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English (5.434Mb) 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 Organization or the World Health Organization. Environmental Health Criteria 223 NEUROTOXICITY RISK ASSESSMENT FOR HUMAN HEALTH: PRINCIPLES AND APPROACHES First draft prepared by Dr J. Harry, US National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, USA; Dr B. Kulig, Kulig Consultancy, The Netherlands; Dr M. Lotti, University of Padua, Italy; Dr D. Ray, MRC Toxi- cology Unit, England; Dr H. Tilson, US Environmental Protection Agency, Research Triangle Park, North Carolina, USA; and Dr G. Winneke, Medical Institute of Environmental Hygiene, Germany Published under the joint sponsorship of the United Nations Environment Programme, the International Labour Organization and the World Health Organization, and produced within the framework of the Inter-Organization Programme for the Sound Management of çhThà / T World Health Organ izatllm i Geneva, 2001 I.... :.. -.., '•.' The International Programme on Chemicat Safety (IPCS), established in 1980, is a joint venture of the United Nations Environment Programme (UNEP), the International Labour Organization (lLO) and the World Health Organization (WHO). The overall objectives of the IPCS are to establish the scientific basis for assessment of the risk to human health and the environment from exposure to chemicals, through international peer review processes as a prerequisite for the promotion of chemical safety, and to provide technical assistance in strengthening national capacities for the sound management of chemicals, The Inter-Organization Programme for the Sound Management of Chemicals (IOMC) was established in 1995 by UNEP, ILO, the Food and Agriculture Organization of the United Nations, WHO, the United Nations Industrial Development Organization, the United Nations Institute for Training and Research and the Organisation for Economic Co-operation and Development (Participating Organizations), following reconsmendations made by the 1992 UN Conference on Environment and Development to strengthen cooperation and increase coordination in the field ofcheniical safety. The purpose of the IOMC is to promote coordination of the policies and activities pursued by the Participating Organizations, jointly or separately, to achieve the sound management of chemicals in relation to human health and the environment. WHO Library Cataloguing-in-Publication Data Ncurotoxicity risk assessment for human health : principles and approaches. (Environmental health criteria 223) i.Nervous system - drug effects 2,Chernicals -toxicity 3.Neurotoxicity syndromes - etiology 4.Risk assessment - methods 5,Environnwntai exposure l,International Programme for Chemical Safety Il.Series ISBN 924 157223 X (NLM classification: WL 100) ISSN 0250-863X The World Health Organization welcomes requests for permission to reproduce or translate its publications, in part or in foil. Applications and enquiries should be addressed to the Office of Publications, World Health Organii.ation, Geneva, Switzerland, which will be glad to provide the latest information on any changes made to the text, plans for new editions, and reprints and translations already available. ©Wortd Health Organization 2001 Publications of the World Health Organization enjoy copyright protection in accordance with the provisions of Protocol 2 of the Universal Copyright Convention. All rights reserved. The designations employed and the presentation of the material in this publication do not imply the expression of any opinion whatsoever on the part of the Secretariat of the World Health Organization conceming the legal status of any country, territoty, 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, Printed in Finland 2001 / 3704 - Vammala - 5000 CONTENTS ENVIRONMENTAL HEALTH CRITERIA FOR NEUROTOX1CITY RISK ASSESSMENT FOR HUMAN HEALTH: PRINCIPLES AND APPROACHES PREAMBLE IX ACRONYMS AND ABBREVIATIONS xix 1 SUMMARY AND RECOMMENDATIONS Li Summary 1.2 Recommendations 4 2. INTRODUCTION 7 2.1 Purpose of the publication 7 2.2 General principles of neurotoxicity risk assessment 9 2.3 Examples of chemical-induced neurotoxicity 10 2.4 Definitions and critical concepts in neurotoxicology 17 2.4.1 Neurotoxicity versus adverse effects 17 2.4.2 Direct versus indirect effects 18 2.4.3 Primary versus secondary effects 18 2.4.4 Transient versus persistent effects 19 2.4.5 Compensation 19 2.5 Assumptions in neurotoxicity risk assessment 20 2.6 Criteria for quality of data used in risk assessment 21 2.6.1 Sensitivity 22 2.6.2 Specificity 22 2.6.3 Reliability/validity 23 2.6.4 Dose—response 23 3. BASIC PRINCIPLES FOR NEUROTOXICITY RISK ASSESSMENT 25 3.1 Neurobiological principles 25 3.1.1 Structure of the nervous system 25 3.1.2 Transport processes 28 3.1.3 Ion channels 29 EHC 223: Neurotoxicity Risk Assessment for Human Health 3.1.4 Neurotransmission 30 3.1 .5 Metabolism 32 3.1.6 Blood—brain and blood—nerve barriers 32 3.1 .7 Regenerative ability 35 3.1.8 Neuroendocrine system 37 3.1.9 Integrative function of the nervous system 38 3.2 Toxicological principles 38 3.2.1 Neurotoxicity 38 3.2.2 Structure—activity relationships 39 3.3 Susceptible populations 40 3.3.1 Developing nervous system 41 3.3.2 Aged nervous system 43 3.3.3 Genetic susceptibility 44 3.4 Types of effects on the nervous system 44 3.4.1 Neurotransmitter function 45 3.4.2 Morphological effects 45 3.4.3 Behaviour 46 3.5 Summary 47 4. HUMAN NEUROTOXICITY 49 4.1 Introduction 49 4.2 Methods for assessing human neurotoxicity 51 4.2.1 Clinical neurological evaluation 51 4.2.2 Neuropsychological and neurobehavioural testing 52 4.2.2.1 Individual neuropsychological assessment 52 4.2.2.2 Cognitive testing batteries 55 4.2.2.3 Psychiatric and symptom questionnaires 61 4.2.2.4 Behavioural neurophysiological tests 62 4.2.3 Electrophysi o logical tests 65 4.2.4 Neuroimaging techniques 69 4.3 Types of human studies 70 4.3.1 Clinical case-studies 70 4,3.2 Epidemiological studies 7' 4.3.2.1 Assessment of exposure and dose 75 4.3.2.2 Causal inferences and confounding factors 82 iv 4.3.3 Human experimental exposure studies 85 4.3.4 Developmental human neurotoxicity studies 87 4.4 Ethical considerations in human studies 89 4.5 Summary 90 5. ANIMAL NEIJROTOXICITY 92 5. 1 Animal models 92 5.1.1 Role of animal models 92 5.1.2 Special considerations in animal models 93 5.1.2.1 Dosing scenario 93 5.12.2 Species differences 94 5.1.2.3 Other factors 95 5.1.2.4 Statistical considerations 96 5.1.2.5 Animal welfare issues 97 5.2 End-points of neurotoxicity 98 5.2.1 Introduction 98 5.2.2 Behavioural end-points 98 5.2.2.1 Observational batteries 101 5.2.2.2 Motor activity 104 5.2.2.3 Neuromotor function 106 5.2.2.4 Sensory function 107 5.2.2.5 Learning and memory 108 5.2.2.6 Attention flU 5.2.2.7 Schedule-controlled behaviour Ill 5.2.2.8 Pharmacological challenges 113 5.2.3 N europhysio logical end-points 114 5.2.3.1 Peripheral nerve function studies 116 5.2.3.2 Sensory evoked potentials 117 5.2.3.3 Electroencephalography 119 5,2.3.4 Seizure activity 119 5,2.3.5 Electromyography 120 5.2.3.6 Spinal reflex excitability 120 5.2.3.7 Ion channel function and synaptic transmission 121 5.2.3.8 1-Iippocampal field potentials 121 5.2.4 Neurochemical end-points 122 5.2.4.1 General biochemical measures 123 5.2.4.2 Cholinesterase-inhibiting compounIs 124 5.2.4.3 Cellular protein markers 125 V EHC 223: Neurotoxicity Risk Assessment for Human Health 5.2.5 Neuroendocrine end-points 126 5.2.6 Structural end-points 127 5.2.7 Axonal transport 135 5.3 Special issues in developmental neurotoxicity 137 5.4 In vitro methods 141 5.5 Testing strategies for neurotoxicity 144 5.6 Emerging issues 146 5.6.1 Genetic approaches to neurotoxicology 146 5.6.2 Neuroimmunotoxicology 147 5.6.3 Endocrine dysfunctionldisruption 148 5.7 Summary 148 6. NEUROTOXICITY RISK ASSESSMENT 150 6.1 Introduction 150 6.2 Hazard identification 150 6.2.1 Human studies 151 6.2.2 Animal studies 151 6.2.3 Special issues 152 6.2.3.1 Animal-to-human extrapolation 152 6.2.3.2 Susceptible populations 152 6.2.3.3 Cumulative toxicity 152 6.2.3.4 Recovery of function 153 6.2.4 Characterization of the database and classification schemes 154 6.3 Dose—response assessment 160 6.4 Exposure assessment 166 6.5 Risk characterization 167 6.5.1 Introduction 167 6.5.2 Integration 168 6.5.3 Quality of the database 169 6.5.4 Descriptors of neurotoxicity risk 170 6.5.4.1 Estimation of the number of individuals 170 6.5.4.2 Presentation of specific scenarios 170 6.5.4.3 Risk characterization for highly exposed individuals 170 6.5.4.4 Risk characterization for highly sensitive or susceptible individuals 171 6.5.4.5 Other risk descriptors 172 vi 6.6 Summary 173 REFERENCES 174 RESUME ET RECOMMANDATIONS 211 RESUMEN Y RECOMENDACIONES 218 vii EHC 223: Neurotoxicity Risk Assessment for Human Health NOTE TO READERS OF THE CRITERIA MONOGRAPHS Every effort has been made to present information in the criteria monographs as accurately as possible without unduly delaying their publication.
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