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TOTAL WATER AND TAPWATER INTAKE IN THE UNITED STATES:

6,04

POPULATION-BASEDESTIMATES OF QUANTITIES AND SOURCES

144

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6046

National Cancer Institute

1998

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CONTENTS

Tables viii

Figures xii

Foreword xiii

Preface . xiv

Authors and Reviewers xv

Acknowledgements xviii

Symbols xvix

1. INTRODUCTION 1-1

PART 1. PRINCIPLES OF DERMAL EXPOSURE ASSESSMENT . 2-1

2. MECHANISMS OF DERMAL ABSORPTION . 2-1

2.1. STRUCTURE AND FUNCTION OF THE SKIN . 2-1

2.2. FATE OF COMPOUNDS APPLIED TO THE SKIN . 2-5

2.2.1. Transport Processes Occurring in the Skin . 2-5

2.2.2. Loss Processes Occurring in the Skin 2-8

2.2.2.1. Evaporation from the Surface of the Skin 2-8

2.2.2.2. Binding of Compounds in the Skin 2-9

2.2.2.3. Metabolism 2-10

2.3. FACTORS THAT INFLUENCE PERCUTANEOUS ABSORPTION 2-13

2.3.1. Skin-Specific Factors . 2-13

2.3.1.1. Site of Application or Exposure . 2-13

2.3.1.2. Age of the Skin . 2-19

2.3.1.3. Skin Condition 2-21

2.3.1.4. Hydration . 2-23

2.3.1.5. Circulation to the Skin . 2-23

2.3.1.6. Skin Temperature 2-24

2.3.1.7. Miscellaneous Factors . 2-26

2.3.2. Compound-Specific Factors . 2-26

2.3.2.1. Partition Coefficients . 2-26

2.3.2.2. Polarity 2-28

2.3.2.3. Chemical Structure . 2-30

2.3.2.4. Volatility . 2-31

2.3.2.5. Compound Concentration . 2-32

2.4. SUMMARY AND CONCLUSIONS . 2-33

2.4.1. Structure . 2-34

2.4.2. Fate 2-34

2.4.3. Factors 2-35

3. TECHNIQUES FOR MEASURING DERMAL ABSORPTION . 3-1

3.1. IN VIVO STUDIES . 3-3

3.1.1. Quantification of Radioactivity, Parent Compound, or Metabolite Levels in Excreta (Indirect

Method) . 3-4

3.1.2. Quantitation of Radioactivity, Parent Compound, or Metabolite Levels in Excreta, Air, and

Tissues (Direct Method) . 3-5

3.1.3. Quantification of Parent Compound or Metabolite in Blood, Plasma, or Tissues . 3-5

3.1.4. Quantification of the Disappearance of the Compound from the Surface of the Skin or from

the Donor Solution 3-6

3.1.5. Measurement of a Biological Response . 3-7

3.1.6. Stripping Method . 3-8

3.2. IN VITRO TECHNIQUES 3-9

3.2.1. Diffusion Cells . 3-10

3.2.2. Isolated Perfused Tubed-Skin Preparation 3-17

3.2.3. Stratum Corneum Binding Technique . 3-18

3.3. COMPARISON OF IN VITRO AND IN VIVO PERCUTANEOUS ABSORPTION VALUES . 3-19

3.4. INTERSPECIES COMPARISON OF PERCUTANEOUS ABSORPTION VALUES 3-21

3.5. SUMMARY, CONCLUSIONS, AND RESEARCH RECOMMENDATIONS 3-26

4. MATHEMATICAL DESCRIPTION OF DERMAL ABSORPTION 4-1

4.1. THEORETICAL BASIS OF K AND J VALUES 4-3 P SS

4.2. DERMAL (PERCUTANEOUS) ABSORPTION RATE EQUATION PARAMETERS 4-5

4.2.1. Partition Coefficient . 4-5

4.2.2. Pathlength of Chemical Diffusion . 4-9

4.2.3. Diffusion Coefficient 4-10

4.2.4. Concentration Gradient 4-11

4.3. EVALUATION OF PERMEABILITY COEFFICIENTS K FROM EXPERIMENTAL P,S STUDIES 4-

4.3.1. In Vitro Approaches 4-12

4.3.2. In Vivo Approaches 4-15

4.4. DEFINITIONS OF PERMEABILITY COEFFICIENTS WHEN THE MEDIUM IS NOT WATER . 4-

4.4.1. Nonaqueous Solvent 4-18

4.4.2. Pure Liquid 4-19

4.4.3. Vapor Phase . 4-19

4.4.4. Soil . 4-20

4.5. THE VALUE OF THE LIMITING K FOR CHEMICALS OF HIGH LIPOPHILICITY P,S . 4-20

4.6. ESTIMATION OF ABSORBED DOSE . 4-22

5. DERMAL ABSORPTION OF COMPOUNDS FROM WATER . 5-1

5.1. EXPERIMENTALLY DERIVED K VALUES . 5-1 P

5.1.1. Strategy for Reviewing Experimental Data . 5-1

5.1.2. Recommended K Values 5-8 p

5.2. METHODS FOR PREDICTING PERMEABILITY COEFFICIENT OF AQUEOUS

CONTAMINANTS 5-11

5.2.1. Empirical Correlations 5-11

5.2.2. Theoretical Skin Permeation Models 5-21

5.2.2.1. Scheuplein Laminate Model with Parallel Follicular Pathway . 5-33

5.2.2.2. Michaels' Two-Phase Model for Stratum Corneum 5-33

5.2.2.3. Two Parallel Pathway Model 5-34

5.2.2.4. Albery and Hadgraft Model . 5-34

5.2.2.5. Kasting, Smith, and Cooper Model 5-35

5.2.3. Statistical Algorithms for K Based on Literature Data 5-38 p

5.2.4. Conclusions for How to Predict K Values 5-37 p

5.3. ESTIMATING THE DERMALLY ABSORBED DOSE PER EVENT . 5-47

5.3.1. Estimating DA for Inorganics 5-48 event

5.3.2 Estimating DA for Organics . 5-49 event

APPENDIX: SUMMARY OF COMPOUND-SPECIFIC K DATA 5-65 p

6. DERMAL ABSORPTION OF COMPOUNDS FROM SOIL . 6-1

6.1. FACTORS AFFECTING THE DERMAL (PERCUTANEOUS) ABSORPTION OF COMPOUNDS

FROM SOIL . 6-2

6.2. USING EXPERIMENTALLY DERIVED VALUES 6-9

6.2.1. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) 6-11

6.2.1.1. Experimental Results 6-11

6.2.1.2. Analysis of Data 6-18

6.2.2. 3,3´,4,4´-Tetrachlorobiphenyl (TCB) . 6-19

6.2.2.1. Experimental Results 6-20

6.2.2.2. Analysis of Data 6-21

6.2.3. Benzo[a]Pyrene (BaP) . 6-22

6.2.3.1. Experimental Results 6-23

6.2.3.2. Analysis of Data 6-24

6.2.4. DDT . 6-25

6.2.4.1. Experimental Results 6-26

6.2.4.2. Analysis of Data 6-26

6.2.5. Cadmium . 6-27

6.2.5.1. Experimental Results 6-27

6.2.5.2. Analysis of Data 6-28

6.2.6. Benzene, Toluene, and Xylene . 6-28

6.2.7. Hexadecane . 6-28

6.3. PREDICTIVE APPROACHES TO ESTIMATING DERMAL UPTAKE . 6-29

6.3.1. Use of Structural Analogues . 6-30

6.3.2. Upper Bounding Estimates of Dermal Bioavailability and Percutaneous Absorption . 6-32

6.3.2.1. Data on Absorption from Other Vehicles . 6-33

6.3.2.2. Soil Extraction Data 6-34

6.3.2.3. Combined Upper Bounding Estimate . 6-35

6.3.2.4. Data on Oral Bioavailability . 6-35

6.3.3. Theoretical Modeling of Percutaneous Absorption from Soil 6-36

6.4. ESTIMATION OF DERMALLY ABSORBED DOSE 6-43

7. DERMAL ABSORPTION OF CHEMICAL VAPORS . 7-1

7.1. FACTORS AFFECTING THE DERMAL ABSORPTION OF VAPORS 7-2

7.1.1. Chemical Characteristics 7-3

7.1.2. Chemical-Biological Parameters . 7-4

7.1.3. Biological Parameters 7-5

7.1.4. Exposure Parameters 7-5

7.2. EXPERIMENTALLY DERIVED VALUES . 7-7

7.2.1. Human In Vivo 7-7

7.2.2. Human In Vitro . 7-10

7.2.3. Primates In Vivo 7-13

7.2.4. Rodents In Vivo . 7-13

7.3. EQUATIONS FOR ESTIMATING THE DERMAL ABSORPTION OF CHEMICAL VAPORS . 7-16

7.3.1. When Permeability Constant Is Available 7-16

7.3.2. When Permeability Constant Is Not Available but Flux or Total Absorbed Is Available . 7-21

7.3.3. When No Permeability Data Are Available . 7-21

7.4. DECISION TREE FOR RISK CHARACTERIZATION OF TOXICITY DUE TO DERMAL

ABSORPTION OF CHEMICAL VAPORS . 7-22

7.4.1. Determination of Maximum Achievable Concentration 7-22

7.4.2. Determination of Permeability Constant . 7-24

7.4.3. Potential for Contact Site Toxicity . 7-25

7.4.4. Choice of Health Risk Estimates 7-26

7.4.5. Risk Characterization . 7-27