Environmental Neurotoxicology (1992)

The Committee on Neurotoxicology and Models for Assessing Risk identified the following six major gaps in information or conceptual development in environmental neurotoxicology (listed in a sequence to parallel the structure of the report):

• The extent to which disease and dysfunction of the human nervous system are the result of exposure to toxic environmental agents

• The neurotoxicity of most chemicals in commerce

• Biologic markers of neurotoxic exposures or effects that could be applied in epidemiologic and clinical studies

• Well-designed, hypothesis-driven neuroepidemiologic research to increase knowledge about the scope of the problem of neurotoxicity

• Strategies for the rational, efficient testing of chemical substances for neurotoxicity

• Risk-assessment paradigms for evaluation of neurotoxic end points.

The committee's specific conclusions and recommendations to address these gaps are as follows.

The committee concludes that neurotoxic effects can be caused by exposure to chemical agents in the environment. Environmental chemicals have been shown to cause neurotoxic effects in individual cases and in epidemics. Neurotoxicity caused by environmental toxicants results in a range of neurologic and psychiatric disorders; the complexity of the disorders reflects the enormous diversity of the nervous system's functions and the presence in the nervous system of a large number of cellular and subcellular targets. Neurotoxic outcomes range from devastating illnesses, such as parkinsonism and dementia, to subtle changes, such as alterations in behavior and limitations on memory and cognition. In addition to immediate and progressively developing effects, there is increasing evidence that neurotoxic effects can occur after long latent periods. It is postulated that intervals as long as many decades can elapse between exposure to a chemical and the appearance of neurologic illness. Concern over the potential neurotoxic effects of chemical substances is greatest for agents that cause irreversible or progressive changes. Chemicals can permanently alter brain development and cause subclinical dysfunction, or they can reduce reserve capacity of the nervous system, which

may become manifest as disease in the elderly. On the basis of the available evidence, the committee hypothesizes that an as-yet-unspecified fraction of human neurologic and psychiatric disease is attributable to chemical agents in the environment.

The committee concludes that a major obstacle to assessing the extent to which chemicals in the environment cause nervous system diseases and dysfunction is that little qualitative or quantitative information is available on possible adverse effects of most environmental chemicals on the nervous system. Some chemicals in commerce are known to have neurotoxic potential, but most commercial chemicals have not been assessed for neurotoxicity. Although resources are not readily available to undertake across-the-board testing of all chemicals already in commerce, prudent public policy dictates that all chemicals, both old and new, be subject to at least basic screening for neurotoxicity when use and exposure warrant. There is a particular lack of data on chronic and long-latency neurotoxic effects. Structure-activity relationships, now the most widely used approach to assessment of toxicity, provide a poor basis for predicting neurotoxic potential; however, greater understanding of chemical structural correlations and the underlying mechanisms of toxicity can be expected to lead to the discovery of more useful applications of structure-activity relationships.

The committee recommends that a more accurate estimate of the extent of the problem of neurologic and psychiatric dysfunction attributable to chemical agents in the environment be made.

The estimate must be based on a combination of clinical, epidemiologic, and toxicologic studies coupled with the techniques of quantitative risk assessment.

The committee concludes that additional biologic markers for the assessment of subclinical neurotoxic effects are needed. Such markers can be biochemical, structural, or functional. They can be developed either through in vitro analyses, through animal studies, or during observational studies in human populations exposed to environmental neurotoxicants. Although associations between biologic markers and disease are usually established initially in cross-sectional studies, a particular need exists to validate putative biologic markers in prospective studies. Only in longitudinal prospective studies can the ability of biologic markers to predict the occurrence of disease be accurately assessed.

The committee recommends that putative biologic markers in animal species be evaluated and validated in in vivo and in vitro systems. The committee further recommends that biologic markers be regularly incorporated into epidemiologic and clinical studies of neurologic disease, particularly prospective studies.

The primary goal of the incorporation of biologic markers into such studies should be to validate their predictive accuracy and to test hypothesized quantitative relationships between specific markers that are likely to be on or close to causal pathways and neurotoxic outcomes.

The legislated authorities of the federal regulatory agencies (the Occupational Safety and Health Administration, the Environmental Protection Agency, the Consumer Product Safety Commission, and the Food and Drug Administration) to regulate or to require neurotoxicity testing might be too narrow to encourage investigation of neurotoxicity. The potential authority of the existing mandates of those agencies to control toxic substances, including neurotoxicants, has not been fully used.

The committee concludes that tests are available to construct a tiered approach to neurotoxicity testing. The first tier, or screen, is intended for hazard identification. The results of the screen and a chemical's

exposure pattern would determine further characterization of dose-response relationship (second tier) and mechanisms (third tier). No validated system satisfies all the necessary requirements for a screening program to detect the neurotoxic potential of chemicals. The range of such a program should extend to the detection of neurodevelopmental effects and effects on cognitive function and of neuroendocrine effects. No comprehensive effort has yet been made to determine the predictive ability of individual screening tests by examining the relationship between test results and data from long-term studies in animals or epidemiologic and clinical studies in humans.

The committee recommends that a rational, cost-effective neurotoxicity testing strategy be developed and adopted.

It should allow an accurate and efficient progression from the results of hazard-identification studies (screening) to the selection and application of appropriate test methods for defining mechanisms of toxicity and for quantitative characterization of neurotoxic hazards.

Benefits to be gained are several. First, it would permit development of tests that would confirm or disprove each other at each of several levels of complexity; thus, it would incorporate a series of checks and balances. Second, the results of the later phases of testing would provide the data necessary to evaluate and validate initial screening batteries and thereby help to identify tests that should be excluded from or incorporated into an efficient battery. Third, the information generated by such a strategy would reveal which types of data are most useful for accurate, quantitative prediction of the risks to humans associated with exposure to similar chemical compounds.

For reasons of efficiency, integrative studies combining a variety of end points need to be explored in the development of the strategy. For example, tests of neurotoxicity on chronically exposed animals might be carried out in conjunction with tests of other chronic effects. An objective testing strategy rationally applied would enhance risk assessment by providing data rapidly for decision-making. Moreover, testing would identify toxic effects of substances not previously known to be neurotoxic. To maximize detection of toxicity, some toxicity studies encompassing the full life span of experimental animals should be encouraged.

The committee recommends that existing in vitro test methods be exploited more extensively than at present to identify and analyze the mechanisms of neurotoxic action at cellular levels.

To that end, it is necessary to undertake a program to test the relationship between in vitro and in vivo findings and between animal and human results for a set of welldefined substances. It should be understood that some in vitro test methods will be most useful only for screening substances and will have little application in assessing mechanisms. It is necessary to question how effective those methods will be in predicting chronic effects in whole animals-a continuing objective of method validation. Additional validation might be accomplished by determining the concordance between the results of tests and the findings of epidemiologic studies.

The committee recommends that studies to define mechanisms of neurotoxicity in as much detail as possible be encouraged, as well as studies to identify hazards.

Data are needed on the influence of dose, route of exposure, toxicokinetics, metabolism, and elimination on the effects of a given neurotoxicant, and data are needed on interspecies differences. Moreover, a detailed understanding of the pathogenesis of the neurotoxic injury caused by various agents is needed. What are the toxic metab-

olites? What are the molecular targets within the nervous system? How does the reaction of a toxicant or metabolite with a target trigger the sequence of events that lead to functional changes or degenerative events? What is the sequence of events? What biologic factors determine vulnerability, resistance, and capacity for reversibility and repair? What is the basis for interspecies differences? Such understanding will make possible the better prediction of relationships between exposure and neurotoxic response, the development of strategies to prevent exposure, and eventually the treatment of the exposed.

Development of a mechanistic understanding of neurotoxicity might facilitate the discovery of biologic markers of exposure to toxicants, as well as markers of early, subclinical neurotoxic effects. More complete understanding of neurotoxic disease at a molecular level should also improve the ability to evaluate new chemicals on the basis of structure-activity relationships, which as currently used can provide only minimal guidance for hazard identification.

The committee concludes that attempts to quantify the exposure of populations to neurotoxic chemicals have been limited. Clinical evaluation of neurotoxic illness and epidemiologic surveillance of populations at high risk for neurotoxicity have been fragmentary and inadequate. Few attempts have been made to explore the possible relationships between chemical exposures and chronic or progressive neurologic and behavioral disorders. The disorders include developmental delays in the young and some forms of dementia and parkinsonism in the elderly.

The committee recommends that exposure-surveillance systems cover a much broader range of chemicals and use improved monitoring techniques for long-term assessment.

The committee also recommends that existing disease-surveillance systems, such as those of the Social Security Administration, the Department of Veterans Affairs, and the National Center for Health Statistics, be modified to provide more useful data on the incidence and prevalence of chronic neurologic and psychologic disorders, some of which are likely to be of occupational and environmental origin.

A broader range of neurologic disease end points should be covered by surveillance programs.

The committee further recommends that anecdotal reports of neurotoxicity in humans be pursued vigorously with clinical surveillance and followup.

The first step is to identify the substance or combination of agents apparently responsible for observed effects. When animal models of the human disease have been established, laboratory studies can then determine the mechanistic details that would assist in controlling the original situation and facilitate risk assessment.

The committee concludes that recognition of the possible environmental origin of neurologic and psychiatric disease is hampered by the inadequate training of most physicians and other health providers in occupational and environmental medicine. The committee concludes that uniform clinical definitions of neurotoxic disorders are needed, to provide a common basis for reporting by physicians.

The committee recommends that improved disease reporting be supported by the dissemination of information on neurotoxic illnesses to physicians and other health professionals, to increase their awareness of environmental neurotoxicity as a possible explanation of specific illnesses or sets of symptoms.

The committee further recommends that

all physicians should be trained to take a thorough occupational-exposure history and to be aware of other possible sources of toxic exposure, such as hobbies and selfmedication.

The committee recommends that standardized national reporting systems be established for physicians to report outbreaks of suspected environmentally and occupationally caused neurologic and psychiatric disorders.

The incorporation in surveillance systems of the concept of sentinel health events (SHEs) specifically for neurotoxic illnesses should be encouraged.

The committee concludes that commonly used paradigms for risk assessment do not accurately or adequately model the risks associated with exposure to neurotoxicants. Neurotoxicologic risk assessment has been largely limited to the application of no-observed-effect levels and uncertainty factors, so it has not generated specific risks for given magnitudes of exposure.

The committee recommends that further attention be paid to experimental designs for studies of neurotoxic agents that provide information needed in the risk-assessment process.

Such variables as age, sex, duration of exposure, and route of exposure need to be more systematically evaluated. Speciesspecific effects need to be recognized. Experiments should include a range of doses that spans those relevant to expected human exposures. In addition to providing a firmer basis for estimating human risk, such designs permit tests of the assumption that results obtained at high doses predict the pattern of effects at low doses. The usefulness of that kind of information for quantitative risk assessment would be greatly amplified by serial measures of neurotoxic end points and biologic markers.

The committee recommends that researchers make complete, original data sets available to other investigators to facilitate full exploration of relationships and development of risk-assessment models.

The committee further recommends that to improve the assessment of the human risks associated with exposure to possible neurotoxic agents, risk-assessment methods that capture the complexities of the neurologic response, including dose-time-response relationships, multiple outcomes, and integrated organ systems be developed.

A single model will not be adequate for all conditions of exposure, for all end points, or for all agents. It might be necessary to build risk-assessment models to deal simultaneously with several end points produced by a toxicant. Such models should incorporate biologic markers of neurologic dysfunction and be based on fundamental information on mechanisms derived from experimental test systems and epidemiologic data.