of the population, or data gaps:

(4.3)

Consistent with the approach applied in WRF-05-005, a composite uncertainty factor of 3,000 was used. This approach assumes that the lowest therapeutic dose is effectively equivalent to a LOAEL. In the WRF-05-005 process that we applied here, an additional UF of 10 was also applied if the substance was determined to be either a nongenotoxic carcinogen or an EDC.

Derivation of Comparison Levels for Antibiotics Based on Minimum Inhibitory Concentrations

Comparison levels for antibiotics were developed based on the minimum inhibitory concentration (MIC) to human gastrointestinal flora, defined as the lowest concentration of the antibiotic that will inhibit the visible growth of the microorganism (WHO 1997, EMEA 1998b, Schwab et al. 2005, WHO 2006). Comparison levels were developed from MICs using the following equation (WHO 1997, 2006):

(4.4) Where:

MIC50 = Minimum inhibitory concentration of 50% of strains of the most sensitive relevant organism (mg/g, equivalent to µg/mL) [WHO (1997, 2006) is clear that the MIC50, as opposed to the MIC, should be applied in the calculation] MCC = Mass of colonic contents (g/day) FA = Fraction of the dose available to the gastrointestinal microflora SaF = Safety factor, with a magnitude depending on the quality and quantity of the microbiological data available BW = Body weight (kg)

To develop comparison levels for antibiotics, the MIC for the most sensitive bacterial strain determined in susceptibility assays was selected; these values were readily available for most of the study antibiotics. Fraction available (FA) was determined from the results of human clinical studies, or assumed to be 50% when no data were available. The mass of colonic contents (MCC) was assumed to be 220 g/day, as estimated by WHO (1997), and the assumed body weight (BW) of 70 kg was selected based on EPA’s default body weight for adults. A safety factor (SaF) of 10 was applied to account for limitations in the database.

Derivation of Comparison Levels for Carcinogenicity Based on Tumor Incidence Data

For chemicals with positive evidence of genotoxicity in laboratory experiments and reported evidence of carcinogenicity in high dose animal studies, a linear extrapolation model was used to predict the tumorigenic response at low doses. These types of models assume a linear relationship between risk and dose at low doses (EPA 2005a). The slope of the risk/dose line, known as the slope factor (SF), is an upper-bound estimate of risk per increment of dose (e.g., per 1 mg/kg-day of exposure) that can be used to estimate risk probabilities for different exposure levels. In this assessment, if sufficient data on tumor incidence per dose level were available for a given compound with evidence of carcinogenicity in animal bioassays, and data indicate that the compound is genotoxic and assumed to have a linear relationship between carcinogenicity and dose, a multi-stage carcinogenicity model was used to estimate a SF. For these compounds, EPA’s Benchmark Dose Software v.2.3 (BMDS 2.3) (EPA 2012a) was used to model the data in the observed range and estimate a benchmark dose level (BMDL) for a benchmark response of 10% extra risk, which is generally at the low end of the observable range for standard cancer bioassay data. This BMDL serves as the “point of departure” for linear extrapolation (EPA 2002b). Comparison levels were then calculated assuming an acceptable lifetime excess cancer risk of 1 in one million (10-6) and that a person is exposed to the chemical at this dose daily over a lifetime (EPA 2005a). Specifically, a comparison level was calculated as follows:

(4.5) In some cases, a chemical was reported to show evidence of carcinogenicity in animal studies, but no data on tumor incidence were located that could be used to develop a cancer SF. To be conservative and avoid dismissing a compound because of lack of data, a methodology for deriving a comparison level was used as agreed upon by the WRF-05-005 expert panel: if the compound is a nongenotoxic carcinogen and no tumor incidence data were identified, an additional UF of 10 was applied to the lowest therapeutic dose or the NOAEL/ LOAEL. If the compound is a genotoxic carcinogen and no tumor incidence data were identified, a comparison level was derived by dividing the maximum tolerated dose by 740,000 (the Gaylor and Gold 1998 VSD approach for genotoxic carcinogens, discussed below).

Derivation of a Virtually Safe Dose for Carcinogens

For compounds with evidence of carcinogenicity in animals and with evidence of genotoxicity, but for which no tumor incidence data were identified, a virtually safe dose (VSD) was calculated using the method of Gaylor and Gold (1995). Gaylor and Gold (1995) proposed a method for calculating a VSD without the need to conduct multi-year laboratory studies for carcinogenicity. Gold et al. created the Carcinogenic Potency Database summarizing results from 6,540 chronic, long-term animal cancer tests on 1,547 chemicals, as published in the general literature through 2001 and by the National Cancer Institute (NCI) or the National Toxicology Program (NTP) through 2004 (Gold et al. 2011). Gaylor and Gold (1995) reviewed the results of two-year cancer bioassays for 139 chemicals tested by the NTP and determined that a “virtually safe dose” corresponding to a cancer risk of 1 in a million can be estimated by dividing a chemical’s maximum tolerated dose from 90-day studies in rodents by 740,000. The maximum tolerated dose is the highest dose predicted to produce minimal systemic toxicity over the course of a carcinogenicity study, estimated from 90- day dose range finding studies, and in practice is usually the high dose selected for a carcinogenicity study (FDA 2005). For purposes of this project, the genotoxicity assumptions applied to assess carcinogenicity potential were based on data identified for four different in vitro genotoxicity test types: the Ames test, mouse lymphoma assay (MLA), the in vitro micronucleus assay (MN), and the in vitro chromosomal aberration assay (CA). Based on results from these tests, the determination of genotoxicity was made as follows:

 Compounds that tested negative in all tests for which data were available were assumed to be nongenotoxic (negative), and  Compounds that tested positive in one or more tests for which data were available were assumed to be genotoxic (positive).

However, caution is recommended with regard to interpreting negative genotoxicity tests as indicative of noncarcinogenicity, since these compounds may be carcinogenic via nongenotoxic mechanisms (e.g., liver enzyme induction, peroxisome proliferation, hormonal carcinogens).

Derivation of Comparison Levels Based on Thresholds of Toxicologic Concern

For compounds without comparison levels derived using other approaches, a threshold of toxicologic concern (TTC) was identified. The TTC approach assigns an exposure level (or concentration) that is thought very unlikely to produce an adverse effect from exposure to a given compound, based on an assessment of the body of toxicological data for structurally and chemically similar compounds. The concept was originally developed for food additives (Cheeseman et al. 1999, Kroes et al. 2004) and has been expanded to consider ingredients of pharmaceuticals (Dolan et al. 2005) and personal and household care products (Blackburn et al. 2005). The stated goal of application of TTCs is to help focus research efforts on those chemicals likely to pose the greatest toxicologic risk. In general, TTCs are considered best applied to compounds for which very limited or no toxicity data are available to conduct a traditional toxicity assessment (Kroes et al. 2004, Dolan et al. 2005).

Several TTC schemes have been developed, and all rely on assumptions about a chemical’s activity based on chemical structure. Cramer et al. (1978) defined three chemical classes to which compounds can be assigned according to the presence of structural groups and other features based on a decision tree approach. The former European Chemicals Bureau provides open source software (ToxTree) that was used to assign chemicals of interest to a Cramer class based upon the compound’s SMILES (simplified molecular input line entry specification) code. The software is currently available at the SourceForge website (http://toxtree.sourceforge.net/). Two of the most popular schemes, Cheeseman et al. (1999) and Kroes et al. (2004), were applied in this evaluation. Cheeseman et al. (1999) extracted data on 709 carcinogens from the Gold carcinogenic potency database to examine the utility of using short-term toxicity data, the results of genotoxicity testing, and structural alerts to identify more and less potent subsets of compounds in the dataset. Kroes et al. (2004) further refined the structural groups identified by Cheeseman et al. (1999). TTCs are generally expressed as an intake (e.g., in micrograms per person/day). These levels can be converted to comparison levels (in units of μg/kg-d) based on an assumed adult body weight (e.g., 70 kg; EPA 2011f) as follows:

(4.6) When applying TTCs, it is important that they only be applied to compounds that are structurally similar to those upon which the TTCs are based. Several authors have reviewed the application of TTCs to specific compound types. While TTCs have in general been developed using data for industrial compounds, Blackburn et al. (2005) evaluated the appropriateness of use of the TTCs determined by Munro et al. (1996) for evaluating ingredients of personal and household care products, by assigning 43 chemicals used in household and personal care products to the three Cramer classes, and comparing the range of no observed effect levels (NOELs) for those compounds to the range of NOELs used by Munro et al. (1996) to develop the TTCs. The results showed that the distribution of NOELs for household and personal care product ingredients fell well within the range of the NOELs for the larger database analyzed by Munro et al. (1996), and that the published TTC values for the three Cramer classes are adequately protective benchmarks (Munro et al. 1996). Of note, the application of TTCs to pharmaceuticals is largely a hypothetical exercise, in that none of the TTC schemes evaluated explicitly considered in their derivation deliberately biologically active compounds such as pharmaceuticals. As such, the appropriateness of application of the TTCs to pharmaceuticals is uncertain. Furthermore, both Cheeseman et al. (1999) and Kroes et al. (2004) caution against applying TTCs to EDCs. However, since Munro et al. (1996) determined that TTC schemes are protective of a broader range of compound types than industrial compounds, and since one of the goals of this project is to derive a screening level for each compound to aid utilities in decision making, TTCs were derived for all pharmaceuticals for comparison purposes and for EDCs when no other data was available.

Conversion of the Lowest Comparison Level to a DWEL

The lowest (most health-protective) identified comparison level for each compound was converted to a DWEL assuming that a person consumes 2 liters of water per day (the EPA default value for water consumption; EPA 2000a) with this concentration as follows:

(4.7)

A DWEL is similar to a maximum contaminant level goal (MCLG), which is calculated by EPA based on health data using similar approaches, to represent a concentration that is not likely to be associated with adverse health effects. A maximum contaminant level (MCL) is an enforceable level based on the MCLG that also takes other considerations into account, such as economic feasibility. In WRF-05-005 it was noted that the ADIs and DWELs that are developed using this approach are conservative, in part because of the multiplicative conservative UFs that were determined by the panel to be health-protective without the need to apply resource intensive investigation of the mechanism of action and toxicity of each compound. However, it was noted that alternatively, individually chosen UFs can be applied for each compound if a written rationale for the selection of specific values is provided.

SUMMARY OF IDENTIFIED ADIS AND DWELS

Table 4.3 and 4.4 present the DWELs identified using the decision tree approach for the PPCPs and EDCs, respectively that were detected in drinking water, based on the occurrence data gathered in this study. Detailed data compiled to support calculation of comparison levels and selection of DWELs are presented in Appendix B.

Table 4.3 DWELs for PPCPs derived using the decision tree approach DWEL* Chemical Basis of value (µg/L) Acesulfame (Sweet One, Ace K, Sunnet) NOAEL/LOAEL 16,000 Acetaminophen Therapeutic dose 11 Albuterol Therapeutic dose 0.0032 Alprazolam NOAEL/LOAEL 0.0039 Amitriptyline Therapeutic dose 13 Amoxicillin Therapeutic dose 130 Amphetamine Therapeutic dose 2.1 Ampicillin Therapeutic dose 560 Antipyrine or Phenazone NOAEL/LOAEL 350 Aspirin Therapeutic dose 56 Atenolol Therapeutic dose 0.42 Atorvastatin Therapeutic dose 0.35 Azithromycin Therapeutic dose 100 Bacitracin NOAEL/LOAEL 130 Bendroflumethiazide Therapeutic dose 0.84 Benzatropine Therapeutic dose 0.42 Benzoylecgonine Therapeutic dose 25 Benzylpenicllin Therapeutic dose 21 Benzyl salicylate Therapeutic dose 53 Bezafibrate Therapeutic dose 67 Bupropion VSD 42 Butalbital Therapeutic dose 8.1 Caffeine NOAEL/LOAEL 2.9 Camphor NOAEL/LOAEL 24,000 Carbadox CSF 0.039 Carbamazepine Therapeutic dose 1.2 (continued)

Table 4.3 (Continued) DWEL* Chemical Basis of value (µg/L) Carisoprodol Therapeutic dose 42 Cefotaxime Therapeutic dose 84 Cephalexin Therapeutic dose 29 Chloramphenicol Therapeutic dose 0.16 Chlortetracycline NOAEL/LOAEL 290 Cimetidine Therapeutic dose 6.7 Ciprofloxacin Therapeutic dose 42 Citalopram Therapeutic dose 0.34 Clarithromycin Therapeutic dose 84 Clinafloxacin MIC 2,800 Clindamycin Therapeutic dose 88 Clofibrate/Clofibric acid CSF 0.67 Cloxacillin Therapeutic dose 42 Cocaine NOAEL/LOAEL 2.3 Codeine Therapeutic dose 2.3 COOH-ibuprofen Therapeutic dose 34 Cotinine NOAEL/LOAEL 2.8 Cyclophosphamide CSF 0.026 Dehydronifedipine Therapeutic dose 4.9 Demeclocycline Therapeutic dose 25 Desmethyldiltiazem Therapeutic dose 20 Dexamethasone Therapeutic dose 0.13 Diazepam Therapeutic dose 0.34 Diclofenac Therapeutic dose 17 Digoxin Therapeutic dose 0.0016 Diltiazem Therapeutic dose 20 Diphenhydramine Therapeutic dose 4.2 Doxycycline Therapeutic dose 1.6 Duloxetine Therapeutic dose 6.7 Enalapril Therapeutic dose 1.7 Enalaprilat Therapeutic dose 1.7 (continued)

Table 4.3 (Continued) DWEL* Chemical Basis of value (µg/L) Enrofloxacin NOAEL/LOAEL 60 Ephedrine NOAEL/LOAEL 1.2 Epi-anhydro-tetracycline Therapeutic dose 170 Epi-chlorotetracycline Therapeutic dose 170 Epi-tetracycline Therapeutic dose 170 Erythromycin Therapeutic dose 350

Erythromycin-H2O MIC 2.8 Fenoprofen Therapeutic dose 33 Flumequine NOAEL/LOAEL 35 5-Fluorouracil NOAEL/LOAEL 120 Fluoxetine Therapeutic dose 3.9 Fluvoxamine Therapeutic dose 17 Furosemide CSF 3.2 Gabapentin Therapeutic dose 30 Gemfibrozil Therapeutic dose 20 Glipizide Therapeutic dose 0.84 Glyburide Therapeutic dose 0.42 Guaifenesin Therapeutic dose 33 Hexylsalicylate Therapeutic dose 53 Homomenthyl salicylate Therapeutic dose 53 Hydrochlorothiazide Therapeutic dose 2.1 Hydrocodone Therapeutic dose 0.84 10-Hydroxy-amitriptyline Therapeutic dose 13 2-Hydroxy-ibuprofen Therapeutic dose 34 Hydrocortisone Therapeutic dose 1.6 Ibuprofen Therapeutic dose 34 Ibuprofen methyl ester Therapeutic dose 34 Indomethacin CSF 0.027 Iohexol NOAEL/LOAEL 180 Iopromide NOAEL/LOAEL 180 Iso-chlorotetracycline Therapeutic dose 170 (continued)

Table 4.3 (Continued) DWEL* Chemical Basis of value (µg/L) Iso-epi-chlorotetracyline Therapeutic dose 170 Ketoprofen Therapeutic dose 33 Ketorolac Therapeutic dose 6.7 Lasalocid NOAEL/LOAEL 18 Lidocaine Therapeutic dose 35 Lincomycin Therapeutic dose 120 Lomefloxacin Therapeutic dose 67 Meclofenamic acid NOAEL/LOAEL 110 Meprobamate Therapeutic dose 77 Menthol NOAEL/LOAEL 7,000 Metformin Therapeutic dose 17 Methadone Therapeutic dose 0.70 Methamphetamine Therapeutic dose 7.7 Methocarbamol Therapeutic dose 84 Methotrexate Therapeutic dose 0.70 Metoprolol Therapeutic dose 0.42 Miconazole Therapeutic dose 17 Minocycline Therapeutic dose 3.3 Monensin NOAEL/LOAEL 49 Naproxen Therapeutic dose 46 Narasin NOAEL/LOAEL 88 Nicotine Therapeutic dose 0.080 Nifedipine Therapeutic dose 4.9 Norfloxacin Therapeutic dose 130 Norfluoxetine Therapeutic dose 3.9 6-O-des-methyl-naproxen Therapeutic dose 46 Ofloxacin Therapeutic dose 67 OH-ibuprofen Therapeutic dose 34 o-Hydroxy atorvastatin Therapeutic dose 0.35 Oleandomycin Therapeutic dose 42 Ormetoprim Therapeutic dose 42 (continued)

Table 4.3 (Continued) DWEL* Chemical Basis of value (µg/L) Oxacillin MIC 5,600 Oxolinic acid NOAEL/LOAEL 15 Oxycodone Therapeutic dose 42 Oxytetracycline Therapeutic dose 42 Penicillin G Therapeutic dose 21 Penicillin V Therapeutic dose 21 Pentoxifylline VSD 21 Phenobarbital CSF 0.74 Phenoxymethylpenicillin Therapeutic dose 21 Phenytoin CSF 29 p-Hydroxy atorvastatin Therapeutic dose 0.35 Prednisone Therapeutic dose 0.070 Primidone CSF 0.070 Propranolol Therapeutic dose 13 Ranitidine Therapeutic dose 46 Risperidone Therapeutic dose 0.018 Roxithromycin Therapeutic dose 49 Salicyclic acid Therapeutic dose 49 Salinomycin NOAEL/LOAEL 95 Sarafloxacin MIC 2,800 Simvastatin Therapeutic dose 0.18 Simvastatin (hydroxyl acid) Therapeutic dose 0.18 Sucralose NOAEL/LOAEL 5,300 Sulfachloropyridazine MIC 2,800,000 Sulfadiazine NOAEL/LOAEL 170 Sulfadimethoxine MIC 53,000 Sulfamerazine Therapeutic dose 220 Sulfamethazine Therapeutic dose 22 Sulfamethizole Therapeutic dose 17 Sulfamethoxazole Therapeutic dose 150 Sulfasalazine Therapeutic dose 35 (continued)

Table 4.3 (Continued) DWEL* Chemical Basis of value (µg/L) Sulfathiazole NOAEL/LOAEL 210 Tetracycline and metabolites Therapeutic dose 170 Theobromine NOAEL/LOAEL 23 Theophylline Therapeutic dose 2.3 Thiabendazole NOAEL/LOAEL 310 Trimethoprim Therapeutic dose 95 Tylosin MIC 120,000 Valproic acid Therapeutic dose 0.070 Virginiamycin MIC 5,600 Warfarin Therapeutic dose 0.35 CSF − cancer slope factor; DWEL – drinking water equivalent level; LOAEL – lowest observed adverse effect level; MIC – minimum inhibitory concentration; NA – not available; NOAEL – no observed adverse effect level; VSD – virtually safe dose *DWELs are calculated as follows: lowest value of the existing ADI and the comparison level (µg/kg-d) × 70 (kg) / 2 (L/d). Note that ADIs and DWELs for PPCPs and EDCs published in previous WRF work (i.e., Project #3085, Snyder et al. 2008) may differ somewhat from those presented here since somewhat differing methodologies were applied. Consistent with the approach applied in WRF-05-005, to simplify the process of developing screening values for this project, a more generic screening protocol, as presented in Figure 4.1, was applied. Alternative levels may be appropriate if the assumptions used to derive the levels are provided and justified.

Table 4.4 DWELs for EDCs derived using the decision tree approach DWEL* Chemical Basis of value (µg/L) 1,4-Dichlorobenzene EPA MCL† 75 17 α-Estradiol Derived from therapeutic dose 0.0070 17 β-Estradiol CalEPA NSRL 0.010 17α-Ethynylestradiol Derived from therapeutic dose 0.00035 2,4’-DDD CalEPA NSRL 1.0 2,4’-DDT CalEPA NSRL 1.0 2,4-D EPA MCL 70 2,4-D Methyl ester EPA MCL 70 2-Hydroxy atrazine EPA MCL 3.0 2-Methyl naphthalene EPA RfD 140 2-Methyl-4-chlorophenoxyacetic acid (MCPA) EPA RfD 18 2-Phenoxyethanol Derived from NOAEL/LOAEL 11,000 3,4-Dichloroaniline Equal to Linuron, Diuron 70 3-Indole-butyric acid NOAEL/LOAEL 110,000 4,4’-DDD EPA SF 0.2 4,4’-DDE EPA SF 0.1 4,4’-DDT EPA SF 0.1 4-Methylphenol ATSDR MRL 3,500 5-Chloro-m-cresol ATSDR MRL 3,500 5-Methyl-1H-benzotriazole Derived from NOAEL/LOAEL 35,000 6-acetyl- 1,1,2,4,4,7-hexamethyltetralin (AHTN, Tonalide) Derived from NOAEL/LOAEL 18 Acetochlor EPA RfD 700 Acetochlor ethanesulfonic acid (ESA) Equal to Acetochlor 700 Acetochlor oxanilic acid Equal to Acetochlor 700 Acetochlor sulfynilacetic acid Equal to Acetochlor 700 Acetochlor/metolachlor ethane sulfonic acid 2nd amide Equal to Acetochlor 700 Acetyl cedrene Derived from NOAEL/LOAEL 1,800 Acridine Derived from NOAEL/LOAEL 420 Alachlor EPA and CalEPA MCL 2 Alachlor ethanesulfonic acid (ESA) Equal to Alachlor 2 (continued)

Table 4.4 (Continued) DWEL* Chemical Basis of value (µg/L) Alachlor ethanesulfonic acid (ESA) 2nd amide Equal to Alachlor 2 Alachlor oxanilic acid Equal to Alachlor 2 Alachlor sulfynilacetic acid Equal to Alachlor 2 Alpha-chlordane EPA MCL 2 Androstenedione Derived from NOAEL/LOAEL 840 Androsterone NA 0.00049‡ Atrazine EPA MCL† 3 Atrazine desethyl (DEA) EPA MCL† 3 Atrazine-desethyl-desisopropyl (DACT) Equal to Atrazine† 3 Bendiocarb JMPR ADI 140 Benomyl EPA RfD 1,800 Bentazone CalEPA MCL 18 Benzophenone JECFA ADI 350 Benzyl acetate Derived from CSF 3.2 Beta-BHC EPA SF 0.019 Biochanin A Derived from CSF 0.095 Bisphenol A EPA RfD 1,800 Bromodichloromethane EPA SF 0.6 Bromoform EPA SF 4.4 Butylated hydroxyanisole (BHA) CalEPA SF 180 Butylated hydroxyl toluene (BHT) EPA SF 9.7 Butylbenzyl phthalate CalEPA NSRL 600 Campesterol JEFCA ADI 1.4E6 Carbaryl JMPR ADI 280 Chlorimuron ethyl EPA RfD 700 Chloroform CalEPA SF 1.1 Chlorophene Derived from NOAEL/LOAEL 35 Chlorothalonil CalEPA SF 11 Chlorpyriphos ATSDR MRL 35 Chlorpyriphos-oxon Equal to Chlorpyriphos 35 Cholestanol Derived from NOAEL/LOAEL 1,500 (continued)

Table 4.4 (Continued) DWEL* Chemical Basis of value (µg/L) Cholesterol Derived from NOAEL/LOAEL 6.0 Chrysin Derived from CSF 0.095 cis-1,2-Dichloroethene EPA RfD 700 Cis-Nonachlor EPA MCL 2.0 Cis-Permethrin JMPR ADI 1,800 cis-Testosterone Assume 10x < potent than testosterone 7.0E-4 Coprostanol Derived from NOAEL/LOAEL 6.0 Coumestrol JEFCA ADI 1.4E6 Cyanazine EPA SF 0.042 Cypermethrin EPA RfD 350 Dacthal EPA RfD 350 Deethyldeiso propyl atrazine (DDA) Equal to Atrazine† 3 Deisopropyl atrazine (DIA) Equal to Atrazine† 3 Desmosterol Derived from NOAEL/LOAEL 6.0 Desulfinyl fipronil Equal to Fipronil 7.0 Desulfinyl fipronil amide Equal to Fipronil 7.0 Di(ethylhexyl) phthalate (DEHP) CalEPA MCL 4 Diazinon ATSDR MRL 25 Diazinon, oxygen analog Equal to Diazinon 25 Dibromochloromethane EPA SF 0.4 Dibutyl phthalate EPA RfD 3,500 Dicamba EPA RfD 1,100 Dichlorvos EPA SF 0.1 Dieldrin EPA SF 0.0022 Diethyl phthalate ATSDR MRL 210,000 Digoxigenin JEFCA ADI 1,400,000 Dimethenamid EPA RfD 1,750 Dimethyl phthalate Derived from NOAEL/LOAEL 2,800 Dinoseb CalEPA MCL 7 Diuron EPA RfD 70 Endosulfan I ATSDR MRL 180 Endosulfan sulfate JMPR ADI 210 (continued)

Table 4.4 (Continued) DWEL* Chemical Basis of value (µg/L) Epicoprostanol Derived from NOAEL/LOAEL 6.0 Equilenin Derived from therapeutic dose 0.0053 Equilin Dervied from therapeutic dose 0.0053 Ergosterol Derived from NOAEL/LOAEL 4.6 Estriol Derived from NOAEL/LOAEL 23 Estrone Derived from therapeutic dose 0.00025 Ethyl citrate Derived from NOAEL/LOAEL 23,000 Fipronil JMPR ADI 7.0 Fipronil sulfide Equal to Fipronil 7.0 Fipronil sulfone Equal to Fipronil 7.0 Flumetsulam US EPA HED 35,000 Formononetin Derived from CSF 0.095 Galaxolide (HHCB) Derived from NOAEL/LOAEL 180 Gamma-BHC (Lindane) EPA and CalEPA MCL 0.2 Gamma-chlordane EPA MCL 2 Genistein Derived from CSF 0.095 Glycitein Derived from CSF 0.095 Heptachlor Epoxide EPA MCL† 0.2 Hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX) EPA SF 0.3 Hexazinone EPA RfD 1,200 Hexylcinnamaldehyde Derived from TTC 0.74 Hydrocinnamic acid Derived from TTC 0.74 Imazaquin EPA RfD 8,800 Imazethapyr EPA RfD 8,800 Imidacloprid JMPR ADI 2,100 Indole Derived from NOAEL/LOAEL 16,000 Iprodione EPA RfD 1,400 Isobornyl acetate NOAEL/LOAEL 530 Linuron EPA RfD 70 Malaoxon Derived from NOAEL/LOAEL 24 Malathion EPA RfD 700 Mecoprop EPA RfD 35 (continued)

Table 4.4 (Continued) DWEL* Chemical Basis of value (µg/L) Mestranol Dervied from therapeutic dose 0.00021 Methoxychlor EPA MCL† 40 Methyl tert-butyl ether (MTBE) CalEPA MCL 13 Methylene chloride EPA MCL 5.0 Methyl-parathion EPA RfD 8.8 Metolachlor EPA RfD 5,300 Metolachlor ethanesulfonic acid Equal to Metolachlor 5,300 Metolachlor oxanilic acid Equal to Metolachor 5,300 Metribuzin EPA RfD 880 Metsulfuron methyl EPA RfD 8,800 Musk ketone Derived from NOAEL/LOAEL 8.8 Musk xylene Derived from NOAEL/LOAEL 26 Myclobutanil EPA RfD 880 N,N- Diethyltoluamide (DEET) Derived from NOAEL/LOAEL 81 N-EtFOSAA EU Panel 5.3 N-nitrosodiethylamine (NDEA) EPA SF 0.00023 N-nitrosodimethylamine (NDMA) EPA SF 0.00069 N-Nitroso-di-n-butylamine (NDBA) EPA SF 0.0065 N-nitroso-methylethylamine (NMEA) EPA SF 0.0016 N-nitrosopyrrolidine (NPYR) EPA SF 0.017 Nonylphenol diethoxylates (NP2EO) Derived from NOAEL/LOAEL 5.3 Nonylphenol monoethyoxylates (NP1EO) Derived from NOAEL/LOAEL 5.3 Nonylphenols (NP) Derived from NOAEL/LOAEL 5.3 Norethindrone Derived from therapeutic dose 0.0056 Octyl methoxy cinnamate Derived from NOAEL/LOAEL 290 Octylphenols (OC) Derived from NOAEL/LOAEL 46 Oxybenzone Derived from NOAEL/LOAEL 350 PBDE-100 ATSDR MRL 250 PBDE-153 ATSDR MRL 250 PBDE-154 ATSDR MRL 250 PBDE-183 ATSDR MRL 250 PBDE-209 (Decabromo-diphenyl ether) Derived from NOAEL/LOAEL 350 (continued)

Table 4.4 (Continued) DWEL* Chemical Basis of value (µg/L) PBDE-28+PBDE-33 ATSDR MRL 250 PBDE-47 ATSDR MRL 250 PBDE-99 ATSDR MRL 250 p-Chloroaniline EPA SF 0.2 p-chloro-m-xylenol (PCMX) EU Panel 5.3 Pendimethalin EPA RfD 1,400 Perchlorate California MCL 1 Perfluorobutane-sulfonate EU Panel 5.3 Perfluorobutanoic acid (C4) EU Panel 5.3 Perfluorobutyric acid (PFBA) Derived from NOAEL/LOAEL 24 Perfluoro-decanoic acid (C10) EU Panel 5.3 Perfluoro-dodecanoic acid (C12) EU Panel 5.3 Perfluoroheptanoic acid (C7) EU Panel 5.3 Perfluorohexane sulfonic acid EU Panel 5.3 Perfluorohexane-sulfonate EU Panel 5.3 Perfluorohexanoic acid (C6) EU Panel 5.3 Perfluorononanoic acid (C9) EU Panel 5.3 Perfluorooctane sulfinate EU Panel 5.3 Perfluorooctane sulfonamide EU Panel 5.3 Perfluorooctane sulfonamide acetic acid EU Panel 5.3 Perfluorooctane sulfonic acid (PFOS) EU Panel 5.3 Perfluorooctanoic acid (C8) EU Panel 53 Perfluoropentanoic acid (C5) EU Panel 5.3 Perfluoropropionic acid EU Panel 5.3 Perfluoro-undecanoic acid EU Panel 5.3 Permethrin EPA RfD 1,800 Perthane Derived from NOAEL/LOAEL 290 Phathalic anhydride EPA RfD 70,000 Progesterone JEFCA ADI 0.0011 Prometon EPA RfD 530 Propyzamide EPA RfD 2,600 Simazine EPA and CalEPA MCL 4 (continued)

Table 4.4 (Continued) DWEL* Chemical Basis of value (µg/L) Sitosterol, beta- JEFCA ADI 1,400,000 Stigmastanol, beta- JEFCA ADI 1,400,000 Stigmasterol JEFCA ADI 1,400,000 Terbufos sulfone JMPR ADI 7.0 Testosterone JEFCA ADI 7.0E-5 Total perfluorinated sulfonyls EU Panel 5.3 Total PFA EPA MCL 600 Total short-chain chlorinated paraffin (SCCP) Derived from CSF 11 Trans-Nonachlor Equal to chlordane 2 Trans-Permethrin JMPR ADI 1,800 Traseolide Derived from NOAEL/LOAEL 8.8 Tri (dichloro-propyl) phosphate CalEPA NSRL 2.7 Triclocarban Derived from NOAEL/LOAEL 88 Triclopyr EPA TRED 1,800 Triclosan EPA HHBP 2,100 Trifluralin EPA SF 4.5 Trihalomethanes EPA MCL 80 Triphenyl phosphate ATSDR MRL 7,000 Tris (2-butoxyethyl) phosphate (TBEP) ATSDR MRL 3,200 Tris (2-chloroethyl) phosphate (TCEP) EPA SF 1.8 Tris (dichlorisopropyl phosphate) (TDCPP) CalEPA NSRL 190 Tris(2,3-dichloro-propyl) phosphate Equal to TCEP 1.8 ADI − Acceptable Daily Intake; CSF − cancer slope factor; DWEL – drinking water equivalent level; EU – European Union; HHBP – Health Based Benchmarks for Pesticides; JECFA − Joint FAO/WHO Expert Committee on Food Additives; JMPR – Joint FAO/WHO Meeting on Pesticide Residues; LOAEL – lowest observed adverse effect level; MCL – EPA Maximum Contaminant Level; NA – not available; MRL − Minimum Risk Level estimated by ATSDR; NOAEL – no observed adverse effect level; NSRL – No Significant Risk Level estimated by California EPA for Proposition 65; RfD − reference dose determined by EPA; SF − cancer slope factor estimated by EPA or CalEPA; TRED − Tolerance Reassessment Progress and Risk Management Decision; TTC – threshold of toxicologic concern; VSD – virtually safe dose *DWELs are calculated as follows: ADI (µg/kg-d) × 70 (kg) / 2 (L/d). Note that ADIs and DWELs for PPCPs and EDCs published in previous WRF work (i.e., Project #3085, Snyder et al. 2008) may differ somewhat from those presented here since somewhat differing methodologies were applied. Consistent with the approach applied in WRF-05-005, to simplify the process of developing screening values for this project, a more generic screening protocol, as presented in Figure 4.1, was applied. Alternative levels may be appropriate if the assumptions used to derive the levels are provided and justified. †Compound has a lower California MCL (see Table B.1). ‡No data available; Assumed to be 1/7 as potent as testosterone (Scott, T., ed. 1996)

COMPARISON OF DRINKING WATER CONCENTRATIONS TO DWELS

To put the comparison of DWELs and detected concentrations into understandable terms to support risk communication, the amount of water with the maximum detected concentration of each substance in drinking water that a person would have to consume, in 8-ounce glasses of water per day, to reach a dose equal to the ADI was calculated. The calculation used to compute these values is as follows:

(4.8)

Tables 4.5 (PPCPs) and 4.6 (EDCs and non-pharmaceuticals) present the results of these calculations, based on the maximum-detected concentrations in drinking water identified in the occurrence data gathered in this evaluation. These results (using Equation 4.8) answer the question, “How much water would a person have to drink per day to get a dose equal to the ADI for the substance?” As shown in Table 4.5, a person would have to drink at least 39 8-oz glasses of water a day (about 2.4 gallons) to reach a dose equal to the ADI calculated for any of the PPCPs. As shown in Table 4.6, for two hormones (17α-ethynylestradiol and estrone) and one herbicide (atrazine), the maximum concentration detected in drinking water exceeds the calculated DWEL. For the two hormones, the amount of water to one would need to consume per day to get a dose equal to the ADI is less than one glass, and for atrazine it is 7.5 glasses. It is critical to remember that the ADI values identified using the decision tree approach and extrapolated to DWELs are meant to be “screening level” values in that if the concentration of a substance in water is at or above the screening value, then more detailed evaluation of the toxicity and occurrence of the substance is recommended. Concentrations above or near the DWEL do not indicate that adverse effects are likely to occur. This is because the assumptions used to calculate these screening levels are very conservative, specifically:

 They are based either on the lowest dose that caused an adverse effect in any toxicological study, taking into consideration effects on sensitive populations, or the lowest therapeutic dose for pharmaceuticals.  This lowest dose is then divided by multiple uncertainty factors (with a combined value ranging from 1,000 to 30,000 for each substance) such the resulting screening level is well below any dose that has been associated with adverse effects.

Further, the calculations shown in Tables 4.5 and 4.6 assume a person repeatedly consumes, day after day over a lifetime, the maximum concentration detected anywhere in the country. The average concentration in drinking water to which a person may be exposed over time would be much lower, if it is detected at all.

Table 4.5 Comparison of Drinking Water Equivalent Levels (DWELs) and highest level detected in drinking water for PPCP ingredients Required water Freq. of Maximum consumption detection conc. DWEL (8-oz Compound Group % (µg/L) (µg/L) glasses/day)* Sweet One (Ace K, Sunnet) Artificial sweetener 50% 0.022 16,000 6,150,000 Meprobamate Psychotropic 36% 0.042 77 15,500 Propranolol Antihypertensive 33% 0.0008 13 137,000 Atenolol Antihypertensive 32% 0.018 0.42 197 Caffeine Caffeine 31% 0.22 2.9 111 Carbamazepine Anticonvulsant 29% 0.258 1.2 39 Phenytoin Anticonvulsant 28% 0.019 29 12,900 Cotinine Nicotine 24% 0.077 2.8 307 Gemfibrozil Antilipidemic 22% 0.0021 20 80,500 Nicotine Nicotine 17% 0.005 0.08 135 Furosemide Diuretic 14% 0.053 3.2 510 Theobromine Caffeine 12% 0.06 23 3,240 Camphor Fragrance/ flavoring 11% 0.021 24,000 9,660,000 Methadone Analgesic 11% 0.016 0.7 370 Ketoprofen Analgesic 8% 0.026 33 10,700 Ibuprofen Analgesic 8% 1.35 34 213 Acetaminophen Analgesic 7% 0.002 11 46,500 Ibuprofen methyl ester Analgesic 7% 0.33 34 871 Sulfamethoxazole Antibiotic 6% 0.006 150 211,000 Codeine Analgesic 5% 0.03 2.3 648 Dehydronifedipine Antihypertensive 5% 0.07 4.9 592 Fluoxetine Psychotropic 5% 0.00082 3.9 40,200 Tylosin Antibiotic 4% 0.001 120,000 >10,000,000 Norfluoxetine Psychotropic 3% 0.00077 3.9 42,800 Risperidone Psychotropic 3% 0.0029 0.018 52 Iopromide X-ray contrast agent 2% 0.011 180 138,000 Sulfathiazole Antibiotic 2% 0.01 210 177,000 Monensin Antibiotic 2% 0.004 49 103,000 Diazepam Psychotropic 1% 0.00033 0.34 8,710 Naproxen Analgesic 1% 0.003 46 129,000 *Approximate required water consumption (8 oz glasses/day) calculated as [DWEL (µg/L)  2 L/d  4.23 glasses/L]/Detected water concentration (µg/L)

Table 4.6 Comparison of Drinking Water Equivalent Levels (DWELs) and highest level detected in drinking water for EDCs Freq. of Maximum Required water detection conc. DWEL consumption (8-oz Compound Group % (µg/L) (µg/L) glasses/day)* PFOS PFC 100% 0.0028 5.3 16,000 DACT Herbicide 83% 0.1 1 85 Stigmasterol Sterol 50% 0.16 1,400,000 >10,000,000 cis-Testosterone Hormone 33% 0.0002 0.0007 30 TCPP Flame retardant 31% 0.51 2.7 44 DEET Insect repellant 29% 0.097 81 7,060 Coprostanol Sterol 29% 0.002 6.0 25,000 Atrazine Herbicide 28% 3.4 3 7.5 Metolachlor Herbicide 27% 0.47 5,300 95,400 Cyanazine Herbicide 17% 0.023 0.042 15 TBEP Flame retardant 17% 0.32 3,200 84,600 Perchlorate Explosives 13% 2.2 6 23 Butylbenzyl phthalate Plasticizer 12% 0.911 600 5,570 TCEP Flame retardant 11% 0.47 1.8 32 Estriol Hormone 10% 0.0028 23 69,400 4-n-Nonylphenol Alkylphenol 9% 1.1 5.3 41 Deisopropyl atrazine Herbicide 9% 0.12 3 210 17α-Ethynylestradiol Hormone 8% 0.0039 0.00035 <1 DEHP Plasticizer 8% 2.68 4 12 Simazine Herbicide 8% 0.73 4 46 2,4-D Methyl ester Herbicide 8% 0.46 70 1,290 BHA Preservative 7% 0.23 180 6,620 Diethyl phthalate Plasticizer 7% 0.16 210,000 >10,000,000 Dimethyl phthalate Plasticizer 7% 0.04 2,800 592,000 Octyl methoxy cinnamate Sunscreen 7% 0.03 29 8,170 Desethyl atrazine Herbicide 5% 0.13 3 195 Progesterone Hormone 4% 0.0006 0.0011 16 17 β-Estradiol Hormone 3% 0.0035 0.010 24 Benzophenone Sunscreen 3% 0.13 350 22,700 BHT Preservative 3% 0.026 9.7 3,150 Sitosterol, beta- Sterol 3% 1.4 1,400,000 8,460,000 Linuron Herbicide 3% 0.0062 70 95,500 Bisphenol A Plasticizer 3% 0.44 1,800 34,600 Estrone Hormone 2% 0.0045 0.00025 <1 Dibutyl phthalate Plasticizer 2% 0.18 3,500 164,000 Triclosan Antimicrobial 1% 0.734 2,100 24,200 HHCB Fragrance/ flavor 1% 0.3 180 5,080 2,4-D Methyl ester Herbicide NR 0.063 70 9,400 2-Hydroxy atrazine Herbicide NR 0.3 3.0 84 3,4-Dichloroaniline Misc ingredient NR 0.009 70 65,800 4-n-Octylphenol Alkylphenol NR 0.25 46 1,560 Acetochlor Herbicide NR 0.14 700 42,300 (continued)

Table 4.6 (Continued) Required water Freq. of Maximum consumption detection conc. DWEL (8-oz Compound Group % (µg/L) (µg/L) glasses/day)* Acetochlor ESA Herbicide NR 0.31 700 19,100 Acetochlor ESA 2nd amide Herbicide NR 0.08 700 74,000 Acetochlor oxanilic acid Herbicide NR 0.4 700 14,800 Acetochlor sulfynilacetic acid Herbicide NR 0.17 700 34,800 AHTN Fragrance/ flavor NR 0.3 18,000 507,000 Alachlor Herbicide NR 0.017 2 995 Alachlor ESA Herbicide NR 0.37 2 46 Alachlor ESA 2nd amide Herbicide NR 0.07 2 242 Alachlor oxanilic acid Herbicide NR 0.12 2 141 Alachlor sulfynilacetic acid Herbicide NR 0.05 2 338 Bendiocarb Insecticide NR 0.019 140 62,300 Benomyl Fungicide NR 0.008 1,800 1,900,000 Bentazon Herbicide NR 0.02 18 7,610 Carbaryl Insecticide NR 0.035 280 67,600 Chlorimuron ethyl Herbicide NR 0.006 700 987,000 Chlorothalonil Herbicide NR 0.71 11 131 Dacthal Herbicide NR 0.005 350 592,000 Desulfinyl fipronil Insecticide NR 0.008 7.0 7,400 Desulfinyl fipronil amide Insecticide NR 0.006 7.0 9,870 Diazinon Insecticide NR 0.006 25 352,300 Diazinon, oxygen analog Insecticide NR 0.0011 25 192,000 Dicamba Herbicide NR 0.071 1,100 131,000 Dichlorvos Insecticide NR 0.005 0.10 169 Dimethenamid Herbicide NR 0.12 1,750 123,000 Dinoseb Herbicide NR 0.006 35 49,300 Diuron Herbicide NR 0.18 70 3,290 Fipronil Insecticide NR 0.009 7.0 6,580 Fipronil sulfide Insecticide NR 0.008 7.0 7,400 Fipronil sulfone Insecticide NR 0.007 7.0 8,460 Flumetsulam Herbicide NR 0.049 35,000 6,040,000 Hexazinone Herbicide NR 0.021 1,200 483,000 Imazaquin Herbicide NR 0.025 8,800 2,970,000 Imazethapyr Herbicide NR 0.026 8,800 2,860,000 Imidacloprid Insecticide NR 0.021 2,100 846,000 Indole Fragrance/ flavor NR 0.003 16,000 >10,000,000 Iprodione Fungicide NR 0.018 1,400 658,000 Malaoxon Insecticide NR 0.01 24 20,300 Malathion Insecticide NR 0.009 700 658,000 MCPA Herbicide NR 0.39 18 390 Metolachlor ESA Herbicide NR 1.9 5,300 23,500 Metolachlor OA Herbicide NR 0.46 5,300 97,400 Metribuzin Herbicide NR 0.016 880 465,000 (continued)

Table 4.6 (Continued) Required water Freq. of Maximum consumption detection conc. DWEL (8-oz Compound Group % (µg/L) (µg/L) glasses/day)* Metsulfuron methyl Herbicide NR 0.058 8,800 1,280,000 MTBE Gasoline additive NR 0.56 13 196 Myclobutanil Fungicide NR 0.018 880 413,000 Nonylphenol diethoxylate Alkylphenol NR 5.9 5.3 7.6 Octylphenol monoethoxylate Alkylphenol NR 0.7 46 556 Octylphenol, 4-tert- Alkylphenol NR 0.016 46 24,300 OP2EO Alkylphenol NR 0.24 46 1,620 Pendimethalin Herbicide NR 0.025 1,400 473,000 Prometon Herbicide NR 0.2 530 22,400 Propyzamide Herbicide NR 0.007 2,600 3,140,000 Stigmastanol, beta- Sterol NR 1.6 1,400,000 7,400,000 Triclopyr Herbicide NR 0.035 1,800 435,000 Trifluralin Herbicide NR 0.006 4.5 6,340 Triphenyl phosphate Flame retardant NR 0.16 7,000 370,000 TDCPP Flame retardant NR 5.5 190 292 *Approximate required water consumption (8 oz glasses/day) calculated as [DWEL (µg/L)  2 L/d  4.23 glasses/L]/Detected water concentration (µg/L).

Exceedance of a screening level does not mean that adverse health effects are likely or expected, but rather, provides a “first cut” to identify those compounds more likely to be of health concern and therefore that warrant further study. Table 4.7 provides another perspective on the maximum detected concentrations of PPCPs or EDCs used medicinally (or for DEET, as a deliberately applied insect repellant) in drinking water. Concentrations are compared to the dose of the pharmaceutical or substance one would receive if they consumed a typical medicinal dose (e.g., a single pill) or exposure unit of the substance (e.g., one 12-oz soda or one 8-oz cup of coffee for acesulfame and caffeine, respectively, or one ounce of chocolate for theobromine). The amount of drinking water with the maximum concentration that a person would have to consume to get a dose equal to that in a pill or other exposure unit was calculated as follows:

(4.9)

These results (using Equation 4.9) answer the question, “How much water would a person have to drink per day to equal the dose in one pill (or unit, 12-oz soda, cup of coffee, etc.)?” As shown in Table 4.7, a person would have to drink more than 600,000 8-oz glasses of water a day (more than 4,600 gallons) to reach a dose equal to that in one pill of any of the pharmaceuticals. Also, one would have to drink more than 4,100 8-oz glasses of water with the maximum concentration of cotinine (a metabolite of nicotine) to get the dose one would get from smoking one cigarette.

Still another approach to put these concentrations of PPCPs or medicinal EDCs (or for DEET, as a deliberately applied insect repellant) in perspective is to consider the length of time that a person would have to ingest water containing the maximum detected concentration in drinking water, at the accepted “default” rate of 2 L/day (about 64 fluid ounces, or eight 8-oz glasses), to equal the dose in one pill (or exposure unit). The calculation used to compute these values is as follows:

(4.10)

These results (using Equation 4.10) answer the question, “How long would a person have to drink water with the maximum detected concentration to equal the dose in one pill (or unit, 12-oz soda, cup of coffee, etc.)?” As shown in Table 4.8, a person would have to drink 2 liters per day of the water for nearly 200 years to reach a dose equal to the typical unit dose associated with one pill of any of the pharmaceuticals. Also, one would have to drink this amount of water with the maximum concentration of cotinine (a metabolite of nicotine) for one and one-third years to get the dose one would get from smoking one cigarette.

Table 4.7 Amount of water required to consume to equal amount in one typical pill or exposure unit, at maximum concentration of PPCPs or EDCs detected in drinking water Maximum Amount in Required water conc. pill or unit consumption (8- Substance Group Brand Name (µg/L) (mg)* oz glasses/day) † PPCPs Acesulfame Sweetener Sweet One® 0.022 50‡ 9,610,000 Meprobamate Psychotropic Equanil® 0.042 200 20,100,000 Propranolol Antihypertensive Inderal® 0.0008 20 105,000,000 Atenolol Antihypertensive Tenormin® 0.018 25 5,870,000 Caffeine Caffeine NA 0.22 80§ 1,530,000 Carbamazepine Anticonvulsant Tegretol® 0.258 200 3,270,000 Phenytoin Anticonvulsant Dilantin® 0.019 100 22,200,000 Cotinine Nicotine NA 0.077 0.075** 4,120 Gemfibrozil Antilipidemic Lopid® 0.0021 600 1,200,000,000 Nicotine Nicotine NA 0.005 0.1†† 84,600 Furosemide Diuretic Lasix® 0.053 20 1,600,000 Theobromine Caffeine NA 0.06 293‡‡ 20,600,000 Camphor Fragrance/ flavor NA 0.021 NA - Methadone Analgesic Methadone® 0.016 5 1,320,000 Ketoprofen Analgesic Nexcede® 0.026 75 12,200,000 Ibuprofen Analgesic Advil® 1.35 200 627,000 Acetaminophen Analgesic Tylenol®, Excedrin® 0.002 325 687,000,000 Ibuprofen methyl ester Analgesic Advil® 0.33 200 2,560,000 Sulfamethoxazole Antibiotic Bactrim®, Septra® 0.006 400 282,000,000 Codeine Analgesic Tylenol with Codeine® 0.03 30 4,230,000 Dehydronifedipine Antihypertensive Nifedipine® 0.07 10 604,000 Fluoxetine Psychotropic Prozac® 0.00082 10 51,500,000 Tylosin Antibiotic Tylan® 0.001 NA§§ - Norfluoxetine Psychotropic Prozac® (metabolite) 0.00077 10 54,900,000 Risperidone Psychotropic Risperdal® 0.0029 1 1,450,000 Iopromide X-ray contrast NA 0.011 NA - Sulfathiazole Antibiotic NA 0.01 NA§§ - Monensin Antibiotic Rumensin® 0.004 NA§§ - Diazepam Psychotropic Valium® 0.00033 5 64,100,000 Naproxen Analgesic Aleve®, Anaprox® 0.003 220 310,000,000 EDCs DEET Insect repellant OFF®, Cutter® 0.097 54.6*** 23,800,800 17β-Estradiol Hormone Estrace® 0.0035 0.5 6,040,000 Ethinyl estradiol Hormone Yasmin®, Ocella® 0.0039 0.035 380,000 Progesterone Hormone Prometrium® 0.0060 100 >10,000,000 *Source: Drugs.com unless otherwise noted †Approximate required water consumption (8 oz glasses/day) ‡ Amount in one 12-fl oz serving of Coke Zero (Beverage Institute for Health and Wellness 2013) § Amount in one 8-oz cup of brewed coffee, drip method (range 65-120; CSPI 2007) **A metabolite of nicotine typically excreted in urine. Assume 75% of nicotine from one cigarette is converted to cotinine (Benowitz et al. 2009) ††Amount absorbed from one cigarette (MedHealth.net 2014) ‡‡Amount in one ounce of a 65% cacao bar (Merck, Sharp, and Dohme 2013) §§Veterinary drugs—typical human doses not available ***Average dermal absorbed dose after a single application for a woman, 65 kg, based on usage surveys of DEET insect repellant (CDPR 2000).

Table 4.8 Number of years of exposure to equal dose in one typical pill or exposure unit, at maximum concentration of PPCPs or EDCs detected in drinking water (assuming 2 L water/d) Maximum Amount in conc. pill or unit Number of years Substance Group Brand Name (µg/L) (mg)* at 2 L/d † PPCPs Acesulfame Artificial sweetener Sweet One® 0.022 50‡ 3,110 Meprobamate Psychotropic Equanil® 0.042 200 6,520 Propranolol Antihypertensive Inderal® 0.0008 20 34,200 Atenolol Antihypertensive Tenormin® 0.018 25 1,900 Caffeine Caffeine NA 0.22 80§ 498 Carbamazepine Anticonvulsant Tegretol® 0.258 200 1,060 Phenytoin Anticonvulsant Dilantin® 0.019 100 7,210 Cotinine Nicotine NA 0.077 0.075** 1.3 Gemfibrozil Antilipidemic Lopid® 0.0021 600 391,000 Nicotine Nicotine NA 0.005 0.1†† 27.4 Furosemide Diuretic Lasix® 0.053 20 517 Theobromine Caffeine NA 0.06 293‡‡ 6,690 Camphor Fragrance/ flavor NA 0.021 NA NA Methadone Analgesic Methadone® 0.016 5 428 Ketoprofen Analgesic Nexcede® 0.026 75 3,950 Ibuprofen Analgesic Advil® 1.35 200 203 Acetaminophen Analgesic Tylenol®, Excedrin® 0.002 325 223,000 Ibuprofen methyl ester Analgesic Advil® 0.33 200 830 Sulfamethoxazole Antibiotic Bactrim®, Septra® 0.006 400 91,300 Codeine Analgesic Tylenol with Codeine® 0.03 30 1,370 Dehydronifedipine Antihypertensive Nifedipine ® 0.07 10 196 Fluoxetine Psychotropic Prozac® 0.00082 10 16,700 Tylosin Antibiotic Tylan® 0.001 NA§§ NA Norfluoxetine Psychotropic Prozac® (metabolite) 0.00077 10 17,800 Risperidone Psychotropic Risperdal® 0.0029 1 472 Iopromide X-ray contrast NA 0.011 NA NA Sulfathiazole Antibiotic NA 0.01 NA§§ NA Monensin Antibiotic Rumensin® 0.004 NA§§ NA Diazepam Psychotropic Valium® 0.00033 5 20,800 Naproxen Analgesic Aleve®, Anaprox® 0.003 220 100,000 EDCs DEET Insect repellant OFF®, Cutter® 0.097 54.6*** 771 17β-Estradiol Hormone Estrace® 0.0035 0.5 196 Ethinyl estradiol Hormone Yasmin®, Ocella® 0.0039 0.035 12.3 Progesterone Hormone Prometrium® 0.0060 100 228,000 *Source: Drugs.com unless otherwise noted †Approximate number of years of exposure, assuming consumption of 2 L of water with the maximum concentration per day ‡ Amount in one 12-fl oz serving of Coke Zero (Beverage Institute for Health and Wellness 2013) § Amount in one 8-oz cup of brewed coffee, drip method (range 65-120; CSPI 2007) **A metabolite of nicotine typically excreted in urine. Assume 75% of nicotine from one cigarette is converted to cotinine (Benowitz et al. 2009) ††Amount absorbed from one cigarette (MedHealth.net 2014) ‡‡Amount in one ounce of a 65% cacao bar (Merck, Sharp, and Dohme 2013) §§Veterinary drugs—typical human doses not available ***Average dermal absorbed dose after a single application for a woman, 65 kg, based on usage surveys of DEET insect repellant (CDPR 2000).

CHARACTERIZATION OF “HIGHEST RISK” COMPOUNDS

As shown in Table 4.6, for three EDCs the estimated amount of water one would need to consume per day to get a dose equal to the ADI is less than 8 glasses. The potential sources of these compounds in water, the drinking water concentrations used as the basis for the calculation results presented in Table 4.6, health effects that have been reported, the basis of the estimated DWEL, and options for treatment in water are described below.

17α-Ethynylestradiol

Use/Source

17α-Ethynylestradiol (also known as ethinyl estradiol) is a synthetic steroid hormone that is used as an estrogenic component in oral contraceptives. It is also used for the treatment of menopausal and post-menopausal symptoms, and is marketed under such brand names as Alesse®, Tri-Cyclen®, Triphasi®, and Yasmin® (DrugBank 2013a).

Concentrations in Drinking Water

Ethynylestradiol is insoluble in water. In 2005, ethynylestradiol was detected in finished drinking water collected prior to leaving the treatment plants in Ann Arbor, Grand Rapids, and Monroe, Michigan (Skadsen et al. 2006). The maximum detected concentration in drinking water was 3.9 ng/L at the Ann Arbor plant. Secondary treatment of source water consisted of recarbonation after softening (pH adjustment), clarification, ozonation, and disinfection. Ethynylestradiol was not detected in finished drinking water or distribution water collected from 19 water utilities around the United States. in 2006-2007 (limit of detection = 1 ng/L) (Benotti et al. 2009).

Health Effects/Carcinogenicity

Ethynylestradiol is in FDA Pregnancy Category X, meaning that studies in animals or humans have demonstrated fetal abnormalities and/or there is positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experience, and the risks involved in use of the drug in pregnant women clearly outweigh potential benefits. In humans, ethynylestradiol has been associated with an increased risk of hypertension, thromboembolism, myocardial infarction, and stroke, as well as endometrial, cervical, and breast cancer. In males, ethynylestradiol was thought to have an effect on sperm motility (NLM 2012f).

Basis of DWEL

The DWEL applied in this evaluation (0.35 ng/L) for ethynylestradiol was based on its lowest therapeutic dose of 0.02 mg/d as hormone replacement therapy, divided by a composite uncertainty factor of 3,000 with an additional factor of 10 applied because it is an EDC and shows evidence of nongenotoxic carcinogenicity.

Treatment Approaches

Coagulation was ineffective at removing ethynylestradiol (0%) (Westerhoff et al. 2005). Ethynylestradiol was more effectively removed by activated carbon (e.g., at ~97% with a powdered activated carbon (PAC) dose of 5 or 20 mg/L, Westerhoff et al. 2005, Snyder et al. 2007a), conventional activated sludge (e.g., 71-94%, Joss et al. 2004), membrane bioreactors (e.g., ≥75%, Joss et al. 2004), and ozonation (e.g., 99%, Westerhoff et al. 2005). Riverbank filtration has also been demonstrated to be effective at removal of ethynylestradiol, with removal of greater than 80% (Benotti et al. 2012, Storck et al. 2010).

Atrazine

Use/Source

Atrazine is a chlorotriazine herbicide (others include cyanazine, propazine, and simazine) that is registered for use in the United States. on a variety of commodities including vegetables, grains, fruits, and nuts, as well as turf grasses (EPA 2006a).

Concentrations in Drinking Water

The maximum detected concentration of atrazine in drinking water was 3,400 ng/L. This concentration was reported by Kingsbury et al. (2008) in a study of source water withdrawn from streams in nine community water systems and the associated finished drinking water conducted in 2004 and 2005. The source waters were the Cache la Poudre River, CO; Truckee River, NV; Clackamas River, OR; Running Gutter Brook, MA; Chattahoochee River, GA; Neuse River, NC; Potomac River, MD; Elm Fork Trinity River, TX; and White River, IN. Atrazine was detected at a frequency of 87% in the finished water (detected in 75 of 87 samples). The maximum source water concentration of atrazine was 5,000 ng/L. At two of the locations (Texas and Indiana), agriculture was assumed to comprise more than 50% of the land use in the watershed and atrazine was detected in 100% of the source water samples. A wide range of treatment approaches were used at the facilities, and are described in the report. Atrazine was also detected in finished drinking water or distribution water in a study of 19 water utilities by Benotti et al. (2009) in 2006-2007. The maximum detected concentration was 930 ng/L.

Health Effects/Carcinogenicity

All four of the chlorotriazine herbicides and their metabolites deisopropylatrazine (DIA), desethylatrazine (DEA), and diaminochlorotriazine (DACT) are assumed to share the same neuroendocrine mechanism of toxicity, with effects on the female reproductive system due to alterations in the hypothalamic control of luteinizing hormone (LH) and prolactin, and suppression of ovulation (EPA 2006a). According to California EPA (CalEPA 1999), human epidemiologic data suggesting adverse reproductive and developmental effects from exposure to atrazine are equivocal. In Iowa communities, an association was found between exposure to an average of 2.2 μg/L atrazine in drinking water and an increased risk of intrauterine growth retardation and cardiac, urogenital, and limb reduction defects. A study of farm couples living year-round on farms in Ontario,

Canada and exposed to atrazine (exposure level not available) indicates that the sex ratio was not altered and the risk of small for gestational age deliveries was not increased in relation to pesticide exposure (ATSDR 2003). The carcinogenic potential of atrazine has been investigated in a number of epidemiology studies, including cohort studies of workers at triazines manufacturing facilities, case-control studies of farmers using atrazine or triazines, and ecological studies of populations living in agricultural areas with high atrazine use and residents living in areas with atrazine-contaminated drinking water. Collectively, these studies provide suggestive evidence of a possible association between atrazine exposure and non-Hodgkin’s lymphoma, but a causal relationship cannot be established (ATSDR 2003). EPA has classified atrazine as “not likely to be carcinogenic to humans”; they concluded that the development of mammary tumors in rodents was not likely to relevant to humans because the mode of action in the rat is not likely to be operative in humans (EPA 2006a).

Basis of DWEL

The DWEL for atrazine applied in this evaluation is equal to its EPA MCL of 3 µg/L (3,000 ng/L). This MCL is equal to the MCLG for atrazine of 3 µg/L which is based on a multi- generation study in rats that showed decreased body weight gain in pups, with a NOAEL of 0.5 mg/kg-d. EPA applied a combined uncertainty factor of 5,000 (10 for interspecies variation, 10 for intraspecies variation, and 50 for the possibility of carcinogenic effect, based on the equivocal evidence of mammary tumors in rats) to arrive at the MCLG (CalEPA 1999). Note that since 2003, atrazine has been the subject of an intensive EPA monitoring program of raw and finished water in community water systems (CWSs) in the United States. (EPA 2014f).

Treatment Approaches

Sanches et al. (2010) showed that low pressure direct photolysis using a high ultraviolet (UV) fluence (1500 mJ/cm2) was extremely effective in removing atrazine, as well as other pesticides (alachlor and pentachlorophenol) from surface water and groundwater. Atrazine was moderately removed by ozonation (e.g., 47%, Westerhoff et al. 2005) and by PAC (60-69%, Westerhoff et al. 2005). It was not effectively removed by coagulation (0%, Westerhoff et al. 2005). Riverbank filtration was ineffective at removal of atrazine (<20%) (Benotti et al. 2012, Storck et al. 2010).

Estrone

Use/Source

Estrone is an endogenous (natural) estrogen hormone. It is less abundant in the female body than estriol and estradiol, but is the primary circulating estrogen in women after menopause. It is excreted in urine. Medicinally, it is used to treat abnormalities related to gonadotropin hormone dysfunction, vasomotor symptoms, vaginitis, and vulvar atrophy associated with menopause, and for the prevention of osteoporosis due to estrogen deficiency (DrugBank 2013b).

Concentrations in Drinking Water

In 2005, estrone was detected in finished drinking water collected prior to leaving the treatment plants in Ann Arbor and Grand Rapids, Michigan (Skadsen et al. 2006). The maximum detected concentration was 4.5 ng/L at the Grand Rapids plant. The concentration of estrone in source water (from the Grand River, which is directly connected to Lake Michigan) at this plant was 4.3 ng/L. Details on the treatment methods were not provided. Estrone was not detected in finished drinking water or distribution water collected from 19 water utilities around the United States. in 2006-2007 (limit of detection = 0.2 ng/L) (Benotti et al. 2009), or in samples of water from the City of Chicago from 2009-2011 (limit of detection = 0.3 ng/L) (CDWM 2011).

Health Effects/Carcinogenicity

Estrone is in FDA Pregnancy Category X, meaning that studies in animals or humans have demonstrated fetal abnormalities and/or there is positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experience, and the risks involved in use of the drug in pregnant women clearly outweigh potential benefits. In humans, estrone has been associated with birth defects (teratogenicity). In humans, estrogen therapy has also been associated with an increased risk of cardiovascular events such as myocardial infarction, stroke, venous thrombosis, and pulmonary embolism (NLM 2012b). Some studies suggest it may stimulate mammary tumors that have already developed. Its estrogenic potency is one-third that of estradiol. There is sufficient evidence in humans for the carcinogenicity of post-menopausal estrogen therapy, and sufficient evidence in experimental animals for the carcinogenicity of estrone. Estrone is listed as a Proposition 65 carcinogen in California, but neither EPA nor CalEPA have derived a cancer slope factor for this compound.

Basis of DWEL

The DWEL applied in this evaluation (0.25 ng/L) for estrone was based on the lowest therapeutic dose of 0.5 mg/d (or 7.1 µg/kg-d assuming a body weight of 70 kg) for treatment of symptoms of menopause and ovary problems in woman. An ADI of 0.00020 µg/kg-d was derived by dividing the therapeutic dose by an uncertainty factor of 3,000, with an additional uncertainty factor of 10 because the compound is an endocrine disruptor and shows evidence of being a nongenotoxic carcinogen.

Treatment Approaches

Coagulation was only minimally effective at removing estrone (e.g., 5%, Westerhoff et al. 2005). Estrone was more effectively removed by activated carbon (e.g., 76%, Westerhoff et al. 2005), conventional activated sludge (e.g., 49- ≥99%, Joss et al. 2004), membrane bioreactors (e.g., 96%, Joss et al. 2004), reverse osmosis (>99%, Snyder et al. 2007a), and ozonation (e.g., 99%, Westerhoff et al. 2005). Riverbank filtration has also been demonstrated to be effective at removal of estrone, with removal of greater than 80% (Benotti et al. 2012, Storck et al. 2010).

ASSESSING TOTAL EXPOSURE FROM WATER, DIET, AND OTHER SOURCES

The calculation of the number of glasses of water one would need to consume per day to get a dose equal to the ADI assumes exposure only through drinking water; however, a person is likely to have multiple sources of exposure to these substances, including from food or medication, in the workplace, from personal care and household products, etc. In addition, a person could be exposed to multiple other substances with the potential to produce the same or similar effects in the body. Determining the potential effects of exposures to a single compound from multiple sources or to multiple compounds from single or multiple sources is challenging because real- world exposures are always changing, whereas scientific studies typically examine fixed exposure levels to one or a limited set of compounds. As a result, significant uncertainty exists about the effects of exposure to mixtures. Nonetheless, research to understand the effects of mixtures is on-going, and scientists and risk assessors are developing improved methods to predict the effects of mixtures. To provide perspective on the current understanding of the effects of mixtures, some studies that have evaluated exposures to mixtures of PPCPs or EDCs are described below, as are several approaches that can be used to predict the potential health risk from exposure to a substance through multiple sources or from exposure to multiple substances.

Studies that Evaluate Exposures to Multiple Sources of PPCPs or EDCs

A potentially significant source of exposure to emerging compounds is food, including meat and produce. Like humans, livestock and aquatic organisms can be exposed to PPCPs and EDCs in the environment through contact with water or consumption of food containing PPCPs or EDCs. This can potentially result in uptake of these substances into tissues and thus introduction into the food supply. In addition, plants can take up substances from soil, water, and air. Other substances can leach from packaging materials into food and beverages. The potential contribution of these sources to total exposure to PPCPs and EDCs is discussed below.

Exposure to PPCPs in Food

Studies that have assessed exposure to pharmaceuticals in food are more limited than studies that have examined EDCs. Examples of studies that have measured or estimated the uptake of PPCP ingredients into fish are summarized in Table 4.9. In one study, EPA (2009c) measured the occurrence of PPCPs in fish at six sites across the United States, analyzing fish tissues for 24 pharmaceuticals and 12 personal care product ingredients. The study detected two antidepressants, diphenylhydramine (an antihistamine), diltiazem (a blood pressure drug), and carbamazepine (an anti-epileptic) in fillet tissue as well as the personal care product ingredients galaxolide and tonalide (fragrances) (Table 4.10).

Table 4.9 Selected studies on PPCP ingredients and EDCs in fish Compounds Study Conclusions Citation 36 PPCPs Uptake in fish (liver and Five pharmaceuticals EPA 2009c fillet) from 5 effluent- (norfluoxetine, sertraline, dominated streams across the diphenylhydramine, United States. diltiazem, carbamazepine) and two as well as two fragrances (galaxolide and tonalide) were detected in fish fillet tissue 3 PPCPs Risk assessment model based Concentrations in drinking Kumar and (meprobamate, on estimated concentrations water and fish were Xagoraraki 2010 carbamazepine, considered safe phenytoin 44 PPCPs Risk assessment model based Concentrations in drinking Cunningham and on estimated concentrations water and fish were Binks 2009 considered safe 26 PPCPs Risk assessment model based Concentrations were at least Schwab et al. on estimated concentrations 6-fold lower for drinking 2005 water, 150-fold lower for

eating fish and 3-fold lower for drinking water and eating fish combined, than what is predicted to cause potential health effects 4 PPCPs (aspirin, Risk assessment based on No human health risks for Schulman et al. clofibrate, measured environmental drinking water and fish 2002 cyclophosphamide, concentrations consumption and indomethacin) 3 PPCPs Risk assessment model based Levels were over 140-fold Bercu et al. 2008 (duloxetine, on estimated concentrations lower than what is needed atomoxetine, and to cause potential health olanzapine) effects from drinking water and fish consumption.

Table 4.10 PPCPs detected in fish tissues Average detected concentration in Representative fish filet tissue Chemical name brand names Use (ppb wet weight) Norfluoxetine (active Prozac®, Sarafem® Antidepressant 3.7 metabolite of Fluoxetine) Sertraline Zoloft® Antidepressant 8.0 Diphenylhydramine Benadryl®, Unisom® OTC antihistamine, sleep-aid 1.4 Diltiazem Cardizem® Prescription drug to treat high 0.14 blood pressure Carbamazepine Carbatrol®, Tegretol® Prescription drug to treat 2.3 epilepsy Galaxolide None Fragrance used in PPCPs 1,160 Tonalide None Fragrance used in PPCPs 132 Source: data from EPA 2009c

Kumar and Xagoraraki (2010) estimated potential consumption of three PPCPs in fish (meprobamate, carbamazepine, and phenytoin) based on concentrations estimated in fish using modeling approaches and data on concentrations in stream water. They concluded that potential combined average daily exposures to the PPCPs through fish consumption and incidental ingestion of surface water (such as might occur during fishing or wading) was less than what would be taken in from direct ingestion of drinking water (using finished drinking water concentrations), but that both types of exposure were not of concern for human health and were considered safe. Another study reached similar conclusions, determining that concentrations found in drinking water were safe and that for 39 of 44 pharmaceuticals studied, average daily exposures from fish consumption were 4% or less of exposures associated with drinking water ingestion (Cunningham and Binks 2009). These studies suggest that exposures to PPCPs from fish are even lower than the levels of exposure found in drinking water. Another study compared model-predicted total doses of PPCPs from drinking water and fish consumption to ADIs for 26 substances (Schwab et al. 2005). Table 4.11 shows the margin of safety (i.e. the amount the study-estimated ADI exceeded the estimated dose from water, fish, or both) for each compound for children. The estimated doses from drinking water were at least 6.5-fold lower than the ADI, the doses from eating fish were at least 148-fold lower than the ADI, and the doses from drinking water and eating fish combined were at least 6.2-fold lower than the ADI. For 25 of 26 substances, drinking water contributed at least 95% of the total dose. For dehydronifedipine, drinking water contributed 63% of the total dose. Relative exposure levels compared to the ADI were highest for the antibiotic ciprofloxacin.

Table 4.11 Margin of safety compared to Schwab et al. (2005) ADIs for exposure to PCPPs in drinking water, fish, and drinking water and fish combined for children Margin of safety (based on modeled water concentrations) Compound Drinking water Fish Combined Acetaminophen 23 508 22 Albuterol 341 7,860 327 Cimetidine 96 2,190 92 Ciprofloxacin 6.5 148 6.2 Codeine 27 585 25 Dehydronifedipine 1,327 2,220 831 Digoxigenin 162 8,640 159 Digoxin 162 6,370 158 Diltiazem 35 819 33 Doxycycline 442 10,000 424 Enalaprilat 34,100 780,000 32,600 Erythromycin-H2O 167 3,850 160 Fluoxetine 68 1,570 65 Gemfibrozil 100 2,270 96 Ibuprofen 25 5,940 25 Lincomycin 37,200 836,000 35,700 Metformin 19 444 18 Norfloxacin 37,500 834,000 35,900 Oxytetracycline 476,000 10,900,000 456,000 Paroxetine metabolite 78 1,850 75 Ranitidine 21 483 20 Sulfamethoxazole 223 5,070 214 Sulfathiazole 56,200 1,250,000 53,700 Tetracycline 141 3,240 135 Trimethoprim 34 797 33 Warfarin 19 449 19 Source: data from Schwab et al. 2005

Schulman et al. (2002) concluded that there would be no human health risks for acetylsalicylic acid (aspirin), clofibrate and clofibric acid (drugs for treating high cholesterol), cyclophosphamide (a chemotherapeutic agent), and indomethacin (an anti-inflammatory) from drinking water and consuming fish based on drinking or surface water levels detected in several field studies (Schulman et al. 2002).

Another study determined the acceptable water concentration assuming daily consumption of water and fish—called the “predicted no-effect concentration” (PNEC)— for three pharmaceuticals: atomoxetine (used to treat attention deficit hyperactivity disorder, ADHD), duloxetine (brand name Cymbalta®), and olanzapine (brand name Zyprexa®) (Bercu et al. 2008) (Table 4.12). The PNEC was then compared to the 99th percentile of the “predicted environmental concentration” (PEC) from modeling to determine the margin of safety for these compounds in children. The 99th percentile PECs of duloxetine—the compound with the smallest margin of safety—were still 147-fold lower than the minimum concentration needed to cause potential health effects from drinking water and fish consumption.

Table 4.12 Margin of safety for children exposed to neuropharmaceuticals PNEC in water 99th percentile Margin of Compound Use (children) PEC in water safety Atomoxetine ADHD 25.7 ppb 0.12 ppb 214 Duloxetine Depression/anxiety 19.1 ppb 0.13 ppb 147 Olanzapine Schizophrenia, bipolar 35.9 ppb 0.07 ppb 524 disorder Source: data from Bercu et al. 2008 ADHD − attention deficit hyperactivity disorder; PEC − predicted environmental concentration; PNEC − predicted no-effect concentration

Some studies have investigated the potential for PPCPs to bioaccumulate, or be taken up and stored, in fish. While it is known that some chemicals, like PCBs and DDT, bioaccumulate in animals, less is known about bioaccumulation of PPCPs and hormones in animals that humans may consume. According to the EPA, a chemical substance is considered to not be bioaccumulative if it has a bioconcentration factor (BCF) less than 1,000 (EPA 1999a). A laboratory study on medoxyprogesterone acetate (MPA), a steroid hormone used in oral and injectable contraceptives, showed little tendency to bioaccumulate in fish (BCF 4.3-37.8) (Steele et al. 2013). Similar results were found for fish exposed to ibuprofen in a lab setting, with a BCF ranging from 0.08 to 1.4 (Nallani et al. 2011). Another study found that carbamazepine did not bioaccumulate in fish in a lab setting (BCF of 1.8-1.9 for muscle tissue) or in fish found at a WWTP in Texas (BCF of 2.5-3.8) (Garcia et al. 2012). In a field study, fish from a pond affected by storm water runoff and reclaimed water from a local WWTP were analyzed for bioaccumulation of carbamazepine, caffeine, and diphenhydramine (Wang and Gardinali 2012). While BCFs were higher than those found in the other studies, they were still below 1,000 indicating these compounds do not have the tendency to bioaccumulate (Table 4.13). In addition, the EPA is conducting a national-scale study (under the National Rivers and Streams Assessment) from 2008 through 2014 on emerging contaminants in fish from urban rivers including PPCPs and EDCs (EPA 2013b).

Table 4.13 Bioaccumulation of PPCPs in fish Mean detected Mean detected concentration in pond concentration in fish Compound water (ppb) tissue (ppb) BCF Lincomycin ND ND NA Trimethoprim 1.3 ND NA Caffeine 81 1.3 29 Sulfamethoxazole 8.0 ND NA Diphenhydramine 0.67 0.55 821 Diltiazem ND ND NA Carbamazepine 4.5 0.20 108 Erythromycin ND ND NA Fluoxetine ND ND NA Norfluoxetine ND ND NA Sertraline ND ND NA Source: data from Wang and Gardinali 2012 NA − not applicable as the compound was not detected in fish tissue; ND − not detected

It is also possible that people could be exposed to PPCPs through consumption of fruit and vegetables, as some of these substances have been detected in soils irrigated with wastewater (Duran-Alvarez et al. 2009, Gibson et al. 2010). However, Munoz et al. (2010) estimated potential exposures to 13 pharmaceuticals from ingestion of crops irrigated with wastewater, and concluded that potential human health risks were very low because these chemicals were present in amounts many times lower than would cause health effects. Another study determined uptake of diclofenac and ibuprofen into soybeans and wheat following application of sludge as fertilizer (Cortes et al. 2013): diclofenac and ibuprofen were detected in the sludge at concentrations of 22 ppb and 217 ppb, respectively, but uptake into the plants was less than 2% for diclofenac and 0.8% for ibuprofen. Another greenhouse study determined the uptake of bisphenol A, diclofenac sodium (an anti-inflammatory), naproxen (Aleve®), and 4-nonylphenol (a surfactant) in lettuce and collard greens (Dodgen et al. 2013). The amount found in plant tissue ranged from 0.22 ppb to 927 ppb with bisphenol A showing the highest accumulation followed by 4-nonylphenol, diclofenac and naproxen. In addition, this study found that these chemicals tended to accumulate more in the roots than in the leaves and stems. A study of cabbage using soil amended with sludge from WWTPs showed that carbamazepine (an anticonvulsant), salbutamol (a bronchodilator), and triclosan (an antibacterial) were found in leaves and roots (Holling et al. 2012) (Table 4.14). However, the BCFs in this study were low, ranging from 0.05 for triclosan in leaves to 6.19 for salbutamol in roots, and indicate that these compounds have little or no tendency to bioaccumulate. Bioaccumulation of metformin, a drug used to control type 2 diabetes, was found to be low in tomatoes (BCF 0.02-0.06), squash (BCF 0.12-0.18), beans (BCF 0.88), carrots (BCF 1-4), potatoes (BCF 1-4), and wheat, barley, and oats (BCF 0.29-1.35) (Eggen and Lillo 2012).

Table 4.14 Bioaccumulation of PPCPs in cabbage leaves and roots Detected Detected Detected median median median concentration concentration BCF concentration BCF Compound in soil (ppb) in leaves (ppb) (leaves) in roots (ppb) (roots) Carbamazepine 93.1 317.6 3.41 416.2 4.47 Sulfamethoxazole 67.4 ND NA ND NA Salbutamol 30.3 21.2 0.70 187.6 6.19 Triclosan 433.7 22.9 0.05 1220.1 2.81 Trimethoprim 24.7 ND NA ND NA Source: data from Holling et al. 2012 BCF − bioconcentration factor; NA − not applicable as the compound was not detected in plant tissue; ND − not detected

Exposure to EDCs in Food and Beverages

More studies have been conducted that have investigated exposure to EDCs in food, particularly because of the potential persistence of many of these compounds in the environment and their potential to be taken up into fish and meat, and the presence of many of these compounds in packaging material. One study examined the contribution of drinking water and a variety of food products to the estimated daily dose of the hormone 17α- ethinylestradiol (EE2), the antibiotic phenoxymethylpenicillin (Pen V), and the cancer drug cyclophosphamide (CP) (Christensen 1998) (Table 4.15). For cyclophosphamide, 92% of the daily dose came from drinking water, whereas for EE2 93% of the dose was from fish. The contribution of the daily dose from crops, meat, and dairy was relatively low. Table 4.15 Contribution of drinking water and foods to human daily dose Estimated Percentage of human daily dose from each source human daily dose Drinking Leaf Root Dairy Compound (mg/kg-d) water crops crops Fish products Meat EE2 1.37 × 10-7 6% 0.1% 0.4% 93% 0.004% 0.006 % Pen V 6.06 × 10-6 57% 4% 0.2% 39% 0.008% 0.002% CP 7.59 × 10-8 92% 0.1% 0.01% 8% 0.01% 0.0006% Source: data from Christensen 1998 CP − cyclophosphamide; EE2 − 17α- ethinylestradiol; Pen V − phenoxymethylpenicillin

Cao et al. (2010) evaluated the relative doses of three hormones, estrone, ethinyl estradiol, and 17β-estradiol from drinking water and eating fish from a reservoir receiving recycled wastewater, assuming consumption of about 3.8 ounces of fish per day and ingestion of 2 L/d of water. When human daily dose was calculated, human exposure to EDCs from the

consumption of fish was about 10 times higher than that from the consumption of drinking water, implying fish was a major source of exposure. However, the calculated dose was less than the ADI and showed negligible health risks to humans. Food packaging is another potential source of exposure to EDCs, due to migration of such substances as phthalates, alkylphenols, and bisphenol A from polycarbonate plastics, coatings, and epoxy resins. A number of different phthalates, used as plasticizers, were detected in edible vegetables oils in a U.S. retail market: dibutyl phthalate and diethyl phthalate were detected at rates of 90.5% in oil samples and concentrations of total plasticizers in oil samples ranged from 201-7,558 ppb (Li et al. 2013). Di(2-ethylhexyl) phthalate was detected in a few cheese samples in Canada at levels from 290 to 15,000 ppb, with an average of 2,800 ppb, thought to be due to environmental contamination from packaging (Cao et al. 2014). Tris(nonylphenyl)phosphite (TNPP) used as an antioxidant in polyethylene resins for food applications has been reported to be a source of 4-nonylphenols in packaged foods (Mottier et al. 2014). Migration of bisphenol A from polycarbonate bottles and epoxy resins into foods and beverages has been reported in a number of studies (Lu et al. 2012). At room temperature, the concentration of bisphenol A migrating from polycarbonate bottles into water was estimated to range from 200 to 300 ppb, while the migration from aluminum bottles lined with epoxy-based resins was estimated to range from 80 to 1,900 ppb (Cooper et al. 2011). Daily intakes of bisphenol A, 4-nonylphenol, and triclosan from baby bottles were estimated to be 1,340, 705, and 5 ng/day, respectively, from drinking 1 L of tap water from a baby bottle that had held water at 40 degrees C. Concentrations of these same compounds in bottled water were estimated to be 17.6 to 324 ng/L (0.017 to 0.324 ppb), 108 to 298 ng/L (0.108 to 0.298 ppb), and 0.6 to 9.7 ng/L (0.0006 to 0.0097 ppb), respectively, while the highest concentrations in tap water samples from six drinking water plants were 317, 1987, and 14.5 ng/L (0.317, 1.987 and 0.0145 ppb), respectively (Li et al. 2010). Several studies have attempted to characterize the total exposure to certain EDCs from water, diet (including fish and packaged foods), and other beverages. Schecter et al. (2010) measured bisphenol A in 105 fresh and canned foods sold in plastic packaging collected from Dallas, TX grocery stores in 2010. Detected levels ranged from 0.23 to 65.0 ppb wet weight (ww) and were not associated with type of food or packaging but did vary with pH. Bisphenol A levels were higher for foods of pH 5 compared to more acidic and alkaline foods. The highest levels were measured in canned green beans, followed by several canned soups. Liao and Kannan (2013) measured bisphenol A levels in nine categories of foodstuffs collected in Albany, NY, including beverages, dairy products, fats and oils, fish and seafood, cereals, meat and meat products, fruits, and vegetables. Bisphenols were found in the majority (75%) of the food samples, and the concentrations of bisphenol A were in the range 0.235 ppb (beverages) to 9.97 ppb fresh weight (“others”, which included condiments and preserved, ready- to-serve foods). Concentrations of bisphenol A in fruits (0.532 ppb) were low. On the basis of measured concentrations and daily ingestion rates of foods, the daily dietary intakes of bisphenol A (calculated from the mean concentration) were estimated to be 114, 195, 91.2, and 44.6 ng/kg body weight/day for toddlers, infants, children, and adults, respectively. By comparison, the estimated daily dose of bisphenol A based on the maximum detected concentration in drinking water recorded in the current evaluation (440 ng/L, reported by Kingsbury et al. 2008) would be 880 ng/d assuming consumption of 2 L of water per day, or 12.6 ng/kg-d assuming a body weight of 70 kg. Thus, using the data collected by Liao and Kannan

(2013), drinking water would contribute a maximum of about 7% of the total daily bisphenol A dose for a child based on the maximum concentration detected in drinking water that we identified (440 ng/L). Comprehensive evaluations of exposure to some other EDCs have also been conducted. For example, the estimated mean daily exposures to total parabens from all foodstuffs, based on a market basket survey for eight food categories in Albany, New York, for adults was estimated to be 307 ng/kg-d (Liao et al. 2013). Fish are also reported to be a significant source of exposure to PFOS, and hand-to-mouth transfer of dust can also be a significant source of exposure to PFOS for children (Hollander et al. 2010). Exposures to phytoestrogens (naturally present plant-based estrogenic compounds), such as daidzein, zenistein, genistein, and coumestrol, in foods and beverages can also be significant. Some commonly-consumed sources of these compounds include soybeans and other legumes, and grains. Substantial variability in the intake of these compounds has been reported (Nilsson 2000, Thompson et al. 2006, NTP 2010, Zamora-Ros et al. 2012), with some suggesting that the potential estrogenicity associated with dietary intake of these compounds is greater than that from exposure to synthetic EDCs (Nilsson 2000, Kwack et al. 2009).

Exposures to PPCPs or EDCs in Personal Care Products

Personal care products are another significant source of exposure to certain EDCs. For example, triclosan is used in toothpastes, soaps, disinfectants, shampoos, antiperspirants/deodorants, and cosmetics products, and nonylphenols and octylphenols are widely used as surfactants in many PCP products (Liao and Kannan 2014). Estimated mean dermal intakes for these substances as well as bisphenol A in the United States are shown in Table 4.16, based on concentrations measured in 114 samples of PCPs collected in Albany, NY.

Table 4.16 Estimated geometric mean dermal intakes of EDCs from personal care products by U.S. women (ng/d) Sum of Sum of Product 4-Nonylphenol octylphenols* bisphenols† Triclosan Shampoo 0.150 0.166 0.520 0.234 Hair conditioner 14.5 0.951 0.566 1.63 Body shower gel 0.018 0.025 0.067 0.406 Facial cleanser 0.005 0.009 0.044 0.080 Toilet soaps 0.245 0.980 0.650 1.67 Body lotions 159 39.6 99.7 44.7 Face creams 70.9 7.82 11.6 18.2 Liquid foundations 95.6 3.99 6.78 0.962 Total 340 53.5 120 67.8 Source: data from Liao and Kannan 2014 *4-Octylphenol and 4-t-octylphenol †Bisphenol A, AF, AP, B, F, P, S, and Z

Based on these studies, it is likely that the relative contribution of other sources of exposure (e.g., food) to total exposure to most PPCPs is minimal. However, for many EDCs, it is clear that exposure from food or other beverages can be significant.

Studies that Evaluate Exposure to Mixtures of PPCPs or EDCs

Most toxicological studies that assess the potential effects of exposure to chemicals evaluate exposure to each substance in isolation. Typically, risk assessments using these data assume effects are additive, i.e., equal to the sum of the predicted effects of the substances individually. However, the ideal approach for evaluating mixtures is to examine the mixture as a whole, especially since, if exposure levels are sufficient, some components of mixtures may act in a manner that is synergistic (the effect of all is greater than the substances added together) or antagonistic (the effect from one decreases the effect of another). Examples of each of these three types of effects can be cited for pharmaceuticals. For example, at medicinal levels, treatment with multiple antidepressants can result in additive effects, yielding potentially serious effects on the nervous system (Flockhart 2012). However, drugs with different mechanisms of action can have synergistic effects. For example, exposure to both propranolol and verapamil (two drugs that act in different ways to treat high blood pressure) has a synergistic effect, leading to drastic decreases in heart rate and blood pressure (Bailey and Carruthers 1991). Antagonistic effects can result from exposure to incompatible drugs. For example, antibiotics can act antagonistically to make oral contraceptives less effective (Dickinson et al. 2001). However, there is no evidence that significant synergistic effects are likely at exposure levels below doses used medicinally. Table 4.17 summarizes several studies that assessed the effect of mixtures of PPCP ingredients or EDCs. Pomati et al. (2008) evaluated the effects of different combinations of 13 pharmaceuticals on cellular processes in human cells grown in a petri dish. Of the 13 pharmaceuticals tested, the combination of atenolol, bezafibrate, ciprofloxacin, and lincomycin produced the greatest effects on cell growth. Another study examined the combined endocrine effects of eight EDCs, including hydroxylated PCBs, benzophenones, parabens, bisphenol A, and genistein (Silva et al. 2002). While the individual compounds had little effect at very low levels, when combined they caused endocrine changes to cells grown in petri dishes. The presence of mixtures of PPCPs in surface water is also a concern for organisms living in the aquatic environment. For example, one laboratory study found that a mixture of anti-inflammatory drugs had considerable toxicity to water fleas, even at concentrations where the chemicals by themselves showed little or no effect (Cleuvers 2004).

Table 4.17 Selected studies of toxicological effects from mixtures of PPCP ingredients and EDCs Mixture Study system Effect Citation 13 drugs Human and zebra fish Identified a subset of most (Pomati et al. 2008) cells in the laboratory concern (atenolol, (in vitro) bezafibrate, ciprofloxacin, and lincomycin) based on effects on cell growth when in a mixture

Eight weak Laboratory bioassay Observed endocrine (Silva et al. 2002) estrogenic chemicals for screening changes in cells exposed (hydroxylated PCBs, estrogenic compounds to mixture at benzophenones, concentrations parabens, bisphenol individually below no A, and genistein) effect concentrations

Four anti- Laboratory bioassay Observed toxicity to fleas (Cleuvers 2004) inflammatory drugs using water fleas exposed to mixture at (diclofenac, concentrations ibuprofen, naproxen, individually below no and acetylsalicylic effect concentrations acid) Four EDCs (DEHP, Male rats in laboratory Observed sex organ (Christensen et al. vinclozolin, changes in male rats 2003) prochloraz, exposed to mixture at finasteride) concentrations individually below no effect concentrations

Eight EDC pesticides Study in a human Observed association (Damgaard et al. (p,p-DDE, p,p-DDT, population between maternal 2006) beta-HCH, HCB, exposure and reproductive alpha-endosulfan, development in sons oxychlordane, exposed to mixture dieldrin, and cis-HE) beta-HCH − beta-hexachlorocyclohexane; cis-HE − cis-heptachloroepoxide; DEHP −bis (2-ethylhexyl) phthalate; p,p –DDE −1,1-dichloro-2,2-bis(4-chlorophenyl) ethylene; p,p-DDT −1,1,1-trichloro-2,2-bis(4- chlorophenyl) ethane; HCB −hexachlorobenzene; PCB −polychlorinated biphenyl

Numerous studies have investigated the estrogenicity of mixtures of compounds in surface water and municipal wastewater using in vitro or in vivo assays. Estrone, 17β-estradiol, 17α-ethynylestradiol and to some extent, estriol have been shown to be responsible for the majority of estrogenic activity of municipal WWTP effluents when evaluated in in vitro tests (Jarošová et al. 2014). The estimated relative potencies of the substances relative to estradiol are shown in Table 4.18. To assess whether the estrogenicity of mixtures of compounds can be estimated by assuming additivity, Thorpe et al. (2006) used an addition model to predict the estrogenic activity of mixtures of four estrogenic compounds, 17β-estradiol, estrone,

ethynylestradiol, and nonylphenol, based on the concentration of each compound and the relative potency of each substance as measured using an in vitro recombinant yeast estrogen screen (rYES) assay and a short-term (14-day) in vivo rainbow trout vitellogenin induction assay. These predictions were then compared to assay results measured for mixtures using the assays.

Table 4.18 Estimated relative estrogenic potencies of four estrogenic compounds in wastewater, based on the rYES in vitro assay Substance EC50 (ng/L) Relative potency Ethynylestradiol 21.2 1.8 Estrone 37.7 1 17β-Estradiol 55.3 0.68 Nonylphenol 81,045 0.00047 Source: data from Thorpe et al. 2006 EC50 − median effect concentration for in vitro recombinant yeast estrogen screen (rYES) assay

Overall, the predicted responses of various mixtures of two compounds (binary mixtures) were within the range of measured estrogenic responses for the mixtures. However, for more complex mixtures of all four substances, the measured estrogenic response differed substantially from that predicted based on the additive model, in some cases higher and in others lower. In general, this was thought to be due largely to inaccuracies in measurements of chemical concentrations in the mixture, as well as the inability of the additive model to predict the interactions between chemicals. Overall, the results demonstrate that use of assays can provide useful assessment of the estrogenicity of mixtures of estrogenic chemicals. Like these examples, most toxicological studies that have evaluated mixtures have used cell-based bench top laboratory (in vitro) tests to determine the potential for chemicals to interact with each other. These types of studies can help identify priority chemicals and combinations of chemicals for further testing; however, it is difficult to extrapolate from these results to predict effects on humans because of the complexities of whole body systems. Further, the specific chemical mixture at points of exposure will vary over space and time. Computerized models offer a promising approach for predicting the health effects of mixtures in more complex systems and in humans (Han and Price 2011, Price and Han 2011).

Risk Assessment Approaches to Predict Potential Effects of Mixtures or Multiple Source Exposure

Summing Estimated Exposures

A multipathway risk assessment considers exposure to a substance through all potential exposure routes, whereas a cumulative risk assessment characterizes aggregate exposures from multiple chemicals through multiple routes. Potential exposure routes include ingestion of food and water, contact with soil and water, and inhalation of dust and airborne materials. One common example of a cumulative risk assessment is the assessment of effects of exposure to a group of pesticides that act by the same mode of action and cause the same effect. To predict the potential for adverse effects from a cumulative dose of several substances in a cumulative risk assessment, in the absence of other information, there is general consensus

that assuming an “additive” response is conservative. This is because in any mixture there are likely to be a combination of additive, antagonistic, and synergistic effects, such that the antagonistic and synergistic effects may cancel out while a purely additive assumption in most cases will overpredict the toxicity (especially when uncertainty factors are included in the calculation of ADIs). Typically, in risk assessments for mixtures, one of two approaches is used to predict the potential additive effect associated with a combined dose: “dose addition” or “response addition” (EPA 1999a, EPA 2000a). Dose addition is applied when chemicals are toxicologically similar or share the same or similar modes of action. Examples would include evaluating all pharmaceuticals that act as calcium channel blockers, or all sulfa antibiotics, or all estrogenic hormones. In dose addition, the estimated doses for individual compounds are scaled based on their relative potency for a common toxicity endpoint, then all of the scaled doses are added together and an ADI corresponding to the benchmark compound is applied to the group. Response addition is applied when compounds are toxicologically dissimilar and is accomplished by calculating the “hazard index” or relative response separately for each compound, by dividing the estimated dose for each substance by its toxicity criterion, then summing all of the hazard indices or responses.

Applying Relative Source Contribution (RSC) Factors to Drinking Water Criteria

The information in Tables 4.5 through 4.8 shows that the highest levels of all PPCP ingredients and almost all EDCs that have been detected in drinking water based on the occurrence data gathered herein, when evaluated alone, do not suggest a significant risk of adverse health effects, based on current knowledge. However, people can be exposed to these substances from other sources in addition to drinking water. If the contribution from these sources is significant, the person’s total exposure will be greater than that from water alone and the human water quality criterion should be scaled down (i.e., made lower or more stringent) to make “room” for these other sources. One approach to achieve this is to multiply the calculated DWEL by a corresponding relative source contribution (RSC) factor, defined as the decimal fraction that represents the amount of a person’s average daily exposure to a substance that is expected to be contributed by drinking water relative to the person’s daily exposure from all sources. The equation is as follows:

(4.11)

Alternatively, one can multiply the required volume of water one would need to consume per day to get a dose equal to the ADI by the RSC, to give the adjusted daily water volume:

(4.12)

Several agencies and authoritative bodies have proposed RSCs for substances in water that are potentially endocrine active (Table 4.19). For other substances that show no evidence of carcinogenicity, EPA suggests using a default RSC of 20% unless there is sufficient evidence to propose a higher value (EPA 2012l). They also suggest that regardless of available data, the RSC for drinking water should not exceed 80% in order to accommodate unknown exposures.

Table 4.19 Published relative source contribution (RSC) factors for EDCs and PPCPs in drinking water Substance RSC factor Source 2,4-D 0.2 California, EPA Acetaminophen 0.2 MDH* Acetochlor 0.5 (short-term), 0.2 (chronic) MDH Acetochlor ESA 0.5 (short-term), 0.2 (chronic) MDH Acetochlor OA 0.5 (short-term), 0.2 (chronic) MDH AHTN 0.5 (short-term), 0.2 (chronic) MDH Alachlor 0.5 (short-term), 0.2 (chronic) MDH Alachlor ESA 0.2 MDH Alachlor OA 0.2 MDH Bisphenol A 0.2 MDH Butyl benzyl phthalate 0.2 MDH Carbamazepine 0.8 MDH DEET 0.2 MDH DEHP 0.2 California, MDH Dibutyl phthalate 0.2 MDH Dieldrin 0.5 (short-term), 0.2 (chronic) MDH Lindane 0.2 California, EPA Methoxychlor 0.2 California Metolachlor 0.5 (short-term), 0.2 (chronic) MDH Metolachlor ESA 0.2 MDH MTBE 0.2 California MTBE 0.5 (short-term), 0.2 (chronic) MDH PFBA 0.5 (short-term), 0.2 (chronic) MDH PFBS 0.5 (short-term), 0.2 (chronic) MDH PFCs 0.2 MDH PFOA 0.2 MDH PFOS 0.2 MDH Simazine 0.2 California, EPA Sulfamethazine 0.8 MDH TCEP 0.5 (short-term), 0.2 (chronic) MDH TDCP 0.2 MDH TDCPP 0.2 MDH Triclocarban 0.2 MDH Triclosan 0.2 MDH Source: data from EPA 2012l, MDH 2013 *MDH – Minnesota Department of Health

OTHER EFFECTS: ANTIMICROBIAL RESISTANCE

Antimicrobial medicines (i.e., antibiotics, antivirals, antimalarials) are used to treat pneumonia, tuberculosis, malaria and other infections caused by bacteria, viruses, or parasites. Antibacterial resistance occurs when bacteria acquire resistance genes that render a particular antibiotic ineffective. Long-term antibiotic use can lead to resistance to not only that particular

drug but to other antibiotics as well, a process termed multi-drug resistance (MDR). Antibiotic and multi-drug resistance are topics of public health concern given that Methicillin-resistant Staphylococcus aureus (MRSA), and MDR-gonorrhea, MDR-tuberculosis, and MDR-malaria are becoming more common world-wide (as reviewed in Levy and Marshall 2004). MDR infections are costly, requiring longer hospital stays and the use of sometimes up to six or seven different drugs the treat the disease (as reviewed in Levy and Marshall 2004). In addition, these infections are more prone to treatment failure resulting in increased morbidity and mortality (as reviewed in Levy and Marshall 2004). Antimicrobial medicines can enter the environment through human and animal waste, improper drug disposal, and agricultural runoff from manure enriched croplands and dusting of fruit trees for disease prophylaxis. They can contribute to selection of resistant organisms, where non-susceptible strains can over-populate susceptible strains in the environment. For example, in an extreme case, antibiotic resistant bacteria was found downstream from a wastewater treatment plant in India that released drugs into its effluent, sometimes at levels equivalent to the high therapeutic dose (Lubick 2011). The antibiotic detected at the highest level was sulfonamide but bacterial resistance to other drugs dominated, demonstrating that bacteria in the environment can develop MDR when exposed to very high levels of antibiotics in water. Studies have not demonstrated that exposure to antimicrobials at very low concentrations in water can lead to increased MDR in humans. However, MDR in humans is a “societal problem” since resistance in an individual can lead to resistance in the community, even in individuals not taking the drug. Immuno-compromised individuals are particularly susceptible as well as children and individuals who reside in close-quarters (i.e., hospitals, prisons, military barracks, student dorms). Reduced use of antibiotics can be effective in combatting MDR, as demonstrated by a Finnish study where a 20% decrease in resistance to macrolide was reported after two years of reduced use (as reviewed in Levy and Marshall 2004). Reducing overall exposure to antibiotics may be beneficial in combating the growing issue of MDR.

RELEVANT WATER RESEARCH FOUNDATION PROJECTS

Past or present research projects funded by the Water Research Foundation addressing issues associated with potential health effects of PPCPs and EDCs in water include:

 Project 2598: Endocrine Disruptors and Pharmaceuticals in Drinking Water (1999). This project examined the potential implications of EDCs and PPCPs in drinking water and wastewater, providing an overview of health effects, occurrence, and potential treatment options, as well as a future research agenda.  Project 2642. Assessment of Waters for Estrogenic Activity (2003). This project modifies, validates, and utilizes in vitro screening tests for the presence of estrogenic compounds in water samples, and performs in vivo tests in combination with in vitro tests to determine the significance of the presence of estrogenic compounds in source waters, finished drinking waters, and effluent streams.  Project #3033: State of Knowledge of Endocrine Disruptors in Pharmaceuticals in Drinking Water (2008). This project synthesizes existing knowledge on EDCs and PPPCs in drinking water supplies, including what is known about health effects, analysis, occurrence, and behavior in drinking water treatment processes.  Project #3085: Toxicological Relevance of EDCs and Pharmaceuticals in Drinking Water

(2008). This project, conducted as a Tailored Collaboration with Southern Nevada Water Authority, conducted an extensive literature review on the known toxicity of EDCs and PPCPs including naturally occurring EDCs and pharmaceutically active compounds. Raw and finished drinking waters were analyzed for a suite of EDCs and pharmaceuticals, and various bottled waters, beverages, and food products were screened. The project also used an in vitro bioassay to assess the estrogenicity of various waters, beverages, and foods, and conducted risk assessments for chemicals of interest based on findings.  Project 4261: The EDC Network for Water Utilities (2014). This project produced The EDC Network for Water Utilities, an online network to promote collaboration among water utilities and improve utility responses to challenges posed by EDCs and PPCPs. The EDC Network provides a secure Website resource for utilities to share best practices, documents, other tools, and materials related to EDCs and PPCPs. The EDC Network is open only to utility professionals.  Project 4267: “Screening Endocrine Activity of DBPs” (in progress). This project is screening a limited number of disinfection by-products (DBPs) for endocrine activity using bioassays. It also screens regulated DBPs, a few typical DBP mixtures, and a few non- regulated, as well as emerging DBPs based upon their structure, genotoxicity, and/or occurrence.  Project 4396: “Transformation of EDCs/ PPCPs and Resulting Toxicity Following Drinking Water Disinfection” (in progress). This project using computational chemistry and toxicology approaches to predict the likely transformation products of relevant EDCs/PPCPs with a range of disinfection and oxidation options commonly used in the production of drinking water. Then, in vitro toxicity testing is used to determine their toxicity profile.

ADDITIONAL SOURCES OF INFORMATION ON HEALTH-BASED EXPOSURE LIMITS AND POTENTIAL HEALTH EFFECTS

General sources of information on potential health effects of PPCPs in the environment on humans include the following:

 EPA bibliographic list of published documents on PPCPs as environmental contaminants http://www.epa.gov/ppcp/lit.html  World Health Organization (WHO) (2012) on Pharmaceuticals in Drinking Water http://www.who.int/water_sanitation_health/publications/2011/pharmaceuticals/en/

General sources of information on potential health effects of EDCs in the environment on humans include the following:

 Endocrine Society Scientific Statement on endocrine-disrupting chemicals http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2726844/  European Commission State of the Art Assessment of Endocrine Disruptors (2011) http://ec.europa.eu/environment/chemicals/endocrine/pdf/sota_edc_final_report.pdf  European Environment Agency Weybridge report on The Impacts of Endocrine Disruptors on Wildlife, People, and their Environments http://www.eea.europa.eu/publications/the-impacts-of-endocrine-disrupters  EPA general information on Endocrine Disruptors

http://www.epa.gov/endo/pubs/edspoverview/whatare.htm  University of Ottawa website providing up-to-date information on the potential health risks of EDCs http://www.emcom.ca/welcome/index.shtml  WHO/ United Nations Environment Programme (UNEP) (2013) on the State of the Science of Endocrine Disrupting Chemicals http://www.unep.org/chemicalsandwaste/UNEPsWork/EndocrineDisruptingChemicalsE DCs/tabid/79616/Default.aspx

General sources of information on toxicity criteria and health-based exposure limits for drinking water include the following:

 Australian Department of Health ADIs for Agricultural and Veterinary Chemicals http://www.health.gov.au/internet/main/publishing.nsf/content/ocs-adi-list.htm  Australian Drinking Water Guidelines for managing drinking water quality, including guidelines for monitoring and fact sheets on a wide range of substances http://www.nhmrc.gov.au/_files_nhmrc/publications/attachments/eh34_adwg_11_06.pdf  California EPA Office of Environmental Health Hazard Assessment (OEHHA) Public Health Goals for Chemical Substances in Drinking Water http://www.oehha.ca.gov/water/phg/allphgs.html  California Ocean Protection Council, the National Water Research Institute, and others workshop report on Managing Contaminants of Emerging Concern, including guidelines for establishing thresholds of concern http://www.sfei.org/sites/default/files/CA%20CEC%20Workshop%20Final%20Report% 20Sept%202009.pdf  International Programme on Chemical Safety (IPCS) Chemical Safety Information from Intergovernmental Organizations database of information and documents addressing chemical safety issues http://www.inchem.org/  National Library of Medicine (NLM) Hazardous Substances Data Bank (HSDB) – Toxicology Data Network (TOXNET), which provides a scientifically peer-reviewed data bank of information on human and animal toxicity, safety and handling, environmental fate and more http://toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen?HSDB  EPA Drinking Water Standards and Health Advisories Tables summarize the drinking water regulations and health advisory values for substances in drinking water, including MCLGs and MCLs, as well as the reference dose and cancer risk values http://water.epa.gov/action/advisories/drinking/upload/dwstandards2012.pdf  EPA Integrated Risk Information System (IRIS) website, which summarizes reference doses and cancer risk values for environmental contaminants and their scientific basis http://www.epa.gov/IRIS/  WHO Guidelines for Drinking Water Quality (2008) http://www.who.int/water_sanitation_health/dwq/gdwq3rev/en/

CHAPTER 5: STATUS OF FEDERAL AND STATE LEGISLATION, REGULATIONS, AND PROGRAMS

Federal and state agencies have established legislation and regulations addressing contaminants in water, but few specifically address PPCPs and EDCs. To characterize the status of this activity, information was compiled and summarized on the status of federal and state legislation, regulations, and guidance affecting PPCPs and EDCs in the environment, particularly source and drinking water. In addition, ongoing research programs by federal, state, and other entities that address PPCPs and EDCs in the environment are also summarized.

FEDERAL LEGISLATION AND REGULATION ADDRESSING PPCPS AND EDCS IN WATER

Table 5.1 summarizes current and proposed federal legislation and regulations addressing PPCPs and EDCs in water or their disposal as waste. These are discussed below.

EPA Water Legislation and Regulations

The Federal Water Pollution Control Act (commonly known as the Clean Water Act) provides the basic structure for regulating discharges of pollutants into the waters of the United States through the National Pollutant Discharge Elimination System (NPDES) permit program and for regulating quality standards for surface waters (EPA 2002a). Section 402 of the Clean Water Act specifically requires EPA to develop and implement the NPDES program. The act does not explicitly regulate pharmaceuticals or most EDCs, but states:

Notwithstanding any other provisions of this Act it shall be unlawful to discharge any radiological, chemical, or biological warfare agent, any high-level radioactive waste, or any medical waste, into the navigable waters [Section 301(3)(B)(f)]

And,

The term ‘‘medical waste’’ means isolation wastes; infectious agents; human blood and blood products; pathological wastes; sharps; body parts; contaminated bedding; surgical wastes and potentially contaminated laboratory wastes; dialysis wastes; and such additional medical items as the Administrator shall prescribe by regulation [Section 502 (20)]

Under the Clean Water Act, total maximum daily loads (TMDLs) have been established in some states for the EDCs atrazine, chlordane, and PCBs (EPA 2012b, 2014c). A TMDL is the maximum amount of a pollutant that a water body can receive and still meet water quality standards, providing allocation of that load among the various point and nonpoint sources of that pollutant (EPA 2013e). Point sources include all sources subject to regulation under the (NPDES program including wastewater treatment facilities, some stormwater discharges, and concentrated animal feeding operations (CAFOs). Nonpoint sources include all remaining

sources of the pollutant as well as anthropogenic and natural background sources. TMDLs also account for seasonal variations in water quality, and include a margin of safety (MOS) to account

Table 5.1 Summary of federal current or proposed legislation, regulations, and guidance impacting PPCPs and EDCs in source or drinking water or their disposal Agency Current or proposed legislation, regulation, or guidance* Website EPA-Water Clean Water Act (1972) http://www2.epa.gov/laws-regulations/summary-  Regulates discharges of pollutants from point sources into U.S. clean-water-act waters through EPA’s National Pollutant Discharge Elimination http://water.epa.gov/lawsregs/lawsguidance/cwa/tmdl/i System (NPDES) permit program ndex.cfm  Requires technology-based standards for point source discharges; standards are developed by EPA for categories of dischargers based on performance of pollution control technologies  Regulates surface water quality standards, including designated uses, water quality criteria, an antidegredation policy, and general policies, through collaboration among EPA, States, territories, and tribes  Under the Act, total maximum daily loads (TMDLs) have been established in some states for EDCs including atrazine, chlordane, and PCBs Safe Drinking Water Act (1974, with amendments in 1986 and 1996) http://water.epa.gov/drink/contaminants/index.cfm#Pri  Requires the EPA to set National Primary Drinking Water mary Regulations (NPDWRs) for drinking water quality and oversee all states, localities, and water suppliers who implement these standards. o NPDWRs set enforceable Maximum Contaminant Levels http://water.epa.gov/drink/contaminants/ (MCLs) for drinking water from public water systems for: . Microorganisms . Disinfectants . Disinfection Byproducts . Inorganic Chemicals . Organic Chemicals . Radionuclides MCLs include a number of putative EDCs, including pesticides, phthalates, PCBs, and industrial compounds (see Table 5.2). (continued)

Table 5.1 (Continued) Agency Current or proposed legislation, regulation, or guidance* Website EPA-Water  Provides process by which EPA must identify and list unregulated http://water.epa.gov/scitech/drinkingwater/dws/ccl/ccl3 (cont.) contaminants that may require a national drinking water regulation in .cfm the future. EPA must periodically publish this list (the Contaminant Candidate List or CCL) and decide whether to regulate at least five or more contaminants on the list. The current CCL3 consists of: o 116 contaminants that may require regulation under the SDWA but are currently not subject to any proposed or promulgated national primary drinking water regulations and are known or anticipated to occur in public water systems. o Putative EDCs that include pesticides, hormones, MTBE, nitrosamines, PFCs, butylated hydroxyanisole, and RDX; also includes one PPCP (erythromycin) (Table 5.3).  SDWA Amendments of 1996 provide for monitoring of no more than https://www.federalregister.gov/articles/2012/05/02/20 30 unregulated contaminants suspected to be present in water but 12-9978/revisions-to-the-unregulated-contaminant- without NPDWRs every 5 years. EPA collects these data through the monitoring-regulation-ucmr-3-for-public-water- Unregulated Contaminant Monitoring (UCM) program. The current systems UCM Rule 3 (UCMR3)(June, 2012): o Requires monitoring for 30 contaminants suspected to be present in drinking water but without health-based standards set under SWDA. Monitoring is during a 12-mo period between January 2013 and December 2015. o Includes several hormones and perfluorinated compounds. Human Health Benchmarks for Pesticides (HHBPs) in Drinking Water, http://iaspub.epa.gov/apex/pesticides/f?p=HHBP:home announced 2010 with the first HHBPs published in 2012 o Developed to help states, tribes, water systems, public and others determine whether detection of a pesticide in drinking water or source water may indicate a potential human health risk o Health risk-based concentrations for acute and chronic exposures have been developed for approximately 350 pesticides, including some that are putative EDCs (continued)

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Table 5.1 (Continued) Agency Current or proposed legislation, regulation, or guidance* Website EPA –Waste Resource Conservation and Recovery Act (RCRA) (1976) http://www.epa.gov/epawaste/inforesources/online/ind  Gives EPA the authority to control hazardous waste from the ex.htm “cradle-to-grave” and sets forth a framework for the management of non-hazardous solid wastes  Provides regulations for solid and hazardous waste management  Agents listed as hazardous waste under the P-list and U-list include 24 agents currently used in medicine (Table 5.5) and numerous pesticides that are putative EDCs (Table 5.6) Standards for Universal Waste http://www.epa.gov/osw/hazard/wastetypes/universal/i  Govern the collection and management of widely generated ndex.htm wastes, including pesticides as well as batteries, mercury- containing equipment, and bulbs (lamps) in a way that will prevent release to the environment. Implemented by EPA, but states can modify the universal waste rule and add additional universal waste(s) in individual state regulations.  The 2014 Proposal to Address the Management of Hazardous http://www.epa.gov/waste/hazard/generation/pharmace Waste Pharmaceuticals proposes: uticals.htm o To establish appropriate standards for the management and disposal of hazardous waste pharmaceuticals generated by healthcare facilities, by adding them to the Universal Waste Program o Only pertains to those pharmaceutical wastes that meet the current definition of a RCRA hazardous waste and that are generated by healthcare-related facilities U.S. DEA Secure and Responsible Drug Disposal Act of 2010 http://www.deadiversion.usdoj.gov/drug_disposal/non_  Gives the Attorney General authority to promulgate new registrant/s_3397.pdf regulations within the framework of the Controlled Substances Act that will allow patients to deliver unused pharmaceutical controlled substances to appropriate entities for disposal in a manner consistent with effective controls against diversion (continued)

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Table 5.1 (Continued) Agency Current or proposed legislation, regulation, or guidance* Website U.S. DEA (cont.) Disposal of Controlled Substances- Proposed Rule (12/21/2012); http://www.deadiversion.usdoj.gov/fed_regs/rules/201 Public comment period ended 2/19/2013 2/fr1221_8.htm  Proposes requirements to govern the secure disposal of controlled substances by both DEA registrants and ultimate users o Expands the options available to collect controlled substances from ultimate users for purposes of disposal to include take-back events, mail-back programs, and collection receptacle locations o Expands the authority of authorized retail pharmacies to voluntarily maintain collection receptacles at long term care facilities EPA 2010 Best Management Practices Guidance Document for Unused http://water.epa.gov/scitech/wastetech/guide/upload/un Pharmaceuticals at Health Care Facilities (Draft) useddraft.pdf  Interim guidance until 2013 Proposal to Address the Management of Hazardous Waste Pharmaceuticals is finalized  Focuses on reducing or avoiding unused pharmaceuticals  Advises development of a tracking system for pharmaceuticals and their disposal Managing Pharmaceutical Waste: A 10-step Blueprint for Health http://www.hercenter.org/hazmat/tenstepblueprint.pdf care Facilities in the United States (August, 2008)  Overview of regulations  BMP for non-regulated pharmaceutical waste  Assessing current practices and drug inventories  Minimizing pharmaceutical waste (continued)

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Table 5.1 (Continued) Agency Current or proposed legislation, regulation, or guidance* Website U.S. FDA Guidance: How to Dispose of Unused Medicine http://www.fda.gov/ForConsumers/ConsumerUpdates/  Provides guidelines for proper disposal of unused prescription ucm101653.htm drugs and rational for safe disposal  Outlines environmental concerns regarding drug residues in water Guidance: Disposal of Unused Medicines: What You Should Know http://www.fda.gov/Drugs/ResourcesForYou/Consume  Overview of disposal methods (Take-Back Programs, household rs/BuyingUsingMedicineSafely/EnsuringSafeUseofMe trash, flushing) dicine/SafeDisposalofMedicines/ucm186187.htm  FAQs section  Lists medications recommended for disposal by flushing Endocrine Disruptor Screening Program Comprehensive http://www.epa.gov/endo/pubs/EDSP-comprehensive- Management Plan (June 2012) management-plan.pdf  Provides strategic guidance for 2012-2017  Reviewed annually to reflect adjustments to program priorities and resources US Office of National 2012 National Drug Control Strategy http://www.whitehouse.gov/sites/default/files/ondcp/lis Drug Control Policy  Action item “Increase Prescription Return/Take-Back and t_of_actions.pdf Disposal Programs” under the “Seek Early Intervention Opportunities in Health Care” section EPA/USDA/FDA/ Memorandum of Understanding on Sustainability of Federal http://water.epa.gov/scitech/swguidance/ppcp/upload/ USGS Collaboration on Pharmaceuticals in Drinking Water (Dec, 2012) mou_pharm_drinking_water12182012.pdf  Formal mechanism to improve and sustain federal collaboration and coordination on issues related to PPCPs in drinking water *Bold text identifies legally binding regulations BMP − best management practices; CCL − Contaminant Candidate List; DEA − Drug Enforcement Agency; EPA − Environmental Protection Agency; FAQ − frequently asked question; FDA − Food and Drug Administration; HHBP − Human Health Benchmarks for Pesticides; MCL − maximum contaminant level; NPDES − National Pollution Discharge Elimination System; MTBE − methyl tert-butyl ether; PCB − polychlorinated biphenyl; PFC − perfluorinated compound; RCRA − Resource Conservation and Recovery Act; SDWA − Safe Drinking Water Act; TMDL − total maximum daily load; UCMR − Unregulated Contaminant Monitoring Rule

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for uncertainty in predicting how well pollutant reductions will result in meeting water quality standards. The Safe Drinking Water Act (SDWA), passed in 1974 and amended in 1986 and 1996, gives EPA the authority to set drinking water standards to control the level of contaminants in the nation’s drinking water. Under the SDWA, the EPA sets Maximum Contaminant Levels (MCLs) via the National Primary Drinking Water Regulations for certain microorganisms, disinfectants, disinfection byproducts, inorganic chemicals, organic chemicals, and radionuclides. The first National Primary Drinking Water Regulations were set in 1976 for 22 contaminants, with new regulations being added over the next 24 years for a total of 87 contaminants regulated in 2000. Some of these contaminants are considered to be EDCs (Table 5.2). Table 5.2 Potential EDCs regulated by the National Primary Drinking Water Standards Year Common sources in Compound MCL (ppb) adopted drinking water Alachlor 2 1992 Runoff from herbicide used on row crops Atrazine 3 1992 Runoff from herbicide used on row crops Benzo(a)pyrene 0.2 1994 Discharge from factories; leaching from gas storage tanks and landfills Carbofuran 40 1992 Leaching of soil fumigant used on rice and alfalfa Chlordane 2 1992 Residue of banned termiticide 2,4-D 70 1992 Runoff from herbicide used on row crops 1,2-Dibromo-3- 0.2 1992 Runoff/leaching from soil fumigant used on chloropropane (DBCP) soybeans, cotton, pineapples, and orchards o-Dichlorobenzene 600 1992 Discharge from industrial chemical factories Dichloromethane 5 1994 Discharge from drug and chemical factories Di(2-ethylhexyl) adipate 400 1994 Discharge from chemical factories Di(2-ethylhexyl) phthalate 6 1994 Discharge from rubber and chemical factories Dinoseb 7 1994 Runoff from herbicide used on soybeans and vegetables Dioxin (2,3,7,8-TCDD) 0.00003 1994 Emissions from waste incineration and other combustion; discharge from chemical factories Diquat 20 1994 Runoff from herbicide use Endrin 2 1994 Residue of banned insecticide Epichlorohydrin 0.01% dosed 1992 Discharge from industrial chemical factories; at 0.020 ppb an impurity of some water treatment chemicals Ethylene dibromide 0.05 1992 Discharge from petroleum refineries Glyphosate 700 1994 Runoff from herbicide use (continued)

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Table 5.2 (Continued) MCL* Year Common sources in Compound (ppb) adopted drinking water Heptachlor 0.4 1992 Residue of banned termiticide Heptachlor epoxide 0.2 1992 Breakdown of heptachlor Hexachlorobenzene 1 1994 Discharge from metal refineries and agricultural chemical factories

Lindane 0.2 1992 Runoff/leaching from insecticide used on cattle, lumber, gardens Methoxychlor 40 1992 Runoff/leaching from insecticide used on fruits, vegetables, alfalfa, livestock Oxamyl (Vydate) 200 1994 Runoff/leaching from insecticide used on apples, potatoes, and tomatoes Polychlorinated biphenyls 0.5 1992 Runoff from landfills; discharge of waste (PCBs) chemicals Pentachlorophenol 1 1993 Discharge from wood preserving factories Picloram 500 1994 Herbicide runoff Simazine 4 1994 Herbicide runoff Styrene 100 1992 Discharge from rubber and plastic factories; leaching from landfills Tetrachloroethylene 5 1992 Discharge from factories and dry cleaners Toluene 1000 1992 Discharge from petroleum factories Toxaphene 3 1992 Runoff/leaching from insecticide used on cotton and cattle 2,4,5-TP (Silvex) 50 1992 Residue of banned herbicide 1,2,4-Trichlorobenzene Discharge from textile finishing factories 1,1,1-Trichloroethane 200 1989 Discharge from metal degreasing sites and other factories 1,1,2-Trichloroethane 5 1994 Discharge from industrial chemical factories Xylenes (total) 10 1992 Discharge from petroleum factories; discharge from chemical factories Source: data from EPA 2009b *MCL − maximum contaminant level

Drinking water contaminants being considered for regulation under the SDWA are included in the Contaminant Candidate List (CCL) (EPA 2009a). The list is comprised of pathogens and chemicals, including pesticides, disinfection byproducts, chemicals used in commerce, and pharmaceuticals. EPA is required to periodically publish this list and make Regulatory Determinations to regulate at least five or more contaminants on the list. Chemicals are added to the CCL by the National Drinking Water Advisory Council (NDWAC), the

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scientific community, and the public. The first CCL was established in 1998 and contained 60 compounds, 51 of which were carried over to the CCL2 in 2005. In 2009, CCL3 was established and included 19 compounds from CCL2 along with 8 new pathogens and 89 new chemicals. CCL4 is currently in development; the public comment period for nominating chemicals ended June 2012. The CCL1 and 2 lists included a number of putative EDCs including pesticides and MTBE (Table 5.3). EDCs on the CCL3 list includes pesticides, hormones, MTBE, nitrosamines, PFCs, and butylated hydroxyanisole; one PPCP (erythromycin) was also included (Table 5.4).

Table 5.3 Contaminant Candidate List (CCL)1 and 2 EDCs Type Compound Pesticide Acetochlor (CCL1 and 2) Alachlor ESA* (CCL1 and 2) DDE* (CCL1 and 2) Diazinon (CCL1 and 2) Dieldrin (CCL1 only) Linuron (CCL1 and 2) Metolachlor (CCL1 and 2) Triazines & degradation products of triazines (CCL1 and 2) Volatile organic chemicals MTBE* (CCL1 and 2) Source: data from EPA 2009a *DDE − dichlorodiphenyldichloroethylene; ESA − ethanesulfonic acid; MTBE − methyl tert-butyl ether

Table 5.4 Contaminant Candidate List (CCL)3 EDCs and PPCPs Type Compound Pesticide Acetochlor Acetochlor ethanesulfonic acid (ESA) Acetochlor oxanilic acid (OA) Alachlor ethanesulfonic acid (ESA) Alachlor oxanilic acid (OA) alpha-Hexachlorocyclohexane (HCH) Ethylene thiourea Metolachlor Metolachlor ethanesulfonic acid (ESA) Metolachlor oxanilic acid (OA) Vinclozolin Hormones and steroids 17 alpha-Estradiol Equilenin Equilin Erythromycin Estradiol (17-beta estradiol) Estriol Estrone Ethinyl Estradiol (17-alpha Ethynyl Estradiol) Mestranol Norethindrone (19-Norethisterone) (continued)

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Table 5.4 (Continued) Type Compound Volatile organic chemicals Methyl-t-butyl ether (MTBE) N-nitrosamines N-Nitrosodiethylamine (NDEA) N-nitrosodimethylamine (NDMA) N-Nitroso-di-n-propylamine (NDPA) N-Nitrosodiphenylamine N-Nitrosopyrrolidine (NPYR) Perfluorinated compounds Perfluorooctane sulfonic acid (PFOS) Perfluorooctanoic acid (PFOA) Antioxidants Butylated hydroxyanisole (BHA) Pharmaceuticals Erythromycin Source: data from EPA 2009a

Amendments to the SDWA in 1996 established the Unregulated Contaminant Monitoring Program to collect data for contaminants suspected to be present in drinking water. Under this program, public water systems (PWSs) that serve more than 10,000 people and a subset of PWSs that serve less than 10,000 people must conduct water sampling surveys to test for specified contaminants that are suspected to be present in drinking water but that do not have health-based standards set under SDWA. Samples are analyzed by State laboratories and reported to the EPA for inclusion in the National Contaminant Occurrence Database (NCOD). The first Unregulated Contaminant Monitoring Rule (UCMR1) was published in 1999 for a list of 26 contaminants, and covered the monitoring period 2001-2005 (EPA 2014d). UCMR2 was published in 2007 for a list of 25 contaminants and covered the monitoring period 2008-2010 (EPA 2013e). The most recent rule, UCMR3, monitors 30 contaminants in drinking water, including several hormones and perfluorinated compounds during a 12-month period from January 2013 through December 2015 (EPA 2012e) (Table 5.5). The UCMR divides contaminants into three types of monitoring: assessment monitoring (List 1), screening survey (List 2), and pre-screen testing (List 3) based on the types of analytical methods used by drinking water laboratories. List 1 contaminants are analyzed using common analytical method technologies used by drinking water laboratories while List 2 and 3 use specialized or newer methods, respectively.

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Table 5.5 2013-2015 UCMR3 compounds Monitoring type Chemical class Compound List 1 Volatile organic compounds 1,1-dichloroethane 1,2,3-trichloropropane 1,3-butadiene Bromochloromethane (halon 1011) Bromomethane (methyl bromide) Chlorodifluoromethane (HCFC-22) Chloromethane (methyl chloride) Synthetic organic compounds 1,4-Dioxane Metals Chromium Chromium-6 Cobalt Molybdenum Strontium Vanadium Oxyhalide anion Chlorate (disinfectant in drinking water) Perfluorinated compounds* Perfluorobutanesulfonic acid (PFBS) Perfluoroheptanoic acid (PFHpA) Perfluorohexanesulfonic acid (PFHxS) Perfluorononanoic acid (PFNA) Perfluorooctanesulfonic acid (PFOS) Perfluorooctanoic acid (PFOA) List 2 Hormones* 16-α-hydroxyestradiol (estriol) 17-α-ethynylestradiol (ethinyl estradiol) 17-β-estradiol 4-androstene-3,17-dione Equilin Estrone Testosterone List 3 Viruses Enteroviruses Noroviruses Source: data from EPA 2012e *Putative EDCs

Federal Waste Legislation and Regulations

The Resource Conservation and Recovery Act (RCRA) is a U.S. law that provides, in broad terms, the general guidelines for the waste management program set forth by Congress (EPA 2012c). Regulated entities that generate hazardous waste are subject to waste accumulation, manifesting, and recordkeeping standards. Facilities that treat, store, or dispose of hazardous waste must obtain a permit, either from EPA or from a state agency that EPA has

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authorized to implement the permitting program. Although RCRA is a federal statute, many states implement the RCRA program. Currently, EPA has delegated its authority to implement various provisions of RCRA to 46 of the 50 states (EPA 2013d). Under this Act, pharmaceutical waste can be classified as one of the following:

 Hazardous waste (as defined by 40 CFR 261 under RCRA). For example K-List waste includes wastewater treatment sludge from the production of veterinary pharmaceuticals. Exemptions have been made to pharmaceutical companies that treat their waste streams before discharge. About 30 drugs are regulated as hazardous waste under the RCRA P- list and U-list (discarded commercial chemical products) (see Table 5.6 for a list of those currently used in medicine).  Medical waste (defined as “any solid waste that is generated in the diagnosis, treatment, or immunization of human beings or animals, in research pertaining thereto, or in the production or testing of biological” by the Medical Waste Tracking Act of 1988).  Nonhazardous waste  Controlled substance

Table 5.6 Pharmaceuticals considered hazardous waste by RCRA Compound RCRA P/U list code Use Arsenic trioxide P012 Chemotherapy Epinephrine P042 Allergic reactions Nicotine P075 Smoking cessation products Nitroglycerin P081 Angina Phentermine P046 Weight-loss aid Physostigmine P204 Glaucoma Physostigmine salicylate P188 Glaucoma Warfarin P001, U248 Prevent blood clots Melphalan U150 Chemotherapy Mitomycin C U010 Chemotherapy Uracil mustard U237 Chemotherapy Azaserine U015 Chemotherapy Chlorambucil U035 Chemotherapy Cyclophosphamide U058 Chemotherapy Daunomycin U059 Chemotherapy Diethylstilbesterol U089 Synthetic estrogen Lindane U129 Lice or scabies Hexachlorophene U132 Antiseptic Paraldehyde U182 Sedative Phenacetin U187 Pain relief Reserpine U200 Hypertension, sedative Resorcinol U201 Antifungal Selenium sulfide U205 Anti-infective agent Streptozotocin U206 Chemotherapy Source: data from EPA 2013d

RCRA includes an exemption for all hazardous waste generated by households [40 CFR 261.4(b)(1)]. Therefore, pharmaceuticals that are unwanted by consumers are not regulated as

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hazardous waste and are generally considered municipal solid wastes and disposed of as regular trash. This practice may lead to the leaching of discarded medications into source water. Like drinking water standards, state, and/or local governments may have additional regulations regarding household pharmaceutical waste as long as they are more stringent than the federal regulations. Similarly, compounds that are potential endocrine disruptors can be classified in the same way as pharmaceutical wastes (for example, hazardous, medical, non-hazardous, controlled substance) depending on the type of chemical. Although RCRA does not explicitly regulate a compound based on endocrine disruption endpoints, several EDCs are included under RCRA because of other chemical characteristics such as ignitability, corrosively, reactivity, or toxicity (Table 5.7). Table 5.7 EDCs regulated under RCRA RCRA List Waste F-list: Hazardous wastes from non-specific sources Wastes from the production or manufacturing use of pentachlorophenol, or of intermediates used to produce its derivatives

Wastes from the manufacturing use of tetra-, penta-, or hexachlorobenzenes K-list: Hazardous wastes from specific sources Wood preservation: Bottom sediment sludge from the treatment of wastewaters from wood preserving processes that use creosote and/or pentachlorophenol

Pesticides: Wastewater an residues from the production of chlordane, 2,4-D, toxaphene and maneb P- and U-list: Discarded commercial chemical Atrazine products Benzo[a]pyrene Chlordane Cyclophosphamide DDT DDD Diethyl Phthalate Diethylhexyl phthalate Dibutyl phthalate Hexachlorobenzene Kepone Lindane Methoxychlor Pentachlorobenzene Pentachlorophenol Resorcinol Tetrachlorobenzene Thiram Toxaphene Source: data from EPA 2013d

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In conjunction with RCRA, pesticides, including those that may be EDCs, are regulated under EPA Universal Waste Regulations (EPA 2012d). Under these regulations, which were promulgated in 1995, any pesticide that is recalled or unused and considered waste must be disposed of in a way that will prevent release into the environment. A proposal is currently under development to include pharmaceutical wastes under the Universal Waste Regulations (EPA 2013a). Until this proposal is finalized, EPA provides interim guidance for pharmaceutical waste disposal in the Best Management Practices for Unused Pharmaceuticals at Health Care Facilities document (EPA 2010a). These guidelines recommend that health care facilities keep an inventory of the pharmaceuticals they use and take steps to reduce the amount of unused medications. In addition, these facilities should be familiar with proper disposal of unused medications and implement an on-site waste management program.

Drug Enforcement Agency (DEA) Legislation and Regulations

Existing regulations regarding proper drug disposal are provided by the DEA Secure and Responsible Drug Disposal Act of 2010 (the “Disposal Act”) (DEA 2010). This act enables consumers to dispose of unused and unwanted controlled substances to authorized personnel such as local law enforcement officials. Currently, the DEA has proposed a “Disposal of Controlled Substances” rule that would expand disposal options for controlled substances to include take-back events, mail-back programs, and collection receptacles at local pharmacies (DEA 2012). The public comment period ended in February 2013.

FEDERAL GUIDANCE AND OTHER RESOURCES

EPA

To provide additional information about potential health risks associated with exposures to pesticides in drinking water, the EPA has developed Human Health Benchmarks for Pesticides (HHBPs) for approximately 360 pesticides, some of which are EDCs (EPA 2013c, 2014e). HHBPs are levels in water at or below which adverse health effects are not anticipated from one- day (acute) or lifetime (chronic) exposures. EPA develops HHBPs using the same methodologies used by EPA to develop other health advisories for drinking water (e.g., MCLs), using peer- reviewed data on health effects, including endocrine disruption and cancer, and focus on sensitive populations (children and women of reproductive age). Compared to the DWELs developed in this project, few of the compounds are found on both lists. However, where they are, the input values are the same (e.g., EPA reference doses for noncancer effects) although HHBPs assume a Relative Source Contribution (RSC) of 20% in their derivation. These values can be useful for utilities in interpreting the relative significance of measured levels in drinking water monitoring data and determine how to respond to monitoring results and prioritize resources.

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Food and Drug Administration (FDA)

While there are no FDA regulations regarding PPCPs and EDCs in drinking water, the agency provides guidance on proper disposal of unused prescription drugs (FDA 2011, 2013c, 2014). They recommend that drug take-back programs are the best way to dispose of unwanted medications; if such a program is not available, they recommend that medicines should be disposed of in the household trash. The FDA recommends that some drugs be flushed down the sink or toilet because of the danger they pose if accidentally ingested by children or pets—i.e., they can be especially harmful, and in some cases, fatal with just one dose if they are used by someone other than the person for whom the medicine was prescribed (Table 5.8).

Table 5.8 Drugs recommended for disposal by flushing by the FDA because they can be especially harmful to children or pets Active ingredient Representative brand names Uses Buprenorphine Suboxone® (film), Zubsolv® Pain relief Diazepam Diastat® Cluster seizures Fentanyl Abstral®,Duragesic®, Onsolis® Pain relief Hydromorphone hydrochloride Dilaudid®, Exalgo® Pain relief Meperidine hydrochloride Demerol® Pain relief Methadone hydrochloride Methadose®, Dolophine® Pain relief Methylphenidate Daytrana® ADHD Morphine sulfate Avinza®, Embeda®, MS Contin® Pain relief Oxycodone hydrochloride Oxycodone®, Oxycontin®, Percocet®, Percodan® Pain relief Oxymorphone hydrochloride Opana® Pain relief Sodium oxybate Xyrem® Narcolepsy Tapentadol Nucynta ER® Pain relief Source: data from FDA 2014

Note that of the compounds listed in Table 5.8, diazepam has been detected at a fairly high rate in WWTP effluent (e.g., in 100% of 35 samples collected at a WWTP in New York from 2004-2009, Phillips et al. 2010) and at a moderate rate in surface water (e.g., in 25%, or 3 of 12 samples collected in source water for New York City, NYC DEP 2010), but only very infrequently in drinking water (e.g., detected in 1/76 samples in our occurrence database, in finished drinking water collected from one of 19 water utilities across the United States from 2006-2007 by Benotti et al. 2009). Methadone has also been analyzed for and detected in WWTP influent samples (7/7 samples at seven municipal WWTPs around the United States; Chiaia et al. 2008) and WWTP effluent samples (in samples collected at WWTPs in New York, at variable rates; Phillips et al. 2010), and was detected in 1/9 finished drinking water samples collected by the City of Chicago from 2009-2011 (CDWM 2011). We did not identify any analyses for the other pharmaceuticals in reports and articles that we reviewed. However, fenantyl has been reported to be unlikely to undergo hydrolysis and to have a significant potential for bioconcentration in aquatic organisms (NLM 2014). As such, further research to address the potential for these substances to persist in water may be warranted. The FDA together with the White House Office of National Drug Control have also developed federal guidelines on Drug Disposal (FDA 2011). These guidelines recommend:

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 Follow any specific disposal instructions on the drug label or patient information that accompanies the medication. Do not flush prescription drugs down the toilet unless this information specifically instructs you to do so.  Take advantage of community drug take-back programs that allow the public to bring unused drugs to a central location for proper disposal. Call your city or county government's household trash and recycling service (see blue pages in phone book) to see if a take-back program is available in your community. The Drug Enforcement Administration, working with state and local law enforcement agencies, is sponsoring National Prescription Drug Take Back Days throughout the United States.  If no instructions are given on the drug label and no take-back program is available in your area, take them out of their original containers and mix them with an undesirable substance, such as used coffee grounds or kitty litter — to make the medication less appealing and unrecognizable — then put them in a sealable bag, empty can, or other container to prevent the medication from leaking or breaking out of a garbage bag.  Before throwing out a medicine container, scratch out all identifying information on the prescription label to make it unreadable. This will help protect your identity and the privacy of your personal health information.  Do not give medications to friends. Doctors prescribe drugs based on a person's specific symptoms and medical history. A drug that works for you could be dangerous for someone else.  When in doubt about proper disposal, talk to your pharmacist.

The same disposal methods for prescription drugs could apply to over-the-counter drugs as well.

STATE-SPECIFIC PROGRAMS ADDRESSING PPCPS AND EDCS IN DRINKING WATER

Each state may adopt alternative standards for contaminants in drinking water, given these standards are not less stringent than the federal regulations. Most states adopt the national primary and secondary drinking water standards of the federal government, and create additional rules to fulfill state requirements. EPA provides links to websites for individual U.S. state drinking water programs (EPA 2012p; http://water.epa.gov/drink/local/). Table 5.9 highlights legislation, regulations, and guidelines adopted by individual states that specifically address PPCP ingredients or EDCs in drinking water. The reader is encouraged to determine whether additional legislation or guidance specific to PPCP ingredients or EDCs exist for individual states. Examples of specific state programs that address PPCP ingredients or EDCs are discussed below.

California

The California Department of Public Health (CDPH) adopts MCLs as regulations for drinking water in the State of California. California MCLs have been established for approximately 90 compounds including some pesticides and industrial compounds that are potential EDCs (CDPH 2014a) (Table 5.10). These MCLs are health protective drinking water standards to be met by public water systems and take into account potential health risks as well

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as factors such as their detectability and treatability, as well as costs of treatment. California Health & Safety Code §116365(a) requires CDPH to MCLs at a level as close to Public Health Goals (PHGs) as is technologically and economically feasible (CDPH 2011, 2014b). PHGs are established by California’s Office of Environmental Health Hazard Assessment (OEHHA). They are concentrations of drinking water contaminants that pose no significant health risk if consumed for a lifetime, based on current risk assessment principles, practices, and methods. PHGs are based on health risk assessments for non-carcinogenic compounds and a lifetime excess cancer risk level of 1 × 10-6 for carcinogens (CalEPA 2011). PHGs for potential EDCs are also listed in Table 5.10. For some compounds that lack MCLs, CDPH has also established health-based advisory levels known as drinking water notification levels (DWNLs) (Table 5.10). When chemicals are found at concentrations that exceed DWNLs, CDPH recommends that the utility inform its customers and consumers about the presence of the chemical, and about health concerns associated with exposure to it. They recommend, for example, that utilities consider reporting this information in annual Consumer Confidence Reports, a separate mailing, or another method. If a chemical is present in drinking water provided to consumers at concentrations considerably greater than the notification level, CDPH recommends that the drinking water system take the source out of service (CDPH 2010, CDPH 2012b). Drinking water-related statutes for the state provide funding for pilot projects for treatment or removal of PPCPs and EDCs from water. Projects to address emerging contaminants, including perchlorate, hexavalent chromium, and EDCs are given priority. The California State legislature has appropriated one hundred million dollars for pilot and demonstration projects for treatment or removal of NDMA, pesticides and herbicides, and pharmaceuticals and endocrine disrupters (CDPH 2012a).

Massachusetts

Massachusetts 2013 Senate bill S399 proposes to establish drinking water areas, such as private drinking water wells and municipal drinking water supplies, which are protected from pharmaceutical facility and agricultural animal wastewater. The bill was scheduled for a hearing in the Joint Environment, Natural Resources and Agriculture Committee in September 2013; however, no updates are yet available (Senate of the Commonwealth of Massachusetts 2013).

Minnesota

Two Minnesota laws (2009 Session Laws, Chapter 172, Article 2, Section 7 and 2011 First Special Session Laws, Chapter 6, Article 2, Section 8) allocate funds “for addressing public health concerns related to contaminants found in drinking water for which no health-based drinking water standard exists” (MDH 2014). The Minnesota Department of Health (MDH) established a Contaminants of Emerging Concern Program that “investigates and communicates the exposure potential and health risk of contaminants of emerging concern in drinking water.” Risk managers, stakeholders, and the public can nominate contaminants for further evaluation in the CEC program. To date, 57 substances have been nominated.

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Table 5.9 Selected state-specific programs specifically addressing PPCPs and EDCs in water* State Program† Website California Maximum Contaminant Levels (MCLs) adopted as regulations for http://www.cdph.ca.gov/certlic/drinkingwate drinking water (Title 22 of California Code of Regulations) r/pages/chemicalcontaminants.aspx  Established for ~90 compounds, including some pesticides and industrial compounds that are EDCs (though most set 1977-1994 w/o explicit consideration of ED potential)  MCLs are set as close to PHGs as is technologically and economically feasible, placing primary emphasis on the protection of public health

Public Health Goals (PHG) for chemicals in drinking water (California http://oehha.ca.gov/water/phg/allphgs.html Health and Safety Code Section 116365 (c) (1))  Established by OEHHA; reflect concentrations of drinking water contaminants that pose no significant health risk if consumed for a lifetime

Drinking Water Notification Levels (California Health and Safety Code http://www.waterboards.ca.gov/drinking_ Section 116455) water/certlic/drinkingwater/NotificationLe  Established by CDPH for chemicals in drinking water that lack MCLs; vels.shtml reflect health based concentrations in drinking water that if above require notification of customers and consumers

Drinking Water-Related Statutes (2012) http://www.cdph.ca.gov/certlic/drinkingwate  Chapter 4 § 79532: (f). Provides funding for pilot projects for treatment r/Documents/Lawbook/DWstatutes-2012-01- or removal of PPCPs and EDCs from water. Projects to address 01a.pdf emerging contaminants, including perchlorate, hexavalent chromium, and EDCs are given priority.  Chapter 6 §79545: Appropriates one hundred million dollars ($100,000,000) for pilot and demonstration projects for treatment or removal of the following contaminants: (2) N- NDMA, (5) Pesticides and herbicides, (7) Pharmaceuticals and endocrine disrupters. (continued)

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Table 5.9 (Continued) State Program† Website Massachusetts S399 (Senate Bill). Relative to regulation of discharge of pharmaceutical and http://legiscan.com/MA/text/S399/id/7467 personal care product-laden wastewater into private drinking water wells and 73 municipal drinking water supplies (Introduced 9/26/2013)  Establishes “drinking water protection areas” protected from pharmaceutical facility and animal wastewater , defined as recharge areas for public water supplies, private drinking water wells, and interim wellhead protection areas Minnesota Minnesota Rules, Chapter 4717. Health Risk Limit Rules for http://www.health.state.mn.us/divs/eh/risk/ru Groundwater (Revision 2012/2013) les/water/hrlrule.html  Promulgates health risk limits (HRLs) for substances found to degrade Minnesota groundwater  HRLs specify a minimum level of quality for water used for human consumption 2014/2015 Amendment to Health Risk Limit Rules for Groundwater http://www.health.state.mn.us/divs/eh/risk/  Adds new or updated HRLs for 12 groundwater contaminants rules/water/overview.html  Currently awaiting administrative review and governor approval Human Health-Based Guidance for Water http://www.health.state.mn.us/divs/eh/risk/g  Three types of guidance uidance/gw/table.html o HRLs- adopted through formal rulemaking process o Health based values (HBVs)- interim guidance until adopted as an HRL o Risk Assessment Advice (RAA)- quantitative or qualitative value based on limited data or new methodology (continued)

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Table 5.9 (Continued) State Program† Website New Jersey NJ 2012-2013 S271. Establishes NJ Water Supply and Pharmaceutical http://www.govtrack.us/states/nj/bills/2012- Product Study Commission (referred to Senate Environment and Energy 2013/s271 Committee)  Investigates, quantifies and evaluates the potential risks associated with pharmaceutical products in the State’s water supply  Develops recommendations for proper disposal methods and potential filtering techniques to remove pharmaceutical products from the waste stream *This table provides an overview of State programs and regulations that specific address EDCs or PPCPs in the State’s water supply. The reader is encouraged to determine whether additional relevant legislation or guidance exist for specific states. † Bold text identifies legally binding regulations. CDPH − California Department of Public Health; HBV − health based value; HRL − health risk limit; MCL − maximum contaminant level; NDMA − N-nitrosodimethylamine; OEHHA − Office of Environmental Health Hazard Assessment; PHG − Public Health Goal; RAA − risk assessment advice

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Table 5.10 California Department of Public Health (CDPH) Public Health Goals (PHGs) and Maximum Contaminant Levels (MCLs) for EDCs in water Substance PHG (ppb) MCL (ppb) DWNL (ppb) 1,4-Dichlorobenzene 6 5 2,4-Dichlorophenoxyacetic acid (2,4-D) 20 70 Alachlor 4 2 Atrazine 0.15 1 Bentazon 200 18 Dalapon 790 200 Diazinon 1.2 Di(2-ethylhexyl)adipate 200 400 Di(2-ethylhexyl)phthalate (DEHP) 12 4 Dinoseb 14 7 Diquat 15 20 Endrin 1.8 2 Heptachlor 0.008 0.01 Heptachlor epoxide 0.006 0.01 Lindane 0.032 0.2 Methoxychlor 0.09 30 Molinate 1 20 MTBE 13 13 NDEA 0.01 NDMA 0. 003 0.01 NDPA 0.01 Oxamyl 26 50 Pentachlorophenol 0.3 1 Perchlorate 1 NA Picloram 500 500 Polychlorinated biphenyls (PCBs) 0.09 0.5 RDX 0.3 Simazine 4 4 Source: data from CDPH 2010, CDPH 2014b

As part of this program, MDH has promulgated Human Health-Based Guidance Values for Water, which include Health Risk Limits (HRLs), Health-Based Values (HBV), and Risk Assessment Advice (RAA) for a number of CECs (MDH 2013). HRLs are regulations specifying a maximum contaminant level for compounds in drinking water, while HBVs provide interim guidance until a compound is adopted as an HRL. RAAs provide quantitative or qualitative values for compounds in drinking water based on limited data or new methodology. New or updated HRLs for twelve contaminants, including the PPCPs/EDCs carbamazepine, ATHN, metribuzin, 1,2,4-trichlorobenzene, 1,2,3-trichloropropane, tris (2-chloroethyl) phosphate, and DEET, were adopted in September 2013 (Table 5.11).

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Table 5.11 Minnesota Department of Health (MDH) Contaminants of Emerging Concern (CEC) Program guidance values for PPCPs or EDCs in water Chemical MDH Health-based Guidance Value (ppb) Acetaminophen 200 (acute, short-term, subchronic, chronic) AHTN 200 (short-term) 40 (subchronic) 20 (chronic) Biphenyl 300 (chronic) (“Re-evaluation of value is warranted”) Bisphenol A 300 (acute and short-term) 100 (subchronic and chronic) Butyl benzyl phthalate 100 (acute, short-term, subchronic, chronic) Carbamazepine 40 (acute, short-term, subchronic, chronic) Chlorpyrifos 20 (chronic)(“Re-evaluation of value is warranted”) DEET 200 (short-term, subchronic, chronic) Dibutyl phthalate 20 (acute, short-term, subchronic, chronic) 2,4-D 70 (chronic)(“Re-evaluation of value is warranted”) DEHP 20 (acute, short-term, subchronic, chronic) 7 (cancer) 1,4-Dioxane 300 (subchronic) 1 (cancer) Sulfamethazine 100 (short-term, subchronic, chronic) Sulfamethoxazole 100 (short-term, subchronic, chronic) Triclocarban 100 (chronic) Triclopyr 300 (chronic) Triclosan 200 (acute) 50 (short-term, subchronic, chronic) Tris(2-chloroethyl)phosphate (TCEP) 300 (short-term) 200 (subchronic, chronic) 5 (cancer) Tris(1,3-dichloroisopropyl)phosphate (TDCPP) 20 (subchronic) 9 (chronic) 0.8 (cancer) Source: data from MDH 2013

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MDH has also developed Contaminants of Emerging Concern Information Sheets for 20 compounds, including acetaminophen, carbamazepine, sulfonamide antibiotics, triclosan, and a number of EDCs, available at the MDH website: http://www.health.state.mn.us/divs/eh/risk/guidance/dwec/chemunderrev.html FAQs addressed on the sheets include the following:

 What is the compound?  How much of the compound is in Minnesota drinking water?  Has the compound been found in other waters in Minnesota?  What is the MDH guidance value for the compound in water?  How can I safely use products containing the compound?  Can the compound in drinking water affect my health?  How does the compound get into the environment?  How long does the compound stay in the environment?  What are the potential environmental impacts of the compound?  How can I reduce my environmental impact?

New Jersey

New Jersey has proposed to create the Water Supply and Pharmaceutical Product Study Commission to investigate, quantify, and evaluate the potential risks associated with PPCPs in the state’s water supply (State of New Jersey 2012). In addition, the commission is tasked with developing recommendations for proper disposal methods and potential filtering techniques to remove PPCPs from the waste stream.

STATE LEGISLATION AND REGULATIONS ADDRESSING PRESCRIPTION DRUG RETURN, RECYCLING, OR DISPOSAL

Many states have passed or proposed legislation regarding the collection or disposal of pharmaceuticals (i.e., “drug take-back” efforts), at least in part to prevent their access to wastewater streams, including California, Connecticut, Illinois, Kentucky, Maine, Michigan, New Hampshire, New Jersey, New York, Pennsylvania, Rhode Island, Vermont, and West Virginia. These are summarized in Table 5.12. Similar legislation in Florida, Oregon, and Washington State was proposed but was voted down by the legislature. This list is not necessarily comprehensive; while an effort was made to capture existing legislation and guidance, the reader is encouraged to check whether additional relevant legislation or guidance exist for specific states. Alameda County in California passed the first ever legislation requiring pharmaceutical companies to fund and operate drug take-back efforts. The ordinance was upheld in U.S. District Court despite a lawsuit by the drug industry arguing that the program interfered with interstate commerce and was therefore unconstitutional (County of Alameda 2012, Egelko 2013). Similar bills in Florida, Maine, Minnesota, Oregon, and Washington have been proposed but did not pass legislation. Some additional information on State prescription drug, return, and recycling laws is provided by the National Conference of State Legislatures (NCSL, 2012).

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Table 5.12 Summary of state regulations regarding prescription drug return, recycling, or disposal* State Regulations† Website California Medical Waste Management Act: California Health and Safety http://www.cdph.ca.gov/certlic/medicalwaste/Do Code Sections 117600-118360 cuments/MedicalWaste/2013/MWMAfinal2013.  Comprehensive regulations regarding collection and disposal of pdf medical waste from large and small quantity generators CA 2011-2012 Ab1442. Pharmaceutical waste (approved 9/28/2012, http://www.leginfo.ca.gov/pub/11- Chapter 689, Statutes of 2012) 12/bill/asm/ab_1401-  Exempts a pharmaceutical waste generator or parent organization 1450/ab_1442_bill_20120928_chaptered.html that employs health care professionals who generate pharmaceutical waste from specified medical waste hauling requirements if the generator, health care professional, or parent organization retains specified documentation and meets specified requirements and if the facility receiving the waste retains specified documentation and meets specified requirements. Alameda Drug Disposal Program http://www.acgov.org/aceh/safedisposal/docume  First-in-nation ordinance requiring pharmaceutical companies to nts/SDD_Ordinance.pdf fund and operate drug take-back efforts (similar bills in FL, ME, MN, OR and WA have not passed legislation) Connecticut HB05140. An Act Establishing A Program For The Collection Of http://www.cga.ct.gov/2013/TOB/H/2013HB- Unwanted Pharmaceuticals (1/10/2013, referred to committee) 05140-R00-HB.htm Illinois IL 97 HB2056. Household Pharmaceuticals (Passed 8/24/2011) http://ilga.gov/legislation/BillStatus.asp?DocNu  Amends the State Finance Act to create the Household m=2056&GAID=11&DocTypeID=HB&LegId= Pharmaceutical Disposal Fund as a special fund in the State treasury. 59263&SessionID=84&GA=97  Authorizes a law enforcement agency to collect pharmaceuticals from residential sources and to incinerate the collected pharmaceuticals in a manner that is consistent with rules adopted by the Agency. (continued)

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Table 5.12 (Continued) State Regulations† Website Illinois (cont.)  Authorizes the Department of State Police to use moneys in the Household Pharmaceutical Disposal Fund to make grants to local law enforcement agencies for the purpose of facilitating the collection and incineration of pharmaceuticals from residential sources. 210 ILCS 150/1. Safe Pharmaceutical Disposal Act. Effective 1/1/10. http://www.ilga.gov/legislation/ilcs/ilcs3.asp?Act  States that except for medications contained in intravenous fluids, ID=3121&ChapterID=21 syringes, or transdermal patches, no health care institution, nor any employee, staff person, contractor, or other person acting under the direction or supervision of a health care institution, may discharge, dispose of, flush, pour, or empty any unused medication into a public wastewater collection system or septic system. HB0072/HB1343. Safe Pharmaceutical Disposal-Proposed (re-referred http://www.ilga.gov/legislation/BillStatus.asp?D to rules committee on 3/22/2013) ocNum=72&GAID=12&DocTypeID=HB&Sessi  Amends the Safe Pharmaceutical Disposal Act to provide that any onID=85&GA=98 licensed pharmacy may publically display a container suitable for use as a receptacle for used, expired, or unwanted pharmaceuticals Kentucky KY 2011 HB152. An Act relating to the safe disposal of prescription http://www.govtrack.us/states/bills/browse?text= medications and making an appropriation therefor (recommitted to pharmaceuticals#state=ky Appropriations & Revenue)  Establishes “safe drop off drug programs for the purpose of properly disposing of unused prescription medications”  Directs Energy and Environment Cabinet to work with pharmaceutical companies in developing a prescription drug recycling program  Allows use of Kentucky Pride funds to establish safe drop off drug programs (continued)

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Table 5.12 (Continued) State Regulations† Website Maine Title 22 Part 5 Chapter 604. Disposal of Unused Pharmaceuticals http://www.mainelegislature.org/legis/statutes/22  Creates a system for the return of unused pharmaceuticals by /title22sec2700.html publicly available prepaid mailing envelopes  Pharmaceuticals will be returned to a single collection location and handled by ME DEA officials Michigan MI 96R HB5090. Health; pharmaceuticals; acceptance and http://www.govtrack.us/states/mi/bills/96r/hb509 destruction or disposal of drugs or medications not eligible for 0 distribution; require. Amends 1978 PA 368 (MCL 333.1101 - 333.25211) (Assigned Pa 384'12 12/27/2012)  A pharmacy, health professional, or charitable clinic shall accept a prescription drug or other medication for destruction and disposal New Chapter 318-E. Controlled and Non-controlled Pharmaceutical http://www.govtrack.us/states/nh/bills/2011/hb71 Hampshire Drug Take-back Programs  Enables individuals with dispensed drugs to voluntarily return the unused drugs for collection, storage, and disposal New Jersey NJ 2010-2011 A2089/S541. Establishes the Safe Drop Off of Drugs https://www.govtrack.us/states/nj/bills/2010- Program for the collection and disposal of unused prescription drugs and 2011/a2089 other medicines; authorizes use of recycling tax (referred to committee)  Establishes a program for the secure collection and proper, safe disposal of unused prescription drugs and other medicines, by developing and implementing the safe, secure collection of unused prescription drugs and other medicines at municipal police stations and the proper and safe disposal of those drugs and medicines by pharmaceutical companies  Authorizes the use of municipal recycling tax moneys to cover municipal costs related to the program and establishes a Corporation Business Tax credit for the costs of disposal for any company that provides for the proper and safe disposal of the drugs (continued)

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Table 5.12 (Continued) State Regulations† Website New York Drug Management and Disposal Act http://www.dec.ny.gov/chemical/67736.html  Applies to pharmacies, retail businesses that sell drugs and veterinary offices  Requires posting of a notice on how to dispose of unwanted medications, at pick-up counter, checkout counter or in drug display aisle Management of Medical Waste: Guidelines for Implementation of http://www.health.ny.gov/facilities/waste/ Public Health Law 1389 AA-GG and Environmental Health Regulations of 10 NYCRR, Part 70  Guidelines on disposal of cultures and stocks, human pathological wastes, human blood and blood products, sharps, and animal waste NY 2013-2014 A01609/S07095. Relates to the disposal of drugs, drug http://assembly.state.ny.us/leg/?default_fld=&bn disposal sites and home pharmaceutical collection =A01609&term=&Summary=Y&Actions=Y&V  Requires the Office of Alcoholism and Substance Abuse Services otes=Y&Memo=Y&Text=Y (OASAS) in cooperation with the Department of Environmental Conversation to post on their website information related to conducting a pharmaceutical collection event  Allows OASAS to assist DEC in the development of a public information program on the proper disposal of drugs and drug disposal sites Environmental Conservation Law Article 27 Title 27*2 http://law.justia.com/codes/new-  Develops and implements a public information program on the york/2012/env/article-27/title-27-2-ast/ proper storage and disposal of drugs and on drug disposal sites  Requires a notice containing information on the proper storage  and disposal of drugs be displayed in pharmacies and retail businesses authorized to sell drugs Pennsylvania HB1194. Requiring retailers of pharmaceutical drugs to have in place a http://legiscan.com/PA/text/HB1194 system for the acceptance and collection of pharmaceutical drugs for proper disposal (to House 4/15/2013) (continued)

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Table 5.12 (Continued) State Regulations† Website Rhode Island A Special Legislative Commission To Study Public Health Threats http://sos.ri.gov/govdirectory/index.php?page= From Pharmaceutical Human Waste Contamination In The Water DetailDeptAgency&eid=6085  Duties include: o A comprehensive review of methods currently used in this state by consumers, health care providers, and others for disposing of unused pharmaceuticals so that they do not enter the wastewater system o A review of programs and systems developed in other local, state, and national jurisdictions for disposing of unused pharmaceuticals so that they do not enter the wastewater system o Recommendations regarding the development of public education and outreach program concerning the proper disposal of unused medications o Recommendations, if necessary, regarding statutory and/or regulatory changes to current processes concerning pharmaceutical and contamination of our water supply Vermont Sec. 1. 18 V.S.A. § 4201. An Act Relating To The Discharge Of http://www.leg.state.vt.us/docs/2012/Acts/ACT0 Pharmaceutical Waste To State Waters (effective July 1, 2011) 27.pdf  Authorizes a person who lawfully obtained a prescription drug to deliver the drug for disposal without being registered by the state as a pharmacy if federal law authorizes the person to dispose of the drug and the person receiving the drug is authorized by state or federal law to engage in such activity. West Virginia WV 2013 HB2113. Establishing a two year pilot program on the http://legiscan.com/WV/text/HB2113 disposal of unused pharmaceuticals (to House HHR 2/13/2013)  Program must use publically available prepaid mailing envelopes into which the unused pharmaceuticals are placed and returned to a single collection location *This list is not necessarily comprehensive; while an effort was made to capture existing legislation and guidance, the reader is encouraged to check whether additional relevant legislation or guidance exist for specific states. †Bold text identifies legally binding regulations.

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OTHER STATE PROGRAMS ADDRESSING EXPOSURES TO CONTAMINANTS OF EMERGING CONCERN

In addition to the program described above, a number of states have implemented legislation to attempt to limit exposures to CECs, including EDCs in the environment. For example, several states (California, Connecticut, Delaware, Illinois, Main, Maryland, Massachusetts, Minnesota, New York, Vermont, Washington, Wisconsin, and the District of Columbia) have enacted legislation to ban bisphenol A in certain products including food and beverage containers (NCSL 2014). Maine passed a law requiring the Department of Environmental Protection to publish a list of Chemicals of High Concern (CHC) (MDEP 2013). The list of no more than 70 chemicals is to be cooperatively determined by the Maine Department of Health and Human Services, Maine Center for Disease Control and Prevention, and the Maine Department of Environmental Protection. A chemical currently listed on Maine’s chemicals of concern list may be included on the CHC list if there is a determination of strong, credible scientific evidence that the chemical is a reproductive or developmental toxicant, endocrine disruptor or human carcinogen, and there is strong, credible scientific evidence that the chemical meets one or more of the following criteria: it has been found through biomonitoring studies to be present in human blood, human breast milk, human urine or other bodily tissues or fluids; it has been found through sampling and analysis to be present in household dust, indoor air or drinking water or elsewhere in the home environment; it has been added to or is present in a consumer product used or present in the home. The list currently includes 49 chemicals including a number of EDCs such as phthalates, phenols, parabens, and BHA.

PPCP AND EDC RESEARCH

International, federal, state, and other entities have initiated a number of research programs that address PPCPs and EDCs in the environment (Table 5.13). In addition, even in absence of regulation, water utilities have been proactive in funding and conducting research related to EDCs and PPCPs through organizations like WRF, the Water Environment Research Foundation (WERF), and the WateReuse Research Foundation (WRRF), particularly in the area of treatment and removal, but also on sources, monitoring, communication, and potential health effects (see summaries of relevant WRF projects in Chapters 4, 6, and 7). Internationally, many organizations are involved in research on PPCPs and EDCs. In 2012, the World Health Organization (WHO) published the WHO Report on Pharmaceuticals in Drinking Water (WHO 2012), and in 2013, together with the United Nations Environment Program (UNEP), they published a report on the State of the Science of Endocrine Disrupting Chemicals (WHO/UNEP 2013). The Organisation for Economic Co-operation and Development (OECD), recognized internationally for their toxicological testing guidelines, published a conceptual framework for the testing and assessment of EDCs, and published a Guidance Document on the Assessment of Chemicals for Endocrine Disruption (OECD 2010). The European Commission is engaged in a number of activates, including coordinating and funding research with other international organizations, to assess the presence and effects of EDCs in the environment (European Commission 2012). The United Kingdom and Japan are engaged in joint research on EDCs to assess their fate in the environment, develop molecular and genetic approaches to assess effects in fish, and determine human population impacts (UK-Japan 2014).

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At the U.S. federal level, the EPA, National Institute of Environmental Health and Safety (NIEHS), the National Toxicology Program (NTP), Centers for Disease Control (CDC), and the U.S. Geological Survey (USGS) have extensive programs studying PPCPs and EDCs in the environment (summarized in Table 5.13). As a result of new interest in the effects of EDCs, brought on by the work of Theo Colborn and others (Carson 1962, Colborn et al. 1996), in 1996 Congress passed the Food Quality Protection Act (FQPA) and amendments to the SDWA. The EPA’s 1996 FQPA and the 1996 Amendments to the SDWA require EPA to:

Develop a screening program, using appropriate validated test systems and other scientifically relevant information, to determine whether certain substances may have an effect in humans that is similar to an effect produced by a naturally occurring estrogen, or other such endocrine effect as the Administrator may designate.

The two acts target different sets of chemical substances. Section 304 of the FQPA states that in carrying out the program, the Administrator shall:

(A) Provide for the testing of all pesticide chemicals; and (B) provide for the testing of any other substance that may have an effect that is cumulative to an effect of a pesticide chemical if the Administrator determines that a substantial population may be exposed to such a substance.

Section 136 of the SDWA Amendments states that:

In addition to the substances referred to in (FQPA), the Administrator may provide for testing under the screening program authorized by (FQPA) for any other substance that may be found in sources of drinking water if the Administrator determines that a substantial population may be exposed to such substance.

In response, EPA convened the Endocrine Disruptor Screening and Testing Advisory Committee (EDSTAC) to make recommendations on how to develop the screening and testing program called for by Congress (EPA 2011c). Representatives from industry, government, environmental and public health groups, worker safety groups, and academia comprised EDSTAC. The members of EDSTAC were tasked with developing consensus-based recommendations for a screening program that would provide EPA with the information needed to make regulatory decisions about chemicals that disrupt the endocrine system. EDSTAC presented the final report of its deliberations to EPA in September 1998. This information was used by the EPA to create the Endocrine Disruptor Screening Program (EDSP) that same year to identify how some 87,000 chemicals now in commercial use affect the endocrine system. The EDSP uses a two-tiered screening and testing process. Tier 1 aims to identify chemicals that have the potential to interact with the endocrine system, while Tier 2 aims to determine the endocrine-related effects caused by each chemical and obtain information about effects at various doses. In 2009, the EPA announced an initial list of chemicals and has now developed a second list for Tier I testing. Testing will eventually be expanded to cover all pesticide chemicals, as well as substances that may occur in sources of drinking water to which a substantial population may be exposed.

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Table 5.13 International, federal, and state research programs on PPCPs and EDCs in the environment

Agency or Institution Program or Content Website International WHO World Health Organization (WHO) Task Force http://water.epa.gov/scitech/swguidance/ppcp/who.cfm on PPCPs in drinking water: Published WHO http://www.who.int/water_sanitation_health/publications Report on Pharmaceuticals in Drinking Water /2011/pharmaceuticals/en/ (WHO 2012) WHO and UNEP Report on State of the Science http://www.who.int/ceh/publications/endocrine/en/ of Endocrine Disrupting Chemicals (2012) OECD Organisation for Economic Co-operation and http://www.oecd.org/chemicalsafety/testing/46436593.pd Development (OECD) Guidance Document on f the Assessment of Chemicals for Endocrine Disruption. Provides a framework for the testing and assessment of potential endocrine disruptors EC European Commission: Published a strategy http://ec.europa.eu/environment/chemicals/endocrine/stra identifying short, medium, and long-term actions to tegy/being_en.htm address EDCs, including:  Establishing a priority list for further evaluation  Monitoring EDCs in the environment  Identifying vulnerable groups  Coordination and funding of research with other international organizations EFSA European Food Safety Authority (EFSA) http://www.efsa.europa.eu/en/topics/topic/eas.htm Endocrine Active Substances Task Force: Provides scientific opinion on the hazard assessment of endocrine disruptors in the EU (continued)

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Table 5.13 (Continued)

Agency or Institution Program or Content Website UK-Japan UK-Japan joint research on endocrine http://www.uk-j.org/ disruptors: Carries out research on:  Fate of EDCs and emerging contaminants in the environment and their remediation  Advanced testing systems  Molecular and genomic approaches in fish  Environmental risk assessment and population impacts Federal EPA Endocrine Disruptor Screening Program http://www.epa.gov/scipoly/oscpendo/ (EDSP): Established under the FQPA and SDWA http://www.epa.gov/research/endocrinedisruption/index.h Amendments of 1996. Establishes a two-tiered tm screening and testing process: http://www.epa.gov/endo/pubs/EDSP-comprehensive- 1) Identify chemicals with the potential to management-plan.pdf interact with the endocrine system (initial list announced April 15, 2009; second list in November 2010 then revised in June 2013) 2) Determine the endocrine-related effect caused by the chemical and the effects at various doses Research includes:  Human health effects  Testing to prioritize chemicals  Ecosystem and environmental effects Office of Research and Development (ORD) http://www.epa.gov/ppcp/work.html PPCP Research: Funds and conducts research focusing on sources, fate, and transport of PPCPs in the environment, as well as exposure, health effects, and monitoring. (continued)

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Table 5.13 (Continued)

Agency or Institution Program or Content Website EPA (cont.) National Rivers and Streams Assessment (2008- http://water.epa.gov/type/rsl/monitoring/riverssurvey/ 2014). Includes:  Assessing CECs in fish from urban rivers including PPCPs and EDCs Assessment of the Occurrence and Potential http://www.epa.gov/ppcp/projects/edc-cafo.html Risks of EDCs that are pharmaceuticals or natural in Discharges from Concentrated Animal Feeding Operations (2010-2014). Research to characterize:  Types and amounts of hormones and metabolites in waste and effluent from CAFOs with animals of different livestock species, ages, and feeding regimens  Environmental fate of steroids and their metabolites from stored and land applied wastes in soil and water  How waste management practices influence the fate, environmental exposures, and effects of hormones from CAFOs  Assess regional differences and effect of seasonal variability on exposures and effects. Fate of Selected EDCs under Redox Conditions http://www.epa.gov/ppcp/projects/redox.html Typical of Wastewater and Sediments (2006- 2014). Research to characterize the degradability of selected EDCs under environmentally relevant redox conditions and concentrations. (continued)

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Table 5.13 (Continued)

Agency or Institution Program or Content Website EPA (cont.) Natural and Synthetic EDCs from Wastewater http://www.epa.gov/ppcp/projects/nat-syn.html Treatment - Source Characterization, Environmental Fate, and Risk Management (2000-2014). Research to:  Determine fate of EDCs in conventional WWTPs.  Determine if typical WWTP design and operational strategies maximize removal of EDCs.  Determine the treatment capability of onsite wastewater treatment systems for EDCs. Persistence of Contaminants from Wastewater http://www.epa.gov/ppcp/projects/persistence.html Discharges During Drinking Water Treatment: Identification of Compounds and Degradation/ Disinfection Byproducts, Evaluation of Removal, and Potential Exposure (2006-2140). Research to determine effect of drinking water treatment technologies on compound removal by examining the occurrence and fate of pharmaceuticals through drinking water treatment. USGS Emerging Contaminants in the Environment; http://toxics.usgs.gov/regional/emc/ Source Water-Quality Assessment (SWQA) http://water.usgs.gov/nawqa/swqa/ Program. Major research areas are:  Analytical method development  Environmental occurrence  Characterizing sources and source pathways  Transport and fate  Ecological effects (continued)

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Table 5.13 (Continued)

Agency or Institution Program or Content Website State and Local Agencies Arizona Department of Supporting research at Arizona universities on http://www.azdeq.gov/environ/water/wastewater/pharm.h Environmental Quality (ADEQ) PPCPs and wastewater. tml California Department of Toxic Preparing assessment of the California http://www.dtsc.ca.gov/PollutionPrevention/SB14Pharm Substances Control (DTSC) pharmaceutical industry’s efforts to reduce a.cfm hazardous waste. Delaware River Basin Commission With Temple University, conducting a study on http://www.state.nj.us/drbc/quality/reports/emerging/ (DRBC) CECs in Pennsylvania tributaries to the Delaware River Illinois Sustainable Technology Grant from USDA to study the fate and transport of http://www.istc.illinois.edu/special_projects/ppcp-env/ Center (ISTC) steroid hormones and veterinary antibiotics from dairy and beef farms; PPCP Symposium on April 25, 2008 Massachusetts Department of Developed multi-component approach for http://www.mass.gov/eea/agencies/massdep/toxics/sourc Environmental Protection (MADEP) addressing PPCPs and EDCs in water, including: es/pharmaceutical-and-personal-care-products-faqs.html  Established an Emerging Contaminants Work Group  Initiated collaborative research with UMass (Amherst), the American Water Works Association Research Foundation, and AECOM on the effects of different treatment technologies at removing PPCPs and EDCs in source water  Supporting research by USGS to determine occurrence and fate of PPCPs New York City Department of 2009 and 2010 studies of PPCPs in source waters of http://www.nyc.gov/html/dep/html/drinking_water/ws_p Environmental Protection (NYC NYC water supply pcp.shtml DEP) Potomac River Basin Drinking Summary of research on PPCPs in the Potomac http://www.potomacdwspp.org/index.php?option=com_c Water Source Protection Partnership River Basin ontent&view=article&id=51&Itemid=2

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EPA is currently implementing EDSP on three fronts (EPA 2014b):

 Developing protocols to conduct specific assays, evaluate their effectiveness, and ensure that the assay can be performed reliably and consistently in different laboratories  Prioritizing chemicals for screening and testing  Establishing policies and procedures to require testing

In October 2001, the Endocrine Disruptor Methods Validation Subcommittee (EDMVS) was established under the EPA’s National Advisory Council for Environmental Policy and Technology (EPA 2011d). The EDMVS task was to provide advice and counsel to EDSP on scientific issues associated with the validation of screening tests, including the development and choice of initial protocols. In June 2004, the Endocrine Disruptor Methods Validation Advisory Committee (EDMVAC) was established to replace EDMVS (EPA 2011e). The EDMVAC continues to function like EDMVS by providing advice and recommendations to EPA on scientific and technical aspects of the screening tests being considered for the Endocrine Disruptor Screening Program. The committee evaluates relevant scientific issues, protocols, data, and interpretations of the data for the assays during the validation process. The EPA’s Office of Research and Development (ORD) is engaged in a large number of research programs regarding PPCPs in the environment (EPA 2010b). Research focuses on the sources, fate, and transport of PPCPs in the environment, human and ecological exposure pathways and potential exposure effects, and tools for monitoring and detecting PPCPs in the environment. To date the EPA has funded 23 completed projects and has another 24 projects scheduled for completion in 2014. The USGS Toxic Substances Hydrology Program has developed the Emerging Contaminants Project to address CECs in the environment and evaluate the potential threat to environmental and human health (USGS 2014). The USGS also works with state agencies to conduct monitoring of CECs in source and drinking water around the United States. USGS Emerging Contaminants Project research activities include:

 Developing analytical methods to measure chemicals and microorganisms or their genes in a variety of matrices (for example, water, sediment, waste) down to trace levels  Determining the environmental occurrence of these potential contaminants  Characterizing the sources and source pathways that determine contaminant release to the environment  Defining and quantifying processes that determine their transport and fate through the environment  Identifying potential ecologic effects from exposure to these chemicals or microorganisms

The U.S. Department of Human Health Services (HHS) encompasses several agencies that conduct research regarding PPCPs and EDCs including the National Institutes of Health (NIH), NIEHS, and the NTP. The NIH together with the CDC launched a study of blood and urine samples to determine to what extent Americans have been exposed to 250 chemicals. The most recent data was published in September 2013 based on data collected from 2005-2010 (CDC 2013a). NIEHS has focused its efforts to characterize the mechanism by which EDCs

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cause changes in the body and what effects long-term exposure may have on human health (NIEHS 2014). In addition, NIEHS aims to identify biomarkers (i.e., molecules found in the blood or urine that indicate exposure to a chemical) of EDC exposure and conduct epidemiological studies in human populations exposed to EDCs. Research conducted by the NTP aims to identify the toxicologic, carcinogenic, reproductive, and developmental effects of PPCP and EDC exposure. Several states and other local agencies also have research programs to address PPCPs and EDCs in the environment including Arizona, California, the Delaware River Basin Commission, Illinois Sustainable Technology Center, Massachusetts, New York City, and the Potomac River Basin Drinking Water Source Protection Partnership (Table 5.13). These programs focus on CECs, which may include PPCPs and EDCs, and aim to identify occurrence, fate, and transport of CECs, as well as exposure potential and health risks associated with that exposure.

OTHER FEDERAL AND STATE INFORMATION SOURCES ON PPCPS AND EDCS IN THE ENVIRONMENT

Other sources of information from state and local agencies on PPCPs or EDCs in the environment, including websites, frequently asked questions (FAQs), presentations, and brochures, are summarized in Table 5.14.

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Table 5.14 Other federal and state information sources on PPCPs and EDCs in the environment

Agency or Institution Program or Content Website Federal EPA Websites on PPCPs and EDCs http://www.epa.gov/ppcp/ http://www.epa.gov/ppcp/projects/evaluation.html http://water.epa.gov/scitech/swguidance/ppcp/index.cfm http://www.epa.gov/ppcp/work2.html http://www.epa.gov/endocrine/ http://www.epa.gov/endo/ US Office of National Drug Control National Drug Take-Back Day http://www.whitehouse.gov/blog/2012/04/27/take-action- Policy find-national-take-back-day-site-near-you Other State and Local Agencies Alabama State Water Program FAQ on PPCPs in the environment http://www.aces.edu/waterquality/faq/faq_results.php3?r owid=4237 Alaska Department of Fish monitoring program, including PPCPs and http://dec.alaska.gov/eh/docs/mercury/EnvironContamin Environmental Conservation EDCs antsFishMonitoringProgram.pdf Arizona Department of Website addressing wastewater management and http://www.azdeq.gov/environ/water/wastewater/pharm.h Environmental Quality (ADEQ) PPCPs tml California Department of Toxic Website addressing PPCPs http://www.dtsc.ca.gov/AssessingRisk/PPCP/index.cfm# Substances Control (DTSC) Other_DTSC_Associated_Activities Connecticut Department of Public Fact Sheet on Pharmaceuticals in the Environment; http://www.ct.gov/dph/lib/dph/drinking_water/pdf/Pha Health (DPH) information on disposal of medications rmaceutical_Fact_Sheet.pdf http://www.ct.gov/deep/cwp/view.asp?a=2708&q=33548 0&depNav_GID=1763 Florida Department of Presentation on PPCPs, an emerging issue http://www.dep.state.fl.us/waste/quick_topics/publication Environmental Protection s/shw/meds/PPCPBriefingForWeb112006.pdf Drug disposal http://www.dep.state.fl.us/waste/categories/medications/ default.htm (continued)

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Agency or Institution Program or Content Website Idaho Department of Environmental Brochure on proper disposal of pharmaceuticals http://www.deq.idaho.gov/media/656966- Quality pharmaceutical_disposal_0409.pdf Presentation on EDCs and PPCP activities in Idaho http://www.pnws- awwa.org/uploads/PDFs/conferences/2009/Tanner_EDC _%20PPCP_%20Idaho.pdf Kansas Department of Health and Op-Ed column by Department Director on PPCPs in http://www.kdheks.gov/news/web_archives/2010/080420 Environment Our Environment 10.htm Maine Center for Disease Control Presentation on Non-traditional Contaminants and http://www.maine.gov/dhhs/mecdc/environmental- and Prevention Septic Systems, including EDCs health/plumb/documents/training/2013/PPCP-and- Septic-Systems.pdf Montana Department of FAQs about PPCPs http://deq.mt.gov/wqinfo/swp/PDFs/PPCPs_FAQ_Aug0 Environmental Quality 8.pdf Nebraska Department of Medications and Infectious Waste Disposal http://www.deq.state.ne.us/Publica.nsf/23e5e39594c064e Environmental Quality e852564ae004fa010/5baf8c9d1b655d1786257754005e7d 0c!OpenDocument New England Interstate Water Summary of PPCP information with “PPCP Talking http://www.neiwpcc.org/ppcp/index.asp Pollution Control Commission Points” (NEIWPCC) New Hampshire Department of FAQs on PPCPs in Drinking Water and Aquatic http://des.nh.gov/organization/commissioner/pip/factshee Environmental Services (NH DES) Environments and other information ts/dwgb/documents/dwgb-22-28.pdf http://des.nh.gov/organization/divisions/water/dwgb/dws pp/pharmaceuticals.htm New York City Department of FAQs on PPCPs http://www.nyc.gov/html/dep/html/drinking_water/ws_p Environmental Protection (NYC pcp_faq.shtml DEP) New York Department of Website on Drugs in New York’s Waters http://www.dec.ny.gov/chemical/45083.html Environmental Conservation (DEC) (continued)

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Table 5.14 (Continued)

Agency or Institution Program or Content Website Oregon Department of Disposal Recommendations for Household http://www.deq.state.or.us/lq/sw/hhw/pharmaceuticals.ht Environmental Quality Pharmaceuticals m Oregon Health Authority Website on Drug Take-Back and Disposal http://public.health.oregon.gov/HealthyEnvironments/Dri nkingWater/SourceWater/Pages/takeback.aspx Penn State College of Agricultural Website on Pharmaceutical Disposal and Water http://extension.psu.edu/natural- Sciences: Penn State Extension Quality resources/water/drinking-water/water- testing/pollutants/pharmaceutical-disposal-and-waterquality Potomac River Basin Drinking Website on Proper Pharmaceutical Disposal http://www.potomacdwspp.org/index.php?option=com_c Water Source Protection Partnership ontent&view=article&catid=35:new- contaminants&id=82:pharm-disposal Texas Water Resources Institute Website: “This is your stream. This is your stream http://twri.tamu.edu/publications/txh2o/winter-2010/this- on drugs.” is-your-stream/ Virginia Department of Website on Microconstituents in the Environment http://www.deq.virginia.gov/Programs/Water/Permitting Environmental Quality (DEQ) Compliance/PollutionDischargeElimination/Microconstit uents.aspx Virginia Department of Health Website on PPCPs http://www.vdh.state.va.us/news/Alerts/DrinkingWater.h tm Washington Department of Ecology PPCPs in Municipal Wastewater and their Removal https://fortress.wa.gov/ecy/publications/summarypages/1 by Nutrient Treatment Technologies 003004.html Wisconsin Department of Natural Collecting Unwanted Household Pharmaceuticals http://dnr.wi.gov/files/pdf/pubs/wa/wa1024.pdf Resources

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CHAPTER 6: TREATMENT APPROACHES AND SOURCE WATER PROTECTION

In general, treatment technologies currently in place at most WWTPs or DWTPs were not designed or intended to remove PPCPs or most EDCs. However, substantial research has been conducted to characterize the efficiency of different treatment technologies for PPCPs and EDCs. In addition, source water protection programs that engage the public and local businesses can be implemented as a way of reducing costs and/or efforts to decontaminant waters from source to point-of-use. This chapter addresses the following questions:

 What treatment technologies can remove PPCPs and EDCs from water?  How effective are these methodologies?  What low-cost source water protection options are available, and which are the most effective?

In addition, links to sources of additional information on these topics are provided.

SUMMARY OF EFFECTIVENESS OF TREATMENT TECHNOLOGIES

To compile information on PPCP ingredient and EDC treatment technologies, a literature search was conducted for published studies conducted throughout the United States and the world that report the removal of emerging contaminants of concern from source water (e.g., rivers, lakes, reservoirs, groundwater) and from influent and effluent at wastewater treatment plants and water reclamation plants by both commonly used and innovative treatment technologies. Studies included laboratory-scale (systems that are operated from a laboratory bench and tests are run in batches), pilot-scale (systems that run as non-permanent subunits of a full-scale system), and full-scale (fully-functioning, permanent) treatment systems. Where available, the search focused on full-scale systems because they closely reflect actual treatment scenarios. In addition, findings from relevant Water Research Foundation projects were reviewed and summarized. For more information, the reader is also referred to the results of an extensive literature review, and accompanying searchable database, sponsored by EPA on wastewater treatment technologies and their ability to remove a number of chemical contaminants of emerging concern (CECs) (EPA, 2010d).

Relevant Water Research Foundation Projects

Past or present research projects funded by the Water Research Foundation addressing removal of EDCs and PPCPs and drinking and source water treatment processes include:

 Project #2758: Removal of EDCs and Pharmaceuticals in Drinking and Reuse Treatment Processes (2007). This project determined removal efficiencies of conventional and

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advanced treatment processes for an environmentally and chemically relevant suite of compounds classified as EDCs and PPCPs.  Project #2897: Impact of UV and UV-Hydrogen Peroxide AOP on EDC Activity in Water (2007). This project assessed, through the use of bioassays and chemical analyses, the degradation, by-product formation, and subsequent toxicity of endocrine-disrupting compounds following UV and UV-oxidation treatment of water.  Project #3012: Comparing Nanofiltration and Reverse Osmosis for Treating Recycled Water (2008). This project evaluated the feasibility of nanofiltration (NF) and ultra-low- pressure reverse osmosis (ULPRO) membranes for rejecting total organic carbon, total nitrogen, and unregulated trace organic compounds under a range of experimental conditions at the laboratory-, pilot-, and full-scale to produce water suitable to augment drinking water supplies. It also provided utilities with guidance on selecting membranes and predicting solute rejection during NF-ULPRO membrane treatment.  Project #3071: PPCPs and EDCs-Occurrence in the Detroit River and Their Removal by Ozonation (2009). This tailored collaboration project with the Windsor Utilities Commission and Ministry of the Environment Canada investigated the occurrence and fate of selected EDCs/PPCPs in surface water, and their removal by conventional ozonation and advanced oxidation treatment processes. It examined the concentrations of target compounds before and after various treatment processes and as a function of pertinent parameters including ozone dose, hydrogen peroxide dose, pH, alkalinity, total organic carbon, turbidity, and temperature.  Project #3136: Removal and Fate of EDCs and PPCPs in Bank Filtration Systems (2010). This project evaluated the effectiveness of riverbank filtration as a water treatment process for removing organic trace pollutants in general and PPCP and EDCs in particular. The project assessed the impact of important boundary conditions such as infiltration regime, temperature, underlying redox conditions, and retention times on organic trace pollutant removal. Of special interest was the transferability of results obtained in Germany to U.S. sites.  Project #3180: Removal of Bulk Organic Matter, Organic Micropollutants, and Nutrients During Riverbank Filtration (2010). This project (1) quantified the degree of removal of key water quality constituents such as total organic carbon (TOC), unregulated organic micropollutants, and nutrients (ammonia, nitrate, and phosphorus) in full-scale riverbank filtration (RBF) systems as a function of geo-hydrological, operational, and water quality conditions; (2) characterized at the mechanistic level the boundary conditions and relevant transport parameters for the removal of unregulated organic chemicals during RBF; (3) and summarized findings regarding removal potential and limitations in recommendations for design and operation of RBF systems.  Project #4066: Oxidation of Pharmaceutically Active Compounds During Water Treatment (2010). This project characterized the oxidation of important classes of pharmaceutically active compounds by potassium permanganate and ferrate, and assessed the potential use of these reactions to treat PhAC-contaminated drinking water sources.  Project #4135. Fate and Impact of Antibiotics in Slow-Rate Biofiltration Processes (2012). This project investigated the synergistic impact of multiple antibiotics on biofilm bacteria that are the heart of slow-rate biofiltration processes used worldwide for the production of drinking water. The research also provided parameters necessary for

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predicting the fate and impact of antibiotics in drinking water treatment processes such as slow sand filtration and bank filtration.  Project #4168: “Quantitative Structure Property Relationships (QSPR) to Predict Removal of EDCs/PPCPs in Water Treatment Processes” (in progress). This project is evaluating the feasibility of using Quantitative Structure Property Relationships (QSPRs) for process models to predict the behavior of emerging contaminants during various conventional and advanced drinking water treatment processes. It will also provide the details and the rationale used in the development of the models and include guidance to utilities on how to predict the removal of emerging contaminants.  Project #4213: “Ozone-Advanced Oxidation of Pharmaceuticals and its Impact on Residual Pharmacological Activity in Treated Water” (in progress). This project is characterizing the impact of background organic matrices on the efficiency of ozone- based advanced oxidation processes for removal of pharmaceutically active compounds (PhACs), developing a strategy that employs bioassays for assessing the ability of treatment processes to remove PhACs, and evaluating the potential of the bioassay residual testing strategy to predict the impact of background organic matter on treatment performance.  Project #4221: Removal of Unregulated Organic Chemicals in Full-Scale Water Treatment Processes (2013). This project investigated the effectiveness of full-scale conventional and advanced water treatment processes for the removal of unregulated organic chemicals such as EDCs, PPCPs, and industrial and household use organic chemicals.  Project #4231: A Monitoring and Control Toolbox for Biological Filtration (2013). This project benchmarked current biological filtration (BF) design, operational, monitoring, and control practices by North American utilities; identified and evaluated a suite of monitoring and control tools for management of BF; and developed a practical and user- friendly Guidance Manual for BF monitoring and control.  Project #4241: “Advanced Oxidation and Transformation of Organic Contaminates” (in progress). This project is evaluating the treatment of a representative list of CCL3 chemicals via UV- and ozone-based advanced oxidation processes (AOPs). The project will develop results that will be both fundamental in furthering the understanding of biological relevant endpoints for AOP transformation by-products of CCL3 contaminants and provide practical benefits to utilities by evaluating the process engineering implications of these results. The research team will also suggest a suite of biological screening tests that can be performed for various CCL3 chemicals in moderately equipped water quality laboratories.  Project #4322: “Removal of Perfluorinated Chemicals by North American Water Treatment Practices” (in progress). This project is conducting a literature review covering the global occurrence and treatability of perfluorinated compounds (PFCs). A second objective is to conduct a limited, strategically targeted assessment to determine the fate of these compounds in North American water treatment plants (from source to finished water) in order to validate the findings from the literature.  Project #4344: “Removal of Perfluorinated Compounds by Powdered Activated Carbon Blends, Superfine Powdered Activated Carbon, and Magnetic Anion Exchange Resins” (in progress). This project is assessing the effectiveness of innovative powdered activated carbon (PAC) adsorption and magnetic anion exchange processes for the removal of

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perfluorinated compounds (PFCs) from drinking water sources. Apart from the more commonly studied perfluorooctanic acid and perfluorooctane sulfonate, the removal of eight additional PFCs that are commonly detected in water will be studied at environmentally relevant concentrations.  Project #4397: “Transformation of EDCs/PPCPs and Resulting Toxicity Following Drinking Water Disinfection” (in progress). This project is using novel concepts in computational chemistry and toxicology to predict the likely transformation products (TP) of relevant EDCs/PPCPs with a range of disinfection and oxidation options (such as chlorine, chlorine dioxide, and chloramines) commonly used in the production of drinking water, and then apply comprehensive in vitro toxicity testing to determine their likely toxicity profile.

Some key findings from these projects with regard to the effectiveness of treatment technologies for the removal of PPCPs and EDCs from drinking water and source water are summarized in Table 6.1.

Table 6.1 Key findings from Water Research Foundation projects on effectiveness of treatment technologies for removal of PPCPs and EDCs from drinking and source water Project # Treatment technology Conclusions 2897 UV photolysis Did not effectively degrade bisphenol A, but did degrade ethinyl estradiol and estradiol.

UV/H2O2 AOP More effective than direct UV photolysis at degrading bisphenol-A, ethinyl estradiol, estradiol, and nonylphenol; significantly removed bisphenol A, ethinyl estradiol, estradiol. Removal rates of the mixture of all four were less than individual compounds. Can consistently meet potable water quality 3012 Low-pressure RO (ULPRO) membranes requirements for treating source water of impaired quality with respect to TOC, total nitrogen, and both regulated and unregulated trace organic compounds (including PPCPs and EDCs) (continued)

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Table 6.1 (Continued) Project # Treatment technology Conclusions 4221 Coagulation/ 2/37 compounds were appreciably (>75%) flocculation removed, while 20/37 were removed at <25% Filtration 4/32 compounds were appreciably (>75%) removed, and in some cases analytes appeared or were at increased concentrations in filtrates Ozonation An effective treatment for the removal of many analytes, especially heterocyclic or aromatic compounds (>90% transformation) Activated carbon 8/28 were consistently removed at ≥75%, 11/28 were removed to some degree, and 9/28 were not well removed (≤25%) Biological filtration Biological filtration has a potential role as a supplement to these processes, as literature suggests it can remove compounds with biodegradable properties. [General] Some compounds resisted treatment and were often present in finished water: caffeine, DDET, and phosphate ester flame retardants (TCEP, TDCPP, TBEP) AOP − advanced oxidation process; RO − reverse osmosis; TOC − total organic carbon, UV − ultraviolet

Summary of Literature Review of Treatment Methodologies

We identified over 150 studies addressing occurrence and treatment technologies for removal of PPCPs and EDCs from wastewaters and drinking water treatment plant influent and selected 27 studies for more comprehensive evaluation of select treatment technologies. In general, we focused on studies conducted in the last ten years (2004-2014), although some earlier studies were considered because of their size and emphasis. The studies investigated removal effectiveness by membrane bioreactors (MBRs) and membrane filtration and or a combination of other treatment technologies; advanced oxidation processes (AOP) and/or a combination of other treatment technologies; and reverse osmosis and/or a combination of other treatment technologies. Tables 6.2 through 6.5 summarize information from these studies on microconstituent removal effectiveness from different water types by different treatment technologies. Table 6.2 provides summary information from 12 investigations of PPCP and EDC removal by MBR processes, alone or in combination with other treatment technologies. Overall, the summary suggests:

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Table 6.2 PPCP and EDC removal using membrane bioreactors (MBR) alone or in combination with other treatment technologies Chemical/ class Treatment group, # of Treatment Source/type of technology compounds technology type Location analyzed water scale evaluated Comments Reference MBR, ozonation, County Hospital WWTP; 1) Full-scale Total organic MBR treatment was highly efficient in Beier et al. activated carbon hospital in evaluated removal MBR; 2) pilot carbon (TOC), removal of solids, nutrients, bacteria, 2012 adsorption and Waldbröl, efficiency for raw scale organic halogen and carbon compounds from hospital nanofiltration Germany hospital (ozonation, compounds (AOX) wastewater. MBR technology is (NF), and reverse wastewater vs. activated carbon recommended as a suitable pre- osmosis (RO) MBR effluent adsorption and treatment for hospital wastewater. NF, and RO) MBR and CAS Austria, Conventional Three full-scale 8 pharmaceuticals, Removal rates for bisphenol-A, Clara et al. including a WWTP influent activated sludge two polycyclic ibuprofen, bezafibrate, and the natural 2005 rural (from domestic WWTPs with musk fragrances, 9 estrogens were >90%, and community sewage) and varying SRTs, EDCs (including concentrations were strongly correlated w/o industrial effluent and three MBR bisphenol A and with solid retention time (SRT). influents pilot systems at nonylphenols) Carbamazepine concentrations were not (specific the premises of affected by treatment. Effluent location not conventional concentrations and removal rates were given) WWTPs with comparable for conventional WWTP vs. varying SRTs MBR. Concludes that low effluent concentrations can be achieved in WWTPs operating SRTs > 10 days, but that the MBRs tested did not allow any further retention of the substances due to size exclusion (dense membranes as in nanofiltration would be required). (continued)

Table 6.2 (Continued) Chemical/ class Treatment group, # of Treatment Source/type of technology compounds technology type Location analyzed water scale evaluated Comments Reference MBR- RO WWTP at Municipal Pilot-scale 20 pharmaceuticals: Combination of MBR and RO treatment Dolar et al. Castell-Platja wastewater MBR-RO psychotropics, showed excellent overall removal of 2012a d’Aro, Spain (influent and antibiotics, β- target contaminants with removal rates effluent) at WWTP blockers, histamine >99% for all. For some compounds H2 receptor (metronidazole, hydrocodone, codeine, antagonists, anti- ranitidine) MBR provided high removal inflammatories, efficiency (up to 95%). RO membrane nitroimidazole, β- showed removal rates always higher agonist and than 99%. antiplatelet agent

MBR, Kloten/Opfik Municipal Full-scale + Estrone (E1), Compounds found to be removed Joss et al. conventional on (K/O) and wastewater from a pilot (Full-scale estradiol (E2), and mainly in activated sludge 2004 activated sludge Altenrhein combined sewer CAS, with a ethinyl-estradiol compartments with low substrate (CAS), and fixed (A), (K/O) and mixed pilot-scale MBR (EE2) loading. Removal of ≥96% by MBR for bed reactor Switzerland sewage (A) and FBR E1 and E2, and ≥75% for EE2. Removal (FBR) (activated (influent and treatment) by CAS was varied, ranging from 49 to sludge effluent) ≥99% for E1, 88 to ≥97% for E2, and 71 WWTPs) to 94% for EE2. By FBR, removal of E1, E2, and EE2 was 90%, ≥ 95%, and 69%, respectively. of >90% for all estrogens in activated sludge process. Removal of 77% and ≥ 90% for E1 and E2, respectively, were reported for the FBR using a short retention time of 35 min. (continued)

Table 6.2 (Continued) Chemical/ class Treatment group, # of Treatment Source/type of technology compounds technology type Location analyzed water scale evaluated Comments Reference MBR, CAS, and Kloten/Opfik Municipal Full-scale 7 pharmaceuticals Removal of ibuprofen >90% by all Joss et al. fixed bed reactor on (K/O) and wastewater from a (carbamazepine, treatment methodologies (CAS, MBR, 2005 (FBR) Altenrhein combined sewer diclofenac, and FBR), thought due to biological (A), (K/O) and mixed galaxolide, transformation. Virtually no removal of Switzerland sewage (A) ibuprofen, carbamazepine by any of the (activated (influent and iopromide, technologies. Removal of sludge effluent) naproxen, sulfamethoxazole was greater for MBR WWTPs) roxithromycin, (~75-96%) compared to CAS (~0-80%) sulfamethoxazole) but comparable to FBR. Removal of and two fragrances diclofenac (~20-35%), naproxen (~80%) (N-acetyl-sulfam, were comparable by all methods. and tonalide) Removal of roxithromycin and iopromide was variable but incomplete. Neither SRT nor high retention time (HRT) affected removal of seven pharmaceuticals in MBRs MBR (SRTs of Soseigawa Municipal Full-scale 6 acidic PPCPs: MBRs produced greater elimination Kimura et al. 15 and 65 d) Municipal wastewater from a clofibric acid, rates than functional WWTP w/o MBRs. 2007 WWTP, combined sewer diclofenac, Longer MBR SRTs exhibited better Sapporo, system (influent ibuprofen, performance, especially for ketoprofen Japan and effluent) ketoprofen, and diclofenac. The large specific mefenamic acid, sorption capacities of the MBRs was the naproxen main elimination mechanism, vs. biodegradation for the conventional WWTP. (continued)

Table 6.2 (Continued) Chemical/ class Treatment group, # of Treatment Source/type of technology compounds technology type Location analyzed water scale evaluated Comments Reference MBR and CAS Rubí Mixture of Bench (MBR) 22 (analgesics, lipid Removal efficiency with MBR was Radjenovic et Municipal municipal, and full-scale regulators and statin better than CAS treatment (removal al. 2007 WWTP in hospital, and (CAS) drugs, antibiotics, rates > 80% for 11/22 by MBR vs. 4/22 Barcelona, industrial psychiatric drugs, by CAS). MBR did not completely Spain wastewater an antiepileptic remove some micropollutants (e.g., (influent and drug, β-blockers, carbamazepine), and thus should be effluent) anti-histaminics, optimized by modification of anti-ulcer agents, an membranes (variation of the materials anti-diabetic and reduction of molecular mass cut-off (glibenclamide), and limits) and/or by modification of a diuretic treatment process (inoculation with (hydrochloro- special microorganisms). thiazide))

Nanofiltration DWTP in NE- DWTP influent Full-scale 31 pharma- NF and RO effectively removed Radjenovic et (NF) MBR and Spain from 3 ceuticals: pharmaceuticals (>85%). Deteriorations al. 2008 RO groundwater wells analgesics, in retentions on NF and RO membranes directed influenced betablockers, observed for acetaminophen (44.8–73 by infiltration from carbamazepine, %), gemfibrozil (50–70 %), and the Besós River, sulfamethoxazole, mefenamic acid (30–50%). Sotalol and and effluent gemfibrozil, metoprolol were retained on the hydrochloro- membranes with very high efficiency thiazide (>90%). NF and RO membranes very efficient in removing nearly all of the pharmaceutical residues detected.

(continued)

Table 6.2 (Continued) Chemical/ class Treatment group, # of Treatment Source/type of technology compounds technology type Location analyzed water scale evaluated Comments Reference MBR and CAS Terrassa Mixture of Full-scale CAS, 31 PPCPs: Enhanced removal of several PPCP Radjenovic et WWTP in municipal and and two pilot- analgesics, anti- residues that were poorly removed by al. 2009 Barcelona, industrial (mostly scale MBRs epileptic, CAS (e.g., mefenamic acid, Spain pharmaceutical and antibiotics, lipid indomethacin, diclofenac, textile industry) regulators, beta- propyphenazone, pravastatin, wastewater blockers, diuretics gemfibrozil), whereas in some cases (influent and more stable operation of one of the effluent) MBR reactors at prolonged SRT was detrimental to elimination of some compounds (e.g., beta-blockers, ranitidine, famotidine, erythromycin). Carbamazepine and hydrochlorothiazide by-passed all three treatments investigated.

MBR Pilot-scale Influent simulating Pilot-scale 12 PPCPs: Removal efficiency depends on physico- Reif et al. MBR in Spain domestic sewage carbamazepine, chemical characteristics. Hydrophobic 2008 diazepam., organic substances, e.g., musk ibuprofen, fragrances, were partially sorbed on naproxen, sludge, with an overall removal diclofenac, efficiency of 50%. Other substances, roxithromycin, e.g., ibuprofen and naproxen were erythromycin, eliminated completely (98% and 84 %) sulfamethoxazole, while others, e.g., carbamazepine or trimethoprim and diclofenac, had limited removal, < 9%. three polycyclic musk fragrances (galaxolide, tonalide, celestolide) (continued)

Table 6.2 (Continued) Chemical/ class Treatment group, # of Treatment Source/type of technology compounds technology type Location analyzed water scale evaluated Comments Reference MBR (two Aachen, Effluent of the pre- Pilot-scale 3 NSAIDs NSAIDs were removed with higher Schroder et MBRs with Germany settling tank of the (acetaminophen, efficiencies than the antibiotics for both al. 2012 sludge retention municipal STP ketoprofen and MBRs, and the MBR-30 presented times of 15 and naproxen) and 3 higher removal efficiencies for all the 30 days (MBR- antibiotics compounds than obtained by MBR-15. 15, MBR-30)) (roxithromycin, Removal rates ranged from 55% sulfamethoxazole, (sulfamethoxazole) to 100% and trimethoprim) (acetaminophen, ketoprofen).

MBR United States Secondary effluent Bench-, pilot-, 36 (pharma- MBR was effective at removing many Snyder et al. microfiltration (various, from municipal full-scale ceuticals, steroids, PPCPs and EDCs (e.g., acetaminophen, 2007a (MF) and unspecified) WWTP for UF pesticides, PAHs, androstenedione, caffeine, ultrafiltration pilot-scale; fragrance, carbamazepine, diclofenac, fluoxetine, (UF), RO, GAC, primary antimicrobial, and gemfibrozil, hydrocodone, naproxen, and combination wastewater other PPCPs) oxybenzone, sulfamethoxazole, triclosan of systems effluent for MBR and trimethoprim). Less effective at pilot-scale tests; removing DEET, dilantin, saline groundwater erythromycin-H2O, ibuprofen, and for RO pilot-scale meprobamate. Using MF/UF tests; municipal membranes, with MBRs show promise WWTP influent for at removing hormones/steroids. full- scale MBR Removal is likely due to biodegradation followed by pilot and results were found to vary greatly RO; tertiary treated wastewater for pilot MF followed by RO; secondary treated wastewater for full-scale MF CAS – conventional activated sludge, DEET – N,N-diethyltoluamide; DWTP – drinking water treatment plant; GAC – granular activated carbon; MBR – membrane bioreactor; MF/UF – microfiltration/ultrafiltration; NF – nanofiltration; NSAID – nonsteroidal anti-inflammatory drug; PAH – polycyclic aromatic hydrocarbon; PPCP – pharmaceutical and personal care product; RO – reverse osmosis; STP – sewage treatment plant; UF ultrafiltration; WWTP – wastewater treatment plant

Table 6.3 PPCP and EDC removal using advanced oxidation processes (AOP) alone or in combination with other treatment technologies Source/type Treatment Chemical/ class group, Treatment of analyzed technology # of compounds technology type Location water scale evaluated Comments Reference Advanced Advanced RO retentate Bench-scale 27 PPCPs in RO AOPs can effectively remove PPCPs from Abdelmelek oxidation Water from the retentate waters RO retentates in the presence of both et al. 2011 processes Purification AWPF organic and inorganic constituents (AOPs)/RO Facility (AWPF) at Orange County Sanitation District (Fountain Valley, CA)

UV photolysis WWTP at WWTP Bench-scale Antimicrobial For the sulfa drugs, solution pH affected Baeza et al. and UV/H2O2 Cary, NC effluent and compounds direct photolysis rates but had little effect 2011 advanced and lake lake water sulfamethoxazole, on hydroxyl radical oxidation rate. For oxidation water from sulfamethazine, sulfamethoxazole, the neutral form processes Lake sulfadiazine, and photolyzed more easily than the anionic Wheeler, trimethoprim the EDC form, with reverse for sulfamethazine and Raleigh, NC bisphenol A, and the sulfadiazine. For trimethoprim, hydroxyl analgesic diclofenac radical oxidation rate was higher for the cationic form (pH 3.6) than the neutral form (pH 7.85). For a H2O2 dose of 10 mg L 1, the required UV dose to achieve 90% sulfamethoxazole and diclofenac transformation was <860 and <330 mJ cm 2, respectively. For the remaining compounds, UV doses >900 mJ cm 2 were required to achieve 90% transformation in lake water and WWTP effluent. (continued)

Table 6.3 (Continued) Source/type Treatment Chemical/ class group, Treatment of analyzed technology # of compounds technology type Location water scale evaluated Comments Reference UV DWTP of Pure water Bench- and 4 pharmaceuticals: 17 By applying a UV dose of 400 Jm -2, Canonica et Neuilly sur (spiked) and full-scale α-ethinylestradiol which is standard for drinking water al. 2008 Marne treated water (EE2), diclofenac, disinfection using UV-C light, a relevant (suburb of from DWTP sulfamethoxazole, and degree of phototransformation could be Paris, after sand iopromide observed in most cases. However, this was France) filtration or strongly dependent on the target GAC pharmaceutical, varying from <1% to ~ filtration 50%. Depletion of tested pharmaceuticals in the DWTP was due to direct phototransformation, except for EE2, which showed a strong enhancement of depletion rates in the pre-treated natural water.

Conventional “Real Lake water Bench -scale Para-chlorobenzoic acid AOPs such as O3/H2O2 applied to these Katsoyiannis ozonation, AOPs waters” and (pCBA), atrazine, waters increased the transformation rates et al. 2011 (O3/H2O2 and from Lake wastewater sulfamethoxazole and of compounds and contributed to reduced UV/H2O2) Zurich and effluent NDMA bromate formation; and UV/H2O2 Lake required more energy (~ 5-20 times) than Greifensee ozonation or O3/H2O2, depending on the in optical path length, H2O2 concentration, Switzerland, water matrix and type of micropollutant. and Lake Investigators concluded that UV/H2O2 is a Jonsvatnet viable solution for the transformation of in Norway; organic micropollutants with low O3 and wastewater •OH reactivity but high photoactivity such effluent as NDMA. from Dübendorf, Switzerland (continued)

Table 6.3 (Continued) Source/type Treatment Chemical/ class group, Treatment of analyzed technology # of compounds technology type Location water scale evaluated Comments Reference O3 alone and Southern WWTP Full-scale 17 PPCPs including Most compounds were removed > 90% at Snyder et O3/H2O2 Nevada effluent and WWTP analgesics, antibiotics, O3 exposures commonly used for al. 2006 Water spiked effluent, caffeine, psychotropics; disinfection. Atrazine, iopromide, Authority, Colorado bench-scale, 16 potential EDCs meprobamate, and TCEP were most Henderson, River water pilot-scale including fragrances, recalcitrant using O3, generally <50%. The NV and from drinking pesticides, DEET, addition of H2O2 for advanced oxidation Clark water intakes hormones, triclosan was of little benefit compared to O3 alone. County at Lake Mead O3/H2O2 provided a marginal increase in Water removal of dilantin, diazepam, DEET, Reclamation iopromide, and meprobamate, while District, Las decreasing the removal efficacy of Vegas, NV pentoxifylline, caffeine, testosterone, progesterone, and androstenedione. In wastewater, O3 and O3/H2O2 removed in vitro estrogenicity.

Oxidative Missouri Ultra-high Bench-scale 8 EDCs and Removal efficiency varied significantly Wu et al. treatment, University purity DI pharmaceuticals, between different oxidation processes. 2012 permanganate of Science water, including triclosan, Free chlorine, permanganate, and O3 oxidation, ozone and Mississippi ibuprofen, estrone, treatments were effective for triclosan and (O3) oxidation, Technology, river water estriol, clofibric acid, estrone removal, while they were not for free chlorine, Rolla, MO iopromide, estradiol ibuprofen, iopromide, and clofibric acid. monochloramine (bench- and ethynylestradiol pH was important in the removal (MCA) oxidation scale) efficiency of the selected EDCs and pharmaceuticals during free chlorine, permanganate, and ozone treatments.

AOP − advanced oxidation process; AWPF − advanced water purification facility; DI − deionized; DWTP − drinking water treatment plant; EDC – endocrine-disrupting compound; EE2 − 17 α-ethinylestradiol; Jm-2 – joules/square meter; mJ/cm2 – milliJoules/square centimeter; LP − low pressure; MCA − monochloramine; NDMA − N-nitrosodimethylamine; O3/H2O2 – ozone/hydrogen peroxide; •OH – hydroxyl radical; RO – reverse osmosis; UV/H2O2 - ultraviolet/hydrogen peroxide; UV/TiO2 – ultraviolet/titanium oxide; UV − ultraviolet; WWTP − wastewater treatment plant

Table 6.4 PPCP and EDC removal using reverse osmosis (RO) alone or in combination with other treatment technologies Treatment Chemical/ class group, Treatment Source/type of technology # of compounds technology type Location analyzed water scale evaluated Comments Reference RO, ozonation, Three water Influent Full-scale 11 PPCPs Raw wastewater concentrations Al-Rifai et al. biological reclamation (composite raw (acetaminophen, were low, but removal efficiency for 2007 activated carbon plants in wastewater) and carbamazepine, the 3 treatment systems was (BAC) filtration Australia: effluent from clofibric acid, effective. RO was the most effective Gerringong water diclofenac sodium, treatment in removing PhACs and Gerroa reclamation gemfibrozil, non-steroidal estrogenic Sewerage plants ibuprofen, ketoprofen, compounds. Removal efficiencies Scheme, SE naproxen, primidone, for all processes > 90% for all Australia; Water phenytoin and compounds except ketoprofen Reclamation salicylic acid) and two (80%). Remaining concentrations of and non-steroidal all compounds were less than Management estrogenic compounds detection limits except ketoprofen, Scheme, (bisphenol A and 4- primidone, and naproxen. Sydney, nonylphenol, NP) Australia; Luggage Point Water Reclamation Plant, Brisbane, Australia UF followed by DWTP in NE- DWTP influent Full-scale 13 drugs of abuse and Substances were efficiently Boleda et al. UV disinfection Spain and effluent, with 26 pharmaceuticals removed. 32/39 pharmaceuticals 2011 and RO source water and drugs of abuse were removed at from Llobregat 95% or greater. All others were River removed at 85% or greater: nicotine = 94%, diatrozic acid = 89%, iohexol = 88%, pravastatin = 91%, salicylic acid = 85%, Sulfadimethoxine = 91%, and sulfamethazine = 91%. (continued)

Table 6.4 (Continued) Treatment Chemical/ class group, Treatment Source/type of technology # of compounds technology type Location analyzed water scale evaluated Comments Reference MBR- RO WWTP at Municipal Pilot-scale 20 pharma-ceuticals: Combination of MBR and RO Dolar et al. Castell-Platja wastewater MBR-RO psychotropics, treatment showed excellent overall 2012a d’Aro, Spain (influent and antibiotics, β-blockers, removal of target contaminants with effluent) at histamine H2 receptor removal rates >99% for all. For WWTP antagonists, anti- some compounds (metronidazole, inflammatories, hydrocodone, codeine, ranitidine) nitroimidazole, β- MBR provided high removal agonist and efficiency (up to 95%). RO antiplatelet agent membrane showed removal rates always higher than 99%.

Coagulation, Pilot unit at Wastewater Laboratory- Veterinary Pretreatment with coagulation/MF Dolar et al. microfiltration, pharmaceutical (influent and and pilot-scale pharmaceuticals (VPs) did not remove VPs from 2012b RO, factory in effluent) at (sulfamethoxazole, wastewater, while NF/RO was nanofiltration Kalinovica, WWTP trimethoprim, efficient at removing contaminants (NF) Croatia ciprofloxacin, from water. Removal percentage of dexamethasone, and VPs ranged from 94-< 100%. febantel) Observed differences in retention between laboratory and pilot tests due to raw wastewater quality and recovery and hydrodynamics of the systems. Suggested that integrated membrane treatment (coagulation, MF, NF and RO) should be employed for the treatment of wastewater contaminated with pharmaceutical compounds.

(continued)

Table 6.4 (Continued) Treatment Chemical/ class group, Treatment Source/type of technology # of compounds technology type Location analyzed water scale evaluated Comments Reference Nanofiltration DWTP in NE- DWTP influent Full-scale 31 pharmaceuticals: NF and RO effectively removed Radjenovic et (NF) MBR and Spain from 3 analgesics, pharmaceuticals (>85%). al. 2008 RO groundwater betablockers, Deteriorations in retentions on NF wells directed carbamazepine, and RO membranes observed for influenced by sulfamethoxazole, acetaminophen (44.8–73 %), infiltration from gemfibrozil, gemfibrozil (50–70 %) and the Besós hydrochlorothiazide mefenamic acid (30–50%). Sotalol River, and and metoprolol were retained on the effluent membranes with very high efficiency (>90%). NF and RO membranes very efficient in removing nearly all of the pharmaceutical residues detected.

RO United States Saline Bench-, pilot-, 36 (pharmaceuticals, RO treatment using virgin Snyder et al. (various, groundwater for full-scale steroids, pesticides, membranes nearly removed all 2007a unspecified) RO pilot-scale PAHs, fragrance, compounds except caffeine, and tests; municipal antimicrobial, and pentoxifylline. RO treatment using WWTP influent other PPCPs) fouled membranes had minimal for full- scale effect on removal, but RO MBR followed membranes are capable of removing by pilot RO; nearly all compounds to levels < tertiary treated MRL. Trace levels of some wastewater for contaminants still detectable in RO pilot MF permeates. Full scale double-pass followed by RO RO system showed the second pass removed compounds not removed during the first pass, suggesting that a multi-barrier approach is most successful. (continued)

Table 6.4 (Continued) Treatment Chemical/ class group, Treatment Source/type of technology # of compounds technology type Location analyzed water scale evaluated Comments Reference Coagulation, One WWTP Effluents from Full-scale 12 pharmaceuticals, The MF/RO treatment reduced Soliman et al. granular media and two water one WWTP and antioxidants, concentrations to levels benzyl butyl phthalate) were River Delta outlets; detected in MF/RO product waters. collected at the recharged outlet of Lake groundwater Matthews originating (Colorado from one of the River Water) water and Castaic reclamation Lake plants (Sacramento- San Joaquin River Delta Water) BHT – butylated hydroxytoluene; MBR – membrane bioreactor; MF/RO – microfiltration/reverse osmosis; MRL – minimum reported level; PAH – polycyclic aromatic hydrocarbon; PPCP - pharmaceutical and personal care product; PhAC – pharmaceutically active compound; RO – reverse osmosis

Table 6.5 PPCP and EDC removal using activated carbon (AC) processes alone or in combination with other treatment technologies Treatment Chemical/ class group, Treatment Source/type of technology # of compounds technology type Location analyzed water scale evaluated Comments Reference PAC (single- and Pilot plant at Municipal Pilot and full- 19 PPCPs including Single-stage application resulted in no Boehler et al. double-stage Eawag, WWTP influent scale antibiotics, analgesics, or minor elimination for some 2012 application) Switzerland; and effluent contrast agents, substances (sulfamethoxazole, WWTP at antilipidemics primidone, iohexol, iopromide). Kloten/Opfikon, Counter-current use of PAC by Switzerland recycling waste PAC from post- treatment in a contact tank with an additional clarifier to the biology tank improved the overall removal by 10 to 50% compared with effluent PAC application alone. The sorption efficiency of PAC was reduced with increasing dissolved organic carbon (DOC). Prechlorination, DWTP in NE DWTP influent Full-scale 35 pharmaceuticals, All but 5 compounds were completely Huerta-Fontela coagulation, sand Spain; surface with source hormones, and removed (>99%). Compounds not et al. 2011 filtration, water from water from the metabolites, including fully removed were atenolol (97%), ozonation, GAC, Llobregat River Llobregat River psychiatric drugs, sotalol (93%), hydrochlorothiazide and post- in NE Spain angiotensin (98%), carbamazepine epoxide (99%), chlorination agents, and phenytoin (96%). antihistaminics, beta blockers and cardiac agents, 4 EDCs (estrone, estriol, ethinyl estradiol, and tamoxiphen) and 6 main metabolites

(continued)

Table 6.5 (Continued) Treatment Chemical/ class group, Treatment Source/type of technology # of compounds technology type Location analyzed water scale evaluated Comments Reference GAC, and GAC Source waters Source waters : Full-scale 4 compounds: Removal of the compounds by the two Kleywegt et al. followed by UV and 17 drinking 8 from rivers, 7 carbamazepine (CBZ), processes were: carbamazepine = 71- 2011 water systems in from lake gemfibrozil (GFB), 93% by GAC, 75% by GAC + UV; Ontario, Canada sources, and 2 ibuprofen (IBU), and gemfibrozil = 44-55% by GAC, 82% from bisphenol A (BPA) by GAC + UV; bisphenol A = 80% by groundwater GAC, 99% by GAC + UV sources; finished drinking water Denitrification, South WWTP influent Full-scale 54 PPCPs including 50/54 were removed to below their Reungoat et al. pre-ozonation, Caboolture and effluent analgesics, LOD representing (≥90%) by the 6 2010 dissolved air Water betablockers, stage sequence. Denitrification flotation-sand Reclamation antibiotics, decreased concentrations by <20% for filtration Plant in psychotropics, contrast most, and pre-ozonation by <30%. (DAFF), main Australia agents Effectiveness of DAFF varied from ozonation, and <20%- 44%. The main ozonation activated carbon stage decreased most compounds (AC) filtration, below the LOQ, ranging from 55- and final >90%. AC further removed ozonation for compounds and only two were disinfection (6 quantified above their LOQ after: stages). roxithromycin and gabapentin. After the final ozonation step, DEET and caffeine were also detected. Biological activity was reduced from 62% (AhR response) to > 99% (estrogenicity). The key processes responsible were the coagulation/ flocculation/DAFF, main ozonation and activated carbon filtration. The effect of these 3 processes varied from one compound or bioassay to another but their combination was almost totally responsible for the overall observed reduction. (continued)

Table 6.5 (Continued) Treatment Chemical/ class group, Treatment Source/type of technology # of compounds technology type Location analyzed water scale evaluated Comments Reference MBR, UF, RO, United States Secondary Bench-, pilot-, 36 (pharmaceuticals, PAC and GAC was highly effective in Snyder et al. PAC, GAC, and (various, effluent from full-scale steroids, pesticides, removing nearly all compounds 2007a combination of unspecified) municipal PAHs, fragrance, (>90% for most compounds), with systems WWTP for UF antimicrobial, and greater removal at greater contact pilot-scale; other PPCPs) times. However, compounds with primary greater hydrophilicity breach activated wastewater carbon faster than hydrophobic effluent for compounds. In full-scale applications, MBR pilot- the impact of regeneration was scale tests; observed as activated carbon filters saline that received regular regeneration had groundwater for minimal breakthrough of organic RO pilot-scale contaminants, while non-regenerated tests; municipal filters displayed no removal of target WWTP influent compounds. for full- scale MBR followed by pilot RO; tertiary treated wastewater for pilot MF followed by RO; secondary treated wastewater for full-scale MF AC – activated carbon; DAFF – dissolved air flotation-sand filtration; DOC – dissolved organic carbon; GAC – granular activated carbon; LOQ – limit of quantitation; MBR – membrane bioreactor; PAC – powdered activated carbon; PAH – polycyclic aromatic hydrocarbon; PPCP – pharmaceutical and personal care product; RO – reverse osmosis; UF – ultrafiltration; WWTP – wastewater treatment plant

 In general, MBRs were more effective in removing PPCPs and EDCs than conventional activated sludge (CAS) processes; e.g., the removal efficiency with MBR was better than CAS treatment (removal rates > 80% for 11 of 22 constituents from a mixture of municipal, hospital, and industrial wastewater by MBR vs. 4 of 22 constituents by CAS Radjenovic et al. 2007, Radjenovic et al. 2009), and removal of >75% of sulfamethazole from municipal wastewater by MBR vs. 0-80% by CAS (Joss et al., 2005)). However, Joss et al. (2004) reported similar removal of estrogenic hormones by MBR and CAS in batch experiments with municipal WWTPs, and Joss et al. (2005) reported virtually no removal of carbamazepine from municipal wastewater by either technology and comparable removal of diclofenac (~20-35%) and naproxen (~80%) in full-scale experiments.  Longer solid or sludge retention times (SRTs) in the MBR process enhanced removal of poorly degradable compounds from municipal wastewater (Kimura et al. 2007, Schroder et al. 2012).  Biodegradation, sorption, or a combination of both in the sludge and membrane are the main mechanisms for PPCPs and EDCs removal by the MBR processes.  MBRs were highly efficient in removal of traditional wastewater parameters including total organic carbon (TOC), total suspended solids (TSS), chemical oxygen demand (COD), and nutrients, in full-scale experiments involving raw hospital wastewater at a hospital WWTP (Beier et al. 2012).  MBRs cannot achieve complete removal of all PPCPs and EDCs, and some chemicals show particular resistance. Limited elimination was observed in five studies at WWTPs, including municipal, hospital, and industrial wastewater, for some compounds such as carbamazepine, diclofenac, DEET, erythromycin-H2O, ibuprofen, meprobamate, and phenytoin (Clara et al. 2005, Joss et al. 2005, Radjenovic et al. 2007, Radjenovic et al. 2009, Reif et al. 2008, Snyder et al. 2007a).  Nanofiltration (NF) MBR with reverse osmosis (RO) membranes was very efficient in removing pharmaceuticals from DWTP influent from groundwater wells (>85%), including analgesic and anti-inflammatory drugs, β-blockers, antiepileptic drugs, antibiotics, lipid regulators and diuretics (Radjenovic et al. 2008).  In another study, the combination of MBR and RO treatment showed excellent overall removal rates for selected pharmaceuticals from municipal wastewater at a WWTP, including psychiatric drugs, macrolide antibiotics, β-blockers, sulfonamide and fluoroquinolone antibiotics, histamine H2 receptor antagonists, anti-inflammatories, nitroimidazole, β-agonist, and antiplatelet agents, with removal rates above 99% for all of them (Dolar et al. 2012a).

Table 6.3 summarizes information from six investigations of PPCP and EDC removal by advanced oxidation processes (AOP) employing ozone (O3), hydrogen peroxide (H2O2) or ultraviolet (UV) light, alone or in combination with other treatment technologies. Overall, the summary suggests:

 AOPs performed better when they were used in combination with other wastewater treatments, in studies of reverse osmosis retentates at a water reclamation facility (Abdelmelek et al. 2011).

 Advanced wastewater treatment by O3/H2O2 had little effect on contaminant removal as compared to O3 alone, in studies of WWTP effluent and spiked Colorado River water from drinking water intakes (Snyder et al. 2006).  UV/H2O2 was characterized as a viable solution for the transformation of organic micropollutants with low O3 and •OH reactivity but high photoactivity such as N- nitrosodimethylamine (NDMA), in studies using lake water and wastewater effluent (Katsoyiannis et al. 2011).  Type of pharmaceutical, pH, H2O2 concentration, UV dose, and water type influenced the transformation of EDCs and pharmaceuticals in studies of spiked pure water, treated water from a DWTP, WWTP effluent, and lake water (Canonica et al. 2008, Baeza and Knappe 2011).  The removal efficiency of EDCs and pharmaceuticals varies significantly between different oxidation processes. Free chlorine, permanganate, and ozone treatments were effective for triclosan and estrone removal, while they were not effective for removing ibuprofen, iopromide, and clofibric acid from Mississippi River water. pH plays an important role in the removal efficiency of the selected EDCs and pharmaceuticals during free chlorine, permanganate, and ozone treatments (Wu et al. 2012).

Table 6.4 summarizes information from seven investigations of PPCP and EDC removal by RO alone or in combination with other treatment technologies. Overall, the summary suggests:

 RO processes were effective at removing nearly all compounds studied to levels less than the MRL, in studies of raw wastewater and effluent from water reclamation plants and WWTPs (Al-Rifai et al. 2007, Snyder et al. 2007a, Dolar et al. 2012a) as well as source water at a DWTP (Boleda et al. 2011)  Using a multi-barrier approach was most successful in the removal of trace contaminants in tests using municipal WWTP influent and tertiary treated wastewater (Snyder et al. 2007a);  The removal efficiency of RO was enhanced when used in combination with other processes, such as nanofiltration, and/or microfiltration, and/or MBR, in tests that evaluated DWTP influent and effluent, municipal WWTP influent and effluent, groundwater originating from a water reclamation plant, and surface water outlets (Boleda et al. 2011, Soliman et al. 2007, Radjenovic et al. 2008, Dolar et al. 2012a, Dolar et al. 2012b). These investigators suggest than using integrated membrane treatments (e.g., coagulation, microfiltration (MF), NF and RO) has the potential to efficiently remove PPCPs in wastewater;  RO is effective at removing veterinary pharmaceuticals such as sulfamethoxazole, trimethoprim, ciprofloxacin, dexamethasone, febantel, and tylosin, in studies of DWTP influent and effluent and WWTP influent and effluent (Boleda et al. 2011; Dolar et al. 2012b). It was also effective at removing drugs of abuse such as cocaine, ketamine, and MDMA (an amphetamine) (Boleda et al. 2011).

Table 6.5 summarizes information from five investigations of PPCP and EDC removal by activated carbon (AC) adsorption processes in either powdered activated carbon (PAC) or

granular activated carbon (GAC), and/or a combination of other treatment technologies. Overall, the summary suggests:

 AC processes in sequence with other technologies (e.g., dissolved air flotation-sand filtration (DAFF) and ozonation) were effective at removing nearly all compounds studied to levels less than the limit of quantitation, including carbamazepine, diclofenac, and phenytoin, in a study of WWTP influent and effluent (Reungoat et al. 2010). However, in studies of influent at a DWTP, GAC in sequence with prechlorination, coagulation, sand filtration, ozonation, and post-chlorination removed all pharmaceuticals and four hormones completely except for atenolol, sotalol, hydrochlorothiazide, carbamazepine epoxide, and phenytoin, which were removed from 93 to 99% (Huerta- Fontela et al. 2011).  Both PAC and GAC were effective at removing a wide range of microconstituents, including pharmaceuticals, steroids, pesticides, PAHs, fragrances, and antimicrobials (>90% for most compounds) from a range of waters including WWTP effluent and municipal WWTP influent, but compounds with greater hydrophilicity breach activated carbon faster than hydrophobic compounds. In full-scale applications, the impact of regeneration was observed as activated carbon filters that received regular regeneration had minimal breakthrough of organic contaminants (Snyder et al. 2007a).  When used in a single-stage, removal of some PPCPs (sulfamethoxazole, primidone, iohexol, iopromide) from municipal WWTP influent and effluent by PAC was limited, but increased by 10 to 50% by recycling waste PAC from post-treatment in a contact tank with an additional clarifier to the biology tank (Boehler et al. 2012). Removal of three compounds was also limited by GAC at DWTPs: carbamazepine removal ranged from 71-93%, gemfibrozil from 44-55%, and bisphenol A was 80%. Except for carbamazepine, removal efficiency increased when GAC was followed by UV, to 82% for gemfibrozil and 99% for bisphenol A (Kleywegt et al. 2011).

The removal effectiveness of each treatment process differs. Some processes, like membrane bioreactors or reverse osmosis, are very effective at removing nearly all PPCPs and EDCs from wastewater. Other processes, like activated carbon absorption, are effective at removing chemicals that are resistant to other types of treatment, such as carbamazepine. Table 6.6 summarizes the results from investigations on the removal efficiencies of several treatment processes for PPCPs and EDCs in drinking water, surface water, and wastewater.

Table 6.6 PPCP and EDC removal efficiencies by treatment process Treatment process Removal efficiency <25% 25-74% >75% Activated carbon Ibuprofen Acetaminophen Estriol Androstenedione Pentoxifylline absorption Aldrin Galaxolide Caffeine Progesterone (Adams et al. 2002 Atrazine Gemfibrozil Carbadox Sulfachlor- [surface water], BHC Heptachlor Carbamazepine pyridazine Chlordane Hydrocodone DDD Sulfadimethoxine Westerhoff et al. 2005 DDE Iopromide Estradiol Sulfamerazine [drinking water DDT Meprobamate Estrone Sulfamethazine treatment], Rossner et al. DEET Metolachor Ethynylestradiol Sulfathiazole 2009 [surface water]) Diazepam Mirex Fluoxetine Testosterone Diclofenac Musk ketone Methoxychlor Triclosan Dieldrin Naproxen Oxybenzone Trimethoprim Dilantin Phenytoin Endrin TECP Erythromycin-H2O

Coagulation Acetaminophen Galaxolide Aldrin (Westerhoff et al. 2005 alpha-Chlordane Gemfibrozil DDE [drinking water Androstenedione Hydrocodone DDT treatment]) Atrazine Ibuprofen Erythromycin-H20 BHC Iopromide gamma-Chlordane Caffeine Meprobamate Heptachlor Carbamazepine Methoxychlor DDD Musk ketone DEET Naproxen Diclofenac Pentoxifylline Dieldrin Progesterone Dilantin Sulfamethoxazole Estradiol TCEP Estriol Testosterone Estrone Triclosan Ethynylestradiol Trimethoprim Fluoxetine (continued)

Table 6.6 (Continued) Treatment process Removal efficiency <25% 25-74% >75% Conventional activated Atenolol Clofibric acid Mefenamic acid Acetaminophen Ethynylestradiol sludge Carbamazepine Diclofenac Pravastatin Bisphenol A Hydrochlorothiazide (Joss et al. 2004 Erythromycin Gemfibrozil Propyphenazone Estradiol Ibuprofen [wastewater], Clara et al. Indomethacin Glibenclamide Ranitidine Estriol Paroxetine Metoprolol Ketoprofen Sulfamethoxazole Estrone 2005 [wastewater], Ofloxacin Radjenovic et al. 2007 [wastewater])

Membrane bioreactor Carbamazepine Celestolide Mefenamic acid Acetaminophen Ibuprofen (Joss et al. 2004 Clofibric acid Metoprolol Atenolol Ketoprofen [wastewater], Clara et al. Clopidogrel Pravastatin Bezafibrate Metronidazole 2005 [wastewater], Diazepam Propranolol Bisphenol A Nadolol Galaxolide Propyphenazone Codeine Naproxen Radjenovic et al. 2007 Glibenclamide Sotalol Diclofenac Paroxetine [wastewater], Reif et al. Hydrochlorothiazide Sulfamethoxazole Erythromycin Ranitidine 2008 [wastewater], Indomethacin Tonalide Estradiol Roxithromycin Schroder et al. 2012 Lorazepam Trimethoprim Estriol Salbutamol [wastewater]) Estrone Ethynylestradiol Famotidine Gemfibrozil Hydrocodone Reverse osmosis Acetaminophen Androstenedione Ibuprofen (Al-Rifai et al. 2007 Caffeine Bisphenol A Iopromide [wastewater], Snyder et al. Gemfibrozil Carbamazepine Ketoprofen 2007a [wastewater, Mefenamic acid Ciprofloxacin Metoprolol Pentoxifylline Clofibric acid Naproxen groundwater], Radjenovic Dexamethasone 4-nonylphenol et al. 2008 [drinking Diclofenac Oxybenzone water], Boleda et al. 2011 Dilantin Phenytoin [drinking water]) Estradiol Primidone Estriol Progesterone Estrone Propyphenazone Ethynylestradiol Salicylic acid Febantel Sotalol Fluoxetine Sulfamethoxazole Glibenclamide Triclosan Hydrochlorothiazide Trimethoprim (continued)

Table 6.6 (Continued) Treatment process Removal efficiency <25% 25-74% >75% Ozonation alpha-BHC AHTN (Tonalide) Fenofibric acid Acetaminophen Iopamidol (Adams et al. 2002 alpha-Chlordane Aldrin Heptachlor Androstenedione Iopromide [surface water], Ternes et Diatrizoate Atrazine Indomethacin Atenolol Methoxychlor al. 2003 [wastewater], Dieldrin Clofibric acid Meprobamate Caffeine Metolachlor gamma-BHC DDE Mirex Carbadox Metoprolol Westerhoff et al. 2005 gamma-Chlordane DDT Propranolol Carbamazepine Naproxen [drinking water Musk ketone Endrin Celiprolol Oxybenzone treatment]) TCEP Clarithromycin Pentoxifylline DDD Phenytoin DEET Progesterone Diclofenac Roxithromycin Erythromycin-H20 Sotalol Estradiol Sulfachloro- Estriol pyridazine Estrone Sulfadimethoxine Ethynylestradiol Sulfamerazine Fluoxetine Sulfamethazine Galaxolide Sulfamethoxazole Gemfibrozil Sulfathiazole Hydrocodone Testosterone Ibuprofen Triclosan Iomeprol Trimethoprim

Washington Aqueduct (2013) conducted a review of the relative incremental degree of improvement in removal of different compound types, including nitrosamines and atrazine and its degredates, provided by different treatment technologies compared to the existing or baseline treatment. For example, reverse osmosis and ozone treatment were found to offer a moderate degree of improvement in removal of nitrosamines compared to the baseline treatment (consisting of conventional coagulation/ flocculation, conventional sedimentation, granular media filtration, free chlorination, chloramination, and chemical addition for corrosion control), while the improvement offered by post-filter GAC contactors was nominal. For atrazine, reverse osmosis and post-filter GAC offered significant improvement in removal, while the improvement offered by ozone/peroxide + BAF was nominal. Washington Aqueduct (2013) also provides estimates of the capital, operations and maintenance, and present worth financial costs for different treatment technologies, and the relative impact on other parameters including energy usage, chemical and media resource consumption, and waste production.

SOURCE WATER PROTECTION PROGRAMS

Drinking water comes from a number of sources, including streams, lakes, reservoirs and underground aquifers. Although public water utilities treat most drinking water before it enters the home, the cost of this treatment and risks to public health can be reduced by protecting source waters from contamination (EPA 2012g). Source water protection (SWP) programs are implemented by U.S. states as a way of reducing costs and/or efforts to decontaminate waters from source to point-of-use. Under the Safe Drinking Water Act (SDWA) Amendments of 1996, EPA requires states to develop and implement source water assessment programs (SWAPs) to analyze existing and potential threats to the safety of public drinking water sources throughout the state. The four major components of the federally mandated SWAP program are (EPA 2012i):

1. Delineate source water protection areas (SWPAs) for each source (well, spring, surface water intake). 2. Inventory each SWPA for potential contaminant sources. 3. Conduct a susceptibility assessment for each drinking water source. 4. Make the findings of the 1-3 readily available to interested parties.

SWAPs may be used by local entities and help determine whether more protective measures are needed. The source water assessment results provide a starting point for developing a SWP plan. States have completed SWAPs for all public water systems in the nation, from major metropolitan areas to the smallest towns (EPA 2012h). Local entities may choose to manage their source water protection areas in various ways, with the choice determined by site-specific factors such as the size and nature of the area, the type of source water (e.g., mountain streams, highly developed rivers, reservoirs, groundwater), the development and landuse of the contributing area, the potential sources and characteristics of contamination, and the nature of stakeholder organizations and their available resources and authority. Both non-regulatory and regulatory management techniques can be implemented. Developing a source water protection program consists of three main steps:

 Gather data (e.g., identify sources, identify protection areas, identify threats)  Conduct analysis (e.g., determine risks, establish current context, weigh options, evaluate tools)  Prioritize actions (e.g., education, land use controls, groundwater reclassification, BMP management, land conservation, social marketing)

A literature search was conducted to identify examples and resources describing source water protection programs. In addition, key findings from relevant Water Research Foundation projects addressing source water protection programs were summarized.

The Multibarrier Approach to Source Water Protection

A recommended approach to source water protection is the “multibarrier approach” that uses multiple barriers to prevent contamination from affecting drinking water. Among the “barriers” identified for stages in the process from raw, untreated source water to delivery of treated finished water are the following (EPA 2006b):

 Risk Prevention: selecting and protecting the best source of water  Risk Management: using effective treatment technologies, properly designed and constructed facilities, and employing trained and certified operators to properly run system components.  Monitoring and Compliance: detecting and fixing problems in the source and/or distribution system  Individual Action: Providing customers with information on water quality and health effects so they are better informed about their water system

Examples of Options for Source Water Protection Programs

Examples of relatively source water protection programs that can be implemented, including farm conservation and management practices, forest management, low impact development (LID)/smart growth initiatives, river and habitat protection, watershed partnerships, and other watershed protection measures are provided in Table 6.7. Examples of measures of the relative effectiveness of different source water protection programs on improving water quality are shown in Table 6.8.

Table 6.7 Examples of source water protection strategies/programs Strategy/ Program Approach/ Benefits Resources/ Examples Agricultural  Programs enhance water  The State of New Jersey publishes On Farm Strategies to Protect Water conservation supplies, improve water Quality http://www.nj.gov/agriculture/divisions/anr/pdf/BMPManual.pdf and quality, reduce soil erosion,  Under the Conservation Reserve Program administered by the USDA management and reduce damages caused FSA, enrolled farmers agree to remove environmentally sensitive farm programs by floods and other natural land from agricultural production and plant species that improve disasters. environmental health and quality in exchange for a yearly rental payment  BMPs include use of http://www.fsa.usda.gov/FSA/webapp?area=home&subject=copr&topic alternative fertilizers, buffer =crp zones, crop rotation, and  A number of sources of financial assistance and cost sharing are terracing shown to reduce available to farmers including from USDA Natural Resource herbicide, nutrient, and Conservation Service (NRCS) and Farm Service Agency (FSA) sediment runoff programs. http://www.nrcs.usda.gov/wps/portal/nrcs/main/national/programs/  Examples include: • New York City and the farm community jointly developed a Watershed Agricultural Program (WAP) to avoid the need for regulatory controls on agricultural operations in the watershed. The program is based on voluntary farmer participation in the development and implementation of whole farm plans that protect water quality while maintaining farming as a preferred land use in the watershed. As of January 2006, 290 commercial farms (representing 95.7% of commercial farms in the watershed) are enrolled in the program and 288 of these farms have whole farm plan agreements (EPA 2011b). http://water.epa.gov/infrastructure/drinkingwater/sourcewater/protecti on/casestudies/upload/Source-Water-Case-Study-NY-NY-City-7- Upstate-Counties.pdf (continued)

Table 6.7 (Continued) Strategy/ Program Approach/ Benefits Resources/ Examples Forest  Forest lands intercept  The USDA Forest Service Watershed team provides guidance and documents on management precipitation, promote water evaluating and managing watersheds http://www.fs.fed.us/biology/watershed/ infiltration, reduce storm water  The State of Wisconsin publishes Forest Management Guidelines that outline runoff, moderate stream flows, practical considerations that land managers can take when they plan and carry recycle nutrients and chemicals, out forestry operations. stabilize soils, reduce soil http://dnr.wi.gov/topic/ForestManagement/guidelines.html erosion and sedimentation, and provide clean water.  Examples include:  Concentrations of nitrate from • The cities of New York and Boston rely on heavily forested and protected forested watersheds typically water supplies to provide high quality drinking water to its citizens. New average 1 mg/L or less, York City has estimated that if water quality degraded and it was required to compared to a drinking water filter water that the additional treatment would cost nearly $ 7 billion, with standard of 10 mg/L and are over $300 million in annual operating costs (Trust for Public Lands 2004). much lower than from • The City of Baltimore supported the development of a Comprehensive agricultural users (MD DNR Forest Conservation Plan for the 17,856 acres of city-owned land around its 2014) three water supply reservoirs (MD DNR 2014). Low Impact  Reduces stormwater runoff and  Low Impact Development (LID) techniques include use of: Development/ related pollutants by conserving • Bioretention cells (i.e., rain gardens) to absorb and filter runoff Smart growth forests and green spaces, • Cisterns and rain barrels to harvest and store rainwater collected from roofs protecting stream buffers, and • Green roofs to help mitigate the urban “heat island” effect reducing impervious surfaces • Permeable and porous pavements to reduce stormwater runoff by allowing  Increases infiltration to recharge water to soak through the paved surface into the ground beneath. groundwater for water supply • Grass swales alongside roadways to slow stormwater runoff, filter it, and and maintenance of stream allow it to soak into the ground. baseflow  The California Waterboards provide a list of FAQs on implementing LIDs  Improved water quality in lakes, http://www.waterboards.ca.gov/rwqcb3/water_issues/programs/stormwater/docs/ rivers, and streams lid/CA_LID_FAQ_05_20_2011.pdf  Protects aquatic habitats (continued)

Table 6.7 (Continued) Strategy/ Program Approach/ Benefits Resources/ Examples Low Impact  The Sustainable DC initiative in Washington .D.C. announced a plan to make Development/ DC the greenest, healthiest, and most livable city in the nation. With regard to Smart growth water, initiatives include installing 2 million new square feet of green roofs, (cont.) increasing the use of green infrastructure along public rights of way, building 25 miles of green alleys, and establishing pervious surface minimums http://sustainable.dc.gov/sites/default/files/dc/sites/sustainable/page_content/atta chments/SDC%20Summary%20Document%202-19_0.pdf  EPA Office of Sustainable Communities provides a number of publications and tools on Smart Growth http://www.epa.gov/smartgrowth/index.htm  EPA summarized the 10 core principles of Smart Growth including: http://www.epa.gov/smartgrowth/about_sg.htm • Mix land use. • Take advantage of compact building design. • Create a range of housing opportunities and choices. • Create walkable neighborhoods • Foster distinctive, attractive communities with a strong sense of place. • Preserve open space, farmland, and critical environmental areas. • Strengthen and direct development toward existing communities. • Provide a variety of transportation choices. • Make development decisions predictable, fair and cost effective. • Encourage community and stakeholder collaboration.  The State of Massachusetts provides a Smart Growth Toolkit and compares costs http://www.mass.gov/envir/smart_growth_toolkit/pages/mod-lid.html

(continued)

Table 6.7 (Continued) Strategy/ Program Approach/ Benefits Resources/ Examples River and  Many state agencies maintain  The Vermont Agency of Natural Resources’ River Management Program (RMP) habitat habitat protection programs and developed a technical river corridor planning guide that provides methods for protection river protection programs that identifying and implementing river corridor protection and restoration projects. programs seek to protect riparian areas http://www.vtwaterquality.org/rivers/htm/rv_restoration.htm and river corridors.  The Carl Vinson Institute of Government of the University of Georgia publishes  Management and protection of a guidebook for establishing riparian buffer ordinances, including a model river corridors promotes the ordinance transport the flow and sediment http://www.rivercenter.uga.edu/publications/pdf/riparian_buffer_guidebook.pdf of its watershed in such a  The Virginia Interactive Stream Assessment Resource (INSTAR) program manner that it maintains its provides an interactive mapping and data visualization application that allows dimension, pattern, and profile users to access a database of aquatic resources statewide. without aggrading or degrading. http://gis.vcu.edu/instar/  Creation of riparian zones  Examples of implementation of projects include: provides an effective tool for reducing non-point source • The Maryland Department of Natural Resources (DNR) has implemented pollutant concentrations in areas upgrades to wastewater treatment plants located in the Upper Western Shore impacted by livestock grazing Rivers, managing stormwater runoff and retrofitting septic systems. and agricultural watersheds Stormwater retrofits have reduced nitrogen loadings and prevented nearly 50,000 pounds of nitrogen from entering the rivers since 2003, and 191

septic system retrofits were completed in 2008 to 2010 (MD DNR 2013a). • To improve the water and habitat quality of the Potomac River, DNR fenced more than 13,700 acres of farmland to keep livestock out of the stream and prevent stream bank erosion (MD DNR 2013b). • Through the implementation of BMPs on agricultural lands (riparian buffer protection, reduced fertilizer use, tillage practices), North Carolina met 30% nitrogen reduction, and impaired acreage in the estuary was reduced by 90% (U.S. EPA 2012n). (continued)

Table 6.7 (Continued) Strategy/ Program Approach/ Benefits Resources/ Examples Innovative  Use of oyster shells to minimize  The Port of Seattle is using oyster shells to remove dissolved copper from stormwater stormwater hardness and water, by pouring shells directly into stormwater catch basins. The shells treatment remove copper filter free copper by absorption. http://www.portseattle.org/Environmental/Water-Wetlands- Wildlife/Stormwater/Pages/default.aspx

Watershed  Public utilities, customers and  EPA’s Adopt Your Watershed program promotes opportunities for the public to partnerships local watershed groups work get involved in such activities as volunteer water monitoring, stream cleanups, together in citizen-based and storm drain marking. It maintains a database of more than 2,600 watershed partnerships to protect groups, and provides a Watershed Stewardship Toolkit with eight things watersheds. citizens can do to make a difference in their watershed (EPA 2005b, 2012j).  Examples include: • The Lower Susan River Watershed Partnership Project was formed in 2010 to protect water quantity and quality in the 168,773 acre watershed in Northern California. Practices to improve water quality include using cover crops, irrigation canals, pest management, and filter strips. Other focuses include wetland restoration, noxious weed removal, and planting more drought tolerant crops. Over the five-year project period (2010-2014) the partnership will contribute nearly $8 million in non-Federal resources and services (USDA 2014). • The Erie County, Ohio Firelands Coastal Tributaries Watershed Coordinator Grant and Partnership developed a number of demonstration projects to encourage practices that can reduce contamination of source waters, including building rain gardens, conducting rain barrel workshops, and building riparian plantings. Volunteers also developed a water quality monitoring program (ODNR 2014). (continued)

Table 6.7 (Continued) Strategy/ Program Approach/ Benefits Resources/ Examples Watershed  Vegetation and soils filter out  EPA publishes a summary of watershed management resources at EPA, protection contaminants and trap sediment including a Handbook for Developing Watershed Plans, a Watershed Plan areas purifying water at low cost. Builder, free online seminars and courses, and funding sources. http://water.epa.gov/type/watersheds/datait/watershedcentral/upload/WMR_fact  Reduces vulnerability to sheet_508.pdf invasive species, climate changes, and future land use  USDA provides watershed program planning services. changes. http://www.nrcs.usda.gov/wps/portal/nrcs/main/national/programs/landscape/  The nonprofit Association of State Wetland Managers provides support to wetland management efforts, including education and training. http://www.aswm.org/aswm/about-aswm  Examples include: • The town of Auburn, Maine saved $30 million in capital costs and $750,000 in annual operating costs, by spending $570,000 to acquire land in their watershed. By protecting 434 acres of land around Lake Auburn, the water systems are able to maintain water quality standards and avoid building a new filtration plant (Trust for Public Lands 2004). • The Metropolitan District Hartford (MDC), Connecticut implements a forested watershed program as the first line of defense for protecting water from pollution and maintaining high quality drinking water. The MDC conducts annual sanitary surveys of watershed properties; identifies and inspects watershed conditions; and works closely with watershed towns on land use planning and development issues that may affect water supplies (MDC 2014). • The Lake Champlain Basin Agricultural Watersheds National Monitoring Program (NMP) Project evaluates the effectiveness of low-cost livestock exclusion, streambank protection, and riparian restoration practices in reducing concentrations and loads of diffuse-source pollutants from grazing land at the watershed level. Significant reductions in phosphorus concentrations and loads were achieved. Treatment effectiveness is evaluated through water quality monitoring (Meals and Hopkins 2002).

Table 6.8 Measures of effectiveness of source water protection approaches on improving water quality SWP approach Effectiveness CAFO management Application of alum (aluminum sulfate), a water utility treatment plant residual, to agricultural land can provide an inexpensive disposal option for utilities while helping to bind phosphorus after land application of manure and litter (Gullick et al. 2007) Forest management 27 US water suppliers determined that for every 10% increase in forest cover in the source area (up to about 60% forest cover), treatment and chemical costs decreased approximately 20% (Ernst 2004). The cities of New York and Boston rely on heavily forested and protected water supplies to provide high quality drinking water to its citizens. New York City has estimated that if water quality degraded and it was required to filter water that the additional treatment would cost nearly $ 7 billion, with over $300 million in annual operating costs (Trust for Public Lands 2004). Green The Green Values Stormwater Toolbox allows the user to determine the infrastructure costs and benefits associated with different types of green infrastructure, including raingardens, native landscaping, porous pavement, green roofs, and planting of trees. Benefits calculated include the reduction in lot discharge and the increase in average annual groundwater recharge. http://greenvalues.cnt.org/calculator/calculator.php Low impact 17 case studies demonstrated that LID practices can reduce project costs and development improve environmental performance. Total capital cost savings ranged from 15-80% in most cases. http://water.epa.gov/polwaste/green/factsheet.cfm#cost Low impact Restoration of streams damaged by runoff from development, and BMPs to development/ reduce impacts of rapid development, were assessed in North Carolina to Green determine impacts on drinking water quality. Analysis showed that stream infrastructure restoration is the most cost-effective way to immediately control sediment. The Capitol Region Watershed District determined that LID/GI approaches could achieve stormwater runoff goals for its watershed management project at a lower cost than proposed construction of a 60-inch storm sewer pipe. A new storm sewer for conveying untreated, frequent floodwaters to Lake Como was estimated to cost $2.5 million compared to $2.0 million for implementing GI infiltration. Benefits included improved water quality. http://water.epa.gov/polwaste/green/upload/lid-gi-programs_report_8-6- 13_combined.pdf Planting trees in Installation of 173 trees in structural cells along a new bus corridor in urban scapes Minneapolis, MN in 2010 was expected to result in a 10% reduction in peak urban stormwater runoff flows during peak storm events. http://water.epa.gov/polwaste/green/upload/stormwater2streettrees.pdf Reduced herbicide Application of agricultural BMPs addressing herbicide use reduced atrazine use runoff typically by 25-50%. http://ianrpubs.unl.edu/epublic/live/rp197/build/rp197.pdf (continued)

Table 6.8 (Continued) SWP approach Effectiveness Stormwater BMPs Concentrations of total suspended solids for urban stormwater BMPs decreased by the following approximate percentages (based on median concentrations):  grass strip 56%  biorentention 78%  bioswale 37%  composite 81%  detention basin 64%  green roof 72%  manufactured device 47%  media filter 83%  porous pavement 80%  retention pond 81%  wetland basin 56%  wetland channel 29% http://www.bmpdatabase.org/ 2012 Water Quality Analysis Addendum/BMP Database Categorical Summary Addendum Report

Relevant Water Research Foundation Projects

Past or present research projects funded by the Water Research Foundation addressing development and management of source water protection programs include:

 Project #903: Source Water Protection Reference Manual (2002). This project produced a CD-ROM guide to assist water suppliers in finding information that is relevant to their utility and source water and to use this information to develop, enhance, and implement comprehensive source water protection management activities with maximum efficiency and minimum stress.  Project #3020: Source Water Protection for Concentrated Animal Feeding Operations: A Guide for Drinking Water Utilities (2007). This project summarized the potential and known impacts of CAFO-derived contaminants such as pathogens and EDCs on drinking water utilities, and described potential control strategies that could be implemented to protect drinking water supplies.  Project # 4176: Developing a Vision and Roadmap for Source Water Protection for U.S. Drinking Water Utilities (2012). This project presented a Vision and Roadmap to guide U.S. water utilities and supporting groups with a unified strategy for coherent, consistent, cost-effective, and socially acceptable source water protection programs.  Project #4334: Constructed Wetlands for Treatment of Organic and Nonmaterial Pollutants (2014). This project determined hydraulic and carbon loading rates for constructed wetlands required to achieve different levels of EDC/PPCP and engineered nanomaterial removal as a function of hydraulic loading rates. In addition, the project determined dominant removal mechanisms (abiotic, biotic) for the different classes of emerging pollutants as well as developed design relationships, assessed other water quality changes that may impact downstream water utilities, and made recommendations to utilities on the potential benefits of constructed wetlands for treating surface waters.

 Project #4494: “Evaluation of Current and Alternative Strategies for Managing CECs in Water” (in progress). This project is aggregating and evaluating management plans for CECs that have been employed or are being considered in North America, Europe, and Australia. Strengths and weaknesses of each will be identified, considering a holistic water approach that takes into account environmental and public health. Alternative approaches that combine the best features of existing approaches will be considered as well. CEC management strategies will then be prioritized to evaluate the costs and benefits of selected approaches in form of a triple bottom line analysis.

WATER PROTECTION PRACTICES FOR THE PUBLIC

Utilities can help prevent contaminants from entering source water by advising consumers on best management practices (BMPs) to reduce the amount and number of chemicals that can find their way into source water. Some examples of BMPs that can be implemented by the public, and examples of resources providing more information, are described below.

Animal Wastes

 Pick up pet wastes  Prevent contact of livestock and poultry waste with water  Resources o EPA http://water.epa.gov/polwaste/npdes/swbmp/Pet-Waste-Management.cfm

Boating

 Follow clean boating practices with regard to fuel use, maintenance, sewage management, and cleaning  Resources o California State Parks http://www.dbw.parks.ca.gov/Environmental/CleanGreen/Default.aspx o Boat U.S. Foundation http://www.boatus.org/clean-boating.asp

Disposal of Household Hazard Wastes

 Utilize local household hazardous waste collection services to dispose of oil, antifreeze, paint or other household chemicals.  Do not dump them down the drain.  Resources o EPA http://www.epa.gov/epawaste/conserve/materials/hhw.htm o Minnesota Pollution Control Agency o http://www.pca.state.mn.us/index.php?option=com_k2&Itemid=818&layout=categor y&view=itemlist o Utah State University Extension http://extension.usu.edu/waterquality/htm/bmps

Disposal of Medications

 Do not flush medications down the toilet  Dispose of medications at official drop off events  Bring inhalers to GlaxoSmithKline-sponsored collection sites (in at least 31 cities)  Resources: o FDA: http://www.fda.gov/forconsumers/consumerupdates/ucm101653.htm o EPA: http://water.epa.gov/scitech/swguidance/ppcp/upload/ppcpflyer.pdf o National Take Back Initiative: http://www.deadiversion.usdoj.gov/drug_disposal/takeback/index.html o GlaxoSmithKline: http://www.terracycle.com/en-US/pages/gsk-respiratory-inhaler- recycling

Erosion Control

 Use plants to control erosion  Build terraces or retaining walls  Add organic matter to your soil, and use mulch around trees and shrubs  Resources o Virginia Cooperative Extension http://pubs.ext.vt.edu/426/426-722/426-722.html o USDA ftp://ftp-fc.sc.egov.usda.gov/CA/programs/EWP/2007/eEC.pdf o Utah State University Extension http://extension.usu.edu/waterquality/htm/bmps

Fertilizers and Pesticides

 Follow application directions for fertilizers, pesticides, and herbicides  Properly store and dispose of fertilizers, pesticides, and herbicides  Eliminate excess use of fertilizers, pesticides, and herbicides, and avoid application near drinking water wells or surface water  Plant native plants and grasses that require less use of fertilizers, pesticides, and water  Resources o University of California http://www.ipm.ucdavis.edu/QT/gardenchemicalscard.html o Utah State University Extension http://extension.usu.edu/waterquality/htm/bmps o Florida Department of Environmental Protection http://www.sfwmd.gov/portal/page/portal/xrepository/sfwmd_repository_pdf/fl_green _bmp.pdf

Household Cleaning Products

 Use safe alternatives to commercial cleaning products  Resources o State of Connecticut http://www.ct.gov/deep/cwp/view.asp?a=2708&q=323956&deepNav_GID=1763 o Los Angeles County http://dpw.lacounty.gov/epd/hhw/alternative.cfm o Utah State University Extension http://extension.usu.edu/waterquality/htm/bmps

Septic Systems

 Have septic systems checked regularly and maintained regularly and maintain minimum required distances between septic systems and private water wells  Resources o University of Arizona http://ag.arizona.edu/pubs/water/az1161.pdf o Oregon Department of Environmental Quality http://www.deq.state.or.us/wq/onsite/aboutseptic.htm o Washington Department of Ecology http://www.deq.state.or.us/wq/onsite/aboutseptic.htm

Vehicle Washing

 Use commercial car washes  Use soap sparingly  Dispose of buckets of soapy water in the sink, or wash your car in a grassy area  Resources o City of Seattle http://www.seattle.gov/util/EnvironmentConservation/MyHome/PreventPollution/Car Washing/index.htm o City of Ashland, VA http://www.town.ashland.va.us/index.aspx?NID=324 o Utah State University Extension http://extension.usu.edu/waterquality/htm/bmps

Water Use and Gardening

 Plant rain gardens and use rain barrels  Conserve water by using low flow showerheads, running your dishwasher and washing machine with full loads only, and watering your lawn in the morning or evening  Plant native trees  Resources o City of Seattle http://www.seattle.gov/util/groups/public/@spu/@usm/documents/webcontent/spu01 _006287.pdf o Rain Garden Network http://www.raingardennetwork.com/rainbarrels.htm o Florida Department of Environmental Protection http://www.sfwmd.gov/portal/page/portal/xrepository/sfwmd_repository_pdf/fl_green _bmp.pdf

EPA has published a number of Source Water Protection Practice Bulletins that outline BMPs that can be implemented by businesses, communities, citizens, and others to prevent contamination of drinking water, addressing the following issues http://cfpub.epa.gov/safewater/sourcewater/sourcewater.cfm?action=Publications&view=filter& document_type_id=103 :

 Above ground storage tanks  Agricultural fertilizer application

 Aircraft and airfield deicing operations  Highway deicing  Large- and small-scale application of pesticides  Livestock, poultry, and horse waste  Pet and wildlife waste  Sanitary sewer overflows and combined sewer overflows  Storm water runoff  Turfgrass and garden fertilizer application  Underground storage tanks  Vehicle washing

ADDITIONAL SOURCES OF INFORMATION ON TREATMENT TECHNOLOGIES AND SOURCE WATER PROTECTION

General sources of information on treatment technologies for CECs and source water protection programs include the following:

 Health Canada From Source to Tap—The Multi-Barrier Approach to Safe Drinking Water http://www.hc-sc.gc.ca/ewh-semt/pubs/water-eau/tap-source-robinet/index- eng.php http://www.hc-sc.gc.ca/ewh-semt/water-eau/drink-potab/multi-barrier/index- eng.php  EPA database of treatment technologies for CECs http://water.epa.gov/scitech/swguidance/ppcp/results.cfm  EPA general website on Source Water Protection http://water.epa.gov/infrastructure/drinkingwater/sourcewater/protection/index.cfm  EPA schematic illustrating sources of PPCPs to the environment, potentially useful for communicating the importance of source water protection approaches http://www.epa.gov/ppcp/pdf/drawing.pdf  EPA The Multiple Barrier Approach to Public Health Protection http://www.epa.gov/ogwdw/smallsystems/pdfs/guide_smallsystems_mba_09-06-06.pdf  EPA website on steps in conducting a Source Water Assessment http://water.epa.gov/infrastructure/drinkingwater/sourcewater/protection/sourcewaterasse ssments.cfm  No Drugs Down the Drain links to resources http://www.nodrugsdownthedrain.org/NoDrugs/further.asp

CHAPTER 7: MONITORING AND COMMUNICATION APPROACHES APPLIED BY DRINKING WATER UTILITIES

Prior to implementing a monitoring program for PPCPs and EDCs in water, utilities must give careful consideration to the design of the program and how the results of the program will be communicated. This chapter addresses the following questions:

 What monitoring efforts have been implemented by utilities to characterize PPCPs and EDCs in source and drinking water? What have been the drivers for these monitoring programs?  What factors should drinking water utilities consider when implementing a water monitoring program for PPCPs and EDCs?  What are some of the advantages and disadvantages of implementing monitoring programs?  What are some communication strategies and tactics that have been used by drinking water utilities and regulatory agencies to communicate about EDCs/PPCPs or other trace contaminants? What have been the outcomes of these approaches?  What other general communication strategies and tactics have been recommended with regard to risk communication?

In addition, links to sources of additional information on these topics are provided.

MONITORING APPROACHES IMPLEMENTED BY UTILITIES

To support selection of options that utilities may consider when choosing to implement monitoring and communication programs about PPCPs and EDCs in water, we gathered information on monitoring efforts that have been implemented by utilities to characterize PPCPs and EDCs in source and drinking water. Under the Safe Drinking Water Act (SDWA), water utilities are required to conduct routine monitoring of source and drinking water to demonstrate compliance with EPA’s federal regulations to ensure that contaminants present in drinking water are below what EPA considers safe. All public water systems, at a minimum, conduct routine monitoring for total coliform bacteria, nitrate and nitrite, and if using a surface water source, conduct monitoring for other microbiological contaminants. Other contaminants such as radiological agents are also routinely monitored. Compliance monitoring in the distribution system ensures any problems that arise can be dealt with as quickly and efficiently as possible, thus ensuring that water reaching consumers is clean, safe, and reliable. While utilities are not currently required under the SDWA to monitor for PPCPs and most EDCs in source or drinking water, laboratories and public water systems participate in EPA’s Unregulated Contaminant Monitoring Rule (UCMR), including for some EDCs. EPA uses UCMR data to help evaluate whether to regulate contaminants suspected to be present in sufficient quantity in drinking water but that do not have health-based standards under the SDWA.

In addition, some major water utilities in the United States have tested either source and/or treated water for emerging contaminants such as PPCPs and hormones as part of national and regional studies, or to better understand the sources and occurrence. Source water monitoring provides useful information to support the selection of treatment solutions. Once treatment is in place, on-going monitoring at the intake allows plant operators to modify treatment if water quality fluctuates. Monitoring in other parts of the treatment plant ensures treatment is working properly and that water leaving the plant is safe for human consumption. Examples of utility monitoring studies for PPCPs and EDCs in source and drinking water are listed in Table 7.1. While this list is not exhaustive, it is representative of studies that have been conducted and data published by utilities on their websites. More detailed descriptions of several of these studies follow, below. Several utilities have implemented short term studies of PPCPs or EDCs. For example, in 2004 and 2005, the cities of Ann Arbor, Grand Rapids, and Monroe, Michigan conducted one of the nation’s first comprehensive water testing studies of PPCPs and EDCs in municipal drinking water. In 2004, Ann Arbor tested for PPCPs and EDCs in the city’s source water, drinking water, raw sewage, and treated wastewater. In 2004, water samples were collected four times throughout the year and tested for the presence of 22 compounds including seven antibiotics, two analgesics, one anti-epileptic, nine hormones and stabilizers, caffeine, a nicotine metabolite, and a solvent stabilizer. Of the 22 compounds, 17 were found in raw sewage, 15 were detected in the treated wastewater, 10 were found in the source water, and four (cholesterol, ibuprofen, sitosterol, and stigmasterol) were detected in finished water. In a follow up study in 2005, 22 PPCP and EDCs were tested, but 11 of them were different compounds than in the 2004 study. Eleven compounds were detected in drinking water in the parts per trillion range: one beta blocker (propranolol), six hormones or sterols (17α-ethinylestradiol, 17β-estradiol, estriol, estrone, cholesterol, and coprostanol), one anti-epileptic (carbamazepine), one analgesic (ibuprofen), one veterinary antibiotic (tylosin), and caffeine. Initial studies indicated that concentrations of these contaminants at the levels detected were not a human health risk (Skadsen et al. 2006). In 2008, the Metropolitan Washington Council of Governments together with the Washington Suburban Sanitary Commission (WSSC), Fairfax Water, and Washington Aqueduct, conducted a regional study to monitor for select pharmaceuticals, personal care products, and other potential compounds in source and treated water (WSSC 2008). Twenty factors were analyzed and only two contaminants were detected in drinking water at less than one parts per billion levels (atrazine and carbamazepine). Atrazine and carbamazepine, as well as sulfamethoxazole, were also detected in source water. In 2009 and 2010, the New York City Department of Environmental Protection conducted studies to characterize the occurrence of PPCPs, including hormones, as well as the surfactant PFOS in source water of the New York City water supply (NYC DEP 2010, 2011). Samples were collected quarterly from the Catskill, Delaware, and Croton untreated source waters. Analyses were done for 78 analytes in 2009 and 72 in 2010. In 2009, 16 compounds were detected in at least one sampling event. The most frequently detected compounds, in at least three of the four sampling periods, were butalbital, caffeine, carbamazepine, cis-testosterone, cotinine, diazepam, gemfibrozil, sulfamethoxazole, and PFOS. In 2010, 14 compounds were detected in at least one sampling event. The most frequently detected compounds, in at least three of the four sampling periods, were butalbital, caffeine, carbamazepine, cotinine, DEET, and sulfamethoxazole. Five compounds detected in 2009 were not detected in 2010 (diazepam,

182 ©2015 Water Research Foundation. ALL RIGHTS RESERVED. Table 7.1 Examples of utilities that have conducted water monitoring for PPCPs and unregulated EDCs Utility information Nature of monitoring for PPCPs/EDCs Monitoring results

Huntsville Utilities Monitoring of PPCPs and EDCs in source water in 2012 PPCP monitoring: Huntsville, AL 2012 (reported in special report).  Number of compounds: 84 https://www.hsvutil.org/ac/wp-  Number of samples: NA Population Served: 219,168 content/uploads/2013/10/PharmaceuticalTesting2012.p  Analytical method: NA Source Type: Surface Water df  Detected: Cotinine, DEET, galaxolide, carbamazepine, perchlorate, gemfibrozil, General report link: https://www.hsvutil.org/hu- Routine monitoring of source water for unregulated meprobamate, primidone, theobromine, hub/publications/ contaminants (reported in annual Water Quality nicotine, sulfamethoxazole Reports). Results for 2011 reported here: https://www.hsvutil.org/ac/wp- 2011 unregulated contaminants monitoring content/uploads/2013/10/WQR2011.pdf (includes some EDC pesticides):  Number of compounds: 48  Number of samples: NA  Analytical method: NA  Detected: Bromodichloromethane, chloroform, dibromomethane

City of Phoenix Monitoring of water within city’s distribution system 2009-2010 UCMR2 monitoring: Phoenix, AZ and from WTPs for UCMR2 compounds from July  Number of compounds: 25 2009-summer 2010 and again UCMR3 compounds  Number of samples: 1,959 Population Served: 1,533,582 beginning in February 2013 (reported in annual Water  Analytical method: NA Source Type: Surface Water Quality Reports).  Analytical method: NA  No UCMR2 compounds were detected General report link: https://www.phoenix.gov/waterservices/waterqu 2013 UCMR3 monitoring: ality  Number of compounds: 27  Number of samples: NA  Detected: molybdenum, strontium, vanadium, chlorate, bromochloromethane, total chromium, chromium-6 (continued)

City of Scottsdale Monitoring in 2010 for UCMR2 compounds (reported 2010 UCMR2 monitoring: Scottsdale, AZ in 2013 Water Quality Report).  Number of compounds: 25  Number of samples: NA Population Served: 180,000 http://www.scottsdaleaz.gov/AssetFactory.aspx?did=4  Analytical method: NA Source Type: Surface Water 8316  Detected: NDMA

General report link: http://www.scottsdaleaz.gov/water/quality.asp

City of Tucson Monitoring in 2013 for UCMR3 compounds (reported 2013 UCMR3 monitoring: Tucson, AZ in 2013 Water Quality Report).  Number of compounds: 27  Number of samples: NA Population Served: 675,000 http://www.tucsonaz.gov/files/water/docs/2013_Annua  Analytical method: NA Source Type: Ground Water l_Water_Quality_Report.pdf  Detected: molybdenum, strontium, vanadium, chlorate, total chromium, General report link: chromium-6, 1,1-dichloroethane, 1,4- http://www.tucsonaz.gov/water/wqreport dioxane, chlorodifluoromethane, PFOS, PFHxS

South Logan County Water Monitoring in 2013 for UCMR2 compounds (reported 2013 UCMR2 monitoring: Booneville, AR in 2013 Drinking Water Quality Report).  Number of compounds: 25  Number of samples: NA Population Served: 1,420 http://slcpwf.com/CCR13_South_Logan_Co_851.pdf  Analytical method: NA Source Type: Purchased Surface Water  Detected: bromodichloromethane, chloroform General link: http://slcpwf.com/index.htm

(continued)

Beverly Hills-City Water Dept. Monitoring in 2012 for UCMR2 compounds (reported 2012 UCMR2 monitoring: Beverly Hills, CA in 2012 Consumer Confidence Report).  Number of compounds: 25  Number of samples: NA Population Served: 44,290 http://www.beverlyhills.org/living/utilities/waterservic  Analytical method: NA Source Type: Purchased Surface Water es/consumerconfidencereports/  Detected: NDMA

General report link: http://www.beverlyhills.org/living/utilities/water services/ Colorado Springs Utilities Monitoring in 2008 for UCMR2 compounds (reported 2010 UCMR2 monitoring: Colorado Springs, CO in 2013 Water Quality Report).  Number of compounds: 25 https://www.csu.org/pages/water-quality-r.aspx  Number of samples: NA Population Served: 411,989  Analytical method: NA Source Type: Surface Water  Detected: NDMA

General report link: https://www.csu.org/pages/water-quality-r.aspx

District of Columbia Water and Sewer Authority Monitoring of water entering DC Water’s Distribution 2013 monitoring for “Contaminants without Washington, DC system for “Contaminants without Primary MCLs or MCLs or treatment techniques” that are potential Treatment Techniques” (reported in 2013 Water EDCs: Population Served: 581,530 Quality Report).  Number of compounds (EDCs): 3 Source Type: Purchased Surface Water  Number of samples: NA Fact sheet “Your Questions Answered:  Analytical method: NA General report link: Pharmaceuticals and Emerging Contaminants”  Detected: NDMA, NDBA, perchlorate http://www.dcwater.com/waterquality/test_result DC Water's Q&A on Pharmaceuticals and Emerging s.cfm Contaminants in Drinking Water (PDF 232 kb) No data for PPCPs summarized on website. indicates that “The Washington Aqueduct, responsible for treating the water, has participated in multiple studies to understand pharmaceuticals and emerging contaminants in water.” For example, they participated in the AwwaRF 3085 study.

(continued)

Washington Aqueduct Monitoring of source and treated drinking water for 2008 PPCP and EDC monitoring: Washington, DC PPCPs and EDCs in 2008, as part of a regional effort  Number of compounds: NA with Fairfax Water and Washington Suburban Sanitary  Number of samples: 5 total source water Population Served: 581,530 Commission (see WSSC). locations (2 Washington Aqueduct locations) Source Type: Surface Water and 6 total treated water locations (2 Monitoring of raw and finished water for EDCs in Washington Aqueduct locations). General report link: 2012 (reported in Annual Report of Water Analysis  Analytical method: NA http://www.nab.usace.army.mil/Missions/Washi 2012)  Detected at Washington Aqueduct locations: ngtonAqueduct/WaterQuality.aspx http://www.nab.usace.army.mil/Portals/63/docs/Washi Potomac River samples: Atrazine, ngton_Aqueduct/2012_Annual_Water_Quality_Report Carbamazepine, Sulfamethoxazole .pdf Treated water samples (from Potomac Plants): Atrazine, Carbamazepine

2012 monitoring:  Number of compounds: 7 haloacetic acids, 5 trihalomethanes, 52 volatile organic compounds, 8 oxygenates, 110 synthetic organic compounds (including pesticides), 6 nitrosamines  Number of samples: 2 finished water locations sampled at least quarterly  Analytical method: NA  Detected: NDMA; no synthetic organic compounds detected

(continued)

City of Chicago Department of Water Monitoring of source and drinking water from 2009- 2009-2011 PPCP and EDC monitoring: Management (CDWM) 2011 for PPCPs and EDCs, in the City of Chicago  Number of compounds: 147 Chicago, IL Emerging Contaminant Study.  Number of samples: 6 locations (4 source, 2 https://www.cityofchicago.org/city/en/depts/water/sup finished) Population Served: NA p_info/water_quality_resultsandreports/city_of_chica  Analytical method: NA; Three laboratories, to Source Type: Surface Water go_emergincontaminantstudy.html determine inter-laboratory variability  Detected: 34 compounds General report link:  16 compounds with low frequency (<10%) http://www.cityofchicago.org/city/en/depts/water  8 compounds with medium frequency (11- .html 30%)  10 compounds with high frequency (31- 100%)  Compounds with frequency of detection 61-100%: atrazine, DEA, DACT, DIA, cotinine, PFOS, and simazine City of Chicago and four other communities Monitoring of source and drinking water from 2008 2008 PPCP monitoring: (Elgin, Aurora, Rock Island, East St. Louis) for PPCPs  Number of compounds: 56 IL http://www.epa.state.il.us/water/pharmaceuticals-in-  Number of samples: 4 communities drinking-water.pdf  Analytical method: Underwriters Laboratories Source Type: Surface Water certified methods L220 and L221 for Pharmaceutically Active Compounds  Detected: 16 compounds  Source water: caffeine, carbamazepine, cotinine, DEET, diltiazem, fluoxetine, lincomycin, monensin, nicotine, paraxanthine, total sulfa, Sulfadimethoxine, sulfamethoxazole, trimethoprim, gemfibrozil, naproxen  Finished water: caffeine, carbamazepine, cotinine, DEET, diltiazem, fluoxetine, lincomycin, monensin, nicotine, paraxanthine, total sulfa, Sulfadimethoxine, sulfamethoxazole, gemfibrozil, naproxen (continued)

Cedar Rapids Utilities- Water Monitoring of source water from 2009-2010 for 2010 UCMR2 monitoring of source water: Cedar Rapids, IA UCMR2 nitrosamine compounds (reported in 2012  Number of compounds: 6 Water Quality Report)  Number of samples: 4 Source Type: Surface and Ground Water  Analytical method: NA http://www.cedar-rapids.org/resident-  Detected: NDMA General report link: http://www.cedar- resources/utilities/water/Water%20Quality/Documents/ rapids.org/resident- 2012%20Cedar%20Rapids%20Water%20Quality%20 resources/utilities/water/water%20quality/pages/ Report.pdf default.aspx Washington Suburban Sanitary Commission Monitoring of source and treated drinking water for 2008 PPCP monitoring: (WSSC) PPCPs in 2008, as part of a regional effort with Fairfax  Number of compounds: NA Laurel, MD Water and Washington Aqueduct.  Number of samples: 5 total source water http://www.wsscwater.com/file/Communications/FAQ locations (1 WSSC location) and 6 total General report link: Pharmaceuticals_inDrinkingWater.pdf treated water locations (2 WSSC locations). http://www.wsscwater.com/home/jsp/content/wa Monitoring quarterly samples between July 2013 and  Analytical method: NA ter-quality.faces April 2014 for UCMR3 compounds.  Detected at WSSC locations: http://www.wsscwater.com/file/EngAndConst/Environ Patuxent River sample: atrazine, mental/Webpage%20- carbamazepine %20Results%20of%20Detected%20Contaminants%20 Treated water samples (from Potomac and as%20of%20Jan%202014.pdf Patuxent Plants): atrazine, carbamazepine

UCMR3 monitoring (as of January 2014):  Number of compounds: 28  Number of samples: 6 locations (2 source, 4 tap)  Analytical method: NA  Detected: strontium, vanadium, chlorate, total chromium, chromium-6 Massachusetts Water Resources Authority Monitoring of source and treated drinking water for 2008 PPCP and EDC monitoring: (MWRA) PPCPs and EDCs in 2008  Number of compounds: 31 Boston, MA http://www.mwra.com/01news/2008/042708nopharm.h  Number of samples: NA tm  Analytical method: NA General report link:  Detected: tris(2-butoxyethyl) phosphate http://www.mwra.com/04water/html/wat.htm

(continued)

City of Ann Arbor Monitoring in 2004-2005 of source water, drinking 2004 PPCP and EDC monitoring: Ann Arbor, MI water, raw sewage, and treated wastewater for PPCPs  Number of compounds: 22 and EDCs (reported in special reports).  Number of samples: 4 locations Population Served: 125,000 http://www.a2gov.org/departments/water- (surface/source water, drinking water, Source Type: Surface and Ground Water treatment/Documents/Archive/PPCP_Study_November WWTP influent, WWTP effluent) _2004.pdf  Analytical method: LC/MS/MS and GC/MS General report link: http://www.a2gov.org/departments/water-  Detected in drinking water: cholesterol, http://www.a2gov.org/departments/watertreatment/Documents/Archive/PPCP_Study_Septembe ibuprofen, sitosterol, stigmasterol treatment/Pages/default.aspx r_2006.pdf 2005 PPCP and EDC monitoring: Monitoring in 2008 of reservoir samples for EDCs  Number of compounds: 22 Water Treatment Plant Laboratory Report. Reservoir  Number of samples: 4 locations water samples were analyzed for eight potential EDCs. (surface/source water, drinking water, http://www.a2gov.org/departments/water- WWTP influent, WWTP effluent) treatment/Documents/Archive/08lab%20rptEndocrine  Analytical method: LC/MS/MS and GC/MS %20Disruptors_UL.pdf  Detected in drinking water: 17α- ethinylestradiol, 17β-estradiol, caffeine, carbamazepine, cholesterol, coprostanol, estriol, estrone, ibuprofen, propranolol, tylosin

2008 monitoring for EDCs:  Number of compounds: 8  Number of samples: 1  Analytical method: L200 for Semi-volatiles  Detected: none (continued)

Table 7.1 (Continued) Utility information Nature of monitoring for PPCPs/EDCs Monitoring results

New York City Department of Environmental Monitoring in 2009 and 2010 for PPCPs and EDCs in 2009 PPCP and EDC monitoring: Protection source water of the New York City water supply  Number of compounds: 78 New York, NY (reported in special reports).  Number of samples: 3 locations quarterly http://www.nyc.gov/html/dep/pdf/quality/nyc_dep_200  Analytical method: HPLC and LC/MS/MS Source Type: Surface Water 9_ppcp_report.pdf  Detected: 16 compounds in at least one http://www.nyc.gov/html/dep/pdf/quality/nyc_dep_201 event. Compounds detected in at least 3 of 4 General report link: 0_ppcpreport.pdf periods: butalbital, caffeine, carbamazepine, http://www.nyc.gov/html/dep/html/drinking_wat cis-testosterone, cotinine, diazepam, er/index.shtml gemfibrozil, sulfamethoxazole, and PFOS

2010 PPCP and EDC monitoring:  Number of compounds: 72  Number of samples: 3 locations quarterly  Analytical method: HPLC and LC/MS/MS  Detected: 14 compounds in at least one event. Compounds detected in at least 3 of 4 periods: butalbital, caffeine, carbamazepine, cotinine, DEET, and sulfamethoxazole (continued)

Table 7.1 (Continued) Utility information Nature of monitoring for PPCPs/EDCs Monitoring results

Cincinnati Public Water System Monitoring in 2013 for UCMR3 compounds (reported 2013 UCMR3 monitoring: Cincinnati, OH in 2103 Water Quality Report).  Number of compounds: 12 http://www.cincinnati-  Number of samples: NA Population Served: 1.1 million oh.gov/water/linkservid/8E6AB2AE-C445-C413-  Analytical method: NA Source Type: Surface Water AE0FD65F34EA21CB/showMeta/0/  Detected: molybdenum, strontium, vanadium, chlorate, total chromium, General report link: Memo to City Council regarding 2008 Associated chromium-6, 1,4-dioxane http://www.cincinnati-oh.gov/water/ Press story: “Pharmaceuticals Found in Drinking Water” indicates that they tested for pharmaceuticals in 2008 PPCP study: the drinking and source water (Ohio River).  Number of compounds: NA http://city-egov.cincinnati-  Number of samples: NA oh.gov/Webtop/ws/fyi/public/fyi_docs/Blob/2237.pdf;j  Analytical method: NA sessionid=4313B3C46A2C2B07BD9C74EF339D326B  Detected: ?rpp=-10&m=1&w=doc_no%3D'1837'  Drinking water –trace amounts (ppt) of

caffeine, but “has not found pharmaceuticals in their finished or drinking water.”  Source water- trace amounts (ppt) of gemfibrozil, ibuprofen, sulfamethoxazole, and ethinyl estradiol

Portland Water Bureau Monitoring in 2012 for unregulated contaminants from 2012 unregulated contaminants monitoring: Portland, OR entry points to distribution system (reported in 2013  Number of compounds: NA Drinking Water Quality Report).  Number of samples: NA Population Served: 930,000 http://www.portlandoregon.gov/water/article/244813  Analytical method: NA Source Type: Surface Water  Detected: nickel, sodium, vanadium

General report link: http://www.portlandoregon.gov/water/ (continued)

Table 7.1 (Continued) Utility information Nature of monitoring for PPCPs/EDCs Monitoring results

Fairfax Water Monitoring for 30 PPCPs and EDCs in source and 2008-2013 PPCP and EDC monitoring: Fairfax, VA treated waters quarterly since 2008.  Number of compounds: 30 http://www.fairfaxwater.org/current/monitoring_progra  Number of samples: 2 source and 2 drinking Source Type: Surface Water m.htm water locations, quarterly  Analytical method: NA General report link:  Detected: Compounds detected in treated http://www.fcwa.org/ water include: 2,4-D, atrazine, bisphenol A, carbamazepine, DEET, DEHP, diuron, hexavalent chromium, monensin, naproxen, perchlorate, simazine, sulfamethoxazole, TCEP

City of Milwaukee Monitoring of finished water in 2013 for PPCPs and 2013 monitoring for PPCPs and EDCs: Milwaukee Water Works EDCs (as reported in Finished Water Undetected  Number of compounds: NA Milwaukee, WI Chemical Contaminant List)  Number of samples: NA http://milwaukee.gov/ImageLibrary/Groups/WaterWor  Analytical method: NA General report link: ks/files/2013TreatedWaterListofUndetect.pdf  Not detected include estrogens and other http://city.milwaukee.gov/water/about/WaterQua Per website, the Milwaukee Water Works was one of hormones , fluoropolymers, nitrosamines, lity.htm the first utilities in the United States to begin testing PPCPs, phenolic EDCs source and treated drinking water for EDCs (2004) and for PPCPs (2005). www.milwaukee.gov/water

lasalocid, nicotine, estrone, and progesterone) and one compound detected in 2009 was not analyzed in 2010 (cis-testosterone, though testosterone was not detected in 2010). One compound detected in 2010 was not detected in 2009 (diltiazem), and two compounds detected in 2010 were not analyzed for in 2009 (meprobamate and primidone). The City of Chicago Department of Water Management tested for emerging contaminants, including EDCs, PPCPs, and hexavalent chromium, from 2009 to 2011 (CDWM 2011). Sampling sites included offshore crib intakes and shore intakes at Lake Michigan, finished water outlets, and drinking water samples. A total of 147 unique PPCP and EDC compounds were included in the study. Thirty-four compounds were detected above the laboratory reporting limits in at least one sample over the course of the study. Compounds with a frequency of detection ranging from 31 to 60% were DEET, nicotine, and sulfamethoxazole. Compounds with a frequency of detection ranging from 61 to 100% were the herbicide/ herbicide degradates atrazine, DEA, DACT, DIA, and simazine; cotinine; and PFOS. Since 2008, Fairfax Water of Fairfax, Virginia has conducted quarterly monitoring for PPCPs and EDCs in source and treated waters. Source water undergoes treatment by granular activated carbon and ozonation. PPCPs detected in treated water include carbamazepine, monensin, naproxen, and sulfamethoxazole. EDCs that have been detected in drinking water include 2,4-D, bisphenol A, DEET, DEHP, diuron, simazine, and TCEP. Fairfax Water provides comprehensive information on the monitoring program on their website, including the results of quarterly monitoring for source and drinking water for PPCPs and EDCs. To select the 30 compounds included in the water monitoring program, they state, “Fairfax Water carefully considered the most prudent use of its resources in researching a suitable list of compounds to test in both source and treated waters. We looked at influences in the Potomac and Occoquan River Watersheds (industrial, agricultural uses, etc.) to determine which compounds are most likely to be present. We then looked at our treatment process to determine which compounds would not be readily removed through treatment. Finally, we looked at which compounds could be measured in water” (Fairfax Water 2008 – 2013).

DESIGN OF MONITORING PROGRAMS FOR PPCPS AND EDCS IN WATER

For those utilities that choose to implement programs for PPCPs and EDCs in source and drinking water, several important questions should be considered in designing monitoring programs:

 What compounds should be monitored?  How often should monitoring be conducted?  What analytical methods and detection limits are appropriate?  What are some problems/ challenges that can arise in the collection and analysis of samples for PPCPs and EDCs?  How can results be communicated? What potential negative outcomes could arise from communication of this information, and are we prepared to address these issues?

Some factors to consider in answering these questions are discussed below.

Selection of Compounds to Monitor

Criteria to consider when selecting compounds for monitoring include:

 Evidence of past detection in source or treated drinking water in the United States, and frequency and levels of occurrence, or evidence of detection in adjacent water sources  Rate of use by the population (e.g., for prescription drugs) or evidence of use in watershed  General watershed land use  Potential health hazards, particularly to sensitive populations (e.g., the very young, very old, pregnant women, immune compromised)  Potential mobility and/or persistence in water systems  Likelihood of removal in water treatment processes  Availability of analytical methods for the compound  Nature and intensity of public/media interest and/or scientific concern

These are discussed below.

Past Occurrence

Tables 3.6, 3.7, and 3.8 in Chapter 3 showed the most frequently detected PPCPs in drinking and source water, and Table 3.9 and 3.10 showed the most frequently detected EDCs in drinking and source water. Compounds that are detected most frequently warrant consideration for selection. Compounds that have never been detected in these media, assuming that a sufficient number of samples have been collected and the detection limits were sufficiently low, warrant less consideration for inclusion in the monitoring program. Table A.2 (Appendix A) shows PPCPs that have never been detected in drinking water, DWTP influent water, or surface water, based on the occurrence data we compiled.

Rate of Use or Evidence of Use in Watershed

Utilities should continue to reevaluate their monitoring programs over time to assess whether “new” compounds warrant inclusion in the program. Insurance agencies and others provide lists of the most frequently prescribed drugs based on volume, that also include generic drugs (e.g., for example, a regional list provided by BlueCross BlueShield of Texas (2014)).

Watershed Land Use

The following land use categories could be potentially significant sources of PPCPs and EDCs to source water: agriculture (pesticides, fertilizers), animal feedlots (antibiotics, hormones, antibacterials, pesticides), healthcare facilities (pharmaceuticals), industrial facilities (surfactants, nonylphenols, phthalates, nitrosamines, PFCs), and urban development (PPCPs, hormones, surfactants, phthalates).

Potential Health Significance

Table 4.5, 4.7, and 4.8 highlights the PPCPs and Table 4.6 highlights the EDCs that have been detected in drinking water that are of greatest potential significance with regard to health risk, based on comparison of maximum detected concentrations reported in the reviewed literature to DWELs. Note that the ADIs upon which the DWELs are based take into account concerns for potentially sensitive subpopulations, including pregnant women and children, since they are based on toxicological measurements that address the most sensitive effects (e.g., on reproduction or fetal or child development, or carcinogenicity). The ADIs also incorporate several uncertainty factors such that they are well below levels that have been associated with adverse health effects, even in sensitive populations. The only PPCP that has been detected in drinking water at a frequency of 5% or greater and for which it is estimated that a person must consume fewer than 50 8-ounce glasses of water to get a dose equal to the ADI (at the maximum detected concentration) is the anticonvulsant carbamazepine. The EDCs of greatest potential significance per the same criteria are cis- testosterone, TCPP, atrazine, cyanazine, perchlorate, TCEP, 17α-ethynylestradiol, DEHP, and simazine. The hormones progesterone, 17β-estradiol, and estrone may also warrant consideration because of their potential health risks at low exposure levels and the potential for mixture effects when combined with other estrogenic hormones. Lack of historical detection in drinking water does not necessarily indicate that a compound should not be considered for monitoring in drinking water: it may never have been analyzed or may have been analyzed infrequently, its limit of detection may have been high, or land use changes may have occurred. Table 7.2 lists PPCPs that were either never analyzed in drinking water or were analyzed infrequently (less than 10 total samples), based on the data we evaluated, but that were detected in DWTP influent and/or surface water, and compares maximum detected concentrations in DWTP influent or surface water to the DWELs. As shown, several substances were detected in surface water at relatively high levels (>10% of the DWEL), but were never or were infrequently analyzed in drinking water. These substances may warrant further consideration for monitoring in drinking water.

Table 7.2 Comparison of maximum detected concentrations of PPCPs that were detected in DWTP influent or surface water, but not in drinking water, to DWELs (based on data gathered in this evaluation)* DWTP influent Surface water Max Max conc. Freq. conc. Freq. DWEL Compound Group (µg/L) Det (µg/L) Det (µg/L) Diphenhydramine Antihistamine NA 3/12 616.2 12/201 4.2 Clindamycin Antibiotic NA NA 1.3 3/3 88 Methamphetamine Illicit drug NA NA 62.6 6/9 7.7 Fenoprofen Analgesic NA NA 142 28/78 33 Anhydro- Antibiotic NA NA 1,210 5/22 2.8 erythromycin Cyclophosphamide Cancer drug NA NA 5 3/15 0.026 Clarithromycin Antibiotic NA NA 9 4/22 84 Indomethacin Analgesic NA NA 18 25/159 0.027 Ofloxacin Antibiotic NA 0/12 270 6/41 67 Metformin Antidiabetic NA NA 140 5/145 17 Thiabendazole Antiparasitic NA 0/12 27.3 3/119 310 Ranitidine Antacid NA 0/12 27 5/296 46 *Maximum concentrations > 10% of the DWEL are boxed NA – data not available for given water type

Table A.1 (Appendix A) lists all the PPCPs that were never detected in drinking water, based on the data collected in this evaluation, but that were detected in either DWTP influent or surface water, and Table A.2 lists PPCPs that were analyzed for but never detected in any of those three media. Table A.3 lists EDCs that were analyzed for but not detected in drinking water.

Potential Mobility and/or Persistence

Several PPCPs and natural and synthetic EDCs are acknowledged to be persistent in wastewaters, as demonstrated by their identification in EPA’s Guidelines for Water Reuse (EPA 2012o) as substances typically detected in reclaimed water (Table 7.3). These compounds may warrant consideration for inclusion in monitoring programs.

Table 7.3 PPCPs and natural and synthetic EDCs identified as typically detected in reclaimed water Group Examples Industrial chemicals 1,4-Dioxane, pefluorooctanoic acid, MTBE, tetrachloroethane Pesticides, biocides, and Atrazine, lindane, diuron, fipronil herbicides Natural chemicals Hormones (17β-estradiol), phytoestrogens, geosmin, 2-methylisoborneol Pharmaceuticals and Antibacterials (sulfamethoxazole), analgesics (acetaminophen, metabolites ibuprofen), betablockers (atenolol), antiepileptics (phenytoin, carbamazepine), veterinary and human antibiotics (azithromycin), oral contraceptives (ethinyl estradiol) Personal care products Triclosan, sunscreen ingredients, fragrances, pigments Household chemicals and Sucralose, bisphenol A, dibutyl phthalate, alkylphenol polyethoxylates, food additives flame retardants (perfluorooctanoic acid, perfluorooctane sulfonate) Transformation products NDMA, halogenic acetic acids, and trihalomethanes Source: data from EPA 2012o

Physical/ chemical properties of compounds can also be considered when attempting to predict the likelihood that a compound will be detected. Properties predictive of resistance to treatment and potential to migrate include the following:

 Water solubility. Water soluble compounds are assumed to have a greater potential for migration in the environment. However, water solubility in and of itself has not been shown to be a good indicator of potential occurrence at levels of concern as data indicate the occurrence of some chemicals with low water solubility. Therefore, water solubility can be considered as only one criterion used in combination with others to select between compounds more or less likely to be present.  Acid dissociation constant (pKa). The partitioning behavior of an organic compound depends significantly on whether it is in an ionized or neutral state. The acid dissociation constant (Ka) describes a compound’s tendency to donate a proton to solution and thus to be charged or neutral at a given pH. The negative logarithm (pKa) is provided to facilitate comparison to pH; the ionized and neutral forms of an organic acid are in equal concentrations when pKa = pH. The neutral form of an organic acid is expected to sorb to particulate matter to a higher degree than the ionized form; chemicals that sorb to particulates tend to be removed to a greater degree than those that remain in solution during wastewater treatment processes. Thus, if an organic compound is in its ionized form, it can be expected to be more likely to remain in water (Reible 1999). For example, if a compound has a pKa well below the range of pH in natural waters (range about 6.5 to 8.5), it can be expected to be completely dissociated and to be less likely to sorb to particulate matter (and more likely to remain in water). Compounds with a pKa well above the pH for natural waters (i.e., greater than 9.5) can be considered for exclusion as a compound of interest, in combination with other criteria.  Octanol water partition coefficient (log KOW). Log KOW values range from -3 to 7, with higher values indicating a greater likelihood that the contaminant will be removed from solution via adsorption to existing particles in the aquifer or via treatment with activated carbon (Lyman et al. 1990). Organic compounds with log KOW > 3 or 3.5 are expected to be removed efficiently with activated carbon, for example (Snyder et al. 2008).

Likelihood of Removal in Water Treatment Processes

Chapter 6 discusses the relative removal efficiency of different classes of PPCPs and EDCs by different advanced treatment technologies. Those compounds that are likely to be efficiently removed by the treatment processes in place at a utility can be considered for exclusion from the monitoring program. However, including these compounds in monitoring of source and treated water can provide information on the relative effectiveness of treatment.

Availability of Sampling and Analytical Methods for the Compound

EPA provides guidance for collection of drinking water samples (EPA 2005c). Among the recommendations are developing a Sampling Plan before initiating sampling and, if collecting samples for organics from drinking water taps, opening the faucet and thoroughly flushing (up to 2-3 minutes) before collecting the sample. For collection of UCMR3 samples, EPA requires the collection of field blanks, especially for compounds considered to be susceptible to contamination from outside sources—in general, UCMR analytical methods are not in common use and are very sensitive, such that greater validation of results may be required (EPA 2009e). Specifically, EPA requires the collection of field blanks for all methods with the exception of chlorate, hexavalent chromium and 1,4-dioxane. If a target analyte is found in a field sample at a reportable level, a field blank that was collected with this sample must be analyzed. If the amount of analyte found in the field blank is at a concentration greater than 1/3 the minimum reporting level, the testing results for the field sample are invalid and a new sample must be collected. Reports published by the New York City Department of Environmental Protection describing sampling of source water for PPCPs provide insights into design of sampling programs for measurement of PPCPs in water, including collection of field and trip blanks and duplicates (NYC DEP 2010, 2011). Validated analytical methods are not available for all PPCPs or EDCs. Table 7.4 lists some EPA analytical methods for contaminants of emerging concern in drinking water, including phthalates, pesticides, PBDEs, PPCPs, and steroids and hormones. These methods have been peer-reviewed and tested in a single lab (EPA 2012k). Table 7.5 lists the PPCPs included in Method 1694, and Table 7.6 lists the steroids and hormones included in Method 1698.

Table 7.4 EPA analytical methods for Contaminants of Emerging Concern in drinking water EPA Method Compounds analyzed Instrumentation 506 Phthalates GC 525.2 Phthalates, pesticides GC/MS 1614 PBDEs HRGC/HRMS 1694 PPCPs HPLC/MS/MS 1698 Steroids and hormones HRGC/HRMS 1699 Pesticides HRGC/HRMS Source: data from EPA 2012k HPLC − high performance liquid chromatography; HRGC − high resolution gas chromatography; MS − mass spectroscopy

Table 7.5 PPCPs analyzed by EPA Method 1694 PPCP CAS # Classification Ibuprofen 15687-27-1 analgesic Cimetidine 51481-61-9 anti-acid reflux Ranitidine 66357-35-5 anti-acid reflux Albuterol 18559-94-9 antiasthmatic Warfarin 81-81-2 anticoagulant Carbamazepine 298-46-4 anticonvulsant Metformin 657-24-9 anti-diabetic drug Miconazole 22916-47-8 antifungal agent Diphenhydramine 58-73-1 antihistamine Diltiazem 42399-41-7 antihypertensive Gemfibrozil 25812-30-0 antilidepemic Triclocarban 101-20-2 antimicrobial, disinfectant Triclosan 3380-34-5 antimicrobial, disinfectant Acetaminophen 103-90-2 antipyretic, analgesic 1,7-Dimethylxanthine 611-59-6 antispasmodic, caffeine metabolite Digoxin 20830-75-5 cardiac glycoside Cefotaxime 63527-52-6 cephalosporin antibiotic Anhydrochlortetracycline 13803-65-1 chlorotetracycline degradate Anhydrotetracycline 4496-85-9 chlorotetracycline degradate 4-Epianhydrochlortetracycline 158018-53-2 chlorotetracycline degradate 4-Epianhydrotetracycline 4465-65-0 chlorotetracycline degradate 4-Epichlortetracycline 14297-93-9 chlorotetracycline degradate Isochlortetracycline 514-53-4 chlorotetracycline degradate Sarafloxacin 98105-99-8 fluoroquinolone antibiotic Thiabendazole 148-79-8 fungicide and parasiticide Norgestimate 35189-28-7 hormonal contraceptives Digoxigenin 1672-46-4 immunohistochemical marker steroid Lincomycin 154-21-2 lincosamide antibiotic Azithromycin 83905-01-5 macrolide antibiotic Clarithromycin 81103-11-9 macrolide antibiotic Erythromycin 114-07-8 macrolide antibiotic (continued)

Table 7.5 (Continued) PPCP CAS # Classification Ormetoprim 6981-18-6 macrolide antibiotic Roxithromycin 80214-83-1 macrolide antibiotic Tylosin 1401-69-0 macrolide antibiotic Virginiamycin 11006-76-1 macrolide antibiotic Erythromycin anhydrate 59319-72-1 macrolide antibiotic Cotinine 486-56-6 nicotine metabolite Dehydronifedipine 67035-22-7 nifedipine metabolite Naproxen 22204-53-1 NSAID Codeine 76-57-3 opiate 4-Epioxytetracycline 14206-58-7 oxytetracycline degradate Trimethoprim 738-70-5 pyrimidine antibiotic Ciprofloxacin 85721-33-1 quinoline antibiotic Clinafloxacin 105956-97-6 quinoline antibiotic Enrofloxacin 93106-60-6 quinolone antibiotic Flumequine 42835-25-6 quinolone antibiotic Lomefloxacin 98079-51-7 quinoline antibiotic Norfloxacin 70458-96-7 quinoline antibiotic Ofloxacin 82419-36-1 quinoline antibiotic Oxolinic acid 14698-29-4 quinolone antibiotic Carbadox 6804 07 05 quinoxaline antibiotic Ampicillin 69-53-4 β-lactam antibiotics Cloxacillin 61-72-3 β-lactam antibiotics Oxacillin 66-79-5 β-lactam antibiotics Penicillin V 87-08-1 β-lactam antibiotics Penicillin G 61-33-6 β-lactam antibiotics Fluoxetine 54910-89-3 ssri antidepressant Caffeine 58-08-2 stimulant Sulfachloropyridazine 80-32-0 sulfonamide antibiotic Sulfadiazine 68-35-9 sulfonamide antibiotic Sulfadimethoxine 122-11-2 sulfonamide antibiotic Sulfamerazine 127-79-7 sulfonamide antibiotic Sulfamethazine 57-68-1 sulfonamide antibiotic Sulfamethoxazole 723-46-6 sulfonamide antibiotic Sulfanilamide 63-74-1 sulfonamide antibiotic Sulfathiazole 72-14-0 sulfonamide antibiotic Sulfamethizole 144-82-1 sulfonamide antibiotic Chlortetracycline 57-62-5 tetracycline antibiotic Demeclocycline 127-33-3 tetracycline antibiotic Doxycycline 564-25-0 tetracycline antibiotic Minocycline 10118-91-8 tetracycline antibiotic Oxytetracycline 79-57-2 tetracycline antibiotic Tetracycline 60-54-8 tetracycline antibiotic 4-Epitetracycline 23313-80-6 tetracycline degradate Source: data from EPA 2012k

Table 7.6 Steroids and hormones analyzed by EPA Method 1698 Steroid/Hormone CAS # Classification Androstenedione 63-05-8 anabolic agent Androsterone 53-41-8 hormone metabolite Equilenin 517-09-9 hormone replacement Equilin 474-86-2 hormone replacement 17a-Ethynyl Estradiol 57-63-6 ovulation inhibitor Desogestrel 54024-22-5 ovulation inhibitor Mestranol 72-33-3 ovulation inhibitor Norethindrone 68-22-4 ovulation inhibitor Norgestrel 6533-00-2 ovulation inhibitor Campesterol 474-62-4 phytosterol (plant sterol) beta-Sitosterol 83-46-5 phytosterol (plant sterol) Stigmasterol 83-48-7 phytosterol (plant sterol) Beta-Stigmastanol 83-45-4 phytosterol (plant sterol) 17a-Estradiol 57-91-0 sex hormone 17b-Estradiol 50-28-2 sex hormone Estriol 50-27-1 sex hormone Estrone 53-16-7 sex hormone Progesterone 57-83-0 sex hormone Testosterone 58-22-0 sex hormone 17a-Dihydroequilin 651-55-8 sterol Cholestanol 80-97-7 sterol Cholesterol 57-88-5 sterol Desmosterol 313-04-2 sterol Ergosterol 57-87-4 sterol b-Estradiol-3-benzoate 50-50-0 sterol Coprostanol 360-68-9 sterol Epi-Coprostanol 516-92-7 sterol Source: data from EPA 2012k

Water Research Foundation Project #4463, National Dialogue on Contaminants of Emerging Concern and Public Health (Deeb et al. 2014), noted that utilities interested in developing in-house analytical capabilities for CECs may wish to consider efforts made by other utilities or commercial laboratories to establish analytical methods with sufficient detection capabilities. These include an inter-laboratory comparison study with water utility and commercial laboratories to evaluate the analysis of EDCs and PPCPs at low ppt levels (Vanderford et al. 2012), as well as research efforts by the City of Calgary (Chen et al. 2006, Ohman et al. 2010).

Public/Media Interest

Stated interest in or concern about particular compounds or compound types by the public/media or the scientific community may be considered, particularly if certain substances are of local interest. For example, drugs or EDCs that have been very widely and frequently detected in water or wastewater systems and have been the subject of articles in the popular media can be considered for further analysis. Such EDCs as bisphenol A, the alkylphenols (nonylphenol, octylphenol), phthalates, and PFCs are widely addressed in the media, as are such

well known drugs as Valium (diazepam), Prozac (fluoxetine), Aleve (naproxen), and Advil (ibuprofen).

Determination of Sufficient Analytical Method Reporting Limits

When selecting analytical methods and appropriate reporting limits, an important consideration is that the method reporting limit is below regulatory criteria or health-risk based guidelines. Selecting reporting limits that are sufficiently low ensures that if a substance is not detected, one can be confident that it is not present at a level that poses a health risk. Note that in some cases, the levels of interest may be near, at, or below detection limits, which can lead to high standard deviations and sometimes questionable data. Therefore, results should be evaluated and reported carefully. Further, achieving low detection limits with sensitive methodologies may be expensive, and costs of analyses should be considered. Tables 4.3 and 4.4 listed the DWELs that were identified in this project for PPCPs and EDCs, respectively. Values less than 10 ng/L (0.010 µg/L) are predicted to pose the greatest potential health hazards at low concentrations, and may warrant particular consideration in the design of analytical programs to avoid contamination and to ensure that detection limits are sufficiently low. Note that these DWELs do not incorporate RSCs to account for other potential sources of exposure (see Chapter 4); if a RSCs are integrated into the DWEL calculations, adjusted concentrations might be 20% to 80% of the DWELs listed.

Motivations for Monitoring and Risk Communication

Three partnering utilities were queried to provide information on motivating factors for conducting monitoring for CECs in water. Full responses are presented in Appendix C. In summary, in response to the question, “What prompted you to conduct monitoring?” answers included to respond to community members’ inquiries regarding safety of the water and increasing media attention, to be proactive, to evaluate treatment performance, and as voluntary participation in State-sponsored studies. In response to the question, “How did you decide what to monitor for?” answers included based on experience from case studies in other jurisdictions, laboratory method reliability and detection limits, ecological and human health issues, recalcitrance to degredation, information from the scientific literature, changing regulatory requirements, and public perception. In response to the question, “How frequently do you conduct monitoring?” answers included one-time, quarterly, or “regularly.” In response to the question, “What are some of the advantages or disadvantages of a proactive approach to monitoring?” answers regarding advantages included building trust with stakeholders and the community and demonstrating the efficacy and reliability of treatment processes. Responses regarding disadvantages include costs especially if there is no regulatory requirement, monitoring is time-consuming, and it can be a challenge to communicate complex concepts without causing worry or appearing to make light of possible risks.

Relevant Water Research Foundation Projects

Past or present research projects funded by the Water Research Foundation addressing issues associated with monitoring of PPCPs and EDCs in water include:

 Project #2758: Removal of EDCs and Pharmaceuticals in Drinking and Reuse Treatment Processes (2007). This project developed an analytical method capable of trace detection and quantification of a diverse group of EDCs and pharmaceuticals in drinking water, and evaluated the effectiveness of different conventional and advanced water treatment processes.  Project #2776: Risk Communication for Emerging Contaminants (2004). The purpose of this project was to develop strategies and tools that would improve risk communication about these contaminants. With regard to the value of monitoring programs, they note that ongoing monitoring of emerging contaminants can give the utility greater lead time to initiate the appropriate type of risk communication approach and get out in front of potential misunderstandings and problems before they expand into larger problems. Important issues related to designing monitoring systems are noted, including a) designing systems with sufficient resolution to identify emerging contaminants that merit strategic responsiveness, b) obtaining resources to keep the systems active on a routine and substantive basis, c) developing criteria to interpret the data, d) sustaining positive relationships with key media, and e) placing contaminants in a relevant perspective.  Project # 4167: Evaluation of Analytical Methods for EDCs and PPCPs via Inter- Laboratory Comparison (2012). This project evaluated existing methods for the analysis of CECs at low ng/L detection levels in water and provided analytical guidelines for future work.  Project #4169: Water Utility Tool for Responding to Emerging Contaminant Issues (2012). This Web tool will help drinking water utilities to address emerging contaminant challenges, especially EDCs and PPCPs. The tool has two major features: (1) an array of worksheets for evaluating an emerging contaminant with currently available resources, and (2) an example of a structured process or framework for considering emerging contaminant issues, including monitoring. The framework portion was created to be easily visualized and sufficiently broad for general use while referencing more specific information.  Project #4260: “EDC/PPCP Benchmarking and Monitoring for Drinking Water Utilities” (in progress). The project will develop, justify, and document statistical tools and protocols that water utilities can use to design and implement monitoring programs for EDCs and PPCPs within a watershed. The project will demonstrate the applicability of these tools and protocols by designing and executing a sampling program on a minimum of two watersheds. In addition to the final report, a guidance document will be produced to advise utilities on developing robust EDC/PPCP monitoring programs for their watersheds, including target analyte lists, analytical methods, and quality assurance metrics.  Project 4261: The EDC Network for Water Utilities (2014). This project produced The EDC Network for Water Utilities, an online network to promote collaboration among water utilities and improve utility responses to challenges posed by EDCs and PPCPs. The EDC Network provides a secure Website resource for utilities to share best practices, documents, other tools, and materials related to EDCs and PPCPs. The EDC Network is open only to utility professionals.  Project #4269: “Detection and Quantification of EDCs/PPCPs in Source Waters Containing Dissolved and Colloidal Organic Matter” (in progress). This project will assess the influence of dissolved and colloidal organic matter (DOM and COM) on standard practices of EDC/PPCP extraction from water and subsequent analysis using

liquid and gas chromatography tandem mass spectrometry. It will determine the effects of various watershed DOM/COM sources and constituent fractions on EDC/PPCP detection and quantification.  Project #4386: “Decision Support Program for Reducing EDCs and PPCPs in Drinking Water” (in progress). This project will develop an electronic decision support system to guide water and wastewater utilities in determining the most cost effective measures for reducing consumer exposure to EDCs and PPCPs in drinking water.  Project #4463: National Dialogue on Contaminants of Emerging Concern and Public Health (2014). To enhance communication and dialogue about the potential human health risks of CECs in drinking water among water utilities, public health agencies, researchers, and other organizations, the Water Research Foundation hosted an inter - disciplinary workshop that was attended by representatives from each of these groups. A series of overview papers was developed addressing Risk Communication about CECs, Regulation of CECs in Drinking Water, Public Health Research on CECs, Medical Practitioners and CECs, Water Utility Activities Related to CECs, and Water Quality Research on CECs.

APPROACHES TO COMMUNICATING PPCP AND EDC WATER MONITORING RESULTS

Examples of Utility Risk Communication on PPCPs and EDCs in Water

Drinking water utilities are required to inform consumers about drinking water contaminants that are detected in compliance samples from their distribution systems. This information is usually included in the annual Consumer Confidence Report, commonly known as a Water Quality Report (EPA 2010c). In addition, some utilities have published communication materials addressing PPCPs or EDCs in water, either on their websites or in other publically available documents. Examples of frequently asked questions (FAQs) about monitoring and PPCPs and EDCs in water presented by water utilities on their websites include the following:

 What is the source of these chemicals in our water supplies?  What’s still in the water after treatment?  Are these chemicals in our drinking water?  How did you select the suite of chemicals that you are testing for? Does that list of chemicals to be monitored provide a fair assessment of potential risks?  Will you consider risks to both human health and ecological health?  How will you assess risks that take into account everyone? ADIs and other thresholds are not always set based on the most vulnerable populations.  How will you assess risks from combinations of chemicals and/or cumulative effects of chemicals?  What do the results mean?  What will you do if the study shows there are risks to infiltrating reclaimed water?  Why are you spending all this money on monitoring for unregulated compounds?  Is there value in generating repeated non-detect results?  How do you use the monitoring data?

 Should endocrine disrupting compounds be treated differently when it comes to establishing screening levels?

Information that can be used to respond to each of these questions is provided in this Technical Report. Some examples of communication approaches implemented by water utilities to address issues associated with PPCPs and EDCs in water, and the information provided are described below. In addition, numerous other public health and environmental protection or other government entities (e.g., the Connecticut Department of Public Health Drinking Water Section, California Research Bureau of the California Sate Library, Delaware Health and Social Services, Missouri Department of Natural Resources, Washington Department of Ecology, Wisconsin Department of Health Services) have published fact sheets and other information pieces about PPCPs and EDCs in drinking water (CDPH DWS 2008, CRB 2014, DHSS 2008, MDNR 2011, WDOE no date, WDHS 2014).

City of Tempe, Arizona

City of Tempe’s website provides “Frequently Asked Questions About Tempe’s Water” including one addressing PPCPs, i.e., what is Tempe doing about pharmaceuticals in the water? (http://www.tempe.gov/city-hall/public-works/water/water-quality/faq-water).

Anaheim Public Utilities, California

The City of Anaheim Public Utilities’ website provides a discussion of “Pharmaceuticals and Water Supplies”, including a discussion of investigations by the Orange County Water District (OCWD) to monitor the presence of PPCPs in their groundwater supply, and a discussion of safe disposal practices for pharmaceuticals. (http://www.anaheim.net/article.asp?id=1197)

Contra Costa Water District (CCWD), Concord, California

The Contra Costa Water District website addresses several FAQs about PPCPs in water, including a discussion of the results of testing of CCWD water for PPCPs and EDCs in 2009 in partnership with the Water Research Foundation, the California Department of Public Health, and the California Department of Water Resources, a response to “How long have pharmaceuticals been in water?,” and a response to “Do pharmaceuticals pose a threat?” They indicate that the 2009 study found that treatment with ozone and granular activated carbon (CCWD's existing treatment process) removed greater than 90 percent of the compounds tested. (http://www.ccwater.com/waterquality/Endocrine.asp)

California Water Service Co. (Cal Water), San Jose, California

California Water Service’s Water Quality Reports include a section on “Pharmaceuticals” that refers to a recent study that detected trace amounts of pharmaceuticals in some water sources, and describes how much water a person would have to drink at levels detected to get a dose of ibuprofen equal to one over-the-counter headache tablet. A graphic is included describing a part per trillion as being equal to a square inch in 250 square miles, etc.

(https://www.calwater.com/waterquality/water-quality-reports/sln/).

Colorado Springs Utilities, Colorado

Colorado Springs Utilities provides a fact sheet on PPCPs in the environment and potential health effects (https://www.csu.org/CSUDocuments/ppcps.pdf).

Denver Water, Denver, Colorado

Denver Water’s website responds to FAQs about “Trace Pharmaceuticals,” including what they are, why they are being detected, what Denver Water has found (in a study conducted in 2005 with Colorado State University), if the water is safe, and how to properly dispose of pharmaceuticals: http://www.denverwater.org/WaterQuality/WaterSafety/TracePharmaceuticals/

District of Columbia Water and Sewer Authority, Washington, DC

The District of Columbia Water and Sewer Authority provides a fact sheet: “Your Questions Answered: Pharmaceuticals and Emerging Contaminants” and FAQs on pharmaceuticals and emerging contaminants: http://www.dcwater.com/waterquality/test_results.cfm, http://www.dcwater.com/waterquality/faqs.cfm.

Washington Suburban Sanitary Commission, Washington DC

WSSC presents a brochure about Pharmaceutical Drugs and Drinking Water, a FAQ sheet about emerging contaminants, and in the testing results from the 2008 regional study on PPCPs in source and drinking water with Fairfax Water and Washington Aqueduct, they report the number of glasses of water that would have to be consumed per day to exceed ADI levels (http://www.wsscwater.com/file/Communications/PharmaceuticalBrochure.pdf; http://www.wsscwater.com/file/Communications/EmergingContaminantsInfo.pdf ; http://www.mwcog.org/environment/water/watersupply/Regional_Results_of_testing_for_19_co mpounds.pdf).

City of Chicago Department of Water Management (CDWM), Illinois

The City of Chicago’s website describes the City of Chicago Emerging Contaminant Study, which included monitoring for PPCPs and EDCs (https://www.cityofchicago.org/city/en/depts/water/supp_info/water_quality_resultsandreports/ci ty_of_chicago_emergincontaminantstudy.html).

Massachusetts Water Resources Authority (MWRA), Boston, Massachusetts

The MWRA provides a fact sheet entitled “Pharmaceuticals and Drinking Water” describing the results of testing in 2008 for PPCPs and EDCs in the water supply and finished water, and providing information on appropriate disposal of pharmaceuticals (http://www.mwra.com/04water/html/pharmaceuticals.htm ).

City of Ann Arbor, Michigan

The City of Ann Arbor website provides a press release, “City of Ann Arbor Leader in Testing for Pharmaceuticals in Drinking Water” that includes a description of PPCPs in water. In its FAQs, it includes a discussion of the 2004-2005 monitoring of city drinking water for PPCPs and EDCs, and links to relevant reports (http://www.a2gov.org/departments/watertreatment/Documents/Archive/waterplant_pharmaceuticals_2008_03_12.pdf#search=pharmaceut icals; http://www.a2gov.org/departments/water-treatment/Pages/faq.aspx#ppcp).

City of Grand Rapids, Michigan

The City of Grand Rapids website provides a letter from the Filtration Plant Superintendent addressing PPCPs in the Water. Topics include testing conducted by Grand Rapids in 2005, an interpretation of the meaning of parts per billion and parts per trillion, and proper disposal of pharmaceuticals (http://grcity.us/enterprise-services/Water- System/Pages/PCPPs-In-The-Water.aspx).

City of Rochester, Minnesota

The City of Rochester 2012 Water Quality Report describes their Contaminants of Emerging Concern Program. Their website also provides a link to the “Rochester Water Primer: An Introduction to our Water Sources.” Per the introductory letter, “The Rochester Water Primer will help us understand the many ways we use and impact water—right here in Rochester, today and in the future.” The Wastewater Treatment System section includes one page briefly discussing PPCPs (http://www.rpu.org/environment/water-quality/; http://www.rpu.org/documents/2012_water_quality_report.pdf; http://www.rpu.org/documents/water_primer_2013.pdf).

New York City Department of Environmental Protection, New York

The NYC DEP website provides FAQs on PPCPs in water, and includes a description of how many glasses of water containing the maximum amount of caffeine detected in the study that one would have to drink to equal the amount of caffeine in one cup of coffee (http://www.nyc.gov/html/dep/html/drinking_water/ws_ppcp_faq.shtml).

Philadelphia Water Department, Philadelphia, Pennsylvania

In their 2014 Water Quality Report, the Philadelphia Water Department includes a section discussing “Pharmaceuticals in Drinking Water, including tips for safe disposal of medications. (http://www.phila.gov/water/wu/Water%20Quality%20Reports/2014WaterQuality.pdf)

Charleston Water System, South Carolina

Charleston Water System’s website includes general information on PPCPs in drinking water and proper disposal of prescription medicines (http://www.charlestonwater.com/225/Tap- Water-Your-Health).

Fairfax Water, Virginia

Fairfax Water’s website includes several materials related to PPCPs and EDCs in water, including a link to a graphic summarizing the results of their 2008-2013 occurrence monitoring studies for PPCPs and EDCs in source and drinking water, which includes an indication of the number of glasses of water one would need to drink per day at detected concentrations to reach the ADI (http://www.fairfaxwater.org/current/monitoring_program.htm).

Milwaukee Water Works, Milwaukee, Wisconsin

Milwaukee Water Works addresses a FAQ about PPCPs in drinking water, including a discussion of the results of tests of Milwaukee’s water system and the significance with regard to potential human health effects. (http://milwaukee.gov/water/customer/FAQs/qualityandhealth#13)

Other Water Utility Insights on Communication and Monitoring

Partnering utilities were queried to collect information on approaches taken to communicating about the potential presence of PPCPs and EDCs in water and presenting monitoring results. Full responses are presented in Appendix C. In response to the question, “How have you communicated monitoring results?” responses included that results are compiled and presented at public meetings, through fact sheets or short videos posted on the website and/or distributed to a mailing list, provided to the local media who publish an article, and reported in annual reports submitted to regulators and available to the public. In response to the question, “What risk communication approaches have you used?” responses included holding focus groups to understand the response to specific terminology (e.g., “medicines and household and personal care products” was preferred to PPCPs), using neutral language, using graphics to support complex concepts, providing concentration equivalency measures (e.g., a ppb is equal to one second in 32 years), and comparing water concentrations to ADIs and DWELs or to equivalent doses of pharmaceuticals.

Recommendations for Communication of Information about PPCPs and EDCs in Water

Numerous Water Research Foundation projects provide recommendations for communications regarding contaminants of emerging concern in source and drinking water, including PPCPs and EDCs. Some key recommendations from these projects are summarized in Table 7.7.

Table 7.7 Key recommendations from Water Research Foundation Projects for communications regarding CECs in source and drinking water Topic Recommendation Initiation of a When determining when to communicate about emerging communication contaminants, a utility must be able to determine if doing so is program strategic for its operations; i.e., are emerging contaminants likely to affect the credibility of leadership, utility operations, or other critical elements adversely? If so, to what degree can a risk communication strategy help minimize the impacts? (Parkin et al. 2004) Factors that are crucial in assessing the value of a risk communication effort are whether senior managers support the decision process, the company has a history of a positive and ongoing presence in the community, media activity has occurred, the public has raised concerns about a contaminant, and particular segments of the population are involved in the issues. (Parkin et al. 2004) Utilities can prepare to minimize harm when they communicate about CECs by building positive relationships in advance of a contaminant event with the community, key subpopulations and stakeholders, the media, key resources (health agencies and providers, faith leaders, etc.), and decision-makers. (Parkin et al. 2004) Risk communication and issues management can help protect a utility’s reputation and possibly its bottom line financially. (Mobley et al. 2010) Several utilities, including East Bay Municipal Utilities District and the San Francisco Public Utilities Commission, have developed decision frameworks to support decisions about how to address CECs. CEC activities to consider include sampling, analysis, data analysis, literature review, participation in applied research projects, risk assessment, and public outreach. (Deeb et al. 2014). Content of Doing too much with a single piece of communication can lead to communications “information overload” and undermine the overall effectiveness. (Lazo et al. 2004) When customers were asked what information about their water they would like to have, the two most common responses were “What’s in it?” and “Is it safe?” Other questions raised were: How and how often is it tested? Where does it come from? How is our drinking water processed? What affects the taste of our drinking water? Is there a change in water quality as it is transported to the home? How does local water quality compare to other locations? How effective are home filtration systems? (Lazo et al. 2004) (continued)

Table 7.7 (Continued) Topic Recommendation Customers evaluate reports on water issues using at least three criteria: informational content, readability, and appearance. Informational content was judged most important, with appearance second. (Lazo et al. 2004) Respondents said they want to know what type of contaminant was found, what the hazards were, what the utility planned to do about it, and what action they should take to protect themselves. (Parkin et al. 2004) With regard to communications, the public most values openness and reliability, while utilities want accurate science. (Mobley et al. 2010) Communications should emphasize the credibility of scientific resources relied upon, the accuracy of the message and any suggested action, and openness and fairness about how the message was constructed and delivered. (Mobley et al. 2010) In responding to CEC issues, it is important to continually incorporate new information and to investigate using sound science— monitor new developments and check any previous assumptions in light of new knowledge. (Daniel and Bywater 2012) Communicating about CECs is difficult because the science around it is evolving and uncertain which is disconcerting to consumers and the public, and the utility can expect diverse and contradictory input from consumers and stakeholders. (Mobley et al. 2010) Lessons learned regarding risk communication from six case studies highlighted in Halwey et al. (2009) include 1) pay attention to risk communication, 2) build trust, 3) poll public participation, 4) emphasize benefits, 5) adopt inclusive decision-making processes, and 6) recognize the role and implications of stigma. (Deeb et al. 2014) Some of the key messages (i.e., risk communication content) will be general and others will be specific to the organization or to a particular contaminant. For example, all water utilities could provide consumers with the same general information on CEC health effects, based on scientific research. Information about a water district’s water quality, watershed activities, and CEC monitoring/treatment programs is utility-specific. Some statements may apply generally to multiple CECs while other information may be contaminant- specific. (Deeb et al. 2014).

(continued)

Table 7.7 (Continued) Topic Recommendation Language Simplify technical and statistical language. (Lazo et al. 2004) Unqualified reassurances that the drinking water is “safe” deter people from reading further and detract from the purpose of the reports, which is to give consumers a full range of drinking water information so they can make informed choices and to interest them in efforts to improve water quality. (Lazo et al. 2004) Blanket statements such as “your tap water is safe” may be true for some members of the population but not certain vulnerable populations. (Lazo et al. 2004) Words such as “death”, “cancer”, and “toxic” create the perception of dread. (Lazo et al. 2004, Parkin et al. 2004, Rundblad et al. 2013) Respondents said an 11th grade reading level was clearest to understand, but older people and those with less than a high school education were more likely to choose the 5th grade level. (Parkin et al. 2004) Communication materials should be translated into languages prevalent in the community. (Mobley et al. 2010) Factors that affect Demographic factors that affect risk perception include risk perception socioeconomics, neighborhood/geography, race/culture/ethnicity, and gender (women feel more personally threatened by environmental problems than men). (Parkin et al. 2004, Rundblad et al. 2013) Communication piece Materials should be eye-catching and written in an interesting design manner, without scientific jargon. (Lazo et al. 2004) Design elements customers responded positively to included use of color to draw attention and guide readers, use of maps for visual appeal and to present information that complements text, an FAQ section, a description of the water treatment process, and simple information tables that are self-explanatory and do not require interpretation or reading instructions. (Lazo et al. 2004, Mobley et al. 2010) Fact sheets and communication materials should address risks for important segments of the population, for example children under five, the elderly, pregnant women, and immunocompromised persons. (Mobley et al. 2010, Rundblad et al. 2013) Fact sheets, public notices, and media releases need fewer words and simpler language. (Mobley et al. 2010)

(continued)

Table 7.7 (Continued) Topic Recommendation Presentation of data Most customers want narrative to accompany tables, and larger type to make them easier to read. They prefer the use of whole numbers and find decimals and exponents confusing. (Lazo et al. 2004) Customers desire information that compares the quality of their tap water to that of other water utilities and bottled water. (Lazo et al. 2004) Zero is the only acceptable level of exposure among many members of the public. (Mobley et al. 2010) Spokespeople Citizens would trust a community spokesperson who communicated promptly on radio or television when a contaminant is detected. (Parkin et al. 2004) Partnerships can improve the effectiveness of messages in addition to increasing public trust in the message. Consider including university researchers and public health agencies. Partnerships with other organizations often work well on a regional scale. (Deeb et al. 2014) Access to additional Most customers like knowing that more information was available information and being told where to find it. (Lazo et al. 2004)

Project #2776, Risk Communication for Emerging Contaminants (Parkin et al. 2004), provided useful diagnostic questions to determine whether a specific emerging contaminant issue is a strategic issue for their operations (Table 7.8). The report notes that if the utility lacks the essential capacity to respond effectively, serious consideration must be given to whether a rapid but non-strategic release of information will do more harm than good. In this circumstance, it may be better to identify a credible third-party to whom customers and stakeholders can be referred for more information.

Table 7.8 Questions to establish the need and utility’s preparedness to respond to an emerging contaminant issue Category Questions Contaminant  Has the presence of the contaminant been demonstrated in any water supply, anywhere?  Is there sufficient scientific knowledge about the nature and potential health risks associated with the contaminant?  Can uncertainties in the existing knowledge base be confidently addressed? Concerns  Are there public concerns about the contaminant?  Are public concerns increasing in intensity?  Have scientists expressed concerns about the contaminant?  Is media coverage about the contaminant occurring? (continued)

Table 7.8 (Continued) Category Questions Population  Have vulnerable subpopulations (especially children or pregnant women) been linked to the contaminant?  Has the consumer population demonstrated interest in or concern about water issues? Society  Are advocacy or stakeholder groups raising concern about the contaminant? Utility  Is the contaminant present in the utility’s water supply?  Will the contaminant have financial or resource impacts on the utility?  Does the utility have a spokesperson who is seen as credible by the public?  Is the utility able to predict the consequences of the contaminant on its consumers’ health?  Does the utility have low confidence that the public will respond effectively to potential risk communication activities?  Does the utility have a visible, positive presence in the community? Source: Adapted from Water Research Foundation Project # 2776 (Parkin et al. 2004)

Project #4323, Consumer Perceptions and Attitudes Toward EDCs and PPCPs in Drinking Water (Rundblad et al. 2013), characterized consumer conceptualizations and understandings of water contaminants, especially EDCs and PPCPs. Table 7.9 lists the main conclusions and recommendations.

Table 7.9 Main conclusions and recommendations regarding consumer perceptions and attitudes toward EDCs and PPCPs in drinking water (Water Research Foundation Project # 4323) Theme Conclusions Recommendations Knowledge  Consumer knowledge about water  Construct a functional classification of contaminants is limited, especially contaminants, preferably with about EDCs and PPCPs clickable links to definitions, health risks, etc. Worry  There is lingering uncertainty about  Transparent communication about whether tap water containing contaminants is needed, with synergy contaminants is safe between utilities, regulators, and  Although most consumers have not health organizations; it is important to changed their behavior, those that have communicate about current research did so due to worry not risk perception initiatives the water industry is undertaking (continued)

Table 7.9 (Continued) Theme Conclusions Recommendations Vulnerable  Heterogenic vulnerable groups of  Information about water quality groups consumers include: should be tailored to different o Older consumers and recently consumer groups pregnant consumers were less likely  Vulnerable consumers may not label to think tap water with themselves “vulnerable”, so contaminants was safe alternative labels are needed  Consumers with an illness/disability  Particular efforts need to be made to were more likely to be worried about engage with consumers with an contaminants but not more likely to illness/disability to understand why seek information they worry and how best to reach them, e.g. focus groups Females  Being female was a key driver of  Particular efforts need to be made to worry about contaminants engage with women to understand  Women were also significantly more why they worry and how best to reach likely to worry about tap water quality them, e.g. focus groups with female and to change their tap water behavior participants  Despite the strong associations between females and worry, females were not more likely to seek information Information  The internet is a well-used source of  Set up a “neutral” website at a national Sources information level as a platform for communication  Water utilities are a well-used and about water quality issues to trusted information source consumers  Water utilities are less trusted when  Provide links from water utility seen as corporate enterprises webpages to proposed neutral national website Terms  Different terms are used to refer to  Employ lay language in media reports contaminants in media and outreach about contaminants so that consumers material can find utility information when  Media reports typically emphasize the using lay language in search engines potential risk to humans and were a  Improve internal search engine key driver of worry about indexing to help the public find contaminants information they want from reliable  Consumers demonstrated a healthy sources skepticism and media also reiterates that contaminated water can be safe to drink (continued)

Table 7.9 (Continued) Theme Conclusions Recommendations Technical  Many consumers are primarily  Two stages of communication: details interested in reassurance o lay language with minimal technical  Consumers are open to technical details details and educated consumers  more detailed technical information specifically want more detail  Consumers do not equate technical detail with technical language but water professionals do Negative  Contamination as a concept and  Tailor language used in associations language associated with contaminants communication to consumer have very strong negative connotations conceptualizations so that it does not  Man-made contaminants have strong cause undue worry negative associations  Avoid terms with negative  Outreach texts use a range of terms associations that have strong negative associations  Avoid use of “low levels” to refer to that may be evoked even if the quantities -insignificant levels is message is positive potentially a better term  Language used to refer to quantities in outreach texts has negative connotations or is vague Positive  Tap water is typically perceived as a  The fact that contaminants are associations public good and its safety is taken for unregulated should be downplayed granted but also strongly linked to  Highlight that monitoring and testing (assumed) regulations for contaminants is a regulatory  As regulations have strong positive activity, e.g. enforcing a “standard of associations with safety and security; care” the notion of “unregulated  The water industry needs to contaminants” is the most worrying of investigate what regulation means to all consumers Scientific  Scientific uncertainty causes  Highlight what is known (there is no uncertainty frustration and ties into fears of the evidence) and downlight what is unknown unknown (we do not know)  Long term educational action should address how to improve public understanding of science, risk and regulation Source: data from Rundblad et al. 2013

Additional Tools and Recommendations for Communication

Many additional tools and recommendations have been produced by a variety of organizations that provide helpful methodologies for communicating effectively with the public. Some of these are described below. The World Health Organization published a two page guide summarizing 7 Steps to Effective Media Communications During Public Health Emergencies (WHO 2005). The Steps elaborated are:

1. Assess media needs, media constraints, and internal media-relations capabilities 2. Develop goals, plans, and strategies 3. Train communicators 4. Prepare messages 5. Identify media outlets and media activities 6. Deliver messages 7. Evaluate messages and performance

The Centers for Disease Control developed a Drinking Water Advisory Communication Toolbox that includes several templates and worksheets to help with communication planning and addressing special groups (CDC 2013b). Among the recommendations are:

 How to address low literacy or limited English proficiency audiences, including use of radio and television news stations to disseminate information and utilizing translation services and ethnic media outlets.  How to address the deaf or hard of hearing, including working with interpretation resources, encouraging television news stations to use on-screen scrolls, and using text and email messaging.  How to work with older adults and frail elderly, including identifying resources such as home health services that can provide assistance in emergencies.  How to address the needs of pregnant women, including coordinating with local health departments, clinics, hospitals, and schools to disseminate information, and crafting specific messages.  How to address the needs of people with compromised immune systems, including coordinating with local health departments, clinics, hospitals, and schools to disseminate information, and designing messages with a clear alternatives for those with sensitive health issues.

The U.S. Army Corps of Engineers Shared Vision Planning Method provides a series of specific steps for creating collaborative discussions, including building teams, developing objectives and metrics for evaluation, collaboratively formulating and evaluating alternatives, and implementing a plan (U.S. Army Corps of Engineers 2011). Applying collaborative approaches to management of natural resource issues has been shown to be affective in developing common-ground solutions, and offers several advantages including fairer processes, creative thinking and enhanced information, conflict prevention, easier implementation of decisions, and reduced litigation (USDA no date).

The Nuclear Regulatory Commission (NRC) in their Guidelines for External Risk Communication Quick Reference Guide provides several suggestions for crafting effective messages (NRC no date):

 Determine your purpose—to educate, change perceptions, gain consensus, raise awareness, etc.  Settle on three or four key messages, backed by two to four supporting facts.  Provide the context to help the stakeholder(s) evaluate a risk in terms of the big picture.  Be honest about the inherent uncertainties in risk assessment.  Be brief, accurate, straightforward, easy to understand, and consistent.  Tailor the language to the audience’s reading level, education, concerns about the issue, experience with risks, and science understanding.  Don’t use technical terms that dehumanize people. Distant, abstract, and unfeeling language about death, injury, and illness sends the message that you don’t care about people as individuals.  Use familiar units of measure and transform scientific notation.  Use simple and focused graphical materials to reinforce your key message.  Use analogies and stories to illustrate technical information.  Use comparisons to put risks in perspective, but be careful. Comparing risks to lifestyle choices or other risks the public voluntarily assumes may appear manipulative.

Several studies have addressed the use of social marketing to achieve source water protection goals. Social marketing is defined as “marketing concepts and techniques applied to behavioral goals to advance social goods, such as improved health of a group, ecosystem or society” (Cadmus Group 2012). To apply social marketing to source water protection, suggested steps include (West Virginia University 2008):

1. focus on a key issue (e.g., public participation in source water protection) 2. focus on a key objective (e.g., get small communities to engage in source water protection planning) 3. focus on reaching key audiences with messages that work (audience focus) recognizing that you cannot and should not try to reach everyone

Suggested social marketing approaches for source water protection (in order from that with the greatest potential for individual behavior change but lowest reach to that with the highest reach but smallest potential for individual behavior change) include one-on-one personal contact, group discussion, personalized media, impersonal direct contact (e.g., direct mail), and information/awareness by mass media (e.g., TV, radio, billboard) (Cadmus Group 2012). Prioritized audiences for source water protection include local/elected officials, water system operators, homeowners/landowners, and watershed groups/associations (first priority audiences); and homeowner associations, septic professionals, and civic groups (second priority audiences) (West Virginia University 2008). An example of social marketing implemented by a water utility is provided by the Southwest Florida Management District, who implemented a number of programs to interact with target audiences and effect change with regard to source water protection (http://www.swfwmd.state.fl.us/projects/social_research/).

Other potentially useful communication tools and resources include:

 The American Water Works Association Public Communications Toolkit (AWWA 2014)  The California Department of Health Services Crisis & Emergency Risk Communication Tool Kit (CDHS 2006)  The Washington State Department of Health Division of Drinking Water Emergency Response Planning Guide for Public Drinking Water Systems (WDOH 2003)  A Template for Strategic Communications Plan (W.K. Kellogg 2006)  A guideline for audience segmentation analysis to identify like-minded audiences for public engagement campaigns (Maibach et al. 2011),  A study describing global experience in communicating about arsenic, of particular interest with regard to communications theory and practice (Galway no date),  A paper exploring media discourse and public opinion about nuclear power that provides insights into message framing (Gamson and Modigliani 1989),  A paper exploring communicating issues addressing chlorinated drinking water and cancer (Driedger and Eyles 2003),  A paper exploring message mapping (Covello no date), and  An article from the U.S. Public Health Service regarding Risk Communication: Working With Individuals and Communities to Weigh the Odds (USPHS 1995).

RELEVANT WATER RESEARCH FOUNDATION PROJECTS

Numerous additional past or present research projects funded by the Water Research Foundation have addressed communication issues faced by water utilities with regard to the presence of CECs in drinking water. Many of these projects implemented surveys or case studies of water utility professionals to gather information on the effectiveness of communication approaches in practice. In addition, Hawley et al. (2009) (Communication Principles and Practices, Public Perception, and Message), conducted for the Water Environment Research Foundation, reviewed case studies of communication practices at several chemical manufacturing industries, the nuclear energy industry, and pharmaceuticals manufacturers. The reader is encouraged to consult the extensive information provided in these project reports. Relevant projects include:

 Project #2613: Customer Attitudes, Behavior, and Impact of Communications Efforts (2004). The project evaluated factors that influence residential water utility customer attitudes and behaviors toward water utilities, assessed how communication can be used by water utilities to positively affect the attitudes and behaviors of residential water utility customers, and identified the types of information that should be communicated to enhance customer satisfaction. The research showed that customers who reported that they were “very informed” about water quality issues were significantly more likely to report that they were satisfied with their water utility than customers who were “not informed.”  Project #2692: Understanding and Enhancing the Impact of Consumer Confidence Reports (2004). The project evaluated the effectiveness of Consumer Confidence Reports (CCRs) for water utility customers. The specific goals were (1) to evaluate whether and

how CCRs influence consumer perceptions and (2) to determine what attributes of CCRs most in fluence consumers’ perceptions. When reports are easy to read and understand, they are much more likely to be perceived as being worthwhile and to make people feel confident that their water is safe and healthy to drink. For individuals willing to make the commitment to reading the CCR more thoroughly, the information should be presented in a credible, accessible, and understandable format. Approaches to improving information communication include having a short but prominent listing of contents, offering an FAQ section or a similarly abbreviated section that allows the customer to quickly locate a particular topic of interest, supplying contact information for individuals who want more information, describing the water treatment process, keeping information tables as simple as possible, and not avoiding a discussion of contaminants found at measurable levels in the water.  Project #2766: Effective Communications (2005). The project developed a communication strategy guide and workbook to address the need for strategic planning and program implementation assistance in the water industry. The guide offers self- assessment tools that help managers establish the level of their current communication capability, communication tips and tools, a step-by-step guide that leads managers through the development or improvement of a communication plan, and suggested strategies for rollout and execution of a communication plan.  Project #2776: Risk Communication for Emerging Contaminants (2004). The purpose of this project was to develop strategies and tools that would improve risk communication about CECs. The researchers interpreted results from scientific and organizational management literature and three case studies and conducted research utilizing methods from several disciplines.  Project #2851: Advancing Collaborations for Water-Related Health Risk Communication (2006). The purpose of this project was to develop communication strategies and tools that would enable water utilities, the public health community, and clinicians to collaborate and strengthen their capabilities for addressing water-related health risk issues in normal and emergency conditions. A Cost-Benefit Scorecard was developed to guide the decision-making process for risk communication approaches.  Project #2919: Understanding Public Concerns and Developing Tools to Assist Local Officials in Planning Successful Potable Reuse Projects (2004). This project was designed to develop a better understanding of public perceptions of indirect potable reuse, and to develop a set of best practices and tools to help utilities improve the community dialogue.  Project #2939: Risk Analysis Strategies for Credible and Defensible Utility Decisions (2007). This project (1) completed a baseline assessment summarizing current risk management frameworks, techniques, case studies, best practice examples, and decision- making capability among selected utilities; (2) gathered alternative approaches to managing risk; and (3) conducted and analyzed case studies.  Project #2955: Strategic Communication Planning: A Guide for Water Utilities (2005). The project researched the role of strategic communication planning in the performance and success of drinking water utilities; identified how strategic communications can become an integral component of planning and operations; determine the level of resources and funding necessary to achieve an effective strategic communication plan; and developed a guide to help drinking water utilities develop their own strategic communication plans.

 Project #4001: Contaminant Risk Management Communication Strategy and Tools (2010). This project was developed to help drinking water utilities answer the question: “Is my water safe to drink?” The project provided drinking water utilities with guidelines and audience-tested tools to provide customers, media, and the public with timely, clear information about different types of contaminants.  Project #4012: Water Conservation: Customer Behavior and Effective Communications (2010). This project evaluated the linkages and relationships between the water conservation behavior of residential customers and the communication approaches that seek to influence that behavior. The research team implemented the evaluation through telephone interviews with water agency personnel, surveys of residential water customers, analyses of current and past billing records supplied by water agency partners, in-depth case studies of water agencies and their water conservation communication campaigns, and an evaluation of communication methods implemented by the six participating utilities.  Project #4169: Water Utility Tool for Responding to Emerging Contaminant Issues (2012). This project developed a tool for drinking water utilities to use in addressing CEC challenges. The tool has two major features: (1) an array of worksheets for evaluating an emerging contaminant with currently available resources, and (2) an example framework for considering emerging contaminant issues. Worksheets include: Contacting regulatory agencies, Describing the emerging issue, Mapping stakeholders and desired schedule, Initial research on occurrence, health effects, physical/chemical properties, and treatment, Source characterization, Gap analysis, Setting goals, Alternatives development and evaluation, Plan finalization, Implementation, Building collaborations, Communicating, Determining audience and medium, Developing a message, Example communications, and Sources for continued information.  Project #4261: The EDC Network for Water Utilities (2014). This project produced The EDC Network for Water Utilities, an online network to promote collaboration among water utilities and improve utility responses to challenges posed by EDCs and PPCPs. The EDC Network provides a secure Website resource for utilities to share best practices, documents, other tools, and materials related to EDCs and PPCPs.  Project #4323: Consumer Perceptions and Attitudes Toward EDCs and PPCPs in Drinking Water (2013). The project assessed consumer conceptualizations and understandings of water contaminants, especially EDCs and PPCPs, contaminant detection processes, treatment options, and the role of regulation. The project particularly focused on factors that influence consumer beliefs, such as belonging to a vulnerable population, preferences and trust in information sources, the aesthetic features of drinking water, and willingness to pay for additional treatment. It also assessed water and health professionals’ beliefs about consumer perceptions of EDCs and PPCPs. A series about major findings with regard to communication is provided. http://www.waterrf.org/Pages/Projects.aspx?PID=4323  Project #4457: “Core Messages for Priority Contaminants of Emerging Concern” (in progress). This project will develop core messages for the water community to communicate with different audiences about the risks of priority CECs that help explain the risks and account for consumer risk perceptions. It will also provide guidance to water utilities regarding risk communication for different types of CECs.  Project #4463: National Dialogue on Contaminants of Emerging Concern and Public Health (2014). This project developed an inter-disciplinary workshop to enhance

dialogue about the potential human health risks of CECs in drinking water among water utilities, public health agencies, researchers, and other organizations. A series of overview papers was developed addressing Risk Communication about CECs, Regulation of CECs in Drinking Water, Public Health Research on CECs, Medical Practitioners and CECs, Water Utility Activities Related to CECs, and Water Quality Research on CECs.

ADDITIONAL SOURCES OF INFORMATION ON MONITORING AND COMMUNICATION FOR PPCPS AND EDCS IN WATER

General sources of information on considerations for monitoring and communicating about PPCPs and EDCs, or other emerging contaminant issues, in water include the following:

 California Ocean Protection Council, the National Water Research Institute, and others workshop report on Managing Contaminants of Emerging Concern including guidelines on selecting substances of monitoring http://www.sfei.org/sites/default/files/CA%20CEC%20Workshop%20Final%20Report% 20Sept%202009.pdf  Centers for Disease Control and Prevention Drinking Water Advisory Communication Toolbox (2011) http://www.cdc.gov/healthywater/pdf/emergency/drinking-water- advisory-communication-toolbox.pdf  McKenzie-Mohr & Associates Fostering Sustainable Behavior: Community-Based Social Marketing; resources for Social Marketing http://www.cbsm.com/public/world.lasso  National Centers for Coastal Ocean Science database on pharmaceuticals in the aquatic environment provides physical chemical properties for substances that may be useful in predicting their persistence in the environment http://products.coastalscience.noaa.gov/peiar/default.aspx  Social Marketing National Excellence Collaborative. The Basics of Social Marketing: How to Use Marketing to Change Behavior. http://www.turningpointprogram.org/Pages/pdfs/social_market/smc_basics.pdf  Sustainable Solutions for a Thirsty Planet risk communication fact sheets to support communicating about the risks of recycled water, from WateReuse Research Foundation projection number WRF-09-07 http://www.athirstyplanet.com/real_life/valuable_research/reuse_safe  U.S. Department of Health and Human Services Communicating in a Crisis: Risk Communication Guidelines for Public Officials (2002) http://www.hhs.gov/od/documents/RiskCommunication.pdf  EPA Communication Strategies http://www.epa.gov/superfund/community/pdfs/toolkit/comstrats.pdf  EPA Risk Communication in Action: The Tools of Message Mapping (2007) http://nepis.epa.gov/Adobe/PDF/60000IOS.pdf  EPA The Seven Cardinal Rules of Risk Communication http://www.epa.gov/care/library/7_cardinal_rules.pdf  U.S. Nuclear Regulatory Commission (NRC) Effective Risk Communication: The Regulatory Commission’s Guidelines for External Risk Communication (2004) and Quick

Reference Guide http://pbadupws.nrc.gov/docs/ML0406/ML040690412.pdf http://pbadupws.nrc.gov/docs/ML0406/ML040690441.pdf  Washington Department of Health Translations for Public Notification regarding communicating important water system information to non-English speaking populations http://www.doh.wa.gov/CommunityandEnvironment/DrinkingWater/DrinkingWaterEme rgencies/PublicNotification/TranslationsforPublicNotification.aspx  Water Resources Education Network resources on Social Marketing including publications http://wren.palwv.org/library/SocialMarketing.html and websites http://wren.palwv.org/SocialMarketingWebsites.html

CHAPTER 8: SUMMARY AND CONCLUSIONS

The results and conclusions from this project are summarized below.

SOURCES AND OCCURRENCE

Data on occurrence of PPCPs and EDCs in source and drinking water were gathered from over 65 published sources for more than 440 different PPCP ingredients and putative EDCs, from studies published through 2013. Data included samples collected from streams, rivers, lakes, reservoirs, influent and effluent points from WWTPs, DWTP influent, finished drinking water (that has undergone treatment), and distribution drinking water (collected somewhere in the distribution system between water utility and tap). Summary data for each sampling program and compound were compiled in spreadsheets. These data were used to rank or sort PPCPs and EDCs based on frequency of detection, concentration, location, chemical type, water type, and other criteria. Estimates of frequency of detection and ranges of detected concentrations tabulated based on these data reflect the publications summarized in this project and as such do not represent national occurrence statistics; however, these summaries do provide a snapshot of the relative detection frequency and concentrations that have been detected. In general, analgesics/anti-inflammatories, antibiotics, antihypertensives (blood pressure medication), and psychotropics (antidepressants, antianxiety agents, and antipsychotics) were the most frequently detected families of pharmaceutical compounds. Herbicides and insecticides, alkylphenols, flame retardants, plasticizers/surfactants, and hormones/sterols were the most frequently detected EDCs. Concentrations of emerging contaminants decreased with increasing treatment, from WWTP influent to WWTP effluent, surface water, DWTP influent, and finished drinking water.

TOXICOLOGICAL SIGNIFICANCE

Data on potential health effects were compiled for each PPCP or EDC identified as detected in drinking water, and ADIs and DWELs were derived by applying a decision tree approach. Overall, ADIs and DWELs were identified or derived for 159 non-EDC pharmaceuticals, 11 hormones, and 210 EDCs and non-pharmaceutical compounds. The ADIs and DWELs calculated using these approaches are screening levels and do not reflect concentrations at or above which adverse effects are expected or likely. They are set using very conservative (health protective) assumptions incorporating multiple uncertainty factors (ranging from 1,000 to 30,000 for most compounds), so if the concentration of a substance found in water is below the screening level, then one can be confident that no health effects are likely. If the concentration is at or above its screening level, then more detailed evaluation of the toxicity and occurrence of the substance is recommended. Maximum detected concentrations in drinking water, based on the data compiled in this project, were then compared to these DWELs. To put the comparisons into understandable terms to support risk communication, the amount of water with the maximum detected concentration of each substance that a person would have to consume, in 8-ounce glasses of water per day, to reach a dose equal to the ADI was calculated. Based on these results, a person would have to drink at least 39 8-oz glasses of water a day (about 2.4 gallons) to reach a dose equal to the ADI

calculated for any of the PPCPs. For two hormones (17α-ethynylestradiol and estrone) and one herbicide (atrazine), the maximum concentration detected anywhere in drinking water exceeded the DWEL. For the two hormones, the amount of water one would need to consume per day to get a dose equal to the ADI is less than one glass, and for atrazine it is 7.5 glasses. Ethynylestradiol, a synthetic hormone used for birth control, and estrone, an endogenous female hormone also used medicinally, were both detected in drinking water in one study in the Midwest U.S. in 2005, but not in another study where samples were collected from 19 utilities around the United States in 2006-2007 or in a study in Chicago in 2009-2011. Atrazine, an herbicide, is frequently detected in drinking water particularly in agricultural areas, and was detected at the maximum concentration in an area with a very high rate of agricultural land use. In addition, atrazine is regulated in drinking water in the United States, with an MCL, and is the subject of an intensive EPA monitoring program of raw and finished water in community water systems. Effective drinking and wastewater treatment methodologies are available for these substances, with ethynylestradiol and estrone effectively removed by activated carbon, ozonation, conventional activated sludge, membrane bioreactors, and riverbank filtration. Atrazine is moderately removed by ozonation and by activated carbon (47-69%), but effectively removed by high UV fluence. It was not effectively removed by coagulation or riverbank filtration. The assessment of potential effects of exposure to multiple sources of these substances and exposures to mixtures of substances is an ongoing area of research. Application of relative source contribution (RSC) factors to adjust water quality criteria to account for other sources of exposure is recommended, with a default of 20% of total exposure assumed to be from water when data regarding potential exposure sources is limited. In general, uptake of pharmaceuticals into fish and produce in the environment appears to be limited, but uptake of EDCs into fish or produce can be significant and result in exposures from these routes that exceed those from drinking water. Exposures to some EDCs such as surfactants and plasticizers in foods and beverages due to leaching from packaging materials and resins can also be significant. Exposures to phytoestrogens (naturally present plant-based estrogenic compounds), such as daidzein, zenistein, genistein, and coumestrol, in foods and beverages can also be significant, with some suggesting that the potential estrogenicity associated with dietary intake of these compounds is greater than that from exposure to synthetic EDCs.

FEDERAL AND STATE LEGISLATION AND REGULATIONS

The EPA is the primary agency charged with addressing potential concerns with PPCPs and EDCs in water, with the Clean Water Act (CWA) providing the basic structure for regulating discharges of pollutants into the waters of the US through the NPDES permit program. Under the Safe Drinking Water Act (SDWA), EPA has set MCLs for drinking water for some EDCs (mostly pesticides) but not pharmaceuticals. The current Contaminant Candidate List (CCL3) of drinking water contaminants being considered for regulation under the SDWA includes 30 compounds that have been characterized as EDCs, including pesticides, hormones and steroids, nitrosamines, perfluorinated compounds, and an antioxidant, and one pharmaceutical (an antibiotic). Amendments to the SDWA in 1996 established the Unregulated Contaminant Monitoring Program to collect data for contaminants suspected to be present in drinking water. Under this program, public water systems (PWSs) that serve more than 10,000 people and a subset of PWSs

that serve less than 10,000 people must conduct water sampling surveys to test for specified contaminants that are suspected to be present in drinking water but that do not have health-based standards set under SDWA. Samples are analyzed by State laboratories and reported to the EPA for inclusion in the National Contaminant Occurrence Database (NCOD). The most recent rule, UCMR3, monitors 30 contaminants in drinking water, including several hormones and perfluorinated compounds during a 12-month period from January 2013 through December 2015. Two states—California and Minnesota—have drinking water regulations for some EDCs or pharmaceuticals that may be stricter than federal guidelines. Therefore, utility managers should be familiar with the regulations in their specific state. Due to the way waste is regulated under the RCRA and Universal Waste federal waste laws, PPCPs and EDCs may enter the environment and source water from wastes generated by consumers and household trash. Proposed changes to the Universal Waste laws may alter how pharmaceutical wastes are treated by healthcare facilities. Both the DEA and FDA recommend public participation in drug take-back programs to reduce contamination of drinking water by PPCPs and medicinal hormones. However, FDA recommends disposal of several compounds by flushing because of their potential danger to children or pets if ingested, and at least two of these (diazepam and methadone) have been detected in source and drinking water. Numerous ongoing research programs sponsored by government and state agencies are investigating how PPCPs and EDCs behave in the environment, what their potential ecological and human health risks are, and how they can be treated.

TREATMENT APPROACHES AND SOURCE WATER PROTECTION

A number of treatment options are available that have been shown to effectively reduce or eliminate PPCPs and EDCs from drinking water, with effectiveness varying by type of compound and treatment parameters. However, treatment technologies currently in place at most WWTPs and DWTPs were not designed or intended to remove PPCPs or most EDCs. Some research on the relative costs and benefits of these treatment methods has been done, but in general available information is limited. Source water protection programs present an alternative to costly treatment methodologies by preventing contamination from reaching source water supplies. Numerous alternatives are available including farm conservation and management practices, forest management, low impact development (LID)/smart growth initiatives, river and habitat protection, watershed partnerships, and other watershed protection measures. Some information on cost/benefits of these approaches is available but limited. Utilities can benefit from increasing public awareness on how to properly dispose of household hazardous wastes and medications, and how to implement BMPs to prevent contamination from entering source waters. For example, many chemicals and medications can be disposed of at local collection sites, and erosion control, water conservation, and wise pesticide and household chemical use practices can be implemented.

MONITORING AND COMMUNICATION APPROACHES

Some major water utilities have tested source and/or treated water for emerging contaminants such as PPCPs and unregulated EDCs. Testing for these contaminants is not required under the SDWA. Initiation of monitoring efforts has been motivated by participation in national and regional studies to improve understanding of the presence and behavior of PPCPs and EDCs, the desire to understand the effectiveness of treatment methodologies, and the desire to proactively respond to concerns by the public and others. Criteria that should be considered when selecting compounds for monitoring include evidence of past detection, frequency of occurrence, evidence of increased usage rates of substances or knowledge of specific watershed land uses, potential health significance of the compounds particularly to vulnerable populations, the potential mobility and/or persistence of the compounds, the likelihood of removal by treatment methodologies that are in place, the availability of analytical methods, and the level of public or scientific interest. In addition, consideration should be given to ensuring that selected method detection limits are below DWELs, such that one can be confident that if not detected a compound is not present at a level that poses a health risk. Several sensitive new analytical methods are available for EDCs and PPCPs in water, and method development for additional compounds is continually underway. Sensitive sampling methods are also required to minimize sample contamination. Communication regarding CECs in water is a challenge due to the lack of existing regulatory criteria and uncertainties regarding the potential health effects of exposure to these compounds. Numerous Water Research Foundation projects have conducted research on recommended communication approaches for CECs in water and the effectiveness of these approaches for the intended audiences. Particular attention should be paid to the availability of resources to appropriately respond to questions should a monitoring program be initiated, building positive relationships with the community before a crisis occurs, designing messages for the appropriate target audiences, avoiding alarmist language, ensuring that communication pieces have appropriate information content, readability, and appearance, providing sufficient but not overly technical content, ensuring that spokespeople are recognized as credible by the community, and striving to achieve openness and reliability in all communications. Risk communication approaches applied by participating utilities included presenting results at public meetings and to community groups, and preparing fact sheets and short videos posted on the utility website. Some utilities have convened focus groups to obtain information about community members’ response to specific language regarding CECs. Risk perspectives given included providing dose equivalency measures to understand how doses of CECs that would be associated with extremely low water concentrations compare to the amount in a typical medication tablet or to ADIs

CHAPTER 9: RECOMMENDATIONS FOR UTILITIES

Questions from the public and the scientific community regarding the significance of PPCPs and EDCs in source and drinking water will only continue to increase, as more data are generated and are more easily accessible, and increasing technological abilities allow the detection of more compounds at lower levels. The products of the research conducted for this project provide a centralized up-to-date resource of the current state of knowledge of PPCPs and EDCs in water. Moving forward, several recommendations for utilities are offered:

 Utilities should strive to continually monitor new scientific developments regarding the occurrence and health significance of PPCPs and EDCs in the environment, and incorporate new information using sound science. This should include information about analytical detection methods and treatment technologies, detection of additional or unique compounds, and information about the potential health effects of PPCPs and EDCs.  Utilities should monitor regulatory developments that affect PPCPs and EDCs in water, at both the federal and state levels.  Because of the public’s role in the use of pharmaceuticals and chemical agents, utilities should develop strategies to engage the public in source water protection programs.  Utilities should tailor risk communication messages to reach target audiences and deliver them using appropriate mechanisms. Effective communications can improve customer and stakeholder trust of and support for a water utility.  Utilities should strive to communicate the results of monitoring promptly, but take sufficient time to provide scientifically accurate context regarding what data mean in terms of risks.

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ABBREVIATIONS

AC activated carbon ADEQ Arizona Department of Environmental Quality ADHD attention deficit hyperactivity disorder ADI acceptable daily intake AHTN acetyl hexamethyl tetrahydro naphthalene AL action level AOP advanced oxygen process APE alkylphenol ethoxylate ATSDR Agency for Toxic Substances and Disease Registry AWPF advanced water purification facility

BCF bioconcentration factor BHA butylated hydroxyanisole BHC benzene hexachloride BHT butylated hydroxytoluene BMDL Benchmark Dose Level BMP best management practice BPA bisphenol A BW body weight

CA chromosomal aberration CAS conventional activated sludge CAS Chemical Abstract Services CCRIS Chemical Carcinogen Research Information System CCL Contaminant Candidate List CDC Centers for Disease Control CDPH California Department of Public Health CDWM Chicago Department of Water Management CEC contaminant of emerging concern CFC chlorofluorocarbon CFR Code of Federal Regulations CHC Chemicals of High Concern COD chemical oxygen demand COG Council of Governments CP cyclophosphamide CWA Clean Water Act CWS community water system

DACT atrazine-desethyl-desisopropyl DAFF dissolved air flotation-sand filtration DBCP 1,2-dibromo-3-chloropropane DCR Department of Conservation and Recreation DDA deethyldeiso propyl atrazine

DDD dichlorodiphenyldichloroethane DDE dichlorodiphenyldichloroethylene DDT dichlorodiphenyltrichloroethane DEA Drug Enforcement Agency DEC Department of Environmental Conservation DEET N,N-diethyltoluamide DEHP diethyl hexyl phthalate DHS Department of Health Services DI deionized DIA deisopropyl atrazine DOC dissolved organic carbon DPH Department of Public Health DRBC Delaware River Basin Commission DTSC Department of Toxic Substances Control DWEL drinking water equivalent level DWNL drinking water notification level DWTP drinking water treatment plant

EC European Commission ED endocrine disruption EDC endocrine disrupting compound EDMVAC Endocrine Disruptor Methods Validation Advisory Committee EDMVS Endocrine Disruptor Methods Validation Subcommittee EDSP Endocrine Disruptor Screening Program EDSTAC Endocrine Disruptor Screening and Testing Advisory Committee EE2 17 α-ethinylestradiol EfOM effluent organic matter EFSA European Food Safety Authority EPA Environmental Protection Agency ESA ethanesulfonic acid EtFOSAA N-ethyl perfluorooctane sulfonamido acetic acid EU European Union

F female FA fraction available FAQ frequently asked question FDA Food and Drug Administration FQPA Food Quality Protection Act

GAC granular activated carbon GC gas chromatography GD gestation day GWR Ground Water Rule

HBV health based value HCB hexachlorobenzene

HCH hexachlorocyclohexane HE heptachloroepoxide HHBP Human Health Benchmark for Pesticides HHCB 1,3,4,6,7,8-Hexahydro-4,6,6,7,8,8,-hexamethylcyclopenta[γ]-2- benzopyran HPLC/MS/MS high performance liquid chromatography with tandum mass spectrometry HRGC high resolution gas chromatography HRL health risk level HRMS high resolution mass spectrometry HRT high retention time HSDB Hazardous Substances Data Bank

IARC International Agency for Research on Cancer ISTC Illinois Sustainable Technology Center

JEFCA Joint FAO/WHO Expert Committee on Food Additives JMPR Joint FAO/WHO Meeting on Pesticide Residues

LD50 lethal dose to 50% of a test population LID low impact development LOAEL lowest observed adverse effect level LOQ limit of quantitation LP low pressure

M male MADEP Massachusetts Department of Environmental Protection MBR membrane bioreactor MCA monochloramine MCC mass of colonic contents MCL maximum contaminant level MCLG maximum contaminant level goal MCPA 2-methyl-4-chlorophenoxyacetic acid MDR multi-drug resistance MDH Minnesota Department of Health MDMA 4-methylenedioxy-N-methylamphetamine MEK methyl ethyl ketone MF microfiltration MIC minimum inhibitory concentration MLA mouse lymphoma assay MN micronucleus MPA medoxyprogesterone acetate MRDL maximum residual disinfectant level MRDLG maximum residual disinfectant level goal MRL minimum reporting level MRL minimal risk level MRSA methicillin-resistant Staphylococcus aureus

MTBE methyl tert-butyl ether

NA not available NCI National Cancer Institute NCOD National Contaminant Occurrence Database ND Not detected NDBA N-nitrosodibutylamine NDEA N-nitrosodiethylamine NDMA N-nitrosodimethylamine NDPA N-nitroso-di-n-propylamine NDWAC National Drinking Water Advisory Council NEIWPCC New England Interstate Water Pollution Control Commission NF nanofiltration NH DES New Hampshire Department of Environmental Services NIEHS National Institute of Environmental Health NIH National Institutes of Health NOAEL no observed adverse effect level NOEL no observed effect level NP nonylphenol NP1EO nonylphenol monoethoxylates NP2EO nonylphenol diethoxylates NPDES National Pollutant Discharge Elimination System NPYR N-nitrosopyrrolidine NSAID nonsteroidal anti-inflammatory drug NSRL no significant risk level NTP National Toxicology Program NAWQA National Water Quality Assessment NYC DEP New York City Department of Environmental Protection

OA oxanolic acid OASAS Office of Alcoholism and Substance Abuse Services OECD Organisation for Economic Co-operation and Development OEHHA Office of Environmental Health Hazard Assessment OP octylphenol OP2EO octylphenol diethoxylate ORD Office of Research and Development OSHA Occupational Safety and Health Administration OTC over the counter

PAC powdered activated carbon PAH polycyclic aromatic hydrocarbon PBDE polybrominated diphenyl ethers PCB polychlorinated biphenyl PCS potential contaminant source PCP personal care product PEC predicted environmental concentration

PFA perfluorinated fatty acid PFBA perfluorobutyric acid PFC perfluorinated compound PFBS perfluorobutanesulfonic acid PFHpA perfluoroheptanoic acid PFHxS perfluorohexanesulfonic acid PFNA perfluorononanoic acid PFOA perfluoroctanoic acid PFOS perfluorooctane sulfonic acid PFOSA perfluorooctane sulfonamide acetic acid PFS perfluorinated sulfonyl PhAC pharmaceutically active compound PHG public health goal PND postnatal day PNEC predicted no effect concentration ppb parts per billion PPCP pharmaceutical and personal care product Ppt parts per trillion PWS public water system

RAA risk assessment advice RCRA Research Conservation and Recovery Act RDX Research Department Explosive RfD reference dose RO reverse osmosis RSC relative source contribution RTECS Registry of Toxic Effects of Chemical Substances

SaF safety factor for calculation of screening levels from MICs SCCP short chain chlorinated paraffin SDWA Safe Drinking Water Act SDZ sulfadiazine SF slope factor SMCL secondary maximum contaminant level SMILES simplified molecular input line entry specification SMX sulfamethoxazole SMZ sulfamethazine SOC synthetic organic compound SRT sludge retention time STP sewage treatment plant SWAP source water assessment program SWP source water protection SWPA source water protection area SWQA source water quality assessment

TBEP tris (2-butoxyethyl) phosphate

TCDD tetrachlorodibenzodioxin TCEP tris (2-chloroethyl) phosphate TCPP tris (1,3-dichloro-2-propyl) phosphate TDCPP tris (dichlorisopropyl) phosphate TDI tolerable daily intake TMDL total maximum daily loads TMP trimethoprim TOC total organic carbon TRED Tolerance Reassessment Progress and Risk Management Decision TSCA Toxic Substances Control Act TSH thyroid stimulating hormone TSS total suspended solid TT treatment technique TTC threshold of toxicologic concern

UCMR Unregulated Contaminant Monitoring Rule UF ultrafiltration UF uncertainty factor UK United Kingdom UNEP United Nations Environment Programme USDA United States Department of Agriculture US EPA United States Environmental Protection Agency US FDA United States Food and Drug Administration USGS United States Geological Survey UV ultraviolet

VOC volatile organic compound VSD virtually safe dose

WAP watershed agricultural program WERF Water Environment Research Foundation WHO World Health Organization WRF Water Research Foundation WRRF WateReuse Research Foundation WSSC Washington Suburban Sanitary Commission WUD Water Utilities Division WWTP wastewater treatment plant

YES2678 yeast estrogenic screen

SUPPORTING DOCUMENTATION ON RELATIVE OCCURANCE OF SUBSTANCES IN WATER

Table A.1 Comparison of detection frequencies of PPCPs in drinking water, DWTP influent, and surface water (based on compiled data from sources identified in Table 3.2)* Drinking Water DWTP Influent Surface Water Name Drug group % Freq % Freq % Freq Detected in Drinking Water Acesulfame Sweetener 50% 1/2 NA NA 0% 0/3 Meprobamate Psychotropic 36% 28/77 74% 20/27 13% 11/86 Propranolol Antihypertensive 33% 1/3 NA NA 50% 3/6 Atenolol Antihypertensive 32% 20/63 52% 12/23 2% 8/358 Caffeine Caffeine 31% 60/191 27% 33/121 33% 299/911 Carbamazepine Anticonvulsant 29% 35/122 86% 54/63 39% 257/660 Phenytoin Anticonvulsant 28% 21/74 67% 18/27 5% 5/109 Cotinine Nicotine 24% 38/158 43% 17/40 33% 215/653 Gemfibrozil Antilipidemic 22% 20/90 27% 14/51 14% 110/786 Nicotine Nicotine 17% 2/12 0% 0/4 34% 17/50 Furosemide Diuretic 14% 2/14 0% 0/12 6% 4/67 Theobromine Caffeine 12% 3/25 0% 0/4 4% 3/68 Camphor Fragrance/ flavor 11% 12/108 4% 4/108 1% 1/190 Methadone Analgesic 11% 1/9 NA NA 0% 0/18 Ketoprofen Analgesic 8% 1/12 NA NA 21% 27/130 Ibuprofen Analgesic 8% 8/106 13% 3/23 7% 27/411 Acetaminophen Analgesic 7% 4/56 56% 20/36 13% 58/457 Ibuprofen methyl ester Analgesic 7% 1/15 NA NA NA NA Sulfamethoxazole Antibiotic 6% 8/133 52% 33/63 18% 145/804 Codeine Analgesic 5% 1/19 17% 4/24 7% 24/344 Dehydronifedipine Antihypertensive 5% 1/20 25% 9/36 8% 25/318 Fluoxetine Psychotropic 5% 5/108 6% 3/53 2% 7/436 Tylosin Antibiotic 4% 1/27 0% 0/16 4% 20/496 Norfluoxetine Psychotropic 3% 1/33 0% 0/19 NA NA/47 Risperidone Psychotropic 3% 1/33 0% 0/19 NA NA Iopromide X-ray contrast 2% 1/43 29% 2/7 1% 1/97 Sulfathiazole Antibiotic 2% 1/47 4% 1/28 1% 8/627 Monensin Antibiotic 2% 1/50 0% 0/4 65% 170/260 Diazepam Psychotropic 1% 1/76 9% 2/23 2% 3/121 Naproxen Analgesic 1% 1/108 55% 17/31 20% 88/437 Never Detected in Drinking Water, Detected in DWTP Influent Erythromycin-H2O Antibiotic 0% 0/16 63% 15/24 12% 34/275 Flumequine Antibiotic 0% 0/12 58% 7/12 0% 0/64 1,7-Dimethylxanthine Caffeine 0% 0/10 38% 9/24 24% 86/359 Trimethoprim Antibiotic 0% 0/90 36% 21/59 17% 181/1089 Diphenhydramine Antihistamine 0% 0/4 25% 3/12 6% 12/201 Diclofenac Analgesic 0% 0/68 17% 4/23 12% 37/317 (continued)

Table A.1 (continued) Drinking Water DWTP Influent Surface Water Name Drug group % Freq % Freq % Freq Atorvastatin Antilipidemic 0% 0/33 16% 3/19 46% 6/13 o-hydroxy atorvastatin Antilipidemic 0% 0/33 16% 3/19 NA NA p-hydroxy atorvastatin Antilipidemic 0% 0/33 16% 3/19 NA NA Clofibric acid Antilipidemic 0% 0/30 14% 1/7 16% 43/266 Erythromycin Antibiotic 0% 0/31 11% 3/27 21% 74/348 Lincomycin Antibiotic 0% 0/46 11% 3/28 36% 215/600 Sulfamethazine Antibiotic 0% 0/47 7% 2/28 16% 117/715 Albuterol Bronchodilator 0% 0/16 4% 1/24 1% 2/326 Sulfadimethoxine Antibiotic 0% 0/47 4% 1/28 3% 21/626 Never Detected in Drinking Water or DWTP Influent, Detected in Surface Water Clindamycin Antibiotic NA NA NA NA 100% 3/3 Desmethyldiltiazem Antihypertensive NA NA NA NA 100% 1/1 Hydrochlorothiazide Diuretic NA NA NA NA 100% 1/1 Oxycodone Analgesic NA NA NA NA 100% 1/1 Triamterene Diuretic NA NA NA NA 100% 1/1 Valsartan Antihypertensive NA NA NA NA 100% 1/1 Methamphetamine Illicit drug NA NA NA NA 67% 6/9 Fenoprofen Analgesic NA NA NA NA 36% 28/78 Butalbital Analgesic 0% 0/23 0% 0/4 33% 8/24 Fragrance/ Indole flavoring NA NA NA NA 32% 6/19 Anhydro-erythromycin Antibiotic NA NA NA NA 23% 5/22 Cyclophosphamide Cancer drug NA NA NA NA 20% 3/15 Clarithromycin Antibiotic NA NA NA NA 18% 4/22 Indomethacin Analgesic NA NA NA NA 16% 25/159 Ofloxacin Antibiotic NA NA 0% 0/12 15% 6/41 Bezafibrate Antilipidemic 0% 0/23 0% 0/4 10% 25/260 Pentoxifylline Antihypertensive 0% 0/23 NA NA 9% 7/74 Diltiazem Antihypertensive 0% 0/16 0% 0/28 9% 31/358 Hydrocodone Analgesic 0% 0/11 NA NA 8% 3/36 Paraxanthine Caffeine NA NA 0% 0/4 8% 2/24 Cimetidine Antacid 0% 0/16 0% 0/24 8% 25/309 Sulfachloropyridazine Antibiotic 0% 0/27 0% 0/28 7% 34/516 Metoprolol Antihypertensive 0% 0/15 NA NA 4% 1/24 Metformin Antidiabetic NA NA NA NA 3% 5/145 Roxithromycin Antibiotic 0% 0/16 0% 0/16 3% 14/484 Azithromycin Antibiotic 0% 0/12 0% 0/4 3% 5/182 Thiabendazole Antiparasitic 0% 0/4 0% 0/12 3% 3/119 Lasalocid Antibiotic 0% 0/12 0% 0/4 2% 1/47 Salicylic acid Keratolytic agent 0% 0/34 0% 0/4 2% 1/52 (continued)

Table A.1 (continued) Drinking Water DWTP Influent Surface Water Name Drug group % Freq % Freq % Freq Ciprofloxacin Antibiotic 0% 0/32 0% 0/28 2% 7/370 Ranitidine Antacid 0% 0/4 0% 0/12 2% 5/296 Sulfadiazine Antibiotic 0% 0/27 0% 0/28 2% 2/120 Chlortetracycline Antibiotic 0% 0/16 0% 0/24 1% 6/583 Doxycycline Antibiotic 0% 0/16 0% 0/28 1% 4/495 Enalaprilat Antihypertensive NA NA NA NA 1% 1/126 Norfloxacin Antibiotic 0% 0/19 0% 0/28 1% 2/370 Tetracycline Antibiotic 0% 0/12 0% 0/16 1% 3/575 Bupropion Psychotropic NA NA NA NA Detect NA/31 Citalopram Psychotropic NA NA NA NA Detect NA/31 COOH-ibuprofen Analgesic NA NA NA NA Detect NA/24 Enrofloxacin Antibiotic 0% 0/16 0% 0/16 Detect NA/329 Norsertraline Psychotropic NA NA NA NA Detect NA/31 Oxytetracycline Antibiotic 0% 0/16 0% 0/16 Detect NA/595 Paroxetine Psychotropic NA NA NA NA Detect NA/32 Sarafloxacin Antibiotic 0% 0/4 0% 0/24 Detect NA/301 Sertraline Psychotropic NA NA NA NA Detect NA/32 Sulfamethizole Antibiotic 0% 0/31 0% 0/4 Detect NA/357 Venlafaxine Psychotropic NA NA NA NA Detect NA/31 * Estimates of frequency of detection and ranges of detected concentrations are based on the publications summarized in this project and as such do not represent national occurrence statistics. NA − not analyzed or available

Table A.2 PPCPs not detected in drinking water, DWTP influent, or surface water* Drinking DWTP Surface Water influent water Name Drug group #† #† #† 10-hydroxy-amitriptyline Psychotropic NA NA 1 2-hydroxy-ibuprofen Antibiotic NA NA 1 MDMA Illicit drug NA NA 2 6-O-des-methyl-naproxen Analgesic NA NA 24 Alprazolam Psychotropic NA NA 1 Amitriptyline Psychotropic NA NA 1 Amoxicillin Antibiotic 10 12 317 Amphetamine Illicit drug NA NA 1 Ampicillin Antibiotic NA 12 41 Anhydrochlortetracycline Antibiotic NA 12 41 Anhydrotetracycline Antibiotic NA 12 19 Antipyrine Analgesic NA 4 12 Antipyrine or Phenazone Analgesic 13 NA NA Bacitracin Antibiotic 12 4 47 Bendroflumethiazide Diuretic 12 NA 23 Benzatropine Anticholinergic NA NA 1 Benzylpenicillin Antibiotic 12 NA 23 Butalibital Barbituate NA NA 47 Carbadox Antibiotic 27 16 467 Carisoprodol Muscle relaxant 12 NA 23 Cefotaxime Antibiotic NA 12 41 Cephalexin Antibiotic NA NA 17 Chloramphenicol Antibiotic 23 4 196 Chlorotetracycline Antibiotic NA 4 12 Clinafloxacin Antibiotic NA 12 41 Clofibrate Antilipidemic 15 NA NA Cloxacillin Antibiotic NA 12 41 Demeclocycline Antibiotic 4 24 190 Dexamethasone Glucocorticoid 8 4 27 Digoxigenin Cardiac glycoside NA NA 7 Digoxin Cardiac glycoside NA NA 83 Duloxetine Psychotropic NA NA 31 Enalapril Antihypertensive 18 19 NA Epi-anhydrochlortetracycline Antibiotic NA NA 19 Epi-anhydro-tetracycline Antibiotic NA NA 19 Epi-chlortetracycline Antibiotic NA NA 19 Epi-oxytetracycline Antibiotic NA NA 19 Epi-tetracycline Antibiotic NA NA 19 Fluvoxamine Psychotropic NA NA NA/16 Glipizide Antidiabetic NA NA 1 Glyburide Antidiabetic NA NA 1 Guaifenesin Expectorant NA NA NA Homomenthyl salicylate Sunscreen NA NA NA (continued)

Table A.2 (continued) Drinking DWTP Surface Water influent water Name Drug group #† #† #† Iohexol X-ray contrast agent 12 NA 23 Iso-chlortetracycline Antibiotic NA NA 19 Iso-epi-chlortetracyline Antibiotic NA NA 19 Ketorolac Analgesic 12 NA 23 Lidocaine Anesthetic 10 NA 19 Lisinopril Antihypertensive NA NA 17 Lomefloxacin Antibiotic NA 12 41 Meclocycline sulfosalicylate Antibiotic NA NA 125 Meclofenamic acid Analgesic 12 NA 23 Menthol Fragrance/ flavoring NA NA 19 methotrexate Cancer drug 4 NA 149 Miconazole Antifungal 4 12 112 Minocycline Antibiotic 4 12 190 Narasin Antibiotic 12 4 47 Nifedipine Antihypertensive 12 NA 23 Norverapamil Antihypertensive NA NA 1 Oleandomycin Antibiotic 12 4 47 Ormetoprim Antibiotic NA 12 41 Oxacillin Antibiotic NA 12 41 Oxolinic acid Antibiotic 12 12 64 Paroxetine metabolite Psychotropic NA NA 116 Penicillin G Antibiotic NA 16 65 Penicillin V Antibiotic NA 16 65 Phenazone Analgesic NA NA 39 Phenoxymethylpenicillin Antibiotic 12 NA 23 Prednisone Glucocorticoid 16 4 55 Promethazine Antihistamine NA NA 1 Propoxyphene Analgesic NA NA 1 Salinomycin Antibiotic 16 4 67 Sarfloxacin Antibiotic NA NA 22 Simvastatin Antilipidemic 12 4 47 Simvastatin (hydroxy acid) Antilipidemic 18 NA NA Sucralose Artifical sweetener 12 NA 23 Sulfamerazine Antibiotic 31 16 635 Sulfasalazine Analgesic 8 NA 15 Theophylline Bronchodilator 23 NA 58 Valproic acid Anticonvulsant NA NA 240 Verapamil Antihypertensive NA NA 1 Virginiamycin Antibiotic 20 16 499 Warfarin Anticoagulant 16 12 319 * Estimates of frequency of detection and ranges of detected concentrations are based on the publications summarized in this project and as such do not represent national occurrence statistics. †Total number of individual sample results identified in the publications summarized in this project NA − not analyzed or available

Table A.3 EDCs analyzed for but never detected in drinking water* EDC Group #† LOD (ng/L) 17 α-Estradiol Hormone 23 0.5 2,4,6-Trichlorophenol Alkylphenol 12 100 2,6-Di-tert-butylphenol Alkylphenol 10 25 2-Phenylphenol Alkylphenol 12 100 3-methyl-1(h)-indole Fragrance/ flavor 100 1000 4-Methylphenol Antimicrobial 10 25 5-methyl-1H-benzotriazole Anti-corrosive 96 2000 Acetophenone Fragrance/ flavor 96 500 Alpha-chlordane Herbicide 10 25 Androstenedione Hormone 27 0.3 Bensulfuron methyl Herbicide 89 18 Bromacil Herbicide 93 5-18 Butylparaben Preservative 6 5 Chloridazon Herbicide 6 5 Chlorpyriphos Insecticide 93 5-25 Chlortoluron Herbicide 6 5 Clorophene Preservative 2 0.1 DEHP Plasticizer 38 600 Dieldrin Herbicide 97 9-25 Diethylhexyl phthalate Plasticizer 33 120 Diethylstilbestrol Hormone 23 0.5 Digoxigenin Sterol 4 0 Dimethenamid ESA Herbicide 48 20 Equilenin Hormone 4 50 Equilin Hormone 4 0.3 Estradiol Hormone 31 1 Ethylparaben Preservative 12 20 Ethynylestradiol Hormone 84 0.3-0.5 Isobutylparaben Preservative 12 5 Isoproturon Herbicide 10 20 Levothyroxine Hormone 16 2 Lindane Insecticide 22 20 Metalaxyl Fungicide 87 7 Metazachlor Herbicide 12 5 Methoxychlor Herbicide 22 100 Methylparaben Preservative 12 20 Methyl-parathion Insecticide 10 25 Nonylphenol Alkylphenol 51 25-500 Norethisterone, 19- Hormone 12 5 (continued)

Table A.3 (continued) EDC Group #† LOD (ng/L) Octylphenol Alkylphenol 22 500 Oxybenzone Sunscreen ingredient 11 1.9 Pentachlorophenol Herbicide 87 100-2000 Prometryn Herbicide 87 5.9 Propazine Herbicide 12 5 Propoxur Insecticide 87 8 Propylparaben Preservative 12 5 Roxarsone Feed additive 8 0 Siduron Herbicide 0 20 Sulfometuron methyl Herbicide 89 90 Testosterone Hormone 70 0.3-200 Tetrabromobisphenol A Plasticizer 12 100 trans-Testosterone Hormone 12 0.1 Trichlorofluoromethane (CFC-11) Refrigerant 94 80 Triclocarban Antimicrobial 8 5 Tris(2,3-dichloro-propyl) phosphate Flame retardant 13 5 * Estimates of frequency of detection and ranges of detected concentrations are based on the publications summarized in this project and as such do not represent national occurrence statistics. †Total number of individual sample results identified in the publications summarized in this project CFC − chlorinated fluorocarbon; ESA − ethanesulfonic acid; LOD − limit of detection; NA − not available

SUPPORTING DOCUMENTATION FOR CHARACTERIZING POTENTIAL TOXICOLOGICAL SIGNIFICANCE AND HUMAN HEALTH EFFECTS

281 ©2015 Water Research Foundation. ALL RIGHTS RESERVED. Information was compiled to characterize the potential human health effects of PPCPs and EDCs identified as analyzed for in drinking or source water (data were compiled for compounds that were both detected and not detected), using the decision tree approach (Figure 3.1). The information compiled from literature sources includes (as appropriate and available) published ADIs or DWELs, group or chemical structure class, drug indication, mode/mechanism of action, minimum therapeutic dose, FDA pregnancy category, target organs, reported adverse effects and dose response data [including reported NOAELs and LOAELs]), MICs, and carcinogenicity and genotoxicity data. Data compiled for this task are summarized in Tables B.1 to B.13. These tables summarize:  Table B.1. Existing ADIs and MCLs from authoritative bodies for EDCs and non- pharmaceutical compounds detected in water. As shown, ADIs or MCLs were identified for 163 of 228 detected EDCs.  Table B.2 (non-EDC pharmaceuticals) and B.3 (pharmaceutical hormones). Lowest therapeutic doses and FDA pregnancy category. Comparison levels were calculated using a composite UF of 3,000, with an additional UF of 10 if the compound is either a nongenotoxic carcinogen or an EDC. As shown, comparison levels were derived using this approach for 128 PPCP ingredients and 10 EDCs.  Tables B.4 (non-EDC pharmaceuticals), B.5 (pharmaceutical hormones), and B.6 (EDCs and other non-pharmaceutical compounds without existing ADIs). NOAELs and LOAELs for noncarcinogenic endpoints, particularly endpoints assumed to be of most concern for long-term, low-dose exposure of sensitive population groups (e.g., reproductive and developmental effects), that resulted in the lowest calculated comparison level for each compound. Comparison levels were derived by dividing the selected “effect dose” by uncertainty factors. The majority of selected NOAELs / LOAELs were based on developmental or reproductive effects, or for EDCs, on endocrine-mediated effects. Overall, we identified NOAELs or LOAELs for 132 non- EDC pharmaceuticals, 10 pharmaceutical hormones, and 44 EDCs and other non- pharmaceutical compounds without existing ADIs.  Table B.7: Comparison levels for pharmaceuticals that are antibiotics based on MICs. MIC50 values were identified for 39 antibiotics were identified. Comparison levels were derived for these compounds.  Table B.8 (non-EDC pharmaceuticals), B.9 (hormones), and B.10 (EDCs and other non- pharmaceutical compounds without existing ADIs). Results of chronic carcinogenicity studies in animals and in vitro genotoxicity testing. Tumor incidence data were identified where available, and SFs and corresponding comparison levels were derived assuming an acceptable lifetime excess cancer risk of 1 × 10-6. Thirty-one non-EDC pharmaceuticals, three pharmaceutical hormones, and 15 EDCs and other non-pharmaceutical compounds without existing ADIs reportedly showed equivocal or positive evidence of genotoxic carcinogenicity in animal studies; of these compounds, tumor incidence data were located for nine, one, and eight compounds, respectively, and SFs were derived using a multi- stage carcinogenicity model (EPA 2012a).  Table B.11 (non-EDC pharmaceuticals) and B.12 (hormones): Use of the VSD approach proposed by Gaylor and Gold (1995) for compounds with evidence of genotoxic carcinogenicity in animals but without available tumor incidence data, to derive

comparison levels based on evidence of cancer. The lowest maximum tolerated dose identified from animal carcinogenicity studies for each compound was divided by a factor of 740,000 to derive a VSD assumed to correspond to a cancer risk of 1 in a million. Comparison levels were derived for four PPCP ingredients and one hormone using this approach.  Table B.13 (EDCs and other-nonpharmaceutical compounds without existing ADIs): Use of the TTC approach to assign comparison levels for compounds without available NOAELs or LOAELs or other toxicity data. Only two compounds— hexylcinnamaldehyde and hydrocinnamic acid— did not have values developed using other methods. For both of these, a TTC based on the scheme of Cheeseman et al. (1999) was applied.

Table B.1 Existing Acceptable Daily Intakes (ADIs) for EDCs and non-pharmaceutical compounds detected in water

from from Lowest EPA ATSDR Cal JEFCA Other EPA Cal EPA DWEL RfD MRL NSRL ADI ADI Oral SF Oral SF Oral SF Lowest Cal MCL or (mg/kg (mg/kg- (mg/kg- (mg/kg- (mg/kg- (mg/kg- (mg/kg- (mg/kg- DWEL MCL (µg/ MCL* Chemical -d) d) d) d) d) d)-1 d) d) (µg/L) (µg/L) L) (µg/L) Basis 0.07 0.0054 0.0001 1,4-Dichlorobenzene NA (chronic) 0.00029 NA NA (Cal) NA 9 6.5 5 75 75 EPA MCL

17 α-Estradiol NA NA NA NA NA NA NA NA NA NA NA NA

CalEPA 17 β-Estradiol NA NA 2.9E-7 5.0E-05 NA NA NA NA 0.010 NA NA 0.010 NSRL

17α-Ethynylestradiol NA NA NA NA NA NA NA NA NA NA NA NA

0.01 CalEPA 2,4’-DDD NA NA 2.9E-5 NA (JMPR) NA NA NA 1.0 NA NA 1.0 NSRL

0.01 CalEPA 2,4’-DDT NA NA 2.9E-5 NA (JMPR) NA NA NA 1.0 NA NA 1.0 NSRL

2,4-D Methyl ester NA NA NA NA NA NA NA NA NA 70 70 70 EPA MCL

2,4-Dichlorophenoxyacetic acid 0.01 (2,4-D) 0.01 NA NA NA (JMPR) NA NA NA NA 70 70 70 EPA MCL

20 2-Hydroxy atrazine NA NA NA NA (JMPR) NA NA NA 70,000 NA 3 3.0 EPA MCL

2-Methyl naphthalene 0.004 NA NA NA NA NA NA NA 140 NA NA 140 EPA RfD

2-methyl-4- chlorophenoxyacetic acid (MCPA) 0.0005 NA NA NA NA NA NA NA 18 NA NA 18 EPA RfD

2-Phenoxyethanol NA NA NA NA NA NA NA NA NA NA NA NA

Equal to 3,4-Dichloroaniline NA NA NA NA NA NA NA NA NA NA NA 70 Diuron

3-Indole-butyric acid NA NA NA NA NA NA NA NA NA NA NA NA (continued)

Table B.1 (continued)

from from Lowest EPA ATSDR Cal JEFCA Other EPA Cal EPA DWEL RfD MRL NSRL ADI ADI Oral SF Oral SF Oral SF Lowest Cal MCL or (mg/kg (mg/kg- (mg/kg- (mg/kg- (mg/kg- (mg/kg- (mg/kg- (mg/kg- DWEL MCL (µg/ MCL* Chemical -d) d) d) d) d) d)-1 d) d) (µg/L) (µg/L) L) (µg/L) Basis 0.01 0.24 4,4’-DDD NA NA 2.9E-5 NA (JMPR) (EPA) 4.2E-6 NA 0.2 NA NA 0.2 EPA SF

0.01 0.34 4,4’-DDE NA NA 2.9E-5 NA (JMPR) (EPA) 2.9E-6 NA 0.1 NA NA 0.1 EPA SF

0.0005 0.01 0.34 4,4’-DDT 0.0005 (int) 2.9E-5 NA (JMPR) (EPA) 2.9E-6 NA 0.1 NA NA 0.1 EPA SF

0.1 ATSDR 4-Methylphenol NA (chronic) NA NA NA NA NA NA 3500 NA NA 3500 MRL

4-n-Octylphenol NA NA NA NA NA NA NA NA NA NA NA NA

0.1 ATSDR 5-Chloro-m-cresol NA (chronic) NA NA NA NA NA NA 3500 NA NA 3500 MRL

5-Methyl-1H-benzotriazole NA NA NA NA NA NA NA NA NA NA NA NA

6-acetyl- 1,1,2,4,4,7- hexamethyltetralin (AHTN, Tonalide) NA NA NA NA NA NA NA NA NA NA NA NA

Acetochlor 0.02 NA NA NA NA NA NA NA 700 NA NA 700 EPA RfD

Acetochlor ethanesulfonic acid Equal to (ESA) NA NA NA NA NA NA NA NA 700 NA NA 700 Acetachlor

Equal to Acetochlor oxanilic acid NA NA NA NA NA NA NA NA 700 NA NA 700 Acetachlor Equal to Acetochlor sulfynilacetic acid NA NA NA NA NA NA NA NA 700 NA NA 700 Acetachlor Acetochlor/metolachlor ethane Equal to sulfonic acid 2nd amide NA NA NA NA NA NA NA NA 700 NA NA 700 Acetachlor (continued)

Table B.1 (continued)

Acridine NA NA NA NA NA NA NA NA NA NA NA NA 0.056 Alachlor 0.01 NA NA NA NA (Cal) NA 1.8E-5 0.6 2 2 2 EPA MCL

Alachlor ethanesulfonic acid Equal to (ESA) NA NA NA NA NA NA NA NA NA NA NA 2 Alachlor

Alachlor ethanesulfonic acid Equal to (ESA) 2nd amide NA NA NA NA NA NA NA NA NA NA NA 2 Alachlor

Equal to Alachlor oxanilic acid NA NA NA NA NA NA NA NA NA NA NA 2 Alachlor

Equal to Alachlor sulfynilacetic acid NA NA NA NA NA NA NA NA NA NA NA 2 Alachlor

0.0005 0.35 Alpha-chlordane 0.0005 NA 7.1E-6 NA (JMPR) (EPA) 2.9E-6 NA 0.1 NA 2 2 EPA MCL

Androstenedione NA NA NA NA NA NA NA NA NA NA NA NA

Androsterone NA NA NA NA NA NA NA NA NA NA NA NA

0.003 0.02 0.23 Atrazine 0.035 (int) NA NA (JMPR) (Cal) NA 4.4E-6 0.2 1 3 3 EPA MCL

Equal to Atrazine desethyl (DEA) NA NA NA NA NA NA NA NA 0.2 1 3 1 Atrazine

Atrazine-desethyl-desisopropyl Equal to (DACT) NA NA NA NA NA NA NA NA 0.2 1 3 1 Atrazine

0.004 Bendiocarb NA NA NA NA (JMPR) NA NA NA 140 NA NA 140 JMPR ADI (continued)

Table B.1 (continued)

from from Lowest EPA ATSDR Cal JEFCA Other EPA Cal EPA DWEL RfD MRL NSRL ADI ADI Oral SF Oral SF Oral SF Lowest Cal MCL or (mg/kg (mg/kg- (mg/kg- (mg/kg- (mg/kg- (mg/kg- (mg/kg- (mg/kg- DWEL MCL (µg/ MCL* Chemical -d) d) d) d) d) d)-1 d) d) (µg/L) (µg/L) L) (µg/L) Basis 0.1 Benomyl 0.05 NA NA NA (JMPR) NA NA NA 1800 NA NA 1800 EPA RfD

0.09 Bentazone 0.03 NA NA NA (JMPR) NA NA NA 1100 18 NA 18 Cal MCL

JECFA Benzophenone NA NA NA 0.01 NA NA NA NA 350 NA NA 350 ADI

Benzyl acetate NA NA NA NA NA NA NA NA NA NA NA NA

0.0006 5 1.8 Beta-BHC NA (int) NA NA (JMPR) (EPA) 5.6E-7 NA 0.019 NA NA 0.019 EPA SF

Biochanin A NA NA NA NA NA NA NA NA NA NA NA NA

Bisphenol A 0.05 NA NA NA NA NA NA NA 1800 NA NA 1800 EPA RfD

0.02 0.062 Bromodichloromethane 0.02 (chronic) 7.1E-5 NA NA (EPA) 1.6E-5 NA 0.6 NA NA 0.6 EPA SF

0.02 0.0079 Bromoform 0.02 (chronic) 0.00091 NA NA (EPA) 0.00013 NA 4.4 NA NA 4.4 EPA SF

Butylated hydroxyanisole 2.0E-4 (BHA) NA NA 0.057 500 NA (Cal) NA 0.005 180 NA NA 180 CalEPA SF

Butylated hydroxyl toluene 0.0036 (BHT) 0.3 NA NA 300 NA (EPA) 0.00028 NA 9.7 NA NA 9.7 EPA SF

CalEPA Butylbenzyl phthalate NA NA 0.017 NA NA NA NA NA 600 NA NA 600 NSRL

Campesterol JEFCA NA NA NA 40 NA NA NA NA 1.4E6 NA NA 1.4E6 ADI (continued)

Table B.1 (continued)

from from Lowest EPA ATSDR Cal JEFCA Other EPA Cal EPA DWEL RfD MRL NSRL ADI ADI Oral SF Oral SF Oral SF Lowest Cal MCL or (mg/kg (mg/kg- (mg/kg- (mg/kg- (mg/kg- (mg/kg- (mg/kg- (mg/kg- DWEL MCL (µg/ MCL* Chemical -d) d) d) d) d) d)-1 d) d) (µg/L) (µg/L) L) (µg/L) Basis 0.008 Carbaryl 0.1 NA NA NA (JMPR) NA NA NA 280 NA NA 280 JMPR ADI

Chlorimuron ethyl 0.02 NA NA NA NA NA NA NA 700 NA NA 700 EPA RfD

0.01 0.031 Chloroform 0.01 (chronic) 0.00029 NA NA (Cal) NA 3.2E-5 1.1 NA NA 1.1 CalEPA SF

Chlorophene NA NA NA NA NA NA NA NA NA NA NA NA

0.02 0.0031 Chlorothalonil 0.015 NA 0.00059 NA (JMPR) (Cal) NA 3.2E-4 11 NA NA 11 CalEPA SF

0.001 0.01 ATSDR Chlorpyriphos NA (chronic) NA NA (JMPR) NA NA NA 35 NA NA 35 MRL

Equal to Chlorpyrip Chlorpyriphos-oxon NA NA NA NA NA NA NA NA 35 NA NA 35 hos

Cholestanol NA NA NA NA NA NA NA NA NA NA NA NA

Cholesterol NA NA NA NA NA NA NA NA NA NA NA NA

Chrysin NA NA NA NA NA NA NA NA NA NA NA NA

0.5 cis-Nonachlor NA NA NA NA (JMPR) NA NA NA 18000 NA 2 2.0 EPA MCL

0.05 cis-Permethrin NA NA NA NA (JMPR) NA NA NA 1800 NA NA 1800 JMPR ADI cis-Testosterone NA NA NA NA NA NA NA NA NA NA NA NA

Coprostanol NA NA NA NA NA NA NA NA NA NA NA NA (continued)

Table B.1 (continued)

from from Lowest EPA ATSDR Cal JEFCA Other EPA Cal EPA DWEL RfD MRL NSRL ADI ADI Oral SF Oral SF Oral SF Lowest Cal MCL or (mg/kg (mg/kg- (mg/kg- (mg/kg- (mg/kg- (mg/kg- (mg/kg- (mg/kg- DWEL MCL (µg/ MCL* Chemical -d) d) d) d) d) d)-1 d) d) (µg/L) (µg/L) L) (µg/L) Basis JEFCA Coumestrol NA NA NA 40 NA NA NA NA 1.4E6 NA NA 1.4E6 ADI

0.84 Cyanazine 0.002 NA NA NA NA (EPA) 1.2E-6 NA 0.042 NA NA 0.042 EPA SF

0.02 Cypermethrin 0.01 NA NA NA (JMPR) NA NA NA 350 NA NA 350 EPA RfD

Dacthal 0.01 NA NA NA NA NA NA NA 350 NA NA 350 EPA RfD

Daidzein NA NA NA NA NA NA NA NA NA NA NA NA

Deethyldeiso propyl atrazine Equal to (DDA) NA NA NA NA NA NA NA NA NA NA 3 3 Atrazine

Equal to Deisopropyl atrazine (DIA) NA NA NA NA NA NA NA NA NA NA 3 3 Atrazine

Desmosterol NA NA NA NA NA NA NA NA NA NA NA NA

Equal to Desulfinyl fipronil NA NA NA NA NA NA NA NA NA NA NA 7.0 Fipronil

Equal to Desulfinyl fipronil amide NA NA NA NA NA NA NA NA NA NA NA 7.0 Fipronil

Di(ethylhexyl) phthalate 0.014 (DEHP) 0.02 NA 0.003 NA NA (EPA) 7.1E-5 NA 2.5 4 6 4 Cal MCL

0.0007 0.005 ATSDR Diazinon NA (chronic) NA NA (JMPR) NA NA NA 25 NA NA 25 MRL

Equal to Diazinon, oxygen analog NA NA NA NA NA NA NA NA NA NA NA 25 Diazinon (continued)

Table B.1 (continued)

from from Lowest EPA ATSDR Cal JEFCA Other EPA Cal EPA DWEL RfD MRL NSRL ADI ADI Oral SF Oral SF Oral SF Lowest Cal MCL or (mg/kg (mg/kg- (mg/kg- (mg/kg- (mg/kg- (mg/kg- (mg/kg- (mg/kg- DWEL MCL (µg/ MCL* Chemical -d) d) d) d) d) d)-1 d) d) (µg/L) (µg/L) L) (µg/L) Basis 0.084 Dibromochloromethane 0.02 NA NA NA NA (EPA) 1.2E-05 NA 0.4 NA NA 0.4 EPA SF

Dibutyl phthalate 0.1 NA NA NA NA NA NA NA 3500 NA NA 3500 EPA RfD

0.3 Dicamba 0.03 NA NA NA (JMPR) NA NA NA 1100 NA NA 1100 EPA RfD

0.0005 0.004 0.29 Dichlorvos 0.0005 (chronic) NA NA (JMPR) (EPA) 3.5E-6 NA 0.1 NA NA 0.1 EPA SF

0.0000 0.00005 0.0001 16 Dieldrin 5 (chronic) 5.7E-07 NA (JMPR) (EPA) 6.3E-8 NA 0.0022 NA NA 0.0022 EPA SF

ATSDR Diethyl phthalate NA 6 (int) NA NA NA NA NA NA 210000 NA NA 210,000 MRL

JEFCA Digoxigenin NA NA NA 40 NA NA NA NA 1.4E6 NA NA 1.4E6 ADI

0.07 Dimethenamid 0.05 NA NA NA (JMPR) NA NA NA 1750 NA NA 1750 EPA RfD

Dimethyl phthalate NA NA NA NA NA NA NA NA NA NA NA NA

Dinoseb 0.001 NA NA NA NA NA NA NA 35 7 NA 7 Cal MCL

Diuron 0.002 NA NA NA NA NA NA NA 70 NA NA 70 EPA RfD

0.005 0.006 ATSDR Endosulfan I 0.006 (chronic) NA NA (JMPR) NA NA NA 180 NA NA 180 MRL

0.006 Endosulfan sulfate NA NA NA NA (JMPR) NA NA NA 210 NA NA 210 JMPR ADI

Epicoprostanol NA NA NA NA NA NA NA NA NA NA NA NA (continued)

Table B.1 (continued)

Equilin NA NA NA NA NA NA NA NA NA NA NA NA

Ergosterol NA NA NA NA NA NA NA NA NA NA NA NA

Estriol NA NA NA NA NA NA NA NA NA NA NA NA

Estrone NA NA NA NA NA NA NA NA NA NA NA NA

Ethyl citrate NA NA NA NA NA NA NA NA NA NA NA NA

0.0002 Fipronil NA NA NA NA (JMPR) NA NA NA 7.0 NA NA 7.0 JMPR ADI

Equal to Fipronil sulfide NA NA NA NA NA NA NA NA NA NA NA 7.0 Fipronil

Equal to Fipronil sulfone NA NA NA NA NA NA NA NA NA NA NA 7.0 Fipronil

1.0 (US EPA Flumetsulam NA NA NA NA HED) NA NA NA 35000 NA NA 35,000 EPA HED

Formononetin NA NA NA NA NA NA NA NA NA NA NA NA

Galaxolide (HHCB) NA NA NA NA NA NA NA NA NA NA NA NA

0.00001 0.005 1.1 Gamma-BHC (Lindane) 0.0003 (int) NA NA (JMPR) (Cal) NA 9.0E-7 0.032 0.2 0.2 0.2 EPA MCL

Gamma-chlordane NA NA NA NA NA NA NA NA NA NA 2 2 EPA MCL

Genistein NA NA NA NA NA NA NA NA NA NA NA NA

Glycitein NA NA NA NA NA NA NA NA NA NA NA NA (continued)

Table B.1 (continued)

from from Lowest EPA ATSDR Cal JEFCA Other EPA Cal EPA DWEL RfD MRL NSRL ADI ADI Oral SF Oral SF Oral SF Lowest Cal MCL or (mg/kg (mg/kg- (mg/kg- (mg/kg- (mg/kg- (mg/kg- (mg/kg- (mg/kg- DWEL MCL (µg/ MCL* Chemical -d) d) d) d) d) d)-1 d) d) (µg/L) (µg/L) L) (µg/L) Basis 0.0001 9.1 Heptachlor Epoxide 1.3E-5 NA 1.1E-6 NA (JMPR) (EPA) 1.1E-7 NA 0.0038 0.01 0.2 0.2 EPA MCL

Hexahydro-1,3,5-trinitro-1,3,5- 0.1 0.11 triazine (RDX) 0.003 (chronic) NA NA NA (EPA) 9.1E-6 NA 0.3 NA NA 0.3 EPA SF

Hexazinone 0.033 NA NA NA NA NA NA NA 1200 NA NA 1200 EPA RfD

Hexylcinnamaldehyde NA NA NA NA NA NA NA NA NA NA NA NA

Hydrocinnamic acid NA NA NA NA NA NA NA NA NA NA NA NA

Imazaquin 0.25 NA NA NA NA NA NA NA 8800 NA NA 8800 EPA RfD

Imazethapyr 0.25 NA NA NA NA NA NA NA 8800 NA NA 8800 EPA RfD

0.06 Imidacloprid NA NA NA NA (JMPR) NA NA NA 2100 NA NA 2100 JMPR ADI

Indole NA NA NA NA NA NA NA NA NA NA NA NA

0.06 Iprodione 0.04 NA NA NA (JMPR) NA NA NA 1400 NA NA 1400 EPA RfD

Isobornyl acetate NA NA NA NA NA NA NA NA NA NA NA NA

Linuron 0.002 NA 0.0066 NA NA NA NA NA 70 NA NA 70 EPA RfD

Malaoxon NA NA NA NA NA NA NA NA NA NA NA NA

0.02 0.3 Malathion 0.02 (chronic) NA NA (JMPR) NA NA NA 700 NA NA 700 EPA RfD

Mecoprop 0.001 NA NA NA NA NA NA NA 35 NA NA 35 EPA RfD

Mestranol NA NA NA NA NA NA NA NA NA NA NA NA (continued)

Table B.1 (continued)

from from Lowest EPA ATSDR Cal JEFCA Other EPA Cal EPA DWEL RfD MRL NSRL ADI ADI Oral SF Oral SF Oral SF Lowest Cal MCL or (mg/kg (mg/kg- (mg/kg- (mg/kg- (mg/kg- (mg/kg- (mg/kg- (mg/kg- DWEL MCL (µg/ MCL* Chemical -d) d) d) d) d) d)-1 d) d) (µg/L) (µg/L) L) (µg/L) Basis 0.0005 0.1 Methoxychlor 0.005 (chronic) NA NA (JMPR) NA NA NA 18 30 40 40 EPA MCL

0.0018 0.0005 Methyl tert-butyl ether (MTBE) NA 0.3 (int) NA NA NA (Cal) NA 6 19 13 NA 13 Cal MCL

0.0002 Methyl-parathion 5 NA NA NA NA NA NA NA 8.8 NA NA 8.8 EPA RfD

Metolachlor 0.15 NA NA NA NA NA NA NA 5300 NA NA 5300 EPA RfD

Equal to Metolachlor ethanesulfonic acid Metola- (ESA) NA NA NA NA NA NA NA NA NA NA NA 5300 chlor

Equal to Metola- Metolachlor oxanilic acid (OA) NA NA NA NA NA NA NA NA NA NA NA 5300 chlor

Metribuzin 0.025 NA NA NA NA NA NA NA 880 NA NA 880 EPA RfD

Metsulfuron methyl 0.25 NA NA NA NA NA NA NA 8800 NA NA 8800 EPA RfD

Musk ketone NA NA NA NA NA NA NA NA NA NA NA NA

Musk xylene NA NA NA NA NA NA NA NA NA NA NA NA

0.03 Myclobutanil 0.025 NA NA NA (JMPR) NA NA NA 880 NA NA 880 EPA RfD

N,N-Diethyltoluamide (DEET) NA NA NA NA NA NA NA NA NA NA NA NA

N-Ethyl-perfluorooctane sulfonamide acetic acid (N- 0.00015 EtFOSAA) NA NA NA NA (EU) NA NA NA 5.3 NA NA 5.3 EU Panel (continued)

Table B.1 (continued)

from from Lowest EPA ATSDR Cal JEFCA Other EPA Cal EPA DWEL RfD MRL NSRL ADI ADI Oral SF Oral SF Oral SF Lowest Cal MCL or (mg/kg (mg/kg- (mg/kg- (mg/kg (mg/kg- (mg/kg (mg/kg- (mg/kg DWEL MCL (µg/ MCL* Chemical -d) d) d) -d) d) -d)-1 d) -d) (µg/L) (µg/L) L) (µg/L) Basis 150 N-nitrosodiethylamine (NDEA) NA NA 2.9E-7 NA NA (EPA) 6.7E-9 NA 0.0023 NA NA 0.00023 EPA SF

N-nitrosodimethylamine 51 0.0006 (NDMA) 8E-6 NA 5.7E-7 NA NA (EPA) 2.0E-8 NA 9 NA NA 0.00069 EPA SF

N-Nitroso-di-n-butylamine 5.4 (NDBA) NA NA 8.6E-7 NA NA (EPA) 1.9E-7 NA 0.0065 NA NA 0.0065 EPA SF

N-nitroso-methylethylamine 22 (NMEA) NA NA 4.3E-7 NA NA (EPA) 4.6E-8 NA 0.0016 NA NA 0.0016 EPA SF

2.1 N-nitrosopyrrolidine (NPYR) NA NA 4.3E-6 NA NA (EPA) 4.8E-7 NA 0.017 NA NA 0.017 EPA SF

Nonylphenol NA NA NA NA NA NA NA NA NA NA NA NA

Nonylphenol monoethoxylates NA NA NA NA NA NA NA NA NA NA NA NA

Nonylphenol diethoxylates (NP2EO) NA NA NA NA NA NA NA NA NA NA NA NA

Nonylphenol ether carboxylates NA NA NA NA NA NA NA NA NA NA NA NA

Nonylphenol ethoxylates NA NA NA NA NA NA NA NA NA NA NA NA

Nonylphenol triethyoxylate NA NA NA NA NA NA NA NA NA NA NA NA

Norethindrone NA NA NA NA NA NA NA NA NA NA NA NA

Octyl methoxy cinnamate NA NA NA NA NA NA NA NA NA NA NA NA

Octylphenol NA NA NA NA NA NA NA NA NA NA NA NA

(continued)

Table B.1 (continued)

from from Lowest EPA ATSDR Cal JEFCA Other EPA Cal EPA DWEL RfD MRL NSRL ADI ADI Oral SF Oral SF Oral SF Lowest Cal MCL or (mg/kg (mg/kg- (mg/kg- (mg/kg- (mg/kg- (mg/kg- (mg/kg- (mg/kg- DWEL MCL (µg/ MCL* Chemical -d) d) d) d) d) d)-1 d) d) (µg/L) (µg/L) L) (µg/L) Basis Octylphenol diethoxylate (total) (OP2EO) NA NA NA NA NA NA NA NA NA NA NA NA

Octylphenol diethoxylate, 4- NA NA NA NA NA NA NA NA NA NA NA NA

Octylphenol monoethoxylate (total) NA NA NA NA NA NA NA NA NA NA NA NA

Octylphenol monoethoxylate, 4- NA NA NA NA NA NA NA NA NA NA NA NA

Octylphenol, 4-tert- NA NA NA NA NA NA NA NA NA NA NA NA

Oxybenzone NA NA NA NA NA NA NA NA NA NA NA NA

0.007 ATSDR PBDE-100 0.1 (int) NA NA NA NA NA NA 250 NA NA 250 MRL

0.007 ATSDR PBDE-153 0.2 (int) NA NA NA NA NA NA 250 NA NA 250 MRL

0.007 ATSDR PBDE-154 0.2 (int) NA NA NA NA NA NA 250 NA NA 250 MRL

0.007 ATSDR PBDE-183 NA (int) NA NA NA NA NA NA 250 NA NA 250 MRL

PBDE-209 NA NA NA NA NA NA NA NA NA NA NA NA

0.007 ATSDR PBDE-28+PBDE-33 NA (int) NA NA NA NA NA NA 250 NA NA 250 MRL

0.007 ATSDR PBDE-47 0.1 (int) NA NA NA NA NA NA 250 NA NA 250 MRL

PBDE-99 ATSDR 0.1 NA NA NA NA NA NA 250 NA NA 250 MRL (continued)

Table B.1 (continued)

from from Lowest EPA ATSDR Cal JEFCA Other EPA Cal EPA DWEL RfD MRL NSRL ADI ADI Oral SF Oral SF Oral SF Lowest Cal MCL or (mg/kg (mg/kg- (mg/kg- (mg/kg- (mg/kg- (mg/kg- (mg/kg- (mg/kg- DWEL MCL (µg/ MCL* Chemical -d) d) d) d) d) d)-1 d) d) (µg/L) (µg/L) L) (µg/L) Basis 150 N-nitrosodiethylamine (NDEA) NA NA 2.9E-7 NA NA (EPA) 6.7E-9 NA 0.0023 NA NA 0.00023 EPA SF

N-nitrosodimethylamine 51 0.0006 (NDMA) 8E-6 NA 5.7E-7 NA NA (EPA) 2.0E-8 NA 9 NA NA 0.00069 EPA SF

N-Nitroso-di-n-butylamine 5.4 (NDBA) NA NA 8.6E-7 NA NA (EPA) 1.9E-7 NA 0.0065 NA NA 0.0065 EPA SF

N-nitroso-methylethylamine 22 (NMEA) NA NA 4.3E-7 NA NA (EPA) 4.6E-8 NA 0.0016 NA NA 0.0016 EPA SF

2.1 N-nitrosopyrrolidine (NPYR) NA NA 4.3E-6 NA NA (EPA) 4.8E-7 NA 0.017 NA NA 0.017 EPA SF

Nonylphenol NA NA NA NA NA NA NA NA NA NA NA NA

Nonylphenol monoethoxylates NA NA NA NA NA NA NA NA NA NA NA NA

Nonylphenol diethoxylates (NP2EO) NA NA NA NA NA NA NA NA NA NA NA NA

Nonylphenol ether carboxylates NA NA NA NA NA NA NA NA NA NA NA NA

Nonylphenol ethoxylates NA NA NA NA NA NA NA NA NA NA NA NA

Nonylphenol triethyoxylate NA NA NA NA NA NA NA NA NA NA NA NA

Norethindrone NA NA NA NA NA NA NA NA NA NA NA NA

Octyl methoxy cinnamate NA NA NA NA NA NA NA NA NA NA NA NA

Octylphenol NA NA NA NA NA NA NA NA NA NA NA NA

Octylphenol diethoxylate (total) (OP2EO) NA NA NA NA NA NA NA NA NA NA NA NA

(continued)

Table B.1 (continued)

from from Lowest EPA ATSDR Cal JEFCA Other EPA Cal EPA DWEL RfD MRL NSRL ADI ADI Oral SF Oral SF Oral SF Lowest Cal MCL or (mg/kg (mg/kg- (mg/kg- (mg/kg- (mg/kg- (mg/kg- (mg/kg- (mg/kg- DWEL MCL (µg/ MCL* Chemical -d) d) d) d) d) d)-1 d) d) (µg/L) (µg/L) L) (µg/L) Basis 0.2 p-Chloroaniline 0.004 NA 2.1E-05 NA NA (EPA) 5.0E-06 NA 0.2 NA NA 0.2 EPA SF

0.00015 p-chloro-m-xylenol (PCMX) NA NA NA NA (EU) NA NA NA 5.3 NA NA 5.3 EU Panel

Pendimethalin 0.04 NA NA NA NA NA NA NA 1400 NA NA 1400 EPA RfD

0.0007 Perchlorate 0.0007 (chronic) NA NA NA NA NA NA 25 6 NA 6 CalMCL

0.00015 Perfluorobutane-sulfonate NA NA NA NA (EU) NA NA NA 5.3 NA NA 5.3 EU Panel

0.00015 Perfluorobutanoic acid (C4) NA NA NA NA (EU) NA NA NA 5.3 NA NA 5.3 EU Panel

0.00015 Perfluoro-decanoic acid (C10) NA NA NA NA (EU) NA NA NA 5.3 NA NA 5.3 EU Panel

Perfluoro-dodecanoic acid 0.00015 (C12) NA NA NA NA (EU) NA NA NA 5.3 NA NA 5.3 EU Panel

0.00015 Perfluoroheptanoic acid (C7) NA NA NA NA (EU) NA NA NA 5.3 NA NA 5.3 EU Panel

0.00015 Perfluorohexane sulfonic acid NA NA NA NA (EU) NA NA NA 5.3 NA NA 5.3 EU Panel

0.00015 Perfluorohexane-sulfonate NA NA NA NA (EU) NA NA NA 5.3 NA NA 5.3 EU Panel

0.00015 Perfluorohexanoic acid (C6) NA NA NA NA (EU) NA NA NA 5.3 NA NA 5.3 EU Panel

Perfluorononanoic acid (C9) 0.00015 NA NA NA NA (EU) NA NA NA 5.3 NA NA 5.3 EU Panel (continued)

Table B.1 (continued)

from from Lowest EPA ATSDR Cal JEFCA Other EPA Cal EPA DWEL RfD MRL NSRL ADI ADI Oral SF Oral SF Oral SF Lowest Cal MCL or (mg/kg (mg/kg- (mg/kg- (mg/kg- (mg/kg- (mg/kg- (mg/kg- (mg/kg- DWEL MCL (µg/ MCL* Chemical -d) d) d) d) d) d)-1 d) d) (µg/L) (µg/L) L) (µg/L) Basis 0.00015 Perfluorooctane sulfinate NA NA NA NA (EU) NA NA NA 5.3 NA NA 5.3 EU Panel

0.00015 Perfluorooctane sulfonamide NA NA NA NA (EU) NA NA NA 5.3 NA NA 5.3 EU Panel

Perfluorooctane sulfonamide 0.00015 acetic acid NA NA NA NA (EU) NA NA NA 5.3 NA NA 5.3 EU Panel

Perfluorooctane sulfonic acid 0.00015 (PFOS) NA NA NA NA (EU) NA NA NA 5.3 NA NA 5.3 EU Panel

0.0015 Perfluorooctanoic acid (C8) NA NA NA NA (EU) NA NA NA 5.3 NA NA 53 EU Panel

0.00015 Perfluoropentanoic acid (C5) NA NA NA NA (EU) NA NA NA 5.3 NA NA 5.3 EU Panel

0.00015 Perfluoropropionic acid NA NA NA NA (EU) NA NA NA 5.3 NA NA 5.3 EU Panel

0.00015 Perfluoro-undecanoic acid NA NA NA NA (EU) NA NA NA 5.3 NA NA 5.3 EU Panel

Perflurobutyric acid NA NA NA NA NA NA NA NA NA NA NA NA

0.05 Permethrin 0.05 0.2 (int) NA NA (JMPR) NA NA NA 1800 NA NA 1800 EPA RfD

Perthane NA NA NA NA NA NA NA NA NA NA NA NA

Phathalic anhydride 2 NA NA NA NA NA NA NA 70000 NA NA 70000 EPA RfD

JEFCA Progesterone NA NA NA 3.0E-8 NA NA NA NA 0.0011 NA NA 0.0011 ADI

Prometon 0.015 NA NA NA NA NA NA NA 530 NA NA 530 EPA RfD

(continued)

Table B.1 (continued)

from from Lowest EPA ATSDR Cal JEFCA Other EPA Cal EPA DWEL RfD MRL NSRL ADI ADI Oral SF Oral SF Oral SF Lowest Cal MCL or (mg/kg (mg/kg- (mg/kg- (mg/kg- (mg/kg- (mg/kg- (mg/kg- (mg/kg- DWEL MCL (µg/ MCL* Chemical -d) d) d) d) d) d)-1 d) d) (µg/L) (µg/L) L) (µg/L) Basis Propyzamide 0.075 NA NA NA NA NA NA NA 2600 NA NA 2600 EPA RfD

0.12 Simazine 0.005 NA NA NA NA (EPA) 8.3E-06 NA 0.3 4 4 4 EPA MCL

JEFCA Sitosterol, beta- NA NA NA 40 NA NA NA NA 1.4E6 NA NA 1,400,000 ADI

JEFCA Stigmastanol, beta- NA NA NA 40 NA NA NA NA 1.4E6 NA NA 1,400,000 ADI

JEFCA Stigmasterol NA NA NA 40 NA NA NA NA 1.4E6 NA NA 1,400,000 ADI

0.0002 Terbufos sulfone NA NA NA NA (JMPR) NA NA NA 7.0 NA NA 7.0 JMPR ADI

50 JEFCA Testosterone NA NA NA 2.0E-9 (JMPR) NA NA NA 7.0E-5 NA NA 7.0E-5 ADI

0.00015 Total perfluorinated sulfonyls NA NA NA NA (EU) NA NA NA 5.30 NA NA 5.3 EU Panel

Total PFA NA NA NA NA NA NA NA NA NA NA 600 600 EPA MCL

Total SCCP NA NA NA NA NA NA NA NA NA NA NA NA

Equal to Trans-Nonachlor NA NA NA NA NA NA NA NA NA NA 2 2 chlordane

0.05 Trans-Permethrin NA NA NA NA (JMPR) NA NA NA 1800 NA NA 1800 JMPR ADI

Traseolide NA NA NA NA NA NA NA NA NA NA NA NA

Tri (dichloro-propyl) phosphate 0.02 CalEPA NA (chronic) 7.7E-5 NA NA NA NA NA 2.7 NA NA 2.7 NSRL (continued)

Table B.1 (continued)

0.05 Triclopyr NA NA NA NA TRED NA NA NA NA NA NA 1800 EPA TRED

3000 EPA Triclosan HHBP NA NA NA NA NA NA NA NA NA 2100 2100 HHBP

Trifluoroacetic acid NA NA NA NA NA NA NA NA NA NA NA NA

0.0077 Trifluralin 0.0075 NA NA NA NA (EPA) 0.00013 NA 4.5 NA NA 4.5 EPA SF

Trihalomethanes NA NA NA NA NA NA NA NA NA 80 80 80 EPA MCL

ATSDR Triphenyl phosphate NA 0.2 NA NA NA NA NA NA 7000 NA NA 7000 MRL

Tris (2-butoxyethyl) phosphate 0.09 ATSDR (TBEP) NA (int) NA NA NA NA NA NA 3200 NA NA 3200 MRL

Tris (2-chloroethyl) phosphate 0.2 0.02 (TCEP) 0.007 (chronic) NA NA NA (EPA) 5.0E-5 NA 1.8 NA NA 1.8 EPA SF

Tris (dichlorisopropyl 0.02 CalEPA phosphate) (TDCPP) NA (chronic) 0.0054 NA NA NA NA NA 190 NA NA 190 NSRL

Tris(2,3-dichloro-propyl) Equal to phosphate NA NA NA NA NA NA NA NA NA NA NA 1.8 TCEP *DWELs are calculated as follows: lowest value of the existing ADIs (mg/kg-d) 1000 µg/mg × 70 (kg) / 2 (L/d). ADI –Acceptable Daily Intake; EU – European Union Panel; JECFA – Joint FAO/WHO Expert Committee on Food Additives (http://apps.who.int/food- additives-contaminants-jecfa-database/chemical.aspx?chemID=1835); JMPR – Joint FAO/WHO Meeting on Pesticide Residues (http://www.who.int/foodsafety/chem/jmpr/en/), MCL – EPA Maximum Contaminant Level (http://water.epa.gov/drink/contaminants/); MRL – Minimum Risk Level from Agency for Toxic Substances and Disease Registry (ATSDR) (http://www.atsdr.cdc.gov/mrls/mrllist.asp); NA – not available, NSRL – No Significant Risk Level for California EPA for Proposition 65 (http://oehha.ca.gov/prop65/getNSRLs.html), PFA perfluorinated fatty acid; PBDE polybromodiphenyl ether; RfD – reference dose from EPA (http://www.epa.gov/region9/superfund/prg/), SCCP short chain chlorinated paraffins; SF – cancer slope factor estimated by the EPA or CalEPA (http://www.epa.gov/region9/superfund/prg/); TRED Tolerance Reassessment Progress and Risk Management

Table B.2 Lowest therapeutic doses for non-EDC pharmaceutical compounds and corresponding comparison levels Lowest Age group and Minimum UF and therapeutic dose assumed body therapeutic dose Pregnancy category & adverse Comparison value Compound (mg/d) Treatment endpoint weight (kg) (µg/kg-d) effects (µg/kg-d) Acetaminophen 650 Pain relief Adult, 70 9,000 NA 3,000 × 10* 0.31 µg/kg-d Albuterol 0.18 Reversible obstructive Adult, 70 2.6 C 3,000 × 10* airway disease 0.000090 µg/kg-d Alprazolam 0.5 Anxiety Adult, 70 7.1 D (neonatal flaccidity, 3,000 respiratory problems) 0.0020 µg/kg-d Amitriptyline (and 75 Antidepressant Adult, 70 1,100 C (delayed ossification, 3,000 metabolites) malformations) 0.36 µg/kg-d

Amoxicillin 750 Ear/nose/throat Adult, 70 11,000 B 3,000 infection 3.6 µg/kg-d Amphetamine 5.0 Attention deficit Child , 30 160 C (premature delivery, low 3,000 hyperactivity disorder birth weight) 0.060 µg/kg-d Ampicillin 1000 Respiratory tract Adult, 70 14,000 B 3,000 infections 16 µg/kg-d Antipyrene NA (topical Pain relief, NA NA C NA solution) inflammation Aspirin 325 Pain relief Adult, 70 4,600 NA 3,000 1.6 µg/kg-d Atenolol 25 Hypertension Adult, 70 360 D (low birth weight) 3,000 × 10* 0.012 µg/kg-d Atorvastatin 10 Hyper-cholesterolemia Child, 30 300 X (risk of congenital 3,000 × 10* abnormalities) 0.010 µg/kg-d Azithromycin 600 Infections caused by Adult, 70 8,600 B 3,000 Mycobacterium avium 2.9 µg/kg-d complex (continued)

Table B.2 (continued) Lowest Age group and Minimum UF and therapeutic dose assumed body therapeutic dose Pregnancy category & adverse Comparison value Compound (mg/d) Treatment endpoint weight (kg) (µg/kg-d) effects (µg/kg-d) Bacitracin NA No data on oral NA NA NA NA administration—IM administration only Bendroflumethiazide 5 Hypertension Adult, 70 71 C (evidence of embryo-and 3,000 fetotoxicity in rabbits at doses 0.024 µg/kg-d 5- 10 times greater on a mg/kg basis than maximum indicated human dose. No teratogenic potential observed). Benztropine 0.5 Anticholinergic drug Adult, 70 7 NA 3,000 0.012 µg/kg-d Benzylpenicillin Same as Same as Penicllin G Same as Penicllin G Same as Same as Penicllin G 0.60 µg/kg-d Penicllin G Penicllin G Benzyl salicylate Same as Same as salicylic acid Same as salicylic Same as Same as salicylic acid 1.5 µg/kg-d salicylic acid acid salicylic acid Bezafibrate 400 Antilipidemic Adult, 70 5,700 NA 3,000 1.9 µg/kg-d Bupropion 300 Antidepressant Adult, 70 4,300 C (fetal malformations, 3,000 skeletal variations) 1.4 µg/kg-d Butalbital 50 Tension headache Adult, 70 700 C (seizure) 3,000 0.23 µg/kg-d Camphor NA For topical use NA NA NA NA Carbadox NA Veterinary use NA NA NA NA Carbamazepine 10 Epilepsy Child <6, 10 1,000 D (developmental delays, 3,000 × 10* congenital abnormalities); 0.033 µg/kg-d severe and sometimes fatal dermatologic reactions Carisoprodol 250 Muscle relaxant Adult, 70 3,600 C (adverse effects on fetal 3,000 growth and postnatal survival) 1.2 µg/kg-d (continued)

Table B.2 (continued) Lowest Age group and Minimum UF and therapeutic dose assumed body therapeutic dose Pregnancy category & adverse Comparison value Compound (mg/d) Treatment endpoint weight (kg) (µg/kg-d) effects (µg/kg-d) Cefotaxime 500 Antibiotic 70 7,100 B 3,000 2.4 µg/kg-d Cephalexin 25 Antibiotic Pediatric, 10 2,500 B 3,000 0.83 µg/kg-d Chloramphenicol 1 Antibiotic Adult, 70 14 C (early embryonic 3,000 resorptions in animals) 0.0047 µg/kg-d Chlortetracycline NA Animal feed, weight NA NA NA NA (Aureomycin) gain and improved feed efficiency Cimetidine 400 Duodenal ulcer Adult, 70 5,700 B 3,000 ×10* 0.19 µg/kg-d Ciprofloxacin 250 Uncomplicated urethral Adult,70 3,600 C 3,000 and cervical 1.2 µg/kg-d gonoccoccal infection Citalopram 20 Antidepressant Adult, 70 290 C (decreased fetal growth and 3,000 survival, cardiovascular and 0.097 µg/kg-d skeletal defects) Clarithromycin 500 Antibiotic Adult, 70 7,100 C 3,000 2.4 µg/kg-d Clinafloxacin No data NA NA NA NA NA Clindamycin 75 Antibiotic Pediatric, 10 7,500 B 3,000 2.5 µg/kg-d Clofibric acid/ 2000 Antilipidemic Adult, 70 28,500 C (increased mortality) 3,000 clofibrate 9.5 µg/kg-d 3,000 Cloxacillin 250 Antibiotic Adult, 70 3,600 B 1.2 µg/kg-d Codeine 15 Pain relief Adult, 70 200 C 3,000 0.067 µg/kg-d Cyclophosphamide 70 Antineoplastic agent Adult, 70 1,000 D (ectrodactylia) 3,000 0.33 µg/kg-d (continued)

Table B.2 (continued) Lowest Age group and Minimum UF and therapeutic dose assumed body therapeutic dose Pregnancy category & adverse Comparison value Compound (mg/d) Treatment endpoint weight (kg) (µg/kg-d) effects (µg/kg-d) Demeclocycline 150 Antibiotic Adult, 70 2,100 D (congenital malformations) 3,000 0.71 µg/kg-d Dexamethasone 0.75 C Adult, 70 11 C (teratogenic in many species 3,000 when at doses equivalent to 0.0037 µg/kg-d the human dose; increased incidence of cleft palate) Diazepam 2 Antianxiety Adult, 70 29 D (congenital abnormalities, 3,000 neonatal respiratory and 0.0097 µg/kg-d feeding difficulties) Diclofenac 100 Pain relief Adult, 70 1,400 C (ductus arteriosus defects) 3,000 0.48 µg/kg-d Digoxin 0.01 Anti-arrythmia drug Adult, 70 0.14 C (no information on 3,000 developmental/reproductive 0.000047 µg/kg-d toxicity) Diltiazem (and 120 Anti-hypertensive Adult, 70 1,700 C 3,000 metabolites) 0.57 µg/kg-d Diphenhydramine 25 Upper respiratory Adult, 70 360 B (retrolental fibroplasia in 3,000 allergies premature infants, cleft palate) 0.12 µg/kg-d Doxycycline 100 Malaria prophylaxis Adult, 70 1,400 D (congenital abnormalities) 3,000 × 10* 0.047 µg/kg-d Duloxetine 40 Depression, anxiety 70 571 C (decreased fetal weight in 3,000 animal studies) 0.19 µg/kg-d Enalapril (and 10 Antihypertensive Adult, 70 143 D (increased mortality) 3,000 metabolites) 0.048 µg/kg-d Enrofloxacin NA Veterinary use NA NA NA NA Ephedrine 25 Stimulant Adult, 70 357 C 3,000 0.12 µg/kg-d Erythromycin 300 Antibiotic Pediatric, 10 30,000 B 3,000 10 µg/kg-d (continued)

Table B.2 (continued) Lowest Age group and Minimum UF and therapeutic dose assumed body therapeutic dose Pregnancy category & adverse Comparison value Compound (mg/d) Treatment endpoint weight (kg) (µg/kg-d) effects (µg/kg-d) Fenoprofen 200 Pain relief Adult, 70 2,900 C-D ( premature closure of the 3,000 ductus arteriosus) 0.95 µg/kg-d Flumequine Removed from Antibiotic NA NA NA NA clinical use Fluorouracil NA Topical use only NA NA NA NA Fluoxetine (and 10 Depression, obsessive Pediatric (children 330 C (shortened gestation, 3,000 metabolites) compulsive disorder & adolescents), 30 reduced birth weight, poor 0.11 µg/kg-d neonatal adaptation) Fluvoxamine 100 Obsessive-compulsive Adult, 70 1,400 C (decreased fetal body weight 3,000 disorder and survival) 0.48 µg/kg-d Furosemide 200 Diuretic Adult, 70 290 C (maternal death, fetal 3,000 abortions) 0.095 µg/kg-d Gabapentin 1800 Anticonvulsant Adult, 70 25,700 C (delayed ossification, renal 3,000 × 10* malformations) 0.86 µg/kg-d Gemfibrozil 1,200 Lipid regulation Adult, 70 17,000 C; gall bladder disease 3,000 × 10* 0.57 µg/kg-d Glipizide 5 Anti-diabetic Adult, 70 71 C (fetal toxicity, neonatal 3,000 hypoglycemia) 0.024 µg/kg-d Glyburide 2.5 Type II diabetes Adult, 70 36 C (fetal toxicity, neonatal 3,000 hypoglycemia) 0.012 µg/kg-d Guaifenesin 200 Expectorant Adult, 70 2,900 C 3,000 0.95 µg/kg-d Hydrochlorothiazide 12.5 Antihypertensive Adult, 70 180 C-D (fetal/neonatal morbidity 3,000 and mortality) 0.060 µg/kg-d Hydrocodone 5 Pain relief Adult, 70 71 C (neonatal withdrawal) 3,000 0.024 µg/kg-d Hydrocortisone 100 Corticosteriod Adult, 70 1,400 C 3,000 × 10† 0.047 µg/kg-d (continued)

Table B.2 (continued) Lowest Age group and Minimum UF and therapeutic dose assumed body therapeutic dose Pregnancy category & adverse Comparison value Compound (mg/d) Treatment endpoint weight (kg) (µg/kg-d) effects (µg/kg-d) Ibuprofen (and 200 Pain relief Adult, 70 2,900 C 3,000 metabolites) 0.97 µg/kg-d Indomethacin 75 Pain relief Adult, 70 1,100 C ( premature closure of the 3,000 ductus arteriosus) 0.36 µg/kg-d Ketoprofen 200 Pain relief Adult, 70 2,900 C ( premature closure of the 3,000 ductus arteriosus) 0.95 µg/kg-d Ketorolac 40 Pain relief Adult, 70 570 C (no evidence of reproductive 3,000 effects in animals) 0.19 µg/kg-d Lasalocid NA Veterinary use NA NA NA NA Lidocaine 90 Anesthesia Child, 30 3,000 B (no evidence of harm to 3,000 fetus in studies in rats) 1.0 µg/kg-d Lincomycin 100 Antibiotic Pediatric, 10 10,000 C 3,000 3.3 µg/kg-d Lomefloxacin 400 Antibiotic Adult, 70 5,700 C (maternal and fetal toxicity 3,000 in animals) 1.9 µg/kg-d Meclofenamic acid 2,000 Pain relief Adult, 70 28,600 C (no evidence of reproductive 3,000 effects in animals) 9.5 µg/kg-d Meprobamate 200 Anxiety Child, 30 6,700 NA ( congenital 3,000 malformations) 2.2 µg/kg-d Metformin 1000 Type 2 diabetes Adult, 70 14,000 B 3,000 × 10* 0.48 µg/kg-d Methadone 5 Pain relief Adult, 70 71 C (teratogenic, increased 3,000 neonatal mortality) 0.02 µg/kg-d Methotrexate 5 Antineoplastic agent Adult, 70 71 X (teratogenic, fetal mortality) 3,000 0.02 µg/kg-d Metoprolol 25 Antihypertensive Adult, 70 360 C (decreased neonatal 3,000 × 10* survival) 0.012 µg/kg-d Miconazole 100 Yeast infection Adult, 70 1,400 C 3,000 0.48 µg/kg-d (continued)

Oleandomycin 250 Antibiotic 70 3,600 NA 3,000 1.2 µg/kg-d

Ormetoprim NA Veterinary use NA NA NA NA

Oxacillin 250 Antibiotic 70 3,600 B 3,000 1.2 µg/kg-d

Oxolinic acid NA Veterinary use NA NA NA NA Oxytetracycline 250 E. coli infection Adult, 70 3,600 D ( Enamel hypoplasia) 3,000 1.2 µg/kg-d Penicillin G (and 125 Antibiotic 70 1,800 B 3,000 metabolites) 0.60 µg/kg-d Penicillin V 125 Antibiotic 70 1,800 B 3,000 0.60 µg/kg-d Pentoxifylline 800 Blood viscosity- Adult, 70 11,000 C 3,000 reducing agent 3.7 µg/kg-d Phenytoin 300 Epilepsy Adult, 70 4,300 D (congenital abnormalities) 3,000 1.4 µg/kg-d (continued)

Table B.2 (continued) Lowest Age group and Minimum UF and therapeutic dose assumed body therapeutic dose Pregnancy category & adverse Comparison value Compound (mg/d) Treatment endpoint weight (kg) (µg/kg-d) effects (µg/kg-d) Prednisone 5 Corticosteroid Adult, 70 71 C 3,000 × 10† 0.002 µg/kg-d Primidone 100 Anticonvulsant Adult, 70 1,400 NA 3,000 0.48 µg/kg-d Propranolol 80 Hypertension, angina Adult, 70 1,100 C ( bradycardia, hypotension, 3,000 and hypoglycemia) 0.37 µg/kg-d Ranitidine 120 Duodenal and gastric Child, 30 4,000 B 3,000 ulcer 1.3 µg/kg-d Risperidone 1 Antipsychotic Adult, 70 14 C (neonatal withdrawal) 3,000 × 10* 0.0005 µg/kg-d Roxithromycin 300 Antibiotic Adult, 70 4,300 NA (not marketed in US) 3,000 1.4 µg/kg-d Salicylic acid (and 325 (based on Pain reflief Adult, 70 4,600 D 3,000 metabolites) acetyl salicylic 1.5 µg/kg-d acid) Salinomycin NA Veterinary use NA NA NA NA Sarafloxacin NA Veterinary use NA NA NA NA Simvastatin (and 100 Antilipidemic Adult, 70 140 X 3,000 × 10* metabolites) 0.005 µg/kg-d Sulfachloropyridazine NA Veterinary use NA NA NA NA Sulfadiazine 1,000 Rheumatic fever Adult, 70 14,000 C ( neonatal jaundice and 3,000 prophylaxis kernicterus) 4.8 µg/kg-d Sulfadimethoxine NA Veterinary use NA NA NA NA Sulfamerazine 1,336 Antibiotic Adult, 70 19,000 C 3,000 6.3 µg/kg-d Sulfamethazine 1,336 Antibiotic Adult, 70 19,000 C 3,000 × 10* 0.63 µg/kg-d Sulfamethizole 1,000 Antibiotic Adult, 70 14,300 C 3,000 × 10* 0.48 µg/kg-d (continued)

308 ©2015 Water Research Foundation. ALL RIGHTS RESERVED. Table B.2 (continued) Lowest Age group and Minimum UF and therapeutic dose assumed body therapeutic dose Pregnancy category & adverse Comparison value Compound (mg/d) Treatment endpoint weight (kg) (µg/kg-d) effects (µg/kg-d) Sulfamethoxazole 400 Urinary tract infection Child (>2 months), 13,000 C 3,000 30 4.3 µg/kg-d Sulfasalazine 90 Antibiotic Child, 30 3,000 C 3,000 1.0 µg/kg-d Sulfathiazole Animal use NA NA NA NA NA Tetracycline (and 1000 Bacterial infection Adult, 70 14,000 D ( congenital defects, enamel 3,000 metabolites) hypoplasia) 4.8 µg/kg-d Theophylline 2 Bronchodilator Pediatric, 10 200 C 3,000 0.067 µg/kg-d Thiabendazole 500 Trichinosis, roundworm Child, 14 35,700 C 3,000 12 µg/kg-d Trimethoprim 80 Urinary tract infection Pediatric, 10 8,000 C 3,000 2.7 µg/kg-d Tylosin NA Veterinary use NA NA NA NA Valproic acid 5 Anticonvulsant Adult, 70 71 D (congenital malformations, 3,000 × 10* neural tube defects) 0.0020 µg/kg-d Virginiamycin NA Veterinary use NA NA NA NA Warfarin 2 Anticoagulant Adult, 70 29 D (congenital malformations, 3,000 fetal mortality) 0.010 µg/kg-d (Source: RxList.com 2013b) *Additional UF of 10 was applied because compound shows evidence of being a nongenotoxic carcinogen †Additional UF of 10 was applied because the compound is a purported EDC ADHD – Attention deficit hyperactivity disorder, NA – Not available, UF – Uncertainty factor

Table B.3 Lowest therapeutic doses for pharmaceutical hormones (EDCs) and corresponding comparison levels Age group and UF and Lowest therapeutic assumed body weight Minimum therapeutic Pregnancy category & comparison level Compound dose (mg/d) Treatment endpoint (kg) dose (µg/kg-d) adverse effects (µg/kg-d) Equilenen 0.3125 (conjugated Hormone replacement Adult, 70 4.5 X 3,000 × 10† estrogens) therapy (atrophic 0.00015 µg/kg-d Vaginitis and Kraurosis Vulvae) Equilin 0.3125 (conjugated Hormone replacement Adult, 70 4.5 X 3,000 × 10† estrogens) therapy (atrophic 0.00015 µg/kg-d Vaginitis and Kraurosis Vulvae) Ergosterol 1.25 (ergocalciferol) Hypoparathyroidism Adult, 70 18.0 C; fetal abnormalities 3,000 × 10† (supravalvular aortic 0.00060 µg/kg-d stenosis, elfin facies, mental retardation) Estradiol 0.5 Vulvar atrophy, Adult, 70 7.1 X; Increased risk of 3,000 × 10*† atrophic vaginitis, myocardial 0.00020 µg/kg-d ovary problems, infarction and stroke, symptoms of endometrial menopause cancer, gall bladder disease Estrone 0.014 (injected) Ovary problems Adult, 70 0.20 X; Increased risk of 3,000 × 10*† (female myocardial infarction 0.0000070 µg/kg-d hypogonadism or and stroke, failure or removal of endometrial cancer, both ovaries) breast cancer Ethynylestradiol 0.02 Hormone replacement Adult, 70 0.29 X; Increased risk of 3,000 × 10† therapy thromboembolism, 0.000010 µg/kg-d myocardial infarction and stroke, endometrial cancer, breast cancer Mestranol 0.0125 Hormone replacement Adult, 70 0.18 X 3,000 × 10† therapy 0.0000060 µg/kg-d (continued)

Table B.3 (continued) Age group and UF and Lowest therapeutic assumed body weight Minimum therapeutic Pregnancy category & comparison level Compound dose (mg/d) Treatment endpoint (kg) dose (µg/kg-d) adverse effects (µg/kg-d) Norethindrone 0.35 (oral) Oral contraceptive Adult, 70 5.0 X; (vaginal adenosis, 3,000 × 10*† squamous cell 0.00016 µg/kg-d dysplasia of the uterine cervix, and vaginal cancer development in female offspring and an increased risk of urogenital abnormalities and testicular cancer in male offspring.) Progesterone 400 (oral) Secondary Adult, 70 5,700 B 3,000 × 10*† amenorrhea 0.19 µg/kg-d Testosterone 50 (topical) Replacement therapy Adult, 70 710 X (teratogenic) 3,000 × 10*† in adult males for 0.023 µg/kg-d deficiency or absence of endogenous testosterone *Additional UF of 10 was applied because compound shows evidence of being a nongenotoxic carcinogen (see Table B.8) †Additional UF of 10 was applied because compound shows evidence of being a potential endocrine disrupting compound UF – uncertainty factor

Table B.4 Lowest effect doses for noncancer toxicity endpoints for non-EDC pharmaceuticals and corresponding comparison levels UF and Species/Gender/ Effect dose Comparison Compound Study duration (mg/kg-d) Effect Reference level (µg/kg-d) Acetaminophen Rat/M/28 wks 200 (NOAEL) No changes in weight gain, gross (Thomas et al. 1977) 1,000 × 10* pathology, or histologic findings in 20 µg/kg-d liver, kidney, heart, or lungs Albuterol (aka Salbutamol) Mice/F/Gestation 0.025 (NOAEL) Developmental (cleft palate) (Drugs.com 2010a) 1,000 × 10* 0.0025 µg/kg-d Alprazolam Mice/F/GD18 0.32 (LOAEL) Developmental (postnatal behavioral (Christensen et al. 2003) 3,000 changes in exposed pups) 0.00011 µg/kg-d Amitriptyline Rat/F/Gestation 25 (LOAEL) Developmental (delayed ossification) (Drugs.com 2012b) 3,000 8.3 µg/kg-d Amoxicillin Rats/ Multi-generation 500 (NOAEL) Reproductive (Drugs.com 2012c) 1,000 500 µg/kg-d Amphetamine Rat/F/GD 12-15 0.5 (LOAEL) Reproductive/developmental (NTP 2005) 3,000 (decreased pups/litter at birth) 0.16 µg/kg-d Ampicillin Rat/ /103 wks 750 (LOAEL) Systemic (Gastrointestinal tract) (Pfizer Inc. 2007a) 3,000 250 µg/kg-d Antipyrine or Phenazone Rat/ F/ GD 6-15 10 (NOAEL) Developmental/Reproductive (CalEPA 1990) 1,000 (maternal decreased food 10 µg/kg-d consumption and body weight) Aspirin Rat/F/GD19-21 10 (LOAEL) Developmental (increased fetal (NLM 2008) 3,000 mortality, delayed parturition) 3.3 µg/kg-d Atenolol Human/F/Gestation 0.8 (LOAEL) Developmental (decreased (Bayliss et al. 2002, Lip et al. 3,000 × 10* infant birth weights) 1997, Lydakis et al. 1999) 0.027 µg/kg-d Atorvastatin Rat/ M/ 20 (LOAEL) Developmental (reduced acoustic (Henck et al.1998) 3,000 × 10* GD7-PND21 startle) 0.67 µg/kg-d Azithromycin Dog/Neonatal 10 (LOAEL) Phospholipidosis in the eye, dorsal (Drugs.com 2012e) 3,000 root ganglia, liver, gallbladder, 3.3 µg/kg-d kidney, spleen, and pancreas (continued)

Table B.4 (continued) UF and Species/Gender/ Effect dose Comparison Compound Study duration (mg/kg-d) Effect Reference level (µg/kg-d) Bacitracin Rat/F/GD 7-17 11 (LOAEL) Developmental/Reproductive (EMEA 1998a) 3,000 (maternal decreased body weight 3.7 µg/kg-d gain, increased water intake) Bendoflumethiazide Dog/M,F/ 6 months 20 (LOAEL) Systemic toxicity (increased serum (FDA 1983) 3,000 potassium, increased adrenal weight) 6.7 µg/kg-d Benzatropine No data NA NA NA NA Benzoylecgonine Metabolite of cocaine See parent See parent compound See parent compound 0.7 µg/kg-d compound Benzylpenicillin Same as Penicillin G NA NA NA NA Benzyl salicylate No data NA NA NA NA Bezafibrate No data NA NA NA NA Bupropion Rat/2yr 100 (LOAEL) Hepatic lesions (NLM 2010a) 3,000 33 µg/kg-d Butalbital No data NA NA NA NA Caffeine Human/F/Early childhood 2.5 (LOAEL) Behavioral (increased anxiety) (Nawrot et al. 2003) 3,000 × 10† 0.083 μg/kg-d Camphor Rabbit/F/Gestation 681 (NOAEL) Developmental/Reproductive (NLM 2010b) 1,000 (teratogenicity) 680 μg/kg-d Carbadox Rat/F/GD 8-15 10 (LOAEL) Developmental/Reproductive (Yoshimura 2002) 3,000 (decreased maternal body weight) 3.3 µg/kg-d Carbamazepine Human/F /Gestation 3 (LOAEL) Developmental (neural tube, (Hernandez-Diaz et al. 2000, 3,000 × 10* cardiovascular, oral clefts, urinary Samren et al. 1997, Samren 0.10 µg/kg-d tract defects) et al.1999) Carisoprodol Rat/M,F/13 wks 100 (NOAEL) Systemic toxicity (NTP 2000b) 1,000 100 µg/kg-d Cefotaxime Rat (specific details not 250 (NOAEL) Developmental/Reproductive (RxList.com 2011a) 1,000 given) (impaired fertility) 250 µg/kg-d (continued)

Table B.4 (continued) UF and Species/Gender/ Effect dose Comparison Compound Study duration (mg/kg-d) Effect Reference level (µg/kg-d) Cephalexin Mice, Rat/F/Gestation 66 (NOAEL) Developmental/Reproduction (Drugs.com 2013a) 1,000 66 µg/kg-d Chloramphenicol Mice/F/Gestation 25 (LOAEL) Developmental (neurobehavioral (IARC 1990) 3,000 deficits in pups) 8.3 µg/kg-d Chlortetracycline Humans/premature infants 25 (LOAEL) Developmental (decreased fibula (CorePharma 2012) 3,000 growth rate) 8.3 µg/kg-d Cimetidine Rat/ 150 (LOAEL) Reproductive (reduced prostate and (Drugs.com 2011a) 3,000 × 10* 2 years seminal vesicle weights) 5.0 µg/kg-d Ciprofloxacin Dog (juvenile)/2 wks 10 (NOAEL) Systemic toxicity (arthropathy) (NLM 2011a) 1,000 10 µg/kg-d Citalopram Rat/F/Gestation through 12.8 (NOAEL) Developmental/Reproductive (Drugs.com 2007) 1,000 weening (offspring mortality, decreased 13 µg/kg-d mating) Clarithromycin Rabbit/F/ GD6-15 125 (NOAEL) Developmental (Drugs.com 2012f) 1,000 130 µg/kg-d Clinafloxacin No data NA NA NA NA Clindamycin Rat 300 (NOAEL) Reproductive (fertility and mating) (Drugs.com 2012g) 1,000 300 µg/kg-d Clofibrate/Clofibric acid Rat/M,F/Before mating 200 (LOAEL) Developmental/Reproductive (IARC 1980) 3,000 through gestation (decreased litter size) 67 µg/kg-d Cloxacillin Mice/F/ GD11 and 15 21 (LOAEL) Immunotoxicity (increased spleen (Dostal et al. 1994) 3,000 anti-SRBC IgM) 7.0 µg/kg-d Cocaine Monkey/M 0.2 (LOAEL) Reproductive (male copulatory (Pomerantz et al. 1994) 3,000 behavior) 0.067 µg/kg-d Codeine Mice/F/Gestation 100 (LOAEL) Developmental (delayed ossification (Drugs.com 2012h) 3,000 in the offspring) 33 µg/kg-d (continued)

Table B.4 (continued) UF and Species/Gender/ Effect dose Comparison Compound Study duration (mg/kg-d) Effect Reference level (µg/kg-d) COOH-ibuprofen Metabolite of ibuprofen See parent See parent compound See parent compound 1.0 µg/kg-d compound Cotinine Metabolite of nicotine See parent See parent compound See parent compound 0.080 μg/kg-d compound Cyclophosphamide Mice/F/GD 6-18 2.5 (NOAEL) Developmental (maternal toxicity, (Liakopoulou et al. 1989) 1,000 neonatal mortality) 2.5 µg/kg-d Dehydronifedipine Metabolite of nifedipine See parent See parent compound See parent compound 2.0 µg/kg-d compound Demeclocycline Humans/premature infants 25 (LOAEL) Developmental (decreased fibula (CorePharma 2012) 3,000 growth rate) 8.3 µg/kg-d Desmethyldiltiazem Metabolite of diltiazem See parent See parent compound See parent compound 11 µg/kg-d compound Dexamethasone Human/ pre-term infants 0.125 (LOAEL) Developmental (left ventricular (Zecca et al. 2001) 3,000 PND 4-7 myocardial hypertrophy) 0.042 µg/kg-d Diazepam Rat/F/Gestation 80 (NOAEL) Developmental/Reproductive (Drugs.com 2012i) 1,000 (offspring survival) 80 µg/kg-d Diclofenac Mouse/F/Gestation 20 (NOAEL) Developmental (no effect) (Novartis 2002) 1,000 20 µg/kg-d Digoxin Rat/M/4 wks 0.1 (NOAEL) Systemic toxicity (acetylcholine (NLM 2003) 1,000 concentration in atrium, increased 0.10 µg/kg-d heart rate, decreased weight gain) Diltiazem Mouse, rat, 32 (LOAEL) Reproductive/ developmental (Drugs.com 2011c) 3,000 rabbit/F/Pregnancy 11 µg/kg-d Diphenhydramine Rat/ 2 yrs 15 (NOAEL) Liver toxicity (Pfizer Inc. 2007b) 1,000 15 µg/kg-d Doxycycline Rat/ GD15-19; PND1 8 (LOAEL) Developmental (delayed skeletal (Siddiqui and Janjua 2002) 3,000 × 10* (pups) differentiation) 0.27 µg/kg-d

(continued)

Table B.4 (continued) UF and Species/Gender/ Effect dose Comparison Compound Study duration (mg/kg-d) Effect Reference level (µg/kg-d) Duloxetine Rat/F/Gestation through 5 (NOAEL) Developmental/Reproductive (RxList.com 2012) 1,000× 10* lactation (decreased pup weight) 1.0 µg/kg-d Enalapril Rabbit/ F/ GD 6-18 1 (LOAEL) Developmental/Reproductive (fetal (NLM 2012b) 3,000 and maternal toxicity) 0.33 µg/kg-d Enalaprilat Metabolite of Enalapril See parent See parent compound See parent compound 0.33 µg/kg-d compound Enrofloxacin Dog/14 days 5 (LOAEL) Systemic toxicity (Traş et al. 2001) 3,000 1.7 µg/kg-d Ephedrine Rat/F/GD 9-11 0.1 (LOAEL) Developmental/Reproductive (NLM 2007) 3,000 (cardiovascular malformations) 0.033 µg/kg-d Epi-anhydro-tetracycline Metabolite of Tetracycline See parent See parent compound See parent compound 8.3 µg/kg-d compound Epi-chlorotetracycline Metabolite of See parent See parent compound See parent compound 8.3 µg/kg-d Chlortetracycline compound Epi-tetracycline Metabolite of tetracycline See parent See parent compound See parent compound 8.3 µg/kg-d compound Erythromycin Rabbit/F/Gestation 125 (NOAEL) Developmental (Drugs.com 2012j) 1,000 130 µg/kg-d

Erythromycin-H2O Metabolite of See parent See parent compound See parent compound 130 µg/kg-d Erythromycin compound Fenoprofen Rats, rabbits 50 (NOAEL) Reproductive/developmental (RXList.com 2009) 1,000 50 µg/kg-d Flumequine Mice/M,F/90 days 10 (NOAEL) Systemic toxicity (hepatotoxicity) (EMEA 1999) 1,000 × 10* 1.0 µg/kg-d 5-Flourouracil Mice/F/ GD 9-12 10 (LOAEL) Developmental/Reproductive (fetal (Drugs.com 2012l) 3,000 malformations) 3.3 µg/kg-d (continued)

Table B.4 (continued) UF and Species/Gender/ Effect dose Comparison Compound Study duration (mg/kg-d) Effect Reference level (µg/kg-d) Fluoxetine Human/ F/ 0.29 (LOAEL) Developmental (shortened (NTP 2004) 3,000 Gestation gestation, reduced birth 0.97 µg/kg-d weight, poor adaptation) Fluvoxamine Rat/F Gestation through 5 (LOEAL) Developmental/Reproductive (Drugs.com 2013b) 3,000 lactation (decreased pup body weight and 1.7 µg/kg-d survival) Furosemide Rabbit/F/gestation 25 (LOAEL) Developmental/Reproductive (Drugs.com 2012m) 3,000 (maternal mortality, abortion) 8.3 µg/kg-d Gabapentin Rabbit/F/Gestation 60 (LOAEL) Developmental/Reproductive (Drugs.com 2013c) 3,000 ×10* (postimplantation fetal loss) 2.0 µg/kg-d Gemfibrozil Rat/ F/ GD15-PND21 92 (LOAEL) Developmental (reduced (Fitzgerald et al. 1981) 3,000 × 10* offspring body weights) 3.1 µg/kg-d Glipizide Rat/F/Gestation 5 (LOAEL) Developmental/Reproductive (mild (Drugs.com 2013d) 3,000 fetotoxicity) 1.7 µg/kg-d Glyburide No data NA NA NA NA Guaifenesin No data NA NA NA NA Hexylsalicylate No data NA NA NA NA Homomenthyl salicylate No data NA NA NA NA Hydrochlorothiazide Mice, Rat/M,F/Mating 100 (NOAEL) Developmental/Reproductive (Drugs.com 2012o) 1,000 through gestation (fertility, fetotoxicity) 100 µg/kg-d Hydrocodone No data NA NA NA NA 10-Hydroxy-amitriptyline Metabolite of See parent See parent compound See parent compound 8.3 µg/kg-d Amitriptyline compound 2-Hydroxy-ibuprofen Metabolite of Ibuprofen See parent See parent compound See parent compound 1.0 µg/kg-d compound Hydrocortisone Rat/F/GD 17-19 1.5 (LOAEL) Developmental/Reproductive (Piffer and Pereira 2004) 3,000 × 10† (fertility) 0.050 µg/kg-d (continued)

Table B.4 (continued) UF and Species/Gender/ Effect dose Comparison Compound Study duration (mg/kg-d) Effect Reference level (µg/kg-d) Ibuprofen Rat/F/GD21 1 (NOAEL) Cardiovascular/ (Momma and Takeuchi 1,000 developmental 1983) 1.0 µg/kg-d Ibuprofen methyl ester Metabolite of Ibuprofen See parent See parent compound See parent compound 1.0 µg/kg-d compound Indomethacin Rat/F/Third trimester 2.0 (LOAEL) Developmental/reproductive (Drugs.com 2012p) 3,000 (reduction and muscularization of 0.67 µg/kg-d pulmonary blood vessels) Iohexol NA (Note: compound is Assume same Assume same as iopromide Assume same as iopromide 5.0 µg/kg-d similar to Iopromide) as iopromide Iopromide Human/ M,F/PND 3-7 150 (LOAEL) Endocrine (higher mean thyrotropin (Parravicini et al. 1996) 3,000 × 10 and lower free triiodothyronine and 5.0 µg/kg-d thyroxine in infants) Iso-chlorotetracycline Metabolite of See parent See parent compound See parent compound 8.3 µg/kg-d Chlortetracycline compound Iso-epi-chlorotetracyline Metabolite of See parent See parent compound See parent compound 8.3 µg/kg-d Chlortetracycline compound Ketoprofen Rat/F/Gestation 6 (LOAEL) Developmental/Reproductive (Drugs.com 2012q) 3,000 (decreased implantation) 2.0 µg/kg-d Ketorolac Rat/M,F (duration not 9 (NOAEL) Reproductive (impaired fertility) (FDA 2009) 1,000 given) 9.0 µg/kg-d Lasalocid Rat/multi-generational 0.5 (NOAEL) Developmental/Reproductive (EMEA 2004) 1,000 (decreased pregnancy and fertility 0.50 µg/kg-d rates, survival, litter size) Lidocaine Sheep/F/ Continuous IV 5.8 (LOAEL) Systemic toxicity (convulsions, (Morishima et al. 1990) 3,000 infusion in pregnant hypotension, respiratory arrest, and 1.9 µg/kg-d animals circulatory collapse) Lincomycin Dog/F/Gestation 50 (NOAEL) Developmental (Pharmacia & Upjohn 1995) 1,000 50 µg/kg-d (continued)

Table B.4 (continued) UF and Species/Gender/ Effect dose Comparison Compound Study duration (mg/kg-d) Effect Reference level (µg/kg-d) Lomefloxacin Rat/F/GD7-17 30 (NOAEL) Developmental/Reproductive (Tesh et al. 1988) 1,000 (decreased maternal body weight 30 µg/kg-d gain and food intake) Meclofenamic acid Rat/M,F/Multigenerational 3 (NOAEL) Developmental/Reproductive (Petrere et al. 1985) 1,000 (prolonged gestation,decreased 3.0 µg/kg-d weanling weights, and increased weanling mortality) Meprobamate Mouse/ 13 wks 75 (NOAEL) Systemic (increased liver (NTP 2000a) 1,000 weights) 75 µg/kg-d Menthol Rat/28 d 200 (LOAEL) Increased liver weight and (Thorup et al. 1983) 1,000 vacuolization of hepatocytes 200 µg/kg-d Metformin Rat, Rabbit/M, F 600 (NOAEL) Reproductive/ (Drugs.com 2012r) 1,000 × 10* developmental 60 µg/kg-d Methadone Mice/F/GD 9 22 (LOAEL) Developmental/Reproductive (Drugs.com 2010b) 3,000 (exencephaly) 7.3 µg/kg-d Methotrexate Cat/F/Gestation 0.5 (LOAEL) Developmental/Reproductive (IARC 1981) 3,000 (maternal toxicity, skeletal and 0.17 µg/kg-d visceral abnormalities) Metoprolol Rat/F/Gestation 50 (LOAEL) Developmental/Reproductive (McEvoy 2003) 3,000 × 10* (implantation loss, neonatal 1.7 µg/kg-d mortality) Miconazole Rat, Rabbit/F/Gestation 80 (LOAEL) Developmental (prolonged gestation, (Ortho Pharmaceutical 3,000 dystocia, fetal and embryonic Corporation 1996) 27 µg/kg-d toxicity) Minocycline No data NA NA NA NA Monensin Rat/M,F/Multigenerational 1.43 (NOAEL) Reproductive (EMEA 2007) 1,000 1.4 µg/kg-d Naproxen Rat & Rabbit/ Gestation 20 (NOAEL) Reproductive/ Developmental (Roche 2006) 1,000 (no evidence of impaired 20 µg/kg-d fertility or harm to fetus) (continued)

Table B.4 (continued) UF and Species/Gender/ Effect dose Comparison Compound Study duration (mg/kg-d) Effect Reference level (µg/kg-d) Narasin Rat/2-yrs 7.5 (LOAEL) Systemic toxicity (effects on body (European Commission 3,000 weight) 1982) 2.5 µg/kg-d Nicotine Rat/F/Gestation through 2.4 (LOAEL) Developmental/Reproductive (NLM 2009c) 3,000 × 10† lactation (abnormal lutenizing hormone levels, 0.080 μg/kg-d delayed vaginal opening) Nifedipine Animal developmental 6 (LOAEL) Developmental/Reproductive (NLM 2010c) 3,000 studies (teratogenic, embryotoxic, or 2.0 µg/kg-d fetotoxic effects) Norfloxacin Monkey/F/GD 21-50 200 (LOAEL) Developmental/Reproductive (Cukierski et al. 1989) 3,000 (maternal toxicity, embryolethality) 67 µg/kg-d Norfluoxetine Metabolite of Fluoxetine See parent See parent compound See parent compound 0.97 µg/kg-d compound 6-O-des-methyl-naproxen Metabolite of Naproxen See parent See parent compound See parent compound 20 µg/kg-d compound Ofloxacin Dog (juvenile)/M/ 20 (LOAEL) Systemic (arthropathy) (Yabe et al. 2004) 3,000 Single dose 6.7 µg/kg-d OH-ibuprofen Metabolite of Ibuprofen See parent See parent compound See parent compound 1.0 µg/kg-d compound o-Hydroxy atorvastatin Metabolite of Atorvastatin See parent See parent compound See parent compound 0.67 µg/kg-d compound Oleandomycin No data NA NA NA NA Ormetoprim Swine/F/gestation 22 (LOAEL) Developmental/Reproductive (Blackwell et al. 1989) 3,000 (congenital goiter) 7.3 µg/kg-d Oxacillin No data NA NA NA NA Oxolinic acid Rat/2-yrs 4.2 (NOAEL) Developmental/Reproductive (EMEA 1998c) 1,000 × 10* (increased serum LH) 0.42 µg/kg-d Oxytetracycline Humans/premature infants 25 (LOAEL) Developmental (decreased fibula (CorePharma 2012) 3,000 growth rate) 8.3 µg/kg-d (continued)

Table B.4 (continued) UF and Species/Gender/ Effect dose Comparison Compound Study duration (mg/kg-d) Effect Reference level (µg/kg-d) Penicillin G No data NA NA NA NA Penicillin V No data NA NA NA NA Pentoxifylline Mouse/Before mating and 50 (NOAEL) Reproductive (Shepard and Lermire 2004) 1,000 during the first 7 days or 50 µg/kg-d GD6-15 Phenoxymethylpenicillin Same as Penicillin V NA NA NA NA Phenytoin Human/ 4.3 (LOAEL) Developmental (congenital (Hernandez-Diaz et al. 2000) 3,000 Gestation effects) 1.4 µg/kg-d p-Hydroxy atorvastatin Metabolite of Atorvastatin See parent See parent compound See parent compound 0.67 µg/kg-d compound Prednisone Human/Children 1.35 (LOAEL) Bone demineralization, retardation of (Chesney et al. 1978) 3,000 × 10† statural growth 0.045 µg/kg-d Primidone Rat/F/GD 8-17 80 (LOAEL) Developmental/Neurobehavioral (Pizzi et al.1996) 3,000 (deficits in neurobehavioral tests) 27 µg/kg-d Propranolol Rat/F/Pregnancy & 80 (NOAEL) Developmental (reduced litter size, (Drugs.com 2012u) 1,000 lactation increased resorption rates, neonatal 80 µg/kg-d death) Ranitidine Dog 225 (LOAEL) Systemic toxicity (muscular tremors, (DrugLib.com 2012) 3,000 vomiting, and rapid respiration) 75 µg/kg-d Risperidone Rat/M, F/Mating and 0.16 (LOAEL) Developmental/Reproductive (McEvoy 2003) 3,000 × 10* gestation (impaired mating) 0.0053 µg/kg-d Roxithromycin No data NA NA NA NA Salicylic acid Rat/F/GD 20-21 20 (LOAEL) Developmental/Reproductive (NLM 2009d) 3,000 (increased time to parturition, 6.7 μg/kg-d bleeding during parturition) Salinomycin Swine/2 wks 8 (LOAEL) Systemic toxicity (loss of appetite, (NLM 2002) 3,000 locomotor disturbances) 2.7 µg/kg-d Sarafloxacin No data NA NA NA NA (continued)

Table B.4 (continued) UF and Species/Gender/ Effect dose Comparison Compound Study duration (mg/kg-d) Effect Reference level (µg/kg-d) Simvastatin Dog 10 (LOAEL) Reproductive (testicular atrophy, (Drugs.com 2008) 3,000 × 10* decreased spermatogenesis, 0.33 µg/kg-d spermatocytic degeneration) Simvastatin (hydroxy acid) See parent compound See parent See parent compound See parent compound 0.33 µg/kg-d compound Sucralose Rat/F/ multigenerational 150 (NOAEL) Developmental/reproductive (Kille et al. 2000) 1,000 (decreased food consumption and 150 µg/kg-d weight gain, increased kidney weight, decreased thymus weight) Sulfachloropyridazine No data NA NA NA NA Sulfadiazine Dog 25 (NOAEL) Systemic toxicity (hypothyroidism) (USPC 2007) 1,000 25 µg/kg-d Sulfadimethoxine No data NA NA NA NA Sulfamerazine No data NA NA NA NA Sulfamethazine Rat/F/GD 6-15 685 (LOAEL) Developmental (visceral (NIEHS 1985) 3,000 × 10* malformations, hydroureter, 23 µg/kg-d hydronephrosis) Sulfamethizole NA NA NA (A population-based (Ratanajamit et al. 2003) NA observational study in humans suggests increased risk of miscarriage, dose not given, typical approximately 14.2 mg/kg-d) Sulfamethoxazole No data 512 (NOAEL) Reproductive performance (Monarch Pharmaceuticals 1,000 2006) 510 µg/kg-d Sulfasalazine Rat/M/(duration not 800 (LOAEL) Reproductive (male fertility) (FDA 2013a) 1,000 given) 800 µg/kg-d Sulfathiazole Dog/90 day 6 (NOAEL) Systemic (increased thyroid weight) (Inchem 1989) 1,000 6.0 µg/kg-d (continued)

Table B.4 (continued) UF and Species/Gender/ Effect dose Comparison Compound Study duration (mg/kg-d) Effect Reference level (µg/kg-d) Sweet One (Acesulfame, Ace Rat/F/multigenerational 450 (NOAEL) Developmental/reproductive (WHO 1991) 1,000 K, Sunnet) (decreased growth rate in pups) 450 µg/kg-d Tetracycline Humans/premature infants 25 (LOAEL) Developmental (decreased fibula (CorePharma 2012) 3,000 growth rate) 8.3 µg/kg-d Theobromine Mice/F/Gestation through 2 (LOAEL) Developmental/Reproductive (Chorostowska-Wynimko et 3,000 lactation (decreased weight and immune al. 2004) 0.67 μg/kg-d function on offspring) Theophylline Mice/M,F/Mating 120 (LOAEL) Developmental/Reproductive (litter (Drugs.com 2012v) 3,000 size, pup mortality) 40 µg/kg-d Thiabendazole Mouse/F/GD9 26.4 (LOAEL) Developmental (Ogata et al. 1984) 3,000 8.8 µg/kg-d Trimethoprim Rat/ M, F 14 (NOAEL) Fertility/reproduction (Micomedex Thomson 1,000 Health Care 2002) 14 µg/kg-d Tylosin No data NA NA NA NA Valproic acid Dog 90 (LOAEL) Fertility (reduced spermatogenesis, (Micromedex Thomson 3,000 × 10* testicular atrophy) Health Care 2002) 3.0 µg/kg-d Virginiamycin No data NA NA NA NA Warfarin Human 0.029 (LOAEL) Increased prothrombin time (Huff 1985) 3,000 0.097 µg/kg-d *Additional UF of 10 was applied because compound shows evidence of being a nongenotoxic carcinogen (see Table B.8) † Additional UF of 10 was applied because compound shows evidence of being a potential endocrine disrupting compound F – female; GD – gestation day; LOAEL – lowest observed adverse effect level; M – male; NA – not available; NOAEL – no observed adverse effect level; PND – postnatal day; UF – uncertainty factor

Table B.5 Lowest effect doses for hormones and corresponding comparison levels UF and Species/Gender/ Effect dose comparison level Compound Study duration (mg/kg-d) Effect Reference (µg/kg-d) Equilenin No data NA NA NA NA Equilin Human/F/5-7 yrs 0.625 (LOAEL) Cardiovascular (stroke and deep (Shumaker et al. 2004, 3,000 × 10† vein thrombosis), dementia Hendrix et al. 2006) 0.020 µg/kg-d Ergosterol Dog 4 (LOAEL) Systemic toxicity (Drugs.com 2012k) 3,000 × 10† 0.13 µg/kg-d Estradiol (17-α and 17β Human / Postmenopausal 0.005 (NOAEL) Endocrine (changes in several (Mashchak et al.1982) 1,000 × 10*† estradiol) women trial hormone-dependent parameters in 0.00050 µg/kg-d healthy postmenopausal women) Estriol Human/F 20 (LOAEL) Reduced prolactin (Adlercreutz and 3,000 × 10† Vähäpassi 1984) 0.67 μg/kg-d Estrone Human / Postmenopausal 0.004 (NOAEL) Endocrine (evaluated several (Mashchak et al.1982) 1,000 × 10*† women trial hormone and hormone binding 0.00040 μg/kg-d globulin capacities) Ethynylestradiol Mice/F/GD 10-18 0.05 (LOAEL) Developmental/Reproductive (Kirigaya et al. 2006) 3,000 × 10† (includes17-α (increased polyovular follicles and 0.0020 µg/kg-d ethynylestradiol) vaginal stratification in offspring) Mestranol Mice/M,F/4-8 days after 0.05 (LOAEL) Developmental/Reproductive (NLM 2012c) 3,000 × 10† mating (increased fetal resorptions) 0.0020 µg/kg-d Norethindrone Mouse/F/GD 8-15 10 (LOAEL) Developmental (embryolethality) (IARC 1979) 3,000 × 10*† 0.33 μg/kg-d Progesterone Bonnet Macaque/M/90 days 0.01 (LOAEL) Reproductive (reduced sperm (Moudgal et al. 1985, 3,000 × 10*† counts) OEHHA 2004) 0.00030 μg/kg-d Testosterone (includes cis- Rat/F/GD 5-11 4 (LOAEL) Reproductive/developmental (IARC 1979) 3,000 × 10*† and trans-testosterone) (prevention of implantation, fetal 0.13 μg/kg-d loss, delayed parturition) *Additional UF of 10 was applied because compound shows evidence of being a nongenotoxic carcinogen (see Table B.8) †Additional UF of 10 was applied because the compound is a purported EDC F – female; GD – gestation day; LOAEL – lowest observed adverse effect level; M – male; NA – not available; NOAEL – no observed adverse effect level; PND – postnatal day; UF – uncertainty factor

Table B.6 Lowest effect doses for EDCs and non-pharmaceutical compounds without existing ADIs and corresponding comparison levels UF and Species/Gender/ Effect dose comparison level Compound Study duration (mg/kg-d) Effect Reference (µg/kg-d) 2-Phenoxyethanol Rabbit/F/GD 6-18 300 (NOAEL) Developmental/Reproductive (maternal (NLM 2012a) 1,000 toxicity) 300 μg/kg-d 3-Indole-butyric acid Rat/F/GD 12-14 1000 (LOAEL) Developmental/Reproductive (decrease (Furukawa et al. 2005) 3,000 in absolute brain weight in embryos) 333 μg/kg-d 5-Methyl-1H- Rat/M,F/14 days 100 (NOAEL) Systemic toxicity (Komsta et al. 1989) 1,000 benzotriazole 100 μg/kg-d 6-acetyl- 1,1,2,4,4,7- Rat/F/GD 7-17 5 (NOAEL) Developmental/reproductive (Christian et al. 1999) 1,000 × 10† hexamethyltetralin 0.5 μg/kg-d (AHTN, Tonalide) Acetyl cedrene Rat/F/GD 7-17 50 (NOAEL) Developmental/reproductive (maternal (Lapczynski et al.2006) 1,000 toxicity) 50 μg/kg-d Acridine Rat/M,F/13 wks 12 (NOAEL) Systemic toxicity ( body and organ (Moir et al. 1997) 1,000 weights) 12 μg/kg-d Androstenedione Human/Single dose 0.71 (LOAEL) Endocrine (Leder et al. 2002) 3,000 × 10*† 0.024 µg/kg-d Androsterone No data NA NA NA NA Benzyl acetate Rat/M,F/90 days 425 (LOAEL) Systemic toxicity (decreased body (NLM 2009a) 3,000 weight) 142 μg/kg-d Biochanin A Rat/M,F/Conception 5 (NOAEL) Endocrine disruption (aberrant estrous (NTP 2008) 1,000 × 10† (Isoflavones grouped, through 2 years cycle, decreased body weight) 0.50 µg/kg-d most data available for Genistein) Chlorophene (o-benzyl- Rat/M,F/2 yrs 30 (LOAEL) Systemic toxicity (kidney toxicity) (EPA 1995) 3,000 × 10* p-chlorophenol) 1.0 μg/kg-d Cholestanol Rabbit/4-12 wks 125 (LOAEL) Systemic (inflammatory changes in the (Buchmann and Clausen 3,000 liver) 1986) 42 μg/kg-d Cholesterol Rat/F/GD 8-14 5 (LOAEL) Developmental (cleft palate) (IARC 1983) 3,000 × 10* 0.17 µg/kg-d Chrysin (Isoflavones Rat/M,F/Conception 5 (NOAEL) Endocrine disruption (aberrant estrous (NTP 2008) 1,000 × 10† grouped, most data through 2 years cycle, decreased body weight) 0.50 µg/kg-d available for Genistein) (continued)

Table B.6 (continued) UF and Species/Gender/ Effect dose comparison level Compound Study duration (mg/kg-d) Effect Reference (µg/kg-d) Coprostanol Assume same as NA NA NA 3,000 × 10* cholesterol 0.17 µg/kg-d Daidzein (Isoflavones Rat/M,F/Conception 5 (NOAEL) Endocrine disruption (aberrant estrous (NTP 2008) 1,000 × 10† grouped, most data through 2 years cycle, decreased body weight) 0.50 µg/kg-d available for Genistein) Desmosterol Assume same as NA NA NA 3,000 × 10* cholesterol 0.17 µg/kg-d Digoxigenin No data NA NA NA NA Dimethyl phthalate Rat/F/GD6-15 800 (NOAEL) Developmental/ Reproductive (maternal (NTP 1989) 1,000 × 10† toxicity, decreased water consumption) 80 μg/kg-d Epicoprostanol Assume same as NA NA NA 3,000 × 10* cholesterol 0.17 µg/kg-d Ergosterol Dog 4 (LOAEL) Systemic toxicity (Drugs.com 2012k) 3,000 × 10† 0.13 µg/kg-d Ethyl citrate Rat/M,F/ 2 years 2000 (LOAEL) Systemic toxicity (decreased body (WHO 1984) 3,000 weight) 667 μg/kg-d Flumetsulam No data NA NA NA NA

Formononetin Rat/M,F/Conception 5 (NOAEL) Endocrine disruption (aberrant estrous (NTP 2008) 1,000 × 10† (Isoflavones grouped, through 2 years cycle, decreased body weight) 0.50 µg/kg-d most data available for Genistein) Galaxolide (HHCB) Rat/ F/ GD7-17 50 (NOAEL) Systemic (maternal; clinical (Christian et al. 1999) 1,000 × 10† signs, reduced weight gain) 5.0 μg/kg-d

Genistein (Isoflavones Rat/M,F/Conception 5 (NOAEL) Endocrine disruption (aberrant estrous (NTP 2008) 1,000 × 10† grouped, most data through 2 years cycle, decreased body weight) 0.50 µg/kg-d available for Genistein) Glycitein (Isoflavones Rat/M,F/Conception 5 (NOAEL) Endocrine disruption (aberrant estrous (NTP 2008) 1,000 × 10† grouped, most data through 2 years cycle, decreased body weight) 0.50 µg/kg-d available for Genistein) Hexyl-cinnamaldehyde No data NA NA NA NA (continued)

Table B.6 (continued) UF and Species/Gender/ Effect dose comparison level Compound Study duration (mg/kg-d) Effect Reference (µg/kg-d) Hydrocinnamic acid (3- No data NA NA NA NA phenylpropanic acid) Indole Rat/M/28 days 450 (NOAEL) Systemic toxicity (decreased food (Roe 1971) 1,000 consumption and weight gain) 450 μg/kg-d

Isobornyl acetate Rat/M,F/13 wks 15 (NOAEL) Systemic (liver and kidney toxicity) (Gaunt et al. 1971) 1,000 15 μg/kg-d Malaoxon Rat/ M,F/2 yr 20 M, 25 F Increased gastric ulcers. (NTP 1979) 3,000 × 10† (LOAEL) 0. 67 µg/kg-d Mestranol Mice/M,F/4-8 days 0.05 (LOAEL) Developmental/Reproductive (increased (NLM 2012c) 3,000 × 10† after mating fetal resorptions) 0.0017 µg/kg-d Musk ketone Rat/F/GD 14 through 2.5 (NOAEL) Developmental/reproductive (decreased (NLM 2011b) 1,000 × 10† weening body weight, delayed sexual 0.25 μg/kg-d maturation) Musk xylene Rat/F/ GD 14-21 7.5 (NOAEL) Developmental/reproductive (decreased (NLM 2009b) 1,000 × 10*† maternal and neonatal body weight) 0.75 μg/kg-d N,N- Diethyltoluamide Rat/ 60 day 6.8 (LOAEL) Neurological (Abou-Donia et al. 1997, 3,000 (DEET) Abdel-Rahman et al. 2001) 2.3 μg/kg-d Nonylphenol No data NA NA NA NA diethoxylates (NP2EO) Nonylphenol No data NA NA NA NA monoethoxylates (NP1EO) Nonylphenols (NP) Rat / (M&F) / 1.5 (NOAEL) Systemic (renal (Tyl et al. 2006) 1,000 × 10† 3-Gen histopathology) 0.15 μg/kg-d repro/devel Octyl methoxy Rat/F/3 days 250 (LOAEL) Systemic (decreased body weight gain) (European Commission 2001) 3,000 × 10† cinnamate 8.3 μg/kg-d Octylphenols (OP) Rat/M,F/PND 1-5 12.5 (NOAEL) Developmental/reproductive (decreased (Nagao et al. 2001) 1,000 × 10† (p-octophenol) body weight, delayed sexual 1.3 μg/kg-d maturation) Oxybenzone Rat/M,F/90 days 100 (NOAEL) Systemic toxicity (Lewerenz et al. 1972) 1,000 × 10† 10 μg/kg-d (continued)

Table B.6 (continued) UF and Species/Gender/ Effect dose comparison level Compound Study duration (mg/kg-d) Effect Reference (µg/kg-d) PBDE-209 Mouse/M,F/60-90 100 (NOAEL) Developmental/reproductive (NLM 2009e) 1,000 × 10*† (Decabromodiphenyl days prior to mating (fetotoxicity) 10 μg/kg-d ether) through lactation Perfluorobutyric acid Rat/90 days 6.9 (NOAEL) Systemic toxicity (liver weight changes, (MDH 2011) 1,000 × 10† (PFBA) morphological changes in liver and 0.69 μg/kg-d thyroid, decreased TT4, and decreased red blood cells, hematocrit and hemoglobin) Perthane Dog/M/ 25 (LOAEL) Degeneration and focal dystrophy of (NTP 2013) 3,000 34 days adrenal cortex 8.3 μg/kg-d Phenanthrene No data NA NA NA NA

Total perfluorinated carboxylic acids Total perfluorinated See individual PFSs NA NA NA NA sulfonyls (PFSs) for data Total short-chain Rat/F/GD 6-19 500 (LOAEL) Developmental/reproductive (maternal (WHO 2009) 3,000 × 10*† chlorinated paraffin toxicity) 17 μg/kg-d (SCCP) Traseolide Assume same as NA NA NA 0.25 μg/kg-d lowest value musk (musk ketone) Triclocarban Rat/M,F/ 2 yrs 25 (NOAEL) Systemic toxicity (decreased body (European Commission 2005) 1,000 × 10† weight, increased organ weights, 2.5 μg/kg-d anemia) Triclosan Rat/M,F/8 days 1 (LOAEL) Developmental/reproductive (decreased (Rodríguez and Sanchez 3,000 × 10† before mating- total serum T(4) and T(3) in pregnant 2010) 0.033 μg/kg-d PND21, pups exposed rats, lowered sex ratio, lowered pup post-weaning body weights on PND 20, and delayed vaginal opening in offspring) *Additional UF of 10 was applied because compound shows evidence of being a nongenotoxic carcinogen (see Table B.8) †Additional UF of 10 was applied because the compound is a purported EDC F – female; GD – gestational day; HHCB 1,3,4,6,7,8-hexahydro-4,6,6,7,8,8,-hexamethylcyclopenta[γ]-2-benzopyran; LOAEL – lowest observed adverse effect level; M – male; NA – not available; NOAEL – no observed adverse effect level; PBDE − polybromodiphenyl ether; PND – postnatal day; UF – uncertainty factor

Table B.7 Minimum inhibitory concentrations (MICs) for antibiotics and corresponding comparison levels Comparison

MIC50* MCC BW level Antibiotic (mg/g) (g/d) FA† SaF (kg) (µg/kg-d) Amoxicillin 0.016 220 0.82 10 70 6.1 Ampicillin 0.125 220 0.8 10 70 49 Azithromycin 0.064 220 0.38 10 70 53 Bacitracin 8 220 0.5 10 70 5,000 Cefotaxime 0.016 220 0.6 10 70 8.4 Cephalexin 2 220 0.9 10 70 700 Chloramphenicol 0.5 220 1 10 70 160 Ciprofloxacin 0.5 220 0.7 10 70 220 Clarithromycin 1 220 0.5 10 70 630 Clinafloxacin 0.125 220 0.5 10 70 79 Clindamycin 0.125 220 0.9 10 70 44 Cloxacillin 0.25 220 0.5 10 70 160 Demeclocycline 0.2 220 0.5 10 70 130 Doxycycline 0.4 220 1 10 70 130 Enrofloxacin 0.064 220 0.5 10 70 40 Erythromycin (and metabolites) 0.064 220 1 10 70 20 Minocycline 0.125 220 0.5 10 70 79 Monensin 0.25 220 0.5 10 70 160 Norfloxacin 0.064 220 0.4 10 70 50 Ofloxacin 0.016 220 0.98 10 70 5.1 Oleandomycin 50 220 0.5 10 70 31,000 Ormetoprim 5 220 0.5 10 70 3,100 Oxacillin 0.25 220 0.5 10 70 160 (continued)

Table B.7 (continued) Comparison

MIC50* MCC BW level Antibiotic (mg/g) (g/d) FA† SaF (kg) (µg/kg-d) Penicillin NA 220 0.5 10 70 NA Roxithromycin 0.064 220 0.5 10 70 40 Salinomycin 0.2 220 0.5 10 70 130 Sarafloxacin 0.125 220 0.5 10 70 79 Sulfachloropyridazine 128 220 0.5 10 70 80,000 Sulfadiazine 2.375 220 0.5 10 70 1,500 Sulfadimethoxine 2.375 220 0.5 10 70 1,500 Sulfamerazine 16 220 0.5 10 70 10,000 Sulfamethazine 0.13 220 0.5 10 70 81 Sulfamethizole 16 220 0.5 10 70 10,000 Sulfamethoxazole 8 220 0.5 10 70 5,000 Sulfasalazine NA 220 0.5 10 70 80,000 Sulfathiazole 128 220 0.5 10 70 450 Tetracycline (and metabolites) 0.5 220 0.35 10 70 70 Trimethoprim 0.125 220 0.56 10 70 6.1 Tylosin 5.4 220 0.5 10 70 3,400 Virginiamycin 0.25 220 0.5 10 70 160 *Data obtained from KnowledgeBase (2013) Antimicrobial Index BW ̶ body weight; FA ̶ fraction available; MCC ̶ mass of colonic contents; MIC50 ̶ minimum inhibitory concentration of 50% of strains of the most sensitive relevant organism; SaF ̶ safety factor

Table B.8 Carcinogenicity and genotoxicity data for non-EDC pharmaceuticals and corresponding comparison levels Genotoxicity Comparison assumption level based (NLM, CCRIS Availability of tumor Cancer SF on CSF Compound Evidence or Gene-Tox) incidence data (mg/kg-d)-1 (µg/kg-d)* Acetaminophen Increased incidence of liver and bladder tumors (Flaks et al. 1985) Positive (Flaks et al. 1985) 18 0.002 0.50 (negative in months, rat (M, F); Ames) liver neoplastic nodules 0 mg/kg-d = 0/40 250 mg/kg-d = 0/49 500 mg/kg-d = 10/50 Albuterol Dose-related increase in the incidence of benign leiomyomas of the Negative (Jack et al. 1983) 2 yrs, NA† NA mesovarium (Jack et al. 1983) rat (F); leiomyomas of the mesovarium 0 mg/kg-d = 1/105 2 mg/kg-d = 0/55 20 mg/kg-d = 16/55 Alprazolam No evidence of carcinogenic potential was observed during 2-year Negative NA NA NA bioassay studies of Alprazolam in rats at doses up to 30 mg/kg/day and in mice at doses up to 10 mg/kg/day (Drugs.com 2012a) Amitriptyline (and Long-term studies in animals have not been performed to evaluate Negative NA NA NA metabolites) carcinogenic potential (NLM 2004) Amoxicillin Long-term studies in animals have not been performed to evaluate Negative NA NA NA carcinogenic potential (Drugs.com 2012c) Amphetamine No evidence of carcinogenic activity of d,l-amphetamine sulfate in Positive NA NA NA male or female F344/N rats or B6C3F1 mice (NTP 2005) (negative in Ames) Ampicillin Not listed as a carcinogen by IARC, NTP or OSHA (Pfizer Inc. 2007a) Negative Not located NA NA Anydro- Metabolite of chlortetracycline See parent See parent compound See parent NA chlorotetracycline compound compound Anydro-tetracycline Metabolite of tetracycline See parent See parent compound See parent NA compound compound Aspirin Two-year studies in rats and mice showed no evidence of Positive NA NA NA carcinogenicity (NLM 2008) (negative in Ames) (continued)

Table B.8 (continued) Genotoxicity Comparison assumption level based (NLM, CCRIS Availability of tumor Cancer SF on CSF Compound Evidence or Gene-Tox) incidence data (mg/kg-d)-1 (µg/kg-d)* Atenolol Increase of benign adrenal medullary tumors in males and females, Negative Not located NA NA mammary fibroadenomas in females, and anterior pituitary adenomas and thyroid parafollicular cell carcinomas in males was observed at 24 months in rats receiving 500-1,500 mg/kg of atenolol daily Atorvastatin Increase in liver adenomas and carcinomas in mice, and Negative Not located NA NA rhabdomyosarcoma and fibrosarcoma in female rats (Pfizer Inc. 2003) Azithromycin Long-term studies in animals have not been performed to evaluate Negative NA NA NA carcinogenic potential. Azithromycin has shown no mutagenic potential in standard laboratory tests (Drugs.com 2012e) Bacitracin Long-term studies in animals to evaluate carcinogenic or mutagenic No data NA NA NA potential have not been conducted. Bendroflumethiazide Studies have not been performed to evaluate carcinogenic potential. No data NA NA NA Benzoylecgonine Metabolite of cocaine See parent See parent compound See parent NA compound compound Benzatropine No data NA NA NA NA Bezafibrate No data No data NA NA NA Bupropion Two-year studies in rats and mice were equivocal for evidence of Positive Not located NA NA carcinogenicity (NLM 2010a) Butalbital No adequate studies have been conducted in animals to determine Not located NA NA NA whether butalbital has a potential for carcinogenesis, mutagenesis (Drugs.com 2011d) Camphor No evidence of carcinogenicity in long-term rodent bioassays (NLM Negative NA NA NA 2010b) Carbadox Increase in benign nodular hyperplasia in the liver of rats exposed for Positive (Stebbins and Coleman 0.94 0.0011 two years (Stebbins and Coleman 1967) 1967): 2 yr, rat (M/F); benign nodular hyperplasia of the liver 0 mg/kg-d = 0/13 5 mg/kg-d = 5/13 10 mg/kg-d = 11/13 25 mg/kg-d = 15/13 (continued)

Table B.8 (continued) Genotoxicity Comparison assumption level based (NLM, CCRIS Availability of tumor Cancer SF on CSF Compound Evidence or Gene-Tox) incidence data (mg/kg-d)-1 (µg/kg-d)* Carbamazepine Increase in liver carcinomas in rats (Novartis 2002; Singh et al. 2005) No conclusion Not located NA NA Carisoprodol No evidence of carcinogenicity in dietary studies in rats (1 year) or Negative NA NA NA dogs (6 months) (Berger et al. 1959) Cefotaxime No data Negative NA NA NA Cephalexin Long-term studies in animals have not been performed to evaluate No data NA NA NA carcinogenic potential (Drugs.com 2013a) Chloramphenicol Induces aplastic anemia, and this condition is related to the occurrence Positive Not located NA NA of leukemia; probably carcinogenic to humans (Group 2A) (IARC (negative in 1980) Ames) Chlortetracycline No evidence of carcinogenicity in rats (Dessau and Sullivan 1958) No data NA NA NA Cimetidine Increase in benign Leydig cell tumor incidence (Drugs.com 2011a) No conclusion Not located NA NA Ciprofloxacin Long-term carcinogenicity studies in rats and mice resulted in no Positive NA NA NA carcinogenic or tumorigenic effects (Drugs.com 2011b) Citalopram Increased incidence of small intestine carcinoma in rats (Micromedex Positive Not located NA NA Thomson Health Care 2002) Clarithromycin Long-term studies in animals have not been performed to evaluate Negative NA NA NA carcinogenic potential (Drugs.com 2012f) Clinafloxacin No data No data NA NA NA Clindamycin Long-term studies in animals have not been performed to evaluate Negative NA NA NA carcinogenic potential (Drugs.com 2012g) Clofibric acid Increased incidence of hepatocellular carcinoma and acinar-cell Positive (Reddy and Qureshi 0.054 0.019 carcinoma in rats (Reddy and Qureshi 1979) 1979); 2-yr, rat (M); hepatocellular carcinoma 0 mg/kg-d = 0/15 200 mg/kg-d = 10/15 Cloxacillin No data No data NA NA NA Cocaine No data Negative NA NA NA

Genotoxicity Comparison assumption level based (NLM, CCRIS Availability of tumor Cancer SF on CSF Compound Evidence or Gene-Tox) incidence data (mg/kg-d)-1 (µg/kg-d)* Codeine Two year carcinogenicity studies have been conducted in F344/N rats No conclusion NA NA NA and B6C3F1 mice. There was no evidence of carcinogenicity in either species (Drugs.com 2012h) COOH-ibuprofen Metabolite of ibuprofen See parent See parent compound See parent NA compound compound Cotinine Metabolite of nicotine See parent See parent compound See parent NA compound compound Cyclophosphamide Increased incidence in a variety of tumors in both rats and mice Positive (CPDB 2007d); 32 1.36 0.00074 (CPDB 2007d) months, rat (M/F); all sites 0 mg/kd-d = 9/74 0.221 mg/kd-d = 22/77 0.450 mg/kd-d = 27/78 0.893 mg/kd-d = 26/73 1.79 mg/kd-d = 22/72 Dehydronifedipine Metabolite of nifedipine See parent See parent compound See parent NA compound compound Demeclocycline No data No data NA NA NA Desmethyldiltiazem Metabolite of diltiazem See parent See parent compound See parent NA compound compound Dexamethasone No adequate studies have been conducted in animals to determine No data NA NA NA whether corticosteroids have a potential for carcinogenesis or mutagenesis. Diazepam No increase in incidence of tumors in both mice and rats (CPDB Positive NA NA NA 2007e) (negative in Ames) Diclofenac No evidence of carcinogenicity in long-term studies in mice Negative NA NA NA (Micromedex Thomson Health Care 2002) Digoxin No data Negative NA NA NA Diltiazem A 24-month study in rats and a 21-month study in mice showed no Negative NA NA NA evidence of carcinogenicity (Drugs.com 2011c) (continued)

Table B.8 (continued) Genotoxicity Comparison assumption level based (NLM, CCRIS Availability of tumor Cancer SF on CSF Compound Evidence or Gene-Tox) incidence data (mg/kg-d)-1 (µg/kg-d)* Diphenhydramine Not carcinogenic in 2-year rat carcinogenicity study (Pfizer Inc. No data NA NA NA 2007b) Doxycycline Increase in uterine polyps in female rats but no tumor formation No data NA NA NA (RxList.com 2010) Duloxetine Increased incidence of hepatocellular adenomas and carcinomas in Negative Not located NA NA female mice (RxList.com 2012) Enalapril No evidence of carcinogenicity in long-term studies in rats and mice Negative NA NA NA (NLM 2012b) Enalaprilat Metabolite of enalapril Negative NA NA NA Enrofloxacin No evidence of carcinogenicity in long-term studies in rats and mice Negative NA NA NA (WHO 1997) Ephedrine No evidence of carcinogenicity in long-term studies in rats or mice Negative NA NA NA (NLM 2007) Epi-anhydro- Metabolite of tetracycline See parent See parent compound See parent NA tetracycline compound compound Epi-chlorotetracycline Metabolite of chlortetracycline See parent See parent compound See parent NA compound compound Erythromycin Long-term oral dietary studies conducted with erythromycin stearate in Negative NA NA NA rats and mice did not provide evidence of tumorigenicity (Drugs.com 2012j) Erythromycin-H2O Metabolite of erythromycin See parent See parent compound See parent NA compound compound Ethyl citrate Non-carcinogenic in a limited oral study in rats Negative NA NA NA Fenoprofen Long-term studies in animals have not been conducted to evaluate No Data NA NA NA carcinogenic potential (RXList.com 2009) (continued)

Table B.8 (continued) Genotoxicity Comparison assumption level based (NLM, CCRIS Availability of tumor Cancer SF on CSF Compound Evidence or Gene-Tox) incidence data (mg/kg-d)-1 (µg/kg-d)* Flumequine Increased incidence of liver tumors in mice (EMEA 1999) Negative (EMEA 1999) 18- NA (not NA months, Mice (M); enough Liver tumors info) 0mg/kg-d= 9% 400 mg/kg-d= 37% 800 mg/kg-d= 88% 5-Fluorouracil No evidence of carcinogenicity in rats after oral exposure once a week Positive NA NA NA for 1 year (Drugs.com 2012l) Fluoxetine No evidence of carcinogenicity in 2-yr Negative NA NA NA studies of mice and rats (Bendele et al. 1992) Fluvoxamine No evidence of carcinogenicity in long-term studies in rodents Negative NA NA NA (Drugs.com 2013b) Furosemide Increased incidence of mammary tumors in mice (CPDB 2007h) Positive (CPDB 2007h); 2-yr, 0.011 0.091 (negative in mice (F); Mammary Ames) gland; 0 mg/kg-d = 0/50 89.3 mg/kg-d = 2/50 180 mg/kg-d = 5/50 Gabapentin Increased incidence of pancreatic tumors in male rats (CPDB 2007a) Negative CPDB 2007a; 2-yr, rat NA† NA (M); acinar-cell carcinoma; 0 mg/kg-d = 0/50 250 mg/kg-d = 4/50 1000 mg/kg-d = 3/50 2000 mg/kg-d = 8/50 Gemfibrozil Increased adrenal, pancreatic, liver, and teste tumors in male rats Negative (Fitzgerald et al. NA† NA (Fitzgerald et al. 1981) 1981),: 2 yr, rat (M); Interstitial cell tumors of the testes 0 mg/kg-d = 1/50 30 mg/kg-d = 8/50 300 = 17/50 (continued)

Table B.8 (continued) Genotoxicity Comparison assumption level based (NLM, CCRIS Availability of tumor Cancer SF on CSF Compound Evidence or Gene-Tox) incidence data (mg/kg-d)-1 (µg/kg-d)* Glipizide No evidence of carcinogenicity in long-term studies in rodents Negative NA NA NA (Drugs.com 2013d) Glyburide No evidence of carcinogenicity in long-term studies in rats (Drugs.com Negative NA NA NA 2012n) Guaifenesin Long-term studies in animals have not been conducted to evaluate No data NA NA NA carcinogenic potential (RxList.com 2013a) Hydrochlorothiazide No evidence of carcinogenicity in long-term studies in rodents Positive NA NA NA (Drugs.com 2012o) Hydrocodone Long-term studies in animals have not been conducted to evaluate No data NA NA NA carcinogenic potential (RxList.com 2011c) 10-hydroxy- Metabolite of amitriptyline See parent See parent compound See parent NA amitriptyline compound compound 2-hydroxy-ibuprofen Metabolite of ibuprofen See parent See parent compound See parent NA compound compound Hydrocortisone No evidence of carcinogenicity in long-term studies in rats (CPDB Positive NA NA NA 2007i) Ibuprofen No increased incidence of tumors in mice or rats of either sex given Negative NA NA NA the drug continuously for 43 or 56 weeks (Adams et al. 1970) Ibuprofen methyl ester Metabolite of ibuprofen See parent See parent compound See parent NA compound compound Indomethacin Increased incidence of mammary tumors in rats (CPDB 2007k) Positive (CPDB 2007k); 2-yr, 1.3 0.00077 rat (F); mammary gland; 0 mg/kg-d = 1/49 0.887 mg/kg-d = 5/48 Iohexol Long-term animal studies have not been conducted No data NA NA NA Iopromide Long-term animal studies have not been conducted Negative NA NA NA Iso-chlorotetracycline Metabolite of chlortetracycline See parent See parent compound See parent NA compound compound (continued)

Table B.8 (continued) Genotoxicity Comparison assumption level based (NLM, CCRIS Availability of tumor Cancer SF on CSF Compound Evidence or Gene-Tox) incidence data (mg/kg-d)-1 (µg/kg-d)* Iso-epi- Metabolite of chlortetracycline See parent See parent compound See parent NA chlorotetracyline compound compound Ketoprofen No evidence of carcinogenicity in long-term studies in rodents Negative NA NA NA (Drugs.com 2012q) Ketorolac No evidence of carcinogenicity in long-term studies in rodents Negative NA NA NA Lasalocid No evidence of carcinogenicity in long-term rodent studies Negative NA NA NA Lidocaine Studies in animals to evaluate the carcinogenic and mutagenic No data NA NA NA potential have not been conducted. Lincomycin Not listed as carcinogenic by IARC, NTP or OSHA (Pharmacia & Positive Not located NA NA Upjohn 1995) Lomefloxacin No evidence of skin tumors with lomefloxacin alone (Pfizer Inc. 2005) Positive NA NA NA Meclofenamic acid An 18 month study in rats revealed no evidence of carcinogenicity Negative NA NA NA Menthol No evidence of carcinogenicity in two year studies in rats and mice Negative NA NA NA (WHO 1999) Meprobamate No data No Data NA NA NA Metformin Increased incidence of benign stromal uterine polyps in female rats Negative Not located NA NA (Drugs.com 2012r) Methadone No evidence of carcinogenicity in long-term studies in rodents Positive NA NA NA (Drugs.com2010b) Methotrexate No evidence of carcinogenicity in long-term studies in rodents (CPDB Positive NA NA NA 2007n) (negative in Ames) Metoprolol Increased incidence of benign lung tumors in female mice. No increase Negative NA NA NA in neoplasms in rats (McEvoy 2003) Miconazole Long-term animal studies to determine carcinogenic potential have not Negative NA NA NA been performed (Ortho Pharmaceutical Corporation 1996) Minocycline Increased incidence of papillary thyroid carcinoma in humans Negative NA NA NA chronically exposed for more than 30 years (Kandil et al. 2011) (continued)

Table B.8 (continued) Genotoxicity Comparison assumption level based (NLM, CCRIS Availability of tumor Cancer SF on CSF Compound Evidence or Gene-Tox) incidence data (mg/kg-d)-1 (µg/kg-d)* Monensin No evidence of carcinogenicity in 2-yr study in mouse and rat (EMEA Negative NA NA NA 2007) Naproxen No evidence of carcinogenicity in 2-yr study in rats (Roche 2006) Negative NA NA NA Narasin No evidence of carcinogenicity in long term studies in rats (European No data NA NA NA Commission 1982) Nicotine No positive carcinogenicity tests in mouse or rat Negative NA NA NA Nifedipine No evidence of carcinogenicity in long-term studies in rats Negative NA NA NA (RxList.com 2011b) Norfloxacin No evidence of carcinogenicity in long-term studies in rats (NLM Positive NA NA NA 2012d) Norfluoxetine Metabolite of fluoxetine See parent See parent compound See parent NA compound compound Ofloxacin Long-term studies to determine carcinogenic potential have not been Positive NA NA NA conducted (Drugs.com 2012s) OH-ibuprofen Metabolite of ibuprofen See parent See parent compound See parent NA compound compound o-hydroxy atorvastatin Metabolite of atorvastatin See parent See parent compound See parent NA compound compound Oleandomycin No data No data NA NA NA Ormetoprim No data No data NA NA NA Oxacillin No data No data NA NA NA Oxolinic acid Increased incidence of Leydig cell tumors and Leydig cell hyperplasia Negative Not located NA NA in male rats (EMEA 1998c) Oxytetracycline Not carcinogenic in rodents (Dietz et al. 1991) Negative NA NA NA Penicillin G No data No data NA NA NA Penicillin V No data No data NA NA NA Pentoxifylline Statistically significant increase in benign mammary fibroadenomas in Positive (No Not located NA NA females rats (Drugs.com 2012t) Ames) (continued)

Table B.8 (continued) Genotoxicity Comparison assumption level based (NLM, CCRIS Availability of tumor Cancer SF on CSF Compound Evidence or Gene-Tox) incidence data (mg/kg-d)-1 (µg/kg-d)* Phenytoin Liver neoplasms in female mice and male rats (NTP 1993) Positive (NTP 1993): 2 yr, 0.0012 0.83 (Positive in mouse (F); liver Ames) adenomas and carcinomas in females 0 mg/kg-d = 5/48 50 mg/kg-d = 14/49 160 mg/kg-d = 30/50 p-hydroxy atorvastatin Metabolite of atorvastatin NA Prednisone No evidence of carcinogenicity in long-term studies in mice (CPDB Negative NA NA NA 2007o) Primidone Increased incidence of liver and thyroid tumors in mice (CPDB 2007p) Positive (CPDB 2007p); 1-yr, 0.51 0.0020 mouse (F); liver tumors 0 mg/kg-d = 16/50 37.9 mg/kg-d = 42/50 75.8 mg/kg-d = 46/50 164 mg/kg-d = 50/50 Propranolol No evidence of drug-related tumorigenesis in rats or mice (Drugs.com Negative NA NA NA 2012u) Ranitidine No indication of tumorigenic or carcinogenic effects in life-span Negative NA NA NA studies in mice and rats (DrugLib.com 2012) Risperidone Increased incidence of a variety of tumors in both rats and mice Negative Not located NA NA (McEvoy 2003) Roxithromycin No data Negative NA NA NA Salicylic acid Negative in studies in mice and rats (SCCNFP 2002) Postive NA NA NA (negative in Ames) Salinomycin No data No data NA NA NA Sarafloxacin No data Negative NA NA NA Simvastatin (and Increased incidence of thyroid and liver tumors in rat and lung and Negative Not located NA NA metabolites) liver tumors in mice, lung mice (McEvoy 2003) (continued)

Table B.8 (continued) Genotoxicity Comparison assumption level based (NLM, CCRIS Availability of tumor Cancer SF on CSF Compound Evidence or Gene-Tox) incidence data (mg/kg-d)-1 (µg/kg-d)* Sulfachloropyridazine No data No data NA NA NA Sulfadiazine No evidence of carcinogenicity (RxList.com 2008) Negative NA NA NA Sulfadimethoxine No data No data NA NA NA Sulfamerazine No data No data NA NA NA Sulfamethazine Follicular cell hyperplasia of the thyroid gland and splenic changes in Negative (Littlefield et al. 1989) NA† NA specific–pathogen-free mice (Littlefield et al. 1989) 2 yr, mouse (M); follicular cell adenomas of the thyroid gland 0 mg/kg-d = 3/191 36 mg/kg-d = 0/96 72 mg/kg-d = 1/96 144 mg/kg-d = 5/92 288 mg/kg-d = 3/96 576 mg/kg-d = 44/94 Sulfamethizole Thyroid malignancies observed in rats, which are sensitive to the Negative NA NA NA goitrogenic effects of sulfonamides Sulfamethoxazole No data Positive NA NA NA Sulfasalazine Increased incidence of urinary bladder neoplasms in rats, and increased Positive NA NA NA liver tumors in mice. (Negative in Ames) Sulfathiazole No data Negative NA NA NA Tetracycline No indication of tumorigenic or carcinogenic effects in life-span Positive NA NA NA studies in mice and rats (Dietz et al. 1991) (No Ames test) Theophylline No evidence of carcinogenicity in long-term rodent studies (CPDB Negative NA NA NA 2007q) Thiabendazole No evidence of carcinogenicity in rodent studies (Fujii et al. 1991) Positive NA NA NA Trimethoprim No data Positive NA NA NA Tylosin No evidence of carcinogenicity in long-term mouse bioassays (CPDB No data NA NA NA 2007r) (continued)

Table B.8 (continued) Genotoxicity Comparison assumption level based (NLM, CCRIS Availability of tumor Cancer SF on CSF Compound Evidence or Gene-Tox) incidence data (mg/kg-d)-1 (µg/kg-d)* Valproic acid Increased incidence of a variety of tumors in long-term rodent studies Negative NA NA NA (Micromedex Thomson Health Care 2002) Virginiamycin No data No data NA NA NA Warfarin No data No data NA NA NA *Calculated assuming an acceptable lifetime excess cancer risk of 1 in one million and that a person is exposed to the chemical at this dose daily for a lifetime, or comparison level = 10-6  1000 μg/mg/ SF. †Tumor incidence data is available but SF was not calculated because compound is non-genotoxic. CCRIS – Chemical Carcinogenesis Research Information System; CSF – cancer slope factor; F – female; IARC – International Agency for Research on Cancer; M – male; NA – not available; NLM – National Library of Medicine; NTP – National Toxicology Program; SF – slope factor

Table B.9 Carcinogenicity and genotoxicity data for hormones and corresponding comparison levels Comparison Genotoxicity Availability of tumor Cancer SF level based on Compound Evidence assumption incidence data (mg/kg-d)-1 CSF (µg/kg-d)* Equilenin Inadequate evidence in experimental No data NA NA NA animals for the carcinogenicity of d- equilenin (IARC 2012) Equilin Estrogen-only menopausal therapy causes Positive Not located NA NA cancer of the endometrium and of the ovary. Also, a positive association has been observed between exposure to estrogen-onlymenopausal therapy and cancer of the breast. (IARC 2012) Ergosterol No long-term animal studies have been No data NA NA NA performed to evaluate carcinogenicity (Drugs.com 2012k) Estradiol Evidence of mammary tumors in mice Negative (CPDB 2007f); 1 yr, NA† NA (CPDB 2007f) mouse (F), mammary tumors, 0 mg/kg-d = 2/43 0.013 mg/kg-d = 1/34 0.13 mg/kg-d = 1/34 0.65 mg/kg-d = 7/45 Estriol Evidence of carcinogenicity in rodents Positive Not located NA NA (mammary, kidney) and humans (uterine) with subcutaneous implants (IARC 1979) (continued)

Table B.9 (continued) Comparison Genotoxicity Availability of tumor Cancer SF level based on Compound Evidence assumption incidence data (mg/kg-d)-1 CSF (µg/kg-d)* Estrone Although there is evidence from literature Negative NA NA NA searches that estrone may stimulate mammary gland tumors that have already developed, the secondary sources studied (CPDB, EPA, etc.) have not found studies that are appropriate for derivation of cancer slope factors. Estrone is listed as a Proposition 65 carcinogen in California, but the CalEPA has not derived a cancer slope factor for this compound. Ethynylestradiol One study found increases in liver tumors Positive (negative (CPDB 2007g) 1yr, rat 0.19 0.0053 in rats. Listed as a Proposition 65 in Ames) (F), liver tumors; carcinogen in California. The NTP has a 0 mg/kg-d = 0/8 study completed on this compound that 0.429 mg/kg-d = 4/13 currently is in review (preliminary data are available that indicate there is “equivocal” evidence of carcinogenicity). Mestranol No evidence of carcinogenicity on long- Positive (negative NA NA NA term mouse studies (CPDB 2007m) in Ames) Norethindrone Increased incidence of liver and lung Negative Not located NA NA tumors (IARC 1979) Progesterone Increased incidence of ovarian, uterine and Negative Not located NA NA mammary tumors in mice (IARC 1987) Testosterone Cervical-uterine tumors and hepatomas in Negative Not located NA NA rodents (Drugs.com 2012d) Source: Genotoxicity data obtained from NLM, HSBD for each chemical *Calculated assuming an acceptable lifetime excess cancer risk of 1 in one million and that a person is exposed to the chemical at this dose daily for a lifetime, or comparsion level = 1  10-6  1000 μg/mg/ SF. †Tumor incidence data is available but SF was not calculated because compound is non-genotoxic. CPDB – Carcinogenic Potency Database; CSF – cancer slope factor; F – Female; IARC – International Agency for Research on Cancer; M – male; NA – not available; NLM – National Library of Medicine; NTP – National Toxicology Program; PAH – polycyclic aromatic hydrocarbon; SF – slope factor

Table B.10 Carcinogenicity and genotoxicity data for EDCs and non-pharmaceutical compounds without existing ADIs and corresponding comparison levels Comparison level Genotoxicity Availability of tumor Cancer SF based on CSF Compound Evidence assumption incidence data (mg/kg-d)-1 (µg/kg-d)* 2-Phenoxyethanol No data Negative NA NA NA

3-Indole-butyric acid No data Negative NA NA NA

5-Methyl-1H- No data Negative NA NA NA benzotriazole 6-acetyl- 1,1,2,4,4,7- No data Negative NA NA NA hexamethyltetralin (AHTN, Tonalide) Acetyl cedrene No data No data NA NA NA Acridine No evidence of carcinogenicity when Positive NA NA NA administered to lungs of rats (CCRIS 1991)

Androstenedione Increased incidence of liver and pancreatic Negative (NTP 2011) 2-yr mouse NA† NA tumors (NTP 2011) (F), hepatocellular adenoma or carcinoma 0 mg/kg-d = 17/50, 2 mg/kg-d = 23/50, 10 mg/kg-d = 27/50, 50 mg/kg -d= 32/50 Androsterone No data No data NA NA NA Benzyl acetate Increased incidence of stomach an liver tumors Positive (negative in CPDB 2007c; 2 yrs, mice, 0.011 0.091 in mice (CPDB 2007c) Ames) M; Liver tumors; 0 mg/kg-d = 10/50 300 mg/kg-d = 18/50 704 mg/kg-d = 23/50 Biochanin A (Isoflavones Evidence of mammary and pituitary gland Positive (NTP 2008); 2 yr, Rat (F), 0.37 0.0027 grouped, most data tumors in rats (NTP 2008) Pituitary gland; available for Genistein) 0 mg/kg-d = 38/54 0.3 mg/kg-d = 40/50 5 mg/kg-d = 34/50 29 mg/kg-d = 46/49 (continued)

Table B.10 (continued) Comparison level Genotoxicity Availability of tumor Cancer SF based on CSF Compound Evidence assumption incidence data (mg/kg-d)-1 (µg/kg-d)* Chlorophene Increased incidence of renal tumors in male Negative Not located NA NA mice (NTP 1994) Cholestanol No evidence of carcinogenicity (IARC 1983) Negative NA NA NA Cholesterol Increase in malignant tumors in rats (IARC Negative No located NA NA 1983) Chrysin (Isoflavones Evidence of mammary and pituitary gland Positive (NTP 2008); 2 yr, Rat (F), 0.37 0.0027 including Genistein) tumors in rats (NTP 2008) Pituitary gland; 0 mg/kg-d = 38/54 0.3 mg/kg-d = 40/50 5 mg/kg-d = 34/50 29 mg/kg-d = 46/49 Coprostanol Assume same as Cholesterol Assume same as NA NA NA Cholesterol Daidzein (Isoflavones Evidence of mammary and pituitary gland Positive (NTP 2008); 2 yr, Rat (F), 0.37 0.0027 grouped, most data tumors in rats (NTP 2008) Pituitary gland; available for Genistein) 0 mg/kg-d = 38/54 0.3 mg/kg-d = 40/50 5 mg/kg-d = 34/50 29 mg/kg-d = 46/49 Desmosterol Assume same as Cholesterol Assume same as NA NA NA Cholesterol Digoxigenin No data No data NA NA NA Dimethyl phthalate Data considered inadequate to determine Positive NA NA NA carcinogenicity (EPA 2003a) Epicoprostanol Assume same as Cholesterol Assume same as NA NA NA Cholesterol Ergosterol No long-term animal studies have been No data NA NA NA performed to evaluate carcinogenicity ((Drugs.com 2012k) Ethyl citrate Non-carcinogenic in a limited oral study in rats Negative NA NA NA (WHO 1984) Flumetsulam “…did not cause cancer in long-term animal No data NA NA NA studies” (DuPont 2003)

(continued)

Table B.10 (continued) Comparison level Genotoxicity Availability of tumor Cancer SF based on CSF Compound Evidence assumption incidence data (mg/kg-d)-1 (µg/kg-d)* Formononetin Evidence of mammary and pituitary gland Positive (NTP 2008); 2 yr, Rat (F), 0.37 0.0027 (Isoflavones grouped, tumors in rats (NTP 2008) Pituitary gland; most data available for 0 mg/kg-d = 38/54 Genistein) 0.3 mg/kg-d = 40/50 5 mg/kg-d = 34/50 29 mg/kg-d = 46/49 Galaxolide (HHCB) No data Negative NA NA NA

Isoflavones (Genistein) Evidence of mammary and pituitary gland Positive (NTP 2008); 2 yr, Rat (F), 0.37 0.0027 tumors in rats (NTP 2008) Pituitary gland; 0 mg/kg-d = 38/54 0.3 mg/kg-d = 40/50 5 mg/kg-d = 34/50 29 mg/kg-d = 46/49 Glycitein (Isoflavones Evidence of mammary and pituitary gland Positive (NTP 2008); 2 yr, Rat (F), 0.37 0.0027 grouped, most data tumors in rats (NTP 2008) Pituitary gland; available for Genistein) 0 mg/kg-d = 38/54 0.3 mg/kg-d = 40/50 5 mg/kg-d = 34/50 29 mg/kg-d = 46/49 Hexylcinnamaldehyde No data No data NA NA NA

Hydrocinnamic acid No data Negative NA NA NA

Indole Only one oral rodent carcinogenesis study has Negative NA NA NA been conducted. No evidence of urinary bladder tumors (CPDB 2007j) Isobornyl acetate No data No data NA NA NA

Malaoxon NTP showed no evidence of carcinogenicity in Negative NA NA NA long-term mouse and rat studies, including after reexamination of histopathology slides (CPDB 2007l). In another study, rats developed neoplasms in multiple organ systems, though not confirmed by NTP (Reuber 1985). (continued)

Table B.10 (continued) Comparison level Genotoxicity Availability of tumor Cancer SF based on CSF Compound Evidence assumption incidence data (mg/kg-d)-1 (µg/kg-d)* Mestranol No evidence of carcinogenicity on long-term Positive (negative in NA NA NA mouse studies (CPDB 2007m) Ames) Musk ketone No studies on carcinogenicity have been Negative NA NA conducted (NLM 2011b) Musk xylene Increased incidence of liver tumors in mice Negative (CPDB 2007c), 2 yr, NA† NA (CPDB 2007b) mouse (M); liver tumors; 0 mg/kg-d = 11/50 80 mg/kg-d = 27/50 160 mg/kg-d = 33/50 N,N- Diethyltoluamide No evidence of carcinogenicity in 2 year rodent Negative NA NA NA (DEET) or 1 year canine studies (Schoenig et al. 1999) Nonylphenol No data No data NA NA NA diethoxylates (NP2EO) Nonylphenol No data No data NA NA NA monoethoxylates (NP1EO) Nonylphenols (NP) No data Negative NA NA NA

Octyl methoxy No data Negative NA NA NA cinnamate Octylphenols (OP) No data Positive (positive in NA NA NA Ames) Oxybenzone No data Negative NA NA NA

PBDE-209 Increased incidence of neoplastic nodules in the Negative NA NA NA (Decabromodiphenyl liver and follicular cell hyperplasia (NTP 1986) ether) Perfluorobutyric acid No data No data NA NA NA (PFBA) Perthane No evidence of carcinogenicity in rats or male Positive NA NA NA mice. Results for female mice were equivocal (NCI 1979). Phenanthrene Only one oral rodent carcinogenesis study has Positive Not located NA NA been conducted. No evidence of mammary tumors (IARC 1983) (continued)

Table B.10 (continued) Comparison level Genotoxicity Availability of tumor Cancer SF based on CSF Compound Evidence assumption incidence data (mg/kg-d)-1 (µg/kg-d)* Total perfluorinated See data above from PFPeA-PFNA NA NA NA NA carboxylic acids (PFA) Total perfluorinated NA NA NA NA NA sulfonyls (PFSs) Total short-chain Sufficient evidence for carcinogenicity of Positive (negative in (WHO 2009) 2-yr, rat 0.035 0.3 chlorinated paraffin chlorinated paraffin of average carbon-chain Ames) (M,F), Liver adenomas (SCCP) length C12 and average degree of chlorination and carcinomas; 60% in experimental animals (WHO 2009) 0 mg/kg-d = 20/50 125 mg/kg-d = 34/50 250 mg/kg-d = 38/50 Traseolide Assume same as lowest value musk (musk Negative NA NA NA ketone) Triclocarban No evidence of carcinogenicity in 2-yr study in Negative NA NA NA rats (European Commission 2005) Triclosan No evidence of carcinogenicity in 2-yr study in Positive (negative in NA NA NA rats (Barbolt 2002) Ames) Source: Genotoxicity data obtained from NLM Hazardous Substances Data Bank for each chemical *Calculated assuming an acceptable lifetime excess cancer risk of 1 in one million and that a person is exposed to the chemical at this dose daily for a lifetime, or comparison level = 10-6 x 1000 μg/mg/ SF. †Tumor incidence data is available but SF was not calculated because compound is non-genotoxic. CPDB – Carcinogenic Potency Database; CSF – cancer slope factor; F – female; IARC – International Agency for Research on Cancer;M – male; NA – not available; NLM – National Library of Medicine; NTP – National Toxicology Program; PAH – polycyclic aromatic hydrocarbon; SF – slope factor

Table B.11 Comparison levels for non-EDC pharmacueticals with evidence of genotoxic carcinogenicity but no tumor incidence data, based on the Virtually Safe Dose (VSD) Method Genotoxicity assumption Comparison level (NLM, CCRIS or Gene- Maximum tolerated dose based on VSD Compound Evidence Tox) (mg/kg-d) Source (µg/kg-d) Bupropion Two-year studies in rats and mice were Positive 895 (rat) (NCBI 2014) 1.2 equivocal for evidence of carcinogenicity (NLM2010a) Chloramphenicol Induces aplastic anemia, and this Positive 300 (mouse) (NLM 2012e) 0.41 condition is related to the occurrence of leukemia; probably carcinogenic to humans (Group 2A) (IARC 1980) Citalopram Increased incidence of small intestine Positive NA NA NA carcinoma in rats (Micromedex Thomson Health Care 2002) Pentoxifylline Statistically significant increase in Positive 450 (mouse) (Drugs.com 0.61 benign mammary fibroadenomas in 450 (rat) 2012t) female rats (Drugs.com 2012t) Sulfasalazine Increased incidence of urinary bladder Positive 15,000 (mouse) (Pfizer Canada 10 neoplasms in rats, and increased liver 7,500 (rat, rabbit) 2013) tumors in mice. CCRIS – Chemical Carcinogen Research Information System, NA – not available, NLM – National Library of Medicine, VSD – virtually safe dose

Table B.12 Comparison levels for pharmaceutical hormones with evidence of genotoxic carcinogenicity but no tumor incidence data, based on the Virtually Safe Dose (VSD) Method Comparison Genotoxicity assumption level based (NLM, CCRIS or Gene- Maximum tolerated on VSD Compound Evidence Tox) dose (mg/kg) Source (µg/kg-d) Equilin Estrogen-only menopausal therapy causes Positive 1.63 (IARC) 0.0020 cancer of the endometrium and of the ovary. Also, a positive association has been observed between exposure to estrogen-only menopausal therapy and cancer of the breast (IARC 1979) Estriol Evidence of carcinogenicity in rodents Positive No data NA NA (mammary, kidney) and humans (uterine) with subcutaneous implants (IARC 1979) CCRIS – Chemical Carcinogen Research Information System; IARC – International Agency for Research on Cancer; NA – not available; NLM – National Library of Medicine; VSD – virtually safe dose

Table B.13 Comparison levels for EDCs and non-pharmaceuticals without values derived using other methods, based on the threshold of toxicologic concern (TTC) method Structural alert or TTC-based comparison level Cramer class as Genotoxicity (µg/kg-d) described by assumption Minimum oral LD Based on the Based on Compound CAS No. 50 Cheeseman et al. (NLM, CCRIS or (mg/kg) scheme of the scheme (1999)/Kroes et al. Gene-Tox) Cheeseman et al. of Kroes et (2004) (1999) al. (2004) Hexylcinnamaldehyde 101-86-0 I No data 3,100 (rat) 0.021 26

Hydrocinnamic acid 501-52-0 I No data NA 0.021 26

* TTC method not recommended for these compounds due to high potency for carcinogenicity † TTC method not recommended for these compounds due to structural alerts ‡ No structural class data available to estimate comparison level using TTC approach CAS – Chemical Abstract Service; CCRIS – Chemical Carcinogen Research Information System; LD50 – lethal dose to 50% of test animals; NA – not available; NLM – National Library of Medicine; TTC – threshold of toxicologic concern

Table B.14 Summary of comparison levels for non-EDC pharmaceuticals (µg/kg-d)(shaded values indicate lowest value for each compound) and DWELs based on lowest value Comparison Levels (µg/kg-d) Based on lowest Based on Based therapeutic NOAEL/ on Based Based on DWEL Compound dose LOAEL MIC on CSF VSD (µg/L) Acesulfame (Sweet One, NA 450 NA NA NA 16,000 Ace K, Sunnet) Acetaminophen 0.31 20 NA 0.50 NA 11 Albuterol 0.000090 0.0025 NA NA NA 0.0032 Alprazolam 0.0020 0.00011 NA NA NA 0.0039 Amitriptyline 0.36 8.3 NA NA NA 13 Amoxicillin 3.6 500 6.1 NA NA 130 Amphetamine 0.060 0.16 NA NA NA 2.1 Ampicillin 16 250 49 NA NA 560 Antipyrine or Phenazone NA 10 NA NA NA 350 Aspirin 1.6 3.3 NA NA NA 56 Atenolol 0.012 0.027 NA NA NA 0.42 Atorvastatin 0.010 0.67 NA NA NA 0.35 Azithromycin 2.9 3.3 53 NA NA 100 Bacitracin NA 3.7 5,000 NA NA 130 Bendroflumethiazide 0.024 6.7 NA NA NA 0.84 Benzatropine 0.012 NA NA NA NA 0.42 Benzoylecgonine NA 0.7 NA NA NA 25 Benzylpenicllin 0.60 NA NA NA NA 21 Benzyl salicylate 1.5 NA NA NA NA 53 Bezafibrate 1.9 NA NA NA NA 67 Bupropion 1.4 33 NA NA 1.2 42 Butalbital 0.23 NA NA NA NA 8.1 Caffeine NA 0.083 NA NA NA 2.9 Camphor NA 680 NA NA NA 24,000 Carbadox NA 3.3 NA 0.0011 NA 0.039 Carbamazepine 0.033 0.10 NA NA NA 1.2 Carisoprodol 1.2 100 NA NA NA 42 Cefotaxime 2.4 250 8.4 NA NA 84 Cephalexin 0.83 66 700 NA NA 29 Chloramphenicol 0.0047 8.3 160 NA 0.41 0.16 (continued)

Table B.14 (continued) Comparison Levels (µg/kg-d) Based on lowest Based on Based therapeutic NOAEL/ on Based Based on DWEL Compound dose LOAEL MIC on CSF VSD (µg/L) Chlortetracycline NA 8.3 NA NA NA 290 Cimetidine 0.19 5.0 NA NA NA 6.7 Ciprofloxacin 1.2 10 220 NA NA 42 Citalopram 0.0097 13 NA NA NA 0.34 Clarithromycin 2.4 130 630 NA NA 84 Clinafloxacin NA NA 79 NA NA 2,800 Clindamycin 2.5 300 44 NA NA 88 Clofibrate/Clofibric acid 9.5 67 NA 0.019 NA 0.67 Cloxacillin 1.2 7.0 160 NA NA 42 Cocaine NA 0.067 NA NA NA 2.3 Codeine 0.067 33 NA NA NA 2.3 COOH-ibuprofen 0.97 1.0 NA NA NA 34 Cotinine NA 0.080 NA NA NA 2.8 Cyclophosphamide 0.33 2.5 NA 0.00074 NA 0.026 Dehydronifedipine 0.14 2.0 NA NA NA 4.9 Demeclocycline 0.71 8.3 130 NA NA 25 Desmethyldiltiazem 0.57 11 NA NA NA 20 Dexamethasone 0.0037 0.042 NA NA NA 0.13 Diazepam 0.0097 80 NA NA NA 0.34 Diclofenac 0.48 20 NA NA NA 17 Digoxin 0.000047 0.10 NA NA NA 0.0016 Diltiazem 0.57 11 NA NA NA 20 Diphenhydramine 0.12 15 NA NA NA 4.2 Doxycycline 0.047 0.27 130 NA NA 1.6 Duloxetine 0.19 1.0 NA NA NA 6.7 Enalapril 0.048 0.33 NA NA NA 1.7 Enalaprilat 0.048 0.33 NA NA NA 1.7 Enrofloxacin NA 1.7 40 NA NA 60 Ephedrine 0.12 0.033 NA NA NA 1.2 Epi-anhydro-tetracycline 4.8 8.3 70 NA NA 170 Epi-chlorotetracycline 4.8 8.3 70 NA NA 170 Epi-tetracycline 4.8 8.3 70 NA NA 170 Erythromycin 10 130 20 NA NA 350 (continued)

Table B.14 (continued) Comparison Levels (µg/kg-d) Based on lowest Based on Based therapeutic NOAEL/ on Based Based on DWEL Compound dose LOAEL MIC on CSF VSD (µg/L)

Erythromycin-H2O 10 130 0.080 NA NA 2.8 Fenoprofen 0.95 50 NA NA NA 33 Flumequine NA 1.0 NA NA NA 35 5-Fluorouracil NA 3.3 NA NA NA 120 Fluoxetine 0.11 0.97 NA NA NA 3.9 Fluvoxamine 0.48 1.7 NA NA NA 17 Furosemide 0.095 8.3 NA 0.091 NA 3.2 Gabapentin 0.86 2.0 NA NA NA 30 Gemfibrozil 0.57 3.1 NA NA NA 20 Glipizide 0.024 1.7 NA NA NA 0.84 Glyburide 0.012 NA NA NA NA 0.42 Guaifenesin 0.95 NA NA NA NA 33 Hexylsalicylate 1.5 NA NA NA NA 53 Homomenthyl salicylate 1.5 NA NA NA NA 53 Hydrochlorothiazide 0.060 100 NA NA NA 2.1 Hydrocodone 0.024 NA NA NA NA 0.84 10-Hydroxy- 0.36 8.3 NA NA NA 13 amitriptyline 2-Hydroxy-ibuprofen 0.97 1.0 NA NA NA 34 Hydrocortisone 0.047 0.050 NA NA NA 1.6 Ibuprofen 0.97 1.0 NA NA NA 34 Ibuprofen methyl ester 0.97 1.0 NA NA NA 34 Indomethacin 0.36 0.67 NA 0.00077 NA 0.027 Iohexol NA 5.0 NA NA NA 180 Iopromide NA 5.0 NA NA NA 180 Iso-chlorotetracycline 4.8 8.3 70 NA NA 170 Iso-epi-chlorotetracyline 4.8 8.3 70 NA NA 170 Ketoprofen 0.95 2.0 NA NA NA 33 Ketorolac 0.19 9.0 NA NA NA 6.7 Lasalocid NA 0.50 NA NA NA 18 Lidocaine 1.0 1.9 NA NA NA 35 Lincomycin 3.3 50 NA NA NA 120 Lomefloxacin 1.9 30 NA NA NA 67 (continued)

Table B.14 (continued) Comparison Levels (µg/kg-d) Based on lowest Based on Based therapeutic NOAEL/ on Based Based on DWEL Compound dose LOAEL MIC on CSF VSD (µg/L) Meclofenamic acid 9.5 3.0 NA NA NA 110 Meprobamate 2.2 75 NA NA NA 77 Menthol NA 200 NA NA NA 7,000 Metformin 0.48 60 NA NA NA 17 Methadone 0.020 7.3 NA NA NA 0.70 Methamphetamine 0.22 NA NA NA NA 7.7 Methocarbamol 2.4 NA NA NA NA 84 Methotrexate 0.020 0.17 NA NA NA 0.70 Metoprolol 0.012 1.7 NA NA NA 0.42 Miconazole 0.48 27 NA NA NA 17 Minocycline 0.095 NA 79 NA NA 3.3 Monensin NA 1.4 160 NA NA 49 Naproxen 1.3 20 NA NA NA 46 Narasin NA 2.5 NA NA NA 88 Nicotine NA 0.080 NA NA NA 0.080 Nifedipine 0.14 2.0 NA NA NA 4.9 Norfloxacin 3.8 67 50 NA NA 130 Norfluoxetine 0.11 0.97 NA NA NA 3.9 6-O-des-methyl- 1.3 20 NA NA NA 46 naproxen Ofloxacin 1.9 6.7 5.1 NA NA 67 OH-ibuprofen 0.97 1.0 NA NA NA 34 o-Hydroxy atorvastatin 0.010 0.67 NA NA NA 0.35 Oleandomycin 1.2 NA 31,000 NA NA 42 Ormetoprim 1.2 7.3 3,100 NA NA 42 Oxacillin NA NA 160 NA NA 5,600 Oxolinic acid NA 0.42 NA NA NA 15 Oxycodone 1.2 16 NA NA NA 42 Oxytetracycline 1.2 8.3 70 NA NA 42 Penicillin G 0.60 NA NA NA NA 21 Penicillin V 0.60 NA NA NA NA 21 Pentoxifylline 3.7 50 NA NA 0.61 21 Phenobarbital 0.14 16.7 NA 0.021 NA 0.74 (continued)

Table B.14 (continued) Comparison Levels (µg/kg-d) Based on lowest Based on Based therapeutic NOAEL/ on Based Based on DWEL Compound dose LOAEL MIC on CSF VSD (µg/L) Phenoxymethylpenicillin 0.60 NA NA NA NA 21 Phenytoin 1.4 1.4 NA 0.83 NA 29 p-Hydroxy atorvastatin 0.010 0.67 NA NA NA 0.35 Prednisone 0.0020 0.045 NA NA NA 0.070 Primidone 0.48 27 NA 0.0020 NA 0.070 Propranolol 0.37 80 NA NA NA 13 Ranitidine 1.3 75 NA NA NA 46 Risperidone 0.00050 0.0053 NA NA NA 0.018 Roxithromycin 1.4 NA 40 NA NA 49 Salicyclic acid 1.4 6.7 NA NA NA 49 Salinomycin NA 2.7 130 NA NA 95 Sarafloxacin NA NA 79 NA NA 2,800 Simvastatin 0.0050 0.33 NA NA NA 0.18 Simvastatin (hydroxyl 0.0050 0.33 NA NA NA 0.18 acid) Sucralose NA 150 NA NA NA 5,300 Sulfachloropyridazine NA NA 80,000 NA NA 2,800,000 Sulfadiazine 4.8 25 1,500 NA NA 170 Sulfadimethoxine NA NA 1,500 NA NA 53,000 Sulfamerazine 6.3 NA 10,000 NA NA 220 Sulfamethazine 0.63 23 81 NA NA 22 Sulfamethizole 0.48 NA 10,000 NA NA 17 Sulfamethoxazole 4.3 510 5,000 NA NA 150 Sulfasalazine 1.0 800 80,000 NA 10 35 Sulfathiazole NA 6.0 450 NA NA 210 Tetracycline and 4.8 8.3 70 NA NA 170 metabolites Theobromine NA 0.67 NA NA NA 23 Theophylline 0.067 40 NA NA NA 2.3 Thiabendazole 12 8.8 NA NA NA 310 Trimethoprim 2.7 14 6.1 NA NA 95 Tylosin NA NA 3,400 NA NA 120,000 Valproic acid 0.0020 3.0 NA NA NA 0.070 (continued)

Table B.14 (continued) Comparison Levels (µg/kg-d) Based on lowest Based on Based therapeutic NOAEL/ on Based Based on DWEL Compound dose LOAEL MIC on CSF VSD (µg/L) Virginiamycin NA NA 160 NA NA 5,600 Warfarin 0.010 0.097 NA NA NA 0.35 CSF – cancer slope factor; DWEL – drinking water equivalent level; LOAEL – lowest observed adverse effect level; MIC – minimum inhibitory concentration; NA – not available; NOAEL – no observed adverse effect level; TTC – threshold of toxicologic concern; VSD – virtually safe dose

Table B.15 Summary of comparison levels for hormones (µg/kg-d) (shaded values indicate lowest value for each compound) and DWELs based on lowest value Comparison Levels (µg/kg-d) Based on lowest Based on Based Existing therapeutic NOAEL/ on Based on ADI(µg/kg- DWEL Compound dose LOAEL CSF VSD d) (µg/L) Equilenin 0.00015 NA NA NA NA 0.0053 Equilin 0.00015 0.020 NA 0.0020 NA 0.0053 Ergosterol 0.00060 0.13 NA NA NA 0.021 Estradiol 0.00020 0.00050 NA NA 0.00029 0.0070 Estriol NA 0.67 NA NA NA 23 Estrone 0.0000070 0.00040 NA NA NA 0.00025 Ethynylestradiol 0.000010 0.0020 0.0053 NA NA 0.00035 Mestranol 0.0000060 0.0020 NA NA NA 0.00021 Norethindrone 0.00016 0.33 NA NA NA 0.0056 Progesterone 0.19 0.00030 NA NA 0.000030 0.0011 Testosterone 0.023 0.13 NA NA 0.0000020 0.000070 ADI – acceptable daily intake; CSF − cancer slope factor; DWEL – drinking water equivalent level; LOAEL – lowest observed adverse effect level; MIC – minimum inhibitory concentration; NA – not available; NOAEL – no observed adverse effect level; TTC – threshold of toxicologic concern; VSD – virtually safe dose

Table B.16 Summary of comparison levels for EDCs and non-pharmaceutical compounds without existing ADIs (µg/kg-d) (shaded values indicate lowest value for each compound) and DWELs based on lowest value Comparison Levels (µg/kg-d) Based on NOAEL/ Based on Based on DWEL Compound LOAEL CSF TTC (µg/L) 2-Phenoxyethanol 300 NA NA 11,000 3-Indole-butyric acid 3,000 NA NA 110,000 5-Methyl-1H-benzotriazole 1,000 NA NA 35,000 6-acetyl- 1,1,2,4,4,7- 0.50 NA NA 18 hexamethyltetralin (AHTN, Tonalide) Acetyl cedrene 50 NA NA 1,800 Acridine 12 NA NA 420 Androstenedione 0.024 NA NA 0.84 Androsterone NA NA NA 0.00049* Benzyl acetate 140 0.091 NA 3.2 Biochanin A 0.50 0.0027 NA 0.095 Chlorophene 1.0 NA NA 35 Cholestanol 42 NA NA 1,500 Cholesterol 0.17 NA NA 6.0 Chrysin 0.50 0.0027 NA 0.095 Coprostanol 0.17 NA NA 6.0 Daidzein 0.50 0.0027 NA 95 Desmosterol 0.17 NA NA 6.0 Dimethyl phthalate 80 NA NA 2,800 Epicoprostanol 0.17 NA NA 6.0 Ergosterol 0.13 NA NA 4.6 Ethyl citrate 667 NA NA 23,000 Formononetin 0.50 0.0027 NA 0.095 Galaxolide (HHCB) 5.0 NA NA 180 Genistein 0.50 0.0027 NA 0.095 Glycitein 0.50 0.0027 NA 0.095 Hexylcinnamaldehyde NA NA 0.021 0.74 Hydrocinnamic acid NA NA 0.021 0.74 Indole 450 NA NA 16,000 Isobornyl acetate 15 NA NA 530 Malaoxon 0.67 NA NA 24 Mestranol 0.0017 NA NA 0.060 Musk ketone 0.25 NA NA 8.8 Musk xylene 0.75 NA NA 26 (continued)

Table B.16 (continued) Comparison Levels (µg/kg-d) Based on NOAEL/ Based on Based on DWEL Compound LOAEL CSF TTC (µg/L) N,N- Diethyltoluamide (DEET) 2.3 NA NA 81 Nonylphenols (NP) 0.15 NA NA 5.3 Nonylphenol diethoxylates (NP2EO) 0.15 NA NA 5.3 Nonylphenol monoethyoxylates 0.15 NA NA 5.3 (NP1EO) Octyl methoxy cinnamate 8.3 NA NA 290 Octylphenols (OC) 1.3 NA NA 46 Oxybenzone 10 NA NA 350 PBDE-209 (Decabromo-diphenyl 10 NA NA 350 ether) Perfluorobutyric acid (PFBA) 0.69 NA NA 24 Perthane 8.3 NA NA 290 Total short-chain chlorinated 17 0.3 NA 11 paraffin (SCCP) Traseolide 0.25 NA NA 8.8 Triclocarban 2.5 NA NA 88 * No data available. Assumed to be 1/7 as potent as testosterone (Scott, T. 1996. Concise Encylopedia of Biology. p. 49). CSF – cancer slope factor; DWEL – drinking water equivalent level; LOAEL – lowest observed adverse effect level; NA – not available, NOAEL – no observed adverse effect level; TTC – threshold of toxicologic concern; VSD – virtually safe dose

INFORMATION FROM UTILITIES ON RATIONALE FOR MONITORING AND RISK COMMUNICATION OF CECS

Utility: LOTT Clean Water Alliance, Olympia, WA

1. What prompted you to conduct monitoring for PPCPs and EDCs in your source and/or drinking (treated/distribution) water?

LOTT’s Reclaimed Water Infiltration Study was initiated for a number of reasons:  Community members ask if chemicals for medicines and personal care and household products remain in reclaimed water after treatment, and they ask if it is safe to use the reclaimed water to recharge groundwater because of risks posed by residual chemicals. Increasing media attention to the issue of chemicals in water in recent years has made these inquiries more frequent. Also, Thurston County updated their Critical Areas Ordinance in 2011-2012, and as part of that process, struggled with similar questions. Draft updates to the regulations related to Critical Aquifer Recharge Areas prohibited recharge using reclaimed water because of uncertainty regarding potential risks. The County agreed to defer final critical area reclaimed water infiltration regulations until more information is available, and is still prohibiting recharge until then.  LOTT also voluntarily participated in two studies by EPA/Ecology in which LOTT effluent and reclaimed water were monitored for PPCPs and EDCs. Those were our initial steps at having some monitoring done, although they were just snapshots in time. They did provide some basic information that gave us an idea of how our treatment systems perform.

2. How did you decide what list of compounds to include in your monitoring program?

The list of compounds was developed based on case studies in other jurisdictions where the focus was Soil Aquifer Treatment (SAT) of reclaimed water, laboratory method reliability, detection limits, ecological and human health, degradation recalcitrance, and compounds monitored in the EPA/Ecology studies that have involved LOTT reclaimed water.

3. How regularly do you conduct monitoring? Was it a one-time program or do you conduct routine monitoring?

The final scope of work for the study has not yet been finalized – however we anticipate quarterly monitoring during the field work phase of the study for up to 1.5 years. Monitoring beyond the study is yet to be determined.

4. How have you communicated the results of your monitoring programs for PPCPs, EDCs, or other trace contaminants to the public?

Only limited monitoring has been conducted to date. As field work and monitoring get underway over the next year, results will be compiled and presented to the public through public meetings, presentations at a variety of community groups, and possibly through fact sheets and/or short videos that will be posted on LOTT’s website and distributed to the study mailing list. While the public is very interested in the results, members of the public have suggested that LOTT will need to present data in a timely fashion, but also take the time to provide context for what the data may mean in terms of potential risks.

5. What risk communication approaches have you used to support the information?

LOTT held three citizen focus groups in 2013 to help identify terminology that is meaningful and understandable to the public. They preferred the phrase “medicines and household and personal care products” to refer to where PPCPs come from and the term “residual chemicals” to refer to PPCPs that might be present in water. They also preferred the term “reclaimed water” to “recycled water” because it more specifically reflected that something was done to the water to allow it to be reused. They preferred the phrase “infiltrating reclaimed water to groundwater” rather than “groundwater recharge”. They also indicated that graphics were needed to help explain the complex concept of infiltration, so we have used a simple cartoon depiction.

When referring to concentrations, we have used descriptions like:

Water professionals are finding residual chemicals because we now have the technology and scientific methods to detect more substances at lower levels than ever before, and because of increased use of certain types of compounds. Residual chemicals like medicines are generally detected at extremely low levels, in the parts per billion or trillion range.

 A part per billion (ppb) is equivalent to:

One second in 32 years One drop in two tanker trucks

 A part per trillion (ppt) is equivalent to:

One second in 32,000 years One drop of water in 16 Olympic-size swimming pools

 To get a dose equal to one ibuprofen tablet (200 mg), one would have to drink this much water:

845,000 8-oz glasses containing 1 ppb 845,000,000 8-oz glasses containing 1 ppt

6. What are some of the Frequently Asked Questions (FAQs) you have encountered regarding your monitoring efforts?

 What’s still in the water after treatment?  Are these chemicals in our groundwater already? Are they in our drinking water?  How did you select the suite of chemicals that you are testing for? Does that list of chemicals to be monitored provide a fair assessment of potential risks?  Will you consider risks to both human health and ecological health?  How will you assess risks that take into account everyone? ADIs and other thresholds are not always set based on the most vulnerable populations.  How will you assess risks from combinations of chemicals and/or cumulative effects of chemicals?  What will you do if the study shows there are risks to infiltrating reclaimed water?  What is the risk to fish when treated water is discharged to surface waters?

7. Can you provide a link to or copy of an example of your results and risk communication materials for PPCPs/EDCs in water?

LOTT’s website has a page that includes a fact sheet with an overview of the study and video clips from presentations used at a public workshop to explain the reasons behind the study and the general framework for the study. http://www.lottcleanwater.org/groundwater.htm Display boards used at public workshops are also available but they are not currently posted on the website and are large files. Email lisadennis- [email protected] for copies.

8. How effective have your communication efforts been regarding PPCPs and EDCs in water? Has the response been positive/negative? Have you adjusted your monitoring or communication program in response to initial outcomes and, if so, what have you done?

As described above, focus group results changed the way that we explain the study. The study was actually renamed based on results of the focus groups, from Groundwater Recharge Scientific Study to Reclaimed Water Infiltration Study. Interest in the study to date has been modest because we have spent over a year scoping the study and it has been challenging to get people interested in designing a study. We expect that public interest will increase dramatically when results become available and alternative levels of treatment (and their associated costs) are being discussed.

9. What are some of the advantages/disadvantages you have encountered in initiating a proactive monitoring approach for PPCPs/EDCs?

Disadvantages are that the effort has been incredibly time-consuming and has progressed at a slower rate than anticipated. The study is at least 1 year behind schedule,

and LOTT may run up against the need to develop a new infiltration site before results of the study can be reviewed by the County and regulations can be updated. It has also been a challenge to communicate these complex concepts and issues while walking the fine line between causing worry and appearing to make light of possible risks. Beyond that, the proactive approach is absolutely critical to answering these questions for our local communities so that they have confidence that LOTT takes our mission seriously and will do what is needed to protect public and environmental health. Comments from members of the public show that they appreciate that the study is being conducted and their concerns are being taken seriously.

Utility: Orange County Water District, Fountain Valley, CA

1. What prompted you to conduct monitoring for PPCPs and EDCs in your source and/or drinking (treated/distribution) water?

Our decision to monitor was primarily to be proactive to demonstrate the safety of the recycled water we produce for groundwater recharge. The monitoring programs then further developed to meet regulatory requirements and help access treatment performance.

2. How did you decide what list of compounds to include in your monitoring program?

Our initial list was primarily based on the experience of outside researchers in terms of methods development. The California Department of Public Heath’s Endnote 5 from the early 2000s also had some initial suggested targets that were incorporated into our recycled water recharge permit. The list was then refined over time based on scientific literature, changing regulatory requirements, public perception, and health risk.

3. How regularly do you conduct monitoring? Was it a one-time program or do you conduct routine monitoring?

We conduct regular monitoring of our recycled water projects, some of which is permit-required and some of which is voluntary. We also conduct monitoring/testing in support of special projects, investigations, and research.

4. How have you communicated the results of your monitoring programs for PPCPs, EDCs, or other trace contaminants to the public?

Communication procedures depend on the study/project/program. For our NWRI CEC study, during which Intertox performed a human health risk analysis, we presented the complete final report and a summary to local press, which published an article. Other programs’ results are reported in annual reports which are submitted to regulators and are available to the public upon request.

5. What risk communication approaches have you used to support the information?

We have primarily used the ADI and DWEL approach (see our past work with Intertox). Secondarily, we’ll compare exposures to other sources. We do attempt to use neutral language in these communications.

6. What are some of the Frequently Asked Questions (FAQs) you have encountered regarding your monitoring efforts?

What is the source of these compounds in our water supplies? What does this data mean? Why are you spending all this money on monitoring for unregulated compounds? Is there value in generating repeated non-detect results? How do you use the monitoring data? What is the toxicological effect of mixtures? Is the use of linear extrapolation from dose-response studies appropriate in all cases? Should endocrine disrupting compounds be treated differently when it comes to establishing screening levels?

7. How effective have your communication efforts been regarding PPCPs and EDCs in water? Has the response been positive/negative? Have you adjusted your monitoring or communication program in response to initial outcomes and, if so, what have you done?

I would say that our pro-active communication efforts (e.g., reaching out to the press when we’ve completed a major study and had a significant finding) have been largely effective and largely positive. We’ve been consistent with the approach with respect to water quality even before PPCPs/EDCs became a significant issue.

8. What are some of the advantages/disadvantages you have encountered in initiating a proactive monitoring approach for PPCPs/EDCs?

The advantages have been building of trust with stakeholders and our community by showing transparency and forward-thinking. Other advantages include demonstrating the efficacy and reliability of treatment/purification processes. Disadvantages have been justifying the expense of such monitoring when there is no immediate regulatory requirement or follow-on change in operations.