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. 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. 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 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 recommendations made by the 1992 UN Conference on Environment and Development to strengthen cooperation and increase coordination in the field of chemical safety. The World Health Organization welcomes requests for permission to reproduce or translate its publications, in part or in full.
Publications of the World Health Organization enjoy copyright protection in accordance with the provisions of Protocol 2 of the Universal Copyright Convention. 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 concerning the legal status of any 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. Every effort has been made to present information in the criteria monographs as accurately as possible without unduly delaying their publication. A detailed data profile and a legal file can be obtained from the International Register of Potentially Toxic Chemicals, Case postale 356, 1219 Châtelaine, Geneva, Switzerland (telephone no.
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.
Since its inauguration, the EHC Programme has widened its scope, and the importance of environmental effects, in addition to health effects, has been increasingly emphasized in the total evaluation of chemicals. The original impetus for the Programme came from World Health Assembly resolutions and the recommendations of the 1972 UN Conference on the Human Environment.
The recommendations of the 1992 UN Conference on Environment and Development and the subsequent establishment of the Intergovernmental Forum on Chemical Safety with the priorities for action in the six programme areas of Chapter 19, Agenda 21, all lend further weight to the need for EHC assessments of the risks of chemicals. The criteria monographs are intended to provide critical reviews on the effects on human health and the environment of chemicals and of combinations of chemicals and physical and biological agents. In the evaluation of human health risks, sound human data, whenever available, are preferred to animal data. The EHC monographs are intended to assist national and international authorities in making risk assessments and subsequent risk management decisions. Since the inception of the EHC Programme, the IPCS has organized meetings of scientists to establish lists of priority chemicals for subsequent evaluation.
If an EHC monograph is proposed for a chemical not on the priority list, the IPCS Secretariat consults with the cooperating organizations and all the Participating Institutions before embarking on the preparation of the monograph.
The order of procedures that result in the publication of an EHC monograph is shown in the flow chart. The draft document, when received by the RO, may require an initial review by a small panel of experts to determine its scientific quality and objectivity.
The Task Group members serve as individual scientists, not as representatives of any organization, government or industry.
The three cooperating organizations of the IPCS recognize the important role played by nongovernmental organizations.
All individuals who as authors, consultants or advisers participate in the preparation of the EHC monograph must, in addition to serving in their personal capacity as scientists, inform the RO if at any time a conflict of interest, whether actual or potential, could be perceived in their work.
When the Task Group has completed its review and the RO is satisfied as to the scientific correctness and completeness of the document, the document then goes for language editing, reference checking and preparation of camera-ready copy.
All Participating Institutions are informed, through the EHC progress report, of the authors and institutions proposed for the drafting of the documents. 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. In 1986, IPCS published the EHC document entitled "Principles and Methods for the Assessment of Neurotoxicity Associated with Exposure to Chemicals" (IPCS, 1986).
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.
This document addresses the major scientific principles underlying hazard identification, testing methods and risk assessment strategies in assessing human neurotoxicity. A preliminary draft of the document was circulated to 64 experts in neurotoxicology and IPCS contact points for their review. A Task Group meeting was held in Washington, DC, on 29-31 March 2000, to review a revised draft. The efforts of all who helped in the preparation and finalization of the monograph are gratefully acknowledged. 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.
Even with the improvements made in neurotoxicity risk assessment, there is still worldwide concern about the potential neurotoxic effects of chemicals.
The complexity of the nervous system results in multiple potential target sites and adverse sequelae.
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.
For most neurotoxicological assessments, it is still necessary to rely on information derived from experimental animal models.
As with other toxicities, a variety of factors are critical considerations in evaluating the neurotoxic potential of chemicals in experimental animals. 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. 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. 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.
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.
Better assessment of exposure of individuals and of populations to neurotoxic agents is needed in order to analyse associations between exposure and effect. 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. Biomarkers of exposure, effect and susceptibility should be identified, developed and validated for use in epidemiological studies of neurotoxicity. 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. 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. Efficient animal testing approaches for developmental neurotoxicity need to be developed and validated in international collaborative studies. Research on how chemicals affect the integrated functions of the nervous system, particularly research related to endocrine disruptors, should be promoted. There is a need for further exploration of the value of utilizing structure-activity relationships in identifying the neurotoxic potential of chemicals.
Current risk assessment guidelines focus on assessing single chemicals following exposure via single pathways.
Chemicals have become an indispensable part of human life, sustaining activities and development, preventing and controlling many diseases, and increasing agricultural productivity.
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). This publication summarizes the scientific knowledge base on which principles and methods involved in neurotoxicity risk assessment are based.
The Organisation for Economic Co-operation and Development (OECD) has developed internationally agreed-upon Test Guidelines for the testing of chemicals for potential 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). This document also reviews methods for evaluating effects and deriving exposure guidelines when neurotoxicity is a critical effect. 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.

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. Neurotoxicity is one of several non-cancer end-points that share common default assumptions and principles.
Another example of a Parkinsonian-like syndrome is the movement disorder observed in drug abusers who intravenously injected 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) (Langston et al., 1983). Organic solvents are encountered frequently in occupational settings (Dick, 1995), and some are reported to produce clinical neuropsychological and neurological effects (White, 1995).
Harry, US National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, USA; Dr B. 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 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. Applications and enquiries should be addressed to the Office of Publications, World Health Organization, 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. Errors and omissions excepted, the names of proprietary products are distinguished by initial capital letters. In the interest of all users of the Environmental Health Criteria monographs, readers are requested to communicate any errors that may have occurred to the Director of the International Programme on Chemical Safety, World Health Organization, Geneva, Switzerland, in order that they may be included in corrigenda. In this manner, with the strong support of the new partners, the importance of occupational health and environmental effects was fully recognized.
Animal and in vitro studies provide support and are used mainly to supply evidence missing from human studies. They represent a thorough evaluation of risks and are not, in any sense, recommendations for regulation or standard setting. A designated staff member of IPCS, responsible for the scientific quality of the document, serves as Responsible Officer (RO).
Once the RO finds the document acceptable as a first draft, it is distributed, in its unedited form, to well over 150 EHC contact points throughout the world who are asked to comment on its completeness and accuracy and, where necessary, provide additional material. Their function is to evaluate the accuracy, significance and relevance of the information in the document and to assess the health and environmental risks from exposure to the chemical. Representatives from relevant national and international associations may be invited to join the Task Group as observers.
After approval by the Director, IPCS, the monograph is submitted to the WHO Office of Publications for printing.
A comprehensive file of all comments received on drafts of each EHC monograph is maintained and is available on request.
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.
This publication focused on neurobehavioural, neurophysiological, neurochemical and neuropathological methods that had been successfully applied in neurotoxicity studies.
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. It provides an overview of the current state of neurotoxicity risk assessment for public health officials, research and regulatory scientists, and risk managers. Many reviewers provided substantive comments and text, and their contributions are gratefully acknowledged. Dr Damstra, IPCS, was responsible for the preparation of the final document and for its overall scientific content.
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. 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. No other organ system has the wide variety of specialized cell functions seen in the nervous system. 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. 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. 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. 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.
These processes are relatively similar and typically include hazard identification, dose-response evaluation, exposure assessment and risk characterization. Conventionally, neurotoxicological risk assessments have been based on no-observed-adverse-effect levels and empirical uncertainty factors to derive acceptable exposure limits.
Despite their benefits, chemicals may, especially when misused, cause adverse effects on human health. 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. 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. 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. 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. 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. The interpretation of data as indicative of a potential neurotoxic effect involves the evaluation of the validity of the database. Lead is one of the earliest examples of a neurotoxic chemical with widespread exposure (Gibson, 1904). One major incident of human exposure occurred in the mid-1950s when a chemical plant near Minamata Bay, Japan, discharged mercury sulfate used as a catalyst for the synthesis of acetaldehyde into the wastewater from the plant as part of waste sludge. Exposed manganese miners in several countries have suffered from "manganese madness," characterized by hallucinations, emotional instability and numerous neurological problems. They can include insecticides (used to control insects), fungicides (for blight and mildew), rodenticides (for rodents, such as rats, mice and gophers) and herbicides (to control weeds) (Hayes, 1991). Other publications have been concerned with epidemiological guidelines, evaluation of short-term tests for carcinogens, biomarkers, effects on the elderly and so forth. The EHC monographs have become widely established, used and recognized throughout the world.
It is mandatory that research on human subjects is conducted in full accord with ethical principles, including the provisions of the Helsinki Declaration.
The contact points, usually designated by governments, may be Participating Institutions, IPCS Focal Points or individual scientists known for their particular expertise. A summary and recommendations for further research and improved safety aspects are also required.
While observers may provide a valuable contribution to the process, they can speak only at the invitation of the Chairperson.
At this time, a copy of the final draft is sent to the Chairperson and Rapporteur of the Task Group to check for any errors. The Chairpersons of Task Groups are briefed before each meeting on their role and responsibility in ensuring that these rules are followed. Different expressions of neurotoxicity are generally based on the different susceptibilities of the various subpopulations of cells that make up the nervous system. 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. Exposure levels in humans are difficult to establish, and the neurological status of populations is extremely heterogeneous. Standardization and validation of animal test batteries have improved the quality of the data available for risk assessment. The experimental conditions should take into account the potential route and level of human exposure and any available information on toxicodynamics and toxicokinetics. 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.

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. It does not provide practical advice or specific guidance for the conduct of specific tests and studies.
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 chapter also provides basic toxicological principles concerning how chemicals can interact with the nervous system. The discharged mercury was converted to methylmercury sulfide by microbial organisms, and an epidemic of methylmercury poisoning developed when the local inhabitants consumed contaminated fish and shellfish. Long-term manganese toxicity produces muscle rigidity and a shuffling gait similar to that seen in patients with Parkinson’s disease (Politis et al., 1980). Active ingredients are combined with so-called inert substances to make thousands of different pesticide formulations. Worldwide data are used and are quoted from original studies, not from abstracts or reviews. The first draft, prepared by consultants or, more usually, staff from an IPCS Participating Institution, is based initially on data provided from the International Register of Potentially Toxic Chemicals and from reference databases such as Medline and Toxline. Generally, some four months are allowed before the comments are considered by the RO and author(s). The composition of the Task Group is dictated by the range of expertise required for the subject of the meeting and by the need for a balanced geographical distribution.
Observers do not participate in the final evaluation of the chemical; this is the sole responsibility of the Task Group members.
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 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.
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. Nevertheless, there has been significant progress in the last decade in developing validated methods for detecting neurotoxicity in humans. 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. 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. 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. 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.
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.
Major sources of inorganic lead include industrial emissions, lead-based paints, food, beverages and the burning of leaded gasolines. Affected children displayed a progressive neurological disturbance resembling cerebral palsy and manifested other neurological problems as well. These fungal toxins are notorious for producing the gangrenous and convulsive forms of the disease known as "ergotism" (Bove, 1970). Both published and unpublished reports are considered, and it is incumbent on the authors to assess all the articles cited in the references. A second draft incorporating comments received and approved by the Director, IPCS, is then distributed to Task Group members, who carry out the peer review, at least six weeks before their meeting. 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.
Moreover, certain specialized cells outside the barrier have important integrative neuro-immuno-endocrine functions that orchestrate numerous physiological, metabolic and endocrine processes.
Sources of human data include accidental and occupational exposures, case-studies, clinical evaluations, epidemiological studies, and field and laboratory studies. 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. 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.
Chapter 4 covers an area of neurotoxicology that was not addressed in the 1986 IPCS document: human neurotoxicology. In 1971, an epidemic occurred in Iraq from methylmercury used as a fungicide to treat grain (US OTA, 1990). Workers exposed to methyl n-butyl ketone (an ink solvent and cleaning agent) displayed peripheral neuropathy involving sensory and motor changes of the hands and feet (Dick, 1995).
The organophosphate insecticides have neurotoxic properties and account for approximately 40% of registered pesticides in the USA.
Tilson, US Environmental Protection Agency, Research Triangle Park, North Carolina, USA; and Dr G. 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. Standardized neuropsychological tests, validated computer-assisted test batteries, neurophysiological and biochemical tests, and refined imaging techniques have been improved and become well established. 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. In addition, the Danish Environmental Protection Agency (Ladefoged et al., 1995) issued a document on criteria for evaluating neurotoxicity.
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. A syndrome with such neurological features as tremor and such behavioural symptoms as anxiety, irritability and pathological shyness is seen in people exposed to elemental mercury.
Delayed neurotoxicity can be seen as a result of exposure to certain organophosphate pesticides, producing loss of motor function and an associated neuropathology (Ecobichon & Joy, 1982).
Unpublished data are used only when relevant published data are absent or when they are pivotal to the risk assessment. 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. 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. 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.
Repeated abuse of such solvents can lead to permanent neurological effects due to severe and permanent loss of nerve cells (US OTA, 1990). A detailed policy statement is available that describes the procedures used for unpublished proprietary data so that this information can be used in the evaluation without compromising its confidential nature (WHO (1990) Revised Guidelines for the Preparation of Environmental Health Criteria Monographs. 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.
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. Case-control studies have also shown that a history of organic solvent exposure may be associated with increased risk of deficits similar to those seen with Alzheimer’s disease (Kukull et al., 1995).
Neuropathy has also been reported following consumption of non-pesticide organophosphates, such as tri-o-cresylphosphate (TOCP). 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. A number of reports have noted that many cases of human poisonings due to the ingestion or absorption of neurotoxic pesticides go unreported. 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.
This is especially true in developing countries, where up to 45% of pesticide poisoning cases occur in young children (WHO, 2000).

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