Handbook of Experimental Pharmacology Volume 115 Editorial Board G.V.R. Born, London P. Cuatrecasas, Ann Arbor, MI D. Ganten, Berlin H. Herken, Berlin K.L. Melman, Stanford, CA Toxicology of Metals Biochemical Aspects Contributors N. Ballatori, M.G. Cherian, D.C. Dawson, M. Delnomdedieu P. Druet, B.R Fisher, P. Goering, RA. Goyer, S. Himeno N. Imura, E.H. leffrey, M.M. lones, l.H.R Kagi, S. Kawanishi C.D. Klaassen, l. Koropatnick, l.S. Lazo, M.E.I. Leibbrandt K. Miura, A. Naganuma, E.l. O'Flaherty, L. Pelletier T.G. Rossman, S. Silver, M. Styblo, D.M. Templeton, D.l. Thomas M.P. Waalkes, M. Walderhaug, l.S. Woods, l. Zeng Editors Robert A. Goyer and M. George Cheri an Springer-Verlag Berlin Heidelberg New York London Paris Tokyo Hong Kong Barcelona Budapest ROBERT A. GOYER, M.D. Professor Emeritus Department of Pathology University of Western Ontario Health Sciences Centre London, Ontario, Canada N6A SCI M. GEORGE CHERIAN, Ph.D. Professor Department of Pathology University of Western Ontario Health Sciences Centre London, Ontario, Canada N6A SCI With 37 Figures and 17 Tables ISBN-13:978-3-642-79164-2 e-ISBN-13:978-3-642-79162-8 001: 10.1007/978-3-642-79162-8 Library of Congress Cataloging·in·Publication Data. Toxicology of metals: biochemical aspects/contributors N. Ballatori ... [et al.]; editors, Robert A. Goyer and M. George Cherian. p. cm. - (Handbook of experimental pharmacology; v. 115) Includes bibliographical references and index. ISBN-13:978-3-642-79 164-2 1. Metals - Toxicology. I. Ballatori, N. II. Goyer, Robert. III. Cherian, M. George, 1941- . IV. Series. [DNLM: 1. Metals - toxicity. 2. Maximum Permissible Exposure Level. WI HA51L v. 115 1995/QV 290 T755 1995] QP905.H3 vol. 115 [RA1231.M52] 615'. I s-dc20 [615.9'253] DNLMIDL-C for Library of Congress 94-26484 This work is subject to copyright. All rights are reserved, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilm or in any other way, and storage in data banks. Duplication of this publication or parts thereof is permitted only under the provisions of the German Copyright Law of September 9, 1965, in its current version, and permission for use must always be obtained from Springer-Vedag. Violations are liable for prosecution under the German Copyright Law. © Springer-Vedag Berlin Heidelberg 1995 Softcover reprint of the hardcover 1st edition 1995 The use of general descriptive names, registered names, trademarks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. Product liability: The publishers cannot guarantee the accuracy of any information about dosage and application contained in this book. In every individual case the user must check such information by consulting the relevant literature. Typesetting: Best-set Typesetter Ltd., Hong Kong SPIN: 10096516 27/3130/SPS - 5 4 3 2 1 0 - Printed on acid-free paper List of Contributors BALLATORI, N., Department of Environmental Medicine, University of Rochester School of Medicine, Rochester, NY 14642, USA CHERIAN, M.G., Department of Pathology, University of Western Ontario, Health Sciences Centre, London, Ontario, Canada N6A 5C1 DAWSON, D.C., Department of Physiology, University of Michigan Medical School, 6811 Med.Sci. 2, Ann Arbor, MI 48109-0622, USA DELNOMDEDIEU, M., Center for Environmental Medicine and Lung Biology, . University of North Carolina at Chapel Hill, Chapel Hill, NC 27514, USA DRUET, P., Institut National de la Sante et de la Recherche Medicale (INSERM U28), Hopital Broussais, 96 rue Didot, F-75674 Paris, Cedex 14, France FISHER, B.R., Health Sciences Branch, Division of Life Sciences, Office of Science and Technology, Center for Devices and Radiological Health, Food and Drug Administration, 12709 Twinbrook Parkway, Rockville, MD 20857, USA GOERING, P.L., Health Sciences Branch, Division of Life Sciences, Office of Science and Technology, Center for Devices and Radiological Health, Food and Drug Administration (HFZ-112), 12709 Twinbrook Parkway, Rockville, MD 20857, USA GOYER, R.A., Department of Pathology, University of Western Ontario, Health Sciences Centre, London, Ontario, Canada N6A 5C1 HIMENO, S., Department of Public Health and Molecular Toxicology, School of Pharmaceutical Sciences, Kitasato University, Minato-ku, Tokyo 108, Japan IMURA, N., Department of Public Health and Molecular Toxicology, School of Pharmaceutical Sciences, Kitasato University, Minato-ku, Tokyo 108, Japan JEFFREY, E.H., Institute for Environmental Studies, University of Illinois at Urbana-Champaign, 1101 W. Peabody Drive, Urbana, IL 61801, USA VI List of Contributors JONES, M.M., Department of Chemistry and Center in Toxicology, Vanderbilt University, P.O. Box 1583, Station B, Nashville, TN 37235, USA KAGI, J .H.R., Biochemistry Institute of the University of Zurich, Winter- thurerstraBe 190, CH-8057 Zurich, Switzerland KAWANISHl, S., Department of Public Health, Faculty of Medicine, Kyoto University, Kyoto 606, Japan KLAASSEN, C.D., Department of Pharmacology, Toxicology, and Thera- peutics, University of Kansas Medical Center, 39th and Rainbow, Kansas City, KS 66103, USA KOROPATNICK, J., Department of Oncology, London Regional Cancer Centre, University of Western Ontario, 790 Commissioners Road E., London, Ontario, Canada N64 4L6 LAzo, J.S., Department of Pharmacology, University of Pittsburgh, Ex- perimental Therapeutics Program, Pittsburgh Cancer Institute, E-1340 Biomedical Science Tower, Pittsburgh, PA 15261, USA LEIBBRANDT, M.E.I., Parke-Davis Pharmaceutical Research, General Toxicology, 2800 Plymouth Road, Ann Arbor, MI 48105, USA MIURA, K., Department of Environmental Sciences, Wako University, Machida-shi, Tokyo, 104-01, Japan NAGANUMA, A., Department of Public Health and Molecular Toxicology, School of Pharmaceutical Sciences, Kitasato University, Minato-ku, Tokyo 108, Japan O'FLAHERTY, E.J., Department of Environmental Health, University of Cincinnati College of Medicine, 3223 Eden Ave., Cincinnati, OH 45267- 0056, USA PELLETIER, L., Institut National de la Sante et de la Recherche Medicale (INSERM U28), Hopital Broussais, 96 rue Didot, F-75674 Paris, Cedex 14, France ROSSMAN, T.G., Nelson Institute of Environmental Medicine and Kaplan Cancer Center, New York University Medical Center, 550 First Avenue, New Yark, NY 10016, USA SILVER, S., Department of Microbiology and Immunology, University of Illinois College of Medicine, M/C 790, Room 703, 835 South Wolcott Ave., Chicago, IL 60612-7344, USA STYBLO, M., Curriculum in Toxicology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27514, USA List of Contributors VII TEMPLETON, D.M., Department of Clinical Biochemistry, University of Toronto, Banting Institute, 100 College Street, Toronto, Ontario, Canada M5G 1L5, and Division of Biochemistry, The Research Insti- tute, Hospital for Sick Children, 555 University Ave., Toronto, Ontario, Canada M5G 1X8 THOMAS, D.J., Health Effects Research Laboratory, MD-74, U.S. Environ- mental Protection Agency, Research Triangle Park, NC 27711, USA WA ALKES, M.P., Inorganic Carcinogenesis Section, Laboratory of Com- parative Carcinogenesis, National Cancer Institute, Frededck, MD 21702, USA WALDERHAUG, M., Division of Microbiological Studies, Microbial Ecology Branch, Food and Drug Administration, CFSAN HFS-517, 200 C. Street, SW, Washington, DC 20204, USA WOODS, J.S., Battelle Seattle Research Center, 400 N.E. 41st Street, Seattle, WA 98105,USA ZENG, J., Biochemistry Institute of the University of Zurich, Winter- thurerstraBe 190, CH-8057 Zurich, Switzerland. Present address: Laboratory of Biochemistry, Bldg. 37, Rm. 4A13, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA Preface The toxicology of metals has been concerned in the past with effects that produced clinical signs and symptoms. However, this view of metal toxicology has expanded in recent years due principally to two advances. There has been a considerable increase in our knowledge of the biochemical effects of metals. In addition, biomarkers of toxicity can now be recognized that identify toxicity at levels of exposure that do not produce overt clinical effects. Thus, the toxicology of metals is now focused on nonclinical events that reflect adverse health effects. This new awareness has produced the challenge of determining the lowest adverse level of exposure. With increasing analytical sensitivity and methodologies to detect small changes at the molecular level, the lowest level of exposure of some toxic metals, like lead, is very small. Indeed, for metals in which there is no biologic requirement, it may be questioned whether there is a level of exposure that does not produce some degree of toxicity. For essential metals, the question is being asked as to the levels at which exposure exceeds biologic require- ments and excess exposure becomes toxic. The appropriateness of health decisions and the formation of public policy are dependent on the availability of current scientific information that addresses these questions. The information in this volume is intended to be a resource for this purpose as well as a reference for students of toxicology and other health professionals. Specific topics of current relevance are addressed in chapters on aluminum, cadmium, chromium, lead, and mercury. A number of chapters are concerned with metal-protein interactions, including effects on heat shock proteins and on metallothionein, a protein important in the metabolism of both essential and toxic metals. Zinc-containing finger proteins are related to gene expression, as are chapters on the mutagenicity of metals, plasmid-mediated metal resistance, drug resistance, and the effects of oxygen radicals in the production of DNA damage. Some metals may become involved in basic physiologic processes within cells including transport at the level of the cell membrane and porphyrin meta- bolism. These are effects that may produce new biochemical markers that provide early evidence of toxicity. And, finally, the toxicity of low- level exposures is stimulating increased efforts to develop chelators or therapeutic agents that may be used for intervention and prevention of toxicity. x Preface The field of biochemical toxicology is rapidly expanding in terms of the sophistication of the science base and a corresponding public interest. The editors are hopeful that this volume will contribute to these interests. London, Ontario, Canada M. GEORGE CHERIAN August 1994 ROBERT A. GOYER Contents CHAPTER 1 Transplacental Transfer of Lead and Cadmium R.A. GOYER. With 2 Figures ................................... 1 A. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 I. Comparison of Human and Rodent Fetal-Maternal Blood Barriers. . . . . . . . . . . . . . 2 II. Methods for Sampling the Human Placenta. . . . . . . . . . . . . . 3 B. Placental Transfer of Lead. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 I. Mechanism of Placental Transfer of Lead ............... 3 II. Maternal Blood Lead Levels During Pregnancy . . . . . . . . . . 5 III. Effect of Maternal Lead on Birth Outcomes ... . . . . . . . . . . 6 IV. Effect of Lead on Neurobehavioral and Cognitive Development In Utero. . . . . . . . . . . . . . . . . . . 6 V. Mechanisms for the Neurotoxicity of Lead. . . . . . . . . . . . . . . 7 C. Placental Transfer of Cadmium. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8 I. Cadmium Levels in Human Placenta.. . . ... . . ... . . .. . .. . 9 II. Cadmium Effects on Placenta and Fetus. . . . . . . . . . . . . . . . . 10 III. Interactions in Placenta Between Cadmium, Zinc and Copper, and Metallothionein ...................... 11 D. Summary................................................. 13 References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13 CHAPTER 2 Porphyrin Metabolism as Indicator of Metal Exposure and Toxicity J.S. WOODS. With 8 Figures. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19 A. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19 B. Heme Biosynthesis and Porphyrin Metabolism ................ 19 C. Mechanistic Basis of Metal-Induced Porphyria (Porphyrinuria) .. 23 I. Metal Effects on Specific Steps of the Heme Biosynthetic Pathway . . . . . . . . . . . . . . . . . . . . . 23 II. Metal-Induced Oxidation of Reduced Porphyrins. . . . . . . . . 25 XII Contents D. Metal- and Metalloid-Induced Porphyrinopathies and Porphyrinurias ........................................ 27 I. Lead............................................... 27 1. Erythrocyte ALA Dehydratase. . . . . . . . . . . . . . . . . . . . . . 28 2. Erythrocyte Zinc-Protoporphyrin. . . . . . . . . . . . . . . . . . . . 30 3. Urinary Coproporphyrin. . . . . . . . . . . . . . . . . . . . . . . . . . . 33 II. Mercury . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36 1. Mercury-Directed Alteration of Renal Coproporphyrinogen Metabolism. . . . . . . . . . . . 36 2. Mercury-Facilitated Porphyrinogen Oxidation. . . . . . . . . 38 III. Arsenic............................................. 39 IV. Other Metals. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41 1. Cadmium ........................................ 41 2. Platinum......................................... 41 3. Aluminum....................................... 42 4. Metal Interactions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43 E. Perspectives on the Use of Porphyrins as Biomarkers of Metal Exposure in Human Studies. . . . . . . . . . . . . . . . . . . . . . . . . 43 References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46 CHAPTER 3 Membrane Transporters as Sites of Action and Routes of Entry for Toxic Metals D.C. DAWSON and N. BALLATORI. With 4 Figures... . . . .. . ... . .... . 53 A. Introduction: Metals and Membranes ........................ 53 B. Chemical Properties of Metals in Solutions. . . . . . . . . . . . . . . . . . . . 54 C. Model Systems. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59 D. Mercury Inhibition of NaCI Cotransport: An Example Problem with a Model System ................... 62 E. Metal Entry into Cells. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63 F. Permeation in a Lipid-Soluble Form. . . . . . . . . . . . . . . . . . . . . . . . . . 63 G. Permeation as a Cation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 64 H. Permeation as an Anion. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67 I. Transport of Organic Complexes ............................ 69 J. Physiological Significance of Metal Permeation Pathways. . . . . . . . 71 References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 72