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.

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 Toxicology 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 Chemicals.

World Health Organization Geneva, 2001

The International Programme on Chemical Safety (IPCS), established in 1980, is a joint venture of the United Nations Environment Programme (UNEP), the International Labour Organization (ILO) 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.

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WHO Library Cataloguing-in-Publication Data

Neurotoxicity risk assessment for human health : principles and approaches.

(Environmental health criteria ; 223)

1.Nervous system – drug effects 2.Chemicals – toxicity

3.Neurotoxicity syndromes – etiology 4.Risk assessment – methods

5.Environmental exposure I.International Programme for Chemical Safety II.Series

ISBN 92 4 157223 X (NLM classification: WL 100)

ISSN 0250-863X

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©World Health Organization 2001

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In 1973, the WHO Environmental Health Criteria Programme was initiated with the following objectives:

The first Environmental Health Criteria (EHC) monograph, on mercury, was published in 1976, and since that time an ever-increasing number of assessments of chemicals and of physical effects have been produced. In addition, many EHC monographs have been devoted to evaluating toxicological methodology, e.g., for genetic, neurotoxic, teratogenic and nephrotoxic effects. Other publications have been concerned with epidemiological guidelines, evaluation of short-term tests for carcinogens, biomarkers, effects on the elderly and so forth.

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Dr S.A. Assimon, US Food and Drug Administration, USA

Dr R. Duffard, Laboratorio de Toxicologia Experimental, Argentina

Dr J. Harry, US National Institute of Environmental Health Sciences, USA

Dr B. Kulig, Kulig Consultancy, The Netherlands

Dr O. Ladefoged, Institute of Food Safety and Toxicology, Denmark

Dr M. Lotti, University of Padova, Italy

Dr J. O’Donoghue, Eastman Kodak Company, USA

Dr D. Ray, MRC Toxicology Unit, United Kingdom

Dr J. Ross, Procter & Gamble Company (representing American Industrial Health Council)

Dr H. Tilson, US Environmental Protection Agency, USA (Chair)

Dr G. Winneke, Medical Institute of Environmental Hygiene, Germany

Dr T. Damstra, World Health Organization, IPCS/Interregional Research Unit (IRRU), USA

The IPCS, initiated in 1980 as a collaborative programme of UNEP, the ILO, and WHO, has as one of its major objectives the development and evaluation of principles and methodologies for assessing the effects of chemicals on human health and the environment. Since its inception, IPCS has given high priority to improving scientific methodologies and promoting internationally accepted strategies to assess the risks from exposure to neurotoxic chemicals.

In 1986, IPCS published the EHC document entitled "Principles and Methods for the Assessment of Neurotoxicity Associated with Exposure to Chemicals" (IPCS, 1986). This publication focused on neurobehavioural, neurophysiological, neurochemical and neuropathological methods that had been successfully applied in neurotoxicity studies. The recommendations contained in the 1986 EHC led to a WHO/IPCS-sponsored multilaboratory, collaborative study to ascertain whether a standardized neurobehavioural examination could be developed to assess the effects of chemicals. Several established end-points for neurotoxicity and some well known neurotoxicants were selected in order to assess the validity both within and across laboratories in detecting the neurobehavioural effects (MacPhail et al., 1997). The results of this collaborative study strongly supported the use of behavioural tests for the screening of neurotoxicity and were incorporated into the Neurotoxicity Risk Assessment Guidelines of the US Environmental Protection Agency (EPA) and the Organisation for Economic Co-operation and Development (OECD) Test Guidelines for neurotoxicity testing.

Since 1986, new advances in basic neurobiology research and in the development of new technologies have significantly improved our ability to assess the neurotoxic potential of chemicals. The availability of up-to-date principles and approaches on neurotoxicity is the subject of urgent requests from many countries, and IPCS was advised to update the 1986 publication.

This document addresses the major scientific principles underlying hazard identification, testing methods and risk assessment strategies in assessing human neurotoxicity. It provides an overview of the current state of neurotoxicity risk assessment for public health officials, research and regulatory scientists, and risk managers. It is intended to complement existing monographs, reviews and test guidelines (OECD, 1995, 1997, 1999; Sobotka et al., 1996; Babich, 1998; US EPA, 1998a). It is not intended to be prescriptive in nature or a textbook on neurotoxicology.

A preliminary draft of the document was circulated to 64 experts in neurotoxicology and IPCS contact points for their review. Many reviewers provided substantive comments and text, and their contributions are gratefully acknowledged.

A Task Group meeting was held in Washington, DC, on 29-31 March 2000, to review a revised draft. Dr Damstra, IPCS, was responsible for the preparation of the final document and for its overall scientific content.

The efforts of all who helped in the preparation and finalization of the monograph are gratefully acknowledged. Special thanks are due to the US EPA and the US National Institute of Environmental Health Sciences for their financial support for the planning and review group meetings.

Since the 1986 publication of the IPCS Environmental Health Criteria document on "Principles and Methods for the Assessment of Neurotoxicity Associated with Exposure to Chemicals," basic research in neurobiology has significantly improved our ability to assess how chemicals may adversely affect the nervous system. This progress is reflected in the availability of a number of national and international (e.g., Organisation for Economic Co-operation and Development) neurotoxicity test guidelines, risk assessment guidelines and guidance documents and international neurobehavioural test method validation studies.

Even with the improvements made in neurotoxicity risk assessment, there is still worldwide concern about the potential neurotoxic effects of chemicals. Of particular concern is the lack of data on putative relationships between exposures to low levels of environmental chemicals and effects on neurobehavioural development in children and neurodegenerative diseases in the elderly. Only a small fraction of chemicals have been adequately evaluated for neurotoxicity.

The complexity of the nervous system results in multiple potential target sites and adverse sequelae. No other organ system has the wide variety of specialized cell functions seen in the nervous system. Different expressions of neurotoxicity are generally based on the different susceptibilities of the various subpopulations of cells that make up the nervous system. The status and role of the blood-brain barrier in the central nervous system (CNS) and similar structures in the peripheral nervous system in modulating the access of some chemicals to the nervous system are also unique considerations in assessing neurotoxicity. Moreover, certain specialized cells outside the barrier have important integrative neuro-immuno-endocrine functions that orchestrate numerous physiological, metabolic and endocrine processes. These integrative functions are fundamental for cognition and higher-order neural functions, but knowledge on how they can be disrupted by chemical exposures is limited. In contrast to other tissues, the ability of nerve cells to replace or regenerate is severely constrained and is a limiting factor in achieving full recovery from neurotoxicity under conditions where cell death has occurred.

The biological basis for identification of certain susceptible populations, including the young, the aged and people with genetic predispositions to certain forms of toxicity, is an important consideration in the risk assessment process for neurotoxicity. Many of the factors that convey susceptibility for neurotoxicity will not differ from those that need to be considered in risk assessments of toxicity to other target organs, because they involve metabolic processes that are common to many organ systems. However, the complexity and critically timed events of the long postnatal CNS development process may make the developing nervous system differentially susceptible to certain exposures. Also, the aging process results in a reduction of plasticity and diminished compensatory capacity of the nervous system, making it potentially more susceptible to neurotoxic insults.

Data on the effects of chemicals on humans are often not available or are underreported. The detection of neurotoxicity in human studies provides the most direct means of assessing health risk, but is often complicated by confounding factors and inadequate data. Exposure levels in humans are difficult to establish, and the neurological status of populations is extremely heterogeneous. Nevertheless, there has been significant progress in the last decade in developing validated methods for detecting neurotoxicity in humans. Sources of human data include accidental and occupational exposures, case-studies, clinical evaluations, epidemiological studies, and field and laboratory studies. Standardized neuropsychological tests, validated computer-assisted test batteries, neurophysiological and biochemical tests, and refined imaging techniques have been improved and become well established. These methods can be used to assess a variety of human neurotoxic end-points and have provided useful data for the purpose of neurotoxicity risk assessment.

For most neurotoxicological assessments, it is still necessary to rely on information derived from experimental animal models. Behavioural, biochemical, electrophysiological and histopathological methods, along with validated batteries of functional tests, are now routinely used in animal studies to identify and characterize neurotoxic effects. Standardization and validation of animal test batteries have improved the quality of the data available for risk assessment. Using various combinations of these methods, specific testing protocols, test guidelines and testing strategies for neurotoxicity in adults and developing animals have been developed by intergovernmental organizations and national governments. New guidelines for standard acute and repeated-dose toxicity studies now also include behavioural and histopathological end-points specifically intended to improve the evaluation of the nervous system. Although animal models have been used extensively to study the differential sensitivity of developing organisms to chemical insults, current guidelines for developmental neurotoxicity are complex, and the results are often subject to varying interpretations. Most neurotoxicity testing strategies use a hierarchical or tiered approach. However, in addition to test protocol data, all available sources of data (structure-activity relationships, mechanistic research, etc.) must be considered to provide in-depth information about a specific type of neurotoxic effect.

As with other toxicities, a variety of factors are critical considerations in evaluating the neurotoxic potential of chemicals in experimental animals. These include selection of the appropriate animal models, exposure variables and test methods, an understanding of the biological relevance of the end-points being measured, use of validated measures and quality assurance. The experimental conditions should take into account the potential route and level of human exposure and any available information on toxicodynamics and toxicokinetics.

Many countries have developed risk assessment processes in which relevant data on the biological effects, dose-response relationships and exposure for a particular chemical are analysed in an attempt to establish qualitative and quantitative estimates of adverse outcomes. These processes are relatively similar and typically include hazard identification, dose-response evaluation, exposure assessment and risk characterization. Although principles of risk assessment specifically for neurotoxicity are evolving rapidly, they are still generally limited to qualitative hazard identification and, to some extent, dose-response assessment. Only a few assessments adequately cover exposure assessment or risk characterization.

The application of risk assessment principles for neurotoxic chemicals is generally similar to that for other non-cancer end-points except that issues of reversibility, compensation and redundancy of function in the nervous system require special consideration. Conventionally, neurotoxicological risk assessments have been based on no-observed-adverse-effect levels and empirical uncertainty factors to derive acceptable exposure limits. The evaluation of all available data is the key to providing sound risk assessments. Test methods and strategies in animals need to be continually refined as new data and technologies become available so as to improve the predictive validity of animal models for human neurotoxicity risk assessment.

In order to employ effective control and intervention strategies to prevent human neurotoxicity, an adequate knowledge base on potential neurotoxicity of chemicals must be developed. The following recommendations are made to improve this knowledge base:

1. Surveillance programmes and the use of harmonized formats for the collection of data on the incidence of poisonings and adverse reactions to neurotoxic agents in humans should be promoted and strengthened.
2. Better assessment of exposure of individuals and of populations to neurotoxic agents is needed in order to analyse associations between exposure and effect.
3. There is a need to conduct hypothesis-based epidemiological and experimental studies on the potential association between environmental exposures and neurodegenerative diseases, particularly as it relates to susceptible populations and gene-environment interactions.
4. Biomarkers of exposure, effect and susceptibility should be identified, developed and validated for use in epidemiological studies of neurotoxicity.
5. Research efforts are needed to better identify subpopulations that are potentially susceptible to the effects of neurotoxic agents and to characterize the factors contributing to increased susceptibility.
6. Standardized test methods and the development of norms for evaluating neurotoxicity in infants and children are needed for use in cross-cultural studies of human developmental neurotoxicity.
7. More emphasis should be placed on studies involving perinatal exposure to chemicals and/or mixtures of chemicals to define the relative sensitivity of the developing nervous system to neurotoxic injury.
8. Efficient animal testing approaches for developmental neurotoxicity need to be developed and validated in international collaborative studies.
9. In order to establish the biological significance of the subtle changes in many of the end-points used in neurotoxicology research efforts, improved animal models are needed to elucidate the relationships between molecular/cellular events and the clinical manifestations of neurotoxicity.
10. Research on how chemicals affect the integrated functions of the nervous system, particularly research related to endocrine disruptors, should be promoted.
11. There is a need for further exploration of the value of utilizing structure-activity relationships in identifying the neurotoxic potential of chemicals.
12. In order to reduce the uncertainties in current neurotoxicity risk assessment associated with the reliance on default assumptions and uncertainty factors for extrapolating from animal to human and from acute to chronic, as well as to account for variability within populations, research is needed to (1) delineate mechanisms of neurotoxicity and promote the use of mechanistic data in assessing risk; (2) provide mechanistically based dose-response models and toxicokinetic models that allow for extrapolation across dose, route and species; (3) reduce the use of uncertainty factors in quantitative risk assessment calculations; and (4) promote the availability and use of improved and harmonized risk assessment procedures.
13. Current risk assessment guidelines focus on assessing single chemicals following exposure via single pathways. In order to address aggregrate exposure or cumulative toxicity issues, research is needed to (1) test the hypothesis of additivity for chemicals having a similar mode of action; (2) assess possible non-additive interactions of chemicals with different modes of action; and (3) study potential interactions of multiple chemicals at doses below those required to produce detectable effects following single exposures.

Chemicals have become an indispensable part of human life, sustaining activities and development, preventing and controlling many diseases, and increasing agricultural productivity. Despite their benefits, chemicals may, especially when misused, cause adverse effects on human health. The nervous system has been shown to be particularly vulnerable to certain chemical exposures, and there is increasing global concern about the potential health effects from exposure to neurotoxic chemicals.

There is a lack of available toxicological data for many compounds used commercially, and most chemicals have not been adequately assessed for their neurotoxic potential (US NRC, 1984). The need for a multidisciplinary approach to neurotoxicity risk assessment has been recognized by a number of international and scientific organizations and national governments (IPCS, 1986b; Landrigan et al., 1994; OECD, 1995, 1997, 1999; Simonsen et al., 1995; LeBel & Foss, 1996; SGOMSEC, 1996; Sobotka et al., 1996; Chouaniere et al., 1997; US EPA, 1998a).

This publication summarizes the scientific knowledge base on which principles and methods involved in neurotoxicity risk assessment are based. It is aimed at providing a framework for public health officials, research and regulatory scientists, and risk managers on the use and interpretation of neurotoxicity data from human and animal studies, and it discusses emerging methodological approaches to studying neurotoxicity. It does not provide practical advice or specific guidance for the conduct of specific tests and studies. These guidelines have been developed and issued by international organizations and national governments and vary depending on the types of chemicals being assessed and on national regulations and recommendations.

The Organisation for Economic Co-operation and Development (OECD) has developed internationally agreed-upon Test Guidelines for the testing of chemicals for potential neurotoxicity. OECD is an intergovernmental organization of 29 industrialized countries in North America, Europe and the Pacific, as well as the European Commission (EC), which meet to coordinate and harmonize policies and work together to respond to international concerns. Specific OECD Test Guidelines include those for single-dose toxicity (e.g., OECD 402, 403, 420 and 423) (OECD, 1981, 1987a, 1992, 1996) and repeated-dose toxicity (e.g., OECD 405 and 408) (OECD, 1987b, 1998), as well as Test Guidelines specifically developed for the study of neurotoxicity in adult and young laboratory animals (i.e., OECD 418, 419, 424 and 426) (OECD, 1995, 1997, 1999). OECD is also developing a Guidance Document on Neurotoxicity Testing (in preparation) to ensure that sufficient data are obtained to enable adequate evaluation of the risks of neurotoxicity. The European Union (EC, 1996), European Centre for Ecotoxicology and Toxicology of Chemicals (ECETOC, 1992), US Food and Drug Administration (US FDA, 1970), US Environmental Protection Agency (US EPA, 1998a) and US Consumer Product Safety Commission (Babich, 1998) have also developed testing strategy and evaluation guidelines. In addition, the Danish Environmental Protection Agency (Ladefoged et al., 1995) issued a document on criteria for evaluating neurotoxicity.

This document does not elaborate in detail on developmental neurotoxicology, since issues related to this topic are being addressed in the revised OECD Test Guideline 426: Developmental Neurotoxicity Study (OECD, 1999) and in another IPCS publication, "Principles for Evaluating Human Reproductive Effects of Chemicals" (in preparation). It also does not address in detail recent research and international concerns about the potential adverse developmental and neurotoxic effects from exposure to chemicals that have the potential to disrupt the endocrine system (Kavlock et al., 1996; IUPAC, 1998; EC, 1999; US NRC, 1999). Data on endocrine disrupting chemicals are currently being evaluated in another IPCS monograph, "Global Assessment of the State-of-the-Science of Endocrine Disruptors" (in preparation).

This document also reviews methods for evaluating effects and deriving exposure guidelines when neurotoxicity is a critical effect. The availability of alternative mathematical approaches to dose-response analyses, characterization of the health-related database for neurotoxicity risk assessment, and the integration of exposure information with results of the dose-response assessment to characterize risks are also discussed.

The present chapter provides an overview of the magnitude of the problem, defines key terms and discusses critical concepts, assumptions and criteria for neurotoxicity risk assessment. Chapter 3 discusses basic principles of neurobiology and toxicology that could be useful for risk assessors seeking to understand the scientific basis for specific methods and procedures used in neurotoxicology and the relative vulnerability of specific structures and processes that are essential for normal functioning of the nervous system. This chapter also provides basic toxicological principles concerning how chemicals can interact with the nervous system. In addition, Chapter 3 describes the potential for subpopulations within the larger population to be differentially sensitive to chemical exposure and ends with a general overview of the various types of adverse effects that chemicals can have on the structure and function of the nervous system. Chapter 4 covers an area of neurotoxicology that was not addressed in the 1986 IPCS document: human neurotoxicology. This chapter describes the general procedures that are commonly used to assess chemical effects in humans and discusses important issues of experimental design and data interpretation. Chapter 5 describes the interpretation of data from animal studies. Methods used to assess neurotoxicity in animals were covered in great detail in the 1986 IPCS document, while the present document focuses more on guidance concerning the interpretation of results from such methods. This chapter also includes examples of chemicals that at some dose are known to affect behavioural, neurochemical, neurophysiological or neuroanatomical end-points in animal models. Chapter 6 deals with the emerging area of neurotoxicity risk assessment. This chapter discusses the four-step risk assessment process described by the US National Research Council (US NRC, 1983) and is intended to provide principles that can be used to assess in a qualitative and quantitative manner human health risk based on data from human and animal studies.

Risk assessment is a process intended to identify and then to calculate or estimate the risk for a given target system to be affected by a particular substance, taking into account the inherent characteristics of the substance of concern as well as the characteristics of the specific target system. Risk management is a decision-making process involving considerations of political, social, economic and technical factors with relevant risk assessment information relating to a hazard so as to develop, analyse and compare regulatory and non-regulatory options and to select and implement the optimal response for safety from that hazard. Hazard refers to the inherent property of a substance capable of having adverse effects (OECD/IPCS, 2001).

Neurotoxicity is one of several non-cancer end-points that share common default assumptions and principles. The interpretation of data as indicative of a potential neurotoxic effect involves the evaluation of the validity of the database. There are four principal questions that should be addressed: (1) whether the effects result from exposure; (2) whether the effects are neurotoxicologically significant; (3) whether there is internal consistency between behavioural, physiological, neurochemical and morphological end-points; and (4) whether the effects are predictive of what will happen under various conditions. Addressing these issues can provide a useful framework for evaluating either human or animal studies or the weight of evidence for a chemical (Sette & MacPhail, 1992; Health Canada, 1994; Hertel, 1996; IPCS, 1999).

As can be seen in Table 1, the nervous system is affected by several classes of chemicals found in the environment globally, particularly metals, solvents, insecticides and naturally occurring toxins (US NRC, 1992; Spencer et al., 2000). Lead is one of the earliest examples of a neurotoxic chemical with widespread exposure (Gibson, 1904). This metal is widely distributed. Major sources of inorganic lead include industrial emissions, lead-based paints, food, beverages and the burning of leaded gasolines. If exposure occurs at relatively low levels during development, lead can cause a variety of neurobehavioural problems, including learning disorders and altered mental development (Bellinger et al., 1987; Needleman, 1990; Cory-Slechta & Pounds, 1995; Needleman et al., 1996). Over the years, government regulations have been developed to decrease human exposure to lead, and an intervention level of 10 µg/dl whole blood has been recommended as a goal (US CDC, 1991; WHO, 1995). While adults appear to be less susceptible than children to inorganic lead, occupational exposures to organic lead compounds such as tetraethyl lead have been reported to produce toxic psychosis in adults. Acute solvent intoxication has produced dementia, but this is relatively rare (Cassells & Dodds, 1946; Arlien-Søborg, 1992).