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OCR for page 207
2
DESIGN OF THE PRIORITY-SETTING SYSTEM
Developers of priority-setting systems must decide the following:
the goal of the system; the chemicals to be considered; and the
structure of the system, i.e., the information to be gathered in each
step of the system, the type of analysis to be performed in each step,
and the decision rules that determine which chemicals are to be tested
and which are to be considered for other action (removed from
consideration, placed on a holding list for future consideration,
etc.~. pose tasks can be accomplished by experts, using their skills
and common sense, but some issues are not easily addressed unless the
designers of the system make special provisions for addressing them.
For example, what is the most effective sequence in which to gather
different kinds of information? How effective is the system? What is
the impact of changing some component of the system? To address the
latter two issues, it is helpful to use elements of decision theory and
systems analysis. Such an approach to toxicity testing requires that
the system priority-setting criteria and toxicity tests be described in
measurable terms and that goals be defined to enable the system's
effectiveness to be determined in relation to its goals. This
description requires the system's designers to be explicit about the
assumptions on which the design is based. Components of the system must
also be described explicitly in terms of the number of toxic chemicals
among the chemicals considered, the effectiveness of each procedure or
toxicity test, and the resources required for each such procedure or
test.
The value-of-information concept is used to address the issue of
which information is best to collect in each stage. This concept
underlies a strategy in which decisions are based on the relationship
between the importance of a piece of information and the degree of
uncertainty about it (Raiffa, 1968~. Each additional piece of
information is sought to enable decisions about the potential health
hazard of a chemical to be made with less risk of error. The value of
the information is defined as the difference between the expected costs
of error in classifying the chemical with and without the additional
information.
The value-of-information concept is a simplification that may be
difficult or even impossible to apply in complex decisions about testing
priorities. To apply it rigorously, strong assumptions are needed to
relate the multiple dimensions of chemical hazards to a single objective
that is quantifiable. Although the committee recognizes that full
implementation of a system based solely on these principles may in fact
be impossible, it also holds that value of information is a useful and
important concept. By designing an illustrative priority-setting system
using the concept, the committee sought to analyze the factors that
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are important for priority-setting and to explore how they interact, and
to do so in a systematic and integrated manner. The discipline of a
relatively formal analysis has produced insights that should be useful
in a more flexible and operational priority-setting procedure.
GOAL OF PRI ORI TY-SETTING
When formulating a goal for use in designing a priority-setting
system, one should consider that the goal of the system should reflect
the mission of the user, provide guidance in designing the
priority-setting system, and provide a mechanism to measure the
performance of the system. The Committee on Priority Mechanisms
considers that a goal to meet the need of NTP's priority-setting system
could be the ability to assess accurately the potential public-health
impacts of chemicals to which humans are exposed.
As demonstrated below, that goal influences all elements of the
priority-setting process, including selection of the chemicals to be
considered for priority-setting, measurement of the effectiveness of the
system, and the means for judging the information gathered and how it is
analyzed. It also leads to viewing the priority-setting process and
testing program as related parts of a larger effort to assess the
potential public-health impact of exposure to toxic substances. The
goal thus calls for the system to produce the accurate assessment of all
chemicals, not just the proper selection of chemicals for testing. The
system should, in general, dispose of chemicals of low concern, rather
than selecting them for testing, and should not suggest additional
testing of a chemical if adequate information is already available for
an accurate assessment of its potential public-health impact.
The above goal also implies that toxicity testing and the gathering
of information on human exposure should be considered jointly in
assessing the potential public-health impact of a chemical. Because
concern about a substance depends not only on its intrinsic toxicity,
but also on the extent of human exposure to it, the gathering of
information on the numbers of people exposed to various concentrations
of the chemical may be just as important in setting its priority for
testing as is determining its potential for toxicity.
CHEMICALS CONSIDERED
Defining the universe of chemicals to be considered is an important
design decision and is influenced by the goal chosen for the system. As
indicated above, all chemicals to which there is potential human
exposure should in principle be considered by the system. Although such
a goal might cause the number of chemicals to be too large to manage or
too difficult to estimate, several approaches can be used to solve the
problem. One approach would attempt to define additional categories so
that all chemicals to which there is potential human exposure would be
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included in a category and then estimate the number of chemicals in each
category; another would remove some categories of chemicals. A third
approach could be to redefine the goal.
The universe developed by the Committee on Sampling Strategies--
which consists of food chemicals, pesticide chemicals, cosmetic
ingredients, drug ingredients, and industrial chemicals--totals over
50,000 discrete (although not always well-characterized) substances.
This universe could be expanded by adding categories--such as combustion
products, pollutants, and some categories of naturally occurring
substances--until most chemicals with a substantial potential for human
exposure were included. Adding these categories could expand the
universe of chemicals considered by several thousand chemicals. If a
smaller universe were desired, some categories of chemicals could be
deferred or removed. In either case, the designers could make an
explicit decision concerning the system.
Testing priorities may be set for pure, well-defined compounds,
commercial grades of such compounds, elements and all their compounds,
categories of compounds (e.g., cyanides), mixtures of known or unknown
composition, radicals, or other classes of chemical entities. The terms
"substance" and "chemical" are used interchangeably in this report to
include all these classes. When designing an exposure assessment, a
toxicity assessment, and their interface, however, it is important to
define as precisely as possible the identity of the substances being
considered. The most commonly accepted (and usually unambiguous)
identifier for a substance is its Chemical Abstracts System (CAS)
Registry number.
Establishing the universe of substances usually involves some
initial screening or the exclusion of some candidate chemicals. Some of
the schemes reviewed by the Committee on Priority Mechanisms have been
applied only to specific classes of chemicals (such as food additives or
drugs); others have been applied only to chemicals on existing priority
lists or to chemicals nominated by panels of experts (see Appendix A).
In the latter case, the chemicals have already been screened through a
process that involves scientific judgment, so chemicals on which there
is little information are very likely to have been excluded without
adequate review. Thus, the establishment of the initial universe in
itself constitutes a major step in the priority-setting process.
In several of the schemes reviewed by the committee, the universe is
immediately narrowed by the deletion of substances that are judged to be
either irrelevant to the exercise or difficult to review. Classes of
substances deleted in this way include the following:
0 Chemicals already regulated, such as pesticides, drugs, and food
additives.
· Substances not subject to regulation by a member agency of NTP,
such as natural products.
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· Chemicals only nominally subject to regulation and adequately
tested under existing regulations.
· Substances without CAS numbers, including complex and ill-defined
mixtures.
· Other substances difficult to characterize, including combustion
products, pyrolysis products, and environmental breakdown products.
· Environmental mixtures, such as extracts of air pollutants and
water pollutants.
Although the omission of such substances and mixtures can usually be
understood on the grounds of convenience and practicality, it should be
recognized that the classes of substances that are omitted include many
that are both poorly characterized and potentially harmful.
STRUCTURE OF THE SYSTEM
The entire process of priority-setting and toxicity testing consists
of a series of interconnected steps, each containing an information-
gathering component and a decision-making component. An example of one
such step, or stage, is diagramed in Figure 1. It begins with an
information-gathering activity, which includes a search for and
interpretation of specific data, or "data elements." Combined with
information already on hand, the new information enables one to achieve
a better understanding of the public-health concern of a chemical
(middle box on right side). If the information is useful, the
understanding will be more certain than it was in the initial state of
knowledge (top box on right side). The figure represents concern as a
position on a two-dimensional map of exposure and toxicity. In this
example, the information-gathering activity is a toxicity test that
narrows the uncertainty about toxicity without providing information on
exposure. Other representations could include an estimated probability
distribution for the concern (e.g., the probability that a given number
of people would incur a specific effect during the next year) or a
discrete probability distribution concerning the degree of hazard (e.g.,
the probability that the substance involves or does not involve a
"significant" concern worthy of control activity).
After the new state of knowledge is determined, a decision must be
made (lowest box on right) to determine what additional pieces of
information would be most valuable or that no additional information is
required to make a reliable classification of public-health concern.
The latter decision is usually made when it appears that economic,
health, or other costs of misclassification are unlikely to be reduced
enough to justify additional information-gathering activities. Thus,
exit from a step is followed either by no further consideration of the
substance or by a new information-gathering step.
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Initial state of knowledge: great
uncertainty about a substance's
hazards (both exposure and toxicity).
(ENTER)
I nformation~athering
component:
generating or assembling
and interpreting
data element.
(EX IT , -
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Later state of knowledge: less
uncertainty about hazards because of
new information (thus less uncertainty)
about toxicity.
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Exposure- ~
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Decision-making component:
determining what information
to gather or what action to take.
FIGURE 1 Example of one stage or building block in process of investigation
and control of toxic substances. Information-gathering activity here is
toxicity test that produces useful data.
211
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Any priority-setting and testing scheme can be represented, at least
conceptually, by a network of such information-gathering and
decision-making steps. Traditional methods depend on evaluation by an
expert committee that reviews a dossier on a substance (information-
gathering component) and then makes recommendations about its
disposition (decision-making component).
Systems for screening chemicals for priority-setting may have one
stage or multiple stages. In one-stage systems, the same screening
criteria and procedures are applied to all the chemicals under
consideration. In the simplest type of multistage system, chemicals are
screened out of the system at each successive stage; the only chemicals
considered in the last stage are those which have survived all the
earlier stages. A more complex type of multistage system is the
decision tree, in which the screening criteria applied at each stage
depend on the outcome of the previous stage.
In most multistage systems, the first stage is a simple screen based
on chemical class, use, or production volume; the second stage is based
on criteria that reflect exposure; and the third and later stages are
based on criteria that reflect toxicity or potential risks. Although
this sequence is a feature in six of the different systems reviewed by
the committee (see Appendix A), the reasons for its choice were not made
explicit in them; it was adopted probably because crude indexes of
use--production and exposure--are relatively easy to obtain for large
numbers of chemicals, whereas indexes of toxicity are more difficult to
obtain and require more scientific review and judgment. In more
elaborate systems--e.g., the decision tree of Cramer et al. and the
six-stage linear screen described by Nisbet--the late stages require
fairly extensive compilations of toxicity and exposure data and fairly
detailed scientific review.
Multistage systems are advantageous, in that the screening process
can use simple, readily retrieved data, so many chemicals of low
priority can be eliminated from consideration quickly and scientific
attention can be focused on the chemicals of greatest interest. Systems
of this kind appear to offer a practical way to deal with very large
numbers of chemicals. An offsetting disadvantage is that the criteria
used in the early stages are necessarily crude, so some chemicals may be
eliminated erroneously in an early stage. Another disadvantage is that
exposure information is usually considered in less detail than toxicity
information; hence, chemicals with unusual pathways of exposure may not
be identified. These problems may be alleviated by providing for
reconsideration of chemicals eliminated in early stages or
reconsideration of exposure in later stages. These features are
included in the Interagency Testing Committee's system.
Designing a multistage screening system, under the constraint of an
overall budget, involves balancing of the costs of generating
information on a large number of chemicals in early stages against the
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costs of generating more detailed information on fewer chemicals in late
stages. The efficiency of such a system depends on the number of
stages, the amount of information considered in each stage, and the
number of chemicals correctly classified in each stage. In the systems
reviewed by the committee (Appendix A), these characteristics appear to
have been chosen rather subjectively, and it is not clear that maximal
efficiency was achieved.
Decision-tree systems are in principle more flexible than linear
multistage systems, because they can use more appropriate criteria for
screening at various stages. However, the systems that have been
proposed to date require rather precise information and would be
difficult to apply to several classes of chemicals, especially those
with little or no toxicity testing.
ANALYSIS OF INFORMATION
Data on a chemical must be analyzed so that decisions can be made
about its disposition. Most priority-setting systems assess the public-
health concern about chemicals with respect to exposure, toxicity, and
social considerations.
The different degrees of concern can be thought of as ranges on a
meter, with high readings generally warranting serious social concern
and low ones suggesting that little or no concern is called for. The
meter would register higher readings to the extent that there was an
increase in any of the following:
· Number of people exposed.
Per capita exposure in that population.
Frequency of exposure.
Probability of a toxic response at that exposure.
· Severity of a toxic response at that exposure.
· Cost to society or to an individual related to the manifestation
and treatment of health effects.
because:
smoked.
On such a hazard scale, cigarette smoke would rate high,
· Millions of people smoke cigarettes, and additional millions are
exposed to others' smoke.
· Exposures are high: grams of material are inhaled for every pack
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· Frequencies of exposure are high--one or more packs per day for
many smokers.
· Cigarette smoke is known to increase significantly the
probabilities of lung cancer, other cancers, heart disease, and other
adverse health effects e
· Lung cancer, heart disease, and some of the other effects are
frequently fatal or incapacitating for long periods.
· Costs of treatment and the impl
early death are great.
icit cost of pain, suffering, and
Other chemicals would rate low, for various reasons. In between
would be yet other chemical hazards. For example, one assessment
estimated that vinyl chloride might cause about 10 deaths per year
(Kuzmack and McGaughy, 1975), compared with 1.3 x 105 cancer deaths
per year from cigarette-smoking (U.S. Department of Health and Human
Services, 1981~. This example also demonstrates another feature of such
assessments: their uncertainty. The figure cited for deaths associated
with cigarette smoke is probably an accurate statement of the "true"
value, to within a factor of 3; for vinyl chloride, the uncertainty is
at least a factor of 10, and probably greater. Although there might be
other reasons to test cigarette smoke further, an analysis based on the
value of information would imply that the classification of high public-
health concern was good enough, and that further testing would not
markedly improve it. Another study of the carcinogenicity of vinyl
chloride at very low exposures might or might not be warranted, but it
would probably have a lower priority than a lifetime bioassay on a
chemical that was similar to vinyl chloride in structure, uses, and
exposures and that was mutagenic in vitro, but had never been tested in
a rodent bioassay.
These examples are based on the argument that hazard depends on both
the human exposure to a chemical and toxic responses in humans.
Exposure and responses interact in a complex way. For example, some
carcinogens may be presumed to exhibit a nearly linear relationship
between per capita exposure and the probability of causing cancer. In
this case, the hazard would be similar, regardless of whether 100 people
were each exposed to 1 g/yr or 100,000 people were each exposed to 1
mg/yr. But, if the chemical exhibited a threshold for effects or had a
distinctly nonlinear dose-response relationship, the hazard would depend
markedly on the distribution of doses; 1 g/yr might be fatal to all of
100 people exposed, but 1 mg/yr might have little effect on 100,000
people. Or the outcome could depend on the fractionation of the dose
over the year, on the route of exposure (oral, respiratory, or dermal),
on synergistic exposures, or on the age, sex, race, and health status of
the people exposed.
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An ideal priority-setting system would be able to capture the
importance of all information regarding these subtleties of exposure and
toxicity and to modify accordingly the probabilities with which a
chemical should be assigned to the various degrees of hazard. However,
such information is generally scarce and expensive to retrieve and
interpret, and the system would become excessively complicated if it
attempted to treat the information in such detail. Consequently, the
committee assumes that hazard is defined by the combination of exposure
and toxicity, each capable of being defined and estimated independently
of the other. For example, if the exposure range and the toxicity range
were each divided into three segments (high, medium, and low), there
would be nine categories of hazard, each corresponding to a different
pairing of exposure and toxicity. (Some might turn out to be equivalent
to one another, e.g., high toxicity and low exposure, low toxicity and
high exposure, and medium toxicity and medium exposure.)
Data and tests are selected to help decrease the uncertainty in
estimating the probabilities with which exposure or toxicity will truly
fall into defined categories. For example, production volume is not a
direct measure of human exposure (as are number of people, per capita
exposure, and frequency of exposure); but, in the absence of more direct
information on exposure, knowing the production volume does reasonably
influence our perception of the probability that exposure is high. The
results of an Ames Salmonella/microsome test do not prove or disprove
toxicity in humans, but a positive result would increase, rather than
decrease, our concern that the substance might be carcinogenic.
The following subsections contain more detailed discussions of the
concepts of exposure and toxicity.
ESTIMATING EXPOSURE
In an ideal exposure assessment, the investigator would attempt to
answer each aspect of each of the following questions:
o Who is exposed?
- age
- sex
race
~ health status
· How many are exposed?
· How are they exposed?
- occupationally
- in the community
- as consumers
- environmentally
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· By what route?
- oral
dermal
inhalation
single route of exposure
multiple routes of exposure (e.g., orally and dermally, as
workers and consumers)
· In what pattern?
- g/yr
- g/incident
mg/m3 or mg/L
· How frequently?
- continuously
- regularly, periodically (e.g., 8 in/d, 4 pills/d, once
every month)
- irregularly, but repeatedly
in single incidents
· Trough what chain of events?
-
production or extraction
manufacturing process
transportation
storage
use
environmental transformation
bioaccumulation
industrial discharge
waste disposal
environmental transport
If all such information could be acquired, one could imagine
dividing each dimension of exposure (route, amount, frequency, etc.)
into ranges and then classifying all exposed people into groups defined
by every combination of these ranges. Clearly, however, it would not be
technically feasible to collect such details on most chemicals.
Moreover, it would not be economically possible for a priority-setting
process to acquire and use this much information, nor would it be easily
understood. The committee therefore proposes to use available
exposure-related information (in a given stage of the priority-setting
process) merely to help estimate the probability that human exposure to
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the chemical will be relatively high, intermediate, or low. Thus, if
all other factors were equal, exposure would be considered higher than
average if the data element suggested that:
0 Large numbers of people are or may be exposed.
· Concentrations in air, water, soil, food, or other environmental
sources are higher than average.
· Exposure is more frequent or lasts longer than averages
~ Exposure occurs by a route suspected of eliciting the most toxic
response.
~ Exposure occurs among groups that are especially susceptible
because of age, race, sex, health status, or other conditions.
when a surrogate for exposure data is used, the objective is to
choose a variable that reflects exposure as accurately as possible, in
view of the extent of the toxicity information available at that stage
of the priority-setting process. If, for example, reliable information
shows an abrupt rise in the dose-response curve (e.g., from essentially
zero effect to 100% occurrence of a serious effect), then the
definitions of high, low, and medium exposure would clearly correspond
to the per capita doses above, below, and near the point where the
response curve rises rapidly. At the other extreme, when there is no
toxicity information whatsoever, it is appropriate to assume a linear
dose-response relationship of unknown slope, in which the extent of
hazard varies continuously and proportionally with the extent of
exposure. Here, the definitions of high, medium, and low exposure are
largely arbitrary.
Of the entire universe of chemicals, probably only a few substances
are usually considered to be in the high exposure region, more are in
the medium region, and most are in the low region. This distribution
conforms with common perceptions about the number of toxic chemicals to
which humans are exposed at high concentrations. That is, if toxicity
is rarely produced at a dose less than 1 mg/kg of body weight for single
acute doses, then exposure would be considered high for a 50-kg adult
only if typical doses were higher than approximately 50 mg in a single
exposure incident.
In the absence of a quantitative model of the entire
exposure-toxicity-hazard phenomenon, it will ordinarily be necessary to
work with information that is much more ambiguous than the above
guidelines suggest. For example, recourse only to some crude production
and use information is unlikely to produce a convincing prediction of
the number of people who will breathe a substance in concentrations
greater than 30 mg/m3, even if it is assumed that all other properties
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of the substance are "typical." In such cases, therefore,
classification of exposure could not be based on the concentration at
which humans are actually exposed, but must instead be expressed in
terms of the pieces of information {data elements) that are available.
To continue the example, exposure is likely to be considered high if
production is greater than 106 kg/yr and the substance is used
predominantly in consumer products with high potential for exposure,
e.g., foods, drugs, and cosmetics. This logic is not extended to
estimate that exposure is greater than 106 kg/225 x 106 people) per
year, i.e., 4 g/yr per person on the average; that figure might not be
at all relevant to the assessment of toxicity.
ESTIMATING TOXIC EFFECTS
The process of predicting or estimating the biologic activity and
toxic potential of a chemical is extremely complex. It requires the
consideration of several types of information, coordination of a number
of scientific disciplines, judgment and intuition, and an appropriate
schedule of testing, if warranted. There are no firm rules for
toxicologic prediction, nor are there guidelines that will ensure
reliable Answers. Attention is generally focused on human health
effects for which there are attributable chemical causes. Surrogates
(i.e., laboratory animals) are commonly used in testing for human health
effects. In the best circumstances, toxicologists may be able to
predict a particular activity of a chemical, ascribe a potential effect,
identify a useful end point in an established animal model, elucidate
the mechanism of the effect, and arrive at the conclusion that the
chemical either will have no toxic effect in humans or will cause a
measurable effect.
The toxic response to a chemical is multidimensional because of the
wide variety of possible effects on human health, many of which are
dose-dependent. In some cases, one human health effect may be clearly
more serious (and thus have a higher priority for testing resources)
than is another. For example, many more testing resources are devoted
to cancer bioassay than to skin irritation tests, and severity is a
major reason for the difference. In contrast, the relative severity of
other pairs of effects may be difficult to evaluate and may differ
according to individual perceptions. Nevertheless, choices between
tests for different effects bring with them value judgments about
relative severity, and a systematic priority-setting procedure will
reflect some set of judgments. For the illustrative system in Chapters
3 and 4, the committee evaluated only one health effect--cancer--and
avoided comparing the severity of effects. A complete and general
system would need to consider explicitly the values that society assigns
to different effects.
Chemically induced health effects in humans can be cataloged and
218
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organized in a number of ways. One of the most convenient is to
classify them by target organ. The range of such effects and their
corresponding organs or tissues can be seen in the list of examples
presented in Table 1.
Toxicity data derived from human exposure are necessarily limited--
and are nonexistent for most substances. Therefore, it is customary to
depend on data from toxicity tests in animals, from which extrapolations
are made to predict health effects in humans. The most useful data are
those derived from an accepted animal model for a given chemically
induced condition in humans, but adverse effects in animals not related
to a known disease in humans are also of value. Results of toxicity
tests in animals have been recorded in machine-readable files for
approximately 15,000 chemicals, whereas chemicals to which there is
potential human exposure number several tens of thousands. Therefore,
information on many chemicals is limited merely to molecular structure
and physical constants.
some idea of the relative importance of toxic effects can be gained
from examining their consequences to the injured person and to
societY. For example, is an impairment structural or functional? Is
it reversible or irreversible? Is it progressive? These questions are
implicitly considered in most priority-setting schemes, including those
that depend exclusively on human judgment. They imply value judgments
about relative severity and involve not only judgments about biologic
consequences, but also individual perceptions of harm. To examine
consequences for the individual, a number of factors should be
considered:
· An impairment may be caused by structural or functional damage or
both. Irritation and corrosion may be inconvenient and painful, but are
primarily structural. Lead-induced behavioral changes may be regarded
as functional. Hexane-induced azonal neuropathy is both structural and
functional.
· An impairment will generally be considered to be of greater
concern if it is irreversible than if it is reversible. Many biologic
effects are expressed only in the presence of the causative chemical and
cease with or soon after its disappearance. Others, such as death, are
obviously irreversible. Irritation, depression, and methemoglobinemia
are examples of reversible effects; sensitization, retinal damage,
pulmonary fibrosis, and carcinogenesis may be regarded as irreversible
effects.
~ An impairment may result immediately after acute exposure, may be
delayed until some time after acute exposure, or may require repeated
and prolonged exposure to become manifest. Corrosion is the most
obvious immediately apparent impairment. Delayed hypersensitivity
frequently results from an initially innocuous exposure.
Alcohol-related cirrhosis of the liver is an example of an impairment
manifested only after repeated and prolonged insult.
219
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Y ~:,
U] ~Z
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· Some impairments may be regarded as threats to life. Although many
structural and functional impairments may be undesirable, painful, and
debilitating, they are nevertheless clearly less objectionable than life-
threatening impairments.
These factors exemplify the criteria that may be used for assessing
relative importance of health effects, such as are presented in Table 1.
They are obviously incomplete in a number of respects e For example, no
account is taken of acute lethality, individual susceptibility,
dose-response relationships, and age and sex relationships.
ASSESSMENT AND DECISION-MAKING
Pr for ity-setting sys tems include some procedure to reach a j udgment
about chemicals with the information collected. On the basis of this
judgment, chemicals are considered further, recommended for testing, or
removed f rom cons iteration.
Several assessment procedures may be used: scoring, modeling, sorting,
ordinal ranking, and expert judgment. The choice of procedures depends on
the number of chemicals considered, information available, cost, and type
of personnel required. In addition, designers could consider the
likelihood that the procedure might introduce bias, the ability to function
even though some data are missing, and the ability to respond to uncertain
or inaccurate data.
· In scoring systems, the data used as ranking criteria are assigned
numerical scores (usually integers), and the scores are combined by a rule
(often a weighted addition) to yield a single score that represents
relative toxicity, relative exposure, or relative overall hazard. Scoring
systems have the advantages of being easy to use and providing consistent
treatment of all chemicals considered. However, it is difficult to combine
scores in a valid way. Missing data often require substitution of default
values. Uncertainty in the data is not reflected in the scores.
o Modeling-based systems use the data elements directly (kilograms of
chemical produced, LDso in milligrams per kilogram, etc.) and combine
them into an index that represents the degree of human exposure, the degree
of toxicity, or the overall health hazard. Modeling-based systems require
more analysis than other procedures and require moderately skilled
personnel. Uncertainty in the data can be dealt with more easily in models
than in other procedures.
· Sorting (or screening) procedures answer questions regarding aspects
of exposure and toxicity and sort chemicals into categories in accordance
with the answers. The categories and sorted chemicals in each category are
then ranked according to judgments as to which ones represent greater or
more important hazards. Sorting procedures are easy to use and may be
applied to large numbers of chemicals.
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· In ordinal ranking, chemicals are ranked on each of various
elements of exposure and toxicity, and the ranks are combined, according to
a rule, to derive an overall ranking. Ranking procedures are easy to use
and may be computerized. When rankings are combined, it is difficult to
understand the meaning of the combined ranking. Missing data require
substitution of default values. Uncertainty in the data is not indicated
in the ranking.
· Expert judgment requires one or more highly skilled persons to
review data, make an assessment, and recommend further action, such as
testing. Methods of improving the elicitation of expert judgment are
described in Appendix C. Although the use of experts is probably the most
accurate assessment method, it is also the most expensive and requires
highly skilled personnel.
DESIGN FACTORS
DESCRIBING THE PRIORITY-SETTING SYSTEM
While choosing the elements of the priority-setting system, the
designer should consider that the system must respond to the following
external parameters: the nature of the chosen universe of chemicals,
accuracy of selection stages or other components and accuracy of the
toxicity testis) for which the system is selecting chemicals, and costs of
the system components and toxicity tests. Each of these factors may be
described in as much detail as desired by the designers of the system or as
needed for the analytic technique being applied. The minimal description
is a word description. Use of a mathematical model designed to optimize
system performance requires a quantitative description.
Even a minimal description may be useful, because it requires system
designers to address issues explicitly. For example, if one attempts to
estimate the proportion of chemicals that cause a specific type of
toxicity, several elements must be defined (e.g., what types of toxicity
and which health effects are specified?. And one must specify the
population of chemicals to which the estimate applies.
ACCURACY OF STAGES OR TESTS
Priority-setting systems may be regarded as classification
procedures. Each stage may assess the degree of public-health concern
separated into categories of toxicity and exposure for different types of
health effects. Degree of public-health concern may be based on any number
of categories of exposure or toxicity. The main limitation in defining
categories of exposure and toxicity is the amount of information that is
available. It does little good to define a large number of narrow
categories if almost no information is available for assigning chemicals to
them. Because the information is far from perfect, there will be errors.
If there were only two categories of toxicity (or exposure)--such as toxic
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and nontoxic--there would be four possible classifications: true-positive,
false-positive, true-negative, and false-negative. If the exposure and
toxicity categories were divided into high, medium, and low toxicity and
high, medium, and low exposure, there would be nine possible combinations,
each with some degree of error (see Table 2~.
Figure 2 illustrates misclassification in a complex situation.
Public-health concern is a function of exposure and toxicity. Categories
of concern are labeled S1 to S6, in order of increasing severity. For
example, S1 might refer to a situation of low exposure and low toxicity,
and S6 to one of high exposure and high toxicity. Each cell in the
diagram stands for a classification. For example, if a chemical is truly
in category S2, but is classified in category S5, it would be in cell
C5,2. Chemicals that are correctly classified lie along the
diagonal--Cl,!, C2,2, etc. These diagonal cells represent zero
misclassification. As one moves from the diagonal to either the upper
right or lower left corner, the extent of misclassification becomes
greater. The cell in the top right corner (C1,6) represents the most
serious false-negative classification--a chemical with high public-health
concern (high exposure and high toxicity) classified as one with low
public-health concern (low exposure and low toxicity). The bottom left
corner (C6,1) represents the most serious false-positive classification.
MEASURING PERFORMANCE
In a perfect priority-setting and testing program, all chemicals would
be classified correctly, so they would appear in cells along the diagonal
(Cl,l to C6,6) in Figure 2. Even with unlimited funds, this would not
be possible in practice, because even the best test batteries may sometimes
yield false-positive and false-negative results. For any priority-setting
system, there will be a spread of chemicals away from the diagonal. A
testing and priority-setting program should make this spread as narrow as
possible; more precisely, it should minimize the misclassifications for a
given investment of resources.
In designing a priority-setting process, value judgments are
unavoidable. Two such judgments are especially important. First, it is
necessary to make some judgment about the relative importance of a
false-negative and a false-positive for a given effect. This judgment is
built into the design by the relative weights attached to the upper right
and lower left corners of Figure 2. An illustrative method of deriving the
relative weights is given in Appendix E. Second, it is necessary to make
some judgment about the relative importance of health effects. This is
built into the design by relating the cost of a false-positive for one
effect to the cost of a false-positive for another effect (or comparing the
relative costs of false-negatives). In principle, one type of true
classification could be treated as more important than another type of true
classification. In general, however, available information appears
insufficient to make such a judgment (see Appendix B).
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TABLE 2 Possible Results of Test Having Three Results: High,
Medium, and Low
Result
of
Test
True Toxicity
Low Medium High
Low Correct False-negative Greatest
false-negative
Medium False-positive Correct Greater
false-negative
High Greatest Greater Correct
false-positive false-positive
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TRUE CATEGORIES
S1
s2
S3
S4
S5
s6
1 1 1 1 1 1 ~
S1
in
a: S.
o 2
CD
of:
C:
C)
UJ
in
¢~
in
cl,1
C1 6
C2,2
S3
C3,3
S4
C4,4
S5
c5~2
C5,5
1
s6
c6~1
C6,6
FIGURE 2 Illustration of misclassif ication. concern (S) is based on
exposure and toxicity and ranges from S1 (lowest) to S6 (highest). C
and its subscripts indicate cell into which chemical is categorized and
false and true classifications. Cells C1, 6, C5,2, and C6,1 are
misclassifications. Cells on diagonal (Cl,l, C2,2, etc.) are correct
classifications.
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Once the extent of misclassification is at least conceptually defined,
it is possible to compare alternative designs of priority-setting processes
and to select the one with the lowest cost of misclassification within a
given budget for priority-setting and testing.
COST
The costs of components of priority-setting systems and toxicity tests
(in dollars per substance) are used in designing selection processes to
ensure the selection of the most productive information-gathering
activities per dollar spent. Cost data for toxicity tests are described in
Stage 4 in Chapter 4.
226
Representative terms from entire chapter:
toxicity tests
