Environmental Health Perspectives Volume
102, Supplement 2, June 1994
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in PubMed] [Related
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Environmental Neurotoxic Illness: Research for Prevention
Philip J. Landrigan1, Doyle G. Graham2, and
Richard D. Thomas3
1Mount Sinai School of Medicine, New York, New York; 2Duke
University Medical Center, Durham, North Carolina; 3National
Academy of Sciences, Washington, DC
Abstract
Recognition of the deleterious neurological effects of chemicals has
evolved from anecdotal observation to studies of illness in persons exposed
to high doses. Now, the more subtle effects of exposures to environmental
neurotoxicants are being documented: reduction in intelligence, impairment
in reasoning ability, shortening of attention span, and alteration of behavior.
Substances to which millions of persons are exposed occupationally and in
the general environment that can result in such deficits include lead, organophosphorus
pesticides, certain chlorinated hydrocarbons, carbon disulfide, solvents,
and mercury. The first step in the prevention of neurological impairments
due to environmental exposures is to assess the toxicity of chemicals. Fewer
than 10% of the 70,000 chemicals in commercial use have been evaluated for
neurotoxicity. This knowledge gap needs to be narrowed by building on existing
systems of toxicity testing. Concurrent with assessment of chemicals will
be tiers of in vivo screening tests to measure functional and structural
changes following exposures in vitro. Epidemiologic surveillance
of populations at high risk will continue to inform on the ranking of suspect
or known neurotoxicants. Research and researchers must become more sophisticated
in the development and application of refined biologic markers so the findings
can be used to detect absorption of toxicants and early neurological or
neurobehavioral dysfunction before disability occurs and to protect human
health and the environment. -- Environ Health Perspect 102(Suppl.
2):117-120 (1994).
Key words: environmental toxicants, risk assessment, biologic
markers, epidemiologic surveillance, occupational exposures, populations
at high risk, chemical pollutants, neurotoxicity testing
This work is based on and derived extensively from the
report of the National Academy of Sciences' Committee on Neurotoxicology
and Models for Assessing Risk. The full report of this Committee has been
published by the National Academy Press, Washington, DC in 1992. This manuscript
was submitted with the permission of the National Academy of Sciences.
Address correspondence to Dr. P. J. Landrigan, Department
of Community Medicine, Box 1057, Mount Sinai School of Medicine, 1 Gustave
L. Levy Place, New York, NY 10029-6574. Telephone (212) 241-6173. Fax (212)
996-0407
Introduction
While the recognition of the deleterious neurological effects of exposure
to chemicals such as lead has existed since ancient time, the scientific
documentation of neurologic injury following exposure to certain chemicals
arose from the study of acute illness in persons exposed to high doses of
environmental toxicants. The scenarios leading to illnesses included: children
who ate chips of lead-based paint developed encephalopathy; persons who
consumed wood alcohol (methanol) became blind; exposure to organophosphorus
pesticides led to coma, convulsions, and respiratory paralysis. Some epidemics
of neurotoxic diseases due to environmental contamination have become too
well known: blindness and ataxia due to consumption of fish laden with organic
mercury in Minamata Bay, Japan, and of fungicide-treated grain in Iraq;
spinal cord degeneration and peripheral neuropathy caused by tri-o-cresylphosphate
(TOCP) in cooking oil in Morocco and in patent medicine (Ginger Jake) in
the United States: tremors, anxiety attacks, and loss of coordination due
to the pesticide Kepone (chlordecone) in Hopewell, Virginia; and the parkinsonism
caused by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a contaminant
of synthetic heroin, in California and Hawaii (1). Some are less
well known and others, such as the current outbreak in Cuba, continue to
puzzle us. Past and current experiences that have affected tens of thousands
of persons have clearly established that environmental chemicals can be
toxic to the nervous system, leading to neurologic and psychiatric illnesses.
Injury to the nervous system due to toxic chemicals in the environment
is now being acknowledged as an important public health problem, yet precisely
because it remains so broadly defined, studies therefore remain fragmented.
Part of this too broad definition derives from the imprecise definition
of terms. In this report we too use broad terms. "Environment"
encompasses the wide range of extragenetic factors that cause injury/impairment
to body systems. These factors include ambient exposures (air, water, soil),
diet, occupational exposures (physical and psychosocial elements), recreational
exposures (alcohol, tobacco, drugs) among many. "Neurotoxicology"
is deemed to include the insult(s) to any and all structures and functions
of the nervous systems in all their complexity and diversity and overlap;
motor, sensory, cognition, psychological, emotional elements, separate and
conjoint. A major question is whether any associations observed in epidemics
(large or small) reflect isolated occurrences or are manifestations of pervasive
and widespread associations between toxic environmental chemicals and neuropsychologic
impairment (2). The question remains central to the issues confronting
neurotoxicology today.
Subclinical Neurotoxicity
The newly developed measurement tools that allow detection of more subtle
neurologic damage add the dimension of subclinical damage to the question
of chemicals in the environment exerting dose-related adverse effects. Such
subclinical neurotoxic effects can include lower intelligence, impaired
reasoning ability, shorter attention span, alterations in behavior. Although
subtle in appearance, the changes following exposure to lead, mercury, organophosphorus
pesticides, some chlorinated hydrocarbons, and solvent mixtures, can be
devastating in effect. Because the central nervous system has little capacity
for repair, the damage can be irreversible. The recognition of subclinical
neurotoxicity raises the possibility that some fraction of neurologic and
psychiatric illness, such as parkinsonism, motor neuron disease, demyelinating
illness, and some forms of dementia can be exacerbated and possibly caused
by chronic, low level exposure to environmental neurotoxicants (3).
Biologic Markers in Neurotoxicity
Recent reports in environmental health research have defined biologic
markers as indicators of events or conditions in biologic systems or samples
(4,5). They are most easily classified as markers of exposure,
of effect, and of susceptibility. A marker of exposure is an exogenous substance,
its metabolite, or the product of its interaction with some molecule or
cell as measured in an organism. A marker of effect is a measurable biochemical,
physiologic or other alteration within an organism that can indicate potential
or established impairment. A marker of susceptibility is that indicator
of variation (inherent or acquired) in an organism's response when challenged
by exposure to a specific substance (5,6). The development
and application of biologic markers of neurotoxicity are needed to augment
the sensitivity and specificity of other studies. Measurements of specific
lipids and proteins or of neurotransmitters or their metabolites, as well
as measurement of changes in the number or affinity of specific neurotransmitter
receptors, are some biochemical markers of neurologic function. Structural
markers can be studied in tissues obtained at biopsy. Gaining this edge
in identifying early and subclinical neurotoxic injury would allow intervention
when dysfunction might still be halted, when impairment in others so exposed
could be prevented. In epidemiological and clinical studies, validated biologic
markers would allow the systematic monitoring of populations at high risk
and enhance the findings from other disciplines. Tests that appear to provide
reliable and sensitive information on early injury are becoming more sophisticated
and gaining wide application (7). The development and increased use
of biologic markers of neurotoxic substances in human studies will permit
precise delineation of individual exposures and the detailed assessment
of dose-response relationships (8).
Neurotoxicity Testing
Although about 70,000 chemicals are in commercial use, very few have
been evaluated. Other than pharmaceuticals, fewer than 1/10 of chemicals
in commerce have been tested for neurotoxicity, and fewer yet have been
thoroughly studied. Since it is unknown how many may be neurotoxicants,
it is possible that large numbers of people are exposed to these potential
hazards and may be suffering unrecognized injury as a result.
Closing this gap in knowledge and toxicity testing must be the essential
first step in the prevention of environmental neurotoxicity. The dearth
of information and resources precludes any across the board testing of all
chemicals. New strategies will need to include: the identification of those
chemicals most likely to be hazardous and to which large numbers of persons
are exposed; the setting of priorities for testing the more ubiquitous substances;
the refinement of existing neurotoxicity test systems; the development and
validation of efficient, sensitive new testing systems; and the standardization
of approaches to the interpretation/significance of the findings.
This strategy for neurotoxologic assessment will extend currently available
tests systems (9) based on a tiered structure. Data from the initial,
screening, tier will guide decisions to test chemicals at the higher tiers,
as well as decisions concerning types of testing. The screening tier will
consist of a set of tests to measure chemical, structural, and functional
changes in an integrated fashion, in addition to a functional observational
battery. Such tests will need to be carefully validated at every stage.
To address the broad functional diversity (motor, sensory, learning and
memory) of the nervous system, the tests must examine multiple end points:
a highly specific effect on one function of the nervous system will not
necessarily entail an effect on another. The development of rapid and economical
approaches will do much to overcome the drain of the current labor- and
resource-intensive testing systems.
While in vitro systems are available and appear suitable for detailed
studies of some neurotoxic mechanisms, they have not been used for screening.
A recognized stumbling block is the establishment of a relationship between
effects observed and the expression of effects at a structural or behavioral
level in whole animals, particularly in humans. It is essential that such
studies of the correlation between the results of in vitro systems
and the findings of functional in vivo tests be conducted. In
vitro assays and in whole animals should be conducted conjointly to
determine the correspondence between the two types of assays. This could
validate the use of in vitro assays as quicker, more efficient methods
for screening chemicals for neurotoxicity, and allow a better understanding
of the mechanisms of neurotoxic damage. Studies of neurotoxic reactions
at the molecular and cellular levels might also be used to generate the
more detailed mechanistic information necessary for accurate risk assessment
and for development and evaluation of reliable structure-activity relationships.
In both in vivo and in vitro neurotoxicity testing, the
general objective is to identify neurotoxic potential before the occurrence
of human exposure. The goal is the prevention of human disease.
Epidemiologic Studies and Neurotoxicology
In order to provide additional information on the human neurotoxic effects
of environmental chemicals and to complement screening studies in vitro
and in animals, epidemiologic and clinical studies of populations exposed
to potentially neurotoxic chemicals are needed. High-risk populations must
be identified and monitored. Currently, public health surveillance systems
for the detection of people who are potentially exposed to environmental
neurotoxicants are not well developed. There is little information on the
background incidence and prevalence of the major neurologic diseases in
the American population (10). The evaluation of persons diagnosed
with neurologic illnesses to elicit any possible environmental etiologies
would be very informative.
Ascertainment of the neurotoxic effects of exposure to environmental
chemicals through epidemiologic and clinical studies continues to be complicated
by the very complexity, variety and subtlety of the possible reactions of
the nervous system. Reactions to toxic insult can be as varied as peripheral
neuropathy, alterations in the sense of taste or smell, or impaired mathematical
ability. Months and years can pass between exposure and the appearance of
dysfunction and disease. The subclinical changes are often subtle, unappreciated
by either the subject or coworkers/family. Therefore, populations known
to have been exposed to potential neurotoxicants should be followed for
long periods in prospective studies; in retrospective studies of persons
with neurologic illness, the possibility that exposures may have occurred
many years earlier must be kept in mind. Increasingly, epidemiologic studies
will need to utilize biologic markers of exposure, of toxic effects, and
of susceptibility.
Risk Assessment and Neurotoxicology
Estimating the risks to humans associated with exposure to toxic chemicals
in the environment most often involves extrapolation from high experimental
doses used in animal tests to lower environmental doses. Gaps in available
scientific data are bridged with numerous assumptions. Such risk assessment
techniques have usually be applied to cancer as an end point, and techniques
for assessing other types of risk are just now beginning to be developed
(11). The current approach in estimating noncancer end points, simply
dividing the dose below which effects were not seen by uncertainly factors
to generate a presumably safe exposure level, must be considered inadequate.
Virtually all neurotoxicologic risk assessment today is limited to qualitative
hazard identification and to the early stages of hazard characterization.
Sufficient data or adequate paradigms are not yet available to permit quantitative
evaluation of most neurotoxic risks.
Risk-assessment techniques that incorporate more quantitative information
about dose-time-response relationships and mechanisms of toxicity are being
developed. They will assist in assessing the benefits to human populations
gained from reducing exposures to neurotoxic agents. The construction of
new models for neurotoxicologic risk assessment upon the diverse susceptibilities
of various individuals and populations will be facilitated by the acquisition
of knowledge of the fundamental mechanisms of action of chemical toxicants
on the human nervous system. How environmental chemicals cause injury will
need to be delineated at the molecular and subcellular level (12).
Such information will then allow much improved prediction and quantitation
of the risks whose effects become evident only many years later.
Conclusions
Exposure to chemical agents in the environment can lead to neurotoxic
impairment and illness. This has been demonstrated following exposure to
many different agents and in individuals and in epidemics. Neurotoxicity
caused by environmental toxicants ranges from neurologic to psychiatric
disorders, from devastating illnesses, such as parkinsonism and dementia,
to subtle changes in behavior and limitations on memory and cognition. The
complexity of the disorders reflects the enormous diversity of the nervous
system's functions and the large number of cellular and subcellular targets.
Greatest concern surrounds the fact that some damage in the brain can be
irreversible and permanent, and that in addition to immediate effects, many
neurotoxic effects become evident only after long latent periods. Chemicals
can permanently alter brain development, can cause sublicinical dysfunction,
or reduce reserve capacity of the nervous system. On the basis of available
evidence, it is not unreasonable to hypothesize that a definite, but as
yet unspecified, fraction of human neurologic and psychiatric disease is
attributable to chemical agents in the environment.
The lack of quantitative or qualitative information on possible adverse
effects of most chemicals in commercial use is a major obstacle to assessing
the contribution of environmental chemicals to the causation of nervous
system disease and dysfunction. While some chemicals are known to have neurotoxic
potential, there is a particular lack of data on chronic and long-latency
neurotoxic effects. Though widely used as an approach in assessment of toxicity,
structure-activity relationships are less than optimal for predicting neurotoxic
potential; greater fundamental understanding of mechanisms should lead to
more useful applications of SARs.
The development and application of biologic markers are needed for the
assessment of subclinical neurotoxic effects. Such markers can be developed
through in vitro analyses, through animal studies, or during observational
studies in human populations. While associations between biologic markers
and disease are usually established in cross-sectional studies, a particular
need to validate putative biologic markers in prospective studies exists.
Only in longitudinal prospective studies of populations exposed to suspect
or known neurotoxicants can the reliability of the biologic markers be accurately
assessed and their predictive significance evaluated.
Current testing systems can be expanded using a tiered approach. The
first tier, or screen, is intended for hazard identification. These findings
and the patterns of exposure of the chemical would determine further characterization
of dose-response (second tier) and mechanism (third tier). Since there is
no existing validated system that satisfies all the necessary requirements
for a screening program, the range of any newly developed program should
extend to the detection of neurodevelopmental effects, of effects on cognitive
function, and of neuroendocrine effects. Work has yet to be done to determine
the predictive ability of individual screening tests; the relationship between
test results and data from long-term studies in animals or epidemiologic
and clinical studies will need to be validated.
There have been only limited attempts to quantify the exposure of populations
to neurotoxic chemicals. Clinical evaluations in populations at risk for
neurotoxicity have been inadequate and fragmented. The possibility that
developmental delays in the young and some forms of dementia and parkinsonism
in the elderly might have an environmental etiology is only now becoming
to be appreciated.
Delay in recognition of the possible environmental origin of neurologic
and psychiatric disease derives from inadequate incorporation of the elements
of environmental and occupational medicine into the training of most physicians,
toxicologists, epidemiologists, risk assessors and other health providers.
Greater uniformity and precision in disease definition would improve the
identification of diseases of neurologic interest.
The commonly used paradigms for risk assessment are inadequate to model
the risks associated with exposure to neurotoxicants. The neurotoxicologic
risk assessments, that have been largely limited to the application of no-observed-effect
levels and uncertainty factors, cannot accurately encompass the diversity
of neurologic responses to injury; they cannot (as yet) generate risks estimates
that are applicable to the multitudes and magnitudes of exposures.
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