Copper and the Skin, 1st Edition
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DERMATOLOGY: CLINICAL & BASIC SCIENCE SERIES
COPPER and
the SKIN
Edited by
Jurij J. Hostýnek
University of California at San Francisco School of Medicine
San Francisco, California, U.S.A.
Howard I. Maibach
University of California at San Francisco School of Medicine
San Francisco, California, U.S.A.
New York London
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This monograph on copper is dedicated to Dr. Roberto Milanino of the
University of Verona, Italy. A scientist and teacher, he spent the past 30 years
of his academic career investigating the biological function and importance of
copper in the mammalian organism while navigating the narrows of Italy’s
budget allocated to science. Among the leading authorities on this subject,
he was a guiding light, set the proper accents, and kept things in perspective
over the period of much of our work and writing in assembling this monograph.
The whole is a clear reflection of his qualities as teacher.
J. J. Hostýnek
H. I. Maibach
Preface
Preface
Metals have long interested the dermatologic community in terms of their
toxicity and efficacy. A century ago, mercury enjoyed widespread usage in
the treatment of syphilis.
As the dermatologic sciences evolved, sufficient knowledge also evolved,
leading to the clear assertion that metals may be toxic when applied to the
skin. Nickel has enjoyed the greatest amount of study, especially because of
its frequent induction of clinical allergic contact dermatitis in humans. Cobalt
is also a common contact allergen, but its clinical significance is less clearly
explored. Chromate in cement, leather, and other applications also enjoys
considerable study. Most recently, gold salts have been recognized as a com-
mon inducer of cell-mediated immunity; however, this clinical significance is
currently being investigated in terms of dermatitis and even restenosis.
These data have led to several textbooks dedicated to individual metals.
The first was on chromate (by Desmond Burrows), many metals and the skin
(by R. Guy and J. J. Hostýnek), and most recently nickel (by J. J. Hostýnek
and H. I. Maibach). The current volume on copper presents sufficient infor-
mation to place it among the pantheon of the metallic gods and dermatology.
Our aim was to mold contributions from individuals widely spread over
several disparate disciplines into a cohesive, readily digestible text. The
individual disciplines include basic chemistry (metallurgy), dermatotoxi-
cology (irritant and allergic contact dermatitis), and membrane transport
(percutaneous penetration).
v
vi Preface
Our specific objective is to allow scientists in many fields to more
efficiently focus their attention on this essential element (copper) and the
skin. Hopefully, the parts will simplify understanding the whole.
This volume differs from the others, not only in its extensive dermato-
toxicologic profile of copper and its salts, but also as an equally impressive
data on copper’s possible anti-inflammatory actions in man.
The editors welcome suggestions for the next edition.
Jurij J. Hostýnek
Howard I. Maibach
Acknowledgment
We gratefully acknowledge the partial financial support by the International
Copper Association, Ltd. (ICA) towards publication of this book.
vii
Contents
Preface . . . . v
Acknowledgment . . . . vii
Contributors . . . . xv
1. Copper and Copper Alloys . . . . . . . . . . . . . . . . . . . . . . . . 1
Harold T. Michels
Introduction . . . . 1
Copper: Properties of the Element . . . . 1
Pure Copper . . . . 2
Copper Alloys . . . . 2
Properties of Copper Alloys . . . . 2
Copper Alloy Families . . . . 4
The High Coppers . . . . 4
Conclusions . . . . 6
2. Corrosion Chemistry of Copper: Formation of Potentially
Skin-Diffusible Compounds . . . . . . . . . . . . . . . . . . . . . . . . 7
Jurij J. Hostýnek
Introduction . . . . 7
Electron Configuration and Reactivity of Copper . . . . 8
Corrosion of Copper in the Environment . . . . 8
Corrosion of Copper in Physiologic Media . . . . 9
Conclusions . . . . 15
Glossary . . . . 16
Abbreviations . . . . 16
References . . . . 16
ix
x Contents
3. Basics of Metal Skin Penetration:
Scope and Limitations . . . . . . . . . . . . . . . . . . . . . . . . . . 21
Jurij J. Hostýnek and Howard I. Maibach
Introduction . . . . 21
Structure of Skin and Its Function as
Diffusion Barrier . . . . 23
Descriptors of Dermal Absorption . . . . 25
Permeant Categories and Paths of Diffusion . . . . 28
Compounds Formed by Metals in Contact
with the Skin . . . . 31
Variables Determining Skin Diffusion
of Metal Compounds . . . . 35
Methods for Measuring Percutaneous Absorption . . . . 45
Analytical Methods for Metal Detection . . . . 53
Summary and Conclusions . . . . 56
Abbreviations . . . . 57
References . . . . 58
4. Percutaneous Absorption of Copper Compounds . . . . . . . . 67
Jurij J. Hostýnek and Howard I. Maibach
Introduction . . . . 67
Qualitative Diffusion Data . . . . 68
Semiquantitative Data . . . . 70
Quantitative Data . . . . 71
Discussion and Conclusions . . . . 73
Limitations in Measuring Copper Absorption
In Vivo . . . . 74
Interdependence of Systemic Copper and Zinc Levels . . . . 75
Recommendations for Research to Fill Existing
Data Gaps . . . . 76
Conclusions . . . . 77
Glossary . . . . 78
Abbreviations . . . . 78
References . . . . 79
5. Diffusion of Copper Through Human Skin
In Vivo . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81
Jurij J. Hostýnek, Howard I. Maibach, and Frank Dreher
Introduction . . . . 81
Experimental . . . . 84
Results . . . . 85
Contents xi
Discussion . . . . 88
Conclusions . . . . 92
Glossary . . . . 93
Abbreviations . . . . 93
References . . . . 94
6. Irritation Potential of Copper Compounds . . . . . . . . . . . . 97
Jurij J. Hostýnek and Howard I. Maibach
Introduction . . . . 97
Exposure to Copper . . . . 97
Solubilization of Copper Metal . . . . 98
Incidence and Epidemiology of Irritation
Due to Copper . . . . 100
Pharmacology of Copper . . . . 101
Copper Irritancy in Skin and Mucosa . . . . 103
Conclusions . . . . 111
Abbreviations . . . . 112
References . . . . 112
7. Copper Hypersensitivity: Dermatologic
Aspects—Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . 115
Jurij J. Hostýnek and Howard I. Maibach
Introduction . . . . 115
Metallurgy of Copper and Its Alloys, and Its Role
as Sensitizer . . . . 117
Predictive Immunology Test Results
for Copper . . . . 119
Diagnostic Tests for Hypersensitivity . . . . 119
Test Concentrations for Copper ACD . . . . 123
Immunogenic Potential of Copper . . . . 123
Summaries of Population-Based Studies . . . . 134
Summary of Selected Case Reports of Immune Reactions
to Copper . . . . 138
Selection of Individual Reports of Immune Reactions
to Copper . . . . 138
Comments . . . . 140
Conclusions . . . . 140
Abbreviations . . . . 141
References . . . . 141
xii Contents
8. Copper in Medicine and Personal Care:
A Historical Overview . . . . . . . . . . . . . . . . . . . . . . . . . 149
Roberto Milanino
Introduction . . . . 149
The Sumeric Culture: Circa 4000–2300 B.C. . . . . 150
The Ancient Egyptian Culture . . . . 150
The Babylonian–Assyrian Culture:
Circa 1750–539 B.C. . . . . 152
The Ancient Indian Culture: Circa 2800–1000 B.C. . . . . 152
The Ancient Chinese Culture: Circa 3000 B.C.
to 1100 A.D. . . . . 152
The Pre-Columbian Meso- and South-American Cultures:
Circa 600 B.C. to 1500 A.D. . . . . 153
The Ancient Greek Culture . . . . 153
The Ancient Roman Culture: Circa 600 B.C.
to 476 A.D. . . . . 155
From the High-Medieval Age to the Early
20th Century . . . . 156
Beginning of the Scientific Age for Copper:
1928–1976 . . . . 157
Conclusions . . . . 158
Abbreviations . . . . 159
References . . . . 159
9. The Role of Copper in Onset, Development, and
Control of Acute and Chronic Inflammation . . . . . . . . . . 161
Roberto Milanino
Introduction . . . . 161
Studies on Copper-Deficient, Experimentally
Inflamed Animals . . . . 163
Laboratory Animals: Studies on ‘‘Endogenous’’ Copper
Metabolism in Acute and Chronic Inflammation . . . . 170
Human Subjects: Studies on ‘‘Endogenous’’ Copper Metabolism
in Acute and Chronic Inflammations, with a Particular
Reference to Rheumatoid Arthritis . . . . 179
Effects of ‘‘Exogenous’’ Copper Administration on the
Inflammatory Process . . . . 184
Copper Anti-inflammatory Activity: Hypotheses Explaining
the Possible Mechanisms of Action . . . . 203
Conclusions . . . . 216
Contents xiii
Abbreviations . . . . 219
References . . . . 220
10. Copper Jewelry and Arthritis . . . . . . . . . . . . . . . . . . . . 237
Brenda J. Harrison
Introduction . . . . 237
The Copper Bracelet ‘‘Myth’’ and Hypothesis . . . . 239
The Copper Bracelet Trial . . . . 243
The Present State of the Copper Bracelets ‘‘Issue’’ . . . . 251
Is There Likely to Be a Future for Copper Bracelets
in Arthritis Care? . . . . 256
Appendix A: Position Statements of Support Organizations,
Government Agencies, Etc. . . . . 257
Appendix B: Miscellany . . . . 259
References . . . . 261
11. Role of Copper in Anti-inflammatory Therapy and the
Potential for Its Transdermal Application . . . . . . . . . . . . 267
Jurij J. Hostýnek and Roberto Milanino
Introduction . . . . 267
Traditional and Modern Therapies for RA
and Related Disorders . . . . 268
Drug Therapy . . . . 271
Precedents in Topical Delivery of Anti-inflammatory
Agents . . . . 275
Role of Copper in AI Activity . . . . 275
Past Use of Copper Chelates in the Treatment
of Rheumatoid Arthritis . . . . 278
Transdermal Delivery of Anti-inflammatory Copper
Chelates vs. Conventional (Systemic)
Anti-inflammatory Therapy . . . . 278
Conclusions . . . . 286
Outlook . . . . 288
Abbreviations . . . . 288
References . . . . 289
Index . . . . 295
Contributors
Frank Dreher Neocutis, Inc., San Francisco, California, U.S.A.
Brenda J. Harrison Department of Earth and Ocean Sciences, Copper
Research Information Flow Project, University of British Columbia,
Vancouver, British Columbia, Canada
Jurij J. Hostýnek Department of Dermatology, University of California
at San Francisco School of Medicine, San Francisco, California, U.S.A.
Howard I. Maibach Department of Dermatology, University of California
at San Francisco School of Medicine, San Francisco, California, U.S.A.
Harold T. Michels Copper Development Association, Inc., New York,
New York, U.S.A.
Roberto Milanino Facoltà di Medicina e Chirurgia, Sezione di
Farmacologia, Dipartimento di Medicina e Salute Pubblica, Università di
Verona, Verona, Italy
xv
