# Health Effects Support **Document for Strontium**EPA - OST Preliminary Health Effe cts Support Document for Strontium April 2014

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### Health Effects Support Document

**For Strontium** 

U.S. Environmental Protection Agency Office of Water (4304T) Health and Ecological Criteria Division Washington, DC 20460 www.epa.gov/safewater/ccl/pdf/ Strontium .pdf

EPA Document Number: 820 - P - 14 - 001

Date: April 201 4EPA - OST Preliminary Health Effe cts Support Document for Strontium April 2014

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**FOREWORD** The Safe Drinking Water Act (SDWA), as amended in 1996, requires the Administrator of the U.S. Environmental Protection Agency (U.S. EPA) to establish a list of contaminants to aid the Agency

in regulatory

priority setting for the drinking water program. Inaddition, the SDWA requires U.S. EPA to make regulatory determinations for no fewer than five contaminants five ye ars after publication of the Contaminant Candidate L ist (CCL ). The criteria used to determine whether or not to regulate a chemical on the CCLare the following:

 The contaminant may have an adverse effect on the health of persons.

 The contaminant is known to occur or there is a substantial likelihood that the contaminant will occur in public water s ys tems with a frequency and at levels o f public health concern.

 In the sole judgment of the Administrator, regulation of such contaminant presents a meaningful opportunity

for health risk reduction for persons served by public water sy stems. The agency ’s findings for all three criteria are u sed in making a determination to regulate a contaminant. The agency may determine that there is no need for regulation when a contaminant fails to meet one of the criteria. The decision not to regulate is considered a final Agency action and is subject t o judicial review. This document provides the health effects basis for the regulatory determination for strontium and compounds. In arriving at the regulatory determination, data on toxicokinetics, human exposure, acute and chronic toxicity to animals an d humans, epidemiology , and mechanisms of toxicity

were evaluated. In order to avoid duplication of effort, information from the following risk assessments by the U.S. EPA and other government agencies were used in the development of this document. ATSDR (Agency

for Toxic Substances and Disease Registry). 2004. Toxicological profile for strontium . United States Department of Health and Human Services, Public Health Service, Agency

for Toxic Substances and Disease Registry . Available from: <http://www.atsdr.cdc.gov/toxprofiles/tp159.html>. IOM (Institute of Medicine). 2010. Dietary Reference Intakes for Calcium and Vitamin D. Institute of Medicine, Food and Nutrition Board. Available from: <http://www.nap.edu/catalog.php?record_id=13050 > . U.S. EPA (United States Environmental Protection Agency). 1992. Strontium (CASRN 7440 - 24 - 6). Integrated Risk Information Sy stem (IRIS) . Washington, DC, United States Environmental Protection Agency . Available from: <http://www.epa.gov/ncea/iris/subst/0550. htm>.EPA - OST Preliminary Health Effe cts Support Document for Strontium April 2014

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– DO NOT CITE OR QUOTE iv WHO (World Health Organization). 2010. Concise International Chemical Assessment Document 77. Strontium and Strontium Compounds. Available from: http://www.who.int/ipcs/publicat ions/cicad/cicad77.pdf . In formation from the published risk assessments was supplemented with information from the primary

references for key

studies and recent studies of strontium and compounds identified by

a literature search conducted in 2010. A Ref erence Dose (RfD) is provided as the assessment of long - term toxic effects other than carcinogenicit y. RfD determination assumes that thresholds exist for certain toxic effects, such as cellular necrosis, significant bod y or organ weight changes, blood di sorders, etc. Itis expressed in terms of milligrams per kilogram per day (mg/kg/day). In general, the RfD is an estimate (with uncertainty spanning perhaps an order of magnitude) of a daily oral exposure to the human population (including sensitive subgroups) that is likely to be without an appreciable risk of deleterious effects during a lifetime. The carcinogenicit y assessment for strontium and compounds includes a formal hazard identification and an estimate of tumorigenic potency when available. H azard identification is a weight - of - evidence judgment of the likelihood that the agent is a human carcinogen via the oral route and of the conditions under which the carcinogenic effects may be expressed. Development of these hazard identification and do se - response assessments for strontium and compounds has followed the general guidelines for risk assessment as set forth by the National Research Council (1983). U.S. EPA guidelines that were used in the development of this assessment may

include the foll owing: Guidelines for the Health Risk Assessment of Chemical Mixtures (U.S. EPA, 1986a), Guidelines for Mutagenicity Risk Assessment (U.S. EPA, 1986b), Recommendations for and Documentation of Biological Values for Use in Risk Assessment (U.S. EPA, 1988), Guidelines for Developmental Toxicity Risk Assessment (U.S. EPA, 1991), Interim Policy for Particle Size and Limit Concentration Issues in Inhalation Toxicity (U.S. EPA, 1994a), Methods for Derivation of Inhalation Reference Concentrations and Application of Inhalation Dosimetry (U.S. EPA, 1994b), Use of the Benchmark Dose Approach in Health Risk Assessment (U.S. EPA, 1995), Guidelines for Reproductive Toxicity Risk Assessment (U.S. EPA, 1996), Guidelines for Neurotoxicity Risk Assessment (U.S. EPA, 1998a), Science Policy Council Handbook : Risk Characterization (U.S. EPA, 2000a), Benchmark Dose Technical Guidance Document (U.S. EPA, 2000b), Supplementary Guidance for Conducting Health Risk Assessment of Chemical Mixtures (U.S. EPA, 2000c), A Review of the Reference Dose and Reference Concentration Processes (U.S. EPA, 2002), Guidelines for Carcinogen Risk Assessment (U.S. EPA, 2005a), Supplemental Guidance for Assessing Susceptibility from Early Life Exposure to Carcinogens (U.S. EPA., 2005b ), Science Policy Council Handbook: Peer Review (U.S. EPA, 2006a), and A Framework for Assessing Health Risks of Environmental Exposures to Children (U.S. EPA, 2006b). The chapter on occurrence and exposure to strontium and compounds through potable wate r was developed by

the Office of Ground Water and Drinking Water (OGWDW). It is based primaril y on National Inorganic and Radionuclide Survey (NI RS) data collected under theEPA - OST Preliminary Health Effe cts Support Document for Strontium April 2014

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– DO NOT CITE OR QUOTE v Safe Drinking Water Act ( SDWA ) . The NIRS data are supplemented with ground water data from USGS and States as well as published papers on occurrence in groundwater and drinking water.EPA - OST Preliminary Health Effe cts Support Document for Strontium April 2014

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– DO NOT CITE OR QUOTE vi **ACKNOWLEDGMENT** This document was prepared under the U.S. EPA Contract No EP - C - 1 - 030, Work Assignment No. B - 02 with ToxServices LLC. The Lead U.S. EPA Scientist s is and Joyce M. Donohue , Ph.D., Health and Ecological Criteria Division, Office of Science and Technology , Office of Water.EPA - OST Preliminary Health Effe cts Support Document for Strontium April 2014

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– DO NOT CITE OR QUOTE vii **AUTHORS AND CONTRIBU TORS**  **CHEMICAL MANAGER** Joyce M. Donohue , Ph.D. Office of Water, Office of Science and Technology Health and Ecological Criteria Division U.S. Environmental Protection Agency Washington, DC 20460 **AUTHORS (EPA)** Amal M. Mahfouz, Ph.D. Office of Water, Office of Science and Technology Health and Ecological Criteria Division U.S. Environmental Protection Agency Washington, DC 20460 Joyce M. Donohue, Ph.D. Office of Water, Office of Science and Technology Health and Ecological Criteria Division U.S. Environmental Protection Agency Washington, DC 20460 **AUTHORS (CONTRACT)** Irene M. Baskerville - Abraham, Ph.D. Lyn ne Haber, Ph.D., DABT Toxicology

Excellence for Risk Assessment 2300 Montana Ave, Suite 409 Cincinnati, OH 45211 Contract Number: EP - C - 10 - 030, Work Assignment Number B - 02 and 1 - 02 Under subcontract to ToxServices, LLC 1367 Connecticut Ave N.W., Suite 300 Washington, DC 20036 Contract Number: EP - C - 10 - 030, Work Assignment Number B - 02EPA - OST Preliminary Health Effe cts Support Document for Strontium April 2014

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– DO NOT CITE OR QUOTE viii **PEER REVIEWERS 1**  Marc De Broe, Ph.D. University

of Antwerp Antwerp, Belgium Alan H. Stern, Dr.P.H., DABT Independent Consultant Metu chen, NJ Gensheng Wang, Ph.D., DABT Lovelace Respiratory

Research Institute Albuquerque, NM

1 The Office of Water peer review ed the assessment for strontium for the chapters on pharmacokinetics, hazard identification, and dose response in 2011.EPA - OST Preliminary Health Effe cts Support Document for Strontium April 2014

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– DO NOT CITE OR QUOTE ix **TABLE OF CONTENTS** FOREWORD ................................ ................................ ................................ ................................ I II ACKNOWL EDGMENT ................................ ................................ ................................ ............... VI AUTHORS AND CONTRIBU TORS ................................ ................................ ......................... VII AB BREVIAT IONS AND ACRO NYMS ................................ ................................ .................. XI V 1.0 EXECUTIVE SUMMARY ................................ ................................ ............................. 1 - 1 2.0 ID ENTITY: CHEMI CAL AND PHYSI CALPROPERTI ES ................................ ......... 2 - 1 3.0 USES AND ENVIRONMENT AL FATE ................................ ................................ ....... 3 - 1 3.1 Production and Use ................................ ................................ ................................ ...... 3 - 1 3.2 Environmental Release ................................ ................................ ................................ 3 - 4 3.3 Environmental Fate ................................ ................................ ................................ ...... 3 - 5 3.4 Summary ................................ ................................ ................................ ...................... 3 - 5 4.0 EXPOSURE FROM DRINKING WATER ................................ ................................ ..... 4 - 1 4.1 Introduction ................................ ................................ ................................ .................. 4 - 1 4.2 Ambient Occurrence ................................ ................................ ................................ .... 4 - 1 4.2.1 Data Sources and Methods ................................ ................................ ....................... 4 - 1 4.2.2 Results ................................ ................................ ................................ ...................... 4 - 2 4.3 Drinking Water Occurrences ................................ ................................ ....................... 4 - 3 4.3.1 Data Sources and Methods ................................ ................................ ....................... 4 - 4 4.3.2 Derivation of the Health Reference Value ................................ ............................... 4 - 7 4.3.3 Results ................................ ................................ ................................ ...................... 4 - 8 4.4 Summary ................................ ................................ ................................ .................... 4 - 17 5.0 EXPOSURE FROM MEDIA OTHER THAN WATER ................................ ................. 5 - 1 5.1 Exposure from Food ................................ ................................ ................................ .... 5 - 1 5.1.1 Concentration in Non - Fish Food Items ................................ ................................ .... 5 - 1 5.1.2 Concentrations in Fish and Shellfish ................................ ................................ ....... 5 - 4 5.1.3 Intake of Strontium from Food ................................ ................................ ................ 5 - 4 5.2 Exposure from Air ................................ ................................ ................................ ....... 5 - 5 5.2.1 Concentration of Strontium in Air ................................ ................................ ........... 5 - 5 5.2.2 Intake of Strontium from Air ................................ ................................ ................... 5 - 6 5.3 Exposure from Soil ................................ ................................ ................................ ...... 5 - 6 5.3.1 Concentration of Strontium Soil ................................ ................................ .............. 5 - 7 5.3.2 Intake of Strontium from Soil ................................ ................................ .................. 5 - 7 5.4 Other Residential Exposures ................................ ................................ ........................ 5 - 8 5.5 Summary ................................ ................................ ................................ ...................... 5 - 8 6.0 TOXICOKINETICS ................................ ................................ ................................ ........ 6 - 1 6.1 Absorption ................................ ................................ ................................ .................... 6 - 1 6.2 Distribution ................................ ................................ ................................ .................. 6 - 7 6.3 Metabolism ................................ ................................ ................................ ................ 6 - 11EPA - OST Preliminary Health Effe cts Support Document for Strontium April 2014

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– DO NOT CITE OR QUOTE x 6.3.1 Metabolic Rate Constants ................................ ................................ ...................... 6 - 11 6.4 Excretion ................................ ................................ ................................ .................... 6 - 11 6.5 Pharmacokinetic Considerations ................................ ................................ ................ 6 - 14 6.6 Summary ................................ ................................ ................................ .................... 6 - 14 7.0 HAZARD IDENTIFICATIO N ................................ ................................ ........................ 7 - 1 7.1 Overview of Bone Phy siology and Development ................................ ........................ 7 - 1 7.2 Human Effects ................................ ................................ ................................ ............. 7 - 4 7.2.1 Short - Term Studies and Case Reports ................................ ................................ ..... 7 - 5 7.2.2 Long - Term and Epidemiological Studies ................................ ................................ 7 - 6 7.3 Animal Studies ................................ ................................ ................................ ............. 7 - 8 7.3.1 Acute Toxicity ................................ ................................ ................................ ......... 7 - 9 7.3.2 Short - Term Studies ................................ ................................ ................................ .. 7 - 9 7.3.3 Subchronic Studies ................................ ................................ ................................ . 7 - 14 7.3.4 Neurotoxicity ................................ ................................ ................................ ......... 7 - 17 7.3.5 Developmental/Reproductive Toxicity ................................ ................................ .. 7 - 18 7.3.6 Chronic Toxicity ................................ ................................ ................................ .... 7 - 19 7.3.7 Carcinogenicit y ................................ ................................ ................................ ...... 7 - 20 7.4 Other Key

Data ................................ ................................ ................................ .......... 7 - 20 7.4.1 Mutagenicity

and Genotoxicity ................................ ................................ .............. 7 - 20 7.4.2 Immunotoxicity ................................ ................................ ................................ ...... 7 - 21 7.4.3 Phy siological or Mechanistic Studies ................................ ................................ .... 7 - 21 7.4.3.1 Noncancer Effects ................................ ................................ .......................... 7 - 21 7.4.3.2 Cancer Effects ................................ ................................ ................................ 7 - 23 7.4.3.3 Interactions with Other Chemicals ................................ ................................ . 7 - 23 7.4.4 Structure - Activit y Relationship ................................ ................................ ............. 7 - 24 7.5 Hazard Characterization ................................ ................................ ............................. 7 - 24 7.5.1 Sy

nthesis and Evaluation of Major Noncancer Effects ................................ ......... 7 - 24 7.5.2 Sy

nthesis and Evaluation of Carcinogenic Effects ................................ ................ 7 - 26 7.5.3 Mode of Action and Implications in Cancer Assessment ................................ ...... 7 - 26 7.5.4 Weight of Evidence Evaluation for Carcinogenicity ................................ ............. 7 - 26 7.5.5 Potentially

Sensitive Populations ................................ ................................ ........... 7 - 26 8.0 DOSE - RESPONSE ASSESSMENT ................................ ................................ ............... 8 - 1 8.1 Dose - Response for Noncancer Effects ................................ ................................ ........ 8 - 1 8.1.1 RfD Determination ................................ ................................ ................................ ... 8 - 2 8.1.1.1 Benchmark Dose Approach ................................ ................................ ............. 8 - 5 8.1.1.2 NOAEL/LOAEL Approach ................................ ................................ ........... 8 - 10 8.1.1.3 Comparison with Current I RI S Assessment ................................ .................. 8 - 10 8.1.2 RfC Determination ................................ ................................ ................................ . 8 - 11 8. 2 Dose - Response for Cancer Effects ................................ ................................ ............ 8 - 11 9.0 PRELIMINARY REGULATO RY DETERMINATION AND CHARACTERIZAT ION OF RI SK FROM DRINKIN G WATER ................................ ................................ ...................... 9 - 1 9.1 Preliminary

Regulatory

Determination for Chemicals on the CCL ............................. 9 - 1 9.1.1 Criteria for Regulatory Determination ................................ ................................ ..... 9 - 1EPA - OST Preliminary Health Effe cts Support Document for Strontium April 2014

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– DO NOT CITE OR QUOTE xi 9.1.2 National Drinking Water Advisory Council Rec ommendations ............................. 9 - 2 9.2 Health Effects (Criterion #1) ................................ ................................ ....................... 9 - 2 9.2.1 Hazard Characterization and Mode of Action Implications ................................ .... 9 - 2 9.2.2 Dose - Response Characterization ................................ ................................ ............. 9 - 4 9.2.3 Health Criterion Conclusion ................................ ................................ .................... 9 - 4 9.3 Occurrence in Public Water Sy stems (Criterion #2) ................................ .................... 9 - 5 9.3.1 Monitoring Data ................................ ................................ ................................ ....... 9 - 5 9.3.2 Occurrence Criterion Conclusion ................................ ................................ ............ 9 - 6 9.4 Risk Reduction (Criterion #3) ................................ ................................ ...................... 9 - 6 9.4.1 Exposed Population Estimates ................................ ................................ ................. 9 - 7 9.4.2 Relative Sources of Exposure ................................ ................................ .................. 9 - 7 9.4.3 Sensitive Populations ................................ ................................ ............................... 9 - 8 9.4.4 Risk Criterion Conclusion ................................ ................................ ........................ 9 - 9 9.5 Regulatory

Determination Decision ................................ ................................ ............ 9 - 9 10.0 REFERENCES ................................ ................................ ................................ .............. 10 - 1 APPENDIX A . SUMMARY OF DATA FROM KEY ANIMAL STUDIES ............................ A - 1 APPENDIX B. HRL DERIVATION WITH AGE - RELATED EXPOSURE FAC TORS ........ B - 1 APPENDIX C. BENCHMARK DOSE MODEL ING RESUL TS FOR NON - CANCER ENDPOINTS ................................ ................................ ................................ .............................. C - 1EPA - OST Preliminary Health Effe cts Support Document for Strontium April 2014

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– DO NOT CITE OR QUOTE xii **LIST OF TABLES** Table 2 - 1 Chemical and Phy sical Properties of Strontium ................................ ......................... 2 - 1 Table 3 - 1 Strontium Compounds Production in the United States (pounds) .............................. 3 - 2 Table 4 - 1 STORET Data for Strontium

– Summary of Detected Concentrations ..................... 4 - 2 Table 4 - 2 STORET Data for Strontium

– Summary of Samples, Sites, and States ................... 4 - 3 Table 4 - 3 Strontium Occurrence Data from the NIRS Datab ase – Summary of Detected Concentrations ................................ ................................ ................................ ............................. 4 - 9 Table 4 - 4 Strontium Occurrence Data from the NIRS Database

– Summary of Ground Wate r Sy stem and Population Served Data ................................ ................................ ............................ 4 - 9 Table 4 - 5 Strontium State Drinking Water Occurrence Data

– Summary of Sy stems ............. 4 - 10 Table 4 - 6 Strontium State Drinking Water Occurrence Data

– Summary of Detected Concentrations ................................ ................................ ................................ ........................... 4 - 11 Table 4 - 7 Strontium State Drinking Water Occurrence Data

– Summary of Samples ............ 4 - 12 Table 4 - 8 Strontium STORET Data

– PWS Indiana and Ohio Summary of Detected Concentrations ................................ ................................ ................................ ........................... 4 - 12 Table 4 - 9 Strontium STORET Data

– PWS Indiana and Ohio Summary of Samples and Sites . 4 - 13 Table 4 - 10 Summary

of EWG Strontium Data, 2004 - 2009 ................................ ..................... 4 - 14 Table 4 - 11 Strontium Data from Public - S upply Wells

– Summary

of Detected Concentrations 4 - 15 Table 4 - 12 Strontium Data from Public - Supply Wells

– Summary

of Samples ...................... 4 - 15 Table 4 - 13 Strontium Data from Northern United States Glacial Aquifer Sy stem

– Summary of Concentrations ................................ ................................ ................................ ........................... 4 - 16 Table 5 - 1 Strontium Levels in Fruits and Vegetables ................................ ................................ 5 - 1 Table 5 - 2 Strontium Levels Measured in Various Foods ................................ ........................... 5 - 2 Table 5 - 3 Strontium Levels in Juices ................................ ................................ .......................... 5 - 3 Table 5 - 4 Dietary

Strontium Intakes for Population Subgroups from the 2006 United Kingdom Total Diet Study . ................................ ................................ ................................ .......................... 5 - 5 Table 5 - 5 Levels of Strontium in Soils and Other Geologic Materials (ppm) ............................ 5 - 7 Table 6 - 1 Summary

of Estimates of Absorption of Ingested Strontium in Humans .................. 6 - 2 Table 6 - 2 Summary

of uptake and turnover of 90 Sr in bones of children and adolescents ......... 6 - 9 Table 7 - 1 Genotoxicity

of Strontium In Vitro ................................ ................................ .......... 7 - 20 Table 7 - 2 Genotoxicity

of Strontium In Vivo ................................ ................................ ........... 7 - 21 Table 8 - 1 NOAEL/LOAELData for Oral Subchronic and Chronic Studies of Strontium ........ 8 - 1 Table 8 - 2 Output of Bench mark Dose (BMD) Models using BMR of 1 Standard Deviation ... 8 - 6EPA - OST Preliminary Health Effe cts Support Document for Strontium April 2014

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– DO NOT CITE OR QUOTE xiii **LIST OF FIGURES** Figure 7 - 1 Bone anatomy and growth ................................ ................................ ........................ 7 - 3 Figure 8 - 1 Restricted Poly nomial model, BMR = 1 SD ................................ ............................. 8 - 7EPA - OST Preliminary Health Effe cts Support Document for Strontium April 2014

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– DO NOT CITE OR QUOTE xiv **ABBREVIATIONS AND ACRONYMS** ANL Argonne National Laboratory atm atmosphere ATSDR Agency

of Toxic Substances and Disease Registry AUC ∞ area under the plasma - concentration time curve at the first intestinal absorption

loci AUC2 ∞ area under the plasma - concentration time curve at the second intestinal absorption

loci AUC iv area under the plasma - concentration time curve following intravenous

administration AUC oral area under the plasma - concentration time curve following oral administration AWWA American Water Works Association BMD benchmark dose BMDL benchmark dose

– Lower 95 th percentile confidence bound BMR benchmark response bw body

weight C Cels ius Ca Calcium CAS Chemical Abstracts Service CaSR calcium sensing receptor CCL Contaminant Candidate List CCL2 Contaminant Candidate List 2 CCL3 Contaminant Candidate List 3 C max peak plasma concentration at the first intestinal absorption loci C max2 peak plasma concentration at the second intestinal absorption loci CSF Cancer Slope Factor CUS Chemical Update S ys tem CW concentration in water CWS community water s ys tem d day deg degree DW/kg bw drinking water intake expressed as liters per kg body weight DWI drinking water intake ERK1/2 extracellular - signal - regulated - kinase 1/2 F The fraction of a 70 ye ar lifetime applicable to the age period FDA Food and Drug Administration g gram HRL health reference level HSDB Hazardous Substances Data B ank ICRP International Commission on Radiological Protection IOM Institute of Medicine IR IS Integrated Risk Information Sy stem IU international unit IUR Inventory

Update ReportingEPA - OST Preliminary Health Effe cts Support Document for Strontium April 2014

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– DO NOT CITE OR QUOTE xv i.v. intravenous kg kilogram K oc organic carbon water partitioning coefficient K ow octanol water partitioning coefficient L liter LD 50 Lethal dose for 50% (statistical median) of animals LOAEL lowest observed adverse effect level m meter MAPK Mitogen - activated protein kinase  Ci microcurie MCL G Max imum Contaminant Level Goal  g microgram mg milligram min minute mL milliliter m micrometer mmol millimole mol mole NAWQA National Water Qualit y Assessment NDWAC National Drinking Water Advisory Council ng nanogram NI ER National Institute of Environmental Research NI RS National Inorganics and Radionuclides Survey NOAEL no observed adverse effect level NPDWR National Primary Drinking Water Regulation NRC National Research Council NTNCWS Non - Transient Non - Community Water Sy stem OGWDW Office of Ground Water and Drinking Water OR observed ratio OW Office of Water p38 a class of mitogen - activated protein kinases responsive to stress stimuli PBPK pharmacologically based pharmacokinetic PI 3K Phosphoinositide 3 - kinase ppm parts per million P WS public water s ys tem Reg Det 2 Regulatory Determinations on the Second CCL RfC reference concentration RfD reference dose R iv whole body retention following intravenous administration R oral whole body retention following oral administration RSC relative source contribution SD standard deviation SDWA Safe Drinking Water Act Sr Strontium Sr(C 18 H 36 O 2 ) 2 Strontium StearateEPA - OST Preliminary Health Effe cts Support Document for Strontium April 2014

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– DO NOT CITE OR QUOTE xvi SrCl 2 Strontium Chloride SrCO 3 Strontium Carbonate SrCrO 4 Strontium Chromate Sr(NO 3 ) 2 Strontium Nitrate SrO Strontium Oxide Sr(OH) 2 Strontium Hydroxide SrSO 4 Strontium Sulfate TDS Total Diet Studies TNCWS Transient Non - Community Water S ys tem TRI Toxic Release Inventory TSCA Toxic Substances Control Act UCMR Unregulated Contaminant Monitoring Rule UCMR 1 Unregulated Contaminant Monitoring Rule 1 UCMR 2 Unregulated Contaminant Monitoring Rule 2 U.S. EPA U.S. Environmental Protection Agency USGS U.S. Geological Service VOC volatile organic compound WHO World Health Organization WRF Water Research FoundationEPA - OST Preliminary Health Effe cts Support Document for Strontium April 2014

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– DO NOT CITE OR QUOTE 1 - 1 **1.0 EXECUTIVE SUMMARY**  Strontium (Sr) is a naturally - occurring element (atomic number 38) and a member of the alkaline earth metals. There are several radioactive strontium isotopes formed by nuclear fission of uranium or plutonium. The best known is 90 Sr , a legacy from above ground t esting of the atomic bomb (half

- life 29 y ears). Since drinking water contamination by radioactive isotopes, including beta particle emitters, is covered under the existing radionuclides rule, this health effects source document deals primaril y with nonradioactiv e properties and the occurrence of “total” strontium in the environment . The bulk of environmental strontium (83%) is the stable 88 Sr isotope . Strontium occurs naturally in rocks, soils, and sea water. Strontium was mined in the United States until 195 9. Historically, the most important commercial use of strontium has been in the faceplate glass of cathode - ray tube televisions. As flat panel technology has become widespread in the United States, demand for strontium for this application has fallen. S trontium compounds are still used for applications such as pyrotechnics, magnets, and pigments. Extrapolation from the National Inorganics and Radionuclides Survey (NIRS), conducted from 1984 to 1986, indicate that an estimated national population of 10 .5 million people served by ground water s ys tems was exposed to strontium in drinking water above the health reference level (HRL) of 1500 μg/L during the survey period. The mean concentration for the samples with detections was 603 mg/L and th e median re ported level was 178 μg/L . T he maximum reported level was 43,500 μg/L (a value approximately 30 times the HRL). Approximately 7% percent (69 of 989) of the NIRS public water s ys tems (PWSs) detected strontium at a level greater than the HRL of 1500 μg/L. Li mited data from USGS suggest that sandstone aquifers may have higher levels of strontium than other ty pes . Although strontium is known to occur in food, air, and soil, data on levels in those media are limited, as are estimates of intake from those s ources. Estimated strontium intake from air and soil is very

low compared with that from food and drinking water. The estimated exposure for children from air is 0.1 μg Sr/day and the estimated exposure from soil is 24 μg Sr/day . The dietary intakes bas ed on an FDA Total Diet Study range from 493 to 685 μg/day for ages 6 months to 2 y ears and 928 to 1,388 μg Sr/day for 14 to 16 y ear old adolescents. There are several studies that evaluated the relationship between strontium exposure in the environment or the body burden of strontium (as a measure of internal dose) and development of disease following either occupational or environmental exposures. These studies are of limited utility

for characterizing hazard and assessing dose response due to inadequ ate control for other factors potentially contributing to the endpoint being evaluated. Strontium has low acute toxicity to rodents via the oral and dermal routes; the low volatility of strontium compounds makes inhalation exposure unlikely . The chemical similarity of strontium to calcium allows it to exchange imperfectly for calcium in a variet y of biological processes; the most important of these is the substitution of calcium in bone, affecting skeletal development. Subchronic and chronic studies in r ats show that strontium can decrease theEPA - OST Preliminary Health Effe cts Support Document for Strontium April 2014

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– DO NOT CITE OR QUOTE 1 - 2 calcification of the cartilaginous portion of bone in the y oung , and at therapeutic doses can increase bone formation relative to degradation in the elderl y . Due to the mode of action for strontium toxicity , strontium uptake into bone and the resulting toxicity is affected b y the stage of bone development and intake of nutrients related to bone formation, such as calcium, magphosphorous and vitamin D. The results of clinical studies in people administered str ontium ranelate [Sr2(C12H6N2O8) ] to treat osteoporosis support the conclusion from animal studies that strontium influences bone composition and metabolic processes in ways that can be beneficial as well adverse, vary ing with life - stage and level of exposure. There are no standard one - or two - generation reproductive toxicity studies for any strontium compound, but the available data indicate that strontium does not cause structural or functional effects at doses well above those causing bone effects. In a screening test for reproductive and developmental toxicity , no effects were observed on mating behavior, fertility , gestation period or the histopathology of the reproductive tissues and organs, and no developmental or teratogenic effects were observed. The data relevant to strontium carcinogenicit y are very limited. No increase in tumors was seen in the single available chronic oral stud y, but this study used a small sample size and was inadequate for evaluation of carcinogenic potential. The weight of evidence from the genotoxicity

data is that strontium compounds are negative for gene mutation, chromosome aberrations and DNA damage. Based on these data, there is inadequate information to assess the carcinogenic potential of strontium, due to the la ck of adequate chronic duration studies. The RfD of 0.3 mg Sr/kg - day is based on the critical effect of decreased bone calcification during growth and development . In the principal study , male weanling rats (8/group) were administered strontium in drinki ng water for 9 weeks at concentrations of 0, 0.19, 0.27, 0.34, or 0.40% strontium chloride (estimated by the authors to be equivalent to 0, 316, 425, 525, and 633 mg Sr/kg - day , respectivel y). The RfD was calculated using the benchmark dose (BMD) method, and based on the lower 95% confidence limit on the benchmark dose (defined as a one control standard deviation change in the mean), a BMDL (1 SD) of 328 mg Sr/kg - day was derived. This value was divided by an uncertainty factor of 1000, with a factor of 10 each used to account for human variability , extrapolation from rats, and database uncertainties. The U.S. EPA also evaluated whether health information is available regarding potential effects on children and/or other sensitive populations. Because str ontium can substitute for calcium in growing bone, children and teenagers are expected to be a sensitive population, since they are activel y growing. Strontium exposure in children and teenagers may result in effects on bone structure (poor calcification) with a more severe and/or a long - term impact than similar exposures in adults. The RfD was based on changes in bone growth in weanling rats (i.e., the sensitive population). Accordingl y, strontium at concentrations above the HRL would be expected to hav e the greatest impact during periods of rapid growth in the developing fetus, during childhood and adolescence, particularl y if calcium intake is insufficient, but exposure at the HRLis expected to be protective of the sensitive population s . People with severel y impaired kidney function or disorders affecting the normal equilibrium between the breakdown of old bone and the formation of new bone (such as Paget’s disease) might also be sensitive toEPA - OST Preliminary Health Effe cts Support Document for Strontium April 2014

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– DO NOT CITE OR QUOTE 1 - 3 strontium exposure. In summary , strontium has the potentia l to cause adverse bone effects, based on toxicological data from animal studies, and supported by limited human data and an understanding of its mode of action. Strontium is known to occur in public water s ys tems with a frequency and at levels of public health concern. Due to the large number of people exposed to strontium through drinking water and the potentially high concentration of strontium measured in some PWSs, regulation of strontium presents a meaningful opportunity for health risk reduction es peciall y for those with developing bones (such as infants, children and adolescents), individuals deficient in calcium, and persons with kidney conditions.EPA - OST Preliminary Health Effe cts Support Document for Strontium April 2014

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– DO NOT CITE OR QUOTE 2 - 1 **2.0 IDENTITY: CHEMICAL AND PHYSICAL PROPERTIES**  Strontium is a naturally - occurring element (atomic number 38) and a member of the alkaline earth metals (Group 2 of the periodic table), which also include bery llium, magnesium, calcium, barium, and radium. Of the many known isotopes of strontium, four ar e stable and found in nature: 84 Sr (~0.5%), 86 Sr (~9.9%), 87 Sr (~7.0%), and 88 Sr (~82.6%) (ANL, 2007). There are also several radioactive isotopes formed by nuclear fission of uranium or plutonium (ATSDR, 2004). Notable among these is 90 Sr, a beta parti cle emitter with a half - life of 29 y ears that was released into the atmosphere from above - ground testing of nuclear weapons in the period 1945 - 1980. Since drinking water contamination by radioactive isotopes, including beta particle emitters, is covered under the existing radionuclides rule, this document deals primarily with nonradioactive properties and the occurrence of “total” strontium in the environment. Strontium constitutes approximately 0.02 - 0.03% of the earth’s crust, and is the fifth most abund ant metallic ion in seawater (Hibbins, 1997). In the earth’s crust strontium occurs principally

as strontium sulfate (SrSO 4 ) in the mineral celestite (USGS, 2009a). The elemental form does not exist in nature (ATSDR, 2004). Two common refining methods f or celestite are the black ash method (calcining) and the soda method. Both produce strontium carbonate (SrCO 3 ) (ATSDR, 2004). Strontium may be present as an impurity in coal, and may

be released to air as strontium oxide from coal - burning (ATSDR, 2004). Phy sical and chemical properties and other reference information for select strontium compounds are listed in Table 2 - 1 below. Table 3 - 1 in Section 3.1 identifies some additional strontium - containing compounds that are produced industrially. **Table 2**  **- 1**  **Chemical and Physical Properties of Strontium Property**  **Information**

**Elemental Strontium**  **Strontium**

**Carbonate Strontium** 

**Chromate Strontium** 

**Nitrate Strontium** 

**Hydroxide Strontium** 

**Chloride** Chemical Abstracts Service (CAS) Registry No. 7440 - 24 - 6 1633 - 05 - 2 7789 - 06 - 2 10042 - 76 - 9 18480 - 07 - 4 10476 - 85 - 4 Chemical Formula Sr SrCO 3 SrCrO 4 Sr(NO 3 ) 2 Sr(OH) 2 SrCl 2 Molecular Weight 87.6

g/mol 147.63

g/mol 203.61

g/mol 211.63

g/mol 121.64

g/mol 158.53

g/mol Color/ Phy sical State Pale

ye llow solid White solid Yellow solid Colorless

solid Colorless

solid White solidEPA - OST Preliminary Health Effe cts Support Document for Strontium April 2014

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– DO NOT CITE OR QUOTE 2 - 2 **Property Information** 

**Elemental Strontium**  **Strontium**

**Carbonate Strontium** 

**Chromate Strontium** 

**Nitrate Strontium** 

**Hydroxide Strontium** 

**Chloride** Boiling Point 1,390 deg

C 1,100 deg C, decomposes -- 645 deg C - H 2 0, 710 deg C 1,250 deg C Melting Point 777 deg C 1,497 deg C at 69 atm. pressure -- 570 deg C 375 deg C 875 deg C Density 2.6 g/cm 3

at 4 deg C 3.70 g/cm 3

at 4 deg C 3.895

g/cm 3 at 15 deg C 2.986 g/cm 3

at 4 deg C 3.625 g/cm 3

at 4 deg C 3.052 g/cm 3

at 4 deg C K ow -- -- -- -- -- -- K oc -- -- -- -- -- -- Solubility in Water Reactive 11 mg/L at 18 deg C 1,200 mg/L

at 15 deg C 709,000

mg/L at 18 deg C 4100 mg/L

at 0 deg C 538,000

mg/L at 20 deg C Solubility in Other Solvents Alcohol Acid, ammonium salts Acetic acid Slightly in alcohol and acetone Alcohol Alcohol, acetone Conversion Factors (at 25 deg C, 1 atm) NA NA NA NA NA NA Sources: HSDB (2006b); RAIS (2009); Weast and Astle (1981); ChemIDplus (2011); ATSDR (2004) Note: “ -- ” indicates that no information was found; “NA” indicates that the property is not applicable to the compound.EPA - OST Preliminary Health Effe cts Support Document for Strontium April 2014

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– DO NOT CITE OR QUOTE 3 - 1 **3.0 USES AND ENVIRONMENTAL FATE**  This section summarizes information pertaining to the uses, manufacture, and environmental fate of strontium and select strontium compounds. **3.1 Production and Use**  Strontium mineral mining in the United States ceased in 1959. Imports of strontium minerals and compounds stood at approximately 31,000 - 38,500 metric tons from 1994 to 2001 (ATSDR, 2004). Since then imports have declined. Total U.S. consumption of strontium minerals and compounds was 16,700 metric tons of strontium content in 2004 and approximately 7 , 750 metric tons in 2008 (USGS, 2009a). Historically , the most important commercial use of strontium has been in the faceplate glass of cathode - ray

tube televisions, to block x - ray emiss ions. During manufacturing strontium carbonate is added to liquid glass and converts to strontium oxide (SrO). Strontium oxide constitutes approximately 8% (b y weight) of the picture tube glass (ATSDR, 2004). As flat panel technology

has become widespre ad in the United States in the last decade, demand for strontium for this application has fallen (USGS, 2009a). In 2008, approximately 30% of commercial strontium consumption was in py rotechnics and signals (as strontium nitrate and other compounds ). Str ontium produces a characteristic crimson red flame during combustion (Weast and Astle, 1981). Other uses include 30% in ferrite ceramic magnets (as strontium ferrite), 10% in master alloy s (as strontium metal), 10% in pigments and fillers (as strontium chromate), 10% in electroly tic production of zinc (as strontium carbonate), and 10% in other applications such as fluorescent lights (strontium phosphate), toothpaste (strontium chloride), and medicines (strontium chloride and strontium peroxide). The feed material for most applications is strontium carbonate (Hibbins, 1997; USGS, 1999; USGS, 2002 ; USGS, 2009a ). Production data from the U.S. EPA Inventory Update Reporting (IUR) program are available for several strontium - containing compounds. U.S. EPA col lects information on chemicals manufactured in or imported into the United States in the Toxic Substances Control Act (TSCA) Chemical Substance Inventory . The U.S. EPA IUR regulation of 1986 required chemical manufacturers and importers to report to U.S. EPA every four ye ars the identity

of, and basic manufacturing information for organic chemical substances manufactured and imported annually at individual sites in quantities of 10,000 pounds or more (U.S. EPA, 2010a). Modifications of the IUR rule in 2003 and 2005 expanded the range of chemicals and plant sites reporting, expanded the ty pe of data reported, raised the production volume threshold that triggers reporting from 10,000 pounds to 25,000 pounds, and made other adjustments . Because of changes in minimum thresholds and other program modifications, the results from 2006 might not be directl y comparable to results from earlier years. IUR data are stored in the Chemical Update Sy stem (CUS). The CUS - IUR assigns one of eight production and importation volume ranges for each chemical included in the inventory . Table 3 - 1 presents the reported production of 17 strontium compounds in the United States every four y ears from 1986 to 2006. Not every compound hadEPA - OST Preliminary Health Effe cts Support Document for Strontium April 2014

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– DO NOT CITE OR QUOTE 3 - 2 data reported in every

cycle. Annual productio n of strontium carbonate varied considerabl y over the periods for which data were reported, reaching into the tens of millions of pounds. There was an apparent increase in the production of strontium nitrate between 2002 and 2006. The production of seven other strontium compounds with pre - 2006 data remained relativel y constant in y ears when data were reported, and eight compounds had no data reported until 2006. Three compounds, strontium carbonate, strontium chromate, and strontium nitrate, were produce d or imported in quantities greater than one million pounds in at least one cy cle (U.S. EPA, 2010a). When considering the strontium contribution from complex compounds, such as many of those included in Table 3 - 1, it is important to remember that strontium itself is only a fraction of the total poundage reported. For example, strontium distearate is only 13% strontium by

weight (88 out of 656 g/mol). Dissociation of strontium and various strontium species from degradation of the compounds listed in the table may pose health risks, and some of the compounds themselves may

be of health concern. **Table 3**  **- 1**  **Strontium Compounds Production in the United States (pounds) Chemical Name and**  **CASRN in CUS Databa**  **se Chemical Inventory Update Reporting Cycle** 

**1986 1990**  **1994 1998**  **2002 2006**  Strontium carbonate (SrCO 3 ) 1633 - 05 - 2 > 1

million - 10 million No

reports No reports > 10

million - 50 million 10000 -

500000 10 million

– < 50 million Strontium chromate (SrCrO 4 ) 7789 - 06 - 2 > 1

million - 10 million > 1

million - 10 million No

Reports No

Reports No

Reports < 500000 Strontium stearate (Sr(C 18 H 36 O 2 ) 2 ) 10196 - 69 - 7 10000 -

500000 10000 -

500000 No

Reports No

Reports No

Reports No

Reports Strontium nitrate (Sr(NO 3 ) 2 ) 10042 - 76 - 9 No

Reports No

Reports No

Reports No

Reports 10000 -

500000 1 million

– < 10 million 2 - Naphthalenecarbox yl ic acid, 3 - hy drox y - 4 - [(4 - methy l sulfopheny l)azo] - , strontium salt (1:1) 73612 - 29 - 0 10000 -

500000 10000 -

500000 10000 -

500000 10000 -

500000 10000 -

500000 No

Reports 1 - Naphthalenesulfonic acid, 2 - [(2 - hy drox y - 1 - 1 - napthaleney l)azo] - strontium salt (2:1) No

Reports No

Reports No

Reports No

Reports 10000 -

500000 No

ReportsEPA - OST Preliminary Health Effe cts Support Document for Strontium April 2014

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– DO NOT CITE OR QUOTE 3 - 3 **Chemical Name and CASRN in CUS**  **Databa se**  **Chemical Inventory Update Reporting Cycle**

**1986 1990**  **1994 1998**  **2002 2006**  6371 - 67 - 1 2 - Napthalenecarbox yl ic acid, 3 - hy drox y - 4 - [(4 - methy l - 2 - sulfopheny l)azo] - , calcium strontium salt (2:1:1) 55491 - 44 - 6 No

Reports No

Reports No

Reports No

Reports 10000 -

500000 No

Reports 2 - Napthalenecarbox yl ic acid, 4 - [(5 - chloro - 4 - methy l - 2 - sulfopheny l)azo] - 3 - hy drox y - , strontium salt (1:1) 15782 - 05 - 5 10000 -

500000 10000 -

500000 10000 -

500000 10000 -

500000 10000 -

500000 No

Reports 2 - Naphthalenecarbox yl ic acid, 4 - [(4 - chloro - 5 - methy l - 2 - sulfopheny l)azo] - 3 - hy drox y - , strontium salt (1:1) 67828 - 72 - 2 10000 -

500000 10000 -

500000 No

Reports No

Reports No

Reports No

Reports Strontium oxide (SrO) 1314 - 11 - 0 No

Reports No

Reports No

Reports No

Reports No

Reports < 500000 Strontium titanium oxide (SrTiO 3 ) 12060 - 59 - 2 No

Reports No

Reports No

Reports No

Reports No

Reports 500000 to

- 1 million Phosphoric acid, strontium salt (1:1) 13450 - 99 - 2 No

Reports No

Reports No

Reports No

Reports No

Reports < 500000 Phenol, nony l - , strontium salt (2:1) 31291 - 42 - 6 No

Reports No

Reports No

Reports No

Reports No

Reports < 500000 Phosphoric acid, magnesium strontium salt, tin - doped 68784 - 28 - 1 No

Reports No

Reports No

Reports No

Reports No

Reports < 500000 Strontium fluoride No No No No No < 500000EPA - OST Preliminary Health Effe cts Support Document for Strontium April 2014

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– DO NOT CITE OR QUOTE 3 - 4 **Chemical Name and CASRN in CUS**  **Databa se**  **Chemical Inventory Update Reporting Cycle**

**1986 1990**  **1994 1998**  **2002 2006**  phosphate (Sr 5 F(PO 4 ) 3 ), antimony and manganese - doped 68784 - 78 - 1 Reports Reports Reports Reports Reports

Barium calcium strontium chloride phosphate, europium doped 109037 - 74 - 3 No

Reports No

Reports No

Reports No

Reports No

Reports < 500000 Silicon sodium strontium titanium hy droxide oxide 326855 - 77 - 0 No

Reports No

Reports No

Reports No

Reports No

Reports < 500000 Source: U.S. EPA (2010a) **3.2 Environmental Release**  Naturall y occurring strontium in rocks, soils, and sea water can be mobilized by natural weathering, wind, and sea spray . Higher concentrations of atmospheric strontium in coastal areas relative to inland areas have been attributed to sea spray (Capo et a l., 1998). Human activities that contribute strontium to environmental media include milling, refining, and other industrial activities, plus coal burning and use of phosphate fertilizers and py rotechnic devices (Lee and von Lehmden, 1973; Que Hee et al. , 1982; Ondov et al., 1989; Raven and Loeppert, 1997; Perry , 1999). There are no data on industrial releases of strontium compounds in U.S. EPA’s Toxics Release Inventory

(TRI). (More precisel y: the list of compounds for which TRIreporting is required has never included a compound with “strontium” in its name (U.S. EPA, 2010b)). Strontium concentrations of up to 2718  g/m 3 have been measured in atmospheric emissions from coal - fired power plants in the western United States, and concentrations of approx imately

9800  g/ m 3 have been measured in the eastern U.S (Que Hee et al., 1982; Ondov et al., 1989). In phosphate fertilizers, strontium concentrations are reported to range between 20  g/ g and 4000  g/ g (Lee and von Lehmden, 1973; Raven and Loeppert, 199 7). L ocal atmospheric concentrations of strontium in the range of 0.009  g/m 3 have been observed following p yrotechnic display s (Perry , 1999).EPA - OST Preliminary Health Effe cts Support Document for Strontium April 2014

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– DO NOT CITE OR QUOTE 3 - 5 **3.3 Environmental Fate**  Strontium can exist in oxidation states 0 and +2; under normal environmental conditions it is found primarily

in the +2 oxidation state (ATSDR, 2004). Strontium enters the atmosphere via natural weathering and sea spray (Capo et al., 1998), and as a resu lt of industrial activity , the application of phosphate fertilizers, and the use of py rotechnics (Lee and von L ehmden, 1973; Ondov et al., 1989; Perry , 1999; Que Hee et al., 1982; Raven and Loeppert, 1997). If strontium is released to air as strontium oxi de (e.g., from coal - burning), it will react with moisture to form strontium hy droxide (Sr(OH) 2 ) or with carbon dioxide to form strontium carbonate. Strontium hy droxide will further interact with moisture to release Sr2+ and SrOH + ions. Strontium ions and compounds in the atmosphere are subject to wet and dry

deposition (ATSDR, 2004). Strontium is naturally

present in most soils, and additional strontium may be added b y atmospheric deposition and by direct human activity

such as application of phosphate f ertilizers (ATSDR, 2004). Strontium is considered to have moderate or moderate - to - low mobility in soils (Hay es and Traina, 1998). Mobility is affected by

the ty pe of soil and by

the salinity

of the soil water (ATSDR, 2004). Though strontium is not an es sential nutrient for most plants, uptake does occur. Strontium uptake decreases as the concentration of calcium in soils increases (ATSDR, 2004). Strontium enters freshwater resources (surface and ground water) from the natural weathering of rocks and s oils, from atmospheric deposition, from the leaching of strontium compounds from soils, and from direct discharge of contaminated waste water (ATSDR, 2004). Strontium may

be present in water in an ionic form such as Sr2+ or SrOH + , or in the form of compounds such as strontium carbonate and strontium sulfate, both of which are insoluble at neutral pH (Cotton and Wilkenson, 1980). The mobility of strontium can increase in water bodies with high salt concentrations on account of decreased sorption to sediments (Bunde et al., 1997, 1998). Source waters that contain elevated levels of strontium can also contain calcium and other bone forming minerals according to data from the National Inorganic and Radionuclide Study ( Donohue et al., 2005 ). **3.4 Summary**  Strontium was mined in the United States until 1959. Imports of strontium minerals and compounds stood at approximately 31,000 - 38,500 metric tons from 1994 to 2001 and have since declined. Historicall y, the most important commercial use of strontium has been in the faceplate glass of cathode - ray

tube televisions. As flat panel technology has become widespread in the United States, demand for strontium for this application has fallen. Strontium compounds are still used for applications such as p yrotechni cs, magnets, and pigments. The feed material for most applications is strontium carbonate. U.S. EPA’s CUS database records production information for 17 industrial compounds that contain strontium. No TRIdata are available on industrial releases of str ontium compounds.EPA - OST Preliminary Health Effe cts Support Document for Strontium April 2014

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– DO NOT CITE OR QUOTE 3 - 6 Strontium compounds in the atmosphere may be subject to wet and dry deposition. Strontium is naturally

present in most soils, and additional strontium may be added b y atmospheric deposition and by direct human activity

such as applicati on of phosphate fertilizers. Strontium has moderate - to - low or moderate mobility in soils and can also be taken up b y plants. Strontium may

be present in water in an ionic form such as Sr2+ or SrOH + , or in the form of compounds such as strontium carbonate and strontium sulfate, both of which are insoluble at neutral pH. The mobility of strontium can increase in water bodies with high salt concentrations on account of decreased sorption to sediments.EPA - OST Preliminary Health Effe cts Support Document for Strontium April 2014

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– DO NOT CITE OR QUOTE 4 - 1 **4.0 EXPOSURE FROM DRINKING WATER**  **4.1 Introduction**  This section presents data on the occurrence of strontium in ambient water and drinking water in the United States. As described in 4.3.2, a child - specific health reference level (HRL) of 1,500 μg/L was derived based on the demonstrated inc reased risk for bone development effects in growing infants, children, and adults. The HRL is a risk derived concentration against which to compare the occurrence data from PWSs to determine if a chemical occurs with a frequency and at levels of public he alth concern . Occurrence data from the sources discussed below are anal yz ed with respect to the HRL and 1⁄2 the HRL . When possible, population exposures to the contaminant at concentrations above the HRL and 1⁄2 the HRLare estimated and presented. For gene ral background on occurrence sources and how occurrence and exposure data were used to inform CCL 3 and RegDet3 decision - making, see Protocol for the Regulatory Determinations 3 (U.S. EPA, 2012a) and the introductory chapters of the Regulatory Determinatio ns 3 Support Document (U.S. EPA, 2012b). **4.2 Am**  **bient Occurrence** Lakes, rivers, and aquifers are the ambient sources of most drinking water. Contaminant occurrence in ambient water provides information on the potential for contaminants to adversel y affect dr inking water supplies that draw raw water from the ambient sources represented. **4.2.1 Data Sources and Methods**  **National Water Quality Assessment Data, 1991 -**  **2003** USGS instituted the National Water Quality Assessment (NAWQA) program in 1991 to examine ambient water quality status and trends in the United States. NAWQA is designed to apply nationally

consistent methods to provide a consistent basis for comparisons among study basins across the country and over time. These occurrence assessments serve to faci litate interpretation of natural and anthropogenic factors affecting national water quality . The USGS NAWQA program also reported information on both drinking water source wells and monitoring wells; these data are included with the drinking water data in Section 4.3. **Storage and Retrieval (STORET) Data Warehouse**  **, 19 67**  **- 201**  **1** The U.S. EPA’s STORET Data Warehouse is a collaborative database that has been activel y populated with water qualit y data since 1999. It contains raw biological, chemical, and phy sical data on surface and ground water, and ambient and drinking water collected by federal, state and local agencies, Indian Tribes, volunt eer groups, academics, and others. A wide variet y of data relating to water quality from all 50 states as well as multiple territories and jurisdictions of the United States are represented in this data system. Most data are post - 1999, but someEPA - OST Preliminary Health Effe cts Support Document for Strontium April 2014

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– DO NOT CITE OR QUOTE 4 - 2 earlier s ampling is included. STORET includes strontium records from 1967 to 2011. Few records are available in earlier ye ars. Many (though not all) sample results are accompanied by information on sample location (latitude, longitude, state, county , Hy drologic U nit Code and a brief site identification), sample date, the medium sampled (e.g., water, sediment, fish tissue), and the name of the organization that sponsored the monitoring. In addition, there can be information on why the data were gathered; sampling and analy tical methods used; the laboratory used to analy

ze the samples; the quality control checks used when sampling, handling the samples, and analyzing the data; and the personnel responsible for the data. STORET data have quality limitations. Since data submission to STORET is voluntary , the extent of national coverage and data completeness can differ from parameter to parameter. Data maintained in STORET also reflect a wide range of qualit y since data contributors can range from federal agencies to volunteer groups and there are no restrictions on submission of data based on anal yt ical methods, quality assurance (QA) requirements, etc. For more general STORET data information, please refer to: http://www.epa.gov/storet/index.html . **4.2.2 Results**  **Storage and Retrieval (STORET) Database, 19 67**  **- 201**  **1** The results of the STORET anal ys is by the OGWDW (U.S. EPA, 20 12 c ) are presented in Tables 4 - 1 and 4 - 2. Note that ground water data in STORET are from wells and surface water data are from lakes, rivers/streams, and reservoirs. There were some Public Water Sy stem (PWS) data from the State of Indiana and the State of Ohio in STORET. A summary of those data is included with the State Drinking Water Monitoring P rogram data in Section 4.3.3. Of 12,433 sites where strontium was monitored, 1,541 (12.39%) had concentrations greater than 1⁄2 the HRL, and 653 (5.25%) had concentrations in excess of the HRLof 1,500 μg/L. Minimum detected concentrations are reported i n Table 4 - 1; these minimum values may be indicative of reporting levels used. (A minimum value of zero, on the other hand, could represent a detection that was entered into the database as a non - numerical value (e.g., “Present”).) **Table 4**  **- 1**  **STORET Data for Strontium –**  **Summary of Detected Concentrations Source Water**  **Type Concentration Value of Detections (μg/L)** 

**Minimum a,b**  **Median 90**  **th Percentile**  **Maximum** Ground Water 0 a 240 2,528.40 19,000 Surface Water 0 a 270 1,300 19,034,000 **Total 0**  **a 270**  1,344.83 **19,034,000**EPA - OST Preliminary Health Effe cts Support Document for Strontium April 2014

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– DO NOT CITE OR QUOTE 4 - 3 **Source Water Type**  **Concentration Value of Detections (μg/L)**

**Minimum a,b**  **Median 90**  **th Percentile**  **Maximum** aA minimum value of zero may represent a detection that was entered into the database as a non - numerical value (e.g., “Present”). b The minimum detection level may reflect the minimum reporting level. **Table 4 -**  **2 STORET Data for Strontium**  **– Summary of Samples, Sites, and States**  **Source Water Type**  **Total**

**Number of**  **Samples Samples with** 

**Detections Detections > 1⁄2 HRL** 

**(750 μg/L) Detections > HRL** 

**(1,500 μg/L) Number**  **Percent Number**  **Percent Number**  **Percent** Ground Water Samples 2,320 2,179 93.92% 555 23.92% 322 13.88% Sites 890 865 97.19% 208 23.37% 120 13.48% States a 13 13 100% 7 53.85% 7 53.85% Surface Water Samples 41,121 39,780 96.74% 8,866 21.56% 3,170 7.71% Sites 11,543 11,434 99.06% 1,333 11.55% 533 4.62% States a 31 31 100% 19 61.29% 17 54.84% Total Samples 43,441 41,959 96.59% 9,421 21.69% 3,492 8.04% Sites 12,433 12,299 98.92% 1,541 12.39% 653 5.25% States a 33 33 100.00% 21 63.64% 19 57.58% The STORET data suggest that strontium is found in both surface water and ground water and is widely

distributed across the Un ited States. Median concentrations of strontium are low; only about 8% of samples exceeded the HRL. Among the STORET samples, the highest concentration (19,034,000 μg/L) was found in a surface water sample. The 90 th percentile values and detection rates in surface and ground water indicate that strontium is not merely a ground water problem. **4.3 Drinking Water Occurrences**  The Agency

reviewed a number of data sources for information on contaminant occurrence in drinking water. Data and information on strontium were available from the following sources:

 U.S. EPA’s National Inorganics and Radionuclides Survey (NIRS), 1984 - 1 986  State drinking water monitoring programs, 1998 - 2005  U.S. EPA’s Community Water Sy stem Survey

(CWSS), 2006  Consumer Confidence Reports (CCRs) from PWSs, 2006 - 2007 a Som e states provided information on both surface and ground w ater and others information on groundwater only or surface water only.EPA - OST Preliminary Health Effe cts Support Document for Strontium April 2014

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– DO NOT CITE OR QUOTE 4 - 4  Environmental Working Group (EWG) Drinking Water Database, 1998 - 2009  USGS NAWQA

– Drinking Water Studies, 1991 - 2007 Note that there may

be some overlap in the data because sources may have reported the same underl yi ng data. The NIRS data were the primary data source for the strontium Regulatory Determination because the study was designed to be nationally representative. It has limitations, however, because it covers only ground water sources. The data are expected to reflect the geology of the site to a greater extent than anthropo genic contamination. **4.3.1 Data Sources and Methods**  **U.S. EPA’s N**

**ational Inorganics and Radionuclides Survey (NIRS), 1984 -**  **1986** NI RS was conducted by

the U.S. EPA to provide national data on the occurrence of a select set of radionuclides and inorganic chemicals (IOCs). It is the primary source of the drinking water data for Regulatory Determination for strontium . The data set includes occurrence data from 989 community water s ys tems (CWSs) served by ground water sources. Each of these randoml y s elected PWSs was sampled a single time between 1984 and 1986. Selection of the PWSs was designed so that the results from these PWSs would be representative of national occurrence of contaminants in ground water s ys tems. Further description of the NI RS can be found in Longtin (1988) and U.S. EPA (2008b). NI RS was s tructured as a stratified, random sampling of the nation’s community ground water supplies as they

existed in the mid - 1980s. A random selection of systems from each of several size categories was included, in proportion to the number of PWSs that existed in those size categories nationall y. The sampling frame used in NI RS was designed to be representative of ground water supplies on a national basis, but not necessaril y on a state - by - state, regional, or other geographic basis. The resulting sample of sy s tems represents approximately 2% of the nation’s community

ground water suppl y in each system size category . Since there are man y more small than large PWSs in the United States, most of the NI RS data are from smaller sy stems. The data are from 49 states (there are no data from Hawaii), plus Puerto Rico. For EPA’s detailed anal ys is of strontium data from NIRS, see the Regulatory Determinations 3 Support Document (U.S. EPA, 2012b). **State Drinking Water Monitoring Programs, 1998 -**  **2005** Because there is no national database that receives and stores all relevant data regarding the occurrence of regulated contaminants in public drinking water s ys tems, the U.S. EPA conducted a voluntary

data call - in from the states, territories, and tribes to obtain regulated c ontaminant occurrence data in support of national occurrence assessments conducted for the second Six - Year Review. The U.S. EPA worked with the states and primacy agencies to receive the states’ and agencies’ complete records of compliance monitoring data (public drinking water sy stem regulated contaminant occurrence data) for 1998 through 2005.EPA - OST Preliminary Health Effe cts Support Document for Strontium April 2014

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– DO NOT CITE OR QUOTE 4 - 5 Some states submitted monitoring data for unregulated compounds along with their data for regulated compounds. EPA supplemented these data b y gathering publicly available data on unregulated contaminant occurrence from state websites. The result was a collection of unregulated contaminant monitoring data from nine states , representing those states with vary ing degrees of completeness. The collection includes dr inking water occurrence data for strontium from I llinois, Ohio, and Region 9 Tribes. 2 In addition, there were some PWS data from Indiana and Ohio in STORET. These PWS data from Indiana and Ohio were not included in the totals calculated in the anal ys is o f ambient water data from STORET, above. The Indiana and Ohio PWS monitoring data could not be subcategorized as rel yi ng on ground water or surface water. **U.S. EPA’s Community Water System Survey (CWSS), 2006** The 2006 CWSS (U.S. EPA, 2009b) gathered dat a on the financial and operating characteristics of a random sample of CWSs nationwide. All sy stems serving more than 500,000 people (94 s ys tems in 2006) received the survey , and sy stems in that size category were asked questions about concentrations of unregulated contaminants in their raw and finished water. Of the 94 sy stems asked about unregulated contaminants, 62 percent (58 s ys tems) responded to the survey . Not all s ys tems answered every question. U.S. EPA supplemented the data set by gathering ad ditional information about contaminant occurrence at the 94 s ys tems from publicly available sources such as the CCR reports discussed below. **Consumer Confidence Reports (CCRs) from PWSs, 2006 -** **2007** CCRs are annual water quality reports that CWSs are requ ired to provide to their customers. These reports summarize information on water sources, detected contaminants, and sy stem compliance with U.S. EPA drinking water standards; they may also include general educational material. Under the CCR Rule (40 CFR Subpart O), CWSs with 15 or more connections or serving at least 25 y ear - round residents must prepare and distribute a CCR to all billing units or service connections every y ear. S ystems serving 100,000 or more residents are also required to post their current CCRs on a publicly accessible Internet site. The U.S. EPA (2012a) reviewed CCRs published by the 26 s ys tems that serve over one million customers for unregulated contaminant occurrence information. Data on strontium were available from CCRs prepare d by

two CWSs in New York: Suffolk County and New York City . Reporting levels were not specified in either of the CCRs. **Environmental Working Group (EWG) Drinking Water Database, 1998 -** **2009** In December 2009, EWG released their “National Drinking Water Database,” which includes data on occurrence of drinking water contaminants (regulated and unregulated) collected between 2004 and 2009 from 45 states and the District of Columbia. The 2009 EWG 2 A small amount of strontium data (37 records) we re available for dow nload from the State of Wisconsin , but it was unclear if some of the data represented “Total strontium” or “Strontium - 90” (the radionuclide). Hence, those data are not included in this summary.EPA - OST Preliminary Health Effe cts Support Document for Strontium April 2014

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– DO NOT CITE OR QUOTE 4 - 6 database includes results from approximately 48,000 water s ys tems; data were obtained primarily from state water offices. EWG reviewed the data for inconsistencies, potential outliers, and other errors. Italso invited the American Water Works Associati on (AWWA) and the Association of Metropolitan Water Agencies (AMWA) to review the data and/or have their constituents, the PWSs, review the data. Some corrections apparentl y were made since the public release of the data in December , 2009. The data were downloaded on January 10, 2010. U.S. EPA’s anal ys is is based solely on the data made publicly available by

EWG on its Web site. Reporting levels are not specified in EWG’s database. **USGS NAWQA –**  **Drinking Water Studies, 1991 -** **2007 Public Supply Wells.**  T o assess risks posed b y contaminants in public - supply wells, water samples were collected from source (untreated) ground water from 932 public - supply wells located in parts of 40 NAWQA Study Units in 41 states (Toccalino et al., 2010). Each well was sampl ed once between 1993 and 2007. About half of the samples were anal yz ed for strontium; reporting levels were not specified in this study . **Private Wells.** USGS also conducted an assessment of the quality of water from domestic wells across the United State s using NAWQA data (DeSimone, 2009). The program included the anal ys is of major ions, trace elements, nutrients, radon, and organic compounds (pesticides and volatile organic compounds (VOCs)) at approximately 2100 domestic wells (private drinking water w ells) across 48 states, covering 30 regional aquifers, between 1991 and 2004. As was the case for the Public Wells, not all samples were anal yz ed for strontium. In addition, USGS summarized data from wells sampled for NAWQA agricultural land - use assessme nt studies to provide an indication of the potential effects of agricultural land - use practices on the ground water in the aquifers studied. DeSimone (2009) reported both Method Reporting L evels as well as Long - Term Method Detection Levels (LT - MDL s), but did not differentiate between them in the detection summaries. DeSimone censored the strontium data at a common reporting level of 10 μg/L. I t is not evident whether this value represent ed the Method Reporting Level or the LT - MDL . Bartholomay

et al. (2007) is an additional USGS study of drinking water from private wells that was conducted under the USGS NAWQA programs for the Centers for Disease Control’s (CDC) National Environmental Public Health Tracking Program. The study covere d 16 states with sample collection from 1991 to 2006. Half of the states were located in the Northeastern part of the country ; three states covered the west coast. The remaining states were Wisconsin, Florida, Missouri, Utah, and New Mexico. As part o f the NAWQA program, Lindsey et al. (2008) conducted an assessment of the water qualit y in carbonate aquifers, which account for 22% of the groundwater pumped b y the country ’s PWSs. From 1993 to 2005, the study analyzed 1,042 wells and springs across 12EPA - OST Preliminary Health Effe cts Support Document for Strontium April 2014

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– DO NOT CITE OR QUOTE 4 - 7 a quifer s ys tems and 20 states for major ions, radon, nutrients, pesticides, and volatile organic chemicals ( VOCs ) . Reporting levels for strontium were not specified in this study . Groschen et al. (2009) used NAWQA data collected between 1991 and 2003 to conduct an assessment of the occurrence and distribution of several contaminants in ground water of the glacial aquifer s ys tem in the Northern United States, which underlies portions of New England, the Midwest, the Pacific Northwest, and Alaska. The stud y anal yz ed sample data collected from 1,590 monitoring wells and water suppl y wells. The reporting level for strontium used in this study ranged from 0.08 μg/L to 1.4 μg/L. **4.3.2 Derivation of the Health Reference Value**  To evaluate the s ys tems and populations exposed to strontium in drinking water from PWSs, the monitoring data were anal yz ed against the reporting level and a concentration in drinking water that is termed the Health Reference Level (HRL). The HRL is defined as a concentration agains t which to compare the occurrence data from PWSs to determine if strontium occurs with a frequency and at levels of public health concern. Two different approaches are used to derive HRLs, one for chemicals that cause cancer and exhibit a linear response to dose, and the other for noncarcinogens and carcinogens evaluated using a non - linear approach. The HRL for strontium is based on the Reference Dose (RfD). As mentioned in the introduction, the RfD is an estimate (with uncertainty spanning perhaps an o rder of magnitude) of a dail y oral exposure to the human population (including sensitive subgroups) that is likely to be without an appreciable risk of deleterious effects during a lifetime. The HRL for Strontium is based on the RfD of 0.3 mg/kg/day deter mined to be protective against a decreased rate of calcification in bone, especiall y during the periods of active growth from conception through ad o lescence . The RfD derivation is provided in Section 8.1 of this report. Age - specific exposure factors have been used in the HRL derivation in order to adjust for the increased risk associated with earl y life exposures (Appendix B ) . The HRL is calculated as follows:

Child specific HRL= ( RfD / ∑ ( DWI/BWR x F) ) x RSC HRL= ( 0.3 mg/kg/day ÷ 0.040 L/kg/day) x 0. 2 = 1.5 mg/L =1,500 μg/L w here: RfD = 0.3 mg/kg/day DWI/BWR = Drinking Water Intake Body Weight Ratio (DWI/BWR) expressed as liters per kg bod y weight (L/kg/day)(90th percentile, consumers only) for each age - specific period for the first 18 y ears, the average postnatal duration for bone growth in humans 3

. 3 Because the critical health endpoint had dose - response data associated w ith exposure during a specific period of sensitivity (i.e, sensitive population), EPA used age - specific drinking water intake to body weight ratio values from the Exposure Factors Handbook (2011) to derive the HRL for stro ntium (s ee A ppendix B ).EPA - OST Preliminary Health Effe cts Support Document for Strontium April 2014

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– DO NOT CITE OR QUOTE 4 - 8 F = The fraction of the 18 ye ar exposure duration for each age - specific period . RSC = Relative Source Contribution, or the level of exposure believed to result

from drinking water when compared to other sources (e.g., food, ambient air). In all cases a 20 percent RSC is used for HRL derivation because it is the lowest and most conservative RSC used in the derivation of an MCLG for drinking water. The monitoring results in Section 4.3.3 report the concentrations that exceed the HRL and 1⁄2 HRLwhen the data are available. The number of s ys tems and samples that exceed the HRLare indicators suggesting that strontium has the potential to occur in drinking water at levels of potential human health conc ern. **4.3.3 Results**  The data on the levels of strontium in drinking water sources cover a time period from 1984 to 2009. The primary national data source, NI RS (1984 - 1986), is the oldest of the data sets. NI RS includes ground water data onl y. Because much of the strontium found in ground water is of geochemical origin, the NIRS data retain their value. The NI RS findings are consistent with more recent ground water studies such a s Toccalino et al. (2010) and DeSimone (2009). The available data for strontium in surface waters are more limited. For EPA’s detailed anal ys is of strontium data from NIRS, see the Regulatory Determinations 3 Support Document (U.S. EPA, 2012b). **U.S. EPA’s National Inorganics and Radionuclides Survey (NIRS), 1984 -**  **1986** The NIRS data se t supports anal ys es to estimate national occurrence in ground water PWSs. A total of 989 samples were collected from sy stems serving a population of 1,482,133. Extrapolations from this dataset provide the best available estimate of contaminant occurrence in ground water on a nationwide scale. To extrapolate, the percentage of ground water s ys tems observed to exceed a specified threshold (or percentage of population served) is multiplied by the total national number of ground water s ys tems (or the total n ational population served). The total number of ground water s ys tems (and population served) was calculated in two way s: as the total number of CWSs served b y ground water, and as the sum of CWSs and non - transient non community

water s ys tems (NTNCWSs) served b y ground water. NTNCWSs are public water sy stems that regularl y supply water to at least 25 of the same people at least six months per y ear, but not y ear - round. Some examples are schools, factories, office buildings, and hospitals that have their ow n water s ys tems. Results of the anal ys is of NI RS data are presented in Table 4 - 3 and 4 - 4. Strontium was monitored with a reporting level of 1 μg/L. Approximately 99.1% of ground water PWSs had detections of strontium (i.e., concentrations at or above th e reporting level ). These detections affected about 99.9% of the population served b y t he PWSs. Detected concentrations ranged from 1.53 μg/L to 43,550 μg/L, with a median reported level of 178 μg/L ; the maximum reported level was approximately 30 times the HRL . The data support the conclusion that occurrence of strontium in groundwater is widespread across the country but is most frequentlyEPA - OST Preliminary Health Effe cts Support Document for Strontium April 2014

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– DO NOT CITE OR QUOTE 4 - 9 found at levels below the toxicological level of concern . The mean concentration among detections (not shown in the table) was 603 μg/L. **Table 4**  **- 3 Strontium Occurrence Data from the NIRS Database**  **– Summary of Detected**  **Concentrations Source**  **Water Type**  **Total Number**  **of Samples**  **Number**

**of Detections**  **Percent**

**of Detections**  **Concentration Value of Detections (μg/L)** 

**Minimum a**  **Median 90**  th

**Percentile 99**  th

**Percentile Maximum**  Ground Water Only 989 980 99.09% 1.53 178 1,078 7,339 43,550

a The reporting level for strontium was 1 μg/L. Table 4 - 4 presents strontium occurrence relative to the reporting level , 1⁄2 the HRL(750 μg/L) , and the HRL( 1,500 μg/L). **Table 4 -**  **4 Strontium Occurrence Data from the NIRS Database**  **– Summary of Ground**  **Water System and Population Served Data Detections**  **Number Percent**  **National Extrapolation a**  **Systems Population**  **Systems Population**  **Systems Population**  All detections 980 1,480,581 99.09% 99.9 0 % 39,741 (CWS only

) 93,035,877 (CWS only

) 58,864 (CWS + NTNCWS) 98,406,604

(CWS + NTNCWS)

>1/2HRL 141 245,870 14.26% 16.59% 5,718 (CWS only

) 15,449,834 (CWS only

) 8,469 (CWS + NTNCWS) 16,341,714

(CWS + NTNCWS) >HRL 69 158,557 6.98% 10.70% 2,798 (CWS only

) 9,963,311 (CWS only

)EPA - OST Preliminary Health Effe cts Support Document for Strontium April 2014

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– DO NOT CITE OR QUOTE 4 - 10

**Detections Number**  **Percent National Extrapolation**  **a Systems**  **Population Systems**  **Population Systems**  **Population** 4,145 (CWS + NTNCWS) 10,538,468

(CWS + NTNCWS) a National extrapolations are generated by multiplying the NIRS national statistical sample findings of system/population percentages and national system/population inventory numbers for ground w ater - sourced PWSs developed from EPA’s SDWIS, the CWSS, and UCMR. NI RS data indicate that 7% of ground water CWSs (serving an estimated 10 million persons) may

have strontium present in concentrations that could impact bone development in infants, y oung children, and adolescents. Although only one sample was collected per s ys tem, the levels in ground water are generally of ge ochemical origin and subject to minimal variability . The NIRS data identify

strontium as a contaminant of potential chronic toxicological concern. For EPA’s detailed anal ysis of the strontium data from NI RS, see the Regulatory Determinations 3 Support Document (USEPA, 2012b) **State Drinking Water Monitoring Programs 1998 -**  **2005** Only two states and Region 9 Tribes provided strontium data from their State drinking water monitoring programs (Table 4 - 5). In the case of Illinois, data were available from 19 sy stems representing approximately 1% of CWSs. Results from Ohio (32 sy stems) came from approximately

2.5% of CWSs and less than 1% of NTNCWSs and transient non - community water s ys tems (TNCWSs 4 ). One CWS from the Region 9 Tribes submitted strontium resul ts for a single sample; the contaminant was not detected. The numbers of ground and surface water sy stems are too small to be considered representative of all sy stems. **Table 4**  **- 5**  **Strontium State Drinking Water Occurrence Data –**  **Summary o f Systems** 

**State (Date Range)**  **Source**

**Water Type**  **Total**

**Number of**  **Systems Systems with** 

**Detections Systems with** 

**Detections > 1⁄2 HRL**  **(750 μg/L)**  **Systems with**

**Detections > HRL (1,500**  **μg/L) Number**  **Percent Number**  **Percent Number**  **Percent Illinois**  (1998 - 2005) Ground Water 16 16 100% 4 25.00% 4 25.00%

Surface Water 3 3 100% 1 33.33% 1 33.33%

4 TNCWSs are public w ater sys tem s that provide wa ter in a place such as a gas station or campground where people do not remain for long periods of timeEPA - OST Preliminary Health Effe cts Support Document for Strontium April 2014

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– DO NOT CITE OR QUOTE 4 - 11 **State (Date Range)**  **Source**

**Water Type**  **Total**

**Number of**  **Systems Systems with** 

**Detections Systems with** 

**Detections > 1⁄2 HRL**  **(750 μg/L)**  **Systems with**

**Detections > HRL (1,500**  **μg/L) Number**  **Percent Number**  **Percent Number**  **Percent Total**  **19 19**  **100% 5**  **26.32% 5**  **26.32% Ohio**  (2000 - 2005) Ground Water 28 26 92.86% 8 28.57% 5 17.86%

Surface Water 4 4 100% 2 50.00% 2 50.00% **Total 32**  **30 93.75%**  **10 31.25%**  **7 21.88%**  In Il linois sy stems, strontium was detected in 100% of 21 drinking water samples (Table 4 - 7). These detections occurred at all 19 CWSs reporting data. Concentrations ranged from 71 μg/L to 4,600 μg/L (Table 4 - 6), with 26.32% of s ystems reporting concentrations greater than the HRLof 1,500 μg/L; the same percentage of s ystems reported concentrations greater than 1⁄2 the HRL(750 μg/L). Thirty - two Ohio PWSs detected strontium in 75 (97.40%) of 77 drinking water samples (Table 4 - 7). These detections occurred at 30 (93.75%) of the 32 PWSs reporting data. Concentrations ranged from 4 μg/L to 40,889 μg/L, with 21.88% of sites reporting concentrations greater than the HRL. Table 4 - 6 provides information on the concentrations of strontium rep orted in the State data sets. For both I llinois and Ohio, the concentration at the 90 th percentile was greater than the HRL : for Ohio, the 90 th percentile values in ground and surface water were about 4 times greater than the HRL . **Table 4**  **- 6**  **Strontium State Drinking Water Occurrence Data –**  **Summary of Detected Concentrations**  **State (Date Range)**  **Source Water**

**Type Concentration Value of Detections (μg/L)** 

**Minimum Median**  **90 th**  **Percentile 99**  **th**

**Percentile Maximum**  **Illinois** (1998 - 2005) Ground Water 71 475 2,360 4,243 4,600

Surface Water 81 270 2,614 3,141 3,200 **Total 71**  **450 2,500**  **4,320 4,600**  **Ohio** (2000 - 2005) Ground Water 4 262 6,032 40,193 40,889

Surface Water 131 169 7,109 8,863 9,009 **Total 4**  **257 6,950**  **39,935 40,889**  Table 4 - 7 provides information on the individual sample data provided b y the states. In the case of Illinois, it does not expand the information found in Table 4 - 5 to any extent because an average of one sample per s ys tem was submitted from that state. I n Ohio, on the other hand,EPA - OST Preliminary Health Effe cts Support Document for Strontium April 2014

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– DO NOT CITE OR QUOTE 4 - 12 an average of 2 samples w as submitted per groundwater s ys tem and 5 samples per surface water sy stem. In Ohio, where 50% of the 4 reporting surface water s ys tems exceeded the HRL, 40% of the surface water samples exceeded the HRL . **Table 4**  **- 7**  **Strontium State Drinking Water Occurrence Data –**  **Summary of Samples State**  **(Date Range) Source** 

**Water Type**  **Total Number**  **of Samples**  **All Detections Detections > 1⁄2**  **HRL (750 μg/L) Detections > HRL** 

**(1,500 μg/L) Number**  **Percent Number**  **Percent Number**  **Percent Illinois**  (1998 - 2005) Ground

Water 18 18 100% 4 22.22% 4 22.22% Surface Water 3 3 100% 1 33.33% 1 33.33% **Total 21**  **21 100%**  **5 23.81%**  **5 23.81%**  **Ohio** (2000 - 2005) Ground

Water 57 55 96.49% 13 22.81% 10 17.54% Surface Water 20 20 100% 8 40.00% 8 40.00% **Total 77**  **75 97.40%**  **21 27.27%**  **18 23.38%**  As noted above, the STORET dataset included strontium data from PWSs in Indiana and Ohio. It could not be determined whether the data came from groundwater or surface water sy stems. Tables 4 - 8 and 4 - 9 include the STORET PWS monitoring data. The median c oncentration reported for Indiana and Ohio is higher than the corresponding value s reported in Table 4 - 6, as is the 90 th percentile value. Data submitted to STORET are not necessaril y representative. **Table 4**  **- 8**  **Strontium STORET Data**  **– PWS Indiana and Ohio Summary of Detected**  **Concentrations Source Water**  **Type Concentration Value of Detections (μg/L)** 

**Minimum Median**  **90 th**  **Percentile Maximum**  PWS (I N, OH) a 52 567 18,210 66,200 a It could not be determined from the data in STORET whether the Indiana or Ohio PWS facilities were served by ground water or surface water.EPA - OST Preliminary Health Effe cts Support Document for Strontium April 2014

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– DO NOT CITE OR QUOTE 4 - 13 **Table 4**  **- 9**  **Strontium STORET Data –**  **PWS Indiana and Ohio Summary of Samples and Sites**  **Source Water**  **Type Total** 

**Number Detections**  **Detections > 1⁄2**  **HRL (750 μg/L)**  **Detections > HRL (1,500 μg/L)**  **Number Percent**  **Number Percent**  **Number Percent**  PWS (I N, OH) **a** Samples 3,128 3,110 99.42% 1,345 43.00% 1,039 33.22% PWS (I N, OH) **a** Sites 199 199 100% 99 49.75% 75 37.69%

a It could not be determined from the data in STORET whether the Indiana or Ohio PWS facilities were served by ground water or surface water. **U.S EPA’s Community Water System Survey (CWSS) 2006** In the 2006 CWSS, there was one sy stem from among the 94 PWSs nationwide serving more than 500,000 people that reported monitoring data for strontium. This sy stem reported the results of one sample only . The concentration of strontium in that sample was 330 μg/L and thus did not exceed the HRL(1,500 μg/L) for str ontium. Reporting levels were not specified in this survey . **Consumer Confidence Reports (CCRs) from PWSs 2006 -** **2007** Data on strontium were available from CCRs prepared b y Suffolk Count y New York and New York Cit y. Reporting levels were not specified in either of the CCRs. The highest concentrations from both locales (both located in the southern and coastal portion of New York) were well below the HRL. The Suffolk County Water Authority

included data on strontium - 88 in its 2007 CCR. Samples were colle cted from 30 distribution areas supplied by both treated and untreated ground water from three major aquifers. The number of strontium samples collected in each distribution area varied from four to 255. Strontium - 88 was detected in 26 of the 30 distribution areas. The calculated average annual concentrations for these 26 distribution areas ranged from non - detections to 150 μg/L . The highest detected concentration was 200 μg/L, which is less than the HRL of 1,500 μg/L and less than 1⁄2 the HRL . New York City

included data on strontium in its 2006 and 2007 CCRs. The city is served by two distribution sy stems supplied by surface water from 19 reservoirs and three controlled lakes, and one distribution sy stem supplied by treated ground water. In 2006, one of the surface water s ys tems was off

- line; 319 strontium samples were collected from the other surface water sy stem and six samples were collected from the ground water s ys tem. The number of samples with detections was not reported. The average annual strontium concentration calculated for the surface water s ys tem was 20 μg/L, while that for the ground water s ys tem was 40 μg/L. Maximum concentrations of 30 μg/L and 50 μg/L were reported from the surface water and ground water s ys tems, respectively . In 2 007, strontium monitoring was conducted at the two surface water s ys tems, but not at the ground water sy stem. Four samples were collected at one sy stem and 332 samples were collected at the other sy stem. The number of samples with detects was not reporte d. Average annual concentrations calculated for the two surface water sy stemsEPA - OST Preliminary Health Effe cts Support Document for Strontium April 2014

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– DO NOT CITE OR QUOTE 4 - 14 were 20 μg/L and 70 μg/L. The highest detected concentration was 70 μg/L. No detections exceeded the HRL (1,500 μg/L) or 1⁄2 the HRLfor strontium. **Environmental Working Group (EWG) Drinking Water Database 2004** **- 2009**  EWG data for strontium come from a total of 370 sy stems and were gathered between 2004 and 2009. These data showed detections of strontium in 366 PWSs in five states serving almost 2.4 million people (Table 4 - 10). EWG found that 1 6 PWSs in four states had detections of strontium above a threshold of 4,000 μg/L. These detections were therefore also exceedances of the HRL of 1,500 μg/L. **Table 4**  **- 10**  **Summary of EWG Strontium Data, 2004 -**  **2009 State**  **PWSs with Detections of Strontium PWSs with Detections of Strontium**  **> 4,000**  **μg/L Number of PWSs**  **Population Served Number of PWSs**  **Population Served** Wisconsin 2 64,500 2 64,500 Illinois 340 2,141,804 12 62,865 Ohio 17 117,126 1 18,135 New York 3 9,668 1 1,500 Minnesota 4 32,955 0 0 **Total 366**  **2,366,053 16**  **147,000 USGS NAWQA**  **– Drinking Water Studies 1991**  **- 2007**  The USGS drinking water data collected from public and private wells are semi - national in scope . Li ke the NIRS data, they onl y reflect the concentrations in groundwater. The private well data have been included because, to the extent that the samples are drawn from the same aquifers as the public water, they provide an indication of source water qual ity at nearb y PWSs. **Public Wells.** Results from this study are presented in Table 4 - 11 and Table 4 - 12. The public well data come from 41 states; samples reflect untreated water and each site was onl y sampled once. Not every sample collected as part of the program was analyzed for strontium. Based on a total of 503 samples (Table 4 - 12), 126 (25.05%) exceeded 1⁄2 the HRLand 61 (12.13%) exceeded the HRL(USGS, 2009). The lowest level reported in Table 4 - 11 may be indicative of reporting levels used. The median value is generally consistent with the NI RS data, as is the 90 th percentile. Thus, the USGS data are supportive of the NIRS results. The percent of sy stems that exceeded the HRLis slightly higher than that observed in the NI RS data.EPA - OST Preliminary Health Effe cts Support Document for Strontium April 2014

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– DO NOT CITE OR QUOTE 4 - 15 **Table 4**  **- 11**  **Strontium Data from Public -**  **Supply Wells –**  **Summary of Detected Concentrations**  **Source Water Type Concentration Value of Detections (μg/L)** 

**Minimum a**  **Median 90**  **th Percentile**  **99 th** 

**Percentile Maximum**  Ground Water Onl y 5.61 385 1,810 7,080 43,950 Source: Toccalino et al . (2010) a The minimum detection level may reflect the minimum reporting level. **Table 4 -**  **12 Strontium Data from Public**  **- Supply Wells**  **– Summary of Samples**  **Source Water Type**  **Number**

**of Samples**  **All Detections Detections >**  **1⁄2 HRL (750 μg/L)**  **Detections > HRL**

**(1,500 μg/L) Number**  **Percent Number**  **Percent Number**  **Percent** Ground Water Only 503 503 100% 126 25.05% 61 12.13% Source: Toccalino et al . (2010) The L indsey et al . (2008) study examines water quality

in carbonate aquifers utilized as sources b y man y PWSs. The authors reported 425 “observations” of strontium, but did not specify how man y of the 1,042 samples collected for the study were tested for strontium and did not specify

a reporting level for strontium. From the 425 observations, the 25 th percentile concentration was 92.3 μg/L, the 50 th percentile concentration was 220 μg/L, the 75 th percentile concentration was 606.1 μg/L , and the maximum concentration was 43 ,950 μg/L. Unfortunately data for the 90 th percentile were not reported, preventing a comparison with the other groundwater data sets. Strontium was detected in 551 (99.8%) of a total of 552 samples included in the Groschen et al . (2009) analy sis of ground water in the glacial aquifer s ys tem in the Northern portions of the United States. The mean concentration was 390 μg/L and the 50 th percentile value was 185 μg/L, indicating a distribution skewed towards high rather than low concentrations (Table 4 - 13) . Less than 5% of the samples exceeded the HRL , with about 10% exceeding the 1⁄2 HRL.EPA - OST Preliminary Health Effe cts Support Document for Strontium April 2014

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– DO NOT CITE OR QUOTE 4 - 16 **Table 4**  **- 13**  **Strontium Data from Northern United States Glacial Aquifer System –**  **Summary of Concentrations Element**  **Minimum a,b** 

**Concentration (**  **μ g/L)**  **Mean**

**Concentration (μg/L)**  **Maximum**

**Concentration (μg/L)**  **Percentile Concentrations (μg/L)**

**Estimated from ROS 5**  **th 10**  **th 25**  **th 50**  **th 75**  **th 90**  **th 95**  **th** Strontium 1.47 390 9,120 28 37 84 185 438 800 1,300 Source: Groschen et al. (2009) a The reporting levels for strontium used in this study ranged from 0.08 μg/L to 1.4 μg/L. b The minimum detection level may reflect the minimum reporting level. Note: the minimum, mean, and maximum concentrations are measured values. The percentile concentrations in Table 4 - 13 are estimated statistically using regression on ordered statistics (ROS) techniques. **Private Wells.** In the USGS private well study (DeS imone, 2009) there were a total of 570 samples anal yz ed for strontium. The samples came from 48 states and covered 30 aquifers. The 570 anal ys es for strontium were conducted in a subset of the total samples. In 6.49% of wells, detected concentrations of strontium exceeded a threshold of 4,000 μg/L. In the USGS/CDC study

reported b y Bartholomay et al . (2007), strontium was detected in 100 percent of the 446 wells sampled in 1 6 states, and found in excess of 4,000 μg/L in 2.2% of the wells. Reporting lev els varied. The data in the report are inadequate to support an estimation of the number of wells that exceed the HRL . **Regional Patterns** Review of the NI RS data shows that strontium was detected in all 50 states/entities in which it was sampled (i.e., i n 49 states (all except Hawaii) as well as Puerto Rico). It was detected at levels greater than half the HRL (750 μg/L) in 34 states and at levels greater than the HRL(1,500 μg/L) in 26 states, including states in all regions of the country . The USGS survey

of water from public wells (Toccalino et al., 2010) found the highest concentrations of strontium in sandstone aquifers, especiall y those in the Cambrian

– Ordovician sy stem found in Illinois, Iowa, and Wisconsin. High levels were also found in the E dwards Trinity aquifer s ys tem in Texas. The USGS private well study ( DeSimone, 2009) identified similar areas of vulnerability south - western and south - central areas of the United States. The State data set add Ohio to the list of states with high backgro und levels of strontium. **Temporal Patterns** The available data do not support anal ys is of temporal pattern of exposure. Most of the data reflect a single sample per site and thus cannot be used to evaluate seasonal trends. In the case of ground water from public and private wells, the concentratio ns would be expected to increase during periods of low rainfall and low groundwater recharge. A comparison of the median and 90 th percentile vales for groundwater from NI RS to the more recent USGS publicEPA - OST Preliminary Health Effe cts Support Document for Strontium April 2014

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– DO NOT CITE OR QUOTE 4 - 17 well data suggests that the concentrations in groun d water have been fairl y stable over the last 30 ye ars. **4.4 Summary**  Strontium was detected in 980 of 989 samples collected from 989 CWSs served by ground water sources between 1984 and 1986 as part of NIRS; surface water sy stems were not evaluated in NIRS. Of the 989 sy stems sampled, 141 sy stems serving 245,870 persons exceeded half the HRL, and 69 s ys tems serving 158,557 persons exceeded the HRL. The mean for the samples with detection was 603 mg/L. Although only one sample was collected per s ys tem, the l evels in ground water are generally of geochemical origin and subject to minimal variability . When extrapolated to a national basis, the population exposed to an exceedance of half the HRL in drinking water is approximately 15.4 million persons (or 16.3 mi llion if NTNCWSs are included), while the population exposed to an exceedance of the HRL is approximately 10.0 million persons (or 10.5 million if NTNCWSs are included). Based on USGS public and private well data, higher levels of strontium from geochemic al sources occur in the Cambrian Ordovician aquifer s ys tem (found in I llinois, Iowa, and Wisconsin) and similar areas of vulnerability

in the south western and south - central areas of the United States. More limited monitoring data show that strontium has b een detected in PWSs in Wisconsin, I llinois, New York, Minnesota, and Ohio. However, the scope of the information from the State and EWG monitoring programs is too limited to support inferences regarding the risks within individual states. Monitoring inf

ormation for ambient water is reported by the STORET database and by Groschen et al. (2009) using USGS NAWQA data collected between 1991 and 2003 during a study of the ground water of the glacial aquifer s ystem in the Northern United States. Strontium was detected in 551 (99.8%) samples analyzed for strontium by the USGS. Due to wide variations in concentrations detected and the large geographic area covered in the NAWQA data set, these data are not informative as to the expected population risk. Within the STORET data, strontium was detected in at 1,541 (12.39%) sites (including groundwater and surface water) at concentrations greater than half the HRL and at 653 (5.25%) sites in excess of the HRL . However, the STORET data have quality limitations that prevent them from being used for estimating population risk. Much of the strontium found in groundwater is of geochemical origin. Human activities that may contribute strontium to the environment (and potentially groundwater) include milling, refining, o ther industrial activities, direct discharge of contaminated waste water, and use of phosphate fertilizers (see Chapter 3).EPA - OST Preliminary Health Effe cts Support Document for Strontium April 2014

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– DO NOT CITE OR QUOTE 5 - 1 **5.0 EXPOSURE FROM MEDIA OTHER THAN WATER**  This chapter presents information on human exposure to strontium from food, air, soil, and other residential exposures. Note that the available information addresses strontium concentrations and intakes as the element Sr, and does not provide an y information on the speciation of strontium compounds in these media. **5.1 Exposure**  **from Food 5.1.1**  **Concentration in Non -**  **Fish Food Items** There is limited information available on measured levels of strontium in non - fish food items. The USGS (1980) included strontium among elements anal yz ed for in fruits and vegetables in the US. Their re sults, as summarized in ATSDR (2004), are presented in Table 5 - 1. **Table 5**  **- 1**  **Strontium Levels in Fruits and Vegetables**

**Fruit or Vegetable Average Solid Concentration (**   **g/100g)*** Apple 1358 Bean (Dry) 663 Bean (Snap) 2170 Cabbage 6417 Corn 41.6 Cucumber 2400 Grape (American) 2560 Grape (European) 3840 Lettuce 2226 Orange 2556 Peach 3082 Potato 2562 Tomato 996 Source: USGS (1980) *Values were presented as ppm (  g/g) in ATSDR (2004), but converted here to  g/100g to facilitate comparison with Total Diet Study data Pennington and Jones (1987) reported strontium levels for 234 foods collected in 1994 as part of the FDA’s Total Diet Study . Their results, which inc lude both adult foods and infant foods, are summarized in Table 5 - 2. Strontium concentrations in 84% of the individual food samples were ≤149 μg/100g.EPA - OST Preliminary Health Effe cts Support Document for Strontium April 2014

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– DO NOT CITE OR QUOTE 5 - 2 **Table 5**  **- 2**  **Strontium Levels Measured in Various Foods Food Category**  **Number of Foods in Category**  **Mean (**  **g/100g) Range (**   **g/100g) Adult Foods**  Milk, y ogurt and cheese 11 104 22

– 418 Meat, fish and poultry * 23 135 3

– 2420 Eggs 3 123 101

– 135 Nuts 3 329 181

– 588 Legumes 7 101 68

– 169 Grains and grain prods 25 112 9

– 465 Fruits and fruit juices 28 83 0

– 403 Vegetables 42 171 2

– 893 Mixed dishes and soups 16 108 40

– 326 Desserts 14 94 31

– 195 Sweeteners 9 92 3

– 367 Fats and sauces 9 24 0

– 46 Beverages 11 16 0

– 64 **Infant Foods** Formulas 2 46 39

– 52 Meat and poultry 3 13 3

– 30 Cereals 2 44 26

– 62 Fruit and juices 9 28 10

– 57 Vegetables 7 96 20

– 216 Mixed dishes 9 71 45

– 89 Custard 1 25 - Source: Pennington and Jones (1987) * Note that excluding shrimp from the meat, fish and poultry group results in a mean of 31 and a range of 3 - 81  g/100g. Barnes (1997) included strontium among several trace elements for which she measured concentrations in a variety of fruit juices that were prepared for this study from the raw fruit and diluted to single strength. Note that the primary purpose of the paper was to demonstrate the improved sensitivity

of the “Spectroscopic” method used for multiple element anal ys es. The results for stron tium are summarized in Table 5 - 3.EPA - OST Preliminary Health Effe cts Support Document for Strontium April 2014

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– DO NOT CITE OR QUOTE 5 - 3 **Table 5**  **- 3**  **Strontium Levels in Juices Juice Product**  **Sub -**  **product Concentration (**   **g/mL)*** Apple Juice Apple Juice 1 Apple Juice 2 Apple Juice 3 Apple Juice 4 0.1549 ND (< 0.01  g/L) 0.1176 0.1087 Orange Juice Brazilian California FL Valencia Navel Orange Pineapple Orange 0.0417 0.5368 0.0933 0.5209 0.1612 Lemon Products CA L emon Bottled Lemon Lemonade 0.0986 0.5334 0.1653 Other Citrus Fruits Ruby Red Grapefruit Lime Tangerine 2.577 0.3464 0.0828 Stone Fruit Cultivars Apricot Sour Cherry Peach Plum Prune 0.1566 0.0338 0.0128 0.1052 0.8805 Grape Cultivars Concord Grape Red Grape White Grape 0.3661 0.1086 0.6318 Berry Juices Blackberry Blueberry Bo ys enberry Raspberry Strawberry 0.2619 0.0406 0.9523 2.232 0.3001 Tropical Fruit Juice Banana Kiwi Mango Pineapple 0.1297 1.744 0.5121 0.0604 Papay a Papay a 1 Papay a 2 Papay a 3 1.448 2.130 1.493 Tomato Tomato Sauce 1 Tomato Sauce 2 0.9390 0.8397 Other Fruits Red Currant Pear 1.251 0.5912 Source: Barnes (1997) *Note: These values are shown in ATSDR (2004) as  g/L; however, the original study gives them as  g/mL.EPA - OST Preliminary Health Effe cts Support Document for Strontium April 2014

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– DO NOT CITE OR QUOTE 5 - 4 Tautkus et al. (2007) reported on the strontium levels in milk as determined by flame atomic adsorption spectrometry . Cow’s milk samples were collected from 5 different dairies for anal ys is. The average strontium concentration was 0.036 mg/L with a range of from 0.024 mg/L to 0.055 mg/L . Iyengar et al. (2000) evaluated the levels of a number of trace elem ents, including strontium and calcium, in freeze dried mixed total diet composites from samples collected between 1985 and 1989. Their composite diet was based on the 201 food items consumed by adults and adolescents as used by FDA in its Total Diet Studi es (TDS) for various age - sex groups. The authors did not report the levels of strontium or other elements in the individual food items making up the freeze - dried composite, but only an average for 10 diet composites representing various US regions. The m ean strontium concentration was reported as 3.45 mg/kg dry weight (s.d. = 0.5). (To compare with the other data shown above, this would be 345  g/100 g.) The value for calcium was 1823 ± 150 mg/kg or 182.3 mg/100 g , a calcium:strontium ratio of about 500 mg to 1mg . A recent study of strontium dietary intake was con d

ucted in Ireland between 2001 and 2005 ( FSAI, 2011) . Cereal grains accounted for the largest percentage of the total daily intake (33.1%) followed b y bottled water (22.3%) . Dairy products ac counted for 7.7% , vegetables for 12.0% and fruits and preserves 8% . The United Kingdom (2009) conducted a comparable study in 2006 with similar results: Cereal grains 34%; vegetables 23%, fruits and fruit products 16%; milk and dairy

products 12%, and bev erages 7%. **5.1.2 Concentrations in Fish and Shellfish**  Fish and fish - products contain ed the highest levels of strontium amon g the food groups evaluated b y Millour et al . (2012). The average concentration from 83 samples was 7.7 mg/kg in the f ish shellfish category compared with an average concentration of < 2 mg/kg for the other food groups. Among the fish and shellfish examined shrimp had the highest average concentration (25.4 mg/kg) . The high levels in fish and shellfish likely reflect the fact that strontium is the fifth most abundant metallic cation present in ocean water (Hibbins, 1997). **5.1.3 Intake of Strontium from Food**  Pennington and Jones (1987) estimated that strontium intakes ranged from 493 to 1489  g/day for eight groups of various ages and both sexes. These estimates were based on the measured levels of strontium in the various food products as reported above and the intakes for the eight groups developed as part of the Total Diet Study , as shown b elow: 6 to 11 months: 493  g/day 2 y ears: 685  g/day 14 - 16 y ears, female: 928  g/day 14 - 16 y ears, male: 1388  g/day 25 - 30 y ears, female: 999  g/day 25 - 30 y ears, male: 1489  g/dayEPA - OST Preliminary Health Effe cts Support Document for Strontium April 2014

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– DO NOT CITE OR QUOTE 5 - 5 60 - 65 y ears, female: 979  g/day 60 - 65 y ears, male: 1265  g/day If the strontium level reported by Tautkus et al. (2007) for strontium levels in milk is applicable to infant formula, an infant would be exposed to 22 to 28 μg Sr/day from formula prepared with distilled water. This estimate is based on the IOM (1997) estimate that average breast milk or formula intake is780 mL/day through the first six months of life, and 600 mL/day for the second six months. These exposures are calculated below: Birth to six months: 0.036 mg/L x 0.780 L/day = 0.028 mg/day = 28 μg/day Six months to one y ear: 0.036 mg/L x 0.6 L/day = 0.0216 mg/day

= rounded to 22 μg/day Iyengar et al. (2000) provided an estimate of 1620  g/day (s.d. = 240) for strontium intake from the composite diet of the 25 - 30 y ear old a dult males group based on samples collected during the 1985 - 1989 time period. This was the onl y age/sex group that these authors considered, noting that it was the group with the “highest dail y intake.” For the same age group the calcium intake was 860 ± 150 mg/day (Ca:Sr ratio = ~500 mg Ca :1 mg Sr ) . The current recommended calcium intake for this age group is 1000 mg/day (I OM, 2010). The mean dail y dieta r y intake for the I rish population (958 individuals) was 1 , 58 0 μ g/day (0. 20 μ g/kg/day) with a 97.5 p ercentile value of 2 , 79 0 μ g/day ( 40 μ g/kg/day). The highest intake reported was. 60 μ g/kg/day (FSAI, 2011) . The mean dail y intake from the 2006 United Kingdom (2009) study

was lower than that for the Irish study , 1 , 2 00 μ g/day. The study included 19 food categories divided into 20 food groups. When intakes were evaluated for population subgroups , young children and adolescents had the highest intakes p er unit body weight (Table 5 - 4) . **Table 5**  **- 4**  **Dietary St r**  **on tium Intakes for Population Subgroups fr**  **o m**  **the 2006 United Kingdom Total Diet Study.**  **Population group Descriptor**  **Mean (**  **μ g/**  **kg /day**  **) High** 

**( μ**  **g/ kg**  **/day )**  Toddlers 1.5 - 4.5 y ears 4 2. 8 71 . 1 Young People 4 - 18 y ears 25 . 9 51 . 0 Adults Not Defined 15 . 6 30 . 6 Elderly Free living 14 . 0 26 . 6 Vegetarians Not defined 2 0 . 5 35 . 9 **5.2 Exposure from Air**  **5.2.1 Concentration of Strontium in Air**  WHO (2010) noted that strontium enters the atmosphere, mainl y as particulate strontium oxide, as a result of both natural processes (weathering of rocks, particle entrainment, windEPA - OST Preliminary Health Effe cts Support Document for Strontium April 2014

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– DO NOT CITE OR QUOTE 5 - 6 resuspension, and sea spray), and from human activity (notabl y milling, coa l burning, and use of phosphate fertilizers). Very limited data could be found, however, on measured levels of strontium in that atmosphere. Both ATSDR (2004) and WHO (2010) noted data from studies conducted in the 1970s and 1980s that reported strontium levels observed in air. Strontium in urban air in an unidentified city

in the 1970’s ranged from 4 to 100 ng/m 3 averaging 20 ng/m 3 (Dzubay and Stevens, 1975). Strontium in the L os Angeles basin in 1985 was measured at 29.1 ng/m 3 and averaged 0. 9 - 4.8 ng/m 3 in urban Illinois air between 1985 and 1988 (Witz et al., 1986; Sweet et al., 1993). Atmospheric concentrations of strontium associated with emissions from coal fired plants range from 17 to 2718  g/m 3 in the western states and approximately 9,800  g/m 3 for eastern states (Que Hee et al., 1982; Ondov et al., 1989). Emissions are influenced by the strontium in the coal, the amounts of coal burned, and the efficacy of fl y - ash recovery . Perry (1999) note d a strontium concentration of 9 ng/m 3 in the proximity of a py rotechnic display . **5.2.2 Intake of Strontium from Air**  Using the average urban air concentration for strontium of 20 ng/m 3 noted above, and an estimated 20 m 3 /day

air breathed b y an adult (Dzubay an d Stevens, 1975; Witz et al., 1986), ATSDR (2004) calculated an inhalation exposure of 400 ng/day (0.4  g/day) of strontium from air. Note that these air data are from the earl y 1970s. WHO (2010) did not calculate an intake value from air but noted that the contribution from air to be “insignificant by comparison” with food and drinking water intakes. Estimates of non - occupational exposures to strontium in ambient air for adults can be derived from the arithmetic mean ambient air concentration 20 ng/m 3 u sing the assumption that adult humans breathe 15. 8 m 3 of air per day (U.S. EPA, 2011 ). The estimated adult exposure is: 20 ng/m 3 × 15. 8 m 3 /day

= 3 16 ng/day , rounded to 300 ng/day (= 0.3  g/day) For a children (birth to one y ear) , the average respiratory rate is 5.4 m 3 /day (U S. EPA, 20 11 ) resulting in an exposure of 100 ng/day (0.1  g/day). 20 ng/m 3 × 5.4 m 3 /day

= 108 ng/day , rounded to 100 ng/day (= 0.1  g/day) Individual intakes vary

depending on factors including activity , geographic location, and inhalation rate. **5.3 Exposure from Soil** EPA - OST Preliminary Health Effe cts Support Document for Strontium April 2014

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– DO NOT CITE OR QUOTE 5 - 7 **5.3.1 Concentration of Strontium Soil**  As discussed in Chapter 3, strontium is a naturally occurring element present in nearl y all rocks and soils. Shacklette and Boerngen (1984) provided estimates of the mean concentration of strontium in soils and other geologic materials in the continental US. The values they reported are summarized in Table 5 - 4. **Table 5**  **- 5**  **Levels of Strontium in Soils and Other Ge ologic Materials (ppm)**  **Area Geometric Mean**  **Arithmetic Mean Range**  Eastern US 53 120 <5

– 700 Western US 200 270 10

– 3000 Overall US 120 240 -- Source: Shacklette and Boerngen (1984) Note: “ -- ” indicates that no information was found. **5.3.2 Intake of**  **Strontium from Soil** No published estimates of strontium intake from soil were found. Human exposure to contaminants in soils is usually from dust that infiltrates homes, automobiles, etc. in adults, and from dust and incidental soil ingestion in children . Infants and toddlers ingest soil and household dust by hand - to - mouth transfer during every day activities. They may therefore be exposed to higher levels than adults living in the same contaminated environment. Estimates of intake for soil and dust as sume an ingestion rate of 60 mg/day (0.00006 kg/day) for children < 1 y ear and 100 mg/day (0.0001 kg/day) for children ages 1 to 21 y ears (U.S. EPA, 2011 ). The estimate is 50 mg/day (0.00005 kg/day) for adults (U.S. EPA, 2011 ). Using the overall US arit hmetic mean for strontium in soils of 240 ppm (= 240 mg/kg), soil/dust estimates of the exposures for infants are 14  g/day and for children < age 21 are 24  g/day . The estimate for adult exposures is 12  g/day . In fants: 240 mg/kg × 0.00006 kg/day = 0.014 mg/day

(14  g/day) Children: 240 mg/kg × 0.0001 kg/day = 0.024 mg/day

(24  g/day) Adults: 240 mg/kg × 0.00005 kg/day = 0.012 mg/day

(12  g/day)EPA - OST Preliminary Health Effe cts Support Document for Strontium April 2014

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– DO NOT CITE OR QUOTE 5 - 8 **5.4 Other Residential Exposures**  As noted in Chapter 3, strontium has a number of commercial uses (notably in electronics), but no estimates of exposure from these uses was found. Itis also used in some toothpastes to treat tooth sensitivity (USGS, 2009b), but no exposure estimates related to this use were found in the literature. **5.5 Summary**  Although strontium is known to occur in food, air, and soil, data on levels in those media are limited as are estimates of intake from those sources. Food appears to be a more significant source than air and soil. Dietary intakes based on an FDA Total Diet Study by Pennington and Jones (1987) indicated dietary intakes to range from 493 to 685  g/day for children 6 months to 2 y ears old; 928 to 1388  g/day for 14 to 16 ye ar old adolescents; and 979 to 1489  g/day for adults. Another estimate of dietary intake for 25 - 30 y ear old males b y Iye ngar et al. (2000) was reported to be 1620  g/day . Recent studies from Ireland and England provided estimates of 1 , 580 μ g/day

and 1 , 200 μ g/day , respectivel y for the general population. Both means are consistent with the results from the U.S. studies. Estimated strontium intakes from air and soil are very low compared with those from food. Exposure from air has been estimated from data fo r levels of strontium in non occupational air to be 0.1  g/day for children and 0.3  g/day for adults, while an inhalation exposure for adults of 0.4  g/day has been estimated based on the average urban air concentration of strontium. The estimates of int ake from soil are 14  g/day for infants, 24  g/day for children, and 12  g/day for adults.EPA - OST Preliminary Health Effe cts Support Document for Strontium April 2014

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– DO NOT CITE OR QUOTE 6 - 1 **6.0 TOXICOKINETICS**  The human strontium data reported in this section come from stable isotope and radioactive isotope studies. Stable (nonradio active) isotopes of metals can be found in nature in fixed abundances. Those found in low abundance can be isolated and enriched, and are often used as tracers in studies to follow the kinetics and metabolism of metals in a specific diet or at a specific dose. Strontium has four stable, naturall y occurring isotopes with the following natural abundances: 84 Sr (0.56%), 86 Sr (9.86%), 87 Sr (7.0 0 %), and 88 Sr (82.58%) (WHO, 2010). There are 16 known radioactive isotopes of strontium, but only two, 85 Sr and 9 0 Sr, are mentioned in papers relevant to drinking water exposure and toxicokinetics. 85 Sr is sy nthetic, meaning it is not found in nature. Its relativel y short half - life makes it convenient for use in metabolism studies, thus it is used as a tracer in th e studies described in this section. 90 Sr is a by product of nuclear fission is found in nuclear fallout, and has a half - life of approximately

29 ye ars (ATSDR, 2004). The radioactive strontium ( 90 Sr) exposures used in the studies described in this sectio n are via diet, drinking water or accidental inhalation only . For toxicokinetics studies, both ty pes of isotopes are of use. Both stable tracers and radioactive isotopes can be differentiated from endogenous forms of the element and those consumed at other times. Radioactive isotopes have the additional advantage o f being easily tracked as they

move within the body . **6.1 Absorption**  Human studies show that approximately 20% of ingested strontium or SrCl 2 is absorbed via the gastrointestinal tract (see Table 6 - 1), with more efficient absorption occurring from aqueous s olutions (L i et al., 2006). No age - or gender - related differences in absorption were observed in human studies (Harrison et al., 1965; Kahn et al., 1969); in contrast, animal studies report age - dependent changes in absorption following ingestion (Forbes and Reina, 1972). Increased strontium absorption has been reported during lactation in rats (Kostial et al., 1969), due to the strontium’s common absorption pathway with calcium (Reid et al., 1986; Milsom et al., 1987; Blumsohn et al., 1994; Sips et al., 1994; Bianchi et al., 1999). Although similar studies have not been conducted in humans, there is the potential that absorption is also increased during lactation and pregnancy

in humans. Very limited information is available regarding absorption foll owing inhalation or dermal exposure to strontium.EPA - OST Preliminary Health Effe cts Support Document for Strontium April 2014

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– DO NOT CITE OR QUOTE 6 - 2 **Oral Exposure** Humans Numerous studies have evaluated the fractional absorption of ingested strontium in healthy human subjects or hospital patients who received an oral dose of strontium chloride (SrC l 2 ) or ingested strontium in the diet (see Table 6 - 1). Tracer studies found that absorption of 85 Sr in cancer patients ranged between 14 to 50% of the administered oral dose; doses ranged from 0.1 to 0.3 μCi/kg (i.e., trace amounts of carrier - free 85 Sr; C omar et al., 1957 did not provide body weights, thus the 20 μCi dose was converted using an assumption of 70 kg body weight) (Harrison et al., 1955; Comar et al., 1957; Spencer et al., 1960; Lengemann, 1963). Collectively , these studies indicate that, fol lowing oral exposure, approximately 20% of ingested strontium is absorbed from the gastrointestinal tract. **Table 6**  **- 1**  **Summary of Estimates of Absorption of Ingested Strontium in Humans Dose and**  **media a**  **Subjects**

**(N) b**  **Absorption**

**(% of dose) c**  **Comment Reference**  Tracer g Adults

(9M) 28±3 Health y adults. Absorption estimate based on whole body retention (R): R oral/R iv . Likhtarev et al. (1975) 44 mg, SrCl 2 Adults

(8M) 25±7 Health y, fasted subjects adults. Absorption estimate based on plasma AUC oral/AUC iv . d Sips et al. (1995) 44 mg, SrCl 2 Adults

(8M) 25±6 Health y fasted subjects. Absorption estimate based on plasma AUC oral/AUC iv . Sips et al. (1996) 88 mg, SrCl 2 Adults

(8M) 19±5 Health y subjects. Dose administered with meal. Absorption estimate based on plasma AUC oral/AUC iv . Sips et al. (1996) 219 mg, SrCl 2 Adults

(6M, 11F) 20 Patients with osteoporosis or chronic renal failure. Dose administered with meal. Absorption estimate based on plasma AUC oral/AUC iv . Blumsohn et al. (1994) Tracer g Adults

(3M) 21

(18 - 24) Patients with osteoporosis. Dose

administered with meal. Absorption estimate based on plasma AUC oral/AUC iv . Hart and Spencer (1967) 1.45 mg/kg, SrCl 2 Adults

(6M, 4F) 22±2 Health y fasted subjects. Absorption estimate based on fraction of dose in plasma at 3

hours. Bianchi et al. (1999) Tracer g Adults 17 Health y subjects without a pre - LeRo y et al.EPA - OST Preliminary Health Effe cts Support Document for Strontium April 2014

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– DO NOT CITE OR QUOTE 6 - 3 **Dose and media**  **a Subjects** 

**(N) b**  **Absorption**

**(% of dose) c**  **Comment Reference**  (12) (8 - 34) dosing fast. Absorption estimate based on whole bod y counting. (1966) 44 mg, SrCl 2 Adults

(43M, 20F) 13 Fasted patients with growth hormone deficiency , osteoporosis, hy

pothy roidism or hy percalcuric urinary

tract stones. Absorption estimate based on fraction of dose in plasma at 4

hours. Sips et al. (1994) 219 mg, SrCl 2 Adults

(6M ) 20 Health y fasted subjects. Absorption estimated from cumulative urinary

excretion. Leeuwenkamp

et al. (1990) Tracer in milk g Adults

(5) 11 Health y subjects. Dose administered in milk, daily for 21 - 32 day s. Absorption estimated from whole body retention kinetics. Rundo and Lillegraven (1966)

Tracer g Adults

(4F) 42

(25 - 59) Two health y subjects, two

patients with osteoporosis. Absorption estimated from intake minus 20 - day

fecal excretion, corrected for fecal excretion after an intravenous dose. Uchiy ama et al. (1973) 0.8 mg/day Diet Adults

(11M) 18

( - 17 - 42) Patients with various disorders,

including osteoporosis. Absorption estimate based on 6 - day balance; dietary

intake minus fecal excretion. e Warren and Spencer (1976)

Tracer g Adults

(11M) 18

( - 17 - 42) Patients with various disorders,

including osteoporosis. Absorption estimate based on estimated from 6 - day

balance; dietary intake minus fecal excretion. e Warren and Spencer (1976)

1500 mg/day Adults

(5F, 1M) 22

(20 - 28) Patients with various il lnesses.

Absorption estimated from dietary intake minus fecal excretion minus fecal excretion after an I.V. dose (endogenous fecal excretion). Spencer et al. (1960) Diet Adults

(9) 12

(0 - 48) Patients with various illnesses.

Absorption estimate based on Spencer et al. (1972)EPA - OST Preliminary Health Effe cts Support Document for Strontium April 2014

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– DO NOT CITE OR QUOTE 6 - 4 **Dose and media**  **a Subjects** 

**(N) b**  **Absorption**

**(% of dose) c**  **Comment Reference** 

estimated from 6 - day

balance; dietary intake minus fecal excretion. e 5 - 100 mg, SrCl 2 Children

(5) 4 - 14 y ears 22 Patients with various illnesses. Dose administered for 24 - 28 day s. Absorption estimated from dose minus 14 - day

fecal ex cretion. Sutton et al. (1971b) 100 μg, breast milk In fants

(12) 6 - 8 day s 15

( - 47 f

- 59) Health y breast - feeding subjects.

Absorption estimate based on estimated from 3 - day

balance intake minus fecal excretion. e Harrison et al. (1965) 600 μg Diet In fants

(21) 20 day s - 1 ye ar 28

(12 - 43) Health y subjects. Absorption

estimate based on estimated from seven sequential 28 - day

balances; dietary intake minus fecal excretion. e Kahn et al. (1969)

a Doses are in mass of strontium. bNumber of males (M) or females (F) is presented if reported. c Values are reported means ± standard deviation; values in parentheses are reported ranges. dAUC refers to the area under the plasma strontium concentration - time curve. e Calculated from reported indivi dual subject data. f Sic. Apparent error in ATSDR (2004). g Tracer used is 85 Sr (specific dose unavailable but is toxicologically small) Data in humans suggest there are no age - dependent differences in strontium absorption in contrast to age - related changes that have been observed in animal studies. Similar ranges of strontium absorption (15 - 35%) were observed in infants, children and adul ts in several studies (Harrison et al., 1965; Kahn et al., 1969; Sutton et al., 1971a; Alexander et al., 1974). Most of the studies in Table 6.1 reported absorption of 20 - 30% over a wide range of conditions and doses (health y and osteoporotic adults, heal thy infants, sick children, fed and fasted adults, and doses of <1 - 1500 mg). Although there are some outliers, the data are not sufficient to determine whether these outliers represent true differences, and do not support categorization of levels of absor ption by different groups. Differences by gender were not observed in a study of the area under the curve (AUC) for plasma strontium in adult healthy age - matched subjects versus patients who had calcium - oxalate urinary tract stones but normal levels of ca lcium in urine (10.6 ± 0.6 mmol/L - min male; 9.3 ± 0.6 mmol/L - min female; Vezzoli et al., 1998). The main route of entry

of strontium into the body is the gastrointestinal tract. Leeuwenkamp et al. (1990) reported that two dominant intestinal absorption loci were present in the intestines, with the first locus having a higher uptake capacit y than the second. In this study, six healthy

male volunteers were orally administered 2.5 mmol SrCl 2 (in water). For these subjects, two absorption phases were obse rved in the overall plasma concentration time curve, due to two dominant intestinal absorption loci. The overall peak plasma concentration (Cmax)EPA - OST Preliminary Health Effe cts Support Document for Strontium April 2014

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– DO NOT CITE OR QUOTE 6 - 5 and area under the curve plasma concentration - time curve (AUC ∞) were 33.55 ± 1.22 μg/mL and 9138 ± 1930 μg*m in/mL , respectivel y. For the first locus the terminal plasma elimination half - life time and Cmax were 47.3 ± 7.9 hours and 3.09 ± 0.95 μg/mL , respectivel y. The limited pharmacokinetic parameters for the second locus could only be attained for 3 of the 6 subjects. For the second locus, the Cmax2 and AUC2 ∞ were 0.9 ± 0.4 μg/mL and 1204 ± 565 μg*min/mL , respectivel y. The AUC2 ∞/AUC∞ was 0.14, which indicates that 14% of the absorbed dose was absorbed through the second locus with the remaining 86% being abs orbed through the first locus. The estimated strontium bioavailability was 20%. Li et al. (2006) studied the intestinal absorption of strontium carbonate in 13 healthy adult volunteers using simultaneous administration of oral 86 Sr (0.1 to 5 mg) and intravenous 84 Sr (0.4 mg) in order to understand the effect that various foodstuffs have on strontium absorption. The oral 86 Sr was administered either via an aqueous solution or added to a variet y of food stuffs at the following doses: green/black tea (1 m g), water (0.1 to 5 mg), cress (0.72 mg), milk with or without alginate (1 mg), salad (1.39 mg), calcium solution (1 mg) and bab y food (0.384 to 1 mg). Strontium ingested with black tea had the highest absorption rate (61%), while strontium ingested with alginate in milk had the lowest absorption rate (27%). The 86 Sr tracer was absorbed b y the intestinal wall and reached maximum value in the plasma within 80 - 160 minutes before being cleared from the plasma. Peak strontium absorption occurred between 40 and 120 min, based upon the I CRP GItract model. The authors stated that this implies that the absorption process occurs mostly in the small intestinal wall. Overall, the authors concluded that strontium carbonate is more efficientl y absorbed when dissolv ed in aqueous solutions than intrinsically

labeled food. Zittermann et al. (2000) determined that fractional absorption of 2.27 mmol (200 mg) strontium chloride hexahy drate administered with a meal, dissolved in apple juice, to healthy adults was 12%. N o significant difference in absorption was observed when strontium was co administered with either lactose or glucose/galactose. During pregnancy

and lactation there is an increased demand for calcium (Kostial et al., 1969; ATSDR, 2004). This suggests that pregnant and lactating women would have increased strontium absorption (for a given level of calcium intake), since strontium and calcium absorption share a common mechanism (Reid et al., 1986; Milsom et al., 1987; Blumsohn et al., 1994; Sips et al., 1 994; Bianchi et al., 1999). Animals Limited data on strontium absorption following oral exposure are available in animals. These studies show that calcium and phosphate decrease absorption in rats (Comar et al., 1961; Kostial et al., 1963, 1964, 1967; S lat et al., 1971), and there are substantial age - related differences in absorption of strontium by rats (Forbes and Reina, 1972). Strontium absorption is influenced b y dietary factors. For example, increased dietary concentrations of calcium and phosphat e have been shown to decrease strontium absorption in rats (Comar et al., 1961; Kostial et al., 1963, 1964, 1967; Slat et al., 1971). A diet that mimickedEPA - OST Preliminary Health Effe cts Support Document for Strontium April 2014

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– DO NOT CITE OR QUOTE 6 - 6 the normal human diet and one containing high levels (75 to 100%) of meat products (t ype of meat uns pecified) resulted in a greater absorption of strontium (Kostial et al., 1980; Kargacin and Kostial, 1982, 1984) than the grain - based rat chow diet. Animal studies suggest that strontium is absorbed from both stomach and small intestine. Ex - vivo studies using isolated rat intestine in vitro or in situ provide direct evidence for strontium absorption in the small intestine (ATSDR, 2004). In vivo hamst er studies using tracer doses of 85 SrCl 2 found that strontium absorption was decreased from 37% to 20% when hamsters had their p yl oric sphincters (located at the base of the stomach) ligated (Cuddihy and Ozog, 1973). Since the stomach contents could not enter the intestine, this supports the co nclusion that both the stomach and intestine can absorb strontium. Data in animals suggest that lactating dams absorb more strontium than non - lactating control rats (Kostial et al., 1969). Lactating rats that received a tracer dose of 85 Sr as SrCl 2 in drinking water between 14 and 16 day s after the start of lactation absorbed 11% of the dose compared to 5% absorption in non - lactating rats (Kostial et al., 1969). Forbes and Reina (1972) found that 85% of orally - administered strontium chloride (further in formation on route not available) was absorbed by 15 - day - old rats, while only 8% of the dose was absorbed b y 89 - day old rats. Sips et al. (1997) reported that 19% of orally - administered strontium chloride was absorbed b y adult rats. ATSDR (2004) suggeste d that the difference between the two studies in estimates of absorption by the adult rats was due to differences in method. **Inhalation Exposure** Humans Data from humans and animals suggest that strontium is readily absorbed following inhalation. Radio logically - active strontium has been detected in the urine of workers accidentally

exposed to airborne 90 Sr, demonstrating that inhaled aerosolized strontium can be absorbed (Rundo and Williams, 1961; Petkau and Pleskach, 1972). However, definitive quantit ative information is not available for these exposures. Furthermore, inhalation is not a relevant route of exposure via drinking water except if it is aerosolized and inhaled during showering. Animals Animals studies using direct exposure and intratrach eal instillation show that the rate of absorption following inhalation is dependent upon the chemical form of the strontium aerosol, with compounds of greater solubility having more rapid absorption. Willard and Sny der (1966) exposed rats to various compo unds of aerosolized strontium, showing 99% of the 85 Sr carbonate, phosphate, fluoride or oxide cleared within 5 day s, while 60% of the 85 Sr titanate remained in the lung.EPA - OST Preliminary Health Effe cts Support Document for Strontium April 2014

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– DO NOT CITE OR QUOTE 6 - 7 **Dermal Exposure** Humans Il yi n et al. (1975) found that less than 1% of 85 SrCl 2 (a queous solution with pH of 7) applied to intact forearm skin (average area of 8 cm 2 ) was absorbed after 6 hours, while 38% and 57% of the applied dose was absorbed through scratched and abraded skin after 30 min and 6 hours, respectively . No information w as available on the administered dose. Animals No data were identified on dermal absorption in laboratory animals. **6.2 Distribution**  In general, once absorbed strontium is preferentially (> 95%) and uniformly

distributed in the bones and teeth (Comar et al., 1957; Sowden and Stitch, 1957; Tipton and Cook, 1963; Schroeder et al., 1972; Underwood, 1977; Skory na, 1981; Rosenthal, 1981; Cabrera et al., 1999). The skeletal uptake and distribution of strontium is influenced b y dietary calcium, but a study

of maternal - fetal transfer of strontium suggests it likely undergoes transport via a concentration gradient while calcium transport occurs via active transport (Rossipal et al., 2000). Animal stu dies report tissue concentrations for strontium to be 1,000 - fold higher in the bone than in other tissues following supplementation via drinking water (Skory na, 1981). Strontium has been shown to transfer to the fetus during pregnancy and neonates during lactation (Harrison et al., 1965; Underwood, 1977; Olsen and Jonsen, 1979; Tolsty kh et al., 1998, 2001; Rossipal et al., 2000). **Oral Exposure** Humans Strontium distribution via the blood plasma has been well studied, but there is limited information re garding the partitioning of strontium in the blood. L eeuwenkamp et al. (1990) reported a peak plasma concentration of 3.55 μg/mL approximately

2.5 hours after oral administration of 2.5 mmol SrCl 2 . Further anal ys is of the plasma concentrations relative t o time suggested that two dominant intestinal absorption loci were present, with peak plasma concentrations of 3.09 and 0.9 μg/mLfor the first and second loci, respectively . Measurements of 7.2 μg/L strontium in the ery throcy te fraction and 44 μg/L stron tium in the plasma fraction were obtained using blood from blood banks (Oleh y et al., 1966), and a similar total value (53 μg Sr/L ) was reported in serum from 100 human subjects receiving a normal diet (Skory

na, 1981). An in vitro study (Alda and Escane ro, 1985) and an intravenous study (Harrison et al., 1955) determined that 45% and 60%, respectivel y, of the strontium in serum was ultrafilterable (or able to pass through biologic membranes), unlike protein - bound strontium, which is not diffusible. The remainder was apparentl y protein bound, although theEPA - OST Preliminary Health Effe cts Support Document for Strontium April 2014

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– DO NOT CITE OR QUOTE 6 - 8 specific serum proteins to which strontium binds have not been characterized. The strontium concentrations used in these studies were 300 to 1,000 times higher than those in the general population dietary

studies performed b y Oleh y et al. (1966) and Skoryna (1981). Since strontium plasma binding is believed to be saturable, the lower concentrations measured in the dietary studies may

have resulted in a larger bound fraction of serum strontium (Berg et a l., 1973; Alda and Escanero, 1985). Greater than 95% of the total human body burden of absorbed strontium accumulates in the skeleton (Comar et al., 1957; Sowden and Stitch, 1957; Tipton and Cook, 1963; Schroeder et al., 1972; Underwood, 1977; Skory na, 19 81; Rosenthal, 1981). The remaining < 5% of absorbed strontium is found in most of the body ’s soft tissues (Skory na, 1981; Rosenthal, 1981). Data suggest that strontium uptake and distribution are influenced b y dietary calcium. Based on the results of an unpublished study , Storey (1961) reported that serum strontium levels increased in rats without corresponding changes in the serum level of calcium following 200 - 300 mg/day doses of strontium carbonate over a 20 day period. No information was given on the level of calcium intake in these subjects. Analy sis of bone samples from human autopsies provides information on the skeletal burden of stable strontium (Herring and Keefer, 1971; O’Connor et al., 1980; Papworth and Vennart, 1984; Tanaka et al., 1981 ). For example, Tanaka et al. (1981) reported skeletal burdens of 440 mg strontium and 850 g calcium in Japanese adult males. To determine the amount of strontium taken up into the skeleton following customary dietary intakes, Papworth and Vennart (1984) anal yz ed published data on 90 Sr and calcium concentrations in human bone tissues and diets of people in the United Kingdom during the period from 1955 to 1970. They concluded that approximately

5% of the dietary

intake was distributed to the adult skelet on and 10% was distributed to the infant/adolescent skeleton. The greater skeletal uptake of strontium in infants and during adolescence is likely attributable to the higher bone growth rates during childhood. Papworth and Vennart (1984) studied uptake and turnover of 90 Sr in bone in response to concerns about human health following dietary exposure to 90 Sr (~29 y ear half - life) as a result of nuclear weapons testing in the 1950s. The data gathered and modeled suggests that uptake and turnover of stront ium in bone appears to be a function of age - related bone growth and remodeling. In adults, approximately 4% of dietary

intake of 90 Sr reached the skeleton, with about 7% and 28% of the 90 Sr burden lost each ye ar from cortical and trabecular bone, respectivel y. Uptake and turnover varied with age in children and adolescents (See Table 6 - 2). Assuming an intake of 1 g of calcium per day at all ages, infants had the highest bone uptake of 90 Sr at 10% (reported as picocuries of 90 Sr per gram calcium). Uptake then fell to about 5% b y age 5, remained constant until age 10, after which uptake began to increase. Strontium uptake increased to 10% until age 15 after which it fell to and remained at about 5% throughout adulthood. In terms of 90 Sr turnover, the low rate in newborns rapidl y rose to a y earl y maximum of approximately

38% in 4 - to 5 - ye ar - old children, after which the rate of turnover rapidly decreased to almost zero by age 10 and then s teadily

increased to 12% b y age 15, remaining constant throughout adulthood.EPA - OST Preliminary Health Effe cts Support Document for Strontium April 2014

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– DO NOT CITE OR QUOTE 6 - 9 **Table 6**  **- 2**  **Summary of uptake and turnover of 90**  **Sr in bones of children and adolescents Age Range (in years)**  **Rate of 90**  **Sr uptake ( %)**  **Rate of 90**  **Sr Turnover (%)** 0 - 4  10 to 5 ↑ 0 to 38 5 - 10 5  38 to 0 11 - 15 ↑ 5 to 10 ↑ 0 to 12 16 - adult 5 12 Source: Papw orth and Vennart (1984) * When an increase ( ↑) or decrease (  ) is specified, it occurs from the low est age to the highest age in the specified range. Distribution of strontium in the bone is relativel y uniform, where it replaces the calcium moiety of h ydrox yapatite. The concentration ratio of strontium to calcium (Sr:Ca) in bone has been reported to increase from 0.3 mg Sr/g Ca at birth to 0.5 mg Sr/g Ca in adults (Papworth and Vennart, 1984; Tanaka et al., 1981). It has also been shown that Sr:Ca ratios differ b y bone t yp e, with 10 - 20% higher ratios in the cortical bone than the trabecular bone (Tanaka et al., 1981). Strontium has been shown to transfer to the fetus during pregnancy and to neonates during breastfeeding (Harrison et al., 1965; Underwood, 1977; Rossipal et al., 2000; Tolsty kh et al., 1998, 2001). A study of bone ash from human fetuses and adults reported approxim ately 160 and 240 ppm strontium, respectivel y (Underwood, 1977). A study of people living near the Techa River who were exposed to 90 Sr following releases from a plutonium production plant reported 90 Sr fetal:maternal transfer coefficient of 0.012 to 0.24 becquerels per gram of calcium (Tolsty kh et al., 1998, 2001). In cases where exposure occurred prior to pregnancy the variability

in this transfer coefficient was not related to the maternal strontium burden at pregnancy . Overall, the 90 Sr fetal:materna l ratios on the high end of the range correlated with maternal exposure during adulthood, while those on the lower end correlated with maternal exposures during childhood or adolescence. During breastfeeding, an average concentration of 74 μg/L (this is higher than reported for cow’s milk; see Chapter 5) with a Sr:Ca ratio of 0.24 μg strontium/mg Ca was found in breast milk (Harrison et al., 1965). The strontium concentration in colostrum was reported to be similar to that of serum blood taken 20 minutes before delivery , while in the same women calcium in colostrum was significantly increased over serum blood (Rossipal et al., 2000). Based on these findings the authors concluded that the transfer of strontium was based upon a concentration gradient, whil e calcium transfer occurred b y active transport. Animals Animal studies of distribution following oral exposure provide information about serum blood binding, distribution in soft tissues, and maternal transfer of strontium. Guinea pigs and rabbits ar e reported to have similar values of strontium bound to proteins in the blood plasma (40%) or serum (60%) (Lloy d, 1968; Twardock et al., 1971). Rats exposed to 3.4 mg SrCl 2 in drinking water had a serum concentration of 8.7 mg/L strontium (Skoryna, 1981). The tissue:serum strontium concentration ratios were ≤ 1.3 for liver, heart, muscle, adrenal, and brain, whereas for bone it was > 1000. The strontium:calcium ratio ranged from 0.05 to 0.1 in allEPA - OST Preliminary Health Effe cts Support Document for Strontium April 2014

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– DO NOT CITE OR QUOTE 6 - 10 of the tissues. Rats exposed to 1.9 mg Sr/L in the same study had 5 - fold higher strontium in the mitochondrial, ly sosomal and microsomal fractions of liver than in the cy tosol. A study by Kshirsagar (1977) reported that a major fraction of the strontium in noncalcified tissues, possibly as much as 50 - 80%, appe ars to be bound to protein, thus making this portion of strontium unable to pass through biologic membranes and be further distributed through the bod y. Similarly to humans, studies in animals report the transfer of strontium through the placenta to the fetus, causing the fetus to accumulate strontium as the fetal skeleton develops (Olsen and Jonsen, 1979). The distribution of strontium in the fetus at the end of gestation is similar to that of the mother, with most of the strontium burden in the skelet on. A skeletal:soft tissue strontium concentration ratio was approximately 40 in mouse fetuses and dams (Jacobsen et al., 1978). As in humans, data from animal studies support the likely transfer of strontium from breast milk to newborns during lactation (Hopkins, 1967; Jacobsen et al., 1978; Kostial et al., 1969; Rönnbäck et al., 1968). In lactating rats that received an oral exposure to 0.3 microcuries of 85 Sr per 10 mLdrinking water during the 14th through 16th day s of lactation (Kostial et al., 1969 ), approximately

5% of the ingested dose was recovered in the nursing pups 24 hours after the end of the 2 - day

exposure. The tracer 85 Sr recovery rates in the pups following lactation are consistent with the data from the dams, if one assumes that approxi mately 25% of the oral dose was absorbed b y the dam. **Inhalation Exposure** In formation on the distribution of inhaled strontium in humans is not available; however, it is reasonable to assume that the distribution of strontium absorbed into the sy stemic ci rculation after deposition in the respiratory tract would be similar to that absorbed after ingestion. Distribution of strontium following inhalation exposure of experimental animals has been reported to occur in a similar fashion to that absorbed after i ngestion (Willard and Sny der, 1966; Fission Product Inhalation Project, 1967a,b). **Dermal Exposure** Il yi n et al. (1975) tracked distribution using dermally applied 85 SrCl 2 on the left forearm as compared to external counting of 85 Sr of the untreated areas. At 3 and 6 hours after exposure 85 Sr was detected at the patella and the right forearm; therefore it was concluded that the absorbed strontium had been taken up b y bone. No other studies were located regarding dermal exposure t o strontium; however, it is probable that distribution would be similar to strontium absorbed via the oral route (i.e., most of the bod y burden in the skeleton).EPA - OST Preliminary Health Effe cts Support Document for Strontium April 2014

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– DO NOT CITE OR QUOTE 6 - 11 **Other Routes of Exposure** In human subjects following the intravenous administration of stro ntium gluconate, the rapidly miscible pool of stable strontium was equivalent to 42.7 ± 1.1 L of serum. Dail y turnover rate was 13.5 ±0.6 L(30.9%); of this, 3.9 ±0.2 Lwas excreted b y the kidneys, and the equivalent of 9.6 ±0.4 L of serum was deposited i n bone (Eisenberg and Gordan, 1961). An exchangeable pool of approximately 64 L of serum for stable strontium was estimated in male volunteers following intravenous infusion of 5 mmol strontium gluconate over 1 hour (Moraes et al., 1991). The renal clear ance of strontium was determined to be 57.5% of the total clearance. **6.3 Metabolism**  Because strontium is a divalent metal, its ions do not undergo metabolic conversion. However, strontium does undergo interactions with cellular components, such as protein . Because of similar chemical and ph ys ical characteristics, many of the kinetic studies of strontium have been conducted in conjunction with calcium. It has been suggested that strontium and calcium share similar involvement in several biological proce sses (Sips et al. 1994). Strontium has been shown to mimic the actions of calcium in in vitro experiments of (1) insulin secretion, (2) contractions of the coronary artery and (3) parathy

roid hormone regulation; the response in these studies is reported t o be weaker than that caused b y calcium (Hellman et al., 1997; Pors Nielsen, 2004; Ohashi et al., 1995). In addition to the observed functional mimicry , it is likely

that strontium binds to carboxylic acids (e.g., citrate and lactate), based on the chemic al similarity

to calcium. **6.3.1 Metabolic Rate Constants**  Kinetic data on strontium interactions with proteins or tissues were not identified. **6.4 Excretion**  Urinary excretion is the major route of elimination for absorbed strontium (Harrison et al., 1955; Spencer et al., 1956; Eisenberg and Gordan, 1961; Comar and Wasserman, 1964). A urinary :feces excretion ratio of 3:1 has been reported in humans following several routes of exposure (oral, inhalation and intravenous) (Petkau and Pleskach, 1972; Wenger and Soucas, 1975). Fecal strontium reflects both unabsorbed strontium plus any absorbed strontium lost with gastrointestinal secretions.EPA - OST Preliminary Health Effe cts Support Document for Strontium April 2014

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– DO NOT CITE OR QUOTE 6 - 12 **Oral Exposure** Humans Elimination of ingested strontium primarily occurs through urine and feces. Strontium appears to have both a long - term and a short - term elimination half - life (Müller et al., 1966; Uchiy ama et al., 1973; L ikhtarev et al., 1975; Tolsty kh et al., 1997). Short - term losses after exposure reflect soft - tissue elimination as well as elimination from a mor e rapidly exchangeable pool of strontium in bone. L ong - term elimination half - times reflect primarily

the storage and release of stable strontium in bone. There is evidence for tubular resorption during renal excretion (Leeuwenkamp et al., 1990). Long - t erm whole bod y el imination half - times of strontium (estimated at 28 years in males and 16 years in females) have been determined in people exposed to a release of plutonium fission products for decades in the Techa River area of Russia (Tolsty kh et al., 19 97). The longer elimination half - time in the males is attributed to increased bone resorption in females over the age of 50, which was likel y after menopause. In a study of radium dial painters, a similar long - term elimination half - life of 25 ye ars was r eported (Muller et al., 1966). In studies using 85 Sr tracer or SrCl 2 doses with time periods of 13 - 108 day s after exposure, whole body elimination half

- lives ranged from 2 to 91 day s, reflecting the faster initial elimination phase (Uchi yama et al., 1973; Likhtarev et al., 1975). Warren and Spencer (1976) found that patients on a low calcium diet given a daily dose of 600 mg strontium gluconate transientl y retained about half of the strontium dose, and urinary calcium excretion increased. Once the tre atment was stopped, strontium was excreted via urine and feces within 6 day s. A urinary : fecal strontium excretion ratio of 3 was reported in radium dial painters (Wenger and Soucas, 1975); this observation is consistent with ratios observed following i ntravenous injections of SrCl 2 (ATSDR, 2004). Other studies reported urinary excretion of strontium to be approximately 0.25 mg/day

(18% of the daily

dietary intake) (Harrison et al., 1955; Comar and Wasserman, 1964) and renal plasma clearance of strontium to be 9.7 L/day in adults and 4.0 L/day

in children (Sutton et al., 1971b). In other studies, only 4% of the oral dose was found in urine (Spencer et al., 1960; Bronner et al., 1963). Urinary excretion of ingested or parenterall y administered strontium in humans was maximal on the day

of administration and was directly proportional to the plasma concentration at levels up to 100 - fold the naturall y occurring levels (Spencer et al., 1956; Harrison et al., 1955; Eisenberg and Gordan, 1961). No information was available about the administered dose. Harrison et al. (1955) reported excretion of strontium was mainly in the feces following oral administration, reflecting unabsorbed strontium. Overall, these studies support the conclusion that urine is likely the major route of excretion for absorbed strontium.EPA - OST Preliminary Health Effe cts Support Document for Strontium April 2014

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– DO NOT CITE OR QUOTE 6 - 13 Animals No data were identified on excretion in laboratory animals after oral exposures. **Inhalation Exposure** Human Studies following accidental exposures to radioactive strontium ( 90 SrCl 2 , inspired quantity not known) found that strontium absorbed after deposition in the respiratory tract is excreted in feces and urine, with a urinary :fecal excretion ratio of 3:1 over 800 day s (Petkau and Pleskach, 1972). This ratio is similar to the ratios reporte d following oral (Wenger and Soucas, 1975) and intravenous (ATSDR, 2004) exposures. Humans accidentally exposed to airborne radioactive strontium had a lower urinary : fecal ratio (<1 - 1.4) after shorter observation periods (24 day s) (Rundo and Williams, 19 61). This lower ratio may reflect the fecal excretion of strontium that is cleared from the lungs via the mucociliary escalator, but not absorbed from the gastrointestinal tract Because human data for excretion of strontium following inhalation exposure is limited to case reports of measuring 90 Sr in the urine and feces after an accidental exposure to aerosolized 90 SrCl 2 , it is not conclusively known how Sr gets from the lungs to feces in humans. However, as noted, mechanical clearance via the mucociliary escalator is likely

to play some role. Animal A whole bod y elimination study was performed in dogs following inhalation exposures to 85 SrCl 2 (Fission Product Inhalation Project, 1967a). Three phases of elimination were reported, with elimination hal f

- lives of 0.6 (59%), 9 (12%) and 300 day s (29%). While the slower elimination time reflects skeletal elimination of strontium, the rapid earl y phase (0.6 day) reflects mechanical clearance of strontium in the tracheobronchial region, which is then transf erred to the gastrointestinal tract and feces. In rats and dogs, urinary : fecal excretion ratios are time - dependent following inhalation strontium exposure (Fission Product Inhalation Project, 1967a,b). In dogs, a large fecal component of excretion dur ing the initial 22 minute observation period after 85 SrCl 2 exposure was followed later b y lower fecal excretion and higher urinary: fecal ratios of <1 - 1.4 (Fission Product Inhalation Project, 1967a). In rats, the urinary : fecal excretion ratios increased over time from <1 to 2 - 4 after intratracheal instillation of SrCl 2 (Fission Product Inhalation Project, 1967b; Namén yi et al., 1986). **Dermal Exposure** Il yi n et al. (1975) reported strontium urinary excretion in volunteers exposed to 85 SrCl 2 via dermal application to their left forearm. Fecal excretion was not measured in this study .EPA - OST Preliminary Health Effe cts Support Document for Strontium April 2014

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– DO NOT CITE OR QUOTE 6 - 14 **Other Exposure Routes** Following intravenous injection in humans, 60% of the dose was found in the urine after 14 to 50 day s (McCance and Widdowson, 1939; Harrison et al., 1955; Spencer et al., 1960; Bronner et al., 1963; Warren and Spencer, 1976), while 12 to 13% of the dose was eliminated in the feces (Bronner et al., 1963; Spencer et al., 1960). No information was available about the administered dose. **6.5 Pharmacokinetic**  **Considerations** ICRP (1993) developed a compartmental model of the kinetics of alkaline earth elements, including strontium that is applicable to humans of all ages for inhalation, gastrointestinal, or injection exposures to radioactive strontium ( 89 Sr and 90 Sr). This model has been used b y ICRP (1994a, b) and U.S. EPA (2000d) to calculate inhalation, food and water risk coefficients for several strontium radionuclides (i.e., Sr 80, 81, 82, 83, 85, 85m, 87m, 89, 90, 91, 92). Overall, the model assumes that 99% of the absorbed strontium is transferred to the bones, and the remaining 1% enters the soft tissues. The model assumes that the fractional absorption of ingested strontium decreases from 0.6 in infants to 0.3 in adulthood. Absorbed strontium in the plasma is described as distributing to the bones, liver and other tissues. Excretion is modeled as going from plasma to urine, plasma to feces, and liver to feces. No other PBPK models for strontium were located. **6.6 Summary**  Strontium is toxicokinetical ly similar to calcium. In humans, it is moderately absorbed (20%) after ingestion but poorly absorbed (<1%) through intact skin. Dietary strontium is more readil y absorbed when present as a soluble compound (e.g., SrCl 2 ) and in individuals with low intak es of dietary

calcium. A substantial amount of absorbed strontium is deposited in the tissue. The vast majority

(>95%) of the retained strontium is distributed to the bone and excretion of absorbed strontium occurs primarily via the urine. Strontium has been shown to transfer to the fetus during pregnancy

and neonates during lactation (Harrison et al., 1965; Underwood, 1977; Olsen and Jonsen, 1979; Tolsty kh et al., 1998, 2001; Rossipal et al., 2000). Urinary excretion is the major route of elimination fo r absorbed strontium (Harrison et al., 1955; Spencer et al., 1956; Eisenberg and Gordan, 1961; Comar and Wasserman, 1964). Strontium has been shown to have generall y similar absorption, distribution, and excretion in humans and rodents following ingest ion, with some differences. For example, a substantial age - related difference in absorption of strontium has been observed in rats (Forbes and Reina, 1972), but no such differences have been seen in humans (Harrison et al., 1965; Kahn et al., 1969).EPA - OST Preliminary Health Effe cts Support Document for Strontium April 2014

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– DO NOT CITE OR QUOTE 7 - 1 **7.0 HAZARD IDENTIFICATION**  **7.1 Overview of**  **Bone Physiology and Development** Because an understanding of bone ph ys iology and development is key

to understanding the effects of strontium, this section begins with a brief review of the topic. As described b y several reviews of bone phy siology and development (Cabrera et al., 1999; J avaid and Cooper, 2002; Clarke et al., 2008; Cooper et al., 2008), bone tissue is composed of collagen fibers, noncollagenous proteins, and deposited minerals (50 to 70%), primaril y h ydrox yapatite. Crystals of hy droxy apatite (a complex calcium salt with p hosphate and h ydroxide ions) are located in and on the collagen fibers and in the ground substance (contains gly coproteins and proteogl ycans such as elastin) of bone. There are four general categories of bones: long, short, flat and irregular. This discu ssion focuses upon long bone growth and development. Long bones can be divided into cortical and trabecular bone tissue, with the different ty pes predominating in different portions of the bone. L ong bones are comprised of a hollow shaft (diaph ys is), a flared region (metaph ys es) and two rounded heads (epiphy ses) (see Figure 7 - 1). The diaph ys is is mostly dense compact (cortical) bone tissue, while the other portions of the long bone are spongy

cancellous (trabecular) bone tissue with a shell of cortical bone tissue. Cortical bone comprises approximately 80% of the total skeletal mass and has a slow rate of turnover and high resistance to bending and torsion. Trabecular bone comprises the remaining 20% of the total skeletal mass, but makes up 80% of the total bone surface area, as it forms the interior scaffolding. The primary functional unit of both cortical and trabecular bone tissue is the osteon. Cortical osteons (Haversian s ys tems) are made of concentric lay ers of mineralized bone matrix, called c oncentric lamellae. The concentric lamellae form around the Haversian canal containing a blood and nerve suppl y. Trabecular osteons (packets) also form concentric lamellae, but are arranged in a pattern such that the bone tissue appears spongy but is rig id, and this is integral in bones maintaining their shape. Most of the fetal skeleton is made of cartilage, which is composed ground substance and chondrocy

tes (which produce collagen and maintain the cartilaginous matrix). There are three ty pes of cart ilage, elastic cartilage, hy aline cartilage and fibrocartilage, which differ in the relative amount of chondrocy tes and ground substance. For the purposes of this discussion, only hy aline cartilage will be discussed. L ongitudinal bone growth begins just after birth and continues until closure of the epiphy ses during adolescence. Elongation of the long bones occurs in a region made of h yaline cartilage between the diaphysis and the epiph ysis at either end; this region is called the epiphyseal plate. The chondrocy tes in the epiphy seal plates produce new cartilage cells, which form a template as they migrate towards the diaphy sis. Osteoblasts then move into these areas and begin the process of bone remodeling over this cartilage template. Throughout life , longitudinal and radial bone growth, modeling and remodeling occurs. Longitudinal bone growth ends following pubert y, with the closure of the epiphy seal plates. Bone modeling occurs throughout life and involves the change of the shape of bones in respo nse to biomechanical stress (i.e., weight bearing movements). In adults, bone modeling is usually less frequent than bone remodeling. Following puberty, continued increase in bone density isEPA - OST Preliminary Health Effe cts Support Document for Strontium April 2014

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– DO NOT CITE OR QUOTE 7 - 2 linked to bone modeling (due to weight bearing stressors). Bon e mineral density increases until it reaches a peak level at about 30 y ears of age (Wood, 2000). The process of bone remodeling enables bone strength and mineral homeostasis to be maintained b y renewal of old or damaged bone. Several cell ty

pes are inv olved in bone remodeling and communication. Osteoblasts are responsible for bone formation and osteoclasts for the degradation of bone tissue during remodeling. Osteocy

tes maintain intercellular communication in stable sections of bone (Saladin, 2003). In earl y life, activity of the osteoblasts is greater than that for the osteoclasts (consistent with bone growth predominating). In healthy y oung adults, the amount of new bone formation is balanced with the amount of bone destruction (resorption); howeve r with increasing age bone resorption is more favored. The rate of remodeling varies greatl y among specific bones, with the lumbar vertebral bone turning over most rapidly (Wood, 2000). It is estimated that the adult skeleton completely regenerates every 10 y ears through this process (Manolagas, 2000). The entire bone calcium pool turns over on average every 5 to 6 y ears. Bone remodeling occurs at localized sites in both cortical and trabecular bone via four sequential steps: activation, resorption, re versal and formation. During activation, cy tokines and growth factors (IGF - 1; hormones: thy roid, androgens) act on preosteoclasts, stimulating them, and causing them to differentiate and mature into active osteoclasts. During resorption, the osteoclasts digest the old mineral matrix as regulated by receptor activator of NF - κB ligand (RANKL), osteoprotegerin, interleukins, parath yr oid hormone, vitamin D and calcitonin (Clarke, 2008). In the reversal step, the remodeling process shifts from bone resorption to bone formation and preosteoblasts begin infiltrating to the site in preparation for the final phase of remodeling. Serum vitamin D levels are involved in the differentiation of osteoblasts and stimulate the osteoblast to express bone - specific proteins associated with mineralization. Finally , during the formation step, osteoblasts sy nthesize new cartilage - based organic bone matrix and regulate the incorporation of minerals such as calcium and phosphorus into the matrix. Bone matrix mineralization is a ssociated with calcium and phosphate binding proteins (i.e., alkaline phosphatase, osteocalcin, oestopontin and sialoprotein), which are believed to regulate deposition through controlling the formation (size and quantity) of hy drox yapatite crystals (Clark e, 2008). Serum vitamin D levels are also involved in bone matrix mineralization by stimulating intestinal absorption of calcium and phosphorus, which results in adequate serum levels of calcium and phosphorus for passive mineralization of unmineralized (or newl y formed) bone matrix. Several pathoph ys iological conditions exist for the bone, such as osteomalacia, osteopenia and osteoporosis, which are described in more detail in the following text. Osteomalacia occurs when the incorporation of minerals i nto the bone matrix is disrupted, leading to accumulation of unmineralized bone matrix as the osteoblasts continue to secrete osteoid. Due to the decreased mineral content of the bone matrix, the bone is soft. Structurally (i.e., on a radiograph), osteom alacia can be observed as trabeculae with a washed - out appearance due to decreased bone mineral densit y and content. A similar defect in the mineralization of cartilage in growth plates is observed clinicall y as “rickets”. Structurall y, this can be obser ved as an irregular border between growth cartilage and the bony metaph ys is, and increased width ofEPA - OST Preliminary Health Effe cts Support Document for Strontium April 2014

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– DO NOT CITE OR QUOTE 7 - 3 the epiphy seal plate. These two conditions (osteomalacia and rickets) often coexist while epiphy seal plates are open prior to the end of puberty . These co nditions are biochemicall y identified by

an increase in serum levels of alkaline phosphatase and are generall y linked with a deficient suppl y or uptake of mineral (calcium or phosphorus). Osteopenia is a decreased amount of bone tissue caused b y either insufficient deposition, decreased bone sy

nthesis or increased resorption of the osteoid. I t differs from osteomalacia and rickets in that the incorporation of calcium and phosphate into both osteoid and cartilage of the growth plate are unaffected. Howe ver, bone mineral density and content are decreased as they are in osteomalacia. Structurally it is observed as a decreased thickness of the bone cortex and/ or thickness and number of trabeculae. This condition is usually linked with severe s ys temic dis ease, drug side effect (i.e., corticosteroids), or lack of mechanical stimulation known commonly

as “disuse osteoporosis”. Thus, this condition can be caused by a signal that more bone formation is unnecessary . Osteoporosis is diagnosed when bone minera l density is below - 2.5 standard deviations from the mean of young healthy adults (Rauch and Schoenau, 2001). Bone mineral (hy droxy apatite) provides rigidity and load bearing strength to bone. Thus, bone mineral densit y is linked with bone strength. Ade quate bone calcification at maturity is a protective factor for bone health later in life (Javaid and Cooper, 2002; Cooper et al., 2008). As discussed earlier, there is a shift towards more bone resorption via increased osteoclast activity with increasing age; thus, high bone turnover with more resorption than formation leads to microarchitectural deterioration and reduced bone strength. However, in some cases the development of osteoporosis is due to abnormal bone matrix (Clarke, 2008). **Figure 7**  **- 1**  **Bone anatomy and growth** (a)EPA - OST Preliminary Health Effe cts Support Document for Strontium April 2014

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– DO NOT CITE OR QUOTE 7 - 4 (b)

(c)

Source: http://training.seer.cancer.gov/anatomy/skeletal/tissue.html The figures show

compact (dense) and trabecular (cancellous) bone anatomy (a), anatomy of the long bone (b), and bone grow

th (c). **7.2 Human Effects**  The database on short - term effects of strontium is limited to an oral metabolic balance study of approximately

one month that did not include detailed evaluation of bone, a case report of inhalation exposure to strontium and other compounds, and a study on dermal exposure to strontium reducing sensory irritation. L ong - term studies include studies of general population exposures to strontium through drinking water or soil (and food grown on that soil),EPA - OST Preliminary Health Effe cts Support Document for Strontium April 2014

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– DO NOT CITE OR QUOTE 7 - 5 occupationall y - exposed workers, and patients administer ed “low dose” strontium for bone disorders. **7.2.1 Short**  **- Term Studies and Case Reports**  One oral short - term study was located for strontium, but it was not designed to evaluate sy stemic toxicity

or bone effects. Also, a case report documenting health effects i n humans following an acute inhalation exposure to strontium was identified. Finally , some data are available on the response to single dermal applications. **Intentional and Accidental Acute Ingestion** No studies were identified regarding the intentional or accidental acute ingestion of strontium. **Acute and Short**

**- Term Oral Exposure**  A study by Warren and Spencer (1976) found no adverse effects following oral administration of 1537 mg per day as strontium lactate (corresponding to 507 mg Sr per day , or about 7.2 mg Sr/kg - day , assuming a bod y weight of 70 kg) for 24 - 36 day s as part of a metabolic balance stud y; this study

was not designed to evaluate toxicity and did not include detailed evaluation of the bone. **Acute and Short**

**- Term Inhalation Exposure**  F ederman and Sachter (1997) reported a sudden anaphy lactic reaction in a 35 - ye ar - old female paramedic following the inhalation of fumes from a flare that contained about 75% strontium nitrate, 10% potassium perchlorate, 10% sulfur and 10% sawdust/oil binder . The initial sy mptoms included coughing, wheezing, severe tachy cardia and shortness of breath, and could not be controlled by administration of albuterol, epinephrine or steroids. The paramedic recovered completely

after sedation, intubation and several day s of intensive care. The role of strontium in the anaphy lactic response in this report is uncertain. Each component of the flare could y ield products that would be irritating to the respiratory tract during combustion. **Acute and Short**

**- Term Dermal E** 

**xposure** Two studies involving dermal application of strontium compounds to humans were located (Zhai et al., 2000a,b). However, the endpoint for these studies was not toxicity , but rather a beneficial suppression of sensory irritation. Therefore, the st udies are discussed briefl y in Section 7.3.3.EPA - OST Preliminary Health Effe cts Support Document for Strontium April 2014

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– DO NOT CITE OR QUOTE 7 - 6 **7.2.2 Long**  **- Term and Epidemiological Studies**  **Epidemiological Studies** Several studies examined the relationship between strontium exposure in the environment or the bod y burden of strontium (as a measure of interna l dose) and development of disease following either occupational or environmental exposures. These studies are limited quantitatively

because they

may not have adequately

controlled for other factors potentiall y contributing to the endpoint being evaluate d. The relationship between strontium levels in workers hair and m yo cardial infarction was examined by

Z erbino and Solomenchuk (2007). In this study , strontium content of hair in my ocardial infarction patients was compared with that of healthy individua ls, all of whom worked in occupations associated with “xenobiotic” exposures (presumabl y industrial chemicals). The hair of the my ocardial infarction patients all contained high amounts of various metals, including strontium. Two - thirds of the patients h ad strontium and potassium levels considerabl y exceeding levels that were described as “maximally allowable values”. Özgür et al. (1996) evaluated whether the prevalence of childhood rickets in the Ulaş Health Region of Sivas, Turkey was related to high soil levels of strontium. The prevalence of clinical signs of rickets among 2 , 140 children ages 6 months to 5 y ears in this area was 32%, based on craniotabs, rachitic rib cage rosary , bulging at the wrist , delay ed closure of the fontanels , and/or deformities of the legs compared with a national prevalence of 4.4%. The regional diet was largel y based on locall y - grown grains. The children were divided into two groups based on soil strontium (>350 mg/kg Sr and <350 mg/kg Sr). There was a gr eater proportion of signs and severit y of rickets in the group with high soil strontium (3 1 .5%) versus the group with lower soil strontium (19.5%) ; the differences were statistically significant (p<0.001) . Factors including age, duration of breastfeeding, height and weight of the children had a significant effect on the odds ratio for developing rickets for most of the age groups evaluated . H eights were less than the population third centile for 38.6 % of the children in the high soil strontium area compared to 24.85 % of children in the lower - soil strontium region (p<0.01). This study

is consistent with the observations from animals that elevated strontium exposures during bone growth can lead to altered bone structure. Several studies evaluated the impa ct of elevated strontium exposure in drinking water on targets besides bone, resulting from strontium substituting for calcium. Dawson et al. (1978) evaluated families (subjects aged 5 - 97 y ears) who had resided for at least 10 y ears within low socioeconom ic Texas communities. The authors reported that there was no correlation between strontium concentration (0.4 to 37.8 mg/L) in the drinking water and mortality from arteriosclerotic and degenerative heart disease, or other vascular/heart diseases. Studi es conducted by Lo ngerich et al. (1991) and St. Leger et al. (1980) in Canada (56 participants) and the UK (80 participants), respectively , explored the correlation of strontium levels in tap water with the development of infant neural tube defects. In bo th studies, the mean concentration of strontium was not significantl y l ower in the tap water of mothers who gave birthEPA - OST Preliminary Health Effe cts Support Document for Strontium April 2014

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– DO NOT CITE OR QUOTE 7 - 7 to normal infants versus those with neural tube defects. St. L eger et al. (1980) compared strontium levels in the drinking water of 36 w omen in Cardiff, UK who gave birth to an infant with a neural tube defect (mean 0.09 mg/L ; range 0.02 - 0.13 mg/L) and 44 matched women whose babies had no such defects (mean 0.08 mg/L; range 0.03 - 0.15 mg/L). L ongerich et al. (1991) reported slightl y, but n ot significantl y, higher strontium levels in the tap water of 28 mothers in Newfoundland, Canada, who gave birth to babies with neural tube defects. A similar pattern was observed for 12 of the 13 elements evaluated; thus the data are inadequate to implic ate any

single metal or combination of metals. Curzon and Spector (1977) studied 1,313 children aged 12 - 14 y ears living in Wisconsin and found that lifelong residents, but not immigrants, experienced increased tooth enamel mottling as the average drinki ng water concentration increased from 0.02 to 34 mg Sr/L. Another study

by the same group investigated the prevalence of dental caries in Ohio using 539 children of the same age range, and found that caries decreased as the average drinking water concentr ation increased from 0.2 to 15.3 mg Sr/L (Curzon, 1981). Though fluoride exposure can cause increased tooth enamel mottling (fluorosis) and decreases in dental caries, in both studies, these effects were found to have no association with fluoride concentr ation. **Cancer Studies** Wang et al. (1990) performed a study of the relationship between strontium exposure (as measured b y the strontium concentration in hair) and the incidence of liver cancer mortality in communities on Chongming Island, China with high (41 - 58 per 100,000) ver sus low (17 - 18 per 100,000) liver cancer mortality incidence. There was no correlation between mean strontium concentration in hair and the liver cancer mortality. A case - control analy sis of liver cancer included in this study

found similar mean strontium hair concentrations in cases and controls (3.0 vs. 3.7 mg/kg in hair, respectivel y). An increase in lung cancer mortality was reported in workers in British chromate pigment manufacturing plants between the ye ars of 1950 to 1976 (Davies, 1979; 1984). For workers exposed to high and medium levels of chromates before industrial h ygiene improvements were introduced in 1961, the observed/expected ratio (O/E) was 6/1.61, with a standardized mortality ratio (SMR) of 373 (

p < 0.01) for lung cancer deaths. Wh ile strontium chromate was implicated as a factor for the observed increase in these workers, the carcinogenicity of strontium chromate is attributed to ions in which chromium is present in the 6+ oxidation state and requires transformation to become a gen otoxic agent (ATSDR, 2004). **Long -**  **term Clinical Studies** Administration of “low doses” of strontium (usually as the lactate, gluconate, carbonate or ranelate) over several y ears has been used to treat patients with disorders of bone mineralization, such as osteoporosis (ATSDR, 2004). The term “low dose” was not further defined b y ATSDR, but clearl y includes doses up to at least 24 mg Sr/kg - day , based on the available data. Although strontium is not recognized in the U.S. as a standard therap y for osteop orosis (Krane, 1977), strontium ranelate is prescribed in Europe for treatment ofEPA - OST Preliminary Health Effe cts Support Document for Strontium April 2014

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– DO NOT CITE OR QUOTE 7 - 8 osteoporosis. Strontium ranelate (CAS RN 13549 - 90 - 4 ) is the strontium salt of ranelic acid, which has the following chemical formula [C 12 H 6N 2 O 8 S] 4 - 2Sr2+ . Because calcium and vitamin D also play

key roles in bone formation, these supplements are often are co - administered with strontium, meaning that the doses in these studies cannot be used to identify nontoxic doses of strontium, even for adults. Studies have been conduct ed in post - menopausal women with signs of osteoporosis using exposures ranging from 3 - 4 mg Sr/kg - day (as either strontium lactate or chloride) for at least 3 months to 24 mg Sr/kg - day for 0.25 - 3 y ears (McCaslin and James, 1959; Skory na, 1981; Skory

na and F uskova, 1981). **7.3 Animal Studies**  Strontium has low acute oral toxicity , with an LD 50 above 2,000 mg/kg ( Ll obet et al., 1991; Ghosh et al., 1990; Woodard and Calvery , 1941) . Strontium can substitute for calcium, and studies in rats and mice show that the bone is the primary target of strontium exposure. Short - term and subchronic studies in rats indicate that ingestion of strontium results in more severe skeletal effects in young animals than in adults (Storey , 1961, 1962), although direct comparison is di fficult, due to the higher feed intake of young animals per unit body weight. Limited data on reproductive and developmental toxicity (Kroes et al., 1977; Skory na, 1981; Skory na and Fuskova, 1981; NI ER, 2006c; Shibata and Yamashita, 2001) indicate that strontium does not cause structural or functional reproductive effects at doses well above those causing bone effects, and that bone development is the key developmental endpoint of concern. Because bone growth and development is affected b y levels of multip le nutrients, including levels of calcium, phosphorous and vitamin D, these levels are reported when provided by the study authors. Man y suppliers list the normal level of (calcium), (phosphorus) and (vitamin D) for rat chow. For example, the “laboratory rodent diet 5001,” a common laboratory rodent diet from PMIFeeds Inc., is listed as containing 0.95% calcium, 0.66% phosphorous, and providing 4.5 IU/g of vitamin D 3 (www.labdiet.com). For most studies, there is some uncertaint y in the actual doses of strontium, since reporting was in terms of concentration in food or water, rather than strontium intake. In those cases, strontium intake was estimated using as much study - specific information as possible and feasible, with greater emphasis placed on stud ies testing multiple doses with effects at lower doses. Actual bod y weights were used when available, and bod y weights from U.S. EPA (1988) were used when the study authors did not provide a needed bod y weight. When possible, body weight was estimated as the average of the initial and final body weight. If strontium intake was not reported, food intake was estimated using the allometric equation from U.S. EPA (1988) 5

. An exception to this approach was the stud y of Marie et al. (1985), for which the study authors estimated strontium intake based on bod y weight and water consumption. A summary

table of relevant animal toxicity studies can be found in Appendix A.

5 F = 0.056*(BW) 0.6611 where F = food consumption in kg/day and BW = body w eight in kg.EPA - OST Preliminary Health Effe cts Support Document for Strontium April 2014

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– DO NOT CITE OR QUOTE 7 - 9 **7.3.1 Acute Toxicity**  **Oral Exposure** Oral median lethal doses of strontium have been reported to be between 2.35 and 3.1 g Sr/kg in rodents using the nitrate or chloride salts of strontium (Woodard and Calvery , 1941; Ghosh et al., 1990; L lobet et al., 1991). However, Zy uzy ukin and Makolkina (1979) reported no signs of overt toxicity

following administration of 14 g Sr/kg (as the carbonate) via stomach tube to rats and mice. In light of the low water solubility of strontium carbonate (0.11 g/L, compared with 538 g/L for strontium chloride; Me rck, 1989), the low toxicity of strontium carbonate may reflect low bioavailability, particularl y at high lethal doses. Administration of 950 mg Sr/kg as strontium sulfate (water solubility 0.14 g/L) b y gavage to six female rats showed no toxic effects or histologic changes (NIER, 2006a). Because all of these doses are above 1,000 mg Sr/kg, they indicate that acute oral toxicity is low, and further indicate that water solubility is related to the lethal dose of strontium compounds. **Inhalation Exposure** N o studies were located on the acute inhalation toxicity of strontium to animals. L ack of inhalation data is not a concern based on the low volatility of strontium compounds, which are solids at room temperature (ATSDR, 2004); therefore, there is little li kelihood of exposure via volatilization from tap water. **Dermal/Ocular Exposure** The equivalent of a 950 mg Sr/kg (2 g/kg strontium sulfate) was applied for 24 hours (covered) to the skin of 10 male and female rats. No overt toxicity or histological changes were observed during the 14 - day observation period (NIER, 2006b). No LD 50 values for the dermal route or other data related to ey e or skin irritation were identified. **7.3.2 Short**  **- Term Studies**  **Oral Exposure** No signs of toxicity

were seen in monkey s administered 1100 mg Sr/kg - day as strontium chloride b y capsule for 7 days. However local irritation of the gastrointestinal tract (leading to hemorrhage and erosive lesions of the esophagus and upper duodenum) was observed (Fisch et al., 2006). Since effe cts were seen onl y at the portal - of - entry , the results are consistent with the effects being due to the high local concentration resulting from the capsule administration. No effects on behavior, growth, food intake, liver and kidney weight, liver and kidney histopathology , or hematology were seen in Wistar rats (3/sex/group) fed diets containing up to 3,000 ppm strontium chloride hexahy drate for 2 weeks (about 110 mg Sr/kg - day , based on an average initial body

weight of 0.15 kg and consumption of 0.016 kg food/day , based on anEPA - OST Preliminary Health Effe cts Support Document for Strontium April 2014

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– DO NOT CITE OR QUOTE 7 - 10 allometric equation 6 ) (Kroes et al., 1977). This was a range - finding study ; effects on bone were not evaluated. Other doses tested were reported as 0 (control), 0.11, 1.1, and 11 mg Sr/kg - day (ATSDR, 2004). Bone and cartilage are important targets of strontium toxicity , as shown in several short term repeated oral dose studies. Storey (1961) investigated the impact of strontium on bone structure in groups of yo ung (40 - 60 g) and adult (200 - 250 g) female rats (strain not specified) fed strontium at 0%, 0.19%, 0.38%, 0.75%, 1% (y oung rats only), 1.5%, or 3% of the diet as strontium carbonate for 20 day s. These concentrations correspond to about 0, 190, 380, 750, 1000, 1500, and 3000 mg Sr/kg - day for y oung rats (assuming that young rats consume food equivalent to 10% of their body weight per day) and 0, 95, 190, 375, 750, and 1500 mg Sr/kg day for adult rats assuming food consumption at 5% of body weight . The dose groups apparentl y contained 10/dose for young rats and 3/dose for adult rats, but the number of y oung rats evaluated ranged from 3 to 10, depending on the endpoint. The diets also contained 1.6% calcium and 0.9% phosphorus, which were considered adequate amounts by the stud y authors and are consistent with amounts provided in a normal rat diet (PMI Feeds Inc., Laboratory Rodent Diet 5001). Young rats were affected more severel y and at lower doses than the adults. In the yo ung rats, there was no effect at the low dose, but bone structure was altered at 0.38%. Changes observed at 0.38% and higher included inhibition of calcification, as evidenced by increasing width of epiphy seal cartilage ( the cartilage plate at the end of long bones 7 ) , the presence of uncalcified bone matrix and decreased ash weight of bone. Taken together these changes suggest earl y development of osteomalacia and/or strontium “rickets”. Higher dietary concentrations resulted in more severe effects, including irregularities in the organization of the hy pertrophic zone cells (distorting the usual parallel arrangement of intercellular matrix columns), in the pattern of calcification and in deposition of osteoid, as well as bands of uncalcified cartilage matrix isolated between areas of osteoid tissue. These more severe effects sugges t progression of the osteomalacia - like effects observed at lower strontium concentrations. Growth was reduced at 1.5% and above. The calcium level in the diet in this study was several fold higher than in that in many of the other studies (e.g., compare w ith 0.5% calcium in Marie et al., 1985). This high level of calcium may have provided some protection from the bone effects of strontium. In the adult rats, the first obvious bone change occurred at the 1.5% dietary strontium level (estimated as 750 mg Sr/kg - day by U.S. EPA, 1992) and included histological changes in the tibia (slightly

wider epiphy seal cartilage plate, increased width of metaphy seal osteoid seams [i.e., the seams at the wider portion of the long bone adjacent to the epiph yseal line]). These increased widths of the epiphy seal plate and metaphy seal seam together suggest progression towards strontium “rickets”. More severe effects observed at a dietary concentration of 3% included reduced growth, the deposition of osteoid tissue near vas cular canals, a reduction in the area of bone resorptions, and reductions in the dry weight, ash weight, ash percentage and calcium in ash of bone. Taken together these effects suggest that bone remodeling was disrupted 6 Allometrically - scaled food intake for rats throughout this document was calculated using the equation of U.S. EPA (1988), F = 0.056*(BW) 0.6611 where F = food consumption in kg/day and BW = body weight in kg. 7 In adults that have stopped grow ing, the epiphyseal plate is replaced by the epiphyseal l ine.EPA - OST Preliminary Health Effe cts Support Document for Strontium April 2014

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– DO NOT CITE OR QUOTE 7 - 11 by increased strontium exposure as evidenced b y less formation and resorption with decreased mineralization. In young rats, the dietary level of 0.19% strontium (estimated as 190 mg Sr/kg day by U.S. EPA, 1992) was a NOAEL and 0.38% strontium (estimated as 380 mg Sr/kg - day) was a LOAEL, ba sed on inhibition of calcification. For adult rats, the dietary level of 0.75% strontium (estimated as 375 mg Sr/kg - day) was a NOAEL and 1.5% strontium (estimated as 750 mg Sr/kg - day) was a LOAEL , based on histological changes of the bone. Both effect levels were based on changes in bone structure. This study

is limited by

the small sample size and by the lack of dose reporting as mass per unit body weight. The lack of dose reporting is a common weakness in man y of the studies of effects on bone. Eff ects comparable to those observed b y Storey (1961) were seen in a study of female weanling Wistar rats (6 - 8/group) (Morohashi et al., 1994). This study tested diets containing 0%, 0.05%, 0.1%, or 0.5% strontium carbonate (estimated as doses of 0, 50, 100, and 500 mg Sr/kg - day), and was designed to distinguish therapeutic and toxic doses of strontium, based on the kinetics of bone remodeling (formation and resorption), by study ing the effects of strontium on calcium balance following injection of radiolabel ed calcium. In 36 - day - old rats that ingested 0.1% strontium carbonate in the diet (100 mg Sr/kg - day , based on the authors’ reported Sr intake and an average bod y weight of 0.15 kg) for 27 days, calcium absorption and rates of bone formation and resorption were normal. The diet contained 0.5% calcium, 0.35% phosphorus, and vitamin D3 (supplementation concentration not specified), which are low concentrations of calcium and phosphorus based on a normal rat diet (PMI Feeds Inc., Laboratory

Rodent Diet 5001). Disruption of bone remodeling as evidenced by decreases in bone formation rate (24%), serum calcium (13%), bone resorption rate (28%), and a significant reduction in the calcium content of ashed femurs were observed at an estimated strontium dose of 500 mg/kg bod y weight per day . Higher doses of strontium have been observed to affect bone formation and structure in a number of other studies. Bone abnormalities, including large areas of non - mineralized bone (osteoid) in epiphy seal bone and secondary sp ongiosa, abnormall y wide epiphyseal plates with abnormally

long and dense metaphy ses, longer primary spongiosa of the proximal tibia, and disorganized trabeculae disconnected from the overly ing calcified cartilage, were seen in “y oung” (100 - 125 g) male Spr ague - Dawley rats (18/group) ingesting 500 mg Sr/kg - day in diet (estimated based on average bod y weight and the allometric food intake equation of U.S. EPA, 1988) as strontium carbonate for 3 weeks (Neufeld and Boskey , 1994). Other effects at this dose inc luded reduced ash weight (mineral content) of metaphy seal bone, increased complexed acidic phospholipid content (lipid nucleator of bone mineral) and lower bone density areas in the diaphy ses (shafts of the long bones). These effects suggest defects in bo ne mineralization (osteomalacia/ strontium “rickets”). There was no information provided on dietary calcium, phosphorus or vitamin D; however the strontium fed rats were found to have normal serum calcium levels and there was no evidence of vitamin D defi ciency . The investigators suggested that strontium binds to the surface of initial h ydrox ya patite cry stallites, reducing their further proliferation and resulting in a smaller cry stal size.EPA - OST Preliminary Health Effe cts Support Document for Strontium April 2014

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– DO NOT CITE OR QUOTE 7 - 12 Growth was reduced in male weanling Sprague - Dawley rats (10/grou

p) ingesting 1.6% strontium in their diets in an unspecified form (1,520 mg Sr/kg - day , based on estimated average body weight and the allometric food intake equation of U.S. EPA, 1988) for 26 day s (Svensson et al., 1985, 1987). The authors noted that epip hy seal growth plates had abnormally thick hy pertrophic zones and impaired calcification and resorption at the metaphy seal side, and cartilage contained 75% less calcium and had a 60% lower rate of s ynthesis of gl ycosaminogl yc ans and collagen, all signs of strontium rickets. Serum concentrations of calcium, phosphorus and parath yroid hormone were reported to be normal, but the method used to measure the parath yroid hormone could not distinguish between the active and inactive form of the hormone. A stereol ogical anal ys is found no changes in volumes of parathy roid tissue components relative to body weight. The study

authors concluded that the mechanism of strontium rickets did not involve the parath yroid gland. Similar effects of reduced growth and thicken ed epiphy seal growth plate were seen in weanling (21 - day - old) male England Wright Y rats (5/group) ingesting 1,850 mg Sr/kg - day (form unspecified) for 20 day s in a diet sufficient in calcium (1.2%), phosphorus (1%) and vitamin D (1500 IU/kg) (Reinholt et a l., 1984). Other effects at this dose included larger zones in the epiphy seal regions of long bones (as well as smaller proportional volumes of the resting, proliferative and calcifying zones, and a larger volume of the hy pertrophic zone) and an increase in the volume of extracellular matrix in bone, possibly associated with a reduced rate of extracellular matrix vesicle degradation. The epiphy seal cartilage of these rats had alterations in proteogl yc an composition, which the authors (Reinholt et al., 1985) suggested might affect the process of mineralization. Bone h ypomineralization and increased bone mass, compared to controls giv en the same low - calcium diet, were reported in weanling male Sprague - Dawley rats ingesting 0.4% of strontium chloride while on a low calcium diet (Grynpas and Marie, 1990) for 4 or 8 weeks. This suggests an osteomalacia t ype of effect during bone remodeli ng, where bone growth was not halted, but softer bones were formed. Rats were divided into groups (5/group/exposure duration) receiving 0, 0.19, or 0.40% of strontium chloride in distilled water for 4 or 8 weeks. These concentrations correspond to doses of 0, 222, and 466 mg Sr/kg - day during the 4 - week study , and 0, 146, and 307 mg Sr/kg - day during the 8 - week study , assuming ingestion of 0.211 L/kg - day by a weanling Sprague - Dawley rat and 0.139 L/kg - day

by a Sprague - Dawley

rat during a subchronic stud y (U .S. EPA, 1988) and based on the average reported body weights for the two durations. The diet contained 0.5% calcium, 0.54% phosphorus, 0.16% magnesium, and 2,000 IU/kg vitamin D. No effect was seen at the low dose of 0.19% strontium chloride in water fo r either study

duration. Reduced growth and bone mineralization, compared both to controls given 0.67% in the diet and to controls fed the same low - calcium (0.04% calcium) diet were observed in 4 - week - old male Wistar rats (50 - 60 g, 30/group) given low - c alcium (0.04% calcium) diets providing 1970 mg Sr/kg - day

in the form of strontium carbonate for 4 weeks (Matsumoto, 1976). Tibia length was decreased b y 33% and epiphyseal plate width was increased b y 5 - fold. Rats treated with strontium also had no detec table mineralization in the tibial proximal heads. Thus, rats exposed to strontium, when compared to rats on an identical low - calcium diet, developed effectsEPA - OST Preliminary Health Effe cts Support Document for Strontium April 2014

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– DO NOT CITE OR QUOTE 7 - 13 consistent with osteomalacia and strontium rickets. In a study by Kshirsagar (1976), decreased body weight gain compared to controls was observed in male weanling (21 - day - old, 5 - 6 per group) Wistar rats fed for 2 weeks with diets containing 2% strontium as strontium phosphate, 5000 IU vitamin D per kg diet, 0.4% calcium and 0.4% phosphate (correspon ding to a dose of about 3,000 mg Sr/kg - day, based on the reported bod y weight and the allometric equation of U.S. EPA, 1988) (Kshirsagar, 1976). The study also reported decreased acid phosphatase in the small intestine and liver; alkaline phosphatase was decreased in the small intestine, increased in the bone and unchanged in the liver. The changes in enzy me levels were reversed after two weeks on the control diet, which contained 0.001% strontium (corresponding to about 1.5 mg Sr/kg - day). The author sug gested that strontium may

have stimulated osteoblasts, which secrete osteoid and have a high alkaline phosphatase activity . As mentioned in Section 7.1, osteomalacia and rickets are biochemically identified by

an increase in serum levels of alkaline phosp hatase and are often associated with a deficient suppl y or uptake of mineral. Administration of strontium carbonate in diet to young (50 - 70 g) rats of both sexes (strain not specified, 12 - 50 per group) at a dose of 2160 mg Sr/kg - day for up to 7 months resulted in the rats developing an altered gait characteristic of rickets (Storey , 1962). A few y oung rats that were more severel y affected died following 3 weeks of exposure. Histological abnormalities in long bone differentiation included reduced calci fication, excess growth of epiphy seal cartilage, abnormal deposition of osteoid in the metaphy sis, fragmentation of the epiphy seal plates and isolated nodules of cartilage. The diet also contained 1.5% calcium and 0.9% phosphorus. No effects on exploratory motor activity

were seen in rats that ingested 2,000 mg Sr/L (corresponding to 1,105 mg Sr/kg - day) in drinking water as strontium chloride for 15 day s (Escanero et al., 1985). Other effects were apparently not evaluated. Only one subacute study

that evaluated the effects of strontium in mice was identified (Marie and Hott, 1986). As in rats, it showed that strontium had effects on bone. Exposure to 0.27% strontium chloride in drinking water (350 mg Sr/kg - day , or 640 mg strontium chloride/kg day , ba sed on actual water consumption and estimated average bod y weight) for 29 day s caused minor bone effects in 21 - day - old male C57BL/6J mice (11 - 13/group), including a 10% increase in osteoid surface (percentage of the endosteal surface covered b y an osteoid seam) and an 11% reduction in the number of active osteoclasts. These minor effects are suggestive of early stage rickets and less bone resorption compared to control (due to less osteoclasts available to digest the bone matrix). The authors also suggest ed that some bone resorbing surfaces may have been converted to bone forming surfaces. Onl y one dose was tested and compared with an unexposed control group. The diet also contained 0.5% calcium, 0.74% phosphorus, and 2,000 IU vitamin D/kg. There were n o effects on tibial length, bone mineral content (percent ash, calcium or phosphorus), the osteoblastic surface of the vertebrae (percentage of the endosteal surface showing plump osteoblasts), bone matrix apposition rate, osteoid seam thickness (average w idth of all endosteal osteoid seams) or calcified bone volume. **Inhalation Exposure**EPA - OST Preliminary Health Effe cts Support Document for Strontium April 2014

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– DO NOT CITE OR QUOTE 7 - 14 One study

involving repeated inhalation of a strontium salt was identified. A study from the former Soviet Union (Zy uz yukin, 1974) reported that rats were exposed to str ontium nitrate at 45 mg/m 3 for 4 hours/day for 1 month (83% of particles <5 μm). Reported toxic effects were functional changes in the liver and kidney plus histological changes in the lungs, heart, liver, kidney s and spleen. The authors apparently did n ot conduct histopathological evaluation of the bone. **7.3.3 Subchronic Studies**  **Oral Exposure** Kroes et al. (1977) exposed weanling Wistar rats (10/sex/dose) to strontium chloride hexahy drate at dietary

concentrations of 0, 75, 300, 1,200, or 4,800 ppm for 90 day s. Based on reference bod y weights for males and females, and the U.S. EPA (1988) allometric equation for food intake, these concentrations correspond to estimated doses of 0, 2, 9, 36, and 146 mg Sr/kg day for males and 0, 3, 10, 42, or 166 mg Sr/kg - d ay for females; the corresponding estimated doses of strontium chloride hexahy drate are 0, 7, 27, 109, and 443 mg/kg - day for males and 0, 8, 31, 127, and 505 mg/kg - day for females 8 . The authors described the semi - purified diet as containing “adequate” lev els of calcium (0.85%), magnesium (0.05%), phosphorus (0.75%), and vitamin D3 (1,800 IU/kg); however the levels of calcium provided were relatively high (ATSDR, 2004) as compared with other strontium studies, which may have reduced the effects of strontium exposure. There was no effect on behavior, appearance, growth, food intake, survival, hematology , serum chemistry , blood calcium or phosphorus, liver gly cogen, urinal ys is, weights of the major organs or histopathology

of a wide range of tissues (includ ing bone) at doses up to 300 ppm (9 - 10 mg Sr/kg - day). At 1,200 ppm (36 - 42 mg Sr/kg - day), relative thy roid weight was statistically significantl y increased in males, but the effect was not clearl y dose - related. At 4,800 ppm (146 - 166 mg Sr/kg - day) relative thy roid weight was increased (although not by as much as at the lower dose) and there were histological signs of “moderate th yroid activation.” No further histological details were provided, and no supporting information was provided on thy roid hormone l evels and or effects on the parath yroid. It is difficult to evaluate the implications of the observed changes in the absence of additional information. The thy roid takes up iodide anions; a cation such as strontium would not be expected to have a direct effect on the thy roid. The study authors reported that the diet provided adequate iodine, but did not provide additional details. Strontium stimulation of the extracellular calcium - sensing receptor (CaSR) found in thy roid C - cells has been studied by Cou lombe et al. (2004). CaSR activity modulates the secretions of calciotropic hormones in the thy roid, parathy

roid, and kidney . It is possible that increased C - Cell activity

could be associated with the thy roid changes observed b y Kroes et al. (1977) but n o data were provided that would support this hy pothesis. The Kroes et al. (1977) 8 Strontium chloride hexahydrate doses calculated based on unrounded strontium doses. WHO (2010) presented the doses for males and females as 0, 2.5, 10, 40, and 160 mg Sr/kg - day , based on average body weight and ingestion of 10% of their body w eight per day.EPA - OST Preliminary Health Effe cts Support Document for Strontium April 2014

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– DO NOT CITE OR QUOTE 7 - 15 study provided minimal detail regarding the histological features that were suggestive of thy roid activation. Thus, it is difficult to determine whether the observed the th y roid changes should be classified as adverse or adaptive. Other statistically

significant effects at the high dose included decreased relative pituitary weights in females (without microscopic changes), and decreased liver gl yc ogen levels in females; th ere was also a nonsignificant decrease in liver gl yco gen in males. Although strontium levels of bone were increased, there was no evidence of histological changes in the bone. Based on undefined histological signs of th yroid activation and increased relative thy roid weight, the LOAEL for the Kroes et al. (1977) study was 146 mg Sr/kg - day ; the corresponding NOAEL was 36 mg Sr/kg - day . The South Korean National Institute of Environmental Research (NIER, 2006c) reported on a study

of rats (strain not availab le) administered strontium sulfate by gavage for 40 - 54 day s. There was no effect on survival, growth, sensory and motor functions, urinaly sis, or the microscopic appearance of the tissues and organs evaluated (including bone) at doses up to 950 mg Sr/kg - d ay . Decreased spleen weights were seen in female rats at doses of 500 mg/kg - day strontium sulfate (about 240 mg Sr/kg - day) and higher, and males had increased epididy mis and testis weights at 480 mg/kg - day strontium sulfate (corresponding to 229 mg Sr/kg - day). Decreased reticulocy

te counts and decreased activity of aspartate aminotransferase (AST) were also seen in females at 980 mg/kg - day strontium sulfate (corresponding to 467 Sr /kg - day). Marie et al. (1985) administered strontium to weanling male S prague - Dawley rats. The purpose of this study

was to determine the effect of low doses of strontium on mineral homeostasis and bone histology . Rats (8/group) received 0, 0.19, 0.27, 0.34, or 0.40% strontium chloride in distilled water for 9 weeks. The d iet contained 0.5% calcium, 0.54% phosphorus, 0.16% magnesium and 2,000 IU/kg vitamin D. Based on body weight and water consumption data, the authors estimated average strontium intakes of 0, 316, 425, 525, and 633 mg Sr/kg - day . A dose - related, statist ically significant decrease in the bone calcification rate was reported at doses of 525 mg Sr/kg - day and higher, with no significant change at the next lower dose of 425 mg Sr/kg - day . Rats in the 0.40% (633 mg Sr/kg - day) dose group showed signs of increas ed mineralization lag time; excessive osteoid thickness associated with a decline in the rate of calcification, which resulted in slow growth rate; and a decreased double - labeled osteoid surface, which frequentl y resulted in defective long bone growth. Th ese effects are consistent with the development of osteomalacia, which is disruption of incorporation of minerals into the bone matrix. This leads to accumulation of unmineralized bone matrix as osteoid continues to be secreted b y osteoblasts, causing dev elopment of soft bone. The osteoid volume and percent osteoid surface in relation to bone tissue or endosteal surface increased with dose. These effects likely reflect the continued secretion of osteoid without the mineralization necessary to increase bo ne tissue/endosteal surface. Appendix A, Table A - 2 shows primary data from Marie et al. (1985). The stud y authors identified a NOAEL of 525 mg Sr/kg - day and a LOAEL of 633 mg Sr/kg - day based upon body

growth and bone mineralization. However, based upon the observation of decreased calcification, a LOAEL of 525 mg Sr/kg - day and a NOAEL of 424 mg Sr/kg - day has been identified for this assessment.EPA - OST Preliminary Health Effe cts Support Document for Strontium April 2014

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– DO NOT CITE OR QUOTE 7 - 16 Gry npas and Marie (1990) reported bone h ypomineralization and increased bone mass in weanling male Sprague - Dawley rats administered 0.4% strontium chloride in distilled water while on a low calcium (0.5%) diet for 8 weeks. This suggests an osteomalacia t ype of effect during bone remodeling, where bone growth was not halted, but softer bones were formed. The ful l study description can be found in Section 7.3.2. A limited drinking water study was described b y S kory

na (1981) and Skoryna and Fuskova (1981), in which adult male RVH hooded rats (10/group) were given strontium chloride in drinking water at 0% 9 , 0.09% , 0.19%, or 0.34% for 3 months. These concentrations correspond to doses of 0, 70, 147, and 263 mg Sr/kg - day , assuming water consumption of 0.14 L/kg - day for an adult rat. Microscopic examination showed that the tissues (bone, heart, liver, muscle, lung, brain, adrenal and kidney) were unaffected by treatment. Adequate amounts of calcium (35 mg/L) and magnesium (6.8 mg/L) were given in the drinking water. Johnson et al. (1968) reported respiratory difficulties, hindlimb paraly sis, rickets, osteomalacia and deaths in weanling Sprague - Dawley rats (15/group) administered 0.45% strontium in feed (form not specified) for 43 day s (corresponding to 565 mg Sr/kg - day , based on average bod y weight of 0.092 kg and allometric food intake equation). While the paral ys is could have been related to abnormal calcium signaling, it was not known whether the paral ys is had a neurological or muscular etiology . The paper’s authors noted that it was unlikely that the paral ys is was due to femoral deformation, since even severe ly rachitic and osteomalacic rodents are not usuall y paral yz ed. ATSDR (2004) suggested that the effects may have been due to compression of the h ypertrophic epiphyseal cartilage, which was insufficiently mineralized to support the weight of the body . A s tudy limitation is that only

one dose level was tested. Comparable effects were not observed at similar doses in rats of the same strain and sex in other studies (e.g. Marie et al., 1985) with longer exposure durations. In contrast with the results of Johnson et al. (1968), Kshirsagar (1976) did not find treatment - related effects in weanling male Wistar rats (5 - 6 per group) exposed under similar conditions and at the same exposure level, but did report effects at higher doses. The Kshirsagar (1976) stu dy

treated with the rats for 4 - 6 weeks with 0, 0.5, 1, or 2% strontium in the diet as strontium phosphate (approximately 0, 580, 1270, or 2820 mg Sr/kg - day , based on a reference body weight for Wistar rats of 0.046 kg and allometricall y scaled dietary intake). There were no treatment - related effects at the lowest dose, which was similar to the Johnson et al. (1968) LOAEL. Kshirsagar (1976) did report slowed growth and altered alkaline phosphatase activity starting at 1270 mg Sr/kg - day . Hemorrhage, paraly sis, abnormally thick epiphy seal cartilage plates in the long bones and 30% mortality were reported at 2820 mg Sr/kg - day . In addition to the information presented in Storey (1961), the greater sensitivity of young animals was also demonstrated b y Storey ( 1962). Both y oung (50 - 70 g) and adult (200 - 250 g) rats of both sexes (strain not specified) were provided a diet containing 1.8% strontium as strontium carbonate. The exposure continued for up to 7 months with several interim sacrifices.

9 The control group actually had 0.02 mg Sr/dL, corresponding to a negligible dose of 0.015 mg Sr/kg - day .EPA - OST Preliminary Health Effe cts Support Document for Strontium April 2014

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– DO NOT CITE OR QUOTE 7 - 17 After onl y 3 we eks of exposure, the young rats exhibited a "rachitic gait" with the most obvious changes occurring in the distal end of the femur and the proximal end of the tibia. The epiphy seal plate was reported to be “grossl y widened” and the metaph ys is was “a mass of soft white tissue.” Conversely , it was 3 months before change was observed in the adult rats, in the form of fine traverse lines in the upper tibial metaphy sis. The tooth enamel of the adults was abnormally

white and pitted. The author noted that the abnormal deposition of osteoid in long bones and the skull was less extensive in adults than in the y oung rats, and that the epiphy seal plates were fragmented in the y oung rats, but not the adults. Because young rats consume more food per kg body weigh t that adults, it is difficult to determine how much of the difference in effects is due to a higher dose in the y oung rats, and how much (if an y) is due to greater sensitivity in the y oung rats. ATSDR (2004) calculated that the average intake was 2160 mg Sr/kg - day in the y oung rats and 1570 mg Sr/kg - day in the adult rats, based on bod y weights estimated from the study and reference bod y weights (average of 0.152 kg for the young rats and 0.304 kg for the adult rats) and an allometric equation for food int ake. In contrast to the adverse effects on bone at higher doses, low doses of strontium in the presence of adequate calcium have beneficial effects on bone mineralization. Gry npas et al. (1996) found that exposure of 28 - day - old male Sprague - Dawley rats (8/group) to 0.2% strontium (form unspecified, reported by the authors to correspond to 168 mg Sr/kg - day) in drinking water containing 0.15% calcium for 8 weeks resulted in a 17% increase in mineral bone volume and a 70% increase in the number of bone - for ming sites and no adverse effect on the hy droxy apatite mineral particle size. The rats’ diets contained 0.5% calcium, 0.54% phosphorus, 0.16% magnesium and 2,000 IU/kg vitamin D. There were also no effects on mineral apposition rate, osteoid thickness, i ndicating no deleterious effect. No studies investigating beneficial effects of strontium on young animals were located. **Inhalation Exposure** No subchronic studies regarding the toxicity of strontium following inhalation exposure were identified. **7.3.4 Neurotoxicity**  No studies designed to evaluate neurotoxic effects of strontium were located. As noted in Section 7.3.3, Johnson et al. (1968) reported hindlimb paraly sis in weanling Sprague - Dawley rats (15/group) administered 0.45% strontium in feed (form not specified) for 43 day s (dose estimated as 565 mg Sr/kg - day).EPA - OST Preliminary Health Effe cts Support Document for Strontium April 2014

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– DO NOT CITE OR QUOTE 7 - 18 **7.3.5 Developmental/Reproductive Toxicity**  **Reproductive Effects** The only available studies investigating reproductive effects of strontium were conducted in rats. No standard one - or two - gener ation reproductive toxicity studies exist for any

strontium compound, but the available data indicate that strontium does not cause structural or functional reproductive effects at doses well above those causing bone effects. In a screening test for repro ductive and developmental toxicity , NIER (2006c) found no effects on mating behavior, fertility , gestation period or histopathology of the reproductive tissues and organs. In this study , rats (16/sex/dose; strain not available) were given strontium sulfat e by gavage at up to 2000 mg/kg - day

(corresponding to doses up to 950 mg Sr/kg - day), from 2 weeks before mating until day 4 of lactation. The total dosing period was 42 day s for males and 40 - 54 day s for females. There was no effect on the weights or his topathology of reproductive organs (testes, ovaries, uterus or prostate) in weanling Wistar rats (10/sex/dose) exposed to strontium chloride hexahy drate in the diet at doses up to 4800 ppm in the Kroes et al. (1977) study of s ys temic toxicity . As document ed above in Section 7.3.3, this corresponds to a dose of about 146 - 166 mg Sr/kg - day . The review article b y Skory na (1981) mentions a study in RVH hooded rats that were given strontium supplements of 0, 0.09%, 0.19% or 0.34% in drinking water during a 3 - g eneration breeding period without adverse effects. However, no information was provided on the parameters evaluated, dietary concentrations of calcium or phosphorus, and the basis for the author’s conclusion. The highest concentration is equivalent to a dose of about 260 mg Sr/kg day (U.S. EPA, 1992). **Developmental Effects** The database on the potential developmental toxicity of strontium is limited, with studies focusing primaril y on bone effects. Some limited studies ( Shibata and Yamashita, 2001; NI ER, 2006c) evaluated other developmental endpoints. Overall, there was no indication of fetotoxicity or developmental effects on targets other than bone. Several studies conducted of in utero or postnatal effects on bone development found inhibition of calcification, but it is difficult to evaluate the relative susceptibility of developing fetuses and y oung animals to the bone effects of strontium, because most of the studies cited tested only a single, high - dose exposure level. There were no adverse effects on fetal development (implantations, litter size, live births, viability , sex ratio, body

weight and length, overt malformations on external examination) in the NI ER (2006c) screening te sts. However, there was no microscopic examination for skeletal or visceral alterations. Rats (16/sex/dose; strain not available) were given strontium sulfate by gavage at doses of 500 to 2000 mg/kg - day (corresponding to doses of 240 to 950 mg Sr/kg - day) , from 2 weeks before mating until day 4 of lactation. The total dosing period was 42 day s for males and 40 - 54 day s for females.EPA - OST Preliminary Health Effe cts Support Document for Strontium April 2014

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– DO NOT CITE OR QUOTE 7 - 19 Other studies evaluated the effects of strontium on postnatal bone formation, particularl y endochondral ossification (bone f ormation from centers in the cartilage). As discussed further in Section 7.5.1, bone growth in rats continues throughout life. S tudies on weanlings were discussed in Sections 7.3.2 and 7.3.3., and found that weanlings exhibited more severe skeletal effec ts than adults exposed at the same level in diet or drinking water (Storey , 1961, 1962; Gry npas and Marie, 1990). Several developmental toxicity studies focused on potential bone effects of perinatal strontium exposure. In a limited study conducted with a very

small sample size (4 pregnant dams/dose; strain not available), mice were exposed throughout pregnancy to diets containing 0 or 2% strontium carbonate (corresponding to doses of 0 or about 1500 mg Sr/kg - day), and bone and cartilage development wer e assessed in the newborn pups (Shibata and Yamashita, 2001). There was no effect on maintenance of pregnancy , fetal numbers or fetal viability . However, extensive inhibition of calcification of mandibular bone and cartilage was observed. Ultrastructura l changes in the osteoclasts (on the mandibular alveolar bone) and chondroclasts (in the resorption area of the condylar cartilage) were also present . Increased phagocy tic activity in osteoclasts and chondroclasts was indicative of functional changes in these cells. In another study of female rats (strain and number/group not available) exposed to 2,000 ppm strontium carbonate in diet throughout pregnancy (equivalent to 1187 mg Sr/kg - day), the only reported effects were on fetal bone (Miki and Miy amoto, 1 968). Observed effects included vertebral ky phosis (convex curvature of the spine), reduced vertebral calcification and an irregular arrangement and appearance of the chondrocy tes. These studies are insufficient to identify an threshold effect level for bone effects of perinatal strontium exposure. **7.3.6 Chronic Toxicity**  **Oral Exposure** The reports b y Skor yn a (1981) and Skory na and Fuskova (1981) discuss a study in which small numbers of animals were exposed for longer than the standard duration (increasing the potential for age - related lesions and decreasing study sensitivity); the reports provide inadequate documentation of the methods and results. Based on the available information, male RVH hooded rats (12/dose 10 ) were given strontium chloride in their dri nking water at a concentration of 0, 11 900, 1900, or 3400 mg/L for 3 ye ars. Assuming that an adult rat consumes 0.14 L/kg - day , these concentrations correspond to strontium doses of 0, 70, 147, and 263 mg Sr/kg - day as estimated by

U.S. EPA (1992). The rats received adequate amounts of calcium (35 ppm) and magnesium (6.8 ppm) in the drinking water. No adverse effects on bod y weight or on the microscopic appearance of the bone, kidney , lung, adrenal, brain, heart or muscle were reported. Organ weights were not determined and there was no mention of tumors. Based on the absence of effects, this study

identified the high dose of 263 mg Sr/kg - day as the study

NOAEL.

10 The secondary sources are not clear on the number treated, and the reporting in Skoryna (1981) is vague, although it appears that differe nt numbers of animals were evaluated for different endpoints. Some endpoints apparently evaluated only a subset of the total exposed animals. The reported number of animals/dose is from WHO (2010). 11 The control group actually had 0.02 mg Sr/dL, correspon ding to a negligible dose of 0.015 mg Sr/kg - day .EPA - OST Preliminary Health Effe cts Support Document for Strontium April 2014

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– DO NOT CITE OR QUOTE 7 - 20 **7.3.7 Carcinogenicity**  No studies designed to evaluate the carcinogenicity of strontium compounds b y an y route were located. As noted in Section 7.3.6, the 3 - ye ar study reported b y Skor yna (1981) and Skory na and Fuskova (1981) did not mention tumors. **7.4 Other Key Data**  **7.4.1 Mutagenicity and Genotoxicity**  The only form of strontium that is consistently genotoxic is strontium chromate. The observed effects are attributed to the chromate ion rather than the strontium and are not included in this assessment. Other strontium compounds were negative in tests f or gene mutation in bacterial cells (Kanematsu et al., 1980; Yang, 1984; NI ER, 2006e) and chromosome aberrations in mammalian cells (Tateno and Kamiguchi, 1997; NIER, 2006d) (Table 7 - 1), although not all of the tests were conducted using standard test sy st ems. No studies of gene mutation of strontium compounds in mammalian cells were identified. Strontium compounds were also negative for cell transformation in vitro (Heidelberger et al., 1983) and DNA damage in vitro (L oeb et al., 1977; Casto and DiPaolo, 1983). Thus, overall the data are negative for strontium genotoxicity in vitro . **Table 7**  **- 1**  **Genotoxicity of Strontium In V**  **itro Species**  **(test system) End**  **- point**  **With activation**  **Without**

**activation Reference**  Bacillus subtilis Rec - (strontium chloride) Gene mutation - - Kanematsu et al. (1980) Ames test (strontium carbonate) Salmonella typhimurium strains TA98, TA100, TA1535, TA1537 or TA1538 Gene mutation - - Yang (1984) Ames test (strontium sulfate) Salmonella typhimurium strains TA98, TA100, TA1535 or TA1537 or in Escherichia coli strain WP2 uvr

A Gene mutation - - NI ER (2006e) Chinese hamster oocy

tes (strontium chloride) Chromosomal aberrations, changes in chromosome number N/A b

- Tateno and Kamiguchi (1997)EPA - OST Preliminary Health Effe cts Support Document for Strontium April 2014

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– DO NOT CITE OR QUOTE 7 - 21 **Species (test system)**  **End -**  **point With**  **activation Without** 

**activation Reference**  Chinese hamster lung cells (strontium sulfate) Chromosomal aberrations or poly ploidy - - NI ER (2006d) Sy rian hamster embry o cells (strontium chloride) Cell transformation (?) a - Heidelberger et al. (1983) Sy rian hamster embry o cells (strontium chloride) DNA strand breaks (?) a - Casto and DiPaolo (1983) DNA s ynthesis reaction (strontium chloride) Lack of fidelity in DNA s ynthesis - - Loeb et al. (1977) a Only one set of results was reported. It is unclear whether the chemical was tested both +/ - S9, and if so, whether the results in the presence of S9 w ere the same as in the absence. bN/A - not available Only a single in vivo genotoxicity study is available (Table 7 - 2). In this study , Swiss albino mice were treated with strontium chloride (apparentl y as a single dose) at 240 - 2,400 mg/kg (females) or 260 - 2,600 mg/kg (males) (Ghosh et al., 1990). The corresponding strontium doses were 130 - 1326 mg Sr /kg for females and 140 - 1437 mg Sr/kg for males. There was a dose - related increase in chromosome aberrations in bone marrow cells at 6, 12, and 24 hours “of treatment” (apparently

time after dosing). The response in females was higher than that in males at the lowest dose. However, it is difficult to fully interpret the reported values, due to inconsistencies in the reporting of the number of animals/dose per time point. In addition, no information was provided on the nature of the aberrations, and it appears that poly ploidy was in cluded together with structural aberrations. If five animals per dose per time point were used, then the reported results are consistent with possible genotoxicity , but the reporting limitations raise questions about the overall study quality . It is not clear wh y the results of this study apparentl y differed from those of the in vitro chromosome aberration studies. **Table 7**  **- 2**  **Genotoxicity of Strontium In V**  **ivo Species**  **(test system) End**  **- point**  **Results Reference**  Strontium chloride: Mouse (bone marrow) Chromosomal aberrations poly ploidy + Ghosh et al. (1990) **7.4.2 Immunotoxicity**  No studies designed to evaluate the immunotoxicity of strontium compounds by an y route were located. **7.4.3 Physiological or Mechanistic Studies**  **7.4.3.1 Noncancer Effects** EPA - OST Preliminary Health Effe cts Support Document for Strontium April 2014

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– DO NOT CITE OR QUOTE 7 - 22 There has been considerable interest in potential phy siological effects of strontium due to its potential impact on calcium uptake, transport and function. Strontium treatment has been shown to increase the formation of bone nodules i n vitro , while increased osteoblast number, bone volume and trabecular thickness have been reported in vivo (Ly mperi et al., 2008). As reviewed b y Dahl et al. (2001), strontium at doses of 316 to 634 mg Sr/kg - day , administered as strontium chloride or str ontium ranelate for 9 - 26 weeks, increases bone formation in adult rodents and humans b y i ncreasing the number of osteoblasts (increasing bone formation) and decreasing the activity

of osteoclasts (decreasing bone resorption). This results in increased bon e volume. Because the increased bone formation results in increased mechanical resistance, strontium, generally

as the ranelate salt, has been evaluated as a treatment for osteoporosis. Strontium may

exert its effects on osteoblasts and osteoclasts in part via the extracellular calcium sensing receptor (CaSR) (Marie, 2010). The CaSR is a member of the G - protein coupled receptor family , and is found in bone cells, thy roid (C - cells), kidney , brain, and the parath yroid (Coulombe et al., 2004). The CaSR is a low affinit y receptor that requires mMol concentrations of the agonist, 3 mM for calcium, for activation. Strontium binds to the CaSR as a full agonist, but with lower affinity than calcium. Numerous divalent or trivalent cations can activate the Ca SR, with the following order of potency : La 3 > Gd 3 > Be2 > Ca2 > Ba2 > Sr2 > Mg2. CaSR activation stimulates the activity of phospholipase C and A 2 , mitogen

– activated protein kinase (MAPK), and phosphoinositide kinase 3, inducing the production of a serie s of second messengers that modulate calcium homeostasis through the calciotropic hormones from thy roid C - cells and the parathy roid (Coulombe et al., 2004). The activation of CaSR in thy roid C cells increases calcitonin sy nthesis, storage and secretion, w hich can then lead to reduction in serum calcium (Henley

et al., 2011). In vitro studies of the CaSR in transfected Chinese hamster ovary (CHO) cells demonstrated receptor activation by strontium ranelate but not ranelic acid (Coulombe et al., 2004). Strontium activated apoptosis in cultured osteoclasts through activation of CaSR, suggesting a mechanism for the decrease in bone resorptions in the presence of strontium. Conversel y, strontium ranelate increased osteoblastic cell replication through the ac tivation of CaSR - mediated ERK1/2 signaling. Furthermore, the addition of strontium to parath yroid cells (which regulate bone formation and resorption) results in increased levels of intracellular calcium, presumabl y due to interaction with parathy roid cal cium receptors (Shoback et al., 1995). Marie (2010) noted, however, that it has not y et been determined whether CaSR mediates the response to strontium in bone cells in vivo . The in vitro studies referenced above use strontium concentrations in excess of 4 to 5 mM. Normal serum or blood levels of strontium are in the range of 10 - 50 μg Sr/L, or 0.1 - 0.6 μM (depending on the blood fraction evaluated (Oleh y et al., 1966; Skoryna, 1981). Higher levels, in the range of 7 μM have been reported in dial ys is pat ients receiving contaminated dial ys ate, and up to 0.1 mM in people treated with strontium ranelate. Therefore the highest identified serum strontium concentration in humans is 40 to 50 fold lower than those used in vitro that were associated with calcimim etic effects. In addition, considering that Sr has a lower affinity for the CaSR receptor than five other elements including calcium, it seems unlikely that a calcimimetic effect would occur in humans.EPA - OST Preliminary Health Effe cts Support Document for Strontium April 2014

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– DO NOT CITE OR QUOTE 7 - 23 Calcium also acts as a second messenger for signal transduction pathway s and play s a critical role in regulating neurotransmitter release and in muscle contraction. For example, the Ras/MAPK signaling pathway was altered in mesench ym al stem cells exposed to strontium (Peng et al., 2009) and strontium can p artiall y substitute for calcium in regulating the signaling and insulin release from pancreatic beta cells (Hellman et al., 1997). Thus, there has been some research on potential effects of strontium on the nervous and neuromuscular sy stems. Strontium wa s observed to alter evoked neurotransmitter release in chick ganglions (Yawo, 1999), alter neurotransmission in rat hippocampal cells (Morishita and Alger, 1997), and alter the function of voltage - gated calcium channels (Wakamori et al., 1998). Most of th ese studies were mechanistic studies that were conducted in vitro , often at a single concentration, with no correlation to in vivo concentrations of strontium. Therefore, these studies can contribute to the overall weight of evidence for hazard identification, suggesting potential targets of strontium toxicity , but their biological and risk assessment significance is unclear in the absence of in vivo studies at multiple doses. The biological significance of these studies is unclear in the absence of repor ted clinical signs of neurotoxicity

at high strontium doses in repeated dosing animal studies and the absence of neurotoxicity

studies evaluating sensitive endpoints and lifestages. **7.4.3.2 Cancer Effects**  No studies evaluating the carcinogenic potential of str ontium compounds by any route are available. Genotoxicity

studies of strontium salts, other than chromate salts, were negative with the exception of a single chromosome aberration study that gave positive results. **7.4.3.3 Interactions with Other Chemicals**  Few studies have been conducted on the interaction of strontium with other chemicals. As noted in Sections 7.4.3 and 7.5.1, strontium can act as a mimic of calcium, but calcium is preferentiall y absorbed and preferentiall y binds to relevant targets. As n oted in Section 6.1.1, phosphate decreases strontium absorption. Two subacute studies in chicks administered strontium as part of their diet indicate that strontium inhibits vitamin D - induced calcium binding proteins, intestinal calcium absorption and int erferes with the metabolism of vitamin D to its functional metabolite (i.e., 1,25 - dihy drox yc holecalciferol), leading to strontium “rickets” (Corradino and Wasserman, 1970; Omdahl and DeLuca, 1972). No similar studies performed in mammals were identified that specificall y evaluated vitamin D as it relates to strontium; thus it is unknown whether similar inhibition of vitamin D functionality following strontium exposure occurs in mammalian species. Other interaction studies have found a benefit of strontium in inhibiting effects of some other chemical exposures. The application of 20% strontium nitrate upon the volar forearm (inside, or palm - side, forearm) for 35 minutes suppressed sensory irritatio n in response to a challenge with histamine or when mixed with 70% gl ycolic acid (Zhai et al., 2000a,b). This suggests that dermal exposure to strontium may decrease the irritant effects of other chemicals.EPA - OST Preliminary Health Effe cts Support Document for Strontium April 2014

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– DO NOT CITE OR QUOTE 7 - 24 **7.4.4 Structure**  **- Activity Relationship**  As noted, strontium is structurally - related to calcium because the two ions have the same ionic charge (2+) and ionic radii that are not substantially different (Ca 114 pm vs. 132 pm for Sr; Weast and Astle, 1981). Accordingl y strontium can partiall y substitute for c alcium in some phy siological processes. When it displaces calcium during bone formation alterations to bone histology and structure can result. The implications of these substitutions were discussed in the Sections 7.3 and 7.4.3. **7.5 Hazard Characterization**  **7.5.1 Synthesis and Evaluation of Major Noncancer Effects**  The primary

target of strontium exposure is the bone. The chemical similarity of strontium to calcium allows it to exchange imperfectly for calcium in a variety

of biological processes; the most imp ortant of these is the substitution of calcium in the bone, affecting skeletal development. Those with low or deficient calcium intake are more likely to have increased strontium uptake and bone effects following ingestion. Sufficiently high doses of str ontium can lead to the development of rickets in y oung animals and possibly in children (Özgür et al., 1996), but insufficient information is available to determine the doses associated with this effect. Animal studies show that strontium can decrease the calcification of the cartilaginous portion of bone at doses to weanlings of 525 mg Sr/kg - day and above, and can increase bone formation at 633 mg Sr/kg - day and above (Marie et al., 1985). The decreased calcification results in increased width of the epip hy seal cartilage in growing rats, changes in the pattern of calcification, and abnormally long metaphy ses, effects that were reported by Neufeld and Boskey

(1994) in “young” rats at 500 mg Sr/kg - day . Due to this effect on growing bones, infants, children and teenagers are of particular concern as potentially susceptible populations. There are three studies in which mortality is reported following subacute or subchronic strontium exposure (Storey , 1962; Johnson et al, 1968; Kshirsagar, 1976). The mortal ity (and other adverse effects) observed in the Johnson et al. (1968) study following exposure to 565 mg Sr/kg - day is surprising as comparable effects were not observed at similar doses in rats of the same strain and sex in other studies (e.g. Marie et al. , 1985) with longer exposure durations. For the other two studies, mortality is reported following 2150 mg Sr/kg - day for 3 weeks (Storey , 1962) or 2820 mg Sr/kg - day for 4 to 6 weeks; these exposures are 4 - 5 times the L OAEL from Marie et al. (1985) and near the beginning of the lethal dose range. The oral median L D 50 s for strontium are between 2.35 and 3.1g Sr/kg in rodents (Woodard and Calvery , 1941; Ghosh et al., 1990; L lobet et al., 1991). Thus, there is a potentially steep slope from the LOAEL to frank effects. The effects of strontium at low doses (400 - 500 mg Sr/kg - day) include small changes in bone structure and inhibition of calcification (Storey , 1961; Marie and Hott, 1986), consistent with earl y development of osteomalacia and/or strontium “rickets .” Decreased levels of osteoclasts and associated decreases in bone resorption may also occur at low doses (Marie and Hott, 1986). Higher doses (over about 1500 mg Sr/kg - day in rats) result in more severe boneEPA - OST Preliminary Health Effe cts Support Document for Strontium April 2014

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– DO NOT CITE OR QUOTE 7 - 25 effects including reduced growth, large area s of unmineralized bone, and bone softening (rickets in y oung animals and possibly children, and osteomalacia in adults), excess growth of epiphy seal cartilage and abnormal deposition of osteoid in the metaph ys es (Storey , 1962). Because children and y oung animals are growing rapidly , they are more sensitive than adults, with effects of strontium exposure occurring at lower doses and higher severit y than in adults. Phy siological differences between rats and other mammals (including humans) may make rats mo re sensitive to the bone effects of strontium. In rats, (unlike most mammals, including humans), the epiphy seal cartilage growth plate of the long bones never transforms completely into bone, and so bone growth continues throughout life, although it slows down after 12 months of age. This difference may

make rats more sensitive over longer periods of life due to higher incorporation of strontium into the skeleton of adult rats than adults of other mammals. No standard one - or two - generation reproductive toxicity studies exist for any

strontium compound, but the available data indicate that strontium does not cause structural or functional effects at doses well above those causing bone effects. No effects on mating behavior, fertility , gestation period o r the histopathology of the reproductive tissues and organs were observed in a screening test for reproductive and developmental toxicity (NIER, 2006c). There were no adverse effects on fetal development in this study (implantations, litter size, live bir ths, viability , sex ratio, body

weight and length, overt malformations on external examination). However, since this was a screening stud y, there was no microscopic examination for skeletal or visceral alterations. There was also no effect on organ weigh t or histopathology of reproductive organs (testes, ovaries, uterus or prostate) in weanling rats (10/sex/dose) exposed to strontium chloride hexahy drate in the diet at doses up to 4800 mg/kg (equivalent to about 146 mg Sr/kg - day ; Kroes et al., 1977). In the (NIER, 2006c) reproductive and developmental toxicity screening tests , there were no adverse effects on fetal development (implantations, litter size, live births, viability , sex ratio, body weight and length, overt malformations on external examinati on). However, since this was a screening study , there was no microscopic examination for skeletal or visceral alterations. Several developmental toxicity studies focused on potential bone effects of perinatal strontium exposure (e.g., Miki and Miy amoto, 1968; Shibata and Yamashita, 2001). Overall, there was no indication of fetotoxicity

or developmental effects on targets other than bone. Several studies conducted on in utero or postnatal effects on bone development found inhibition of calcification. H owever, it is difficult to evaluate the relative susceptibility of developing fetuses and young animals to the bone effects of strontium because almost all of the available studies tested only a single, high - dose exposure level. Strontium can also subst itute imperfectl y in other cellular processes that require calcium, including signaling pathway s (e.g., the mitogen - activated protein kinase pathway), and secondary messenger (e.g., inositol triphosphate) and transporter (calmodulin) sy stems that usually i nvolve calcium. Strontium has been reported to activate several calcium - sensitive signaling pathway s in vitro , including pathway s mediated by ERK1/2, PI 3K, protein kinase D, p38, MAPK and protein kinase B. Strontium has also been shown to bind and activa te the calcium - sensing receptor (CaSR) as a full agonist, but with a lower affinity than calcium. The extracellular calcium - induced activation of the calcium - sensing receptor (CaSR) in bone cellsEPA - OST Preliminary Health Effe cts Support Document for Strontium April 2014

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– DO NOT CITE OR QUOTE 7 - 26 has been shown in vitro to induce several intracellular sig naling pathway s that regulate osteoclast and osteoblast activity

(Marie, 2010). However, while effects have been seen in in vitro studies, these effects have either not been seen in in vivo studies, or occur at doses higher than those that affect the bone . **7.5.2 Synthesis and Evaluation of Carcinogenic Effects**  No studies are available that evaluated tumor formation in an adequate number of animals treated with strontium for an adequate duration. Only a single chronic study

is available for oral strontium exposure (Skory na, 1981; Skoryna and Fuskova, 1981), and this study evaluated small numbers of animals for longer than the standard exposure duration (increasing the potential for age - related lesi ons and decreasing study sensitivity). Together, the small sample size and late sacrifice date decreased the study sensitivity , and mean that the study was inadequate for evaluation of carcinogenic potential. Inhumans, there is no evidence for a carcino genic effect of strontium. Strontium chromate was implicated as a cause of increased lung cancer risk in a study of British chromate pigment manufacturing workers (Davies, 1979, 1984), but the effects are attributed to the chromium (VI) oxidation state. Chromium (VI) compounds and ions are known human carcinogens via the inhalation route (U.S. EPA, 1998b). Strontium compounds other than strontium chromate are negative in genotoxicity studies, with the exception of one in vivo chromosome aberration assay that had several limitations in the reporting of stud y design and results (Ghosh et al., 1990). **7.5.3 Mode of Action and Implications in Cancer Assessment**  Strontium has not been observed to cause cancer; thus, a mode of action evaluation is not relevant. **7.5.4 Weig**  **ht of Evidence Evaluation for Carcinogenicity** Based on the evidence, the human carcinogenic potential of strontium cannot be determined because the data relevant to strontium carcinogenicity are very limited. No increase in tumors was seen in the single available chronic oral study (Skory na, 1981; Skory

na and Fuskova, 1981), but this study used a small sample size and was inadequate for evaluation of carcinogenic potential. Increased lung tumors were seen in British chromate pigment workers exposed to strontium chromate, but the effects are attributable to the chromate (VI) moiety in the chromate; chromium (VI) is a known human carcinogen via the inhalation route. The weight of evidence from the genotoxicity data is that strontium is negative for gene mutation and chromosomal damage; positive results were seen with strontium chromate. **7.5.5 Potentially Sensitive Populations**  Because strontium can substitute for calcium in growing bone, children and y oung adults are expected to be a sensitive population, since they are activel y growing. This means that changes in bone structure and homeostasis may have more severe and/or a long - term impact than similar changes in adults. These effects would be expected to have the greatest impact duringEPA - OST Preliminary Health Effe cts Support Document for Strontium April 2014

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– DO NOT CITE OR QUOTE 7 - 27 periods of rapid growth in the developing fetus, during childhood and adolescence, although Recker et al. (1992) reported that bone mineral accretion continues slowl y into the third decade of life, with different skeletal sites reaching peak bone mass at different ages. The expected increased sensitivity

of children and adolescents is consistent with the results of Storey (1961), who found that weanling rats were more sensitive than y oung adult rats to the bone effects of ingested strontium . There are some data from studies in humans that demonstrate a positive association between the incidence of low trauma fractures in children and low bone densit y or low calcium intakes (Farr et al. 2014; Matkovic et al., 2007) . A recent study in embry onic zebrafish found that the relative ratio of calcium to strontium in water was an important fac t or influencing strontium’s impact on embry onic bone development (Psqualetti et al., 2013 ) ; inhibition of bone mineralization increase d as the strontium:calcium r atio increased. In addition to the toxicodynamic sensitivity of young animals, toxicokinetic differences may also apply . Increased strontium absorption has been reported during lactation in rats, due to the strontium’s common absorption pathway with calc ium. Although it has not been directl y studied in humans, similar increased absorption is likely during lactation and pregnancy in humans. Strontium’s mode of action suggests other related sensitive populations. Because man y of the toxic effects of str ontium result from strontium ions substituting for calcium ions, calcium deficiency

would be expected to result in increased sensitivity . According to the NIH Office of Dietary Supplements (NIH, 2011), hy pocalcemia results primarily from medical problems or treatments, including renal failure, surgical removal of the stomach, and use of certain medications (such as diuretics). Groups with higher risks of becoming calcium deficient include: postmenopausal women, amenorrheic women, female athletes, vegans, and individuals with lactose intolerance or cow’s milk allergies. Frank calcium deficiency is uncommon, but long term intake of calcium below recommended levels might have negative health consequences. The potential for calcium deficiency is of particu lar importance immediately prior to and during pubert y. Pubertal development is associated with marked increases in calcium utilization, with calcium supplementation in the prepubertal and pubertal periods resulting in increased bone accretion (Abrams et al., 2000; L ee et al., 1996; Matkovic et al., 2005). IOM (2010) concluded that increased calcium intake during the peripubertal period is associated with increased bone accretion, although the data do not consistently show long - term retention of increased bone mineral content, particularly after supplementation is withdrawn. Median calcium intakes for girls ages 14 to 18 y ears (826 mg/day) are below their recommended intake of 1100 mg/day (IOM, 2010). Together, these studies indicate that pre - teenagers and teenagers (and perhaps particularl y teenage girls) are a sensitive population for strontium exposure, due to the rapid bone growth and importance of calcium levels during this period. Since calcium can help to protect against bone effects of strontium, the below - recommended intake of calcium may make this population more sensitive to the effects of strontium. Although it is not clear if there is a link between decreased pubertal bone mass and later sensitivity to osteoporosis, the finding of such a link would also indicate that the teenage sensitivity to strontium would be related to osteoporosis later in life.EPA - OST Preliminary Health Effe cts Support Document for Strontium April 2014

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– DO NOT CITE OR QUOTE 7 - 28 Based on the potential link between potential effects on pubertal bone mass formation and osteoporosis, one might expect that the elderly, particularl y osteoporotic women, would also be sensitive populations. However, strontium at doses well above the RfD derived in Chapter 8 have been administered to osteoporotic women for months to y ears to treat osteoporosis. Therefore, while strontium at sufficiently high doses would alter the bone structure in the elderl y, it is not expected that the effects would be more adverse in the elderl y than in the general population. Paget’s disease of bone is a disorder in which the normal equilibrium between the breakdown of old bone and the formation of new bone is disturbed, resulting in the formation of abnormal, dense, and brittle bone. The prevalence of Paget’s disease increases with age; juvenile Paget’s disease is very

rare. Because Paget’s disease affects bone metabolism, people with the disease might be expected to be have increased incorporation of strontium int o the bone, and might be more affected by strontium exposure. The first supposition is supported by the data of Tothill et al. (1983), who found increased uptake and removal from bone of radiolabeled strontium in 12 adult patients with Paget’s disease, co mpared with 7 normal controls; no studies on potential health effects associated with the increased bone uptake were located. There is substantial literature indicating that renal dialy sis patients and people with renal failure are more sensitive to stron tium, based on human data, and supported by animal data ( Schrooten et al., 1998, 2003 (rats); D’Haese et al., 1999, 2000 (humans); Vanholder et al., 2002 (humans); Cohen - Solal et al., 2002 (humans); De Broe and D’Haese, 2003 (humans); Oste et al., 2005 (rats)) . This phenomenon is likely due to the potential for strontium to accumulate to a larger extent in the bones of those with disorders of the kidney , as the kidney is one of the main organs involved in elimination of strontium from the body . I n animal s tudies, the development of osteomalacia in rats with chronic renal failure was dose dependent and rapidly reversed after strontium treatment ended. In humans, D’Haese et al. (2000) found that renal dialy sis patients with osteomalacia had higher strontium: calcium ratios than in dialy sis patients with other ty pes of osteody strophy , supporting the hy pothesis that increased strontium exposure may be associated with the osteomalacia. Thus, strontium levels are increased in people with renal failure, possibly because renal failure patients have impaired strontium clearance. Regardless of the reason, the increased strontium levels in the body may lead to increased susceptibility to bone effects. Because strontium can weakl y mimic the action s of calcium in in vitro experiments, it may have an impact on contractions of the coronary artery , pancreatic insulin secretion, and/or parath yroid hormone regulation (Hellman et al., 1997; Pors Nielsen, 2004; Ohashi et al., 1995). Individuals with alter ations in these phy siological functions (e.g., insulin - dependent diabetics) may be sensitive to strontium. However, since these effects lack in vivo confirmation and seem to occur at higher doses than the bone effects of strontium, the limits that protect children from the bone effects would also be expected to protect these populations.EPA - OST Preliminary Health Effe cts Support Document for Strontium April 2014

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– DO NOT CITE OR QUOTE 8 - 1 **8.0 DOSE**  **- RESPONSE ASSESSMENT**  **8.1 Dose**  **- Response for Noncancer Effects**  The derivation of the reference dose (RfD) for strontium is described below. The RfD is an estimate (with uncertainty spanning perhaps an order of magnitude) of a daily oral exposure to the human population (including sensitive subgroups) that is likely to be without an appreciable risk of deleterious effects during a lifetime. Table 8 - 1 summarizes the avail able dose - response data for oral subchronic and chronic animal studies for strontium. Table 8 - 1 also includes shorter - term studies when they are co - critical studies or specifically address the relative sensitivity

of weanling and adult animals. **Table 8**  **- 1**  **NOAEL/LOAEL Data for Oral Subchronic and Chronic Studies of Strontium Species,**  **Sex Form,**  **Dietary Calcium**  **Study**

**Duration / Route**  **NOAEL**

**(mg Sr/kg**   ** day)** **a LOAEL** 

**(mg Sr/kg**   ** day)** **a Critical Effect(s)**  **Reference** Mouse, male Strontium

Chloride, 0.5% Ca 29 day s

Drinking water -- 350 10% increase in osteoid surface and an 11% reduction in the number of active osteoclasts Marie and

Hott (1986) Rat, “y oung” female Strontium

Carbonate, 1.6% Ca 20 day s

Diet 190 380 Inhibition of calcification Storey

(1961) Rat, adult female Strontium

Carbonate, 1.6% Ca 20 day s

Diet 375 750 Changes in bone structure Storey

(1961) Rat, wean ling male Strontium

Chloride, 0.5% Ca 4 weeks

Drinking water 222 466 Bone hy pomineralization and increased bone mass Gry

npas and Marie (1990) Rat, wean ling male Unspecified 43 day s Diet -- 565 Respiratory difficulties, hindlimb paraly sis, rickets and osteomalacia and 40% mortality Johnson et

al. (1968) Rat, wean ling male Strontium

Chloride, 0.5% Ca 8 weeks

Drinking water 146 307 Bone hy pomineralization and increased bone mass Gry

npas and Marie (1990) Rat, Male Strontium

Chloride, 9 weeks

Drinking 425 b 525 b Decreased calcification rate Marie et al.

(1985)EPA - OST Preliminary Health Effe cts Support Document for Strontium April 2014

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– DO NOT CITE OR QUOTE 8 - 2 **Species, Sex**  **Form, Dietary**  **Calcium Study** 

**Duration / Route**  **NOAEL**

**(mg Sr/kg**   ** day)** **a LOAEL** 

**(mg Sr/kg**   ** day)** **a Critical Effect(s)**  **Reference** 0.5% Ca water Rat, wean ling male and female Strontium

Chloride hexa hy drate, 0.75% Ca 90 day s

Diet 36 146 Histological signs of thy roid activation in males and non - dose related increase in thy roid weight Kroes et al.

(1977)

Rat, Male Strontium

Chloride, 0.35% Ca 3 months

Drinking water 263 -- No effect as confirmed b y histological examination; Presented in a review article with limited primary data. Skory

na and Fuskova (1981)

Rat, adult male Strontium

Chloride, 0.35% Ca 3 y ears

Drinking water 263 -- Presented in a review article with limited primary data. No reported adverse effects on growth Skory

na, (1981); Skory na and Fuskova(198 1)

aUnless otherwise specified, doses were calculated for this assessment from concentrations in diet or drinking water, using U.S. EPA (1988) allometric equations, as described in Chapter 7. b Doses calculated by the authors **8.1.1 RfD Determination**  The selection of an endpoint of concern is based on exposure of health y populations, including pregnant women and children, to strontium. People with impaired healt h are considered as part of the human variability , but the RfD is not based on those who require medical assistance to sustain life, such as individuals in chronic renal failure. The animal data suggest that adult animals are less sensitive than young ani mals to bone effects following strontium exposure. However no robust studies were located that would allow focused evaluation regarding the sensitivity of animals during fetal development, perinatal or lactation stages following strontium exposure . Two s tudies are considered co - critical for development of the strontium RfD. Inthe first co - critical stud y, Marie et al. (1985) exposed weanling male Sprague - Dawley

rats (8/group) to 0, 0.19, 0.27, 0.34 or 0.4% strontium chloride in distilled water for 9 week s. The diet contained 0.5% calcium, which is somewhat lower than ty pical rodent diets. Based on bod y weight and water consumption data, the authors estimated average strontium intakes of 0, 316, 425, 525 and 633 mg Sr/kg - day . A dose - related, statistical ly significant decrease in the bone calcification rate was reported at doses of 525 mg Sr/kg bw - dayEPA - OST Preliminary Health Effe cts Support Document for Strontium April 2014

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– DO NOT CITE OR QUOTE 8 - 3 and higher, with no significant change at the next lower dose of 425 mg Sr/kg bw - day ; thus the LOAEL was 525 mg Sr/kg bw - day and the NOAELwas 425 mg Sr/kg bw - day . Based on decreased calcification rate and a BMR of 1 SD change from the mean, a BMDLof 328 mg Sr/kg - day was calculated. This was a well - conducted study with extensive quantitative documentation of the effect data. Although the number of animals /g roup is somewhat smaller than that recommended for a subchronic study (10/sex/group), the number evaluated (8 males /group ) is larger than those in the comparable studies (Storey , 1961: 3 - 10 females, Gry npas and Marie, 1990: 5 males). The use of a low - ca lcium diet in this study and in the other co critical study

(Gry npas and Marie, 1990) may provide an additional measure of protection, since the lower calcium may

have increased the sensitivity of the test animals. In the second co - critical study , Gry npas and Marie (1990) exposed weanling male Sprague - Dawley

rats (5/group/exposure duration) to 0, 0.19, or 0.40% strontium chloride in distilled water for 4 or 8 weeks. This diet also contained 0.5% calcium, which was r eported by the authors as a relativel y low level of calcium, and is somewhat lower than ty pical rodent diets. Bone h ypomineralization and increased bone mass were reported in rats exposed to 0.40% for 4 or 8 weeks. No effect was seen at the low dose of 0 .19% strontium chloride in water for either study duration. The tested concentrations correspond to doses of 0, 222, and 446 mg Sr/kg - day during the 4 - week study , and 0, 145, and 307 mg Sr/kg - day during the 8 - week study , assuming ingestion of 0.211 L/kg - d ay by a weanling Sprague - Dawley rat or 0.139 L/kg - day

by a Sprague Dawley rat during a subchronic study (U.S. EPA, 1988). Thus, the NOAEL in this study is 145 mg Sr/kg - day

and the LOAELis 307 mg Sr/kg - day , based on the 8 - week study . This study is limite d by

the lack of experimentally - determined doses, the absence of an intermediate dose between the 0.19 and 0.4% dose groups, and the use of only 5 rats/group. In another stud y, Storey (1961) exposed young (40 - 60 gram) (specific age not reported) and adul t (200 - 250 gram) female rats (3 - 10/dose group; strain not reported) to 0, 0.19, 0.38, 0.75, 1 (y oung onl y), 1.5 or 3.0% strontium in the diet as strontium carbonate for 20 day s. Assuming yo ung rats consume 10% and adult rats consume 5% of their bod y weigh t in food per day , these doses correspond to 0, 190, 380, 750, 1000, 1500 and 3000 mg Sr/kg - day for y oung rats and 0, 95, 190, 375, 750 and 1500 mg Sr/kg - day for adult rats (U.S. EPA, 1992). The dose groups apparentl y contained 10/dose for young rats and 3/dose for adult rats, but the number of y oung rats evaluated ranged from 3 to 10, depending on the endpoint. The diet was reported to contain 1.6% calcium and 0.9% phosphorous. Young rats were more sensitive than adults. Inhibition of calcification, as evidenced by increasing width of the epiphy seal cartilage and uncalcified bone matrix was observed in young rats at the LOAEL of 380 mg Sr/kg - day ; the NOAEL was 190 mg Sr/kg - day . In adult rats, the LOAEL was 750 mg Sr/kg - day , based on histological chan ges of the bone, and the NOAEL was 375 mg Sr/kg - day . This study is limited by

the small sample size, short exposure duration, lack of information on the animals’ age or strain, and the absence of experimentally - determined doses. Due to these limitations and considerations, the Storey (1961) study is considered closely

supporting, unlike the U.S. EPA (1992) approach of considering this study co - critical. The point of departure is based on the Marie et al. (1985) study because of the uncertainties in the d ose estimate from the Storey (1961) study

and the longer exposure durationEPA - OST Preliminary Health Effe cts Support Document for Strontium April 2014

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– DO NOT CITE OR QUOTE 8 - 4 in the Marie et al. (1985) study . The Storey (1961) study

does provide perspective, on an additional time point to supplement the two critical studies. Appendix A, Table A - 3 pro vides additional information on the Storey (1961) and Marie et al. (1985) studies, supporting the preference for the latter stud y as the basis for the RfD. In addition to the points noted above, the levels of dietary calcium were higher in the Storey (196 1) study , as was reflected in higher Ca:Sr ratios i n serum and bone. Furthermore, the serum levels of strontium at the NOAELin the Storey (1961) study

were higher than those at the dose below the NOAEL in the Marie et al. (1985) stud y. These points sugg est that the doses in the Storey (1961) study as estimated using factors not specific to strain because the authors did not identify the strain of rat studies may not be accurate. In addition, the higher calcium levels in the diet may have more protective than the levels in the Marie et al. (1985) stud y. These observations raise questions about whether the NOAEL in the Storey (1961) study for y oung rats is really

lower than that in Marie et al. (1985), and/ or whether the estimates Storey (1961) doses are accurate . The current IRIS summary (U.S. EPA, 1992) lists information from reports by Skory na (1981) and Skory

na and Fuskova(1981) on a study with male RVH hooded rats (12/group) administered strontium chloride (55% strontium) in drinking water at 0, 900 , 1,900 or 3,400 ppm for 3 years as a co - critical study . Assuming that an adult rat consumes water at a rate of 0.14 L/kg - day , and adjusting to dose of strontium, the experimental doses correspond to 0,70, 147 and 263 mg Sr/kg - day . Based on an observatio n of bone histology , histologic evaluation of selected organs (kidney , lungs, adrenal, brain, heart and muscle), and evaluation of body weight, n o effects were reported; the NOAEL was the highest dose tested, 263 mgSr/kg - day . The information from Skory n a (1981) and Skory

na and Fuskova(1981) is considered supporting rather than co - critical, as described b y U.S. EPA (1992), for several reasons. The publications that mention the study lack important details regarding the study design. In addition, study

s ensitivity

was decreased by

the small sample size and long study duration, which results in increased age - related lesions in the control group. The initial starting weight of 250 grams indicates that exposure did not occur during the sensitive period of a ctive bone growth and calcium accretion. However, recognizing these caveats, this study indicates that a lower effect level is unlikely

to be identified in a chronic study evaluating a broader array of tissues and endpoints than the single target (bone) e valuated in the co - critical studies by Marie et al. (1985), Gry npas and Marie (1990) and Storey (1961). Thus, this study supports the choice of co - critical studies.One study

in Table 8 - 1 had a lower NOAEL and LOAEL, but the results did not support use of this study

as the basis for the RfD because of lack of confirmation of the results in other studies. Kroes et al. (1977) reported histological signs of what they described as moderate thy roid activation in male rats and a non - dose - related increase in thy roid weight, with a NOAEL of 40 mg Sr/kg - day

and a L OAEL of 160 mg Sr/kg - day . (No definition was provided for the term activation.) It is difficult to evaluate the implications of the observed changes because the study reported onl y thyroid weight and unspecified histological changes, with no supporting information on thy

roid’s calciotropic and/or thy roxin - related hormone levels. No other study reported effects on the thy roid, and even the more recent studies of the CaSR (e.g., Coulombe etEPA - OST Preliminary Health Effe cts Support Document for Strontium April 2014

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– DO NOT CITE OR QUOTE 8 - 5 al., 2004) h ave not focused on thy roid C - cell responses or hormones. Johnson et al. (1968) reported respiratory difficulties and hindlimb paral ys is in weanling Sprague Dawley

rats administered 565 mg Sr/kg - day in feed for 43 day s as an unspecified form of strontium. This study

apparentl y tested onl y one dose level. Although this effect level is consistent with the co - critical studies, the severit y of the effects suggests that the NOAEL might be lower than in the co - critical studies. This study was not used as co - cr itical or as the basis for the POD, because of a lack of support for the observed effects, even in studies at much higher doses, and because of the lack of experimental data that could support a mode of action for these effects. While it has been hy pothes ized that the paral ys is could have been related to abnormal calcium signaling in muscle or nerve, paral ys is was not reported at higher doses in other studies. It is unlikel y that the paralysis was due to femoral deformation, as even severel y rachitic rode nts and those with osteomalacia are not generally paraly zed. Instead, ATSDR (2004) suggested that the effects may

have been due to compression of the hy pertrophic epiphy seal cartilage, which was insufficientl y mineralized to support the weight of the body .

**8.1.1.1 Benchmark Dose Approach**  The calcification rate in Marie et al. (1985) was modeled using EPA’s Benchmark Dose Software, version 2.1 , using benchmark response (BMR) definitions of 1 SD and 0.5 SD (one standard deviation and 1⁄2 standard deviation change from the mean, respectively). All of the standard continuous models were run and the data were modeled using both homogeneous and non - homogenous variance (See Appendix C) . Neither approach was able to fit the variance well. Because the variance showed n o clear pattern (both increasing and decreasing with dose), it is not surprising that neither approach was successful. However, the standard deviation estimated by the chosen model (0.11, for the restricted pol yn omial model) closely approximates the contr ol SD (0.12), and so the BMD and the BMDL (the lower 95% confidence limit on the BMD) based on the SD are reliable. Because the BMR is defined in terms of the estimated control SD, a wrong estimate of the control SD will result in a mis - estimate of the BM R, and therefore of the BMDL. Therefore, it is much more important to have a good estimate of the control SD than of the SD at other doses, and the model with a homogenous variance is preferred over the model with a non - homogeneous variance, even though the latter model results in a slightly lower BMDL (317 mg Sr/kg - day). Both models would result in the same ultimate RfD. Of the acceptable fits, the best fits are for the Hill, poly nomial, and power models (all with goodness of fit p values well over 0.1) . The unrestricted pol ynomial model resulted in a slightly U - shaped curve, and so the restricted polynomial model was used instead. Based onl y on the AI C 12 (i.e., not considering other fit measures, such as the p value, local fit or visual fit), the restr icted pol ynomial model clearl y has the best fit. The BMDL for this model is 328 mg Sr/kg - day . Although the value estimated by the Hill model at the dose closest to the BMD (the scaled residual, Table 8 - 2) is closer to the value reported in the study (a m easure of “local fit” 12 The AIC, or Akaike Information Criterion, is a measure of fit that takes into account the number of parameters in the model. For the same goodness of fit, models with fewer parameters are preferred. The Hill model has four parameters, or variables, that can be estimated by the model to provide flexibility in the curve fitting the data. Only three parameters were estimated for the polynomial model, meaning that it is a simpler model.EPA - OST Preliminary Health Effe cts Support Document for Strontium April 2014

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– DO NOT CITE OR QUOTE 8 - 6 near the BMR), the “local fit” was also good for the restricted pol ynomial model, and the AIC for the Hill model is substantially larger. When selecting the appropriate BMD from a variet y of model results, BMDs with smaller AICs (i.e ., to the left on the number line) are preferred. Therefore, although both models have acceptable fit, the restricted pol ynomial model is preferred. Thus, the recommended BMDL based on a BMR of 1 SD is from the restricted poly nomial model, 328 mg Sr/kg - d ay (BMD is 434 mg Sr/kg - day); other BMDLs were 355 (Hill model) and 348 (power model) mg Sr/kg - day (Table 8 - 2). In the absence of information about what degree of change is adverse, the default BMR of 1 SD was used. BMDs were also calculated using a BMR of 0.5 SD for the sake of comparison. These BMDLs were in the range of 186 - 216 mg Sr/kg - day , with a BMDL of 186 mg Sr/kg - day for the restricted pol ynomial model. This BMDL is below the corresponding NOAEL for the decreased calcification rate, and based o n a response that has not been quantified with respect to the degree of change that constitutes an adverse effect. Accordingl y, the BMDL for a one standard deviation change is used for the RfD derivation. **Table 8**  **- 2**  **Output of Benchmark Dose (BMD) Models using BMR of 1 Standard Deviation Model Name**  **BMD BMDL**  **p -**  **value AIC**  **Scaled Residual of**  **Interest a**  Hill 480.06 355.23 0.85 - 127.51 0.07 Exponential2 - 280.51 NA 0.11 - 125.53 2.29 Exponential3 - 280.51 NA 0.11* - 125.53 2.29 Exponential4 NA 0 0.00* - 111.24 0 Exponential5 NA 0 <0.0001* - 109.24 0 Linear 347.55 238.75 0.16 - 126.43 1.38 Poly nomial 490.47 352.75 0.95 - 129.45 - 0.20 **Polynomial (Restricted)**  **434.07 328.36**  **0.82 -**  **130.61 0.30**  Power 485.26 347.71 0.86 - 129.25 - 0.28 a The scaled residual is a measure of the local fit, how close the modeled response is to the observed response at a specified dose, in this case, the dose closest to the BMR. *I ndicates that these results are from p - value tests 5a, 6a, and 7a, as reported in BMDS for exponential models 3, 4, and 5, respectively. NA = not availableEPA - OST Preliminary Health Effe cts Support Document for Strontium April 2014

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– DO NOT CITE OR QUOTE 8 - 7 **Figure 8**  **- 1**  **Restricted Polynomial model, BMR = 1**  **SD**

As discussed above, the RfD is derived from the BMDL (1 SD) of 328 mg Sr/kg - day , for decreased bone calcification rate in male weanling rats (Marie et al., 1985), divided by a composite UF of 1000, resulting in a value of 0.3 mg Sr/kg - day .

RfD = BMD L = 328 mg/kg/day= 0.328 mg/k g/day (rounded to 0.3 mg/kg/day) UF 1000 w here : BMDL = The 95% lower confidence bound on the BMD for a significant decrease

in bone calcification rate UF = A composite uncertainty factor for intraspecies uncertaint y, interspecies uncertaint y and database deficiencies. The net uncertaint y factor was derived as follows: Human intraspecies variability - UF H - 10 The critical effect was observed in young/weanling animals, the sensitive population. However, it is not clear if the window of vulnerability was adequatel y captured, since the weanling rats were exposed only for 28 - 63 day s, a period that did not include exposure during gestation, lactation, and through young adulthood. In particular, fetuses exposed during bone development may

be a sensitive population. As noted in Section 7.5.5, pre - teenagers and teenagers (particularl y teenage girls) may be a sensitiv e population for strontium exposure, due

1 1.1 1.2 1.3 1.4

0 100 200 300 400 500 600MeanResponse

dose Polynomial Model with 0.95 Confidence Level

11:37 11/19 2010 BMD BMDL Polynomial BMD Lower BoundEPA - OST Preliminary Health Effe cts Support Document for Strontium April 2014

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– DO NOT CITE OR QUOTE 8 - 8 to the rapid bone growth and limited calcium intakes relative to need during this period. As discussed in Section 7.5.5, it is likely that sensitivity

to strontium is affected by whether the individual has sufficie nt calcium intake. In addition, the data from the critical study demonstrate considerable heterogeneity among the small group of 8 males, suggesting the potential for a broad range of intraspecies variability . Because of these considerations, and the imp act of inadequate calcification in bone at the end of the human adolescent growth period on the risk of bone fracture later in life, the full factor of 10 is used. Animal to human variability - UF A – 10 Data are not available to develop a data - derived UF A , due to the lack of adequate information on toxicokinetic and toxicody namic differences between rats and humans. Phy siological differences between rats and humans indicate that adult rats may be more sensitive than adult humans to effects of strontium, s ince bone growth in rats continues throughout adulthood. However, this does not mitigate the differences for the critical effect, which occurs in yo ung/weanling rats. Extrapolation from L OAELto NOAEL - UF L – 1 The Point of Departure (POD) for the RfD de termination is a BMDL 1 SD supported by a NOAEL. Therefore, no uncertaint y factor is necessary to adjust from a lowest observed effect level. Extrapolation from subchronic to chronic exposure - UF S – 1 Exposure for a longer duration through adulthood than in the Marie et al. (1985) study is unlikely to be of concern for strontium, since that study was for a subchronic duration, and adults are less sensitive than the y oung rats that were exposed. Bone development in humans extends through adolescence, aft er which dietary calcium requirements, although still important, decrease (IOM, 2010). However, as noted in the context of the intraspecies factor, the critical studies did not include exposure during the entiret y of the expected sensitive window (i.e., n o exposure during gestation and lactation). An additional factor of 3 could be applied, but this concern was much of the rationale for the use of the full factor of 10 for intraspecies variability ; thus, it is not necessary to include an additional UF to account for extrapolation from subchronic to chronic exposure. Database uncertainty

/insufficiency - UF D – 10 Most of the database is from studies conducted in rats. However, a stud y of strontium chloride in weanling mice (Marie and Hott, 1986) reported effects in the same dose range as the Storey (1961) study , indicating that mice are not more sensitive than rat s. Developmental toxicity studies suggest that the effects on bone development are of greatest concern. No standard reproductive studies are available, but several screening studies (NIER, 2006c; Skory na, 1981) found no toxic effects at doses higher than or comparable to those causing bone effects. As screening studies, these studies did not include complete evaluation of histopathology; theEPA - OST Preliminary Health Effe cts Support Document for Strontium April 2014

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– DO NOT CITE OR QUOTE 8 - 9 absence of information on bone histopathology in the exposed fetuses is an important data gap. The review articl e b y Skory na (1981) provided very

limited information regarding the 3 - generation stud y design and results. Countering these considerations, there are a number of uncertainties in the database. The first relates to overall study sensitivity . The overall number of animals used in both of the critical studies is small, ranging from 5 to 8 per group, limiting the sensitivity of the studies, although the number of animals in the Marie et al. (1985) study was onl y slightly less than the 10/group recommended fo r subchronic studies. The 20 - day study by Storey (1961) apparentl y exposed 10 rats/group, however, it seems that as few as 3 were evaluated for the critical endpoint. Concerns about the strontium’s interaction with the thy roid were raised, based upon th e data from Kroes et al. (1977) (see Table 8 - 1); however, the implications of the observed effects are unclear in light of the minimal reporting of the effects and the absence of data on the thy roid’s th yroxin - related and/or calciotropic hormone levels. An additional uncertaint y relates to the potential for other effects not monitored in the Marie et al. (1985) study . Strontium’s chemical similarity

with calcium allows it to exchange for calcium. Therefore, it is possible that exposure could affect s ynapt ic signaling. While further neurotoxicity testing of adult animals is not likely necessary , based on the results of Johnson et al. (1968), ATSDR (2004) noted the lack of developmental neurotoxicity studies and the failure to include exposures during gestation and lactation as a data gap. Differences in the solubility of strontium carbonate (used by Storey , 1961) and strontium chloride were identified as a source of an uncertainty by U.S. EPA (1992). Strontium carbonate is much less soluble in water than strontium chloride, with solubilities of 110 mg/L and 538,000 mg/L, respectivel y. No information was located on the bioavailability of strontium carbonate, but the lower solubility

of the carbonate (solubility product constant 5.6 x 10 - 10 ) would lead t o lower bioavailability

at sufficientl y high doses. However, the implications of this lower solubility cannot be determined, due to many other differences between the studies using strontium chloride (Marie et al., 1985; Gry npas and Marie, 1990) and the s tudy using strontium carbonate (Storey , 1961). These studies used different dosing protocols (in drinking water and food, respectively), different durations, and had differing uncertainties in the actual ingested doses. In addition, the calcium in the di et in the Storey (1961) stud y was more than three times higher than that in the Marie et al. (1985) study , with the Storey (1961) study

providing a more protective calcium:strontium ratio. Despite these differences, there are not large quantitative differ ences in the LOAELs identified by these studies. These uncertainties about how to quantitatively

account for differences in calcium intake and in the amount of absorbed strontium support the application of a10 - fold factor for UF D . In addition, the use of a diet that is somewhat lower in calcium than standard rodent diets may have increased the sensitivity of the critical studies, providing some additional measure of protection.EPA - OST Preliminary Health Effe cts Support Document for Strontium April 2014

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– DO NOT CITE OR QUOTE 8 - 10 **8.1.1.2 NOAEL/LOAEL Approach**  The NOAEL/LOAEL approach was not considered for deter mining an RfD for strontium because the data were amenable to benchmark modeling of dose - response.

**8.1.1.3 Comparison with Current IRIS Assessment**  The on - line IRIS RfD assessment of strontium was verified in 1992. It was based on the studies by Storey (1961) an d Marie et al. (1985) with support from Skory na (1981). The point of departure for the anal ys is was the estimated NOAEL(190 mg Sr/kg - day) from the Storey (1961) study using a 300 - fold uncertaint y factor. A factor of 10 was used for interspecies extrapol ation, and a factor of 10 for an incomplete database (including a lack of developmental and reproductive data) and to account for uncertainties in using data for strontium carbonate to derive a risk estimate that may

apply to other salts of strontium . An uncertainty factor of 3 was applied for sensitive subpopulations; a factor of 10 was not considered warranted because the critical study was performed in young animals, a recognized sensitive subpopulation. The OW has chosen the BMDL of 328 mg Sr/kg - day from the Marie et al (1985) study in establishing the point of departure for their anal ys is for the following reasons:

 The doses were reported by the authors rather than estimated,  The duration of exposure was longer (63 day s versus 20 day s),  The monitoring of the bone effects was more quantitative than the photomicrographs evaluated b y Storey (1961),  The dosing was via drinking water, the medium of interest for the OW,  The strain of rats and the age of the animals at the time that dosing was initi ated and completed were reported, and  The data were amenable to dose - response modeling to identify the BMD and BMDL. The RfD (0.3 mg Sr/kg - day) determined by the OW differs only

slightly (2 - fold) from that determined b y IR IS (1992) (0.6 mg Sr/kg - day). Th e 1000 - fold uncertainty factor utilized in the OW assessment reflects concern for impacts of strontium on developing bone and the nervous s ys tem because of its competitive interactions with calcium. As described in Section 4.3.2, the concentrations of str ontium in drinking water from national monitoring studies were compared to a Health Reference Level (HRL ) to determine the frequency at which the HRLand half the HRL were exceeded . The HRL for strontium was derived from the RfD. Age - specific exposure factors were applied in order to adjust for the risk associated with exposures during infancy , childhood and adolescence, periods of active bone growth and calcification ( Appendix B). The HRL is calculated as follows: HRL= (RfD / ∑(DWI/BWR x F)) x RSC HRL= (0.3 mg/kg/day

÷ 0.040 L/kg/day) x 0.2 = 1.5 mg/L =1,500 μg/LEPA - OST Preliminary Health Effe cts Support Document for Strontium April 2014

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– DO NOT CITE OR QUOTE 8 - 11 where: RfD = 0.3 mg/kg/day DWI/BWR = Drinking Water Intake Body Weight Ratio (DWI/BWR) expressed as liters per kg bod y weight (L/kg/day)(90th percentile, consumers only) for each age - specific period for the first 18 y ears, the average postnatal duration for bone growth in humans. **8.1.2 RfC Determination**  The OW does not generally develop an RfC for drinking water contaminants but does adopt those that are provided in th e I RI S database. The 1992 IRI S assessment of strontium did not determine an RfC. Strontium is not volatile, thus inhalation exposure is not likely . No data were identified that would support derivation of an RfC. **8.2 Dose**  **- Response for Cancer Effects**  As described in Section 7.5.4, there is inadequate information to assess the carcinogenic potential (I) of strontium , due to the lack of adequate studies of chronic duration. The only reports of a stud y that involved a chronic duration (Skory na, 1981; Skoryn a and Fuskova, 1981) included minimal reporting of the stud y design and outcomes. Although the study did not identify an y tumors, the sensitivity was decreased by

the small sample size for a chronic study (12/dose group) and the likely increased backgroun d response resulting from the long study duration. Therefore, no quantitative cancer assessment is appropriate. The on - line IRIS assessment of strontium did not evaluate the carcinogenicity of strontium.EPA - OST Preliminary Health Effe cts Support Document for Strontium April 2014

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– DO NOT CITE OR QUOTE 9 - 1 **9.0 PRELIMINARY REGULATORY DETE**  **RMINATION AND CHARACTERIZATION OF RISK FROM DRINKING WATER**  **9.1 Preliminary Regulatory Determination for Chemicals on the CCL**  The SDWA, as amended in 1996, required the U.S. EPA to establish a list of contaminants to aid the agency in regulatory

priority sett ing for the drinking water program. The list of contaminants is called the Contaminant Candidate L ist (CCL). U.S. EPA has thus far published three CCL s in 1998, 2005, and 2009, respectively . The final CCL 3 was published in the Federal Register on Octob er 8, 2009 (USEPA, 2009 c ; 74 FR 518 5 0 - 5 1 862). The SDWA requires U.S. EPA to make regulatory determinations for no fewer than five contaminants from each CCL . In cases where the agency determines that a regulation is necessary , the regulation should be pr oposed and then promulgated. The agency is given the freedom to determine that there is no need for a regulation if a chemical on the CCL fails to meet one or more of three criteria established b y the SDWA as described in Section 9.1.1. The agency ’s preli minary

regulatory

determination for strontium is presented formally in the Federal Register. This section summarizes the preliminary Regulatory Determination 3 decision for strontium. **9.1.1 Criteria for Regulatory Determination**  These are the three criteria use d to determine whether or not to regulate a chemical on the CCL :  The contaminant may have an adverse effect on the health of persons .  The contaminant is known to occur or there is a substantial likelihood that the contaminant will occur in public water s ys tems with a frequency and at levels of public health concern.  In the sole judgment of the Administrator, regulation of such contaminant presents a meaningful opportunity

for health risk reduction for persons served by public water sy stems. The findings for all criteria are used in making a determination to regulate a contaminant. As required b y the SDWA, a decision to regulate commits the agency to publication of a Maximum Contaminant Level Goal (MCLG) and promulgation of a National Primary Drinking Wat er Regulation (NPDWR) for that contaminant. The agency may determine that there is no need for a regulation when a contaminant fails to meet one or more of the criteria. A decision not to regulate is considered a final agency action and is subject to jud icial review. The agency can choose to publish a Health Advisory (a nonregulatory

action) or other guidance for any contaminant on the CCL , independent of the regulatory determination.EPA - OST Preliminary Health Effe cts Support Document for Strontium April 2014

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– DO NOT CITE OR QUOTE 9 - 2 **9.1.2 National Drinking Water Advisory Council Recommendations**  In March 20 00, the U.S. EPA convened a Working Group under the National Drinking Water Advisory

Council (NDWAC) to help develop an approach for making regulatory determinations. The Working Group developed a protocol for analyzing and presenting the available scient ific data and recommended methods to identify and document the rationale supporting a regulatory

determination decision. The NDWAC Working Group report was presented to and accepted by the entire NDWAC in July 2000. The Working Group developed separate b ut similar protocols for microorganisms and chemicals. The approach for chemicals was based on an assessment of the impact of acute, chronic, and lifetime exposures, as well as a risk assessment that includes evaluation of occurrence, fate, and dose - respo nse. The NDWAC protocol for chemicals provided a semi quantitative , sy stematic approach to addressing each of the three Regulatory Determination criteria. The U.S. EPA utilized NDWAC suggestions for Regulatory Determinations 1, 2, and 3. Because the pro cess used in developing CCL 3 was more data - driven than that used for CCL1 and CCL2, the process used to select the chemicals for Regulatory Determination 3 differed from the earlier Regulatory Determinations. The Regulatory Determination 3 process was formalized in a protocol document that was reviewed by an expert panel in October, 2011 and revised in response to reviewer suggestions (U.S. EPA, 2012b). Strontium was selected for Regulatory

Determination 3 based on the criteria outlined in the Protocol document. The quantitative and qualitative factors considered for each of the three criteria in making the Regulatory

Determination for strontium are presented in the sections that follow. **9.2 Health Effects**  **(Criterion #1)** The first criterion asks if the c ontaminant may have an adverse effect on the health of persons. Because all chemicals have adverse effects at some level of exposure, the challenge is to identify

a health reference level (HRL), a dose below which adverse health effects are considered unl ikel y to occur (threshold toxicant), or below which adverse effects have a defined low probability

of occurrence (non - threshold toxicant). The key elements that must be considered in evaluating the first criterion are the mode of action, the critical effe ct(s), the dose response for critical effect(s), the RfD for threshold effects, and the slope factor for non threshold effects. A full description of the health effects associated with exposure to strontium is presented in Chapter 7 of this document and s ummarized below in Section 9.2.2. Chapter 8 and Section 9.2.3 present dose - response information. **9.2.1 Hazard Characterization and Mode of Action Implications**  Several studies evaluated the relationship between strontium exposure or the body burden of strontium (as a measure of internal dose) and development of human disease following either occupational or environmental exposures (Curzon and Spector, 1977; Dawso n et al., 1978;EPA - OST Preliminary Health Effe cts Support Document for Strontium April 2014

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– DO NOT CITE OR QUOTE 9 - 3 Davies, 1979; 1984; St. Leger et al., 1980; Wang et al., 1990; L ongerich et al., 1991; Özgür et al., 1996). In these studies, the hy pothesis that strontium exposure might be correlated with effects other than those related to bone or teeth (i.e., neural tube defects, cancer mortalit y, or heart disease) was not supported (Dawson et al., 1978; Davies, 1979; 1984; St. Leger et al., 1980; Wang et al., 1990; Longerich et al., 1991), although these studies are limited by inadequate control for other factors potentially contributing to the endpoint being evaluated. Two studies evaluating the effect of environmental strontium exposure on bone (Özgür et al., 1996) or teeth (Curzon and Spector, 1977) reported increased signs and severit y of rickets with increasing strontium exposure and enamel mottling plus decreased dental caries, respectivel y . Several studies show that strontium levels are increased in people with renal failure, possibly

because renal failure patients have impaired strontium clear ance ( D’Haese et al., 1999, 2000; Vanholder et al., 2002; Cohen - Solal et al., 2002; De Broe and D’Haese, 2003 ) . In European clinics, “low dose” strontium as strontium ranelate is used as a therapy for osteoporosis because of its inhibition of bone resorption without reducing bone formation in adults (McClasin and James, 1959; Krane, 1977; ATSDR, 2004). Experimental animal studies indicate that strontium has low acute oral toxicity via ing estion ( Llobet et al., 1991; Ghosh et al., 1990; Woodard and Calvery , 1941) . The primary target of strontium exposure is the bone. The chemical similarity of strontium to calcium allows it to exchange imperfectly for calcium in a variet y of biological pr ocesses; the most important of these is its substitution for calcium in bone, affecting skeletal development and causing effects in animal studies similar to osteomalacia and rickets (Storey, 1961, 1962; Kshirsagar, 1976; Johnson et al, 1968; Marie et al., 1985; Marie and Hott, 1986; Gry npas and Marie, 1990; Neufeld and Boskey , 1994). Concerns have been raised about strontium’s interaction with the thy roid, based upon the data from Kroes et al. (1977) (see Table 8 - 1); however, the implications of the obser ved effects are unclear in light of the minimal reporting b y Kroes et al. (1977) and the absence of other studies reporting th yroid effects or supporting data on the thy roid’s th yroxin related and/or calciotropic hormone levels. Available data from limi ted reproductive/ developmental studies at strontium doses well above those causing bone effects indicate that strontium does not cause fetotoxicity or developmental effects on targets other than bone (Miki and Miy amota, 1968; Kroes et al., 1977; Skory na, 1981; Shibata and Yamashita, 2001; NIER, 2006c). The animal data suggest that adult animals are less sensitive than y oung animals to bone effects following strontium exposure. However no robust studies were located that provided good dose - response inform ation for bone effects in animals exposed to strontium during fetal development or perinatally . No studies are available that evaluated tumor formation in an adequate number of animals treated with strontium for an adequate duration. Only a single chroni c study

is available for oral strontium exposure (Skory na, 1981; Skoryna and Fuskova, 1981), and this study evaluated small numbers of animals for longer than the standard exposure duration (increasing the potential for age - related lesions and decreasing s tudy sensitivity). Therefore, the stud y was inadequate for evaluation of carcinogenic potential. Inhumans, there is no evidence for strontium carcinogenicity . Strontium compounds other than strontium chromate are negative inEPA - OST Preliminary Health Effe cts Support Document for Strontium April 2014

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– DO NOT CITE OR QUOTE 9 - 4 genotoxicity

studies, with the exception of one in vivo chromosome aberration assay that had several limitations in the reporting of stud y design and results (Ghosh et al., 1990). Therefore, the agency

determined that there is inadequate information to assess the carcinogenic poten tial of strontium , due to the lack of adequate studies of chronic duration. **9.2.2 Dose**  **- Response Characterization**  Two studies were considered co - critical for development of the strontium RfD (Marie et al., 1985; Gry

npas and Marie, 1990). The LOAELs in the c o - critical studies were 525 and 307 mg Sr/kg - day , respectively , based on effects such as hy pomineralization, increased bone mass or decreased calcification. These studies used diets containing 0.5% calcium, which is somewhat lower than t ypical rodent diet s; the lower calcium intake may have increased the sensitivity of the test animals. Benchmark dose modeling was performed using EPA’s Benchmark Dose Software, version 2.1, to derive the RfD. The model with the best overall fit was used. The RfD is deriv ed from the BMDL (1 SD) of 328 mg Sr/kg - day , for decreased bone calcification rate in male weanling rats (Marie et al., 1985), divided b y a composite UF of 1000. The composite UF is based on a factor of 10 for interspecies differences, a factor of 10 for protection of sensitive populations, and a factor of 10 for database uncertainties and deficiencies, including the small sample size in the critical studies, the absence of standard developmental or reproductive toxicity studies, and uncertainties regardin g differences in strontium uptake from different strontium compounds, somewhat countered b y the added sensitivity due to the low calcium diets in the critical studies. An RfD of 0.3 mg Sr/kg - day results. EPA calculated a non - cancer HRL of 1,500 μg/L fo r strontium using the RfD of 0.3 mg/kg/day , an RSC of 20%, and age - specific exposure factors (i.e., drinking water intake expressed as liters per kg of body weight) for the sensitive population of birth through 18 y ears to reflect the most active period of bone growth and development. There is inadequate information to assess the carcinogenic potential of strontium . D ue to the lack of adequate studies of chronic duration no cancer slope factor was calculated. **9.2.3 Health Criterion Conclusion**  The available to xicological data indicate that exposure to strontium has the potential to cause adverse health effects in humans and animals; bone is the primary target. A potential link between high strontium exposures and rickets in Turkish children was reported by Özgür et al. (1996), but the data were insufficient for identify ing the doses associated with this effect. No other epidemiology

study was located that evaluated bone effects following strontium exposure. Clinical studies are available (McClasin and James, 1959; Krane, 1977; D’Haese et al., 1999, 2000; Vanholder et al., 2002; Cohen - Solal et al., 2002; De Broe and D’Haese, 2003 ). However , these studies are limited to patients with bone disorders or chronic renal failure; thus, they are considered as part of human variability but are not appropriate for the basis of the RfD. Disruption of normal skeletal development, causing effects simil ar to osteomalacia and rickets in rats (y oung and adult) and mice has been reported following subchronic and chronicEPA - OST Preliminary Health Effe cts Support Document for Strontium April 2014

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– DO NOT CITE OR QUOTE 9 - 5 oral strontium exposure (Storey , 1961, 1962; Kshirsagar, 1976; Johnson et al, 1968; Marie et al., 1985; Marie and Hott, 1986; Gry npas and M arie, 1990; Neufeld and Boskey , 1994). Data to support the potential for effects on sy stems other than the skeleton are limited. Toxicological data from human and animal studies indicate that bone is a target of strontium toxicity . Data on decreased bone calcification in rats support the development of an HRLof 1,500 μg/L for human exposure via drinking water. Based on these considerations, EPA concludes that strontium meets the SDWA statutory criterion #1 for regulatory determinations; it may have an adverse effect on the health of persons. **9.3 Occurrence in Public Water Systems**  **(Criterion #2)** The second criterion asks if the contaminant is known to occur or if there is a substantial likelihood that the contaminant will occur in public water s ys tems w ith a frequency and at levels of public health concern. In order to address this question, the U.S. EPA consulted a variet y of information sources, including data from the National Inorganics and Radionuclides Survey (NIRS), a nationall y representative survey of ground water s ys tems conducted from 1984 to 1986. The U.S. EPA looked at the total number of sy stems that reported detections of strontium, as well as those that reported concentrations of strontium above the drinking water health reference level (HRL) of 1500 μg/L . The available monitoring data, including data that shed light on regional and national occurrence , are presented in Chapter 4 of this document and in Chapter 5 of the Regulatory Determinations 3 Support Document (USEPA, 2012b) , an d are summarized below. Additional information on production, use, and fate are found in Chapters 2 and 3 of this document and in Chapter 5 of the Regulatory Determinations 3 Support Document (USEPA, 2012b) . **9.3.1 Monitoring Data**  Concentrations of strontium f rom CWSs supplied from ground water sources were obtained from the NIRS, a nationally representative survey

conducted from 1984 to 1986. Strontium was monitored with a reporting level of 1 μg/L . The me an reported level was 603 μg/L, the mean for the detection was 603 mg/L and the maximum reported level was 43,500 μg/L (a value approximately 30 times the HRL). Sixty - nine of 989 s ys tems (6.98%) reported detections greater than the HRL . The national extrapolation from these findings suggests an estimat ed 2,79 8 ground water CWSs serving 10.0 million people nationally will have strontium concentrations exceeding the HRL . Review of the NI RS data shows that strontium was detected in all 50 states/entities in which it was sampled (i.e., in 49 states (all e xcept Hawaii) as well as Puerto Rico). I t was detected at levels greater than 1/2 the HRL(750 μg/L) in 34 states and at levels greater than the HRL(1,500 μg/L) in 26 states, including states in all regions of the country . Finished water data for stront ium from Ohio and Illinois are consistent with the NI RS data . The State of Il linois reported results from testing 21 drinking water samples from 19EPA - OST Preliminary Health Effe cts Support Document for Strontium April 2014

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– DO NOT CITE OR QUOTE 9 - 6 PWSs; strontium was detected in all 21 samples (100%) . Approximately 23.8% (5 of 21) of samples from five sy stems (26.3%) had strontium at levels greater than or equal 1⁄2 HRL (750 μg/L), and approximately 23.8% (5 of 21) of samples from five s ys tems (26.3%) had strontium at levels greater than or equal the HRL(1,500 μg/L). The State of Ohio reported results f rom testing 77 samples from 32 PWSs; strontium was detected in 75 samples (97.4%) from 30 sy stems (93.8%). Approximately 27.3% (21 of 77) of samples from 31.3% (10 of 30) of sy stems had strontium at levels greater than or equal 1⁄2 HRL, and approximately 23 .4% (18 of 77) of samples from 21.9% (7 of 30) of s ys tems had strontium at levels greater than or equal to the HRL(USEPA, 2012b). Finished water data from Ohio and Illinois come from both surface water and ground water sy stems; rates of strontium detecti on and HRL exceedance from the two source water t ypes are comparable. More limited monitoring data gathered from states by the Environmental Working Group confirm that strontium has been detected in PWSs within Wisconsin, I llinois, New York, Minnesota, an d Ohio. Ambient water data also show high levels of occurrence, which is expected since strontium is a naturally

occurring element. The NAWQA Quality of Public Supply

Wells (Toccalino et al., 2010) study collected water samples from source (untreated) gr oundwater public supply

wells in 41 states. Each well was sampled once from 1993 - 2007, and strontium was detected in 100% of samples (503 of 503). Of the detections, 25.8% (130 of 503) were above the 1⁄2 HRL (750 μg/L) and 12.3% (62 of 503) were above the HRL (1,500 μg/L). STORET, which includes data on ambient water, records strontium concentrations over 12,000 times greater than the HRL . **9.3.2 Occurrence Criterion Conclusion**  NI RS, a nationally

representative survey

of ground water, indicates that strontium concentrations exceed the HRLof 1,500 μg/L in 6.98% of PWSs, and in some cases the measured concentrations exceed the HRL b y large margins. The national extrapolation from these findings suggests an estimated 2,789 ground water CWSs serving 10.0 million people nationally will have strontium concentrations exceeding the HRL . In addition, the supplemental surface water data for strontium are consistent with the groundwater f indings and demonstrate the potential for high levels of occurrence in surface waters. Based on these considerations, the U.S. EPA concludes that strontium meets the SDWA statutory criterion #2 for regulatory determinations; it is known or likely to occur with a frequency and at levels of public health concern in PWSs . **9.4 Risk Reduction**  **(Criterion #3)** The third criterion asks if, in the sole judgment of the Administrator, regulation presents a meaningful opportunity

for health risk reduction for persons served by public water s ys tems. In evaluating this criterion, the U.S. EPA looked at several factors . Using the monitoring results, the U.S. EPA estimated the total exposed population and the population exposed to levels above the HRL. These estimates are included in Chapter 4 ofEPA - OST Preliminary Health Effe cts Support Document for Strontium April 2014

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– DO NOT CITE OR QUOTE 9 - 7 this document and summarized in Section 9.4.2 below. The U.S. EPA also evaluated the relative contribution of drinking water exposure and other routes of exposure (e.g., in food, via air, etc.) to overall risk. For example, if exposure to a contaminant occurs primarily through ambient air, regulation of emissions to air may provide a more meaningful opportunity for the U.S. EPA to reduce risk than regulation of the contaminant in drinking water. In making the preliminary regulatory

determination, the available information on exposure through drinking water (Chapter 4) and in formation on exposure through other media (Chapter 5) were used to estimate the fraction that drinking water contributes to the total exposure. These findings are discussed in Section 9.4.3 below. In evaluating the third criterion, the U.S. EPA also cons idered effects on potentially sensitive populations, including the fetus, infants, and children. Sensitive population considerations are discussed in Chapter 7 and in Section 9.4.4 below . **9.4.1 Exposed Population Estimates**  The U.S. EPA estimated the populations served by CWSs with water containing strontium at any

level, and at levels in excess of the HRLor 1⁄2 the HRL, based on extrapolation from stratified, random sampling of the nation’s community ground water supplies as they existed in the mid - 1980s, re corded in the NIRS database. According to NIRS data, among the population served nationally by CWSs rely ing on ground water, a total of 93.0 million people (99.9%) may be exposed to strontium in drinking water. A subset of 15.4 million (16.6%) may be exposed to concentrations in excess of 1⁄2 the HRL , and 10.0 million (10.7%) may be exposed to concentrations in excess of the HRL. These estimates do not include people who may be exposed to strontium from CWSs relying on surface water, or from public water supplies other than CWSs. **9.4.2 Relative Sources of Exposure**  The contribution of drinking water to total strontium exposure can be estimated by comparing the exposure expected via drinking water to the exposure from intake of strontium in other media, such as food, air, and soil (See Chapter 5). The intake of strontium from drinking water can be calculated from the NIRS ground water data, where the mean concentration among the detections was 603 μg/L . Using a 90 th percentile daily

intake of 2 L/day

for an adult, the daily

exposure would be 1,206 μg/day . For formula - fed infants, assuming a water intake of 1 L/day , the intake would be 603 μg/day . Although strontium is known to occur in food, air, and soil, data on levels in those media are limited, as are estimates of exposures from those sources. Food appears to be a more significant source than air and soil although the presence of strontium in both agricultural soils and drinking water can influence the levels in the diet . Dietary intakes based on an FDA Total Diet Study

by Pennington and Jones (1987) range from 493 to 685 μg/day for children 6 monthsEPA - OST Preliminary Health Effe cts Support Document for Strontium April 2014

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– DO NOT CITE OR QUOTE 9 - 8 to 2 y ears old , 928 to 1 , 388 μg/day for 14 - to 16 - year - old adolescents , and 979 to 1 , 489 μg/day for adults (ages 25 - 30 and 60 - 65). In another study , Iyengar et al. (2000) estimated dietary intake for 25 - 30 y ear old males to be 1 , 620 μg/day . Note that there is considerable variability in the strontium intake from both diet and water, and the data presented here are only estim ates . Estimated strontium intakes from air and soil are very low compared with those from food. Exposure from air has been estimated from data for levels of strontium in non - occupational air to be 0.1 μg/day

for children and 0.3 μg/day for adults. The estimates of intake from soil are 14 μg/day for infants, 24 μg/day

for children, and 12 μg/day for adults. It is possible to estimate the approximate contribution of drinking water from PWSs to total strontium exposure using the data presented in Chapte r 5 and OW general policies for bod y weight and drinking water intakes. However, many of these data are dated and some aspects of strontium exposure may

have changed. No data were identified on consumer products, such as toothpaste that contain strontium as an ingredient or impurity . Development of a MCL G in response to a positive Regulatory Determination will require an updated and more refined exposure assessment to determine the RSC. **9.4.3 Sensitive Populations**  Because strontium can substitute for calc ium in growing bone, the fetus, newborns, infants, children and young adults are a sensitive population. The estimated populations of pregnant women (and thus fetuses) and of children (<17 ye ars old) in the United States are 6 and 75 million, respectively (U.S. EPA, 1998c). Because many of the toxic effects of strontium result from strontium ions substituting for calcium ions, calcium deficiency would be expected to result in increased sensitivity . Frank calcium deficiency is uncommon, but long - term intake of calcium below recommended levels might have negative health consequences. Groups with higher risks of becoming calcium deficient include: teenage and postmenopausal women, amenorrheic women, female athletes, vegans, and individuals with lactose into lerance or cow’s milk allergies (I OM, 2010; NIH, 2011a) . Less than 1% of the population has an allergy to cow’s milk and approximately

25% of U.S. adults have a limited ability to digest lactose, including 85% of Asians, 50% of African Americans, and 10% of Caucasians (NIH, 2011a). Because the major route of elimination of strontium is via the kidney s, individuals with impaired renal function are another sensitive population. This population may potentiall y have impaired strontium clearance, as has been shown in renal failure patients. There are approximately

20,000,000 people (10%) above the age of 20 with chronic kidney disease (CDC, 2010) and 547,982 people with kidney end - stage renal disease (USRDS, 2010), who may thus be at an increased risk. Peopl e with disorders affecting the normal equilibrium between the breakdown of old bone and the formation of new bone (such as Paget’s disease) might also be sensitive to strontium exposure. According to the National Institute of Arthritis and Musculoskeletal Diseases , there are approximately 1 million people (1.2 people per 100 men and women age 45 to 74) diagnosed with Paget’s disease of the bone (NIH, 2011b). The disease is more common inEPA - OST Preliminary Health Effe cts Support Document for Strontium April 2014

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– DO NOT CITE OR QUOTE 9 - 9 older people and those of northern European heritage. Men are about twice as likely as women to have th is disorder . **9.4.4 Risk Criterion Conclusion**  Based on data from NIRS, an estimated 10.0 million people are exposed nationally to levels of strontium greater than the HRL (1500 μg/L). The measured concentrations in NI RS exceed the HRL b y large margins in some water systems. STORET, which includes data on ambient water, records strontium concentrations up to 13,000 times greater than the HRL . Approximately

40 - 9 0% of strontium exposure is estimated to come from drinking water; food is the second - most - significant source of exposure. Potentially sensitive populations include fetuses, infants and children, as well as calcium - deficient individuals and those with impa ired renal function and Paget’s disease. The U.S. EPA finds that strontium meets the SDWA statutory criterion #3 for regulatory determinations; regulation of strontium presents a meaningful opportunity for health risk reduction in drinking water based on the estimated exposed population and potential impacts on sensitive populations. **9.5 Regulatory Determination Decision**  As stated in Section 9.1.1, a positive finding for all three criteria is required in order to make a determination to regulate a contami nant. The U.S. EPA has made a preliminary determination that strontium meets all three criteria. Strontium has the potential to cause adverse health effects to the bone, based on toxicological data from animal studies, limited human data and an understan ding of its mode of action. Strontium is known to occur in PWSs with a frequency and at levels of public health concern. Data from NIRS indicate that strontium concentrations exceed the HRLof 1,500 μg/L in 6.98% of ground water CWSs, and suggest that an estimated 10.0 million people nationall y may be exposed to strontium in drinking water from PWSs at levels of health concern. Due to the large number of people exposed to strontium through drinking water and the potentially high concentration of strontium measured in these PWSs, regulation of strontium presents a meaningful opportunity

for health risk reduction for persons served by PWSs, especially

for those with developing bones (such as infants, children, and adolescents), individuals deficient in calc ium, and persons with kidney conditions. Additional information about the preliminary regulatory

determination can be found in the Federal Register Notice.EPA - OST Preliminary Health Effe cts Support Document for Strontium April 2014

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– DO NOT CITE OR QUOTE 10 - 1 **10.0 REFERENCES**  Abrams, S. A., K. C. Copeland, S. K. Gunn, et al. 2000. Calcium absorption, bone mass accumulation, and kinetics increase during earl y pubertal development in girls. J. Clin. Endocr. Metab. 85(5):1805 - 1809 (as cited in IOM, 2010). Alda, J.O. and J.F. Esc anero. 1985. Transport of calcium, magnesium and strontium by human serum proteins. Rev. Esp. Fisiol. 41:145 - 150 (as cited in ATSDR, 2004). Alexander, F.W., B.E. Clay ton, and H.T. Delves. 1974. Mineral and trace - metal balances in children receiving norma l and sy nthetic diets. Q. J. Med. XLIII:89 - 111 (as cited in ATSDR, 2004). ANL (Argonne National Laboratory). 2007. Radiological and chemical fact sheets to support health risk anal ys es for contaminated areas. Environmental Science Division. Available from : <http://www.evs.anl.gov/pub/doc/ANL_ContaminantFactSheets_All_070418.pdf>. ATSDR (Agency

for Toxic Substances and Disease Registry). 2004. Toxicological Profile for Strontium. Atlanta, GA: U.S. Department of Health and Human Services, Public Health Serv ice. Available from: <http://www.atsdr.cdc.gov/ToxProfiles/tp.asp?id=656&tid=120>. Barnes, K. 1997. Trace metal determinations in fruit, juice, and juice products using an axially viewed plasma. Atom. Spectrosc. 18(3):84 - 100. Bartholomay , R.C., J.M. Cart er, S.L. Qi, et al . 2007. Summary of Selected U.S Geological Survey Data on Domestic Well Water Quality for the Centers for Disease Control's National Environmental Public Health Tracking Program. U.S. Geological Survey Scientific Investigations Report 200 7 - 5213. 57 pp. Available from : < http://pubs.usgs.gov/sir/2007/5213/ > . Berg, D., E. Oberhausen, and H. Muth. 1973. Interaction of 47 Ca, 85 Sr, 133 Ba, and 226 Ra with serum proteins. Bioph ys ik (German). 10:309 - 319 (as cited in ATSDR, 2004). Bianchi, M.L., G .L . Ardissino, C.P. Schmitt, et al. 1999. No difference in intestinal strontium absorption after an oral or an intravenous 1,25(OH)2D3 bolus in normal subjects. J. Bone Miner. Res. 14(10):1789 - 1795 (as cited in ATSDR, 2004). Blumsohn, A., B. Morris, and R . Eastell. 1994. Stable strontium absorption as a measure of intestinal calcium absorption: Comparison with the double - radiotracer calcium absorption test. Clin. Sci. 87:363 - 368 (as cited in ATSDR, 2004). Bronner, F., J.P. Aubert, L.J. Richelle, et al. 19 63. Strontium and its relationship to calcium metabolism. J. Clin. Invest. 42(7):1095 - 1104. Bunde, R.L., J.J. Rosentreter, M.J. L iszewski, et al. 1997. Effects of calcium and magnesium on strontium distribution coefficients. Environ. Geol. 32(3):219 - 229 (as cited in ATSDR, 2004).EPA - OST Preliminary Health Effe cts Support Document for Strontium April 2014

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– DO NOT CITE OR QUOTE 10 - 2 Bunde, R.L., J.J. Rosentreter, and M.J. L iszewski. 1998. Rate of strontium sorption and the effects of variable aqueous concentrations of sodium and potassium on strontium distribution coefficients of a surficial sediment at the Idaho National Engineering Laboratory, Idaho. Environ. Geol. 34(2/3):135 - 142 (as cited in ATSDR, 2004). Cabrera, W.E., I. Schrooten, M.E. De Broe, et al. 1999. Strontium and bone. J. Bone Miner. Res. 14:661 - 668. Capo, R.C., B.W Stewart, and O.A. Chadwick. 1998. Strontium isotopes as tracers of ecosy stem processes: theory

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– S139. Cohen - Solal, M.E., F. Augry , Y. Mauras, et al. 2002. Fluoride and strontium accumulati on in bone does not correlate with osteoid tissue in dialysis patients. Nephrol. Dial. Transplant. 17:449 - 454 (as cited in De Broe and D’Haese, 2003). Comar, C.L . and R.H. Wasserman. 1964. Strontium, Chapter 23. In: Comar, C.L . and F. Brenner. (eds.). Min eral metabolism, Vol. II, Part A. New York and London: Academic Press. pp. 523 - 572 (as cited in U.S. EPA, 1992). Comar, C.L ., R.H. Wasserman, S. Ulberg, et al. 1957. Strontium metabolism and strontium calcium discrimination in man. P. Soc. Exp. Biol. Med. 95:386 - 391. Comar, C.L ., R.H. Wasserman, and A.R. Twardock. 1961. Secretion of calcium and strontium into milk. Health Phy s. 7:69. Cooper, C., N. Harvey , K. Javaid, et al . 2008. Growth and bone development. In: Barker, D.J.P. (ed). The Window of Opportunity : Pre - Pregnancy to 24 Months of Age. Vol. 61, pp 53 - 68. Basel, Karger. Cotton, F.A. and G. Wilkenson. (eds.). 1980. Beryllium and the group II element: Mg, Ca, Sr,EPA - OST Preliminary Health Effe cts Support Document for Strontium April 2014

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– DO NOT CITE OR QUOTE 10 - 3 Ba, Ra. In: Advanced inorganic chemistry : A comprehensive test. New York, NY: John Wile y & Sons, Inc. (as cited in ATSDR, 2004). Corradino, R.A. and Wasserman, R.H. 1970. Strontium inhibition of vitamin D3 - induced calcium - binding protein (CaBP) and calcium absorption in chick intestine. Proc. Soc. Exp. Biol. Med. 133(3):960 - 963. Coulombe, J., H. Faure, B. Robin, et al. 2004. In vitro effects of strontium ranelate on the extracellular calcium - sensing receptor. Biochem. Biophy s. Res. Com. 323:1184 - 1190. Cuddihy , R.G. and J.A. Ozog. 1973. Nasal absorption of CsCl, SrCl 2 , BaCl 2 and CeCl 3 in Sy rian hamsters. Health Ph ys . 25:219 - 224 (as cited in ATSDR, 2004). Curzon, M.E.J. 1981. An epidemiologic stud y of strontium on human dental caries. Biol. Trace Elem. Res. 3:309 - 316 (as cited in WHO, 2010). Curzon, M.E.J. and P.C. Spector. 1977. Enam el mottling in a high strontium area of the USA. Community

Dent. Oral. 5:243 - 247 (as cited in WHO, 2010). Dahl, S.G., P. Allan, P.J. Marie, et al. 2001. Incorporation and distribution of strontium in bone. Bone. 28(4):446 - 253. Davies, J. 1979. Lung cance r mortalit y of workers in chromate pigment manufacture: an epidemiological survey . J. Oil Colour Chem. As. 62:157 - 163. Davies, J. 1984. Lung cancer mortalit y among workers making lead chromate and zinc chromate pigments at three English factories. Brit. J . Ind. Med. 41:158 - 169. Dawson, E.B., M.J. Frey , T.D. Moore, et al. 1978. Relationship of metal metabolism to vascular disease mortality

rates in Texas. Am. J. Clin. Nutr. 31:1188 - 1197 (as cited in WHO, 2010). De Broe, M.E. and P.C. D’Haese. 2003. Stront ium and osteomalacia in renal failure patients. Nephrol. Dial. Transplant. 18:215 - 218. D’Haese, P.C., M.M. Coutteny e, L.V. Lamberts, et al. 1999. Aluminum, iron, lead, cadmium, copper, zinc, chromium, magnesium, strontium, and calcium content in bone of e nd - stage renal failure patients. Clin. Chem. 45(9):1548 - 1556. D’Haese, P.C., I . Schrooten, W.G. Goodman, et al. 2000. Increased bone strontium levels in hemodialy sis patients with osteomalacia. Kidney I nt. 57:1107 - 1114. DeSimone, L .A. 2009. Quality of Water from Domestic Wells in Principal Aquifers of the United States, 1991 - 2004 . U. S. Geological Survey Scientific Investigations Report 2008 - 5227. 139 pp. Available from : < //pubs.usgs.gov/sir/2008/5227/ > . Accessed July 28, 2009.EPA - OST Preliminary Health Effe cts Support Document for Strontium April 2014

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– DO NOT CITE OR QUOTE 10 - 4 Donohue, J.M., C.O. Abernath y , P. Lassovszky , et al. 2005. The contribution of drinking water to total daily

dietary intakes of selected trace mineral nutrients in the United States. Nutrients in Drinking Water. World Health Organization. Available from: <http://www.who.int/w ater_sanitation_health/dwq/nutrientsbegin.pdf>. Dzubay , T.G. and R.K. Stevens. 1975. Ambient air anal ys is with dichotomous sampler and x - ray fluorescence spectrometer. Environ. Sci. Technol. 9(7):663 - 668 (as cited in ATSDR, 2004; WHO, 2010). Eisenberg, E . and G.S. Gordan. 1961. Skeletal d ynamics in man measured by nonradioactive strontium. J. Clin. Invest. 40:1809 - 1825. EWG. ( Environmental Working Group ) . 2005. A National Assessment of Tap Water Quality . Formerl y available on the Internet. Accessed November 30, 2009. EWG (Environmental Working Group) . 2009. National Drinking Water Database. Available from : < http://www.ewg.org/tap - water/home > . Accessed January 10, 2010. Farr, J.N., S. Amin, L .J. Milton et al. 2014. Bone strength and structural defects in children and adolescents with distal forearm fractures due to mild trauma. J. B one Min. Res. 29 (3):590 - 599 . Federman, J.H. and J.J. Sachter. 1997. Status asthmaticus in a paramedic following exposure to a roadside flare: a case report. J. Emerg. Med. 15(1):87 - 89 (cited in ATSDR, 2004; WHO, 2010). Fisch, C., M. Attia, F. Dargent, et al. 2006. Preclinical assessment of gastroesophageal tolerance of the new antiosteoporotic drug strontium ranelate: an en doscopic stud y in monkey s. Basic Clin. Pharmacol. 98:442 - 446 (as cited in WHO, 2010). Fission Product Inhalation Project. 1967a. Toxicity of inhaled 90 Sr in beagle dogs. In: Fission product inhalation program annual report 1966 - 1967. Albuquerque, NM: Love lace Foundation for Medical Education and Research (as cited in ATSDR, 2004). Fission Product Inhalation Project. 1967b. Toxicity of inhaled 90 Sr in rats. In: Fission product inhalation program annual report 1966 - 1967. Albuquerque, NM: Lovelace Foundation for Medical Education and Research (as cited in ATSDR, 2004). Forbes, G.B. and J.C. Reina. 1972. Effect of age on gastrointestinal absorption (Fe, Sr, Pb) in the rat. J. Nutrition. 102:647 - 652 (as cited in ATSDR, 2004). FSAI (Food Safet y Authority of Ireland). 2011. Report on a T otal D iet S tudy carried out by

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ton, F.E., (eds.). Patty ’s indu strial hy giene and toxicology , 3rd rev. ed. Vol. IIA. New York, NY: Wiley - Interscience, John Wiley & Sons (as cited in WHO, 2010).EPA - OST Preliminary Health Effe cts Support Document for Strontium April 2014

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– DO NOT CITE OR QUOTE 10 - 15 Storey , E. 1961. Strontium "rickets": Bone, calcium and strontium changes. Australas. Ann. Med. 10:213 - 222. Storey , E. 1962 . I ntermittent bone changes and multiple cartilage defects in chronic strontium rickets in rats. J. Bone Joint Surg. (American volume). 44B(1):194 - 208 (as cited in ATSDR, 2004; WHO, 2010). Sutton, A., G.E. Harrison, and T.E.F. Carr. 1971a. Reduction in th e absorption of dietary strontium in children by

an alginate derivative. Int. J. Radiat. Biol. 19(1):79 - 80 (as cited in ATSDR, 2004). Sutton, A., H. Shepherd, G.E. Harrison, et al. 1971b. Excretion and retention of stable strontium in children. Nature. 23 0:396 - 397 (as cited in ATSDR, 2004). Svensson, O., A. Hjerpe, F.P. Reinholt, et al. 1985. The effect of strontium and manganese on freshl y isolated chondrocytes. Acta Path. Micro. Im. A. 93:115 - 120 (as cited in ATSDR, 2004; WHO, 2010). Svensson, O., F.P. Reinholt, and B. Engfeldt. 1987. The parathy roid gland in metal rickets: a stereological stud y. Acta Path. Micro. Im. A . 95:309 - 314 (as cited in ATSDR, 2004; WHO, 2010). Sweet, C.W., S.J. Vermette, and S. L andsberger. 1993. Sources of toxic trace element s in urban air in I llinois. Environ. Sci. Technol. 27(12):2502 - 2510 (as cited in ATSDR, 2004; WHO, 2010). Tanaka, G. I., H. Kawamura, and E. Nomura. 1981. Reference Japanese man -- II: Distribution of strontium in the skeleton and in the mass of mineralized bone. Health Phy s. 40:601 - 614. Tateno, H. and Y. Kamiguchi. 1997. Parthenogenetic activation of Chinese hamster oocy tes b y chemical stimuli and its cytogenetic evaluation. Mol. Reprod. Dev. 47:72 - 78 (as cited in WHO, 2010). Tautkus, S., D. Uzdaviniene, I . Pakutinskiene, et al. 2007. Determination of strontium in milk by flame atomic absorption spectrometry . Polish J. Environ. Stud. 16(5):771 - 775. Tipton, I .H. and M.J. Cook. 1963. Trace elements in human tissue: Part II: Adult subjects from the United States. Health Phy s. 9:103 - 145 (as cited in ATSDR, 2004). Toccalino, P.L., J.E. Norman, and K.J. Hitt. 2010. Quality of Source Water from Public - supply Wells in the United States, 1993 - 2007. U.S. Geological Survey Scientific Investigations Report 2010 - 5024. 206 pp. Available from : <//pubs.usgs.gov/sir/2010/5024/ > . Tolsty kh, E.I., V.P. Kozheurov, O.V. Vy ushkova, et al. 1997.Anal ys is of strontium metabolism in humans on the basis of the Techa river data. Radiat. Environ. Bioph. 36:25 - 29.EPA - OST Preliminary Health Effe cts Support Document for Strontium April 2014

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– DO NOT CITE OR QUOTE 10 - 16 Tolsty kh, E.I., M.O. Degteva, V.P. Kozheurov, et al. 1998. Strontium transfer from maternal skeleton to the fetus estimated on the basis of the Techa river data. Radiat. Prot. Dosim. 79(1 - 4):307 - 310 (as cited in ATSDR, 2004). Tolsty kh, E.I., M.O. Degteva, M.I. Vorobiova, et al. 2001. Fetal dose assessment for the offspring of the Techa riverside residents. Radiat. Environ. Bioph. 40(4):279 - 286 (as cited in ATSDR, 2004). Tothill, P., M.A. Smith, and S.H. Cohn. 1983. Whole - body and part - body

turnover of 85 Sr in Paget's disease. Phy s. Med. Biol. 28(2):149 - 159 (as cited in ATSDR, 2004). Twardock, A.R., E.Y.H. Kuo, M.K. Austin, et al. 1971. Protein binding of calcium and strontium in guinea pig maternal and fetal blood plasma. Am. J. Obstet. Gy necol. 110(7):1008 - 1014 (as cited in ATSDR, 2004). Uchiy ama, M., G. Tanaka, and E. Yabumoto. 1973. 85 Sr retention in Japanese after a single administration. J. Radiat. Res. 14:169 - 179 Underwood, E.J. 1977. Trace elements i n human and animal nutrition, 4th ed. New York, NY: Academic Press. pp. 445 - 448 (as cited in Cabrera et al. 1999). United Kingdom. 2009. Measurement of the concentrations of metals and other elements from the 2006 UK Total Diet Study . http://multimedia.fo od.gov.uk/multimedia/pdfs/fsis0109metals.pdf U.S. EPA (United States Environmental Protection Agency). 1986a. Guidelines for the health risk assessment of chemical mixtures. Fed. Reg. 51(185):34014 - 34025. U.S. EPA (United States Environmental Protection Agency). 1986b. Guidelines for mutagenicit y risk assessment. Fed. Reg. 51(185):34006 - 34012. U.S. EPA (United States Environmental Protection Agency). 1988. Recommendations for and documentation of biological values for use in risk assessment. EPA 600/6 - 87/008. Available from: National Technical Information Service, Springfield, VA; PB88 - 179874/AS. U.S. EPA (United States Environmental Protection Agency). 1991. Guidelines for developmental toxicity risk assessment. Fed. Reg. 56(234):63798 - 63826. U.S. EPA (United States Environmental Protection Agency). 1992. Strontium (CASRN 7440 - 24 - 6). Integrated Risk Information Sy stem (IRI S) . Washington, DC, United States Environmental Protection Agency . Available from: <http://www.epa.gov/ncea/iris/subst/0550.htm>. U.S. EPA (United States Environmental Protection Agency). 1994a. Interim policy for particle size and limit concentration issues in inhalation toxicity studies. Fed. Reg. 59(206):53799.EPA - OST Preliminary Health Effe cts Support Document for Strontium April 2014

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– DO NOT CITE OR QUOTE 10 - 17 U.S. EPA (United States Environmental Protection Agency). 1994b. Methods for derivation of inhalation reference concentrations and application of inhalation dosimetry. EPA/600/8 - 90/066F. Available from: National Technical Information Service, Springfield, VA; PB2000 - 500023, and <http://www.epa.gov/iris/backgrd.html>. U .S. EPA (United States Environmental Protection Agency). 1995. Use of the benchmark dose approach in health risk assessment. U.S. Environmental Protection Agency . EPA/630/R - 94/007. Available from: National Technical Information Service, Springfield, VA; PB 95 - 213765, and <http://www.epa.gov/iris/backgrd.html>. U.S. EPA (United States Environmental Protection Agency). 1996. Guidelines for reproductive toxicity risk assessment. Fed. Reg. 61(212):56274 - 56322. Available from: <http://www.epa.gov/iris/backgrd.html>. U.S. EPA (United States Environmental Protection Agency). 1998a. Guidelines for neurotoxicity risk assessment. Fed Reg 63(93):26926 - 26954. Available from: <http://www.epa.gov/iris/backgrd.html>. U.S. EPA (United States Environmental Protection Agenc y). 1998b. Chromium (VI) (CASRN 18540 - 29 - 9 ). Integrated Risk Information Sy stem (I RI S) . Washington, DC, United States Environmental Protection Agency . Available from: <http://www.epa.gov/iris/subst/0144.htm>. U.S. EPA (United States Environmental Protect ion Agency). 1998c. Demographic distribution of sensitive populations groups. O'Day , R., Rench, J., Oen, R., Castro, A. Office of Science and Technology , Health and Ecological Criteria divisions. Contract Number 68 - C6 - 0036. SRA 557 - 05/14. February

24. U.S . EPA (United States Environmental Protection Agency). 2000a. Science Policy Council Handbook: peer review. 2nd edition. Prepared b y the Office of Science Policy , Office of Research and Development, Washington, DC. EPA 100 - B - 00 - 001. Available from: <http://www.epa.gov/iris/backgrd.html>. U.S. EPA (United States Environmental Protection Agency). 2000b. Benchmark dose technical guidance document [external review draft]. EPA/630/R - 00/001. Available from: <http://www.epa.gov/iris/backgrd.html>. U.S. EPA (Unit ed States Environmental Protection Agency). 2000c. Supplemental guidance for conducting for health risk assessment of chemical mixtures. EPA/630/R - 00/002. Available from: <http://www.epa.gov/iris/backgrd.html>. U.S. EPA (United States Environmental Prote ction Agency). 2000d. Cancer risk coefficients for environmental exposure to radionuclides, CD Supplement [CD - ROM]. Federal Guidance Report No. 13. EPA 402/C - 99 - 001. U.S. EPA (United States Environmental Protection Agency). 2002. A review of the referenceEPA - OST Preliminary Health Effe cts Support Document for Strontium April 2014

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– DO NOT CITE OR QUOTE 10 - 18 dose and reference concentration processes. Risk Assessment Forum, Washington, DC; EPA/630/P - 02/0002F. Available from: <http://www.epa.gov/iris/backgrd.html>. U.S. EPA (United States Environmental Protection Agency). 2005a. Guidelines for carcinogen risk assessment. Risk Assessment Forum, Washington, DC; EPA/630/P - 03/001B. Available from: <http://www.epa.gov/iris/backgrd.html>. U.S. EPA (United States Environmental Protection Agency). 2005b. Supplemental guidance for assessing susceptibility

from earl y - life exposure to carcinogens. Risk Assessment Forum, Washington, DC; EPA/630/R - 03/003F. Available from: <http://www.epa.gov/iris/backgrd.html>. U.S. EPA (United States Environmental Protection Agency). 2006a. Peer review workshop report on “Draft fr amework for assessing health risks of environmental exposures to children”. National Center for Environmental Assessment, Washington, DC; EPA/600/R - 06/123. Available from: <http://www.epa.gov/iris/backgrd.html>. U.S. EPA (United States Environmental Prote ction Agency). 2006b. A framework for assessing health risks of environmental exposures to children. National Center for Environmental Assessment, Washington, DC; EPA/600/R - 05/093F. Available from: <http://www.epa.gov/iris/backgrd.html>. U.S EPA (United S tates Environmental Protection Agency). 2008a. Child - Specific Exposure Factors Handbook. EPA/600/R - 06/096F. Available from: <http://cfpub.epa.gov/ncea/cfm/recordisplay .cfm?deid=199243>. U.S . EPA (United States Environmental Protection Agency). 2008b. The Analy sis of Occurrence Data from the Unregulated Contaminant Monitoring (UCM) Program and National Inorganics and Radionuclides Survey (NI RS) in Support of Regulatory Determinations for the Second Drinking Water Contaminant Candidate List . Office of Water. EPA 815 - R - 08 - 014. 120 pp. U.S . EPA (United States Environmental Protection Agency). 2009a. The Analy sis of Regulated Contaminant Occurrence Data from Public Water Sy stems in Support of the Second Six - Year Review of National Primary Drinking Water Regulat ions. EPA - 815 - B - 09 - 006. October 2009. U.S . EPA (United States Environmental Protection Agency). 2009b. Community Water Sy stem Survey 2006, Draft 3.5. EPA 815 - R - 09 - 001. U.S . EPA (United States Environmental Protection Agency). 2009 c . Drinking Water Contam inant Candidate List 3

–Final. Federal Register. Vol. 74, No. 194, p. 51850, October 8, 2009. U.S . EPA (United States Environmental Protection Agency). 2012a. Protocol for the Regulatory Determination s 3.EPA - OST Preliminary Health Effe cts Support Document for Strontium April 2014

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– DO NOT CITE OR QUOTE 10 - 19 U.S . EPA (United States Environmental Protection A gency). 2012b. Regulatory Determination s 3 Support Document . U.S . EPA (United States Environmental Protection Agency). 2012c. Storage and Retrieval (STORET) Data Warehouse . Available from : <http://www.epa.gov/storet/index.html > . Data Warehouse consulted July 2009. U.S. EPA (United States Environmental Protection Agency). 2010a. Non - confidential Inventory Update Reporting (IUR) Production Volume I nformation. Available from: <http://www.epa.gov/iur/index.html>. U.S. EPA (United States Environmental Protection Agency ). 2010b. TRI Chemicals . Available from: <http://www.epa.gov/tri/trichemicals/>. USGS (United States Geological Survey ). 1980. Elements in fruits and vegetables from areas of commercial production in the conterminous United States: Geological survey professional paper 1178: A biogeochemical study of selected food plants based on field sampling of plant material and soil. USGS (United States Geological Survey ). 1999. Strontium. Minerals Commodity Summaries. 166 - 167. Available from: <http://minerals.usgs.gov/minerals/pubs/commodity/strontium/850399.pdf> (as cited in ATSDR, 2004). USGS (United States Geological Survey ). 2002. Strontium. Minerals Commodity Summaries. 160 - 161. Available from: <http://minerals.usgs.gov/mi nerals/pubs/commodity/strontium/850302.pdf> (as cited in ATSDR, 2004). USGS (United States Geological Survey ). 2009a. Mineral Commodities Summary for Strontium. Available from: <http://minerals.usgs.gov/minerals/pubs/commodity /strontium/mcs - 2009 - stron.pdf >. USGS (United States Geological Survey ). 2009b. 2009 Mineral Yearbook: Strontium [Advance Release]. Available from: <http://minerals.usgs.gov/minerals/pubs/commodity /strontium/my

b1 - 2009 - stron.pdf>. USRDS (United States Renal Data S ys tem). 2010. USRDS 2 010 Annual Data Report. Available online at: www.usrds.org/adr.htm . Accessed November 8, 2010. (The USRDS End - Stage Renal Disease Incident and Prevalent Quarterl y Update is available at www.usrds.org/qtr/default.html .) Vanholder, R., R. Cornelis, A. Dhondt, et al. 2002. The role of trace elements in uraemic toxicity . Nephrol. Dial. Transplant. 17(Suppl 2):2 - 8.EPA - OST Preliminary Health Effe cts Support Document for Strontium April 2014

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– DO NOT CITE OR QUOTE 10 - 20 Vezzoli, G., I . Baragetti, S. Zerbi, et al. 1998. Strontium absorption and excretion in normoclaciuric subjects: Relation to calcium metabolism. Clin. Chem. 44(3):586 - 590. Wakamori, M., M. Strobeck, T. Niidome, et al. 1998. Functional characterization of ion permeation pathway

in the N - ty

pe Ca 2+ channel. J. Neurophy siol. 79:622 - 634. Wang, Y., J. Qin, S. Wu, et al. 1990. Study on the relation of Se, Mn, Fe, Sr, Pb, Zn, Cu, and Ca to liver cancer mortalit y from anal ys is of scalp hair. Sci. Total Environ. 91 :191 - 198 (as cited in WHO, 2010). Warren, J.M. and H. Spencer. 1976. Metabolic balances of strontium in man. Clin. Orthop. Relat. R . 117:307 - 320. Wenger, P. and K. Soucas. 1975. Retention and excretion curves of persons containing 90 Sr and 226 Ra after a chronic contamination. Health Phy s. 28:145 - 152 (as cited in ATSDR, 2004). Weast, R.C. and M.J. Astle. (eds.). 1981. CRC Handbook of Chemistry and Phy sics. 62 nd edition. Boca Raton, FL: CRC Press. WHO (World Health Organization). 2010. Concise Internation al Chemical Assessment Document 77. Strontium and Strontium Compounds. Available from: <http://www.inchem.org/documents/cicads/cicads/cicad77.pdf>. Willard, D.H. and M.D. Sny der. 1966. Strontium inhalation studies. In: Thompson, R.C. and E.G. Swezea. (eds .). Pacific Northwest Laboratory annual report for 1965 in the biological sciences. Richland, WA: Pacific Northwest Laboratory , BNWL - 280. pp. 53 - 55 (as cited in ATSDR, 2004). Witz, S., J.A. Wood, and M.W. Wadley . 1986. Toxic metal and hy drocarbon concentr ations in automobile interiors during freeway transit. Proceedings of the American Chemical Society Division of Environmental Chemistry 192 nd National Meeting. 26:302 - 305 (as cited in ATSDR, 2004; WHO, 2010). Wood, RJ. 2000. Calcium and Phosphorous. In: S tepanuk, MH. Biological and Phy siological Aspects of human Nutrition. WB Saunders company . Philadelphia PA. Woodard, G. and H.O. Calvery . 1941. Unpublished investigation. Washington, DC, United States Food and Drug Administration, Division of Pharmacolog y (as cited in WHO, 2010). Yang, S. 1984. Short - term test programme sponsored b y the Division of Cancer Biology, National Cancer Institute, US . CCRI S record no. 3203. Available from: <http://toxnet.nlm.nih.gov/cgi - bin/sis/htmlgen?CCRI S> (as cited in WHO 2 010). Yawo, H. 1999. Two components of transmitter release from the chick ciliray pres yn aptic terminal and their regulation by protein kinase C. J. Phy siol. 516(2):461 - 470.EPA - OST Preliminary Health Effe cts Support Document for Strontium April 2014

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– DO NOT CITE OR QUOTE 10 - 21 Zerbino, D.D. and T.N. Solomenchuk. 2007. [My ocardial infarction at the age under 50: In fluence of occupational xenobiotics (analy sis of chemical elements in hair of patients)]. Med. Tr. Prom. Eko. 2:17 - 21. Abstract onl y. Zhai, H., W. Hannon, G.S. Hahn, et al. 2000a. Strontium nitrate decreased histamine - induced itch magnitutde and du ration in man. Dermatology. 200:244 - 246. Zhai, H., W. Hannon, G.S. Hahn, et al. 2000b. Strontium nitrate suppresses chemicall y - induced sensory irritation in humans. Contact Dermatitis. 42:98 - 100. Zittermann, A., P. Bock, C. Drummer, et al. 2000. La ctose does not enhance calcium bioavailability

in lactose - tolerant, health y adults. Am. J Clin. Nutr. 71:931 - 936. Zy uzy ukin, Y.V. 1974. [Title not given.] Gigiena i Sanitariia. 39:99 (as cited in Stokinger, 1981; WHO, 2010). Zy uzy ukin, Y.V. and E.P. Makolkina. 1979. [Effect of strontium carbo - nate on the respiratory organs.] Gigiena Truda i Profession - al’n ye Zabolevaniia. 11:53 - 54 (in Russian, translated b y Ralph McElroy

Co., Austin, TX; National Translations Centre PTR - 81 - 162, Code 332 - 5672 - 2) (as cited in WHO , 2010).EPA - OST Preliminary Health Effe cts Support Document for Strontium April 2014

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– DO NOT CITE OR QUOTE A - 1 **APPENDIX A. Summary of Data from Key Animal Studies**  **Table A -**  **1 Summary of Relevant Animal Toxicity Studies** 

**Species, Strain, Sex, Age**  **Form of**

**Strontium and Dosing**  **Medium Doses** 

**(m g Sr/k** **g**   ** bw** **/day) Animals** 

**per sex per dose**  **Exposure**

**Duration NOAEL** 

**mg/kg -**  **day LOAEL** 

**mg/kg -**  **day Critical Effect**  **Comment Reference**  Monkey, NS Chloride, oral

capsule 1100 NA 7 days -- 1100 Local irritation of the GI tract Effects observed occurred at

the portal of entry, do not appear to be systemic effects associated with high dose exposure. Irritation caused hemorrhage and erosive lesions of the esophagus and upper duodenum Fisch et al. (2006)

Rat, Wistar, M/F, Weanling Chloride hexa hydrate, Diet 0, 0.1, 1.1, 11,

110 3 14 days 110 -- No reported effect on bone histology, but effects on bone were not specifically evaluated. No effects on clinical signs, organ weight, tissue histopathology, or hematology. The diet contained 0.85%

Ca, 0.75% P, 0.05% Mg and 1.8 IU Vitamin D3 /g. These am ounts were said to be “adequate” levels by the study author. Assuming young rats consume feed at an amount equivalent to about 10% of their body weight per day. Kroes et al. (1977)EPA - OST Preliminary Health Effe cts Support Document for Strontium April 2014

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– DO NOT CITE OR QUOTE A - 2 **Species, Strain, Sex, Age**  **Form of**

**Strontium and Dosing**  **Medium Doses** 

**(m g Sr/k** **g**   ** bw** **/day) Animals** 

**per sex per dose**  **Exposure**

**Duration NOAEL** 

**mg/kg -**  **day LOAEL** 

**mg/kg -**  **day Critical Effect**  **Comment Reference**  Rat, Wistar, Male, Weanling Phosphate,

Diet 0, 3000 5 - 6 2 weeks -- 3000 Decreased growth The diet contained 0.4% Ca, 0.4% P, and, per kg of diet, 5000 IU of vitamin D. The control diet also contained 0.001% strontium (corresponding to about 1.5 mg Sr/kg - day). Effects caused by strontium exposure were reversed by 2 weeks on the control diet. Kshirsagar (1976)

Rat, NS, Female, Young Carbonate,

Diet 0, 190, 380, 750,

1000, 1500, 3000 3 - 10 20 days 190 380 Inhibition of calcification (increased width of epiphyseal cartilage, uncalcified bone matrix) Diet contained 1.6% calcium

and 0.9% phosphorus. Assuming 10% ingestion of bw - day . Conversions done by EPA (1992). Apparently 10 exposed, but number evaluated ranged from 3 to 10 depending on endpoint. Storey (1961)

Rat, NS, Female, Adult Carbonate,

Diet 0, 95, 190, 375,

750 and 1500 3 20 days 375 750 Changes in bone structure; inc width of epiphyseal cartilage plate Diet contained 1.6% calcium

and 0.9% phosphorus. Assuming 5% ingestion of bw - day . Conversions done by U.S. EPA (1992). Storey (1961)

Rat, England Wright Y, Male, Weanling NS, Diet 0, 1850 5 20 days -- 1850 Reduced growth, thickened epiphyseal growth plate The basic diet contained 1.2%

Ca, 1% P, and 1500 IU of vitamin D per kg, and was described as sufficient in these nutrients Reinholt et al. (1984)EPA - OST Preliminary Health Effe cts Support Document for Strontium April 2014

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– DO NOT CITE OR QUOTE A - 3 **Species, Strain, Sex, Age**  **Form of**

**Strontium and Dosing**  **Medium Doses** 

**(m g Sr/k** **g**   ** bw** **/day) Animals** 

**per sex per dose**  **Exposure**

**Duration NOAEL** 

**mg/kg -**  **day LOAEL** 

**mg/kg -**  **day Critical Effect**  **Comment Reference**  Rat, Sprague Dawley, Male, Weanling Carbonate,

Diet 0, 500 18 3 weeks -- 500 Numerous bone abnormalities No evidence of Vitamin D

abnormality Neufeld and Boskey (1994) Rat, Sprague Dawley, Male, Weanling NS, Diet 0, 1520 10 26 days -- 1520 Numerous bone abnormalities Serum concentrations of

calcium, phosphorus and parathyroid hormone were reported to be normal, but the method used to measure the parathyroid hormone could not distinguish between the active and inactive form of the hormone. Svensson et al. (1985,1987)

Rat, Wistar, Female, Weanling (36 day old) Carbonate,

Diet 0, 50,

100, 500 6 - 8 27 days 100 500 Decreased bone formation rate 0.5% calcium, 0.35%

phosphorus, and supplemented with vitamin D3. Morohashi et al. (1994) Mouse, C57BL/6J, Male, Weanling Chloride,

Drinking water 0, 350 11 - 13 29 days -- 350 10% increase in osteoid surface and an 11% reduction in the number of active osteoclasts The diet contained 0.5% Ca,

0.74% P, and 2,000 IU of vitamin D/kg Marie and Hott (1986) Rat, Wistar, Male, Adult Carbonate,

Diet 0, 1970 30 4 weeks -- 1970 Reduced growth and bone mineralization Diet contained 0.04% Ca

(described as low calcium) Matsumoto (1976) Rat, Sprague Dawley, Male, Weanling Chloride,

Drinking Water 0, 222, and 466 5 4 weeks 222 466 Bone hypomineralization and increased bone mass Diet contained 0.5% calcium,

0.54% phosphorous, 0.16% magnesium, and 2000 IU/kg vitamin D. A low calcium diet was used in order to magnify the effects of strontium. Gr ynpas and Marie (1990)EPA - OST Preliminary Health Effe cts Support Document for Strontium April 2014

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– DO NOT CITE OR QUOTE A - 4 **Species, Strain, Sex, Age**  **Form of**

**Strontium and Dosing**  **Medium Doses** 

**(m g Sr/k** **g**   ** bw** **/day) Animals** 

**per sex per dose**  **Exposure**

**Duration NOAEL** 

**mg/kg -**  **day LOAEL** 

**mg/kg -**  **day Critical Effect**  **Comment Reference**  Rat, Wistar, Male, Weanling Phosphate,

Diet 0, 580, 1270and

2820 5 - 6 4 - 6 weeks 580 1270 Slowed growth and altered alkaline phosphatase activity. The diet contained 0.4% Ca,

0.4% P, and, per kg of diet, 5000 IU of vitamin D. The control diet also contained 0.001% strontium (corresponding to about 1.5 mg Sr/kg - day). Kshirsagar (1976)

Rat, Sprague Dawley, Male, Weanling NS, Diet 0, 565 15 43 days -- 565 Respiratory difficulties, hindlimb paralysis, rickets and osteomalacia and 40% mortality. Cause of the paralysis is

unclear. Johnson et al. (1968)

Rat, Sprague Dawley, Male, Weanling Chloride,

Drinking Water 0, 146, 307 5 8 weeks 146 307 Bone hypomineralization and increased bone mass Diet contained 0.5% calcium,

0.54% phosphorous, 0.16% magnesium, and 2000 IU/kg vitamin D. A low calcium diet was used in order to magnify the effects of strontium. Gr ynpas and Marie (1990) Rat, Sprague Dawley, Male, 28 - day old NS, Drinking

Water 0, 168 8 8 weeks -- 168 Increase in mineral bone volume (17%) and an increase in the number of bone forming sites (70%). Diets containing 0.5%

calcium, 0.54% phosphorus, 0.16% magnesium and 2,000 IU/kg vitamin D, in order to support adequate bone mineralization. Drinking water also contained 0.15% calcium. Gr ynpas et al. (1996)EPA - OST Preliminary Health Effe cts Support Document for Strontium April 2014

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– DO NOT CITE OR QUOTE A - 5 **Species, Strain, Sex, Age**  **Form of**

**Strontium and Dosing**  **Medium Doses** 

**(m g Sr/k** **g**   ** bw** **/day) Animals** 

**per sex per dose**  **Exposure**

**Duration NOAEL** 

**mg/kg -**  **day LOAEL** 

**mg/kg -**  **day Critical Effect**  **Comment Reference**  Rat Sprague Dawley, male, weanling Chloride,

Drinking water 0, 316, 425, 525,

633 8 9 weeks 425 525 Decreased calcification rate Diet contained 0.5% calcium,

0.54 phosphorous, 0.16% magnesium, and 2000 IU/kg vitamin D. Doses calculated by authors BMDL = 328 mg Sr/kg - day , based on a BMR of 1 SD change in the mean Marie et al. (1985)

Rat, Wistar, M/F, Weanling Chloride

hexahydrate, Diet 0, 2, 9, 36, 146

(M); 0, 3, 10, 42, 166 (F) 10 90 days 36 (M) 146 (M) Histological signs of thyroid activation in males and non - dose related increase in thyroid wt. The diet contained 0.85%

Ca, 0.75% P, 0.05% Mg and 1.8 IU Vitamin D3 /g. These am ounts were said to be “adequate” levels by the study author. Assuming young rats consume feed at an amount equivalent to about 10% of their body weight per day. No reported effect on bone histology Kroes et al. (1977)EPA - OST Preliminary Health Effe cts Support Document for Strontium April 2014

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– DO NOT CITE OR QUOTE A - 6 **Species, Strain, Sex, Age**  **Form of**

**Strontium and Dosing**  **Medium Doses** 

**(m g Sr/k** **g**   ** bw** **/day) Animals** 

**per sex per dose**  **Exposure**

**Duration NOAEL** 

**mg/kg -**  **day LOAEL** 

**mg/kg -**  **day Critical Effect**  **Comment Reference**  Rat, RVH hooded , Male NS Chloride,

Drinking Water 0, 70, 147, 263 10 3 months 263 -- No effect on microscopic appearance of organs or bone. The study authors indicate that

“Adequate” amounts of calcium (35 mg/L) and magnesium (6.8 mg/L) ppm) were given in the drinking water. Control drinking water also contained 0.2 mg/dL strontium, corresponding to a dose of 0. 015 mg Sr/kg - day Presented in a review article with limited primary data. Assumes that an adult rat consumes 0.14 L water/kg bw per day (U.S. EPA 1992) Skoryna (1981); Skoryna and Fuskova (1981)

Rat, NS, M/F, Young Carbonate,

Diet 0, 2160 12 - 50 7 months -- 2160 Rachitic gait within 3 weeks in young rats; histological abnormalities of long bone differentiation; changes in adult rats were observed after 3 months of exposure. Diet containing 1.5% calcium,

0.9% phosphorus. Strontium effects seen in yo ung rats were more severe than in older animals. Storey (1962)EPA - OST Preliminary Health Effe cts Support Document for Strontium April 2014

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– DO NOT CITE OR QUOTE A - 7 **Species, Strain, Sex, Age**  **Form of**

**Strontium and Dosing**  **Medium Doses** 

**(m g Sr/k** **g**   ** bw** **/day) Animals** 

**per sex per dose**  **Exposure**

**Duration NOAEL** 

**mg/kg -**  **day LOAEL** 

**mg/kg -**  **day Critical Effect**  **Comment Reference**  Rat, RVH hooded, Male, Adult Chloride,

Drinking Water 0, 70, 147 and

263 12 3 years 263 -- No adverse effects on growth or on microscopic appearance of organs or bone. The study authors indicate that

“Adequate” amounts of calcium (35 mg/l) and magnesium (6.8 mg/l) were given in the drinking - water. Control drinking water also contained 0.2 mg/dL strontium, corresponding to a dose of 0.015 mg Sr/kg - day Presented in a review article with l imited primary data. Assumes that an adult rat consumes 0.14 L water/kg bw per day. Skoryna (1981); Skoryna & Fuskova (1981); U.S. EPA, (1992)

Rat, NS, Male, Adult Sulfate,

Gavage 240, 480, 950 16 42 days, including 2 weeks prior to mating 240 480 Increased epididymis and testis weights Authors reported no effects on

mating behavior, fertility, gestation period or histopathology of the reproductive tissues and organs. NIER, (2006c)EPA - OST Preliminary Health Effe cts Support Document for Strontium April 2014

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– DO NOT CITE OR QUOTE A - 8 **Species, Strain, Sex, Age**  **Form of**

**Strontium and Dosing**  **Medium Doses** 

**(m g Sr/k** **g**   ** bw** **/day) Animals** 

**per sex per dose**  **Exposure**

**Duration NOAEL** 

**mg/kg -**  **day LOAEL** 

**mg/kg -**  **day Critical Effect**  **Comment Reference**  Rat, NS, Female, Adult Sulfate,

Gavage 240, 480, 950 16 40 - 54 days, including 2 weeks prior to mating through day 4 of lactation 950 -- There was no effect on survival, growth, sensory and motor functions, urinalysis, or the microscopic appearance of the tissues and organs evaluated (including bone) at doses up to 95 0 mg Sr/kg - day . There were no adverse effects

on fetal development. However, there was no microscopic examination for skeletal or visceral alterations. Decreased spleen weight observed at 240 mg Sr/kg - day and higher, but no information was available on degree of change or on related hematological measures. No effects on mating behavior, fertility, gestation period or histopathology of the reproductive tissues and organs. NIER (2006c)

Mice, NS, Female, Adult Carbonate,

Diet 0, 1500 4 dams Gestational day 1 - birth -- 1500 In newborn pups, extensive inhibition of calcification of mandibular bone and cartilage No effect on maintenance of

pregnancy, fetal numbers or fetal viability. Sr - exposed group received a diet “deficient in vitamin D3” ( not further described) with low calcium (0.003%) content.” The control group got “normal food”, which apparently not vitamin D deficient or low in calcium Shibata and Yamashita (2001)

Bw = body weight; GI = gastrointestinal; inc = increased; NA=not applicable; NS=not statedEPA - OST Preliminary Health Effe cts Support Document for Strontium April 2014

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– DO NOT CITE OR QUOTE A - 9 **Table A -**  **2 Primary Data Table from Marie et al. (1985), Table V**

**Effects of strontium supplementation on bone growth and on bone formation and resorption** Controls 0.19% SrCl 2 0.27% SrCl 2 0.34% SrCl 2 **0.40% SrCl 2**  Tibia length, cm 3.84±0.16 3.77±0.10 3.80±0.09 3.77±0.13 3.75±0.09 Calcified bone volume, % bone tissue 19.1±2.1 22.8±3.6 a 21.7±3.3 22.9±2.6 c 17.6±2.4 Osteoblastic surface, % osteoid surface 69.9±6.7 64. 3±8.9 61.2±12.5 62.2±10.7 52.5±10.7 c Double - labeled surface, % total endosteal surface 16.7±3.0 21.4±6.8 22.3±7.2 23.1±4.7 c 22.4±3.2 c % osteoid surface 89.9±6.8 83.6±9.4 82.7±9.6 90.3±5.1 65.6±6.6 d Calcification rate, μm/day 1.32±0.12 1.31±0.05 1.25±0.16 1.18±0.09 b 1.10±0.13 c Osteoclastic surface, % total endosteal surface 3.4±0.5 3.2±0.5 3.5±0.7 3.3±0.8 3.5±0.6 Chrondroclast and osteoclast, number/mm 2 26.1±3.6 22.6±4.3 23.3±7.2 25.1±5.1 23.9±3.2 Data are the mean ±SD of 8 values. A significant difference w ith controls is indicated by: a p<0.05; bp<0.02; c p<0.01; d p<0.001.EPA - OST Preliminary Health Effe cts Support Document for Strontium April 2014

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– DO NOT CITE OR QUOTE A - 10 **Table A -**  **3 Comparison of Key Parameters from**  **Marie et al. (1985) and Storey (1961) Parameter**  **Marie et al. (1985) Storey (1961)**  Initial BW 45 - 60 g 40 - 60 g Dietary Ca 0.5% 1.6% Dietary P 0.54% 0.9% Vitamin D 2,000 IU/kg ND Dose medium Drinking Water Diet Food Sr ND ND Water Distilled Distilled Sr Salt SrCl 2 SrCO 3 Number of animals n=8 5 exposed at 0.19%; analy sis for n=3 (serum) or 5 (bone) 8 exposed at 0.38%; analy sis of n= 5 (serum) or 8 (bone) Dosing Duration 4 a and 9 weeks 20 day s Concentrations in Medium and Corresponding Doses 0.19% 316 ± 97.4 b mg Sr/kg - day 190 d mg Sr/kg - day **(NOAEL)** 0.27% 425 ± 149.3 b mg Sr/kg - day **(NOAEL)** No study dose given 0.34% 524 ±193.6 b mg/kg - day **(LOAEL)** No study dose given 0.38% No study dose given 380 d mg Sr/kg - day **(LOAEL)** 0.4% 633 ± 264.3 b mg Sr/kg - day No study dose given **Parameter Comparisons** Serum Sr (0.19%) 2.73 e mg/dL (4 weeks) 1.34 e mg/dL (9 weeks) 0.63 ± 0.4 b mg/dL Serum Sr (0.38% or 0.4% * ) 3.31 e mg/dL (4 weeks) 2.59 e mg/dL (9 weeks) 1.2 ± 0.1 b mg/dL Serum Ca:Sr ratio (0.19%) 3.09 ± 0.87 b (4 weeks) 7.08 ± 2.53 b (9 weeks) 16.8 e Serum Ca:Sr ratio (0.38% or 0.4% * ) 2.53 ± 0.46 b (4 weeks) 3.55 ± 0.83 b (9 weeks) 8.75 e Bone ash Sr (0.19%) 40 mg/g c (9 weeks) 15 e mg/g Bone ash Sr (0.4% * ) 61 mg/g c (9 weeks) 31 e mg/g ND=no data; BW = body weight * Presents results from the high dose in the study

– 0.4% in Marie et al. (1985), or 0.38% in Storey (1961). a No sacrifice at 4 weeks; b As reported by study author; c Estimated from Figure 1 of Marie et al. (1985); d Sr dose estimate as reported by EPA 1992; e Calculated for this reportEPA - OST Preliminary Health Effe cts Support Document for Strontium April 2014

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– DO NOT CITE OR QUOTE B - 1 **APPENDIX B. HRL Derivation with Age**  **- Related Exposure Factors**  **Table B**  **- 1**  **. Derivation of**  **the Health Reference Level (HRL) for Strontium**  **using Age**   ** Specific** **Exposure Factors for the Fi r**  **st 18 years Age Range**  **DWI/BW R** 

**(L/kg/day) Age**  **- Specific** 

**Fractions of a 19 -**  **Year Exposure Duration**  **Time -**  **Weighted**

**DWI/BW R**  **(L/kg/day)** Birth to < 1 month 0.235 0.004 0.001 1 to <3 months 0.228 0.00 9 0.002 3 to <6 months 0.148 0.013 0.002 6 to <12 months 0.112 0.026 0.003 1 to <2 y ears 0.056 0.05 3 0.003 2 to <3 y ears 0.052 0.05 3 0.003 3 to <6 y ears 0.043 0.15 8 0.007 6 to <11 y ears 0.035 0.263 0.009 11 to <16 y ears 0.026 0.263 0.007 16 to <18 y ears 0.023 0.105 0.002 18 to <21 ye ars # 0.026 0.05 3 0.001

**Summation of the Time -**  **W eighted**  **DWI/BW R**  **s =**  **0.040 L/kg/day*** **Reference Dose =**  **0.3 mg/kg/day**

**RSC =**  **20% +**  **HRL = (0.3 mg/kg/day ÷ 0.040 L/kg/day) x .20 =**  **1.500 mg/L**

**Final child specific HRL: 1500 μg/L**  *Rounded; # includes 18 th year; DWI/BWR = drinking water intake to body weight ratio ; HRL= health reference level; RSC = relative source contribution + HRL = **(RfD / ∑(DWI/BWR x F)**  **) x RSC**  The age - specific data on drinking water intakes in units of L/kg/day from birth through age 3 are from Table 3 - 19 in the EPA (2011) Exposures Factors Handbook and from Table 3 - 38 for ages 3 to <19 . The exposure duration adjustment was calculated b y divid ing the a ge - s pecific fraction of a 19 year exposure b y the total exposure in months or y ears as appropriate (e.g., birth to <1 month = (1/12)/19 y ears = 0.00439 ; 6 to <11 y ears = 5/19 y ears = 0.26316 ) . The time - weighted DWI/BW R values are the product of the a ge - specific DWI/BW R multiplied by the a ge – s pecific fraction of a 19 year exposure. The time - weighted DWI/BWRs are summed to obtain the normalize d value.EPA - OST Preliminary Health Effe cts Support Document for Strontium April 2014

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– DO NOT CITE OR QUOTE C - 1 **APPENDIX C. Benchmark Dose Modeling Results for**  **Non -**  **Cancer Endpoints**

====================================================================

Polynomial Model. (Version: 2.16; Date: 05/26/2010) Input Data File: C:/USEPA/BMDS212/Data/ply_toxstratstrontium_Opt.(d) Gnuplot Plotting Fi le: C:/USEPA/BMDS212/Data/ply_toxstratstrontium_Opt.plt Mon Apr 04 11:28:59 2011 ==================================================================== BMDS Model Run

~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ Th e form of the response function is: Y[dose] = beta_0 + beta_1*dose + beta_2*dose^2 + ... Dependent variable = calcrate Independent variable = mgkgday rho is set to 0 The polynomial coefficients are restricted to be negative A constant variance model is fit Total number of dose groups = 5

1 1.1 1.2 1.3 1.4

0 100 200 300 400 500 600MeanResponse

dose Polynomial Model with 0.95 Confidence Level

11:28 04/04 2011 BMD BMDL Polynomial BMD Lower BoundEPA - OST Preliminary Health Effe cts Support Document for Strontium April 2014

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– DO NOT CITE OR QUOTE C - 2 Total number of records with missing values = 0 Maximum number of iterations = 250 Relative Function Convergence has been set to: 1e - 008 Parameter Convergence has been set to: 1e - 008

Default Initial Parameter Values

alpha = 0.0135 rho = 0 Specified beta_0 = 1.32123 beta_1 = 0 beta_2 = - 9.39201e - 007 Asymptotic Correlation Matrix of Parameter Estimates ( *** The model parameter(s) - rho - beta_1 have been estimated at a boundary point, or have been specified by the user, and do not appear in the correlation matrix ) alpha beta_0 beta_2 alpha 1 - 2.7e - 009 - 1.2e - 008 beta_0 - 2. 7e - 009 1 - 0.81 beta_2 - 1.2e - 008 - 0.81 1

Parameter Estimates 95.0% Wald Confidence Interval

Variable Est imate Std. Err. Lower Conf. Limit Upper Conf. Limit alpha 0.0120913 0.0027037 0.00679215 0.0173905 beta_0 1.34382 0.0296139 1.28578 1.40187 be ta_1 0 NA

beta_2 - 5.83595e - 007 1.25112e - 007 - 8.2881e - 007 - 3.38381e 007 NA - Indicates that this parameter has hit a bound implied by some inequality constraint and thus has no standard er ror. Table of Data and Estimated Values of Interest Dose N Obs Mean Est Mean Obs Std Dev Est Std Dev Scaled Res.

------ --- -------- -------- ----------- ----------- ---------- 0 8 1.32 1.34 0.12 0.11 - 0.613 316 8 1.31 1.29 0.05 0.11 0.629 425 8 1.25 1.24 0.16 0.11 0.298 525 8 1.18 1.18 0.09 0.11 - 0.0764EPA - OST Preliminary Health Effe cts Support Document for Strontium April 2014

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– DO NOT CITE OR QUOTE C - 3 634 8 1.1 1.11 0.13 0.11 - 0.238 Model Descriptions for likelihoods calculated Model A1: Yij = Mu(i) + e(ij)

Var{e(ij)} = Sigma^2 Mod el A2: Yij = Mu(i) + e(ij)

Var{e(ij)} = Sigma(i)^2 Model A3: Yij = Mu(i) + e(ij)

Var{e(ij)} = Sigma^2 Model A3 uses any fixed variance parameters that were specified by the user Model R: Yi = Mu + e(i)

Var{e(i)} = Sigma^2

Likelihoods of Interest Model Log(likelihood) # Param's AIC A1 68.771940 6 - 125.543879 A2 73.844578 10 - 127.689155 A3 68.771940 6 - 125.543879 fitted 68.305375 3 - 130.610750 R 59.618353 2 - 115.236707 Explanation of Tests Test 1: Do responses and/or variances differ among Dose levels?

(A2 vs. R) Test 2: Are Variances Homogeneous? (A1 vs A2) Test 3: Are variances adequately modeled? (A2 vs. A3) Test 4: Does the Model for the Mean Fit? (A3 vs. fitted) (Note: When rho=0 the results of Test 3 and Test 2 will be the same.) Tests of Interest Test - 2*log(Likelihood Ratio) Test df p - value Test 1 28.4524 8 0.0003954 Test 2 10.1453 4 0.03805 Test 3 10.1453 4 0.03805 Test 4 0.933129 3 0.8174 The p - value for Test 1 is less than .05. There appears to be a difference between response and/or variances among the dose levels It seems appropriate to model the data The p - value for Test 2 is less than .1. Consider running a non - homogeneous variance model The p - value for Test 3 is less than .1. You may want to consider a different variance model The p - value for Test 4 is greater than .1. The model chosen seemsEPA - OST Preliminary Health Effe cts Support Document for Strontium April 2014

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– DO NOT CITE OR QUOTE C - 4 to adequately describe the data

Benchmark Dose Computation Specified effect = 1 Risk Type = Estimate d standard deviations from the control mean Confidence level = 0.95

BMD = 434.073 BMDL = 328.358