Arsenic in Rice and Rice Products Risk Assessment …

Arsenic in Rice and Rice Products Risk Assessment Report

Center for Food Safety and Applied Nutrition Food and Drug Administration U.S. Department of Health and Human Services

March 2016 Version Released for Public Comment

CONTRIBUTORS

Project Co-Leads: Sherri Dennis, PhD Suzanne Fitzpatrick, PhD, DABT

Project Manager: Dana Hoffman-Pennesi, MS

Risk Modelers: Clark Carrington, PhD, DABT (Retired April 2015) R?gis Pouillot, DVM, PhD

Subject Matter Experts: Katie Egan (Retired July 2013) Brenna Flannery, PhD Richard Kanwal, MD Deborah Smegal, MPH Judi Spungen, MS Shirley Tao, PhD

Technical Writer/Editor: Susan Mary Cahill

CITATION FOR THIS REPORT: U.S. Food and Drug Administration. 2016. Arsenic in Rice and Rice Products Risk Assessment Report. Available at .

Arsenic in Rice and Rice Products Risk Assessment Report Progress: Risk Management Team Review: Draft Risk Assessment Report dated November 2013 Interagency Expert Review: Draft Risk Assessment Report dated December 2013 CFSAN/FDA Review/Clearance ? Draft Risk Assessment Report dated February 2014 HHS Clearance ? Draft Risk Assessment Report dated May 2014 OMB Review: Draft Risk Assessment Report dated May 2014 (revised April 2015) and Addendum to the May 2014 Risk Assessment Report (draft dated May 2015) External Peer Review: Draft Risk Assessment Report dated July 2015 and Addendum dated May 2015 Revised Report based on External Peer Review and Incorporation of Addendum: Risk Assessment Report dated October 2015 Revised Report based on additional comments from OMB: Risk Assessment Report dated December 2015

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ACKNOWLEDGMENTS

The FDA Arsenic in Rice and Rice Products Risk Assessment benefited from contributions, conversations, and information provided by many individuals, organizations, and government officials. We thank and acknowledge, in particular, the following: ? Risk Management/Advisor Team (FDA-CFSAN): Don Zink, PhD (lead); Susan M.

Bernard, JD, DrPH; Nega Beru, PhD; Anne Crawford (Project Manager); Michael M. Landa, JD (Retired January 2015); Susan Mayne, PhD; Stephen Ostroff, MD; Linda Tollefson, DVM, MS (Retired March 2014); David G. White, PhD. ? Risk Communication Team (FDA-CFSAN): Sharon Natanblut (lead); Noah Bartolucci; Steven Bradbard, PhD; Sharmi Das; Theresa Eisenman; Suzanne Fitzpatrick, PhD, DABT; Douglas Karas; Susan Kelly; Ji Sun Lee; Jordan Lin, PhD; Stephen Ostroff, MD; Benson M. Silverman, MD (Deceased). ? Greg Noonan (FDA-CFSAN); Greg Diachenko (FDA-CFSAN); Philip Spiller (FDACFSAN; Retired January 2015), Bill Mindak (FDA-CFSAN), Sean Conklin (FDA-CFSAN), and Patrick Gray (FDA-CFSAN) and the laboratories that assisted in the analysis of FDA's rice and rice products samples and related research ? Mark Wirtz (FDA-CFSAN) and Stephanie Briguglio, MPH, CPH (FDA-CFSAN), for providing Total Diet Study data ? Stuart Chirtel(FDA-CFSAN) for statistical support in data analysis ? Lori Papadakis (FDA-CFSAN) for coordinating and managing peer review ? Andy Meharg, Queen's University Belfast, Belfast, United Kingdom ? National Center for Toxicological Research (NCTR) ? U.S. Environmental Protection Agency (EPA) ? National Institute of Environmental Health Science (NIEHS) ? U.S. Department of Agriculture ? Agricultural Research Service (USDA-ARS) ? Nathan Childs, U.S. Department of Agriculture ? Economic Research Service (USDA-ERS) ? Oak Ridge National Laboratories, for providing literature searches and literature analysis under contract ? Vicki Freimuth, PhD (Center for Health and Risk Communication and Professor, Department of Speech Communication and Grady College of Journalism and Mass Communication) for assistance with risk communication

We thank the experts who participated in a federal interagency peer review of an earlier draft of this risk assessment, including: ? Peter Lurie, MD (FDA-OC) ? Thomas J. Flammang, PhD; Dan Doerge, PhD; James Chen, PhD; Deborah Hansen, PhD,

U.S. Food and Drug Administration ? National Center for Toxicological Research (FDANCTR)

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Acknowledgements |

? Reeder L. Sams II, PhD; John Cowden, PhD; Jeff Gift, PhD; Allen Davis, PhD; David Thomas, PhD; Janice Lee, PhD; Karen Bradham, PhD; Linda Phillips, PhD; Lyle Burgoon, PhD; John Vandenburg, PhD; Kan Shao, PhD; Ellen Kirrane, PhD; Bob Hetes, PhD, U.S. Environmental Protection Agency ? Office of Research and Development (EPA-ORD)

? Santhini Ramasamy, PhD, MPH, DABT, U.S. EPA, Office of Water, Office of Science and Technology (EPA-OW-OST)

? Linda S. Birnbaum, PhD, DABT, ATS , Michael Waalkes, PhD, and Danielle Carlin, PhD, DABT, National Institutes of Health, National Institute of Environmental Health Sciences (NIH-NIEHS)

? (NIH-NIEHS) ? Barbara A. Ellis, PhD, Agency for Toxic Substances and Disease Registry - National Center

for Environmental Health (ATSDR-NCEH) and seven anonymous reviewers We thank Versar, Inc. and the experts who participated in the external peer review of this risk assessment, including: ? David Bottimore, Versar, Inc. ? Tracy Lang, Versar, Inc. ? John Rella, Versar, Inc. ? Aaron Barchowsky, PhD, University of Pittsburgh Dept of Environmental and Occupational

Health ? Rebecca Fry, PhD, University of North Carolina Gillings School of Global Public Health ? Barry P. Rosen, PhD, Florida International University Herbert Werthiem College of

Medicine dept of Cellular Biology and Pharmacology ? Craig M. Steinmaus, MD, MPH, UC Berkeley School of Public Health ? Marie Vahter, Karolinska Institutet Institute of Environmental Medicine

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TABLE OF CONTENTS

Contributors.................................................................................................................................................................... i Acknowledgments .........................................................................................................................................................ii Table of Contents ......................................................................................................................................................... iv List of Tables ................................................................................................................................................................ vii List of Figures.................................................................................................................................................................x Abbreviations and Acronyms...................................................................................................................................... xiii Executive Summary .......................................................................................................................................................1 1 Introduction .............................................................................................................................................................7

1.1 Process for Conducting Risk Assessments ...................................................................................................8 1.2 Objectives and Scope of the Risk Assessment .............................................................................................9 1.3 Collaborations............................................................................................................................................12 2 Hazard Identification..............................................................................................................................................13 2.1 The Contaminant: Arsenic .........................................................................................................................13

2.1.1 Introduction ............................................................................................................................... 13 2.1.2 Absorption, Distribution, Metabolism, and Excretion................................................................14 2.2 Health Effects of Inorganic Arsenic............................................................................................................16 2.2.1 Proposed Mechanisms of Action................................................................................................16 2.2.2 Short-Term and Intermediate Exposure.....................................................................................18 2.2.3 Chronic Exposure........................................................................................................................18 2.2.4 Epidemiological Studies..............................................................................................................19 2.3 Health Effects of MMA and DMA ..............................................................................................................20 2.3.1 Toxicity of Organic Species.........................................................................................................20 2.4 Effects of Early-Life Exposure to Arsenic ...................................................................................................21 2.5 Lung and Bladder Cancer: Background Incidence, Lifetime Risk, and Risk Factors in the U.S...................22 2.6 Non-Cancer Health Effects During Pregnancy (Effects on Fetus), Infancy, and Early Childhood...............23 2.6.1 Effects of Arsenic on Fetal Development During Pregnancy......................................................26 2.6.2 Effects of Arsenic During Infancy and Childhood .......................................................................28 3 Hazard Characterization (Dose-Response) for Lung and Bladder Cancer..............................................................31 3.1 FDA Dose-Response Model for Lung and Bladder Cancer .........................................................................31 3.1.1 Data Selection ............................................................................................................................31 3.1.2 Adjusting the Data for Use in the FDA Dose-Response Model...................................................32 3.1.3 Model Methodology...................................................................................................................34 3.2 Other Published Dose-Response Models for Lung and Bladder Cancer ....................................................37 3.2.1 U.S. EPA Drinking-Water Rule Dose-Response Model ...............................................................37 3.2.2 Liao et al. (2009) Model ............................................................................................................. 38 3.3 Comparison of Dose-Response Models .....................................................................................................38 4 Exposure Assessment ............................................................................................................................................44 4.1 The Exposure Assessment Model (Components) ......................................................................................44 4.2 Inorganic Arsenic Concentration Data.......................................................................................................45 4.2.1 Data Identification and Selection ...............................................................................................45 4.2.2 2013 and 2015 FDA Arsenic in Rice Surveys...............................................................................46 4.2.3 Consumer Reports Survey ..........................................................................................................48 4.2.4 Inorganic Arsenic Concentration Data Used in the FDA Exposure Assessment .........................48 4.2.5 Market Share..............................................................................................................................49

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Table of Contents |

4.2.6 Inorganic Arsenic Contribution from Rice Products ...................................................................51 4.3 Intake of Rice and Rice Products ...............................................................................................................52

4.3.1 Consumption Data......................................................................................................................52 4.3.2 Results: Estimates of Per Capita Rice Intakes.............................................................................54 4.3.3 Results: Estimates of Per Serving (Eating Occasion) Rice Intake................................................57 4.3.4 Results: Frequency of Intake ......................................................................................................58 4.4 Exposure to Inorganic Arsenic from Rice ...................................................................................................59 4.4.1 Results of the Current Study ......................................................................................................59 4.5 Bioavailability and Bioaccessibility of Inorganic Arsenic in Rice ................................................................65 4.6 Conclusions Regarding Exposure to Inorganic Arsenic from Rice..............................................................66 4.7 Exposure to MMA and DMA from Rice and Infant Rice Cereal .................................................................67 5 Risk Characterization of Lung and Bladder Cancer ................................................................................................70 5.1 Description of The Risk Model ...................................................................................................................70 5.2 Baseline Results for Potential Carcinogenic Effects...................................................................................71 5.2.1 Per Capita Estimates...................................................................................................................73 5.2.2 Per Serving (Eating Occasion) Estimates ....................................................................................74 5.2.3 Comparison of FDA and EPA Model Estimates...........................................................................76 5.3 "What If" Scenarios for Cancer Risks .........................................................................................................78 5.3.1 Mandatory or Voluntary Limits ..................................................................................................78 5.3.2 Age-Limit Scenarios ....................................................................................................................81 5.3.3 Consumer Practices (Rinsing and Cooking) ................................................................................82 5.3.4 Changes in Rice Consumption ....................................................................................................84 6 Exposure and Risk Characterization of Non-Cancer Health Effects .......................................................................86 6.1 Pregnant Women.......................................................................................................................................86 6.2 "What If" Exposure Scenarios for Infants ..................................................................................................89 6.3 Mandatory or Voluntary Limits for Rice Intended for Baby Foods............................................................89 6.4 Changes in Infant Rice Cereal Consumption..............................................................................................90 6.5 Mandatory or Voluntary Limits Plus Changes in Infant Rice-Cereal Consumption....................................91 7 Conclusions ............................................................................................................................................................93 7.1 Answers to the Risk Assessment Questions ..............................................................................................93 7.2 Uncertainty and Limitations of the Cancer Risk Assessment.....................................................................96 7.3 Potential Future Research and Risk-Assessment Activities .......................................................................98 7.4 Key Findings ...............................................................................................................................................98 8 References ...........................................................................................................................................................101 9 Appendix ..............................................................................................................................................................123 9.1 Total Arsenic in Select Foods from the Total Diet Study .........................................................................123 9.2 Adjustment of the Dose-Response Models to the Bootstrap Sets ..........................................................126 9.2.1 Maximum Likelihood Procedure ..............................................................................................126 9.2.2 Implementation........................................................................................................................127 9.3 Models .....................................................................................................................................................128 9.3.1 Restricted Dichotomous Gamma Model ..................................................................................128 9.3.2 Logistic Model ..........................................................................................................................128 9.3.3 Restricted Log-Logistic Model ..................................................................................................128 9.3.4 Restricted Log-Probit Model ....................................................................................................129 9.3.5 Probit Model ............................................................................................................................129 9.3.6 Restricted Weibull Model.........................................................................................................129

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Table of Contents |

9.3.7 One-Stage Dose-Response Model............................................................................................130 9.3.8 Restricted Dichotomous Hill Model .........................................................................................130 9.4 Model Weighting .....................................................................................................................................130 9.4.1 Single Model Sensitivity Analysis .............................................................................................131 9.4.2 Best Model ...............................................................................................................................140 9.4.3 Equiprobable Models ...............................................................................................................143 9.4.4 Weight of the Evidence ............................................................................................................144 9.5 Arsenic in Rice and Rice Products (FDA 2013 and 2016 Data Survey) .....................................................150 9.6 Oak Ridge Literature Reviews ..................................................................................................................153 9.6.1 Epidemiology Studies Review...................................................................................................153 9.6.2 FDA Review of 18 New Epidemiology Studies Found by Oak Ridge Literature Review ...........194 9.6.3 Arsenic Exposure Bibliography .................................................................................................197 9.6.4 Arsenic in Rice Market Sample Bibliography............................................................................198 9.7 Estimates of Rice Market Shares .............................................................................................................201 9.8 Detailed Exposure Calculations ...............................................................................................................206 9.8.1 Calculation of Inorganic Arsenic (iAs) in All Brown Rice and All White Rice ............................206 9.8.2 Calculation of Intake of Specific Rice Types .............................................................................209 9.9 NHANES/ WWEIA Data ............................................................................................................................209 9.9.1 Rice-Containing Foods Reported by NHANES/WWEIA Respondents.......................................209 9.9.2 NHANES/WWEIA Food Codes Used in Estimates of Rice Intakes per Eating Occasion ............236 9.10 Estimates of Rice Intake: Factors for Assessing Intake Frequency ..........................................................237 9.11 Estimates of Rice Intake: Per Capita Per Day and Per Eating Occasion ...................................................238 9.12 Comparison of Current Study Results with Inorganic Arsenic Exposure Estimates from Other Sources..................................................................................................................................................... 241 9.13 Non-Cancer Health Effects Literature Review .........................................................................................243 9.14 Causal Determination Framework ...........................................................................................................250 9.15 Update and Discussion of Pertinent Literature from October 2013 ? February 2015 ............................251 9.15.1 An Update of the Literature on Adverse Effects of Inorganic Arsenic Exposure to the

Developing Fetus and to Young Children............................................................................................252 9.15.2 An Update of the Literature on Adverse Effects of Inorganic Arsenic Exposure on

Cancer Endpoints in All Exposed Populations.....................................................................................262 9.15.3 Conclusions..........................................................................................................................269

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LIST OF TABLES

Table 3.1. Association of Bladder Cancer with Arsenic Exposure in Northeastern Taiwan (in person-years).............33 Table 3.2. Association of Lung Cancer with Arsenic Exposure in Northeastern Taiwan (in person-years) .................34 Table 3.3. Estimated Doses of Inorganic Arsenic and Lifetime Cancer Rates for Chen Cohort ...................................36 Table 3.4 Linear Slope Estimates and ED01 from Morales et al. (2000) Model 1 ......................................................37 Table 3.5. Predicted Cases per Million for Bladder Cancer at Five Doses with Lifetime Exposure..............................42 Table 3.6. Predicted Cases per Million for Lung Cancer at Five Doses with Lifetime Exposure ..................................43 Table 4.1. Selection of Data Used for the Exposure Assessment Model .....................................................................46 Table 4.2. Concentration of Inorganic Arsenic in Rice Grain and Infant Rice Cereal Samples Analyzed by FDA .........47 Table 4.3. Concentration of Inorganic Arsenic in Rice Grain and Infant Rice Cereal Samples: Combined FDA

(2013, 2016) and Consumer Reports (2012) Data............................................................................................49 Table 4.4. Market-Share Percentages for Types of Brown and White Rice.................................................................50 Table 4.5. Estimated Inorganic Arsenic Concentrations in All Brown Rice, All White Rice, and All Rice

Combined .........................................................................................................................................................51 Table 4.6. Rice-Intake Data Used in the Risk Assessment ...........................................................................................54 Table 4.7. Frequency of Consumption of Rice and Other Cooked Grains by Ethnicity................................................59 Table 4.8. Mean per Capita Inorganic Arsenic Exposure from Infant Rice Cereal and from All Rice Grain and

Rice Products: Males and Females Less Than 1 Year of Age ............................................................................60 Table 4.9. Mean per Capita Inorganic Arsenic Exposure from Rice Grain and Rice Products: Males and

Females, 0 ? 6 years .........................................................................................................................................61 Table 4.10. Mean per Capita Inorganic Arsenic Exposure from Rice Grain and Rice Products: Male and

Females, 0 ? 50 years .......................................................................................................................................61 Table 4.11. Mean Inorganic Arsenic Exposure from Infant Rice Cereal per Eating Occasion: Males and

Females Less Than 1 Year of Age .....................................................................................................................64 Table 4.12. Mean Inorganic Arsenic Exposure from Rice per Eating Occasion: Males and Females, 0 ? 6 years .......64 Table 4.13. Mean Inorganic Arsenic Exposure from Rice per Eating Occasion: Males and Females, 0 ? 50

years .................................................................................................................................................................65 Table 4.14. Mean per Capita DMA Exposure for U.S. Life Stages, from Infant Rice Cereal and Rice ..........................68 Table 4.15. Mean per Capita DMA Exposure for U.S. Life Stages, per Eating Occasion, from Infant Rice Cereal

and Rice............................................................................................................................................................68 Table 5.1. Predicted Total Lifetime Cancer Risk (Bladder and Lung) Attributable to Inorganic Arsenic in Rice

and Rice Products, by Exposure Period/Life Stage, Using Per Capita Consumption Estimates .......................73 Table 5.2. Predicted Total (Bladder and Lung) Lifetime Cancer Risks Attributable to Inorganic Arsenic in Rice

and Rice Products by Exposure Duration/Life Stage, Using One Eating Occasion per Day Estimates .............75 Table 5.3. Predicted Lifetime (0-50 years) Cancer Risks (Median Estimated Cancer Cases Per Million)

Attributable to Inorganic Arsenic in Rice and Rice Products, (90% CI) ............................................................77 Table 5.4. Estimated Percentage of Market Above Specified Limit (in %)...................................................................79 Table 5.5. Average Concentration (ppb) of Samples Below Specified Limit................................................................79 Table 5.6. Percentage Risk Reduction from a Variety of Mandatory or Voluntary Limits (in %).................................80 Table 5.7. Estimated Cancer-Risk Reduction from the Elimination or Reduction of Childhood Exposure to

Inorganic Arsenic in Rice and Rice Products.....................................................................................................82 Table 5.8. Estimated Cancer-Risk Reduction (Median Estimated Total Cancer Cases Per Million per Daily

Eating Occasion) for Arsenic in Rice from Changes in Cooking-Water Volume ...............................................84

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