for Neurobehavioral Toxicity
Health Perspectives, Volume 104, Supplement 2, April 1996
The Intersection of Risk Assessment and Neurobehavioral Toxicity
Bernard Weiss and Jürg Elsner
-- Environ Health Perspect 104(Suppl 2):173-177 (1996)
This paper introduces the Workshop on Risk Assessment
Methodology for Neurobehavioral Toxicity convened by the Scientific Group
on Methodologies for the Safety Evaluation of Chemicals (SGOMSEC) held
12-17 June 1994 in Rochester, New York. Manuscript received 1 February
1995; manuscript accepted 17 December 1995.
Address correspondence to Dr. Bernard Weiss,
Department of Environmental Medicine, University of Rochester Medical Center,
Rochester, NY 14642. Telephone: (716) 275-1736. Fax: (716) 256-2591. E-mail:
Abbreviations used: SGOMSEC, Scientific Group
on Methodologies for the Safety Evaluation of Chemicals; U.S. EPA, U.S.
Environmental Protection Agency; CDC, Centers for Disease Control and Prevention;
NOAELs, no observed adverse effect levels; FOB, functional observation
After nearly three decades of research in many parts of the world, neurobehavioral
toxicity is now acknowledged as a significant outcome of chemical exposure.
In contrast to the view prevailing even in the recent past, many observers
now concede that its health and economic costs may exceed even those of
cancer, the prototype for risk assessment, by substantial amounts. This
new perspective has been accompanied by a surge of efforts designed to
promote effective test methods, to explore the responsible mechanisms,
to design applicable risk assessment procedures, and to determine the consequent
policy implications (1,2).
The process of recognition did not proceed as smoothly as expected,
given the resonant scientific foundations provided by the behavioral neurosciences.
One of these, behavioral pharmacology, the discipline that emerged in the
1950s in response to the introduction of chemotherapy for psychological
disorders, provided a readily adaptable technology for exploring adverse
effects. Workplace exposure criteria, such as threshold limit values (TLVs),
had long relied on behavioral criteria such as work efficiency and alertness
to danger to infer hazard. Perhaps the problem lay in how easily misunderstandings
can arise about the definition and measurement of behavior.
Although the discipline has generated an abundant literature and established
a robust scientific footing, translating such efforts into policy decisions
remains perplexing, mainly because of the difficulties posed by how to
express them in risk terms. The conventional prototype for risk assessment
is cancer, but numerous dissimilarities between neurobehavioral toxicity
and carcinogenesis render it a rather imperfect model. Because behavior
is often cited as the integrated product of a highly complex system, with
numerous modes of expression, it should come as no surprise that it may
be altered in equally diverse ways by xenobiotic influences and that the
significance of any but the most blatant behavioral change eludes simplistic
measures and interpretation.
After all, behavior is a dynamic and plastic phenomenon. It would be
deceptive to compare it to functions that are much more rigid and deterministic
such as those of the cardiovascular system. Scientists unaccustomed to
phenomena as malleable as behavior sometimes find it difficult to grasp
both its essential lawfulness and the degree to which, concurrently, it
may undergo critical modifications without displaying any overt abnormalities.
Some consider behavioral changes to be analogous to alterations in software
which, by proper reprogramming, may be overcome without major difficulties.
Others may claim that behavioral deficiencies attributed, for example,
to elevated exposure to metals, are more likely the product of deficiencies
in social conditions. Such claims tend to erode when confronted jointly
by data from properly conducted animal research and from epidemiological
studies that deliberately and carefully weigh and balance the influence
of potentially confounding social variables. Several of the joint chapters
and individual papers review these issues.
A broad, permeating issue derives from one of the original aims of SGOMSEC:
to make its contributions pertinent to countries lacking advanced industrial
economies and resources. Chemicals and chemical production facilities tend
to be transferred to such countries without an accompanying transfer of
the technology of toxicology and environmental health science. This discrepancy
results in unsafe control practices, excessive exposure levels, and, ultimately,
mass chemical disasters. SGOMSEC 11 strove to confront this issue by describing
a range of methods from the relatively simple to the rather complex and
by illustrating the different contexts in which different methods are appropriate.
But even in advanced industrial societies, policy analysts, regulators,
and others with decision-making responsibilities are confronted with irksome
questions about neurobehavioral toxicity. In that arena, the challenges
range from how to determine whether the potential for neurotoxicity exists
to how to translate such potential into policy.
SGOMSEC 11 was also designed to learn from the history of neurobehavioral
toxicology. It sometimes proved difficult to convince toxicologists from
other specialties and policy makers that even substances already dispersed
in the human environment require careful evaluation of their neurobehavioral
toxicity, despite no cogent evidence of adverse effects at environmental
levels. Once a substance is widely distributed in the communal, or even
the industrial environment, barriers to its removal are riveted in place.
Especially if the arguments for its control are based, not on immediate
threats to life but on a less tangible behavioral metric, inertia exerts
a potent force. The arguments for premarket testing for neurobehavioral
toxicity flow from such experiences.
The Choice of a Focus on Behavior
The adjective neurobehavioral is commonly applied because the nervous system
determines the contours of its ultimate product, behavior. Any measure
of nervous system status or function incurs immense complexities. Behavior's
credentials as a valid toxicity index are often questioned because its
determinants converge from many paths. The consequences of a specific neurochemical
aberration such as a shift in receptor density, for example, may be expressed
behaviorally in almost limitless ways depending on the specific end points
and indices chosen for measurement and the constitutional capacities and
behavioral history of the individual organism. Consider the numerous behaviors
linked to the neurotransmitter dopamine: a variety of cognitive functions,
mediation of reinforcement processes, tremor and other indices of motor
function, sexual performance and motivation, and even species-specific
behaviors. Naturally, the most appealing situation is one in which neurochemical
findings could be correlated with behavioral data, but most behaviors are
joined to more than one neurotransmitter system and embrace more than a
single brain structure. Such multiple connections explain why neurochemistry,
morphology, and even electrophysiology would normally be introduced only
at the later stages of assessment.
Because it arises from multiple sources, behavior might be viewed as
a confusing index of toxicity. That potential for confusion, however, is
also an argument in its favor. If it is subject to such a wide array of
influences, the argument goes, it can then serve as an apical tool for
testing general toxicity. If such evidence emerges, more specific behavioral
or other measures can be applied to narrow the contributing variables or
mechanisms. The opposing argument claims that, because behavior reflects
the integration of a highly redundant system in which compensatory mechanisms
may obscure a deficit in any particular functional domain, it is not a
sensitive measure of adverse effects in all circumstances.
Both arguments, despite their apparently conflicting stances, invoke
equivalent conclusions: toxic potential should be assessed by choosing
behavioral end points that offer the greatest breadth and precision of
information. It should be recognized that the appeal of simplicity and
economy may prove deceptive and even costly if they merely multiply the
intrinsic ambiguities of risk assessment. SGOMSEC 11 aimed to deal explicitly
with such supramethodological issues while offering critical reviews of
the prevailing approaches.
The final design of SGOMSEC 11 divided the issues into four sections:
neurobehavioral toxicity in humans, neurobehavioral toxicity in animals,
model agents, and risk assessment. Anyone familiar with the discipline
appreciates that these rubrics do not describe fixed boundaries, but convenient
classifications. In fact, the extensive overlap between these categories
proved to be an advantage because members of one group could be enlisted,
in preparing the joint report, to assist another group when their special
qualifications were required.
The outline below provides a list of topics for which individual papers
were commissioned. Each of the participants was asked to feature three
points: How did we get to the current status of the topic? How can we relate
it to risk assessment? What methodological advances should we seek to make
a firmer connection with policy?
Identification of Neurobehavioral Toxicity in Human Populations
This section was designed to explicate the ways in which information about
hazard and risk might be procured from human populations. In some past
instances, this information came from clinical observations, usually on
the basis of extreme exposure levels. The current mode of defining risks
depends mostly on the use of psychological test instruments, but questions
remain about their relevance and suitability.
Clinical Data as a Basis for Hazard Identification
Many of the neurobehavioral toxicants now viewed as hazardous to humans
originally earned recognition through the observations of clinicians. These
toxicants came to their attention because of signs and symptoms overtly
expressed by patients. What are the lessons to be learned from this history?
What tools should clinicians be prepared to deploy in such instances? Is
hazard identification the only role fulfilled by clinical observations?
Is there a series of steps, undertaken in a clinical context, that might
lead to a firmer basis for identifying and estimating risk once such observations
are validated? How can clinical observations be translated efficiently
into epidemiological studies? Can a useful guide be designed for doing
so? Is a tiered strategy, that is, one that builds systematically from
one set of observations to another more complex set the most appropriate
one to adopt, or does such staging of questions tend to delay the risk
assessment process? Are there useful examples of such a progression?
Designing and Validating Test Batteries
Beginning in about the early 1970s, psychological test batteries began
to be applied to the definition and assessment of adverse consequences
stemming from exposure to central nervous system-active agents such as
volatile organic solvents. By now, a plethora of test collections has penetrated
the literature. Although these batteries possess many elements in common,
they also diverge in philosophy and design.
What are the strengths and weaknesses of the present array of batteries?
How might they be improved while maintaining their advantages of ease of
use and broad acceptance? Would they still be suitable for critical applications
in less advanced countries? What about their suitability for longitudinal
assessments? How well do they evaluate sensory and motor function?
The most widely adopted batteries are anchored in diagnosis. Their roots
lie in neuropsychology and the assessment of brain damage and psychopathology.
Should other approaches be considered? Test batteries are generally constructed
to use brief samples of behavior to screen for adverse effects in populations
such as workers. Is the breadth of test items in the typical battery a
problem? What are the advantages and disadvantages of adopting a more intense
focus? This approach might be used for pilot and astronaut selection or
to represent translations from complex performance in animals. Do such
approaches hold any lessons for the evaluation of neurobehavioral toxicity?
Translation of Symptoms into Test Variables
A problem now looming for neuropsychology and neurobehavioral toxicology
is the collection of quasi-clinical, often vaguely defined syndromes labeled
as Multiple Chemical Sensitivity, Sick Building Syndrome, and Chronic Fatigue
Syndrome. All are reflections of patient complaints lacking consistent
objective verification such as that provided, say, by clinical chemistry
profiles. As a result, many clinicians and biomedical scientists tend to
view such complaints skeptically, or find themselves unable to propose
any course of action. Does part of the problem arise from the emphasis
by neuropsychology on diagnosis rather than on functional variables or
on labeling of deficits rather than on determinations of how effectively
the individual functions in his or her environment? How can such data be
collected or synthesized or estimated? Are there especially suitable experimental
designs for such questions, such as single-subject designs? What alternatives
to current assessment procedures hold promise? Would they be suitable for
longitudinal evaluations such as those that might become necessary for
monitoring the aftermath of a poisoning episode?
The period of early brain development is a precarious stage because insults
inflicted during this time seem to ramify in many directions, often first
becoming perceptible only after reaching a particular epoch of the life
cycle. As a consequence, a full evaluation of the neurotoxic impact of
prenatal and neonatal exposure virtually demands longitudinal investigations
for definitive answers. What are the essential elements of such designs?
Which features are absolutely indispensable? What are the most serious
confounders? Can these kinds of studies somehow be streamlined? To what
extent can cross-sectional studies serve as surrogates or, at least, pointers?
Can the procedures of animal testing, which do not require the same degree
of compensation for social and cultural variables, be adapted for testing
Identification and Confirmation of Neurobehavioral Toxicity in Animals
Evaluations in laboratory animals fulfill two purposes. First, for new
chemicals, these evaluations should make it possible to determine whether
an agent presents a significant hazard. They also allow exploration of
the potential dimensions of the hazard. Finally, they may make it possible
to distill quantitative risk estimates for humans, in parallel with the
way in which bioassay data are used in cancer risk assessment. Tumors,
however, are presumed to reflect processes that will occur in human hosts.
Neurobehavioral deficits in animals are less directly translatable into
human functions. What should be the role of animal research and in what
ways can it serve the ultimate purpose of risk assessment?
Many critics attack the validity of extrapolating behavioral data from
animals to humans. Indeed, behavior seems to be highly species-specific
and exquisitely adapted to the organism's and its species survival needs.
Although such critics grant the universality of the genetic code, they
are less willing to grant the universality of the neural mechanisms governing
the operation of nervous systems in different species. In this framework,
humans are viewed as beyond extrapolation, with human behavior accorded
the status of some emergent phenomenon disconnected from the brain structures
they share with other species.
No one denies that the structural differences between rodent and human
brains and the differences in behavioral repertoires vitiate any facile
and superficial extrapolations. But the underlying functional mechanisms
of the brain, and their expression in behavior, are shared by these organisms.
Rat behavior can be used as a model of human behavior if a model is defined
as a system possessing essentially the same functional properties as the
one it simulates, except in a simplified version. Deficits in human behavior
ascribed to neurotoxicants tend to manifest themselves in fundamental functional
properties shared with other species. Labels such as attention, emotional
responsivity, sensory processing, motor coordination, learning disabilities,
and others are not specifically human properties of behavior. Human language
is distinctive, of course, but its acquisition displays a pattern common
to many other behaviors that follow a developmental sequence in which environmental
and constitutional variables merge continuously. The primary source of
confidence in the power of extrapolation though is a body of findings that
supports the congruence of human and animal responses to neurotoxicants.
Natural Populations as Sentinels
Safety evaluation of environmental chemicals has been broadened to include
ecological risk assessment. The U.S. EPA's Science Advisory Board report,
Reducing Risk (3), is one instance of this growing appreciation, but the
impact of chemical pollution on natural populations rose to a subject of
widespread concern after Rachel Carson's seminal book (4). We now acknowledge
that a major element in this impact derives from disruptions in behavior;
one example is a reported diminution of nest attentiveness by birds in
the Great Lakes. What are the indicators that up to now have proven useful
in natural populations? In which directions should improvement in these
methods be pointed? What is the extent of concordance between such observations
and human health effects or with laboratory animal studies? How can ecological
observations be converted into the kinds of quantified variables characteristic
of laboratory experiments without losing essential information?
Laboratory Approaches: Scope and Selection of End Points
For new chemicals, laboratory assays provide the first filtering stage
for potential toxicity. Currently, a standardized set of observations,
such as a functional observation battery (FOB), is used to probe for neurobehavioral
effects. Certain regulatory bodies have also required measures of motor
activity, perhaps accompanied by neuropathology at this stage. These criteria
are acknowledged as broadly suggestive rather than as definitive, especially
at the point when dose-response modeling enters the risk assessment process.
For many purposes, the clinical examination, as in humans, will represent
the first initiative, and often the first clues that a neurotoxic agent
has appeared on the scene. Can a standardized protocol be designed that
will prove feasible, in settings lacking other resources, and sensitive
as well? How should such a protocol be modified for examinations in the
field, as for wild animal populations?
If a more comprehensive evaluation is sought, what should be its constituents?
What considerations should guide the selection of experimental parameters?
What research should be conducted to help refine such a process? What constraints
are imposed by the extrapolation issue? How vital is it to assure that
observations in animals reflect analogous functions in humans? Is it more
important to select end points that reflect the functional capacities of
the particular species?
What economies of approach are feasible when resources are limited?
Does the strategy of tiering, in which assessments branch to increasingly
specific and complex assessments, make sense in such situations? How might
low cost and sensitivity be combined? What should be the priorities in
such a process?
Exposure to chemicals during early development often inflicts toxic consequences
rather different from the consequences inflicted on mature nervous systems.
In addition to the modes of damage, however, differences arise in how the
damage may be expressed. For example, it may emerge only after a prolonged
latency, perhaps as late as senescence. Or, it may appear in different
guises at different phases of the life cycle. U.S. EPA and other regulatory
bodies have prescribed standardized protocols for assessing developmental
neurotoxicity. Do these protocols offer support for a comprehensive, quantitative
risk assessment? If not, how should they be modified? Are they efficiently
designed and are some elements of these protocols possibly redundant? For
example, does the absence of functional impairment at a particular exposure
level preclude morphological aberrations at that level? Or must all potential
sources of information be examined?
The agents discussed in this section offer cogent history lessons. Organic
solvents and chlorinated hydrocarbons were widely used for many years without
much concern over their possibly adverse effects. By the time these properties
had been identified in a painfully slow process, the agents had already
pervaded the environment or had become so essential that their removal,
even if technically possible, became impractical. Methylmercury and lead
had been recognized as neurotoxicants long before their current prominence,
but an appreciation of their more abstruse expression at low exposure levels
required an abundance of resources and investigator dedication in the face
of sometimes monumental skepticism.
Current neurobehavioral toxicology largely owes its standing to these
agents because they exemplify the power of behavioral end points. We asked
the participants to review what we have learned from investigations of
agents now established as prototypes. For example, would a retrospective
analysis of the literature built around such model agents provide guidance
for how to approach new agents? What would have been the most appropriate
testing schemes and toxic end points and which assessment strategy would
have yielded maximum information at the least cost?
Those enumerated below all owe their original identification as neurobehavioral
toxicants to observations in humans, typically at high doses. What might
have been the outcome had these agents first been examined as new chemicals?
Which endpoints would have proven to be sensitive? To what degree, for
each agent, have we observed a convergence between progress in human and
Lead was recognized as a hazard even in antiquity but was frequently ignored.
Only with the accumulating, incremental evidence provided by methodological
refinements did we progress to the present situation. The current Centers
for Disease Control (CDC) guidelines denote blood levels above 10 µg/dl
as a potential index of excessive exposure--a sharp fall from the standards
prevailing only a short time ago. Animal and human data show periods both
of convergence and divergence but, on the whole, took parallel paths. Attaining
convergence, the current situation, required improvements in both sets
of methodologies, but the animal data proved critical because of the criticisms
aimed at the epidemiological studies. In essence, investigators learned
how to ask the appropriate questions. It was not a process that would have
succeeded without the inevitable but instructive blunders.
Not long ago, methylmercury was viewed only as a hazardous chemical confined
to narrow purposes and distribution. A chain of mass chemical disasters
gradually altered this view, but the extrapolation from mass disasters
to broad implications for public health came slowly. On the basis of knowledge
acquired from these disasters, 26 states in the United States have posted
fish advisories. Animal research contributed significantly to our understanding
of the underlying mechanisms of toxicity, but the risk issues are still
being played out, primarily with the human disaster data. How has animal
research illuminated the human risk perspective? What has it taught about
the approach to unevaluated chemicals? What lessons should be drawn about
the longitudinal monitoring of human populations? Do the animal data allow
reasonable dose extrapolation?
Organochlorine Pesticides and Related Compounds
Compounds ranging from dichlorodiphenyltrichloroethane (DDT) to 2,4-dichlorophenoxyacetic
acid (2,4-D) to the polychlorinated biphenyls (PCBs) to 2,3,7,8-tetrachlorobiphenyl-p-dioxin
(TCDD) have been implicated in neurotoxicity. Especially for the last two
classes of chemicals, recognition of their potential neurotoxic properties
emerged only gradually, perhaps because it was submerged by concerns about
carcinogenicity. What is the current perspective about the health risks
of these compounds, and what lessons does its evolution provide for how
other classes of chemicals should be examined? Such substances are also
now implicated as environmental estrogens with a new spectrum of neurobehavioral
issues to address, some of which may even be lurking in data we already
Volatile organic solvents became an early focus of human neurobehavioral
toxicology. Their neurotoxic properties have always been recognized, even
in setting exposure standards in the workplace. Wider recognition of these
properties, especially in the absence of gross dysfunction, is attributable
to the application of psychological testing methods. Because methodological
advances moved in parallel with improvements in study design, the solvents
literature has provided guidance for similar questions. The evolution of
this research area to its current state should offer lessons on how to
cope with related issues such as those stemming from chemical sensitivity
syndromes. As with lead, animal models came on the scene only after solvent
neurotoxicity had been well established. The same degree of parallelism
seen with lead has yet to be achieved and awaits the application of equally
sensitive behavioral criteria.
Quantification, Modeling, and Definition of Risk
The ultimate goal of neurobehavioral toxicology, apart from its inherent
contributions to basic science, is formulating risk. Although, by tradition,
toxicity data are transformed into values such as NOAELs, this is simply
a regulatory convenience rather than a risk assessment. The conversion
of neurobehavioral data into quantitative risk assessments presents numerous
challenges. Cancer risk assessment, the prototype, is based on premises
that cannot be applied to neurobehavioral toxicity. Among these are the
assumption of a unitary biological process, cumulative dose as a valid
exposure parameter, and the irrelevance of acute animal toxicity data for
the prediction of carcinogenic potential.
Translation of Neurobehavioral Data into Risk Figures
Another legacy of the cancer risk model is its dependence on quantal data.
Such measures are easier to handle for risks expressed in probabilistic
terms, but most neurobehavioral measures are continuous rather than discrete.
One result of this disparity is that risk for systemic outcomes is typically
framed in terms such as NOAELs. Furthermore, many effects are graded over
time, so that they present features best expressed, perhaps, as 3-dimensional
surfaces. What are possible models for expressing risks based on such graded
outcome measures? Do they hold implications for experimental design such
as choices between number of dose levels and number of observations at
each dose? How should they reflect repeated measures on the same subjects?
Are there examples from the currently available literature?
Choosing End Points
Unlike the model of cancer, neurobehavioral toxicology is compelled to
rely on several different types of measures as guidance for risk estimates.
For example, the U.S. EPA has requested data from a FOB, motor activity,
schedule-controlled operant behavior, and neuropathology to help it formulate
the health risks of exposure to volatile organic solvents. Even pathology,
which in the past constituted the primary criterion of toxicity, is inadequate
by itself. Furthermore, even a single criterion, such as schedule-controlled
operant behavior, itself comprises multiple measures. Which measures derived
from such techniques might be suitable for guiding the risk assessment
A unique assortment of questions is posed by developmental neurotoxicity
because the process of development itself offers inherent enigmas. Species
extrapolation in this context, despite fundamental commonalities among
species, poses an additional layer of uncertainty upon those already confronting
risk evaluations based on species comparisons. Is the prevailing strategy
adequate for even gross prediction or do its deficiencies herald further
errors or even disasters?
How do neurobehavioral end points coincide with the requirements of epidemiology?
Rather than cases, for example, the data may consist of dose-effect relationships
in which the effect may be expressed as alterations in a spectrum of deficits,
or, because of individual patterns of susceptibility, individuals may differ
in their relative responsiveness to different end points. What would be
an appropriate epidemiological framework for assessing neurobehavioral
Setting Exposure Standards: A Decision Process
Most observers recognize that, barring rejection of an agent at the earliest
stage of risk assessment, a broad but necessarily superficial appraisal
of potential neurobehavioral toxicity may be insufficient for quantitative
risk assessment or even for identifying critical end points that are not
easily appraised with simpler techniques. Under what conditions should
a superficial appraisal be relied upon to formulate risk? Assume that further
investigations beyond the simplest may have to be conducted. Can a cogent
design for a sequential strategy be formulated? What are satisfactory starting
and stopping points? One model of a quasi-tiered approach is the assessment
of developmental neurotoxicity, a model imposed simply by the inability
to reach definitive conclusions about the impact of exposure at one particular
age from results determined at another age. What should be the major decision
points in evaluations not aimed at developmental questions or in evaluations
of developmental toxicity? Is it more efficient to begin with the later
decision points than to proceed, say, from simple to complex in several
stages? That is, would the later decision points embody, as well, the earlier
ones? Are there decision rules that can be constructed to guide such a
process? Can decision nodes be established at which certain paths can be
taken for more definitive conclusions?
Tiered testing schemes generally proceed from simple to complex criteria.
This direction generally implies corresponding dimensions such as from
cheap to expensive, from crude to sensitive, from high-dose to low-dose
effects, from acute to chronic effects, from adult exposure to developmental
toxicity, from hazard identification to quantitative risk assessment. Such
progressions reveal where the problem lies in a tiered testing approach:
If merely the absence of toxicity in tier 1 procedures is legally required
for approval of substances that may invade the environment and expose humans
and animals, new substances will be tested by relatively simple and insensitive
tests following acute high-dose administration in adult animals. Would
such a strategy be adequate to offer protection against the recurrence
of situations such as those described under Model Systems? Will more scientific
battles have to be fought in 10 years to prompt an assessment of the neurobehavioral
toxicity of substances introduced today?
Neurobehavioral toxicology is now established as a core discipline of the
environmental health sciences. Despite its recognized scientific prowess,
stemming from its deep roots in psychology and neuroscience and its acknowledged
successes, it faces additional demands and challenges. The latter, in fact,
are a product of its achievements because success at one level leads to
new and higher expectations. Now the discipline is counted upon to provide
more definitive and extensive risk assessments than in the past. These
new demands are the basis for the appraisals presented in the SGOMSEC 11
workshop. They extend beyond what would be offered in a primer of methodology.
Instead, these appraisals are framed as issues into which what are usually
construed as methodologies have been embedded.
1. National Research Council, Committee on Neurotoxicology
and Models for Assessing Risk. Environmental Neurotoxicology. Washington:National
Academy Press, 1992.
2. Office of Technology Assessment, U.S. Congress. Neurotoxicity.
Identifying and Controlling Poisons of the Nervous System. New York:Van
Nostrand Reinhold, 1990.
3. U.S. EPA. Reducing Risk: Setting Priorities and Strategies
for Environmental Protection. Rpt SAB-EC-90-021. Washington:U.S. Environmental
Protection Agency, 1990.
4. Carson, R. Silent Spring. Boston:Houghton Mifflin,
Last Update: April 28, 1998