Environmental Health Criteria 119 Principles and methods for the assessment of nephrotoxicity associated with exposure to chemicals Please note that the layout and pagination of this web version are not identical with the printed version. Nephrotoxicity associated with exposure to chemicals, principles and methods for the assessment o... INTERNATIONAL PROGRAMME ON CHEMICAL SAFETY ENVIRONMENTAL HEALTH CRITERIA 119 PRINCIPLES AMD METHODS FOR THE ASSESSMENT OF NEPHROTOXICITY ASSOCIATED WITH EXPOSURE TO CHEMICALS This report contains the collective views of an international group of experts and does not necessarily represent the decisions or the stated policy of the United Nations Environment Programme, the International Labour Organisation, or the World Health Organization. Neither the Commission of the European Communities nor any person acting on behalf of the Commission is responsible for the use which might be made of the information contained in this report. (EUR 13222 EN) Published under the joint sponsorship of the United Nations Environment Programme, the International Labour Organisation, and the World Health Organization, and on behalf of the Commission of the European Communities World Health Orgnization Geneva, 1991 The International Programme on Chemical Safety (IPCS) is a joint venture of the United Nations Environment Programme, the International Labour Organisation, and the World Health Organization. The main objective of the IPCS is to carry out and disseminate evaluations of the effects of chemicals on human health and the quality of the environment. Supporting activities include the development of epidemiological, experimental laboratory, and risk-assessment methods that could produce internationally comparable results, and the development of manpower in the field of toxicology. Other activities carried out by the IPCS include the development of know-how for coping with chemical accidents, coordination of laboratory testing and epidemiological studies, and promotion of research on the mechanisms of the biological action of chemicals. WHO Library Cataloguing in Publication Data Principles and methods for the assessment of nephrotoxicity associated with exposure to chemicals. Page 1 of 185 Nephrotoxicity associated with exposure to chemicals, principles and methods for the assessment o... (Environmental health criteria: 119) (EUR ; 13222) 1. Kidney diseases - chemically induced 2. Kidney neoplasms - chemically induced 3. Kidney - drug effects I. Series II. Series EUR; 13222 ISBN 92 4 157119 5 (NLM Classification WJ 300) ISSN 0250-863X (c) World Health Organization 1991 (c) ECSC-EEC-EAEC, Brussels-Luxembourg, 1991 Publications of the World Health Organization enjoy copyright protection in accordance with the provisions of Protocol 2 of the Universal Copyright Convention. For rights of reproduction or translation of WHO publications, in part or in toto, application should be made to the Office of Publications, World Health Organization, Geneva, Switzerland. The World Health Organization welcomes such applications. The designations employed and the presentation of the material in this publication do not imply the impression of any opinion whatsoever on the part of the Secretariat of the World Health Organization concerning the legal status of every country, territory, city, or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. The mention of specific companies or of certain manufacturers' products does not imply that they are endorsed or recommended by the World Health Organization in preference to others of a similar nature that are not mentioned. Errors and omissions excepted, the names of proprietary products are distinguished by initial capital letters. CONTENTS PRINCIPLES AND METHODS FOR THE ASSESSMENT OF NEPHROTOXICITY ASSOCIATED WITH EXPOSURE TO CHEMICALS 1. SCOPE OF THE HEALTH SIGNIFICANCE OF NEPHROTOXICITY 2. NEPHROTOXICITY 2.1. Target selectivity 2.2. The dynamics of renal injury 2.3. Classification of renal disease 2.4. The epidemiology of nephrotoxicity 2.5. Risk factors for toxic nephropathies 2.5.1. Factors related to renal function 2.5.2. Clinical risk factors 2.5.3. Extrapolation of animal data to man 2.5.4. Risk assessment from nephrotoxicity studies in animals 2.5.5. Special risk groups in humans 2.5.6. Multichemical exposure 2.5.7. Renal functional reserve 2.5.8. The effects of chemicals on kidneys with pre-existing renal lesions 2.5.8.1 Nephrotoxicity in the presence of renal and extrarenal disease 3. KIDNEY STRUCTURE AND FUNCTION 3.1. Renal anatomy Page 2 of 185 Nephrotoxicity associated with exposure to chemicals, principles and methods for the assessment o... 3.1.1. Histology 3.1.2. Enzyme histochemistry and quantification 3.1.3. Immunohistochemistry 3.2. The renal blood supply 3.2.1. Renal haemodynamics 3.3. The nephron 3.3.1. Cellular heterogeneity and cell-cell interaction 3.3.2. The glomerulus 3.3.3. The proximal tubule 3.3.4. The medulla 58 3.3.4.1 The loops of Henle 3.3.4.2 Collecting ducts 3.3.4.3 The distal tubule 3.3.4.4 The countercurrent multiplier system and urine concentration 3.3.4.5 The interstitial cells 3.4. Species, strain, and sex differences in renal structure and function 3.5. Renal biochemistry 3.5.1. Biochemistry and metabolism in the cortex 3.5.2. Biochemistry and metabolism in the medulla 3.5.2.1 The biochemistry of renal prostaglandins (PG) 3.5.2.2 Lipid metabolism 3.5.2.3 Carbohydrate metabolism in the medulla 3.5.2.4 Medullary glycosaminoglycan (GAG) 3.6. The metabolism of xenobiotic molecules in the kidney 3.6.1. Oxidases 3.6.1.1 Cytochrome P-450-dependent mixed- function oxidases (monooxygenases) 3.6.1.2 Prostaglandin peroxidase- mediated metabolic activation 3.6.2. Conjugation 3.6.2.1 Glucuronide conjugation 3.6.2.2 Sulfate conjugation 3.6.2.3 Glutathione conjugation 3.6.2.4 Mercapturic acid synthesis 3.6.2.5 Amino acid conjugation 3.6.3. Other enzymes involved in xenobiotic metabolism 4. THE MECHANISTIC BASIS OF CHEMICALLY INDUCED RENAL INJURY 4.1. Immunologically induced glomerular disease 4.2. Direct glomerular toxicity 4.3. Tubulointerstitial disease 4.3.1. Acute interstitial nephritis 4.3.2. Acute tubular toxicity 4.3.3. Chronic interstitial nephritis 4.4. Mechanisms of cellular toxicity 4.5. Factors that modify cellular injury by toxins 4.5.1. Cellular transport and accumulation 4.5.2. Metabolic degradation 4.5.3. Intracellular protein binding 4.5.4. Membrane reactions and pinocytosis 5. THERAPEUTIC AGENTS AND CHEMICALS THAT HAVE THE POTENTIAL TO CAUSE NEPHROTOXICITY 5.1. Therapeutic agents 5.1.1. Analgesics and non-steroidal Page 3 of 185 Nephrotoxicity associated with exposure to chemicals, principles and methods for the assessment o... anti-inflammatory drugs (NSAIDs) 5.1.2. Paracetamol and para-aminophenol 5.1.3. Antibiotics 5.1.3.1 Aminoglycosides 5.1.3.2 Cephalosporins 5.1.3.3 Amphotericin B 5.1.3.4 Tetracyclines 5.1.4. Penicillamine 5.1.5. Lithium 5.1.6. Urographic contrast media (UCM) 5.1.7. Anticancer drugs 5.1.7.1 Cisplatin 5.1.7.2 Adriamycin 5.1.8. Immunosuppressive agents 5.1.8.1 Cyclosporin A 5.1.9. Heroin 5.1.10. Puromycin aminonucleoside 5.2. Chemicals 5.2.1. Ethylene glycol 5.2.2. Organic chemicals and solvents 5.2.2.1 Volatile hydrocarbons 5.2.2.2 Chloroform 5.2.2.3 Halogenated alkenes 5.2.2.4 Hydrocarbon-induced nephrotoxicity 5.2.2.5 Bipyridyl herbicides 5.3. Mycotoxins 5.4. Silicon 5.5. Metals 5.5.1. Lead 5.5.2. Cadmium 5.5.3. Mercury 5.5.4. Gold 5.5.5. Bismuth 5.5.6. Uranium 5.5.7. Chromium 5.5.8. Arsenic 5.5.9. Germanium 6. RENAL CANCER 6.1. Renal tumour classification 6.2. Renal adenocarcinoma 6.3. Upper urothelial carcinoma (transitional cell carcinoma) 6.4. Experimentally induced renal adenomas and adenocarcinomas 6.4.1. Background incidence of spontaneous tumours in experimental animals 6.4.2. Inorganic compounds 6.4.3. Organic molecules 6.4.3.1 Nitrosamines and related compounds 6.4.3.2 Morphological changes 6.4.3.3 Biochemical changes in cells 6.4.3.4 The mechanistic basis of renal carcinoma 6.5. Experimentally induced upper urothelial carcinomas (transitional cell carcinomas) 7. ASSESSMENT OF NEPHROTOXICITY 7.1. In vitro studies Page 4 of 185 Nephrotoxicity associated with exposure to chemicals, principles and methods for the assessment o... 7.1.1. Choice of chemical concentrations for in vitro studies 7.1.1.1 Proximate and ultimate nephrotoxicants in vitro 7.1.2. In vitro investigations of nephrotoxicity 7.1.2.1 Perfusion and micropuncture 7.1.2.2 Renal cortical slice 7.1.2.3 Isolated nephron segments 7.1.2.4 Primary cell cultures 7.1.2.5 Established renal cell lines 7.1.2.6 Subcellular fractions 7.2. In vivo experimental studies 7.2.1. Methods for assessing chemically reactive nephrotoxic metabolites in animals 7.2.2. Evaluation of glomerular function 7.2.3. Evaluation of tubular functions 7.2.4. Proteinuria 7.2.4.1 Total proteinuria and electrophoretic pattern 7.2.4.2 Urinary excretion of single plasma proteins 7.2.4.3 Enzymuria 7.2.4.4 Immunoreactive tissue constituents 7.2.4.5 Urinary excretion of prostaglandins 7.2.5. Clinical context 7.2.6. Radiological techniques 7.2.7. Other non-invasive renal assessment 8. DETECTION OF NEPHROTOXICITY IN HUMANS 8.1. Markers of nephrotoxicity 8.1.1. General requirements 8.1.2. Diagnostic value 8.1.3. Prognostic value 8.2. Screening for nephrotoxicity in humans 8.2.1. Glomerular filtration 8.2.2. Tests designed to assess selective dysfunction 8.2.3. Tests designed to assess tissue damage 8.2.3.1 Enzymuria 8.2.3.2 Immunoreactive tissue constituents 8.3. Clinical investigations 8.3.1.