EPA/600/R-09/057F Nanomaterial Case Studies: Nanoscale Titanium Dioxide in Water Treatment and in Topical Sunscreen November 2010 National Center for Environmental Assessment–RTP Division Office of Research and Development U.S. Environmental Protection Agency Research Triangle Park, NC Disclaimer This document has been reviewed in accordance with U.S. Environmental Protection Agency policy and approved for publication. Mention of trade names or commercial products does not constitute endorsement or recommendation for use. ii Table of Contents List of Figures _________________________________________________________ vi List of Tables _________________________________________________________ vii Authors, Contributors, and Reviewers ____________________________________ viii Abbreviations ________________________________________________________ xiii Foreword ____________________________________________________________ xix Chapter 1. Introduction ________________________________________________ 1-1 1.1. Background _________________________________________________________________ 1-1 1.2. How to Read this Document _____________________________________________________ 1-3 1.3. Terminology _________________________________________________________________ 1-4 1.4. Conventional TiO2 _____________________________________________________________ 1-7 1.5. Nano-TiO2 ___________________________________________________________________ 1-8 1.5.1. Drinking Water Treatment _______________________________________________ 1-12 1.5.2. Sunscreen ___________________________________________________________ 1-13 1.6. Analytical Methods ___________________________________________________________ 1-14 1.6.1. Methods for Laboratory Research _________________________________________ 1-15 1.6.2. Methods and Instrumentation to Assess Environmental Occurrence ______________ 1-16 1.6.3. Methods and Instrumentation to Assess Workplace Exposure ___________________ 1-18 1.6.4. Summary of Analytic Methods ____________________________________________ 1-19 Chapter 2. Life Cycle Stages ____________________________________________ 2-1 2.1. Feedstocks __________________________________________________________________ 2-1 2.2. Manufacturing ________________________________________________________________ 2-2 2.2.1. Drinking Water Treatment ________________________________________________ 2-3 2.2.2. Sunscreen ____________________________________________________________ 2-3 2.3. Distribution and Storage ________________________________________________________ 2-3 2.3.1. Drinking Water Treatment ________________________________________________ 2-4 2.3.2. Sunscreen ____________________________________________________________ 2-4 2.4. Use ________________________________________________________________________ 2-4 2.4.1. Drinking Water Treatment ________________________________________________ 2-4 2.4.2. Sunscreen ____________________________________________________________ 2-6 2.5. Disposal ____________________________________________________________________ 2-7 2.5.1. Drinking Water Treatment ________________________________________________ 2-7 2.5.2. Sunscreen ____________________________________________________________ 2-7 Chapter 3. Fate and Transport __________________________________________ 3-1 3.1. Water ______________________________________________________________________ 3-2 3.1.1. Drinking Water Treatment ________________________________________________ 3-4 3.1.2. Sunscreen ____________________________________________________________ 3-5 3.2. Soil ________________________________________________________________________ 3-5 3.2.1. Drinking Water Treatment ________________________________________________ 3-7 3.2.2. Sunscreen ____________________________________________________________ 3-7 3.3. Air _________________________________________________________________________ 3-7 iii Chapter 4. Exposure–Dose Characterization ______________________________ 4-1 4.1. Biota _______________________________________________________________________ 4-2 4.1.1. Aquatic Species ________________________________________________________ 4-2 4.1.2. Terrestrial Species ______________________________________________________ 4-3 4.2. Humans ____________________________________________________________________ 4-3 4.2.1. General Population _____________________________________________________ 4-3 4.2.1.1. Drinking Water Treatment ________________________________________ 4-3 4.2.1.2. Sunscreen ____________________________________________________ 4-4 4.2.2. Occupational __________________________________________________________ 4-6 4.3. Aggregate Exposure to Nano-TiO2 from Multiple Sources and Pathways __________________ 4-8 4.4. Cumulative Exposure to Nano-TiO2 and Other Contaminants ___________________________ 4-9 4.5. Models to Estimate Exposure ____________________________________________________ 4-9 4.6. Dose ______________________________________________________________________ 4-10 4.6.1. Uptake in Aquatic Species _______________________________________________ 4-11 4.6.1.1. Bioaccumulation _______________________________________________ 4-11 4.6.1.2. Food Web ____________________________________________________ 4-12 4.6.1.3. Cumulative Dose of Nano-TiO2 and Other Pollutants __________________ 4-12 4.6.2. Respiratory (Inhalation and Instillation) _____________________________________ 4-14 4.6.3. Dermal ______________________________________________________________ 4-16 4.6.4. Ingestion ____________________________________________________________ 4-24 4.6.5. Blood Brain Barrier and Placental Transfer __________________________________ 4-24 4.6.6. Dose Metrics _________________________________________________________ 4-26 Chapter 5. Characterization of Effects ____________________________________ 5-1 5.1. Factors that Influence Ecological and Health Effects of Nano-TiO2 _______________________ 5-1 5.1.1. Nano-TiO2 Physicochemical Characteristics __________________________________ 5-2 5.1.1.1. Size __________________________________________________________ 5-2 5.1.1.2. Crystallinity ____________________________________________________ 5-3 5.1.1.3. Surface Chemistry ______________________________________________ 5-3 5.1.1.4. Recommended Characterization of Nanomaterial for Ecological and Toxicological Studies ____________________________________________ 5-4 5.1.2. Experimental Conditions _________________________________________________ 5-6 5.1.2.1. Medium/Vehicle ________________________________________________ 5-7 5.1.2.2. Dispersion Preparation ___________________________________________ 5-8 5.1.3. Environmental Conditions ________________________________________________ 5-9 5.1.4. Summary ____________________________________________________________ 5-10 5.2. Ecological Effects ____________________________________________________________ 5-10 5.2.1. Ecological Effects of Nano-TiO2 Exposure __________________________________ 5-10 5.2.1.1. Effects on Bacteria and Fungi (Terrestrial and Aquatic) ________________ 5-16 5.2.1.2. Effects on Aquatic Organisms ____________________________________ 5-17 5.2.1.3. Effects on Terrestrial Organisms __________________________________ 5-21 5.2.1.4. Indirect and Interactive Ecological Effects ___________________________ 5-23 5.2.1.5. Summary ____________________________________________________ 5-23 5.3. Health Effects _______________________________________________________________ 5-24 5.3.1. Noncarcinogenic Effects ________________________________________________ 5-24 5.3.1.1. Studies in Humans _____________________________________________ 5-24 5.3.1.2. Animal Studies ________________________________________________ 5-25 5.3.1.3. Summary of Noncarcinogenic Effects ______________________________ 5-51 5.3.2. Carcinogenic Effects ___________________________________________________ 5-51 5.3.2.1. Studies in Humans _____________________________________________ 5-52 5.3.2.2. Animal Studies ________________________________________________ 5-52 iv 5.3.2.3. Modes of Action for Carcinogenicity ________________________________ 5-56 5.3.2.4. Summary of Carcinogenic Effects _________________________________ 5-58 Chapter 6. Summary __________________________________________________ 6-1 6.1. Case Study Highlights _________________________________________________________ 6-1 6.1.1. Analytical Methods _____________________________________________________ 6-2 6.1.2. Life Cycle Characterization _______________________________________________ 6-3 6.1.3. Fate and Transport _____________________________________________________ 6-5 6.1.4. Exposure and Dose Characterization _______________________________________ 6-6 6.1.4.1. Exposure Characterization ________________________________________ 6-6 6.1.4.2. Dose Characterization ___________________________________________ 6-8 6.1.5. Ecological and Health Effects ____________________________________________ 6-10 6.1.5.1. Ecological Effects ______________________________________________ 6-10 6.1.5.2. Health Effects _________________________________________________ 6-11 6.2. Role of Case Studies in Research Planning and Assessment Efforts ____________________ 6-12 6.2.1. Workshop on Research Priorities for Nano-TiO2 ______________________________ 6-12 6.2.2. Implications for Research Planning ________________________________________ 6-13 6.2.3. Implications for Future Assessment Efforts __________________________________ 6-13 REFERENCES ______________________________________________________ 6-15 Annex A. Nano-TiO2 in Sunscreen: